Fight Aging!

The average age of populations around the world is rising: improved medicine and greater wealth leads to increased longevity and lower population growth at the same time. The number of old people is rising rapidly, and this at a time when technologies for treating aging as a medical condition are just around the corner, given sufficient funding and support. The World Health Organization (WHO) recently released their report on aging and health for 2015, and I have to say it makes for very strange reading. You might find the exexcutive summary (PDF) easier going than the full report (PDF). As I worked my way through the summary, I became increasingly incredulous that at no point in the document was medical research discussed. Not a single mention. This stands out as an exceptional omission in an otherwise sensible and coherent position statement. Take this for example:

The changes that constitute and influence ageing are complex. At the biological level, ageing is associated with the accumulation of a wide variety of molecular and cellular damage. Over time, this damage leads to a gradual decrease in physiological reserves, an increased risk of many diseases and a general decline in the intrinsic capacity of the individual. Ultimately, it results in death. But these changes are neither linear nor consistent, and they are only loosely associated with a person's age in years.

This report defines Healthy Ageing as the process of developing and maintaining the functional ability that enables wellbeing in older age. Central to this conceptualization of Healthy Ageing is an understanding that neither intrinsic capacity nor functional ability remains constant. Although both tend to decline with increasing age, life choices or interventions at different points during the life course will determine the path - or trajectory - of each individual.

Yet at every point in the report where technological progress in medicine might be mentioned, there is silence on this topic. Where lists are provided of ways to help people retain functional ability as they age, they focus on compensation for disability, on lifestyle choices, on greater availability of services for the elderly, but say nothing on the improvement of therapies to treat aging and age-related conditions. In fact, right up front in the preamble you can find this:

The report aims to move the debate about the most appropriate public health response to population ageing into new - and much broader - territory. The overarching message is optimistic: with the right policies and services in place, population ageing can be viewed as a rich new opportunity for both individuals and societies. The resulting framework for taking public health action offers a menu of concrete steps that can be adapted for use in countries at all levels of economic development.

In setting out this framework, the report emphasizes that healthy ageing is more than just the absence of disease. For most older people, the maintenance of functional ability has the highest importance. The greatest costs to society are not the expenditures made to foster this functional ability, but the benefits that might be missed if we fail to make the appropriate adaptations and investments. The recommended societal approach to population ageing, which includes the goal of building an age-friendly world, requires a transformation of health systems away from disease-based curative models and towards the provision of integrated care that is centred on the needs of older people.

In the context of the report as a whole, I read this as "more coping, less medicine." This seems like well-spoken insanity to me. You can't talk about age-related frailty and disability outside the context of medical research into aging and the development of new and better therapies. You can't herald a world in which growing numbers of people are living longer without talking about the ongoing advances in medicine that have enabled this outcome. Yet here is this policy document, doing just that. Calling for greater accommodation of the consequences of aging while ignoring medical science and the great rate of change in biotechnology is perhaps a manifestation of the instinct to conservatism in all political bodies: the urge to see stasis in the world, even against all the evidence, even in an age of rapid, accelerating progress. Only within a worldview in which aging is set in stone, never to be changed, can this document make any sense to anyone. Yet it clearly acknowledges change throughout, in every other aspect.

In any case, I stand amazed at this output of the bureaucratic process.

The mitochondrial repair project being crowdfunded at Lifespan.io has passed its original $30,000 goal, with nearly 300 people having donated to the cause. This is a solid start for the Lifespan.io team, and I look forward to their future projects. One of the most important things that any of us can be doing - other than raising funds for research - is expanding the community, reaching out to find new supporters. Many of these donors have never given to this cause before, and the Lifespan.io staff have been working hard on outreach these past few months. This should be becoming easier as the years pass and there is ever more incremental progress to show off thanks to past research, but bootstrapping a movement is hard work, a long slog. More hands and new approaches are always welcome. Meanwhile, on the research side, here are a few notes on the work that your generosity has enabled:

Reversing or preventing damage to mitochondrial DNA may be a key factor in slowing the aging process. At the SENS Research Foundation, we are in the early stages of creating an innovative system to repair these mitochondrial mutations. The MitoSENS team has already demonstrated the rescue of cells containing mitochondrial mutations, and has recently generated highly promising preliminary data showing the rescue of the complete loss of a mitochondrial gene. Our next steps will focus on improving the effectiveness of the targeting system, so that we can repeat our success with one mitochondrial gene to all thirteen. We will then transition this work into animal models of mitochondrial dysfunction. This would be a crucial step in what may be the development of an eventual cure for aging and aging related diseases.

We have a talented team of highly trained mitochondrial biologists working on MitoSENS. Right now the rate-limiting factor is the cost of the expensive reagents that we use for these experiments. Increasing our funding with this campaign will allow us to double the pace of our research and bring results to the public that much faster. We have made preliminary progress on rescuing function with a second gene, ATP6, and your support will help us perfect our targeting of both ATP8 and ATP6. This requires more cells, more viruses, and many new synthetic gene sequences. Specifically, we will spend your generous donations on cell culture reagents, oxygen consumption measurements, virus production, quantitative reverse transcription PCR, DNA synthesis services, and publication of our results in a peer-reviewed journal.

Link: https://www.lifespan.io/campaigns/sens-mitochondrial-repair-project/

Here researchers suggest that cross-links in the extracellular matrix can be formed within single collagen molecules as well as between them, and that this can still degrade important properties of tissue. Cross-links form and are broken constantly in the extracellular matrix, consisting of many types of sugary by-products of metabolism. Some are far more resilient than others, and once formed tend to last for a long time. The structural properties of tissue are determined by the particular arrangement of molecules in the matrix, and when hardy forms of cross-link build up over the course of aging the result is loss of elasticity or strength. This is particularly noticeable in skin, but of much greater consequence in blood vessels, where stiffening causes hypertension and all of the cardiovascular dsyfunction that follows on from that.

In humans near all long-lived cross-links involve glucosepane, making clearance an attractive target for rejuvenation treatments, as only one class of compound must be broken down. Yet all too few groups are working on this. Those funded by the SENS Research Foundation might be the only people at the present time trying to build the basic tools needed to work with glucosepane in a cellular environment. It seems crazy to me that such obvious paths forward towards treating the common causes of age-related disease are widely ignored.

The extracellular matrix (ECM) undergoes progressive age-related stiffening and loss of proteolytic digestibility due to an increase in concentration of advanced glycation end products (AGEs). The most abundant AGE, glucosepane, accumulates in collagen with concentrations over 100 times greater than all other AGEs. Detrimental collagen stiffening properties are believed to play a significant role in several age-related diseases such as osteoporosis and cardiovascular disease.

Currently little is known of the potential location of covalently cross-linked glucosepane formation within collagen molecules; neither are there reports on how the respective cross-link sites affect the physical and biochemical properties of collagen. Using fully atomistic molecular dynamics simulations (MD) we have identified six sites where the formation of a covalent intra-molecular glucosepane cross-link within a single collagen molecule in a fibrillar environment is energetically favourable. Identification of these favourable sites enables us to align collagen cross-linking with experimentally observed changes to the ECM. For example, formation of glucosepane was found to be energetically favourable within close proximity of the Matrix Metalloproteinase-1 (MMP1) binding site, which could potentially disrupt collagen degradation.

Link: http://dx.doi.org/10.1016/j.matbio.2015.06.001

Alzheimer's disease is becoming a well-known age-related condition, something that the average fellow in the street has actually heard of, unlike the vast majority of unpleasant things that happen to people as their bodies fail due to the accumulation of cell and tissue damage that causes aging. The widespread awareness of Alzheimer's disease is a function of the large-scale funding for research into its mechanisms; half of the National Institute on Aging budget is focused on this condition and all that needs to be learned to treat it effectively, and a correspondingly large chunk of private funding for neuroscience and the development of therapies for neurodegeneration is aimed in the same general direction.

We might think that Alzheimer's occupies the role of figurehead or rallying flag, a way to draw funds to the principal scientific goal of complete understanding of the biochemistry of the brain. This tends to be how things happen for large scale funding in medicine; three decades ago AIDS had much the same relationship with the broadest extent of viral research aimed at understanding first and therapies second. As is the case for Alzheimer's, it was an overlap of new capabilities in biotechnology, the existence of an effective advocacy community, and the need for funding to push forward the frontiers of scientific knowledge: numerous self-interests coming together.

Below you'll find links to a selection of recent Alzheimer's research. There is a lot going on, as it is a very complex condition, and the study of Alzheimer's really is the study of a very large slice of the biochemistry of the brain as a whole. One of the defining features of the field at present is a divergence of theories and exploration of alternative possible mechanisms beyond the accumulation of amyloid in brain tissues and the direct consequences of higher amyloid levels, meaning the creation of toxic and damaging molecules and the death or dsyfunction of brain cells. This search for alternatives is prompted by years of ongoing difficulties in the production of amyloid clearance therapies. Theorizing and early stage research are very cheap in comparison to later stages of development, and so always race ahead whenever obstacles arise.

Something else to bear in mind when reading the research in this field is that Alzheimer's appears to be almost as much a lifestyle disease as type 2 diabetes, though without the option to turn back at even comparatively late stages via aggressive lifestyle changes and fasting. People who get Alzheimer's are largely those who have been overweight and sedentary for decades: the same risk factors as is the case for diabetes and cardiovascular disease, and many of the underlying mechanisms may overlap in these and other age-related conditions. The degree to which Alzheimer's is an inevitability regardless of good health practices given a long enough life is an interesting question: everyone seems to accumulate more amyloid with age, but in the case of the oldest human beings it isn't the types of amyloid in the brain that cause death.

Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer's disease

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived Aβ and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aβ levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aβ catabolism on AD pathogenesis.

Parabiosis before and after Aβ deposition in the brain significantly reduced brain Aβ burden without alterations in the expression of amyloid precursor protein, Aβ generating and degrading enzymes, Aβ transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aβ and preventing AD pathogenesis. The present work suggests that peripheral Aβ clearance is a valid therapeutic approach for AD, and implies that deficits in the Aβ clearance in the periphery might also contribute to AD pathogenesis.

Misframed ubiquitin and impaired protein quality control: an early event in Alzheimer's disease

Amyloid β (Aβ) plaque formation is a prominent cellular hallmark of Alzheimer's disease (AD). To date, immunization trials in AD patients have not been effective in terms of curing or ameliorating dementia. In addition, Presenilin 1 (PS1) genes are predictive for treatment of all AD patients. However most AD patients are of the sporadic form which partly explains the failures to treat this multifactorial disease.

Recently, pooled GWAS studies identified protein ubiquitination as one of the key modulators of AD. This revealed numerous proteins that strongly interact with ubiquitin (UBB) signaling, and pointing to a dysfunctional ubiquitin proteasome system (UPS) as a causal factor in AD. We reported that DNA-RNA sequence differences in several genes including ubiquitin do occur in AD, the resulting misframed protein of which accumulates in the neurofibrillary tangles (NFTs). This suggests again a functional link between neurodegeneration of the AD type and loss of protein quality control by the UPS.

Vascular pathology: Cause or effect in Alzheimer disease?

The vascular hypothesis emerged as an alternative to the amyloid cascade hypothesis as an explanation for the pathophysiology of AD. This hypothesis locates blood vessels as the origin for a variety of pathogenic pathways that lead to neuronal damage and dementia. Destruction of the organisation of the blood brain barrier, decreased cerebral blood flow, and the establishment of an inflammatory context would thus be responsible for any subsequent neuronal damage since these factors promote aggregation of β-amyloid peptide in the brain. It is difficult to determine whether the vascular component in AD is the cause or the effect of the disease, but there is no doubt that vascular pathology has an important relationship with AD. Vascular dysfunction is likely to act synergistically with neurodegenerative changes in a cycle that exacerbates the cognitive impairment found in AD.

Overestimating the Effects of Healthy Aging

As models of preclinical AD continue to develop, a challenge to the field is to reconcile the evidence of AD-related pathology found in a large number of cognitively normal (CN) elderly people with the notion of "healthy" or "successful" aging. This evidence seems to question the research practice of not considering possible presence of Alzheimer's pathology in CN elderly participants when including healthy elderly persons in cognitive studies. However, without the actual evidence to exclude Alzheimer's pathology, one can assume that some percentage of CN elderly subjects in such studies may represent preclinical AD. This problem has been occasionally recognized. It clearly requires a systematic change in approach, because subtle cognitive changes, reliance on cognitive strategies, and networks' reorganization that one would interpret as the effects of healthy aging might actually reflect the disease progression.

Vasculoprotection as a Convergent, Multi-Targeted Mechanism of Anti-AD Therapeutics and Interventions

In the wake of failed amyloid-targeted drug trials and immune therapies, recent efforts are directed towards a broad range of alternative mechanisms of AD including mitochondrial dysfunction, metabolic stress, altered insulin signaling and, related to the 'vascular hypothesis of AD', cerebrovascular dysfunction. Accumulating evidence in fact supports the notion that cerebro- or neurovascular dysfunction may represent a primary initiator of a cascade of pathogenic events leading to neurodegeneration in AD. This mechanism takes on added significance when one considers increasing evidence linking sporadic AD with a number of vascular disorders including hypertension, hypercholesterolemia, obesity and type 2-diabetes.

Can oral infection be a risk factor for Alzheimer's disease?

Apart from the two main hallmarks, amyloid-beta and neurofibrillary tangles, inflammation is a characteristic feature of AD neuropathology. Inflammation may be caused by a local central nervous system insult and/or by peripheral infections. Numerous microorganisms are suspected in AD brains ranging from bacteria (mainly oral and non-oral Treponema species), viruses (herpes simplex type I), and yeasts (Candida species). A causal relationship between periodontal pathogens and non-oral Treponema species of bacteria has been proposed via the amyloid-beta and inflammatory links. Periodontitis constitutes a peripheral oral infection that can provide the brain with intact bacteria and virulence factors and inflammatory mediators due to daily, transient bacteremias. If and when genetic risk factors meet environmental risk factors in the brain, disease is expressed, in which neurocognition may be impacted, leading to the development of dementia.

Promising results with inhibitors of amyloid formation

When proteins change their structure and clump together, formation of amyloid fibrils and plaques may occur. Such "misfolding" and "protein aggregation" processes damage cells and cause diseases such as Alzheimer's and type 2 diabetes. A team of scientists have now developed molecules that suppress protein aggregation and could pave the way for new treatments to combat Alzheimer's, type 2 diabetes and other cell-degenerative diseases. The scientists designed and studied 16 different peptide molecules in order to find out which of them are able to impede the cytotoxic "clumping" of the proteins amyloid beta (Aß) and islet amyloid polypeptide (IAPP), which are associated with Alzheimer's and type 2 diabetes.

IV Administration of Endothelin B Receptor Drug Reduces Memory Loss, Oxidative Stress in Alzheimer's Disease

"We used the novel approach of stimulating the endothelin B receptors by intravenous injection of IRL-1620 to prevent and repair the damage to the brain caused by Alzheimer's disease. Rats with AD showed impaired learning and memory and increased oxidative stress. We found that treatment with IRL-1620 reversed these effects. Intravenous injection with the drug improved memory deficit by 50 to 60 percent and reduced oxidative stress by 45 to 50 percent. We also found that treatment with IRL-1620 enhanced certain recovery processes within the AD-damaged brain, resulting in more new blood vessels and neuronal cells. This indicates reparative processes occurring in the damaged brain."

Here is a mainstream view of the growth in interest in aging research, a focus on discovery of how exactly aging progresses in fine detail and how that progression is influenced by environment and genes, and no mention of doing more than slightly altering the pace of aging. Growth in the field is ultimately a good thing, however, as at some point in the near future the disruptive approach of damage repair typified by the SENS programs, aiming for rejuvenation treatments that can reverse the progression of age-related degeneration, will produce practical results that are indisputably far better and far cheaper than those emerging from drug development to modestly slow aging. The more researchers available to move over to that line of work once persuaded, the better off we all are.

Aging is at the center of many of the world's most prevalent and deadly diseases, including cancer and heart disease. Over the last 20 years we have seen amazing advances in our understating of the mechanisms behind aging-related processes at the level of genes, cells and whole organisms. Many countries are now facing a growing aging society, with a high prevalence of fatal age-related diseases, such as cancer, cardiovascular, and pulmonary disease.

Exciting new lines of research have shown that aging involves a complex interplay between the genome, epigenome, microbiome, and the environment. Recent work on epigenetic modifications, the chemical signatures branded on our genome that affect gene expression, has revealed surprising links to the aging process and established a connection with environmental factors. Important epigenetic marks such as the methylation of regulatory DNA sequences, covalent modifications of histone proteins, and the expression of regulatory non-coding RNAs are affected during aging. The effect of the environment on this epigenetic landscape is clearly shown by studies using identical twins. As they age, these twins are no longer identical in their epigenome, showing differences in gene expression and ultimately, lifespan. Changes to the epigenetic landscape may affect gene expression and ultimately the aging process, especially through the modification of metabolism.

Food scarcity is one of the most important environmental factors affecting epigenetic modification; it is therefore not surprising that many molecules and signaling pathways that have been implicated in aging, such as mammalian target of rapamycin, sirtuins, and insulin-like growth factor/insulin signaling pathways, are related to metabolism. Thus, how our genes modify our metabolic status, depending on the food intake and consumption, is a central issue of aging science. Another new and exciting area in aging research involves the tiny microbes living in our bodies. Our gut, for example, hosts microorganisms that amount for 10 times as many cells than found in our body and 150 times as many genes as there are in our genome. Understanding the fundamental mechanisms of aging may lead to the development of new treatments that could be applicable to a wide variety of age-related diseases.

Link: http://dx.doi.org/10.1038/npjamd.2015.7

A trial is underway to test the use of embryonic stem cells as a treatment for the wet form of age-related macular degeneration, a conditional characterized by the structural damage and resulting blindness caused by excessive blood vessel growth into the retina:

Surgeons in London have carried out a pioneering human embryonic stem cell operation in an ongoing trial to find a cure for blindness for many patients. The procedure was performed on a woman aged 60 and involved "seeding" a tiny patch with specialised eye cells and implanting it at the back of the retina. The London Project to Cure Blindness was established a decade ago to try to reverse vision loss in patients with age-related macular degeneration (AMD). Ten patients with the wet form of AMD will undergo the procedure. All will have suffered a sudden loss of vision as a result of defective blood vessels in the eye. They will be monitored for a year to check that the treatment is safe and whether their vision improves.

The woman who was the patient had the operation last month. "We won't know until at least Christmas how good her vision is and how long that may be maintained, but we can see the cells are there under the retina where they should be and they appear to be healthy." The cells being used form the retinal pigment epithelium (RPE) - the layer of cells that nourish and support the photoreceptors in the macula - the seeing part of the eye. "This is truly a regenerative project. In the past it's been impossible to replace lost neural cells. If we can deliver the very layer of cells that is missing and give them their function back this would be of enormous benefit to people with the sight-threatening condition".

Link: http://www.bbc.com/news/health-34384073

One of the interesting minor themes to arise from the modern study of the biochemistry of aging is that aging is accompanied by numerous subtle, detrimental changes in the processing of dietary amino acids, both essential amino acids that cannot be constructed by human cellular biology, and the others that can, but which are also obtained from the diet. Here I'll point out recent research into an age-related decline in a process that consumes the amino acid cysteine, but there have been others over the years.

One such decline discovered some years back is that a growing failure to process the essential amino acid leucine is perhaps linked to loss of muscle mass with age, a condition known as sarcopenia, possibly via a chain of issues that upsets the balance between mechanisms breaking down muscle proteins and mechanisms assembling them. This can be overcome to at least some degree by throwing more leucine at the problem: there is evidence for leucine supplementation in older adults to have some impact on outcomes. There are numerous publications on this topic from the past decade or more, but the full details of what it actually going on and why - and especially the nature of the root causes - remain to be firmly pinned down, and the evidence itself is not undisputed. That is the story at present for most of these fine details in the corner of the bigger picture.

This is especially interesting for those of us who practice some form of calorie restriction or protein restriction with the aim of methionine restriction. Low levels of the essential amino acid methionine seems to be the key trigger for much of the beneficial metabolic alteration that occurs in response to calorie restriction. Studies in mice show that life-long restriction in fact blunts sarcopenia. Yet here is another set of evidence to suggest that more of at least some constituents of protein has much the same effect. It is a reminder that outcomes in health and aging are many up of many strands.

The paper linked below presents a fairly similar situation to that of leucine and sarcopenia, but for cysteine and the production of cellular antioxidants necessary for the proper function of metabolism. Again there is some ability to overcome the issue by delivering more cysteine in the diet, perhaps a theme that might be repeated elsewhere in our biochemistry as well:

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly

Restricted dietary intakes of protein or essential amino acids tend to slow aging and boost lifespan in rodents, presumably because they downregulate IGF-I/Akt/mTORC1 signaling that acts as a pacesetter for aging and promotes cancer induction. A recent analysis of the National Health and Nutrition Examination Survey (NHANES) III cohort has revealed that relatively low protein intakes in mid-life (under 10 % of calories) are indeed associated with decreased subsequent risk for mortality. However, in those over 65 at baseline, such low protein intakes were associated with increased risk for mortality. This finding accords well with other epidemiology correlating relatively high protein intakes with lower risk for loss of lean mass and bone density in the elderly. Increased efficiency of protein translation reflecting increased leucine intake and consequent greater mTORC1 activity may play a role in this effect; however, at present there is little solid evidence that leucine supplementation provides important long-term benefits to the elderly.

Aside from its potential pro-anabolic impact, higher dietary protein intakes may protect the elderly in another way-by providing increased amino acid substrate for synthesis of key protective factors. There is growing evidence, in both rodents and humans, that glutathione synthesis declines with increasing age, likely reflecting diminished function of Nrf2-dependent inductive mechanisms that boost expression of glutamate cysteine ligase (GCL), rate-limiting for glutathione synthesis. Intracellular glutathione blunts the negative impact of reactive oxygen species (ROS) on cell health and functions both by acting as an oxidant scavenger and by opposing the pro-inflammatory influence of hydrogen peroxide on cell signaling.

Fortunately, since GCL's K m for cysteine is close to intracellular cysteine levels, increased intakes of cysteine - achieved from whole proteins or via supplementation with N-acetylcysteine (NAC) - can achieve a compensatory increase in glutathione synthesis, such that more youthful tissue levels of this compound can be restored. Supplementation with phase 2 inducers - such as lipoic acid - can likewise increase glutathione levels by promoting increased GCL expression. In aging humans and/or rodents, NAC supplementation has exerted favorable effects on vascular health, muscle strength, bone density, cell-mediated immunity, markers of systemic inflammation, preservation of cognitive function, progression of neurodegeneration, and the clinical course of influenza - effects which could be expected to lessen mortality and stave off frailty.

Hence, greater cysteine availability may explain much of the favorable impact of higher protein intakes on mortality and frailty risk in the elderly, and joint supplementation with NAC and lipoic acid could be notably protective in the elderly, particularly in those who follow plant-based diets relatively low in protein. It is less clear whether the lower arginine intake associated with low-protein diets has an adverse impact on vascular health.

While interesting as a theme, all of this is still small potatoes in the grand scheme of things: a great deal of data boils down to small effects on long-term health. You cannot use diets and supplements to greatly alter the tiny odds of passing beyond 100 years of age in the environment of today's medical technology. This is true for much of the study of aging, with its primary focus on mapping the entirety of cellular metabolism and its changes over time, rather than on the production of far more effective treatments. A different approach to the problem is required for meaningful progress towards greater healthy longevity, a focus on repair of the known root causes of aging, on the actual treatment of aging rather than continued investigation of the fine details of how aging progresses when left untreated, or how to tinker a little more function out of a damaged biochemistry. Repair is the way forward, aiming to reverse the damage, as exemplified by the SENS rejuvenation research programs.

Staff at the longevity research crowdfunding site Lifespan.io are launching their #LifespanChallenge event this Thursday October 1st. This is also the day on which this year's Fight Aging! matching fundraiser in support of SENS rejuvenation research kicks off, as well as being the date for numerous other events related to research into human longevity organized by the advocacy community:

Over the past few years there has been a tradition emerging of longevity researchers and activists around the world organizing events on or around October 1 - the UN International Day of Older Persons, or Longevity Day. This is an excellent idea, and to take it further Lifespan.io will be running a social challenge campaign, not unlike the Ice Bucket Challenge, to raise both funds and awareness for life extension research - the #LifespanChallenge. It will begin on October 1 and run through the month of October.

1) Donate any amount via Lifespan.io to a running campaign or to the Life Extension Advocacy Foundation (LEAF). If you have already done so already, feel free to skip to the next step.

2) Post a short video (or image with description) on social media where you are holding up the #LifespanChallenge sign (which you can print or show on a tablet, etc.). Share a personal reason why you sincerely care about life extension, or express yourself in any way that is linked to this theme.

3) Challenge 3 friends to do the above as well. Add a post description similar to this: "Hey everyone; here is my response to the #LifespanChallenge to help extend healthy lifespan! My reason for helping this cause is _____. If you want to help please donate any amount to https://www.lifespan.io/donate/ or projects at https://www.lifespan.io, make a video like this, and challenge 3 of your friends to do the same. For example @FriendName1, @FriendName2, @FriendName3 I challenge you!"

Facebook has made it easy to upload video directly, so all you should need is a cell phone camera. The text that accompanies your post should be informative, tagging your friends (preface their name with an @ in Facebook, for example) and including the hashtag #LifespanChallenge. This will make the post visible to your friends and easy to find later. One of the goals of this challenge is to introduce more people to the idea of life extension, so make it a point to talk to at least one friend who is not already part of the life extension community about the #LifespanChallenge, and open up a dialogue around this topic.
Don't wait to be challenged; be a part of the first wave and help really get the ball rolling.

That's it! Let's keep up the momentum to #CrowdfundTheCure, and I hope you all have an excellent Longevity Day.

Link: http://www.lifespan.io/the-lifespanchallenge-starting-on-october-1-international-longevity-day/

This article provides a short overview of the work on comparative biology of aging taking place at the laboratory of Steven Austad:

The longest-lived human on record didn't make it much past 120 years. That's nothing compared to the ocean quahog, a fist-sized clam found off the coast of Maine. "They can live 500 years or longer. They've been sitting out there on the sea floor since before Shakespeare was born." Steven Austad's research focuses on understanding the underlying causes of aging at the molecular level. Although his studies take him in many fascinating directions, it's the ancient clams that everyone remembers. So what do animals like the quahog know about healthy aging that we don't? That question drives Austad's studies in comparative gerontology, which look to long-lived animals to identify new molecular targets to help humans.

Clams - technically, bivalve mollusks - live longer than any other animal group; more than a dozen species have lifespans of a century or more. But they are not all masters of aging. Austad's lab is studying mitochondrial function, protein stability and stress resistance across seven species of clams, with lifespans ranging from one year to the ocean quahog's 500-plus years. Austad's research has convinced him that one key to slowing aging is to protect the proteins inside our cells. "Proteins make everything work in the cell, and to do that, they have to be folded precisely like origami. But as we get older they get battered about, and ultimately lose that precise shape. Quahogs, unlike us, keep their proteins in shape century after century." When Austad takes human proteins and adds them to a mix of tissues from the clams, "they become more stable, less likely to unfold." His lab is now working to identify exactly what is protecting the clams' proteins. That mechanism could point to a potential treatment for aging, along with new therapies for Alzheimer's disease and other conditions caused by protein misfolding.

Link: http://www.uab.edu/news/focus-on-patient-care/item/6521-answers-to-age-old-questions-austad-explores-the-science-of-aging

The situation with respect to the effects of medical regulation on scientific and technological progress in the US is horrible and getting worse. Regulators at the FDA follow their incentives: they are only castigated in public when an approved treatment causes issues, but never suffer consequences from increasing the time and cost of development, nor from rejecting treatments outright, nor from the suppression of medical progress by making many viable approaches too costly for profitable development. The outcome is - of course - a continued increase in cost, a continued flow of demands for an extra test, for more data, for more rigorous certainty in an uncertain field, and so ever more money is required to commercialize ever fewer new treatments. To develop a drug a decade ago took a billion dollars all told, accounting for inflation since then, and is now more like two and a half billion. There is no benefit here for all that extra funding - or at least not unless you happen to be a bureaucrat who likes his or her job.

Sooner or later other incentives are going to come into play. Medical tourism is cheap. Entrepreneurs can run viable, professional medical businesses outside the US based on research carried out inside the US, and charge far less money for better and more recent types of treatment. The more that FDA staff protect their own careers at the expensive of commercial development of new therapies, the more likely it becomes that a solid, organized pipeline will emerge to carry the results from US labs to clinics outside the US, rather than the much more ad-hoc process that takes place at the moment. Simple economics will make the FDA irrelevant at some point absent significant reformation, but change is slow in coming, despite the situation for stem cell therapies in which the new and the best treatments have so far been available outside the US for years prior to final capitulation on the part of the regulators.

There are other important incentives here. Regulators and politicians are people too, albeit misguided examples of such. They suffer the same illnesses and age-related degeneration as the rest of us, and so there is only so much that any rational individual will do in order to block progress towards effective medicines for these conditions. Today I'll point out two economics posts from recent months, the first a look at the harms done by the FDA, and the second a note that Japanese regulators are backing off in the face of an aging population and the prospect of new therapies for age-related disease. I see the latter as a modestly encouraging sign for the decades ahead - that at least some bureaucrats are willing to do something other than watch the world burn.

Is the FDA Too Conservative or Too Aggressive?

I have long argued that the FDA has an incentive to delay the introduction of new drugs because approving a bad drug (Type I error) has more severe consequences for the FDA than does failing to approve a good drug (Type II error). In the former case at least some victims are identifiable and the New York Times writes stories about them and how they died because the FDA failed. In the latter case, when the FDA fails to approve a good drug, people die but the bodies are buried in an invisible graveyard.

In an excellent new paper researchers use a Bayesian analysis to model the optimal tradeoff in clinical trials between sample size, Type I and Type II error. Failing to approve a good drug is more costly, for example, the more severe the disease. Thus, for a very serious disease, we might be willing to accept a greater Type I error in return for a lower Type II error. The number of people with the disease also matters. Holding severity constant, for example, the more people with the disease the more you want to increase sample size to reduce Type I error. All of these variables interact. The authors use the U.S. Burden of Disease Study to find the number of deaths and the disability severity caused by each major disease. Using this data they estimate the costs of failing to approve a good drug. Similarly, using data on the costs of adverse medical treatment they estimate the cost of approving a bad drug. Putting all this together the authors find that the FDA is often dramatically too conservative. FDA regulations may appear to be creating safe and effective drugs but they are also creating a deadly caution.

Japan Liberalizes Regenerative Medicine

Japan is liberalizing its approval process for regenerative medicine. Regenerative medicines in Japan can now get conditional marketing approval based on results from mid-stage, or Phase II, human trials that demonstrate safety and probable efficacy. Once lagging behind the United States and the European Union on approval times, there is now an approximately three-year trajectory for approvals. That compares with seven to 10 years before.

Japan is liberalizing because with their aging population treatments for diseases like Alzheimer's and Parkinson's disease are in high demand. Under the new system, a firm with a gene or regenerative therapy (e.g. stem cells) can get conditional approval with a small trial. Conditional approval means that the firm will be able to sell its procedure while continuing to gather data on efficacy for a period of up to seven years. At the end of the seven year period, the firm must either apply for final marketing approval or withdraw the product. The system is thus similar to what Bart Madden proposed for pharmaceuticals in Free to Choose Medicine.

Due to its size and lack of price controls, the US pharmaceutical market is the most lucrative pharmaceutical market in the world. Unfortunately, this also means that the US FDA has an outsize influence on total world investment. The Japanese market is large enough, however, that a liberalized approval process if combined with a liberalized payment model could increase total world R&D. Breakthroughs made in Japan will be available for the entire world so we should all applaud this important liberalization.

I remain of the opinion that all these regulatory bodies would be better gone entirely, not just cutting back to inflict half of the needless cost and suppression of development that is currently the case. In the US that much of a reduction wouldn't even turn the clock back a decade, and the FDA was plenty onerous back then. In a better world, entrepreneurs and a free market would give rise to a competing set of review and certification organizations, just as it has for any number of other fields, and just as already exist for medical services in numerous areas. That is all that is needed to set standards, review effectiveness, and identify fraud, and it can be achieved at a tiny fraction of the cost of the present much worse regulatory edifice.

Transcription factor EB (TFEB) is a regulator of autophagy, one of the processes by which cells clear out unwanted junk and damaged components. Enhancing autophagy via TFEB for therapeutic ends has been explored in a very preliminary fashion to date, such as in the context of treating atherosclerosis. Continuing in this vein, researchers here show that manipulating TFEB can increase clearance of the α-synuclein aggregates whose increased presence is associated with the age-related diseases collectively known as synucleinopathies:

Aggregation of α-synuclein (α-syn) is associated with the development of a number of neurodegenerative diseases, including Parkinson's disease (PD). The formation of α-syn aggregates results from aberrant accumulation of misfolded α-syn and insufficient or impaired activity of the two main intracellular protein degradation systems, namely the ubiquitin-proteasome system and the autophagy-lysosomal pathway.

Novel insights into the mechanisms of autophagy regulation have emerged with the recent discovery that the transcription factor EB (TFEB) controls the coordinated activation of the CLEAR (Coordinated Lysosomal Expression and Regulation) network. TFEB regulates lysosome biogenesis as well as autophagosome formation and autophagosome-lysosome fusion, thereby promoting cellular clearance. Based on this evidence we hypothesized that TFEB activation could prevent accumulation of α-syn aggregates by enhancing autophagic clearance.

We tested this hypothesis by using a human neuroglioma stable cell line that accumulates aggregated α-syn and demonstrated that overexpression of TFEB reduces the accumulation of aggregated α-syn. Specifically, we provide evidence that the reduced accumulation of α-syn aggregates correlates with TFEB activation and with upregulation of the CLEAR network and the autophagy system. We also show that chemical activation of TFEB using 2-hydroxypropyl-β-cyclodextrin (HPβCD) mediates autophagic clearance of aggregated α-syn. These results support the role of TFEB as a therapeutic target for the treatment of PD and potentially other neurodegenerative diseases characterized by protein aggregation.

Link: http://dx.doi.org/10.1371/journal.pone.0120819

Stem cells reside within a stem cell niche, a supporting environment that provides stem cells with the conditions they need. The lack of this niche is why most transplanted stem cells survive only a short time. Many of the potential incremental improvements to stem cell transplants under development work because they incorporate some of the functions of the niche into the therapy, usually by delivering specific signals or nutrients for a period of time. This is an example of the type:

Although stem cells have shown enormous promise in repairing organs after injury, using them in the heart itself has not yielded the expected results because very few of the transplanted cells survive in the heart. When the heart beats, it pushes cells injected into the heart wall out into the lungs before they get a chance to attach to the wall. Additionally, when stem cells move from the culture flasks they are grown in and into a solution for injection in the heart, their metabolism slows, causing them to die in several hours unless they are given the opportunity to attach to tissue. Researchers have tried to improve stem cell retention in the heart by injecting millions, only to have a mere 10-to-20 percent stick around an hour after injection. And even then a large number of these cells die within 24 hours due to a sluggish metabolism. "If we could inject fewer cells soon after heart attacks and coax them to proliferate following transplantation, we could limit scar formation and be more successful with re-growing new heart muscle."

The researchers developed a hydrogel that combines serum, a protein-filled component of blood that contains everything cells need to survive, with hyaluronic acid, a molecule already present in the heart and in the matrix that surrounds and supports cells. By mixing these two components, the researchers created a sticky gel that functioned as a synthetic stem cell niche: It encapsulated stem cells while nurturing them and rapidly restored their metabolism. Tests in petri dishes showed that both adult and embryonic stem cells encapsulated in this material not only survived at levels near 100 percent but thrived for days and proliferated. The encapsulated cells also showed markedly higher production of growth factors known to be involved in cardiac repair compared with stem cells that weren't encapsulated in the gel.

When the cell-gel combination was injected into living rat hearts, about 73 percent of the cells were retained in the hearts after an hour, compared with 12 percent of cells suspended in a solution. Over the next seven days, the number of regular solution-based transplanted cells continued to decline, whereas cells within the hydrogel increased in number. In rat models of heart attack damage, moreover, the team reports that the hydrogel with encapsulated cells improved pumping efficiency of the left ventricle over the four weeks after injection by 15 percent, compared with 8 percent from cells in solution. Even injections of the hydrogel on its own significantly improved heart function and increased the number of blood vessels in the region of the heart attack.

Link: http://www.hopkinsmedicine.org/news/media/releases/sticky_gel_helps_stem_cells_heal_rat_hearts

It is no longer remarkable to modestly extend life via genetic manipulation in worms, flies, and smaller mammals. Many demonstrations pass by without comment, a score or more new approaches explored every year. Below you'll find links to five recently published papers, each a different approach in flies or worms that slows aging and extends longevity by a small amount.

At this point much of the goal of this research is mapping: everything in cellular biochemistry is intricately interconnected, and so while there are probably only a handful of core mechanisms that slow aging, there is a near unlimited set of ways to influence those mechanisms. This situation makes it hard to figure out the identity of many of these biochemical switches, and equally hard to figure out which of the known switches are more important to aging. The operation of cellular metabolism is enormously, fantastically complicated, and still only superficially cataloged. There is a big difference between having a parts list and having full blueprints of the engine, and currently the state of knowledge is somewhere between those two extremes.

Extending life in lower animals through genetic alterations is a tool that can add to the overall knowledge of metabolism and how aging progresses: how the forms of damage that cause aging produce a chain of cause and consequence leading to dysfunction and age-related disease. A great deal is known of this damage, and a great deal is known about age-related diseases, but the middle of the chain is a big empty space on the map. Researchers aim to fill that in, and thus provide a complete accounting of aging at the molecular level. This process is unlikely to lead to methods of meaningfully extending healthy life span in humans in the near term, however. Its output along the way is well demonstrated by sirtuin research, or the focus on metformin, or on drugs influencing the mTOR pathway: marginal therapies capable of only slightly slowing aging, if that. These are all ways of adjusting the operation of metabolism to slightly slow down the rate of damage accumulation. The best path to near-future therapies for aging, a path capable of producing rejuvenation and greatly extended healthy life spans, is instead to build methods of repairing the well-cataloged forms of damage. That should be far less expensive, the roadmap to therapies is far more established, and the benefits provided by those therapies should be far greater.

So which of these approaches to pour funds into? It should be no contest, yet repair remains a hard sell. The disruption of existing institutions of aging research to focus more on repair of the known forms of damage than on exploration of metabolism is an ongoing battle, and repair-based approaches are still a minority concern in the broader field of medicine. Again, the purpose and culture of science is to create knowledge, not outcomes, and perhaps there is the challenge in this particular situation.

Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan

Methionine restriction extends the lifespan of various model organisms. Limiting S-adenosyl-methionine (SAM) synthesis, the first metabolic reaction of dietary methionine, extends longevity in Caenorhabditis elegans but accelerates pathology in mammals. Here, we show that, as an alternative to inhibiting SAM synthesis, enhancement of SAM catabolism by glycine N-methyltransferase (Gnmt) extends the lifespan in Drosophila. Gnmt strongly buffers systemic SAM levels by producing sarcosine in either high-methionine or low-sams conditions. During ageing, systemic SAM levels in flies are increased. Gnmt is transcriptionally induced in a dFoxO-dependent manner; however, this is insufficient to suppress SAM elevation completely in old flies. Overexpression of gnmt suppresses this age-dependent SAM increase and extends longevity. Pro-longevity regimens, such as dietary restriction or reduced insulin signalling, attenuate the age-dependent SAM increase, and rely at least partially on Gnmt function to exert their lifespan-extending effect in Drosophila. Our study suggests that regulation of SAM levels by Gnmt is a key component of lifespan extension.

Bmk-1 regulates lifespan in Caenorhabditis elegans by activating hsp-16

The genetics of aging is typically concerned with lifespan determination that is associated with alterations in expression levels or mutations of particular genes. Previous reports in C. elegans have shown that the bmk-1 gene has important functions in chromosome segregation, and this has been confirmed with its mammalian homolog, KIF11. However, this gene has never been implicated in aging or lifespan regulation. Here we show that the bmk-1 gene is an important lifespan regulator in worms. We show that reducing bmk-1 expression using RNAi shortens worm lifespan by 32%, while over-expression of bmk-1 extends worm lifespan by 25%, and enhances heat-shock stress resistance. Moreover, bmk-1 over-expression increases the level of hsp-16 and decreases ced-3 in C. elegans. Genetic epistasis analysis reveals that hsp-16 is essential for the lifespan extension by bmk-1. These findings suggest that bmk-1 may act through enhanced hsp-16 function to protect cells from stress and inhibit the apoptosis pathway, thereby conferring worm longevity. Though it remains unclear whether this is a distinct function from chromosomal segregation, bmk-1 is a potential new target for extension of lifespan and enhancement of healthspan.

Inhibition of elongin C promotes longevity and protein homeostasis via HIF-1 in C. elegans

The transcription factor hypoxia-inducible factor 1 (HIF-1) is crucial for responses to low oxygen and promotes longevity in Caenorhabditis elegans. We previously performed a genomewide RNA interference screen and identified many genes that act as potential negative regulators of HIF-1. Here, we functionally characterized these genes and found several novel genes that affected lifespan. The worm ortholog of elongin C, elc-1, encodes a subunit of E3 ligase and transcription elongation factor. We found that knockdown of elc-1 prolonged lifespan and delayed paralysis caused by impaired protein homeostasis. We further showed that elc-1 RNA interference increased lifespan and protein homeostasis by upregulating HIF-1. The roles of elongin C and HIF-1 are well conserved in eukaryotes. Thus, our study may provide insights into the aging regulatory pathway consisting of elongin C and HIF-1 in complex metazoans.

Nmdmc overexpression extends Drosophila lifespan and reduces levels of mitochondrial reactive oxygen species

NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase (NMDMC) is a bifunctional enzyme involved in folate-dependent metabolism and highly expressed in rapidly proliferating cells. However, Nmdmc physiological roles remain unveiled. We found that ubiquitous Nmdmc overexpression enhanced Drosophila lifespan and stress resistance. Interestingly, Nmdmc overexpression in the fat body was sufficient to increase lifespan and tolerance against oxidative stress. In addition, these conditions coincided with significant decreases in the levels of mitochondrial ROS and Hsp22 as well as with a significant increase in the copy number of mitochondrial DNA. These results suggest that Nmdmc overexpression should be beneficial for mitochondrial homeostasis and increasing lifespan.

Heart-specific Rpd3 downregulation enhances cardiac function and longevity

Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long-lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart-specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long-lived flies were tested in the heart-specific manner. Interestingly, the expressions of anti-aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart-specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart-specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in cardiac function and longevity to systemically modulate the fly's response to the environment.

It is well known that education level correlates with life expectancy, one link in a web of correlations between wealth, status, intelligence, and a wide range of related statistics derived from demographic and epidemiological studies. There may in fact be a biological link between robust health and greater intelligence, but the general consensus is that these observed correlations arise from better lifestyle choices, better access to medicine, and greater ability to make use of the medical establishment. It is nonetheless interesting to see that the education correlation continues into very late life, when individuals are struggling with a high load of cell and tissue damage, and genetic factors start to become more important in determining remaining life expectancy:

Socioeconomic inequalities in life expectancy have been shown among the middle aged and the youngest of the old individuals, but the situation in the oldest old is less clear. The aim of this study was to investigate trends in life expectancy at ages 85, 90 and 95 years by education in Norway in the period 1961-2009. This was a register-based population study including all residents in Norway aged 85 and over. Individual-level data were provided by the Central Population Register and the National Education Database. For each decade during 1961-2009, death rates by 1-year age groups were calculated separately for each sex and three educational categories. Annual life tables were used to calculate life expectancy at ages 85, 90 and 95.

Educational differentials in life expectancy at each age were non-significant in the early decades, but became significant over time. For example, for the decade 2000-9, a man aged 90 years with primary education had a life expectancy of 3.4 years, while a man with tertiary education could expect to live for 3.8 years. Similar numbers in women were 4.1 and 4.5 years, respectively. Even among 95-year-old men, statistically significant differences in life expectancy were found by education in the two last decades. Education matters regarding remaining life expectancy also for the oldest old in Norway. Life expectancy at these ages is low, so a growth of 0.5 years in the life expectancy differential is sizeable.

Link: http://dx.doi.org/10.1093/ageing/afv128

The research noted here is a good example here of inventively combining presently available technologies to achieve a positive result. The scientists involved have demonstrated a way to work around paralysis following spinal cord injury to allow physical activity. It is interesting to consider that this result could probably have been achieved twenty or more years ago had someone put in the effort. We should all no doubt ask ourselves what else could be achieved today in medicine, and doesn't exist simply because no-one has yet tried in earnest, or assembled the right building blocks in the right way:

The ability to walk has been restored following a spinal cord injury, using one's own brain power. The preliminary proof-of-concept study shows that it is possible to use direct brain control to get a person's legs to walk again. This is the first time that a person with complete paralysis in both legs (paraplegia) due to spinal cord injury was able to walk without relying on manually controlled robotic limbs, as with previous walking aid devices. "Even after years of paralysis the brain can still generate robust brain waves that can be harnessed to enable basic walking. We showed that you can restore intuitive, brain-controlled walking after a complete spinal cord injury. This noninvasive system for leg muscle stimulation is a promising method and is an advance of our current brain-controlled systems that use virtual reality or a robotic exoskeleton."

The participant, who had been paralyzed for five years, walked along a 3.66m long course using an electroencephalogram (EEG) based system. The system takes electrical signals from the participant's brain, which then travel down to electrodes placed around his knees to create movement. Mental training was initially needed to reactivate the brain's walking ability. Seated and wearing an EEG cap to read his brainwaves, the participant trained to control an avatar in a virtual reality environment. He also required physical training to recondition and strengthen his leg muscles. The participant later practiced walking while suspended 5cm above ground, so he could freely move his legs without having to support himself. On his 20th visit, he translated these skills to walk on the ground and wore a body-weight support system for aid and to prevent falls. Over the 19 week testing period, he gained more control and performed more tests per visit.

This proof-of-concept study involved a single patient so further studies are needed to establish whether these results are true for a larger population of individuals with paraplegia. "Once we've confirmed the usability of this noninvasive system, we can look into invasive means, such as brain implants. We hope that an implant could achieve an even greater level of prosthesis control because brain waves are recorded with higher quality. In addition, such an implant could deliver sensation back to the brain, enabling the user to feel their legs."

Link: http://www.eurekalert.org/pub_releases/2015-09/bc-mwa091815.php

Results were recently published for the first trial of CPHPC as a therapy to clear out age-related deposits of the type of amyloid formed from misfolded transthyretin, normally responsible for transporting the thyroid hormone thyroxine in blood and cerebrospinal fluid. Amyloids are one of the distinguishing features of older tissues, and clearing them will be one of the necessary outcomes produced by any comprehensive suite of rejuvenation therapies developed in the near future.

The accumulation of transthyretin amyloid creates a condition known as senile systemic amyloidosis where it occurs to varying degrees for everyone in later life, and TTR amyloidosis when it arises in young people due to inherited mutations. Senile systemic amyloidosis is known to be responsible for a sizable fraction of deaths in supercentenarians, as the amyloid deposits clog the cardiovascular system to the point of failure. This process is also thought to play an underappreciated role in heart failure in the younger old demographic, however, and is involved in other age-related degenerative conditions such as spinal stenosis.

CPHPC works in an indirect way: it attacks an unfortunate aspect of our biochemistry that prevents existing clearance systems from getting rid of transthyretin amyloid. Serum amyloid P component (SAP) binds to amyloids such as misfolded transthyretin and blocks the normal mechanisms of clearance. Removing SAP led to clearance of amyloid, but the action of CPHPC wasn't good enough on its own. The trial combined CPHPC with an antibody also aimed at removing SAP from the picture, as the two together produced far better results in pre-trial studies.

At present there are few good treatments for amyloidosis, and those that do exist are fairly specific to narrow demographics and circumstances. CPHPC is one of a number of potentially broad and effective treatments somewhere in the development process, however, so we have cause to be fairly optimistic about the near future in this field. Some of these potential treatments have been helped along in their early stages by the SENS Research Foundation; take a look back in the Fight Aging! archives at the development of catabolic antibodies for TTR amyloidosis for example. In the case of CPHPC the trial results been a long time in the making: development of CPHPC as a therapy for systemic amyloidosis started more than a decade ago, and the deal to set up a clinical trial was struck back in 2009. The wheels of medical science move very slowly indeed. Still, the news is good by the sound of it:

Potential new approach to the treatment of systemic amyloidosis

In 2009 GSK and Pentraxin Therapeutics Ltd entered into collaboration to develop the world's first dual drug-antibody treatment for the rare disease systemic amyloidosis. The results of the first in human clinical trial have today been published. The publication shows the results of the first 15 patients treated with a therapeutic partnership of CPHPC (a small chemical molecule) and an anti-SAP antibody.

Amyloid is an abnormal protein material that accumulates in the tissues, damaging their structure and function and causing a rare and usually fatal disease called amyloidosis. Present treatments can stabilise some patients and substantially prolong life but about 20% of patients still die within 6 months of diagnosis. The results of the phase I study showed that the antibody was generally well tolerated and produced rapid clearance of amyloid from various organs. Removal of amyloid from the liver was associated with improved function. Whole body anterior amyloid scans of a patient with systemic amyloidosis show abundant amyloid in the liver before treatment and the almost complete absence of amyloid after a single dose of the new anti-SAP antibody.

Therapeutic Clearance of Amyloid by Antibodies to Serum Amyloid P Component

We conducted an open-label, single-dose-escalation, phase 1 trial involving 15 patients with systemic amyloidosis. After first using CPHPC to deplete circulating SAP, we infused a fully humanized monoclonal IgG1 anti-SAP antibody. Patients with clinical evidence of cardiac involvement were not included for safety reasons. Organ function, inflammatory markers, and amyloid load were monitored.

There were no serious adverse events. Infusion reactions occurred in some of the initial recipients of larger doses of antibody; reactions were reduced by slowing the infusion rate for later patients. At 6 weeks, patients who had received a sufficient dose of antibody in relation to their amyloid load had decreased liver stiffness, as measured with the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown by means of SAP scintigraphy and measurement of extracellular volume by magnetic resonance imaging. A reduction in kidney amyloid load and shrinkage of an amyloid-laden lymph node were also observed.

Stem cell activity declines with age, resulting in increased tissue frailty and dysfunction. Researchers are finding a variety of ways to increase the activity of old stem cell populations, with most of this work focusing on the better known and characterized muscle and bone marrow stem cells. It is likely that different populations all require subtly different methodologies given their different cell states, but so far it seems that ramping up the processes of telomere lengthening works broadly, and that this does boost stem cell activity may be the underlying reason why telomerase therapy extends life in mice, though there are other potential mechanisms to consider, and telomere dynamics in mice are quite different from those in humans. In our species the consensus is that more telomerase activity is probably the path to more cancer.

Sufficient control over native stem cells may prove an adequate substitute for stem cell transplants, but there is still the question of just how much risk this entails given the age-related damage accumulated by stem cells and stem cell niches in old tissues. Based on data gathered so far, there is less risk of cancer than was expected, but in the grand scheme of things these are still the early days of manipulating stem cells. Old stem cell populations most likely require repair or replacement as a part of any comprehensive regenerative medicine targeted at the aging process, but it seems plausible that there are benefits to be had by awakening dormant stem cells even without that sort of comprehensive rejuvenation treatment.

Previously, we reported that a novel sub-population of young mesenchymal stem cells (YMSCs) existed in old bone marrow, which possessed high anti-aging properties as well as excellent efficacy for cardiac repair. MicroRNAs (miRNAs) have emerged as key regulators in post-transcriptional gene expression programs, however it is unknown whether miRNAs directly control stem cell senescence. Here we present the first evidence that miR-195 overexpressed in old MSCs (OMSCs) induces stem cell senescence deteriorating their regenerative ability by directly deactivating telomerase reverse transcriptase (Tert), and abrogation of miR-195 can reverse stem cell aging.

MiRNAs profiling analysis in YMSCs and OMSCs by microarray showed that miR-140, miR-146a/b and miR-195 were significantly upregulated in OMSCs, which led us to hypothesize that these are age-induced miRNAs involved in stem cell senescence. Of these miRNAs, we found miR-195 directly targeted 3'-untranslated region of Tert gene by computational target prediction analysis and luciferase assay, and knockdown of miR-195 significantly increased Tert expression in OMSCs. Strikingly, miR-195 inhibition significantly induced telomere re-lengthening in OMSCs along with reduced expression of senescence-associated β-galactosidase. Moreover, silencing miR-195 in OMSCs by transfection of miR-195 inhibitor significantly restored anti-aging factors expression including Tert and Sirt1 as well as phosphorylation of Akt and FOXO1. Notably, abrogation of miR-195 markedly restored proliferative abilities in OMSCs. Transplantation of OMSCs with knocked out miR-195 reduced infarction size and improved left ventricular function in an animal model of myocardial infarction.

In conclusion, rejuvenation of aged stem cells by miR-195 inhibition would be a promising autologous therapeutic strategy for cardiac repair in the elderly patients.

Link: http://dx.doi.org/10.1002/stem.2211

Researchers can measure the level of noise in the signals of neural circuits in the brain, and see that it is higher in older brains. The proximate cause of this noise is an open question. With an eye to finding out more about the mechanisms involved, it would be interesting to see if there is any correlation of magnitude with measures such as epigenetic dysregulation or the low level of demyelination of nerves that occurs in aging.

Researchers found that background noise in key cortical regions of the brain responsible for higher functions was associated with poorer memorization of visual information, and that this noise also was associated with age. They concluded that neural noise might be the mechanism behind aging-associated loss of cognitive ability, slowing of behavioral responses, uncertain memories and wavering concentration. The noise measured in the studies was random signaling that did not fit the pattern of the brain's natural oscillations. These oscillations are rhythmic patterns of electrical activity generated by nerve cells, or neurons, linked within the brain's circuitry. This activity occurs in addition to electrical signals generated by individual neurons.

In recent years brain oscillations have become an intense focus of research by scientists seeking to discover any functional roles they might play. Emerging evidence suggests that oscillations might prime nerve circuits to respond more efficiently to stimuli. "Imagine that individual neurons are like surfers. Nearby surfers experience the same waves, which are like the oscillations linking neurons in the brain. But like noise, additional interfering factors often disrupt the perfect wave at different times and different spots along the beach."

Researchers flashed one, two or three colored squares for less than one-fifth of a second, gave the subjects almost one second to memorize the colors, and then flashed a second display and asked the participants if the colors matched. The researchers used mathematical algorithms to extract measures of noise in the oscillations from EEG data collected during the interval when the subjects were trying to memorize the colors. On average, older subjects performed worse than younger subjects. The scientists determined that this poorer performance was due to additional noise in nerve circuits in the visual cortex; neurons did not appear to coordinate as well in generating lower-frequency oscillations. When the researchers accounted for the noise, age was no longer an independent, significant factor in performance in this experiment.

"Instead of having a normal conversation, the neurons that make up the memory networks in older adults seemed to be talking over one another, leading to a communication breakdown and degrading their memory performance. I think these types of experiments will allow neuroscientists to explore the neural underpinnings of cognitive changes across normal aging and in a variety of disease states, including autism, Parkinson's and schizophrenia, each of which is associated with breakdowns in neural oscillations."

Link: http://www.ucsf.edu/news/2015/09/131706/researchers-identify-possible-physiological-cause-brain-deficits-aging

Researchers have recently demonstrated in pigs the integration of an engineered kidney organoid, a few centimeters of kidney tissue grown from stem cells. The tissue functions as a kidney should, but it is far from full size, and does not bear all of the hallmarks of the real thing. However, enough of the normal suite of additional connections were also produced by the researchers involved to allow surgical integration of the organoid with the excretory system, and thus demonstrate generation of urine.

This work well illustrates the nature of the challenges that lie ahead for the field of tissue engineering. It isn't enough to build correctly functioning organ tissue, challenging as that is and still very much a work in progress. Connections to circulatory and other systems in the body must also exist, and each of these is its own distinct engineering task. A replacement organ whose principal job is chemical processing or filtration of one sort or another doesn't have to be shaped or structured in exactly the same way as the evolved version we're all equipped with at birth, but it does have to integrate with all of the surrounding organs and systems. That places constraints on the development of engineered organs, and presents a set of intricate challenges akin to those involved in carrying out an organ transplant.

The kidney organoids demonstrated in pigs in the research linked below are a step ahead of the first prototypes to get the tissue structure and functionality correct, but they are still many incremental steps removed from something that could replace the need for human kidney donors. Still, things are headed in the right direction, and quite rapidly at that. It was only three years ago that the first kidney organoids were unveiled, so it doesn't seem unreasonable to predict that the first practical proto-kidneys that are medically useful in humans might enter clinical trials in the early 2020s.

Lab-grown kidneys work in animals

Scientists say they are a step closer to growing fully functioning replacement kidneys, after promising results in animals. When transplanted into pigs and rats, the kidneys worked, passing urine just like natural ones. The researchers used a stem cell method, but instead of just growing a kidney for the host animal, they set about growing a drainage tube too, along with a bladder to collect and store the urine. They used rats as the incubators for the growing embryonic tissue. When they connected up the new kidney and its plumbing to the animal's existing bladder, the system worked. Urine passed from the transplanted kidney into the transplanted bladder and then into the rat bladder. And the transplant was still working well when they checked again eight weeks later. They then repeated the procedure on a much larger mammal - a pig - and achieved the same results.

Urine excretion strategy for stem cell-generated embryonic kidneys

There have been several recent attempts to generate, de novo, a functional whole kidney from stem cells using the organogenic niche or blastocyst complementation methods. However, none of these attempts succeeded in constructing a urinary excretion pathway for the stem cell-generated embryonic kidney.

First, we transplanted metanephroi from cloned pig fetuses into gilts; the metanephroi grew to about 3 cm and produced urine, although hydronephrosis eventually was observed because of the lack of an excretion pathway. Second, we demonstrated the construction of urine excretion pathways in rats. Rat metanephroi or metanephroi with bladders (developed from cloacas) were transplanted into host rats. Histopathologic analysis showed that tubular lumina dilation and interstitial fibrosis were reduced in kidneys developed from cloacal transplants compared with metanephroi transplantation. Then we connected the host animal's ureter to the cloacal-developed bladder, a technique we called the "stepwise peristaltic ureter" (SWPU) system. The application of the SWPU system avoided hydronephrosis and permitted the cloacas to differentiate well, with cloacal urine being excreted persistently through the recipient ureter.

Finally, we demonstrated a viable preclinical application of the SWPU system in cloned pigs. The SWPU system also inhibited hydronephrosis in the pig study. To our knowledge, this is the first report showing that the SWPU system may resolve two important problems in the generation of kidneys from stem cells: construction of a urine excretion pathway and continued growth of the newly generated kidney.

Here researchers construct a model to try to identify the precise mechanisms by which the buildup of 7-ketocholesterol (7KCh) in cells with age contributes to the development of macular degeneration. 7-ketocholesterol is one of the forms of metabolic waste that our biochemistry struggles to break down, and its accumulation is associated with a range of conditions from macular degeneration to atherosclerosis - it is one of the causes of aging. The scientific staff of the SENS Research Foundation have been working for years on mining the bacterial world for enzymes that can break down 7-ketocholesterol and other hardy waste compounds that contribute to age-related disease. Progress is slow, but candidates have been identified: a company was recently launched based on that work. Safely breaking down and removing waste compounds like 7-ketocholesterol is a necessary part of any future toolkit of rejuvenation therapies capable of holding back the aging process and preventing age-related disease, so progress on this front is to be encouraged.

The progression of age-related macular degeneration (AMD) involves a transition from an early or intermediate stage, in which extracellular deposits called drusen accumulate on the inner surface of Bruch's membrane, to an advanced stage featuring photoreceptor and retinal pigment epithelium (RPE) atrophy and/or choroidal neovascularization (CNV), which lead to central vision loss. While the mechanisms driving this progression are unknown, they have been linked to lipid transport and metabolism in the retina as variants in genes involved in these processes have been found to confer increased risk of AMD progression in several genome-wide association studies. Additionally, histological studies have demonstrated the accumulation of phospholipids and cholesterol in the Bruch's membrane (BrM)-retinal pigment epithelium (RPE) complex, which increases with aging and AMD stage. In the highly oxidative environment of the outer retina, these lipids have been noted to undergo conversion to oxidized species, which exert deleterious changes resembling those found in advanced AMD.

One particular species of oxidized lipid is 7-ketocholesterol, an oxysterol commonly found in oxidized low-density lipoprotein (oxLDL) that is associated with cellular toxicity in vascular endothelial and smooth muscle cells as well as in RPE cells. Previous studies have shown that 7KCh is formed by photodamage in the rodent retina via a free radical-mediated mechanism, it localizes to presumed lipoprotein deposits in the non-human primate BrM, choriocapillaris, and RPE layer, and it accumulates with increasing age, particularly in RPE-capped drusen in aged human eyes.

Microglia, the resident immune cell of the retina, are responsible for the local modulation of neuroinflammatory change. Microglia in the young, healthy retina are confined to the inner retina, but with aging, these cells migrate to the subretinal space, where they demonstrate increased activation. This subretinal accumulation of microglia have been associated with disease lesions in AMD histological specimens and in AMD-relevant animal models, and have therefore been hypothesized to drive photoreceptor and RPE degeneration, as well as choroidal neovascularization. The mechanisms driving the migration of aging microglia into the outer retina and their subsequent activation have not been well defined.

In this study, we hypothesize that the age-related deposition of 7KCh is related to subretinal microglial recruitment and activation that in turn contributes to progression to neovascular AMD. We evaluated the specific effects that 7KCh exerts on retinal microglial physiology and explored the notion that 7KCh induces pathogenic microglial changes. Our findings described here indicate that 7KCh acts as a chemoattractant capable of inducing the translocation of retinal microglia to the subretinal space. Once there, uptake of 7KCh by microglia can increase microglial activation, M1 polarization, and expression of angiogenic factors in ways that potentiate AMD progression.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4360733/

The tight junctions between cells of the blood brain barrier are a part of the system controlling passage of molecules between the blood system and brain tissue. They appear to change and fail with age, and this may be one of the ways in which ongoing clearance of amyloid-β falters, allowing the buildup of amyloid associated with Alzheimer's disease. Equally some of the changes may be due to increased but still insufficient efforts at clearance via this mechanism due to the failure of other, primary modes of clearance:

Alzheimer's disease is characterized, in part, by the build-up of a small protein ('amyloid-beta') in the brains of patients. Impaired clearance of this protein appears to be a major factor in the build-up of plaques, and then in the disease process itself. While the mode by which amyloid-beta is cleared remains unclear, it is evident that it needs to be removed from the brain via the bloodstream.

Unlike blood vessels anywhere else in the body, those in the brain have properties that strictly regulate what gets in and out of the delicate tissue - this is what is known as the blood-brain barrier (BBB). The BBB functions as a tightly regulated site of energy and metabolite exchange between the brain tissue and the bloodstream. "We have shown that distinct components of these blood vessels termed tight junctions are altered in Alzheimer's disease. We think that this alteration could be an entrained mechanism to allow for the clearance of toxic amyloid-beta from the brain in those living with Alzheimer's disease."

The researchers examined brain tissues of individuals who were affected by Alzheimer's disease during their lifetime and then compared results to those observed in model systems in the laboratory. "Our recent findings have highlighted the importance of understanding diseases at the molecular level. The concept of periodic clearance of brain amyloid-beta across the BBB could hold tremendous potential for Alzheimer's patients in the future. The next steps are to consider how this might be achieved. Given the recent advances in clinical trials of anti-amyloid beta antibodies, we hope our findings may lead to improved and adjunctive forms of therapy for this devastating condition."

Link: http://www.eurekalert.org/pub_releases/2015-09/tcd-trr091715.php

Today an update on the MitoSENS mitochondrial repair project showcased at the Lifespan.io crowdfunding site: after a few weeks of publicity, more than 200 backers have pledged more than $20,000 of the original $30,000 goal. Congratulations are due the Lifespan.io team and their supporters on the progress to date. Have you helped out yet?

MitoSENS is a branch of SENS rejuvenation research coordinated by the SENS Research Foundation: one of a number of efforts to produce the foundations needed to repair the specific known forms of cell and tissue damage that cause aging. MitoSENS is focused on the accumulation of mutations in mitochondrial DNA and their contribution to degenerative aging. DNA provides blueprints for the proteins making up cellular machinery, particularly vital cellular machinery in the case of mitochondria. Thus when the blueprint becomes damaged in certain ways dysfunctional machinery results, and given enough cells fallen into that state over the course of a lifetime, organs and tissues begin to fail. Any method that ensures reliable delivery of the correctly formed proteins to the mitochondria is a possible basis for a therapy, and there are numerous options. The SENS approach is gene therapy to copy vulnerable mitochondrial genes from the mitochondrial DNA to nuclear DNA, a process called allotopic expression, along with sufficient instructions to ensure that proteins are delivered back to the mitochondria after manufacture.

This line of research has been under way in bits and pieces for a decade or more, but not in earnest until fairly recently. The SENS Research Foundation was using donated funds back in 2008 to assist research that has since blossomed into the French company Gensight, where staff are producing an implementation of allotopic expression for a single gene involved in inherited mitochondrial disease. With the sizable commercial funding involved that should go a long way towards hammering out implementation details and robustness of this class of therapy, as well as providing a proof of concept in clinical practice to quell the grumblings of skeptics. In parallel to that the broader task of developing the methodologies needed for transport back to mitochondria for all mitochondrial genes must still be carried out, hence the ongoing MitoSENS project.

We are fortunate to live in in the opening years of the biotechnology revolution, a time when early stage life science and medical research is becoming ever cheaper. Far more can be done with far less, and the trend is accelerating year after year. A few tens of thousands of dollars in the hands of a good researcher with access to an established lab for six months can produce significant incremental progress at the cutting edge of a field, something that would have required millions or tens of millions of dollars and years of effort twenty years ago. This rapid drop in the cost of research is why the crowdfunding of science is becoming much more important. There is a great deal that might be done today in medical research that will never funded by the very conservative and risk-averse traditional sources of institutional research money. But now philanthropy is for everyone, not just the wealthy. We can all band together and help to create meaningful progress that will help our own health in the future, funding early stage work that is ignored by institutions, but which will later go on to pull in millions of dollars for clinical development once the prototypes are constructed and the case made.

Groups like Lifespan.io are important because they bring a different perspective, a different set of networks to the table. You can see them at work on Twitter, for example. In a time when every dollar donated can do so much more, and influential people are talking openly about aging research, it is ever more important to expand the community of people willing to materially support the development of rejuvenation therapies.

This article looks at a few recent papers providing initial evidence for nuclear pore dysfunction to be a important contributing cause of at least some forms of Amyotrophic lateral sclerosis (ALS). This is perhaps of general interest to those of us following aging research, as nuclear pore proteins in at least some long-lived neurons seem to last as long as we do; they are either never replaced over the length of a human life span, or replaced only very slowly. Nuclear pore structures are responsible for the transport of molecules across the nuclear membrane in cells, and there is speculation that accumulated molecular damage to these pores might contribute to aspects of brain aging. From this viewpoint, ALS might be a condition that occurs due to one specific form of age-related cellular damage progressing at a much faster pace than usual, a pattern that exists in a number of age-related diseases only suffered by a portion of the population.

Three studies, analyzing in different ways the leading ALS gene, came to what is being called a remarkably similar conclusion: the most common form of ALS may be caused by clogged pores in brain cell nuclear membranes. One of the studies identified two drug options that eradicated the pore clogging. All identified druggable targets. "These are the first studies to implicate altered nucleo-cytosolic transport as a mechanism of pathology in ALS. The findings are presently limited to the significant subset of ALS cases caused by the C9 mutation that is found in 40 percent of inherited ALS and frontotemporal dementia (FTD)." Two of the papers also showed that TDP-43, a protein known as key in ALS, appears mislocalized by the C9 mutation, and the authors show that this mislocalization can be rescued.

"Discovery of TDP-43 mislocalization - from nucleus into cytoplasm - as a predominant occurrence in ALS and FTD has provided a major change of perspective on these diseases. The complexity of underlying processes that can cause TDP-43 proteinopathy has been highlighted by the discovery of C9 in ground-breaking studies. However, none connected C9 with the major pathology in patients: TDP-43 proteinopathy. These new studies bring this connection closer. They show RNA from C9 mutation can disrupt nuclear pore shuttling by binding to proteins driving this process. The bigger question is whether nuclear import defects contribute to the pathogenesis of sporadic as well as inherited familial ALS. This is being looked at by multiple labs. If the answer is 'yes,' one can imagine modulators of nuclear import might emerge as a major therapeutic avenue in ALS. No doubt such drugs will be given a hard look."

Link: http://www.biosciencetechnology.com/articles/2015/09/three-remarkable-studies-say-clogged-pores-may-cause-als-drug-targets-idd

The use of carefully structured scaffolds to guide tissue regrowth where it would not normally happen shows considerable promise as an approach to regenerative medicine. Here is a recent example of the state of the art for nerve regrowth:

Nerve regeneration is a complex process. Because of this complexity, regrowth of nerves after injury or disease is very rare. In a new study, researchers used a combination of 3D imaging and 3D printing techniques to create a custom silicone guide implanted with biochemical cues to help nerve regeneration. The guide's effectiveness was tested in the lab using rats. To achieve their results, researchers used a 3D scanner to reverse engineer the structure of a rat's sciatic nerve. They then used a specialized, custom-built 3D printer to print a guide for regeneration. Incorporated into the guide were 3D-printed chemical cues to promote both motor and sensory nerve regeneration. The guide was then implanted into the rat by surgically grafting it to the cut ends of the nerve. Within about 10 to 12 weeks, the rat's ability to walk again was improved.

"This represents an important proof of concept of the 3D printing of custom nerve guides for the regeneration of complex nerve injuries. Someday we hope that we could have a 3D scanner and printer right at the hospital to create custom nerve guides right on site to restore nerve function." Scanning and printing takes about an hour, but the body needs several weeks to regrow the nerves. Previous studies have shown regrowth of linear nerves, but this is the first time a study has shown the creation of a custom guide for regrowth of a complex nerve like the Y-shaped sciatic nerve that has both sensory and motor branches. "The exciting next step would be to implant these guides in humans rather than rats."

Link: http://www.newswise.com/articles/3d-printed-guide-helps-regrow-complex-nerves-after-injury

Here I'll point out a recent review of approaches to treat one of the more common synucleinopathies, conditions related to - and thought to be caused by - the abnormal accumulation of α-synuclein in tissues. The pathologies of numerous age-related diseases are linked to various different types of protein aggregate that are observed to build up with age: misfolded or simply overabundant proteins that precipitate to form solid clumps and fibrils. Amyloids are well known for their association with Alzheimer's disease, but there are many types of amyloid and many corresponding amyloidosis conditions. Similarly tau aggregates are linked to the tauopathies. The list goes on, and of course includes α-synuclein.

Why do these various different aggregates appear in old individuals but not young ones? Most of the evidence to support various theories comes out of Alzheimer's research, as that field has far more funding and far more scientists working on the problem. Amyloid levels in the brain are dynamic on a fairly short timescale, and the buildup of amyloid has the look of slowly failing clearance mechanisms. These might include general dysfunction in the choroid plexus filtration of cerebrospinal fluid, or in the drainage channels that carry away metabolic waste from the brain, or the mechanisms of the blood-brain barrier intended to shunt unwanted waste out of the brain and into the blood system. These and related forms of dysfunctions could plausibly arise from many of the forms of cell and tissue damage thought to cause aging, or from their consequences such as inflammation, loss of muscle strength, loss of tissue flexibility, and so forth.

The most promising near term approach to protein aggregates is to build treatments than can be periodically applied to clear out the buildup. Immunotherapies are so far the best of ongoing efforts, enlisting the immune system to attack and break down the aggregates, but there is still a way to go towards robust and reliably outcomes. Clinical trials have so far been disappointing, as is often the case in the first round of attempts in any area of medicine. Equally, other classes of rejuvenation therapy will be needed to repair the problems in clearance of aggregates that cause the buildup in the first place: just getting rid of the aggregrates themselves isn't a full solution, just a much better class of sustaining treatment than is presently available.

Work on clearing α-synuclein runs in parallel to work on amyloid-β, and with the same general pattern of progress, in that immunotherapies look to be the best path forward for now, yet only incremental benefits have been shown to date via this appreach. This review is focused on Lewy body dementia, but the approaches to clearing α-synuclein might be applied to any of the other synucleinopathies, such as Parkinson's disease.

Disease-modifying therapeutic directions for Lewy-Body dementias

Dementia with Lewy bodies (DLB) is the second most common pathologic diagnosis of dementia, following Alzheimer's disease (AD), comprising 25% of all dementias. The pathologic feature of DLB is the presence of Lewy bodies in the cortex and brainstem. Lewy-bodies are neuronal inclusions of abnormal filamentous assemblies of α-synuclein and ubiquitin. It is very difficult to distinguish DLB from dementia-associated with Parkinson's disease (PD), which shares many underlying clinical and pathological features with DLB. The major component of Lewy bodies in DLB and Parkinson's disease (PD) is misfolded α-synuclein. The normal α-synuclein is a soluble protein and is involved in presynaptic processing of neurotransmitters, mitochondrial function and proteasome processing. In DLB and PD, α-synuclein aggregates in Lewy bodies and causes neuronal death. Therefore, various strategies have been employed to reduce α-synuclein directly for the treatment of DLB and PD.

Secreted, extracellular α-synuclein might play a crucial role in the passage of misfolded α-synuclein from one cell to another. Therefore, immunotherapy targeting extracellular α-synuclein has been proposed, and it was found that immunization with recombinant human α-synuclein led to a reduction in α-synuclein accumulation and neurodegeneration without neuroinflammation. It was also found that administration of anti-α-synuclein antibody into the brains of PGDF-α-synuclein transgenic mice prevented cell-to-cell transmission of α-synuclein. The antibodies aid in clearance of extracellular α-synuclein proteins by microglia, thereby preventing their actions on neighboring cells. Misfolded extracellular α-synuclein might interact with antibodies to form antigen-antibody complexes, and these complexes are endocytosed and transferred to the lysosomal compartment for degradation through autophagy.

Recently, AFFiRiS AG, an Austria-based biotech company, developed a vaccine targeting PD and other synucleinopathies. The peptides used in the vaccine are designed to be too small to induce an α-synuclein-specific T cell response, thus avoiding T cell autoimmunity. The vaccine was tested in transgenic mouse models. Active vaccination resulted in decreased accumulation of α-synuclein oligomers in axons and synapses, reduced neurodegeneration, and improvements in motor and memory deficits in both models. Phase I clinical trials are currently ongoing.

Another strategy targeting α-synuclein is RNA interference (RNAi). Direct infusion of siRNA led to the reduction of α-synuclein. Recent studies have employed virally-mediated RNAi delivery, using lentivirus-mediated RNAi to successfully silence human α-synuclein expression in the rat substantia nigra. Other groups have employed AAV-mediated RNAi, but found that this approach caused neurotoxicity. They then tried AAV-mediated RNAi embedded in mircoRNA30 backbone, and they were able to reverse α-synuclein induced forelimb deficit and dopaminergic neuron loss. However, this approach induced inflammation. Transgene delivery using AAV was shown to be safe in previous studies and this technology has been used in human clinical trials in PD.

Other approaches employed to reduce α-synuclein include ribozymes, intracellular expression of single chain antibodies, endogenous microRNA, and mirtrons. A safe and effective approach to reduce the level of α-synuclein will likely slow down or even reverse the progression of DLB.

The stiffening of blood vessels due to cross-linking in the extracellular matrix and other factors such as calcification is known to cause hypertension, and the elevated blood pressure of hypertension causes progressive damage to brain tissue. The degree to which this damage occurs - and might be blamed for cognitive decline with aging - is becoming ever more clear as scanning technologies improve:

A new imaging technique found that some people with high blood pressure also have damage to nerve tracts connecting different parts of the brain. The area of brain damage detected is linked to difficulties in certain cognitive skills, decision-making, and the ability to regulate emotions. "We already have clear ways to explore the damage high blood pressure can cause to the kidneys, eyes, and heart. We wanted to find a way to assess brain damage that could predict the development of dementia associated with vascular diseases." While there has been a lot of research on hypertension-related brain changes in the grey matter, scientists proposed that a look into the brain's white matter could tell if high blood pressure was having an effect even earlier than what is known.

Researchers used diffusion tensor imaging (DTI), an enhancement of magnetic resonance imaging (MRI), to evaluate and compare the structural and functional properties of the main connections between different brain regions. Fifteen participants were on medication for moderate to severe high blood pressure and 15 participants had normal blood pressure. Participants were also given a cognitive assessment. The brain imaging found that, while none of the participants showed abnormalities on a standard MRI, the more advanced DTI revealed that participants with high blood pressure had damage to: 1) brain fibers that affect non-verbal functions; 2) nerve fibers that affect executive functioning and emotional regulation; and 3) limbic system fibers, which are involved in attention tasks. Researchers also found those with high blood pressure performed significantly worse on two different assessments of cognitive function and memory. However, there were no differences in tests evaluating verbal function or ability to perform daily activities.

Link: http://newsroom.heart.org/news/new-imaging-technique-detects-early-brain-damage-from-hypertension

In this research, partly funded by the SENS Research Foundation, the authors investigate improvements to one type of immunotherapy aimed at clearance of amyloid. Amyloids of numerous types build up in tissues with aging to cause harm and disrupt normal function, including the amyloid β associated with Alzheimer's disease and the transthyretin amyloid implicated in heart failure. Efficient means of clearing amyloid must be a part of any future toolkit of rejuvenation therapies, as its presence is one of the noteworthy differences between old tissue and young tissue:

Alzheimer's disease (AD) is the most common of ~30 amyloid disorders that are currently incurable and often fatal. These diseases involve the extracellular self aggregation of a peptide or protein that forms amyloid deposits on organs. AD is a particularly complex disease since it involves the aberrant aggregation of amyloid β peptides (Aβ) and the microtuble-associated tau protein. Other debilitating amyloid disorders, are caused by mutant and wild-type forms of a blood transport protein transthyretin (TTR) that primarily deposit in the heart and/or nerves.

Passive vaccination with humanized anti-amyloid monoclonal antibodies (mAbs) is a primary immunotherapeutic approach for amyloid diseases. A recent novel therapeutic approach for AD has been to boost a patient's pool of amyloid-reactive IgGs using human intravenous immunoglobulin (IVIg). IVIg contains a diverse repertoire of pooled polyclonal human IgGs (pAbs), including anti-amyloid IgGs, from plasmas of thousands of normal individuals. Anti-amyloid pAbs isolated from normal human blood have demonstrated therapeutic potential not only for AD but for other amyloid diseases.

Recently, IVIg was tested in a 18-month phase 3 clinical trial for mild to moderate AD. The antibody did not meet its primary endpoints, but subgroup analysis indicated that IVIg had a slight beneficial effect for AD patients that were ApoE4 carriers and had moderate disease. Presumably, IVIg's ineffectiveness may have been because its anti-amyloid activity was not potent enough, and patients may have benefited more from an IVIg-like preparation that had enhanced activity. However, the development of a more viable and potent therapeutic reagent than IVIg has been hampered by our current poor understanding on its anti-amyloid activity.

We now report the following finding on pAb conformer's binding to amyloidogenic aggregates: pAb aggregates have greater activity than monomers (high molecular weight (HMW) species > dimers > monomers). Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg) had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of IVIg IgGs. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Our findings strongly indicate that an IgG's anti-amyloid activity is enhanced when they aggregate (Dimers and HMW species), and is an intrinsic property that likely has physiological and clinical significance.

Link: http://dx.doi.org/10.1371/journal.pone.0137344

Researchers have recently proposed that at least some stem cell populations make more subtle use of asymmetric division than thought, and that the mechanisms necessary to this process fail with age. Asymmetric cellular division has its origins deep in the evolutionary past, and it is entwined with the origins of aging. It is best cataloged in bacteria, a form of cellular replication in which the lineage maintains itself by segregating more of its waste and damaged components into one of the daughter cells with each division, leaving the other comparatively pristine. In this way bacteria can continually dilute the accumulation of damage that causes dysfunction and maintain a self-replicating lineage indefinitely, using division and one daughter cell as a form of disposal mechanism.

The situation is considerably more complex in multicellular organisms consisting of many specialized cell types with different replacement rates, but still much the same at the root of it all. Tissues lose cells constantly: old cells die and are replaced by new cells created by a population of stem cells dedicated to maintaining that tissue. The stem cells must maintain themselves in good condition, and asymmetric division appears to play a part in this self-renewal. It isn't just a way to ensure that when a stem cell divides the resulting pair consists of one new stem cell and one other type of cell destined to fill out nearby tissue, but it is also waste disposal for stem cells. It has been established that stem cells offload damaged mitochondria into the non-stem daughter cell when they divide, for example. The research linked below is more of the same, but looks at the partitioning of damaged proteins between the two daughter cells:

A barrier against brain stem cell aging

Neural stem cells generate new neurons throughout life in the mammalian brain. However, with advancing age the potential for regeneration in the brain dramatically declines. Researchers have shown that the stem cells of the adult mouse brain asymmetrically segregate aging factors between the mother and the daughter cells. Responsible for this is a diffusion barrier in the endoplasmic reticulum (a channel system within the cell that is for example important for protein synthesis and transport). The barrier prevents retention of damaged proteins in the stem cell daughter cell keeping the stem cells relatively clean. "Neural stem cell divisions appear to be much more asymmetric than we had previously anticipated."

In addition, researchers found that the strength of the barrier weakens with advancing age. This leads to reduced asymmetry of damaged protein segregation with increasing age of the stem cell. This could be one of the mechanisms responsible for the reduced regeneration capacity in the aged brain as stem cells that retain larger amounts of damaged proteins require longer for the next cell division. "This is an exciting new mechanism involved in stem cell division and aging. But as of now we are only just beginning to understand the molecular constituents and the true meaning of the barrier for stem cell division in the brain." One key question to be answered is whether the barrier is established in all somatic stem cells of the body. The answer to this question may open new routes to target age-dependent alterations of stem cell activity in human disease.

A mechanism for the segregation of age in mammalian neural stem cells

Throughout life, neural stem cells (NSCs) generate neurons in the mammalian brain. Using photobleaching experiments, we found that during cell division in vitro and within the developing mouse forebrain, NSCs generate a lateral diffusion barrier in the membrane of the endoplasmic reticulum, thereby promoting asymmetric segregation of cellular components. The diffusion barrier weakens with age and in response to impairment of lamin-associated nuclear envelope constituents. Weakening of the diffusion barrier disrupts asymmetric segregation of damaged proteins, a product of aging. Damaged proteins are asymmetrically inherited by the nonstem daughter cell in embryonic and young adult NSC divisions, whereas in the older adult brain, damaged proteins are more symmetrically distributed between progeny. Thus, these data identify a mechanism of how damage that accumulates with age is asymmetrically distributed during somatic stem cell division.

The endoplasmic reticulum is a complex structure with many roles, and if you look back in the Fight Aging! archives you'll find more information on other lines of research linking it to aging. Why does its behavior change? There is a question. It might be a consequence of fundamental cellular damage that causes aging, or it might be a direct or indirect reaction to that damage. As for so much of aging the lines of cause and consequence are yet to be filled in. The fastest path to drawing those lines is to work on repairing specific forms of damage known to contribute to aging and then see what happens as a result. That is also a path more likely to result in near-future treatments for degenerative aging than the approach of carefully cataloging everything, working backwards from the chaotic end stages of disease.

Here an argument is made for more research into aging and its potential treatment to focus on the oldest segments of the population rather than the younger old. From the perspective of SENS and damage repair to achieve rejuvenation, I'm not sure this matters all that much: what needs to be done to treat aging under that model is well categorized and understood. The challenge is finding the funding and the will for implementation, not further delving into the unknown. From the perspective of investigating and deeply understanding the complex processes of aging, mapping the intricate chains of cause and consequence from initial damage to cells and tissues all the way through to end-stage disease, the concerns are probably more valid:

"Old people" are still being clumped together as one group, with an arbitrary cutoff of age 65. This causes several problems, for example the diseases of young elderly, less than 75-years-old, are often lifestyle-related. Diseases of young-old are primarily cancers, atherosclerotic heart diseases and diabetes. While it is laudable to spend resources ameliorating these conditions, we must face up to facts about aging research. Researching and treating diseases in the young-old constitutes a low-hanging fruit for medicine and pharmaceutical companies. This is in stark contrast to the complicated web of damages accumulated systemically, perpetuating the declining health of people aged over 80. The 85+ group have been historically ignored due to lack of research on aging itself. I refer to "aging itself" to mean the metabolic waste accumulation ultimately causing the systemic frailty syndrome seen in the old old.

A major problem is that aging has not historically been defined as a disease, warranting detailed scrutiny in order to constitute a target for medicine. The world is paying the price for it. It is still not known exactly what diversifies people aged 100+ on a molecular and cellular level, versus people dying of age-related diseases in their 80s. This is due to a significant lack of autopsies, quantifying the aging damage of the centenarians. Therefore it is not understood exactly how this age category succeed in avoiding lethal pathology for so long, and how their accumulated pathology might differ.

This is ultimately the only way forward to successfully get aging under control and truly change the late 80s mortality peak and prolong maximum human lifespan beyond 100. Currently the most common age of death in Sweden is 86 for men and 88 for women, for comparison the life expectancy is 80 and 83.5. From what we can deduce, risk avoidance, as well as avoidance of well known health issues like smoking and obesity, won't give much. These modifiable factors will only shift the life expectancy towards the most common age of death. The geriatric costs are staggering, we cannot afford more short-term thinking chasing low hanging fruits labelled diseases in the young-old. Quantifying the precise systemic tissue damages in the very old is paramount for developing concrete medical targets, targets composing the panel of upcoming therapies bringing aging under medical control.

Link: http://www.longevityreporter.org/blog/2015/9/8/anti-aging-old

A group of researchers are attempting to gain approval to run a human trial of metformin with the aim of evaluating its ability to very slightly slow down the aging process. This is not ambitious at all from a technological perspective. It will make no real difference to aging, in comparison to what is plausible and possible via other methods, and the use of established drugs in this fashion is not a road to human rejuvenation. Instead this is an attempt to force change on the FDA from within the bounds of the system of regulation, which at present does not recognize aging as a medical condition amenable to treatment. By denying commercialization, funding for research and development is stifled all the back back down the chain, and this must change if we are to see faster progress in the future.

On a blazingly hot morning this past June, a half-dozen scientists convened in a hotel conference room in suburban Maryland for the dress rehearsal of what they saw as a landmark event in the history of aging research. In a few hours, the group would meet with officials at the U.S. Food and Drug Administration (FDA), a few kilometers away, to pitch an unprecedented clinical trial - nothing less than the first test of a drug to specifically target the process of human aging.

A scientist named Nir Barzilai tuned up his PowerPoint and launched into a practice run of the main presentation. His practice run kept hitting a historical speed bump. He had barely begun to explain the rationale for the trial when he mentioned, in passing, "lots of unproven, untested treatments under the category of anti-aging." His colleagues pounced. "Nir," interrupted S. Jay Olshansky, a biodemographer of aging from the University of Illinois, Chicago. The phrase "anti-aging ... has an association that is negative." "I wouldn't dignify them by calling them 'treatments,'" added Michael Pollak, director of cancer prevention at McGill University in Montreal, Canada. "They're products." Barzilai, a 59-year-old with a boyish mop of gray hair, wore a contrite grin. "We know the FDA is concerned about this," he conceded, and deleted the offensive phrase.

Then he proceeded to lay out the details of an ambitious clinical trial. The group wanted to conduct a double-blind study of roughly 3000 elderly people; half would get a placebo and half would get an old (indeed, ancient) drug for type 2 diabetes called metformin, which has been shown to modify aging in some animal studies. Because there is still no accepted biomarker for aging, the drug's success would be judged by an unusual standard - whether it could delay the development of several diseases whose incidence increases dramatically with age: cardiovascular disease, cancer, and cognitive decline, along with mortality. When it comes to these diseases, Barzilai is fond of saying, "aging is a bigger risk factor than all of the other factors combined." But the phrase "anti-aging" kept creeping into the rehearsal, and critics kept jumping in. "Okay," Barzilai said with a laugh when it came up again. "Third time, the death penalty."

The group's paranoia about the term "anti-aging" captured both the audacity of the proposed trial and the cultural challenge of venturing into medical territory historically associated with charlatans and quacks. The metformin initiative, which Barzilai is generally credited with spearheading, is unusual by almost any standard of drug development. The people pushing for the trial are all academics, none from industry (although Barzilai is co-founder of a biotech company, CohBar Inc., that is working to develop drugs targeting age-related diseases). The trial would be sponsored by the nonprofit AFAR, not a pharmaceutical company. No one stood to make money if the drug worked, the scientists all claimed; indeed, metformin is generic, costing just a few cents a dose. Patient safety was unlikely to be an issue; millions of diabetics have taken metformin since the 1960s, and its generally mild side effects are well-known.

Finally, the metformin group insisted they didn't need a cent of federal money to proceed (although they do intend to ask for some). Nor did they need formal approval from FDA to proceed. But they very much wanted the agency's blessing. By recognizing the merit of such a trial, Barzilai believes, FDA would make aging itself a legitimate target for drug development.

Link: http://news.sciencemag.org/biology/2015/09/feature-man-who-wants-beat-back-aging

In a recent published article a neurobiologist focused on the study of nematodes calls cryonics "impossible." He declares that the data of the mind is not being preserved and that people who are cryopreserved today cannot be restored. This is followed by another article in which a neuroscientist focused on brain mapping tells the former author that he is full of it and out of touch. It should be noted that the second fellow in this exchange doesn't think all that much of the cryonics industry as it is presently constituted, and favors the as yet commercially unavailable approach of plastination; there are always more than two sides in any argument.

Cryonics is the indefinite low-temperature storage of the brain as soon as possible following clinical death, and the small industry that has carried out this procedure since the 1970s has been in the news of late. The objective is to preserve the fine structure of neural tissue and nerve cell connections that encode the data of the mind. Provided that is stored successfully, then foreseeable forms of technology will in the future enable restoration and repair of this tissue. Early cryonics involved straight freezing, which wrecks tissue due to ice crystal formation. Modern cryonics aims for as-complete-as-possible vitrification via cryoprotectants, a process that suppresses ice crystal formation. There is ample evidence based on present theories of neural data encoding to believe that the necessary information is being preserved, albeit not the final absolute proof that many demand.

One has to be cautious of ascribing too much weight to the discussions of scientists who step beyond their fields; expertise in one area doesn't translate to the pronouncement of scripture for all areas. Indeed, if the error rates of scientific papers are anything to go by, one should think that a scientist's expertise enables them to be reasonably correct in their own specialty about half the time, and that after the expenditure of a great deal of work, collaboration, thought, and error-checking. Advancing the front lines of science is a challenging endeavor. For the purposes of the two articles I'll point out here, attacking and defending the scientific basis for cryonics, the boundaries of specialty and knowledge are such that a neurobiologist doesn't necessarily have the expertise in cryobiology to offer a fully informed opinion on the overlap between those two fields. The neurobiologist doesn't necessarily have the experience in the relevant areas of neurobiology for that matter - it is a very broad field with many deep and narrow specialties.

Anyone with a logical and inquisitive mind can make reasoned arguments, and those arguments are often worthy of engagement, but they should be taken for what they are. My objection here is not the matter of expertise, but the incoherence of the argument made against cryonics. Personally I'm all for arguing against mind uploading as the ultimate destination for cryopreserved individuals; it is possible and plausible, but a copy of you is not you, and only restoration of the original gives you continuity of existence. But if you are going to say that restoration of any sort is impossible then I expect to see a little more than "this is hard, the situation is complex, I don't see how it can be done, therefore it can't be done." At the very least I would expect the outline of a theory as to what it is that the method of preservation destroys. If you are not familiar with the current state of the intersection between cryobiology and neurobiology then fine, but don't write an article based on knowing something about that thin field of practice and theory without first stepping out into the unknown and learning what is going on and who is doing the cutting edge work. An intelligent individual can grasp the bones of a field close to his or her own specialty with a little study, and then say useful things, but that is not what is happening here.

The False Science of Cryonics

The cryonics industry offers to preserve people in liquid nitrogen immediately after death and store their bodies (or at least their heads) in hopes that they can be reanimated or digitally replicated in a technologically advanced future. Proponents have added a patina of scientific plausibility to this idea by citing the promise of new technologies in neuroscience, particularly recent work in "connectomics" - a field that maps the connections between neurons. The suggestion is that a detailed map of neural connections could be enough to restore a person's mind, memories, and personality by uploading it into a computer simulation.

I study a small roundworm, Caenorhabditis elegans, which is by far the best-described animal in all of biology. We know all of its genes and all of its cells (a little over 1,000). We know the identity and complete synaptic connectivity of its 302 neurons, and we have known it for 30 years. If we could "upload" or roughly simulate any brain, it should be that of C. elegans. Yet even with the full connectome in hand, a static model of this network of connections lacks most of the information necessary to simulate the mind of the worm. In short, brain activity cannot be inferred from synaptic neuroanatomy.

Synapses are the physical contacts between neurons where a special form of chemoelectric signaling - neurotransmission - occurs, and they come in many varieties. They are complex molecular machines made of thousands of proteins and specialized lipid structures. It is the precise molecular composition of synapses and the membranes they are embedded in that confers their properties. The presence or absence of a synapse, which is all that current connectomics methods tell us, suggests that a possible functional relationship between two neurons exists, but little or nothing about the nature of this relationship - precisely what you need to know to simulate it.

The features of your neurons (and other cells) and synapses that make you "you" are not generic. The vast array of subtle chemical modifications, states of gene regulation, and subcellular distributions of molecular complexes are all part of the dynamic flux of a living brain. These things are not details that average out in a large nervous system; rather, they are the very things that engrams (the physical constituents of memories) are made of. While it might be theoretically possible to preserve these features in dead tissue, that certainly is not happening now. The technology to do so, let alone the ability to read this information back out of such a specimen, does not yet exist even in principle. It is this purposeful conflation of what is theoretically conceivable with what is ever practically possible that exploits people's vulnerability.

No one who has experienced the disbelief of losing a loved one can help but sympathize with someone who pays $80,000 to freeze their brain. But reanimation or simulation is an abjectly false hope that is beyond the promise of technology and is certainly impossible with the frozen, dead tissue offered by the "cryonics" industry. Those who profit from this hope deserve our anger and contempt.

Ken Hayworth's Personal Response

As a neuroscientist I feel compelled to rebut some of your points. First off, please do not conflate what a small, highly-suspect company like Alcor is offering with what is possible in principle if the scientific and medical community were to start research in earnest. I started the Brain Preservation Prize as a challenge to Alcor and other such companies to 'put up or shut up', challenging them to show that their methods preserve the synaptic circuitry of the brain. After five years they have been unable to meet our prize requirements even when their methods were tested (by a third party) under ideal laboratory conditions. Out of respect for loved ones I will not comment on any particular case, but it is clear from online case reports that their actual results are often far worse than the laboratory prepared tissue we imaged. Speaking personally, I wish that all such companies would stop offering services until, at a minimum, they demonstrate in an animal model that their methods and procedures are effective at preserving ultrastructure across the entire brain. By offering unproven brain preservation methods for a fee they are effectively making it impossible for mainstream scientists to engage in civil discussion on the topic.

Unlike you however, I do think that cryonics and other brain preservation methods are worthy of serious scientific research today. First off, the cryobiology research laboratory 21st Century Medicine has published papers showing that half millimeter thick rat and rabbit hippocampal slices can be loaded with cryoprotectant, vitrified solid at -130 degrees C, stored for months, rewarmed, washed free of cryoprotectant, and still show electrophysiological viability and long term synaptic potentiation. They have so far been unable to demonstrate such results for an intact rodent brain - unlike the in vitro slice preparation, perfusing the cryoprotectant through the brain's vasculature results in osmotic dehydration of the tissue.

However, this same research group now has a paper in press showing that such osmotic dehydration can be avoided if the brain's vasculature is perfused with glutaraldehyde prior to cryoprotectant solution. Their paper reports high quality ultrastructure preservation across whole intact rabbit and pig brains even after being stored below -130 degrees C. I have personally acquired 10x10x10nm resolution FIB-SEM stacks from regions of these "Aldehyde Stabilized Cryopreserved" brains and have verified traceability of the neuronal processes and crispness of synaptic details. Considering these two results together, it seems at least plausible that further research might uncover a way to avoid osmotic dehydration without the need to resort to fixative perfusion, resulting in an intact brain as well preserved as the viable hippocampal slices. Even if glutaraldehyde remains a necessity, this Aldehyde Stabilized Cryopreservation process appears capable of preserving the structural details of synaptic connectivity (the connectome) of an entire large mammalian brain in a state (vitrified solid at -130 degrees C) that could last unchanged for centuries.

You state: "The presence or absence of a synapse, which is all that current connectomics methods tell us, suggests that a possible functional relationship between two neurons exists, but little or nothing about the nature of this relationship--precisely what you need to know to simulate it." Really? Little or nothing is known about the nature of the photoreceptor to bipolar cell synapse in the mammalian retina? Little or nothing is known about the bipolar to ganglion cell synapses? We may not know everything about these retinal cells and synapses but we know enough to have had "simulations" of retinas for two decades. Not based on the EM-level connectome directly but based on the statistics of connectivity as gleaned from coarser mappings. Do you really suspect that we would not be able to tell whether a particular retinal ganglion cell has an on-center or off-center receptive field based on the EM-level connectome alone? The textbooks and recent retinal connectomic studies argue otherwise.

I am certainly not saying that we now know everything about how the brain works, but I am saying that there is more than enough reason to suspect that the structural connectome may be sufficient to successfully simulate a brain given the depth of neuroscience knowledge we should possess by the year 2100 or 2200. Dismissing that as even a possibility hundreds of years in the future based on your failed attempts at understanding some particulars of C. elegans nervous system today seems very shortsighted. If you have real theoretical arguments then present them.

I personally agree, no one should pay $80,000 to freeze their brain without solid, open, scientifically rigorous evidence that at the very least the connectome is preserved. I would go further and say that regulated medical doctors are the only ones that should be allowed to perform such a procedure. But I do not agree that research in this area is doomed to failure. Instead the scientific and medical communities should embrace such research following up on the promising brain preservation results I mentioned above. Scientists should work to perfect ever better methods of brain preservation in animal models, and medical researchers should take these protocols and develop them into robust surgical procedures suitable for human patients.

I should say that Alcor under the leadership of Max More is open about how they preserve tissues, the present limitations and unknowns of the process, and the directions they are taking to improve the practice of cryopreservation under conditions of limited funding. Take a look through their extensive documentation and case studies presented at their website. I think it is far from fair to call that organization suspect. The perfect is the enemy of the good, and improvement in cryonics absolutely requires a practicing industry to drive that change. Within that framework, all challenges to prove effectiveness and improve towards an ideal are good and very welcome. This field, like all others related to preservation of life, is in great need of more funding, more support, and faster progress.

It is known that there are relationships between gut bacteria and aging in many species, though exploration of the details is still at a comparatively early stage. Even without delving into the literature one can imagine numerous possibilities by which these bacteria influence long-term health, such as by playing a role in the degree to which food is converted into nutrients useful for cells, or by interacting with the immune system. Here, researchers examine age-related changes in gut bacteria in flies. The health of the intestine is particularly important in fly aging, much more so than in higher species, so we should probably wait for similar experiments to be conducted in mammals before drawing conclusions:

Why do some people remain healthy into their 80s and beyond, while others age faster and suffer serious diseases decades earlier? A new study suggests that analyzing intestinal bacteria could be a promising way to predict health outcomes as we age. The researchers discovered changes within intestinal microbes that precede and predict the death of fruit flies. "Age-onset decline is very tightly linked to changes within the community of gut microbes. With age, the number of bacterial cells increase substantially and the composition of bacterial groups changes."

In a previous study, the researchers discovered that five or six days before flies died, their intestinal tracts became more permeable and started leaking. When a fruit fly's intestine begins to leak, its immune response increases substantially and chronically throughout its body. Chronic immune activation is linked with age-related diseases in people as well. In the latest research, which analyzed more than 10,000 female flies, the scientists found that they were able to detect bacterial changes in the intestine before the leaking began. As part of the study, some fruit flies were given antibiotics that significantly reduce bacterial levels in the intestine; the study found that the antibiotics prevented the age-related increase in bacteria levels and improved intestinal function during aging.

The biologists also showed that reducing bacterial levels in old flies can significantly prolong their life span. "When we prevented the changes in the intestinal microbiota that were linked to the flies' imminent death by feeding them antibiotics, we dramatically extended their lives and improved their health." Flies with leaky intestines that were given antibiotics lived an average of 20 days after the leaking began - a substantial part of the animal's life span. On average, flies with leaky intestines that did not receive antibiotics died within a week.

Link: http://newsroom.ucla.edu/releases/keeping-gut-bacteria-in-balance-could-help-delay-age-related-diseases-ucla-study-finds

A number of researchers investigate aging and longevity by show little of the signs of aging until very late life. Some scientists believe that there are benefits that could be mined from the biochemistry of these species and used as the basis for therapies to modestly slow aging in humans by altering the operation of our metabolism. This popular press article looks at this field of research:

Just 30 years after the publication of Moby Dick, a group of Alaskan whalers attempted to tame their own ocean giant. Their target was a male bowhead whale, the second largest mammal on Earth. These whalers were armed with the latest technology, however - a "bomb lance", fired with gunpowder on impact to pierce through the thick whale blubber. Yet it was not enough to conquer the whale. The whale would continue to roam free for another 120 years, until 2007, when a group of Inupiat hunters finally caught the beast. They even found fragments of the original lance still embedded in the whale's blubber.

According to many estimates, these whales live at least 150 years, and perhaps as long as 210. Apart from slightly leathery skin, a bit of excess blubber, and its battle scars, they show remarkably few ill-effects of long life, however. And that has made them of keen interest to doctors studying ageing. "They live a lot longer than human beings, yet they are living in the wild, without going to the doctor or any of the perks of human society. So they must be naturally protected from age-related diseases." By studying these whales and other extraordinarily long-lived creatures, researchers hope we can find new medicines that will similarly slow down the human body's decay and delay death.

"Ageing is a mystery - we know relatively little about it compared other biological processes, and yet it's directly the greatest cause of suffering and death in the modern world. If we could retard it even a little, it would have unprecedented human benefit. This is the most important biological question, because the majority of chronic human diseases are the consequences of ageing. The way biomedical science is organised, it has mostly focused on particular diseases, like cancer, Alzheimer's, or diabetes. But if you delay ageing you could delay the incidence of all these diseases at once. We're not just extending the period of decrepitude. We want 70 year olds with the health of a 50 year old - that's the ultimate goal."

Link: http://www.bbc.com/future/story/20150915-the-secrets-of-living-to-200-years-old

Research is ever slower than we would all like it to be, but the foundations of the next generation of stem cell therapies are being assembled at a comparatively rapid pace, thanks to a large and increasing level of funding and support. While it remains the case that as a society we collectively place a very low priority on medical research and development in comparison to the benefits it is capable of delivering, regenerative medicine based on the use and manipulation of stem cells is one of the most active fields within that constraint, rivaling the cancer research edifice. Would that the world wakes up as this age of biotechnology continues, realizing that health and longevity can be purchased at a falling price in time and money, and ever more people vote with their purses for research and medicine over circuses and war. One can hope.

Here is a selection of recent stem cell research, representative of the sort of work taking place in the field. Not a week goes by without the publication of an incremental advance that would have captured the headlines a decade ago, but is now just a matter of course. We'll be making the same comparisons ten years from now, looking back at today's grand advances, made small by progress.

Stem cells could help mend a broken heart, but they've got to mature

Currently, the only treatment options for damaged heart muscle are surgery, if possible, and for the worst cases, a whole heart transplantation. But there's a huge shortage of organs for transplantation, and for this reason, we need to find new strategies to treat heart disease. Stem cells have great potential to fill this void. They're a unique type of cell that starts out unspecialized but can multiply and turn into specialized cells of the adult body - for instance, brain cells or heart muscle cells, officially called cardiomyocytes.

This relies upon turning stem cells into heart muscle cells - but even once they differentiate, the heart cells remain immature. They're not fully developed, having characteristics you'd find in a fetus, not an adult. To advance these possible therapies, we need ways to take these heart muscle cells one step further, to maturity. I'm studying how the heart's natural environment affects that maturation process. I focus on how the extracellular matrix, or scaffold, of the heart affects maturation. The overall goal is to find a way to create from stem cells fully functioning, mature heart cells that can be safely and effectively used for transplantation therapies and drug screening applications.

Filling a void in stem cell therapy

Stem cell therapies have potential for repairing many tissues and bones, or even for replacing organs. Tissue-specific stem cells can now be generated in the laboratory. However, no matter how well they grow in the lab, stem cells must survive and function properly after transplantation. Getting them to do so has been a major challenge for researchers. Possible stem cell therapies often are limited by low survival of transplanted stem cells and the lack of precise control over their differentiation into the cell types needed to repair or replace injured tissues. A team has now developed a strategy that has experimentally improved bone repair by boosting the survival rate of transplanted stem cells and influencing their cell differentiation. The method embeds stem cells into porous, transplantable hydrogels.

Poststroke Cell Therapy of the Aged Brain

The efficacy of stem cell therapies for stroke so far is discouragingly low mainly because the time course of interactions between host neuroinflammatory response, the main obstacle to exogenous-mediated neuronal precursor cells, and exogenously administered stem cells is still unknown. Although mesenchymal stem cell transplantation into the brain has ascribed beneficial effects in preclinical studies of neurodegenerative or neuroinflammatory disorders, only some studies reported that stem cells can survive in a strong neuroinflammatory environment such as an ischemic area in stroke.

To conclude, these findings strongly suggest that UCB derived cells have significant neurogenic potential but this potential has to be used in a more efficient manner to treat neurological diseases like stroke in aged people. Antineuroinflammatory therapies are a potential target to promote regeneration and repair in diverse injury and neurodegenerative conditions by stem cell therapy. Therefore, the challenge now is to determine in detail the cross talk between different populations of immune cells and grafted neural stem progenitor cells at different phases after stroke in aged brain.

Mesenchymal stem cell therapy for osteoarthritis: current perspectives

Osteoarthritis is a prevalent chronic degenerative joint disease that will continue to impose an increasing burden on the aging population unless disease-modifying therapies are developed. The current standard of care with risk factor modification, pain management, and joint replacement will be inadequate to meet the needs of society moving forward. Mesenchymal stem cells (MSCs) offer a potential regenerative solution given their ability to differentiate to all tissues within a joint and modulate the local inflammatory response. Although these characteristics suggest they provide ideal building blocks to restore damaged joints, a strong body of evidence supports MSC-guided regeneration through paracrine stimulation of native tissue.

Further preclinical work will be mandatory to establish the mechanism by which MSCs have demonstrated a proof-of-concept to heal osteoarthritic lesions as this will have critical implications for clinical implementation strategies. Determining the ideal MSC source, processing, and delivery vehicle are further challenges that must be addressed to optimize biologics-based treatment of osteoarthritis. In 2015, the translation of MSCs to clinical therapy for osteoarthritis has been slow; however, signs of progress are evident and ongoing trials may show efficacy to indicate these products can serve as the disease-modifying therapy necessary to stem the tide of osteoarthritis.

Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells

In adult mammals, skeletal muscle is regenerated by a population of tissue-resident muscle stem cells, also known as satellite cells. Quiescent satellite cells in uninjured muscle are activated in response to injury or disease. Owing to a limited understanding of human satellite cell biology, it is still unclear as to what extent findings from mouse studies will translate to human cell-based therapies. A major barrier to the development of stem cell-based therapies is the inability to generate large numbers of transplantable stem cells with the potential to both self-renew and differentiate. In general, the contribution of donor satellite cells to muscle regeneration has been shown to correlate with the number of cells transplanted.

To further our understanding of human satellite biology, we used prospective cell isolation, RNA sequencing (RNA-seq) analyses, and cell transplantation to study a defined population of human myogenic progenitors with the potential to self-renew. This information was leveraged to identify changes in the molecular phenotype and self-renewal potential within the purified satellite cell population. Specifically, we mapped a core transcription factor regulatory network of self-renewal, and we established an essential role for p38 mitogen-activated protein kinase (MAPK) in the regulation of human satellite cell regenerative capacity akin to that observed in the mouse. Reversible pharmacologic inhibition of p38 in cultured human satellite cells resulted in a gene expression program consistent with the promotion of self-renewal, and it allowed for expansion of a population of satellite cells ex vivo with enhanced self-renewal and engraftment potential.

One of the lines of evidence that points to mitochondrial damage as an important contribution to degenerative aging is that the life spans of mammalian species correlate well with varying composition of mitochondrial membranes. Differences in composition produce membranes that have more or less resistance to oxidative damage, such as that caused as a side-effect of the processes taking place inside mitochondria when they generate energy store molecules to power other cellular mechanisms. The membrane pacemaker theory of aging is associated with these details.

Learning more about membrane composition and the fine details of how it interacts with damage processes will not tell us how to fix mitochondrial damage and thus greatly improve matters in aging by reversing its course, however. That is already known: the biotechnologies needed to repair mitochondria or work around the damage are established visions, under development in a preliminary fashion, and emerging from entirely separate fields of research. What we should take away from the work linked here is a sense that there are multiple areas of evidence to suggest that repairing damaged mitochondria throughout the body will be of significant benefit, a form of rejuvenation, and thus worthy of greater investment.

The maximal lifespan (MLS) of mammals is inversely correlated with the peroxidation index, a measure of the proportion and level of unsaturation of polyunsaturated fatty acids (PUFA) in membranes. This relationship is likely related to the fact that PUFA are highly susceptible to damage by peroxidation. Previous comparative work has examined membrane composition at the level of fatty acids, and relatively little is known regarding the distribution of PUFA across phospholipid classes or phospholipid molecules. In addition, data for humans is extremely rare in this area.

Here we present the first shotgun lipidomics analysis of mitochondrial membranes and the peroxidation index of skeletal muscle, liver, and brain in three mammals that span the range of mammalian longevity. The species compared were mice (MLS of 4 years), pigs (MLS of 27 years), and humans (MLS of 122 years). Mouse mitochondria contained highly unsaturated PUFA in all phospholipid classes. Human mitochondria had lower PUFA content and a lower degree of unsaturation of PUFA. Pig mitochondria shared characteristics of both mice and humans. We found that membrane susceptibility to peroxidation was primarily determined by a limited number of phospholipid molecules that differed between both tissues and species.

Link: http://dx.doi.org/10.1016/j.exger.2015.08.011

Researchers here demonstrate the ability to regrow the blood vessel network in a decellularized lung, an important step in creating any sizable amount of engineered tissue. Decellularization is the process of stripping cells from donor tissue, leaving the intricate structure of the extracellular matrix and its chemical cues to guide cell growth. That matrix scaffold can be then be repopulated with a patient's cells to create an organ ready for transplant with minimal rejection risk. Since the scientific community still cannot recreate the full complexity of the extracellular matrix in artificial scaffolds, this remains the only way to create fully functional patient-matched organ tissue at the present time. Even so repopulation of decellularized organs has only been successfully carried out for a few organ and tissue types to date. It is a complicated process to deliver the right types of cells and coax them into recreating tissues correctly, especially when it comes to the all-important blood vessels that will supply the organ's cells:

Bioengineered lungs produced from patient-derived cells may one day provide an alternative to donor lungs for transplantation therapy. Here we report the regeneration of functional pulmonary vasculature by repopulating the vascular compartment of decellularized rat and human lung scaffolds with human cells, including endothelial and perivascular cells derived from induced pluripotent stem cells. We describe improved methods for delivering cells into the lung scaffold and for maturing newly formed endothelium through co-seeding of endothelial and perivascular cells and a two-phase culture protocol.

Using these methods we achieved ~75% endothelial coverage in the rat lung scaffold relative to that of native lung. The regenerated endothelium showed reduced vascular resistance and improved barrier function over the course of in vitro culture and remained patent for 3 days after orthotopic transplantation in rats. Finally, we scaled our approach to the human lung lobe and achieved efficient cell delivery, maintenance of cell viability and establishment of perfusable vascular lumens.

Link: http://dx.doi.org/10.1038/nbt.3354

Today I'll point out an open access paper on the longevity-related gene klotho. Some researchers see therapies to adjust levels of the klotho protein produced from this genetic blueprint as a possible way to slow some of the effects of aging, particularly those connected to regeneration and stem cell activity. Work on this is slow-moving and painstaking, as for any similar approaches.

Yet a fairly large section of the medical research community is now devoted to at least partial and temporary restoration of tissue maintenance by stem cells in the old. A good fraction of the frailty and failure of aging results not just from direct damage such as cross-links in the extracellular matrix and broken mitochondria run amok, but also from the lack of repair of tissues, the faltering of the supply of new cells produced by stem cells in order to replace the old. Stem cell transplants are only the earliest and most direct way to try to temporarily boost regeneration and maintenance. In recent years many other possibilities have blossomed, these approaches involving the adjustment of specific biochemical signals so as to instruct native cells to return to work.

Where researchers have determined what happens to stem cell populations in the old, which is by no means a finished process given the wide range of tissue types still to be investigated fully, it seems that for the most part stem cells are neither missing nor critically impaired, but rather quiescent, simply inactive. This quiescence is thought to be an evolved response to the threat of cancer arising due to damaged DNA and cellular environments, with the present balance between activity and cancer on the one hand versus quiescence and failing organs on the other being the outcome of selection pressure for ever-longer human life spans. We are long-lived among mammals - and even primates - most likely because our intelligence and culture allowed the old to contribute to the success of their grandchildren.

So is it possible to gain meaningful benefits by ramping up a damaged engine, by signaling stem cells to get back to work without actually addressing any of the underlying cell and tissue damage that causes this evolved reaction of growing quiescence? Will this produce an excessive cancer risk, for example? It is of interest that so far there has been a surprising lack of cancer resulting from work in the laboratory and clinic, if anything. It may be that the characteristic stem cell decline with aging is not all that fine-tuned by evolution and that there is considerable wiggle room to produce therapies that can do better than today's medicine despite failing to address other important causes of degeneration. Either way, the stem cell issues ultimately need to be fixed as a part of any comprehensive toolkit of rejuvenation therapies. Damaged stem cells should be replaced or repaired, not just sent back to work.

Klotho, stem cells, and aging

Since klotho was serendipitously identified in 1997, our understanding of it as an aging suppressor has been continuously growing. Klotho protein has pleiotropic actions on many organs and tissues in mammals. However, very limited and premature data about klotho effects on stem cells are available. A better understanding of the effects of klotho on stem cells not only provides novel insights into the role of stem cells in antiaging processes but could also make a significant contribution to the advancement of regenerative medicine clinical practice.

Given that changes of functionality and a decreased number of stem cells contribute to or accelerate aging, implantation of stem cells to replenish new functional stem cells would be one means to attenuate age-associated disease by rebuilding the tissue or organ. This has been shown to be effective in preclinical and clinical trials in some diseases, including multiple sclerosis, myocardial infarction, ischemic stroke, and cancer. However, long-term side effects of stem cell implantation are not fully recognized, and should be a concern in most cases in which stem cells are permanently injected into patients. For example, recipients of genetically altered bone marrow transplants developed leukemia years after their allegedly successful transplants had cured their severe combined immunodeficiency. Despite potential side effects, recent advances in stem cell research and technology have shown promise.

On the other hand, activation or stimulation of endogenous or resident stem cells is another strategy to abate aging and age-associated disease. Current data from animal and in vitro cell-culture studies clearly demonstrated that klotho deficiency is associated with stem cell senescence and depletion. Furthermore, klotho deficiency may not only be a trigger for aging but also a pathogenic intermediate for accelerated aging and development of age-associated diseases, including Alzheimer's disease, hypertension, osteoporosis, cardiovascular disease, and chronic kidney disease (CKD). Conceivably, any therapy that restores or stimulates endogenous klotho or administration of exogenous klotho might provide a novel treatment strategy for aging and age-associated diseases.

To date, klotho gene delivery is shown to effectively rescue many phenotypes observed in klotho-deficient mice. Although gene therapy is effective in animal studies, its safety is still questionable, and clinical application is not in proximity. There are few clinical trials testing gene therapy in specific diseases. Compared to viral delivery of the klotho gene in animals, administration of exogenous klotho protein is a safer, easier, and more direct modality to restore endocrine klotho deficiency. Similarly to the use of erythropoietin or erythropoiesis-stimulating agents to correct anemia in CKD patients and insulin to maintain normal glucose metabolism in type I diabetes, the administration of exogenous klotho protein may be a viable and effective option in the near future to dwindle aging. Klotho protein can potentially reverse or retard stem cell depletion and abate age-associated pathological processes.

To date, no studies of klotho protein administration in humans have been reported. In contrast, animal studies have already provided convincing and encouraging data to support the proof of concept that soluble klotho protein administration is safe and effective. We showed that soluble klotho protein attenuates kidney damage and preserves kidney function in an ischemia-reperfusion injury model causing acute kidney injury, which is a state of acute klotho deficiency. Furthermore, klotho protein inhibited renal fibrosis in a unilateral ureteral obstruction kidney-injury model, which is also a state of low klotho expression in the kidney. Therefore, the preclinical data clearly support the therapeutic potential of soluble klotho protein for age-related disorders and klotho deficiency-associated diseases.

Thus far, animal experiments and in vitro cell-culture studies have shown the effects of soluble klotho protein on abating skin atrophy and skeletal muscle dystrophy during aging. It is anticipated that soluble klotho may play a pivotal role in regenerative medicine by preservation and activation of stem cells, particularly in heart tissue, where stem cells are very scarce or have low ability to replicate after injury. Therefore, if soluble klotho can activate stem cells or induce the replication of stem cells, klotho protein could be used as a promising therapeutic strategy for tissue repair and organ regeneration.

The mainstream press here has a go at summarizing some of the neurobiology and technologies that would lead to whole brain emulation, a copy of a human mind running in software. Many futurists believe that a copy of the mind running as an emulation is an acceptable continuation of the individual. Thus when they advocate brain preservation via cryonics or plastination it is for the purpose of recording the data for later use, not maintaining the actual tissue for later repair and restoration as a biological brain.

To me this seems a strange viewpoint; a copy of you is not you. Good for the copy and best of luck to him or her, but you yourself remain preserved and inactive. The essence of identity is physical continuity of both pattern and material that expresses that pattern, under a slow pace of change. If someone swapped out half of your brain all at once, you stop being you; you as an entity died in the initial removal, and a copy was created with the replacement operation. If half of the neurons in your brain are exchanged for machinery, one at a time, over a decade of active life, then you are still you - each replacement is incorporated into a working pattern and the change in data is little greater than those occurring due to the ongoing process of being alive. These are important differences, the two examples standing on either side of a large grey area.

The size of the futurist faction who advocate mind uploading for continuation of the individual is large enough that anyone undergoing cryopreservation would be wise to take with them some expression of their desires on the matter, perhaps an inscribed metal plate under the tongue or similar: "Please restore the original; do not copy, do not emulate."

Some neuroscientists believe it may be possible, within a century or so, for our minds to continue to function after death - in a computer or some other kind of simulation. Others say it's theoretically impossible, or impossibly far off in the future. A lot of pieces have to fall into place before we can even begin to start thinking about testing the idea. But new high-tech efforts to understand the brain are also generating methods that make those pieces seem, if not exactly imminent, then at least a bit more plausible. Here's a look at how close, and far, we are to some requirements for this version of "mind uploading."

The hope of mind uploading rests on the premise that much of the key information about who we are is stored in the unique pattern of connections between our neurons, the cells that carry electrical and chemical signals through living brains. You wouldn't know it from the outside, but there are more of those connections - individually called synapses, collectively known as the connectome - in a cubic centimeter of the human brain than there are stars in the Milky Way galaxy. The basic blueprint is dictated by our genes, but everything we do and experience alters it, creating a physical record of all the things that make us US - our habits, tastes, memories, and so on. It is exceedingly tricky to transition that pattern of connections into a state where it is both safe from decay and can be verified as intact. But in recent months, two sets of scientists said they had devised separate ways to do that for the brains of smaller mammals. If either is scaled up to work for human brains - still a big if - then theoretically your brain could sit on a shelf or in a freezer for centuries while scientists work on the rest of these steps.

The real challenge for aspiring mind uploaders will be figuring out how to create a fully functioning model of a human brain from a static snapshot of its connectome. To work, that model would have to include the molecular information in its neurons and synapses. Many neuroscientists think extracting that information would require another major step, others say structural details visible in the electron microscope might allow them to infer it. But some progress is being made - enough, anyway, so that the Obama administration signed off last year on a request by the National Institutes of Health for $4.5 billion to deliver a "comprehensive, mechanistic understanding of mental function" by 2025. Private foundations, like the Allen Institute for Brain Science and the Howard Hughes Medical Institute, have also announced major investments in basic brain research in recent years. And this summer, the blue-sky research arm of the United States intelligence agencies, Iarpa, distributed some $50 million in five-year grants to map the connectome in a cubic millimeter of mouse brain linked to learning behavior, record the corresponding neurons in live mouse brains and simulate the circuits in a computer.

Link: http://www.nytimes.com/interactive/2015/09/03/us/13immortality-explainer.html

This lengthy human interest article looks at the cryonics industry through the lens of one person's end of life decisions and efforts to organize a good cryopreservation. Cryonics is the low-temperature storage of at least the brain immediately following clinical death, preserving the fine structure that encodes the data of the mind. It offers the only chance at a longer life in the future for those who will die before the advent of rejuvenation therapies, and it is a great pity that cryonics remains a niche industry while tens of millions go the grave and oblivion every year.

In the moments just before Kim Suozzi died of cancer at age 23, it fell to her boyfriend, Josh Schisler, to follow through with the plan to freeze her brain. As her pulse monitor sounded its alarm and her breath grew ragged, he fumbled for his phone. Fighting the emotion that threatened to paralyze him, he alerted the cryonics team waiting nearby and called the hospice nurses to come pronounce her dead. Any delay would jeopardize the chance to maybe, someday, resurrect her mind.

They knew how strange it sounded, the hope that Kim's brain could be preserved in subzero storage so that decades or centuries from now, if science advanced, her billions of interconnected neurons could be scanned, analyzed and converted into computer code that mimicked how they once worked. But Kim's terminal prognosis came at the start of a global push to understand the brain. And some of the tools and techniques emerging from neuroscience laboratories were beginning to bear some resemblance to those long envisioned in futurist fantasies. Might her actual brain be repaired so she could "wake up" one day, the dominant dream of cryonics for the last half-century? She did not rule it out. But they also imagined a different outcome, that she might rejoin the world in an artificial body or a computer-simulated environment, or perhaps both, feeling and sensing through a silicon chip rather than a brain.

She agreed to let a reporter speak to her family and friends and chart her remaining months and her bid for another chance at life, with one restriction: "I don't want you to think I have any idea what the future will be like," she wrote in a text message. "So I mean, don't portray it like I know." In a culture that places a premium on the graceful acceptance of death, the couple faced a wave of hostility, tempered by sympathy for Kim's desire, as she explained it, "not to miss it all." Family members and strangers alike told them they were wasting Kim's precious remaining time on a pipe dream. Kim herself would allow only that "if it does happen to work, it would be incredible." "Dying," her father admonished gently, "is a part of life." Yet as the brain preservation research that was just starting as Kim's life was ending begins to bear fruit, the questions the couple faced may ultimately confront more of us with implications that could be preposterously profound.

Link: http://www.nytimes.com/2015/09/13/us/cancer-immortality-cryogenics.html

"Life extension" and "radical life extension" are declining terms these days, less frequently used now that the scientific community is stepping closer to being able to build the means of greatly extending healthy life spans. The original overarching visions of far longer lives achieved through medical progress, laid out in the 70s and 80s and vague on the details, will fade away in the face of increasing specificity and concrete implementations. The communities who will in the years ahead launch companies and make money by building and distributing actual, working rejuvenation therapies: it is these people who will coin the new terms we use for the next few decades. For now there are intermediary categories: longevity science; rejuvenation biotechnology; an expansion of regeneration medicine to include treatment of aging. But I have no more idea than you as to what we'll be calling the rejuvenation therapies of the 2030s when those years are upon us. Language is a river, and you take it as it comes.

Aubrey de Grey is the cofounder of the Methuselah Foundation and SENS Research Foundation. He devotes half of his time to the coordination of research needed to speed progress towards working rejuvenation treatments and the other half traveling and speaking to persuade the rest of the world to help. If you ever find yourself doubting that we all live in a madhouse society, blind to what really matters, then consider that it is in fact very hard to persuade people to help with medical research that will prevent their future selves from suffering horribly. The population at large veers between disinterest in ensuring their future health and hostility to the idea that anyone else might be trying to better maintain their health by treating aging as a medical condition. No matter that more than 100,000 lives are lost to aging every day, while millions of others are in pain, decrepit and frail, most people still instinctively defend that status quo.

Here I'll link to a recent interview with de Grey in the technology press. The highly networked venture capital, entrepreneur, and technology community centered in California - but with growing outposts across the US - has been very supportive of SENS rejuvenation research over the years, at least in comparison to the rest of the population. Many of the most influential donors are from this community, and there is no doubt a retrospective to be written at some point at some point in the future, a work that will outline the connections and explain just why it is that the prospect of radically enhanced longevity achieved through medical progress strikes a chord so effectively with programmers and technology entrepreneurs.

Radical lifespan extension: A chat with Aubrey de Grey

Reese: What's the current state of the effort to "cure death"?

de Grey: Well, first off, let's be perfectly clear. I don't work on "curing death." I work on health. I work on keeping people healthy. And, yes, I understand that success in my work could translate into an important side effect, which is that people would, on average, live longer. But ultimately, the main thing people die of is being unhealthy, being sick. And if you can keep people less sick, it means that they're going to live longer. Now, it happens that the particular way in which I am working on stopping people from getting sick is a really comprehensive one that applies to all aspects of the ill health of old age, so the side effect is going to be bigger than people are used to. But still, it's just a side effect. I don't work on longevity. I work on health.

And another big thing to understand is that even if you think, well, this is just words, and I really do work on longevity, the fact is I still don't work on "curing death," because you can die of a whole bunch of other things. You can die by being hit by a truck. We can all die if we get hit by an asteroid. So it's all about health.

Reese: If you achieved all of your aims of curing all disease and promoting health, do you think the human body then has a natural limit to its life span?

de Grey: Absolutely not. I think that as things stand today, before the medicines that we are working on have come to fruition, that there is definitely a natural maximum life span, because there are various types of damage that the body does to itself as a side effect of the way the body works. The best example of this is breathing. Breathing is pretty damn nonnegotiable. But the effect of breathing is the creation of free radicals, which cause a lot of damage. So yes, damage is always happening, and right now there is only so much that we can do to minimize that rate, and there's only so much accumulated damage that we can tolerate.

But our work revolves around repairing that ongoing damage. And that will completely transcend any such limits. It's just like a vintage car. Vintage cars were not designed to last more than ten or 15 years, but preventive maintenance, so long as it's comprehensive, can completely transcend any such limits.

Reese: What do you think are going to be the social impacts of extending people's lives?

de Grey: There will be enormous social consequences, no question. But I think we need to look at this question a little bit more objectively than most people do. The fact is that, yes, we need to figure out issues like, how will we pay the pensions, and so forth, so everybody gets these therapies. But these are not new questions. Think about the Industrial Revolution. We didn't know what we were doing, we figured it out. We've got to remember that the main purpose is to stop people from getting sick just because they were born a long time ago. Ultimately, if you ask anyone - if you ask an audience, whether they want to get Alzheimer's disease, you're going to get a fairly unanimous "no."

And if you ask them whether they would like to get Alzheimer's disease when they reach the age of a hundred, you're still going to get the unanimous "no," and it's the same for cancer. It's the same for all of the diseases of old age. The real reason we get these crazy questions - you know, like "how will we make sure that this is available to everybody?" - is because they have this crazy, crazy idea in their heads that there is this thing called aging, that is in some way completely separate, completely unconnected with any disease. In biological reality, there is no such distinction.

Here I'll point out an open access paper on Wnt signaling in aging. The full paper is PDF format only at the present time. The Wnt signaling pathway plays a range of important roles in embryonic development, cancer, and regeneration. It also changes over the course of aging, one of countless specific reactions to accumulated cell and tissue damage, and these changes are thought to be a part of the characteristic decline in stem cell activity that takes place in later life. Less stem cell activity means less tissue maintenance and the gradual failure of organ function and integrity. There is considerable interest in the scientific community in finding ways to restore tissue maintenance, but most of those involved do not address the underlying damage that causes aging, instead seeking to override some of the reactions to that damage.

Here, however, researchers are looking at the merits of exercise in the context of Wnt signaling and tissue maintenance in old age. There is ample evidence to show that regular exercise is beneficial for even extremely old individuals, and its effects on Wnt signaling may be one of the reasons why this is the case:

Aging is an inevitable physiological process that leads to the dysfunction of various tissues, and these changes may contribute to certain diseases, and ultimately death. Recent research has discovered biological pathways that promote aging. This review focuses on Wnt signaling, Wnt is a highly conserved secreted signaling molecule that plays an essential role in the development and function of various tissues, and is a notable factor that regulates aging. Although Wnt signaling influences aging in various tissues, its effects are particularly prominent in neuronal tissue and skeletal muscle. In neuronal tissue, neurogenesis is attenuated by the downregulation of Wnt signaling with aging. Skeletal muscle can also become weaker with aging, in a process known as sarcopenia. A notable cause of sarcopenia is the myogenic-to-fibrogenic transdifferentiation of satellite cells by excessive upregulation of Wnt signaling with aging, resulting in the impaired regenerative capacity of aged skeletal muscle.

However, exercise is very useful for preventing the age-related alterations in neuronal tissue and skeletal muscle. Upregulation of Wnt signaling is implicated in the positive effects of exercise, resulting in the activation of neurogenesis in adult neuronal tissue and myogenesis in mature skeletal muscle. Although more investigations are required to thoroughly understand age-related changes and their biological mechanisms in a variety of tissues, this review proposes exercise as a useful therapy for the elderly, to prevent the negative effects of aging and maintain their quality of life.

Link: http://www.hh.um.es/Abstracts/Vol_30/30_12/30_12_1411.htm

This is one example of many new approaches to delivering therapeutic proteins into the brain. In this case the aim is to spur greater regeneration and cell resilience in order to compensate for neurodegenerative processes underlying diseases such as Parkinson's:

Researchers genetically modified white blood cells called macrophages to produce glial cell-derived neurotrophic factor, or GDNF, and deliver it to the brain. Glial cells provide support and protection for nerve cells throughout the brain and body, and GDNF can heal and stimulate the growth of damaged neurons. "Currently, there are no treatments that can halt or reverse the course of Parkinson's disease. There are only therapies to address quality of life, such as dopamine replacement. However, studies have shown that delivering neurotrophic factor to the brain not only promotes the survival of neurons but also reverses the progression of Parkinson's disease." In addition to delivering GDNF, the engineered macrophages can "teach" neurons to make the protein for themselves by delivering both the tools and the instructions needed: DNA, messenger RNA and transcription factor.

Successfully delivering the treatment to the brain is the key to the success of GDNF therapy. Using immune cells avoids the body's natural defenses. The repurposed macrophages are also able to penetrate the blood-brain barrier, something most medicines cannot do. The reprogrammed cells travel to the brain and produce tiny bubbles called exosomes that contain GDNF. The cells release the exosomes, which then are able to deliver the proteins to neurons in the brain.

Link: http://uncnews.unc.edu/2015/09/10/unc-smart-cells-teach-neurons-damaged-by-parkinsons-to-heal-themselves/

This is an era of near effortless communication, in which anyone with anything to say can publish to the world at next to no cost. As it turns out nearly everything that is said or written on any given topic is garbage. Back when the cost of communication was much higher, that cost served as a filter to block most casually created junk from widespread propagation, leaving only the earnest or well-backed junk to surround the small proportion of useful and accurate works. Truth is always a small selection at the back of the global library, dwarfed by the reams of propaganda, error, wishful thinking, and irrelevance.

Have you ever noticed that when the popular press publishes on a topic that you know well, such articles are near always easily identified as being misleading and wrong in a dozen ways in as many sentences? It is that way for everything that is published by professional journalists, and for every topic. Yet we go on believing what we read; it is an interesting phenomenon. Popular news of scientific research into human longevity is distorted in many ways between laboratory and press room, and then further degraded in the echo chambers of the media and the online world. This is especially true of anything that the "anti-aging" marketplace takes an interest in; that industry is a font of lies and misdirection, ranging from the blatant to the very subtle, all in service of liberating the gullible from their money. To sift all of this you have to first and foremost always seek out the primary materials, the original published works. Then apply common sense; be skeptical; be somewhat familiar with what researchers are up to in the field; know of a few reputable publications that cover medical progress and the life sciences. Try to fit what you read into the framework of what you know, and be ever ready to throw out whatever looks suspect.

Even within the specialist area of peer reviewed scientific publications and research papers there is a lot of earnest junk, things worth neither time nor attention, and theories hanging out there on the edge, entirely unsupported. Science is a messy process, generating just as much in the way of wildly wrong dead-ends as it does new truths and useful progress. There is a post way back in the Fight Aging! archives on how to read the out of the scientific method. It covers some of the basics, but in essence the advice boils down to a matter of following the numbers and the consensus - unless you happen to be one of those knowledgeable enough to contribute to the fray with papers of your own. The rest of us, as laypeople, should only believe a position to be likely plausible or defensible when many researchers agree.

In any case, here I'll point out an article with a click-bait title that nonetheless manages to say a few sensible things on the topic. At some point everyone investigating the science of human longevity and the prospects for the future has the realization that most of what is written on the topic isn't worth the time it will take to recognize it as junk:

When the science of living longer doesn't make sense

A lot of bizarre things get put on the internet these days. However, given that almost anyone can contribute practically anything they like to the worldwide web of information, it's getting increasingly difficult to separate fact from fiction. Due to the misinterpretation, misuse or misunderstanding of scientific evidence, many minor studies are often seized upon, and portrayed as concrete fact in spite of a lack of basis. One scientific area which is particularly affected by this issue is the field of healthy life extension. There are literally thousands of websites and articles out there which offer advice on how to overcome age-related diseases or radically increase lifespan, many of which are highly misleading. By following some simple rules however, it can be relatively easy to identify what is legitimate and what is not.

Rather than focusing solely on the results of a scientific study, journalists would do well to pay some attention to the methods which have been used to generate them, since this can provide a good indication of how valid and applicable such results might be for their readers. Too often, articles imply that the results of a scientific study are of far greater relevance to the reader than they actually are. When it comes to examining the association between an exposure and an outcome, the most widely trusted approach is the randomized controlled trial. However, it is not always possible to conduct randomized trials. Alternatively, researchers can turn to "nonexperimental" or "observational" database studies. These database studies make use of large sets of data collected from past surveys. Ultimately, no single study is perfect - be it a randomized trial or a non-experimental one. This is why it is better to wait until enough evidence to support a particular hypothesis has accumulated from multiple studies, which make use of a range of methods and have been applied to different populations.

In the absence of studies which test out a specific hypothesis, it can be tempting for journalists to make inferences from other studies, or worse still, attempt to conduct their own 'scientific' research. Be wary of claims which rely on anecdotes rather than scientific studies. Similarly, know that meanings can be distorted through the use of language. Sometimes, for the sake of artistic licence, non-experts reporting the outcomes of a scientific study choose to alter the wording of the phrases being used to describe the results. Whether it is intentional or not, such alterations can grossly distort the implied meaning.

Ultimately, providing a platform for the most unlikely and strange pieces of advice can damage the reputation of any scientific field. In the case of research into increasing healthy lifespan, the spreading of misinformation serves only to slow the rate of progress and acceptance of this relatively new branch of science.

This open access review covers attempts by the research community to produce a cell therapy to treat Parkinson's disease, a condition driven by the accelerated loss of a small but vital population of brain cells. This loss happens to everyone over the course of aging to a much lesser degree, and thus progress towards treatments is of general interest. In theory these lost cells could be replaced, but in practice getting to the point of a reliable treatment along those lines is entwined with the ongoing development of stem cell medicine as a whole. Robust methods of cell production, transplant, and engineering, along with sufficiently comprehensive knowledge of cell biology to steer this work are all still in progress, further along for some types of cell and tissue, less well advanced for others:

Parkinson's disease (PD) is one of the most common neurodegenerative disorders of aging, affecting about 1% of the population aged 60 years and older and 3-5% of the population above the age of 85. The various disruptions in motor control typically appear when 60-80% of dopamine (DA) neurons in the substantia nigra are degenerated. Because DA neurons degenerate to cause a drop in dopamine release, current treatments for PD include dopamine replacement drugs and deep brain stimulation (DBS) to the nucleus subthalamicus. Even though dopamine replacement drugs and DBS are effective in improving the symptoms of the patients, they cannot stop the disease progression. Moreover, current medications can cause the development of involuntary muscle movements, effectively "overshooting" the clinical symptoms of PD.

Recent research progress has provided treatment potential through replacing lost DA neurons using neural stem cells (NSCs) or fully differentiated DA neurons from fetal brain tissue, embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) sourced from adults or fetuses, and induced pluripotent stem cells (iPSCs) reprogrammed from patients' somatic fibroblasts or blood cells. Much work has been done to adapt cells from various sources to potential clinical applications to improve treatments for neurodegenerative diseases including PD. NSCs and DA neurons from fetal brain and hESCs are not suitable for clinical use because of their immune-rejections and ethical issues. The availability of iPSCs and iDA neurons paved the road for autologous cell-based therapy of PD. However, several aspects of iPSCs need to be resolved before they go to clinical use. These include low yields of DA neurons, genetic and epigenetic abnormalities, and the safety of iPSC-derived cells.

Cell replacement therapy is a promising avenue for the treatment of PD and other neurodegenerative disorders. The use of all cell sources derived is fraught with ethical, logistical, and safety concerns. However, scientific research is making great progress in the development and characterization of iPSC derived cells for PD. iPSCs and their derivatives injected into animal models have shown promise in treatment of disorders such as PD; however, iPSCs have not been used in clinical trials for PD. There are some limitations/disadvantages associated with iPSCs. A relevant therapeutic progenitor or mature cell type may be identified and grafted in such treatments; in the case of PD, the options are, of course, iPSC-derived NSCs and iPSC-derived DA neurons. Theoretically, these two should act just like their non-iPSC derived counterparts - in actuality, because of the concerns mentioned above, the unique iPSC heritage of such cells sometimes poses its own unique set of problems.

Pre-clinical studies on viability might also be necessary to establish the scope of the treatment. iPSCs would not be moved to clinical trials at least until iPSCs are better understood and efficient and safe methods for reprogramming and gene correction are developed. The pace of progress will no doubt continue to speed along in the years to come, and it is therefore quite likely that within our lifetime we will witness the jump from dish to clinic.

Link: http://www.translationalneurodegeneration.com/content/4/1/16

A reliable biomarker for biological age would be some measure that reflects the level of cell and tissue damage present in an individual. The existence of such a biomarker would greatly speed up work on treatments for aging, allowing at least preliminary evaluation of the effectiveness of potential rejuvenation therapies based on damage repair very soon after their application in a test subject. The only presently available option is to run life span studies, to take the wait and see approach, which is very expensive and time-consuming, even in mice.

Researchers have made inroads towards a biomarker for aging by looking at DNA methylation patterns, and here is news of an analogous project that analyzes changes in gene expression levels. By the sound of it this new methodology only captures a slice of the wide-ranging cellular responses to accumulating damage, missing some of the important changes related to, for example, deterioration of the cardiovascular system:

Researchers used a process called RNA-profiling to measure and compare gene expression in thousands of human tissue samples. Rather than looking for genes associated with disease or extreme longevity, the researchers discovered that the "activation" of 150 genes in the blood, brain and muscle tissue were a hallmark of good health at 65 years of age. The researchers were then able to create a reproducible formula for "healthy ageing," and use this to tell how well a person is ageing when compared to others born the same year.

The researchers found an extensive range in "biological age" scores of people born at the same time indicating that a person's biological age is separate and distinct to his or her chronological age. Importantly, a low score was found to correlate with cognitive decline, implying that the molecular test could translate into a simple blood test to predict those most at risk of Alzheimer's disease or other dementias and suitable for taking part in prevention trials. A person's score was not, however, found to correlate with common lifestyle-associated conditions, such as heart disease and diabetes, and is therefore likely to represent a unique rate of ageing largely independent of a person's lifestyle choices.

However, the study does not provide insight into how to improve a person's score and thus alter their "biological age." While a low score could be considered as "accelerated ageing," an important aspect of the work suggests that ageing does not now need to be defined only by the appearance of disease. "Given the biological complexity of the ageing process, until now there has been no reliable way to measure how well a person is ageing compared with their peers. Physical capacity such as strength or onset of disease is often used to assess healthy ageing in the elderly but in contrast, we can now measure ageing before symptoms of decline or illness occur. We now need to find out more about why these vast differences in ageing occur, with the hope that the test could be used to reduce the risk of developing diseases associated with age."

Link: http://www.kcl.ac.uk/newsevents/news/newsrecords/2015/September/Researchersdevelopnoveltestwhichcantellhowwellapersonisageing.aspx

Here I'll point out a review paper on the "omics," the younger fields of the life sciences, including genomics, proteomics, and so forth, and their role in aging research. These fields encompass the study of biological molecules and their roles in cellular metabolism and tissue function, broken down by type and class. The study of genes, the study of proteins, the study of proteins only applicable to the immune system, the study of proteins involved in transcription, and many more divisions besides. There are now dozens of omics fields, and they continue to proliferate and specialize, this growth a reflection of the accelerating capabilities and falling costs of biotechnology. Mountains of ever more detailed data are produced each year, and merely focusing on analysis and application occupies much of the field. Indeed it might be argued that the production of omics data far outstrips its productive use at the present time, that there is something of a land grab underway now that commercial ventures focused on omics data are entering the fray, and that we are due a lengthy phase of consolidation and analysis in the years ahead. For now data is the zeitgeist of the life sciences: data on genes, on proteins, on specific clades of proteins, closely followed by the search for relevance and meaning in vast databases.

All of this is entirely in line with the goals of the scientific method: learn everything, discover everything, analyze everything. Take in all that the tools can provide. When it comes to aging, however, I think that the present zeitgeist is a distraction from an existing road to effective treatments for the causes of degeneration, frailty, and disease. It is a very effective distraction: the bulk of the field is turning in that direction, and their activities are best understood as firstly addressing the goal to comprehensively map all of our biology, and then as a distant second trying to make something of that new knowledge. Our biology is fantastically complex when operating in its standard, undamaged, youthful state. When it is disarrayed by the cell and tissue damage of aging, it can fall into a much wider range of dysfunctional operation, every older individual a special snowflake within the broader statistical patterns of disease and organ failure that we observe across populations. There is data enough here to keep the omics organizations busy for the foreseeable future, exploring the limitless differences in biochemistry found between billions of individuals as they age.

This is not the path to treating aging. It is the path to understanding exactly why there are variations in outcome when the initial types of damage that cause aging are the same for everyone. These two end goals are not the same thing at all. You cannot take the complete understanding of how aging progresses and then use it to make an effective therapy by adjusting the biochemistry of person A to make it more like the biochemistry of person B. That changes the outcome in only minor ways, at best slightly slowing the generation of damage that causes aging, or slightly improving its ongoing repair. Yet this is pretty much exactly what the mainstream of the research community is trying to do. As a goal it is enormous and challenging, and yet it will produce few benefits in the grand scheme of things.

The only effective therapy for aging and age-related disease, the only way to add decades or longer to healthy, vital life spans, is to repair the damage that causes aging. We don't need omics data or much in the way of further transformative advances in the life sciences in order to accomplish that goal. The types of damage that cause aging and all of its manifestations are well cataloged and identified. The biotechnologies to repair them could be built with no major new breakthroughs, just painstaking work on the details. Yet this path of repair, to restore the undamaged youthful metabolism that we know works, is still largely overlooked.

The open access paper quoted below is an educational look at the omics fields, and illustrates just how much data there is yet to gather and analyze. The rat hole extends down for a very long way indeed. To plumb its depths will be one of the great works of this century, and I expect to be underway still decades from now. Yet even if none of that happened, the research community could still effectively cure aging and create robust and reliable rejuvenation treatments on much the same timescale, starting from where we are and what we know today about the damage that causes aging. Changing the focus of the field to fall upon periodic repair of damage is the most important thing we can help to achieve.

Integration of 'omics' data in aging research: from biomarkers to systems biology

Age is the strongest risk factor for many diseases including neurodegenerative disorders, coronary heart disease, type 2 diabetes and cancer. Due to increasing life expectancy and low birth rates, the incidence of age-related diseases is increasing in industrialized countries. Therefore, understanding the relationship between diseases and aging and facilitating healthy aging are major goals in medical research. In the last decades, the dimension of biological data has drastically increased with high-throughput technologies now measuring thousands of epigenetic, expression and metabolic variables.

Omics technologies provide valuable tools to study aging on the molecular level. Reductionist data analyses, testing the measured variables separately for association with age, have been extensively applied. Such studies successfully identified hundreds of epigenetic mutations, gene expression levels, metabolite concentrations to be linked with chronological and/or biological age (see below for details). Even though these results improved our understanding of aging as a complex phenotype, the mechanisms underlying these associations and the impact of interactions between different biological entities remain elusive in most cases. In contrast to reductionist approaches, systems biology aims to analyse all components of a biological process simultaneously taking into account their interactions and their intrinsic hierarchical structure. With more and more high-throughput data becoming available, systems biology has led to many new methods and their successful application on age and age-related phenotypes.

Genomics

Genomics was the first omics field for which high-throughput measurements became available. While aging (or rather longevity) itself was found to be only about 20% heritable, many age-related diseases are highly heritable. For instance, Alzheimer's disease (AD) shows a heritability above 70% and osteoarthritis or cataract show 50% heritability.

Epigenomics

Epigenomics describes the study of heritable changes in the genome that are not caused by DNA sequence mutations. The most common epigenetic mechanism is DNA methylation, which is known to often silence gene expression. The epigenome is influenced by environmental and lifestyle factors and is associated with many complex diseases such as neurodegenerative disorders and cancer. Nearly 500 differentially methylated regions were found to be associated with chronological age and age-related phenotypes such as lung function, cholesterol levels and maternal longevity. A recent study showed that methylation patterns of just three sites are sufficient to predict chronological age.

Transcriptomics

Genes are transcribed into RNA molecules, which are further processed in a tightly controlled process. The entirety of the RNA transcripts is referred to as the transcriptome. Similar to the epigenome, gene expression was shown to dramatically change with age. A pioneer study comparing postmortem human frontal cortex tissue samples between 30 individuals of different ages yielded 463 differentially expressed genes. Despite the small sample size, results were replicated in subsequent experiments.

Proteomics

Proteins are translated from coding transcripts. Due to alternative splicing and post-translational protein modifications, the number of proteins is estimated to be two orders of magnitudes higher than the number of genes. However, current proteomic techniques based on immunoassays, protein arrays or mass spectrometry can measure only a small fraction of the proteome. Due to these technicalities, 'proteomics' studies in aging research so far focused on smaller sets of proteins and small sample sizes. A recent study by our group analysed over 1000 proteins in 200 plasma samples. Eleven proteins were found to strongly associate with chronological age as well as age-related phenotypes such as lung function and blood pressure. The results were replicated in an independent cohort. Even though comprehensive proteomics studies are still missing, proteins are likely to be associated with several age-related diseases.

Post-translational modifications - glycomics

Post-translational modifications are important elements of proteins, which can alter their biochemical properties such as protein structure, binding preferences and enzyme activity. There are many different modifications ranging from addition of small molecules (e.g. acetylation or phosphorylation), over addition of larger molecules such as lipids or sugar chains (e.g. glycosylation), to the addition of whole proteins (e.g. ubiquitination). The application of this technology on epidemiological cohorts revealed that glycan structures are stable for one individual over time but very diverse within a population. Differences in glycomes were found to be related with various cancers. Recently, researchers showed that IgG glycans are strongly associated with age: a linear combination of three glycans explained 58% of the observed variance of chronological age in a study of four independent populations with 5117 participants in total.

Metabolomics

Metabolomics investigates the low-molecular-weight molecules in a biological system. The measured molecules are often referred to as metabolites as many of them act as educts, products and intermediates of the cellular metabolism. Currently, the Human Metabolome Database contains more than 40,000 distinct metabolites from different tissues. Similar to proteomics, to date, there is no analytical method available to determine and quantify all metabolites in a single experiment. In 2008, the first metabolome-wide association study on age analysed the plasma metabolome of 269 individuals using an untargeted approach. The authors found 100 of 300 compounds to correlate with chronological age.

Microbiomics

The human microbiome describes the complete set of microbial species (and their genomes) hosted by the human body. The largest microbial community resides in the gut, where microbial cells and their genes outnumber human cells (10:1) and genes (100:1). More than 10,000 different species with millions of protein-coding genes were identified by the Human Microbiome Project. The composition of the microbe flora varies a lot across individuals and even between different parts of the body. It has a huge influence on many biological processes such as immune response, metabolism and disease. While the microbiome seems to be relatively stable during adulthood, it changes significantly in later life. Researchers have observed drastic changes in the gut microbiome of centenarians compared with young adults as well as elderly, namely a general loss of diversity and increased abundance of bacilli and proteobacteria.

Phenomics

Simultaneously with omics data, the dimension of clinical and lifestyle traits, particularly clinically used intermediate traits, keeps increasing. Epidemiological studies collected thousands of clinically relevant phenotypes beyond omics data types. These range from anthropometric measures to health and lifestyle questionnaires. Collecting high-dimensional clinical data is important to unveil pleiotropy of genes and interactions amongst clinical phenotypes such as comorbidities. Phenomics is especially important for aging research. Dozens of clinical phenotypes, such as Parkinson's, AD, body mass index, blood pressure and bone mineral density, as well as lifestyle parameters, such as nutrition, smoking and physical activity, are strongly related to age. Only extensive collection of data and their joint analysis will help to unveil these dependencies and find causal relationships.

Researchers here find a possible neurological contributing cause to the characteristic dysfunction in blood vessels that occurs with aging. This is distinct from the age-related increases in tissue stiffness that sabotage blood vessel flexibility in response to circumstances:

"Aging affects everyone and causes changes throughout our bodies. The purpose of our study was to understand how blood vessels are affected by this process. We found that older arteries had a significantly lower number of sensory nerves in the tissues surrounding them and they were less sensitive to an important neurotransmitter responsible for dilation."

The study focused on mesenteric arteries - a type of artery that supplies blood to the small intestines - of mice that were 4 months and 24 months old. These ages correspond to humans in their early 20s and mid-60s, respectively. Without stimulation, the diameter of the blood vessels of both younger and older mice was approximately the same. However, when stimulated to induce dilation, differences between the age groups became apparent. "The younger arteries dilated as expected. However, when we performed the same stimulation to the arteries of older mice, the vessels did not dilate. When we examined the presence of sensory nerves, we noted a 30 percent decrease in the amount surrounding the older arteries compared to the younger arteries."

Additionally, the researchers found that even when purposefully exposing older mesenteric arteries to defined amounts of the neurotransmitter calcitonin gene-related peptide, or CGRP, the arteries' ability to dilate was greatly reduced. "Poor neurotransmitter function and a reduced presence of sensory nerves surrounding older vessels lead to age-related dysfunction of mesenteric arteries. The importance of this discovery is that if we can identify why this happens to mesenteric arteries, it may be possible to prevent the same thing from happening to other blood vessels throughout the body."

Link: http://medicine.missouri.edu/news/0291.php

Anthony Atala, known for his work on tissue engineering is launching a new company, Atlas Regeneration to focus on pharmacology related to aging. This is in many ways similar to Human Longevity Inc., and it seems a pity to me that someone who was doing something more useful is now going to focus on something less useful when it comes to advancing the state of medicine for healthy longevity.

Numerous groups are now getting into the field of longevity-related genetics and drug discovery with the aim of very modestly slowing down aspects of the aging process. It is probably the case that there is money to be made here, and there is certainly much more data to be gathered on the precise details of the operation of cellular metabolism and its relationship with natural variations in longevity. I do not see it as a viable path towards meaningfully lengthening human life spans, however. Few if any of these initiatives are involved in attempts on the damage repair approach to aging that characterizes SENS, and thus I expect their work to do little but add to our knowledge of metabolism, or move the research community a few steps closer to being able to capture some of the well-established benefits of calorie restriction or exercise through drug treatments. These are small potatoes compared to the rejuvenation that might be achieved through periodic repair of the cell and tissue damage that causes aging, rather than merely slowing down its accumulation.

Atlas Regeneration Inc, a company dedicated to developing novel software platforms and algorithms for drug discovery relating to regenerative medicine and stem cell research, has officially launched. Atlas has partnered with InSilico Medicine, a bioinformatics company, which employs its state of the art Geroscope platform to select and rate personalized anti-aging therapies and identify new drug candidates in longevity.

Aging is an issue that effects all people around the globe universally, but as the babyboomer generation ages, the stress that it places on society becomes greater and the need develop methods for people to remain productive as they age rises in turn. Aging is a very complex multifactorial process that cannot be stopped or reversed by a simple combination of drugs, which is why it is important to develop personalized treatments tailored to individual subjects. The pharmaceutical industry needs a platform to effectively utilize and clinically implement stem cells technology.

"We built our platform, Regeneration Intelligence, on years of experience in regenerative medicine and pharmacology, de novo organ regeneration, body-on-the chip technology just to mention a few of them with a one single goal: develop a reliable tool to convert multi-omics data from individual patient's tissues into unified drug score to predict the effectiveness of targeted compounds and improve clinical decision making, unified iPSC lines score to predict differentiation potential and evaluate clinical safety. We are reinventing this system for drug discovery in regeneration medicine and aging to more effectively employ big data to find solutions for aging, competing with the Google's Calico and Human Longevity companies, to deliver hope that we may see the time when our mutual efforts will start saving lives and increase life span via regeneration in adult humans."

Some of the ideas behind the company's bioinformatics platforms for both regeneration, iPS and aging are rather simple: analyze all available omics profiles of "cells-in-progress" (iPSC line under evaluation, cells/tissues under treatment and so on) and targeted counterpart cells in mature healthy tissues or organs, run computer simulations based on proprietary pathway map to see what drugs or treatments make the old or undifferentiated cell get as close to the norm/healthy counterparts as possible and then validate the results on human cells and model organisms. The same approach may be employed to personalize the drug regimen for individual patients. The core parts of the technology are proprietary signaling pathway map, a unique scoring algorithm along with well-developed biological models which allows us to use all-inclusive gene expression analysis, including microRNA, methylation and proteomics modules among others, and a comprehensive constantly updated drug database.

The position that aging needs personalized treatments is something I see as nonsense, and a symptom of the research community being focused on entirely the wrong approach to the problem. We all age for the same reasons, the damage that causes aging is the same in all of us. The therapies to repair that damage can be the same for all of us, mass produced and cheap once established. Only if you are trying to mess around with the operation of metabolism to slow aging or compensate for damage without actually repairing it - a futile effort, doomed to expensive failure and marginal benefits - do you need to care about exactly how the spiral of simple damage creating complex consequences takes place in any given individual.

Link: http://www.prweb.com/releases/2015/09/prweb12942499.htm

The SENS Research Foundation staff have released their annual report for 2015, and as you can no doubt see it marks the beginning of a new phase for the organization, as well as for the field of rejuvenation research as a whole. Everyday people such as you and I have materially supported SENS research programs over the past decade, initially at the Methuselah Foundation and later at the SENS Research Foundation. The most advanced of these lines of research are now beginning to transfer out to startup companies for development of the first round of therapies. Over the next five to ten years we will see at least a few examples make it into trials and clinical practice, and the data on effectiveness will start to roll in.

This is the first of many steps that will see the SENS approach of periodic repair of cell and tissue damage broaden far beyond the SENS Research Foundation and its present allies. The prevention of age-related frailty and disease via these means will eventually become one of the principal pillars of medicine. As this year's Fight Aging! SENS fundraiser nears its launch, it is important to remember that we helped to make this happen: all of us together, over the years. Take a long look at the progress reported by the SENS Research Foundation and see what you have helped to create: meaningful steps towards a world without frailty and suffering.

SENS Research Foundation 2015 Annual Report (PDF)

Creating partnerships and collaborations to accelerate research

As the landscape of rejuvenation biotechnology broadens, we are seeing increasing opportunities for technology transfer and infrastructure-building efforts, across several categories of transaction.

1) We provide small seed funds - alone or with other funding sources - to companies able to perform mission-related research and development, saving costs against expanding our internal programs. Our research program on Advanced Macular Degeneration has been transferred using this approach, allowing further investigation whilst freeing up our own resources to focus on our next priority.

2) We have supplied small amounts of loan funding to private companies that are developing infrastructure for the rejuvenation biotechnology industry. This includes a loan to assist in the establishment of a tissue cryopreservation company that is working towards the creation of a supply chain for artificial organs.

3) We transfer appropriately mature research to well funded start-up companies pursuing specific disease fields, in return for a stake in those companies.

Case study: technology transfer to Human Rejuvenation Technologies, Inc.

SENS Research Foundation's LysoSENS program had been investigating methods of removal of unwanted intracellular aggregates since 2009. One project focused on aggregates that are the key drivers of the damage underlying plaque formation in atherosclerosis. Removing these aggregates from the immune cells that they disable would reduce plaque formation and dramatically lower the prevalence of heart disease. The project had successfully identified a non-human enzyme that was effective at eliminating some of these aggregates. It became clear that the research was at a stage where significant further investment could greatly accelerate progress, and that such investment could be achieved by transferring the research into a private company. This was done in 2014, when Jason Hope - himself a longterm supporter of the Foundation - formed Human Rejuvenation Technologies, Inc. (HRT). The technologies developed by the Foundation were transferred to HRT in return for a 10% stake in the company.

Case study: seed funding for Oisin Biotech

SENS Research Foundation was considering the creation of an internal project to investigate novel rejuvenation biotechnology solutions to the ablation of senescent cells. Instead we helped in the creation of Oisin Biotech, providing seed funding along with the Methuselah Foundation. Oisin is using licensed liposome technology matched with their own patent-pending DNA construct to perform apoptosis-induced eradication of senescent cells. They have demonstrated that their construct can selectively target senescent cells in vitro.

Delivering a mature and engaged research program

SENS Research Foundation supports a global research effort. Our own scientists are based in our Mountain View, California facility and we fund researchers at field-leading institutions around the world. As we age, we accumulate decades of unrepaired damage to the cellular and molecular structures of our bodies. The types of damage are few in number - we count seven, currently - but cause a great many diseases of aging, including cancer, Alzheimer's and atherosclerosis. Rejuvenation biotechnologies target this underlying damage, restoring the normal functioning of our bodies' cells and essential biomolecules. As preventative interventions they halt the harmful accumulation of damage, stopping disease before it ever starts. Damage and disease have a many-to-many relationship. That simply means that sometimes one type of damage can cause multiple diseases and sometimes one disease is caused by multiple types of damage.

Foundation-funded research includes teams which are:

1) Developing a regenerative medicine approach to treating inflammatory bowel disease, creating underlying technologies vital for future approaches to cancer.

2) Creating therapeutic approaches to intracellular aggregates which build up over time and compromise the functioning of cells in the brain, heart, and muscles.

3) Engineering healthy new tissue for the thymus, helping to restore the vigorous immune response of youth.

4) Engineering new mitochondrial genes to restore function to damaged mitochondria - a source of age-related disease and currently incurable inherited disorders.

5) Exploring non-invasive approaches to the diagnosis and monitoring of certain underdiagnosed forms of heart disease - avoiding the need for cardiac biopsy - and identifying.

6) Ways to remove aggregates which lead to impaired heart function.

7) Understanding the genetic basis of certain cancers which rely on a mechanism called ALT (alternative lengthening of telomeres), to pave the way for new cancer treatments.

8) Developing the tools needed to create therapies which reduce hypertension, stroke and
kidney disease by breaking molecular crosslinks which cause arteries to stiffen with age.

The report contains much longer summaries of current research programs, which are well worth reading. These are exciting times we live in, and it is very welcome to see the work and support of past years beginning to pay off today. As we gear up for this year's fundraiser, starting on October 1st, bear this all in mind. Donating to the SENS Research Foundation this year helps to build the foundation for tomorrows' advances in treating aging. There is no better way I know of to put money to good use.

Plastination is a potential alternative to cryonics for the long-term preservation of the brain following death, a way to maintain the fine neural structure that encodes the data of the mind. Given the pace of technological progress, preserved individuals can expect some unknown chance at restoration to active life in the future. The types of technology required for that feat are well understood, and include a near complete control over cellular biochemistry, along with a molecular nanotechnology industry capable of reconstruction of cells and sequestration of preservation chemicals. Whatever the odds for survival turn out to be, they are considerably better than the other option, which is the grave and oblivion. There is no better path to longevity for the billions who will age to death prior to the widespread availability of rejuvenation therapies, and it is perhaps the greatest shame of our age that cryonics and plastination remain niche concerns.

Plastination has been shown to be feasible as the basis for a preservation technology to much the same degree as cryonics, but unlike cryonics it has not yet developed into a practicing industry. While this lengthy article focuses on plastination, the points are also applicable to cryopreservation:

For the most part bioethics is understandably a conservative business. In the past there has been little tolerance for taking life extension seriously. If the possibility was not scorned as wishful thinking it was dismissed as being selfish and a grave danger to society, usually without any real argument. Yet a new generation of scientists and bioethicists are no longer willing to dismiss radical life extension and have begun to seriously examine these issues. The techno-progressive community as well as the general public are also much more informed about the every increasing pace of technology and are less willing to dismiss potential life extension technologies.

Once the information-theoretic definition of death and the fact that a person is their connectome are accepted, any technique that can preserve the information in the brain has the potential for life extension. In chemical brain preservation, rather than using low temperatures to lock the brain in place as is done in cryonics, the brain is placed in stasis by chemical bonding, a procedure also known as plastination. However, the difference between cryonics and chemical brain preservation is no absolute. Newer forms of cryonics use a process called vitrification. Vitrification uses low temperatures and cryoprotectants to turn tissue into a glass like state where decay is extremely slow. Therefore it may be possible to develop hybrid procedures involving elements of both cryonics and chemical brain preservation.

It may seem obvious to some, but we need ask the question of why would anyone pursue brain preservation? Assuming it works, the obvious answer it that the person wishes to continue living. Many bioethicists argue it is wrong to "unnaturally" extend life and that we need to accept death. This may be good advice if there is nothing we can do about death, but it rings hollow when something can be done. After all, no one argued about refusing public health measures beginning in the late nineteenth century which was arguably the first case of significant life extension.

If the world continues its accelerated pace there is every reason to expect that in a few hundred years we will have a complete science of how the brain gives rise to mind, and the technological prowess to routinely upload memories and minds. Citizens of that future world will have conquered disease and death and overcome countless other biological limitations. And they will viscerally understand what today's neuroscience textbooks try to convey: The mind is computational, and a person's unique memories and personality are encoded in the pattern of physical connections between neurons. From that vantage point, future generations will ask: "Why didn't humanity preserve its most priceless possession -the human brain?"

Link: http://ieet.org/index.php/IEET/more/cerullo20150908

A growing number of scientists and scientific organizations are willing to advocate for, and work towards, the treatment of aging. A great deal of effort over the past decade on the part of organizations like the Methuselah Foundation and SENS Research Foundation and their supporters has helped to change the culture of aging research and increase public awareness of the present state of aging science. This has created a much more receptive environment, one in which more such organizations can thrive.

Painting with very broad strokes, you might think of there being two camps in the aging research community: firstly the majority who see aging as caused by accumulated cell and tissue damage, and secondly a growing minority who see aging as an evolved program caused by epigenetic changes. There are of course a great many opposing factions and different viewpoints within those two large groupings, but I see this as the most important division in the field. With greater progress towards working therapies, we should have a good idea as to which side is correct within the next decade - it will be the one that can produce meaningful prototype rejuvenation treatments.

While SENS research programs are based on damage repair as the ideal approach to therapies for aging, the path that I favor, the Regenerative Sciences Institute takes an epigenetic focus for their otherwise quite similar advocacy for human rejuvenation. In terms of organizational development they are in their very early stages, but then so were the SENS initiatives a decade ago. In an ideal world, there would be scores of young organizations akin to these, pulling in funding for the science and helping to raise awareness for longevity science:

The AMRITA (Abolishing Morbidity by Regeneering and Integrated Technology Advancement) Initiative is RSI's long-term strategy to develop and enhance the regenerative capacity of human beings to live healthier, disease-free lives and transform aging into a benign, beneficial process during which health and vigor are maintained. Aging results primarily from reversible loss of epigenetic/epigenomic information with cell divisions and with chronological time. The key to differences in longevity among mammals is varying fidelities of the biomolecular machines that maintain the epigenome. AMRITA is developing methods to restore a youthful state of the epigenome and enhance regeneration. AMRITA is the logical next step for regenerative medicine - to engineer enhanced regeneration into human beings.

Closely integrated with our innovative education projects, the AMRITA Initiative is divided into three parallel tracks. The first track will identify ways to slow or reverse aging in the immediate future by using systems biology and targeted research to identify aging pathways amenable to intercession. The second track develops the technology to reprogram human cells and tissue in vivo to effectively rejuveneer them, based on breakthroughs in stem cell biology. Our own cells and tissues will be programmed to: 1) undergo a cycle of rejuvenative cell division, 2) remove old dysfunctional cells, and 3) replace them with rejuvenated youthful cells. Increased regenerative power will be a beneficial side effect. In the third track, micro- and nanotechnology are being developed to create biological automatons (biomatons) and robots (biobots) that will be able to carry out repair throughout the body and effectively complement the pure biology based approaches.

Link: http://www.regensci.org/amrita-project/

This year's Fight Aging! matching fundraiser to support the work of the SENS Research Foundation starts on October 1st, just a few weeks away. The SENS Research Foundation is a noted California nonprofit organization that coordinates work in US and European laboratories with the aim of ending frailty and disease in aging. From October 1st until the end of 2015 for every $1 donated to SENS research we will match it with $1 from this year's $125,000 matching fund. We welcome all assistance in meeting our goal, with the aim of speeding the end of aging as a threat to health.

Aging is caused by an accumulation of cell and tissue damage, and these forms of damage are well cataloged and understood. To kickstart meaningful progress in the treatment of aging the research community must focus on therapies capable of repairing this damage. We stand now in the opening years of a process of development: philanthropic fundraising and early stage research coordinated by the SENS Research Foundation over the past decade have led to the first startups and established companies that are today working on new medical technologies that will treat the causes of aging. Senescent cell clearance and preventing the consequences of mitochondrial DNA damage are starting to turn into going concerns, for example, but there is much more left to do.

We want to support and expand this progress, leading the way to human rejuvenation. It is us up to us to shine the lantern and call more attention to this field of research, to fund the prototypes, to speak in public, and call for others to do the same. With this in mind, Fight Aging!, Josh Triplett, Christophe and Dominique Cornuejols, forever-healthy.org, and an anonymous donor have collaborated to create this year's $125,000 matching fund for SENS donations. From October 1st to December 31st 2015 we will match every dollar donated to SENS rejuvenation research with a dollar from the fund. This is our challenge to the community: we came together to raise $60,000 in 2013 and $150,000 in 2014, so let us see if we can hit the target of $250,000 for 2015. You never know the limits of fundraising and support for a worthy cause unless you reach for them.

Much has changed over the past few years in the public view of aging research and the prospects for development of first generation rejuvenation therapies. Researchers are more openly talking about treating aging as a medical condition, and influential backers are also using their soapboxes to discuss this cause. This is the slow tipping point of influence. Ultimately, we want to see the average fellow in the street think of research to treat aging in the same way as he thinks of research to treat cancer today, and that isn't so far away now. To eliminate the suffering, frailty, and death caused by aging is the greatest of goals; aging and its consequences are by far the largest cause of pain in the world. This is in our hands; it is our fundraising and support for organizations like the SENS Research Foundation that enabled the networking and persuasion needed to make rejuvenation research a respected goal, with growing awareness and support.

So, once again, I ask you to join me in helping to speed things along this October 1st. To fund the research, to tell your friends, to put up the posters, and to assist in whatever other way you can. The clock is ticking for all of us, but if the right lines of research are just funded more aggressively, then the widespread availability of therapies that can prevent and cure all age-related disease is just a few decades away now, and the first prototype treatments are considerably closer than that. We have made a difference in the past, we are making a difference now, and the wheel is starting to turn as a result of efforts just like this one.

Researchers here propose a novel method by which stochastic nuclear DNA damage can occur over the course of aging. The paper is open access, but only available in PDF format at the moment:

Whether nucleic acids that circulate in blood have any patho-physiological functions in the host have not been explored. We report here that far from being inert molecules, circulating nucleic acids have significant biological activities of their own that are deleterious to healthy cells of the body. Fragmented DNA and chromatin (DNAfs and Cfs) isolated from blood of cancer patients and healthy volunteers are readily taken up by a variety of cells in culture to be localized in their nuclei within a few minutes. The intra-nuclear DNAfs and Cfs associate themselves with host cell chromosomes to evoke a cellular DNA-damage-repair-response (DDR) followed by their incorporation into the host cell genomes. Whole genome sequencing detected the presence of tens of thousands of human sequence reads in the recipient mouse cells. Genomic incorporation of DNAfs and Cfs leads to dsDNA breaks and activation of apoptotic pathways in the treated cells.

When injected intravenously into Balb/C mice, DNAfs and Cfs undergo genomic integration into cells of their vital organs resulting in activation of DDR and apoptotic proteins in the recipient cells. Cfs have significantly greater activity than DNAfs with respect to all parameters examined, while both DNAfs and Cfs isolated from cancer patients are more active than those from normal volunteers. All the above pathological actions of DNAfs and Cfs described above can be abrogated by concurrent treatment with DNase I and/or anti-histone antibody complexed nanoparticles both in vitro and in vivo. Taken together, our results suggest that circulating DNAfs and Cfs are physiological, continuously arising, endogenous DNA damaging agents with implications to ageing and a multitude of human pathologies including initiation of cancer.

Link: http://www.ncbi.nlm.nih.gov/pubmed/25740145

Researchers here uncover a potential drug target to spur the remyelination of nerves. Accelerated degradation of the myelin sheathing required for correct nervous system function underlies a range of medical conditions, including multiple sclerosis. Evidence suggests that everyone suffers demyelination to a lesser degree over the course of aging, however, and that this may contribute towards the noticeable loss of cognitive function that occurs in even the fittest of older people. So it is worth keeping an eye on progress towards methods of restoring myelin:

In vertebrates, axons extending from nerve cells are covered by insulating sheets called the myelin sheath, made with the cell membranes of oligodendrocytes, enabling fast electrical signaling through saltatory conduction. Normally, myelin is repaired, even if damaged, but the mechanism that controls remyelination was not well understood. In addition, in demyelinating diseases such as multiple sclerosis, the myelin sheath does not recover from damage and gets worse, finally leading to symptoms such as vision loss, limb numbness, and movement disorders.

Researchers performed a detailed examination of the remyelinating process of damaged myelin using disease model mice. Their results show that a growth factor called pleiotrophin is secreted from nerve axons injured by demyelination, and this pleiotrophin inhibits the function of the receptor molecule PTPRZ of oligodendrocyte precursor cells, stimulating cellular differentiation into oligodendrocytes which form the myelin sheath, thereby promoting remyelination.

This achievement shows that it is possible to encourage the regeneration of the myelin sheath by inhibiting the action of PTPRZ in endogenous oligodendrocyte precursor cells, indicating a new potential treatment for demyelinating diseases. "This was made possible by establishing oligodendrocyte precursor cell lines. Pleiotrophin is an endogenous PTPRZ inhibitor, but if synthetic PTPRZ inhibitors were obtained, then effective treatments for multiple sclerosis should become possible. We are currently directing our research in that direction".

Link: http://www.nibb.ac.jp/en/pressroom/news/2015/09/03.html

The Geroprotectors online database was recently announced, a curated reference of lifespan data studies carried out in recent years. It isn't surprising to see João de Magalhães on the list of those involved, given his past focus on producing online databases relevant to aging research: GenAge, AnAge, LongevityMap, the Digital Aging Atlas, LibAge, and so on. The Geroprotectors database is in line with those efforts, being an attempt to make interesting data more accessible to that faction of the research community interested in intervening in the aging process.

I should say that this reference work follows the mainstream of aging research in being entirely focused on pharmacology, the expensive process of finding drugs and supplements to slightly slow down the aging process by adjusting the operation of metabolism. That's fair enough when looking at the last few decades of life span studies; approaches other than calorie restriction, exercise, and drug discovery to alter the operation of metabolism haven't yet progressed to the point of producing more than a sparse handful of animal studies. In particular the SENS approach of periodic damage repair is still largely at earlier stages of research prior to expensive, long-running animal studies, with a few exceptions such as senescent cell clearance and mitochondrial repair technologies that are entering clinical trials, but not for aging.

The point to be made here is that the future of treating aging is not pharmacology in the traditional sense of mining the natural world for compounds that happen to do more good than harm in any one specific situation. There will certainly be a lot of work done there through sheer inertia, but in the fullness of time it will be abandoned as a path towards therapies because it will be proven ineffective in comparison to SENS and related approaches, which look much more like gene therapies, cell therapies, repair of specific molecular breakages, and so on. It is self-evident that in any complex system of machinery we should expect periodic repair of damage to be more effective than slowing down damage accumulation without repair, and that is without taking into account that adjusting metabolism into new safe configurations is harder and more expensive than repairing known forms of damage to maintain the known healthy configuration of metabolism.

That doesn't stop Geroprotectors from being a very interesting set of data, of course. It is important to recognize that scientific knowledge always has value, and there is certainly far too little investment in it in our modern societies, but it isn't necessarily the case that any particular field or approach is capable of laying the foundations for effective therapies. It we were all already ageless that wouldn't matter, but we are not; the clock is ticking, and so there is merit in talking about which strategies are likely to be more or less effective in the treatment of aging.

Geroprotectors

The risk for many chronic diseases increases as we age. These diseases include cardiovascular and metabolic syndrome-related problems such as type II diabetes, atherosclerosis, hypertension, myocardial infarction and stroke, as well as cancer and neurodegenerative diseases. Studies show that some agents which extend the lifespan in animal models may also be effective in humans. Geroscience, which aims to conserve the healthy state of the body, may therefore become a key concept in biomedicine in the near future, as chemicals become available which slow ageing and prevent or delay the onset of age-related diseases.

A "geroprotector" is any intervention that aims to increase longevity, or that reduces, delays or impedes the onset of age-related pathologies by hampering aging-related processes, repairing damage or modulating stress resistance. The Geroprotectors.org database comprises more than 250 life-extension experiments in 11 wild-type model organisms (including M. musculus and C. elegans, among others). We gathered data about more than 200 chemicals promoting longevity, including compounds approved for human use. This database integrates information about lifespan-increasing experiments and related compounds, suppression of aging mechanisms, activation of longevity mechanisms and age-related diseases obtained from research papers and databases. For descriptions of compounds and their effects on model organisms, we have used many sources with information about chemical and biological information. All substances have descriptions including data on their toxicity, clinical use, clinical trials (actual data), biological and pharmacological activities, interactions and so on.

Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease

As the level of interest in aging research increases, there is a growing number of geroprotectors, or therapeutic interventions that aim to extend the healthy lifespan and repair or reduce aging-related damage in model organisms and, eventually, in humans. There is a clear need for a manually-curated database of geroprotectors to compile and index their effects on aging and age-related diseases and link these effects to relevant studies and multiple biochemical and drug databases.

Here, we introduce the first such resource, Geroprotectors. Geroprotectors is a public, rapidly explorable database that catalogs over 250 experiments involving over 200 known or candidate geroprotectors that extend lifespan in model organisms. Each compound has a comprehensive profile complete with biochemistry, mechanisms, and lifespan effects in various model organisms, along with information ranging from chemical structure, side effects, and toxicity to FDA drug status. These are presented in a visually intuitive, efficient framework fit for casual browsing or in-depth research alike. Data are linked to the source studies or databases, providing quick and convenient access to original data. The Geroprotectors database facilitates cross-study, cross-organism, and cross-discipline analysis and saves countless hours of inefficient literature and web searching.

CD47 is a marker for cancer cells in a broad range of cancers, and thus targeting it offers the prospect of a cancer treatment that can be applied to many more patients than is usually the case. A number of research groups are working on refining this basic idea into practical treatments, or improving first attempts, as is the case here:

By changing the mouse model they use to study how the immune system responds to cancer, a team of researchers hopes to shift the focus for one emerging form of cancer immunotherapy back to the standard approach - relying on antigen-presenting dendritic cells - and away from the current upstart, macrophages. Although macrophages, like dendritic cells, also take up antigens, they are more likely to degrade them than present them to T cells. The recent emphasis on macrophages stems, in part, from promising, but problematic, efforts to develop an effective macrophage-driven T cell-mediated immunotherapy.

Researchers report that using a monoclonal antibody called anti-CD47, which blocks the "don't-eat-me" signal on malignant cells, to treat mice with an intact immune system provides a much more lifelike way to study and develop an immune-based cancer therapy. "Tumor rejection requires both innate and adaptive immune responses against tumor cells. We think our approach, along with further investigation of scheduling and dosing, could improve survival and quality of life for patients battling advanced cancer."

The shift of focus from one set of scavengers, dendritic cells, to another, macrophages, was initiated by ground-breaking studies demonstrating that many aging cells, and most cancer cells, display a protein called CD47 on the cell surface. The presence of CD47 protects these cells; it instructs circulating macrophages not to devour them. But as cells age or evolve, many slowly lose their protective CD47 and the macrophage system can confront them. The investigators found that when they used antibodies against CD47 to negate this "don't-eat-me" signal, macrophages were able to chew up many of these cancer cells.

Researchers now point out that these initial studies relied on human tumors transplanted into mice. The mice also had significant immune defects. They argue that a more appropriate model, transplanting tumors from mice into genetically identical hosts with fully intact immune systems, would be more informative and clinically relevant. When they used such mice to test their approach, they found that the bulk of therapeutic effect from CD47 blockade relied not on macrophages but on dendritic cells. These triggered the secretion of interferons, an immune system activator, and the priming of CD8+ T cells. They note that anti-CD47-mediated tumor rejection "requires both innate and adaptive immune responses."

Link: http://www.sciencedaily.com/releases/2015/08/150831120316.htm

As the paper linked here illustrates, pharmacology remains the main focus for that part of the research community interested in intervening in the aging process. Those involved understand that this progress is very slow and very expensive while any near-future drug therapies will be marginal and come with potentially hazardous side-effects: this is a matter of trying to safely adjusting the enormously complex and still poorly understood operation of metabolism to limp along a little better when damaged by aging, or slightly slow down the pace of damage accumulation. The future that I predict is that this approach to research will continue to swallow enormous sums of money and generate nothing of any real value in terms of treatments for aging, and that this state of affairs will last until periodic damage repair approaches like SENS consistently demonstrate far better and far cheaper results in animal studies and clinical trials. There is a great deal of cultural and regulatory inertia driving the relentless focus on old-style pharmacology in medicine, regardless of its actual fit for any given situation.

Aging can be defined as the progressive decline in tissue and organismal function and the ability to respond to stress that occurs in association with homeostatic failure and the accumulation of molecular damage. Aging is the biggest risk factor for human disease and results in a wide range of aging pathologies. Although we do not completely understand the underlying molecular basis that drives the aging process, we have gained exceptional insights into the plasticity of life span and healthspan from the use of model organisms such as the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. Single-gene mutations in key cellular pathways that regulate environmental sensing, and the response to stress, have been identified that prolong life span across evolution from yeast to mammals. These genetic manipulations also correlate with a delay in the onset of tissue and organismal dysfunction.

While the molecular genetics of aging will remain a prosperous and attractive area of research in biogerontology, we are moving towards an era defined by the search for therapeutic drugs that promote healthy aging. Translational biogerontology will require incorporation of both therapeutic and pharmacological concepts. The use of model organisms will remain central to the quest for drug discovery, but as we uncover molecular processes regulated by repurposed drugs and polypharmacy, studies of pharmacodynamics and pharmacokinetics, drug-drug interactions, drug toxicity, and therapeutic index will slowly become more prevalent in aging research. As we move from genetics to pharmacology and therapeutics, studies will not only require demonstration of life span extension and an underlying molecular mechanism, but also the translational relevance for human health and disease prevention.

Link: http://dx.doi.org/10.1016/bs.adgen.2015.06.002

In the open access paper quoted here, researchers suggest that variations in the MOTS-c peptide encoded in mitochondrial DNA may have some effect on life expectancy in at least some human populations. The present landscape of statistical data for human gene variants and longevity points to a complex array of many, many individually tiny contributions to longevity, these contributions interacting with one another so that the patterns and relationships are very different in different populations. The correlations found in one study of genetics and longevity are very rarely replicated in others. Only a few gene variants are reliably associated with longevity in multiple human study populations, and their effects are dwarfed by the contribution of exercise and calorie intake to long-term health.

To a first approximation we all age in the same way, for the same underlying reasons, which is to say the accumulation of unrepaired damage produced as a side-effect of the normal operation of cellular metabolism. Effective treatments for aging will be mass-produced, repairing exactly the same forms of damage in every patient in exactly the same way. That is the path to real results in healthy life extension, not trying to find genetic alterations that might slightly, trivially slow down the damage, or slightly, trivially change the response to damage, and thus slightly, trivially alter the odds of living in suffering and pain for an extra year or two. Deciphering the enormously complex relationship between genes and aging is a worthy goal for the scientific community, but it isn't the path to useful therapies for degenerative aging.

If you were looking for genetic variants associated with longevity, however, then there are far worse places to start than mitochondrial DNA. Unlike nuclear DNA, there are only a handful of different mitochondrial genomes, haplogroups defined by accumulated mutations that spread throughout populations in the generations since the recent common ancestor, Mitochondrial Eve. Each haplogroup is carried by an enormous human population, and many existing sets of epidemiological data include haplogroup identification. This makes obtaining data and running statistical analyses a much easier prospect than is the case for the alternatives, and is one of the reasons why there are numerous studies on whether or not some mitochondrial haplogroups are modestly better than others, linked to small statistical advantages in health or longevity.

The research linked below is a good example of this sort of thing, and gives some insight into the types of investigation underway at the border between relentless genetic information gathering on the one hand and the struggle to understand the details of the progression of degenerative aging on the other. It is a rich mix of data analysis, modeling, inference, collaboration, and genetics:

The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity?

The number of people aged ≥60 years is expected to almost triple by 2050, with the 'oldest old' group (older than 85 years) being the most rapidly expanding segment in Western societies. Among long-lived individuals, those who reach exceptional longevity (EL, i.e., centenarians (≥100 years) and supercentenarians (SCs, ≥110 years)) are arguably the paradigm of successful aging. Several genetic factors might contribute to EL, as suggested by the differences found in the frequency distribution of several genetic variants among centenarians compared with their ethnic-matched referents of younger ages. Factors related to inflammation, metabolism or nutrition, among others, can also influence the likelihood of reaching EL. Japan has clearly the longest life expectancy in the world, as well as the highest number of SCs, as we recently reviewed. Thus, Japanese long-lived people represent an interesting model to study the biology of EL, and to gain insight into the nature vs. nurture debate.

Mitochondrial DNA (mtDNA) can influence EL. Human mtDNA contains 13 genes that codify proteins involved in mitochondrial oxidative phosphorylation (OXPHOS), as well as 2 rRNA and 22 tRNA genes that are necessary for protein synthesis within mitochondria. Mitochondria are one of the most important players to understand the aging process at the cellular level as they are both the main source and target of oxidative damage. Mitochondrial dysfunction is in fact a main hallmark of aging, which is partly caused by accumulation of mtDNA damage as we age. Thus, because mtDNA haplotypes or haplogroups (i.e., characteristic clusters of tightly linked mtDNA polymorphisms that form continent-specific genotypes) might influence individual susceptibility to mtDNA damage, they could also influence EL in a continent- or ethnic-specific manner.

For instance, the association between mtDNA and EL is controversial in Spanish people, with researchers reporting no association between mtDNA haplogroups and EL but others find that the Caucasian haplogroup J (which would be associated with lower mtDNA damage) might confer a higher chance to attain high longevity (85+ years) compared with other haplogroups in Northern Spaniards. On the other hand, although mtDNA haplogroups D4b2b, D4a, and D5 are not associated with type 2 diabetes, they are linked with EL in Japanese population. We also showed that the mtDNA m.1382A>C polymorphism, which is specific for the ancestor haplogroup D4b2, is associated with EL in the Japanese population.

Mitochondrial-derived peptides (MDP) are encoded by functional short open reading frames in the mtDNA. These include humanin, a 24-amino acid peptide encoded in the 16S rRNA region with strong cytoprotective actions and the recently discovered mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), which is a 16-amino acid peptide that regulates insulin sensitivity and metabolic homeostasis. We have recently suggested that MOTS-c might also be involved in the aging process.

The aforementioned m.1382A>C polymorphism is located in the MOTS-c encoding mtDNA, a short open reading frame in the 12S rRNA region. The m.1382A>C variation causes a Lys14Gln replacement in the MOTS-c peptide equivalent to nucleotide position 1382 of the mtDNA; this is likely to have functional consequences, as the physicochemical difference between the original and the altered amino acid residues is relatively high, with a Grantham value of 53, that is, above the average value (=50) that differentiates radical from conservative single amino acid replacements. This amino acid replacement is also predicted to have a functional effect with the PROVEAN (PROtein Variation Effect ANalyzer) tool, that is, yielding a score of −4.000, below the specifically predicted cutoff score (=−2.5) above which the variant would be 'neutral'. The m.1382A>C polymorphism is specific for the Northeast Asian population and may be among the putative biological mechanisms explaining the high longevity of Japanese people. Further, MOTS-c is an important 'mitokine', with this term referring to mitochondrial-derived signals that impact other cells in an endocrine-like manner.

Researchers here argue that failing calcium regulation provides a meaningful contribution to neurodegeneration, and demonstrate improvement in old rats via altered levels of a protein involved in calcium metabolism. As is the case for most research, this identifies only one step of cause and consequence in longer chain of events. We should expect, given the necessary time and resources, for researchers to be able to trace back age-related changes to fundamental forms of cell and tissue damage that occur as a side-effect of the normal operation of cellular metabolism. That is a long road, however, and given that we already have a catalog of those fundamental forms of damage, it would be faster to start by repairing them to see what happens. That approach is still a minority concern in the research community, sadly.

Building on scientific evidence implicating disturbed calcium regulation in brain aging accumulated through the past 30 years, a research team has found a connection between unhealthy brain aging and a protein responsible for regulating calcium at the molecular level, called FKBP1b. Excess calcium in brain cells appears responsible for important aspects of unhealthy brain aging, and may also increase susceptibility to diseases such as Alzheimer's, ALS, Parkinson's and vascular dementia. Until now, the precise molecular cause of the disturbed calcium regulation in brain aging has remained unknown to scientists. After learning about the FKBP1b protein's recently uncovered role in the heart, researchers wondered whether FKBP1b in the hippocampus region declines with brain aging. They then found evidence of reduced FKBP1b gene expression with aging in the hippocampus. This discovery prompted the researchers to test whether boosting FKBP1b in the hippocampus region could reverse or prevent brain aging linked to memory loss.

The team used an advanced gene therapy approach to inject harmless virus particles, which created additional copies of the FKBP1b protein, into the hippocampus of aging rats. The memory abilities of three groups of rats were tested two months after the injections. One group of young rats received a control injection, one group of aged rats received a control injection and one aged group received an injection of the FKBP1b-producing virus particles. The aged group with raised levels of FKBP1b showed restored calcium regulation and dramatically improved cognitive function, allowing them to perform the memory task as well as or better than the young rats. In addition, the researchers have repeated and extended the results in a subsequent study being prepared for publication.

The research provides evidence the manifestations of brain aging can be reversed, and cognition and memory function restored, by altering levels of FKBP1b. This finding is also significant for Alzheimer's patients as the researchers found a decline in the FKBP1b protein in the hippocampus of people who had early-stage Alzheimer's. The research has implications for preventing brain aging associated with the progression of Alzheimer's, and opens the door for pharmaceutical development aimed at sustaining levels of FKBP1b and keeping calcium in check.

Link: http://uknow.uky.edu/content/uk-scientists-explain-underlying-cause-unhealthy-brain-aging-associated-alzheimer%E2%80%99s

It has long been hypothesized that there is a link between autoimmune conditions and the immune response to cancer, and this article covers some of the high points. Autoimmune conditions are a set of complicated failure modes in a very complex system, in which the immune system attacks the patient's own tissues. They are perhaps the least well understood diseases, and this is reflected in the poor state of treatments for autoimmunity: no cures, and the best that can be done for patients is to dampen the overall immune response. Any path forward that grants additional insight into the early development of autoimmunity is welcome.

Generations of in-depth research into human anatomy, histology, and basic physiology have largely explained the physical manifestations of diseases affecting nearly every organ of the body. Yet there remains an entire class of illnesses that present systemically, do not respect the boundaries of organ systems, and wreak havoc on quality of life and longevity. And we still have little idea of what starts the vicious cascade in the first place. This category of maladies is called autoimmune disease, and it is our fundamental lack of knowledge about these disorders that so greatly hinders our ability to prevent, diagnose, and treat them.

There is much we know, or think we know, about the risk factors and manifestations of autoimmune disease, and we even have some diagnostic tests for antibodies that often closely correlate with specific subtypes of disease. However, the fundamental biological mystery remains: What initiates the formation of antibodies that react with the body's own proteins and result in the destructive processes that define autoimmune disease? Have we simply failed to detect an infectious or environmental exposure that initiates the inflammatory cascade? Is there a benefit accrued via autoantibodies that serves an important biological purpose and helps to explain their existence?

While many theories have been and continue to be posited in answer to these etiological questions, a particularly interesting hypothesis first proposed in the 1960s has been reborn and, if it holds true, could have tremendous implications for the fields of rheumatology, oncology, immunology, neurology, endocrinology, and many others: autoimmune disease may represent collateral damage from the body's fight against developing cancers. Scientists have long recognized that patients with certain autoimmune diseases are at increased risk of cancer, but only recently has a possible mechanism been identified. Research involving patients with concurrent cancer and scleroderma revealed somatically mutated genes in the patients' tumors that initiated cellular immunity and cross-reactive humoral immune responses, producing antibodies that reacted to the cancer and are known to play an important role in scleroderma itself. The finding implies that the autoimmune disease may arise as an unintended consequence of the body's own immune response to a developing cancer, which in certain patients will never become clinically evident.

Link: http://www.the-scientist.com/?articles.view/articleNo/43798/title/Body--Heal-Thyself/

Results from the most recent two year CALERIE trial of human calorie restriction were published earlier this year, but the associated publicity materials have only just now made it to the presses.

Calorie restriction, or to be more precise calorie restriction with hopefully optimal but at least adequate nutrition, is the practice of reducing calorie intake while maintaining a suitable level of micronutrients in the diet. Reducing recommended dietary intake by about 25% is a common target, as was the case in this study. That would mean somewhere around 1500 calories per day for the mythical completely average individual. It is just about impossible to achieve this goal without structuring a very healthy diet that is comparatively low in processed sugars and the like, which is an added bonus. When you are settled into a healthy calorie restricted diet, hunger is nowhere near the bugbear that people like to make it out to be, while the short term benefits are fairly obvious and arrive quickly, including lowered chronic inflammation, reduced visceral fat tissue, lower blood pressure, less sleep needed, and so forth.

The short term benefits of a calorie restricted metabolism to health have been established and measured extensively over the past few decades. The evidence shows they are altered in much the same way in people as in mice. Unlike mice, however, people do not live 40% longer when calorie restricted - we would have noticed by now. There have been religious orders across the course of history where this would have been the case, and in our time many members of the Calorie Restriction Society have been practicing calorie restriction with optimal nutrition for somewhat longer than the CALERIE program has existed. There is a good evolutionary explanation for the difference in the calorie restriction response when comparing short-lived and long-lived species: famines are seasonal, and a season is a large fraction of a mouse lifespan but a small fraction of a human life span. Thus only the mouse evolves a relatively large plasticity of life span in response to food scarcity.

But from a mechanistic point of view - how exactly does this all work under the hood, what are cells and tissues actually doing to extend life - there is still a long way to go if you are looking for the complete explanation. The challenge here is that near every measure and aspect of cellular biochemistry changes in response to nutrient availability. Aging is slowed, but why, exactly? Which of the scores of likely candidates are contributing, and to what degree? Picking apart cause and effect has been the subject of decades of ever-expanding research so far, and looks set to take decades more yet. It is a fair wager to suggest that we will likely see the first crude rejuvenation therapies based on repair of cellular damage before the emergence of a comprehensive accounting of the calorie restriction response and its effects on aging.

Don't let that stop you from giving it a try, however. Like exercise, calorie restriction is backed by the gold standard of scientific evidence when it comes to things you can do today that are expected to have a noticeable positive effect on your present and future health. The interesting take in the commentary here, from a perspective of having read the paper a few months back, is that researchers expected to see more in the way of benefits than they did. That might be explained by the lesser degree of calorie restriction obtained versus that aimed for, which itself was smaller than that of some animal studies:

NIH study finds calorie restriction lowers some risk factors for age-related diseases

Results from a two-year clinical trial show calorie restriction in normal-weight and moderately overweight people failed to have some metabolic effects found in laboratory animal studies. However, researchers found calorie restriction modified risk factors for age-related diseases and influenced indicators associated with longer life span, such as blood pressure, cholesterol, and insulin resistance. "The study found that this calorie restriction intervention did not produce significant effects on the pre-specified primary metabolic endpoints, but it did modify several risk factors for age-related diseases. It is encouraging to find positive effects when we test interventions that might affect diseases and declines associated with advancing age. However, we need to learn much more about the health consequences of this type of intervention in healthy people before considering dietary recommendations. In the meantime, we do know that exercise and maintaining a healthy weight and diet can contribute to healthy aging."

CALERIE was a two-year randomized controlled trial in 218 young and middle-aged healthy normal-weight and moderately overweight men and women to measure these outcomes in a CR group, compared with a control group who maintained their regular diets. The calorie restriction participants were given weight targets of 15.5 percent weight loss in the first year, followed by weight stability over the second year. This target was the weight loss expected to be achieved by reducing calorie intake by 25 percent below one's regular intake at the start of the study. The calorie restriction group lost an average of 10 percent of their body weight in the first year, and maintained this weight over the second year. Though weight loss fell short of the target, it is the largest sustained weight loss reported in any dietary trial in non-obese people. The participants achieved substantially less calorie restriction (12 percent) than the trial's 25-percent goal, but maintained calorie restriction over the entire two-year period. The control group's weight and calorie intake were stable over the period.

The study was designed to test the effects of calorie restriction on resting metabolic rate (after adjusting for weight loss) and body temperature, which are diminished in many laboratory animal studies and have been proposed to contribute to its effects on longevity. The study found a temporary effect on resting metabolic rate, which was not significant at the end of the study, and no effect on body temperature. Although the expected metabolic effects were not found, calorie restriction significantly lowered several predictors of cardiovascular disease compared to the control group, decreasing average blood pressure by 4 percent and total cholesterol by 6 percent. Levels of HDL ("good") cholesterol were increased. Calorie restriction caused a 47-percent reduction in levels of C-reactive protein, an inflammatory factor linked to cardiovascular disease. It also markedly decreased insulin resistance, which is an indicator of diabetes risk. T3, a marker of thyroid hormone activity, decreased in the calorie restriction group by more than 20 percent, while remaining within the normal range. This is of interest since some studies suggest that lower thyroid activity may be associated with longer life span.

A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity

To determine CR's feasibility, safety, and effects on predictors of longevity, disease risk factors, and quality of life in nonobese humans aged 21-51 years, 218 persons were randomized to a 2-year intervention designed to achieve 25% CR or to AL diet. We conclude that sustained CR is feasible in nonobese humans. The effects of the achieved CR on correlates of human survival and disease risk factors suggest potential benefits for aging-related outcomes that could be elucidated by further human studies.

The open access paper quoted here provides some insight into present attempts to change the regulatory classification of aging in the lab and the clinic: the prospect for meaningful progress in the science is real, but regulation is holding things back, which is why so many articles have appeared of late on whether or not aging is a disease.

The bureaucracy of what is and is not officially a disease is baroque and slow-moving, a many-faceted entity with areas of different importance depending on whether clinical medicine or research or translation or funding is being considered. There is considerable interest at the present time in doing something about that fact that aging is generally not accepted to be a treatable medical condition in most parts of the system that matter, which is to say those relating to the flow of money into early stage and translational research. That flow of money is tiny at this time; there is very little support for developing any of the clear paths towards treating aging as a medical condition, and this has a lot to do with regulatory barriers. If it is illegal to treat aging, none of the big for-profit concerns are going to go all in on building potential therapies, for example.

Aging is a complex continuous multifactorial process leading to loss of function and crystalizing into the many age-related diseases. Here, we explore the arguments for classifying aging as a disease in the context of the upcoming World Health Organization's (WHO)'s 11th International Statistical Classification of Diseases and Related Health Problems (ICD-11), expected to be finalized in 2018. We hypothesize that classifying aging as a disease will result in new approaches and business models for addressing aging as a treatable condition, which will lead to both economic and healthcare benefits for all stakeholders. Classification of aging as a disease may lead to more efficient allocation of resources by enabling funding bodies and other stakeholders to use quality-adjusted life years (QALYs) and healthy-years equivalent (HYE) as metrics when evaluating both research and clinical programs. We propose forming a Task Force to interface the WHO in order to develop a multidisciplinary framework for classifying aging as a disease

The recognition of a condition or a chronic process as a disease is an important milestone for the pharmaceutical industry, academic community, healthcare and insurance companies, policy makers,and individual, as the presence of a condition in disease nomenclature and classification greatly impacts the way it is treated, researched and reimbursed. However, achieving a satisfactory definition of disease is challenging, primarily due to the vague definitions of the state of health and disease.

Despite the growing abundance of biomarkers of aging, classifying aging as a disease will be challenging due to the absence of the "ideal norm." Despite significant effort from the academic and industry communities, sarcopenia is still not classified as a disease despite clear clinical and molecular representation and similarity with premature musculoskeletal aging and myotonic disorders. One approach to address this challenge is to assume an "ideal" disease-free physiological state at a certain age, for example, 25 years of age, and develop a set of interventions to keep the patients as close to that state as possible. Considering the WHO definition of health, it may be possible to agree on the optimal set of biomarkers that would be characteristic to the "state of complete physical, mental and social well-being, not merely the absence of infirmity" and agree on the physiological threshold after which the net totality of deviation of these biomarkers from norm can be considered a disease.

Link: http://dx.doi.org/10.1101/024877

Researchers here note a correlation between glycemic index, a measure of the impact of carbohydrate content of food on blood glucose, and risk of suffering age-related blindness. Given the comparatively large influence of calorie intake over all aspects of health and metabolism, and the composition of the typical modern diet, I think one has to consider the usual suspects of total overall calories consumed, visceral fat, and chronic inflammation before moving on to look at things like the contribution of diet to cross-links in the eye or lipofuscin formation in the retina.

Extending healthful life is a millennia-old dream and objective. During the intervening centuries a multitude of concoctions and remedies have been offered, usually with few substantiated results. During the last century it was demonstrated that limiting caloric intake is associated with extended life in many mammals, albeit results remain to be clarified in humans. A myriad of modeling studies have revealed signaling pathways that are associated with life extension and the last two decades have seen an interest in the types of dietary carbohydrates that might confer health advantage, and possibly longevity.

Loss of vision due to age-related cataracts or age-related macular degeneration is widely prevalent, affecting about 85% and 15% of the elderly respectively. With centenarians among the fastest growing segments of societies, and with loss of vision a very costly personal and societal burden, there is keen interest in extending vision - that is, delaying age-related macular degeneration and cataract - or diminishing risk for these debilities. Using extensive epidemiologic and nutritional information from the Nurses' Health Study and Age-Related Eye Disease Study (AREDS) we determined that measures of total carbohydrate, and even more so, glycemic index (GI), are associated with visual health. We also modeled this relationship in mice in order to elucidate etiologic relationships between dietary glycemia, visual health, and genetics.

Link: http://dx.doi.org/10.1016/j.mam.2015.08.005

October 1st is the UN International Day of Older Persons, but our community would like it to also be Longevity Day, a time to remind the world that research into human rejuvenation is practical, that near-future therapies are plausible, and that all of this will move much faster with greater funding and support. This year, as last, grassroots advocates will hold events around the globe, many of which are coordinated through the International Longevity Alliance and related groups.

October 1st is also the launch date for this year's Fight Aging! matching fundraiser in support of the rejuvenation biotechnology programs coordinated by the SENS Research Foundation. This is a chance for all of us to do our part to help speed things along; the progress you see today in SENS technologies relevant to treating aging as a medical condition came about as the result of similar fundraising in past years. The matching fund for 2015 weighs in $125,000, and we'll be seeking to raise that much again, matching every $1 donated with $1 from the fund. This is a stretch goal for our community, and all offers of assistance in preparation and fundraising are greatly appreciated.

If you are interested in holding an event this year to mark Longevity Day, then contact the International Longevity Alliance: there is a month left in which to organize, and the Alliance has plenty of helpful materials and references. With regards to the Fight Aging! fundraiser, there are message posters that we'd love to see more widely distributed. Pass them around, show them off, or - even better - improve on them and share the results.

International Longevity Day - October 1, 2015

There has been emerging a tradition by longevity researchers and activists around the world to organize events dedicated to promotion of longevity research on or around October 1 - the UN International Day of Older Persons. This day is sometimes referred to in some parts of the longevity activists community as the "International Longevity Day". As this is the official UN Day of Older Persons, this provides the longevity research activists a perfect opportunity, perhaps even a perfect excuse, to emphasize the importance of aging and longevity research for the development of effective health care for the elderly, in the wide public as well as among decision makers.

Let us maintain and strengthen this tradition! Let us plan and organize a mutually reinforcing network of events worldwide. If you plan to organize an event for that day - either live meetings or on-line publications and promotions - please let us know. Together we can create an activism wave of strong impact.

The critical importance and the critical need to promote biological research of aging derives from the realization that tackling the degenerative processes and negative biological effects of human aging, at once and in an interrelated manner, can provide the best foundations to find holistic and effective ways for intervention and prevention against age-related ill health. Such an approach has been supported by scientific proofs of concept, involving the increase in healthy lifespan in animal models and the emerging technological capabilities to intervene into fundamental aging processes.

The focus on intervention into degenerative aging processes can provide solutions to a number of non-communicable, age-related diseases (such as cancer, heart disease, type 2 diabetes and neurodegenerative diseases), insofar as such diseases are strongly determined by degenerative aging processes (such as chronic inflammation, cross-linkage of macromolecules, somatic mutations, loss of stem cell populations, and others). This approach is likely to decrease susceptibility of the elderly also to communicable, infectious diseases due to improvements in immunity. The innovative, applied results of such research and development will lead to sustainable, economically viable solutions for a large array of age-related medical and social challenges, that may be globally applicable. Furthermore, such research and development should be supported on ethical grounds, to provide equal health care chances for the elderly as for the young.

Therefore it is the societal duty, especially of the professionals in biology, medicine, health care, economy and socio-political organizations, to strongly recommend greater investments, incentives and institutional support for the research and development dealing with the understanding of mechanisms associated with the human biological aging process and translating these insights into safe, affordable and universally available applied technologies and treatments. October 1 - the International Day of Older Persons - provides the researchers and advocates an opportunity to raise these points and make these demands.

The Critical Need to Promote Research of Aging Around the World

Due to the aging of the global population and the derivative increase in aging-related non-communicable diseases and their economic burden, there is an urgent need to promote research on aging and aging-related diseases as a way to improve healthy and productive longevity for the elderly population. To accomplish this goal, we advocate the following policies: 1) Increasing funding for research and development specifically directed to ameliorate degenerative aging processes and to extend healthy and productive lifespan for the population; 2) Providing a set of incentives for commercial, academic, public and governmental organizations to foster engagement in such research and development; and 3) Establishing and expanding coordination and consultation structures, programs and institutions involved in aging-related research, development and education in academia, industry, public policy agencies and at governmental and supra-governmental levels.

The Tasks of Longevity Promotion: Science, Ethics and Public Policy - Potential presentation topics on longevity research

The task of healthy life extension, or healthy longevity extension, dictates a broad variety of questions and tasks, relating to science and technology, individual and communal ethics, and finally public policy, especially health and research policy. Despite the wide variety, the related questions may be classified into 3 groups.

The first group of questions concerns the feasibility of the accomplishment of life extension. Is it theoretically and technologically possible? What are our grounds for optimism? What are the means to ensure that the life extension will be healthy life extension?

The second group concerns the desirability of the accomplishment of life extension for the individual and the society, provided it will become some day possible through scientific intervention. How will then life extension affect the perception of personhood? How will it affect the availability of resources for the population?

Yet, the third and final group can be termed normative. What actions should we take? Assuming that life extension is scientifically possible and socially desirable, and that its implications are either demonstrably positive or, in case of a negative forecast, they are amenable - what practical implications should these determinations have for public policy, in particular health policy and research policy, in a democratic society? Should we pursue the goal of life extension? If yes, then how? How can we make it an individual and social priority?

Given the rapid population aging and the increasing incidence and burden of age-related diseases, on the pessimistic side, and the rapid development of medical technologies, on the optimistic side, these become vital questions of social responsibility.

Trends in technology and increasing wealth improve health due to greater access to better forms of medicine, but also tend to produce a fatter, less fit older population, a consequence of the broadening range of attractive and affordable transportation devices and calories. Gains from medicine compete in many people with the losses due to diminished personal fitness. This is very noticeable in countries like South Korea where the transition from poverty to wealth was rapid, taking place over just a handful of decades. Here researchers show similar trends in European populations:

People over age 50 are scoring increasingly better on tests of cognitive function, according to a new study. At the same time, however, the study showed that average physical health of the older population has declined. The study relied on representative survey data from Germany which measured cognitive processing speed, physical fitness, and mental health in 2006 and again in 2012. It found that cognitive test scores increased significantly within the 6-year period (for men and women and at all ages from 50 to 90 years), while physical functioning and mental health declined, especially for low-educated men aged 50-64. The survey data was representative of the non-institutionalized German population, mentally and physically able to participate in the tests.

Previous studies have found elderly people to be in increasingly good health - "younger" in many ways than previous generations at the same chronological age - with physical and cognitive measures all showing improvement over time. The new study is the first to show divergent trends over time between cognitive and physical function. "We think that these divergent results can be explained by changing lifestyles. Life has become cognitively more demanding, with increasing use of communication and information technology also by older people, and people working longer in intellectually demanding jobs. At the same time, we are seeing a decline in physical activity and rising levels of obesity."

A second study found similar results suggesting that older people have become smarter also in England. "On average, test scores of people aged 50+ today correspond to test scores from people 4-8 years younger and tested 6 years earlier." The studies both provide confirmation of the "Flynn effect" - a trend in rising performance in standard IQ tests from generation to generation. The studies show that changes in education levels in the population can explain part, but not all of the effect. "We show for the first time that although compositional changes of the older population in terms of education partly explain the Flynn effect, the increasing use of modern technology such as computers and mobile phones in the first decade of the 2000s also contributes considerably to its explanation."

Link: http://www.iiasa.ac.at/web/home/about/news/150831-pop-PLOSONE.html

The future of cancer research is targeting, meaning the ability to destroy cancer cells efficiently and with few to no side-effects on normal tissues. Chimeric antigen receptor (CAR) T-cells are a step forward in this regard, and have proven to be an effective treatment for leukemia in trials. Researchers are now attempting to adapt their use to other types of cancer. In this example, the T-cells are engineered to make them more discriminating when targeted at solid tumors:

Many solid cancers have high levels of certain proteins such as ErbB2 and EGFR, which make them suitable targets for anticancer therapies. However, such proteins are also present at low levels in normal cells. Because of this, CAR T cells that are developed to target one of these proteins on tumor cells also recognize and attack normal cells that have the protein, causing severe toxicity.

To develop CAR T cells that can distinguish between cancer and normal cells, researchers first constructed a panel of CARs with the single chain variable fragments (scFv) - the part of the CAR T cell that recognizes the tumor target - using sequences from mutated 4D5 antibodies that had varying affinities to ErbB2, a protein present at high levels in some solid tumors, including breast cancer. Next, they incorporated different scFvs into the CAR backbone or "construct," such that they resulted in a range of CAR T cells - from those that had high affinity to ErbB2 to those that had low affinity to ErbB2. The newly engineered CAR T cells varied in their affinity to ErbB2 by three orders of magnitude. The researchers then conducted a series of experiments to test the functionality of the affinity-tuned CAR T cells and found that high-affinity CAR T cells did not discriminate tumor cells from normal cells and attacked all of them, whereas low-affinity CAR T cells were sensitive to tumor cells that had high levels of ErbB2 and not to normal cells that had low levels of the protein.

Next, they tested the engineered CAR T cells in mice that bore human cells with high levels of ErbB2 on one side of their bodies and human cells with normal levels of ErbB2 on the other side of their bodies. Here again, low-affinity CAR T cells selectively eliminated cells that had high levels of ErbB2 but had no effect on cells that had normal levels of the protein. In order to prove that this technology can be extended to other solid tumor targets, the researchers developed low-affinity CAR T cells targeting EGFR, a protein present in high levels in some lung and colon cancers, among others, and preliminary preclinical results showed that these CAR T cells were able to discriminate between cancer cells and normal cells.

Link: http://www.eurekalert.org/pub_releases/2015-09/aafc-nec082815.php