The Healthspan Imperative

The Healthspan Campaign is more or less the voice of the Longevity Dividend viewpoint of the next few decades of aging research and its applications in clinical medicine. This alliance of advocates and researchers favor large increases in government funding of aging science through the National Institute on Aging and a consequent series of incremental increases in healthy life span. In this vision for tomorrow these increases would be driven by exactly the same sort of mainstream research into aging that has dominated for the past decade or two. By this I mean the standard issue drug discovery process, manipulating metabolism to modestly slow the pace of aging, investigation of the mechanisms of calorie restriction, forcing reversal of epigenetic changes in aging to restore stem cell populations to greater activity, and so forth. There is a little overlap between the Longevity Dividend and the much more ambitious rejuvenation research of SENS, but only a little - just a few areas in which there is common interest.

In the Longevity Dividend view, achieving an additional seven years of healthy life expectancy is an ambitious goal that will require billions in funding and two decades to achieve. I think this is probably about right if the field continues on the present path that characterizes mainstream aging research. Altering metabolism and epigenetic patterns is a very challenging, very expensive way to make slow progress towards treatments that will be of little use for people who are already old. What benefit in slowing down aging when you are already nearly aged to death? Further, the intersection of metabolism and aging is very poorly understood and enormously complex: the whole point of SENS and any similar repair-based approach to aging is that we can bypass most of that complexity by focusing on the known differences between old and young tissue. Just fix the damage, don't worry about exactly how it progresses in detail. Unfortunately the SENS view is not yet as popular in the research community as it deserves to be.

The Healthspan Campaign puts out a regular newsletter and is working on an long term advocacy campaign leading towards the end goal of much greater public funding and support among members of related institutional research organizations. To that end there is a fair amount of effort taking place to raising awareness among the public, and this tends to raise the water for all boats, whether the Longevity Dividend or initiatives like SENS with better prospects for producing meaningful results in our lifetimes. It is very important to have this outreach, in which researchers stand up and sign their names to the idea that we can do something about degenerative aging and thereby increase healthy life spans. Most of the public are either unaware of the potential, or reflexively opposed to longevity research because they think, wrongly, that it would mean being older for longer rather than younger for longer. So at this point every well-forged publicity effort such as this one below moves the needle for all initiatives:

The Healthspan Imperative

The Healthspan Imperative looks at our country's next great priority: solving the challenges brought about by the aging of the American population. Narrated by Emmy Award-winning television show host and bestselling author Martha Stewart, it features exclusive interviews from leading scientists and aging research experts.

For more than a century, the human race has enjoyed an unprecedented increase in its lifespan. Through advances in science and technology, many can expect to live life well into their 80s, 90s and beyond. But this increase in longevity has not come without consequences. With each passing year, the percentage of people in the United States - and much of the world - over age 65 increases. This "Silver Tsunami" is expected to bring a flood of chronic disease and disabilities of aging. A flood which could overwhelm the health care systems of many nations.

It's an issue that has come to the forefront of our national consciousness and a challenge that has been undertaken by some of the world's best scientists, doctors and professionals. The goal: Increase not just our lifespan but our healthspan, the length of time we spend free of the costly and harmful conditions of old age.

The Healthspan Imperative explores the challenges created by the longevity revolution. And the potential of aging research to turn back the clock. Not to make us older for a longer time, but so that we might enjoy more years of healthy, vigorous life. A clear call to action on an issue that affects everyone, The Healthspan Imperative will change the conversation on how we view aging.

More Context on the Goals of Human Longevity, Inc.

The company Human Longevity was recently founded to work on the genetics of aging and health. My thinking is that genetics is a hot field, and there is much to be done in the general context of medicine, but that insofar as longevity goes it is the wrong place to be looking for large benefits. Epigenetic and gene expression changes are secondary consequences in aging, not the root cause, and natural genetic variations have a small effect on aging in comparison to what might be possible through repair biotechnologies such as those of the SENS vision. So for aging the outcome of Human Longevity is likely to be incremental advances in the present day practice of ignoring the comparatively simple causes of degeneration, the accumulation of damage, while trying to patch over the very complex end states by tinkering with enormously complex dysregulations of metabolism and biological systems that occur in response to damage. This is doomed to only marginal success, just like the medicine of today.

Here is a piece that provides more context on where Human Longevity is headed in the near term: undoubtedly useful, just not so much for aging. We all age in the same way, due to the same root causes involving an accumulation of specific, known forms of damage to cells and molecular tissue structures. Fix those causes by repairing them and near all but the most rare and catastrophic genetic variations are irrelevant. They simply don't matter.

Genome scientist and entrepreneur J. Craig Venter is best known for being the first person to sequence his own genome, back in 2001. This year, he started a new company, Human Longevity, which intends to sequence one million human genomes by 2020. Venter says that he's sequenced 500 people's genomes so far, and that volunteers are starting to also undergo a battery of tests measuring their strength, brain size, how much blood their hearts pump, and, says Venter, "just about everything that can be measured about a person, without cutting them open." This information will be fed into a database that can be used to discover links between genes and these traits, as well as disease. But that's going to require some massive data crunching.

In my view there have not been a significant number of advances [in genomics]. One reason for that is that genomics follows a law of very big numbers. I've had my genome for 15 years, and there's not much I can learn because there are not that many others to compare it to. Until now, there's not been software for comparing my genome to your genome, much less to a million genomes. We want to get to a point where it takes a few seconds to compare your genome to all the others. It's going to take a lot of work to do that.

Understanding the human genome at the scale that we are trying to do it is going to be one of the greatest translation challenges in history. Everything in a cell derives from your DNA code, all the proteins, their structure, whether they last seconds or days. All that is preprogrammed in DNA language. Then it is translated into life. People are going to be very surprised about how much of a DNA software species we are.


Resistance to Oxidative Stress in Cells of Long-Lived Species

Here is a small slice of broader efforts to investigate and understand the range of differences in longevity and cellular biochemistry between species. It seems likely that these research programs will provide additional helpful information beyond that derived from the straightforward study of human biochemistry when it comes to work on treating aging:

Species differ greatly in their rates of aging. Among mammalian species life span ranges from 2 to over 60 years. Here, we test the hypothesis that skin-derived fibroblasts from long-lived species of animals differ from those of short-lived animals in their defenses against protein damage. In parallel studies of rodents, nonhuman primates, birds, and species from the Laurasiatheria superorder (bats, carnivores, shrews, and ungulates), we find associations between species longevity and resistance of proteins to oxidative stress after exposure to H2O2 or paraquat. In addition, baseline levels of protein carbonyl appear to be higher in cells from shorter-lived mammals compared with longer-lived mammals.

Thus, resistance to protein oxidation is associated with species maximal life span in independent clades of mammals, suggesting that this cellular property may be required for evolution of longevity. Evaluation of the properties of primary fibroblast cell lines can provide insights into the factors that regulate the pace of aging across species of mammals.


A Different Car Analogy for Increased Human Longevity

The car analogy that shows up most often in my circles relates to repair and the biological damage of aging. We, like cars, are machines. We differ only in complexity, and the same methods arising from reliability theory can be used to model progressive dysfunction and systems failure over time in both vehicles and people. Given sufficient tools and resources a car can be maintained in good working condition indefinitely, a Ship of Theseus pattern progressing forward into the indefinite future. This is something we could achieve now for any model of car in the world, but for the most part choose not to. The only reason we cannot presently achieve the same result for people is that we lack the tools, the rejuvenation toolkit outlined in the SENS research proposals, ways to repair the known forms of damage that distinguish old tissue from young tissue. In principle we could all become Ships of Theseus once rejuvenation therapies exist, with the unit of replacement being individual cells where the precise details of structure and molecular arrangements matter (largely in the brain) and anything up to whole organs elsewhere in the body. This is entirely possible and plausible, and given sufficient funding could arrive soon enough to matter for most of us.

This is the car analogy for rejuvenation research supporters, used as a way to help convince uninformed audiences skeptical about the prospects for prevention and reversal of aging. We can maintain cars, therefore it is reasonable to work on ways to maintain people. Insofar as thinking about maintenance goes, people and cars are basically the same class of entity. The rejuvenation research crowd are not the only set of folk thinking about extending life, however, and they are (unfortunately) far from the most numerous at this time. The majority of people inside and outside the scientific community with an interest in enhanced longevity think in terms of slowing aging and altering the operation of metabolism: incremental, small advances towards better operation of the human machine. In comparison to rejuvenation research vast sums are directed towards that goal, though it is still a very small field in comparison to medicine as a whole. As long-time readers will know by now, I think little of slowing aging as a goal: it is the expensive road to a near-useless end result. What good is slowing aging for those who are already old? Metabolism is fantastically complex and the prospects for significant progress in altering it to extend life are remote, judging by the time and money expended and lack of results obtained to date, and this is generally acknowledged as true by scientists in the field.

Outside the scientific community, people are more enthusiastic about the prospects to extend life by incremental advances in drugs, supplements, and other things I'd consider a pointless waste of time in comparison to the more serious modern applications of biotechnology in SENS research. These folk have their own car analogy, which is sketched in the post quoted below. It is a helpful read if you're looking to understand the mindset that has people chasing the mythical ever-better combination of supplements and prospective new ways to manipulate metabolism to slow aspects of aging:

What do we need to do to live longer, healthier lives? An editorial tale of cars and people

Can we expect to live longer and longer as the first part of this century rolls by? I think so, probably by a large amount. Will this extension of human lives be because of basic new scientific breakthroughs? Yes, but only in part. Collectively, such breakthroughs are likely to be important. Curiously though, I don't think that any single such breakthrough will make an immense difference. What will matter is a process issue, and whether and how such breakthroughs are applied is only one consideration.

So, how then will it happen? I argue here that extended longevity is likely to happen via a number of incremental steps,probably small ones at that. Most will involve improvements in lifestyle and diet. Others will involve selective application of stresses and consumption of health-producing phytosubstances and selected dietary supplements. I think you can move along the increasing longevity curve by pursuing a long string of incremental lifestyle and dietary modifications over time, each of which may seem to produce only modest results. Some steps may seem to be very tiny and insignificant, such as getting up from the computer and walking around a bit every hour.

Let's start by talking about, my grandmother's 1950 Chevy Bel Air, purchased new. . If you were middle class and lived in Detroit you were expected to turn your car in every year for a new car, or at least every 2-3 years. Most cars did not survive the junk heap for more than 4-5 years. A three-year-old car was a seriously old car and you could expect to put less than 50,000 miles on it before it died. [In contrast, consider] our 2005 Subaru Impreza which we purchased in 2004. Expected lifespan: 15-20 years, perhaps 200,000 miles. This 10 year old car is still healthy, vigorous and a reliable family workhorse with no known problems at 100,000 miles. No sign of rust.

What was the big scientific or technical breakthrough that made the difference in lifespan and performance between the earlier cars and our Subarus? Lifespan extension of a factor of at least four and MPG improvement by a factor of two? None! In fact, it wasn't any single big scientific or engineering breakthrough. The difference is because of thousands of incremental improvements made year after year in just about every component and system. Virtually everything has been improved to make cars more reliable, last longer and operate more economically.

To be clear, I think it is arrant nonsense to state, as the author does above, that we could incrementally move to doubling our life spans without the application of modern biotechnology, interventions that meaningfully and directly repair cellular damage. Not diet, not drugs, not random compounds dredged from the natural world because they turn out to do more good than harm, but designed applications of molecular machinery that achieve specific goals in our biochemistry, reverting most or all forms of low-level damage in and between our cells. This is a night and day difference in goals, ambition, and methodology. If you had a perfect diet and lifestyle, you'd still mostly likely die before age 90 in the environment of today's medical technology - because it is medical technology that overwhelmingly determines your life span, not your lifestyle.

Putting that aside, the rest of the article actually has little to do with specific implementation details and is more concerned with a vision of organized incremental improvement in life span. It is long and worth reading as a matter of interest.

A Review of Approaches to Delay Sarcopenia

Sarcopenia is the name given to age-related loss of muscle mass and and strength, although by the time it is processed through the regulatory system into a formal, final disease definition, it will be restricted to referring to only severe levels of loss. Average loss of muscle mass and strength will be called normal, just a part of aging, and therefore something that shouldn't be treated - and indeed, that it is forbidden to treat, as in regulatory systems like that of the FDA in the US, everything that is not explicitly permitted is illegal. This is a major systemic problem with the present system of medical regulation, one that has to be changed, and soon. It is no wonder that we see only slow progress in research and fundraising when treating degenerative aging is largely forbidden, especially any focus on causes and prevention rather than patching over late stage consequences after the fact.

Here is an open access review of a range of approaches in mainstream research aimed at slowing the onset and progression of sarcopenia, most of which haven't made it as far as drug development yet. As for so many of these topics it overwhelmingly focuses on alteration of metabolic processes rather than repair of root causes: slowing the progression of damage only, not reversing it.

The term sarcopenia was originally created to refer age-related loss of muscle mass with consequent loss of strength. There are now four international definitions of sarcopenia. In essence they all agree, requiring a measure of walking capability [either low gait speed or a limited endurance (distance) in a 6-min walk], together with an appendicular lean mass of [less than 2 standard deviations below] of a sex and ethnically corrected normal level for individuals 20-30 years old. Sarcopenia is a prevalent health problem among the elderly. On average, 5-13% and 11-50% of people aged 60-70 years and ≥80 years, respectively suffer sarcopenia with higher prevalences (68%) been reported in nursing home residents ≥70 years.

Sarcopenia needs to be differentiated from cachexia, which is a combination of both muscle and fat loss and is usually attributable to an excess of catabolic cytokines associated with a disease process. Sarcopenia is a prime component of the frailty syndrome, and both sarcopenia and frailty are associated with increased disability, falls, hospitalization, nursing home admission, and mortality.

Medical efforts to develop treatments aiming at preventing aging sarcopenia as well as acute muscle atrophy and frailty in critical patients are considered a step forward in public health. Several hormonal therapies have been proposed for this purpose. However, the secondary effects associated with these therapies make it necessary to find novel non-toxic and non-hormonal therapies. In this way, elderly or bedridden patients may improve muscle function and decrease the degree of dependence associated with these populations. New drugs such as allopurinol or losartan, all of them approved by the Food and Drugs Administration (FDA) and actually prescribed for the treatment of other diseases, could be useful in preventing loss of muscle mass in the described susceptible populations yet new pharmacological targets are needed.

As an essential step for the prevention of aging-related diseases, and specifically, sarcopenia, more basic research is needed on the main cellular hallmarks of muscle senescence. There is a plethora of potential molecular signals that are candidates to be targeted in future treatment strategies aiming at combating sarcopenia, a devastating effect of aging that is often overlooked.


A Review of Age-Related Macular Degeneration

Age related macular degeneration (AMD) is one of the first prospective targets for prototype rejuvenation treatments. This is because the relationship between the condition and one of the primary forms of change between young and old tissue is both direct and comparatively well understood: certain hardy metabolic waste compounds accumulate in long-lived retinal cells to cause increasing dysfunction over the timescale of a human life span, and this occurs because our cellular recycling machinery cannot effectively break down these compounds. The best solution is to develop drugs or make use of tools such as bacterial enzymes that can do this for us; comparatively few groups are working on this angle, however.

Ageing disorders can be defined as the progressive and cumulative outcome of several defective cellular mechanisms as well as metabolic pathways, consequently resulting in degeneration. Environment plays an important role in its pathogenesis. Age related macular degeneration (AMD) is one such retinal degenerative disorder which starts with the progression of age. Metabolism plays an important role in initiation of such diseases of ageing. Cholesterol metabolism and their oxidized products like 7-ketocholesterol have been shown to adversely impact retinal pigment epithelium (RPE) cells. These molecules can initiate mitochondrial apoptotic processes and also influence the complements factors and expression of angiogenic proteins like VEGF etc.

Age related macular degeneration (AMD) is described by irreversible vision loss in older age. The disease pathology emerges with the degeneration of macula which forms the central part of retina. The macula consists of photoreceptor (rods and cones) important for central vision. As AMD symptoms appear, characteristic features such as formation of drusen, consisting of active and inactive complement associated inflammatory products, aggregate of lipoprotein, cell debris, oxysterols, oxidized phospholipids and Alu RNA deposits begin to emerge later in life.

These aggregates deposit in the extra-cellular space between Bruch's membrane and retinal pigment epithelium cells (RPE). Gradual and consistent effects of these aggregates gradually cause degeneration of these cells followed by global atrophy of RPE cells, commonly known as geographic atrophy (GA). Besides, active inflammatory components of these deposits between Bruch's membrane and RPE, stimulate angiogenic factors (e.g., VEGF, TGFB etc.) which act on choriocapillary network beneath the Bruch's membrane and stimulate proliferation to new blood vessels (a process called neovascularization). These newly formed blood vessels can outgrow into the RPE cells and result in disruption of RPE cell integrity and function which is well preserved in early life.


Mitochondrially Targeted Antioxidants as a Way to Suppress Cancer Metastasis

The process of metastasis is why malign cancers of all sorts turn out to be fatal in the end: their cells spread throughout the body to establish new tumors and outpace the ability of present treatments to keep up. The promise of the near future of cancer medicine is largely predicated on its ability to deal with metastasis. One approach is the use of targeted cell killing technologies that recognize cancer cells by their surface chemistry, capable of chasing down errant cells wherever they are in the process of spreading or building tumors. I think this is likely the type of treatment that will dominate the next generation of cancer treatments, as a range of different approaches to targeting are presently well advanced in the laboratory and clinical trials: immune therapies, simple nanomachines, engineered viruses, and so forth.

Another approach is to interfere with the process of metastasis in order to shut it down or at least suppress it, which would make many types of cancer more amenable to successful treatment with present day standards of surgery, radiotherapy, and chemotherapy. There hasn't been a great deal of success in suppressing metastasis in comparison to development of means to target cancer cells, but nonetheless a few approaches have been attempted. In the paper quoted below, researchers suggest that use of mitochondrially targeted antioxidants might be effective as a means of reducing metastasis to very low levels. If this bears out, it may attract more interest in the development of these compounds, which have been demonstrated to modestly extend life in mice as well as showing promise as treatments for a range of conditions.

Mitochondrial DNA damage is implicated in the progression of aging, and one theory is that this damage is caused by the generation of reactive oxygen species (ROS) within the mitochondria in the course of ordinary operation. So in theory life-long treatment with mitochondrially targeted antioxidants, carefully engineered compounds quite different from the antioxidants you can buy in a supplement store, will extend life by soaking up some of those ROS before they cause harm. As an approach to extending life this is poor in comparison to methods of mitochondrial damage repair, however. It can only slow the progression of aging somewhat, not turn back the clock.

Researchers at UCL identify a treatment that prevents tumor metastasis

[Researchers have] succeeded in pinpointing a family of pharmaceutical compounds whose action prevents the appearance of tumor metastasis. The researchers achieved this tour de force by studying the mitochondria in tumor cells. These organelles are considered as the cells' power station. But when their functioning is altered, as [the] researchers observed in tumor cells, the mitochondria can promote cell migration, thus leading to the formation of metastasis.

[The researchers] examined the molecular mechanism responsible for the mitochondria's ability to promote metastasis. They succeeded in showing that, under certain conditions, the mitochondria produce more free radicals known as superoxide ions (O2.-). It is this overproduction of superoxide that leads to the formation of metastasis and, consequently, the growth of a tumor. Involved in other human pathologies such as Parkinson's and Alzheimer's disease, the production of superoxide by the mitochondria can be blocked by very specific antioxidants such as MitoTEMPO. Used in models of murine and human tumors, these compounds turned out to be very efficient at blocking the migration of tumor cells and preventing the spontaneous formation of human tumor metastasis in mice.

A Mitochondrial Switch Promotes Tumor Metastasis

Metastatic progression of cancer is associated with poor outcome, and here we examine metabolic changes underlying this process. Although aerobic glycolysis is known to promote metastasis, we have now identified a different switch primarily affecting mitochondria. The switch involves overload of the electron transport chain (ETC) with preserved mitochondrial functions but increased mitochondrial superoxide production. It provides a metastatic advantage phenocopied by partial ETC inhibition, another situation associated with enhanced superoxide production. Both cases involved protein tyrosine kinases Src and Pyk2 as downstream effectors. Thus, two different events, ETC overload and partial ETC inhibition, promote superoxide-dependent tumor cell migration, invasion, clonogenicity, and metastasis. Consequently, specific scavenging of mitochondrial superoxide with mitoTEMPO blocked tumor cell migration and prevented spontaneous tumor metastasis in murine and human tumor models.

Alcor Working on Field Perfusion for Remote Cryonics Cases

The state of infrastructure technologies in the cryonics industry is improving slowly over time. Most organizations in the community are volunteer based, which puts a greater burden on the few professional groups to work on research and development. Nonetheless, cryonics today is a more reliable undertaking than at any point in the past decades of its existence as an option, even if there is still a lot of room for improvement. That improvement can only arrive rapidly given an expansion of the industry, however, something that has stubbornly refused to occur for a long time now:

For decades Alcor has welcomed members residing overseas, and pledged to attempt to cryopreserve members who suffer legal death while traveling outside the United States. However options for responding to overseas cases have been very limited. Historically there has been a choice between shipping on water ice near 0 degrees Celsius (with or without blood replacement) and attempting subsequent cryoprotective perfusion at Alcor to eliminate or minimize ice formation, or so-called "straight freezing" to dry ice temperature of -79 degrees Celsius without cryoprotective perfusion and shipping to Alcor.

Cryoprotective perfusion after a prolonged period of cold ischemia is usually very difficult, typically leading to the difficult decision to "straight freeze" overseas cases to dry temperature prior to shipping. Freezing without cryoprotectant is extremely damaging to tissue. About all that can be said for it is that it is better than the alternative of not being cryopreserved at all.

There is now a better alternative. Alcor has developed a simple system for perfusing cryoprotectant solution in a remote field setting instead of requiring patients to first arrive at Alcor's facility. After completion of this field cryoprotection, patients can be cooled to dry ice temperature (-79 degC) for shipment to Alcor with less time urgency and a slower rate of biological damage than at 0 degrees. Once at Alcor, cooling is resumed to the temperature of liquid nitrogen (-196 degC) at which temperature tissue is stable for practically unlimited lengths of time.

Alcor's initial implementation of field cryoprotection is still crude compared to cryoprotective perfusion in Alcor's operating room. Temperature and pressure control are limited, the cryoprotectant concentration rises more rapidly than is ideal, and the perfusion time is comparatively brief. Very importantly, the present field cryoprotection procedure only perfuses the head and brain with cryoprotectant, so the body of whole body members receiving field cryoprotection will still be frozen without cryoprotectant. However, this is obviously a better outcome than the entire body, including the brain, being frozen without cryprotectant.


Considering Mitochondrial DNA Deletions in Skeletal Muscle

The organelles known as mitochondria play the role of power plant in the cell, generating energy stores to power cellular operations. As for all cellular components, mitochondria are built of proteins derived from DNA blueprints, but unlike all other cellular components mitochondria have their own DNA, separate from that in the cell nucleus. They are descendants of symbiotic bacteria, and continue to replicate like bacteria within our cells. Certain types of damage to mitochondrial DNA are one of the contributing causes of degenerative aging: mitochondria missing certain proteins become dysfunctional, ultimately taking over a small fraction of all cells by old age, and causing widespread harm in surrounding tissues.

In this paper researchers consider the process by which one bad mutation in one mitochondrion eventually fills the cell with duplicates of itself. This is one of the areas in which there is plenty of room for argument: does it happen because it confers the ability to replicate more readily, because it allows damaged mitochondria to evade quality control mechanisms, or for some other reason? As is often the case negative results in studies still add information to the overall picture:

Large-scale mitochondrial DNA (mtDNA) deletions are an important cause of mitochondrial disease, while somatic mtDNA deletions cause focal respiratory chain deficiency associated with ageing and neurodegenerative disorders. As mtDNA deletions only cause cellular pathology at high levels of mtDNA heteroplasmy, an mtDNA deletion must accumulate to levels which can result in biochemical dysfunction - a process known as clonal expansion. A number of hypotheses have been proposed for clonal expansion of mtDNA deletions, including a replicative advantage for deleted mitochondrial genomes inferred by their smaller size - implying that the largest mtDNA deletions would also display a replicative advantage over smaller mtDNA deletions.

We proposed that in muscle fibres from patients with mtDNA maintenance disorders, which lead to the accumulation of multiple mtDNA deletions, we would observe the largest mtDNA deletions spreading the furthest longitudinally through individual muscle fibres by means of a greater rate of clonal expansion. We characterized mtDNA deletions in patients with mtDNA maintenance disorders from a range of 'large' and 'small' cytochrome c oxidase (COX)-deficient regions in skeletal muscle fibres. We measured the size of clonally expanded deletions in 62 small and 60 large individual COX-deficient f regions. No significant difference was observed in individual patients or in the total dataset. Thus no difference existed in the rate of clonal expansion throughout muscle fibres between mtDNA deletions of different sizes; smaller mitochondrial genomes therefore do not appear to have an inherent replicative advantage in human muscle.


Fundraising Update: $96,000 in the Matching Fund for October

In October we'll be kicking off a grassroots fundraiser to support SENS research programs, work that is aimed at removing the technical roadblocks preventing greater funding and interest in rejuvenation research. At present we are raising a matching fund for that fundraiser, and are seeking matching fund founders. As you can see from the title, we have met with some success - but I think we can do better yet. So help us out here. Join in and push this matching fund to a nice round number at the very least. Here are the folk who have donated so far:

  • Christophe and Dominique Cornuejols
  • David Gobel (Methuselah Foundation)
  • Dennis Towne
  • Håkon Karlsen
  • Jason Hope
  • Michael Achey
  • Michael Cooper
  • Reason (Fight Aging!)

From Håkon Karlsen:

Aging will be cured at some point in time. Of that there is little doubt. Until it is cured, however, a hundred thousand lives are being lost every single day, due to aging. That's more than 35 million people in a year. Nothing even comes close to killing as many people. Curing aging may thus help billions of people avoid the many years of suffering and pain that the age related diseases often cause. Let's try to cure aging now, it might just save (or, at least, greatly improve) your life, or the life of someone you care about. Please consider making a donation to the SENS Research Foundation.

From Michael Achey:

As a primary care physician, I watch the effects of aging every day. In practice for 27 years I have observed many a healthy, hearty, happy person gradually falter physically, dwindle mentally, and give up socially. Many of the diseases responsible for the senescence and death of us folks will be solved in the process of understanding causes of aging. From a strictly selfish standpoint (me and my kids) and a global perspective, I look forward to a day when a human body can live a couple hundred or more years to travel "Where No Man Has Gone Before!"

What is rejuvenation research? By rejuvenation here I mean repair and reversal of the underlying causes of aging: the various forms of cellular and molecular damage that accumulate over time in your tissues, disrupting function, and spawning all sorts of further forms of harm and dysfunction. Like rust in complex metal structures, the many varied failures suffered by old people result from what are comparatively simple root causes.

A great deal is known about these causes of aging, despite the fact that the scientific community argues incessantly over which are more important and how exactly they relate to specific age-related diseases. We can talk in detail about mitochondrial DNA damage, accumulation of senescent cells, build up of misfolded proteins called amyloids between cells and metabolic waste called lipofuscin within cells, harmful cross-links that gum together important proteins, and so forth. For all these forms of damage there exist research plans that lead to plausible treatments. In most cases there is a trickle of progress towards establishing these solutions, ways to reverse damage accumulation and remove the harm that has been done already in old people. That trickle must become a flood if we are to see significant progress towards reversal of aging and defeat of age-related disease in our lifetimes. The first prospective treatments don't even have to fix everything - they just have to fix most of the harm in every category. We go through life in our thirties to our fifties with a fair level of damage, but comparatively low mortality rates: there is a threshold past which things spiral downwards, and for so long as we can maintain ourselves beneath that threshold of damage then we are set for a long term of health and vigor without pain or suffering or disability.

This is why it is important to raise funds for well-run organizations like the SENS Research Foundation, groups that are in a position to remove the roadblock that prevents the small amount of research today from becoming a large amount of research tomorrow. Invariably there is a tipping point in any line of research: before the point is reached every for-profit investor and institutional research fund will look for something else that is further along, with less risk. After the tipping point, the early pioneers are quickly buried and forgotten beneath a torrent of funding and mainstream research interest. Our job is to move SENS rejuvenation research to the tipping point: fund the work that builds the toolkits, the proofs of concept, the initial databases, and all the other comparatively simple, low cost items that are yet pending. We want to be buried in interest: bring it on. Biotechnology is cheap these days; a smart young researcher can undertake significant cutting edge prototype work in medical research in six months and for a few tens of thousands of dollars given an established lab to work in.

What is the greatest difference you can make in the world? To my eyes it is saving as many lives and preventing as much pain as possible. Aging and the death and suffering it causes is the worst thing we suffer, and far more should be done to stop it than is present being accomplished. If you agree with me on this point, then step up and help to do something about it! Make the world a better place in one of the few ways that will touch everyone.

Rapamycin and Its Effects on mTORC1 and mTORC2

The immunosuppressant compound rapamycin has been demonstrated to slow aging in mice, though with unpleasant side-effects, and some debate over whether this is in fact a slowing of aging or just a reduction in cancer incidence. The present consensus on its mode of operation is that it produces longevity-related effects by suppressing the generation of two protein complexes, mTORC1 and mTORC2, both of which include the mTOR protein that has long been associated with rapamcyin. Of these two complexes, the effects of lowered levels of mTORC1 are better understood and more clearly beneficial. Here researchers delve into mechanisms associated with mTORC2, which are much more of a mixed bag. For the research groups involved in this work, the goal is to design new drugs that only trigger the beneficial alterations from the full set of those induced by rapamycin:

The nematode worm Caenorhabditis elegans provides a powerful system for elucidating how genetic, metabolic, nutritional, and environmental factors influence aging. The mechanistic target of rapamycin (mTOR) kinase is important in growth, disease, and aging and is present in the mTORC1 and mTORC2 complexes. In diverse eukaryotes, lifespan can be increased by inhibition of mTORC1, which transduces anabolic signals to stimulate protein synthesis and inhibit autophagy. Less is understood about mTORC2, which affects C. elegans lifespan in a complex manner that is influenced by the bacterial food source. mTORC2 regulates C. elegans growth, reproduction, and lipid metabolism by activating the SGK-1 kinase, but current data on SGK-1 and lifespan seem to be conflicting.

Here, by analyzing the mTORC2 component Rictor (RICT-1), we show that mTORC2 modulates longevity by activating SGK-1 in two pathways that affect lifespan oppositely. RICT-1/mTORC2 limits longevity by directing SGK-1 to inhibit the stress-response transcription factor SKN-1/Nrf in the intestine. Signals produced by the bacterial food source determine how this pathway affects SKN-1 and lifespan. In addition, RICT-1/mTORC2 functions in neurons in an SGK-1-mediated pathway that increases lifespan at lower temperatures.

RICT-1/mTORC2 and SGK-1 therefore oppose or accelerate aging depending upon the context in which they are active. Our findings reconcile data on SGK-1 and aging, show that the bacterial microenvironment influences SKN-1/Nrf, mTORC2 functions, and aging, and identify two longevity-related mTORC2 functions that involve SGK-regulated responses to environmental cues.


More on Klotho and Neurodegeneration

High levels of the protein produced by the klotho gene are associated with longevity in mammals, and recently it has also been associated with greater cognitive performance. Here is another small piece of evidence to add to all that:

Alzheimer's disease (AD) is the most frequent age-related dementia affecting 5.4 million Americans including 13 percent of people age 65 and older and more than 40 percent of people over the age of 85. In AD the cognitive decline and dementia result from the death of nerve cells that are involved in learning and memory. The amyloid protein and the excess of the neurotransmitter glutamate are partially responsible for the neuronal demise.

Nerve cells were grown in petri dishes and treated with or without Klotho for four hours. Amyloid or glutamate then were added to the dish for 24 hours. In the dishes where Klotho was added, a much higher percentage of neurons survived than in the dishes without Klotho. "Finding a neuroprotective agent that will protect nerve cells from amyloid that accumulates as a function of age in the brain is novel and of major importance. We now have evidence that if more Klotho is present in the brain, it will protect the neurons from the oxidative stress induced by amyloid and glutamate."

Klotho is a large protein that cannot penetrate the blood brain barrier so it can't be administered by mouth or injection. However in a separate study the researchers have identified small molecules that can enter the brain and increase the levels of Klotho. "We believe that increasing Klotho levels with such compounds would improve the outcome for Alzheimer's patients, and if started early enough would prevent further deterioration. This potential treatment has implications for other neurodegenerative diseases such as Parkinson's, Huntington's, ALS and brain trauma, as well."


Correlations in Dysfunction Abound in Aging

Aging is a global phenomenon, the spiraling consequences of underlying damage that accumulate in every organ and biological system of the body concurrently. Becoming damaged is a matter of wear and tear; it is a side-effect of the operation of metabolism. Over most of life and for most people at a given age environmental factors make up the largest difference in the pace of aging from individual to individual: who takes care of their health; who becomes fat; who fails to exercise; and so forth. When compared with the differences caused by advances in medical technology, this is small change, however - not something to spend too much time worrying about. Live a sensibly healthy life, and where you do have time and energy for doing more, focus on helping to create new forms of medicine that can break us out of the old traditional length of life, adding decades to healthy life span while preventing and curing the diseases of old age.

Given that aging is a global process, it is comparatively easy to identify correlations between specific forms of dysfunction. If you are further along in failing health in one way, then the odds are very good that the same is true of all every other measure of aging as well. Chronic diseases of aging, and the general loss of function and health that precede them, tend to come in clusters. Everything is failing at once, and then in the end it is just a roll of the dice as to which fatal event happens first. One day people will look back on the ugly realities of aging as we look back on the ugly realities of infectious disease in past centuries. How did they bear it? Why was there any acceptance at all of such widespread death and suffering? Why didn't they try harder to build the medical and other technologies needed to escape that state of affairs?

While you ponder that, here are a few recent examples of correlations in aging and longevity:

Association of exceptional parental longevity and physical function in aging

Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevity-associated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited.

The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance and gait speed. Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.

Slow walking speed and memory complaints can predict dementia

"As a young researcher, I examined hundreds of patients and noticed that if an older person was walking slowly, there was a good chance that his cognitive tests were also abnormal. This gave me the idea that perhaps we could use this simple clinical sign - how fast someone walks - to predict who would develop dementia."

[Researchers] reported on the prevalence of motoric cognitive risk syndrome (MCR) among 26,802 adults without dementia or disability aged 60 years and older enrolled in 22 studies in 17 countries. A significant number of adults - 9.7 percent - met the criteria for MCR (i.e., abnormally slow gait and cognitive complaints). While the syndrome was equally common in men and women, highly educated people were less likely to test positive for MCR compared with less-educated individuals. A slow gait is a walking speed slower than about one meter per second, which is about 2.2 miles per hour (m.p.h.). Less than 0.6 meters per second (or 1.3 m.p.h.) is "clearly abnormal."

To test whether MCR predicts future dementia, the researchers focused on four of the 22 studies that tested a total of 4,812 people for MCR and then evaluated them annually over an average follow-up period of 12 years to see which ones developed dementia. Those who met the criteria for MCR were nearly twice as likely to develop dementia over the following 12 years compared with people who did not.

Association of Hearing Impairment and Mortality in Older Adults

Hearing impairment (HI) is highly prevalent in older adults and is associated with social isolation, depression, and risk of dementia. Whether HI is associated with broader downstream outcomes is unclear. We undertook this study to determine whether audiometric HI is associated with mortality in older adults.

Prospective observational data from 1,958 adults ≥70 years of age from the Health, Aging, and Body Composition Study were analyzed using Cox proportional hazards regression. Participants were followed for 8 years after audiometric examination. Mortality was adjudicated by obtaining death certificates. Of the 1,146 participants with HI, 492 (42.9%) died compared with 255 (31.4%) of the 812 with normal hearing. After adjustment for demographics and cardiovascular risk factors, HI was associated with a 20% increased mortality risk compared with normal hearing. Confirmatory analyses treating HI as a continuous predictor yielded similar results, demonstrating a nonlinear increase in mortality risk with increasing HI.

Restoring Function in Spinal Cord Injury

Researchers are making progress on a variety of ways to encourage nerve regrowth in mammals where it normally doesn't occur, such as in the aftermath of spinal injuries:

A therapy combining salmon fibrin injections into the spinal cord and injections of a gene inhibitor into the brain restored voluntary motor function impaired by spinal cord injury. In a study on rodents, [researchers] achieved this breakthrough by turning back the developmental clock in a molecular pathway critical to the formation of corticospinal tract nerve connections and providing a scaffold so that neuronal axons at the injury site could grow and link up again.

Axons flourish after the deletion of an enzyme called PTEN, which controls a molecular pathway regulating cell growth. PTEN activity is low during early development, allowing cell proliferation. PTEN subsequently turns on, inhibiting this pathway and precluding any ability to regenerate. Salmon fibrin injected into rats with spinal cord injury filled cavities at the injury site, giving axons a framework in which to reconnect and facilitate recovery. Fibrin is a stringy, insoluble protein produced by the blood clotting process and is used as a surgical glue.

In their study, [the researchers] treated rodents with impaired hand movement due to spinal cord injury with a combination of salmon fibrin and a PTEN inhibitor called AAVshPTEN. A separate group of rodents got only AAVshPTEN. The researchers saw that rats receiving the inhibitor alone did not exhibit improved motor function, whereas those given AAVshPTEN and salmon fibrin recovered forelimb use involving reaching and grasping. "The data suggest that the combination of PTEN deletion and salmon fibrin injection into the lesion can significantly enhance motor skills by enabling regenerative growth of corticospinal tract axons."


Stemness of Central Memory T Cells

This research suggests that some aspects of re-engineering an age-damaged immune system to restore its performance may be easier than expected. It is also supportive of work on immune cell transplant therapies as cancer treatments that has taken place over the past few years, as well as a range of other existing and potential immune therapies:

Researchers have proven for the first time that specific individual cells of the immune system, termed central memory T cells, have all the essential characteristics of adult tissue stem cells. Such cells are capable of perpetuating themselves indefinitely as well as generating diverse offspring that can reconstitute "tissue" function. These findings indicate that it should be possible to fully restore specific immunity to pathogens in patients with a compromised immune system by substitution of small numbers of central memory T cells.

The researchers first established that a high potential for expansion and differentiation in a defined subpopulation, called "central memory T cells," does not depend exclusively on any special source such as bone marrow, lymph nodes, or spleen. This supported but did not yet prove the idea that certain central memory T cells are, effectively, adult stem cells. Further experiments, using and comparing both memory T cells and so-called naive T cells - that is, mature immune cells that have not yet encountered their antigen - enabled the scientists to home in on stem-cell-like characteristics and eliminate other possible explanations.

Step by step, the results strengthened the case that the persistence of immune memory depends on the "stemness" of the subpopulation of T cells termed central memory T cells: Individual central memory T cells proved to be "multipotent," meaning that they can generate diverse types of offspring to fight an infection and to remember the antagonist. Further, these individual T cells self-renew into secondary memory T cells that are, again, multipotent at the single-cell level. And finally, individual descendants of secondary memory T cells are capable of fully restoring the capacity for a normal immune response.

One implication is that future immune-based therapies for cancers and other diseases might get effective results from adoptive transfer of small numbers of individual T cells. "In principle, one individual T cell can be enough to transfer effective and long-lasting protective immunity for a defined pathogen or tumor antigen to a patient. These results are extremely exciting and come at a time when immunotherapy is moving into the mainstream as a treatment for cancer and other diseases. The results provide strong experimental support for the concept that the efficacy and durability of T cell immunotherapy for infections and cancer may be improved by utilizing specific T cell subsets."


An Interview with Thiel Fellow Thomas Hunt

One part of the mission of the SENS Research Foundation is to help build the next generation of motivated biogerontologists, scientists who see aging and longevity research as a cutting edge field in which there is a tremendous opportunity for both professional growth and the ability to save lives and improve health. These are the presently young people who will be at the height of their careers twenty years from now, leading varied research groups to complete the first comprehensive rejuvenation toolkit and demonstrating robust reversal of aging in mice. These dedicated researchers of the future won't spring forth from nothing, however, in just the same way as widespread support and funding for the defeat of age-related disease won't arrive fully formed from out of the void. It requires a lot of work and planning to nurture a new field of science, and hence we see the existence of funding for programs such as the Summer Scholars, intended to bring together exceptional life science students and given them the opportunity to join the growing SENS research network.

Long-term and short-term, it is networking that makes the world go round. A lot of this is hidden from the outside; funding and progress just seems to happen of its own accord if you read press releases and newspapers. But behind every printed story lie years of connections, relationships, persuasion, and networking between researchers, funding sources, and advocates. Nothing happens that is not a part of a web of connections.

The SENS Research Foundation has its headquarters in the Bay Area, California, and is very much a part of the highly connected communities of aging research, technology talent, and venture capital that exist in that part of the world. There are several world-class institutes focused on the biology of aging in the Bay Area alone, and more in Southern California. The SENS principals move in the same network that links Google Ventures, the aging researchers being hired for the California Life Company initiative, Peter Thiel's initiatives in advocacy and philanthropy, biotech-focused venture firms, and a collection of further eclectic, intelligent, and motivated individuals who believe in the ability of technological progress to change the world for the better. Building new forms of medicine to treat aging, and the SENS engineering approach of damage repair in particular, has always played well with the technology crowd. Many of the early supporters of SENS are technology industry people: entrepreneurs, software developers, hardware designers.

So one consequence of this highly networked environment is that you will see numerous eclectic, intelligent, and motivated individuals involved with the SENS Research Foundation as the years roll by. That has included a number of very young and highly talented folk who started serious research careers in their early teens and went on to become Thiel Fellows, such as Laura Deming and more recently Thomas Hunt:

The Youngest Thiel Finalist: SRF's Thomas Hunt

At just 15, Thomas Hunt became the youngest 20Under20 Finalist selected by Peter Thiel's Foundation to compete for a $100,000 Fellowship and the chance at two years of freedom to pursue his dreams. But Thomas's entire story is even more amazing. He's been conducting research here at SENS Research Foundation in Mountain View since the age of 13.
Before I joined SRF, I started out as a curious and active member of the Do-It-Yourself (DIY) bio community. As a young teen, I got involved with BioCurious in its earliest days to help build the BioCurious lab. I also participated in other organizations like the Health Extension Salon and Thiel Fellowship Under20 Summits before applying for a 20Under20 Fellowship this past year.

Currently I volunteer at SRF four days a week. I spend my time conducting research to understand a poorly understood pathway that plays a key role in cancer cell immortality called alternative lengthening of telomeres, or ALT. I keep current with new developments in my field by reading scientific papers at the cutting edge of ALT work, and I am currently in charge of studying POT1, a protein that could negatively affect ALT activity. I am also performing experiments on cancer cells to test for ALT activity.

When I'm not at SRF, I've designed my own home schooling curriculum, where I get to choose which subjects I want to study. I take local college classes that I feel will assist me in my research goals, like chemistry and public speaking. I love telling people about the latest discoveries in science, and have spoken at The University of California, Santa Cruz (UCSC) about genetic modification.

Advocacy for Longevity Science Can Take Many Forms

Advocacy for the cause of longevity science doesn't have to mean writing or getting up in front of people to give presentations. There are many ways in which you can go about changing the way in which the rest of the world thinks about aging, so as to grow support for rejuvenation research. Here, for example, delivery of the message is via a simple game about achieving actuarial escape velocity, the point past which advances in medical science add more than one year of additional future life expectancy for each year that passes, thus enabling indefinite healthy life spans.

At the moment the present approach to medicine produces a gain of one year every decade in life expectancy at 60, so there is a great deal of work yet to accomplish. That work will only happen rapidly enough to benefit most of those reading this today in an environment of widespread public understanding and support, but that doesn't exist yet either. Hence the need for advocacy:

The premise of LEV: The Game is the same as the aim of those of us who wish to extend our lives without end. One's character is challenged with living for as long as possible and attaining longevity escape velocity by reversing the damage of senescence at a faster rate than it accumulates. Every year in the game, the character receives an allotment of energy points with which to purchase power-ups, such as stem-cell therapies, applications of nano-medicine, cybernetic enhancements, or simple increments of diet and exercise. Each power-up can either increase the remaining expected lifespan, increase the rate at which energy points accumulate (called "productivity" in the game), or reduce the character's rate of bodily decay. The player needs to achieve a delicate balancing of these power-ups to avoid expiring before he/she accumulates enough energy points to purchase the next life-extending advance.

Our ability to achieve indefinite life extension personally will depend on the amount of resources and support from the general public invested in the overcoming of age-related bodily damage. Most people, unfortunately, continue to either be resigned to the inevitability of death, or to argue against the desirability of indefinite longevity due to extremely basic misconceptions. Even apart from the absurdly false boredom argument, overpopulation argument, and "playing God" argument, there is a more basic fallacy - the Tithonus error, which posits that becoming chronologically older necessarily means becoming biologically more decrepit. Yet the only way indefinite longevity could be achieved would be for people to remain biologically young, so that their susceptibility to deadly diseases does not increase beyond that of people in their twenties today. How could longevity advocates get the general public to understand this? Convincing people through arguments alone may often fail, simply because the Dragon-Tyrant of death is so ubiquitous and so overwhelming that many people will grasp at any straw, no matter how flimsy, to avoid being confronted with the grave injustice of their current predicament.

But a game gives a fresh, different, and engaging way to see and experience what indefinite longevity would truly entail. Anyone playing LEV: The Game would quickly see that becoming increasingly frail is no way to increase life expectancy. Your character will die if he/she experiences sufficient biological decay. You will be able to see a graph of the character's remaining life expectancy and the rate at which decay is expected to proceed during the years they have left. If you apply the most effective combinations of power-ups, you will also see the life-expectancy curve shift upward - sometimes slightly, at other times by massive jumps. The latter situation reflects what can happen once humans begin to undergo periodic rejuvenation therapies to remove age-related damage, as posited in Dr. Aubrey de Grey's SENS approach.

Furthermore, LEV: The Game encourages its players to engage in paradigm-shifting thinking about their own future trajectories. Instead of planning for gradual debilitation and eventual death, as most people do today when projecting their careers, retirements, finances, and family lives, a strikingly different mindset can take hold - the quest for perpetual maintenance and a return to youthfulness that may be possible at any chronological age, with sufficient technological advances and vigilance regarding one's health.


Immune Surveillance of Mitochondrial DNA Deletions?

Regular readers will know that mitochondrial DNA damage is thought to be an important contributing cause of aging. It can lead to dysfunctional mitochondria that overtake cells and turn them into exporters of damaging reactive compounds, harming both surrounding tissues and important proteins that circulate widely in the body.

This is a fascinating paper that suggests the immune system has evolved to detect the presence of mitochondrial DNA deletions and destroy the cells that harbor those damaged mitochondria. Assuming this holds up there are several ways one could interpret this mechanism: firstly that mitochondrial DNA damage is less important than thought because there are more processes controlling it; or secondly that it is more important because it will lead to increased inflammation and immune system activation, which is a serious issue in later life; and either way thirdly that the age-related decline of the immune system should be considered more important because here is yet another fundamental aspect of aging that it influences.

Mutations in mitochondrial (mt) DNA accumulate with age and can result in the generation of neopeptides. Immune surveillance of such neopeptides may allow suboptimal mitochondria to be eliminated, thereby avoiding mt-related diseases, but may also contribute to autoimmunity in susceptible individuals. To date, the direct recognition of neo-mtpeptides by the adaptive immune system has not been demonstrated.

In this study we used bioinformatics approaches to predict major histocompatibility complex binding of neopeptides identified from known deletions in mtDNA. Six such peptides were confirmed experimentally to bind to HLA-A*02. Pre-existing human CD4+ and CD8+ T cells from healthy donors were shown to recognize and respond to these neopeptides. One remarkably promiscuous immunodominant peptide (P9) could be presented by diverse MHC molecules to CD4+ and/or CD8+ T cells from 75% of the healthy donors tested.

The common soil microbe, Bacillus pumilus, encodes a 9-mer that differs by one amino acid from P9. Similarly, the ATP synthase F0 subunit 6 from normal human mitochondria encodes a 9-mer with a single amino acid difference from P9 with 89% homology to P9. T cells expanded from human peripheral blood mononuclear cells using the B. pumilus or self-mt peptide bound to P9/HLA-A2 tetramers, arguing for cross-reactivity between T cells with specificity for self and foreign homologs of the altered mt peptide.

These findings provide proof of principal that the immune system can recognize peptides arising from spontaneous somatic mutations and that such responses might be primed by foreign peptides and/or be cross-reactive with self.

Looking back in the Fight Aging! archives, I see a paper from a couple of years ago in which researchers link inflammation in aging with mitochondrial damage, but via the mechanism of reactive oxygen species production. That seems worth another look in light of the above recent research.


More Researchers are Calling for Efforts to Treat Aging

The aging research community of today is a far cry from that of fifteen years ago. At that time, it was pretty close to career suicide to openly talk about aging as a medical condition amenable to treatment, or tackling the causes of aging to extend healthy life. Few people could get away with it, and those that were attempting to improve the field and open up the doors to clinical applications were largely doing so quietly in order to preserve their work. That sorry state of affairs had persisted for decades by that point, slowing down progress: scientists were not encouraging the view that treating aging was possible, archly conservative funding institutions made it clear there were no resources for that work, and there was no public pressure to see results because the public remained largely ignorant of the possibilities. It was a self-reinforcing deadlock, one that exists in many areas of potential improvement in technology, but here it was been particularly damaging because the cost of aging is so high: a hundred thousand lives lost every day, and countless more suffering from age-related diseases.

The sea change in aging research that has taken place between the turn of the century and today didn't happen by accident. It was the result of hard work and persistence on the part of numerous organizations and outspoken advocates within and without the scientific community. A number of those advocates, most notably Aubrey de Grey, were so horrified by the state of affairs in the aging community that they became scientists in order to try to set matters to rights. Many of us here have supported some of the organizations that helped to bring this all about, such as the Methuselah Foundation and SENS Research Foundation.

The results of all this work have been taking form over the past few years in the mainstream aging research community: plans and intent for the next decade of research strategy are becoming clear, and many more researchers are standing up to declare that treating aging is the way to go. Of course there are as many specific approaches as there are research groups, and nowhere near as many scientists as I'd like are jumping on the SENS bandwagon, but in many ways the most important change is that the voices of the community are now coming around to persuade the public and funding institutions that we should treat aging as the medical condition it is, and do something about it. At that point may the best approach win.

Here is an example that is much closer to the Longevity Dividend approach of modestly slowing aging than the SENS vision for rejuvenation through repair of the cellular damage that causes aging, but again it is progress to have this sort of open, public declaration of intent by noted researchers. It is a sign that we advocates will see a growing number of allies when it comes to convincing the remaining majority of the public that treating aging and extending healthy life is plausible, possible, and desirable.

Strategy proposed for preventing diseases of aging

Medicine focuses almost entirely on fighting chronic diseases in a piecemeal fashion as symptoms develop. Instead, more efforts should be directed to promoting interventions that have the potential to prevent multiple chronic diseases and extend healthy lifespans. Researchers say that by treating the metabolic and molecular causes of human aging, it may be possible to help people stay healthy into their 70s and 80s. A trio of aging experts calls for moving forward with preclinical and clinical strategies that have been shown to delay aging in animals. In addition to promoting a healthy diet and regular exercise, these strategies include slowing the metabolic and molecular causes of human aging, such as the incremental accumulation of cellular damage that occurs over time.

The researchers, at Washington University School of Medicine in St. Louis, Brescia University in Italy, the Buck Institute for Aging and Research and the Longevity Institute at the University of Southern California, write that economic incentives in biomedical research and health care reward treating disease more than promoting good health. "You don't have to be a mathematician or an economist to understand that our current health care approach is not sustainable. As targeting diseases has helped people live longer, they are spending more years being sick with multiple disorders related to aging, and that's expensive."

It's been difficult to capitalize on research advances to stall aging in people. Most clinicians don't realize how much already is understood about the molecular mechanisms of aging and their link to chronic diseases. And scientists don't understand precisely how the drugs that affect aging pathways work. The time is right for moving forward with preclinical and clinical trials of the most promising findings from animal studies. But challenges abound. The most important change is in mindset. Economic incentives in biomedical research and health care reward treating diseases more than promoting good health. "But public money must be invested in extending healthy lifespan by slowing aging. Otherwise, we will founder in a demographic crisis of increased disability and escalating health care costs."

More Physically Aged People Have a Lower Life Expectancy

Aging is no more than damage at the level of cells and tissues and the evolved reactions of biological systems to that damage, not all of them helpful. The pace of damage accumulation is largely determined by lifestyle and environmental factors such as burden of infectious disease and available medical technology over most of a human life span. Only in very old age do common genetic differences rise in importance. Thus if you find that someone at a given chronological age is more frail and is suffering from more evident age-related conditions than their peers, you would expect them to have a shorter remaining life expectancy, since they are more damaged. That is the way it works:

We analyze life expectancy in Medicare beneficiaries by number of chronic conditions [in a] retrospective cohort study using single-decrement period life tables. [The subjects are] Medicare fee-for-service beneficiaries (N=1,372,272) aged 67 and older as of January 1, 2008.

Our primary outcome measure is life expectancy. We categorize study subjects by sex, race, selected chronic conditions (heart disease, cancer, chronic obstructive pulmonary disease, stroke, and Alzheimer disease), and number of comorbid conditions. Comorbidity was measured as a count of conditions collected by Chronic Conditions Warehouse and the Charlson Comorbidity Index.

Life expectancy decreases with each additional chronic condition. A 67-year-old individual with no chronic conditions will live on average 22.6 additional years. A 67-year-old individual with 5 chronic conditions and ≥10 chronic conditions will live 7.7 fewer years and 17.6 fewer years, respectively. The average marginal decline in life expectancy is 1.8 years with each additional chronic condition - ranging from 0.4 fewer years with the first condition to 2.6 fewer years with the sixth condition. These results are consistent by sex and race. We observe differences in life expectancy by selected conditions at 67, but these differences diminish with age and increasing numbers of comorbid conditions.


Speculating on a Viral Cause of Parkinson's Disease

Parkinson's disease is characterized by the progressive loss of a small population of dopamine-generating neurons in the brain. This loss happens to everyone, but progresses much faster and further in Parkinson's sufferers, for reasons that are still not fully understood. Here is a speculative paper in which researchers suggest that there are viral and autoimmune mechanisms at work:

Current concepts regarding the pathogenesis of Parkinson's disease support a model whereby environmental factors conspire with a permissive genetic background to initiate the disease. The identity of the responsible environmental trigger has remained elusive. There is incontrovertible evidence that aggregation of the neuronal protein alpha-synuclein is central to disease pathogenesis.

A novel hypothesis of Parkinson's pathogenesis implicates a pathogen acting in the olfactory mucosa and gastrointestinal tract as the inciting agent. In this point-of-view article, we hypothesize that α-synuclein aggregation in Parkinson's disease is an Epstein-Barr virus (EBV)-induced autoimmune phenomenon. Specifically, we have shown evidence for molecular mimicry between the C-terminal region of α-synuclein and a repeat region in the latent membrane protein 1 encoded by EBV.

We hypothesize that, in genetically-susceptible individuals, anti-EBV latent membrane protein antibodies targeting the critical repeat region cross react with the homologous epitope on α-synuclein and induce its oligomerization. We contend that axon terminals in the lamina propria of the gut are among the initial targets, with subsequent spread of pathology to the central nervous system. While at this time, we can only provide evidence from the literature and preliminary findings from our own laboratory, we hope that our hypothesis will stimulate the development of tractable experimental systems that can be exploited to test it. Further support for an EBV-induced immune pathogenesis for Parkinson's disease could have profound therapeutic implications.


Involvement of the Extracellular Matrix in Age-Related Memory Loss in Mice

All of the myriad conditions of degenerative aging stem from comparatively simple roots: a small number of different types of cellular and molecular damage that accumulate over the decades. From there secondary forms of dysfunction spin off into spirals of cause and effect, becoming ever more complex and challenging to interpret at each new turn. It is just the same as rust in a complex metal framework: a simple root cause, but thousands of ways in which the rust can progress to cause the structure to finally collapse.

Treating the consequences of aging has been difficult for the medical research community because they have traditionally started their investigations at the final and most complicated end point, which is to say full-blown age-related disease. From there researchers try to work backwards towards progressively earlier causes. The first points at which they find ways to intervene are the closest proximate causes, which tend to be complex dysregulations of metabolism or cell state. Treatments involve the use of drugs to produce alterations in protein levels or epigenetic changes which in turn change the operation of cells or metabolism - but since everything in cellular biology influences everything else this is hard to get right, and it is also hard to produce benefits without significant side-effects. Also, since this is a matter of targeting proximate causes rather than root causes, the root cause of the problem continues chewing away underneath it all, making any solution temporary and fragile at best.

This is the present state of medicine. In the future, we would like to see a growth in targeting of root causes in aging and age-related disease, as exemplified by the SENS research program that I'm sure you're all at least passingly familiar with by now. A change of this nature in research and development will produce a sweeping improvement in the quality and capabilities of clinical medicine. This is very much a work in progress, however, and still in the earliest stages. The overwhelming majority of medical research continues to focus on end states and proximate causes rather than root causes, and is consequently the hard path to limited benefits.

Occasionally there are moments of luck in the present process, however, where it turns out that a pocket of comparative simplicity in the progression of degeneration from root cause to end state extends a fair way along the chain of consequences. This recently published research suggests that this might be the case for age-related memory loss in mammals. This is an aspect of cognitive decline that I would not have guessed had any simple points of intervention. The nature of the changes involved is also surprising, as it lies outside cells, not inside:

Rigid connections: Molecular basis of age-related memory loss explained

Brain cells undergo chemical and structural changes, when information is written into our memory or recalled afterwards. Particularly, the number and the strength of connections between nerve cells, the so-called synapses, changes. To investigate why learning becomes more difficult even during healthy ageing, the scientists looked at the molecular composition of brain connections in healthy mice of 20 to 100 weeks of age. This corresponds to a period from puberty until retirement in humans. "Amazingly, there was only one group of four proteins of the so-called extracellular matrix which increased strongly with age. The rest stayed more or less the same."

The extracellular matrix is a mesh right at the connections between brain cells. A healthy amount of these proteins ensures a balance between stability and flexibility of synapses and is vital for learning and memory. "An increase of these proteins with age makes the connections between brain cells more rigid which lowers their ability to adapt to new situations. Learning gets difficult, memory slows down."

Hippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline

Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wildtype mice have hippocampus-dependent proteome changes at 20, 40, 50, 60, 70, 80, 90 and 100 weeks of age.

Extracellular matrix proteins were the only group of proteins that showed a robust and progressive upregulation over time. This was confirmed by immunoblotting and histochemical analysis, indicating that the increased levels of hippocampal extracellular matrix may limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission.

Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance at old age.

Note that the paper is open access, and the full PDF version is available.

Telomere Length is Complicated

Telomeres are lengths of repeated short DNA sequences that cap the ends of chromosomes. The process of cell division shortens telomeres, and they form a part of the cell division counter that gives most somatic cells an expiration date after which they cease dividing. Telomeres are lengthened by the activity of the enzyme telomerase, which is more active in some cells than others - such as in stem cells, which need long telomeres so that they can divide to produce fresh new long-telomere somatic cells to keep tissues healthy and well-maintained.

When researchers measure telomere length in some specific group of cells, they are taking a snapshot of the blurred results of numerous processes in many cells, such as telomerase activity and pace of cell replacement by stem cells, that are themselves affected by near every aspect of health and environment. The most common measure of average telomere length in white blood cells is very dynamic, for example, rising and falling based on day to day health, even though over a lifetime it tends to decrease. But simple measures of average length tend not to capture these effects well, and the precise details of how a telomere length snapshot is taken make the difference between a result that is meaningless, and has no correlation to health, and a result that does tend to correlate with age, health, and future life expectancy.

So we have results like this one in which researchers run a rigorous study and find no correlation whatsoever between telomere length and mortality risk. You can compare that with animal studies that used a variety of techniques for telomere measurement and number crunching, such as proportion of very short telomeres versus average length, that do show good correlations with life expectancy and health. The sum of all this seems to me that rushing out to have your telomere length measured by one of the new services started in recent years is premature:

Human chromosomes are capped by protective ends called telomeres. These ends are shortened during renewal of tissue and eventually become critically short, causing cells to become senescent or die. It is widely believed that lifestyle features such as smoking, obesity, physical inactivity, and possibly alcohol intake enhance shortening of telomeres. However, strong evidence to support such an interpretation is hard to find. We therefore tested whether these lifestyle factors are associated with telomere length change in 4,576 healthy individuals from the general population.

Individuals had relative telomere length measured twice with a 10-year interval, and were then followed for mortality and morbidity for a further 10 years after the second measurement. We found change in telomere length to be more dynamic than previously believed, as we observed both shortening (in 56%) and lengthening (in 44%) among participants. Contrary to previous beliefs, we found telomere length change to be unaffected by lifestyle factors. Instead, we found the strongest association between past telomere length and age with change in telomere length over 10 years. Also, we found no association between change in telomere length and risk of all-cause mortality, cancer, chronic obstructive lung disease, diabetes mellitus, ischemic cerebrovascular disease, or ischemic heart disease.


Mechanisms Linking Peridontitis and Atherosclerosis

Chronic infection and inflammation of the gums, peridontitis, is associated with increased risk of atherosclerosis, a clogging of the arteries. This is because inflammation spreads beyond the mouth, and the process of inflammation in artery walls over the long term contributes to the production of plaques of dead cells and metabolic waste. Here researchers look into the details of this link between the two conditions:

Chronic oral infection with the periodontal disease pathogen, Porphyromonas gingivalis, not only causes local inflammation of the gums leading to tooth loss but also is associated with an increased risk of atherosclerosis. Like other gram-negative bacteria, P. gingivalis has an outer layer that consists of sugars and lipids. The mammalian immune system has evolved to recognize parts of this bacterial coating, which then triggers a multi-pronged immune reaction. As part of the "arms race" between pathogens and their hosts, several types of gram-negative bacteria, including P. gingivalis, employ strategies by which they alter their outer coats to avoid the host immune defense.

[The researchers] focused on the role of a specific lipid expressed on the outer surface of P. gingivalis, called lipid A, which is known to interact with a key regulator of the host's immune system called TLR4. P. gingivalis can produce a number of different lipid A versions, and the researchers wanted to clarify how these modify the immune response and contribute to the ability of the pathogen to survive and cause inflammation - both locally, resulting in oral bone loss, and systemically, in distant blood vessels.

They constructed genetically modified strains of P. gingivalis with two distinct lipid A versions. The resulting bacteria produced either lipid A that activated TLR4 (called "agonist") or lipid A that interacted with TLR4 but blocked activation ("antagonist"). Utilizing these strains, they demonstrate that P. gingivalis production of antagonist lipid A renders the pathogen resistant to host bacterial killing responses. This facilitates bacterial survival in macrophages, specific immune cells that normally not only gobble up the bacteria but also "digest" and kill them.

When the researchers infected atherosclerosis-prone mice with the P. gingivalis TLR4 antagonist strain, they found that this exacerbates inflammation in the blood vessels and promotes atherosclerosis. In contrast, the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A variations, which demonstrates that there are distinct mechanisms for induction of local versus systemic inflammation.


Delivering Stem Cells to Improve the Response to Exercise

There are countless potential ways to use stem cells to improve health. These are still the very early stages of stem cell medicine, when looking at the long term. Researchers have barely scratched the surface of what could be accomplish once patient-matched stem cells of any arbitrary type can be reliably and rapidly generated to order. To give just a few examples that are already possible: deliver vast numbers of immune cells into the body to attack cancer, a specific pathogen, or simply to boost immune function in the elderly; deliver neural stem cells to improve plasticity in the brain; repairing worn joints and heart tissue with stem cells that alter signaling in tissues to instruct native cells to get back to work. But there is much, much more than this presently under investigation in the laboratory.

A great deal of present work on stem cells focuses on muscle and the various types of stem cell that support it. These stem cells are better understood than others, and the techniques for working with them are more robust and reliable. In addition, muscle tissue is easier to work with in animal models in comparison to internal organ tissue. All of this translates to a lower cost of research in money and time, and greater ease in raising funds and producing results. Details matter. On the topic of muscles and stem cells I noticed this report of an interesting application of stem cell infusions today:

Stem cells aid muscle repair and strengthening after resistance exercise

Mesenchymal stem cells (MSCs) occur naturally in the body and may differentiate into several different cell types. They form part of the stroma, the connective tissue that supports organs and other tissues. MSCs also excrete growth factors and, according to the new study, stimulate muscle precursor cells, called satellite cells, to expand inside the tissue and contribute to repair following injury. Once present and activated, satellite cells actually fuse to the damaged muscle fibers and form new fibers to reconstruct the muscle and enhance strength.

By injecting MSCs into mouse leg muscles prior to several bouts of eccentric exercise (similar to the lengthening contractions performed during resistance training in humans that result in mild muscle damage), researchers were able to increase the rate of repair and enhance the growth and strength of those muscles in the exercising mice. "We have an interest in understanding how muscle responds to exercise, and which cellular components contribute to the increase in repair and growth with exercise. But the primary goal of our lab really is to have some understanding of how we can rejuvenate the aged muscle to prevent the physical disability that occurs with age, and to increase quality of life in general as well. Satellite cells are a primary target for the rejuvenation of aged muscle, since activation becomes increasingly impaired and recovery from injury is delayed over the lifespan. MSC transplantation may provide a viable solution to reawaken the aged satellite cell."

Satellite cells themselves will likely never be used therapeutically to enhance repair or strength in young or aged muscle "because they cause an immune response and rejection within the tissue." But MSCs are "immunoprivileged," meaning that they can be transplanted from one individual to another without sparking an immune response.

I think that last prediction about the use of satellite cells will be quickly proven wrong. The trajectory of research is clearly toward the ability to generate large numbers of any type of cell as needed from a sample of a patient's skin or similar. So why not satellite cells? The only good reason that immediately springs to mind is that it may turn out to be more efficient or effective to use patient-matched mesenchymal stem cells instead. Either way, ultimately the transfer of stem cells itself will most likely vanish for the majority of therapeutic applications, to be replaced with direct programming of existing in situ cell populations. Stem cell medicine is a bridge technology in this sense, though one likely to last decades.

Here is another thought for the day: how long before athletes are engaging in the use of stem cell treatments to build muscle? I would not be entirely surprised to find haphazard attempts at this taking place in today's medical tourism industry, but I suspect we are still some years away from more reliably effective treatments if enhancement of youthful muscle is the end goal.

Acquired Inheritance in Response to Starvation

In recent years researchers have discovered that the metabolic response to calorie restriction can extend into following generations, passed along via epigenetic and other mechanisms. The metabolism of descendant individuals is altered from the norm even when they never experience calorie restriction themselves. Data on this effect is harder to establish for humans in comparison to short-lived laboratory species, but it does exist:

Evidence from human famines and animal studies suggests that starvation can affect the health of descendants of famished individuals. Starving women who gave birth during the famine had children who were unusually susceptible to obesity and other metabolic disorders, as were their grandchildren. Controlled animal experiments have found similar results, including a study in rats demonstrating that chronic high-fat diets in fathers result in obesity in their female offspring. But how such an acquired trait might be transmitted from one generation to the next has not been clear.

[Researchers] starved roundworms for six days and then examined their cells for molecular changes. The starved roundworms, but not controls, were found to have generated a specific set of small RNAs. (Small RNAs are involved in various aspects of gene expression but do not code for proteins.) The small RNAs persisted for at least three generations, even though the worms were fed normal diets. The researchers also found that these small RNAs target genes with roles in nutrition.

Since these small RNAs are produced only in response to starvation, they had to have been passed from one generation to another. "We know from other studies that small RNAs can be transported from cell to cell around the body. So, it's conceivable that the starvation-induced small RNAs found their way into the worms' germ cells - that is, their sperm or eggs. When the worms reproduced, the small RNAs could have been transmitted generationally in the cell body of the germ cells, independent of the DNA."

The study also found that the progeny of the starved worms had a longer life span than the progeny of the controls. "We have not shown that the starvation-induced small RNAs were responsible for the increased longevity - it's just a correlation. But it's possible that these small RNAs provided a means for the worms to control the expression of relevant genes in later generations."


Larger Animals and Cancer Rates

Larger animals have more cells in their bodies, and cancer occurs when one cell suffers the right combination of mutations to run amok, so why is it that animals such as whales do not have higher cancer rates? Here researchers propose a partial answer to that question:

Larger species do not have higher cancer rates than smaller species, an observation known as Peto's paradox, named after the eminent Oxford cancer epidemiologist Sir Richard Peto who first remarked on the phenomenon in the 1970s. "Cancer is caused by errors occurring in cells as they divide, so bigger animals with more cells ought to suffer more from cancer. Put simply, the blue whale should not exist."

Now a study of the genomes of 38 mammal species, ranging in size from the mouse to the blue whale, has resulted in a partial explanation for the paradox - larger animals are just better at eliminating cancer-causing viruses from their DNA. A team of [scientists] analysed the genomes for DNA sequences of endogenous retroviruses (ERVs), which are viruses that are able to integrate their DNA within the DNA of the human chromosomes. The researchers found that there was an inverse relationship between the number of endogenous retroviruses - "relics" of viral infections over many millions of years of evolution - and the overall size of the species in question.

In other words, the bigger the animal, the fewer the number of viral relics found in its genome. The mouse for instance has 3,331 endogenous retroviruses, humans have 1,085 and whales have just 55 viral relics. This is seen as important for Peto's paradox on cancer rates because these retroviruses can jump around within the genome and in doing so trigger those kinds of cancer that are linked with viral infections, such as the T-cell leukaemia. Showing that larger species of animals have fewer ERVs in their genomes indicates that these kinds of viruses must be harmful, otherwise there would be no need to remove them. "Logically we think this is linked to the increased risk of ERV-based cancer-causing mutations and how mammals have evolved to combat this risk. So when we look at the pattern of ERV distribution across mammals it's like looking at the 'footprint' cancer has left on our evolution."


Change for Radical Life Extension Starts from the Bottom Up

Change starts from the bottom up and the top down and meets in the oblivious-to-the-very-last middle. Make no mistake, however, the bottom up initiatives always start well in advance of any top-down efforts, and it is the individuals making up the grassroots of any young movement who do most of the hard work to create growth and success. Their job is to prototype, to take the risks, to forge the path on a shoestring, to spread the word: and eventually those at the top finally notice that there is something to see and put their weight behind the movement.

This is the past fifteen years of the rejuvenation research movement in a nutshell. We're doing pretty well, I think, though of course everyone is impatient for much faster progress. We can point to tens of millions of dollars in philanthropic funding, to dedicated research institutions like the SENS Research Foundation that are now a similar size to many mainstream labs in aging research, and to many online and offline communities whose members take seriously today's efforts to treat and control aging through medical science.

When the public view of of aging research and extending healthy life spans finally slips over into approval and support, so that they feel much the same way about it as they presently do about cancer research in the abstract, it will be a sudden thing. All those years of hammering at the door will suddenly turn into a landslide in which everyone agrees we were right all along. That point is growing close thanks to the advocates, donors, and other supporters of longevity science.

Here is a recent post from Maria Konovalenko; while I don't agree with the specific details of the types of research she tends to champion, I agree with the overall sentiment that it is the time for collaboration, work, and growth in the grassroots of biotechnology to match similar progress in other fields. Costs have fallen tremendously in the past five years, to the point at which biotech startups are blossoming, and open biotechnology and garage biotechnology can have a meaningful influence on the overall pace of development. The future here looks a lot like the recent past of software development. In less regulated parts of the world, that means medical biotech can also experience a renaissance, allowing dozens of distinct attempts to produce solutions for every problem, and may the best win.

What Should Be Done to Achieve Radical Life Extension?

Delivering 5-7 gene vectors simultaneously carrying longevity-associated genes into an old animal could prove to be quite beneficial, because similar approach already works. It is also clear that there are several experiments in the area of therapeutic cloning that should be done immediately. There are about 20 other research directions in the area of radical life extension.

Right now it has become obvious how to find the money for radical life extension. It's crowdfunding. 200-300 campaigns need to be created on various crowdfunding platforms on the topics of fighting aging and regenerative medicine. Of course, we may not be able to find the necessary amounts of money right away, but we will be able to delineate the scope of goals, most importantly not using just the general words, but particular scientists, labs and research plans.

Even by only preparing the campaigns we will influence the society by once again providing the proof of the possibility of significant life extension. Unfortunately, molecular biology is not part of an every day's person background. We will make people more educated, show them how diseases originate, progress, and how they relate to aging. We will also tell the people what can be done.

While working on the crowdfunding campaigns we will mobilize our supporters by giving them a concrete tool and a plan of action. Fighting aging crowdfunding will become a very powerful transhumanist organizational solution. In the end we will gather the money, implement our projects and win!

If you are interested in bringing this plan to live, let's collaborate. Every single project requires a manager, analyst, scientist, director, operator, a guy who owns a car and a guy who writes a lot about this on the Internet. There is work for everybody, so let's do this.

An Anti-Deathist FAQ

As used in the longevity science community, deathism is a catch-all term for philosophies and viewpoints that encourage relinquishment of medical progress and acceptance of death by aging rather than the infinitely better alternative of medical research to extend healthy life and prevent age-related disease. If you have ever tried to persuade people that it is in fact a great plan to try to cure aging by controlling its root causes, you will have found that deathism is in fact very prevalent. Strangely, most people march towards a slow and painful death due to degenerative aging with little to no intent of doing anything about it.

Here are sections excerpted from a great short post by GrumplessGrinch at Carcinisation, a little something to show to those of your friends and family who think this way. As is usually the case in Fight Aging! posts, the links are added for reference rather than being in the original:

Q: What is Deathism?

A: Deathism is the belief that everyone should die.

Q: What is Anti-Deathism?

A: Anti-Deathism is the belief that death should not be mandatory.

Q: How the hell is that supposed to work?

A: Medical research. Aging has biological causes which we grow ever closer to unraveling.

Q: What happens when the earth is full of people because the population never stops increasing?

A: Space colonization is one possible answer, as is introducing disincentives for childbearing (like China did, though they went a bit overboard). But the earth's population is increasing regardless, so banning life-extension would only be a delaying tactic.

Q: Poor people already have much lower life expectancies than rich people. Won't life-extension technology just make this gap worse?

A: At first, probably, yes. That's how new technologies work. Two decades ago cell phones were only owned by rich people. Now they're transforming sub-Saharan Africa. Technologies (unlike wealth) trickle down.

Q: But it's wrong to focus on improving the lives of rich people when we could be helping the less fortunate!

A: Why don't you apply this standard to other types of medical research? Should we abandon all research into aging-related diseases like Alzheimer's, and instead use that money on charitable work abroad? I'm in favor of continuing to pursue many goals simultaneously, like humans do.

Q: The rarer something is, the more precious. So too for years. Life extension would devalue human experience.

A: Rarity is one source of value, but there are others. My favorite novel would not be improved just because I was the only one to ever read it.

Q: Extending human lifespans is unnatural!

A: So is polyester.

Q: But I don't want to live forever!

A: Okay. You don't have to.


Stroke Incidence Reduced 40% in the Last 20 Years

Reduction in mortality due to various forms of heart disease is one of the larger recent past drivers of the slow upward trend in adult and elderly life expectancy. A reduction in the incidence of Stroke is most likely due to many of the same underlying advances in medical practice. It is welcome, but worth remembering that the technologies and approaches that have created the present trend in life expectancy have very little to do with what lies ahead. The whole approach to aging is changing, and future trends will be very different from the present ones, because researchers will be trying to actually treat the causes of aging and all age-related disease rather than only patching the symptoms.

A new analysis of data from 1988-2008 has revealed a 40% decrease in the incidence of stroke in Medicare patients 65 years of age and older. This decline is greater than anticipated considering this population's risk factors for stroke, and applies to both ischemic and hemorrhagic strokes. Investigators also found death resulting from stroke declined during the same period. The team identified more than one million stroke events from 1988 to 2008, of which 87.3% were ischemic and 12.7% hemorrhagic strokes. The analysis showed a reduction in ischemic strokes from 927 per 100,000 in 1988 to just 545 per 100,000 in 2008. Hemorrhagic strokes decreased from 112 per 100,000 to 94 per 100,000 over the same time period, primarily among men. Data indicated that stroke mortality also declined. The risk-adjusted 30-day mortality rate for ischemic strokes fell from 15.9% in 1988 to 12.7% in 2008. For hemorrhagic stroke, the mortality rates declined slightly from 44.7% in 1988 to 39.3% in 2008.

The study was constructed to analyze stroke cases over the past two decades, not to investigate causation; however, researchers did find evolving patterns in the risk factors associated with strokes. Although the prevalence of diabetes mellitus increased over time, other risk factors, such as cigarette smoking, measured systolic blood pressure, and total cholesterol values, decreased.

The decline in stroke rates paralleled increasing use of antihypertensive and statin medications and might explain the reduction in stroke rates. "Antihypertensive medications reduce the risk of stroke by approximately 32% and statins by approximately 21%. Stroke rates seem to decrease most sharply after year 1998, approximately when statin use became more prevalent. If true, then this illustrates how medical interventions have resulted in significant improvements in health on a population level."


Working on Regeneration of Pacemaker Tissue

Given greater control over cells and tissue growth there are potentially all sorts of ways in which researchers could augment function for healthy people or compensate for loss due to illness and aging. One near term prospects is the ability to reprogram existing superfluous cells in an organ in order to replace small but crucial cell populations that are diminished by aging. Examples include the dopamine-generating neurons lost in Parkinson's disease, but every older individual also suffers a similar loss of these cells due to the damage of aging, just not to the same level. Parkinson's, like many age-related diseases, is a consequence of the rapid progression of a usually slower process that happens to everyone. Other examples include the loss of some of the specialized cell populations in the kidneys, liver, and pancreas. In most of these cases, there are nearby cells in the organ that could in principle be reprogrammed without consequence, as they will either be replaced fairly quickly or their loss is inconsequential.

In the article linked below the heart is the focus, and cardiac pacemakers are the small cell population of interest. One of the near future goals for cell therapy is to eliminate the need for artificial pacemakers and their numerous drawbacks for individuals suffering forms of dysregulation or loss of pacemaker tissue in the heart. Instead the natural population of pacemaker cells would be augmented and guided to better function. This seems a very plausible goal for the next decade, but work similar to that quoted below has been taking place for the past ten years, and there is a way to go yet before human trials will begin:

Next Generation: Biological Pacemakers

Scientists have been investigating ways to biologically recreate the natural pacemaker cells - a collection of specialized impulse-generating heart cells called the sinoatrial node. One approach has been to express the protein TBX18 in heart muscle cells. TBX18 is a transcription factor that drives development of pacemaker cells in the vertebrate embryo, but it can also directly convert adult heart muscle into pacemaker cells. Indeed, such reprogramming has been achieved in the guinea pig heart, where TBX18 expression has been shown to restore pacemaker function. For such an approach to be applicable to humans, however, the technique needed to be scaled up.

Twelve pigs had their own natural pacemakers experimentally destroyed. They then had back-up electronic pacemakers installed, but also received injections of adenovirus vectors containing the TBX18 gene into their heart muscle. The injected cells adopted the morphology and markers of pacemaker cells and, more importantly, acted like them. After just two days, TBX18-injected pigs had higher heart rates compared with control animals, and after five days they had a less than 1 percent reliance on their electronic pacemakers, while control animals relied on their electronic pacemakers between 8 percent and 40 percent of the time.

"It's an impressive piece of work that shows proof-of-concept, in a large animal, that we could actually harness the potential to convert one cell to another to cure disease." The reprogrammed pacemakers exhibited natural rises and falls in heart rate over day and night cycles as well as increased heart rate during physical exercise. "We're quite excited about that, because we think we can recreate the normal pacemaker function rather than fixing something artificially. Electronic devices cannot really follow the human physiology."

The team monitored the pigs for two weeks after injections and found that the activity of the induced pacemaker cells peaked at day eight and then slowly declined. This was not a surprise because adenovirus-infected cells tend to be cleared from the body. Such short-term reprogramming would be fine for patients requiring a temporary alternative to electronic devices, such as those undergoing treatment for pacemaker-related infections. But for long-term reprogramming, an alternative vector would be necessary.

Developing a Cell Therapy for Alzheimer's Disease

Delivering new neurons to replace those lost in Alzheimer's disease isn't an ideal approach in isolation: it is a patch therapy, something that doesn't attempt to address the root causes of the condition in any way, and thus can have only limited short-term benefits while those causes are still churning away. However this sort of treatment may be needed for people that have advanced Alzheimer's disease at the time a cure is finally deployed. The clinical community will need some way to restore function in those who have suffered irreversible damage in the late stages of the condition.

Scientists transplanted inhibitory neuron progenitors - early-stage brain cells that have the capacity to develop into mature inhibitory neurons - into two mouse models of Alzheimer's disease, apoE4 or apoE4 with accumulation of amyloid beta, another major contributor to Alzheimer's. The transplants helped to replenish the brain by replacing cells lost due to apoE4, regulating brain activity and improving learning and memory abilities. "This is the first time transplantation of inhibitory neuron progenitors has been used in aged Alzheimer's disease models. Working with older animals can be challenging from a technical standpoint, and it was amazing to see that the cells not only survived but affected activity and behavior."

A balance of excitatory and inhibitory activity in the brain is essential for normal function. However, in the apoE4 model of Alzheimer's disease - a genetic risk factor that is carried by approximately 25% of the population and is involved in 60-75% of all Alzheimer's cases - this balance gets disrupted due to a decline in inhibitory regulator cells that are essential in maintaining normal brain activity. The hippocampus, an important memory center in the brain, is particularly affected by this loss of inhibitory neurons, resulting in an increase in network activation that is thought to contribute to the learning and memory deficits characteristic of Alzheimer's disease. The accumulation of amyloid beta in the brain has also been linked to this imbalance between excitatory and inhibitory activity in the brain.

In the current study, the researchers hoped that by grafting inhibitory neuron progenitors into the hippocampus of aged apoE4 mice, they would be able to combat these effects, replacing the lost cells and restoring normal function to the area. Remarkably, these new inhibitory neurons survived in the hippocampus, enhancing inhibitory signaling and rescuing impairments in learning and memory. In addition, when these inhibitory progenitor cells were transplanted into apoE4 mice with an accumulation of amyloid beta, prior deficits were alleviated. However, the new inhibitory neurons did not affect amyloid beta levels, suggesting that the cognitive enhancement did not occur as a result of amyloid clearance, and amyloid did not impair the integration of the transplant.


Reversing Insulin Resistance in Type 2 Diabetes

Type 2 diabetes is largely something that you inflict on yourself. If you don't let yourself get fat and sedentary, the odds are you won't suffer metabolic syndrome or other precursor dsyregulation of metabolism until very late in life, if at all. If you do walk down that road, the progression of the condition can be reversed even quite late by drastic dietary changes and weight loss. But we live in an age of convenience at all cost, and a great deal of research funding goes towards finding treatments that will reverse the effects of type 2 diabetes without asking people to care about managing their health:

In mice with diet-induced diabetes - the equivalent of type 2 diabetes in humans - a single injection of the protein FGF1 is enough to restore blood sugar levels to a healthy range for more than two days. The team found that sustained treatment with the protein doesn't merely keep blood sugar under control, but also reverses insulin insensitivity, the underlying physiological cause of diabetes. Equally exciting, the newly developed treatment doesn't result in side effects common to most current diabetes treatments.

Diabetes drugs currently on the market aim to boost insulin levels and reverse insulin resistance by changing expression levels of genes to lower glucose levels in the blood. But drugs which increase the body's production of insulin, can cause glucose levels to dip too low and lead to life-threatening hypoglycemia, as well as other side effects.

In 2012, [researchers] discovered that a long-ignored growth factor had a hidden function: it helps the body respond to insulin. Unexpectedly, mice lacking the growth factor, called FGF1, quickly develop diabetes when placed on a high-fat diet, a finding suggesting that FGF1 played a key role in managing blood glucose levels. This led the researchers to wonder whether providing extra FGF1 to diabetic mice could affect symptoms of the disease.

[The] team injected doses of FGF1 into obese mice with diabetes to assess the protein's potential impact on metabolism. Researchers were stunned by what happened: they found that with a single dose, blood sugar levels quickly dropped to normal levels in all the diabetic mice. "Many previous studies that injected FGF1 showed no effect on healthy mice. However, when we injected it into a diabetic mouse, we saw a dramatic improvement in glucose. With FGF1, we really haven't seen hypoglycemia or other common side effects. It may be that FGF1 leads to a more 'normal' type of response compared to other drugs because it metabolizes quickly in the body and targets certain cell types."


Calorie Restriction Leads to More Very Small Embryonic-Like Stem Cells in Long-Lived Mice

Very small embryonic-like stem cells (VSELs) are supposed by some researchers to be a population of pluripotent stem cells that support adult tissues throughout life. Pluripotency, the capability to generate most or all of the cell types in the body, makes these stem cells potentially very useful in research and applications of regenerative medicine, where low-cost, reliable sources of large numbers of patient-matched cells for any tissue type are much in demand. The fewer steps along the way to obtaining that supply the better, so the prospect of obtaining pluripotent cells directly from a patient is attractive: that might eliminate the need to generate induced pluripotent stem cells or use some other reprogramming method.

Unfortunately there is some debate over whether VSELs exist at all, or at least in the form proposed by the various groups publishing papers on the topic. VSELs are not the only type of pluripotent stem cell thought to exist in adult tissue, and there are various other names given by various other research groups chasing much the same phenomenon. Independent replication of their work has been patchy however. This may all turn out to be a matter of cells choosing to alter their characteristics in response to circumstances at the end of the day, or the fact that it can sometimes take a few years for techniques in a new field to solidify and standardize. Given the amount of published work on putative pluripotent cells of various sorts in adult tissues I would be surprised to see it all come to nothing in the end, but there are clearly unexplained factors that make it difficult for the community to come to a consensus on this matter.

Here, for example, a research group are far enough down the road of working with VSELs to be comparing the details of their presence with and without calorie restriction in a long-lived mouse breed:

Positive effects of prolonged caloric restriction on the population of very small embryonic-like stem cells

One of the proposed means of increasing life span is caloric restriction (CR). In support of this notion, it has been demonstrated that CR without malnutrition is an effective means to decelerate the aging process, increase median and maximum lifespan, as well as delay reproductive senescence in a variety of species, including mice.

We recently reported that life span in experimental murine strains (e.g., Laron and Ames dwarf mice) correlates with the number of very small embryonic-like stem cells (VSELs) residing in adult tissues. Specifically, long-living murine strains with low levels of insulin-like growth factor 1 (IGF-1) circulating in peripheral blood (PB) display higher numbers of VSELs in bone marrow (BM) than age-matched normal control animals. The higher numbers of BM-residing VSELs in these animals also correlated with higher numbers of hematopoietic stem progenitor cells (HSPCs) in BM.

We envision that VSELs, which express several markers of pluripotency, are a population of early-development stem cells that, due to epigenetic changes in certain paternally imprinted genes involved in insulin/insulin-like growth factor signaling (IIS), are kept as a quiescent population of cells in adult tissues. Importantly, the epigenetic mechanism that attenuates VSELs responsiveness to IIS has a positive effect on maintaining their number in adult tissues. However, VSELS have the potential to become specified into more-differentiated tissue-committed stem cells (TCSCs) after reversing expression of imprinted genes to the somatic type. We also believe that VSELs most likely overlap with other types of early-development pluri/multipotent stem cells (e.g., spore-like stem cells, multipotent adult stem cells, or multipotent adult progenitor cells) in adult tissues described by other investigators.

Interestingly, a population of small cells corresponding to BM-purified VSELs has also been described in murine ovaries and testes. These ovary- and testis-residing VSELs have been postulated to be precursors of gametes both in mice and humans. We observed that long-living Laron dwarf mice, which we have demonstrated to have higher numbers of VSELs in BM, have the period of active ovulogenesis prolonged to an advanced age, and Laron dwarf mice older than 2 years can become pregnant and deliver healthy offspring.

Based on these observations and the well-known facts that CR lowers IGF-1 levels in PB and has a beneficial effect on life span in mice, we became interested in the effect of CR on the number of murine VSELs and HSPCs as well as on the morphology of ovaries and testes. In our studies, 4-week-old female and male mice were subject to CR by permitting feeding ad libitum (AL) only on alternate days for a period of 9 months.

Our data indicate that mice under CR have a higher number of BM- and spleen-residing as well as PB-circulating VSELs than control mice fed AL. CR also correlated with a higher number of HSPCs in hematopoietic tissues as well as with an increase in the number of primordial and primary follicles in ovaries. At the same time, however, no significant changes were observed in the testes of mice on CR. Thus, our data explain the positive effect of CR on longevity in mice by a novel early development stem cell related mechanism.

Can Too Much Exercise Reduce Longevity?

There are many animal studies showing that moderate exercise causes extended health and many human epidemiological studies showing a robust correlation between moderate exercise, better health, and extended life expectancy. This should give us confidence in believing that yes, being sedentary is bad for us and the practice of at least moderate exercise is good for us. Showing causation in human studies is a real challenge, however, which is why there is still uncertainty over whether a lot of exercise is better, worse, or no different for longevity than the moderate 30 minutes a day recommended by most physicians. We can point to the fact that exceptional athletes such as Tour de France bicyclists live longer than the rest of the population, but is that because they exercise a great deal, or because only very robust individuals tend to become athletes competing at that level?

Separately, there is also the question of whether extremely high levels of exercise actually shorten life expectancy when practiced across a broader slice of the population, once you go on to consider more than just professional athletes. Again here we don't have much to go on in terms of causative relationships, but a brief tour of some of the relevant research is provided in this article:

All runners have heard about the tragedies. The marathoner Alberto Salazar, at the age of forty-eight, suffered a heart attack and lay dead for fourteen minutes before a stent opened up a blocked artery and saved his life. Hundreds of studies, as well as our own intuition, associate exercise with cardiac health. But, in recent years, a small group of cardiologists have advanced a hypothesis that suggests these tragedies may not be so shocking, after all: they believe that an excess of exercise actually damages the heart.

For those of us who believe that the "everything in moderation" rule applies to, well, everything, this argument makes sense. Exercise remains one of the best things you can do to improve your cardiovascular health, but you certainly do not need to run marathons to achieve the benefits. Moderate amounts of exercise throughout life are perfectly adequate. Athletes who exercise in extremes generally do so for reasons other than their health - competitiveness, professional requirement, compulsion. But recognizing that exercising more than a certain amount reaps no greater cardiovascular benefits is quite different than suggesting that this level of exercise causes cardiovascular harm.

After reviewing the data and interviewing experts in the field, my own impression is that among people without known cardiovascular disease there is no compelling data to suggest that mortality significantly differs between moderate and extreme exercisers. There is thus no way to precisely define an upper limit of exercise for an average healthy individual. I suspect, though, that part of what sustains the "too much exercise can kill you" myth is the widespread recognition of the so-called exercise paradox. That is, while consistent exercise decreases the likelihood that you will have a heart attack, if you are destined to have one it is more likely to happen while you are exercising. That's why no one can issue a blanket statement that extreme exercise is safe. It's also why so many researchers have attempted to figure out how to make extreme exercise as safe as possible.


Macrophages Needed for Zebrafish Regeneration

A fair number of research groups are investigating the low-level mechanisms of regeneration in animals such as salamanders and zebrafish, which are capable of regrowing limbs and even major internal organs. It is possible that the underlying biological machinery of this exceptional regeneration still exists in humans, but is merely dormant. Even if it has been lost over the course of evolutionary time it might be reintroduced if researchers just knew enough of the details. At this stage it is hard to say what the odds are, or how challenging it will be to achieve this goal - but that is what research is for. In recent years scientists have established that the immune cells known as macrophages are required for salamander regeneration to operate, and here a recent open access paper reports that this is the case for zebrafish as well:

Although wound healing has been extensively studied in mammals, we have a limited understanding of the injury-induced cellular response in a regenerative context. In this study, we utilized a combination of cell tracking and genetic cell ablation approaches to detail the course and role of cellular components of inflammation in zebrafish fin regeneration. Neutrophils and macrophages, as key mediators of inflammation, have defined functionally important roles in mammalian tissue repair. Our data suggest that the relative time frame of inflammatory cell movement to and from sites of injury is similar for adult zebrafish and mammals, where neutrophils are attracted to the wound first through 'homing' from the circulation, followed by circulation-based or resident macrophages.

We first tracked neutrophils and macrophages in adult zebrafish following amputation of the tail fin, and detailed a migratory timecourse that revealed conserved elements of the inflammatory cell response with mammals. Next, we used transgenic zebrafish in which we could selectively ablate macrophages, which allowed us to investigate whether macrophages were required for tail fin regeneration. We identified stage-dependent functional roles of macrophages in mediating fin tissue outgrowth and bony ray patterning, in part through modulating levels of blastema proliferation. Moreover, we also sought to detail molecular regulators of inflammation in adult zebrafish and identified Wnt/β-catenin as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype.

Our findings, coupled with recent research detailing pro-repair roles of inflammatory cells in zebrafish brain regeneration, advocate some degree of anatomical conservation of the role of injury components in regenerative process in zebrafish. Finally, macrophages may indeed form part of a cellular bridge between robustly regenerative organisms such as zebrafish and the less regenerative mammals that could potentially be manipulated for mammalian regenerative therapies.


SENS Research Foundation Newsletter for July 2014

The latest SENS Research Foundation monthly newsletter turned up in my in-box yesterday, along with a reminder that the 2014 Rejuvenation Biotechnology conference will be held on August 21st in Santa Clara, California. This event has a strong focus on creating the stronger ties between academia and industry that will be needed to speed the development of applied longevity science, building the life-extending therapies of tomorrow to help bring aging under medical control. There's still time to register.

Don't miss this landmark event! Here are 4 reasons to attend RB2014:

1) Meet expert researchers from multiple age-related disease areas in a setting designed to enable true cross-functional learning and partnering.

2) Impact the creation of the emerging Rejuvenation Biotechnology industry by sharing your research, regulatory, finance, academic and industry perspective.

3) Participate in meaningful discussion and productive networking opportunities in the heart of Silicon Valley.

4) Engage with industrial and academic leaders like Eli Lilly, California Institute for Regenerative Medicine (CIRM), Harvard University, GE Healthcare Life Sciences, and Wake Forest Institute for Regenerative Medicine.

Visit our website to view and download our new conference agenda brochure.

The speakers list contains the usual impressive line up characteristic of a SENS conference:

Ajay Royan, Mithril Capital

Ajay Royan co-founded Mithril Capital and heads the firm as its managing general partner. At Mithril, he has led investments in innovative companies located both in Silicon Valley and around the world.

Ajay frequently speaks on technology investing at technology and finance conferences as well as public forums, such as Bloomberg, CNBC, the Financial Times, and The Wall Street Journal. He has been a guest lecturer on macro investing at Yale University and has served as a participant in the Hoover Institution's Working Group on Global Markets and as one of the Churchill Club's Tech Trends experts.

Ajay serves as an external adviser to Oak Ridge National Laboratory and the University of Michigan Risk Science Center and also serves on the board of the Thiel Foundation. He was educated at Yale University.

Dr. George Church, Harvard

Dr. George Church is Professor of Genetics at Harvard Medical School and Director of, in addition to being the author of the book, Regenesis: How Synthetic Biology Will Reinvent Nature and Ourselves. His 1984 Harvard thesis work pioneered the first methods for direct genome sequencing, molecular multiplexing and barcoding, which led to the first commercial genome sequence in 1994.

Dr. Church's innovations in "next generation" genome sequencing and synthesis and cell/tissue engineering resulted in 12 companies spanning fields including medical genomics and synthetic biology as well as new privacy, biosafety and biosecurity policies. He is director of the NIH Center for Excellence in Genomic Science, and his honors include election to NAS (National Academy of Sciences), NAE (National Academy of Engineering) and Franklin Bower Laureate for Achievement in Science.

As always the real gem of these newsletters is the scientific question of the month - which this month is actually a question asked in a comment to a recent post here at Fight Aging! The lesson to take away here is that you should always ask questions when you have them, as the world is flat these days and an expert is often closer than you think.

Question Of The Month #5: Must Mitochondrial Mutation Management Account For Humanin?

Q: SENS Research Foundation is working to develop a system of "backup copies" of the genes in the mitochondria that code for proteins as a way to bypass the harmful effects of mutations in mitochondrial DNA. But in addition to these 13 proteins, researchers have found a peptide called humanin that is produced from mitochondrial DNA and that seems to have some physiological functions. How would moving the mitochondrially-encoded genes to the nucleus potentially impact other, less well known, products of mtDNA such as humanin?

A: Humanin is a recent and still somewhat controversial product of mitochondrial DNA. What to do about it as part of generating "backup copies" of the protein-encoding genes in the mitochondrial genome turns on how things ultimately shake out.

First, it's not yet clear whether humanin really is produced by mitochondria to serve a physiological function, or is just a byproduct left over from the of unusual way that mitochondria process their RNA. True, humanin seems to bind to a variety of receptors and to have various functions in models of stress and disease, which some have taken as evidence of function - but of course, the same thing is true of various drugs, including synthetic peptides, and that doesn't mean that they are somehow physiological substances. Also, many of these disease models are very artificial, and may not reflect the real conditions under which cells must respond to stress, or in which humanin would exert any activity. If humanin is just a byproduct of mitochondrial RNA processing, its loss will be harmless.

Second, if humanin is indeed a genuinely physiologically functional peptide, the sequence encoding it may be much less vulnerable to age-associated mutation than the genes encoding the proteins of the electron transport chain. Its putative encoding sequence is located by the minor arc of the mtDNA loop, which is rarely affected by deletions in aging. If that's so, then most of the cells that suffer major deletions in their mitochondrial DNA with age and have to draw on their engineered "backup copies" would still have their native humanin-encoding sequences on which to draw, with no special work on our part.

Third, even if humanin is physiologic and the sequence that encodes it is sufficiently susceptible to mutations as to be problematic for the cell in which that sequence is mutated, the mutation of this sequence isn't necessarily all that big a deal. Remember, only a very small number of cells accumulate large deletions of mtDNA with age. We worry so much about these mutations not so much because of the harm they cause to the individual cells in which they occur, but because such cells appear to adopt an abnormal metabolic regime to continue producing energy, and this abnormal metabolic state seems likely to spread metabolically harmful effects across the rest of the body in turn. So even if we find that a small number of cells do lose the ability to synthesize humanin with age, and even if those cells in isolation might be harmed by its absence, still the dysfunction or death of so small a number of cells will not cause the dysfunction of an entire tissue (or the body generally) in the way that a rising burden of cells unable to produce energy normally probably does. And any cells hypothetically rendered dead or dysfunctional for lack of humanin could be periodically replaced using cell therapy, which is already an essential component of comprehensive human rejuvenation.

Finally: if there turns out to be some really compelling reason why it's important to prevent cells from losing humanin expression with age, we do have the option of developing nuclear "backup copies" of the humanin sequence that can fill in in case of shutdown of translation by age-related mutations.

Beta Cyclodextrins as a Possible Treatment for the Build Up of Lipofuscin

Liposfucin is the name given to a mix of hardy metabolic waste compounds that build up in long-lived cells over the years, such as the vital cell populations of the retina. Cells are not equipped with suitable tools to remove this gunk, but they try anyway and so it ends up concentrated in the cellular recycling structures known as lysosomes. This leads to bloated, poorly functional lysosomes and a decline in cellular housekeeping, which in turn causes cell dysfunction and loss of tissue function. In the retina this process contributes meaningfully to a number of progressive blindness conditions such as age-related macular degeneration.

Here researchers report on a possible drug candidate that renders harmless some fraction of a few of the important lipofuscin constituent compounds when used on retinal cells:

Lipofuscin accumulation in the retinal pigment epithelium (RPE) is a hallmark of aging. Accumulation of lipofuscin bisretinoids (LBs) in the RPE is the alleged cause of retinal degeneration in genetic blinding diseases (e.g., Stargardt) and a possible etiological agent for age-related macular degeneration. Currently, there is no treatment to prevent and/or revert lipofuscin-driven retinal degenerative changes. Hence agents that efficiently remove LBs from RPE would be valuable therapeutic candidates.

In this study, we report that beta cyclodextrins (β-CDs), cyclic sugars composed of seven glucose units, can bind retinal lipofuscin, prevent its oxidation and remove it from RPE. Computer modeling and biochemical data are consistent with the encapsulation of the retinoid arms of lipofuscin bisretinoids (LBs) within the hydrophobic cavity of β-CD. Importantly, β-CD treatment reduced by 73% and 48% the LB content of RPE cell cultures and of eyecups obtained from [mice], respectively. Furthermore, intravitreal administration of β-CDs reduced significantly the content of bisretinoids in the RPE of [mice].

Thus, our results demonstrate the effectiveness of β-CDs to complex and remove LB deposits from RPE cells and provide crucial data to develop novel prophylactic approaches for retinal disorders elicited by LBs. This study opens an avenue to develop small drugs against, currently untreatable lipofuscin-associated blinding disorders.


A Review of Cytomegalovirus in Immune System Aging

There is plenty of evidence to suggest that the persistent herpesvirus species cytomegalovirus (CMV) plays an important role in immune system aging. A majority of people carry the virus by the time they reach old age, and its presence causes an ever-increasing number of immune cells to become uselessly specialized to deal with CMV rather than able to respond to new threats. There are other contributing causes to immune system aging, but this seems like a potentially important one, for all that there is still work to be done to definitively prove the case. It is worth chasing this to a conclusion, because a state of too many CMV-specialized immune cells is reversible by the targeted removal of these cells, which will trigger their replacement with new non-specialized cells. This sort of approach has been demonstrated in laboratory animals for similar situations, and so is a possible tool for the rejuvenation toolkit.

As is the case for many potential causes of aging, it would be faster and cheaper to carry out destruction of CMV-specialized cells and then see what happens rather than to fully investigate all of the mechanisms and come to a conclusion without the data from such a prospective treatment. Nonetheless, the research community tends to take the latter rather than the former path. This open access review paper looks over what is known and still unknown about CMV in the context of immune system aging:

Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and with several age-related diseases. However, current evidence on whether and how human CMV (HCMV) infection is implicated in immunosenescence and in age-related diseases remains incomplete and many aspects of CMV involvement in immune aging remain controversial.

After primary infection, CMV is carried for the lifetime of its host. Viral persistence is based on complex interactions between multiple viral and host determinants. These interactions generally result in a carefully negotiated and clinically "innocuous" balance between the virus and the immunocompetent host. Indeed, CMV rarely produces symptoms in the host unless the balance is upset by reduced immune competency of the host.

The co-existence of human CMV in healthy, and even more so, in elderly individuals is still a poorly understood phenomenon. A number of longstanding questions related to CMV's role as a "driver" or "passenger" in the aging of the immune system, in age-related diseases and in complex comorbidities remain incompletely resolved and rather recalcitrant to being rapidly and conclusively resolved. Part of the obstacle lies in the complexities of longitudinal human studies, with pronounced ethical barriers and genetic and epigenetic variabilities on the one hand, and the imperfect concordance between human infection and more tractable animal models of CMV infection in a specific pathogen-free and genetically homogenized settings, on the other.


Fundraising Update: $66,000 Pledged to the Matching Fund

Starting on October 1st and continuing through to the end of the year we'll be running a grassroots fundraiser for SENS rejuvenation research, with all donations going to the SENS Research Foundation. Initiatives like this help to fund ongoing cutting edge work taking place at noted laboratories around the country, projects that build the foundations for future therapies to reverse the effects of aging and prevent all age-related disease. Aging is just damage to cells and tissue structures, we know what that damage is, and we can envisage the technologies needed to repair it in great detail. All that is lacking for rapid progress is funding: there are any number of researchers who would much rather be working on this exciting initiative than on the projects they can present raise funding to carry out. If you want to work on radical new directions in medicine, or early stage research of any sort for that matter, then you will be reliant on philanthropy, however: there are very few other sources of funding for ambitious rather than incremental work.

Over the next few weeks I and others will be collaborating to raise a matching fund for the October fundraiser, akin to the 3:1 match that we ran successfully last year. I'm pleased to say that a number of individuals and organizations have already answered my call for matching fund founders, and have stepped up to pledge their support:

  • Christophe and Dominique Cornuejols
  • David Gobel (Methuselah Foundation)
  • Dennis Towne
  • Jason Hope
  • Michael Achey
  • Reason (Fight Aging!)

Together we have pledged a total of $66,000 so far, and we hope that some of you will join us. If you are interested in pledging $5,000 to $15,000 dollars to take this matching fund to the next level, then here is your chance to do so. You'll be in the good company of long-standing supporters of SENS rejuvenation research: people with the foresight to see that we must act now if we are to build a better future, in which there is no suffering and no death due to the many medical conditions that accompany aging. One day aging will be looked upon as we see tuberculosis today: a controlled threat from past years, beaten by medical science. If that day is to happen soon enough for us, then we have work to do, however.

It is vitally important for grassroots fundraising to take place year after year: large scale donations from very wealthy sources only arrive after years of proven support and growth from an energetic and enthusiastic community. This is just as true of medical research into aging and longevity as it is for any other endeavor in this world of ours. In this sense, all of the thousands of donors to the SENS Research Foundation and the Methuselah Foundation before it are philanthropic trailblazers, leaders who point the way for those who will come later to put far greater weight behind efforts to develop rejuvenation therapies based on the SENS vision. Without us, the larger donations and next stage of growth will never happen. What we do is essential, but it can't be done without stepping forward, and acting to provide what support you can.

If you can join as a founder to fill out the matching fund, please contact me. I'd be delighted to hear from you.

A Glance at the Russian Network for Longevity Science

Several distinct networks of researchers, advocates, and funding sources for longevity science have arisen in the past decade. There is some overlap between them, but the backers are different and the scientific strategies largely distinct. The Strategies for Engineered Negligible Senescence (SENS) crowd are I think the most important of these, as they are the only group with a plausible plan to generate rejuvenation rather than just slowing aging, but that network is sadly nowhere near as large yet as the genetics-focused mainstream longevity science network in the US. Most groups working on aging in the US and Europe will probably improve medicine, but are not likely to produce technologies that will lead to considerable extension of healthy life spans.

The topic for today, however, is the Russian network that encompasses the Science for Life Extension Foundation, research institutes in Moscow and elsewhere, a few entrepreneurial types who are launching ventures in other countries, and a few attention-shy high net worth backers. The Russian longevity science community is about as focused on the genetics and metabolism of aging as the US mainstream, but that focus is informed by programmed aging theories rather than a consideration of aging as accumulated damage - which leads to a fairly different emphasis on the development of treatments. I still think that this approach is unlikely to produce meaningful near term results in longevity, however, even while it will generate a great deal of new knowledge and associated improvements to medical technology.

This publicity release should be taken as a sign of the times, and that progress is happening elsewhere. The present growth of interest in serious research on longevity is not limited to the US and Europe, and ours is not the only advocacy and fundraising community.

Deep Knowledge Ventures last week sponsored the inaugural 21st Century Medicine Forum on 'Commercialising Longevity Research' and welcomed a host of London-based investors, scientists and entrepreneurs to the London Bioscience Innovation Center for the event, organised by the UK's Biogerontology Research Foundation and Aging Analytics Ltd. The meeting highlighted the need for both philanthropic support and investment in translational research for age-related disease, as well as the crucial role of social awareness of advances in regenerative and preventative medicine. This point was well made by attending actress, campaigner and international model, Katya Elizarova, who said: "It's clear that the most important thing is to support projects for preventing aging. If researchers are clever enough to develop methods to prevent age-related damage accumulating, it's much more likely that they will have an ability to treat with success. If I, as a media person, can increase the awareness of what you are doing here today and involve as many people as I can, then I shall do it."

Deep Knowledge Ventures investment remit includes artificial intelligence research and robotics, as well as longevity related biotechnology. On the subject of investment in pioneering technologies. Deep Knowledge Ventures Senior Partner Dmitry Kaminskiy said: "According to our estimates we are at an exciting historical point - even with a relatively small amount of investment - hundreds of millions of dollars - but with well-organized and inspired teams, it's possible to accelerate the exponential growth in science and medicine. Our first joint task is now to create a convenient format for investing in this field for conventional investors, who got used to think in very narrow categories. But we need to go beyond this and change the paradigm. Investors in this field stand to gain more valuable results than profit alone. The logic is effective: in case of successful investments, they automatically get direct access to the actual technologies of personalized medicine and life prolongation for themselves and their families. What other business could be better? When you prolong life and still earn a lot of money on this."

Speakers during the event included Dr. Alex Zhavoronkov, CEO of Deep Knowledge Ventures portfolio company In Silico Medicine, who explained "By bringing together class-leading researchers, pensions experts, financial heavyweights and science communicators at meetings like this, we hope to facilitate collaboration across disciplines and produce the next generation of projects that will take longevity science from the bench to the clinic".


Making Blood From Stem Cells

Researchers continue to make progress in understanding how to guide stem cells to a desired outcome:

During development, blood cells emerge in the aorta, a major blood vessel in the embryo. There, blood cells, including hematopoietic stem cells, are generated by budding from a unique population of what scientists call hemogenic endothelial cells. The new report identifies two distinct groups of transcription factors that can directly convert human stem cells into the hemogenic endothelial cells, which subsequently develop into various types of blood cells. The discovery gives scientists the tools to make the cells themselves, investigate how blood cells develop and produce clinically relevant blood products.

The factors identified [were] capable of making the range of human blood cells, including white blood cells, red blood cells and megakaryocytes, commonly used blood products. The method [was] shown to produce blood cells in abundance. For every million stem cells, the researchers were able to produce 30 million blood cells. A critical aspect of the work is the use of modified messenger RNA to direct stem cells toward particular developmental fates. The new approach makes it possible to induce cells without introducing any genetic artifacts. By co-opting nature's method of making cells and avoiding all potential genetic artifacts, cells for therapy can be made safer. "You can do it without a virus, and genome integrity is not affected."

While the new work shows that blood can be made by manipulating genetic mechanisms, the approach is likely to be true as well for making other types of cells with therapeutic potential, including cells of the pancreas and heart.


The Strategic Future of the SENS Research Foundation

As I've noted in the past, attention and investment given to research tends to come in waves. Longevity science has been building from the 1970s in a series of growing waves, each lasting ten to fifteen years. That is long enough for new ideas to arise, a few organizations to be founded, networks established, research accomplished, and the groundwork laid for the next cycle to begin. The faces are generally different each time around: new entrepreneurs and researchers pick up the torch with each decade, putting their own spin on things and building their own flavor of progress. Insofar as longevity science goes the wave starting in the 1970s was financially insignificant, and didn't do much more than seed the ideas for what is taking place now. It wasn't until ten years ago that the current wave grew large enough to raise millions of dollars for serious work on the basis for rejuvenation treatments, or for there to be significant - albeit still modest - public interest in aging research. I think that this present wave is ending now and the next beginning, a change in the funding environment characterized by the ability to raise tens of millions of dollars for ventures related to aging and longevity. Human Longevity, Inc. (HLI) and the California Life Company (Calico) are early indicators of what lies ahead.

So what of the SENS Research Foundation in all of this? To my eyes, and I'm far from alone in this, the work done by the Foundation and its allies is presently the best hope for real progress towards rejuvenation therapies in our lifetimes. At this time the Foundation is emerging from the end of the wave that saw its creation with a runway of roughly $5 million per year for the next four to five years. This is largely assured by co-founder Aubrey de Grey's donation of $13 million to research, but without replenishment the vault is empty after that. Four to five years is a long time for a for-profit startup business, but not very long at all in medical research. In the sciences this is a decent amount of time to chase an idea from "this looks plausible" to "now we should start trying it out in animal studies." The goal of the Foundation's staff will be to use this runway to gain access to funding sources of the next wave, and ideally to grow tenfold over the next ten to fifteen years if HLI and Calico are representative of the interest that lies ahead. At this level of funding that would require a foundation similar to the Glenn Foundation to be persuaded to make SENS its cause, or for a billionaire philanthropist with interests in medicine such as Paul Allen to step into the space, or for a similarly sized source of public funding to be established.

The very real prospect of attaining this high road goal is why we folk in the grassroots make the effort to raise a few tens of thousands of dollars here and a few tens of thousands of dollars there. If you want to raise millions from big donors and establishment funding, then you have to be able to demonstrate a continuing ability to attract the support and funding of thousands and then tens of thousands of everyday individuals. Large scale funding follows public interest, and we are the trailblazers lighting the way. It would be nice to believe that bolt from the blue multi-million dollar funding just happens for deserving new technologies and research initiatives, but the reality is it doesn't. Massive philanthropic and investments turn up very late in the game, and only when everyone has heard of the cause they are supporting: they are only just nowadays arriving for stem cell research, for example. The only way to get to that point is to build step by step with the grassroots leading the way.

Simply growing funding to take the research programs to the next level is far from the only thing that the SENS Research Foundation can plan for in the new five years. I recognize that the community here is impatient for results: research is slow, and SENS research has been funded to a level of a few million a year for five years or so now. Supporters always want to see more tangible signs of progress than high profile scientific publications or incremental advances in steps seven through twelve of a twenty step process. The unfortunate truth of the matter is that many parts of SENS are not going to be realized anytime soon at the present rate of funding, and even given a tenfold increase are still a decade or more away. But some parts of SENS are much closer, within just a couple of years of technology demonstrations in mice. I think that the best candidates here are firstly elimination of senescent cells and secondly removal of glucosepane cross-links. In the case of senescent cell removal there is already momentum in the research community towards creating and assembling the necessary tools, and furthermore these tools are nearly ready. For glucosepane removal there is no momentum beyond projects funded by the SENS Research Foundation, but it is really just a matter of developing one way to break down one compound, a far, far simpler goal than any other part of the rejuvenation toolkit.

If either of these items is brought usefully close to fruition within the SENS Research Foundation's present runway, then one possible path for the future of SENS is that the Foundation itself becomes rather irrelevant in comparison to a community of overseas developers who begin to offer prototype treatments via medical tourism. Both removal of senescence cells and glucosepane cross-links should be meaningfully beneficial to all older people. This is exactly the same playbook as for the past fifteen years in stem cell research, and should produce the same outcome: a great influx of funding and attention, and real progress. In this scenario it doesn't really matter all that much what becomes of the Foundation, and whether it succeeds in growing or not. It is just one part of a much larger process at that point, and everyone who was directly involved will no doubt do well for themselves as a result of their earlier activities.

So in the sense that people are impatient for progress because they believe that tangible progress in any one aspect of SENS will unlock doors to growth: I agree with this. The thing that keeps me awake at night, and I'm sure others too, is the prospect of failure, and by that I mean that the SENS Research Foundation reaches the end of its runway without achieving either of the two goals above, nor attracting even a sustaining level of donations. It is perfectly possible to fire up the scientific community, change minds, and then be left sitting on empty coffers while the revolution you inspired arrives only decades later. That has happened numerous times in the history of technological development, so we shouldn't be overconfident. Failure in this sense wouldn't destroy SENS, it would just slow things down and relegate it to obscurity for some period of time - but that is a disaster when every year counts.

What is the best way for us to help ensure that this doesn't happen? That would be the grassroots fundraising and all that goes with it: the networking, the publicity, the spread of knowledge. This is why I undertake these tasks, to do my part to help shift the odds for organizations like the SENS Research Foundation to succeed one way or another. Generating the growth in research and development we want to see in the years ahead is a community effort of many moving parts. The next decade is going to be a fairly wild ride, but only if we all work on making it turn out well.

Promoting October 1st as Longevity Day

The International Longevity Alliance (ILA) is gearing up to promote longevity research on October 1st, presently the UN International Day of Older Persons, and also the date for this year's Eurosymposium for Healthy Ageing conference. This is a step on the way towards establishing an officially recognized Longevity Day at some point in the years ahead, one of the traditional methods of long-term political advocacy for a cause that needs more attention. ILA chapters will be organizing meetings and events, and - coincidentally - here at Fight Aging! we will be kicking off the year-end SENS rejuvenation research fundraiser on October 1st of this year.

Last year, activists of the international longevity movement proposed to celebrate the "UN International Day of Older Persons" on October 1 as a "Longevity Day" - to emphasize on that day that we need to promote longevity research for the benefit of older persons. Events were organized in more than 30 countries, ranging from national conferences to small circle discussions. Let us repeat this outreach this year too! Let us organize events on or around October 1, as a special day, or a week, or even a month dedicated to promotion of "Longevity" and "Longevity Research"!

The main events that could be organized could include: 1) organizing live and online meetings, and 2) writing and distributing texts - including in national languages (petitions, blog posts, flyers, media press releases, etc.). And the methods of their organization are simple: 1) Just thinking what *you* can organize in your area and inviting friends among longevity activists to think what *they* can organize, 2) writing and distributing texts and appeals. As October 1 is the "International Day of Older Persons" officially recognized by the UN, this could be a fantastic opportunity for longevity activists to organize and contact politicians and media to raise interest in the subject of longevity research. Let us celebrate and advance Longevity for All on October 1, and possibly extend the outreach following this date, as convenient, into a week or a month.

We may yet establish a special Longevity Day not to coincide with the International Day of Older Persons (possibly toward the summer). But for now, let us make the best of the International Day of Older Persons to raise the awareness of longevity research as a real way to help the aged. With little effort we can organize a series of highly influential and synergistic events around the world. There are already several initiatives under way. The leading one is the Eurosymposium on Healthy Aging, that will be held in Brussels, Belgium, on October 1-3. You are welcome to attend and/or create a similar event in your country and area! Please spread the word and engage others!


The Rejuvenation Research Advocacy of Aubrey de Grey

This is a decent article under an irrelevant linkbait title, which is about the best you can expect from the Huffington Post. The author takes a look at the public advocacy of Aubrey de Grey, which in conjunction with coordinating the ongoing scientific programs of SENS Research Foundation keeps him quite busy. Perhaps the point to take away from this is that change and progress never happens as fast as we want it to, but it is happening nonetheless:

Almost every week, Aubrey de Grey gives a speech to an audience somewhere in the world. The Oxford-educated researcher walks to the stage, makes a few small jokes, and then tells his listeners about his quest to extend human life by ridding the world of age-related diseases. Over the years, he has become a seasoned speaker. He's mildly provocative and sometimes ironic, but always sharp and convincing. He is now the most familiar face on the conference circuit on the topic of regenerative medicine.

The best way to understand de Grey's vision is to understand his definition of aging: "The life-long accumulation of damage to the tissues, cells, and molecules of the body that occurs as an intrinsic side effect of the body's normal operation." A human body can tolerate some damage, but too much causes diseases. While you cannot eliminate aging from the body entirely, de Grey is convinced that there are ways for medicine to intervene. He proposes regenerative medicine, a process of replacing or regenerating human cells and eliminating all deadly cellular processes along the way.

It all sounds like a science-fiction movie, but de Grey didn't find his ideas in one of those. "They are a pain in the ass and make my life much harder," he says. "Certainly, these movies entrench the misconceptions people have. The movies that are made are movies that are made to sell, and those movies pander to people's preconceptions." And de Grey doesn't like the preconceptions of most people.

The public he usually stands in front of is not really that interested in the scientific processes behind regenerative therapy. They care more about the moral implications and the societal impact of his research. So they ask questions about overpopulation, about clashing generations, about dictators living forever, about people who want to commit suicide, about God and about nature. De Grey is always prepared and has an answer for each of them. "It's been a very long time since I got a question that I haven't heard before," he explains. "My answers have been getting a bit more aggressive over the years, a bit more impatient, but I've always seen it as part of the job."

De Grey is noticing a shift in the general attitude toward regenerative therapy. "Definitely things are getting easier - not nearly quick enough, but the whole tone of this conversation is now very different than it was 10 years ago. Back then you couldn't really have these discussions. People called me controversial, a maverick. Now people ask you questions with an expectation that you actually will be able to teach them something." Still, most people don't seem to like thinking about living forever. "There are a lot of things that people don't like to think about. People don't like to think about getting old and getting sick either. They pretend it's not going to happen, until it does."


Aiming to Remove the Senescent Cell Contribution to Aging and Age-Related Disease

As the years pass ever more of your cells fall into a state of senescence. This is a response to the age of the cell itself, its internal damage, surrounding levels of metabolic waste, the presence of cell-damaging toxins, or other signals that indicate a potentially raised risk of cancer. Senescent cells do not divide or do much else to support the tissue they are a part of, but rather emit a range of potentially harmful chemical signals that encourage other nearby cells to also enter a senescent state. Senescent cells sometimes self-destruct, or they can be removed by the immune system, but the immune system has its own process of age-related decline and this activity falters. Cellular senescence can indeed reduce the risk of cancer, but by the time there are significant numbers of senescent cells gathered in the body their presence causes all sorts of harm: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer due to their generally bad behavior.

Cellular senescence is one of the more exciting areas of the biochemistry of aging, because the research community is very close to being able to produce treatments for the targeted, safe removal of senescent cells. Early animal studies have provided initial evidence that doing so does produce improvements in health and longevity, as expected. Further studies in rodents presently in progress should firmly demonstrate that healthy, normal animals benefit from the removal of senescent cells. After that, it is a matter of pulling together the targeted cell killing techniques pioneered by the cancer research community with one of the new prospective methods for accurately distinguishing senescent cells from their healthy peers. If not for the generally slow, expensive pace of medical regulation this is something that could probably be done within the next five years, or much sooner for technology demonstrations in laboratory animals.

Targeted destruction of senescent cells is an excellent candidate for a treatment that, like early stem cell therapies, could be offered outside the US for years prior to the more formal and straitjacketed medical development community coming to the point of trials. All the prototype parts of the toolkit are nearly ready, and a successful treatment to remove unwanted senescent cells would be an unalloyed benefit for any healthy older adult. Sadly, as is the case for near all of the most important areas of longevity science, there is little interest or funding for this work in comparison to its potential benefits to health. Things are moving more rapidly than for many other important areas of aging research, but funding is still at disappointingly low levels. We can hope that this will change at the point at which it becomes viable to offer prototype clinical treatments via medical tourism, in much the same way as matters proceeded for the development of the first stem cell therapies.

Here is the latest in a series of essays on the details of the SENS vision for rejuvenation therapies penned by philanthropist Jason Hope. Hope is one of the more noteworthy donors to the SENS Research Foundation, and clearly believes in the goals he supports:

Death Resistant Cells

There are two main approaches to the problems associated with senescent cells: develop a drug that is toxic to abnormal cells but harmless to healthy ones, or stimulate an immune response that targets and selectively kills unhealthy cells.

Molecules lining the surface of cells help those cells interact with their surroundings; these molecules are to varying degrees distinctive to their fate. Because each type of cell has different surface molecules, these molecules can serve as markers, or identification for that cell. Liver cells have a different group of molecules on their surface than blood cells, for example.

Abnormal cells have abnormal surface molecules, making these cells easy to target for therapy. Oncologists already use this type of approach when treating some types of cancer with the intent of shutting down the cancer cells' growth with drugs or by stimulating the immune system to do the job. In some cases, killing abnormal cells deters, treats, or prevents illnesses by making room for new, healthy cells.

Using SENS Research Foundation funding, scientists from University of Arizona are investigating ways to restore a healthy immune system in aging mice by purging unhealthy immune cells known as "anergic T-cells" to free up space for new and healthy killer T-cells. The researchers also hope to bolster the immune system by increasing the body's ability to produce new killer T-cells.

With funding from SENS Research Foundation and working in Dr. Judith Campisi's laboratory at the Buck Institute for Research on Aging, PhD candidate Kevin Perrott is investigating how molecules affect one type of senescent skin cell to understand its role in inflammation and the immune system. These scientists also hope to discover how to kill these senescent cells before they can cause a problem. Additionally, these researchers are testing a library of compounds to identify any that are capable of selectively targeting senescent cells.

SENS Research Foundation funding also supports research performed by Nick Schaum in the Campisi lab, which has shed light on the link between the two hallmarks of cell senescence, identifying a key driver of inflammation and halted cell division.

The goal of these research projects is to understand how cell programming can cause illness and to develop ways to control cell senescence, either through therapeutic drugs or by stimulating the immune system so that it destroys only abnormal cells while leaving healthy cells intact. Success will lead to new rejuvenation biotechnologies to prevent, treat, and even reverse the course of the disease and disability caused by these abnormal cells.

Aging, Klotho, and Skeletal Muscle

Klotho is one of numerous genes demonstrated to influence longevity in several species of laboratory animal. Like all of the other genes it influences many fundamental cellular and metabolic processes, which makes deciphering how and why it all works to affect the pace of aging a real challenge. There are probably a few core (and very complex) arrays of biological machinery that influence aging greatly enough to be easily measurable, established long ago in the deep evolutionary past, and thus shared across many different species. However influencing these mechanisms can be accomplished by altering any one of many varied genes, or changing the level of any one of many varied proteins in tissues, and all of these changes produce other effects as well. Biology likes reuse, and any one gene or protein might play a role in dozens of mechanisms.

Thus the low-level details of the progression of aging are a maze, poorly understood at present, even though the actual results in terms of differences between old tissue and young tissue are very well cataloged and understood. This is one of the reasons why attempting to produce age-slowing drugs that work through targeted metabolic manipulation is the slow, expensive road to marginal results. More than a decade of work and upwards of a billion dollars have been poured into simply trying to recreate some aspects of one well-studied metabolic alteration that increases longevity in laboratory species, the response to calorie restriction. There is little to show for it so far but more knowledge. If that same billion dollars had been put into SENS-like repair strategies, aimed at reverting the known changes in tissues that occur with aging and letting metabolism take care of itself, we'd be most of the way towards a rejuvenation toolkit demonstrated in mice by now. But no-one said the world was rational.

Here researchers speculate on the relationship between klotho and muscle metabolism, suggesting that it might shed some more light on why exactly it is that exercise improves long-term health:

Mankind has long sought means to extend longevity and counteract the effects of aging on physical functioning. Modern day scientific discoveries have made considerable strides in our biological understanding of contributing factors in the aging process. Such discoveries are critical for the development of therapeutic strategies to prevent, delay or reverse age-related declines.

Klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Similar anti-aging effects have also been ascribed to exercise and physical activity. While an association between muscle function and Klotho expression has been previously suggested from longitudinal cohort studies, a direct relationship between circulating Klotho and skeletal muscle has not been investigated. In this paper, we present a review of the literature and preliminary evidence that, together, suggests Klotho expression may be modulated by skeletal muscle activity.

Our pilot clinical findings performed in young and aged individuals suggest that circulating Klotho levels are upregulated in response to an acute exercise bout, but that the response may be dependent on fitness level. A similar upregulation of circulating Klotho is also observed in response to an acute exercise in young and old mice, suggesting that this may be a good model for mechanistically probing the role of physical activity on Klotho expression. Finally, we highlight overlapping signaling pathways that are modulated by both Klotho and skeletal muscle and propose potential mechanisms for cross-talk between the two. It is hoped that this review will stimulate further consideration of the relationship between skeletal muscle activity and Klotho expression, potentially leading to important insights into the well-documented systemic anti-aging effects of exercise.


Quantifying the Value of a Healthy Lifestyle

As a companion piece to a recent post on the cost of obesity and lack of exercise, as determined by epidemiological studies, here is another study that looks at the costs and benefits of various lifestyle choices:

Cardiovascular diseases (CVDs), cancer, diabetes and chronic respiratory disorders - the incidence of these non-communicable diseases (NCDs) is constantly rising in industrialised countries. Attention is focusing, amongst other things, on the main risk factors for these diseases which are linked to personal behaviour - i.e. tobacco smoking, an unhealthy diet, physical inactivity and harmful alcohol consumption. For the study the researchers used data from the Swiss National Cohort (SNC). The Zurich public health physicians focussed on CVDs and cancer as they account for the most deaths in Switzerland. The researchers succeeded in correlating data on tobacco consumption, fruit consumption, physical activity and alcohol consumption from 16,721 participants aged between 16 and 90 from 1977 to 1993 with the corresponding deaths up to 2008. The impact of the four forms of behaviour was still visible when biological risk factors like weight and blood pressure were taken into account as well.

Compared with a group of non-smokers, smokers have a 57 percent higher risk of dying prematurely. The impact of an unhealthy diet, not enough sport and alcohol abuse results in an elevated mortality risk of around 15 percent for each factor. An unhealthy lifestyle has above all a long-lasting impact. Whereas high wine consumption, cigarettes, an unhealthy diet and physical inactivity scarcely had any effect on mortality amongst the 45 to 55-year-olds, it does have a visible effect on 65 to 75-year-olds. The probability of a 75-year-old man with none of the four risk factors surviving the next ten years is 67 percent, exactly the same as the risk for a smoker who is ten years younger, doesn't exercise, eats unhealthily and drinks a lot. An individual who smokes, drinks a lot, is physically inactive and has an unhealthy diet has 2.5 fold higher mortality risk in epidemiological terms than an individual who looks after his health. Or to put it positively: "A healthy lifestyle can help you stay ten years' younger."


Stem Cell Decline and Loss of Organ Mass with Aging

There are a few hundred different types of cell in the body, a collection of types for each major organ and variety of tissue. Cell populations turn over at various different rates, with new cells supplied by dedicated supporting stem cells, existing cells in the tissue dividing, and old cells removing themselves from the picture through forms of programmed cell death. The cells that line your gut have a very short life of a few days. Blood cells are usually in circulation for months. Many nervous system cells last your entire life. Unfortunately old cells that have divided many times don't always self-destruct, and instead slide into a form of growth arrest known as senescence. There they stay unless destroyed by the immune system, making life difficult for surrounding cells and degrading tissue function. The growing number of senescent cells in all tissues is one of the causes of degenerative aging.

One of the other problems in this context of tissue maintenance is that the supply of new cells dwindles with age. Stem cells stop doing their jobs and spend more time in dormant states. As a result tissue and organ function begins to falter and eventually fail. The consensus viewpoint in the research community is that this is an evolutionary adaptation that reduces cancer risk. The big important difference between humans and possibly immortal highly regenerative lower animals such as hydra is that we are complex and the continuation of an individual's life depends on maintaining the small-scale accumulated structure of our nervous system - we can't just throw it all out and regenerate it as needed. If you have a brain, or even just a rudimentary central nervous system, that rules out the sort of high-powered always-on stem cell activity that allows a hydra to be (possibly) ageless and renew or regrow any lost part.

One of the manifestations of diminished stem cell activity with aging is that we lose tissue mass in most of the important organs. This may be a straightforward consequence of lack of replenishment, but as the paper linked below notes it starts fairly early in adult life. In this viewpoint, the well-known involution of the thymus at end of childhood is just the most noticeable of a set of similar changes that occur throughout adulthood and into old age. Loss of stem cell activity is something that has to be fixed by any comprehensive rejuvenation toolkit of the near future, or at least it has to be fixed to the extent that it is not just a reaction to forms of tissue damage. It is quite likely that stem cell decline in old age is in fact largely driven by epigenetic changes that in turn arise due to rising levels of - for example - mitochondrial DNA damage, metabolic waste in cells and between cells, accumulated senescent cells, and so forth. If this damage is repaired, then stem cells should return to work.

Greater organ involution in highly proliferative tissues associated with the early onset and acceleration of ageing in humans

We employed published data to estimate representative mean values of cell turnover times for 31 different organs and tissues in adult humans and animals (when data in humans were lacking) as well as functional mass loss for 5 organs, accounting for actual mass loss and tissue conversion to fat, in humans over the adult period, age 25 to 70. Actual and functional organ mass was lost from age 25 to 70 years in all organs studied, except the heart and prostate. We found that greater actual and functional mass loss was significantly associated with the log of shorter cell turnover times. We propose that this is characteristic of stem cell exhaustion and replicative senescence.

We found that, in normal ageing, organ mass loss is associated with high cell turnover. At the Hayflick limit, cells go into a senescent state of persistent cell cycle arrest, or undergo cell death, usually by p53-dependent apoptosis. This increase in apoptotic and senescent cells with ageing represents a loss of actual and functional tissue. We suggest that this mass loss may be characteristic of stem cell exhaustion as seen in muscle and marrow and that "replicative senescence" may play a role in this process. Stem cell pools can diminish with age. For example, the number of satellite cells in human skeletal muscle declines from young to old adults. Furthermore, stem cell exhaustion may be due to cell dysfunction characterised by decreased self-renewal and quiescence, increased doubling time, degraded niches and impaired terminal differentiation.

Our analysis of previously published data indicates that mass loss in major organs generally begins between 21 and 35 years of age for reproductive organs and between 22 and 50 years for non-reproductive organs, although involution of the thymus begins even earlier. Likewise, many physiological functions show a decline from 30 years of age. Similarly some aspects of age-related cognitive decline begin in healthy educated adults when they are in their 20s and 30s. Therefore, our evaluation of organ mass loss, especially in terms of functional tissue reduction, is in parallel with, and likely contributes to, the decline in physiological and cognitive function. Furthermore, these studies also provide substantial, but not universal, evidence for the acceleration of actual and functional mass loss in organs. As the few studies dedicated to these ageing changes indicate that these functional tissue losses may be considerable, this suggests that even measures of body cell mass underestimate the true accelerating loss of functional tissue with ageing. Indeed, accelerated functional mass loss could provide an increased elimination of precancerous cells in the very elderly, perhaps providing an explanation, among others, for the decrease in cancer rates observed after age 75.

The general prevalence of the Hayflick limit in human somatic cells, including stem cells, means this aspect of human ageing is likely an evolutionary adaptation, as antidotes against this shortening, such as telomerase, are not employed at sustaining levels in somatic tissues. However, telomere-maintenance mechanisms are fully operational in human germ cells, most neoplasms (clonal cells) and biologically immortal species such as Hydra vulgaris that reproduce asexually when food is plentiful. The immortality (and lack of reported mass loss) of Hydra is assigned to FoxO stem cell maintenance gene variants, which are also found in human stem cells, albeit at levels insufficient to maintain stem cells. Interestingly, a genetic variant in the FOXO3a gene region is more common in German centenarians compared with younger controls.

Our review supports a strongly significant association between cell proliferation and functional mass loss, the latter being an important indicator of fitness and ageing. We found that two-thirds of the human variability of mass loss can be assigned to the log of tissue turnover times. We suggest that this is likely characteristic of replicative senescence of stem cells, which, as the immortal Hydra demonstrates, is not a biological imperative but an evolutionary adaptation, likely suppressing cancer in humans. The onset of functional mass loss first becomes apparent soon after growth terminates, during the early part of the reproductive period, when selective pressure is still considerable. We make the case that, although the deceleration of cell turnover helps mitigate the erosion of maintenance-deficient telomeres, there is an acceleration of functional mass loss in old age as biological conditions change from those existing in early development, when the selective pressure on genetic trade-offs is most influential.

Trapped by the Conviction that an Extended Life Means Older For Longer, Not Younger For Longer

The belief that extending life through new medical science will lead to people who spend their additional years becoming ever more decrepit and frail is widespread and hard to shake. Scientists have told the public over and again that this is not going to be the outcome: any successful treatment for the causes of aging will produce patients who are younger than their years. Extending life will inevitably mean extending youthful, healthy life, because aging is just an accumulation of damage. The medical conditions that we call age-related diseases are just late manifestations of very high levels of damage. The only sound way to extend life is through reduction or repair of this damage, and that extends the period of health, pushing back the onset of medical conditions and deterioration.

But it doesn't seem to matter how many times this is repeated by members of the research community. People just aren't listening. The article quoted below is a microcosm of this larger picture: an author who hears what is said about aging, medicine, and healthy life, and cruises right on past to conclude with the same fear of extended years of frailty that he started with:

The idea of defeating old age and even death has been with us for a long time. In Greek mythology, there was a handsome young fellow called Tithonius who was in love with Eos, the Goddess of Dawn. Aware that he was getting older while she remained young and beautiful forever, he asked her to make him immortal. She couldn't do it herself but passed on the request to Zeus, who obligingly granted it. Unfortunately, Tithonius had asked only for immortality, not for eternal youth. So he became a horrible-looking old man, suffering aches and pains and unable to die. Eos took pity on him and turned him into a grasshopper, presumably an immortal one. Motto: be careful of what you ask from the gods.

The possibility of extending life far beyond what is now its usual term is apparently becoming a reality. Of course, thanks to medical advances, this has been happening for some time. Most of us can already expect to live quite a bit beyond the Bible's allotted span of 70 years. But the science is marching quickly. Aubrey de Grey, co-founder of SENS (Strategies for Engineered Negligible Senescence), believes that we can eliminate the symptoms of ageing, and live for as long as 1,000 years. Ninety per cent of us apparently die of what is nothing more than old age - bits wearing out and all that - and this, he says, is unnecessary. A thousand years may seem a touch extravagant, but we are already accustomed to being fitted with spare parts that help to keep us going. Then that great killer, cancer, is usually, though not always, a disease of old age, and, if/when a cure is found, then that will be another cause of death that has been abolished.

Now, most of us are quite in favour of staying alive, so long as our bodies and minds keep functioning with reasonable efficiency. For many the real fear is dementia, and most of the over-70s I know will say that if that happens and the mind crumbles, they hope that somebody will be kind enough to put a pillow over their face and press down hard. Unfortunately, for obvious and respectable reasons, few are ready to oblige. Nevertheless, many will agree with me that it's preferable to go to the grave than to go nuts.

However, assuming that the life-extension scientists can also find ways of fending off dementia, how do we feel, individually and as a society, about the prolongation of life? Are we happy about the prospect of so lop-sided a society? Aubrey de Grey, with the enthusiasm of a pioneer, says he hopes to make it possible for people of 90 to wake up feeling as ready to go as they did when they were 30, and with no greater chance of not waking up the next day as they had 60 years previously. However, he admits that this transformation will require "hi-tech intervention", which is what he says he is working on.

It's quite possible that the life-extended might be as useless and miserable as Swift's Strulbrugs. Why prolong life, some sage once asked, save to prolong pleasure? Why indeed? Can the life-extension zealots assure us of continuing pleasure? I don't know. Nobody knows. But evidently the prospect of life-extension is real. We had better start thinking about it. Will it make for individual happiness and social contentment? If not, shouldn't we oldies get ready to shuffle off the mortal coil? One thing is sure: few of us want to end up like Tithonius, condemned to live in decrepitude and misery. Worse than Tithonius indeed, there being no kindly former lover and goddess on hand to change us into a grasshopper.


An Article on the Work of the Gerontology Research Group

The all volunteer Gerontology Research Group is a online notable hub for the aging research community, thanks to a mailing list and a few highly connected scientists who keep things running along with a shoestring budget. This article takes a look at the offline work of the organization, the challenging process of accumulating reliable data on survival and mortality in extreme old age:

Since 1990, the Gerontology Research Group has assumed the role of record keepers for the world's supercentenarians, or persons older than 110. Previously, research groups, individual countries and private hobbyists tracked supercentenarians for studies or for census purposes, or simply out of personal interest. But that information was not compiled into a central, standardized database, and it was largely closed to public viewing. In addition to satiating curiosity and providing world-record listings, the Gerontology Research Group's database also offers scientific insight into the phenomenon of living an exceedingly long life. Expert volunteers with the organization conduct extensive interviews with the people on the list, taking blood samples for DNA analysis from those who are willing. Ultimately, the group's goal is to use such data to design drugs that will slow down the aging process itself, though such breakthroughs - if even possible - are likely years away.

For every supercentenarian that the Gerontology Research Group confirms, probably at least one more slips through the cracks. Some families simply prefer to protect their privacy, so they do not reach out to the group. In other cases, the researchers might not have the logistic capacity to investigate every lead. Although the group includes about 40 volunteer correspondents based around the world who are in charge of tracking down supercentenarians in their country or region, sometimes claims prove impossible to follow-up on. In other cases, individuals who don't make the cut likely are genuine supercentenarians, but they are unable to provide the documentation to prove it. While Japan has kept scrupulous birth records for more than a century (perhaps partly explaining why that country has so many supercentenarians per capita), other countries have historically been less meticulous about that task.

For now, very few make it to 110. "The probability of getting to be a supercentenarian is about one in seven million," and living beyond that milestone is even more exceptional. A 110-year-old's odds of seeing her 111th birthday is about 50-50, meaning that living to 113, 114 or 115 is like getting three, four or five heads in a row in a coin toss. This, of course, leads to the burning question: how do those who make it to 110 and beyond manage that feat?

The short answer is that we do not know. Supercentenarians come from diverse occupations and social backgrounds. Some drink and smoke, while others abstain from the partying lifestyle; some are religious, others atheists; some have rich networks of family and friends, others are virtually on their own. While centenarians tend to cluster in Sardinia, Italy, and Okinawa, Japan, supercentenarians, on the other hand, have no significant association with any particular geographic area. "I've interviewed more supercentenarians than probably anyone else, trying to find out what they have in common. The answer is almost nothing."


Recent Research Data on Lack of Exercise and Obesity

For an allegedly industrious species, we are quite indolent as individuals - or at least just as soon as we achieve a modicum of wealth and success in life. Being wealthier beats the pants off being poorer at every level of improvement, but for most people it comes with some costs as well as a universal array of benefits. You can afford better healthcare, but you are going to need it because you exercise less and eat more. The self-sabotage of an averagely unhealthy lifestyle is enabled by the trappings of modern technology, such as advances in transport, comfort, and entertainment, even as that very same technology is heading towards the establishment of science-fiction-like medicine that will defeat all disease and even aging itself in the decades ahead. For now we're stuck somewhere in the fat and unhealthy middle ground, however: enough technology to seduce us into a lazy, likely shorter life of worse health, but not yet enough technology to reliably rescue us from this fate.

Thus despite the impending golden future of medicine, it remains the case that taking basic, time-worn, good care of your health still matters. Willpower, exercise, and eating less than you want to. If you desire good odds of living to benefit from first generation rejuvenation therapies, then stay healthy on the one hand, and do all you can to help speed initiatives such as the SENS research programs on the other. Here is a small selection of recent research that might incentivize you a little on the good health side of the house:

NCI study finds extreme obesity may shorten life expectancy up to 14 years

Adults with extreme obesity have increased risks of dying at a younger age from cancer and many other causes including heart disease, stroke, diabetes, and kidney and liver diseases, according to results of an analysis of data pooled from 20 large studies of people from three countries. These groups form a major part of the NCI Cohort Consortium, which is a large-scale partnership that identifies risk factors for cancer death. After excluding individuals who had ever smoked or had a history of certain diseases, the researchers evaluated the risk of premature death overall and the risk of premature death from specific causes in more than 9,500 individuals who were class III obese and 304,000 others who were classified as normal weight.

The researchers found that the risk of dying overall and from most major health causes rose continuously with increasing BMI within the class III obesity group. Statistical analyses of the pooled data indicated that the excess numbers of deaths in the class III obesity group were mostly due to heart disease, cancer and diabetes. Years of life lost ranged from 6.5 years for participants with a BMI of 40-44.9 to 13.7 years for a BMI of 55-59.9. To provide context, the researchers found that the number of years of life lost for class III obesity was equal or higher than that of current (versus never) cigarette smokers among normal-weight participants in the same study.

Sitting too much, not just lack of exercise, is detrimental to cardiovascular health

Sedentary behavior involves low levels of energy expenditure activities such as sitting, driving, watching television, and reading, among others. The findings suggest that sedentary behavior may be an important determinant of cardiorespiratory fitness, independent of exercise. "Previous studies have reported that sedentary behavior was associated with an increased risk for cardiovascular outcomes; however, the mechanisms through which this occurs are not completely understood. Our data suggest that sedentary behavior may increase risk through an impact on lower fitness levels, and that avoiding sedentary behavior throughout the day may represent an important companion strategy to improve fitness and health, outside of regular exercise activity."

The team of physician-researchers analyzed accelerometer data from men and women between the ages of 12 and 49 with no known history of heart disease, asthma, or stroke, and measured their average daily physical activity and sedentary behavior times. Fitness was estimated using a submaximal treadmill test, and variables were adjusted for gender, age, and body mass index. The findings demonstrate that the negative effect of six hours of sedentary time on fitness levels was similar in magnitude to the benefit of one hour of exercise.

Less Exercise, Not More Calories, Responsible for Expanding Waistlines

Sedentary lifestyle and not caloric intake may be to blame for increased obesity in the US, according to a new analysis of data from the National Health and Nutrition Examination Survey (NHANES). [In] the past 20 years there has been a sharp decrease in physical exercise and an increase in average body mass index (BMI), while caloric intake has remained steady. Investigators theorized that a nationwide drop in leisure-time physical activity, especially among young women, may be responsible for the upward trend in obesity rates.

By analyzing NHANES data from the last 20 years, researchers from Stanford University discovered that the number of US adult women who reported no physical activity jumped from 19.1% in 1994 to 51.7% in 2010. For men, the number increased from 11.4% in 1994 to 43.5% in 2010. During the period, average BMI has increased across the board, with the most dramatic rise found among young women ages 18-39.

The study looked at the escalation of obesity in terms of both exercise and caloric intake. While investigators did not examine what types of foods were consumed, they did observe that total daily calorie, fat, carbohydrate, and protein consumption have not changed significantly over the last 20 years, yet the obesity rate among Americans is continuing to rise.

Researchers also tracked the rise in abdominal obesity, which is an independent indicator of mortality even among people with normal BMIs. Abdominal obesity is defined by waist circumference of 88 cm (34.65 in) or greater for women and 102 cm (40.16 in) or greater for men. Data showed that average waist circumference increased by 0.37% per year for women and 0.27% per year for men.

TDP43 and Autophagy in Frontotemporal Dementia and ALS

Researchers have been looking into the biochemistry of TDP43 and failure of autophagy for a few years now in the context of some age-related dementias and amyotrophic lateral sclerosis (ALS). The processes of autophagy are cellular housekeeping mechanisms, acting to recycle damaged components and remove unwanted waste. More autophagy is shown to occur in connection with many of the presently known methods of slowing aging and extending life in laboratory animals. The research community has been slow off the mark to make inroads into the development of treatments based on enhanced autophagy, however - there is nowhere near as much interest and funding for this goal as for, say, the production of calorie restriction mimetic drugs.

Still here is one example of this approach gaining traction, though here the aim is to treat conditions in which autophagy is impaired in a specific way, through the presence of too much TDP43. It is unclear as to whether a treatment to reduce levels of TDP43 would be of any application to boosting autophagy in an undamaged metabolism.

Deep inside the brains of people with dementia and ALS, globs of abnormal protein gum up the inner workings of brain cells - dooming them to an early death. But boosting those cells' natural ability to clean up those clogs might hold the key to better treatment for such conditions. Though the team showed the effect worked in animals and human neurons from stem cells, not patients, their discoveries point the way to find new medicines that boost the protein-clearing cleanup process.

The researchers focused on a crucial cell-cleaning process called autophagy - a hot topic in basic medical research these days, as scientists discover its important role in many conditions. In autophagy, cells bundle unwanted materials up, break them down and push the waste products out. [The team] showed how the self-cleaning capacity of some brain cells gets overwhelmed if the cells make too much of an abnormal protein called TDP43. The found that cells vary greatly in how quickly their autophagy capacity gets swamped.

"Using [a] new visualization technique, we could truly see how the protein was being cleared, and therefore which compounds could enhance the pace of clearance and shorten the half-life of TDP43 inside cells. This allowed us to see that increased autophagy was directly related to improved cell survival." Longer-living, TDP43-clearing brain cells are theoretically what people with ALS and frontotemporal dementia need. But only further research will show for sure.


Stochastic Mutations in Mitochondrial DNA are Commonplace

Certain forms of mitochondrial DNA damage are one of the causes of aging. Your mitochondria, the cell's power plants, are the remnants of ancient symbiotic bacteria. Most of their original DNA is lost or migrated to the cell nucleus, but a small number of genes remain. This DNA is much more vulnerable to damage and has worse repair mechanisms than nuclear DNA, but if important parts are lost then the outcome can be dysfunctional mitochondria that overtake the cell because they are more resistant to being cleared out by quality control mechanisms. That cell will then cause harm to surrounding tissues by exporting damaged proteins and reactive molecules: this is the modern mitochondrial free radical theory of aging in a nutshell.

Since this is likely an important cause of aging we should expect to see that everyone has an appreciable load of stochastic damage to their mitochondrial DNA, and that this damage grows over time. As the cost of DNA sequencing continues to fall and thousands of human genomes are being sequenced, this data is becoming available:

Mutations in one or more copies of mitochondrial DNA, known as heteroplasmies, are likely to be much more common in healthy people than previously anticipated. Approximately 90 percent of healthy participants in the 1000 Genomes Project harbored at least one heteroplasmy, and 20 percent bore mitochondrial genome mutations implicated in diseases. "It's been known for a long time that lesions in mitochondrial DNA become more prevalent with age. This study offers the intriguing possibility that maybe everybody has a little bit of something wrong with their mitochondrial DNA and that might play a role in aging."

Because a single cell can contain hundreds to thousands of mitochondria, it also carries multiple copies - and, sometimes, variants - of these maternally inherited genomes. Pathogenic mutations can co-exist with healthy mitochondrial DNA (mtDNA) within a cell or group of cells; clinical signs of disease only occur when the frequency of mutations crosses a threshold, which typically ranges from 60 to 85 percent of mitochondria. Severe mtDNA mutations can cause certain myopathies, epilepsy, and other diseases, while less pathogenic variants have been implicated in complex conditions such as type 2 diabetes, aging, and cancer.

Although these results suggest pathogenic mtDNA mutations are more prevalent than previously thought, the low frequency at which they occur is unlikely to have a negative impact on health. However, if the mutations increase in frequency in some fraction of cells as they divide, they could provide a likely source of mitochondrial dysfunction. "The problem is that mitochondrial DNA isn't stable, so there's nothing to say that a 1 percent load of mutation won't blossom into a different level later." Even though a low-frequency mutation "isn't pathogenic in and of itself, it's harder to develop a mutation later if you don't have one, compared to when you start with some level of mutation."


Fight Aging! Newsletter Delivery Issues to Gmail Accounts

Ensuring that the thousands of emails sent out each week for the Fight Aging! newsletter all end up where they should is an ongoing battle with the forces of entropy. Every mail service has its own quirks, and there are dozens of services large enough to require attention. Anti-spam automation is a complex ecosystem, prone to errors and false positive identifications, and one in which small organizations have little influence or recourse to correct such errors. Much of the categorization of spam is completely automated and networked, machines identifying and publishing analyses in real time. Other networks of machines then build their own conclusions based on each layer of processed data. It is like an immune system, and just like the real immune system it can sometimes produce poor outcomes for reasons that are challenging to determine.

A case in point is that in recent weeks Gmail subscribers have been missing out on the Fight Aging! newsletter. At some point Google's internal systems decided that one past newsletter was spam or a promotional email, not a legitimate mail requested by a list subscriber. This could have happened for any number of obscure and complicated causes, but probably has a lot to do with the fact that I have been talking about fundraising of late. Sending a newsletter that discusses longevity science is already sailing close to the wind from the point of view of the global anti-spam ecosystem, given the amount of junk the frauds and marketing departments of the "anti-aging" industry generate. Mix in mentioning money with that, and apparently I'm just asking for it. Spam automation has always had problems distinguishing between real science and fake science relating to aging and longevity, which may be yet another reflection of the fact that most people - a category that includes most people who work on anti-spam automation - still don't think that there is real science there to be discussed.

Google's anti-spam automation is self-reinforcing. If one newsletter ends up in the spam folder or Promotions tab at Gmail, then all similar following emails will as well. Google's systems cheerfully build upon any mistake, and worse, they propagate that mistake out into the broader anti-spam ecosystem to make it more likely that other systems identify Fight Aging! newsletters as spam and blacklist the Fight Aging! mail server. As anyone who has ever had issues with Google's free products know, there is no way to reach an actual human being at Google unless you happen to represent a large business concern, or you have a large audience and can make Google look bad by complaining. Errors don't get fixed, there is no customer service, and you simply have to deal with whatever breakage they create.

So I am doing what I can at my end, but there are really very few ways to influence this course of events beyond moving the mail server, a task that is presently in progress. Even there the actual thread of identification in Google's systems is the email address and the content of the newsletter, not the mail server's location. Moving the server just helps to minimize some of the other damaging consequences resulting from this issue.

The best solution under the circumstances is for Gmail subscribers to find the recent Fight Aging! newsletters in the spam folder or the Promotions tab in their account and then inform Gmail that (a) these emails are are not spam, and (b) that they want to receive future similar emails in the Primary tab. If enough people do this, then it will go some way towards teaching Gmail's automation not to miscategorize these newsletters.

So if you are subscribed to the Fight Aging! newsletter at a Gmail address, please check your spam folder for copies of the Fight Aging! newsletter from the past few weeks. For each, select the mail and click the "Not Spam" button. This will probably move it to the Promotions tab of your inbox. Then please open the Promotions tab of your inbox, find the newsletter emails there and drag them to the Primary tab. You will see a popup asking you whether all future similar emails should be delivered to the Primary tab. Choose that option. I'd greatly appreciate it.

The Lack of Ambition that Characterizes Much of the Discussion of Aging and Longevity

Near all of the discussion on human aging and longevity that takes place even nowadays, in this age of revolutionary progress in biotechnology, is characterized by a profound lack of ambition. People think about aging and wisely nod their heads and say things like "we should focus on our lifestyle choices" so as to marginally alter the outcome of disability and death. This is disappointing on many levels. It seems that the majority gravitate to tinkering with what is, to doing easy things simply because they are easy, rather than trying in earnest to change matters for the better. The best lifestyle choices in the world will still lead to a 75% mortality rate by age 90: the only way to do better is the creation of new medical technologies, such as the SENS vision of periodic repair of the known forms of cellular and molecular damage that cause aging.

Here is one example of failing to reach far enough: a post on a new longevity blog that glances at the present range of theories of aging, and then concludes that we should focus on lifestyle and environment because that is what we have control over now. It is disappointing to see this sort of response from someone who has actually looked into the science.

By knowing a little about why we age, we can begin to understand the things that we can and can't change about the process. Exerting control in certain areas of our lives, can give us the best chance to lead a longer, healthier, and happier life. There are many theories that offer an explanation of why human beings grow older. It has even been claimed that there are over 300 current hypotheses that attempt to explain aging. Space precludes a full evaluation of all perspectives, but in very general sense the main ideas can be summarized as evolutionary, biological, and wear-and-tear perspectives.

The evolutionary theories of aging suggest that natural selection has optimized the fitness of individuals only until they have conceived and reared children. Beyond middle age, it is theorized that evolution is essentially blind to the fate of individuals as by this time they are likely to have already passed on their genetic material and successfully raised their offspring to the point at which they can fend for themselves. In evolutionary terms, the work of life is done.

The biological theories of aging contend that there are inherent limits within our physiology that constrain individual lifespan. Theorized processes include limits in the number of times that certain cells can divide, the increasing potential for random mutations in the body, and the tendency for bodily systems to become increasingly unreliable over time. These perspectives suppose that we are ruled by the rhythm of a biological clock, which will tick, tick, tick until the main spring loses its charge and we expire.

The rate-of-living and wear-and-tear theories of aging are concerned with the accumulation of damage in the human body that results from either normal bodily functions (such as respiration and the conversion of food into energy that produces free radicals and oxidative damage) or the impacts of negative lifestyle behaviors and exposure to certain environmental conditions. Lifestyle factors that can influence aging are many and include exposure to UV radiation, smoking, body composition (proportion of body fat), exposure to chemicals and pollutants, mechanical injury or overuse, and others. It is in the realm of lifestyle and environment that we have the greatest hope of healthy life extension because these tend to be the domains over which we have the greatest control.


A Telomere-Centric View of the Biochemistry of Aging

Telomeres are lengths of repeated DNA at the end of chromosomes that in part serve as a sort of clock to limit the life span of some cell types. Telomeres shorten with each cell division, but can be lengthened in longer-lived cells (such as stem cells) by the activity of telomerase. Average telomere length tends to shorten in white blood cells with ill health and aging, but this is somewhat dynamic: go out and exercise more and your average telomere length will increase, for example. Looking at the average length is a smeared-out measure of numerous low-level processes in our biology, such as telomerase activity, the pace at which stem cells are generating new cells with long telomeres, rate of cell division, and so on and so forth.

For some years now there has been a contingent of researchers focused on telomeres: producing better ways to measure them, or more ambitiously trying to construct therapies that lengthen telomeres using telomerase. It seems to me that most research indicates shortening telomere length to be a secondary marker of aging, and thus not a helpful target to either slow or reverse aging, but there exist studies in which mouse life span was extended by upregulating the activity of telomerase. This may, however, be one of those areas of biology in which mice are in fact significantly different from people, or it may be the case that telomerase has other effects independent of lengthening telomeres, such as acting to reduce levels of mitochondrial damage.

Why is that telomere lengths are such good predictors of longevity, but too much telomerase can be bad for you? The answer is probably that telomere lengths measured in the white blood cells reflect a broad range of factors, such as our genetic makeup but also the history of a cell. Some of us may be lucky because we are genetically endowed with a slightly higher telomerase activity or longer telomeres, but the environment also plays a major role in regulating telomeres. If our cells are exposed to a lot of stress and injury - even at a young age - then they are forced to divide more often and shorten their telomeres. The telomere length measurements which predict health and longevity are snapshots taken at a certain point in time and cannot distinguish between inherited traits which confer the gift of longer telomeres to some and the lack of environmental stressors which may have allowed cells to maintain long telomeres.

What are the stressors which can affect cellular aging and shortening of telomeres? Oxidative stress, the excess production of reactive oxygen species oxidizes proteins, disrupting their structure and function to the extent that oxidized proteins become either useless or even harmful. Inflammatory stress refers to excessive inflammation which transcends the normal inflammatory response of cells from which they can recover. Prolonged inflammation, for example, can cause cells to activate a cell-death program. Recent studies in mice have shown that activation of inflammation pathways in the brain can suppress cognitive function, muscle strength and overall longevity. Stressors are often interconnected. Prolonged elevation of stress hormones or prolonged inflammation can increase oxidative stress. The higher the level of these stressors, the more prematurely cells will age. This means that the body of a person in their 30s or 40s exposed to high levels of inflammation or oxidative stress may already numerous cells showing signs of aging.

How do these stressors lead to premature aging? Shortening of telomeres could be one answer. If cells are chronically inflamed due to autoimmune diseases or inflammation-associated diseases such as obesity and atherosclerosis then they have to be continuously replaced by cell division which shortens telomeres. However, telomere shortening is not the only route to cell aging. Aging research groups have uncovered multiple additional pathways which can accelerate the premature aging of cells without necessarily requiring the shortening of telomeres. Inflammation or oxidative stress can activate certain aging pathways such as the aging regulator p16INK4a. An inflammatory cytokine can convert highly regenerative blood vessel progenitor cells into aged cells which no longer replicate by activating p16INK4a, and that this occurs without affecting telomere length. Researchers have uncovered an important vicious cycle: Once cells begin aging, they themselves release inflammatory proteins which in turn can activate aging in neighboring cells, thus setting a self-reinforcing cascade of aging in motion.

Where does this interaction of telomere-dependent and telomere-independent aging pathways as well as the influence of known (and many unknown) stressors leave us? The molecular understanding of cellular aging is progressing steadily, but the complexity of cellular aging and the even more complex question of how organs such as the brain and heart age requires a lot more work. There will be no single molecular switch which can reverse or halt aging and triple our lifespan, but most aging researchers do not have this as their goal. Understanding specific aging pathways, as well as the genes and stressors which activate them, will allow us to prevent and treat age-related diseases as well as one day be able to provide personalized advice to individuals on how to maximize their "healthspan".


Microbial Contributions to Alzheimer's Disease

There are a lot of papers on Alzheimer's disease that fall outside the mainstream focus on the formation of amyloid in the brain. This is perhaps in part a consequence of the challenges and delays that have beset efforts to produce practical treatments based on the amyloid view of the progression of Alzheimer's. As soon as any consensus in medical research and development fails to keep up its momentum, there are factions nibbling at its heels and trying out other ideas. The past few decades of the broader field of medical science are littered with promising approaches discarded in favor of others in the course of a few short years. Some of the alternative views of Alzheimer's disease are far out on the fringes, while others explore plausible contributions to the disease process wherein any debate must start with "yes, but is this a meaningful effect in comparison to others?" or "perhaps, but this is happening a long way in to the chain of consequences and dysfunction."

Here is an outline of an interesting view on the contribution of microbial populations to the progression of Alzheimer's disease, both the symbiotic gut microbiota that are considered to influence aging to some degree, and the impact of a lifetime of exposure to hostile pathogens. These may turn out to be proxies for the state of the immune system or metabolic dysfunction due to obesity and old age, both of which are important in the progression of degenerative aging. It makes for interesting reading, but it is worth asking questions such as those above when looking at this sort of thing.

Pathogenic microbes, the microbiome, and Alzheimer's disease (AD)

Here we list 10 recent, highly specific and illustrative insights into the potential contribution of pathogenic microbes, altered microbiome signaling and other disease-inducing agents to the development of AD:

1) Fungal infection of the central nervous system (CNS): Recently yeast and fungal proteins including (1,3)-β-glucan, high levels of fungal polysaccharides and disseminated and diffuse mycoses in the peripheral blood of AD patients suggests that chronic fungal infections may increase AD risk.

2) HSV-1 is associated with AD: Abundant evidence suggests that the herpes simplex virus-1 (HSV-1), can establish lifelong latency in CNS tissues and contribute to AD.

3) Prion diseases: driven by an unusual type of self-replicating "microbe," prion diseases are sporadic, inherited or acquired and ultimately fatal neurological disorders highly similar to AD. The recent discovery that prions can serve as receptors to relay amyloid neurotoxicity, and that peripherally administrated prions reach the brain, has engendered renewed interest in this self-replicating protein and its involvement in AD-like signaling processes that include neuroinflammation, synaptic degeneration and amyloidogenesis.

4) Chlamydophila pneumoniae, other pathogenic bacteria and AD: The association of the gram negative, obligate intracellular bacteria and pneumonia-causing C. pneumoniae of the family Chlamydiaceae with diseases such as coronary artery disease, arthritis, multiple sclerosis, meningoencephalitis, and AD has recently gained serious attention.

5) HIV-1 and AD: HIV-associated neurocognitive disorders (HAND) is a common manifestation of HIV infection and encompasses a variety of neurological disorders. Histopathologically HIV-infected brains exhibit atrophy of neurites and neuronal loss in anatomical areas identical to what is seen in AD.

6) Toxoplasma and neurodegeneration: Toxoplasma species such as Toxoplasma gondii are intracellular protozoan parasites that can cause encephalitis and neurological dysfunction by promoting chronic inflammation of the brain and CNS. Recently AD has been associated with significantly increased anti-T. gondii antibodies suggesting a possible mechanistic link between T. gondii infection and AD.

7) Viroids, miRNAs and AD: viroids are minimalist plant pathogens that consist of a viroid-specific ssRNA that are remarkably similar to miRNAs in their mode of generation, processing, structure and function, mobility and ability to spread disease within the host. We may be able to gain insight on the mechanism of AD neuropathology driven by miRNA from what is already known about plant viroids and their ability to spread systemic degenerative disease.

8) Hepatitis and AD: Hepatitis C virus infection has recently been shown to significantly increase the risk for AD, especially in the aged.

9) Cytomegalovirus and AD: A growing number of common viruses and latent viral infections involving Herpesviridae have been linked to the development of AD, and one of these is the human cytomegalovirus (HCMV).

10) GI tract and blood-brain barrier permeability: Lastly and importantly, the GI tract epithelial barrier and the blood brain barrier both become significantly more permeable over the course of aging. This may make the CNS more susceptible to potential neurotoxins generated by microbiome-resident or environmental pathogens.

Taken together, it is clear that the human CNS is under constant assault by a wide array of extrinsic and intrinsic neurotrophic microbes and pathogens including bacteria, virus, fungus, nucleic-acid free prions, or small non-coding RNAs found both in the environment and contained within the microbiome. Virtually every type of microbe known has been implicated in contributing to the susceptibility and pathogenesis of the AD process. This may be especially important over the course of aging because innate-immune and physiological barriers are often compromised with age, enabling microbes and/or their 'neurotoxic secretions' to gain easier access to CNS compartments. Because AD is clearly a multifactorial disease, and there are multiple biological pathways by which brain cells can dysfunction, perhaps it is not too surprising that multiple and complex microbial insults could contribute to AD, including the spreading of pathological signals throughout the CNS.

Better to Make the Choice to be Healthy, Even Late

There are a range of epidemiological studies showing that carrying excess weight for years is associated with a sizable raised risk of suffering all of the common age related diseases - even if you turn things around and lose that fat later. Keeping the fat is of course worse. Other studies show measurable benefits as a result of choosing to improve your health at near any age. Starting to exercise more rigorously or adopting calorie restriction in old age, for example, are both shown to be beneficial. It is of course more beneficial to have been doing it all along, but the point here is that it is silly to shrug your shoulders if you've been letting things go. You can always produce improvements in your future health prospects by choosing to do better.

When adults in their 30s and 40s decide to drop unhealthy habits that are harmful to their heart and embrace healthy lifestyle changes, they can control and potentially even reverse the natural progression of coronary artery disease, scientists found. "It's not too late. You're not doomed if you've hit young adulthood and acquired some bad habits. You can still make a change and it will have a benefit for your heart." On the flip side, scientists also found that if people drop healthy habits or pick up more bad habits as they age, there is measurable, detrimental impact on their coronary arteries. "If you don't keep up a healthy lifestyle, you'll see the evidence in terms of your risk of heart disease."

For this paper, scientists examined healthy lifestyle behaviors and coronary artery calcification and thickening among the more than 5,000 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who were assessed at baseline (when participants were ages 18 to 30) and 20 years later.

The healthy lifestyle factors assessed were: not being overweight/obese, being a nonsmoker and physically active and having low alcohol intake and a healthy diet. By young adulthood (at the beginning of the study), less than 10 percent of the CARDIA participants reported all five healthy lifestyle behaviors. At the 20-year mark, about 25 percent of the study participants had added at least one healthy lifestyle behavior. Each increase in healthy lifestyle factors was associated with reduced odds of detectable coronary artery calcification and lower intima-media thickness - two major markers of cardiovascular disease that can predict future cardiovascular events.


A Look at Lysosomal Exocytosis, or Throwing the Garbage Out

Lysosomes are one type of recycling unit in the cell, responsible for breaking down damaged cellular components and some unwanted proteins. One of the causes of aging is that in long-lived cells types of metabolic waste that cannot be broken down accumulate in lysosomes. These compounds are collectively called lipofuscin, and their presence in large amounts renders lysosomes bloated and inefficient. Cellular housekeeping as a whole then deteriorates until cells die or fall into dysfunctional states that harm tissue function. Everyone has this to look forward to. There is much less work taking place on a solution to this issue than on the analogous problem of lyososmal storage diseases, however, a collection of rare genetic disorders in which the lysosome lacks some of the tools it needs to break down ordinary, common structures and unwanted molecules. These compounds build up inside the cell and it eventually dies. If you follow the field of aging research you will see this over and and again: the harms that happen to everyone at the end of life are largely ignored, but there is much more interest in tackling similar problems that happen to just a few people in younger years.

Researchers here are looking at lysosomal exocytosis, which is a fancy term for the process in which a lysosome docks at the interior of the cell surface and then throws its cargo of garbage outside the cell. The degree to which this normally happens can be increased greatly, and early indications are that this is a potentially beneficial approach to treating lysosomal storage diseases. Will this be useful in the lysosomal issues that accompany aging, however? The type of garbage at issue is totally different, and it may well be that this would just swap the one problem for another. We have no idea what large amounts of lipofuscin between long-lived cells in nerve tissue will do over the long-term, though this is certainly something that could be investigated. Overall I'd prefer the SENS approach of infusing the body with enzymes that can safely break down lipofuscin constituents, but all of these strategies are at least worth investigation.

Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of endocytic and autophagic substrates such as membranes, proteins, and lipids into their basic building blocks. Lysosomal storage diseases (LSDs) are a group of metabolic disorders caused by genetic mutations in lysosomal hydrolases required for catabolic degradation, mutations in lysosomal membrane proteins important for catabolite export or membrane trafficking, or mutations in nonlysosomal proteins indirectly affecting these lysosomal functions.

A hallmark feature of LSDs is the primary and secondary excessive accumulation of undigested lipids in the lysosome, which causes lysosomal dysfunction and cell death, and subsequently pathological symptoms in various tissues and organs. There are more than 60 types of LSDs, but an effective therapeutic strategy is still lacking for most of them. Several recent in vitro and in vivo studies suggest that induction of lysosomal exocytosis could effectively reduce the accumulation of the storage materials. Meanwhile, the molecular machinery and regulatory mechanisms for lysosomal exocytosis are beginning to be revealed. In this paper, we first discuss these recent developments with the focus on the functional interactions between lipid storage and lysosomal exocytosis. We then discuss whether lysosomal exocytosis can be manipulated to correct lysosomal and cellular dysfunction caused by excessive lipid storage, providing a potentially general therapeutic approach for LSDs.


Reaching the Larger Audience

While it is true that it never crosses the mind of most folk to actually do anything personally to help along progress in medical science, there is an enormously greater level of grassroots support for working on any specific named age-related condition than there is for work on aging itself. Which is somewhat strange, as all of the former are caused by the latter. Yet the nominal and incoherent position of the average fellow in the street is that on the one hand he doesn't want to suffer cancer or heart disease or neurodegenerative conditions, and is generally pleased that there are people out there somewhere trying to build cures, but yet on the other hand he is perfectly fine with aging to death on the same schedule as his grandparents, and is even made a little uncomfortable by the idea that anyone out there is working to slow or reverse aging.

Even if we set aside politics and public funding, the philanthropic and for-profit resources directed towards research and development of treatments for late stage age-related conditions are enormous in comparison to funding for research into aging itself. At this stage the best thing that could happen for the future of all of this medical development is for a sizable and increasing fraction of this flow of funds to be directed towards rejuvenation research, work on repairing the causes of aging so as to prevent and reverse all of its consequences. It is a much more efficient and beneficial path forward than the continued efforts to patch over the consequences after they have happened, but it just doesn't have much support at the moment.

This sorry state of affairs will change for the better, and indeed is changing for the better even now, but progress here will continue far more slowly than it might unless some group figures out the key to the lock. We all know that advocacy can in the best of circumstances change the course of funding and attention for any given cause in medical science, producing a large growth in directed resources and real research in the labs and the clinics. Look at AIDS research for a comparatively recent example of great success in patient advocacy: from near nothing to very large investments in research and development in a very short span of time. It can be done.

The goal that must be accomplished for rejuvenation research is in theory a simpler one than producing support from nowhere for a new condition. It is to take the existing hope and approval for better treatments for age-related conditions and transfer some of that to the development of treatments for the root cause of those conditions, which is to say aging and the few forms of damage in and between our cells that cause us to suffer and die in so many varied ways. This seems simple and obvious, but people have been trying for a while to make this pitch to the public with limited success to show for it to date. It isn't easy, and bringing the world around to this way of looking at aging and ill health is taking time and effort.

The most important of the present generation of advocacy groups, which includes the Methuselah Foundation and SENS Research Foundation have for the past few years been talking far more about changing the approach to aging in the field and curing specific age-related conditions. Talk of extending life spans is far more muted nowadays, but it is still the case that successfully treating the causes of aging will have that outcome. We may well wind up ten or twenty years from now with an incoherent public position on medical research that supports SENS-like research while still being generally opposed to its inevitable outcome, which is to say much healthier, more robust older people who will live longer and are biologically much younger than their years thanks to rejuvenation treatments that actually work. If that comes to pass soon enough then we'll all be living longer as a side-effect of what people actually seem to want, which is not to have Alzheimer's or cancer or heart disease. The only reliable way to not have all these things is to repair the causes of aging: everything else is an expensive waste of time and effort by comparison.

Still, I fear that the incoherent beliefs regarding medical research into aging and the general lack of support for better approaches will drag us through potentially decades of persisting with failed and suboptimal approaches to the effective treatment of age-related disease before there is finally interest in trying something that works. Those decades of wasted time would put paid to the chances of my generation living long enough to benefit from working rejuvenation treatments. Which is something of an incentive to find the key to the lock. No bullet is quite so interesting as the one with your name on it.

Speculating on the Longevity Gap

For some folk, every possible aspect of future progress in technology is a chance to wish for class war. There will always be great differences between the haves and the have nots, but our modern age is distinguished from the past by just how little of medical technology is out of the reach of those comparatively poor people who live in the wealthier regions of the world where one finds most class war enthusiasts. If you are a billionaire you can buy the services of more doctors and assistants to do the legwork of applying for clinical trials, but there is no type of medicine that you can obtain with your wealth today that remains completely unavailable to the masses. This is generally true of most widely used technologies: communications devices, computing, transport, and so on. It is a flat age in which wealth buys you influence but little more than that.

When it comes to disparities in access to medicine, the people who care about such things should focus on those communities in the poorer reaches of the world that have yet to bring themselves up to par with Europe and US. The best way to help them is in fact to support faster progress towards ever better, cheaper, and more effective medical technology in Europe and the US: improvements in availability elsewhere will happen as a matter of course when price drops. Consider that the future of rejuvenation treatments will largely consist of mass-produced infusions: bacterial enzymes and other similar substances to break down metabolic waste, gene therapy vectors for allotopic expression of mitochondrial genes, and so forth. This is a form of medicine that once mature will be durable, easily administered, easily stored, and easily transported. It will be cheap, and it will eliminate the vast majority of all medical conditions, since the vast majority of all medical conditions are caused by aging.

Still, many people seem attached to their fond dreams of class war and immortality treatments that are reserved for the wealthy by virtue of being too expensive for everyone else. They're much more interested in pontificating on this topic than actually helping to support the production of rejuvenation treatments:

The disparity between top earners and everyone else is staggering in nations such as the United States, where 10 per cent of people accounted for 80 per cent of income growth since 1975. The life you can pay for as one of the anointed looks nothing like the lot tossed to everyone else: living in a home you own on some upscale cul-de-sac with your hybrid car and organic, grass-fed food sure beats renting (and driving) wrecks and subsisting on processed junk from supermarket shelves. But there's a related, looming inequity so brutal it could provoke violent class war: the growing gap between the longevity haves and have-nots.

The life expectancy gap between the affluent and the poor and working class in the US, for instance, now clocks in at 12.2 years. College-educated white men can expect to live to age 80, while counterparts without a high-school diploma die by age 67. White women with a college degree have a life expectancy of nearly 84, compared with uneducated women, who live to 73.

This is just a harbinger of things to come. What will happen when new scientific discoveries extend potential human lifespan and intensify these inequities on a more massive scale? It looks like the ultimate war between the haves and have-nots won't be fought over the issue of money, per se, but over living to age 60 versus living to 120 or more. Will anyone just accept that the haves get two lives while the have-nots barely get one? We should discuss the issue now, because we are close to delivering a true fountain of youth that could potentially extend our productive lifespan into our hundreds - it's no longer the stuff of science fiction.

Instead of allowing the wealth gap to turn into a longevity gap, perhaps we'll find a way to use everyone's talents and share the longevity dividend at all levels of income. This kind of sharing could leverage the wisdom of elders, forestall the economic collapse many have predicted when the grey tsunami picks up speed, and avoid an all-out revolt against the one or so per cent. We stand at the threshold of two distinct futures - one where we have a frail, rapidly ageing population that saps our economy, and another where everyone lives much longer and more productive lives.


CISD2 Affects Lifespan in Mice

Yet another new longevity-affecting gene is cataloged in this research. It may work through increased autophagy and thus more active cellular housekeeping activities:

CISD2, an evolutionarily conserved novel gene, plays a crucial role in lifespan control and human disease. Mutations in human CISD2 cause type 2 Wolfram syndrome, a rare neurodegenerative and metabolic disorder associated with a shortened lifespan. Significantly, the CISD2 gene is located within a region on human chromosome 4q where a genetic component for human longevity has been mapped through a comparative genome analysis of centenarian siblings.

We created Cisd2 knockout (loss-of-function) and transgenic (gain-of-function) mice to study the role of Cisd2 in development and pathophysiology, and demonstrated that Cisd2 expression affects lifespan in mammals. In the Cisd2 knockout mice, Cisd2 deficiency shortens lifespan and drives a panel of premature aging phenotypes. Additionally, an age-dependent decrease of Cisd2 expression has been detected during normal aging in mice. Interestingly, in the Cisd2 transgenic mice, we demonstrated that a persistent level of Cisd2 expression over the different stages of life gives the mice a long-lived phenotype that is linked to an extension in healthy lifespan and a delay in age-associated diseases.

At the cellular level, Cisd2 deficiency leads to mitochondrial breakdown and dysfunction accompanied by cell death with autophagic features. Recent studies revealed that Cisd2 may function as an autophagy regulator involved in the Bcl-2 mediated regulation of autophagy. Furthermore, Cisd2 regulates Ca2+ homeostasis and Ca2+ has been proposed to have an important regulatory role in autophagy. Finally, it remains to be elucidated if and how the regulation in Ca2+ homeostasis, autophagy and lifespan are interconnected at the molecular, cellular and organism levels.


A Selection of Recent Progress in Cell Biotechnology

To a large degree the future of medicine is the future of control over cells. Plus some other stuff around the edges relating to clearing up after cells, removing some of the metabolic waste and misfolded proteins that they can't deal with. These items aside, near all of disease and aging might be tamed with a sufficiently good ability to repair and direct the behavior of our cells as they go about the business of life. That is the ultimate goal of medicine: to prevent all death, suffering, and disability, and provide the option of remaining alive and in good health for as long as you desire.

In some ways these are still the very earliest days in the control of cells, despite more than a century of serious work on the topic. The research community is barely starting on programming cells for specific activities or outcomes, and the technologies to do so have only existed for a handful of years. Yet progress in cell biotechnology is accelerating rapidly. Given the knowledge that researchers have today it is not unreasonable to look ahead to envisage very specific technologies that will enable sophisticated cellular control, not just over individual cells in the lab, but eventually for every cell in the body, all at once. This will happen a matter of a few decades from now. Tomorrow's researchers will mass-produce merged assemblies of novel protein nanomachines and natural cell components to improve, repair, and direct cells in very sophisticated ways.

The advances of today are modest in comparison with this vision for decades to come, and the tools used to change cell behavior very crude in comparison. But this progress is important, and the resulting treatments provide real benefits. Present day stem cell medicine is just a first pass at doing something useful, and yet where it is proven it is life-changing and life-saving for patients. Much more interesting and effective therapies lie ahead. Here is a random selection of some recent work in the field of cell biotechnology:

Researchers Regrow Human Corneas: First Known Tissue Grown from a Human Stem Cell

Limbal stem cells reside in the eye's basal limbal epithelium, or limbus, and help maintain and regenerate corneal tissue. Their loss due to injury or disease is one of the leading causes of blindness. In the past, tissue or cell transplants have been used to help the cornea regenerate, but it was unknown whether there were actual limbal stem cells in the grafts, or how many, and the outcomes were not consistent.

In this study, researchers were able to use antibodies detecting ABCB5 to zero in on the stem cells in tissue from deceased human donors and use them to regrow anatomically correct, fully functional human corneas in mice. "Limbal stem cells are very rare, and successful transplants are dependent on these rare cells. This finding will now make it much easier to restore the corneal surface. It's a very good example of basic research moving quickly to a translational application."

New Reprogramming Method Makes Better Stem Cells

The gold standard is human embryonic stem cells (ES cells) cultured from discarded embryos generated by in vitro fertilization, but their use has long been limited by ethical and logistical considerations. Scientists have instead turned to two other methods to create stem cells: Somatic cell nuclear transfer (SCNT), in which genetic material from an adult cell is transferred into an empty egg cell, and induced pluripotent stem cells (iPS cells), in which adult cells are reverted back to a stem cell state by artificially turning on targeted genes.

Until now, no one had directly and closely compared the stem cells acquired using these two methods. The scientists found they produced measurably different results. "The nuclear transfer ES cells are much more similar to real ES cells than the iPS cells. They are more completely reprogrammed and have fewer alterations in gene expression and DNA methylation levels that are attributable to the reprogramming process itself."

"If you believe that gene expression and DNA methylation are important, which we do, then the closer you get to the patterns of embryonic stem cells, the better. Right now, nuclear transfer cells look closer to the embryonic stem cells than do the iPS cells. I think these results show that the SCNT method is a far superior candidate for cell replacement therapies. I truly believe that using this method of producing stem cells will someday help us cure and treat a wide range of diseases that are defeating us today."

Engineered Red Blood Cells Could Carry Precious Therapeutic Cargo

Red blood cells (RBCs) are an attractive vehicle for potential therapeutic applications for a variety of reasons, including their abundance - they are more numerous than any other cell type in the body - and their long lifespan (up to 120 days in circulation). Perhaps most importantly, during RBC production, the progenitor cells that eventually mature to become RBCs jettison their nuclei and all DNA therein. Without a nucleus, a mature RBC lacks any genetic material or any signs of earlier genetic manipulation that could result in tumor formation or other adverse effects.

Exploiting this characteristic, [researchers] introduced genes coding for specific slightly modified normal red cell surface proteins into early-stage RBC progenitors. As the RBCs approach maturity and enucleate, the proteins remain on the cell surface, where they are modified. Referred to as "sortagging," the approach relies on the bacterial enzyme sortase A to establish a strong chemical bond between the surface protein and a substance of choice, be it a small-molecule therapeutic or an antibody capable of binding a toxin. The modifications leave the cells and their surfaces unharmed.

"Because the modified human red blood cells can circulate in the body for up to four months, one could envision a scenario in which the cells are used to introduce antibodies that neutralize a toxin. The result would be long-lasting reserves of antitoxin antibodies."

More Research on Sedentary Behavior and Mortality Rates

There seems to be an infinite fund of resources for any epidemiological research that involves television. Here researchers are trying to get a handle on the degree to which sedentary behavior negatively influences health, but their data strongly suggests that the correlation between increased mortality rates and more time spent watching television is only a correlation, as other similar forms of sedentary behavior do not show the same relationship, or at least not in this group of younger study participants.

Thus we are left reaching for the web of other factors that correlate with fewer hours spent watching television, such as wealth, education, intelligence, and so on - all of which themselves correlate with greater life expectancy. This is the challenge inherent in this sort of study, where obtaining even simple answers to simple questions from the data can be a struggle. There is plenty of evidence from other studies to suggest that less exercise and more time spent sitting both increase mortality rates, but when different - but really very similar - sitting activities have widely divergent statistical relationships with health it seems necessary to ask harder questions about the underlying mechanisms.

Adults who watch TV for three hours or more each day may double their risk of premature death compared to those who watch less. "Television viewing is a major sedentary behavior and there is an increasing trend toward all types of sedentary behaviors. Our findings are consistent with a range of previous studies where time spent watching television was linked to mortality."

Researchers assessed 13,284 young and healthy Spanish university graduates (average age 37, 60 percent women) to determine the association between three types of sedentary behaviors and risk of death from all causes: television viewing time, computer time and driving time. The participants were followed for a median 8.2 years. Researchers reported 97 deaths, with 19 deaths from cardiovascular causes, 46 from cancer and 32 from other causes.

The risk of death was twofold higher for participants who reported watching three or more hours of TV a day compared to those watching one or less hours. This twofold higher risk was also apparent after accounting for a wide array of other variables related to a higher risk of death.

Researchers found no significant association between the time spent using a computer or driving and higher risk of premature death from all causes. Researchers said further studies are needed to confirm what effects may exist between computer use and driving on death rates, and to determine the biological mechanisms explaining these associations.


Improving Lysosomal Function is a Good Thing

Lysosomes are recycling units inside cells responsible for breaking down damaged cellular components and unwanted proteins. Lysosomal function declines with age in important long-lived cells, such as those of the nervous system, as they accumulate metabolic waste products that they are unequipped by evolution to destroy. They become bloated and inefficient, and as a consequence garbage piles up in their cells harming the surrounding tissues. This is seen in diseases such as macular degeneration, in which cells of the retina are overwhelmed by certain types of metabolic waste.

The SENS rejuvenation research approach to this aspect of aging is to find ways to safely break down these waste products, thus rescuing the lysosomes. Other researchers have in past years demonstrated that there are benefits to be had from enhancing lysosomal function to at least partially compensate for the consequences of waste buildup. This paper is another in line with this latter approach:

Healthful cell maintenance requires the efficient degradative processing and removal of waste material. Retinal pigmented epithelial (RPE) cells have the onerous task of degrading both internal cellular debris generated through autophagy as well as phagocytosed photoreceptor outer segments. We propose that the inadequate processing material with the resulting accumulation of cellular waste contributes to the downstream pathologies characterized as age-related macular degeneration (AMD).

The lysosomal enzymes responsible for clearance function optimally over a narrow range of acidic pH values; elevation of lysosomal pH by compounds like chloroquine or A2E can impair degradative enzyme activity and lead to a lipofuscin-like autofluorescence. Restoring acidity to the lysosomes of RPE cells can enhance activity of multiple degradative enzymes and is therefore a logical target in early AMD.

We have identified several approaches to reacidify lysosomes of compromised RPE cells; stimulation of beta-adrenergic, A2A adenosine and D5 dopamine receptors each lowers lysosomal pH and improves degradation of outer segments. Activation of the CFTR chloride channel also reacidifies lysosomes and increases degradation. These approaches also restore the lysosomal pH of RPE cells from aged ABCA4−/− mice with chronically high levels of A2E, suggesting that functional signaling pathways to reacidify lysosomes are retained in aged cells like those in patients with AMD. Acidic nanoparticles transported to RPE lysosomes also lower pH and improve degradation of outer segments. In summary, the ability of diverse approaches to lower lysosomal pH and enhance outer segment degradation support the proposal that lysosomal acidification can prevent the accumulation of lipofuscin-like material in RPE cells.


Summer Scholars at the SENS Research Foundation

Every year a group of exceptional young scientists come to work on projects at the SENS Research Foundation in California and in allied laboratories around the country. Producing the rejuvenation therapies of tomorrow is a project that will last for decades: the researchers who will lead companies and academic laboratories into the final stretches to produce the first comprehensive rejuvenation toolkit are still undergraduates and postgraduates today, just starting their careers. It is a very exciting time to be in biotechnology.

It is of great importance that today's leaders in the field of aging research do better than their predecessors when it comes to presenting their field as the groundbreaking, revolutionary, exciting place that it will be over the next twenty years. The world is changing, biotechnology is advancing at a breakneck pace, and the medicine of ten or twenty years from now will look like science fiction already. Radical new possibilities are on the horizon, and doors are opening. Today's scientists must cultivate a next generation of researchers who see aging as the most important medical condition yet be treated in earnest, and who find the new tools for producing those future treatments to be exciting: worth devoting a career to. Hence advocacy and progress isn't just about getting the job done today and raising the funds for today's researchers, but it is also about creating the research community of tomorrow.

A series of posts at the SENS Research Foundation profiles this year's summer scholars and the work they are carrying out relevant to aging and rejuvenation:

2014 SRF Summer Scholar Profile: Christine Wu

At the SENS Research Foundation, I work in the OncoSENS department with Dr. Haroldo Silva. My project will study a specific pathway used by cancer cells called the Alternative Lengthening of Telomeres (ALT) pathway with the use of the ALT-associated promyelocytic leukemia (PML) nuclear bodies (APB) assay.

I will be performing Dr. Silva's version of the APB assay on two specific cell lines: an ALT cell line, called U2OS, and a telomerase control cell line, called 143B. I will be treating each of these cell lines with four drugs provided to us by Dr. Robert J. Shmookler Reis of the University of Arkansas for Medical Sciences, which are all known inhibitors of different proteins in homologous recombination-mediated pathways. My project will assess the effect of these drugs on the ALT pathway. The results generated by the APB assay will provide new data to better assess the potential of these drugs for cancer therapy, particularly for tumors associated with the ALT mechanism.

2014 SRF Summer Scholar Profile: Joi McLaughlin

This summer, at the Buck Institute For Research on Aging, I will be working on a project in the laboratory of Dr. Heinrich Jasper. I will be examining the effect of unfolded proteins in fruit fly mitochondria on stem cell maintenance. Previous studies have shown that fruit fly gut stem cells tend to divide and generate new cells more frequently in stressful environments. Coincidently, the stress of numerous unfolded proteins in the mitochondrion triggers the mitochondrial unfolded protein response.

Recently, the response to mitochondrial unfolded proteins has been shown to control the aging rate of various organisms and has been associated with many renowned aging modulators. We also know that activating the response in certain body parts can have global effects, and these effects could greatly impact the aging process. Yet, there remains uncertainty regarding which proteins initiate the active pathway that alters aging, as opposed to those that are just associated with the process, and also the exact difference between mitochondrial unfolded protein response and other stress responses that seem to have no influence on aging. Thus, this project aims to provide some clarity concerning these aspects of the response.

2014 SRF Summer Scholar Profile: Megan Harper

Cellular senescence is a state of irreversible growth arrest that serves to protect against cancer. Senescent cells are accumulated with age or induced by anti-cancer therapies, such as chemotherapy and irradiation, in the tissue microenvironment. Senescent cells experience deep morphological and functional changes, and they activate a secretory program known as the senescence-associated secretory phenotype (SASP). The SASP includes several pro-inflammatory factors for which levels are increased during aging and cancer treatment.

The secretory program is regulated by multiple molecular events. Among those, the transcription factor hypoxia-inducible factor (HIF)-1a has been linked to many pathways and factors involved during senescence. HIF-1a responds to oxygen levels to promote the formation of new blood vessels in hypoxic conditions. During my internship, I will address the following questions: 1) Which chemotherapy drug or irradiation dose currently used for treatment of cancer patients induces senescence in the tissue microenvironment? and 2) How does the phenotype of senescent cells respond to HIF-1a regulation and to different oxygen concentrations?

2014 SRF Summer Scholar Profile: Haben Tesfamariam

This summer I will be working with Dr. Mark McCormick in the laboratory of Dr. Brian Kennedy at the Buck Institute for Research on Aging. We are working in the budding yeast Saccharomyces cerevisiae and the nematode worm Caenorhabditis elegans. These model organisms live for only a few weeks, making it possible to quickly study changes in their lifespan. Because they have long been used to study many other biological processes, there are many existing tools available to us when working with these organisms, such as genome-wide deletion collections. Finally, it has been shown repeatedly in many diverse biological processes that fundamental mechanisms first uncovered in simple model organisms are often conserved in higher organisms, such as humans. In the case of aging, changes in yeast genes in the TOR (target of rapamycin) signaling pathway, including the yeast gene TOR1 itself, were shown to extend lifespan, and subsequent work has shown that treatment with the TOR targeting drug rapamycin extends lifespan when fed to middle-aged mice, leading us to hypothesize that this drug target or others we uncover may allow us to extend human lifespan as well.

2014 SRF Summer Scholar Profile: Ethan Bassin

Recent progress in whole organ engineering techniques based on decellularization of organs and recellularization of the resulting collagen-based matrix suggests that this method could eventually be used in transplantation. The Wake Forest Institute for Regenerative Medicine team has developed a combination cell seeding system for efficient and functional re-endothelialization of the entire vasculature of an acellular renal scaffold.

In their previous study, the team developed a surface modification method to reinforce endothelial cell attachment onto renal vasculature via CD31 antibody conjugation. CD31 antibody binds to an antigen found on endothelial cells. Encouraged by their promising results using an endothelial cell line, the WFIRM team has recently attempted to re-endothelialize the kidney scaffolds using autologous cell sources for long-term porcine kidney implantation. This approach could potentially be applied to a translational clinical trial.

For my project, I plan to isolate and characterize primary endothelial cells from pigs to determine if the conjugation of CD31 antibody on vasculatures of kidney scaffolds will enhance primary endothelial cell attachment.

2014 SRF Summer Scholar Profile: Shruti Singh

This summer, I am working on a thymus regeneration project in Dr. John Jackson's lab at the Wake Forest Institute for Regenerative Medicine. The thymus is a specialized organ in the immune system, and it is involved in the maturation of T-cells. T-cells recognize and attack foreign substances, called antigens, thus protecting the body from developing infections. In old age, the thymus starts to lose its functional abilities, rendering the immune system ineffective. One approach to restore the immune system in aged individuals is the regeneration of the thymus. Thymic tissue regeneration and T-cell maturation also have application in the treatment of autoimmune diseases, immunodeficiencies, and transplant rejection.

During the summer, I will work on one part of this larger project. I plan to decellularize a small piece of pig thymus, which entails getting rid of all the cells in the thymus, leaving behind the extracellular structure called a scaffold. After decellularizing the thymus, I will reseed the thymus scaffold with thymus epithelial cells and bone marrow cells from mice, providing a 3-D environment to the cells that resembles their natural environment in the body. I will then analyze the proliferation of these cells in the scaffold and look for the production of mature T-cells. The success of this project will be an important step forward towards the overarching goal of whole thymus regeneration.

Another Approach to Bioprinting Vascular Networks

The principle challenge in tissue engineering is supplying blood to the tissues being grown from scratch. Producing networks of blood vessels is a real challenge, and this is one of the reasons why the use of decellularized donor organs is attracting attention - it works around the problem by using an existing set of blood vessel structures as a guide for new cell growth. At some point, however, researchers will establish a cost-effective method of producing new tissue that is laced with a suitable web of capillaries. Here is one of a number of such efforts from recent years, which like most of the others is based on fabricating a scaffold with suitable features and chemical cues to guide the formation of blood vessels:

[Scientists] have bio-printed artificial vascular networks mimicking the body's circulatory system that are necessary for growing large complex tissues. "Thousands of people die each year due to a lack of organs for transplantation. Many more are subjected to the surgical removal of tissues and organs due to cancer, or they're involved in accidents with large fractures and injuries. Imagine being able to walk into a hospital and have a full organ printed - or bio-printed, as we call it - with all the cells, proteins and blood vessels in the right place, simply by pushing the 'print' button in your computer screen. We are still far away from that, but our research is addressing exactly that. Our finding is an important new step towards achieving these goals. At the moment, we are pretty much printing 'prototypes' that, as we improve, will eventually be used to change the way we treat patients worldwide."

The research challenge - networking cells with a blood supply. Cells need ready access to nutrients, oxygen and an effective 'waste disposal' system to sustain life. This is why 'vascularisation' - a functional transportation system - is central to the engineering of biological tissues and organs. "One of the greatest challenges to the engineering of large tissues and organs is growing a network of blood vessels and capillaries. Cells die without an adequate blood supply because blood supplies oxygen that's necessary for cells to grow and perform a range of functions in the body. Replicating the complexity of these networks has been a stumbling block preventing tissue engineering from becoming a real world clinical application."

Using a high-tech 'bio-printer', the researchers fabricated a multitude of interconnected tiny fibres to serve as the mold for the artificial blood vessels. They then covered the 3D printed structure with a cell-rich protein-based material, which was solidified by applying light to it. Lastly they removed the bio-printed fibres to leave behind a network of tiny channels coated with human endothelial cells, which self organised to form stable blood capillaries in less than a week.


Progress Towards Inducing Greater Remyelination

Nerves are sheathed in myelin. That sheathing deteriorates to some degree with age, and more dramatically in demyelinating conditions such as multiple sclerosis (MS). Some of the approaches taken by researchers working on conditions such as MS may prove applicable to reversal of the lesser deterioration of myelin in aging, a process that correlates with some forms of cognitive decline.

Stem cell therapy is seen as having dramatic potential for treating MS, but there are key obstacles, especially the length of time it takes for progenitor cells to turn into oligodendrocytes, the brain's myelin-making cells. Using currently available methods, it can take as long as a year to generate a sufficient number of human oligodendrocyte cells to treat a single MS patient. That's partly because there are so many steps: the skin or blood cell must be turned into induced pluripotent stem cells, which can differentiate into any other type of cell and from which neural progenitor cells can be produced. Those progenitor cells then must undergo differentiation to oligodendrocyte progenitors that are capable of ultimately producing the oligodendrocytes.

Using fetal brain stem cells, the researchers searched for transcription factors that are absent in neural progenitor cells and switched on in oligodendrocyte progenitor cells. While neural progenitor cells are capable of producing myelin, they do so very poorly and can cause undesirable outcomes in patients, so the only candidate for transplantation is the oligodendrocyte progenitor. "The question was, could we use one of these transcription factors to turn the neural progenitor cell into an oligodendrocyte progenitor cell?"

"We narrowed it down to a short list of 10 transcription factors that were made exclusively by oligodendrocyte progenitor cells. Among all 10 factors that we studied, only SOX10 was able to make the switch from neural progenitor to oligodendrocyte progenitor cell." In addition, the researchers found that SOX10 could expedite the transformation from oligodendrocyte progenitor cell to differentiation as an oligodendrocyte, the myelin-producing cell and the ultimate treatment goal for MS. "Ideally, we'd like to get directly to oligodendrocyte progenitors. The new results are a stepping stone to the overall goal of being able to take a patient's skin cells or blood cells and create from them oligodendrocyte progenitors."