The Aging Chart Resource

Here I'll point out the Aging Chart site, a new resource on aging and longevity research assembled by a group of largely Russian researchers. Over the past decade, the Russian-language side of the longevity science community, especially the folk associated with the Science for Life Extension Foundation, has produced all sorts of publicity and explanatory materials aimed at both laypeople and researchers. These range from glossy advocacy for development of effective treatment of aging to quite detailed visualizations of portions of the known molecular biology of aging and roadmaps for the future of rejuvenation research. The people involved here have always demonstrated a good sense of the need for advocacy and public support to bring lasting life to research efforts.

Collectively, the Russian aging research community has a vision that overlaps somewhat with that of the SENS Research Foundation in technical details, but is in general far more focused on tinkering with the operation of metabolism and epigenetic alterations than I would agree is the best path forward. In that it is perhaps closer to the Hallmarks of Aging opinions on how to classify the mechanisms of aging and thereby approach its treatment. You can see this at the detail level if you take a look at Alexey Moskalev's blog. You'll find a lot of the original Russian visualizations there, but sadly very few of them had been translated into English and made available until recently. Thanks to a closer collaboration between the English-language and Russian-language research communities in recent years, and a growing number of fluently bilingual researchers, more of these resources are becoming available to peruse in English.

Aging Chart

Aging Chart is a collection of community-curated pathways and knowledge related to aging. Aging Chart makes its debut stocked with 114 pathways, networks, and concept maps on all topics related to aging, from gene-centered pathways to those describing aging processes, age-related diseases, longevity factors, and anti-aging strategies. Contributions are openly encouraged. The pathway diagrams are interactive, with clickable nodes for user-led exploration that link to related pages and pathways for any particular element of interest.

Aging Chart: a community resource for rapid exploratory pathway analysis of age-related processes

As the world population is rapidly aging, the prevalence of aging-related diseases and the demand for expensive, long term health care is also rising. To offset the burden of this shift, scientific knowledge and innovation will become increasingly crucial, and anti-aging and disease prevention strategies will become national and international priorities. Aging research as a field will boom. Nevertheless, it faces several challenges, and the growth will need direction. One of the challenges is the current lack of a freely available, comprehensive collection of aging-related biological pathways and encyclopedia of aging knowledge. Biological pathways are one of the most powerful visualization tools in biology. They provide an intuitive, systems view of the interactions between the multitude of individual elements in any given process. They can be interactive for user-directed exploration and amenable to computational methods, and they are indispensable in making sense of large-scale data sets, where a multitude of individual changes may reflect a small number of more biologically important (and more statistically powerful) changes at the pathway level. Pathway collections are a key feature of many biological data repositories in the public domain.

The lack of an aging pathway collection until now may reflect the fledgling nature of the field but also stems in part from the sheer diversity of aging-related processes. Characterizing these is a monumental task. Aging itself is a complex process that occurs at all levels in all systems of the body, leads to a loss of function and triggers a number of diseases. There is ongoing debate as to whether aging is itself a treatable disease. As such, aging research involves a highly diverse community of researchers with various perspectives. If any single narrative of aging mechanisms is to be constructed, the community needs a platform where knowledge can be pieced together collaboratively into pathways, node by node, and ultimately into a unified theory. There have been many previous attempts at structuring aging data and knowledge on the web, but there is still a need for a rapid, intuitive, visual overview of aging processes, from environmental triggers down to molecular interactions. To our knowledge, no such resource yet exists. To fill this gap, we have developed Aging Chart, a wiki-based, community-curated biological pathway collection and encyclopedia of aging processes. Aging Chart will complement and add to the existing set of public aging-related data- and knowledge bases on the web.

An Example of Present Work on Improving Vitrification

Interest in developing means of reversible vitrification for tissue preservation has been growing outside the cryonics community in recent years. This is a good thing for cryonics as an industry, as a greater interest in reversible tissue preservation in the broader research community will lead to both technological improvements that can be used by cryonics providers and a greater acceptance of cryonics. Cryonics is a legitimate approach to medical intervention where there is no other option for the patient, but despite greater public support for cryonics from scientists, there remains considerable and unfounded hostility within some portions of the research community. Hopefully this will change in the years ahead with meaningful progress towards the broader use of vitrification:

Researchers have discovered a new approach to "vitrification," or ice-free cryopreservation, that could ultimately allow a much wider use of extreme cold to preserve tissues and even organs for later use. Cryopreservation has already found widespread use in simpler applications such as preserving semen, blood, embryos, plant seeds and some other biological applications. But it is often constrained by the crystallization that occurs when water freezes, which can damage or destroy tissues and cells. To address this, researchers have used various types of cryoprotectants that help reduce cell damage during the freezing process - among them is ethylene glycol, literally the same compound often used in automobile radiators to prevent freezing. A problem is that many of these cryoprotectants are toxic, and can damage or kill the very cells they are trying to protect from the forces of extreme cold.

In the new research, the engineers developed a mathematical model to simulate the freezing process in the presence of cryoprotectants, and identified a way to minimize damage. They found that if cells are initially exposed to a low concentration of cryoprotectant and time is allowed for the cells to swell, then the sample can be vitrified after rapidly adding a high concentration of cryoprotectants. The end result is much less overall toxicity. The research showed that healthy cell survival following vitrification rose from about 10 percent with a conventional approach to more than 80 percent with the new optimized procedure. "The biggest single problem and limiting factor in vitrification is cryoprotectant toxicity, and this helps to address that. The model should also help us identify less toxic cryoprotectants, and ultimately open the door to vitrification of more complex tissues and perhaps complete organs."

If that were possible, many more applications of vitrification could be feasible, especially as future progress is made in the rapidly advancing field of tissue regeneration, in which stem cells can be used to grow new tissues or even organs. Tissues could be made in small amounts and then stored until needed for transplantation. Organs being used for transplants could be routinely preserved until a precise immunological match was found for their use. Conceptually, a person could even grow a spare heart or liver from their own stem cells and preserve it through vitrification in case it was ever needed.


Cytomegalovirus Impairs the Immune Response to Exercise

Here researchers provide evidence for one of the many detrimental consequences of cytomegalovirus (CMV) infection. CMV is a near ubiquitous persistent herpesvirus, present in the majority of the population by the time they reach old age. It is thought responsible for some fraction of the age-related disarray of the immune system, as it cannot be cleared and its presence over the years causes ever more memory cells to be uselessly specialized to track it, leaving ever less room for immune cells capable of taking action. One possible approach to this issue is to destroy the excess memory cells to free up space, possibly coupled with delivering new immune cells via cell therapy, but there is little work taking place on that front, as is true of most potential rejuvenation treatments.

The rapid redeployment of natural killer (NK) cells between the tissues and the peripheral circulation is an archetypal feature of the acute stress response. The response can be evoked using acute bouts of dynamic exercise and is often considered to be an accurate representation of an organism's ability to mount an effective immune response during fight-or-flight scenarios when tissue injury and infection are likely to occur. Acute exercise is associated with increased levels of stress hormones which interact with β-adrenergic receptors (β-AR) on the surface of lymphocytes. NK-cells express more β-AR than other lymphocytes and, as a result, they are the most responsive lymphocyte subset to exercise.

Cytomegalovirus (CMV) is a prevalent beta herpesvirus infecting 50-80% of the US population. We have shown that prior exposure to CMV profoundly impacts the redistribution of lymphocytes to an acute exercise bout. While those with CMV have an augmented redeployment of CD8+ T-cells and γδ T-cells, NK-cell mobilization is dramatically impaired. This blunted NK-cell response appears to be attributable to a CMV-induced accumulation of specific NK-cell subsets that have a lower expression of β2-AR and an impaired ability to produce cyclic AMP in response to in vitro stimulation with the β-agonist isoproterenol. Moreover, those with CMV fail to exhibit exercise-induced enhancements in NK-cell function, indicating that CMV may compromise NK-cell mediated immunosurveillance after an acute bout of strenuous exercise.

In addition to infection history, aging is known to have a profound impact on the cellular response to acute stress and exercise; however, studies investigating the effects of aging on NK-cell exercise responsiveness are lacking. While aging has been reported in some studies to have no effect on NK-cell mobilization with exercise, several of the phenotypic hallmarks of aging overlap with those associated with latent CMV infection in the young. Despite CMV prevalence increasing with age, previous studies have compared NK-cell responses between young and old exercisers without accounting for this confounding variable. We showed recently that CMV was associated with enhanced redeployment of CD8+ T-cells regardless of age, while, conversely, aging impairs the redeployment of γδ T-cells independently of CMV. However, no study to our knowledge has compared NK-cell responses to a single bout of exercise between different age groups while controlling for CMV status. Given that CMV prevalence increases with age and many of the effects of CMV mirror those attributable to aging, it is important to resolve the effects of age and CMV infection on the frequency and exercise responsiveness of distinct NK-cell subsets.

The aim of this study was to determine if latent CMV infection blunts the redeployment of NK-cells to a single exercise bout in older individuals as it does in the young and to delineate the effects of age and CMV on the redeployment of discrete NK-cell subsets. We show here that CMV has a potent blunting effect on exercise-induced NK-cell mobilization in both younger (23-39 yrs) and older (50-64 yrs) subjects with the greatest mobilization being seen in the CMV-negative older group.


The National Geographic's Breakthrough on Aging Research

The National Geographic has been fairly heavily engaged in promoting Breakthrough, a new popular science and technology show that edges its way around the outskirts of topics such as artificial general intelligence, transhumanism, and, of course, the medical control of aging, which in time will lead to extension of healthy life spans and elimination of age-related disease. Judging from what is out so far, this largely has the air of presenting a very watered-down, safe, unambitious vision of these goals to the public at large, while at the same time painting that as edgy and radical. So both condescending and missing the point at one and the same time. Still, they're sinking a fair amount of time and effort into this judging from the panoply of surrounding articles and the high-tech series website with its 3-D vision sphere effect. Also, albeit buried several layers deep in that set of marginally interactive spheres, you'll find video commentary from some of the folk in our community on the topic of radical life extension through medical science: Aubrey de Grey, Jason Silva, Sonia Arrison, Maria Konovalenko, and so forth.

Apart from that, most of what is on offer is focused on research efforts with marginal goals, such as the metformin trial that aims to be one small step towards very slightly slowing human aging, and researchers who believe that there is little more that can be done than this. For those who reject the SENS view of rejuvenation through targeted damage repair, or similar visions based on the Hallmarks of Aging viewpoint, research plans that could lead to radical life extension within decades if fully funded, there is little to see but a long, very expensive process of cataloging all of cellular metabolism and all of its age-related dysfunctions, and along the way using the traditional process of drug discovery to try to eke out very tiny beneficial alterations to the way in which aging occurs. This is a disappointing vision for anyone to be stuck embracing in a time of radical and rapid progress in biotechnology.

What Do Centenarians Know That the Rest of Us Don't?

Only about 5 people out of 1,000 live longer than a century. For the most part, these people get the same illnesses as everyone else - they just get ill a few decades later. Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York, is trying to understand why. He's been studying large numbers of centenarians who share similar genetics. Barzilai is conducting a major study on the diabetes drug metformin, which he has shown can delay the diseases of aging in animals.

"You have to be careful. Is metformin going to be good only? We hope. For 60 years, millions of [people have used it] and nothing bad has happened. But we'll see. Metformin is the way to pave the road. Once the pharmaceuticals jump into this field, we will get better drugs. That's why we think the next decade is really exciting. The fountain of youth is not what we're doing, but this is the first time that we understand enough about the biology and mechanisms [of aging] so we can really think of drugs that can help us."

The Secrets to Unlocking a Longer Life

Aging might not be such a crisis if people not only lived longer, but also stayed healthier and were able to continue to lead productive lives. That's why researchers are working to solve some of the mysteries of aging, and to figure out ways to counteract its effects. And while they haven't yet found a way to slow the aging process, in recent years they've made promising progress.

In recent years, scientists have discovered that longevity apparently has less to do with lifestyle than genes. A study published in 2011 found that those who made it to 95 or older were no more virtuous than the rest of us when it came to what they ate, how much they exercised, and whether they smoked or drank. Indeed, only 43 percent of male centenarians - those over 100 years old - reported engaging in regular exercise of moderate duration. 24 percent of long-lived men consumed alcohol on a daily basis, a slightly higher rate than the general population. "The study suggests that centenarians may possess additional longevity genes that help to buffer them against the harmful effects of an unhealthy lifestyle."

Of interest, there is a small section on senescent cell clearance stuck in the middle of that second article on longevity genes. This is the trouble with translating the essence of longevity science and its goals to the public at large. Those tasked with that effort are usually incapable of determining the difference between lines of research that absolutely cannot ever, even in principle, greatly extend healthy human life and produce rejuvenation, versus those that can. To them there is no difference between (a) hunting for genetic differences that raise the odds of living to be a centenarian from exceedingly low to slightly less exceedingly low, with an eye to giving other people that tiny extra boost to the odds, and (b) work on clearing senescent cells, which is one of the ways of repairing the fundamental causes of aging that could produce significant rejuvenation for any patient. It is all the same to the eyes of the layperson: here is a scientific program, here the scientist is working on something related to aging and longevity, check the box, move on.

I hear occasional complaints that I am partisan in my support of damage repair over, for example, drug discovery or epigenetic alteration as an approach to treating aging. That is because from where I stand the evidence strongly supports SENS-like programs aimed at damage repair as the best, indeed the only, way to achieve radical life extension soon enough to matter. There is a big, big difference in expected outcomes between the likes of carrying out trials for metformin and the likes of trying to make senescent cell clearance a viable treatment. It isn't all the same, and we are still stuck in the situation wherein most of the funding that comes into aging research is going to what is in effect purely investigative science, slightly dressed up with hopes of results because that works to raise funding, but like the metformin trial and the genetic studies in centenarians, these are efforts likely to produce nothing of use beyond more data on metabolism and aging. That's great in the pure science world, where no data goes to waste, but it won't get us to actual, working rejuvenation therapies. There are solid, sensible reasons for being an advocate of SENS and similar efforts, and front and center is the point that, given even a fraction of the funding that went to sirtuin development, SENS is much more likely to produce results that are big enough and happen soon enough to matter to you and I personally.

Nrf2 in Aging and Longevity

The transcription factor nrf2 regulates levels of antioxidant proteins, a part of the response to everyday cellular stress, such as that induced by raised mitochondrial activity and greater generation of reactive oxygen species (ROS) during exercise. Greater nrf2 activity shows up in long-lived species and in the modest slowing of aging that can be achieved via hormesis in some species. Here is an open access review paper on this topic:

The role of Nrf2 in responding to cytotoxic stressors is well defined. However, only within the last few years have studies elucidated how Nrf2 function changes with age and how changes in Nrf2 activity contribute to the aging phenotype. Aged mice show similar losses in cellular redox capacity to those observed in Nrf2 knockout mice, suggesting that Nrf2 dysregulation with age may be responsible for the loss of cellular redox status. Diminished Nrf2 target gene expression with age is accompanied by increased muscle ROS production, glutathione depletion, and increased oxidant damage to proteins, DNA, and lipids in both humans and rodents. Therefore, given that Nrf2 activity decreases with age alongside increased oxidant stress, interventions that activate Nrf2 may impact the aging process and longevity.

Support for the role of Nrf2 in regulation of lifespan comes from Nrf2 gain of function and loss of function studies. For example, experimental deletion of the antielectrophilic gene glutathione transferase (gGsta4) activated Nrf2 and significantly extended lifespan in mice. This mutation increased electrophilic lipid peroxidation products and increased nuclear Nrf2 activity by 43% and 38% in liver and skeletal muscle, respectively. The authors propose that deletion of this glutathione transferase gene resulted in chronic moderate Nrf2 activation and presumably elevated downstream Nrf2 signaling throughout the mouse lifespan. Studies of the Nrf2 homolog SKN-1 in Caenorhabditis elegans (C. elegans) further suggest that Nrf2 may be implicated in longevity processes. Upon activation, SKN-1 upregulates genes involved in the oxidative stress response, including many orthologs to those regulated by mammalian Nrf2. Similar to mouse Nrf2 knockouts, SKN-1 mutants show diminished resistance to oxidative stress and shortened lifespan. On the other hand, moderate overexpression of a constitutively active SKN-1 increases lifespan, alongside increased resistance to oxidative stress.

The naked mole rat is an exceptionally long-lived species, with a lifespan four times longer than similarly sized rodents, thus making the naked mole rat an important model for longevity studies. Naked mole rats do not have typical lifespan curves in which mortality rates increase with age, but rather they experience few of the biological changes typically associated with aging. Naked mole rats also have significantly elevated proteasome quality control mechanisms. The high breakdown and clearance of damaged proteins is suspected to be largely due to increased Nrf2 expression. In support of the hypothesized role of Nrf2 in naked mole rat longevity, under nonstressed conditions, naked mole rats have greater protein levels of Nrf2 and greater expression of Nrf2-regulated enzymes in fibroblasts and liver. These data suggest Nrf2 may be responsible for the heightened quality control mechanisms in naked mole rats and may be associated with their exceptional longevity.


A Mechanism By Which Amyloid-β Attacks Synapses

Researchers here provide evidence for a fairly direct link between the growing levels of amyloid-β associated with Alzheimer's disease and the loss of synapses characteristic of the condition. Since the mechanism is so direct, success in present efforts to clear amyloid-β from the brain, such as via immunotherapy, should also minimize this part of the pathology of Alzheimer's disease:

"One of the first signs of Alzheimer's disease is the loss of synapses - the structures that connect neurons in the brain. Synapses are required for all brain functions, and particularly for learning and forming memories. In Alzheimer's disease, this loss of synapses occurs very early on, when people still only have mild cognitive impairment, and long before the nerve cells themselves die. We have identified a new molecular mechanism which directly contributes to this synapse loss - a discovery we hope could eventually lead to earlier diagnosis of the disease and new treatments."

The team studied a protein in the brain called neural cell adhesion molecule 2, or NCAM2 - one of a family of molecules that physically connects the membranes of synapses and help stabilise these long lasting synaptic contacts between neurons. Using post-mortem brain tissue from people with and without the condition, they discovered that synaptic NCAM2 levels in the part of the brain known as the hippocampus were low in those with Alzheimer's disease. They also showed in mice studies and in the laboratory that NCAM2 was broken down by another protein called beta-amyloid, which is the main component of the plaques that build up in the brains of people with the disease. "Our research shows the loss of synapses is linked to the loss of NCAM2 as a result of the toxic effects of beta-amyloid. It opens up a new avenue for research on possible treatments that can prevent the destruction of NCAM2 in the brain."


A Few Recent Research Results on Fitness, Exercise, and Age-Related Decline

It is no big secret that regular exercise and greater fitness leads to better health and a longer life expectancy, though it remains uncertain as to where the point of greatest benefit lies. What is the dose-response curve for exercise? How does it vary by circumstances and type of exercise? Given the glacial pace of demographic studies, I fully expect good answers to those questions, with robust data behind them, to arrive only decades from now, after the point at which the first rejuvenation therapies exist. What we know today about exercise and aging, gathered from large long-running studies of past decades, is but an outline of the full picture. Athletes at the top of their profession go on to live from a few years to a decade longer on average than the rest of the population, but the data doesn't tell us whether that is because of exercise and fitness, or because only more robust people tend to succeed at becoming professional athletes. At the other end of the scale, there is a few year difference in life expectancy and sizable health difference in the outcomes resulting from being sedentary versus undertaking regular moderate exercise. It is much more certain that this is an effect of the choice to work on fitness versus the case that more resilient people tending to exercise more frequently.

When it comes to a high expectation of positive results for the future of your health, there really are only three options at the present time: regular moderate exercise, some form of calorie restriction or equivalent intermittent fasting, and working to accelerate the right research programs, such as through philanthropic donations. In my eyes that means SENS and SENS-like work focused on the repair of the cell and tissue damage that causes aging, but other people will have other opinions. As for any of the other stuff that the supplement and anti-aging industry will try to sell you on, it is either the case that the scientific evidence is sparse, sketchy, and changeable, the benefits are small and uncertain in comparison to exercise or calorie restriction, or the solid scientific consensus is that there is no benefit.

In an age of rapidly progress in biotechnology, and thus the potential for radical advances in medicine from decade to decade, it makes sense to keep yourself fit. Quite aside from better long-term health being a more pleasant and less expensive experience than worse long-term health, unlike our ancestors we now find ourselves in a situation in which every extra year counts. Will we live to enjoy the first therapies capable of repairing the causes of aging and thus producing at least partial rejuvenation, or will we miss out? That's up to us, not just by staying fit, but more importantly by helping to speed progress towards the development of these therapies. On this topic, here are a couple of recent research publications that, like many others of a similar nature, are an incentive to stay fit and avoid more of the consequences of aging:

Can physical exercise enhance long-term memory?

Exercise can enhance the development of new brain cells in the adult brain, a process called adult neurogenesis. These newborn brain cells play an important role in learning and memory. A new study has determined that mice that spent time running on wheels not only developed twice the normal number of new neurons, but also showed an increased ability to distinguish new objects from familiar objects.

As rodents prefer to spend more time with novel objects than familiar ones, the researchers first exposed the mice to two identical objects (cones or pyramids, in either black or white). After 1.5 hours, one of the objects was replaced with a new object (cone for pyramid or vice versa) and the mice were observed. After 24 hours elapsed, the new object was again swapped, either with a similar object (same color but different shape) or a distinct object (different color and shape). After the short 1.5-hour interval, both running and sedentary mice were able to distinguish similar and distinct objects. However, after 24 hours, a difference was observed. Whereas distinct objects were remembered and recognized by both cohorts of mice, only the running mice could faithfully distinguish similar looking objects. Investigators determined therefore that the running mice had developed better pattern separation capabilities than sedentary mice.

To investigate further, the researchers looked for changes in the brains of the mice. By using markers that could identify newly-formed brain cells, they found that running mice developed about twice as many new cells, and those cells had longer dendrites, compared to the sedentary mice, which facilitates the formation of new synaptic contacts between the nerve cells.

Walking faster or longer linked to significant cardiovascular benefits in older adults

In a large prospective community-based study of older Americans, modest physical activity was associated with a lower risk of cardiovascular disease (CVD). This was true even among men and women older than age 75 at baseline - a rapidly growing population for whom regular activity has been advised, but with little supportive empirical evidence. The researchers studied 4,207 men and women who had been enrolled in the Cardiovascular Health Study (CHS) and who were then followed for 10 years. After adjustment for other risk factors and lifestyle behaviors, those who were more active had significantly lower risk of future heart attacks and stroke. Adults who walked at a pace faster than three miles per hour (mph) had a 50%, 53%, 50% lower risk of coronary heart disease (CHD), stroke and total CVD, respectively, compared to those who walked at a pace of less than two mph. Those who walked an average of seven blocks per day or more had a 36%, 54% and 47% lower risk of CHD, stroke and total CVD, respectively, compared to those who walked up to five blocks per week. Those who engaged in leisure activities such as lawn-mowing, raking, gardening, swimming, biking and hiking, also had a lower risk of CHD, stroke and total CVD, compared to those who did not engage in leisure-time activities.

Higher resting heart rate linked to increased risk of death from all causes

A higher resting heart rate is associated with an increased risk of death from all causes in the general population, even in people without the usual risk factors for heart disease, according to new research. Current evidence for resting heart rate and risk of death and risk of death from heart disease is inconsistent. To understand if resting heart rate is correlated with an increased risk of death, researchers assessed 46 studies involving 1,246,203 patients and 78,349 deaths from all causes, and 848,320 patients and 25,800 deaths from heart disease. "Results from this meta-analysis suggest the risk of all-cause and cardiovascular mortality increased by 9% and 8% for every 10 beats/min increment of resting heart rate. The risk of all-cause mortality increased significantly with increasing resting heart rate in a linear relation, but a significantly increased risk of cardiovascular mortality was observed at 90 beats/min ... consistent with the traditionally defined tachycardia threshold of 90 or 100 beats/min for prevention of cardiovascular disease."

The authors found that people with a resting heart rate of more than 80 beats/min had a 45% higher risk of death from any cause than those with a resting heart rate of 60-80 beats/min, who had a 21% increased risk. However, the absolute risk is still small. Findings were similar for people with cardiovascular risk factors.

Resting heart rate is correlated with fitness, and becoming fitter tends to reduce it. Given the relationship between fitness and mortality, this is probably enough to explain the results observed in the last study noted above.

An Interesting Opinion on Metformin

The evidence for metformin to slightly slow the aging process is all over the map. It is sketchy and contradictory in comparison to the robust results from rapamycin, for example. This isn't preventing a coalition of researchers from pushing forward on a clinical trial with the FDA, but I suspect that trial is much more a means of changing the FDA position on treatments for aging, which are currently not permitted, than an attempt to show results from metformin. Metformin is useful there because it is an established drug with a much lower set of regulatory barriers for reuse in other contexts, making it harder for regulators to throw roadblocks in the way of a trial to treat aging.

A researcher offers an interesting opinion on metformin in this open access paper. In his view the evidence for modestly reduced cancer rates resulting from metformin use is already good enough that, given the very low cost of the drug, it should be formally adopted and verified for cancer prevention in the general population. This is perhaps best considered in the context of the debate of two years ago over whether rapamycin extends life by reducing cancer risk or slowing aging:

During the last decade, there has been a burst of interest in the antidiabetic biguanide metformin as a candidate drug for cancer chemoprevention. Analysis of the available data has shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters in a wide range of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. It is very important to note that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides.

The history of biguanides in oncology started in the 1970s, is rather dramatic, and seems not to come to "a happy end" at the present time. The first publications in 1974-1982 showing the high potential of PF and BF in prevention of spontaneous and induced carcinogenesis were not met an interest adequate to the degree of real importance of these finding. Whereas both in vitro and in vivo experiments provide new evidence of anti-carcinogenic potential of biguanides, and the majority of clinical observations clearly demonstrates protective effect of MF in relation to many localization of cancer, there are some publications on results of clinical trials that are inconclusive and sometime were demonstrated adverse effect of MF. Recently a researcher explaining possible reasons for this inconsistency cited the rather sardonic comment of a leading scientist in the field: "The problem with metformin is it's cheap, it's widely available, it has a great safety profile, and anyone can use it". Really, it is difficult to say better... In PubMed, under the words such as "metformin and cancer" the number of indexed papers were increasing exponentially from zero in 1990 to more than 2500 last September. Among them around 185 reviews on the topic were published just in the last 5 years. There are too many works and still no final conclusion. It may be the time to make this long story short; we believe that efficacy of MF should be evaluated according to criteria, experience and rules of the WHO International Agency for Research on Cancer.


Yet More Mapping of Age-Related Epigenetic Changes

Epigenetic changes occur constantly, altering the production of proteins in response to circumstances, and thus changing cell and tissue behavior. Some of these changes occur in reaction to the cell and tissue damage of aging, and are characteristic enough to allow development of a measure of biological age, an assessment of how damaged an individual is. This is a work in progress, but a good, cheap measure of biological age is a needed tool in the field of longevity science. Currently the only way to establish that potential rejuvenation treatment works in the sense of extending healthy life is to wait and see what it does to life expectancy, which makes exploration of ideas prohibitively expensive, and slows progress across the whole field:

To examine the changes that occur in blood as an individual ages, researchers conducted an extensive study using thousands of patient blood samples. In a remarkable show of replication, the study was initially performed with blood samples from individuals of European ancestry and then replicated in additional European ancestry samples, totaling an amazing 14,983 individual European ancestry samples. The study was then extended to various ethnic groups, including samples from individuals of Hispanic, African, or Native American ancestry. The study identified 1,497 genes in blood cells and/or brain tissue that showed significantly differential expression patterns in older individuals when compared to younger individuals.

There were three distinct groups of genes that were negatively correlated with chronological age. The first group included three subgroups: ribosomal genes (factories on which a RNA is translated into a protein), mitochondrial genes (energy factories of the cells), and genes associated with DNA replication and repair (DNA maintenance and fidelity). All of the genes associated with these subgroups are vitally important to the health of a cell and tissue. The second large group consisted of genes associated with immunity. The third large group was composed of genes that code for the actual ribosomal subunits. Decreased gene expression could help explain the decreased "health" of older cells and increased mutation rates in older cells. There were also four groups of genes positively correlated with age, which were focused on cellular structure, immunity, fatty acid metabolism, and lysosome activity.

Another interesting finding in this study involved epigenetic patterns, specifically methylation on cytosines (one of the four nucleotide bases in DNA). This study showed that those genes whose expression pattern changed with age were highly enriched for the presence of regulatory cytosines. This could indicate how gene expression is controlled as the individual ages. There are several targeted methylation therapies in development that might potentially offer the ability to effectively and safely alter these methylation patterns for therapeutic purposes. The authors found that by combining the transcriptomic expression patterns and the epigenetic patterns a "chronological" age predictor could be used to better understand an individual's "age" in terms of health. Further refinement is needed, but this type of predictor could have a substantial impact on prediction, diagnosis and treatment of individuals, perhaps even allowing for preventive treatments before symptoms progress to disease level changes.


The MitoAge Database: Mitochondrial DNA and Longevity Compared Between Numerous Species

Here I'll point out a recent addition to the set of open data interfaces that are both interesting and relevant to aging research: the MitoAge database, cataloging mitochondrial DNA and longevity in a wide range of species. Mitochondria, the descendants of ancient symbiotic bacteria, swarm in herds inside our cells. The research of past years provides compelling data to suggest that the details of mitochondrial composition, particularly in respect to their resistance to oxidative damage, has a fair-sized effect on life span. Why is oxidative damage an important consideration? Because mitochondria work to create energy store molecules used to power the rest of the cell, a process that involves the generation of reactive oxidizing molecules as a side-effect. A cell is a fluid sack of structures and chemical reactions, all of these components moving around in close proximity, engaged in constant activity. Newly created oxidants don't have far to go in order to react with some important piece of molecular machinery in a way that causes damage and dysfunction. Some are rendered harmless by natural antioxidants, but damage is constant and ongoing, albeit usually repaired very rapidly.

The closest structure for mitochondrially generated oxidants to react with and harm is the mitochondrion itself, and in particular its DNA. Every mitochondrion has at least one copy of the left-over remnant genome from its bacterial ancestry, encoding necessary proteins used in its structure and energy store construction machinery. This DNA isn't as well protected and repaired as is nuclear DNA, and certain rare forms of damage can produce mitochondria that are both dysfunctional and more likely to replicate and survive within their cell. It isn't completely open and shut that this is the way in which cells become overtaken by broken mitochondria and go on to harm surrounding cells and tissues; this contribution to the aging process might have more to do with errors in mitochondrial replication than oxidative damage, for example. But there is certainly a good solid correlation in mammals between longevity and mitochondrial resistance to oxidative damage. When we look at birds and bats, the details of their mitochondrial biochemistry is entwined with the metabolic requirements of flight, and the comparatively long life spans in these species when considering their size may once again be a factor of adaptation to higher levels of oxidative stress generated during flight. Further, there are the studies showing modestly increased health or life span in mice due to increased levels of natural mitochondrial antioxidants, or mitochondrially targeted antioxidant drugs.

To my eyes all of this work and knowledge as a whole should really be taken as a big pointer to suggest that repair of damaged mitochondria is an important part of any future regenerative medicine to produce rejuvenation. The SENS Research Foundation has helped to pioneer the allotopic expression approach to maintaining undamaged mitochondria that is currently under clinical development for inherited mitochondrial disease at Gensight, and continues to work towards a more comprehensive version of the treatment that can be used to treat aging. Funding - as ever - is very limited for this line of research given the potential benefits, but the fastest path to results remains to get this working in mice and see what happens. Given what we know of the effects of more subtle and limited manipulations in mitochondrial biochemistry, we should probably expect the benefits to health and longevity to be sizable enough to draw attention.

Welcome to MitoAge!

The rapidly increasing number of species with fully sequenced mitochondrial DNA (mtDNA), together with accumulated data on longevity records, provide new fascinating opportunities for the analysis of the links between mtDNA features and longevity across animals. To facilitate such an analysis, and to support the scientific community in carrying it out, we developed MitoAge - a curated, publicly available database, containing an extensive collection of calculated mtDNA data records, and integrated it with longevity records. The MitoAge website also provides the basic tools for comparative analysis of mtDNA, with a special focus on animal longevity.

Mitochondria are the most "hard-working" organelles and the only organelles in the animal cell that have their own genome. They have long been considered one of the major players in the mechanisms of aging, longevity and age-related diseases1. We and others have shown strong correlative links between mammalian maximum lifespan and mtDNA base composition. In particular, the mtDNA GC content appears to be an independent and powerful predictor of mammalian longevity.

MitoAge: a database for comparative analysis of mitochondrial DNA, with a special focus on animal longevity

The stability of the mitochondrial DNA (mtDNA) is vital for mitochondrial proper functioning; therefore, changes in mtDNA may have far-reaching consequences for the cell fate and, ultimately, for the whole organism. Not surprisingly, due to a key role in energy production, generation of damaging factors (ROS, heat), and regulation of apoptosis, mitochondria and mtDNA in particular have long been considered one of the major players in the mechanisms of aging, longevity and age-related diseases.

We developed the MitoAge database containing calculated mtDNA compositional features of the entire mitochondrial genome, mtDNA coding (tRNA, rRNA, protein-coding genes) and non-coding (D-loop) regions, and codon usage/amino acids frequency for each protein-coding gene. MitoAge includes 922 species with fully sequenced mtDNA and maximum lifespan records. The database is available through the MitoAge website, which provides the necessary tools for searching, browsing, comparing and downloading the data sets of interest for selected taxonomic groups across the Kingdom Animalia. The MitoAge website assists in statistical analysis of different features of the mtDNA and their correlative links to longevity.

Slowing Aging Slows Parkinson's Development, Even When Caused By Genetic Mutations

In some patients Parkinson's disease is associated with genetic variants, most likely because those differences increase susceptibility to damage in the small but critical population of neurons that are destroyed as the disease progresses. It is all very much a matter of levels of damage, however, and so we shouldn't be surprised to see that established methods of modestly slowing aging in laboratory animals also slow the progression of Parkinson's-like model conditions created through genetic alteration. Aging, after all, is also a matter of accumulating damage - the less damage you have, the less aged, dysfunctional, and frail you are.

Scientists have shown in disease models that slowing aging reduces degeneration related to Parkinson's. "It is unknown why symptoms take many decades to develop when inherited mutations that cause the disease are present from birth. Aging is the greatest risk factor for developing Parkinson's - we believe changes that occur during the aging process make brain cells more susceptible to disease-causing mutations that don't cause issues in younger people."

In the brain, Parkinson's is marked by the dysfunction and death of the nerve cells that produce dopamine - a chemical that plays a key role in many important functions, including motor control. Clumps of a protein called alpha-synuclein also are found in brain cells of most people with Parkinson's, although scientists are still trying to pin down their exact role. As part of their search for ways to prevent the disease, researchers delayed the aging process in genetic models of Parkinson's disease. They demonstrated that slower aging imparts protection against the loss of dopamine-producing cells in the brain and decreases the formation of alpha-synuclein clumps - ­both hallmark features of Parkinson's. "This work suggests that slowing aging can have protective effects on the brain cells that otherwise may become damaged in Parkinson's. Our goal is to translate this knowledge into therapies that slow, stop or reverse disease progression."

The team used the worm Caenorhabditis elegans as a genetic model for Parkinson's. Thanks to its simple and well-mapped nervous system, and the ease of genetic manipulation and maintenance of the worm, C. elegans is well-suited for the identification of novel treatment strategies for neurodegenerative diseases. Worm models of Parkinson's disease that expressed either a mutated LRRK2 gene or a mutated alpha-synuclein gene - both of which cause Parkinson's - were crossed with a long-lived strain of the worm to create two new strains with longer lifespans. The researchers found that long-lived LRRK2 and alpha-synuclein worms lost dopamine neurons at a much slower rate than their counterparts with normal lifespans. In fact, the long-lived LRRK2 worms had more dopamine neurons left on day 30 of the study than the LRRK2 worms with a normal lifespan of three weeks had on day eight of adulthood. Slowing aging also effectively reduced motor deficits related to the loss of dopamine-producing cells and eliminated the increased sensitivity to stress shown by worms with a normal lifespan.


The Question of Whether to Build Rejuvenation Therapies

Should we build rejuvenation therapies? Hell yes. Are we? Barely, as nowhere near enough of an effort is being made. This is an opinion piece by Aubrey de Grey of the SENS Research Foundation:

Aging is a hot topic among the chattering classes these days. What with biotech companies like Calico and Human Longevity Inc. being founded with the mission to defeat aging, and venerable institutions such as Prudential proclaiming the imminence of superlongevity on billboards, there's no denying that this is a time of great interest in our oldest and deepest-held dream - to escape from the tyranny of inexorable and ultimately fatal physiological decline.

But hang on - is the buzz around aging really reflective of what's being done to realize this goal? The briefest dispassionate analysis reveals a different story altogether. The proportion of government spending allocated in the industrialized world to diseases and disabilities of old age is appropriately high, but it is overwhelmingly dedicated to the transparently quixotic approach of attacking those ailments directly - as if they were infections - rather than attacking their lifelong accumulating causes. The latter approach is the focus of biomedical gerontology. Researchers in this field recognize that any direct attack on late-life disease is doomed to become progressively less effective as the causes of those diseases continue to accumulate, so they focus instead on those causes - the "damage" that the body inflicts on itself throughout life in the course of its everyday operation. But they comprise a tiny coterie of scientists - far too few, and with access to far too little funding, to allow progress to occur at anywhere near the maximum rate that the simple technical difficulty of the problem would allow.

I believe that the main reason for this tragic myopia is a phobia about aging so ancient and deep-seated that it overpowers the rationality of nearly all of us, even the most intelligent and educated. Aging holds us in a psychological stranglehold, preventing us from even contemplating the idea of its medical conquest. Thus it is that grown adults find it possible to argue that we should forever continue to let everyone endure the number one cause of human suffering. Unfortunately for us - by which I mean, for the whole of humanity - those adults include the overwhelming majority of the people who control enough money (whether their own, their company's or the taxpayer's) to make a difference. Even without getting into the debate about what approaches to this challenge are the most promising, one can no longer escape the fact that most biomedical gerontologists now agree that we are approaching a time of sharply accelerated progress in extending healthy lifespan. Except, of course, by letting that expert opinion go in one ear and out the other. And that, I'm afraid to say, is what most decision-makers are still doing. The marginalization of anti-aging research is our most shameful humanitarian failure.


The Methuselah 300 Monument is Unveiled

The Methuselah Foundation has unveiled the Methuselah 300 monument in the US Virgin Islands, a lasting record of the generous donors of the Methuselah 300 who have helped fund the work of the Methuselah Foundation over the past decade: the M Prize for longevity science; the seed funding of bioprinting company Organovo; the SENS rejuvenation research programs and creation of the SENS Research Foundation; the launch of the New Organ prize series; and much more.

The Methuselah Foundation was the first longevity science initiative that I chose to materially support with my donations and my time. The third post I wrote here at Fight Aging! back in 2004 covers the just-getting-started initiative of the Methuselah 300: aiming to find a group of regular donors to contribute to bold initiatives in aging research. It was an ambitious plan at a time when raising funding to accelerate progress towards rejuvenation therapies was near unheard of, mocked by the press and the scientific establishment where it did happen, and all in all considerably harder than it is today. But why is it now easier to raise funds for rejuvenation research, and why is it now the case that up and coming scientists can talk seriously about treating aging without risking reputation and career? In large part because the Methuselah 300 worked, people joined in to a degree not seen in earlier initiatives with similar aims, the Methuselah Foundation became a going and influential concern within the small aging research community atop the foundation provided by 300 member donations, and the staff and allies of the Methuselah Foundation went on to change the culture of that community, spinning off the SENS Research Foundation along the way, having a hand behind the scenes in many important activities and decisions.

This is something like the eleven thousandth post at Fight Aging!, and a decade has passed since the first member of the Methuselah 300 sent in the first donation to help fund the then small M Prize for longevity science. The reasons for joining the 300 are just the same as they were back then, with the additional guarantee that now it isn't a step into the unknown. You might read Michael Rae's call to action from that time, for example. Joining the Methuselah 300 is a way to make a real difference to the future of health and aging, to materially support an organization with a proven track record of getting things done in longevity science. Just this year, for example, the Methuselah Foundation joined with the SENS Research Foundation in providing seed funding to Oisin Biotech, a startup company aiming to build a viable senescent cell clearance therapy, a technology we hope to see reach the clinic in the near future, the first true rejuvenation therapy capable of removing some of the damage that causes aging and age-related disease.

The Methuselah 300 Monument

In 2005, The Methuselah 300 initiative began with a few brave and dedicated people willing to fight for life itself. These individuals are now honored by a monument in St. Thomas. Their story is presented by the founders of the Methuselah Foundation in the following video. In it, we pay tribute to their continued courage and generosity, which fuels the real hope for extended healthy human life.

Will you join the legacy?

Methuselah Foundation Announces the Official Unveiling of the Methuselah 300 Monument

In 2003, the Methuselah Foundation was formed to take action on a remarkable idea: that the world's greatest scientific and medical minds, given the right spark of innovation, could bring about sweeping changes in the longevity and quality of life for people everywhere. Exciting and innovative ideas find like minds, and the Methuselah Foundation moved quickly to encourage innovative creativity in the fields of medical and longevity research. With the establishment of the first "M Prize", scientific researchers saw this prize as an opportunity to be rewarded for results rather than just research itself, and teams of scientists and doctors began to get on board.

None of this was accomplished alone. Integral to the Methuselah Foundation and it's work are the men and women who early on saw the amazing possibilities the foundation's work could accomplish. These men and women were the foundation of a collective group that came to be known as the 300. Since 2005, 150 dedicated men and women have committed to giving $25,000 over 25 years to help us eradicate needless suffering and extend healthy human life. In the over 10 years since the foundation was formed with the help of these ones, research has reached the point that things once considered impossible are now on the horizon; advances like bio-printing organic material, and the organic generation of new organs.

In the foundation's desire to thank the selfless compassion and generosity of this group who continues to make these things possible, we are pleased to announce the official unveiling of the Methuselah 300 Monument! Just as the original 300 Spartans were later memorialized in a monument at Thermopylae, we have memorialized our own 300 with a unique monument located on a breathtaking hillside in St. Thomas in the U.S. Virgin Islands. The monument total size including surround is 9 feet wide x 17 feet long, and the granite plaques are 4 feet wide by 10 feet long. This monument will draw attention to those who generously give so that other's lives may be extended, or have their quality of life raised by the research the Methuselah foundation continues to inspire and encourage. The monument will be available for all to see by webcam at anytime; seeing not only the names already inscribed, but also the names of future 300 members to be added.

We would also like to extend the invitation for you to become a member of the 300, or support the foundation's work to whatever extent you are able. We will continue working to accomplish our goal of "making 90 the new 50 by 2030"! Will you join us?

Energy-Carrying Molecules to Boost Aging Mitochondria?

Here I'll point out the latest in the Question of the Month series from the SENS Research Foundation, in which the staff are far more polite than I regarding the unmerited hype that seems to accompany both supplement research in general and research emerging from the Sinclair lab at Harvard in specific:

Q: In recent months, I've seen quite a lot of promotional material for a dietary supplement called nicotinamide riboside (NR). The companies involved say that Harvard researchers showed that this supplement restores mitochondrial function in the cells of aging mice, completely reversing the aging process in muscles. Some of them add that other research has shown that it improves metabolism, fights fat and obesity, and is protective of brain function. What do you think of this supplement?

A: It must be clarified that the substance used in the Harvard research was not actually NR, but another compound called nicotinamide mononucleotide (NMN). But NMN is unsuitable for oral supplementation, so the Harvard researchers injected their mice with NMN rather than giving it to them in their feed. With the excited coverage that greeted the research, supplement companies have promoted NR as a substitute, because it was already in production and can be taken orally. Because NR is a precursor to NMN, which in turn is used for the synthesis of the energy shuttle molecule nicotinamide adenine dinucleotide (NAD), many supplement vendors assert or imply that the results with NMN can also be gained with NR.

That all may sound promising, and it certainly makes for effective marketing copy. But no study has actually been done demonstrating that NR has similar effects to NMN in the muscles of otherwise-healthy aging mice. In fact, one study found that high-dose NR supplementation was unable to increase NAD+­ levels in muscle tissue or the mitochondrial fraction of normal, healthy mice. Additionally, overexpressing the gene that converts NR to NMN in these animals' muscles still didn't affect muscle mitochondrial function in the way that the Harvard researchers reported with NMN, suggesting that the effects observed with injected NMN may involve some kind of systemic response to having NMN itself circulating in the bloodstream. This casts considerable doubt on the assumption that either NR, or some other supplement that raises cellular NAD+­ levels, will replicate the effects of NMN on aging muscle. Additionally, interpretation of the Harvard report is greatly hampered by the lack of information of the animals' weight or food intake, which raises the possibility of effects mediated by calorie restriction or (contrariwise) by the simple overfeeding of all the animals in the study.

It's also important for readers of the press coverage to understand just what was involved when such stories reported that NMN treatment "reversed the effects of aging" on the mice's muscles. Readers would be forgiven for imagining the muscles of frail, elderly mice suddenly swelling to youthful size, able to perform tiny rodent bench presses with the strength and endurance of much younger animals. In reality, though, as the investigators were careful to point out in the original scientific paper, while their treated animals' muscle cells exhibited biochemical evidence of improved ("rejuvenated") metabolism and insulin-stimulated glucose uptake, "we did not observe an improvement in muscle strength." This important detail was missing from almost all of the reporting in the popular press. While it's possible, as the scientists speculate, that longer-term treatment would have led to some recovery of muscle function, the lack of any observed improvement in actual muscle strength calls into question the functional significance of the biochemical "rejuvenation" they report.


Considering the Possibility of a Type 4 Age-Related Diabetes

Type 1 diabetes is an autoimmune disease, type 2 diabetes is a lifestyle disease largely caused by being overweight, some researchers have suggested that Alzheimer's disease is a type 3 diabetes, and here evidence is presented for the existence of a type 4 age-related diabetes:

Diabetes is often the result of obesity and poor diet choices, but for some older adults the disease might simply be a consequence of aging. New research has discovered that diabetes - or insulin resistance - in aged, lean mice has a different cellular cause than the diabetes that results from weight gain (type 2). And the findings point toward a possible cure for what the scientists are now calling a new kind of diabetes (type 4). "A lot of diabetes in the elderly goes undiagnosed because they don't have the classical risk factors for type 2 diabetes, such as obesity. We hope our discovery not only leads to therapeutics, but to an increased recognition of type 4 diabetes as a distinct disease."

Researchers set out to compare the immune systems of healthy mice, those with obesity-related diabetes and those with age-related diabetes. The mice with age-related disease, they found, had abnormally high levels of immune cells called T regulatory cells (Tregs) inside their fat tissue. Mice with obesity-related diabetes, on the other hand, had normal levels of Tregs within the tissue, despite having more fat tissue. Normally, Tregs help calm inflammation. Because fat tissue is constantly broken down and built back up as it stores and releases energy, it requires low levels of inflammation to constantly remodel itself. But as someone ages, the new research suggests, Tregs gradually accumulate within fat. And if the cells reach a tipping point where they completely block inflammation in fat tissue, they can cause fat deposits to build up inside unseen areas of the body, including the liver, leading to insulin resistance. "It was a little bit surprising since normally Tregs are supposed to be beneficial for the body."

When the scientists blocked Treg cells from accumulating in the fat by targeting a molecule that the immune cells require, mice no longer developed type 4 diabetes in old age. However, if mice became obese, blocking the Tregs in fat did not prevent type 2 insulin resistance. "It turns out that for this type of diabetes, the treatment is not losing weight. The treatment is actually losing these cells, and we show that it's possible to do that." The researchers now want to find out exactly how Tregs interact with fat tissue and whether the immune cells accumulate in other organs during normal aging. They're also planning studies to see whether the results hold true in humans. "We're working with clinicians to get samples from older, lean people with diabetes to see if this cell type is also implicated in human disease."


Triple Matching of SENS Donations on Giving Tuesday, Coming Up on December 1st

Giving Tuesday is the Black Friday of the non-profit world, a collaborative event organized across the whole of the non-profit community in which activists and advocates raise awareness, coordinate activities, and inform the decisions that people make about charitable donations at the end of the year. This year Giving Tuesday falls on December 1st. As I'm sure you're all aware, we're in the midst of raising funds for SENS rejuvenation research, the best and most effective of initiatives aimed at bringing aging under medical control. We have a little under $60,000 to go before the end of the year to hit our targets, and I'm pleased to note that if you donate to the SENS Research Foundation on December 1st your donation will be matched threefold - by the Fight Aging! matching fund, the Croeni Foundation, and Aubrey de Grey:

SENS Research Foundation is getting ready to celebrate #GivingTuesday on December 1st. GivingTuesday is now a global event celebrated by supporters of various charities giving to their favorite causes. If you've been planning on contributing to the fight against age-related disease this year, GivingTuesday is a great opportunity to make a difference.

So far, SENS Research Foundation has 3 matching grants set up for GivingTuesday. The first is our FightAging! Challenge which will match every dollar you give us up to $125,000. On GivingTuesday, the first $5,000 we raise will not be doubled or even tripled - it will be quadrupled thanks to the generosity of the Croeni Foundation and Aubrey de Grey. Help us turn $5000 into $20,000 and accelerate the fight against age-related diseases! Donate at on December 1st.

Seize this chance to make a real difference in the future of human health and longevity! The staff and allies of the SENS Research Foundation have demonstrated over the past decade that they can produce real, meaningful results with our donations, pushing forward the state of the art closer to the realization of effective therapies for aging. The potential to fundamentally change the world of medicine is very real: those of us yet to be old have a shot at ensuring that treatments arrive soon enough to prevent us from suffering age-related pain, disability, and frailty. The causes of aging, well-cataloged forms of cell and tissue damage, can in principle be repaired, and the path to doing so is just about as clear as research and development can ever be.

This is the time for it. We stand in the initial years of a revolution in the capabilities and cost of biotechnology. Early stage research in the life sciences has become very cheap; a few tens of thousands of dollars can go a long way in an established laboratory, producing real progress at the cutting edge when spent wisely. Yet much of the necessary, revolutionary work in aging research is only funded by philanthropy, as traditional funding institutions are risk-averse and don't become involved until the prototypes are built, the case proven. In essence all important progress in medicine depends on the early participation of people like you and I, who are both aware of the possibilities, and interested enough in the outcome of greater healthy longevity to help make it happen.

For most people, medical research is invisible. They'll never read about it, never think about it, until it is too late to have made a difference that mattered. Reading this, you have a chance to avoid that scenario. The more that is done now to start the avalanche of rejuvenation biotechnology development, the greater the results decades from now, at a time when aging is encroaching upon your health. Don't let this opportunity slip away: help fund the work of the SENS Research Foundation on the scientific basis needed to bring an end to degenerative aging.

Skepticism of a Causative Role for Telomeres in Aging

A researcher here takes a skeptical look at telomerase studies, such as those shown to extend life in mice, most likely by boosting stem cell activity. There is a school of thought that suggests the role of telomerase in lengthening telomeres is an important mechanism in the induced longevity attained in these studies, but I think it is correct to be skeptical on this count. Erosion of average telomere length occurs over a life span, but this really does not look like a root cause of degenerative aging. Instead the average length of telomeres in immune cells, where it is commonly measured, appears to be a consequence of some combination of stem cell activity and immune health. In any given tissue, cells with long telomeres are created at some pace by stem cells, telomeres shorten with each cell division, and old cells with short telomeres destroy themselves or become senescent. Stem cell activity declines with age, and it isn't a leap to suggest that this will tend to produce shorter average telomere lengths as the supply of new cells diminishes.

Telomeres are repetitive DNA sequences at the ends of linear chromosomes and serve to maintain chromosome integrity. Additional properties have made telomeres a focus in the biology of aging: (i) telomeres shorten at each cell division due to incomplete replication of their ends; (ii) they are shortened by oxidative damage; and (iii) when telomeres reach a critical length, cells enter a senescent state and cell division ceases. This latter property has been demonstrated in now classic experiments, showing that telomere length predicts the in vitro replicative capacity of human fibroblasts and that over-expressing telomerase - the enzyme that can reverse transcribe telomeric sequence - immortalizes fibroblast cell cultures. These experiments suggest the possible causal involvement of telomeres in the aging process and this hypothesis has increased in popularity since the finding that telomere length predicts human mortality and that, in vivo, human telomeres shorten during aging.

It is rarely acknowledged in telomere biology that such associations do not necessarily dictate causality. Of course in principle associations can never show causality, and experimental evidence is a starting point. Such inference is useful interpreting data in terms of biological mechanism and for policy, but can also be harmful when such causality is prematurely inferred or assumed. This can lead to reduced or misfocused research effort to uncover the mechanisms actually responsible for the associations that are reported or false inference of the associated biology. In the biology of aging it is tempting to infer causality from biomarkers of aging because aging mechanisms remain so elusive. It is therefore not surprising that causality of telomere length in aging is often inferred from associations or from the available experimental evidence.

Here I question such causal involvement of telomeres in aging. I review the telomerase knockout and overexpression studies that are often cited and hailed as providing the necessary evidence for the causal involvement of telomere biology in aging. I collated studies on the effects on longevity and conclude that, together; the results are surprisingly mixed and provide weak support. In the cases where lifespan changed as predicted in response to the manipulation of telomerase, the effect on telomere length was either outside the normal range of telomere shortening or telomere elongation was not conclusively demonstrated, thereby limiting any strong conclusions. In addition, the causality hypothesis assumes that there is a critical telomere length at which senescence is induced. This generates the prediction that variance in telomere length decreases with age. In contrast, using meta-analysis of human data, I find no such decline. Inferring the causal involvement of telomeres in aging from current knowledge is therefore speculative and could hinder scientific progress.


A View of the Important Divide in Longevity Science from the Other Side of the Fence

Here I'll point out a view of the great divide in aging research from the other side. I have long argued that the most important divide in the field of aging research is between (a) the minority position of those who see aging as an evolved program, so that, for example, epigenetic changes occur that cause altered cellular behavior that in turn leads to an accumulation of damage, dysfunction, and death, and (b) the majority position of those who see aging as a matter of accumulated damage occurring as a side-effect of the normal operation of metabolism, and that damage results in epigenetic changes, dysfunction, and death. There is a horse and a cart, and some argument over which is which.

Researchers in fact know a great deal about the differences between old tissue and young tissue. They have a very good catalog of those differences. They also have a pretty good catalog of the dysfunctions in specific organs and tissues that accompany age-related disease. The middle ground between those two things, the enormously complex biochemical interactions spanning decades of time that produce aging, is much more of a blank spot on the map. Only tiny slices have been mapped, and it is this gap that allows the freedom to theorize over whether change produces damage or damage produces change.

Why is this important? Because whether you stand on one side or the other of this theoretical divide determines which approach to treating aging you should favor. Treatments for aging must aim at root causes to be effective. If change, such as epigenetic change leading to altered levels of proteins in cells, is the root cause of the damage of aging, then treatments should consist of restoring the right protein levels and epigenetic markers rather than addressing damage. But if damage is the root cause of aging then treatments should be repairing that damage. The potential rejuvenation therapies that are on the wrong side of the line will likely be ineffective in comparison to those on the right side of the line.

Obviously, given my support for the SENS approach to treating aging, I'm in the damage camp. I think that the evidence, such as the presence in old tissues of harmful cross-links that our biochemistry cannot break down, strongly supports the view that aging is caused by damage accumulation, and the observed epigenetic and protein level changes are reactions to that damage. Here, however, is a view from the other side, the programmed aging camp:

Aging is an accumulation of damage. If we want to return the body to a more youthful state, we're going to have to repair that damage. Or ... the body never forgets how to be young. Given the appropriate signaling environment, the body will restore itself to a youthful state. The future of medicine is the future of anti-aging medicine. I don't think anyone seriously disputes this. Infectious diseases are a minuscule problem compared to a century ago, and with hygiene, good public health practices, and responsible restraint in applying antibiotics, we may hope to avoid a return to the days when tuberculosis and syphilis were pandemic. We are fast learning to treat congenital disorders, and safe gene therapies are already being tested.

This leaves diseases of old age as the next frontier. To slow the progress of aging, there is no doubt that signaling approaches work in animals, and will work (probably with less efficacy) in humans. Caloric restriction (CR), exercise and other forms of hormesis are the best approaches we know at present. Pills (e.g. metformin) may offer some of the benefits of CR without the hunger, and an "exercise pill" has been proposed. The next step is to actually reverse aging, to restore the body to a more youthful state. Among those of us who advocate research in the technology of age reversal, there are two prevailing paradigms. I am with the school that says the same signaling approach can be extended to trick the body into thinking it is younger than it is, and the body will renew its cells and replace damaged biomolecules on cue. The other school says that once the toothpaste is out of the tube, it's not going back in. We will have to engineer prosthetics, use bioengineering and regenerative medicine to replace body parts that have worn out.

In the beginning, anti-aging medicine was thought to be fanciful, if not impossible. How could human engineering improve on processes that Nature has been perfecting for a billion years? Then a science of regenerative medicine began very slowly chipping away at that conventional wisdom, and a glimmer of hope pointed to promise of fixing the body directly with engineering, at least in the long run. But a funny thing happened along the way. There are indications in many areas that the body knows perfectly well how to rejuvenate itself, and we need only learn to speak the body's (biochemical) language in order to say, "Have at it!" A few people like me are pointing out that this contradicts everything we thought we knew about evolutionary biology, and that the "selfish gene" is in need of an overhaul. But bench scientists are choosing to sidestep this theoretical debate and simply to do the practical thing. They are pursuing a signaling approach because it works.

I would argue that the signaling approach is largely characterized by failure to obtain meaningful outcomes, and at great cost. Just look at the end result of sirtuin research; enough money expended to fully implement SENS rejuvenation programs in mice, and nothing to show for it but greater knowledge of a small slice of our biochemistry. Where there are successes in more recent years, these seem to result from activation of stem cells in old tissues - and restoring stem cell populations is on the SENS agenda - without any accompanying repair of other root cause damage. This will produce benefits, and fortunately it seems that putting damaged cells in damaged tissues back to work has far less of an effect on cancer risk than was feared, but this doesn't do anything to clear out issues such as amyloids, lipofuscin, and persistent cross-links.


Transthyretin Amyloid May Contribute to the Progression of Cartilage Damage and Osteoarthritis

Earlier this year researchers published evidence suggesting that rising levels of transthyretin (TTR) amyloid may contribute to age-related damage to cartilage tissue in joints and consequent development of osteoarthritis. Amyloids of various types accumulate in tissue with advancing age, each resulting from a different misfolded protein whose altered properties in that state cause it to form solid deposits. The biochemistry of this process is different in each case, and usually complex and incompletely understood. You don't have to look any further than the field of Alzheimer's research and the still dominant amyloid hypothesis to see that investigations of amyloid biochemistry are enough to keep most of a sizable scientific industry busy for decades. Knowledge of amyloid-β has grown in proportion to the funding and attention directed to the Alzheimer's research community, but for many of the other forms of amyloid it isn't entirely clear as to exactly how their presence contributes to the age-related conditions that correlate with the presence.

In some cases this is because the data is still arriving: researchers were not looking in the right place, or not paying enough attention, or lacked funding for the necessary investigations. TTR amyloidosis is an excellent example of this situation, as until fairly recently the majority of research interest focused on the rare inherited form of the condition, which is caused by genetic mutation and leads to an abnormally rapid accumulation of amyloid. Then it was discovered that a sizable fraction of supercentenarians die due to TTR amyloidosis, the condition called senile systemic amyloidosis in this case to distinguish it from the inherited form. In essence this form of amyloid builds up in the cardiovascular system of the most elderly people, attaining a large enough presence to choke proper function of the heart. Later, in the past couple of years, researchers have found signs of the damage done by TTR amyloid in a range of age-related conditions: as a contributing cause of spinal stenosis; as an unsuspected contribution to heart failure in a much wider group of old people; and now in the progressive destruction of cartilage.

The silver lining here is that promising therapies capable of breaking down TTR amyloid are under development. The more that we see this amyloid involved in age-related degeneration, the happier we should be given ongoing progress towards a basis for effective treatments. The SENS Research Foundation has funded work on catabodies that can degrade TTR amyloid, other groups have made inroads into disrupting amyloid formation, while earlier this year a human trial of small molecule drugs to clear TTR amyloid reported good results.

Transthyretin Deposition in Articular Cartilage: A Novel Mechanism in the Pathogenesis of Osteoarthritis

Amyloid deposits are prevalent in osteoarthritic joints. We undertook this study to define the dominant precursor and to determine whether the deposits affect chondrocyte functions. Amyloid deposition in human normal and osteoarthritic knee cartilage was determined by Congo red staining. Transthyretin (TTR) in cartilage and synovial fluid was analyzed by immunohistochemistry and Western blotting. The effects of recombinant amyloidogenic and nonamyloidogenic TTR variants were tested in human chondrocyte cultures.

Normal cartilage from young donors did not contain detectable amyloid deposits, but 7 of 12 aged normal cartilage samples (58%) and 12 of 12 osteoarthritic cartilage samples (100%) had Congo red staining with green birefringence under polarized light. TTR, which is located predominantly at the cartilage surfaces, was detected in all osteoarthritic cartilage samples and in a majority of aged normal cartilage samples, but not in normal cartilage samples from young donors. Chondrocytes and synoviocytes did not contain significant amounts of TTR messenger RNA. Synovial fluid TTR levels were similar in normal and osteoarthritic knees. In cultured chondrocytes, only an amyloidogenic TTR variant induced cell death as well as the expression of proinflammatory cytokines and extracellular matrix-degrading enzymes. The effects of amyloidogenic TTR on gene expression were mediated in part by Toll-like receptor 4, receptor for advanced glycation end products, and p38 MAPK.

These findings are the first to suggest that TTR amyloid deposition contributes to cell and extracellular matrix damage in articular cartilage in human osteoarthritis and that therapies designed to reduce TTR amyloid formation might be useful.

A Demonstration of Engineered Vocal Cord Tissue

Here is news of a technology demonstration in which yet another part of the body has some of its component parts constructed in the laboratory and successfully tested for functionality:

Tissue engineers have for the first time made structures that not only resemble real vocal cords but also function like them. Impaired vocal cords make it hard or impossible for people to speak. There is currently no way to fix severe damage, which can result from surgery, traumatic injury, or diseases like cancer. The researchers implanted the engineered tissue into a larynx that had been taken from a dog and had one of its vocal cords removed. They demonstrated that the lab-made tissue vibrates and sounds like healthy tissue. Further tests in mice showed that the tissue elicited a minimal immune response, raising the researchers' hopes that such implants could eventually work in people.

Vocal cords are bands of tissue stretched horizontally on either side of the larynx, or voice box, just above the trachea, or windpipe. In recent years researchers have tried to re-create that structure in the lab, using polymer scaffolds to culture and grow stem cells in three dimensions - a well-established tissue engineering approach. But while they've made tissues that look the part, the engineered tissue has not vibrated effectively. Those previous attempts may have been limited because they didn't use cells from vocal cord tissue. This latest effort retrieved such cells from human cadavers and from donors who had healthy tissue removed during surgery. The researchers used a collagen scaffold to culture and grow the cells, and after a couple of weeks they had what resembled vocal cords. Subsequent protein analysis confirmed that it contained a large portion of the specific kinds of proteins found in the real tissue.

It will take at least several more years of development and testing before this process might be used in vocal cord transplants on people. But if further studies confirm the observation that tissue engineered from the cells of unrelated donors doesn't cause a harmful immune response, it should be possible to generate a large amount of vocal cord tissue from a small number of sources.


The Latest on DNA Methylation as a Biomarker of Aging

Over the past few years, researchers have been working to construct and validate a biomarker of aging based on changes in DNA methylation patterns that occur over a lifetime. DNA methylation is constantly in flux, part of the complex system of epigenetic regulation that alters the output of proteins in response to circumstances in order to regulate cellular behavior. Some of these changes are driven by the accumulation of forms of cell and tissue damage that cause aging, and measurements of those should correlate well with biological age: how damaged you are, and thus how aged you are, and further how high your mortality risk is as a result.

A low-cost, quick, and reliable measure of the degree to which an individual is are damaged and aged will be a necessary tool for future research into aging and longevity. Currently the only way to assess whether or not a putative rejuvenation therapy works as intended to extend healthy life is to wait and see. That is very costly, even in studies that use short-lived species, and a therapy has to be tested in longer-lived mammals at some point on the road to clinical application. Given a reliable biomarker that measures biological age, it will be possible to rapidly assess many more potential therapies that treat the causes of aging, steering the community towards the most effective approaches, and reducing the time spent on dead ends or less effective research programs.

Several recent studies have made use of the age-related changes in methylation profiles to construct DNA methylation signatures, a DNA methylation age (DNAm age) or 'epigenetic clock', with impressively high correlations with chronological age, of about 0.7 or greater. Considering that methylation profiles are modifiable by lifestyle and other environmental influences, it has been proposed that DNAm age is a biomarker of aging, that is, that DNAm age provides a better estimate of biological age than chronological age and is associated with current and future health and mortality.

In this study, we estimated DNAm age using the frequently applied Horvath prediction model and confirmed it using the Hannum prediction model. The study sample consisted of 378 twins aged 30-82 years from the Danish Twin Registry. The oldest 86 twins (mean age 76.2 years at intake) were resampled in a 10-year follow-up study and had methylation age determined again at mean age 86.1 years. The mortality in this sample was subsequently followed for 8 years. The twin design enabled us to control partly for genetic and rearing environment in the mortality study.

We found that the DNAm age is highly correlated with chronological age across all age groups, but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co-twin and a 'dose-response pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging.


JAK-STAT Inhibition and Consequent Reduction of SASP as a Mechanism to Lower Inflammation in Aging

Here I'll point out a paper in which researchers link the suddenly popular JAK-STAT signaling pathway with the harmful activities of senescent cells in old tissues and the rising level of chronic inflammation that contributes to the progression of most age-related diseases. The varied roles of the genes and proteins involved in the JAK-STAT signaling pathway have been studied by a number of research groups of late. There are four Janus kinases (JAK) and at least seven Signal Transducer and Activator of Transcription (STAT) proteins involved in this very small slice of cellular metabolism, and of course their activities influence and are influenced by scores of other mechanisms. Nothing ever happens in isolation inside a cell. The JAK-STAT pathway is of interest because inhibition of some of its components and activities appears to somewhat restore the activity of old stem cell populations, and has also been shown to reduce the growth in chronic inflammation that accompanies aging.

In the open access paper linked below, the authors propose that reductions in inflammation resulting from JAK inhibition occur because the intervention damps down the harmful output of senescent cells. Cellular senescence is a mechanism that removes cells from the cycle of replication in response to damage or stress. It may be an evolved adaptation of a tool of embryonic development that serves to suppress cancer risk, but it unfortunately also produces damage as these cells grow in number - and aging is nothing more than an accumulation of damage and reactions to that damage. Senescent cells generate a disruptive mix of signal molecules known as the senescence-associated secretory phenotype; this alters the behavior of surrounding cells, damages nearby tissue structures, and to the point of this paper, creates inflammation. When few senescent cells are present, as is the case in younger life, there is little harm done. Most are destroyed by the immune system or by their own programmed cell death processes, but over time an ever-increasing number of senescent cells evade these fates to linger indefinitely. In old age a substantial proportion of some tissues are made up of these dysfunctional cells, and tissue function declines as a direct result. Even the cancer suppression falters in the end, with the inflammatory and other effects of SASP promoting cancerous growth more effectively than the removal of cellular replication suppresses it.

The direct approach to cellular senescence is to periodically destroy senescent cells to keep their numbers low. It doesn't matter how exactly they are causing havoc if they can be safely removed. This is the best and fastest path to therapies, but is nonetheless very much a minority concern in the research community. Shortcuts carried out in advance of understanding, even when they work as this destructive approach does, go against the grain of scientific culture. The usual preferred approach is to gather full understanding of what is going on under the hood and then alter the operation of cellular metabolism in targeted ways to reduce undesirable outcomes. Never mind that this is far harder, slower, more expensive, and - for the foreseeable future - less effective. What is important to the research community is that it aligns with the goal of mapping cellular metabolism. Along these lines, it is interesting to note that the paper below, essentially advocating modulation of SASP via JAK inhibition as a desirable approach to therapies, is written by the very same researchers who recently demonstrated improved healthspan via partial elimination of senescent cells.

This is why we need philanthropy and advocacy and organizations like the SENS Research Foundation to get out there and push forward down the fast and effective path. No distractions, no mapping, just straight to the first generation therapies capable of meaningfully treating the causes of aging. It is far from an academic question as to how rapidly effective treatments can be created to address the effects of cellular senescence in aging. Countless lives depend upon this and the other necessary components of a toolkit of rejuvenation therapies. So I'd say that the point to take away from this particular research paper is that it provides one more set of evidence to confirm that, yes, destroying senescent cells to remove SASP as soon as possible is a great idea. In that I'm not in agreement with the authors' summary on possible ways forward:

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

A hallmark of aging is chronic, low-grade, "sterile" inflammation. Elevated proinflammatory cytokines and chemokines are closely associated with mortality and with a variety of age-related diseases, including atherosclerosis, depression, cancers, diabetes, and neurodegenerative diseases. Inflammation also is associated with frailty, a geriatric syndrome characterized by decreased strength and incapacity to respond to stress.

The underlying mechanisms of age-related chronic inflammation, tissue dysfunction, and frailty remain elusive. Cellular senescence, stable arrest of cell growth in replication-competent cells, is a plausible contributor. Senescence can be induced by a number of stimuli and stresses. Senescent cells accumulate with aging in the skin, liver, kidney, the cardiovascular system, and other tissues in various species. The senescence-associated secretory phenotype (SASP), largely comprised of proinflammatory cytokines and chemokines, links senescent cells to age-related inflammation and diseases. We found that elimination of senescent cells delayed the onset of age-related phenotypes and enhanced healthspan. Therefore, senescent cells and the SASP could play a role in age-related pathologies, particularly those that involve systemic inflammation.

The JAK/STAT pathway plays an important role in regulating cytokine production. We hypothesized that it may directly affect the SASP. We demonstrate here that senescent preadipocytes, fat cell progenitors, accumulate in adipose tissue with aging and can contribute to adipose tissue inflammation. We found that JAK inhibitors decrease the SASP in preadipocytes and human umbilical vein endothelial cells (HUVECs). They also decrease age-related adipose tissue and systemic inflammation as well as frailty. Our findings provide insights into the possible contribution of senescent cells to age-related inflammation and, in turn, to age-related pathologies, as well as potential therapeutic targets to alleviate age-related dysfunction.

There are three potential approaches for targeting senescent cells. One is to prevent them from arising by disabling p16- or p53-related processes or other upstream mechanisms that drive the generation of cellular senescence. This approach, however, is likely to induce cancer. The second is to eliminate senescent cells that already have formed. The third is to blunt the proinflammatory nature of the SASP. Mounting evidence suggests that senescent cells can have both harmful and beneficial effects. Therefore, partial suppression of the SASP seems to be a reasonable option, particularly when short-term alleviation of age-related dysfunction might be indicated.

Human ARF Gene Blocks Zebrafish Regeneration

Usually it isn't worth noting that researchers have found a way to break a specific biological process; typically that is a very early stage in finding out how things work, pull out the pieces one by one and see what happens, taking place long before the emergence of a decent overall picture of the situation. Here, however, researchers have broken regeneration in a much more interesting way, a part of ongoing efforts to identify exactly why it is that zebrafish, like salamanders, can regrow entire limbs and organs while mammals cannot. The ultimate goal here is to find out whether the necessary machinery for adult organ regrowth exists at all in humans, a suppressed part of our evolutionary heritage, and if so, build a way to safely turn it on:

Insights from creatures like zebrafish and salamanders, which routinely regrow damaged tails, limbs, jaws and even hearts, may one day endow humans with heightened regenerative abilities. "In the last 10 to 15 years, as regenerative organisms like zebrafish have become genetically tractable to study in the lab, I became convinced that these animals might be able to teach us what is possible for human regeneration. Why can these vertebrates regenerate highly complex structures, while we can't?" Whether the regenerative powers of zebrafish and salamanders represent ancient abilities that mammals have lost, perhaps in exchange for advanced tumor-suppression systems remains an open question for biologists. Most tumor suppressor genes, being extremely useful for preventing cancer and for forming tissues during development, are broadly distributed and conserved across many different species. Recent studies, however, suggest that one, the ARF gene, arose more recently in the avian and mammalian lineage, and has no equivalent in the genomes of highly regenerative animals.

To explore whether this gene might play a role in preventing tissue regeneration in humans, the researchers added human ARF to the zebrafish genome and assessed how it affected the fishes' normal ability to regrow damaged fins after injury. They found that human ARF had no effect on the fishes' normal development or response to superficial injury, but when the researchers trimmed off the tip of a fish's tail fin, the gene became strongly activated and almost completely prevented fin regrowth by activating a conserved tumor-blocking pathway. "It's like the gene is mistaking the regenerating fin cells for aspiring cancer cells. And so it springs into action to block it. Humanizing a lower vertebrate species to study regeneration has not generally been used before, and to our surprise it turned out to be remarkably tractable. The gene fits right in very cleanly and completely alters the organism's response."

The discovery suggests that future efforts to promote regeneration in humans will likely require carefully balanced suppression of this anti-tumor system. The same pathway in humans theoretically could be blocked to enhance researchers' ability to grow model organs from stem cells in a laboratory dish, to enhance patients' recovery from injury. Since tumor suppressors are thought to play a role in aging by limiting the rejuvenating potential of stem cells, blocking this pathway could even be a part of future anti-aging therapies. However, any such interventions would come with significant risk of removing an important brake on the growth of tumors.


Regenerative Medicine for Infected Teeth

This is an example of a comparatively straightforward approach to regenerative medicine, in which researchers mix existing drugs and promising signal molecules with a scaffold gel, aiming to spur regrowth that would not normally occur. In this case, this sort of approach has the potential to regenerate the pulp tissue damaged in infected teeth:

A researcher is developing an advanced nanogel formula that roots out endodontic infections and encourages the recovering tooth to rejuvenate itself. The most common treatment for endodontic infection is the dreaded root canal, which requires several clinic visits to complete. This new therapy would be a one-shot solution. The treatment consists of two antibiotics, ciprofloxacin and metronidazole, along with a dose of nitric oxide. These are encapsulated in an injectable, self-assembled "biomimetic" nanomatrix gel.

Nanogels are a hot area of research because they can be injected directly into a desired target and formulated to release medications over a specific timeframe. In this case, that allows the UAB team to defeat common endodontic infections with low concentrations of those two antibiotics and avoid a third antibiotic used in current therapies. That third antibiotic, minocycline, often stains teeth and causes other side effects. The gel also mimics the natural extracellular matrix (hence the term "biomimetic"), which encourages the formation of new blood vessels in formerly infected pulp tissue. "The reason a tooth dies is due to lack of blood vessels. By removing the infection and recruiting new blood vessels to the tooth, we believe we can rejuvenate it."


Declaring the Importance of Classifying Aging as a Disease

To follow on from a recently linked article on the present regulatory state of affairs for aging research, below find another recent call for regulators and administrators to classify aging as a disease. Numerous researchers have issued opinions and position papers on the topic in the past few years, and to understand why this is the case requires an understanding of how regulation impacts the research funding landscape. From a regulatory standpoint aging is not currently considered a medical condition per se. In some classifications, deviation from normality is one of the baseline criteria, and hence universal phenomena like aging are not included, no matter how ugly the end result. In the case of regulation tied to the legal matter of whether or not it is permitted to offer a particular treatment, and in the US the FDA adopts an "all that isn't listed is forbidden" position, the omission of aging as a treatable condition is a big deal. It means that there is no straightforward path to commercialization of potential therapies for aging within the current framework, and this greatly raises the difficulty of obtaining funding for that goal.

Attempts to change this state of affairs are slow, expensive, drawn out affairs of official and unofficial lobbying. You can see one of the approaches presently underway in the forthcoming clinical trial of metformin, a drug highly unlikely to produce meaningful results in my opinion, but which is the thin end of the wedge when it comes to the scientific community trying to force change on the FDA in the matter of aging. The recent increase in calls to classify aging as a disease should be considered in this context: the word "disease" is just shorthand for "something that I'm allowed to try to treat, and can thus raise funding for." Now that slowing aging and the medical control of aging are accepted as a plausible, possible near future goal by much larger fractions of the research community, the regulatory straitjacket is becoming ever more uncomfortable.

In the case of the World Health Organization's International Statistical Classification of Diseases and Related Health Problems the situation is still all about money, but in this case the benefits sought are a little more indirect. Adding aging to the WHO classification scheme is a way to induce various bureaucracies around the world to direct thought, funding, and verbiage to aging in the context of possible treatments. This falls somewhere between an attempt to amplify advocacy for the treatment of aging and an attempt to expand government research funding, such as the National Institute on Aging budget, via existing mechanisms requiring adherence to the WHO classifications.

For my part, I think that striving to change the regulatory system from within is just another way of implicitly endorsing its existence. None of the vast costs imposed on medical research and development by FDA bureaucrats will go away if aging officially becomes a disease. The better way forward would be for researchers in the US to develop relationships with developers elsewhere in the world, such as the more advanced Asia-Pacific nations in which medical regulation isn't so overbearing and costly: commercialize elsewhere, and deliver services and therapies to the market via medical tourism. The result will be more new treatments, delivered more rapidly, and at lower cost. If the FDA continues to pile on the costs and time for regulatory acceptance of new therapies, more than doubled in the past ten years, alternative commercial ecosystems will develop. Not before time, to my eyes, and it is a pity that this process is not further along now. The best path ahead is to make the FDA and its ilk irrelevant, to bypass the broken system and grasp greater freedom, not to support the present bureaucratic suppression of medical research by spending years to slightly change its parameters.

Why Classifying Aging As A Disease Is Of Crucial Importance To Humanity

Most people have probably heard many times the idea that one can "grow old gracefully" and in a healthy way. This message is perpetuated by the fitness and health industry and pension companies love to show the image of happy, relatively healthy 65-year-olds who can finally escape dreaded work and do what they enjoy in life, for at least a few years before a period of serious disability and death. It is true that some people live over a century and delay many specific pathologies. I also agree that it is a more desirable scenario to die frail at 100 than earlier, but the fact is that what we define as biological aging is in itself a pathological problem, a problem that still suffers from a lack of research. While not every age-related change is studied, the damages can be broadly classified into categories, and specific biomolecular problems can be directly targeted.

While there is a small decrease in function between 20 and 40, the human body still remains "very healthy" until mid 40s when disease correlated to the aging process overtakes accidents/suicides as most common cause of death. Keeping the human body biologically under 50 years old would take away the vast majority of all disease, and even if biologically young people were obese and smoked, there would likely only be a small number of cases where these "unhealthy" habits caused lethal health problems. The problem with WHO and governmental programs is that these systemic pathologies destroying the body and generating ill health in the elderly are not yet considered to be a disease. I have worked trying to change this paradigm. Earlier this year I coauthored "It is time to classify biological aging as a disease", and Alex Zhavoronkov and his company In Silico Medicine have recently published a paper on this issue, to persuade the World Health Organisation to classify aging as a disease as a part of the International Statistical Classification of Diseases and Related Health Problems (ICD-11).

When I was a child I was told wrinkles signified wisdom and life experience, but didn't impact one's health in any way. Nowadays my brain is wired to spot the pathologies behind them; skins laxity and jowls linked to blood sugar crosslinking and destruction of collagen, dysfunction of matrix metalloproteinases and subsequent extracellular matrix degradation. Wrinkled skin is not simply a cosmetic issue, as senile skin is failing to perform its duties properly, similar to burned and scarred skin. Many old people become easily dehydrated, are less able to cope with temperature fluctuations, and they injure and bruise themselves easily due to the loss of components making up the main skin layer, the dermis. Skin aging in itself is yet not classified as a disease, but lesions have pathological names, and photo-aging caused by sun exposure, which shares molecular pathologies with intrinsic skin aging, is considered a pathological condition. What is humanity gaining by this hypocrisy?

Google Life Sciences to Fund Heart Disease Program

An interesting next step from Google Life Sciences: they are putting forward $50 million in search of a laboratory to propose a program that pushes forward the state of the art in research and treatment of heart disease. Spent over ten years, that would produce an organization about the present size of the SENS Research Foundation, or a tenth of the Buck Institute, for purposes of comparison - and smaller than many of the research groups presently dedicated to the study of heart disease. So this is a sizable and welcome investment in medical research, but the significance is overhyped by the reporting organization here; no-one is going to cure heart disease with a $50 million project, since heart disease is caused by aging, and in the most general sense. This is an effort to change the funding landscape, stir things up, and make some progress.

If you walk through the list of forms of cell and tissue damage that causes degenerative aging, near every one of them contributes to structural failure of the cardiovascular system. The loss of stem cell activity and consequent decline in repair of tissues is only one of these: oxidized lipids that contribute to atherosclerosis in blood vessel walls; extracellular cross-links stiffen blood vessel walls and cause hypertension and consequent structural weakening in the heart; senescent cells wreck havoc on all the tissues they accumulate in; transthyretin amyloids that accumulate with age are implicated in heart disease via their ability to clog the cardiovascular system; and the loss of lysosomal function in long-lived cells, including those of the heart, progressively damages their function. Curing heart disease, removing it from the picture, requires treatments that effectively address near all of the causes of aging.

Cardiovascular disease people on Earth than anything else - over 17 million a year, and the number keeps going up. Of those deaths, more than 40 percent is due to coronary heart disease. Medicine has drugs that can treat it and practices that can help prevent it, but nobody really knows what causes it or how to cure it. Now, Google and the American Heart Association aim to change that by dropping a $50 million funding bomb on the problem. And as you might expect from a Silicon Valley giant that believes in moving fast and breaking things - an approach that hasn't always transferred well to basic scientific research - the company isn't spreading the money around. Google Life Sciences and the AHA said the money would go to one team over five years. "Traditional research funding models are often incremental and piecemeal, making it difficult to study a long-term, multifaceted subject. AHA and Google Life Sciences have committed to a bold new approach."

The AHA, already the largest funder of cardiovascular research in the US outside of the federal government, says the program will be its most heavily funded initiative in nearly a century. Applications begin in January and if all goes according to plan, they'll be due by February 14th. (Valentine's Day. Get it?) If you want the $50 million, your idea has to fit on a single page. And Google won't take a financial or intellectual property stake in the results. The organizations hope that the program will accelerate the field of heart research much like Google's self-driving car eventually compelled the entire automobile industry to follow its lead.


An Analysis of Social Media Life Extension Advocacy

One of the younger initiatives here takes a look at discussions of longevity science and living longer on social media. While I don't disagree with the general thrust of the article, that social media is largely filled with less helpful chatter, I would argue that it is hard to demonstrate that the initial premise is correct, that there is any usefully direct link between social media and success in the sense of raising funding for the right lines of research and development. Money is the present key to progress in rejuvenation biotechnology, as funding is the present bottleneck, but we can debate the ways and degrees to which that is influenced by the flow of discussion. Following various initiatives for the past decade, one of the things that has stood out for me is the disconnect from month to month between how much discussion takes place in various forms of media and how much money is coming in via philanthropy. Only at longer time scales, comparing now with a few years ago, are there correlations between increased discussion and increased funding.

This research aims to evaluate the capacity of social media to support the development of science combating age related disease. The study will explore whether this particular area of science is benefiting from social media promotion and advocacy, or instead failing to inspire or achieve any of these things. Key to this is determining the percentage of facebook posts which offer legitimate information in relation to prolonging lifespan. The results were obtained by analysing a sample of 100 Facebook posts from each of the most popular (in terms of membership) facebook groups related specifically to life extension. Each post was categorised by purpose and topic, and then those intended to spread seemingly legitimate information were given a legitimacy ranking. From the results, it is clear that these posts, on the whole, are not acting to stimulate development or progress in this area of science. Of most concern was a lack of legitimacy and scientific evidence behind many posts on the subject of life extension. The research highlights a range of issues which, if not improved upon, represent a genuine obstacle for popularising and advancing science combating age-related disease.

14.71% of posts were raising awareness of a potential cure for aging or age-related disease, 2.55% were raising awareness of a potential cause for age-related disease, 17.59% were analysis/opinion on subjects related to life extension, 31.02% were general advocacy, 5.86% were related to fundraising, 1.06% promoted commercial ventures, and 27.18% had no identifiable purpose or were unrelated to life extension. Only 14.71% of all posts were related to potential cures, and 82.61% of these were suitable for the legitimacy scale. Of these, 0% were actual studies, 55.9% were links to an analysis of a study, and 22.81% were articles based on opinion rather than a scientific study. If we take a look at the overall picture of life extension on social media, taking into account all the data we have collected, only 26.4% of posts could be considered as scientifically informative. Of these, a tiny 1.21% could be considered as a top grade legitimate source.

This is concerning, as legitimate information about developments in science are integral to spreading awareness among the mainstream. Advocacy is clearly a double-edged sword, as even advocacy based on memes and images is positive for the overall picture. However, advocating posts based on memes, images, and promotion, seem to play a more self gratifying role, and offer little in terms of legitimising the cause, particularly to a mainstream audience. Above all else, although attempts to raise awareness and gain greater advocacy through social media are admirable, and absolutely essential to the cause, the results show that a great deal more caution, and in many cases vigilance needs to be exerted when sharing information.


The Immortals Among Us

Let us define immortality as being a state of agelessness, which seems a common colloquial usage these days. More precisely this means that the risk of death due to intrinsic causes such as wear and tear damage of vital organs remains the same over time, perhaps due to advanced medical interventions. Falling pianos are still going to kill you, and a hypothetical biologically young immortal in a hypothetical environment maintaining today's first world extrinsic mortality rate would have a half-life of 500 years or so, meaning that at any age, there is a 50% chance of evading a life-ending event for another 500 years. There are no human immortals by this criteria of a static intrinsic mortality rate, it seems, though for a while it looked like very old humans might have essentially flat but very high mortality rates in the same way as very old flies do. Immortality in a state of advanced frailty and coupled with a 90% or higher yearly mortality rate isn't the sort of circumstance that most people would aspire to, of course. It barely improves on the actual circumstance that the oldest of people find themselves in, all too briefly.

However, let us think beyond the box. Consider the small horde of children that you'll find playing and running in any junior schoolyard here and now. By the time the survivors of their cohorts reach a century of age, the 2100s will have arrived. If the current very slow trend in increasing adult life expectancy continues, adding a year of remaining life expectancy at 60 for every passing decade, then something like 25% of these present children will live to see that centenary. But I don't for one moment believe that this trend will continue as it has in the past. Past increases in life expectancy were an incidental side-effect of general improvements in medicine across the board, coupled with increasing wealth and all the benefits that brings. Across all of that time, no-one was seriously trying to intervene in the aging process, to address the causes of aging, or to bring aging under medical control. Times are changing, and now many groups aiming to build some of the foundations needed to create exactly this outcome. You may even have donated to support some of them, such as the SENS Research Foundation. The trend in longevity in an age in which researchers are trying to treat the causes of aging will be very different from the trend in longevity in an age in which no such efforts are taking place.

You don't have to dig very far into the state of the science to see that the first rejuvenation treatments are very close, their advent limited only by funding. If funding were no issue for senescent cell clearance, for example, it would absolutely, definitively be in clinics a decade from now. Other necessary technologies are more distant, but not that much more distant - the 2030s will be an exciting time for the medical sciences. For the occupants of today's junior playground, it seems foolish to imagine that by age 60 they will not have access to rejuvenation treatments after the SENS model at various stages of maturity, many having having been refined for more than 30 years, at the height of their technology cycle, and just giving way to whatever radical new improvement happens next.

Take a moment for a sober look at the sweeping differences and expanded technological capabilities that exist between today, the 1960s, and the 1910s. So very much has been achieved, and that pace of progress is accelerating. Those junior playground athletes of today will live to see a world even more radically different and advanced than our present time is in comparison to the First World War era. These are the immortals among us. The majority of them will have the opportunity to attain actuarial escape velocity, to keep on using ever-improving versions of rejuvenation treatments until they are gaining life expectancy at a faster rate than they are aging. Their cellular damage, the wear and tear created by the normal operation of metabolism, will be repaired as fast as it is is generated. It is the rest of us, those of us who are no longer spring chickens, who are faced with much more of a race to the goal. The degree to which we can successfully fund and advocate the necessary research is the determinant of whether we can scrape by into the age of rejuvenation treatments, or whether we will gain modest benefits but still age to death - because we were born too soon, and because the rest of the world didn't get its collective act together rapidly enough in what is now the very tractable matter of building a cure for aging.

Another Call to Classify Aging as a Disease

In the stifling, costly regulatory systems surrounding medical research and commercial application of therapies, aging is not classified as a disease for which one can develop treatments. This is a good deal of the reason why it is hard to raise funding for potential interventions in the aging process, and it is why, now that those interventions are more broadly recognized as plausible, we are seeing a growing chorus of calls for change. For my part, I'd rather see the whole corrupt, backwards system of medical regulation torn down, or for the research and development community to make regulators irrelevant by carrying out their work in other jurisdictions, supplying the resulting therapies via medical tourism. But the mainstream will always want to work to adjust the system from within, leaving most of the harms and unnecessary costs intact, rather than take more radical steps to speed up progress:

Aging itself is the process of the human body deteriorating over time, and its effects are now attributed to a wide range of illnesses. People gradually lose their sight and vision, their organs suffer decreased function, and in some cases people's very minds change so much that they cease being who they used to be. Several diseases and conditions are labeled as the culprits of aging, with research and treatments being directed at each of them individually. This work is certainly important, but several scientists argue that this approach is too piecemeal. According to them, such ailments represent the side effects of a greater disease, one that in fact can be treated and prevented. That disease is aging itself.

The notion of aging as a disease is not an entirely revolutionary one, and several scientists have been pushing for such recognition. Scientists have recently called on the World Health Organization to classify aging as a disease in the 11th iteration of its International Statistical Classification of Diseases and Related Health Problems (ICD-11). The ICD is the standard tool for identifying and classifying diseases used by medical professional throughout the world. Our current biological understanding of aging is shifting along with societal attitudes towards what can be classified as a disease, and that the ICD-11 needs to be updated to reflect this.

A change in nomenclature may not sound like it has much effect, but it has great potential. History has shown that the classification of mental disorders, such as autism, as diseases has led to increased attention to the subject, the development of more accurate diagnostic methods, and increased involvement of the pharmaceutical industry and policy makers. It also provides the basis for clinical trials, which are critical in creating specific anti-aging treatments. A formal World Health Organization classification of aging as a disease would involve the creation of a dedicated task force, in a fashion similar to what is being done for chronic pain. It would also allow for the recognition of an "ideal norm" of a disease-free state of a specified age (such as 25), which would provide a clear goal for treatments to strive towards. If we consider aging a disease, it doesn't just represent a nomenclatural change in thinking but rather a paradigm shift. The first step in tackling a problem is to define it, and while people may not specifically consider aging a disease as of yet, we have always been striving for longer and healthier lives. It is, after all, the entire purpose of medicine, and this classification is a logical next step. Science and medicine only make progress once the problem is properly identified.


Investigating the Removal of Stemness from Cancer Cells

Most types of cancer are made dangerous by malignancy and metastasis, the ability to grow and spread rapidly. For many cancers these capabilities have been shown to be driven by a comparatively small population of cancer stem cells. One of the possibilities arising from the growing knowledge of stem cell biology is to turn off the stemness of cancer cells, reprogramming them to cease aggressive replication. As this paper indicates, however, efforts on this front are still in the very early stages of research:

Metastasis is the major factor responsible for the lethality of malignant breast cancer in human patients. Although various targeted and non-targeted therapies can occasionally control the progress of breast cancer, a significant portion of patients develop resistance to chemotherapy and experience metastatic recurrence. The epithelial to mesenchymal transition (EMT), a key developmental program in embryogenesis, has been found to be closely intertwined with the occurrence of metastasis in various human cancers. EMT can be prompted by the expression of multiple transcriptional factors and is controlled by several signaling pathways.

Towards the goal of understanding breast cancer metastasis, our group performed a cross-species expression profiling and identified Foxq1 as an EMT- and metastasis-promoting gene in breast cancer. Following this discovery, Foxq1 expression has been shown to promote EMT and metastasis in a wide array of human cancers. In line with the previously-mentioned link between EMT and stemness, we demonstrated that ectopic expression of FOXQ1 led to an increase in the stem-like phenotype. This increase in the stem cell population correlated with the induction of EMT. Mechanistically, we identified the receptor tyrosine kinases PDGFR α and β as downstream targets of FoxQ1.

Our study showed that knockdown of PDGFR α and β significantly decreased cell proliferation, migration and invasion. The effects were greatest when both α and β were knocked down. Knockdown of PDGFR α and β decreased lung metastases in vivo. These results strongly suggest that FoxQ1's role as a promoter of the cancer stem cell's phenotype is regulated in part by PDGFR activity. Our study demonstrates that EMT and stemness properties are not controlled by identical gene programs, at least in some cell lines. Inhibiting PDGFR α and β significantly reduced the stemness properties without impacting the mesenchymal-like phenotype of those cells. Since this inhibition correlated with a marked decrease in malignancy, our study suggests that the acquisition of stem-like properties may drive malignancy to a greater degree than EMT alone. Further studies must be done to identify other pharmacological targets that synergize with the stemness-promoting activity of PDGFRs. Reversing cancer stemness, together with conventional chemotherapy, could provide an ideal approach for prevent cancer recurrence and metastasis by eradicating both the bulk tumor cells and the cancer stem cells with self renewal capability.


Halfway to Our SENS Research Fundraising Goal, and Giving Tuesday is Coming Up on December 1st

This year's Fight Aging! matching fundraiser has a $125,000 fund provided by generous philanthropists, and we are seeking to raise a further $125,000 from the community to fund progress in longevity science. All charitable donations made before the end of 2015 will be matched dollar for dollar, with the funds going to the SENS Research Foundation to support their work on rejuvenation biotechnology. This includes programs aimed the safe removal of senescent cells and glucosepane cross-links, both of which are counted among the root causes of degenerative aging. I'm pleased to note that we're half way to the goal, with a month a half left to go: more than 390 donors have collectively given $67,000 in the last six weeks. There is another $58,000 left to go to hit the target, and if we manage this before the end of the year then we'll have collectively given a cool quarter of a million dollars this year to speed up the best approaches to human rejuvenation therapies.

With this in mind, remember that Giving Tuesday is coming up on December 1st. If you haven't yet donated - or know people who might be persuaded - then that will be a great time to jump in. Medical science doesn't emerge from nothing: it needs your support, and here is a chance for your donations to be matched by other funds as well. From the latest SENS Research Foundation newsletter:

SENS Research Foundation is getting ready to celebrate #GivingTuesday on December 1st. GivingTuesday is now a global event celebrated by supporters of various charities giving to their favorite causes. If you've been planning on contributing to the fight against age-related disease this year, GivingTuesday is a great opportunity to make a difference.

So far, SENS Research Foundation has 3 matching grants set up for GivingTuesday. The first is our FightAging! Challenge which will match every dollar you give us up to $125,000. On GivingTuesday, the first $5,000 we raise will not be doubled or even tripled - it will be quadrupled thanks to the generosity of the Croeni Foundation and Aubrey de Grey. Help us turn $5000 into $20,000 and accelerate the fight against age-related diseases! Donate at on December 1st.

If there are any in the audience interested in adding their own $5,000 matching grant to this Giving Tuesday initiative, then by all means contact us with the offer of help, and we'll connect you with the SENS Research Foundation to arrange the details.

It is thanks to philanthropy that SENS research is making progress. Just take a look at the SENS Research Foundation's 2015 annual report: seed funding the US startup Oisin Biotechnology to work on senescent cell clearance; transferring lysosomal aggregate clearance technology to Human Rejuvenation Technologies for development; the French company Gensight is now devoting significant funding to to clinical development of the mitochondrial repair technologies whose early stage research was supported under the SENS banner; progress towards the toolkit needed for glucosepane cross-link clearance was published in the prestigious journal Science. All of these initiatives were funded in part by everyday philanthropists just like you and I, alongside people like Peter Thiel, Jason Hope, and Aubrey de Grey.

The wheel is turning, and meaningful progress towards rejuvenation treatments is taking place. Our donations continue to move SENS research closer to realization, and closer to becoming the mainstream of aging research. The more that we can help to fund the demonstrations of effectiveness at every stage of early research through to early clinical translation, the sooner that therapies to treat and control aging will arrive.

Heat Shock Proteins and Hormesis as a Basis for Therapy

As this open access paper demonstrates, researchers continue to discuss manipulation of heat shock proteins and the hormetic response to mild levels of cell damage or stress as a basis for possible therapies to slow some of the consequences of aging. These proteins are a crucial part of cellular housekeeping mechanisms, and increasing their activity has been fairly conclusively demonstrated to be beneficial in a variety of species. Despite more than a decade of intent to do something along these lines, and some recent signs of progress, there has been little to no concrete movement beyond the laboratory, however.

Modulation of endogenous cellular defense mechanisms via the stress response signaling represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration, for example is reported how drugs that modulate proteostasis by inhibiting Hsp90 function or promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models. Efficient functioning of maintenance and repair processes seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Consistently, by maintaining or recovering the activity of vitagenes can be possible to delay the aging process and decrease the occurrence of age-related diseases with resulting prolongation of a healthy life span.

There is now strong evidence to suggest that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to Alzheimer's disease pathogenesis. Brain-accessible antioxidants, potentially, may provide the means of implementing this therapeutic strategy of delaying the onset of Alzheimer's disease, and more in general all degenerative diseases associated with oxidative stress. As one potentially successful approach, potentiation of endogenous secondary antioxidants systems can be achieved by interventions which target the heme oygenase/carbon monoxide and/or Hsp70 systems.

Reports exist of enhanced longevity via treatment with a large number of agents in a wide range of animal models displaying hormetic dose responses. The generality of the hormetic dose response, being independent of biological model, endpoint, inducing agent and mechanism and with its quantitative features being a measure of plasticity constrained biological performance, strongly suggests that attempts to extend normal lifespan via alteration of metabolism will be likewise limited to the 30-60% as has been typically reported. Thus, hormesis has a fundamental role in aging research, affecting both the quality and the length of life as well as affecting the research methods (e.g., study design, statistical power, etc.) by which such biological concepts are studied.


The Health Optimizer's Point of View

Below find linked a profile of one of a number of modest health optimization initiatives that are driven by the desire to raise the odds of living to see the arrival of real, working rejuvenation therapies, such as the anticipated results of the SENS research programs. There is a large marketplace to serve people who are convinced they can do better than the 80/20 of calorie restriction and regular moderate exercise in personal health and longevity. This seems like a valid hobby for someone with time and money to burn, but I don't believe that that it is in fact possible to know whether or not you are in fact doing better or worse than the 80/20 approach. At least not at the present time. The data is far too uncertain and the possible gains too small for near all possible optimizing action that people might take today beyond calorie restriction and exercise. You are better off taking that time and effort and directing it to support progress in SENS research.

Your risk of death each year doubles every eight years. I've got one in a thousand chances of dying of natural causes this year. In eight years' time, it's two in a thousand. In 16 years' time, it's four in a thousand. Today, we're just trying to find those extra few years. In 20 years time, finding an extra five years will be huge. Maybe in those extra five years, they can cure aging. The idea is that increasing your life expectancy every year so you can live a bit longer massively increases your chance of living forever.

Rule number one: Stop smoking. If you smoke, you give up half your chances of getting there. And there's normal things, like diet and exercise. There are things you can do at home, like reducing blood pressure and heart rate, that have a huge impact on your general health. But that's all science and research-based. I'm certainly hoping there will be more radical approaches as well. There's also going to be things like storing your stem cells. I'd like to investigate who's offering that service. I want to be storing stem cells today - before the outside starts aging - so when we develop the technology to grow my own parts, I don't have to get a replacement organ and I can actually repair my own heart or repair my own lungs using my own stem cells. I'll be doing it with my 40-year-old stem cells rather than my 60-year-old stem cells. There are definitely going to be clinics out there offering longevity solutions without any science basis at all. I want to weed those out and avoid those ones as well.

Plenty of people have that ethical debate about whether or not you should extend life. But do people want to live forever? I think the answer's no. The people who do, really do. You don't half-want to live forever. If you want to, you definitely want to. There's this online survey, where they ask that question every year, and around 35% of people say yes. I thought that was amazingly low. Imagine a 90-year-old - a bit in pain, not doing anything exciting. If we cure aging, then it'll be a few years after that when we can reverse aging. If you could have a 20-, 30-year-old body again, which is going to be far more useful for you and certainly pain free, then you'd want to live forever. Still, an awful lot of people think that death is a natural thing and we shouldn't fight it.


Slowing Aging in Accelerated Aging Mice Should Always Be Taken with a Grain of Salt

A publicity release has been doing the rounds and a number of people have pointed it out to me in the past day, something that usually only tends to happen for items much more interesting than this one. The release covers research into J147, a drug candidate for Alzheimer's disease that has been under investigation in animal studies for the past few years. It has now been tested in the SAMP8 lineage of engineered mice that suffer from accelerated aging, and the researchers are touting a slowing of that acceleration of aging as measured by cognitive decline and changes in gene expression. As is often the case, omissions and oversimplification of necessary details occurred somewhere between the lab and the publicity office, and as a consequence people are paying more attention to this research than it merits. The most important of these omissions is the fact that J147 was tested on an accelerated aging mouse lineage; without that detail, the publicity release makes the research sound much more useful than it is.

Researchers frequently start work in animal models that have been altered to allow for shorter studies. The cost of these studies is large in comparison to working with cells, so being able to cut that cost in half, for example, by using an accelerated aging lineage is often worth it. Mouse studies can cost millions and take years, and a million dollars goes a long way in early stage research; there are always other projects that need funding. Unfortunately when it comes to research potentially relevant to aging this use of accelerated aging lineages usually means that the results are very technical in nature and largely meaningless for anyone trying to judge whether not the outcome is useful. The literature is littered with examples of researchers slowing the progression of - or partly reversing - accelerated aging by somewhat fixing the issue that caused that accelerated aging, and then later finding that their work had little to no effect on the progression of normal aging. Part of the problem here is that there really is no such thing as "accelerated aging." Aging is an accumulation of cell and tissue damage, yes, and what looks like accelerated aging can be created by piling on damage, such as by interfering with DNA repair mechanisms. But the end result bears only a tenuous relationship to the progression of normal aging, and once you're down to the detail level of building therapies based on manipulating specific cellular mechanisms it is unlikely that benefits to an accelerated aging lineage also accrue in the same way for a normal aging lineage.

There are always exceptions. Senescent cell clearance was first demonstrated in accelerated aging mice, and then later showed the same sort of benefits in normal mice. In that case there were good technical reasons and a weight of evidence to lead researchers to expect that the results would carry over. That isn't something that a layperson can be expected to wade through for every line of research, however. The exceptions to the general rule are infrequent enough that, personally, I'd advise people to just ignore published research results in accelerated aging mouse lineages. The press invariably makes much more of it than it is worth, and most of this work loses any possible relevance to normal aging as it progresses. It never hurts to wait and see rather than get excited over this sort of result.

Below find excerpts from the publicity materials and open access paper for the latest research into the effects of J147, and judge for yourself the poor quality of the release materials when it comes to representing the nature of the research. It is an undeniably interesting set of results, but this is something that I'd want to see repeated in normal mice before paying any great attention to it. In fact I'd be inclined to see this more in the way of a trial balloon to gather support for the longer and more expensive lifespan study in normal mice that might be carried out next:

Experimental drug targeting Alzheimer's disease shows anti-aging effects

Research expanded upon their previous development of a drug candidate, called J147, which takes a different tack by targeting Alzheimer's major risk factor - old age. In the new work, the team showed that the drug candidate worked well in a mouse model of aging not typically used in Alzheimer's research. When these mice were treated with J147, they had better memory and cognition, healthier blood vessels in the brain and other improved physiological features. "Initially, the impetus was to test this drug in a novel animal model that was more similar to 99 percent of Alzheimer's cases. We did not predict we'd see this sort of anti-aging effect, but J147 made old mice look like they were young, based upon a number of physiological parameters."

The old mice that received J147 performed better on memory and other tests for cognition and also displayed more robust motor movements. The mice treated with J147 also had fewer pathological signs of Alzheimer's in their brains. Importantly, because of the large amount of data collected on the three groups of mice, it was possible to demonstrate that many aspects of gene expression and metabolism in the old mice fed J147 were very similar to those of young animals. These included markers for increased energy metabolism, reduced brain inflammation and reduced levels of oxidized fatty acids in the brain. Another notable effect was that J147 prevented the leakage of blood from the microvessels in the brains of old mice.

A comprehensive multiomics approach toward understanding the relationship between aging and dementia

One model of aging is the senescence-accelerated prone 8 (SAMP8) mouse, that has a progressive, age-associated decline in brain function similar to human AD patients. As they age, SAMP8 mice develop an early deterioration in learning and memory as well as a number of pathophysiological alterations in the brain including increased oxidative stress, inflammation, vascular impairment, gliosis, accumulation and tau hyperphosphorylation.

Because age is the greatest risk factor for sporadic Alzheimer's disease (AD), phenotypic screens based upon old age-associated brain toxicities were used to develop the potent neurotrophic drug J147. Since certain aspects of aging may be primary cause of AD, we hypothesized that J147 would be effective against AD-associated pathology in rapidly aging SAMP8 mice and could be used to identify some of the molecular contributions of aging to AD.

An inclusive and integrative multiomics approach was used to investigate protein and gene expression, metabolite levels, and cognition in old and young SAMP8 mice. J147 reduced cognitive deficits in old SAMP8 mice, while restoring multiple molecular markers associated with human AD, vascular pathology, impaired synaptic function, and inflammation to those approaching the young phenotype. The extensive assays used in this study identified a subset of molecular changes associated with aging that may be necessary for the development of AD.

An Example of Engineering Immune Cells to Target Cancer

Here I'll point out a recent update on one line of targeted cancer therapies presently under development. These forms of treatment will ultimately replace the much less discriminating therapies of today, and will be used to control and clear cancers with few side-effects for the patient. Forms of immunotherapy that involve altering immune cells to target the distinctive chemistry of cancer cells are one of the most promising of present strategies, as they have been shown to be effective against metastatic cancer. If metastasis can be controlled, most cancers will become far less threatening as a result:

Biomedical engineers have developed specialized white blood cells - dubbed "super natural killer cells" - that seek out cancer cells in lymph nodes. For tumor cells, the lymph nodes are a staging area and play a key role in advancing metastasis throughout the body. In the study, the biomedical engineers killed the cancerous tumor cells within days, by injecting liposomes armed with TRAIL (Tumor necrosis factor Related Apoptosis-Inducing Ligand) that attach to "natural killer" cells - a type of white blood cell - residing in the lymph nodes. Tthese natural killer cells became the "super natural killer cells" that find the cancerous cells and induce apoptosis, where the cancer cells self-destruct and disintegrate, preventing the lymphatic spread of cancer any further. "In our research, we use nanoparticles - the liposomes we have created with TRAIL protein - and attach them to natural killer cells, to create what we call 'super natural killer cells' and then these completely eliminate lymph node metastases in mice."

In cancer progression, there are four stages. At stage I, the tumor is small and has yet to progress to the lymph nodes. In stages II and III, the tumors have grown and likely will have spread to the lymph nodes. At the stage IV, the cancer has advanced from the lymph nodes to organs and other parts of the body. Between 29 and 37 percent of patients with breast, colorectal and lung cancers are diagnosed with metastases in their tumor-draining lymph nodes - those lymph nodes that lie downstream from the tumor, and those patients are at a higher risk for distant-organ metastases and later-stage cancer diagnoses. In January 2014, the researchers published research that demonstrated by attaching the TRAIL protein to white blood cells, metastasizing cancer cells in the bloodstream were annihilated. "So, now we have technology to eliminate bloodstream metastasis - our previous work - and also lymph node metastases."


Investigating Mitochondrial Rejuvenation During Cellular Reprogramming and Embryonic Development

The changes involved in producing induced pluripotent stem cells from ordinary somatic cells, such as those from a skin sample, are accompanied by mitochondrial rejuvenation, a clearance of mitochondrial damage associated with aging. This also occurs in the earliest stages of embryonic development, turning old parental cells into young child cells. It is not beyond the bounds of the possible to suggest that perhaps just this mitochondrial part of the transformation could be split off and used as the basis for a therapy - though other approaches to mitochondrial repair are far closer to realization. Also, it may well be that mitochondria are so vital to cellular function that it is impossible to safely induce such radical changes in adult tissues given the way in which cells are presently structured. As usual, the only way to find out is to dig deeper into what is going on under the hood, as researchers are doing here. The original research release is in PDF format only, unfortunately, but it provides a better explanation than any of the other available resources:

A new study suggests that old mitochondria - the oxygen-consuming metabolic engines in cells - are roadblocks to cellular rejuvenation. By tuning up a gene called Tcl1, which is highly abundant in eggs, researchers were able to suppress old mitochondria to enhance a process known as somatic reprogramming, which turn adult cells into embryonic-like stem cells. Researchers found that Tcl1 does its job by suppressing mitochondrial polynucleotide phosphorylase (PnPase), thereby inhibiting mitochondrial growth and metabolism.

Stem cell researchers had known that egg (or oocyte) cytoplasm contains some special unknown factors that can reprogramme adult cells into embryonic-like stem cells, either during egg-sperm fertilisation or during artificial cloning procedures. While researchers had invented a technology called induced pluripotent stem cell (iPSC) reprogramming to replace the ethically controversial oocyte-based reprogramming technique, oocyte-based reprogramming was still deemed superior in complete cellular reprogramming efficiency. To address this shortfall, researchers combined oocyte factors with the iPSC reprogramming system. Their bioinformatics-driven screening efforts1 led to two genes: Tcl1 and its cousin Tcl1b1. After a deeper investigation, the team found that the Tcl1 genes were acting via the mitochondrial enzyme, PnPase. "We were quite surprised, because nobody would have thought that the key to the oocyte's reprogramming powers would be a mitochondrial enzyme. The stem cell field's conventional wisdom suggests that it should have been some other signalling genes instead."

Tcl1 is a cytoplasmic protein that binds to the mitochondrial enzyme PnPase. By locking PnPase in the cytoplasm, Tcl1 prevents PnPase from entering mitochondria, thereby suppressing its ability to promote mitochondrial growth and metabolism. Thus, an increase in Tcl1 suppresses old mitochondria's growth and metabolism in adult cells, to enhance the somatic reprogramming of adult cells into embryonic-like stem cells. These new insights could boost efficacy of the alternative, non-oocyte based iPSC techniques for stem cell banking, organ and tissue regeneration, as well as further our understanding of how cellular metabolism rejuvenates after egg-sperm fertilisation.


Recent Research on Blood Pressure and Aging

Here I'll point out a couple of recent research publications on the topic of blood pressure in aging. Blood pressure is a useful metric in the progression of aging, not least because it can be cheaply and reliably measured. It is also a good example of the split between primary and secondary aging, as processes from both categories lead to higher blood pressure.

Primary aging is made up of the processes we cannot avoid, and only modestly slow via lifestyle choices. It is damage that accumulates as a consequence of the normal operation of metabolism. The accumulation of cross-links in the extracellular matrix and calcification of tissues leads to a progressive stiffening of blood vessel walls, and this loss of elasticity in blood vessels appears to be enough to explain the age-related rise in blood pressure that in some people is large enough to lead to clinical hypertension. Even lesser levels of high blood pressure slowly deform and weaken important structures in the cardiovascular system, exacerbate the processes causing atherosclerosis to develop in blood vessel walls, and increase the harm done to the brain by breakages in tiny blood vessels.

Secondary aging is caused by poor lifestyle choices. Most of the truly bad choices known to negatively impact life expectancy - including lack of exercise and being overweight - raise blood pressure in addition to their other effects, and this increase in blood pressure has all of the same detrimental effects as the increase caused by the processes of primary aging. Becoming fit in the general sense, through exercise and maintaining a sane weight, tends to lower blood pressure. One of the mediating mechanisms here is the influence of visceral fat on metabolism, but there are numerous other possibilities, all with varying degrees of supporting evidence.

What is known of the role of high blood pressure in the chain of cause and consequence that leads to age-related disease and death provides many good reasons to work on reducing your own personal pace of secondary aging. In fact the medical community is starting to think that past guidelines on blood pressure goals have been, if anything, too lax. If you spend too long with high blood pressure, and even the best of presently available treatments, drugs to reduce blood pressure, while capable of reducing risk of death cannot undo the restructuring and weakening of the cardiovascular system that has already taken place.

How Low to Go for Blood Pressure?

A new study finds that at least 16.8 million Americans could potentially benefit from lowering their systolic blood pressure (SBP) to 120 mmHg, much lower than current guidelines of 140 or 150 mmHg. The scientists calculated the potential impact of preliminary results from the Systolic Blood Pressure Intervention Trial (SPRINT). The initial analysis of SPRINT showed that using antihypertensive medications to reach a lower SBP target of 120 mmHg could greatly reduce risk for heart failure, heart attack, and death, compared to a target of 140 mmHg (SBP is the top number in a blood pressure reading). It's estimated that one in three U.S. adults have high blood pressure, or hypertension, a significant health concern. "SPRINT could have broad implications. Millions of Americans whose blood pressure is under control according to current guidelines may be considered uncontrolled if new guidelines adopt the intensive target of less than 120 mmHg studied in SPRINT."

A Randomized Trial of Intensive versus Standard Blood-Pressure Control

The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain. We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year).

Blood Pressure Medication Can't Undo All Damage

Treating out-of-control blood pressure with antihypertensive medication can greatly reduce your risk for heart attack, stroke and heart failure, but the current approach to treatment can't undo all of the previous damage or restore cardiovascular disease risk to ideal levels, a new study suggests. "The best outcomes were seen in those who always had ideal levels of blood pressure and never required medications. Those who were treated with medication and achieved ideal levels were still at roughly twice the risk of those with untreated ideal levels. And, of course, people with untreated or uncontrolled high blood pressure were at even greater risk." The new findings strongly suggest that there should be an even greater effort to maintain lower blood pressure levels in younger adults to avoid increases in blood pressure over time that may eventually require medication.

Those of us following SENS rejuvenation research should be thinking at this point that all of the data above only reinforces how important it is to make inroads in repairing the damage of primary aging. In this case that means finding a way to break down the most common cross-links that contribute to loss of elasticity in human tissues, those based on glucosepane. The SENS Research Foundation is one of the few organizations funding gluosepane research with the aim of a treatment to clear these cross-links. An effective therapy here would likely provide a greater and more reliable impact on cardiovascular aging and blood pressure than any presently available treatment, since it would be removing one of the root causes of blood vessel stiffening, which is in turn a root cause of high blood pressure.

Researchers Aim for Limb Regeneration by 2030

It is interesting to see more researchers willing to place timelines on the regeneration or tissue engineering of replacement limbs, as is the case here. It is a sign of confidence and progress in the foundations of the field. So far the closest approach to this goal has been the decellularization of donor rat limbs, followed by replacement of cells with those of a potential recipient to produce a leg ready for transplantation, but it seems to me just as likely that human limb regrowth will result from advances in the understanding of regeneration in species like salamanders, in which individuals are capable of regenerating lost limbs.

The University of Connecticut has announced the launch of its new grand research challenge: regeneration of a human knee within 7 years, and an entire limb within 15 years. This major international research undertaking, called The HEAL Project, stands for Hartford Engineering a Limb. This is a collaboration of top tissue engineering, regenerative medicine, and bioengineering experts dedicated to the mission of advancing the fields and developing future therapies for patients living with musculoskeletal defects or who have limb injury or loss. "The launch of the HEAL Project is a transformative moment for science and medicine. This is the first international effort ever for knee and limb engineering. The time is now to pursue this much needed grand challenge to benefit those patients suffering from debilitating knee injuries, osteoarthritis, or affected by the devastating effects of limb injury or loss."

Researchers project it will take 7 to 15 years for first knee and then limb regeneration breakthroughs based on the time it took to successfully regenerate bone and ligaments. To work toward its milestones, HEAL will be building upon the latest advances in regenerative engineering, tissue regeneration, stem cell research, nano-materials science, physics, developmental biology, and advanced manufacturing. In addition, researchers will conduct clinical trials to test any new promising therapies. "Our research group will harness the concepts of convergence, bringing together our talents, latest scientific knowledge, research advances, and cutting-edge tools to help make our grand challenge of knee and limb regeneration a reality."


Progress Towards Engineered Extracellular Matrix

Tissue engineers cannot yet construct sufficiently complex extracellular matrix structures with the correct mechanical and other properties to support the growth of entire organs from scratch. This is why the use of decellularized organs is one line of development, providing a donor extracellular matrix scaffold that can be repopulated with the recipient's cells. This news release is an example of the present state of the art in progress towards building sections of extracellular matrix:

Imitation may be the sincerest form of flattery but the best way to make something is often to co-opt the original process and make it work for you. In a sense, that's how scientists accomplished a new advance in tissue engineering. The team reports culturing cells to make extracellular matrix (ECM) of two types and five different alignments with the strength found in natural tissue and without using any artificial chemicals that could make it incompatible to implant. ECM is the fibrous material between cells in tissues like skin, cartilage, or tendon that gives them their strength, stretchiness, squishiness, and other mechanical properties. To help patients heal wounds and injuries, engineers and physicians have strived to make ECM in the lab that's aligned as well as it is when cells make it in the body. So far, though, they've struggled to recreate ECM. Using artificial materials provides strength, but those don't interact well with the body. Attempts to extract and build upon natural ECM have yielded material that's too weak to reimplant.

The team tried a different approach to making both collagen, which is strong, and elastin, which is stretchy, with different alignments of their fibers. They cultured ECM-making cells in specially designed molds that promoted the cells to make their own natural but precisely guided ECM. The strategy built on the insight that when cells clump together and grow in culture, they pull on each other and communicate as they would in the body. The molds therefore were made from agarose so that cells wouldn't stick to the sides or bottom. Instead they huddled together.

To guide ECM growth in particular alignments, the researchers used molds with very specific shapes, often constrained by pegs the cells had to grow around. For instance, to make a rod with collagen fibers aligned along its length (like a tendon) they cultured chondrocyte cells in a dog bone-shaped mold with loops on either end. To make a skin-like "trampoline" of elastin, where the ECM fibers run in all directions, they cultured fibroblast cells to grow in an open area suspended at the center of a honeycomb shape. After the researchers grew various forms of ECM, they did some stress testing. They took the dog bone-shaped tissues made precise measurements of the tissue strength under the force of being pulled apart. The measurements confirmed the self-assembled tissue was about as strong as that found in some of the body's tissues, such as skin, cartilage or blood vessels.


Lower Protein Replacement Rates Observed in Various Methods Producing Enhanced Longevity in Mice

Today I'll point out an interesting open access paper in which the authors discuss what is probably an aspect of the observation that greater proteostasis correlates with greater longevity. Proteostasis is just a fancy way of saying the types, behaviors, and amounts of proteins produced by cells and present in tissues remain essentially the same over time, taking into account cyclic short term variations in response to repeated circumstances such as sleep, eating, and so on. As an individual ages, however, all these things change as the operation of cellular metabolism reacts to growing levels of damage. Since protein levels are the signals and controlling dials and switches of cells, ongoing age-related change in cellular behavior implies a lack of proteostasis and vice versa.

Given this, discussing proteostasis in connection with longevity and aging has always seemed a little tautological to me. It is a measure of consequences, another way of saying that aging has occurred. Aging is caused by damage, so of course there is a correlation between reactions to damage and longevity. However, it is probably the case that some measures of proteostasis will be useful as biomarkers of aging, in much the same way that some measures of epigenetic changes seem promising. A robust biomarker of aging would be a very useful tool indeed, as it could be used to rapidly test putative rejuvenation treatments, scoring their outcome on the whole of an individual's biology, rather than only their targets. For example, when senescent cell clearance therapies are deployed, determining their effects on senescent cell counts will be a part of the process, but at the moment is still necessary to wait around to see what the effects on long term health and life span will be. Even in rodents that takes years and millions of dollars. Replacing that cost with a simple test a month after treatment will greatly speed up the field.

In this paper the researchers look at the replacement rates of proteins, which is probably a function of at least the level of ongoing damage to proteins that would require them to be replaced, and rates of cellular replication, which have been observed to be lower in some forms of enhanced longevity in laboratory animals. They find that the former but not the latter correlates with life span:

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

Over the last 50 years, several dietary, genetic, and pharmacological interventions have been identified that extend maximum life span in laboratory animals, including mice. Understanding the molecular underpinnings of the aging process and the biochemical pathways affected by interventions that attenuate the development of age-related diseases is a high priority. In particular, identifying metrics of biological processes, or biomarkers (BMs), that are involved in the slowing of aging in laboratory mammals will be essential for guiding the future development of interventions to extend human healthspan.

To identify such processes that play an etiologic role in age-related disease, our approach has been to test potential flux-based BMs of maximum life span extension. The concept underlying this strategy is that the activity of a metabolic process is best characterized by the molecular flux rate traversing the pathway and that changes in the flux rates of metabolic processes that play a causal role in the functional alterations of the condition may manifest earlier and more sensitively than static pathologic changes or complex clinical outcomes. Optimally, the functional role and measurement technique for these molecular processes will be translatable into human studies.

This rate-based BM approach may be particularly promising in combination with what is currently the most robust program for testing proposed interventions for extension of maximum life span in mammals: the National Institute on Aging's (NIA) Interventions Testing Program. These studies are the current gold standard for evaluating changes in lifespan in genetically heterogeneous mice but are time- and resource-intensive, limiting the number of interventions that can be tested each year. An initial screening strategy based on a panel of early BMs of maximum life span extension could be used to further refine which candidate interventions should be prioritized for inclusion into life span studies in mice. This represents an attractive approach for identifying interventions with the potential to extend human healthspan.

Here, we used stable-isotope mass spectrometric measurement tools to screen for BMs based on the activity of targeted physiologic pathways believed to be involved in the aging process. These measurements were performed in three different yet well-established mouse models of maximum life span extension, each on a different genetic background and each at relatively early time points in the life span of the model. The three models evaluated were Snell Dwarf mice, which are homozygous for a loss-of-function mutation in the Pit1 gene involved in anterior pituitary development; calorie-restricted (CR) mice, in which calories are reduced without malnutrition; and mice treated with rapamycin (Rapa).

A reduction in cell proliferation rates has been hypothesized to contribute to maximum life span extension by inhibiting the promotional phase of carcinogenesis and delaying cellular replicative senescence. A reduction in protein synthesis rates or slowing of protein replacement rates (RRs) (turnover) might in principle reflect preserved proteome homeostasis (proteostasis), which normally declines with age. A reduction in protein synthetic burden may preserve proteostasis by limiting the accumulation of misfolded and/or damaged proteins, possibly by increasing translational fidelity, chaperone capacity, and/or proteolytic capacity. Accordingly, the goal of the work presented here was to test the hypothesis that reduced cell proliferation rates, reduced protein synthesis rates, reduced protein RRs (prolonged half-lives), or other proteome alterations are early BMs of maximum life span extension in mice.

The major findings of this work are as follows: (i) A reduction in hepatic proteome RRs (longer half-lives) is a common feature of all three models evaluated (Snell Dwarf, CR, and Rapa-treated mice); (ii) a strong correlation exists between the degree to which hepatic proteome RRs are reduced and the degree of maximum life span extension in these models; and (iii) in vivo cell proliferation rates are not consistently reduced at early time points in all these models.

The first observation could have more than one underlying cause. We do not believe that our data suggest that a reduction in hepatic proteome RRs is an initiating factor that directly promotes maximum life span extension in the three models evaluated here. Rather, our hypothesis is that reduced hepatic proteome RRs reflect a reduced demand for protein renewal, and thus improved proteostasis in these models, likely due to reduced levels of misfolded and/or damaged proteins. The data presented here differentiate between several potential mechanisms of improved hepatic proteostasis in these models. In principle, a variety of cellular adaptations could reduce the levels of misfolded and/or damaged proteins, including an increase in proteolytic editing capacity, an increase in chaperone capacity, a reduction in the levels of damaging metabolites, or an increase in translational fidelity. The data presented here are not consistent with increased proteolytic editing as a major contributing factor to improved proteostasis, as reduced rather than increased proteome RRs (proteolytic rates) were consistently observed in all three models. We also found that the levels of the chaperones that we assessed were either unchanged or reduced in all three models, suggesting that an increase in chaperone capacity is an unlikely contributing factor to improved proteostasis. Consistent with improved proteostasis, as well as an absence of accumulated unfolded proteins in the ER in these three models, our proteomic analyses revealed that the synthesis of proteins involved in protein processing in the endoplasmic reticulum was reduced relative to the synthesis of all other proteins in the three models.

Towards an Implanted Artificial Kidney

Filtration in biology is a tractable problem to solve, to build devices that can carry out at least part of the function of organs like the kidneys by removing unwanted substances from the blood. There are already numerous fairly effective means of carrying out dialysis outside the body, for example. These technologies will improve and minimize in the years ahead until the state of the art is a durable, implanted artificial organ intended to augment or largely replace the kidneys. One group of researchers here provide an update on their current progress towards this goal:

A surgically implantable, artificial kidney based on advances in nanofilter technology could be a promising alternative to kidney transplantation or dialysis for people with end stage renal disease (ESRD). Currently, more than 20 million Americans have kidney diseases, and more than 600,000 patients are receiving treatment for ESRD. "We aim to conduct clinical trials on an implantable, engineered organ in this decade, and we are coordinating our efforts with both the NIH and the U.S. Food and Drug Administration."

One component of the new artificial kidney is a silicon nanofilter to remove toxins, salts, some small molecules, and water from the blood. Researchers designed it based on manufacturing methods used in the production of semiconductor electronics and microelectromechanical systems. The new silicon nanofilters offer several advantages - including more uniform pore size - over filters now used in dialysis machines. The silicon nanofilter is designed to function on blood pressure alone and without a pump or electrical power.

The project's goal is to create a permanent solution to the scarcity problem in organ transplantation. "We are increasing the options for people with chronic kidney disease who would otherwise be forced onto dialysis." The artificial kidney being developed is designed to be connected internally to the patient's blood supply and bladder and implanted near the patient's own kidneys, which are not removed. A national team of scientists and engineers at universities and small businesses are working toward making the implantable artificial kidney available to patients.


The Prospects for Pig to Human Xenotransplantation

The use of pigs to expand the supply of donor organs for human patients is coming closer to reality. A number of new technologies are enabling researchers to remove the various blocking issues in cross-species transplantation: cheap and efficient gene therapy, decellularization, and so forth. It is still proving to be challenging. Ultimately this will be, I suspect, a comparatively brief transitional technology, eclipsed in the decades ahead by the ability to grow organs from a patient's own cells. Here is an update on the state of the xenotransplantation field:

A US lab has performed about 50 pig-to-primate transplants to test different combinations of genetic modifications in the pig and immune-suppressing drugs in the primate. Even so, the team has not had a primate survive for longer than a few days. The complexities of the immune system and the possibility of infection by pig viruses are formidable and drove large companies out of the field in the early 2000s. That trend may now be reversing, thanks to improved immunosuppressant drugs and advances in genome-editing technologies such as CRISPR/Cas9. These techniques allow scientists to edit pig genes, which could cause rejection or infection, much more quickly and accurately than has been possible in the past.

Some researchers now expect to see human trials with solid organs such as kidneys from genetically modified pigs within the next few years. United Therapeutics has spent $100 million in the past year to speed up the process of making transgenic pigs for lung transplants - the first major industry investment in more than a decade. It says that it wants pig lungs in clinical trials by 2020. But others think that the timeline is unrealistic, not least because regulators are uneasy about safety and the risk of pig organs transmitting diseases to immunosuppressed humans. "I think we're getting closer, in terms of science. But I'm not yet convinced we've surpassed all the critical issues that are ahead of us. Xenotransplantation has had a long enduring reality that every time we knock down a barrier, there's another one just a few steps on."

Over a decade of little progress towards whole organ transplants, a few research teams and start-up companies began pursuing pig tissue transplants: a much simpler goal than using solid organs because the immune response is not as severe. In April, Chinese regulators approved the use of pig corneas from which all the cells have been removed. Also on the near horizon are pig insulin-producing islet cells that might be transplanted into people with diabetes. The first commercially available islets are likely to come from technology designed by Living Cell Technologies, that has developed a process to encapsulate pig islet cells in a gelatinous 'dewdrop' that protects them from the human immune system. The product is currently in late-stage clinical trials in several countries. Patients implanted with the cells have survived more than nine years without evidence of immune rejection or infection. "I think people are coming around to look at xenotransplantation in a more-favourable light knowing that we have strong safety data."

Solid organs still pose a challenge. The handful of researchers who have continued to work with them have solved some of the problems, such as identifying other key pig antigens and the correct combinations of immunosuppressant drugs. But different organs have different problems: kidneys may be safer than hearts, for instance. Lungs are extremely difficult to transplant, because they have extensive networks of blood vessels, which provides more opportunities for primate blood to meet pig proteins and to coagulate.


UK Cryonics and Cryobiology Research Group Launched

A group of UK researchers have recently banded together to coordinate research into cryonics and cryobiology, the low-temperature preservation of tissues. Only small collections of cells can presently be reversibly cryopreserved, but there is a strong incentive to build the means to reversibly preserve whole organs and other large tissue structures. This is probably a matter of firstly developing a better form of cryoprotectant, one that is minimally toxic and easily cleared, and secondly putting more effort into producing robust, minimally damaging cooling and warming protocols. When developed, the ability to store whole organs indefinitely will prove useful in the very near future to expand the pool of donor organs, and remain useful in the decades ahead to reduce the cost of producing and delivering organs as needed. Never underestimate how much money can be saved by the ability to warehouse products as needed.

The lack of any present ability to reverse the state of cryopreservation in complex tissues is not an impediment to the use of indefinite low-temperature storage as a form of emergency medical care, as has been the case in the cryonics industry for decades now. A good cryopreservation as rapidly as possible after clinical death means that the fine structure of the brain is likely preserved, based on present evidence, the data of the mind is thus retained, and the patient can wait for as long as it takes for medical technology to advance to the point at which restoration and repair is feasible. A future in which a cryopreserved brain can be restored to life is also a future in which the cell and tissue damage that causes aging can be repaired, or indeed a new body built to order. Both of those goals in advanced medicine are well understood and near term in comparison to the sort of molecular nanotechnology industry needed to clear out toxic cryoprotectant and go cell by cell to repair the other harms caused by present means of preservation.

In any case, this new research effort is coordinated by João de Magalhães, whom regular readers will recognize as one of the members of the transhumanist community of past decades who followed his inclinations into aging research, and now leads a laboratory in that field, doing his part to push forward the state of the art. A whole range of figures and initiatives relating to human longevity, including the Aubrey de Grey and the SENS Research Foundation, can be traced back to that small community of futurists with a strong interest in radical life extension. If you can clearly see the future you want, you should reach for it, help to make it real.

It is interesting that de Magalhães chooses to now make some inroads into supporting progress in cryonics alongside his work on aging. It is perhaps in the nature of a calculation that everyone should make: at what point do you think that the intersection of progress towards rejuvenation therapies and your own personal decline into old age makes it smart to put more effort towards advancing the state of the cryonics industry? Cryonics and cryopreservation is the only viable backup plan for those of us who will age to death before the advent of working rejuvenation treatments. If I were a decade older or SENS-style rejuvenation research was not making at least slow progress then I'd certainly be putting more of my efforts into supporting the cryonics industry. I should probably be doing more than I am on that front regardless. People in the middle of the present span of life shouldn't be complacent; research in the life sciences takes a long time, and the backup plan of cryonics is there for a reason. I encourage you to think over your own balance of choices.

In the meanwhile, congratulations are due de Magalhães for setting up this initiative and in doing so helping to improve the state of cryonics. One of the best things that can happen for the small cryonics industry is for organ cryopreservation to prosper and be adopted by the medical mainstream; it will mean more funding and legitimacy for lines of research and improvement in methodologies that can also be applied to cryonics, meaning cryopreservation as emergency medical care for people who cannot be saved in any other way.

New UK cryobiology research network launched

A new network has been established by UK scientists to advance and promote research into cryobiology - the effects of extremely low temperature on living organisms and cells. The UK Cryonics and Cryopreservation Research Network is being coordinated by Dr Joao Pedro de Magalhaes, a Senior Lecturer at the University of Liverpool's Institute of Integrative Biology, who studies the molecular basis of ageing.

At present, cryopreservation technology is only successful for cell lines and very small tissues. More research is required before whole organs can successfully be cryopreserved while retaining their biological integrity. Dr de Magalhaes said: "Cryobiology is a crucial area of research for modern biotechnology due to the importance of biobanking; from developing reliable stem cell storage systems, organ banking for transplants as well as storage for engineered tissues."

Cryonics has been a topic of much debate over the years, with many scientists doubting whether current cryogenically frozen individuals can ever be brought to life. Dr de Magalhaes said: "Although cryonics is not feasible at present, technological breakthroughs in cryobiology may, in the future, decrease the amount of damage to levels that permit reversible cryopreservation. One of the goals of our research network is to discuss the ethical, medical, social and economic implications of these potential breakthroughs that would radically change our perceptions of life and death."

UK Cryonics and Cryopreservation Research Network

We are the UK Cryonics and Cryopreservation Research Network The UK Cryonics and Cryopreservation Research Network is a group of UK researchers who, together with international advisors, aim to advance research in cryopreservation and its applications.

Although we are a small group, we hope to promote academic and industrial activity on cryopreservation, and discuss its potential applications, including the idea of cryopreserving whole humans, commonly known as cryonics. We acknowledge that cryonics is a controversial topic, but like any unprovable approach we think its scientific discussion is necessary to permit its understanding by the public and by the wider scientific community, and it allows us to address many of the misunderstandings surrounding cryonics. We also think that cryopreservation, cryogenics and cryonics are fields with a huge potential impact on human medicine whose societal implications should be considered and debated.

We hope to attract and excite students and other researchers about cryobiology, contribute to knowledge exchange and help attract interest and funding to the field.

Inhibiting Wnt Signaling to Treat Osteoarthritis

Wnt signaling has long been investigated in connection with the processes of adult regeneration and embryonic development. This latest news notes progress towards a class of therapies that inhibit the Wnt pathway, potentially producing regeneration in adult tissues where it would not normally occur, or slowing damage caused by inappropriate growth in tissues where the Wnt pathway is overactive in aging.

Researchers have unveiled pre-clinical and clinical research that demonstrated successful modulation of the Wnt pathway for potential applications in regenerative medicine. They have developed an injectable investigational drug that inhibits the Wnt pathway, causing endogenous stem cells to regenerate knee cartilage in animals.

Osteoarthritic joints are characterized by degradation of the articular cartilage, which provides the cushioning between bones, and by bony protrusions called osteophytes, which interfere with function and exacerbate the pain associated with osteoarthritis. An overactive Wnt pathway in the affected joint causes the formation of more (spurious) bone instead of (healthy) cartilage, leading to pain, loss of function, stiffness, and deformity.

Clinical data indicate that the small molecule inhibitor of the Wnt pathway SM04690 may slow joint space narrowing and possibly increase joint space in the knee. Clinicians generally perceive an increase in joint space as evidence of preservation or regrowth of cartilage. The researchers recently concluded a 24 week placebo-controlled, double-blind, randomized Phase I clinical trial, studying the safety and preliminary efficacy of SM04690 in patients with moderate to severe osteoarthritis of the knee. The results also suggested that a single injection with SM04690 appeared to be safe and potentially effective in improving function and reducing pain for patients with osteoarthritis of the knee. Subsequently, researchers began enrollment in an approximately 400-patient Phase II clinical trial.


Exercise Slows Aspects of Cardiac Aging in Rats

Exercise is known to improve health and modestly slow the progression of age-related degeneration. Here is one example of numerous ongoing research programs that seek to define the effects of exercise on specific aspects of the aging process:

Aging is an inevitable trend of the world's population, and it is accompanied with serious age-related health issues in modern society that must be investigated. Aging is the most important risk factor in cardiovascular disease (CVD), which is the leading cause of death worldwide. The major factor in heart failure during aging is heart remodeling, including long-term stress-induced cardiac hypertrophy and fibrosis. Exercise is good for aging heart health, but the impact of exercise training on aging is not defined.

This study used 3-, 12- and 18-month-old rats and randomly divided each age group into no exercise training control groups (C3, A12 and A18) and moderate gentle swimming exercise training groups (E3, AE12 and AE18). The protocol of exercise training was swimming five times weekly with gradual increases from the first week from 20 to 60 min for 12 weeks.

Analyses of protein from rat heart tissues and sections revealed cardiac inflammation, hypertrophy and fibrosis pathway increases in aged rat groups (A12 and A18), which were improved in exercise training groups (AE12 and AE18). There were no heart injuries in young rat hearts in exercise group E3. These data suggest that moderate swimming exercise training attenuated aging-induced cardiac inflammation, hypertrophy and fibrosis injuries of rat hearts.


Why Does Cancer Risk Result from Excess Fat Tissue?

Here I'll point out a recent popular science article on the mechanisms underlying the correlation between cancer and obesity. It is well known and well proven by the scientific community that being overweight is bad for you, even if large sections of the public appear to be solidly in a state of denial on this topic. If you choose to carry excess visceral fat tissue for any great length of time as an adult, even decades later, even having lost that weight, the demographic data strongly suggests that you have a significantly increased risk of suffering all of the common age-related conditions: cancer, heart disease, dementia, and so forth. If you maintain that fat - or keep adding to it over the years, as an increasingly large fraction of the population does - then your odds become even worse. The more fat tissue you have, and the longer you have it for, the shorter your life expectancy, the more you will spend on medical expenses, and the less healthy you will be over the long term.

When trying to explain why this is the case, what it is under the hood that connects fat tissue to ill health, the first candidate mechanism on the list is chronic inflammation. In fact, whether or not you put on weight with age, the growing dysfunction of your immune system will cause rising levels of chronic inflammation, and this inflammation contributes to the pathology of near all of the common and fatal age-related conditions. Fat tissue makes this progression faster and a lot worse, however. Visceral fat is metabolically active; it does a lot to shift the alteration of human biochemistry, and the more of it there is the more it distorts the normal operation of metabolism. The inflammation is most likely caused by some combination of signals from visceral fat tissue that aggravates the immune system, producing results such as a feedback loop of abnormal behavior in macrophage cells.

Nothing in biology has only a single cause, however. Everything is complicated, everything interacts with other mechanisms. The relationship between fat tissue and age-related disease is going to be a story that spreads far beyond inflammation, for all that inflammation is the obvious starting point given what is known of its importance in aging. Take a look at this article, for example, which focuses only on the interactions of cancer and fat tissue:

Breaking the Cancer-Obesity Link

The most recent data from the National Center for Health Statistics indicate that 69 percent of US adults are overweight and half of those are obese. Worldwide, an estimated 2.2 billion adults are overweight or obese, and many of these individuals exhibit the hallmarks of metabolic syndrome: elevated blood pressure and high levels of blood sugar and cholesterol. Increased circulating levels of insulin, inflammatory cytokines, and other factors are also common in obese individuals. And while these metabolic and immune changes are problems in and of themselves, they are not the only health issues faced by the obese population. Through these and other possible mediators, obesity increases the risk and/or worsens the outcome of several chronic diseases, including many types of cancer. This year, obesity overtook smoking as the top preventable cause of cancer death in the U.S., with some 20 percent of the 600,000 cancer deaths per year attributed to obesity.

A major challenge in understanding the complex relationship between obesity and cancer has been distinguishing which host factors are causally linked and which are simply bystanders. Obesity can induce a complex state of systemic metabolic dysregulation characterized by insulin resistance and high levels of circulating insulin and glucose. Over the last two decades, however, researchers have used genetic or pharmacologic approaches to make progress in deciphering which of the many changes mediates the obesity-cancer link. Intercellular signaling is undoubtedly one contributing factor. Proteins, lipid intermediates, and other molecules secreted or shed from cells - collectively referred to as the secretome - carry messages between distant organ systems and tumor cells, as well as among tumor and host cells in their microenvironment. These signaling pathways involve an increasingly large roster of obesity-related hormones, growth factors, nutrient metabolites, chemokines, and cytokines that promote tumor development and/or progression. For example, insulin resistance in obese individuals drives insulin production in the pancreas and results in excess insulin in circulation. High levels of insulin can promote cancer growth through interaction with tumor cells' insulin receptors and/or IGF-1 receptors. Expression of the IGF-1 receptor is also necessary for the transformation of normal epithelial cells into cancer cells by numerous oncogenes, suggesting that greater IGF-1 signaling can also enhance the early stages of cancer development. In addition to the secretome, the tumor microenvironment encompasses extracellular matrix components and multiple cell types, including adipocytes and macrophages, which in obese people are highly active and capable of secreting a large number of cancer-promoting hormones and cytokines.

Another factor that appears to be involved in the obesity-inflammation connection, but has not yet been strongly linked to cancer risk and progression, is the gut microbiome. Obesity is associated with an overall reduction in gut bacterial diversity, and decreased bacterial richness has been linked to elevated systemic inflammation. These studies suggest that obesity-related perturbations of the gut microbiome and barrier function associated with a high-calorie diet can induce chronic systemic and adipose tissue inflammation, which is known to play a role in the progression of several cancer types.

In addition to putting people at an increased risk for developing cancer, obesity also worsens a cancer patient's prognosis. Research from our group and others has shown that a variety of cancers grow at faster rates in obese patients than in lean individuals. Furthermore, obesity appears to increase the chances that a patient's cancer will metastasize. A variety of factors may underlie the obesity-metastasis link, including circulating factors such as leptin, adiponectin, and IGF-1; adipose tissue remodeling, including alterations in adipose-derived stem cells; and other changes to the tumor microenvironment.

Towards a Blood Test for Alzheimer's Disease

Researchers are working on the assessment of patterns of autoantibodies in the blood as a way to determine progression towards Alzheimer's disease and other age-related conditions. The levels of these autoantibodies appear to reflect the presence of specific forms of damage to tissues and systems in the body and brain, and that in turn can be linked to the early-stage pathology of a number of age-related diseases.

Researchers are nearing development of a blood test that can accurately detect the presence of Alzheimer's disease, which would give physicians an opportunity to intervene at the earliest, most treatable stage. The work focuses on utilizing autoantibodies as blood-based biomarkers to accurately detect the presence of myriad diseases and pinpoint the stage to which a disease has progressed.

By detecting Alzheimer's disease long before symptoms emerge, the researchers hope those with disease-related autoantibody biomarkers will be encouraged to make beneficial lifestyle changes that may help to slow development of the disease. While the cause of Alzheimer's remains elusive, it is clear that maintaining a healthy blood-brain barrier is a critical preventative measure. Diabetes, high cholesterol, high blood pressure, stroke and being overweight jeopardize vascular health. As blood vessels in the brain weaken or become brittle with age, they begin to leak, which allows plasma components including brain-reactive autoantibodies into the brain. There, the autoantibodies can bind to neurons and accelerate the accumulation of beta amyloid deposits, a hallmark of Alzheimer's pathology.

The blood test developed by the researchers has also shown promise in detecting other diseases, including Parkinson's, multiple sclerosis and breast cancer. All humans possess thousands of autoantibodies in their blood, and these autoantibodies specifically bind to blood-borne cellular debris generated by organs and tissues all over the body. An individual's autoantibody profile is strongly influenced by age, gender and the presence of specific diseases or injuries. Diseases cause characteristic changes in autoantibody profiles that, when detected, can serve as biomarkers that reveal the presence of the disease.


A Measure of Reduced Mortality through Increased Exercise

Researchers find an association between reduced mortality and increased daily walking distance in a long-term study that used pedometers to measure participant activity. The 10,000 steps mentioned as a reference point sums to about five miles of walking, taking an hour to an hour and a half depending on pace, which might be considered in the context of recent work on the dose-response curve for exercise. It has been suggested that the present health body recommendations of half an hour a day are too low, and doubling that level is worth it from the point of view of additional gains.

A study finds that an increase in the number of steps walked each day has a direct correlation with long term mortality. This was the first time research had been able to make the link between exercise, measured directly through pedometers, and reduced mortality over time in people who appeared healthy at the outset. "Inactivity is a major public health problem, with conditions like obesity costing the economy tens of billions of dollars every year. This shows more clearly than before that the total amount of activity also affects life expectancy. Previous research measured physical activity by questionnaire only, but these results are more robust and give us greater confidence that we can prevent death from major diseases by being more active. This study should greatly encourage individuals to ensure they do regular exercise and prompt governments to create more opportunities for physical activity in communities."

The study monitored 3,000 Australians over 15 years. "The participants were given pedometers and data was collected at the beginning and again approximately five years later during the trial to measure the number of steps they took each day. Participants were an average age of 58.8 years old at commencement and the major end point was death due to any cause." A sedentary person who increased his or her steps from 1,000 to 10,000 per day had a 46% lower mortality risk. A sedentary person who increased his or her steps to 3,000 per day, five days a week had a 12% reduction in death. The association between daily steps and mortality was largely independent of factors such as Body Mass Index (BMI) and smoking.


The Relevance of SEC Changes to Crowdfunding Rules

Crowdfunding of scientific research is a matter of great interest to our community. We want to see more rapid funding of the foundation technologies needed for rejuvenation therapies, treatments capable of repairing the causes of degenerative aging, a field in which most of the early stage nuts and bolts are clearly envisaged but still have to be built. Here at Fight Aging!, we're raising funds for SENS rejuvenation research programs right now, in fact, matching charitable donations until the end of the year.

This sort of comparatively cheap, early stage, high risk science is normally funded by some combination of philanthropy and outright creative accounting when it comes to tracking grant expenditures. Donors are pitched on a regular basis, and a little kept back from every grant to fund unrelated explorations. For the most part what the average fellow in the street would call scientific funding, of the sort provided by large companies and government agencies, is in fact development funding. The real scientific discovery and the greatest risk of failure happens prior to the arrival of funds granted by these institutional sources: they have little interest in underwriting that initial stage of the process, and want to see proven mechanisms, complete understanding, and a clear plan on how to proceed before becoming involved. So it isn't unfair to suggest that the pace of progress in our modern society is actually governed by how much philanthropic support there is for true early stage research.

Back to crowdfunding. That is how people like you and I, who have woken up and realized that rejuvenation therapies are a near-future possibility provided that the necessary early stage work is supported, can collaborate to raise the profile and speed the progress of this work. We lead the pack, we hold up a lantern, we start things moving, and all of this effort is a way to draw in much larger dononations from a few institutions or individuals who ultimately donate a majority of the funding. Behind every successful scientific project there is a power law distribution of funds, but those high net worth individuals who can donate large sums of money to charitable causes such as research are typically highly conservative and risk averse. They are only willing to reinforce success, they only step in when they see strong and growing grassroots support, and the larger the donation the more this is the case.

There are other ways in which this process of growing a crowd to draw in large-scale funding can play out, and we've seen the makings of some of them in for-profit Kickstarter-style crowdfunding. Here crowdfunding can act somewhat like a voting and preorder infrastructure, and when conducted well it allows startup companies to quickly show proof of viability, making it much easier obtain venture funding and move ahead on that basis. These transactions from the crowd are not investments, however: they are still just purchases. The shape of this situation is changing right now, however. The SEC, the US body that claims regulatory jurisdiction over investment in startups, is moving to allow crowdfunding of investment in young companies. This is probably a thing that you were not aware was forbidden to you, not being a member of that modestly privileged set of people having both the money and the interest in becoming an angel investor. Shortly, however, there will be an ecosystem in which tens of thousands of people buy tiny slices of young companies, most of which will evaporate, in the same way as they presently vote with their dollars at Kickstarter.

A majority of the resulting fun and games will be irrelevant to the goals of this community vis a vis funding scientific research and clinical applications of that research. Certainly there will be all sorts of adverse selection effects and gnashing of teeth on the part of the venture community interested in keeping more of a hold over funding opportunities. It does, however, open some doors for us, creating a few new possibilities for collaborative fundraising. As you'll know if you've been following Fight Aging! for a while, the Methuselah Foundation has used charitable donations to seed fund startups here and there for some years; one of them was Organovo, and another, Oisin Biotech, is presently working on senescent cell clearance, one of the most likely SENS therapies to come to fruition in the near future. Good opportunities for seed stage investment in clinical development of first generation rejuvenation therapies, to my eyes meaning SENS technologies and some cancer and regenerative medicine projects, are still pretty thin on the ground at this point. You have to know a lot of the right people and know the field very well to even know that these opportunities exist. That will change in the next few years.

It is important to note that early stage research in the laboratory, of the sort we're funding with charitable donations today, overlaps with early stage clinical development of the sort carried out by Oisin Biotech. There is no clear dividing line between the two, and in many cases whether the work takes place in a non-profit or for-profit environment is simple happenstance, a matter of the inclinations and connections of those involved. So were there an opportunity to crowdfund work that takes place in a startup company, where participants were treated as seed investors, I'd support that goal if the science and development looked like an opportunity to move closer to rejuvenation therapies. I see little practical difference between this and charitable funding: one has a small shot at a profit some years ahead, the other has a present tax deduction. But in both cases, these are ways for people of modest means to collaborate and speak out in large numbers, to make the case to wealthier investors or donors to participate, to vote the opinion that a cause or a company or a line of research is viable and worthy of support. At the moment we are only talking to the donors, the philanthropists interested in funding research. The much larger community of wealthy investors are focused elsewhere, but gaining their attention as described above seems a very viable project.

In the years ahead, this will happen, I think. We'll see the arrangement of crowdfunded investment as a way to raise the profile of specific startups, and to pull in seed funding for their initial scientific development. We will support such ventures when we think they can carry out important steps forward in the finalization and clinical translation of research if all goes well. The need for networking and transparency and connections and insider advisers who can tell good from bad will never go away, but the door is opening for greater community participation and coordination in more of the development process. We will be able to reach out to and persuade new sources of for-profit funding, which are generally much larger than those provided by the non-profit philanthropic community. But ultimately the crowdfunding of rejuvenation research startups will not look all that different from the crowdfunding of rejuvenation research laboratory programs when it comes to the basics of persuasion, fundraising, and the end goals of getting things done. I am looking forward to seeing how it all shakes out.

Brain Connectivity and Fitness in Older Adults

Here is yet another study that demonstrates a correlation between a moderate level of physical fitness and a slower progression of specific aspects of aging in the brain. The conventional wisdom is that this sort of association is mediated by the effects of fitness on cardiovascular health, slowing the deterioration of blood vessel networks in the brain and the damage caused by their structural failure. There are no doubt numerous other mechanisms at work as well, however:

A new study shows that age-related differences in brain health - specifically the strength of connections between different regions of the brain - vary with fitness level in older adults. The findings suggest that greater cardiorespiratory fitness - a measure of aerobic endurance - relates to stronger brain connections and likely improves long-term brain function in aging populations. There are many ways to measure brain health across the lifespan. One popular technique measures the strength of connections between different parts of the brain while the person is completing a task or during wakeful rest. The latter is known as resting-state functional connectivity. Research has shown that some of these connections weaken with increasing age and indicate deteriorating brain health. Using functional magnetic resonance imaging, researchers measured the strength of these connections throughout the brain in younger and older adults at rest. As expected, the team confirmed that most connections were weaker for older adults when compared with younger adults.

Building on these findings, the researchers examined the role of cardiorespiratory fitness on resting-brain connectivity in older adults. Fitness is determined by how efficiently someone uses oxygen during physical activity such as running on a treadmill. Other factors aside from habitual physical activity may alter how fitness affects brain health. For example, a person's genetic makeup can influence his or her fitness and general brain health. The researchers found a relationship between fitness and the strength of the connections between certain brain regions in older adults at rest that was independent of their level of physical activity. "An encouraging pattern in the data from our study and others is that the benefits of fitness seem to occur within the low-to-moderate range of endurance, suggesting that the benefits of fitness for the brain may not depend on being extremely fit. The idea that fitness could be related to brain health regardless of one's physical activity levels is intriguing because it suggests there could be clues in how the body adapts for some people more than others from regular activity. This will help our understanding of how fitness protects against age-related cognitive decline and dementia."


New Sterols Clear Amyloid Protein Aggregates in Cataracts

Some types of cataract involve the formation of amyloid deposits in the lens of the eye made up of damaged crystallin. Researchers have made progress of late in finding sterols that clear this form of amyloid. This is of general interest as there are many types of amyloid that form in tissues in increasing amounts with advancing age, some of which are clearly linked to the pathology of specific age-related conditions. Progress towards effective means of clearance for any one amyloid might turn out to be the starting point for the development of a broader technology platform for therapies, so it is worth paying attention. Here is an update on the development of sterol compounds targeting crystallin amyloid:

In order for our lenses to function well, a permanent, finite reservoir of crystallins must maintain both the transparency of fiber cells and their flexibility, as the eyes' muscles constantly stretch and relax the lens to allow us to focus on objects at different distances. The crystallins accomplish these duties with the help of aptly named proteins known as chaperones, which act "kind of like antifreeze, keeping crystallins soluble in a delicate equilibrium that's in place for decades and decades." This state-of-affairs is "delicate" because pathological, clumped-together configurations of crystallins are far more stable than properly folded, healthy forms, and fiber-cell chaperones must continually resist the strong tendency of crystallins to clump. A similar process underlies other disorders related to aging, such as Alzheimer's disease, but in each of these diseases the specific protein that clumps together and the place in the body that clumping occurs is different. In all cases, these clumped-together proteins are called amyloids.

Because the melting point of amyloids is higher than that of normal crystallins, the team focused on finding chemicals that that lowered the melting point of crystallin amyloids to the normal, healthy range. The group began with 2,450 compounds, eventually zeroing in on 12 that are members of a chemical class known as sterols. One of these, known as lanosterol, was shown to reverse cataracts, but because lanosterol has limited solubility the group who published that study had to inject the compound into the eye for it to exert its effects. Using lanosterol and other sterols as a clue, the researchers assembled and tested 32 additional sterols, and eventually settled on one, which they call "compound 29," as the most likely candidate that would be sufficiently soluble to be used in cataract-dissolving eye drops. In laboratory dish tests, the team confirmed that compound 29 significantly stabilized crystallins and prevented them from forming amyloids. They also found that compound 29 dissolved amyloids that had already formed. Through these experiments, "we are starting to understand the mechanism in detail. We know where compound 29 binds, and we are beginning to know exactly what it's doing."

In addition to compound 29's potential for cataract treatment, the insights gained through the research could have broader applications. "If you look at an electron micrograph at the protein aggregates that cause cataracts, you'd be hard-pressed to tell them apart from those that cause Alzheimer's, Parkinson's, or Huntington's diseases. By studying cataracts we've been able to benchmark our technologies and to show by proof-of-concept that these technologies could also be used in nervous system diseases, to lead us all the way from the first idea to a drug we can test in clinical trials."


Changes in Regeneration Across a Lifespan in Various Species

Here I'll point out an open access review paper that looks over what is known of regenerative capacity and aging in a variety of species in which individuals have quite different trajectories of health and degeneration over a life span. A whole section of the research community is very interested in cataloging the processes of aging as they occur in other species: the comparative biology of aging. Near all species age in the sense of suffering growing damage, degeneration, and frailty as we do, but life spans can be wildly different even in very similar species. A factor of ten difference in life span between near relatives is not unknown; consider the three years of ordinary laboratory rats versus the thirty years of naked mole rats, for example.

Within the context of a given life span, the panoply of well-known species exhibit enormous differences in susceptibility to specific forms of disease and dysfunction. Some species of whale can live for centuries, have many times as many cells as we humans, and yet experience similar or lower rates of cancer than we do over our shorter life spans. Rats and mice are little cancer factories, but naked mole rats seem entirely immune to cancer. They are further considered one of the negligibly senescent species, a list that includes rockfish, turtles, possibly lobsters, and a number of lower organisms such as hydra that might even be entirely ageless in a suitably forgiving environment. Individuals of these negligibly senescent species typically show next to none of the familiar progressive decline of aging until the very end of their lives.

Moving on to consider the matter of regeneration from injury alone, a number of species with the capacity to regrow organs without scarring, such as salamanders and zebrafish, also exhibit little or no reduction in regenerative capabilities over the course of a lifetime. Hydra feature here again as paragons of always-on regeneration, capable of regrowing and replacing any part of their structure if given the chance to do it. It is fair to say that there is a suspiciously good correlation between negligible senescence and greater regeneration when surveying the animal kingdom.

Some research groups aim to go beyond observation in order to mine the biology of these unusually regenerative, long-lived, and cancer-resistant species. They are in search of the basis for potential therapies, ways to port over these varied benefits to the less capable and more vulnerable human biology. It is an open question as to whether or not it will be practical to do this in the near future in any particular case. It depends absolutely on the details, and those have yet to be fully deciphered, even for salamander regeneration, which has been studied with the tools of modern biotechnology for many years now.

Changes in Regenerative Capacity through Lifespan

From the onset of development until the end of their lifespan, most organisms experience a progressive decline in their regenerative abilities. From a biological perspective, regeneration can be subdivided into the ability to replace lost or damaged cells, which includes tissue turnover and limited injury responses found in the majority of organisms including mammals, and the ability to regenerate complex structures, which is mostly absent in mammals but finds expression in a number of other animals. During aging, mammals exhibit changes in their ability to regenerate vital biological structures such as the vascular, nervous, muscular, haematopoietic and skeletal systems as well as many organs and cell types, which correlate with the overall organismal decay.

Although metazoan species exhibit a diverse range of lifespans, it is notable that in most organisms studied so far there is a strong association between the decline in regenerative capacity and the aging process. Indeed, it has been proposed that aging results from the inability to maintain proper tissue structure and function due to insufficiencies in regenerative capacity. Hence, regeneration and aging could represent two sides of the same coin. This idea is supported by the existence of organisms with extreme regenerative capacities, such as planarians and salamanders, which exhibit negligible signs of aging, as indicated by the lack of measurable functional declines with age.

The principles that underlie the decline in regenerative abilities through lifespan are currently being unravelled. However, it is already clear that both cell-intrinsic (such as cellular senescence) as well as cell-extrinsic factors (such as alterations in the regenerative environment) play significant roles. Notably, these factors show extensive overlap with those known to underlie the aging process, highlighting the interconnection between aging and regeneration and stressing that therapeutic approaches designed towards enhancement of regenerative abilities could also result in considerable health/lifespan improvements.

This review discusses the nature of the changes in regenerative abilities that take place through lifespan and across phylogeny, the factors which underpin such changes and the avenues for therapeutic interventions which leverage off this body of research. A particular emphasis is placed on knowledge derived from the classic regeneration models, organisms capable of extensive regeneration of complex structures in which age related declines in regenerative abilities are not observed, as this can shed light on important mechanisms with potential therapeutic application. It is becoming increasingly clear that certain factors, such as cellular senescence, constitute common denominators which impact on various regenerative systems and thus hold great promise for clinical intervention. However, despite the progress made so far, it is also evident that we are far from reaching a full understanding of the interplay between regenerative capacity and aging. Further research will benefit from studies in both vertebrate and invertebrate models of age-related regenerative decline, as well as from work in organisms where these capacities are not affected by aging, such as salamanders. Together, these approaches will deliver important insights into the variations of regenerative capacity through lifespan.

Raised SIGIRR Levels May Mediate Reduced Chronic Inflammation via Calorie Restriction

Here researchers investigate some of the mechanisms involved in the relationship between calorie restriction (CR) and inflammation. The practice of calorie restriction is known to reduce inflammation in the short term, and over the long term it also reduces the growth in chronic inflammation that occurs with aging and which contributes to the development of many age-related conditions. Given that excess visceral fat tissue provides a potent contribution to inflammation, it is tempting to think that the effects of calorie restriction in this case result from practitioners becoming lean. However lack of visceral fat is never the whole story in anything relating to calorie restriction; a lot of other changes take place in cellular biochemistry in response to reduced nutrient intake:

Much of the aging phenotype, including immunosenescence, can be explained by an imbalance between inflammatory and anti-inflammatory networks, resulting in a chronic low-grade pro-inflammatory status. In previous studies, CR has been shown to play a significant role in the anti-inflamm-aging process by decreasing the levels of inflammatory markers in aging tissues. However, thus far, the anti-inflammatory effects of CR have only been superficially examined, and the underlying mechanism has not yet been elucidated. The present study is for the first time to demonstrate the possible regulatory mechanism by which CR induces anti-inflamm-aging and to explore the expression of the upstream and downstream molecules.

Toll-like receptor (TLR) 4 is a type of pattern recognition receptor (PRR) that recognizes molecules that are broadly shared by pathogens but distinguishable from host molecules; collectively, these molecules are referred to as pathogen-associated molecular patterns (PAMPs). TLRs, together with the interleukin-1 (IL-1) receptor (IL-1R), form a receptor superfamily known as the 'IL-1R/TLR superfamily'; all of the members of this family have a so-called Toll/IL-1R (TIR) domain in common. TLRs recognize PAMPs and initiate an intracellular kinase cascade to trigger an immediate defense response.

Fisher 344 rats in a CR group were fed an amount of food corresponding to 60% of that fed to an ad libitum-fed (AL) group for 8 months. Biochemical analyses and renal pathological grading were used to analyze physiological status. Important signaling molecules in the Toll-like receptor/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR/NF-κB) pathway were also analyzed. Compared with AL feeding, CR decreased aging-mediated increases in both biochemical marker levels and renal pathological grading. Single immunoglobulin IL-1 (IL-1)-related receptor (SIGIRR) expression decreased with increasing age, but CR led to overexpression. The expression of TLR4 was significantly higher in the CR group than in the AL group. SIGIRR overexpression decreased the expression of the adaptor molecules myeloid differentiation factor 88 (MyD88), IL-1 receptor-associated kinase 4 (IRAK4) and tumor necrosis factor receptor-associated factor 6 (TRAF6). The levels of the inflammatory markers phospho-IκBα and phospho-NF-κB p65 decreased in the CR group.

We conclude that the inflammatory response might be alleviated by SIGIRR via blockade of the TLR4/NF-κB signaling pathway. Therefore, CR can decrease inflammation via SIGIRR overexpression, and SIGIRR might be a new target to delay aging.


A Caution on Muscle Stem Cells

A lot of the present work on stem cell biology in aging focuses on the muscle stem cells known as satellite cells. This includes some of the interesting lines of research aimed at restoring the activity of old stem cell populations via the use of signal molecules such as GDF-11 identified in parabiosis studies. This open access paper is a caution for those following the field, noting that outside of limb muscles comparatively little is known of the biochemistry of muscle stem cells, and they are perhaps better thought of as scores of different populations with different characteristics, one per muscle group. In other words there is probably a lot more work ahead here than you might have thought was the case:

The human body contains approximately 640 individual skeletal muscles. Despite the fact that all of these muscles are composed of striated muscle tissue, the biology of these muscles and their associated muscle stem cell populations are quite diverse. Skeletal muscles are affected differentially by various muscular dystrophies (MDs), such that certain genetic mutations specifically alter muscle function in only a subset of muscles. Additionally, defective muscle stem cells have been implicated in the pathology of some MDs. The biology of muscle stem cells varies depending on the muscles with which they are associated, and such diversity likely contributes to the pathologic sensitivities of different skeletal muscles to aging and disease.

Skeletal muscles are composed of myofibers, large syncytial cells containing hundreds of post-mitotic myonuclei. Juxtaposed between the basal lamina and the myofiber cell membrane, satellite cells reside at the periphery of skeletal myofibers. Recent studies have demonstrated that satellite cells expressing paired box protein 7 (Pax7) are the primary myogenic cell required for muscle regeneration. The majority of knowledge concerning satellite cell biology arises from studies examining larger muscles of the limbs, which collectively represent less than 2% of all skeletal muscles. Intriguingly, satellite cells present in other muscle groups, including trunk, diaphragm, larynx, tongue, extraocular, masseter, and pharynx, deviate from the canonical biology of their limb counterparts.

Unfortunately, little is known about the effects of age or disease on non-limb muscles as a whole or what factors predispose them to the effects of pathologic conditions. Additionally, satellite cells could serve as pathologic determinants in some dystrophies; however, our knowledge of non-limb satellite cells and their role in muscle biology is severely lacking. Recognizing and elucidating the distinct differences in satellite cell biology between different skeletal muscles could be the key to unraveling the conundrum of muscle specificity between the various MDs.


Considering Longevity Annuities

Conservative models for the next few decades of human life spans in the wealthier regions of the world, those used by insurance industry giants to create their products, predict only a gentle continuation of present trends towards greater life expectancy. These gains clock in at the moment at 2.5 years every decade for life expectancy at birth and one year every decade for adult life expectancy. The actuarial community has for the past decade increasingly hedged its models with pronouncements of uncertainty, which is eminently sensible in an age of accelerating progress in biotechnology. Still, despite this, the financial industry is comfortable offering a class of products varying called longevity insurance, longevity annuities, deferred income annuities, life annuities, or a variety of other terms: pay the company a lump sum now, and starting at some point in the future you are paid a regular income until you die. As for any such transactions, the company makes money on this proposition by correctly predicting demographics such that, on average, it pays out less than it can make with the lump sum.

A secure retirement, no matter how long you live

Longevity annuities have actually been around in various forms for a decade or more. They've been getting a lot more attention lately, however, because the U.S. Treasury Department issued rules last year that make it easier and more attractive to buy a certain type of longevity annuity within retirement accounts such as 401(k)s and IRAs.

Essentially, a longevity annuity is a twist on a somewhat more familiar type of annuity, the immediate annuity. With an immediate annuity, you hand over a sum of money to an insurer in return for guaranteed monthly payments that start at once and continue for the rest of your life. (You can also opt for payments to continue as long as either you or your spouse or partner is alive.)

Like an immediate annuity, a longevity annuity provides guaranteed income for life, except that while you invest your money now, the payments don't begin until later, typically much later, say, 10 to 20 years in the future. In effect, buying a longevity annuity is a bit like buying a life insurance policy, but instead of making a payment to your heirs when you die, a longevity annuity makes monthly payouts to you for the rest of your life, assuming you're still alive when those payments are scheduled to begin.

Now in the world of yesterday, in which there was only a little uncertainty in the possibly unexpected upside of life expectancy, this is all fine and well. Some people want the assurance that they will not run out of money in later retirement, and judge the direct and opportunity costs of setting up a longevity insurance policy to be worth it for the end result of peace of mind. Fortunately we no longer live in that world. We live in a world in which there is a good chance that a range of rejuvenation therapies after the SENS model will start arriving for early adopters - people willing to dive into medical tourism - from five to twenty years from now, depending on circumstances. Interestingly, however, those of us reading this now are in a small minority in buying into this vision of the future. Very few people follow medical research closely, and comparatively few people think that the future of aging will be radically different from aging today.

This arguably presents an opportunity to profit from being in the know. As I put it some years ago, take the money and run: sign a longevity insurance policy with a large company, making sure that the fine print doesn't sabotage the plan, and then strive not to die from any accidental cause as we enter the age in which medical control over the causes of aging becomes possible. In making use of future rejuvenation therapies, your healthy longevity will likely prove to be significantly greater than that predicted by the current actuarial consensus. However, it is worth remembering that adherence to contracts over the long term is for people who can't afford to buy the political process:

It would seem to be the case that either:

a) enough people die at younger ages than you that the offering company makes money and stays in business. In other words, healthy life extension research did not succeed rapidly enough to help you either - you will age, suffer and die.

b) healthy life extension takes off and the insurer is left with a huge liability, which may or may not actually be paid. That depends on how well the insurer handled the funds, the level of economic growth across the years, and the level of interest in the original product, amongst other items. Bribing politicians to write new law to remove obligations is a very predictable out, however.

c) the product is of poor enough value that the company can offer it even though healthy life extension research succeeds - in which case you would likely have been better off placing your funds elsewhere.

So in addition to betting that the company you sign with remains solvent for long enough to make it worthwhile, you are also betting that the losses from longevity insurance caused by large gains in life expectancy across most of the population will not otherwise sink the industry. There is no free lunch, and it seems likely that creating an exceptionally good deal for yourself that lasts decades or longer is only possible when few other people also think they can get a free lunch from longevity insurance and act accordingly.

Proposing Alzheimer's to be Several Distinct Conditions

The research linked below isn't the first time scientists have proposed that what we currently call Alzheimer's disease is in fact a collection of different and distinct ways to end up with a similar end result. You might lump this in with other portions of the theorizing and exploration of alternatives that is taking place at least partially in reaction to the slow pace of progress towards working therapies based on the dominant amyloid hypothesis. The development of immunotherapies to clear amyloid is the current leading edge of that work, but trials have been disappointing to date. It may well be that this is simply because building a robust platform for immunotherapies targeting the brain is inherently challenging, rather than issues with amyloid as a target, but that hasn't stopped a great many competing hypotheses from emerging in the meanwhile.

Deciphering the mechanism that underlies the development of Alzheimer's disease in certain families but not in others, researchers have proposed that the malady is actually a collection of diseases that probably should be treated with a variety of different approaches. The late onset feature typical to distinct neurodegenerative diseases, and the common temporal emergence patterns of these maladies, raise key questions: first, why do individuals who carry disease-linked mutation show no clinical signs until their fifth or sixth decade of life? In addition, why do apparently distinct disorders share a common temporal emergence pattern? One possible explanation is that as people age, the efficiency of the mechanisms that protect younger people from the toxic aggregation of proteins declines, thus exposing them to disease. Indeed, previous studies clearly indicate that the aging process plays key roles in enabling neurodegenerative disorders to onset late in life.

Since neurodegenerative disorders stem from aberrant protein folding, an international research team postulated that an aging-associated decline in the activity of proteins that assist other proteins to fold properly may be one mechanism that exposes the elderly to neurodegeneration. To identify such mechanisms, they searched for similar mutational patterns in different proteins that are linked to the development of distinct neurodegenerative disorders. Their research showed that the development of Alzheimer's disease in certain families, and of a familial prion disorder in other families, originate from very similar mutational patterns. Based on this discovery, they identified that the malfunction of the protein cyclophilin B, which helps nascent proteins to attain their proper spatial structures, is responsible for the manifestation of both maladies. They also comprehensively characterized the mechanism that underlies the development of Alzheimer's disease in individuals who carry these mutations, and found that it has no relevance to the emergence of the disease in patients who carry other Alzheimer's-linked mutations. "This study provides important new insights: first, it shows that the development of distinct neurodegenerative disorders stems from a similar mechanism. More importantly, it indicates that Alzheimer's disease can emanate from more than one mechanism, suggesting that it is actually a collection of diseases that should be classified."


Arterial Stiffening Correlates with Raised Calcium Levels

Researchers here note a correlation between age-related arterial stiffening, likely the primary cause of hypertension, and rising levels of calcium in the blood. It is an open question as the degree to which calcification contributes to stiffening of blood vessel tissues in comparison to the contribution of cross-links to that stiffening. The processes leading to calcification are arguably not as comprehensively understood as those of cross-linking, but at least some of it is a secondary consequence of specific mechanisms - such as inflammation - in blood vessel walls that lead to atherosclerosis.

The progression of arterial stiffness is accelerated by aging, although the underlying mechanisms have not yet been clarified. This prospective observational study was conducted to clarify whether longitudinal changes in the serum calcium/phosphate levels are associated with the accelerated progression of arterial stiffness with age. In a cohort of employees at a construction company (1507 middle-aged Japanese men), the serum calcium/phosphate levels and brachial-ankle pulse wave velocity (baPWV) were measured at the start and at the end of a 3-year study period.

A general linear model multivariate analysis revealed a significant interaction of the 2 factors - age and longitudinal changes of the serum calcium levels (delCa) during the follow-up period - on the longitudinal changes of the baPWV during the study period (delPWV). The delCa was significantly correlated with the delPWV even after adjustments for covariates in subjects aged ≥48 years. The delPWV in subjects aged ≥48 years with the delCa in the upper tertile was significantly larger than that in the other groups even after adjustments for covariates. Thus the association between the arterial stiffness and serum calcium levels differed with age. Pathophysiological abnormalities related to increased serum calcium levels appeared to be associated with accelerated progression of arterial stiffness with age.


An Approach to Solving the Blood Vessel Problem in the Tissue Engineering of Organs

Blood vessels are very important, and so it is always worth paying attention to progress such as that noted below, research that inches closer to the goal of being able to grow suitable blood vessel networks to supply large sections of engineered tissue. It is no great exaggeration to say that the shape and progress of the field of tissue engineering is determined by the thorny issue of building blood vessels - or rather the inability to build blood vessels. Cells must be continually supplied with nutrients and oxygen, and in anything larger than a thin slice of tissue this must be accomplished by an intricate web of tiny blood vessels, in turn joined to larger blood vessels, and which would be connected into the circulatory system if transplanted into a living individual.

Unfortunately it is still a little beyond the present state of the art to construct a blood vessel network that is up to the job of supplying a complete organ - though things are certainly moving closer to that goal in some labs. Larger individual blood vessels can be made in a variety of ways, such as by bioprinting a layered sheet and rolling it up, but building a spreading tree of hundreds or thousands of branching tiny vessels is still a problem in search of a robust solution. This is perhaps the biggest reason why the development of decellularization has seen such support among organ engineers: it bypasses the issue by using a donor organ with the cells stripped from it to provide the extracellular matrix scaffold complete with blood vessel structures. Its chemical cues can guide new, patient-matched cells to repopulate the organ and recreate all of its necessary blood vessels. Other applications of tissue engineering carried out so far have largely been limited to thin structures that can be nurtured without blood vessels, and which are quickly populated by new blood vessels when grafted.

Now that researchers are at the point of actually constructing complex, functional organ tissues from a small sample of patient-derived cells, it is becoming even more pressing to find a practical solution to the blood vessel network issue. If you have wondered why cutting edge tissue engineering has focused on the production of small tissue sections for use in research and testing, the creation of what are called organoids, accomplished for neural tissue, kidneys, livers, the thymus, and so forth, then let me tell you that the challenge of blood vessel network creation is a big part of the answer.

So here we have an interesting approach, which should probably be considered in the context that not all engineered organs don't actually have to look like their corresponding evolved organs. They just have to work. In some cases form follows function, so researchers are very constrained, but for chemical factories and filters like kidneys, livers, the pancreas, and so forth, the situation is different. If the engineered organ is a strange and unsightly collection of lumps assembled specifically to make the blood vessel problem more tractable, but still carries out its necessary jobs because it has all the right cells doing all the right things, then it is a viable candidate for transplantation.

Researchers create implant with network of blood vessels

Using sugar, silicone and a 3-D printer, a team of bioengineers and surgeons have created an implant with an intricate network of blood vessels that points toward a future of growing replacement tissues and organs for transplantation. The research may provide a method to overcome one of the biggest challenges in regenerative medicine: How to deliver oxygen and nutrients to all cells in an artificial organ or tissue implant that takes days or weeks to grow in the lab prior to surgery. The study showed that blood flowed normally through test constructs that were surgically connected to native blood vessels.

One of the hurdles of engineering large artificial tissues, such as livers or kidneys, is keeping the cells inside them alive. Tissue engineers have typically relied on the body's own ability to grow blood vessels - for example, by implanting engineered tissue scaffolds inside the body and waiting for blood vessels from nearby tissues to spread to the engineered constructs. That process can take weeks, and cells deep inside the constructs often starve or die from lack of oxygen before they're reached by the slow-approaching blood vessels.

Using an open-source 3-D printer that lays down individual filaments of sugar glass one layer at a time, the researchers printed a lattice of would-be blood vessels. Once the sugar hardened, they placed it in a mold and poured in silicone gel. After the gel cured, the team dissolved the sugar, leaving behind a network of small channels in the silicone. Collaborating surgeons connected the inlet and outlet of the engineered gel to a major artery in a small animal model. The team observed and measured blood flow through the construct and found that it withstood physiologic pressures and remained open and unobstructed for up to three hours. "This study provides a first step toward developing a transplant model for tissue engineering where the surgeon can directly connect arteries to an engineered tissue. In the future we aim to utilize a biodegradable material that also contains live cells next to these perfusable vessels for direct transplantation and monitoring long term."

In vivo anastomosis and perfusion of a 3D printed construct containing microchannel networks

The field of tissue engineering has advanced the development of increasingly biocompatible materials to mimic the extracellular matrix of vascularized tissue. However, a majority of studies instead rely on a multi-day inosculation between engineered vessels and host vasculature, rather than the direct connection of engineered microvascular networks with host vasculature. We have previously demonstrated that the rapid casting of 3D printed sacrificial carbohydrate glass is an expeditious and reliable method of creating scaffolds with 3D microvessel networks. Here, we describe a new surgical technique to directly connect host femoral arteries to patterned microvessel networks. Vessel networks were connected in vivo in a rat femoral artery graft model. We utilized laser Doppler imaging to monitor hind limb ischemia for several hours after implantation and thus measured the vascular patency of implants that were anastomosed to the femoral artery. This study may provide a method to overcome the challenge of rapid oxygen and nutrient delivery to engineered vascularized tissues implanted in vivo.

On the Role of α-synuclein in Parkinson's Disease

Parkinson's disease, like dementia with Lewy bodies, is a synucleinopathy, a condition characterized by the buildup of aggregates of misfolded, toxic α-synuclein that cause cell death in the brain. The mix of age-related cellular damage, evolved reactions to that damage, and individual genetic variance that leads to the creation of these aggregates is highly complex and poorly understood. As for other diseases involving forms of protein aggregate that harm tissues, such as the varied forms of amyloidosis, one possible shortcut to meaningful treatment is to clear the aggregates on a regular basis. The research community is making some inroads in this direction, such as the production of immunotherapies that can target misfolded proteins, but it has been slow going so far:

Accumulation and misfolding of the α-synuclein protein are core mechanisms in the pathogenesis of Parkinson's disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson's disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology.

Ninety percent of all diagnosed Parkinson's disease cases have a multifactorial origin, which is likely to combine genetic and environmental components. Changes in the expression level and folding state of the α-syn protein, combined with the formation of various α-syn multimeric species, define the transition towards pathological conditions. Although it is recognized that aging is a major risk factor for Parkinson's disease, the time-dependent molecular changes that underlie the development of the pathology are only partially understood. Rationally, pathways implicated in protein and organelle recycling by the proteasome and autophagy, as well as the biogenesis and quality control of mitochondria are gaining attention, because they are critically affected both in Parkinson's disease and aging. In neurons exposed to the combined effects of α-syn and aging, these cellular mechanisms may undergo vicious circles precipitating neuronal demise.

However, compared to normal aging, Parkinson's disease pathology has clear specificities showing that this process cannot be merely considered as a form of accelerated aging. Therefore, it is critical to explore the effect of the α-syn pathology in the context of the neurons that are selectively vulnerable to the converging effects of aging and α-syn proteotoxicity. In particular, the morphology and the metabolic needs of dopamine neurotransmission, are critical factors for α-syn to exert its toxic effects. Using animal models dedicated to the study of the aging process, it will be important to understand the interaction between aging and α-syn in nigral dopaminergic neurons. By identifying therapeutic targets in this context, disease-modifying treatments may be found, that could be applicable to a broad population of patients.


Janus Kinases as a Target to Reduce Chronic Inflammation

Researchers have of late investigated the role of Janus kinases in the processes of chronic inflammation, with an eye towards intervening to reduce inflammation levels. Chronic inflammation grows with aging due to a variety of underlying causes, such as immune system dysfunction and the presence of senescent cells, but is also generated by with poor lifestyle choices such as smoking or being overweight. Inflammation contributes to the development of many common age-related conditions, ranging from dementia to sarcopenia to cardiovascular conditions. Thus methods of safely and greatly reducing chronic inflammation should prove helpful when it comes to improving the health of older people:

Chronic inflammation, closely associated with frailty and age-related diseases, is a hallmark of aging. Researchers found that Janus kinase (JAK) inhibitors, drugs that work to block activity of JAK enzymes, decreased the factors released by human senescent cells in culture dishes. Senescent cells are cells that contribute to frailty and diseases associated with aging. Also, these same JAK inhibitors reduced inflammatory mediators in mice. Researchers examined aged mice, equivalent to 90-year-old people, before and after JAK inhibitors. Over the course of two months, the researchers found substantial improvement in the physical function of the aged mice, including grip strength, endurance and physical activity.

"One of the things we want to do is find some kind of treatment for frailty other than prescribing better wheelchairs or walkers, or other kinds of things that we are stuck with now that are Band-Aid solutions. Our goal is not necessarily to increase life span, and certainly not life span at all costs. Our goal is to enhance health span - the period during life when people are independent. This drug approach and others we are developing look like they might hold some promise in reaching that goal."


Fight Aging! Matching Fundraiser Update: A Third of the Way

The Fight Aging! matching fundraiser launched a month ago, and is now a third of the way to success: more than $57,000 of the $125,000 goal has been donated, and until the end of the year every further donation is matched dollar for dollar from the matching fund provided by a few generous philanthropists. All of these charitable donations go towards supporting and expanding the ongoing rejuvenation research programs coordinated by the SENS Research Foundation. This work, carried out collaboration with renowned laboratories in the US and Europe, aims to bring aging under medical control by repairing its root causes, the forms of cell and tissue damage that occur as a side-effect of the normal operation of metabolism, and which accumulate with age to cause disease and dysfunction.

The SENS Research Foundation has had a banner year in terms of progress towards the goal of bringing the causes of aging under medical control, as noted in the 2015 annual report: seed funding the US startup Oisin Biotechnology to work on senescent cell clearance; transferring lysosomal aggregate clearance technology to Human Rejuvenation Technologies for development; the French company Gensight is now devoting significant funding to to clinical development of the mitochondrial repair technologies whose early stage research was supported under the SENS banner; progress towards the toolkit needed for glucosepane cross-link clearance was published in the prestigious journal Science; a second Rejuvenation Biotechnology conference continued the work of bringing industry and academia together to smooth the path for future development in this field; a crowdfunding initiative brought in hundreds of donors and tens of thousands of dollars for mitochondrial repair research. The efforts of past years, funded in part by everyday philanthropists just like you and I, alongside people like Peter Thiel, Jason Hope, and Aubrey de Grey, are bearing fruit. Everyone who donated in the past should be feeling pretty good about the foundations of new medicine that they have helped to build right around now. The wheel is turning, the avalanche begun.

The future is still to be constructed, however. Science is a slow business, and the breakthrough progress towards therapies for aging that will occur in the first years of the 2020s must be funded in its earliest stages today if it is ever to see the light of day. The SENS programs, and the staff and allies of the SENS Research Foundation, are collectively a proven vehicle for getting this job done; they are picking the right laboratories, programs, and lines of research to back in order to produce meaningful results. We have $68,000 left to raise in the 2015 Fight Aging! fundraiser, every dollar donated matched by philanthropists who put up the Fight Aging! fund, and all donations used well to create progress in this vital field of medicine. We have two months to do it in, the deadline being the end of the year. Help us to hit this target!

An Attempt to Quantify the Degree to Which Alzheimer's is a Lifestyle Disease

To what degree is Alzheimer's disease a consequence of poor lifestyle choices such as being sedentary and overweight, as is largely the case for type 2 diabetes, versus a consequence of the unavoidable accumulation of cell and tissue damage that causes degenerative aging? Researchers here run the numbers to obtain a partial answer. You'll note a couple of interesting associations such as with low body mass index (BMI) in later life, as considerable loss of weight in old age is usually a sign of systematic health issues, and the fact that people with cancer tend not to get Alzheimer's, an phenomenon noted in recent years, but which as of yet has no full explanation.

Age-standardized prevalence of Alzheimer's disease (AD) for those aged ≥60 years varied in a narrow band, 5-7% in most world regions. AD accounts for approximately 60% of dementia incidence. Over the past 100+ years, researchers have never stopped to investigate the pathogenic mechanisms, prevention and therapy for AD. However, we had currently no effective drugs for this disease. Hence, it is increasingly attracting people's attentions to figure out how to prevent its occurrence. In the preventative perspective, Alzheimer's risk factors can be roughly categorized into two types: unmodifiable factors and modifiable factors. The former majorly refers to genetic underpinnings, aging and sex (female), et al.; and the latter comprises seven domains, including pre-existing physical disease, lifestyle, occupation, clinical drugs/therapy, blood biochemistry, diet, and mental psychology, which are exactly the potential targets for preventative strategies.

The team spent about one year in database searching, paper screening, data collecting and analyzing. Finally, 323 eligible papers in which 93 modifiable factors were identified were selected from roughly 17,000 literatures. The study found the significant associations of 36 factors categorized into six domains (including drugs, diet, biochemistry, mental health, lifestyle and pre-existing disease) with Alzheimer's occurrence. The most significant risk factor is heavy smoking while the most significant protective factor is healthy diet, for example the Mediterranean diet. Furthermore, we graded the evidence strength of meta-analysis for each factor based on two major domains: pooled sample size and the heterogeneity of each analysis. We found 11 risk factor with grade I evidence strength, including heavy smoking, low diastolic blood pressure, high BMI in midlife, carotid atherosclerosis, type 2 diabetes in Asian population, low BMI, low educational attainment, high total homocystein level, depression, systolic blood pressure more than 160 mmHg and frailty.

Among these risk factors, a total of 9 risk factors (including obesity in mid-life, current smoking in Asian population, carotid atherosclerosis, type 2 diabetes in Asian population, low educational attainment, high total homocysteine level, depression, high systolic blood pressure ≥160 mmHg, and frailty) for which global prevalence was accessible were selected for calculating population attributable risk (PAR). The combined PAR% indicated that these nine potentially modifiable risk factors were associated with up to roughly 66% of AD cases globally. Additionally, our study also found grade I evidence for 18 protective factors, including coffee/caffeine drinking, high folate intake, cognitive activity, high vitamin E intake, high vitamin C intake, current statin use, arthritis, light-to-moderate drinking, ever alcohol use, ever use of estrogens, anti-hypertensive medications, NASIDs use, high BMI in late-life, high Aβ42/40 ratio and some pre-existing diseases including arthritis, heart disease, metabolic syndrome, and cancer.


Investigating the Role of GDF-10 in Brain Regeneration

Following a stroke, the survivors exhibit varying degrees of limited regeneration in the brain. Researchers are interested in finding reliable ways to enhance that process. Beyond the context of recovering from such injuries, it is important in the development of treatments for aging to be able to spur greater ongoing growth and regeneration in the aging brain:

Looking at brain tissue from mice, monkeys and humans, scientists have found that a molecule known as growth and differentiation factor 10 (GDF10) is a key player in repair mechanisms, such as axonal sprouting, that are activated following stroke. During axonal sprouting, healthy neurons send out new projections ("sprouts") that re-establish some of the connections lost or damaged during the stroke and form new ones, resulting in partial recovery. Before this study, it was unknown what triggered axonal sprouting. Previous studies suggested that GDF10 was involved in the early stages of axonal sprouting, but its exact role in the process was unclear. Examining animal models of stroke as well as human autopsy tissue, researchers found that GDF10 was activated very early after stroke. Then, using rodent and human neurons in a dish, the researchers tested the effect of GDF10 on the length of axons, the neuronal projections that carry messages between brain cells. They discovered that GDF10 stimulated axonal growth and increased the length of the axons.

Researchers treated mouse models of stroke with GDF10 and had the animals perform various motor tasks to test recovery. The results suggested that increasing levels of GDF10 were associated with significantly faster recovery after stroke. When the researchers blocked GDF10, the animals did not perform as well on the motor tasks, suggesting the repair mechanisms were impaired - and that the natural levels of GDF10 in the brain represent a signal for recovery. It has been widely believed that mechanisms of brain repair are similar to those that occur during development. The team conducted comprehensive analyses to compare the effects of GDF10 on genes related to stroke repair with genes involved in development and learning and memory, processes that result in connections forming between neurons. Surprisingly, there was little similarity. The findings revealed that GDF10 affected entirely different genes following stroke than those involved in development or learning and memory. "We found that regeneration is a unique program in the brain that occurs after injury. It is not simply Development 2.0, using the same mechanisms that take place when the nervous system is forming."