Fight Aging! Newsletter, January 15th 2018

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Exercise Can Reverse Cardiac Secondary Aging Resulting from a Sedentary Lifestyle
  • Fight Aging! Newsletters Translated into French at Long Long Life
  • Two Examples of Recent Work on Novel Drug Candidates to Treat Alzheimer's Disease
  • Sarcopenia as an Inflammatory Condition, Driven in Part by Cellular Senescence
  • How to Plan and Carry Out a Simple Self-Experiment, a Single Person Trial of Chemotherapeutic Senolytic Drug Candidates
  • Clonal Expansion of Stochastic Nuclear DNA Damage as a Contributing Cause of Aging
  • A Role for Alpha-2-Macroglobulin in the Cancer Immunity of Naked Mole-Rats
  • Simple Assessments of Resilience as Potential Biomarkers of Aging
  • Specific Risk Factors can Appear to Decline in Importance in Later Life, as the High-Risk Individuals are Already Dead
  • Those Who Reject Rejuvenation Research and Longer Lives Do Little More than Repeat Old, Worn Objections
  • Functional Muscle Tissue Grown from Induced Pluripotent Stem Cells
  • Stem Cells Enhanced with Platelet-Derived Coatings are More Effective at Cardiac Tissue Repair
  • Bioethicists Consider the Search for a Treatment for Aging
  • Y Combinator Shows an Interest in Investing in the Treatment of Aging
  • An Approach to Starving Cancer Cells that is Applicable to Many Cancers

Exercise Can Reverse Cardiac Secondary Aging Resulting from a Sedentary Lifestyle

It is never too late to exercise in order to obtain benefits to health - there are any number of studies showing beneficial outcomes to result from structured exercise, especially resistance exercise, even for people in very late life. That said, the study of exercise noted here suggests that at some point in middle age it does become too late to reverse consequences of secondary cardiac aging such as hypertrophy, stiffening of heart muscle leading to diastolic heart failure, and the like. Up until that point, however, even the earnestly idle among us can choose to undo some of the portion of overall loss of function that results from a sedentary lifestyle.

What is secondary aging? There is no bright dividing line between primary aging and secondary aging, but one possible definition is that primary aging results from the normal operation of cellular metabolism in a healthy individual in an optimal environment, while secondary aging results from detrimental environmental factors: long-term exposure to toxins or pathogens, lingering latent viral infections, poor diet leading to excess fat tissue, a smoking habit, lack of exercise, and so forth. The reason I say that there is no bright dividing line is that if you look under the hood at the types of damage and molecular mechanisms involved, there is considerable overlap between primary and secondary aging. Chronic inflammation and common ways in which cells can malfunction feature prominently on both sides, for example. Aging is damage, and for many forms of that damage it is a matter of origin and semantics as to whether we consider it a part of aging, the pathology of a disease, a self-inflicted injury, or something else.

Exercise can only take you so far. Given that it is essentially free, and reliably produces benefits, of course everyone should exercise if capable of doing so. But three quarters of the fittest, most diligent people nonetheless die from age-related disease, largely cardiovascular disease, before reaching 90 years of age, and those still alive at 90 are pale shadows of their former, youthful selves. The gains of exercise are small when considered against the bigger picture of what will become possible though near future medical technology. So exercise by all means, but also put some thought towards supporting the development of rejuvenation therapies capable of repairing and reversing the various forms of cell and tissue damage that cause aging. Success in that line of work is the only way forward to live in good health, and with a youthful physiology, for far longer than is presently possible.

Middle-aged couch potatoes may reverse heart effects of a sedentary life with exercise training

The researchers analyzed the hearts of 53 adults ages 45-64 who were healthy but sedentary at the start of the study - meaning they tended to sit most of the time. Study participants received either two years of training, including high- and moderate-intensity aerobic exercise four or more days a week (exercise group), or they were assigned to a control group, which engaged in regular yoga, balance training, and weight training three times a week for two years.

The exercise group committed to a progressive exercise program which monitored participants' recorded heart rates. People in this group worked up to doing exercises, such as four-by-fours - foue sets of four minutes of exercise at 95 percent of their maximum heart rate, followed by three minutes of active recovery at 60 percent to 75 percent peak heart rate. In this study, maximum heart rate was defined as the hardest a person could exercise and still complete the four-minute interval. Active recovery heart rate is the speed at which the heart beats after exercise.

They found that, overall, the committed exercise intervention made people fitter, increasing VO2max, the maximum amount of energy used during exercise, by 18 percent. There was no improvement in oxygen uptake in the control group. The committed exercise program also notably decreased cardiac stiffness. There was no change in cardiac stiffness among the controls. Sedentary behaviors - such as sitting or reclining for long periods of time - increase the risk of the heart muscle shrinking and stiffening in late-middle age and increases heart failure risk.

Previous studies have shown that elite athletes, who spent a lifetime doing high-intensity exercise, had significantly fewer effects of aging on the heart and blood vessels. However, the six to seven days a week of intense exercise training that many elite athletes perform throughout their life isn't a reality for many middle-aged adults, which led researchers to study different exercise doses, including casual exercise at two to three days a week and "committed exercise" at four to five days a week. "We found that exercising only two or three times a week didn't do much to protect the heart against aging. But committed exercise four to five times a week was almost as effective at preventing sedentary heart aging as the more extreme exercise of elite athletes. We've also found that the 'sweet spot' in life to get off the couch and start exercising is in late-middle age, when the heart still has plasticity."

Reversing the Cardiac Effects of Sedentary Aging in Middle Age - A Randomized Controlled Trial: Implications For Heart Failure Prevention

Sedentary aging is strongly associated with deleterious changes in cardiovascular function, including an increase in left ventricular (LV) stiffness. Sedentary seniors have small stiff LVs, which are comparable to patients with heart failure with a preserved ejection fraction (HFpEF). In contrast, competitive athletes have large, compliant LVs equivalent to much younger individuals, suggesting that exercise training, performed at a very high level over a lifetime, may counteract the detrimental effects of aging and inactivity on the LV.

Although competitive athletes are a useful model for characterizing the upper limits of cardiovascular protection from prolonged exercise training, the volume of training performed by these individuals (≥6 days/wk plus competitions) is not feasible for the general population. Although it appears that 4 to 5 days of committed exercise training over decades is adequate to achieve most of this benefit, it is unclear whether exercise training can restore or improve LV compliance in previously sedentary individuals, and if so, when is the optimal stage of life to intervene.

Epidemiological studies show that a measurement of fitness in middle age is the strongest predictor of future heart failure. Moreover, in observational studies, the dose of exercise associated with reduced heart failure incidence is much higher than that associated with reduced mortality. However, if exercise is started too late in life (i.e. after 65 years) in sedentary individuals, there is little effect on LV stiffness. Thus, a lifetime of sedentary aging is associated with a reduction of cardiac plasticity, which cannot be overcome with a year of moderate-intensity exercise training. We recently documented that this LV stiffening begins to be identifiable during middle age with a leftward shift in the LV end-diastolic pressure volume curve. We hypothesize that middle-aged hearts retain some degree of cardiac plasticity and may represent a more optimal time to intervene with aggressive lifestyle modification aimed at improving cardiac stiffness.

This study is the longest, prospective randomized controlled trial that has documented the physiological effects of supervised, structured exercise training in a group of sedentary but healthy middle-aged adults. The key finding is that 2 years of exercise training performed for at least 30 minutes, 4 to 5 days per week, and including at least 1 high-intensity interval session per week results in a significant reduction in LV chamber and myocardial stiffness. The use of high-resolution, invasively measured LV pressure-volume curves and comparison with an attention control group enhances the confidence in this conclusion. This study also demonstrated that exercise training can be adhered to by middle-aged adults over a prolonged period, suggesting that this may be an effective strategy to mitigate the deleterious effects of sedentary aging on the heart and forestall the development of HFpEF.

Fight Aging! Newsletters Translated into French at Long Long Life

The team behind the Long Long Life site has been translating recent Fight Aging! newsletters into French, using a mix of automated translation systems and professional editing. I'm all in favor of more of this: language barriers are a terrible impediment for an initially sparse movement, made up of people scattered around the world. As we've seen over the past decade in the increasing cooperation between longevity science communities in different countries, even crude translation automation makes a huge difference to the degree to which groups can become aware of one another and help out. The reason why Fight Aging! is published under a Creative Commons license is to encourage people to do exactly this sort of thing without having to ask. The flattery along the way doesn't hurt, of course:

I represent the Long Long Life website, and I'm writing to inform you that we have been translating excerpts from the Fight Aging! newsletter into French for a couple of weeks using DeepL and professional post-editing. The pace looks sustainable for now so it's looking like we will be doing this regularly. If you know of any French-speaking enthusiasts who would like to benefit from your news and incredible work, some of it is now available on our site. Thank you so much for the amazing work you are putting in!

As for DeepL, my professional opinion is that it is a great tool for communication, especially in science since there are less subtleties in the discourse. I find it a promising tool with great potential. It demands however to be carefully post-edited by professionals, or the translation memory it relies on risks being polluted by the many unreliable entries that the general public is okay with. The grammar is still somewhat feeble when it comes to abstract thinking and opinion pieces, which is why we are focusing on hard science for now when we translate FA! content. We are working to increase the exposure of our website so that more people have access to the scientific content we want to share.

I point this out today to note that automated translation, particularly the DeepL system used here, has advanced to the point at which it is cost-effective for small volunteer and other low-expense groups to translate heavily scientific content on a regular basis. In the past the challenge for translating resources such as Fight Aging! has always been that the life sciences speak a language all of their own. It happens to bear some resemblance to English, but diverges fairly heavily into an extended vocabulary of trade words, neologisms, and situational redefinitions that are anything but intuitive. Plus many papers are written by people for whom English is a second language, and who have a tendency to omit many of the useful little words that make sentences hang together, such as indefinite articles.

The current advocacy groups whose local audiences speak a language other than English could benefit from following the Long Long Life example here, and looking into DeepL and similar tools. There is a great deal of very useful English-language work produced over the past decade of advocacy and science for rejuvenation that has yet to be translated. The non-English speaking populations of Europe, Africa, and Asia are large, and most of them have yet to be introduced in any serious way to SENS rejuvenation research or the advocacy movements that have grown in the English-language and Russian-language worlds. Similarly, we in the English-language world see only a fraction of the efforts and advocacy that take place in those other communities. The cost of translation has fallen to be low enough that we as a community can now start to do better than this, I think.

Two Examples of Recent Work on Novel Drug Candidates to Treat Alzheimer's Disease

Absent any greater context on Alzheimer's disease research, one might look back at the past twenty years of clinical trials and consider this medical condition to be an insurmountable obstacle at our present stage of progress in biotechnology. The history is an unremitting series of abject and expensive failures. The underlying context is more promising, however - Alzheimer's research is the sharp, applied end of two massive, distributed research projects that are still somewhere in their middle stages. The first of these is the effort to map and understand the biochemistry and cellular function of the brain in detail. The second is the effort to produce functional, safe, reliable immunotherapies, which in turn requires researchers to map and understand the biochemistry and cellular function of the immune system in detail. At some point, immunotherapies to remove the protein aggregates associated with Alzheimer's will start to work, as tremendous progress has been made in the underlying understanding of the brain and the immune system over the past decade or two. Early signs of that stage of progress emerged last year, but they are still only early signs.

Failure has consequences, however. As the primary focus of amyloid clearance continues to fail to produce results, it is the case that ever more effort and funding flows in other directions. Some of these are quite promising and genuinely new approaches that have yet to be fully explored, such as restoration of lost drainage of cerebrospinal fluid. Others seem more like the business as usual approach of the pharmaceutical research community, which is to say (a) tinkering with ways to compensate for the disease state rather than addressing something closer to a root cause, and (b) screening and repurposing existing drugs that are already approved for use in humans, even if the effects are only marginal, because that is cheaper than looking for new approaches. That sometimes this tinkering turns up items that might be worth developing as stop-gap therapies is either a blessing or a curse: a blessing because some benefits are better than no benefits, and a curse because it distracts significant effort from addressing the causes of the condition. It is hard to say which is more the case, especially in the scenario in which a direct assault on root causes is proving to be much, much harder than expected.

The two separate lines of drug development noted below are examples of largely compensatory approaches, even though they touch on aspects of the cellular biochemistry of the brain known to change with age. They do not address the underlying causes of the dysfunctions they ameliorate, but rather try to force the behavior of brain cells and their component parts into a more youthful configuration - overriding the evolved reactions to the damage of aging. One of these approaches focuses on growth factors that govern many fundamental aspects of cellular behavior, such as replication, while the other touches on mitochondrial function. Mitochondria, the power plants of the cell, are known to suffer a general malaise of reduced function and altered dynamics in aging, and since the brain is an energy-hungry organ, it is perhaps the most profoundly affected by this form of decline.

Diabetes drug "significantly reverses memory loss" in mice with Alzheimer's

A drug developed for diabetes could be used to treat Alzheimer's after scientists found it "significantly reversed memory loss" in mice through a triple method of action. "With no new treatments in nearly 15 years, we need to find new ways of tackling Alzheimer's. It's imperative that we explore whether drugs developed to treat other conditions can benefit people with Alzheimer's and other forms of dementia. This approach to research could make it much quicker to get promising new drugs to the people who need them."

This is the first time that a triple receptor drug has been used which acts in multiple ways to protect the brain from degeneration. It combines GLP-1, GIP, and Glucagon which are all growth factors. Problems with growth factor signalling have been shown to be impaired in the brains of Alzheimer's patients. The study used APP/PS1 mice, which are transgenic mice that express human mutated genes that cause Alzheimer's. Those genes have been found in people who have a form of Alzheimer's that can be inherited. Aged transgenic mice in the advanced stages of neurodegeneration were treated. In a maze test, learning and memory formation were much improved by the drug which also: enhanced levels of a brain growth factor which protects nerve cell functioning; reduced the amount of amyloid plaques in the brain linked with Alzheimer's; reduced both chronic inflammation and oxidative stress; slowed down the rate of nerve cell loss.

Alzheimer's drug turns back clock in powerhouse of cell

The experimental drug J147 is something of a modern elixir of life; it's been shown to treat Alzheimer's disease and reverse some measures of aging in mice and is almost ready for clinical trials in humans. Now, scientists have solved the puzzle of what, exactly, J147 does. They report that the drug binds to a protein found in mitochondria, the energy-generating powerhouses of cells. In turn, they showed, it makes aging cells, mice and flies appear more youthful.

Researchers developed J147 in 2011, after screening for compounds from plants with an ability to reverse the cellular and molecular signs of aging in the brain. J147 is a modified version of a molecule (curcumin) found in the curry spice turmeric. In the years since, the researchers have shown that the compound reverses memory deficits, potentiates the production of new brain cells, and slows or reverses Alzheimer's progression in mice. However, they didn't know how J147 worked at the molecular level.

In the new work, the team used several approaches to home in on what J147 is doing. They identified the molecular target of J147 as a mitochondrial protein called ATP synthase that helps generate ATP - the cell's energy currency - within mitochondria. They showed that by manipulating its activity, they could protect neuronal cells from multiple toxicities associated with the aging brain. Moreover, ATP synthase has already been shown to control aging in C. elegans worms and flies. Further experiments revealed that modulating activity of ATP synthase with J147 changes the levels of a number of other molecules - including levels of ATP itself - and leads to healthier, more stable mitochondria throughout aging and in disease. The team is already performing additional studies on the molecules that are altered by J147's effect on the mitochondrial ATP synthase-which could themselves be new drug targets. J147 has completed the FDA-required toxicology testing in animals, and funds are being sought to initiate phase 1 clinical trials in humans.

Sarcopenia as an Inflammatory Condition, Driven in Part by Cellular Senescence

Sarcopenia is the name given to the characteristic loss of muscle mass and strength that occurs with age, though insofar as the slow progress towards an official clinical definition is concerned, this only counts in the more advanced stages. We could do with less of that sort of thinking in medicine and research, as all age-related declines are a problem, and the earlier they can be addressed, the better. If a therapy addresses the root causes of an age-related condition, then it should be just as usefully applied every so often starting at 40, as a preventative treatment, as it would be starting at 70, in order to turn back much larger amounts of damage.

Sarcopenia is a great example of the way in which many areas of research into aging resemble the parable of the blind men and the elephant; every specialized research group looking at just one layer in a complex, interacting set of mechanisms and outcomes, and claiming their layer to be the most important. When reading the literature on sarcopenia, there are many theories and causes, most of which are backed by good evidence. Think of disruption of regenerative processes via chronic inflammation and stem cell decline, the role of cellular senescence in achieving that disruption, or, separately, neurological decline in the links between muscle and nervous system, reduced protein intake and lack of exercise in older individuals, and an age-related failure to process dietary amino acids.

As things stand, I think the stem cell researchers have a compelling last word with regard to the size of the contribution of declining stem cell activity on muscle atrophy in aging versus other possible causes. We then have to ask, however, why does muscle stem cell activity falter with age? What are the mechanisms driving that change? Research in recent years points to inflammatory signals as one of the ways in which regeneration and tissue maintenance are disrupted, and some portion of that inflammation arises from the signaling generated by growing numbers of senescent cells. Still, each of these named items is just one layer in a complex system - a system that is too complex to model well today. There are plenty of other causes of stem cell decline with evidence to support them. The true size of any specific contribution, the importance of any specific connection, will only be determined in the near future through some form of therapy that removes it. The best and fastest way to understand aging in detail is to fix the known forms of damage, one by one, and observe the results.

The paper here considers inflammation in sarcopenia, but not from the perspective of stem cell tissue maintenance. Rather, the authors focus on the way in which age-related increases in chronic inflammation might interfere with the protein synthesis needed to build muscle - which comes back around to the various studies suggesting that disruption in the processing of nutrients is a contributing cause of sarcopenia. Eventually everything is connected to everything else in aging and cellular biochemistry, given enough time to find the links. Advances in senolytic therapies to clear senescent cells and their inflammatory signaling, coupled with ways to reverse the age-related dysfunction of the immune system should in years ahead help to determine the degree to which sarcopenia is caused by inflammation.

The Role of Inflammation in Age-Related Sarcopenia

One of the major problems in the aging population is a progressive loss in skeletal muscle mass, muscle strength, and/or functionality, described as age-related sarcopenia. Several strategies to attenuate the loss of muscle mass and other muscle impairments that comes with aging have been developed. However, none of these have been proven successful to fully reverse the muscle wasting condition. Given the high prevalence of sarcopenia in the aging population and the associated high health care costs, it is of importance to reveal and elucidate the working mechanisms which underlie muscle protein metabolism in the elderly, in order to optimize the classic interventions and/or to develop new ones.

Muscle protein metabolism is carefully regulated by counterbalanced fluctuations in muscle protein breakdown (MPB) and muscle protein synthesis (MPS). In the elderly, the balance between MPB and MPS seems to be disturbed, which progressively increases the loss of skeletal muscle mass. Many underlying factors such as hormonal changes, decreased activity, diminished nutrient intake, and neuronal changes were reported in the literature, but lately, the role of inflammation on the regulation of muscle protein metabolism has gained more and more interest among gerontologists.

Generally, aging is associated with a chronic state of slightly increased plasma levels of pro-inflammatory mediators, such as tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and C-reactive protein (CRP). This state is often referred to as a low-grade inflammation (LGI) and is, at least partly, the manifestation of increased numbers of cells leaving the cell cycle and entering the state of cellular senescence. Indeed, senescent cells acquire a Senescence-Associated Secretory Phenotype, which induces the production of pro-inflammatory cytokines (TNFα, IL-6 and an overactivation of NF-κB). Moreover, there is a growing interest in the association between the telomere/telomerase system and LGI, as cellular senescence can be triggered by critically short telomeres, representing irreparable DNA damage. Also, there are indications that LGI can directly cause telomere/telomerase dysfunction, enforcing the vicious LGI circle and stimulating an accelerated aging phenotype.

Although it has been suggested that inflammatory mediators affect muscle protein metabolism, it is not fully understood to what extent and through which signaling pathways they induce muscle wasting. Population-based data suggest that circulating concentrations of IL-6 and TNFα are significantly elevated in sarcopenic elderly and it was reported that higher IL-6 and CRP levels increase the risk of muscle strength loss. In a 10-year longitudinal study in community-dwelling elderly, plasma concentrations of TNFα, IL-6, and IL-1 were shown to be strong predictors of morbidity and mortality in older subjects. Furthermore, systemic inflammation was also reported as one of the primary mediators of skeletal muscle wasting and it was shown to accelerate aging in general. Without pronouncing on causality, these findings suggest that there is a link between inflammatory mediators and muscle mass and function.

A number of mechanisms have been shown to contribute to the etiology and/or progression of muscle wasting with advancing age. Somehow, many of these mechanisms interfere with inflammatory mediators. However, further research is required to determine through which mechanisms inflammation directly or indirectly affects MPB and MPS with aging. Classic interventions such as protein supplementation and resistance exercise are generally accepted to be the most appropriate to positively affect muscle protein metabolism in elderly. However, not all studies univocally support the effectiveness of these strategies for long-term treatment of age-related muscle wasting. Elderly, and very old or frail seniors in particular, might benefit from a strategy primarily focused on alleviating their muscle insensitivity to anabolic stimuli. In this regard, the treatment of LGI in these elderly might play an important role.

How to Plan and Carry Out a Simple Self-Experiment, a Single Person Trial of Chemotherapeutic Senolytic Drug Candidates

This lengthy post walks through the process of setting up and running a self-experiment - a trial of one - of candidate senolytic drugs capable of removing some portion of the senescent cells that accumulate with age to cause aging and age-related disease. Metrics are assessed beforehand and afterwards in order to shed some light on whether or not it worked, in the sense of producing some degree of rejuvenation, turning back specific measures of age-related decline.

The outline here is optimized for simplicity, cost, and ability to conduct the experiment without much outside assistance, rather than for maximal effectiveness. There are better candidate pharmaceuticals and better metrics that those settled on here, at least from the point of view of likely effectiveness, fewer side-effects, and relevance to the task at hand, but they require more work, more funds, more complicated logistics, and the assistance of laboratories and physicians. Given these self-imposed constraints, this does mean that the outline here ends up focused on repurposed chemotherapeutics, which make up the majority of the current senolytic drug candidates. That in turn means that side-effects and related risks to health are an important consideration.

The purpose in publishing this outline is not to encourage people to immediately set forth to follow it. If you come away thinking that you should do exactly that, and as soon as possible, then you have failed at reading comprehension. This post is intended to illustrate how to think about self-experimentation in this field: set your constraints; identify likely approaches; do the research to fill in the necessary details; establish a plan of action; perhaps try out some parts of it in advance, such as the measurement portions, as they never quite work as expected; and most importantly identify whether or not the whole plan is worth actually trying, given all that is known of the risks involved. Ultimately that must be a personal choice.


  • Why Self-Experiment with Senolytics?
  • Caveats in More Detail
  • Choosing Senolytic Drug Candidates
  • Establishing Dosages
  • Obtaining Senolytic Pharmaceuticals
  • Storage of Senolytics
  • Validating the Purchased Senolytics
  • Ingestion Logistics for Powders
  • Establishing Tests and Measures
  • Guesstimated Costs
  • Schedule for the Self-Experiment
  • Where to Publish?
  • Final Thoughts: Why Not Wait?

Why Self-Experiment with Senolytics?

Senolytic therapies are those that selectively destroy senescent cells. The build up of senescent cells is one of the causes of aging. So obviously, one hope is to benefit personally from such a therapy sooner than would otherwise be the case, balancing that against incurring some unknown degree of risk of failure or harm. The first human trials, those that establish numbers for that risk, will take another few years to wind through to robust conclusions, and further years beyond that will be required for the medical community to become willing to prescribe senolytics generally. Further, those trials will almost all test only a single candidate therapy, and the evidence to date in mice suggests that different senolytics with different mechanisms are tissue-specific in their effects on senescent cells. Multiple different compounds may be more effective than one - but that won't be discovered in the formal trial process. Lastly, well run self-experimentation carried out by a number of people, where the results are published, can help to guide the direction of later, formal studies.

All of these reasons must be balanced against a sober assessment of the risks involved in obtaining and using pharmaceutical compounds, and an acceptance of personal responsibility for consequences should one choose to run those risks.

Caveats in More Detail

There are two areas of personal responsibility to consider here. Firstly, this involves taking chemotherapeutic pharmaceuticals with known side-effects. One should read the relevant papers on their effects, side-effects, and dosages, and make an individual decision on risk and comfort level base on that information. This is true of any pharmaceutical, whether or not approved for use. Do not trust other opinions you might read online: go to the primary sources, the scientific papers, and read those. Understand that where the primary data is sparse, it may well be wrong or incomplete in ways that will prove harmful. Also understand that older physiologies can be frail and vulnerable to the side-effects of specific chemotherapeutic pharmaceuticals in ways that do not occur in younger people and that are not well covered by the studies; pharmacokinetic studies necessary to establish side-effects and tolerances don't tend to be carried out in very old humans, and most cancer trials have participants that almost entirely fall into the 50-80 age range.

Secondly, obtaining and using pharmaceuticals in the manner described here is illegal: choosing to do so would be a matter of civil disobedience, as is the case for anyone obtaining medicines outside the established national system of prescription and regulation. People are rarely prosected for doing so for personal use in the US - consider the legions of those who obtain medicines overseas for reasons of cost, despite the fact that doing so is illegal - but "rarely" is not "never." If you believe that the law is unjust, then by all means stand up against it, but accept that doing so carries the obvious risks of arrest, conviction, loss of livelihood, and all the other ways in which the cogs of modern society crush those who disagree with the powers that be.

Lastly, senolytics is a fast-moving field. This post will become outdated quite rapidly in its specifics regarding candidate pharmaceuticals, as new knowledge and new candidate therapies arrive on the scene. Nonetheless, the general outline should still be a useful basis for designing new self-experiments involving later and hopefully better compounds, as well as tests involving more logistical effort.

Choosing Senolytic Drug Candidates

The criteria for choosing senolytic drug candidates for the purposes of this outline are: (a) it must be taken by mouth, rather than through injection, as the logistics for assembling materials and carrying out injections are considerably more complicated; (b) it must have shown senolytic effects in animal studies, not just in cell studies, as there are all too many failures to make the leap from cell to mouse in pharmaceutical development; (c) there must be enough human data to determine the effects and side-effects of doses used. The more human data, the better, in fact. Finding a list of senolytics and assessing them against these criteria involves research: dig through PubMed in search of senolytic studies and review articles, and then follow chains of references to find other papers. Carefully check the magnitude and other details of the results claimed in animal studies: some senolytics are better than others. Armed with the names of drug candidates, then look up studies of dosage and effects for cancer and other trials in both mice and humans. Not all papers are open access. Where they are not, taking advantage of the efforts of the copyright heretics of Sci-Hub is the best approach to obtain a copy.

At the present time, the criteria above narrow the field to a few repurposed chemotherapeutics, one of which was shown to synergize with the flavonoid quercetin. These are: (a) dasatinib in combination with quercetin, while noting that the data shows it isn't worth trying either one on its own, (b) navitoclax / ABT-263, and (c) alvespimycin / 17-DMAG. Navitoclax, however, has side-effects that are common enough and severe enough to want to avoid it; it causes a loss of platelets in the blood to the point of producing noticable medical consequences, and did so in about half of cancer trial participants.

There is also venetoclax / ABT-199 to consider, however, a modified form of navitoclax intended (and shown) to reduce the worst of its platelet-destroying side-effects, but lacking animal data for senolytic effects. Navitoclax and venetoclax are both BCL-2 family inhibitors, operating on roughly the same mechanism, and another member of this family of pharmaceuticals, ABT-737, has been shown to have senolytic effects. So while venetoclax lacks mouse data for senolytic effects, at first glance it makes some sense to include it in a test: the trade-off is a matter of losing some of the unpleasant side-effects and gaining uncertainty in whether or not the senolytic effects will carry over. There is a very helpful paper from a few years back that covers the relationships between these BCL-2 family inhibitors, and that does a good job of explaining why venetoclax is a favored alternative to navitoclax, at least for the cancer research community.

Of the other compounds we might consider, A1331852, A1155463, piperlongumine, and fisetin are ruled out for lacking published animal data on senolytic effects. FOXO4-DRI is ruled out for being injected and for lacking any human data on dosage or side-effects - though in principle, it should be the best of all the drug-like options so far discovered, if the animal data carries over into human tests. ABT-737 is ruled out for being injected - unlike other BCL-2 family inhibitors it doesn't really interact usefully with mammalian biochemistry if ingested.

Establishing Dosages

The only definitive way to establish a dosage for a pharmaceutical in order to achieve a given effect is to run a lot of tests in humans. Testing in mice can only pin down a likely starting point for experiments to determine a human dose, but the way in which you calculate that starting point is fairly well established for most cases. That established algorithm is essentially the same for most ingested and intravenously (or intraperitoneally in small animals) injected medicines, but doesn't necessarily apply to other injection routes. The relationship between different forms of injection, dosage, and effects is actually a complicated and surprisingly poorly mapped topic, and we'll set that to one side here. Some compounds - as always - are exceptions to the rule, and the only way that scientists discover that any specific compound is an exception is through testing at various doses in various species.

Given that, the discussion here should be taken to apply only to orally administered drugs, as that is the deliberately restricted scope of this post. Further, when considering pharmaceutical dosage, it is important to emphasise that more is not better; this cannot be approached in the way people tend to naively approach the (over)use of dietary supplements. The primary goal, if self-experimenting, is to take as little as necessary of any chemotherapeutic, senolytic compound, as they are all toxic in any meaningful dose. I enourage a careful reading of the papers in which the side-effects in patients at chemotherapeutic doses and treatment durations are described, as well as the studies showing aggressive chemotherapy to produce a higher, rather than lower load of senescent cells. That the dose makes the poison is an ancient adage, but no less true today.

The steps to figure out a suitable starting point for a human test of an orally administered senolytic pharmaceutical are as follows: firstly read the mouse studies for the senolytic compound in question, in order to find out how much was given to the mice and for how long. Doses for most ingested pharmaceuticals of interest will usually be expressed in mg/kg. Secondly apply a standard multiplier to scale this up to human doses, which you can find in the open access paper "A simple practice guide for dose conversion between animals and human". Do not just multiply by the weight of the human in kilograms - that is not how this works. The relative surface area of the two species is the more relevant scaling parameter. Read the paper and its references in order to understand why this is the case. Again, note that the result is only a ballpark guess at a starting point in size of dose. The duration of treatment translates fairly directly, however. For the period of treatment, start with the same number of doses, spacing of doses, and duration as takes place in senolytic studies in mice.

If there isn't enough data to do more than guess at a dose, then that is a good indication to write off that particular compound. Wait for more data, or look for different compounds with better existing data.

Dasatinib and Quercetin

In the case of the dastinib and quercetin combination, the mouse study of senolytic effects used a single dose of 5 mg/kg dasatinib plus 50 mg/kg quercetin. For a 60kg human this scales up to a little less than 25mg dasatinib and 250mg quercetin. For comparison, mouse studies of dasatinib as a chemotherapeutic can be found that use 50 mg/kg per day for multiple days to evaluate its ability to kill cancer cells. A very useful study on dose effects and duration for dasatinib in humans used a dose of 100mg in volunteers, and you can find other trials of dasatinib as a cancer treatment at that dose. Quercetin is an established and widely sold supplement, and it would be a real challenge to consume enough of it to cause any ill effects, never mind significant ones, judging by the toxicology data.

Another way of thinking about dosage is to aim at producing the same concentration of the pharmaceutical in blood that was used in cell culture studies, or observed in mouse studies. To do this you will need existing human data on how a dose maps to concentration in blood or tissues. The senolytic mouse study noted above and the useful human study provide sufficient numbers to make an estimate at this. In the cell culture section of the mouse study, 100-200 nM/L (nanoMoles per liter) is the effective concentration - more than that adds no greater benefit. Given the molecular weight of dasatinib, one can convert the observed blood concentration of 104.5 ng/ml (nanograms per milliliter) in the human study for a 100mg dose to get something in the ballpark of 200 nM/L. Why doesn't everyone use the same units? Well, we wouldn't want to make this too easy. The human study also provides results for a 180mg dose if you want to try scaling up or down to estimate the dose needed to hit different concentrations.

So via one method, the single dose for a 60kg human is 25mg dasatinib and 250mg quercetin. Via the other method the single dose is in the vicinity of 75-100mg dasatinib and 750-1000mg quercetin, assuming that we scale up the quercetin to match the dasatinib, and depending on where we are aiming for in the 100-200 nM/L concentration. The second dose is at chemotherapy trial levels, but is a single dose rather than taken daily over weeks or months, so the impact will accordingly be more limited. You can look at the single dose study for a summary of side-effects at this dosage level. Remember that there is no evidence to suggest that dosing with a senolytic treatment like the dasatinib and quercetin combination frequently will achieve any better result than dosing once every few years: the treatment kills the senescent cells it is capable of killing, and until more of those cells are created in significant numbers, then more of the treatment will most likely do nothing helpful. There are apparently senolytic self-experimenters out there taking dasatinib regularly; I think this shows a poor understanding of the situation, and is probably harmful.


Because there are no published senolytic studies using venetoclax, coming to some kind of ballpark human dose for that purpose involves analogy and educated guesswork. The approach is to compare cancer studies of navitoclax and venetoclax, of which there are many, and then scale the venetoclax cancer study dose down in accordance with the difference between the cancer and senolytic study doses of navitoclax. This is far from ideal, but I'm including this discussion here to point out exactly why one should only choose pharmaceuticals with animal and human senolytic data; as soon as any of that data is absent, there is all too much trial and error and guesswork involved. It is far better to wait rather then venture into the complete unknown, given that more data and better alternative senolytics will emerge in the years ahead.

Firstly, the senolytic dosage for navitoclax in mice from the 2015 study is 50 mg/kg daily for two periods of 7 days spaced 14 days apart - one thing you'll notice fairly quickly in all of this data is that BCL-2 family inhibitors compare unfavorably to dasatinib in terms of the amount needed and duration of treatment. That translates to a 60kg human dose of around 250mg.

A good place to start researching comparative dosages for venetoclax and navitoclax is the 2015 summary paper "ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development". From there, and the references, the chemotherapeutic human dose of navitoclax was settling to somewhere in the 200-300 mg per day range for 14 to 21 days before it was discarded in favor of other tools, with the upper end of that dose range producing the aforemention ugly side-effects related to platelet loss. Dosage for human cancer trials of venetoclax is, on the other hand, all over the map: doses range from 200mg to 1200mg daily carried out over a period of a few weeks to a month, with the dose given cycling in sometimes complex ways. To keep things simple, one point of comparison is to look at the trials versus chronic lymphocytic leukemia for navitoclax and for venetoclax, as they are quite similar. For navitoclax the tested doses ranged from 100mg to 300mg - essentially the same as the senolytic dosage. For venetoclax, the tested doses were 200mg to 1200mg. In both cases, these were daily doses taken for a period of a week or more.

So if one were forced to put a pin into the map based on these numbers, the senolytic human dosage of venetoclax would probably be in the 400-600 mg/day range, every day for a week. Note that this is firmly in chemotherapy with side-effects territory, and there is no direct supporting evidence for effectiveness in mammals whatsoever. All said and done, the rough back of the envelope estimation comes to a result that looks very unattractive, given that we expect better options in the future.


Alvespimycin is an HSP90 inhibitor, and this class of pharmaceutical may produce senolytic effects through less direct BCL-2 family inhibition. Certainly the effects and side-effects look broadly similar to those of navitoclax and venetoclax. One thing to note when researching this compound is that it is used in both injected and oral forms, so one has to be careful to work with only the papers that cover the oral delivery mode, at least in the present context. The senolytic study in mice used an oral dose of 10 mg/kg provided 3 times every other day. This scales up to something like 50mg with the same dosage schedule for a 60kg human.

For comparison, looking at a mouse cancer study, the researchers there used dosages in the 5-15 mg/kg, with a variety of daily and intermittent schedules. A human cancer study also used a wide range of doses, and is a good resource if you are interested in reading up on the potential side-effects. Based on their data, the authors recommended either 40mg every other day or 20mg daily for a period of four weeks of every six weeks for the follow on study.

From these numbers, a human senolytic treatment of three 50mg doses on alternate days once again sounds like something that veers into full blown chemotherapy territory, just not to the same degree as venetoclax above. Anyone considering this would have to make their own decision about risk, as there just isn't enough information out there to talk sensibly about risk and side-effects resulting from a much shorter exposure than was carried out in the human cancer studies.

Use Small Test Doses Prior to Any Study

Near all studies of chemotherapeutics start with low doses, a tenth of the expected study dose. Near all studies report a couple of patients who experience enough of a reaction to the chemotherapeutic at those low doses to drop out or require adjustment of the protocol. If risking chemotherapeutics yourself for senolytic purposes, even single doses or doses for a short time only, it is still important to first test a low dose at a tenth of the desired level of so, to help ensure that there is no adverse reaction. As is true for all of the rest of the considerations here, if you try this, it is entirely your own responsibility to identify, understand, and manage the risks involved.

Verify All of the Above

Assume that anything written anywhere other than the primary materials might be incorrect or misleading. Do not take my word for any of the above information; chase down the primary sources, run the numbers, and make the judgement calls yourself. Is it foolish to self-experiment with chemotherapeutics rather than waiting for better information from human trials or some better form of treatment to emerge? Only you can answer that question, and only you are responsible for any consequences resulting from the answer.

Obtaining Senolytic Pharmaceuticals

For individuals without suitable connections, the easiest way to obtain pharmaceuticals is to order them from manufacturers in China or other overseas locations. As noted at the outset of this post, this is illegal - it would be an act of civil disobedience carried out because the laws regarding these matters are unjust, albeit very unevenly enforced. Many people regularly order pharmaceuticals from overseas, with and without prescriptions, for a variety of economic and medical reasons, and all of this is illegal. The usual worst outcome for individual users is intermittent confiscation of goods by customs, though in the US, the FDA is actually responsible for this enforcement rather than the customs authorities. Worse things can and have happened to individuals, however, even though enforcement is usually targeted at bigger fish, those who want to resell sizable amounts of medication on the gray market, or who are trafficking in controlled substances. There is a fair amount written on this topic online, and I encourage reading around the subject.

Open a Business Mailbox

A mailbox capable of receiving signature-required packages from internal shipping concerns such as DHL and Fedex will be needed. Having a business name and address is a good idea. Do not use a residential address.

Use Alibaba to Find Manufacturers

Alibaba is the primary means for non-Chinese-language purchasers to connect to Chinese manufacturers. The company has done a lot of work to incorporate automatic translation, to reduce risk, to garden a competitive bazaar, and to make the reputation of companies visible, but it is by now quite a complicated site to use. It is a culture in and of itself, with its own terms and shorthand. There are a lot of guides to Alibaba out there that certainly help, even if primarily aimed at retailers in search of a manufacturer, but many of the specific details become obsolete quickly. The Alibaba international payment systems in particular are a moving target at all times: this year's names, user interfaces, and restrictions will not be the same as next year's names, user interfaces, and restrictions.

Start by searching Alibaba for suppliers of the senolytic pharmaceuticals of interest. There are scores of resellers and manufacturing biotech companies in China for any even somewhat characterized pharmaceutical or candidate pharmaceutical. Filter the list for small companies, as larger companies will tend to (a) ignore individual purchasers in search of small amounts of a compound, for all the obvious economic reasons, and (b) in any case require proof of all of the necessary importation licenses and paperwork. Shop around for prices - they may vary by an order of magnitude, and it isn't necessarily the case that very low prices indicate a scam of some sort. Some items are genuinely very cheap to obtain via some Chinese sources.

Many manufacturers will state that they require a large (often ridiculously large) minimum order; that can be ignored. Only communicate with gold badge, trade assurance suppliers with several years or more of reputation and a decent response rate. Make sure the companies exist outside Alibaba, though for many entirely reliable Chinese businesses there are often sizable differences between storefronts on Alibaba, real world presence, and the names of owners and bank accounts. Use your best judgement; it will become easier with practice.

Arrange Purchase and Shipping via Alibaba

Given the names of a few suppliers, reach out via the Alibaba messaging system and ask for a quote for a given amount of the senolytic pharmaceutical in question. Buy twice what you'll think you need, as some of it will be used to validate the identity and quality of the compound batch, and buy that much from at least two different suppliers present in widely separated regions. Payment will most likely have to be carried out via a wire transfer, which in Alibaba is called telegraphic transfer (TT). Alibaba offers a series of quite slick internal payment options that can be hooked up to a credit card or bank account, but it is hit and miss whether or not those methods will be permitted for any given transaction. Asking the seller for a pro-forma invoice (PI), then heading to the bank to send a wire, and trusting to their honestly is good enough for low cost transactions. It should work just fine when dealing with companies that have a long-standing gold badge.

To enable shipping with tracking via carriers such as DHL, the preferred method of delivery for Chinese suppliers shipping to the US or Europe, you will need to provide an shipping address, email address, and phone number. Those details will find their way into spam databases if you are dealing with more than a few companies, and will be, of course, sold on by Alibaba itself as well. Expect to see an uptick of spam after dealing with suppliers via Alibaba, so consider using throwaway credentials where possible.

Chinese manufacturers active on Alibaba are familiar with international shipping practices, and smaller companies will, on their own initiative, apply whatever description to packages will most likely get it past customs. Since declared pharmaceuticals may well be taken aside and confiscated, the description will therefore not involve pharmaceuticals. This is as much motivated by dealing with customs at the Chinese end as pushing things past the US authorities; it is again a form of widespread civil disobedience that reflects a popular disdain for petty laws and regulators where they act as impediments to useful activity.

Quercetin is a Supplement, Buy it at the Store

Any specialist vitamin store will sell quercetin, or at worst it can be ordered online from any reputable retailer.

Storage of Senolytics

Dasatinib, venetoclax, and similar compounds are manufactured as fairly resilient powders and then formed into pills where sold as medications. In powder or pill form, put them in airtight containers in a fridge, and they have a shelf-life of a few years; the specific storage recommendations are easy enough to find online. The same is true of quercetin. This is one of the big advantages of most ingested pharmaceuticals versus injected pharmaceuticals; they are comparatively low-maintenance, stable, and long-lasting. That in turn means less logistical planning and effort.

Validating the Purchased Senolytics

A senolytic compound may have been ordered, but that doesn't mean that what turns up at the door is either the right nondescript powder or free from impurities or otherwise of good quality. Even when not ordering from distant, infrequent suppliers, regular testing of batches is good practice in any industry. How to determine whether a compound is what it says it is? Run the compound through a process of liquid chromatography and mass spectrometry, and compare the results against the standard data for a high purity sample of that compound. Or rather pay a small lab company to do that.

Obtain the Necessary Equipment

Since this process will involve weighing, dividing up, and shipping powders in milligram amounts, a few items will be necessary: spatulas or scoops for small amounts of a substance; a reliable jeweler's scale such as the Gemini-20; sealable vials; small ziplock bags; labels; and shipping and packing materials. All of these are easily purchased online. The recommended shipping protocol is to triple wrap: a labelled vial, secured within a ziplock bag and tape, and then enclosed within a padded envelope.

Use Science Exchange to Find Lab Companies

Science Exchange is a fairly robust way to identify providers of specific lab services, request quotes, and make payments. Here again, pick a small lab company to work with after searching for LC-MS (liquid chromatography and mass spectrometry) services. Large companies will want all of the boilerplate registrations and legalities dotted and crossed, and are generally a pain to deal with in most other ways as well. Companies registered with Science Exchange largely don't provide their rates without some discussion, but a little over 100 per sample is a fair price for LC-MS to check the identity and purity of the compound.

Work with the Company to Arrange the Service

The process of request, bid, acceptance, and payment is managed through the Science Exchange website, with questions and answers posted to a discussion board for the task. Certainly ask if you have questions; most providers are happy to answer questions for someone less familiar with the technologies used. Service providers will typically want a description of the compounds to be tested and their standard data sheets, as a matter of best practice and safety. It is good enough to provide the name for established pharmaceuticals, as the data sheets, mass spectrometry profiles, and other detailed information are freely available online from databases such as DrugBank.

Ship the Samples

Measure out 50mg or so from each separate order as a distinct sample, label it carefully, make sure you have a record linking the sample label to the specific supplier, and package it up. More in the sample is better than less, as several attempts might be needed to get a good result out of the machines used, but each attempt really only needs a very tiny amount of the compound. Ship the sample via a carrier service such as DHL, UPS, or FedEx. Some LC-MS service companies may provide shipping instructions or recommendations. These are usually some variety of common sense: add a description and invoice to the package; reference the order ID, sender, and receiver; clearly label sample containers; and package defensively with three layers of packing; and so forth.

Examine the Results

Once the LC-MS process runs, the lab company should provide a short summary regarding whether or not the compound is in fact the correct one and numbers for the estimated purity. Also provided are the mass spectra, which can be compared with the standard spectra for the compound, which can be found at DrugBank or other sources online.

Ingestion Logistics for Powders

To match to the way in which ingested compounds are taken in most studies, in pill form, it is probably best to make up pill capsules rather than just, for example, taking a measure of the powder in water or wrapped in bread. This is fairly easy to manage, given the tools already obtained for measuring out small powder samples. Specialist vitamin stores, and a range of other vendors, sell empty gelatin pill capsules for supplement enthusiasts, and they will do just fine here. Putting powder into capsules is a fiddly business that only becomes more frustrating with age; I'd suggest trying it out with flour if you haven't done this before. It is a lot harder than one might think. Fortunately, there are a variety of simple, inexpensive tools to help with that; references and video guides are easy to find by searching online. At the very least, unless you happen to have three hands, a capsule holding tray is essential, and I'd recommend some form of small powder funnel.

Establishing Tests and Measures

Unfortunately there is no established, proven, useful test that can directly assess senescent cell level in humans or human biopsies. It is possible to use immunohistochemistry to assess cellular senesence in tissue samples, which is a standard approach in animal studies, but no-one appears to have yet validated that in humans, given biopsies taken from a living individual. Since senescent cells are generated temporarily by wounding, it is quite possible that anything that starts with a biopsy will prove to be unhelpful as a before and after comparison measure for senolytic trials - the levels measured may not bear any resemblance to the normal levels absent a wound.

Without a direct measure, we must fall back on indirect assessments of the detrimental effects of senescent cells. The objective here is a set of tests that anyone can run without the need to involve a physician, as that always adds significant time and expense. Since we are really only interested in the identification of large and reliable effects as the result of an intervention, we can plausibly expect a collection of cheaper and easier measures known to correlate with age to be useful. Once that hill has been climbed, then decide whether or not to go further - don't bite off more than is easy to chew for a first outing.

From an earlier exploration of likely tests, I picked the following items on the basis of a likely connection to the actions of senescent cells, reasonable cost and effort, and ability to carry out the test without a physician's office being involved. Note that this does rule out, to pick one example, the interesting and relevant examination of kidney and liver function, as it would have to be carried out via the radioactive tracer methods of nuclear medicine to obtain decent results. That leaves the tests below quite focused on (a) the cardiovascular system, particularly measures influenced by vascular stiffness, and (b) inflammatory and other markers in the bloodstream:

  • A standard blood test, with inflammatory markers.
  • Resting heart rate and blood pressure.
  • Heart rate variability.
  • Pulse wave velocity.
  • Biological age assessment via DNA methylation patterns.

The cardiovascular health measures in that list are those that are impacted by changes in the elasticity or functional capacity of blood vessels, such as would be expected to occur to some degree following any rejuvenation therapy that addresses senescent cells, chronic inflammation, or other factors that stiffen blood vessels, such as calcification or cross-linking. Positive change of the average values in most of these metrics are achievable with significant time and effort spent in physical training, so movement in the numbers in a short period of time as the result of a treatment should be an interesting data point.


There exist online services such as WellnessFX where one can order up a blood test and then head off the next day to have it carried out by one of the widely available clinical service companies. Of the set of test packages offered by WellnessFX, the Baseline is probably all that is needed for present purposes. But shop around; this isn't the only provider.

Resting Heart Rate and Blood Pressure

A simple but reliable tool such as the Omron 10 is all you need to measure heart rate and blood pressure. It is worth noting here a couple of general principles for cardiovascular measures. Firstly, the further away from the center of the body that the measurement is taken, the less reliable it is - the more influenced by any number of circumstances, such as position, mood, stress, time of day, and so forth. Fingertip devices are convenient, but nowhere near as useful as something like the Omron 10 that uses pressure on the upper arm. Secondly, all of the above-mentioned line items also influence every cardiovascular measure, so when you are creating a baseline or measuring changes against that baseline, carry out each measure in the same position, at the same time of day, and make multiple measurements over a week to gain a more accurate view of the state of your physiology. The Omron 10 is solid: it just works, and seems quite reliable.

Heart Rate Variability

Surprisingly few of the numerous consumer tools for measuring heart rate variability actually deliver the underlying values used in research papers rather than some form of aggregate rating derived by the vendor; the former is required for any serious testing, and the latter is useless. Caveat emptor, and read the reviews carefully. As an alternative to consumer products, some of the regulated medical devices are quite easy to manage, but good luck in navigating the system to obtain one. The easiest way is to buy second hand medical devices via one of the major marketplaces open to resellers, but that requires a fair-sized investment in time and effort - which comes back to the rule about keeping things simple at the outset.

After some reading around the subject, I settled on the combination of the Polar H10 device coupled with the SelfLoops HRV Android application. I also gave the EliteHRV application a try. Despite the many recommendations for Polar equipment, I could not convince either setup to produce sensible numbers for heart rate variability data: all I obtained during increasingly careful and controlled testing was a very noisy set of clearly unrealistic results, nowhere near the values reported in papers on the subject. However, plenty of people in the quantified self community claim that these systems work reasonably well, so perhaps others will have better luck than I. Take my experience as a caution, and compare data against that reported in the literature before investing a lot of time in measurement.

Pulse Wave Velocity

For pulse wave velocity, choice in consumer tools is considerably more limited than the sitation for pulse wave velocity. Again, carefully note whether or not a device and matching application will deliver the actual underlying data used in research papers rather than a made-up vendor aggregate rating. I was reduced to trying a fingertip device, the iHeart, picked as being more reliable and easier to use than the line of scales that measure pulse wave velocity. Numerous sources suggest that decently reliable pulse wave velocity data from non-invasive devices is only going to be obtained by measures at the aorta and other core locations, or when using more complicated regulated medical devices that use cuffs and sensors at several places on the body.

Still, less reliable data can be smoothed out to some degree by taking the average of measures over time, and being consistent about position, finger used for a fingertip device, time of day, and so forth when the measurement is taken. It is fairly easy to demonstrate the degree to which these items can vary the output - just use the fingertip device on different fingers in succession and observe the result. All of this is a trade-off. A good approach is to take two measures at one time, using the same finger of left and right hand, as a way to demonstrate consistency. While testing an iHeart device in this way, I did indeed manage to obtain consistent and sensible data, though there is enough day to day variation to require multiple measurements over time to build up a complete picture. Certainly it was much better than the situation for heart rate variability.

DNA Methylation

DNA methylation tests can be ordered from either Osiris Green or Epimorphy / Zymo Research - note that it takes a fair few weeks for delivery in the latter case. From talking to people at the two companis, the normal level of variability for repeat tests from the same sample is something like 1.7 years for the Zymo Research test and 4.8 years for the Osiris Green tests. The level of day to day or intraday variation between different samples from the same individual remains more of a question mark at this point in time. This means that using these tests as a single measure before and after for most interventions will most likely reveal nothing - it can't detect small changes, and any observed change will likely simply be random noise. To gain a better ability to see smaller changes, you would need to take a fair number of daily tests both before and after the study, say five for Zymo Research and twenty or more for Osiris Green, and for most of us that is simply not cost-effective. If taking this approach, as is the case for the cardiovascular measures, it is wise to try to make everything as similar as possible when taking an epigenetic age test before and after a treatment: time of day, recency of eating or exercise, recent diet, and so forth.

An Example Set of Daily Measures

An example of one approach to the daily cardiovascular measures is as follows, adding extra measures as a way to demonstrate the level of consistency in the tools:

  • Put on the Polar H10; this is involved enough to increase heart rate a little for a short period of time, so get it out of the way first.
  • Sit down in a comfortable position and relax for a few minutes.
  • Measure blood pressure and pulse on the left arm using the Omron 10.
  • Measure blood pressure and pulse on the right arm using the Omron 10.
  • Measure pulse wave velocity on the left index fingertip over a 30 second period using the iHeart system.
  • Measure pulse wave velocity on the right index fingertip over a 30 second period using the iHeart system.
  • Measure heart rate variability for a ten minute period using the Polar 10 and Selfloops.

Consistency is Very Important

Over the course of an experiment, from first measurement to last measurement, it is important to maintain a consistent weight, diet, and level of exercise. Sizable changes in lifestyle can produce results that may well prevent the detection of any outcome resulting from a first generation senolytic pharamaceutical using the simple tests outlined here. Further, when taking any measurement, be consistent in time of day, distance in time from last exercise or meal, and position of the body. Experimentation with measurement devices will quickly demonstrate just how great an impact these line items can have.

Guesstimated Costs

The costs given here are rounded up for the sake of convenience, and in some cases are blurred median values standing in for the range of observed prices in the wild.

  • Business mailbox, such as from UPS: 250 / year
  • Baseline tests from WellnessFX: 220 / test
  • MyDNAage kits: 310 / kit
  • Osiris Green sample kits: 70 / kit
  • Omron 10 blood pressure monitor: 80
  • Polar H10 heart monitor: 100
  • iHeart monitor: 210
  • American Weigh Gemini-20 microscale: 90
  • Miscellenous equipment: spatulas, labels, vials, pill capsules, etc: 60
  • 2 x 2g orders of dasatinib via Alibaba: 300
  • 2 x 5g orders of venetoclax via Alibaba: 1300
  • 2 x 2g orders of alvespimycin via Alibaba: 400
  • Store-purchased quercetin capsules: 10
  • Shipping and LC-MS analysis of samples: 120 / sample

Schedule for the Self-Experiment

One might expect the process of discovery, reading around the topic, ordering materials, and validating the pharmaceuticals to take a couple of months. Once all of the decisions are made and the materials are in hand, pick a start date. The schedule for the self-experiment is as follows:

  • Day 1-10: Once or twice a day, take measures for blood pressure, pulse wave velocity, and heart rate variability.
  • Day 10: Bloodwork and DNA methylation test.
  • Day 11-15: Test a 1/10 dose of the senolytic compounds used, one by one, and abandon the effort if issues are experienced.
  • Day 16: Start to carry out the program of treatment.
  • Day 31-40: Repeat the blood pressure, pulse wave velocity, and heart rate variability measures.
  • Day 40: Repeat the bloodwork and DNA methylation test.

The exact timing is not really important, but it is a good idea to allow enough time following the end of the dosage for things to settle down. In animal studies, senolytic effects occurred fairly rapidly, as did the benefits, but allowing a few weeks of time in a human self-experiment still sounds like a good idea. Certainly it costs nothing to take that step.

Where to Publish?

If you run a self-experiment and keep the results to yourself, then you helped only yourself. The true benefit of rational, considered self-experimentation only begins to emerge when many members of community share their data, to an extent that can help to inform formal trials and direction of research and development. There are numerous communities of people whose members self-experiment with various compounds and interventions, with varying degrees of rigor. One can be found at the LongeCity forums, for example, and that is a fair place to post the details and results of a personal trial with senolytics. Equally if you run your own website or blog, why not there?

When publishing, include all of the measured data, the compounds and doses taken, duration of treatment, and age, weight, and gender. Fuzzing age to a less distinct five year range (e.g. late 40s, early 50s) is fine. If you wish to publish anonymously, it should be fairly safe to do so, as none of that data can be traced back to you without access to the bloodwork provider. None of the usual suspects will be interested in going that far. Negative results are just as important as positive results. For example, given the measures proposed in this post it is entirely plausible that positive changes as a result of present senolytic treatments in a basically healthy late 40s or early 50s individual will be too small to identify - they will be within the same range as random noise and measurement error. Data that confirms this expectation is still important and useful for the community, as it will help to steer future, better efforts.

Final Thoughts: Why Not Wait?

Given all of the cautions above, why not wait? Waiting can be a very sensible strategy. The state of senolytic therapies is progressing rapidly. New and less chemotherapeutic senolytics are emerging, such as FOXO4-DRI. At some point in the next few years, reliable direct tests for senescence will arrive on the scene, allowing a much better view of whether or not these treatments are actually achieving the claimed results. That said, it doesn't hurt to plan, and it doesn't hurt to tinker with some of the component parts of a plan. That is how we can determine whether or not it is worthwhile to experiment now versus waiting to experiment later with better tools.

Clonal Expansion of Stochastic Nuclear DNA Damage as a Contributing Cause of Aging

Damage to the nuclear DNA in our cells is constant and ongoing, either due to reactive molecules, or errors during replication of DNA. Near all of this damage is rapidly and successfully repaired by a panoply of highly efficient maintenance processes. Nonetheless, damage slips through to accumulate over a lifetime, particularly in long-lived cell populations. The most obvious consequence of this damage is cancer, resulting when the blueprint driving cellular operations changes in ways that allow unfettered and uncontrolled replication. Other than cancer, however, does this random damage to cells in fact contribute meaningfully to aging, through disarray in normal cellular metabolism? The consensus is that it does, but there are dissenters from that view, as well as evidence to cast doubt on a necessary causal connection between high levels of stochastic DNA damage and age-related disease and mortality.

The authors of the open access paper noted here consider that the more important aspect of stochastic DNA damage is not its occurrence, but the degree to which it is then replicated: that some DNA damage does result in significant replication of cells containing that damage, even in the absence of cancer. This is a somewhat more plausible argument for a connection to tissue dysfunction than is stochastic DNA damage on its own. It would require far fewer persistent mutations in individual cells in order to produce resulting changes in tissue or organ function, and it dovetails fairly well with what is observed in the DNA of old tissues with more modern genetic technologies.

DNA encodes the basic instructions to construct an organism during its development, and its stability is essential to life. However, DNA mutations are also necessary for evolution because they provide the requisite genetic variation for natural selection. Thus, opposing forces act on DNA maintenance: stability to preserve the quality of the genetic information within individuals and instability to warrant intergenerational genetic diversity.

For new genetic information to have its phenotypic effect, the zygote must divide and clonally expand during embryonic development. While the cells that make up the resulting organism may differ in morphology and physiology, their underlying genetic code should be, in principle, identical. However, much like how genetic variation drives selection within organismal populations, genetic variation arising within a single individual enables selection for or against somatic cells. The stochastic nature of mutagenesis, the sparse gene content of the human genome, and the limited degeneracy of the genetic code imply that most mutations have neutral or deleterious consequences. Occasionally, however, mutations provide a selective advantage that leads to the expansion of the mutant cell into a clone. This process can be influenced by the timing of mutations during an organism's lifecycle, their frequency, and their functional consequence to a cell's physiology. The result is genetically distinct populations of cells within an individual, a phenomenon known as somatic mosaicism.

The existence of somatic mosaicism is well documented. However, the occurrence of somatic mosaicism is not limited to development and has been recognized as an aging phenotype for decades. An increase of somatic mutations with age has been reported for a variety of target genes. Similarly, age-associated accumulation of chromosomal alterations has been documented. These early findings appear to be only the tip of an iceberg in terms of somatic mutations in normal tissue. The advent of Next Generation Sequencing (NGS) technologies has led to the striking revelation that older individuals not only accumulate chromosomal alterations but also abundant mutations in cancer driver genes. As error-correction NGS (ecNGS) technologies have improved the limit for mutation detection, the prevalence of cancer-associated mutations in adults now appears close to 100%.

Furthermore, recent single-cell studies point to the possibility that essentially all cells have unshared mutations in their genomes. In view of this extensive genetic diversity, it is perhaps not surprising that mutations that confer a proliferative advantage are readily detected as clonal populations of increasing abundance and size in the elderly. These clonal populations might lead to loss of organismal health through the functional decline of tissue and/or the promotion of disease processes, such as cancer. In this review, we summarize recent research that supports the notion that aberrant clonal expansion (ACE) resulting from cancer-associated mutations are common in noncancerous tissue and accumulate with age. We propose ACE to be a previously underappreciated aging phenotype that is universal in most organisms, affects multiple tissues, and likely helps explain why aging is the biggest risk factor for cancer.

A Role for Alpha-2-Macroglobulin in the Cancer Immunity of Naked Mole-Rats

Naked mole-rats are near immune to cancer, in addition to living far longer and with far less of a functional decline over the course of a lifetime than is the case for other, similarly sized rodent species. Research into this cancer resistance has so far led to evidence for greater efficiency in cancer suppression genes, particularly with regard to being triggered by cell crowding of the sort that takes place in tumors, and higher prevalence of high molecular weight hyaluronan in naked mole-rat tissues. These are unlikely to be the only factors involved.

Here researchers outline a role for alpha-2-macroglobulin (A2M) in cancer suppression; it appears to inhibit tumor growth in multiple mammalian species through a variety of mechanisms that are as yet not all that well characterized. Naked mole-rats are found to have a very high level of A2M in their tissues, which may be an important component of their resilience to cancer. Older humans exhibit lower levels of A2M than their younger counterparts, which may be one of the numerous contributions to age-related vulnerability to cancer. Unfortunately, A2M interacts with a sizable number of other proteins, which will no doubt ensure that confirmation of its mode of action will require significant further time and investment. Even absent that confirmation, however, there is now evidence of significant tumor suppression in mice through delivery of A2M. That seems quite promising.

The naked mole-rat (NMR), a subterranean rodent, tolerates hypoxia, hypercapnia, avoids many physiological characteristics associated with aging and, most importantly, exhibits pronounced resistance to cancer. Transcriptome analysis of NMR liver compared to wild-derived mice revealed very high expression of cell adhesion molecules involved in tumour development as well as the pan-proteinase inhibitor alpha2-macroglobulin (A2M).

Earlier, we have shown that the level of A2M in human blood decreases with age and exposition of tumour cells with activated A2M (A2M*) inhibited many malignancy-associated properties of tumour cells in vitro by inhibition of members of the WNT/ß-catenin pathway. Therefore, we hypothesized that the reduction of A2M in aged humans may facilitate tumour development. A2M is capable of binding to most proteinases and many growth factors, hormones, and cytokines. Binding to its receptor, the low density lipoprotein receptor-related protein 1 (LRP1, also known as CD91), mediates fast clearance of tethered peptides and proteins. A specific role of A2M in cancer cell metabolism and development has not been elaborated in detail yet.

Here we show that A2M* modulates tumour cell adhesion, migration, and growth by inhibition of central signalling pathways such as phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and SMAD. A2M* up-regulates the tumour suppressor PTEN, CD29, and CD44 but does not evoke epithelial-mesenchymal-transition (EMT). Furthermore, A2M* was found to down-regulate microRNA-21 (miR-21), which is a dominant inhibitor of PTEN expression.

Notably, A2M* inhibits growth of tumours in nude mice independent of their origin, and induces tumour necrosis in tumour tissue and tumour slices cultures. Transcriptome analysis displayed fundamental and unexpected insights in regulatory power of this ancient and highly conserved human plasma protein. The unique features of using A2M* as a novel anti-tumorigenic therapeutic in cancer patients prompted us to perform this study: increasing the fraction of activated A2M* in humans might represent a novel approach for cancer prophylaxis and treatment.

Simple Assessments of Resilience as Potential Biomarkers of Aging

The search for low-cost, reliable measures of biological age continues apace in the research community. The more the better. Even if an individual measure is only loosely correlated, or produces fairly fuzzy, variable data, it may be still be possible to build an algorithm that combines many such different measures into a more accurate overall biomarker of aging. Given such a biomarker, the research community could more rapidly explore and assess potential rejuvenation therapies, and progress in the field of longevity science would accelerate as a result.

Physical resilience is the ability of an organism to respond to physical stress, specifically, stress that acutely disrupts normal physiological homeostasis. It is the ability to quickly resolve these unexpected or unusual environmental, medical or clinical challenges that should be relevant to a better understanding of the underlying health status of the animal. By definition, resilience would be expected to decrease with increasing age, while frailty, defined as a decline in tissue function and measured by parameters such as walking speed, gait, and grip strength, increases with increasing age. The loss of resilience occurs earlier in life and so may be a causative factor in the development of frailty. Therefore, assessment of resilience could be a highly informative early paradigm to predict absence of biological dysfunction, i.e. healthy aging, compared to frailty, which only measures late life dysfunction.

Unfortunately, parameters for resilience in the mouse are not well defined, and no single standardized stress test exists. Because aging is a multifactorial process, integrative responses involving multiple tissues, organs, and activities need to be measured to reveal the overall resilience status. Therefore, a panel of stress tests, rather than a single all-encompassing one, might be more informative. An ideal battery should have enough dynamic range in the response to allow characterization of an individual in easily distinguishable groups as being resilient or non-resilient. Each test should also be simple, reliable, and inexpensive so the panel can easily be duplicated by many different groups. As a panel, three stressors, cold, sleep deprivation (SD), and the chemotherapeutic drug cyclophosphamide (CYP), fit these criteria. The mechanisms of response to cold are multifactorial. SD is a risk factor for insulin resistance and diabetes, memory loss, heart disease, and cancer. CYP targets several different systems but most specifically cells of lymphoid and neutrophilic lineage.

These stressors are also relevant to human medicine and aging. For example, humans can develop intolerance to cold environmental temperatures with increased sensitivity to hypothermia with increasing age. SD is a major health concern in developed countries and is associated with increasing age. Normal aging produces sleep disturbances including sleep fragmentation and sleep loss in humans. CYP is a representative chemotherapeutic agent used extensively in patients for a variety of conditions including cancer and rheumatoid arthritis. Short-term side effects are more severe with increasing age, and intermediate and long-term effects are associated with a general accelerated aging-like state.

The resilience stressor panel described in this report represents a multisystem approach for preclinical testing of anti-aging therapeutics that could be utilized at an earlier age and more accurately than frailty assessment in the mouse. The panel is ideal because the individual stressors have a combined dynamic range in the response to allow characterization into easily distinguishable levels of resilience. Each test is simple, reliable, and inexpensive so the panel can easily be duplicated by many different groups. The stressors are also relevant to human medicine and aging. The panel therefore has the potential of being an attractive translational perturbation for resilience testing in mice to measure the effectiveness of interventions that target basic aging processes. These stressor tests, either singly or as a panel, could be adapted to humans in the clinic or in the laboratory on primary cells such as myeloid cells or fibroblasts, to approximate resilience to declining dysfunction associated with increasing age.

Specific Risk Factors can Appear to Decline in Importance in Later Life, as the High-Risk Individuals are Already Dead

As this 40-year longitudinal study illustrates, when measuring the correlation between specific risk factors on specific forms of mortality, their influence can appear to decline in later life. That is to say that mortality rates keep rising with advancing age, but they are less obviously influenced by any one cause for a given cohort of individuals. This effect occurs because the fatal consequences of a particular form of age-related dysfunction will tend to occur earlier in old age for individuals with the highest risk. With each passing year, a given age group is ever more made up of resilient survivors, people who - for whatever reason - do not have an overall mortality risk that is strongly determined by the specific dysfunction examined in the study. If they did, they would be dead already.

The age range over which this effect occurs is different depending on the risk factor in question and how it is linked to forms of harm. The cardiovascular risk factors examined here are more important or less important in a quite different set of ages in later life than, say, the advanced transthyretin amyloidosis that seems to be a majority cause of death for supercentenarians. The end of life is a set of overlapping curves of risk and influence for many different mechanisms, rising and falling out of lockstep due to the continued loss of those individuals most at risk, even as overall mortality rate rises inexorably.

Despite efforts during recent years to identify new risk factors or biomarkers that can predict cardiovascular diseases, no major breakthrough has been made in the clinical setting to beat the traditional risk factors that have been known for decades: blood pressure, diabetes mellitus, low-density lipoprotein (LDL)- and HDL, high-density lipoprotein (HDL)-cholesterol, smoking, and obesity. These traditional risk factors thus appear robust, and a deeper understanding of their usefulness is therefore desirable.

It is likely that the impact of a risk factor would decline by aging, given that there is a survival bias in the elderly: Many of those with high levels of risk factors at midlife would have experienced an event or died before being included in an investigation of risk factors in the elderly. And, indeed, the impact of a risk factor is usually lower than expected from studies in middle-aged samples when elderly populations are investigated. However, using this approach, it is hard to compare the strength of a risk factor in younger versus elderly subjects.

In order to study the impact of aging on the strengths of risk factors in a longitudinal fashion, we have, in the present study, used a sample of men all aged 50 years at a baseline examination in the early 1970s who has, so far, been followed for 4 decades. We tested the interactions between age and the traditional risk factors regarding incident cases of 3 major cardiovascular diseases: myocardial infarction, ischemic stroke, and heart failure, with the hypothesis that the strength of most, but not all, traditional risk factors would decline by aging. The major question to be answered was which of the risk factors that still retained an important impact in the elderly.

The present study showed, as expected, that most risk factors measured at middle age lost in power during the aging process regarding associations with incident cardiovascular disease. However, some exceptions from this general rule were noted: LDL-cholesterol was significantly related to incident myocardial infarction, whereas body mass index and fasting glucose were related to incident heart failure also in the elderly. The main reason for the general decline in the power of the risk factors over time is likely to be attributed to the fact that individuals with the highest values of the risk factors at midlife will experience an event at an early age, and therefore mainly low-risk individuals will remain at risk as the cohort becomes older. Thus, every cohort will consist of "survivors" when the follow-up increases, and in this group of survivors the impact of risk factors will be diminished.

Those Who Reject Rejuvenation Research and Longer Lives Do Little More than Repeat Old, Worn Objections

As Aubrey de Grey notes in this policy-focused interview, advocates for the significant extension of healthy human life spans through rejuvenation research after the SENS model are not exactly faced with high-quality opposition. Much of the time, we might as well be talking to a recording, one that continually repeats the same tired, well-refuted objections. The opposition doesn't engage with any of our arguments, its members just say the same things over and again. In some ways that makes this easy. In others ways that makes this hard: a very large number of people are out there repeating variants on the few broken record objections to living longer in youthful health and vigor. That crowd seems to soak up any amount of rational argument in favor of an end to aging with little apparent change in the short term. Nonetheless, our community of researchers, advocates, and investors has clearly made considerable progress over the past twenty years. Attitudes are changing, alongside progress towards the clinic for the first rejuvenation therapies. It is still a battle at every step of the way, but one that we are slowly winning.

Erich: I'll ask you a question here,s inspired by a piece authored by political scientists Francis Fukuyama, a member of George W. Bush's Council on Bioethics between 2001 and 2004. He's getting at this idea that in his mind and maybe in the minds of some other people, if life extension technologies are limited: A. Who gets them? B. Is it possible that, in a world where some people have access to these technologies and others do not, there might become a two-tier hierarchy between the haves and have nots?

Aubrey: Yeah this is one of the standard objections or concerns that are raised about these things, and they've been raised since the dawn of time. I've been answering them since the dawn of time. To be honest, I'm getting frustrated that people - and I'm not talking about people like you, I know you have to ask these questions - but that people like Fukuyama continue to insist on repeating these concerns despite the fact that they have never actually provided any kind of rebuttal to the rebuttals that I provide.

They never say, "Oh no, this answer to my concern is actually not going to work." They just repeat the concern, which of course is intellectually dishonest. The actual answer is very simple. There is no chance whatsoever that we will actually have this divide. The reason there is no chance is because in contrast to medicine that we have today, high-tech medicine for the elderly, that costs a lot and really is limited by ability to pay - in contrast to that medicine, the medicine we're talking about will actually work. In other words, it will genuinely keep people truly youthful and able-bodied for as long as they live, and that will be a lot longer.

And that means that those medicines, unlike today's medicines, will pay for themselves. This is because they will allow the people who get the medicines to continue to contribute wealth to society. Now that, of course, is over and above all the other savings we will have. For example, kids will be more productive since they will no longer have to look after their sick parents, and so on. But the fact is that any way you do the arithmetic, even if you make pessimistic presumptions as to what the therapies will actually cost to deliver, and of course, those numbers will inevitably come down over time anyway, it is still perfectly clear that it will be economically suicidal for any country not to make these therapies available to everybody who is old enough to need them.

Erich: For our last question, what are some of the general shifts you'd like to see politically in order to make the national climate more receptive to technologies such as the ones you're pioneering?

Aubrey: I honestly don't think that that's quite the right question. I don't think that we need changes to government and so on with regard to new technologies. I think what we need is a little bit of long-term anticipation because the fact is that we're going to get these technologies one way or another. It's just a question of how soon. But the second question is how ready we will be to implement them and to disseminate them and generally to introduce them in a smooth manner. We all know that the industrial revolution was a bit turbulent, and that was kind of like it was bound to be that way. We suddenly had these new machines, and we suddenly had a lot of people without jobs. Nobody really saw it coming; they couldn't have seen it coming.

But this we can see coming because we've got all this work going on at the laboratory, and it's publicized, a lot. That means, that there will come a point when we get these therapies, and people will have seen them coming. In particular, it means that it will come at a point much sooner, maybe even five years from now, as little as that. Then, results in the laboratory, just on life, are sufficiently impressive that the general public begins to believe that, yes, this whole "rejuvenation thing," this whole "longevity escape velocity" thing really is probably going to happen soon.

Now, at that point, it doesn't really matter who's right and who's wrong and who's optimistic and who's pessimistic. What matters is: it's going to be complete pandemonium. Everyone's going to change how they make their life choices, how they spend their money and so on because of the change that will have occurred in how long they expect to live. And it's governments that have been putting their heads in the sand right up until that point, not listening to people like me who are telling them it's coming. It's going to be much more chaotic and turbulent than it will be if governments starting today start to pay attention to the wave that is coming and to how it's going to roll out.

Functional Muscle Tissue Grown from Induced Pluripotent Stem Cells

Progress in tissue engineering consists of many small technology demonstrations similar to the one noted here. Researchers establish that a specific source of cells can be used with a specific recipe for culture and growth in order to generate organoids of a specific tissue type. Given success there as a starting point, further progress becomes possible towards a better quality of structured tissue, and all of the other line items needed on the way to the mass production of patient-matched tissues for use in clinical medicine.

Biomedical engineers have grown the first functioning human skeletal muscle from induced pluripotent stem cells. The advance builds on work published in 2015 when researchers grew the first functioning human muscle tissue from cells obtained from muscle biopsies. The ability to start from cellular scratch using non-muscle tissue will allow scientists to grow far more muscle cells, provide an easier path to genome editing and cellular therapies, and develop individually tailored models of rare muscle diseases for drug discovery and basic biology studies.

"Starting with pluripotent stem cells that are not muscle cells, but can become all existing cells in our body, allows us to grow an unlimited number of myogenic progenitor cells. These progenitor cells resemble adult muscle stem cells called 'satellite cells' that can theoretically grow an entire muscle starting from a single cell." Induced pluripotent stem cells are cells taken from adult non-muscle tissues, such as skin or blood, and reprogrammed to revert to a primordial state. The pluripotent stem cells are then grown while being flooded with a molecule called Pax7 - which signals the cells to start becoming muscle. As the cells proliferated they became very similar to - but not quite as robust as - adult muscle stem cells. While previous studies had accomplished this feat, nobody has been able to then grow these intermediate cells into functioning skeletal muscle.

"It's taken years of trial and error, making educated guesses and taking baby steps to finally produce functioning human muscle from pluripotent stem cells. What made the difference are our unique cell culture conditions and 3-D matrix, which allowed cells to grow and develop much faster and longer than the 2-D culture approaches that are more typically used." Once the cells were well on their way to becoming muscle, the researchers stopped providing the Pax7 signaling molecule and started giving the cells the support and nourishment they needed to fully mature. After two to four weeks of 3-D culture, the resulting muscle cells form muscle fibers that contract and react to external stimuli such as electrical pulses and biochemical signals mimicking neuronal inputs just like native muscle tissue.

The researchers also implanted the newly grown muscle fibers into adult mice and showed that they survive and function for at least three weeks while progressively integrating into the native tissue through vascularization. The resulting muscle, however, is not as strong as native muscle tissue, and also falls short of the muscle grown in the previous study that started from muscle biopsies. Despite this caveat, the researchers say this muscle still holds potential. The pluripotent stem cell-derived muscle fibers develop reservoirs of "satellite-like cells" that are necessary for normal adult muscles to repair damage, while the muscle from the 2015 study had much fewer of these cells. The stem cell method is also capable of growing many more cells from a smaller starting batch than the earlier biopsy method.

Stem Cells Enhanced with Platelet-Derived Coatings are More Effective at Cardiac Tissue Repair

The broad and well-funded field of regenerative medicine is giving rise many new and varied areas of development, one of which is the engineering of stem cells to make them perform more effectively following transplantation. This includes a range of additions that do not occur in nature. For example, in past years, researchers have enhanced stem cells with add-ons such as timed release packages of supportive molecules to steer their behavior and sustain their activities for longer in the patient. In the research presented here, scientists instead coat stem cells with particles based on the exterior of platelets, causing the cells to adhere to tissues in areas of damage, where they can do the most good via signaling and other mechanisms. In effect, it is a way to improve the localization of delivery and activity of stem cells, even when lacking information on the exact location of damage in the patient. As might be expected, that turns out to improve the end result in terms of regeneration and restoration of tissue function.

Although cardiac stem cell therapy is a promising treatment for heart attack patients, directing the cells to the site of an injury - and getting them to stay there - remains challenging. In a new pilot study using an animal model, researchers show that "decorating" cardiac stem cells with platelet nanovesicles can increase the stem cells' ability to find and remain at the site of heart attack injury and enhance their effectiveness in treatment. "Platelets can home in on an injury site and stay there, and even in some cases recruit a body's own naturally occurring stem cells to the site, but they are a double-edged sword. That's because once the platelets arrive at the site of injury, they trigger the coagulation processes that cause clotting. In a heart-attack injury, blood clots are the last thing that you want."

The researchers wondered if it would be possible to co-opt a platelet's ability to locate and stick to an injury site without inducing clotting. They found that adhesion molecules (a group of glycoproteins) located on the platelet's surface were responsible for its ability to find and bind to an injury. So the team created platelet nanovesicles from these molecules, and then decorated the surface of cardiac stem cells with the nanovesicles, "The nanovesicle is like the platelet's coat. There isn't any internal cellular machinery that could activate clotting. When you place the nanovesicle on the stem cell, it's like giving the stem cell a tiny GPS that helps it locate the injury so it can do its repair work without any of the side effects associated with live platelets."

In a proof-of-concept study involving a rat model of myocardial infarction, twice as many platelet nanovesicle (PNV) decorated cardiac stem cells (CSCs) were retained in the heart than non-decorated cardiac stem cells. The rodents were monitored for four weeks. Overall, the rats in the PNV-CSC group showed nearly 20 percent or higher cardiac function than the control CSC group. A small pilot study in a pig model also demonstrated higher rates of stem cell retention with PNV-CSCs, though the team did not perform functional studies. A future follow-up study is planned.

Bioethicists Consider the Search for a Treatment for Aging

This press release from a UK bioethics organization announces a recently published and comparatively innocuous short PDF primer for policy makers on the present state of research into the treatment of aging as a medical condition. Innocuous or not, it still contains a fair dose of utter nonsense mixed in with its view of the field, as is fairly standard for this sort of thing. Professional bioethics, it has to be said, has done little to make itself useful in the past generation in my view, and in fact has used regulation to slow progress in those areas where bioethicists have attracted the most attention. It is a corruption of the older, actually useful field of medical ethics, which had the merits of being simple, valuable, and requiring little upkeep. Bioethics, on the other hand, has become a cancerous political institution, ever growing, and its practitioners ever incentivized to justify their budgets by making up obstacles where none actually exist.

Geroscience, also called biogerontology, is a field of research that is exploring the biological processes that underlie ageing. Researchers working in this field believe that intervening in these processes could be a more efficient way of increasing health span - the number of years we are healthy - than tackling each condition individually. Recent advances in the tools of research are likely to accelerate our understanding of ageing processes in the near future.

Compressing the period of poor health experienced by many in old age could have a transformative effect on the lives of older people and is widely considered to be the primary goal of geroscience research. Biomedical interventions, along with environmental, social and lifestyle modifications, have already contributed to the extension of human lifespan. Depending on other factors that could affect lifespan, ageing interventions could lead to a further delaying of death. Some suggest that a realistic target of geroscience research is to delay all ageing-related disorders by about seven years. Other commentators believe that scientific advances will lead to much more radical effects on ageing and human lifespan in the near future.

There are differences of opinion about the value and morality of extending lifespan, even moderately. Some philosophers believe that we think of our lives as having a certain shape, which underpins how long we think people should work and how long it is appropriate to be old. Increased longevity therefore might threaten the shape we envisage for our lives and our sense of personal identity. The benefits of experiencing the pleasures of life over a longer time period are used by some to justify life extension; others argue it is quality not quantity of years that matters. Some equate extending life with saving lives, and suggest there is a strong moral imperative to pursue treatment for disease, even if the side effect is an increase in lifespan.

A common concern of lifespan extension is that it would accelerate population growth, and that this would have a range of adverse consequences, particularly for the environment. However, one study suggests that population changes would be surprisingly slow in response to even a dramatic extension of lifespan and would not necessarily lead to overpopulation. It has also been argued that using finite resources in a nonsustainable manner is a problem that needs to be solved independently of how long people live.

Estimations of the impact of increasing health span on the economy are generally positive. For example, one analysis suggests increasing human health span would reduce healthcare spending and lead to significant economic savings. Another suggests that delayed ageing could mean increases in social benefit and public healthcare costs, but that these would be far outweighed by economic gains as a result of a healthier workforce who remain employed for longer and are given more time to save for retirement. These effects would depend on the relative increases in health span and lifespan that could be achieved by ageing interventions, which currently are highly uncertain.

Ageing interventions are likely to be available only through the private sector initially. As with any paid for therapy, it is probable that access to ageing interventions will be unequal, leading to an exacerbation of existing health inequalities according to income, socioeconomic status, and geography. In addition, personal choices about uptake of ageing interventions could have implications for entitlement to state care and health insurance. There are calls for government policies to ensure unequal access to ageing interventions is avoided. Global health inequalities present particular challenges in this context, given that the citizens of some countries still have low life expectancies owing to poor sanitation, nutrition, and healthcare provision. The duties of developed countries to put efforts into addressing these problems, in relation to the efforts put into research on ageing interventions, require consideration.

Some argue that the focus on finding medical treatments for ageing is unhelpful, in that it suggests ageing is a problem that requires fixing and reinforces negative views of ageing. There are parallels with how the medical community view frailty. Frailty is commonly regarded as a state of overall poor health, weakness and vulnerability, but diagnosing people with frailty may serve to marginalise them from society and unfairly label people as being destined to decline. There is also concern that other important elements of successful ageing, such as personal relationships, social position, physical environment and independence, are side-lined by geroscientists.

An important question for geroscience research is whether potential interventions should be tested in younger people, before biological ageing has started, or in older adults already experiencing symptoms of ageing. In the past, involving older adults in research was thought to be difficult and of no benefit to them. This view has broadly changed. The challenges of research have been found to be much the same whatever the age of the participant, and medical interventions in people aged over 80 can have beneficial effects on their health. In addition, 'older adults' are a diverse group and generalisations about people's ability and willingness to take part in research should be avoided.

Y Combinator Shows an Interest in Investing in the Treatment of Aging

The Y Combinator community is one of the more influential parts of the Bay Area, California technology-focused venture industry. Many of the long-term supporters of SENS rejuvenation research can be found in that part of the world and in related professions - it isn't a coincidence that the SENS Research Foundation is based in the Bay Area. There is a big difference between quiet private support and loud public support for a cause, however. It is thus interesting to see that the Y Combinator principals are now, better late than never, putting their best foot forward to declare interest in the development of therapies to extend human health span and life span.

When established mainstream entities start to throw their support into the ring, it is a sign that the tipping point has arrived and passed. The underlying psychology is that the people involved now see little in the way of any threat to their reputations in supporting efforts to treat aging as a medical condition, which tends to be a self-fulfilling prophecy when the majority goes along with it. No-one ever wants to be the first to commit, of course. Now it seems that the long years of bootstrapping the foundations for a rejuvenation research community in the face of a hostile research community and an uncaring public are just about over. This is all to the good, and everyone who helped to support the SENS community since the turn of the century should be feeling justifiably pleased with the way things have gone over the past few years. Y Combinator now joins the Longevity Fund, Kizoo Technology Ventures, Methuselah Fund, Apollo Ventures, Jim Mellon's Juvenescence venture, and others in a focus on turning back the impact of aging on human health and life span.

I'm excited to announce a new experiment we're going to try: YC Bio. YC Bio is a new way for us to fund early-stage life science companies that are still in the lab phase. Because biology is such a large field, we're going to try concentrating on one sub-area at a time (we've found the companies working in similar areas get a lot of value from being around each other). The first area we're going to focus on is healthspan and age-related disease - we think there's an enormous opportunity to help people live healthier for longer, and that it could be one of the best ways to address our healthcare crisis.

We've been funding bio companies for a little while now, and we've learned a bit about what works and doesn't. We will try to design the program in light of what we've learned, and almost certainly we'll make a lot of changes as we go along. This will be a special track - the companies will go through the regular YC batch, but there will be a few differences. Instead of the standard deal for YC companies (which is 120,000 invested for 7% ownership) we'll offer these companies any amount between 500k and 1 million for 10-20% ownership, scaling linearly.

We'll also offer the companies free lab space (we're still looking for one lab space partner, and we'd love for interested partners to get in touch). In addition, we'll have a number of other special deals for YC bio companies, and access to a wide range of experts. There will be a specific Request for Startup in our application system for companies to indicate they're interested in this system. Other bio companies are of course welcome to apply for the standard YC program.

An Approach to Starving Cancer Cells that is Applicable to Many Cancers

Cancer research will proceed by leaps and bounds just as soon as a larger fraction of the research community aims at the production of therapies that are applicable to all cancers, or at least large categories of cancers. One of the reasons why progress has been slow in the past is that all too many groups work hard to produce therapies that are very narrowly specific to a single type of cancer. There are only so many researchers in the world, only so much funding for cancer research, and a very large number of types of cancer.

So when we watch the work of the cancer research community, we should be looking for research of the sort noted here, something that might be applicable to all cancers or a large majority of cancers, and for preference targets a fundamental mechanism that even rapidly evolving cancerous cells would struggle to bypass. As an added bonus, the strategy outlined here could in principle be applied generally to a patient, not needing to be targeted specifically to cancer cells, as it doesn't seem to have much of an effect on normal cells.

The circadian cycle, the intrinsic clock that exists in all living things, is known to help control when individual cells produce and use nutrients, among many other functions. Scientists previously discovered that proteins known as REV-ERBα and REV-ERBβ are responsible for turning on and off cells' ability to synthesize fats, as well as their ability to recycle materials - a process called autophagy - throughout the day. In healthy cells, fat synthesis and autophagy are allowed to occur for about 12 hours a day when REV-ERB protein levels remain low. The rest of the time, higher levels of the REV-ERB proteins block the processes so that the cells are not flooded with excessive fat synthesis and recycled nutrients. In the past, researchers developed compounds to activate REV-ERBs in the hopes of stopping fat synthesis to treat certain metabolic diseases.

Researchers wondered whether activating REV-ERBs would slow cancer growth, since cancer cells heavily rely on the products of both fat synthesis and autophagy to grow. "Given the importance of the circadian clock in the regulation of many cellular and physiological processes we hypothesize that targeting the circadian clock with drugs may open the way to novel anticancer strategies. This study is very exciting because it sheds light on a new uncharacterized way to treat cancer with very limited toxicity."

Although cancer cells contain REV-ERB proteins, somehow they remain inactive. The researchers used two REV-ERB activators that had already been developed - SR9009 and SR9011 - in studies on a variety of cancer cells, including those from T cell leukemia, breast cancer, colorectal cancer, melanoma, and glioblastoma. In each cell line, treatment with the REV-ERB activators was enough to kill the cells. The same treatment on healthy cells had no effect. "When we block access to these resources, cancer cells starve to death but normal cells are already used to this constraint so they're not affected." The researchers then went on to test the drugs on a new mouse model of glioblastoma. Once again, the REV-ERB activators were successful at killing cancer cells and stopping tumor growth but seemed not to affect the rest of the mice's cells.


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