Quercetin is Probably Not a Useful Senolytic

Senolytic compounds are those that preferentially destroy senescent cells. Since these cells are one of the root causes of aging, there is considerable interest in finding and then quantifying the effectiveness of senolytic compounds. The known and alleged senolytics vary widely in effectiveness and quality of evidence, and quercetin is one of the more dubious examples. I don't think that anyone expects quercetin, on its own, to have a useful level of impact on senescent cells and their contribution to degenerative aging. The study here comes to the plausible conclusion that quercetin really can't achieve that goal. Yes, it is true that the 2015 mouse study of the chemotherapeutic dasatinib and quercetin demonstrated that the two together cleared more senescent cells than dasatinib alone, but synergy with other compounds is a very different story from unilateral effects. Quercetin is a widely used and extensively tested supplement compound. Any significant effect on health resulting from quercetin alone would likely have been discovered many years ago.

Previously, quercetin was reported to be a senolytic in irradiation-induced senescent human umbilical vein endothelial cells (HUVECs). HUVECs are derived from the umbilical cord of newborn babies, and for a long time were the only model of primary human endothelial cells (EC); however, these cells are not the best model of diseases associated with human arterial aging. HUVECs have been shown to differ substantially from primary endothelial cells derived from adult human vasculature. In the current study, we investigated whether quercetin is a senolytic in adult EC, and evaluated whether quercetin 3-D-galactoside (Q3G; hyperoside) would be a more selective senolytic.

Quercetin's low therapeutic/toxic ratio in the HUVEC study raised the possibility that quercetin could significantly injure non-senescent cells. It was unclear whether the proliferation of non-senescent cells could be compensating for some of the quercetin-mediated cell death, thus masking its toxicity to the young cells at the lower concentrations found to be selectively cytotoxic to senescent cells. We used adult human coronary artery endothelial cells (HCAEC), which are microvascular cells, as a relevant model, and generated two groups of cells from them to better understand the effect of quercetin: EP (early passage; young) and SEN (senescent), as a model of an aging tissue.

Our key findings are that quercetin at a concentration that reduced SEN EC also caused significant EP EC cell death, and that there was no evidence of senescent cell-specific cell death mediated by quercetin. Thus, quercetin is not a selective senolytic in adult human arterial endothelial cells, where both EP and SEN cells responded similarly to quercetin's toxicity.

To circumvent quercetin's toxicity on healthy, non-senescent cells, we investigated Q3G, a derivative of quercetin with limited toxicity to endothelial cells, which is processed by senescence-associated beta-galactosidase (SABG) enriched in senescent cells to release quercetin in situ. Q3G could act as a selective prodrug in senescent cells. However, Q3G had no significant toxicity to either EP or SEN EC. The lack of Q3G's toxicity in the current study may be due to Q3G being unable to enter the beta-galactosidase-rich lysosomes, or alternatively, Q3G being able to translocate to the lysosomes to release quercetin, which is further processed into an inert compound.

Link: https://doi.org/10.1371/journal.pone.0190374

An Attempt at Using Protein Levels Rather than Epigenetic Patterns to Build a Biomarker of Aging

The current best candidates for a sufficiently robust biomarker of aging are based on patterns of DNA methylation, epigenetic markers that control the pace at which specific proteins are produced, and which are constantly shifting in response to circumstances. The best of these epigenetic clocks have degrees of error in assessed age that are five years or less, depending on implementation. The researchers here have chosen to investigate patterns of protein levels in blood rather than epigenetic markers, in part driven by economic considerations, as the needed tools of biotechnology are more mature and less expensive. They use modern computational techniques to try to build useful biomarker algorithms through an analysis of raw data obtained from large numbers of people at various ages. Their efforts result in a degree of error of around six years, which might be taken as encouraging; it may well be possible to do better via this method.

To perform this study, we trained a series of deep neural networks on anonymized blood tests for patients from three distinct ethnic populations: Korean, Canadian, and Eastern European. We compared the predictive accuracy of our deep learning models first when trained using population-specific data, and then when using a combined and ethnically-diverse dataset that includes patients from all three patient populations. We used the same feature space of 20 blood biochemistry markers, cell counts, and sex to train three separate deep networks on three specific ethnic populations.

We present several novel hematological aging clocks. The best-performing predictor achieved a mean absolute error (MAE) of 5.94 years having greater predictive accuracy than the best-performing predictor of our previously-reported aging clock (which achieved an MAE of 6.07 years), despite being trained on a narrower feature space (21 compared to 41 features). These results are in line with the hypothesis that ethnically-diverse aging clocks have the potential to predict chronological age and quantify biological age with greater accuracy than generic aging clocks. Furthermore, they have a greater capacity to account for the confounding effect of ethnic, geographic, behavioral and environmental factors upon the prediction of chronological age and the measurement of biological age.

Albumin, glucose, urea, and hemoglobin were among the most important blood biochemistry parameters for all three population-specific predictors. Albumin is the most prevalent protein in blood and its primary function is the regulation of oncotic pressure, which is critical for transcapillary fluid dynamics, and hypoalbuminemia is often associated with malnutrition, liver disease, injury, chronic inflammation and the aging process. Blood glucose levels, on the contrary, tend to increase with age, and glucose is able to modify proteins via irreversible glycosylation, a feature that is directly associated with the aging process. Levels of serum urea also increase with age, which is associated with age-related decrease in muscle mass. Age-related decreases in hemoglobin is common in the elderly, a condition that increases the risk of cardiovascular disease, cognitive decline and an overall decline in quality of life.

Our hematological clock is consistent with what is already known about the biology and pathophysiology of aging. While the blood parameters are not accurate biomarkers of aging by themselves, when analyzed in combination they can be used to reasonably accurately predict chronological and biological age. Deep learning based hematological aging clocks, even when trained on a limited feature space, demonstrate reasonably high accuracy in predicting chronological age.

Link: https://doi.org/10.1093/gerona/gly005

Heart Muscle Patches as a Vehicle to Improve Cell Engraftment and Survival

Heart muscle patches are thin engineered sections of tissue, lacking blood vessels because construction of microvasculature is still an unsolved challenge, and small because without blood vessels there is a size limit on engineered tissue. The study here suggests that we should be thinking of a present-day heart muscle patch, and most of its structure and cells, as a disposable vehicle to deliver only a fraction of its cells, keeping them alive long enough to engraft alongside native cells. The rest of the cells in the patch last only long enough to temporarily change the balance of signaling in an aged or injured heart. That signaling ensures that native cells alter their behavior, and it may be those cells, rather than the surviving new arrivals, that perform most of the work needed to produce some form of regeneration or lasting benefit.

It is the case that most types of modern stem cell therapy work via the beneficial signals produced by the transplanted cells in the short time before they die. Comparatively few classes of cell therapy deliver cells that stick around to some degree, engrafting and prospering in the patient, and these are largely the older, more established transplant therapies. Obviously there is a continuum between all of the transplanted cells dying rapidly and most cells engrafting to become productive members of the local population, and the research community is working its way along that line, tissue by tissue. The technology demonstration here is an improvement over past work on heart tissue, but at 10% engraftment there is clearly a way to go yet when it comes to building better approaches. Cells are fragile.

In the near future, the development of regenerative medicine for each tissue type is likely to split into two quite different approaches, a first that gives up on cells and just delivers the signals, assuming progress in the mapping and categorization of those signals, and a second that works towards more reliably replacing worn and malfunctioning native cells with new cells that survive the transfer process in large numbers. The former will most likely happen first, given that numerous research groups have been working on it for some years now, but the latter is far more relevant to human rejuvenation. The research community will need to be able to reliably replace cells of many types in order to achieve the SENS vision of repair of cell loss and atrophy. Simply adjusting the signaling to try to override the age-related reaction to cell and tissue damage is limited in the benefits it can achieve, even while those benefits can look impressive in comparison to past medical capabilities.

Heart-muscle patches created from human cells improve recovery from heart attacks

Large, human cardiac-muscle patches created in the lab have been tested, for the first time, on large animals in a heart attack model. Each patch is 1.57 by 0.79 inches in size and nearly as thick as a dime. Researchers found that transplanting two of these patches onto the infarcted area of a pig heart significantly improved function of the heart's left ventricle, the major pumping chamber. The patches also significantly reduced infarct size, which is the area of dead muscle; heart-muscle wall stress and heart-muscle enlargement; as well as significantly reducing apoptosis, or programmed cell death, in the scar border area around the dead heart muscle. Furthermore, the patches did not induce arrhythmia in the hearts, a serious complication observed in some past biomedical engineering approaches to treat heart attacks.

Each patch is a mixture of three cell types - 4 million cardiomyocytes, or heart-muscle cells; 2 million endothelial cells, which are well-known to help cardiomyocytes survive and function in a micro-environment; and 2 million smooth muscle cells, which line blood vessels. The three cell types were differentiated from cardiac-lineage, human induced pluripotent stem cells, or hiPSCs, rather than using hiPSCs created from skin cells or other cell types. Each patch was grown in a three-dimensional fibrin matrix that was rocked back and forth for a week. The cells begin to beat synchronously after one day.

Past attempts to use hiPSCs to treat animal models of heart attacks - using an injection of cells or cells grown as a very thin film - have shown very low rates of survival, or engraftment, by the hiPSCs. The present study had a relatively high rate of engraftment, 10.9 percent, four weeks after transplantation, and the transplantation led to improved heart recovery. Part of the beneficial effects of the patches may occur through the release of tiny blebs called exosomes from cells in the patches. These exosomes, which carry proteins and RNA from one cell to another, are a common cell-to-cell signaling method that is incompletely understood. In tissue culture experiments, the researchers found that exosomes released from the large heart-muscle patches appeared to protect the survival of heart-muscle cells.

Large Cardiac-Muscle Patches Engineered from Human Induced-Pluripotent Stem-Cell-Derived Cardiac Cells Improve Recovery from Myocardial Infarction in Swine

Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm × 2 cm × 1.25 mm). The hCMP matures in vitro during 7 days of dynamic culture. The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force-generation suggesting a maturation process during the dynamic culture.

In vivo assessments were conducted in a porcine model of myocardial infarction (MI). The engraftment rate was 10.9±1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular (LV) function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the peri-scar border zone myocardium. hCMP transplantation also reversed some MI-associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that improved cardiomyocyte survival. The hCMP treatment is not associated with significant changes in arrhythmogenicity.

ZIPAR Staff Consider the Consequences of Engineering an End to Aging

The folk at ZIPAR, the Zurich Institute of Public Affairs Research, have academic futurist interests somewhat analogous to those of the Future of Humanity Institute (FHI) in the UK, though with more of a short-term horizon and consequent consideration of what some might consider fiddly, unimportant policy details. If the true legacy of the FHI and its network is to give rise to many peer organizations, where an increasing number of people put time into thinking seriously about the future of technological progress and radical enhancement of the human body and mind ... well, there are certainly worse legacies than that. It might be regarded as one facet of the later stages of the quiet, sweeping victory of the past generation of futurist and transhumanist thought, in which it becomes a field of policy academia, at the same time as the first transformative technologies are implemented in order to remove limits on the human condition.

Technology is intertwined with epistemic progress: technology is the practical application of knowledge and skills obtained through rational inquiry, and in turn, technology allows us to further our rational understanding of the world. However, technology is more than just the product of and the means to a more accurate and a more complete understanding of the world. Technology allows us to do things that are beyond the natural limits of our biology. For the most part, we do not think much about this property of technology. When we ride a bicycle, for example, we are using a piece of technology that allows us to go from A to B in a much more efficient way than by going on foot.

Sometimes, however, transcending the limits of human biology via technology does not only raise eyebrows, but widespread concerns. Most people intuitively accept most ways in which technology changes or completely removes biological limits. Some biological limits, however, seem to be off-limits, so to speak. One such limit is the finite natural lifespan of humans: death is a natural part of life, and trying to end natural death might seem outlandish. Our visceral response to the idea of ending death, of course, is little more than status quo bias coupled with a variant of the is-ought-fallacy. Whether something is morally desirable is not determined by whether it is the status quo.

Ending natural biological death has a number of benefits that go beyond the intuitive idea that not existing feels weird. We humans are systematically irrational in many domains, due to our cognitive biases. One such domain is the assessment of risks. One source of our biased risk perception is our natural life cycle. Things that will happen some time in the future matter less to us than things that will happen immediately, simply because there is uncertainty about the future. If we end natural biological death, then we are radically changing our future prospect. We are not trying to imagine a world in which we do not exist anymore, but we are instead thinking about a future world that is some time off, but that we will be part of nonetheless. Such a radical shift in perspective might help alleviate some problems of the present bias.

Our biased time-preferences are not only present in the domain of risk perception, but also in the ostensibly simple domain of planning ahead. Ending natural biological death through rejuvenation could have a positive impact on our long-term planning capabilities. From an individual, micro-level perspective, knowing that the long-term future (in terms of traditional human lifespan) is not some uncertain world that one might not even live to see, but instead a state of the world that will come about in due time, might nudge individuals towards automatically correcting some of their planning biases. After all, if I know that 50 years into the future, I will still be physically the same as I am now, thanks to rejuvenation, then I might think more carefully about the decisions I make today that might affect me in the future.

Humans are capable of remarkable rationality, both in the sense of epistemic as well as instrumental rationality. Unfortunately, all sorts of "afflictions" prevent us from realizing our rational potential to the fullest. There are two ways in which an end to natural death could cumulatively increase individual rationality levels. First, active epistemic engagement by individuals would have a positive effect. Increasing human lifespan (potentially practically indefinitely) would mean that humans would experience changes in the world of the kind that was previously observable only on an intergenerational level. The second way in which the end of natural death might result in cumulatively higher rationality is accidental experience. The longer a person lives, the more probable it is that some strongly held belief will be accidentally challenged. Accidental contact with members of the outgroup can challenge our beliefs and reduce intergroup bias.

Most people fear death, or at least feel uneasy about death. Fear of death is a unique feeling that is, at once, both perfectly understandable and irrational. Ending natural biological death would mean removing death dread, either completely or to a large degree. Fear of death is probably one of the most unpleasant negative feelings because, contrary to almost all other causes of negative feelings, we cannot do anything about death (yet). Death dread is an unnecessary, cruel burden of nature; humankind loses nothing by getting rid of it.

But our lives do not consist only of the search for ways of higher-order progress. In our lives, there are many things that we simply enjoy. Enjoying things means that, every day and mostly without being fully aware of it, we experience some form or another of pleasure. Experiencing pleasure is something we value on an individual level, but it is also a general moral goal. Ending natural biological death could increase the amount of pleasure people experience. One reason why is obvious: The longer a person lives, the more pleasureable experiences can she or he have. But there is also a second reason why doing away with natural death would have a positive impact on pleasure: Technological and social progress. One of the most notable effects of technological and social progress is that it makes human life more pleasurable, in all kinds of ways.

Creating as much pleasure for as many people is a classical utilitarian goal, but pleasure is only one side of the utilitarian medal. The other, and perhaps more important moral aspect of existence is suffering. All things being equal, we should reduce suffering for as many people as much as possible. Ending natural death would reduce would almost certainly have a great positive impact on reducing suffering. Human morbidity is compressed towards later stages in life. Ending natural death through rejuvenation would mean avoiding the stage of compressed morbidity altogether, and with it, avoiding a lot of suffering associated with afflictions that are likely in later life stages. If we assume diagnostic and therapeutic medical treatments to advance in the future, then the overall suffering caused by disease will gradually approach zero. This means that people who live beyond their natural biological age limit will experience less and less disease-induced suffering the longer they live.

In conclusion, death is a natural part of human existence, but human progress is essentially a story of overcoming undesirable natural limits. In the near future, technological progress might make it possible to stop natural biological death. Should humankind embrace such technology? Yes: Even though such technology would not be without risks, the risks are almost certainly manageable. The benefits of ending natural death, on the other hand, are immense. Death is an obstacle that is slowing down human progress. If we remove that obstacle, humankind could increase the speed of both its moral and its epistemic progress.

Link: https://zipar.org/discussion-paper/killing-death/

BMP4-Generating Endothelial Cells Spur Regeneration of the Thymus

The research community is interested in regeneration and tissue engineering of the thymus, as this could in principle resolve one of the causes of age-related decline in immune system function. It is worth keeping an eye on present efforts, such as the one noted here, at an early stage of exploration. The thymus is where cells of the adaptive immune system mature, and is thus one of two important gating factors determining the pace at which new immune cells enter the body, ready for action. The other is the quality and activity of the hematopoietic stem cell population in the bone marrow, where immune cells are created.

The thymus is very active in childhood, but in early adulthood much of the specialized tissue - that hosts immune cells as they mature - atrophies to be replaced by fat. The remaining portion of that tissue fades away more slowly over a lifetime, and the pace at which new immune cells arrive fades with it. A sizable part of the failure of the immune system in later life derives from the ever slower pace at which immune cells are introduced. Malfunctioning, exhausted, and senescent immune cells accumulate. The immune system is eventually overwhelmed by the wear and tear of its duties, its component parts not replaced often enough. Restoring the active portions of the thymus to a youthful size has been shown to help in mice, and the hope is that it will do the same in humans.

The thymus, an organ in the lymphatic system, plays a critical role in immune function, producing the T cells essential to the immune response. The thymus, which gets smaller as we age, is highly sensitive to damage from stress and infection. And while it can recover from such insults - the process is known as endogenous thymic regeneration - more serious injury, for example, from chemotherapy or radiation, can extend recovery time considerably. That can result in an increased susceptibility to infections and even cancer relapse in patients while their T-cell count is low. "We don't really understand why the thymus shrinks as we get older, or how to make it bigger in patients where it would likely be helpful to have T cells be made."

That the thymus can regenerate itself has been known for nearly a century, but the mechanisms that control this process have not been widely studied. So researchers performed a transcriptome analysis of a section of the mouse thymus following damage from total body irradiation (TBI). They found a suite of genes that were significantly upregulated, including several already known to be involved in thymic function, as well as Bmp4. "We're really interested in understanding these processes of endogenous regeneration so that we may exploit them into clinically relevant and innovative strategies to boost thymic function."

The researchers treated mice with a BMP inhibitor starting one day before TBI to determine whether BMP signaling is necessary for endogenous regeneration. The treated mice had significantly worse recovery than controls, indicating BMP's importance in the process. In a related experiment, the researchers then injected endothelial cells into the bloodstreams of mice 72 hours after TBI, and found that doing so increased the number of thymic cells compared to controls. When they injected the cells directly into the thymus, 100-fold fewer endothelial cells were required to result in the same capacity for endogenous regeneration than when they injected them intravenously. This suggests that some endothelial cells from the bloodstream do make it to the thymus, they wrote in their report.

Therapies based on the research would be more likely to use isolated BMP4 than an endothelial cell line. Another future interesting direction would be whether this same pathway could be used in the aging thymus. In this scenario, or in damage associated with chronic conditions, perhaps boosting BMP4 activity would also drive thymic regeneration.

Link: https://www.the-scientist.com/?articles.view/articleNo/51329/title/Researchers-Develop-a-Technique-to-Regenerate-the-Mouse-Thymus/

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.

Contents

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.

Venetoclax

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

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 honesty 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 a 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:

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.

Bloodwork

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.

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.

Link: https://www.salk.edu/news-release/salk-scientists-curb-growth-cancer-cells-blocking-access-key-nutrients/

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.

Link: https://blog.ycombinator.com/yc-bio/

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.

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.

Link: http://nuffieldbioethics.org/news/2018/live-research-treatments-ageing-examined-council-briefing-note

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.

Link: https://news.ncsu.edu/2018/01/decorated-stem-cells/

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.

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.

Link: http://pratt.duke.edu/news/ipsc-muscle

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.

Link: http://merionwest.com/2018/01/08/an-interview-with-anti-agings-pioneer/

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.