Fight Aging! Newsletter, June 12th 2017

Oisin Biotechnologies has been hard at work for a year and a half since the last Fight Aging! interview; what has been accomplished?

Lots. In June and August of last year we demonstrated that naturally-aged, 80-week-old B6 mice, could be safely treated with our therapeutic and have their senescent cells (SCs) reduced significantly in a dose-dependent fashion. For example, a single treatment reduced senescence-associated β-galactosidase (β-gal) staining (a well-accepted marker for senescence) by more than 50% in the kidneys, and restored the tissue appearance to that of about 18-week-old animals. This reduction in SCs was also confirmed by DNA PCR analysis.

We were then challenged by one of our investors (the Methuselah Foundation) to explore the use of our therapeutic in oncology applications. Specifically, they asked us to explore our ability to target tumors with p53, in place of the p16 targeting we use in our anti-aging applications. The work was first done in immunodeficient NSG mice so the mice couldn't reject the human PC3 prostate cancer cells that were implanted in their flanks. Surprisingly, we saw as much as 90% reductions in tumor mass in 24-48 hours of treatment. These results were astonishing and virtually unprecedented.

We subsequently repeated these studies in immunocompetent mice intravenously infused with the aggressive B16 melanoma cell line and showed a reduction in lung tumor metastases of nearly twenty-fold over controls.

Has the Oisin cell killing technology evolved significantly since we last talked, with the new focus on cancer in addition to cellular senescence?

The platform technology is evolving, but the core idea remains the same. We've got a hammer we can wield to kill cells via apoptosis, and it's pretty effective. Exactly which cells we choose to kill will change as we target various age-related diseases. So far, we've gone after p16 and p53 expressing cells.

It might be helpful for readers if I recap our basic technology. The technology uses two elements. First, we design a DNA construct that contains the promoter we wish to target. This promoter controls an inducible suicide gene, also called iCasp9 (no relation to CRISPR's Cas9). Next, we encapsulate that DNA in a specialized type of liposome known as a fusogenic lipid nanoparticle (LNP). The LNP protects the DNA plasmid during transit through the body's vasculature, and enables rapid fusion of the LNP with cell membranes. This LNP vector is consider "promiscuous" as it has no particular preference for senescent cells - it will target almost any cell type. Once it does, the DNA plasmid is deposited into the cytoplasm and traffics to the nucleus. There it remains dormant unless the cell has transcription factors active that will bind to our promoter. If that happens, then the inducible iCasp9 is made. The iCasp9 doesn't activate unless a small molecule dimerizer is injected; the dimerizer causes the iCasp9 protein halves to bind together, immediately triggering apoptosis. This process insures that the target cells and bystander cells are left unharmed. So far, we have not observed any off-target effects.

We've also got some tweaks to both the promoter side and the effector side of the constructs that will provide even more interesting and useful extensions to the basic capability, but I can't discuss those until later this year for IP reasons.

The adaptability of the Oisin technology seems to me a big deal. Beyond cancer, what else can usefully be accomplished in medicine by killing specific cells? Do you see further diversification of the company's efforts ahead?

We've only begun to explore some of the more exotic possibilities. But clearance of immune cells that have become aberrant in some manner is on the list. No doubt many opportunities will emerge as people become more familiar with our technology. As I mentioned earlier, we only have a hammer, but it can be both powerful and yet have exquisite precision when swung properly.

If a company turns up at your door with a compelling use for the Oisin technology and the desire to license it, is that interesting? Is being a hub for many third party cell-killing efforts a viable future vision for Oisin?

Definitely. We've begun such conversations with several parties already and are eager for more.

Have you established any ongoing collaboration with other companies and research groups?

We've been talking to a number of groups, both academic and industrial, and expect to enter into collaborative agreements with several later this year.

I understand you are starting in on a larger fundraising round. How is that going?

We have begun a Series A round and have it partially filled at this time. Negotiations have begun with "the usual suspects" to fill out the subscriptions to the round. Unlike the earlier seed rounds, which were primarily filled by angel investors, it looks like this round will also have family offices, VCs, and pharmaceutical industry partners.

We're all waiting for a successful senolytic therapy to arrive at the clinic. When do you see Oisin's approach being tested in humans? What are the steps yet to be accomplished on that road?

The next step for us is a toxicology study. We will begin our first non-human primate toxicology studies in about six weeks, and expect results by September. This pilot study will be followed by GLP toxicology studies in multiple species, in compliance with regulatory guidance for pre-clinical studies that will allow us to embark on Phase 1 and 2 human trials. We haven't yet picked the indication we'll be targeting in those trials, but very likely it will be prostate cancer. Cancer is a good first indication since it provides an easier path to the clinic than is the case for more subtle aging indications. But once we have completed Phase 1 and 2, we can reuse most of the data to ease the path to the clinic for purely aging-associated indications such as COPD, atherosclerosis, or liver diseases, to name some potential targets.

I've previously mentioned companion animals as another possible route to early commercialization, and we haven't lost interest in that option, but it is frankly easier to treat humans (who don't mind holding still for a few hours while we do an infusion of LNPs) compared with a dog or cat that needs to be lightly anesthetized to be similarly treated.

When it comes to reaching the clinic more rapidly, what are your thoughts on medical tourism and privately run, transparent trials as an alternative to the FDA process for Oisin?

It's a tricky course to navigate. Naturally, we have a fiduciary duty to our shareholders, and a moral duty to our patients, not to do anything that compromises our ability to be approved for a wide range of indications in the US and Europe, among other jurisdictions. But it is also true that the barriers to market here are difficult for a small company to overcome. That's why we are talking to potential pharma partners, for example relating to our oncology indications. But we've also found that certain "western" jurisdictions are a bit easier in which to operate (Canada and Australia come to mind). So we don't have to necessarily "go offshore" - in the piratical sense - to get the first therapies to market. Yet it may be that some regulatory environments will be more conducive to treating aging indications - or indeed aging as the indication - earlier than the U.S. If so, we will work with local authorities in compliance with law to do everything we can to accelerate the approval process.

The field of senolytics has certainly blossomed in the past year; putting the Oisin approach to one side for the moment, do you have opinions on the relative quality of other senolytic technologies and companies?

Oisin believes a healthy senolytic industry will require a number of different approaches to the problem of clearing SCs. We certainly don't want to say on approach is to be preferred over another for all SC targets, at least at this stage of our ignorance. For my part, I like the "information-based" approach we are taking more than small-molecule approaches, due to the unlikeliness of off-target effects. But successful whole body repair and rejuvenation is likely to require several complementary therapies.

What can our community do to help Oisin succeed in this stage of its development?

Public interest in the field of aging therapy must, sooner or later, be translated into public policy action. Letting legislators know that working on repair and regeneration is a "public good" is the first step towards getting the FDA to accept aging as a legitimate indication for treatment.

I'd like to close by saying that SENS technology is too important to be left to a handful of us who have pledged our lives, fortunes and honor to the task. We need more researchers, more companies, and more money. Get out there and do it!

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN, also known as MMAC1 and TEP1) was first discovered in 1997 by two independent groups and recognized as the long sought after tumor suppressor gene frequently lost on human chromosome 10q23. This locus is highly susceptible to mutation in human cancers: the frequency of mutations have been estimated to be 50%-80% in sporadic tumors such as glioblastomas, prostate cancers and endometrial carcinomas; and 30%-50% in lung, colon and breast tumors. PTEN is often associated with advanced cancers and metastases, due to loss of PTEN having been observed at its highest frequency in late stages of cancers. Together with p53, Ink4a and Arf, PTEN makes up the four most important tumor suppressors in mammals as evidenced by their overall high frequency of inactivation across a variety of cancer types. Because of this, it is vital to understand the mechanisms of how PTEN functions.

The main function of PTEN is to antagonize the PI3K/AKT pathway, thereby opposing the pathway's cell proliferative response and, more important to longevity, opposing AKT's downregulation of antioxidant genes and proteins. In concert with this function, PTEN has been reported to bind with another antioxidant gene, p53, and arresting the cell cycle whilst positively regulating protein dealing with DNA-damage. These functions serve not only to extend cellular longevity but also prevent deleterious DNA-damage that can lead to malignant tumors.

The purpose of the report is to serve as a comprehensive review of the links that have been made between PTEN and the potential effects it may have on ageing. It will cover various issues such the regulators of PTEN, the regulatory effects of PTEN, its cellular functions, its associations with cancer and its direct effects on longevity in the effort to understand the many and varied pathways that PTEN is a part of, and how these intricate and integral pathways are key to effecting longevity. While Ponce de León's dream of a fountain of youth may be unobtainable as of yet, this report will show that extended longevity is highly possible. This paper follows in the theme of recent papers which show the strides that anti-ageing research have made over recent years. PTEN has the potential the play a crucial role alongside these other studies as, beyond its documented ability to extend longevity, its function as a tumor repressor is vital to any lasting extended longevity to prevent the rise of tumors often associated with extended longevity.

To sum up a lengthy report: PTEN has significant implications for extending human longevity through its actions on DNA-damage reduction, antioxidant activity, caloric restriction, inhibition of replication and tumor suppression. The importance cannot be overstated as PTEN overexpression can assist a variety of maladies including weight-related diseases such as diabetes to age-related diseases such as Alzheimer's and Parkinson's. Its function as a tumor suppressor can maintain an anguish-free life. It is because of this variety and necessity of function that PTEN is a vital subject for further research. Through studies done on invertebrates and on mammals we have seen that the application of this knowledge is successful, that PTEN's effect on longevity is not merely theoretical but practical. That PTEN can enhance longevity is no longer questionable, but neither is it irrefutable. Before any final concluding statements can be made, human trials with PTEN transfection must first be done. The authors of this study are currently working on cell culture trials, which is only the first step.

PTEN alone cannot extend longevity indefinitely, however, as a past study demonstrated only a 9%-16% increase in longevity, and while this is a significant milestone, this is hardly the fountain of youth that Ponce de León dreamt of. This is not to say that such a dream may not happen, merely that PTEN alone would not accomplish it. Others presented findings that telomerase can reverse tissue damage in aged mice. This rejuvenative quality bodes well as a potential partner for PTEN, and its most important feature, that of telomere extension, could potentially extend longevity as long as needed. PTEN is well suited as a partner for telomerase due to its tumor suppressive quality. This is because of two reasons. Telomerase have been commonly associated with cancer and a tumor suppressor may prevent this. However, more importantly, the longer one lives, the probability of having cancer increases. It is PTEN's tumor suppressive quality that sets it apart from other recent studied genes such as SIRT1.

The variety of genes, proteins and enzymes being studied today show how the interconnectivity of the human system also necessitates a complex solution to longevity. Whether this is achieved through the main pathways of telomerase, SIRT1, PTEN or others remains to be seen. What must be done now is testing, and further testing, until an answer is found. With the importance of such work, it deserves no less. While human trials oblige a lengthy testing time, it is an inevitable obstacle that must be overcome if Pons de León's dream is to be fulfilled.

Heart muscle is one of the least renewable tissues in the body, which is one of the reasons that heart disease is the leading cause of death. Researchers have studied pathways known to be involved in heart cell functions and discovered a previously unknown connection between processes that keep the heart from repairing itself. "We are investigating the question of why the heart muscle doesn't renew. In this study, we focused on two pathways of cardiomyocytes or heart cells: the Hippo pathway, which is involved in stopping renewal of adult cardiomyocytes, and the dystrophin glycoprotein complex (DGC) pathway, essential for cardiomyocyte normal functions."

Previous work had hinted that components of the DGC pathway may somehow interact with members of the Hippo pathway. The researchers genetically engineered mice to lack genes involved in one or both pathways, and then determined the ability of the heart to repair an injury. These studies showed for the first time that dystroglycan 1, a component of the DGC pathway, directly binds to Yap, part of the Hippo pathway, and that this interaction inhibited cardiomyocyte proliferation. "The discovery that the Hippo and the DGC pathways connect in the cardiomyocyte and that together they act as 'brakes,' or stop signals to cell proliferation, opens the possibility that by disrupting this interaction one day it might be possible to help adult cardiomyocytes proliferate and heal injuries caused by a heart attack, for example."

Heart disease remains the leading cause of death worldwide, yet the few available treatments are still mostly unsuccessful once the heart tissue has suffered damage. Mammalian hearts are actually able to regenerate and repair damage - but only up to around the time of birth. Afterward, that ability disappears, seemingly forever. Research at has uncovered a molecule in newborn hearts that appears to control the renewal process. When injected into adult mouse hearts injured by heart attacks, this molecule, called Agrin, seems to "unlock" that renewal process and enable heart muscle repair.

Following a heart attack in humans, the healing process is long and inefficient. Once damaged, muscle cells called cardiomyocytes are replaced by scar tissue, which is incapable of contracting and thus cannot participate in pumping. This, in turn, leads to further stress on the remaining muscle and eventual heart failure. Heart regeneration into adulthood does exist in some of our fellow vertebrates. Fish, for example, can efficiently regenerate damaged hearts. Closer relatives on the evolutionary tree - mice - are born with this ability but lose it after a week of life. That week gives researchers a time window in which to explore the cues that promote heart regeneration.

Researchers believed that part of the secret might lay outside of the heart cells themselves - in the surrounding supportive tissue known as the extracellular matrix, or ECM. Many cell-to-cell messages are passed through this matrix, while others are stored within its fibrous structure. So the team began to experiment with ECM from both newborn and week-old mice, clearing away the cells until only the surrounding material was left, and then observing what happened when bits of the ECM were added to cardiac cells in culture. The researchers found that the younger ECM, in contrast to the older, elicited cardiomyocyte proliferation.

A screening of ECM proteins identified several candidate molecules for regulating this response, among them Agrin. Agrin was already known for its effects on other tissues - particularly in the neuromuscular junction, where it helps regulate the signals passed from nerves to muscles. In mouse hearts, levels of this molecule drop over the first seven days of life, suggesting a possible role in heart regeneration. The researchers then added Agrin to cell cultures and noted that it caused the cells to divide.

Next, the researchers tested Agrin on mouse models of heart injury, asking whether it could reverse the damage. Indeed, they found that following a single injection of Agrin mouse hearts were almost completely healed and fully functional, although the scientists were surprised to find that it took over a month for the treatment to impart its full impact on cardiac function and regeneration. At the end of the recovery period, however, the scar tissue was dramatically reduced, replaced by living heart tissue that restored the heart's pumping function. The researchers speculate that in addition to causing a certain amount of direct cardiomyocyte renewal, Agrin somehow affects the body's inflammatory and immune responses to a heart attack, as well as the pathways involved in suppressing the fibrosis, or scarring, which leads to heart failure. The length of the recovery process, however, is still a mystery, as the Agrin itself disappears from the body within a few days of the injection.

The mission of healthy life extension, or healthy longevity promotion, raises a broad variety of questions and tasks, relating to science and technology, individual and communal ethics, and public policy, especially health and science policy. Despite the wide variety, the related questions may be classified into three groups. The first group of questions concerns the feasibility of the accomplishment of life extension. Is it theoretically and technologically possible? What are our grounds for optimism? What are the means to ensure that the life extension will be healthy life extension?

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

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

Quite surprisingly (at least for the proponents of healthy longevity), for decades and centuries, there has been expressed strong opposition to the very idea of life extension. The opposition has been frequent among philosophers, and even among physicians and researchers of aging. There has been a strong tendency among well-established physicians and scholars to consider aging as inexorable and therefore "normal," and to see the lifespan as fixed and immutable. Accordingly, any attempts to "meddle" with the aging process or to significantly extend longevity would be considered foolish, futile and even somehow unethical.

The apparent weight of authority of the critics and skeptics, and the wide popularity of the skeptical views, may emphasize the question: "Is increasing longevity, especially healthy longevity, really desirable, for the individual or the society?" The answer that may be given by the proponents of life extension is very simple: "Yes. People want to live longer and to live healthier." Or to put it even more bluntly, "it is better to be healthy, wealthy, wise and long-lived, than otherwise." And that may conclude the discussion. Yet, some explanations and arguments are still required. Usually, the arguments against extending longevity are standard and are refutable in standard ways. The questions and answers below may provide a short summary of such debates.

Would extending longevity enhance human suffering, or conversely, is death a solution against suffering? No. Death is not a solution against suffering. Suffering is not inevitable. Human beings have the ability to actively influence their fate and relieve suffering. And essentially, the desire to extend life does not imply a desire to prolong suffering, but a desire to prolong health (increase the healthspan).

Would extending longevity lead to extending boredom? Arguably no, as extended life also implies extended ability to learn and change. The sense of boredom does not necessarily depend on the period, and often comes and goes periodically. And generally, the feeling of boredom does not seem to be a sufficient reason to abandon the pursuit of life. And if it is (for some people) - their choices are in their hands, and should not diminish the choices and chances of others.

Would extending longevity make human life meaningless? Arguably no, as life may carry a meaning of its own, independent of death. It is difficult or even impossible to place a temporal limit on the meaning, love and enjoyment of life. Human beings are entitled to choose a prolonged existence, and that choice and pursuit alone may give their life meaning.

Would not extending longevity stop progress, make individuals and societies stagnant? Rather to the contrary, the potential for learning will be increased by longer life-spans, and such a prolonged "cultural adaptation" may be sufficient and necessary for the survival of the society. Moreover, rationally controlled development and care for the survival of the weak may be more advantageous for progress than blind and cruel Darwinian selection.

Are not aging and death from aging natural and inevitable? Does not their acceptance as natural and inevitable give comfort in facing them? Concerning the inexorable "natural" limit to the human life, however comforting a reconciliation with death may be, it should not replace an active quest for life preservation. Almost never is a particular cause of death completely "inevitable," but is always due to some identifiable material agent, and thus subject to prevention or amelioration. There is no limit "set in stone" to either the lifespan or the healthspan.

Would not the life-extending means be made available only for the rich and powerful, or some other select groups? How can we prevent this injustice? Indeed, perhaps the most frequent type of worry relates to the future availability of resources due to life extension. The common assumption is that 'there will never be enough for everybody'. Yet, in any case, the inequality of access does not seem to be a reason to hinder the emergence of new medical technologies, but only to intensify their development. The sooner they emerge, the faster they will likely become available for the people, hopefully for all.

Would not extending longevity lead to shortage of resources for the society, or "overpopulation"? It has been a persistent fear that extending longevity would lead to a shortage of resources for the global population as a whole due to its unsustainable increase. This scenario is also commonly known as 'the problem of overpopulation due to life extension'. Yet, it must be argued that the term "overpopulation" does not simply relate to the number of people on a certain territory. Rather, it indicates the degree of availability of resources, especially food, for people at that territory. And, based on the available evidence and trends of development, scarcity of resources should not be anticipated as a result of increasing longevity. It was calculated already in the 1960s by the Agricultural Economics Research Institute, Oxford, that the agricultural productivity, even at that time, would be more than sufficient to feed 45 billion people globally. Since that time the agricultural capabilities in the developed countries increased dramatically, way ahead of increases in life expectancy or population. The technological capabilities are here to feed the world.

Would not increasing life quantity mean decreasing life quality? In other words, wouldn't we have "too many old sick people"? It must be emphasized that the improvement in life quantity is commonly (though not always) inseparable from the improvement in life quality. A robust organism (similar to a robust machine) as a rule both operates efficiently and for longer periods of time. Essentially, it is the extension of the human healthspan (healthy and productive lifespan) and not just of the lifespan that is pursued in the research and development of new medical means and technologies.

The main obstacle slowing down progress in the development of anti-aging and life-extending therapies is perhaps the immense scientific difficulty of the problem itself. Aging is an extremely complex process, with many uncertainties. Hence, any potential attempts at intervention will yet require a vast amount of careful thought and effort. This does not mean that such attempts should be abandoned. On the contrary - we need to tackle the problem, "not because it is easy, but because it is hard." The payoff from its solution would be too great to abandon. But we need to admit that the problem is difficult and therefore its solution will require strong efforts. People would need to make such efforts, and they are not always willing or ready to make them. Hence one of the major bottlenecks is perhaps the general deficit in the ability or willingness of many people to invest time, effort, money and thought for the development of healthspan and lifespan extending therapies and technologies. Clearly, the more people become supportive and involved for their development, the more resources are intelligently and productively invested in it, the faster the technologies will arrive and the wider will be their availability.

A wealth of biomedical data supports a key role of impaired mitochondrial bioenergetics functionally linked to marked dysregulation of diverse cellular processes as a unifying causative factor in the etiology and persistence of major pathological conditions afflicting human populations. It appears that the contextual bases of normal aging, genetically determined lifespan, and mortality are intrinsically linked to the total number of tissue- and organ-specific multicellular complexes competing for relatively limited energy sources during temporal stages of growth and development. It follows that the stereotypically defined lifespans of diverse species of higher animals reflect the existential "price" to pay for the exquisite cellular diversity required for integrated regulation of complex organ function. Variations in longevity within individual members across species of higher animals may then be effectively sorted according to age-dependent losses of single-cell metabolic integrity functionally linked to impaired mitochondrial bioenergetics within compromised complex organ systems.

Recent studies have focused on the functional role of mitochondrial heteroplasmy, defined as a dynamically determined co-expression of wild-type (WT)-inherited polymorphisms and somatic mutations in varying ratios within individual mitochondrial DNA (mtDNA) genomes. Based on the empirically determined number of mitochondria with differing mtDNA copy numbers distributed in tissue-specific cell types, the total concentration of mtDNA molecules exceeds the number of nuclear DNA molecules by two to five orders of magnitude. It is also apparent that high levels of heteroplasmic mtDNA genomes within the intra-mitochondrial compartment in individual human cell types is required for normative mitochondrial bioenergetics that is markedly compromised in human disease states.

A potential window of opportunity for practical achievement of aging reversal and extended longevity in human populations is alluded to in a study that has highlighted the importance of functional mitochondria in the maintenance of differentiation and reprogramming of induced pluripotent stem cells (iPSCs). A transition from somatic mitochondrial oxidative metabolism to glycolytic metabolism, highly reminiscent of cancer cells, was observed to be required for successful reprogramming of iPSCs. Importantly, somatic mitochondria and associated oxidative bioenergetics were extensively remodeled with the induction of an iPSC-like phenotype. Preservation of tissue-selective patterns of mtDNA heteroplasmy within a viable reserve of iPSCs would appear to represent a key molecular target for practical augmentation of anti-aging therapies and lifespan extension.

State-dependent transfer of functional mitochondria from healthy to metabolically compromised cell types has been extensively documented. Interestingly, within developing and/or reparative cellular systems, intercellular trafficking of optimally functional mitochondria is achieved using tunneling nanotubes or cellular derived vesicles in an elaborate transfer system. Thus, technological transplantation of functionally viable mitochondria comes with the anticipation of the significant restoration of normative cellular function functionally linked to the preservation of cell-specific mosaic patterns of heteroplasmic mtDNA expression. From a translational perspective, restoration of genetically determined patterns of mitochondrial heteroplasmy has the potential to restore and maintain mitochondrial dynamics in multiple organ systems. Long-term restoration and preservation of tissue- and organ-specific patterns of mitochondrial heteroplasmy and mtDNA copy number represent practical goals for bioengineering strategies designed to overcome age-related limitations in meeting physiological energy demands.

Cell-specific patterning of mtDNA heteroplasmy encompassing thousands of mitochondrial genomes within a single cell may be viewed as a reservoir required to effect minute changes in energy requirements critically linked to physiological demands. Normative cellular expression of mtDNA heteroplasmy may effectively represent a sophisticated molecular coping strategy with critical biological importance to cellular/organismic survival and health, and mechanistic relevance to lifespan extension and longevity. Within this context, chronic dysregulation of mitochondrial function leading to the initiation and persistence of diverse pathophysiological states may be attributed to a temporal loss of ongoing restorative processes that appear to be inherently dependent on normal mitochondrial heteroplasmy. We surmise that the extent of short- and long-term cellular and mitochondrial damage may be effectively ameliorated by the selective targeting and reversal of debilitating somatic mutations in mtDNA. Restoration of relatively slow, age-related, perturbations of normative mitochondrial heteroplasmy is then proposed to promote enhanced quality of life via prolonged maintenance of essential cellular signaling pathways that have been widely associated with age-related metabolic rundown.

Calorie restriction (CR) without malnutrition of micronutrients has been known for decades to profoundly increase lifespan and healthspan in multiple strains of laboratory rodents. More recent studies in model organisms and nonhuman primates also provide support for increased survival or prevention of age-related pathology in these widely diverse animal models. There is interest in understanding if CR and genetic interventions that increase survival actually reduce rates of aging at the molecular level. Gene expression profiling studies of multiple tissues in aging mice have shown that CR initiated in early to mid-life delays age-related gene expression changes, suggesting a delay in aging at the molecular level. Analysis of age-dependent mortality rates suggests that CR delays aging at early ages, but is associated with a pattern that resembles a compression of the aging process in the late component of the lifespan. The mechanisms of action of CR remain unclear, and understanding how different tissues and strains of mice respond to this dietary intervention is likely to be useful in understanding how CR impacts the aging process.

Two major, interrelated CR research directions are the following: (i) the identification of mechanisms which underlie CR's favorable health outcomes and (ii) the discovery of agents which may mimic at least some of the desirable outcomes of CR in subjects fed a normal caloric intake. The development of CR mimetics (CRMs) is important because the widespread practice of CR itself is unlikely to be practical in humans. An early consideration of how to approach the identification of CRMs focused on metabolic interventions. This metabolic theme proved to be a productive avenue for the discovery of CRMs.

CRMs, in large part, are either drugs or phytochemicals. Regarding phytochemical compounds, the most widely studied compound shown to mimic CR is resveratrol. Interestingly, high-dose resveratrol does not appear to extend longevity of lean (genetically normal) mice. However, we reported that mice from a long-lived strain treated from 14 to 30 months of age with either a relatively low dose of resveratrol or CR showed fewer signs of cardiac aging than age-matched controls, implying positive effects on healthspan. Furthermore, there was striking mimicry of CR-induced transcriptional shifts by resveratrol in heart, muscle, and brain in old animals. These conflicting observations suggest that CRMs may have tissue-specific effects in aging and that a tissue-specific screening strategy may be useful in evaluating CRMs.

In this study, we utilized a gene expression profiling approach to identify robust tissue-specific transcriptional markers of CR that were significantly altered in expression in the majority of mouse strains tested. We focused on heart, gastrocnemius, white adipose tissue (WAT), and brain neocortex. Using quantitative PCR, we then screened seven candidate CRMs for their ability to influence the expression of some of the novel CR transcriptional markers in vivo. We also measured the effects of the candidate CRMs on previously characterized, nontranscriptional CR biomarkers.

Importantly, we have shown that a drug that has strong activity in modulating CR transcriptional markers (pioglitazone) also modulates physiological measures of CR, such as reduced adipocyte size and mitochondrial mass. However, pioglitazone increased the levels of the inflammatory marker TNF-α, a finding suggestive of drug side effects. The putative CR mimetic L-carnitine, an amino acid involved in lipid metabolism, exhibited even stronger effects on CR transcriptional markers while modulating adipocyte size in a manner consistent with CR mimicry. These findings support the use of tissue-specific, robust transcriptional markers of CR as an effective approach to screen and identify compounds that have the potential to mimic the beneficial effects of CR on lifespan and healthspan. We also note that based on the finding that different compounds display tissue-specific CRM activity, it appears likely that stronger CR mimicry at the organismal level may be achieved by combining different CRMs.

Although diseases related to the aging process are problematic themselves, they rarely occur in isolation and the effects of one may spark the onset of another. As such ailments progress, the importance of physical activity (PA) remains high, with previous research confirming that regular PA is essential for healthy aging. Specifically, PA plays a substantial role in lowering the risk of coronary heart disease, as well as many other age-related conditions. Although PA may have an indirect impact on some health aspects, it has a direct impact on muscle quality and quantity.

Sarcopenia, which was first described as the progressive decrease in muscle mass and strength during aging, is a syndrome that is directly affected by PA. Soon after sarcopenia was defined, muscle mass assessment had been recommended as the main sarcopenia diagnosing method. Later, several groups were formed for sarcopenia consensus on definition and diagnosis. These groups recommended including muscle strength and physical performance measurement as the additional methods for sarcopenia diagnosing.

Previous research has shown that physical inactivity contributes to the development of sarcopenia, and other studies have shown that PA increases muscle strength and muscle mass in older adults. Therefore, a strong link has emerged between PA and a lower prevalence of sarcopenia. Specifically, resistance training is generally considered to be the best countermeasure for preventing sarcopenia. Although many reviews and meta-analyses have summarized the effects of individual or combined interventions (e.g., resistance training and nutritional supplementation) on sarcopenia, a systematic review and meta-analysis of the effects of PA defined as general activity that requires more energy than resting metabolic rate (e.g., exercising, strengthening, walking, working in the garden, and so on) on sarcopenia has not been published. Therefore, the main aim of this systematic review and meta-analysis was to describe the relationship between PA and the presence of sarcopenia.

We searched for articles addressing the relationship between PA and sarcopenia. Twenty-five articles were ultimately included in the qualitative and quantitative syntheses. A statistically significant association between PA and sarcopenia was documented in most of the studies, as well as the protective role of PA against sarcopenia development. Furthermore, the meta-analysis indicated that PA reduces the odds of acquiring sarcopenia in later life (odds ratio 0.45). The results confirm the beneficial influence of PA in general for the prevention of sarcopenia.

Our cells each contain close to 20,000 genes, which provide the instructions needed to build our bodies and keep us alive. At any one time in the life of the cell, only some of these genes are active. The activity of each gene is constantly regulated to allow the cell to respond to changes in its environment. Enhancers are sections of DNA, outside of the genes, that act as molecular switches controlling the activity of genes. A gene can have many such enhancers; each enhancer is linked to a particular set of signals and having multiple enhancers allows the same gene to be activated by different signals in different tissues in the body.

Changes to enhancers can have serious consequences. By altering the activity of genes, an enhancer can have widespread effects on the health and behavior of a cell, including transforming it from healthy to cancerous. The small differences in enhancers also make some people more susceptible to cancers than others. If we can identify enhancers whose activity is commonly altered in cancers, it could be possible to target them through treatment. Yet, it is not clear whether targeting enhancers in this way could be effectively used to treat cancer without damaging healthy cells.

Now, researchers have examined a large enhancer region with known links to several different cancers - including prostate, breast and colon cancers - to uncover whether it also plays a critical role in healthy cells and if it could be safely targeted for treatment. The region has multiple enhancers for a cancer-linked gene called MYC and is implicated in many cancer-associated deaths every year. This particular enhancer region is found in both humans and mice, which share many genes in common. Using genetic engineering, researchers removed this enhancer region from the genetic information of a group of mice. The experiment showed that mice without the enhancer region were completely healthy. Also, when tested for cancer development, these mice were much less susceptible to several major types of cancer.

The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kilobase deletion of the entire MYC upstream super-enhancer region in mice results in 50% to 80% decrease in Myc expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. These results reveal that only cells whose MYC activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer therapy.

In an early clinical trial, 33 out of 35 (94%) patients had clinical remission of multiple myeloma upon receiving a new type of immunotherapy - chimeric antigen receptor (CAR) T cells targeting B-cell maturation protein or BCMA. Most patients had only mild side effects. "Although recent advances in chemotherapy have prolonged life expectancy in multiple myeloma, this cancer remains incurable. It appears that with this novel immunotherapy there may be a chance for cure in multiple myeloma, but we will need to follow patients much longer to confirm that."

CAR T-cell therapy is custom-made for each patient. The patient's own T cells are collected, genetically reprogrammed in a lab, and injected back into the patient. The reprogramming involves inserting an artificially designed gene into the T-cell genome, which helps the genetically reprogrammed cells find and destroy cancer cells throughout the body. Over the past few years, CAR T-cell therapy targeting a B-cell biomarker called CD19 proved very effective in initial trials for acute lymphoblastic leukemia (ALL) and some types of lymphoma, but until now, there has been little success with CAR T-cell therapies targeting other biomarkers in other types of cancer. This is one of the first clinical trials of CAR T cells targeting BCMA, which was discovered to play a role in progression of multiple myeloma in 2004.

The authors report results from the first 35 patients with relapsed or treatment-resistant (refractory) multiple myeloma enrolled in this ongoing phase I clinical trial in China. First signs of treatment efficacy appeared as early as 10 days after initial injection of CAR T cells (patients received three split doses of cells over a week). Overall, the objective response rate was 100%, and 33 (94%) patients had an evident clinical remission of myeloma (complete response or very good partial response) within two months of receiving CAR T cells. To date, 19 patients have been followed for more than four months, a pre-set time for full efficacy assessment by the International Myeloma Working Group (IMWG) consensus. Of the 19 patients, 14 have reached stringent complete response (sCR) criteria, one patient has reached partial response, and four patients have achieved very good partial remission (VgPR) criteria in efficacy. There has been only a single case of disease progression from VgPR; an extramedullary lesion of the VgPR patient reappeared three months after disappearing on CT scans. There has not been a single case of relapse among patients who reached sCR criteria. The five patients who have been followed for over a year (12-14 months) all remain in sCR status and are free of minimal residual disease as well (have no detectable cancer cells in the bone marrow).

Cytokine release syndrome or CRS, a common and potentially dangerous side effect of CAR T-cell therapy, occurred in 85% of patients, but it was only transient. In the majority of patients symptoms were mild and manageable. CRS is associated with symptoms such as fever, low blood pressure, difficulty breathing, and problems with multiple organs. Only two patients on this study experienced severe CRS (grade 3) but recovered upon receiving tocilizumab, an inflammation-reducing treatment commonly used to manage CRS in clinical trials of CAR T-cell therapy. No patients experienced neurologic side effects, another common and serious complication from CAR T-cell therapy.

Researchers have discovered that loss of muscle stem cells is the main driving force behind muscle decline in old age in mice. Their finding challenges the current prevailing theory that age-related muscle decline is primarily caused by loss of motor neurons. Study authors hope to develop a drug or therapy that can slow muscle stem cell loss and muscle decline in the future. As early as your mid 30s, the size and strength of your muscles begins to decline. The changes are subtle to start - activities that once came easily are not so easy now - but by your 70s or 80s, this decline can leave you frail and reliant on others even for simple daily tasks. While the speed of decline varies from person to person and may be slowed by diet and exercise, virtually no one completely escapes the decline.

All adults have a pool of stem cells that reside in muscle tissue that respond to exercise or injury - pumping out new muscle cells to repair or grow your muscles. While it was already known that muscle stem cells die off as you age, the study is the first to suggest that this is the main driving factor behind muscle loss. To better understand the role of stem cells in age-related muscle decline, researchers depleted muscle stem cells in mice without disrupting motor neurons, nerve cells that control muscle. The loss of stem cells sped up muscle decline in the mice, starting in middle, rather than old age. Mice that were genetically altered to prevent muscle stem cell loss maintained healthier muscles at older ages than age-matched control mice.

At the same time, researchers did not find evidence to support motor neuron loss in aging mice. Very few muscle fibers had completely lost connection with their corresponding motor neurons, which questions long-held and popular theory. According to the theory, age-related muscle decline is primarily driven by motor neurons dying or losing connection with the muscle, which then causes the muscle cells to atrophy and die. "I think we've shown a formal demonstration that even for aging sedentary individuals, your stem cells are doing something. They do play a role in the normal maintenance of your muscle throughout life."

Studying mice, researchers have shown that a natural sugar called trehalose revs up the immune system's cellular housekeeping abilities. These souped-up housecleaners then are able to reduce atherosclerotic plaque that has built up inside arteries. Such plaques are a hallmark of cardiovascular disease and lead to an increased risk of heart attack. "We are interested in enhancing the ability of these immune cells, called macrophages, to degrade cellular garbage - making them super-macrophages."

Macrophages are immune cells responsible for cleaning up many types of cellular waste, including misshapen proteins and excess fat droplets. "In atherosclerosis, macrophages try to fix damage to the artery by cleaning up the area, but they get overwhelmed by the inflammatory nature of the plaques. Their housekeeping process gets gummed up. So their friends rush in to try to clean up the bigger mess and also become part of the problem. A soup starts building up - dying cells, more lipids. The plaque grows and grows."

The showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured in the aortic root were variable, but on average, the plaques measured 0.35 square millimeters in control mice compared with 0.25 square millimeters in the mice receiving trehalose, which translated into a roughly 30 percent decrease in plaque size. The difference was statistically significant, according to the study. The effect disappeared when the mice were given trehalose orally or when they were injected with other types of sugar, even those with similar structures.

Past work by many research groups has shown trehalose triggers an important cellular process called autophagy, or self-eating. But just how it boosts autophagy has been unknown. In this study, researchers show that trehalose operates by activating a molecule called TFEB. Activated TFEB goes into the nucleus of macrophages and binds to DNA. That binding turns on specific genes, setting off a chain of events that results in the assembly of additional housekeeping machinery - more of the organelles that function as garbage collectors and incinerators. "Trehalose is not just enhancing the housekeeping machinery that's already there. It's triggering the cell to make new machinery. This results in more autophagy - the cell starts a degradation fest. Is this the only way that trehalose works to enhance autophagy by macrophages? We can't say that for sure - we're still testing that. But is it a predominant process? Yes."

"Targeting signs of aging". It sounds more like a punch-line of a TV commercial, than a consequence of fundamental science. But as we observed recently, it might actually be possible to achieve just that, using a prospectively designed FOXO4-p53 interfering peptide that targets so-called "senescent" cells. More research is needed to fully assess its true translational potential and whether it is even safe to remove such cells. However, these findings pose a very attractive starting point to develop ways to live out our final years in better health.

Aging has often been considered as an integral part of life; a form of "noise" that cannot be targeted or tampered with. This is in part because for long the underlying causes of organismal aging were simply too elusive to comprehend, let alone modify. The chronic build-up of DNA damage has now evidently been established as a major cause for aging, but to counteract the genomic damage that has occurred over a lifetime is an entirely different challenge altogether. One approach to overcome this issue, is to eliminate those cells that are too damaged to faithfully perform their duty and to replace them by fresh and healthy counterparts. Senescent cells are exciting candidates for such an approach.

Comparable to formation of rust on old equipment, like a bicycle, senescent cells accumulate during aging and especially at sites of pathology. They develop a chronic secretory profile that is thought to impair tissue renewal and contribute to disease development, for instance by keeping neighboring cells "locked" in a permanent state of stemness. Senescence can be beneficial in a transient setting, but the genetic removal of senescent cells over a prolonged period of time was found to be safe and to potently extend health- and lifespan of naturally aging mice. Thus, senescence is an established cause for aging and targeting senescent cells is warranted. But can they also be eliminated therapeutically? And are such methods then safe on their own? And last, but not least, would such methods be applicable to not merely delay, but also to reverse aging?

Aging is still inevitable. But perhaps it can be strongly postponed, or even reversed, when independent anti-aging therapies are combined? It remains to be determined whether extension of lifespan is possible in humans, let alone whether this is desirable and then to what age? After all, life could at some point not simply "complete"? While this might be true for some, nobody likes being sick and frail. Imagine the possibilities if we would be able to enjoy our time with loved ones, exercise and travel more and simply just enjoy life in good health, instead of spending it in a retirement home.

Extending the healthy years of life is now closer than ever, but we are still not there yet. While mechanics can remove defective parts from an old bicycle, it is far more challenging to remove damaged parts from an old body. Anti-aging strategies have therefore necessarily focused thus far on stalling the inevitable for as long as possible by eating less and exercising more. A multitude of new diets make it to the mainstream public each year, but ironically, people tend to exercise less and gain more and more weight. This argues that instead of focusing so much on dietary interventions, independent approaches deserve to be investigated. Here, we underscored the potential of therapeutic elimination of senescent cells, for instance by FOXO4-DRI. In addition, exciting developments were recently reported in the field of stem cell biology, where it was shown that transient expression of the Yamanaka stem cell factors can promote tissue rejuvenation. This is not yet therapeutically applicable, but most likely this will only be a matter of time.

It is no longer merely science-fiction to restore healthspan with rationally designed approaches. To fully achieve the best possible outcome, it will therefore deserve special consideration to combine existing methods to delay aging with the recently developed therapies that counter senescence and promote tissue rejuvenation. With these, we finally have exciting tools to maintain and repair the aging cycle of life. Time to gear up and head for the finish!

When external calories stop fueling an animal's metabolism, stores of triglycerides in fat cells are mobilized, and levels of ketones - chemicals that result from the burning of fat for fuel - rise. Decreases in body weight follow. Scientists are further detailing both the underlying metabolic dynamics and interesting physiological phenomena aside from weight loss as they study permutations of fasting in animal models and in humans. Data has recently emerged from research on several forms of so-called intermittent-fasting regimens, including alternate-day fasting, the so-called 5:2 diet, time-restricted feeding, and periodic fasting. Although these regimens vary, they all involve a rhythmic disruption in the typical flow of calories into the metabolic machinery. As the body of scientific literature around fasting has grown, results have been cherry-picked and molded into fad diets. But as books of dubious scientific merit extolling the virtues of fasting fill the shelves, serious researchers continue to probe the genetic, immunologic, and metabolic dynamics that occur in fasting animals to separate hype from reality.

For the majority of genus Homo's more than 2 million year evolution, hominins' access to nutrients and calories was spotty, at best. Perhaps our ancestors, and their digestive systems, evolved to endure periodic bouts of starvation. Oscillations between feast and famine may even have served as a selective pressure, tuning early human physiology to function optimally in an environment where resources were unpredictable. "Individuals whose brains and bodies and physical performance were optimal in a fasted state would be more likely to get food and compete with other individuals who were not able to function at quite as good a level. So the assumption then is that we evolved probably most of our organ systems to be able to function optimally in intermittent fasting-type conditions."

Results from studies in both animal models and humans point to distinct benefits of withholding food in one temporal pattern or another. In recent years, scientists have learned that fasting might trigger not only weight loss and life-span extension - benefits that have long been linked to caloric restriction - but also boost the performance of the brain, the immune system, and organs central to metabolism, such as the liver and pancreas. Fasting, some researchers claim, can even alter the course of some diseases, from cancer and multiple sclerosis to diabetes and Alzheimer's.

Fasting that involves longer periods of food deprivation can cause changes to the immune system and the hematopoietic stem cells that support it. Researchers are finding that periodic fasting, less frequent but longer bouts of severe calorie restriction, can reshape immune cell populations in the body. One research group employs the fasting-mimicking diet (FMD). Using a periodic three-day FMD regimen for 30 days in a mouse model of multiple sclerosis, the researchers showed that the fast-and-feed cycles pruned away populations of autoimmune T cells, replacing them with immune cells that were no longer bent on attacking neural tissue. Oligodendrocyte precursor cells regenerated and remyelinated axons, and the clinical severity of the autoimmune disorder declined. "One in five of the mice went to back to no symptoms at all. One in two of the mice went down to very low levels of the symptoms. The real benefit that we've shown in a number of papers is about killing damaged cells and then turning on stem cells. And then in the refeeding period, [stem cells are] replacing the dead cells with newly generated cells. I think that is where the real benefit is."

The goal of the symposium was to bring together leaders in the fields of aging and drug development to discuss strategies for identifying and developing therapeutic approaches to extend human healthspan. This symposium made it highly evident that the biology of aging field is moving quickly toward translational research. At the symposium, there were numerous reports of successful drug screens and drug testing in a variety of model systems. There was also an overall sense of excitement, given that multiple therapeutic modalities, including young plasma, recombinant proteins, and small molecules, extend healthspan and lifespan in model organisms and that clinical trials to test the efficacy of these treatment modalities on healthspan and resilience have been initiated.

The concept of geroscience, defined as the understanding of the relationship between aging and age-related diseases and preventing/delaying disease by targeting fundamental mechanisms of aging, was an underlying theme of the symposium. As reiterated by the keynote speakers, aging is the main risk factor for most chronic diseases. Thus, developing approaches to therapeutically target aging should be a funding priority for the majority of institutes at the National Institutes of Health, as well as other funding agencies, philanthropists, and foundations. The socioeconomic need to extend human healthspan also was made clear. As a consequence of the advances in prevention and treatment of infectious diseases, there will be an unprecedented increase in the number of persons over 65 over the next decades. By 2035, the cost of treating Americans 65 years and older is expected to be over 2 trillion annually. Thus, finding ways to prevent all age-related diseases is one of the most imperative biomedical pursuits.

A common theme arising from the symposium was the need for appropriate model organisms to study aging and age-related disease including models carrying reporters of senescence, mitochondrial function, autophagy and reactive oxygen species (ROS). The use of these reporters or testing of therapeutics needs to be performed in aged model organisms, a problem that has also plagued the cancer field because of the cost and time involved, at least in rodent models. Here, the National Institute on Aging (NIA) Interventions Testing Program in mice (ITP) and in Caenorhabditis elegans (C. elegans) (CITP) have made significant contributions to the identification of drugs/compounds able to extend lifespan. Despite the ITP, CITP, and new models of aging, there still is a need for an expansion of efforts to measure the effects of drugs/compounds on healthspan or resilience, which has greater translational relevance. Thus, many investigators are beginning to incorporate functional analysis of aged mice undergoing therapeutic interventions.

An emerging paradigm in the field of aging is that the burden of senescent cells increases with age in multiple tissues and reducing this senescent cell burden improves healthspan. The reduction of senescent cells in mice reduced atherosclerosis, improved metabolism, prevented tumor metastasis and reduced osteoarthritis in an injury model. Thus, the hunt is on for senolytics or drugs that specifically kill senescent cells. Whether optimized senolytics will have similar positive effects on human healthspan is still unclear, but clinical trials are being planned to determine their effectiveness. It is important to note that it is likely that no one senolytic will be effective in eliminating all types of senescent cells. Individual senolytic compounds are apt to have tissue-specific and even cell type-specific effects. Furthermore, there is increasing evidence that different drivers of senescence can lead to differences in how senescence manifests, which in turn could have a variable impact on the senescent cell's environment.

Adult stem cell function is known to decline with aging. However, it has taken longer to demonstrate that the loss of stem cell function contributes to aging and is not simply a consequence of it. Treatment of a mouse model of accelerated aging with two types of young stem cells extends healthspan and lifespan. Although the exact mechanism for how these stem cell populations affect aging is unknown, preliminary data suggest that their effect is mediated by factors secreted by young, but not old stem cells. These factors appear to reduce cellular senescence and improve the function of endogenous, aged stem cells. Whether these stem cell-derived soluble factors are the same as those found in young plasma is currently unknown. This will undoubtedly remain an area of intense research spanning from continued investigations into fundamental mechanisms of aging to clinical trials.

Clear evidence that the field of aging is moving forward quickly is the number of ongoing or soon-to-be-initiated clinical trials. Importantly, the use of specific short-term clinical endpoints to determine if resilience or function of a specific tissue could be improved is employed to reduce study size, duration, and cost. For example, short-term treatment of a cohort of elderly people with a rapamycin analogue (rapalog) was tested for its ability to improve immune function. The inclusion of additional endpoints provides further information about not only the effect of the intervention on immune function, but also on other aspects of aging that might be modulated and measured in future clinical trials. Similarly, short-term clinical trials with the mitochondrial-targeted SS-31 peptide are in progress for heart disease based on very promising preclinical data. These short-term treatment trials with well-defined, disease-specific endpoints are in contrast to the highly anticipated Treating Aging with Metformin (TAME) trial. The TAME trial is designed to enable evaluating whether metformin extends the healthspan of humans albeit in a rapid 3-5 year format. It is hoped that the TAME trial will serve as a template for pharmaceutical companies to do future testing of drugs aimed at targeting fundamental mechanisms of aging.

It also is clear that support from the private sector will be essential for moving clinical trials forward as there is a huge need for funding from sources other than the NIH to expedite aging research. The successful completion of the first clinical trial demonstrating that human healthspan can be extended is anticipated to instigate tremendous interest in the field by biotech investors and potentially philanthropists. Thus, this first proof-of-principle clinical trial and funding support for it is considered a significant hurdle that must be crossed to accelerate funding and progress in the field.

Aging causes disease progress and a gradual decline in physical and mental function. Because of the rapid aging of the population, the risk of economic collapse in developed countries is increasing. Therefore, anti-aging and disease prevention has become a high priority science challenge. Although geroprotector discovery is a popular biomedical trend and more than 200 compounds can slow aging and increase the lifespan of animal models, there are still no geroprotectors on the market. The reasons may be related to the lack of a unified concept of aging mechanisms, the problem of translation of geroprotectors studies results from model organisms to humans, low level of interest from big pharma since aging has no status as a disease.

But one of the main obstacles, in our opinion, is the lack of a concept of geroprotector accepted by the scientific community. Such concept as a system of criteria for geroprotector identification and classification can form the basis for an analytical model of geroprotectors, help consolidate the efforts of various research initiatives in this area and compare their results. This model can serve as a platform for formulating and solving a variety of tasks, from a selection of the most promising and efficient existing candidate geroprotectors to possible constructing of a model geroprotector that can be searched in the libraries of compounds or synthesized purposefully.

The most significant main rule for geroprotectors is evidently the ability to increase lifespan. Candidate geroprotectors should ameliorate molecular, cellular, and physiological biomarkers to a younger state or slow the progression of age-related change in these markers. The therapeutic lifespan extending dose of a geroprotector should be several orders of magnitude less than the toxic dose. Potential geroprotectors should improve health-related quality of life: physical, mental, emotional, and social functioning of the treated person. The target or mechanism of action of the geroprotector should be evolutionarily conserved. Reproducibility of geroprotective effects on different model organisms increases the possibility of effects will also be discovered in humans, even in the absence of a known conserved target. Candidate geroprotectors should be able to delay the progress of one or several age-associated disorders. Potential geroprotectors should increase the organism's resistance to unfavorable environmental factors.

The compliance of a substance with at least the majority of these criteria allows the claim that we are dealing with a candidate geroprotector. With the help of modern mathematical tools for data analysis and decision-making, such a system would facilitate formulating and solving a number of important scientific and applied problems, the most significant of which is the selection of geroprotectors with the largest and most reliable effect on life expectancy.