Fight Aging! Newsletter, January 25th 2016

January 25th 2016

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

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  • Interleukin-21 Partially Restores T Cell Counts in Aged Mice
  • Investigating the Role of Monocytes in Inflammaging
  • Do Current Stem Cell Therapies Produce Rejuvenation?
  • The Centenarian Population is Growing
  • Views on Death and Aging (and What to Do About It)
  • Latest Headlines from Fight Aging!
    • Researchers and Advocates Push to Change the WHO Vision for Aging Research and Treatment
    • Temporary Reversal of Hair Graying Observed in Stem Cell Transplant Recipients
    • More on the Dose-Response Curve for Exercise
    • Aubrey de Grey in the Chinese Media
    • Calorie Restriction Enhances Human Cellular Quality Control
    • Considering Preservation of Extracellular Space in the Brain
    • Ephrin Signaling and Restored Activity in Tendon Stem Cells
    • Delivering Engineered Neural Networks into the Living Brain
    • The Possibility of Suppressing Detrimental Growth of Heart Tissue in Response to Hypertension
    • Considering the Most Significant Cause of Aging


In the open access paper I'll point out today, researchers demonstrate a comparatively straightforward way to enhance the diminished functions of the thymus in old mice, and thus partially reverse the dysfunction in immune response that accompanies aging. The thymus might be thought of as an incubator for the varied types of cell belonging to the active immune system that are collectively known as T cells. In childhood the thymus is very active, producing a flood of new cells. Unusually among mammalian organs, however, the thymus atrophies very early in adulthood in a process known as thymic involution, reducing the supply of new T cells to a trickle. This in effect limits the size of the immune system, and that limit becomes an increasing problem as the years pass. Ever more T cells are focused on specific pathogens and ever fewer remain capable of tackling new threats, for example.

Any and all methods that might prove effective in breaking the natural limits on T cells are of interest, given the importance of immune dysfunction in the progression of age-related frailty. The immune system doesn't just fight off invaders: it is also involved in wound healing, destruction of potentially cancerous and senescent cells, and a variety of other necessary tasks. As the effectiveness of the immune system winds down, many contributions to aging and age-related disease accelerate as a result.

How to restore the legions of competent, useful immune cells, however? Destroying the many duplicate cells that are uselessly focused on specific pathogens, and as a consequence take up space to no good end, seems to work based on animal studies carried out to date. That destruction provokes their replacement with competent new cells, albeit at a slow pace, and - fortunately - targeted cell destruction is a going concern these days thanks to the work taking place in the cancer research community. Another possibility is to use the techniques of stem cell medicine to culture large numbers of patient-matched immune cells and infuse them on a regular basis. This is technically well within the grasp of the clinical community, but not yet adopted. Other approaches focus on restoration of the thymus to its childhood state of activity, such as via tissue engineering and transplantation, or reprogramming of thymic cell state with gene therapy.

That brings us to this simpler approach to alter the behavior of the cells making up the thymus, as well as those involved in the many complicated stages that make up the production of T cells. A T cell doesn't just spring into being, but is rather the result of numerous steps of cellular migration and differentiation that starts with hematopoietic stem cells in the bone marrow, and winds its way via thymocytes, a type of progenitor cell in the thymus, before eventually giving rise to forms of T cell. Here, researchers are using a very blunt tool to achieve their results, simply injecting the mice in their study with the cytokine interleukin-21 (IL-21). Eyeing the data, the results look like a temporary doubling or more of relevant counts of cells, but that isn't enough to pull things back to where they were in youth. Still, the outcome is good given that it is such a simple approach:

Interleukin-21 administration to aged mice rejuvenates their peripheral T-cell pool by triggering de novo thymopoiesis

The vaccination efficacy in the elderly is significantly reduced compared to younger populations due to thymic involution and age-related intrinsic changes affecting their naïve T-cell compartment. Interleukin (IL)-21 was recently shown to display thymostimulatory properties. Therefore, we hypothesized that its administration to ageing hosts may improve T-cell output and thus restore a competent peripheral T-cell compartment. We show in this report that administration of recombinant IL-21 (rIL-21) enhances thymopoiesis in aged mice through expansion of both the stromal and responsive thymocytes compartments without the induction of any apparent pathology in peripheral organs.

Enhanced production of naïve T cells improved the T-cell receptor (TCR) repertoire diversity and re-established a pool of naïve CD4+ and CD8+ T cells displaying potent effector functions in response to TCR stimulation. This increase in the availability and potency of naïve T cells augmented the responsiveness of aged mice to vaccination and tumor challenge.

Besides physiological ageing, contraction of the TCR repertoire is commonly observed in patients suffering from infections, cancers, or following bone marrow transplantation. There are currently no effective therapies capable of exerting a positive impact on broadening the spectrum of TCR. Studies involving IL-21R−/− mice clearly showed that IL-21 is dispensable for immune cell development as normal proportions of lymphocytes, monocytes, and granulocytes have been reported. Our data nevertheless suggest that rIL-21 administration to ageing hosts could have potent clinical uses related to its ability to promote the expansion of thymic progenitor cells, which can be further enhanced if combined with other thymostimulatory compounds.


Today I'll point you to an interesting paper in which the authors investigate one of the contributing factors that cause ever greater levels of chronic inflammation to accompany aging, in this case the factor being detrimental changes in the behavior of monocyte immune cells in older individuals. The researchers demonstrate that monocytes are influenced by rising levels of the inflammatory cytokine TNF, and either removing TNF or the problem monocytes improves the impaired immune response in aged mice.

The immune system is enormously complex, one of the many aspects of our biology in which the high level sketch - information that fills books in and of itself - must still be painted in at the detail level. One measure of what is left to learn is the present lack of understand of the root causes of many autoimmune diseases, intricate failure modes in the regulation of immune activities in which immune cells attack healthy tissue. If the research community understood the immune system completely, the scientists involved would also understand autoimmunity well enough to prevent it and reverse it. As it is, there are only hints and connections made in a growing, ceaseless river of data, while cures are yet to be found. The situation for the aging of the immune system is much the same. A variety of theories backed by differing levels of evidence explain why the immune system in aged individuals becomes both progressively less effective and progressively more active at the same time, chasing its tail to no good end. Greater activity means more inflammation, and sustained inflammation is a source of tissue damage and cellular dysfunction, a potent contribution to the pathology of many age-related diseases. Researchers have given the name "inflammaging" to this unfortunate end stage of the immune system and its detrimental effects on health.

Today we are at a point at which the research community can present a convincing story of immune aging based upon processes such as the atrophied thymus reducing the supply of new immune cells, the limited number of immune cells increasingly consisting of those uselessly devoted to a few persistent pathogens rather than capable of dealing with new threats, and so on and so forth. The relevance and importance of these processes can still be argued, however. Given the pace of progress in biotechnology, I believe that the proof of theories on immune aging will be provided by therapies capable of addressing the causes of immune decline, and this will happen long before proof can be provided via a full mapping of the biochemistry and processes of the immune system. Therapies that work will point the way, and the cost of testing any given hypothesis in mice continues to fall year after year.

Studying 'inflammaging': Monocytes, cytokines, and susceptibility to pneumonia

Researchers are interested in how the immune system ages. In this study, they focus on monocytes, immune cells that are central to the process of inflammation. Monocytes multiply and mature in the bone marrow and circulate in the blood stream. They are recruited to sites of injury or infection and there turn into macrophages that ingest pathogens, infected cells, or cellular debris. Monocytes are also potent producers of pro-inflammatory cytokines, small molecules that promote an inflammatory immune response.

Comparing younger and older mice, the researchers found that the latter have higher numbers of monocytes both in the bone marrow and in the blood. They also saw higher levels of TNF and IL-6, two pro-inflammatory cytokines, in blood from older mice and blood from older human donors. Studying mouse monocytes in more detail, the researchers found that the increase in TNF levels that occurs with age causes premature release of immature monocytes from the bone marrow into the blood stream. When stimulated with bacterial products, these immature monocytes themselves produce more inflammatory cytokines, thus further increasing levels in the blood.

The researchers then infected younger and older mice with the bacteria Streptococcus pneumoniae, which causes so-called pneumococcal pneumonia. They found that, although the older mice had higher numbers of monocytes in the blood and at the sites of infection, their monocytes were not able to clear the bacteria and successfully fight the infection. However, when the researchers used drugs or mouse mutations that reduced the number of monocytes or removed TNF, they were able to restore antibacterial immunity in aged mice. The researchers conclude that "monocytes both contribute to age-associated inflammation and are impaired by chronic exposure to the inflammatory cytokine TNF, which ultimately impairs their anti-pneumococcal function." They go on to suggest that "lowering levels of TNF may be an effective strategy in improving host defense against S. pneumoniae in older adults."

TNF Drives Monocyte Dysfunction with Age and Results in Impaired Anti-pneumococcal Immunity

As we age, levels of inflammatory cytokines in the blood and tissues increase. Although this appears to be an inevitable part of aging, it ultimately contributes to declining health. Epidemiological studies indicate that older adults with higher than age-average levels of inflammatory cytokines are at increased risk of acquiring, becoming hospitalized with and dying of pneumonia but how age-associated inflammation increased susceptibility to was not entirely clear. We demonstrate that the increase in the inflammatory cytokine TNF that occurs with age cause monocytes to leave the bone marrow prematurely and these immature monocytes produce more inflammatory cytokines when stimulated with bacterial products, thus further increasing levels of inflammatory cytokines in the blood. Furthermore, although old mice have higher levels of these inflammatory monocytes arriving at the site of S. pneumoniae, they are not able to clear the bacteria. By pharmacologically or genetically removing the inflammatory cytokine TNF or reducing the number of inflammatory monocytes we were able to restore antibacterial immunity in aged mice.


Here is an interesting question for today's discussion: do present stem cell therapies produce results that we might in any way classify as rejuvenation? The therapies presently available in numerous clinics around the world vary in the type and quality of cells used, and whether they are derived from the patient's tissues. Simple approaches extract cells from fat tissue or cord blood or similar sources and use limited purification to enrich the proportion of stem cells and progenitor cells of various types. More sophisticated approaches standardize to proven, narrow methodologies for a single cell type at high purity levels, such as the widely used mesenchymal stem cells. Further variants involve the addition of scaffolds, nutrient gels, or adjuvant treatments to try to keep the transplanted cells alive and doing their thing for longer. The evidence gathered to date strongly suggests that near all of the stem cell transplant therapies deployed over the past fifteen years produce benefits through signaling: the transplanted cells don't as a rule hang around for long, but they alter the behavior of native cells, such as stem cells and immune cells.

This is a far cry from the class of stem cell treatment envisaged for the future of rejuvenation treatments after the SENS model. That would include the delivery of populations of engineered stem cells, derived from the patient, but with their age-related molecular damage removed. The intention would be for these cells to take up residence, possibly at the same time as the existing damaged stem cell populations are cleared out. It may involve repair of the stem cell niche as well, a more complex and daunting prospect given the complexities of the niches that are well understood. Many more are not, and even if simply delivering new stem cells for the long term, something that is presently beyond the state of the art, there are scores of such cell types. Each will require their own special handling, if the challenges seen so far in regenerative medicine continue to hold true. The reason that only a few cell types are widely used in today's stem cell treatments is that each cell type requires a very different recipe and methodology. It has taken a great deal of time and effort to arrive at the recipes presently in circulation. This SENS approach to stem cell replacement is clearly rejuvenation, however. The old is cast out and the youthful ushered back in.

The closest thing to a SENS-style stem cell therapy that has taken place are the immune system reboot treatments for type 1 diabetes and multiple sclerosis. Chemotherapy is used to kill off the old immune cells and stem cell therapy delivers a new set of cells, albeit not a set of cells with any age-related damage removed. Chemotherapy is an unpleasant thing to go through, but it actually worked. This is quite an old approach in comparison to much of what is discussed here; if you go digging you'll see that it was even attempted with mixed results for rheumatoid arthritis long enough ago to predate the advent of the modern standard treatment of biologics for immune suppression. The need for aggressive chemotherapy seems to have discouraged adoption of this approach, at least until targeted cell killing is a safer, less unpleasant undertaking.

Is this rejuvenation, however? Neither type 1 diabetes nor multiple sclerosis are age-related diseases; they are not a part of aging, though like all non-age-related disease they interact with aspects of aging in ways that are never good for the patient. I think we can all agree that fixing a broken leg isn't rejuvenation, and for the same reasons neither is fixing an immune system that breaks because of inherited genetic mutation, inflammatory injury, or simple bad luck. How about the rest of the modern panoply of stem cell therapies, the much more common and straightforward transplantation to enhance regeneration? These treatments produce benefits by providing a temporary period of (a) increased healing, sometimes regeneration that would never normally happen, such as in heart tissue, in other cases a matter of restoring more youthful levels of healing, (b) reductions in chronic inflammation via interaction with immune cells, and (c) other, less well cataloged changes such as lowered oxidative stress in tissues.

Perhaps the most common form of present day stem cell therapy are those intended to partially address joint wear in the old, such as early osteoarthritis, and the less dramatic but still potentially debilitating cases of middle-aged muscle and tendon damage. There is a high expectation of attaining modest benefits in terms of reduced pain and increased capacity for use, the risks are minimal, and the costs are reasonable - as little as a few thousand with some footwork, even in the broken US medical system. You probably know someone who has investigated the treatment, and if not today then you will a few years from now. If an age-worn joint is marginally improved, but via the actions of your old cells, shoring up old tissues with more age-damaged cells, is that rejuvenation? You are better off, but the joint is no younger in any biochemical measure of aging. I can see the way to argue either side of that question with little difficulty, but on the whole I'm inclined to say that if there is room for debate then the results are not rejuvenation - and thus we're not close enough to the point in the road ahead where we can relax.


The recent increase in size of the centenarian population, happening as it did over a comparatively short period of time, is one measure of the steady increase in human life expectancy at older ages, achieved through progress in medical science and a growing wealth that grants access to the resulting treatments. The size of the very aged population is also subject to variations in the size of birth cohorts, however. It is far from true that the same number of people were born in every year over the past century, or even that the historical numbers are a smooth increase that matches the growth in overall population. The 1940s to 1960s saw a large rate of births in the US in comparison to later decades, for example. From the data for the first decades of the 20th century, a time of declining births in the US, we might expect the present centenarian population to fall over the next few decades if birth cohort size year after year were the only determinant. It isn't, of course.

In extreme old age, the greatest determinants of continued survival are at present some combination of genetics and use of medical technology. The latter will outstrip the former in its degree of influence over life span and health in old age, but over the course of recent decades gains in remaining life expectancy in old age have been very slow in coming. This is a trend of perhaps one year gained for every decade of progress when considering life expectancy at 60, for example. Such slow improvement is the result of a medical and research community that has focused on treating end stages of age-related disease without aiming for prevention in any significant way and without aiming to treat the true root causes, which is to say the processes of aging that produce accumulating cell and tissue damage. Patching over the problem of an age-related disease is expensive and produces marginal results: patches don't last when the damage, the underlying cause of the problem, continues to grow unaddressed.

This will change dramatically in the years ahead as rejuvenation technologies after the SENS model emerge from the laboratories. The difference between not treating the causes and treating the causes will be night and day in terms of the effects on age-related disease and mortality rates. A great upward discontinuity in life expectancy lies ahead, ultimately making the genetics of survival in old age irrelevant. After the advent of a complete toolkit of rejuvenation treatments capable of repairing the damage that causes aging, no-one will have to suffer in the state of being heavily damaged and on the brink of organ failure for years on end. In the average adult individual who bears little of that damage, currently only people not yet in their 40s, genetic variation has next to no effect on mortality rates.

More Americans Living Past 100, Thanks to Modern Medicine

More Americans than ever before are living past the age of 100, according to a new report (PDF) from the U.S. Centers for Disease Control and Prevention (CDC). The agency finds the number of the centenarians increased by 43.6 percent between 2000 and 2014 - from 50,281 to 72,197. Currently, there are some 317,000 centenarians worldwide, and that number is projected to rise to about 18 million by the end of this century, according to one report published in 2014.

In 2014, the top five causes of death among the oldest of the old were heart disease, Alzheimer's disease, stroke, cancer, influenza and pneumonia. Unfortunately, the number of super seniors dying from Alzheimer's disease continues to rise. Between 2000 and 2014, the rates of Alzheimer's disease-related deaths increased by 119 percent. Rates of deaths from other causes also spiked within the same time period, including hypertension (88 percent), chronic lower respiratory disease (34 percent) and unintentional injuries (33 percent). However fewer centenarians are dying from other causes. Between 2000 and 2014 the rate declined by 48 percent for influenza and pneumonia, 31 percent for stroke and 24 percent for heart disease.

Mortality Among Centenarians in the United States, 2000-2014 (PDF)

National Vital Statistics System mortality data for years 2000 through 2014 were analyzed to determine the number of deaths, age-specific death rates by race and ethnicity, and sex-specific leading causes of death among centenarians. As the population in the United States has aged, the number of deaths among centenarians continues to increase. Death rates increased for both male and female centenarians from 2000 through 2008 and decreased from 2008 through 2014. Deaths for females accounted for more than 82% of total deaths each year, and females accounted for 80%-84% of the total centenarian population from 2000 through 2014. Heart disease remained the leading cause of death in 2014 as in 2000 for both male and female centenarians.


Death, aging, and politics: insofar as I have views on these things, I'm against them all. There are deep mysteries in this universe of ours, the Fermi Paradox central to them all, and you can't make progress in these things if you are dead, dying, or drowned in the yammering of those who seek to divide a present stasis rather than build a dynamic, better future. The only thing that matters in the long term is technology, and of that technology the most important facets at present are those involved in the development of rejuvenation therapies that will enable either us or our immediate descendants to remain here, in this world, to see the long term up close and in person. That isn't exactly philosophy, but it does the job for me.

I don't think it is any big secret that the history of philosophy is replete with people giving serious consideration to death and the principle modes of getting to that state, such as aging, and from there what to do about it. In ancient times, the development of strategies for coping with the inevitability of suffering and death was a fine art. The best of these, such as the varieties of stoicism, are so good that they have survived for more than two thousand years in much the same form. We still have access to copies of the original advice as it was written in many cases, and that is only the case because forty generations of humanity have found worth in these thoughts. A great change is underway at present, however, a discontinuity in the making that within our lifetimes will separate both us and our descendants from thousands of years of civilized rumination on the human condition. We are building technology that will radically change what it is to be human in many ways - and of course the part of this great transition that I am most interested in is the end of aging and involuntary death. Ultimately there will be an end to suffering too, and any need for stoicism will be buried by the paradise engineering of the more distant future, but we have to start at the top of the list.

Over at The Meaning of Life, you'll find a recently posted collection of interesting references to various positions on death, suffering, and aging. It is worth perusing. After all, we should be able to deploy a good answer to anyone who earnestly asks why we do this, why we care, why we seek to bring an end to aging and age-related disease. The first place to look for good answers is in the works of those who have spend a good deal more time than you and I thinking on the topic. A part of that reading is a matter of understanding the mistaken paths, as sadly many of these people arrived at positions on death and suffering that supporters of radical life extension would reject out of hand. The world is full of those who embrace the march towards death, or even the extinction of all life, and who believe that longer healthy lives would somehow be a loss rather than a gain. This contingent of humanity has its philosophers, just as do those who, instead of accepting what is, reach to make something greater and better of the human condition.

Summary of Nick Bostrom's, "The Fable of the Dragon-Tyrant"

Bostrom's article, "The Fable of the Dragon-Tyrant," tells the story of a planet ravaged by a dragon (death) that demands a tribute which is satisfied only by consuming thousands of people each day. Given the ceaselessness of the dragon's consumption, most people did not fight it and accepted the inevitable. Finally, a group of iconoclastic scientists figured out that a projectile could be built to pierce the dragon's scales.

Summary - We should try to overcome the tyranny of death with technology.

Summary of James Lenman's Immortality: A Letter"

Lenman's article, "Immortality: A Letter," (1995) concerns a letter from a fictional philosopher to her fictitious biological friend in which she presents arguments against taking his immortality drug. She worries that if only some people get the drug, those who don't will regret it; while if everyone gets the drug, overpopulation will ensue unless people stop having children. But this will lead to more unhappiness, as people want to have children. Most importantly immortality would undermine our humanity by transforming us into different kinds of beings. In addition an immortal life might become boring. And finally the value of life derives in large part from its fragility, which would be undermined by immortality.

Summary - More value will be lost than gained if we become immortal.

John Leslie's, "Why Not Let Life Become Extinct?"

In the end, we cannot show conclusively that we should not let life become extinct because we can never go from saying that something is - even happiness or pleasure - to saying that something should be. And it is also not clear that maximizing happiness is the proper moral goal. Perhaps instead we should try to prevent misery - which may entail allowing life to go extinct. Philosophers do not generally advocate such a position, but their reluctance to do so suggests that they are willing to tolerate the suffering of some for the happiness of others.

Summary - There are strong arguments for letting life go extinct, although Leslie suggests we generally reject them because life has intrinsic goodness.

Summary of David Benatar's, Better Never to Have Been

It is commonly assumed that we do nothing wrong bringing future people into existence if their lives will, on balance, be good. This assumes that being brought into existence is generally beneficial. In contrast Benatar argues that: "Being brought into existence is not a benefit but always a harm." While most maintain that living is beneficial as long as the benefits of life outweigh the evil, Benatar argues that this conclusion does not follow. Benatar concludes by saying: "One implication of my view is that it would be preferable for our species to die out."[ii] He claims that it would be heroic if people quit having children so that no one would suffer in the future. You may think it tragic to allow the human race to die out, but it would be hard to explain this by appealing to the interests of potential people.

Summary - It is better never to come into existence as being born is always a harm.

Summary of Steven Luper's, "Annihilation"

In his essay "Annihilation," Luper argues that death is a terrible thing and that Epicurus' indifference to death is badly mistaken. Death is a misfortune for us primarily because it thwarts our desires. If we have a desire we want fulfilled, then death may prevent its fulfillment; if we enjoy living, then dying prevents us from continuing to do so; if we have hopes and aspirations; then they will be frustrated by our deaths; if we have reasons to live, then we have reasons not to want to die. For all these reasons death is a grave misfortune.

Summary - Death is a misfortune because it thwarts our desires.

Summary of George Pitcher's, "The Misfortunes of the Dead"

By definition harms are events or states of affairs contrary to your desires or interests. Of course we cannot be killed or experience pain after death - the post mortem person can't be harmed - but we can have desires thwarted after death - the ante mortem person can be harmed. If I desire to be remembered after I die with a statue on campus and you destroy the statue, then you have defeated my desire and harmed the ante-mortem person I was. Pitcher doesn't think he needs to invoke backward causation to make his argument work. All he needs to show is that being harmed does not entail knowing about the harm.

Summary - We are harmed by death because while alive the knowledge of death harmed us.

Oswald Hanfling on Death and Meaning

Hanfling accepts as obvious the claim that meaning is affected by our knowledge of death, and agrees that "death casts a negative shadow over our lives." Moreover, while the naturalness of death may provide some consolation from our anxiety, it does not show that our apprehension about death is misplaced. But are there any overriding reasons to regard death as mostly evil? Hanfling does not think such reasons are convincing. For while I may wish to fulfill some goal and regret that I cannot, I will not be harmed after my death by the fact that I didn't fulfill that goal. Or though one might argue that death is bad because life is good, it is unclear whether life in general is good.

Summary - The thought of death is unpleasant, but we cannot determine the implications of death for meaning.

Summary of Stephen Rosenbaum's "How to Be Dead and Not Care: A Defense of Epicurus"

In his 1986 piece, "How to Be Dead and Not Care: A Defense of Epicurus," he rejects the view that death is bad for the person that dies, undertaking a systematic defense of the Epicurean position. As we have seen, while we ordinarily think that death is bad for the person that dies, Epicurus argued that this is mistaken. And, since fear of something that is not bad is groundless, it is irrational to fear death.

Summary - The Epicurean argument that death is not bad and nothing to fear is sound. Being dead is not bad for the dead person.

Summary of Vincent Barry's Philosophical Thinking about Death and Dying

One of Barry's main concerns is whether death is or is not bad for us. As he notes, the argument that death is not bad derives from Epicurus' aphorism: "When I am, death is not; and when death is, I am not." Epicurus taught that fear in general, and fear of the gods and death in particular, was evil. Consequently, using reason to rid ourselves of these fears was a primary goal of his speculative thinking. A basic assumptions of his thought was a materialistic psychology in which mind was composed of atoms, and death the dispersal of those atoms. Thus death is not then bad for us since something can be bad only if we are affected by it; but we have no sensation after death and thus being dead cannot be bad for us.

Epicurus' argument relies on two separate assumptions - the experience requirement and the existence requirement. Counter arguments attack one of the two requirements. Either they try to show that someone can be harmed without experiencing the harm, or that someone who is dead can still be harmed. While there are many arguments that death makes life meaningless, there are also many philosophical arguments, in addition to religious ones, that death makes life meaningful. These latter arguments all coalesce around the idea that death is necessary for a life to be truly human. In opposition to all those who think death does or does not give meaning to life are those who argue that life has or lacks meaning independent of death. In other words, they argue that life gives or does not give meaning to death, thereby turning all our previous considerations upside down. But how does a life give or not give death a meaning?

Summary - It is uncertain if death is a good or bad thing. The connection between death and meaning is that thinking about death can make a life subjectively meaningful.

Summary of Tolstoy's, The Death of Ivan Ilyich

Leo Tolstoy's short novel,The Death of Ivan Ilyich, provides a great introduction to connection between death and meaning. It tells the story of a forty-five year old lawyer who is self-interested, opportunistic, and busy with mundane affairs. He has never considered his own death until disease strikes. Now, as he confronts his mortality, he wonders what his life has meant, whether he has made the right choices, and what will become of him. Tolstoy's story forces us to consider how painful it is to reflect on a life lived without meaning, and how the finality of death seals any possibility of future meaning. If, when we approach the end of our lives, we find that they were not meaningful - there will be nothing we can do to rectify the situation.

Summary - Confronting the reality of death forces us to reflect on the meaning of life.


Monday, January 18, 2016

The World Health Organization (WHO) position on aging is, as noted a few months back, well-written, incoherent, bureaucratic garbage. In essence it is a call to do nothing meaningful to treat the causes of aging, produced by people distant from the research community, who disregard the last decade of work and current scientific views on aging and longevity. This is unfortunately par for the course for large governmental organizations of this nature. Some researchers and advocates, such as those involved with the International Longevity Alliance, are keen on using the WHO as a megaphone to amplify advocacy for the treatment of aging as a medical condition, however, and so have been working behind the scenes to try to make the WHO position statement less terrible.

The World Health Organisation has revised its Draft Global Strategy and Action Plan on Aging and Health after the consultation with a delegation of experts as well as an extensive online survey. Here we report on the developments of the consultation where some members of our parent organization the International Longevity Alliance (ILA) attended and many of our organization participated in the online survey about aging. The Consultation meeting was organized at WHO headquarters in Geneva following the survey on October 28-30, which brought together all regional WHO offices, delegates from 75 member states and around 35 non governmental organizations. The delegations included a wide range of research institutions, regional, national and international organizations, as well as experts from various WHO technical departments and other leaders in the field of aging research.

Based on the findings of this Global consultation meeting and survey, a new revised Draft Global Strategy and Action Plan on Aging and Health, has been proposed for consideration by the WHO Executive Board. A summary of this consultation is available to view at the WHO website and a PDF of the proposed action plan can be downloaded directly. There is now clear evidence that the longevity community is having a decisive impact. This includes the work done by the Russian and Kazakhstanian delegations and, of course, the ILA letter writing campaign! There were interventions in favor of longevity and biomedical research promotion by many delegations including experts from Algeria, Belarus, Brazil, Finland, Germany, India, Nigeria, Norway, Qatar, Sri Lanka, Switzerland, and the United Kingdom.

The good news is that it looks like the WHO agrees that biological aging leads to many of the recognised diseases of aging, whether or not that means aging is a disease itself! So now let's take a look at some of the highlights of this consultation below.

1. The WHO Strategy Vision is reworded here: "25. The strategy's vision is a world in which everyone can live a long and healthy life" instead of "A world in which everyone experiences Healthy Aging" as per the initial draft. This is a historical recognition of healthy longevity as a priority goal at the UN level.

2. The destructive and complex nature of the biological aging process is described, perhaps for the first time at the UN level: "15. The changes that constitute and influence aging are complex. At a biological level, the gradual accumulation of a wide variety of molecular and cellular damage leads to a gradual decrease in physiological reserves, an increased risk of many diseases and a general decline in capacity. But these changes are neither linear nor consistent, and they are only loosely associated with age in years".

This demonstrates that despite using the controversial term "healthy ageing" (while some researchers are calling for acknowledging ageing as a disease), the WHO recognises ultimately that biological aging is counter to good health. The Revised Draft Global Strategy and Plan puts greater emphasis on the goal of maintaining people's health while they grow chronologically older, while keeping functional ability maintenance in case of age-related disabilities as another priority. It is a promising change in stance, that recognises biological aging as a factor of ill health. This seems to proceed a changing view on how aging should be viewed and the consideration that it is amenable to intervention.

Of course we aren't quite finished yet, but all the same there is clear movement in established opinions. Now we have established impetus in the right direction, it is hopefully only a matter of time, before our hard work pays off in terms of medical interventions that will be available to people worldwide. It is becoming increasingly obvious that things cannot remain the same, that aging is a problem to public health, and that it is indeed desirable to do something about it.

Monday, January 18, 2016

A group of clinicians involved in delivering stem cell transplants to patients to treat various age-related conditions have observed temporary reversal of hair graying following treatment. Their open access paper is offered in the spirit of "look at this interesting thing that happened," and there is no deep analysis of underlying mechanisms - though it isn't hard to speculate based on what is known. The approach used mesenchymal stem cells (MSCs), which in the current standard treatment models are thought to produce benefits through signaling that alters the behavior of native cells. The transplanted cells don't live for very long and don't themselves work to maintain tissues. MSC transplantation is known to temporarily reduce chronic inflammation and measures of oxidative stress in tissues, as well as spurring native stem cells to restored activity.

Hair graying is generally considered to be some mix of (a) damage and decline of the melanocyte cells responsible for coloring hair, present in the hair follicles, and (b) dysfunction in the activity of melanocytes and related cell populations caused by the higher levels of oxidative stress that accompany aging. These cells are more sensitive to that increase than most, and so this is one of the first signs of aging. Hair greying can be reversed by treatments that suppress oxidative stress, as has been demonstrated in recent years. So joining all the dots, it isn't unreasonable to propose that stem cell transplantation is temporarily reducing oxidative stress to levels low enough to put melanocytes back to work - but that would have to be confirmed with more careful studies.

Adipose derived autologous mesenchymal stem cells have been transplanted and tested for their ability to regenerate tissues for several indications. We treated a total number of 14 patients between the age group 38-75 years, out of them 4 subjects had completely grey hair. Three subjects were males and one female. While treating these patients for their various age related neurodegenerative disorders with autologous mesenchymal stem cells for their regenerative and rejuvenating properties, we accidentally observed a transition of hair colorations from mostly grey to black in all the 4 elderly patients. Each patient received more than one session within a time frame of 2-3 weeks. Each time the MSCs were administered by spinal intrathecal route (20 million) and intravenously (20 million) after over a period of 20 minutes. There were no notable complications post transplantations. We observed remarkable improvement in the neurological status (being reported separately) and the only adverse effect was transient headache.

In observed patients about 50% of the hairs were seen turning black after duration of 3-6 weeks. This was observed on the scalp and on the beard as well. However, the effect was not permanent; as the age progressed the greying process continued. The longest period of follow up was 20 months for all the 4 patients. All the subjects continue to have some black hairs but were now lesser in density and number. This may be through positive activation and regeneration of melanocyte stem cells in the hair follicular niche. In this paper we intend to report this unique observation which may lead to further research. We do not view MSCs as a treatment modality for grey hair. However this is an incidental finding, so far not reported in the literature.

Tuesday, January 19, 2016

Near all studies on the matter show that regular moderate exercise improves health and extends healthy life span, though the effects on overall life span are mixed, unlike the data for calorie restriction. With the advent of small, cheap accelerometers, the research community is now making headway into determining the dose-response curve for exercise, the degree to which more is better:

The majority of citizens in developed countries should not be concerned by potential harm from exercise but rather by the lack of exercise in their lives. Small amounts of physical activity, including standing, are associated with a lower risk of cardiovascular disease, but more exercise leads to even greater reduction in risk of death from cardiovascular disease. "The evidence with regard to exercise continues to unfold and educate the cardiovascular clinical community. The greatest benefit is to simply exercise, regardless of the intensity, while the danger is two-fold: to not exercise at all or to exercise intensely, without due preparation." Studies have shown that regular physical activity reduces a person's risk of death from cardiovascular disease; however, only half of U.S. adults meet the federally recommended guidelines of 150 minutes per week of moderate intensity exercise or 75 minutes per week of vigorous intensity exercise.

Scientists examined recent research on the volume and intensity of aerobic exercise required for favorable cardiovascular health. With the rise in participation in endurance races over the past three decades, they also address the question of whether or not there is an amount of exercise that increases cardiovascular disease risk. They found that moderate and vigorous intensity exercise in amounts lower than the 2008 Physical Activity Guideline recommendations still significantly lower mortality risk in different populations around the globe. Increasing the amount of moderate intensity exercise a person engages in results in increased reductions in cardiovascular disease mortality; however, the reductions in cardiovascular mortality benefits from vigorous intensity exercise do level out at a certain point.

There is no evidence for an upper limit to exercise-induced health benefits and all amounts of both moderate and vigorous intensity exercise result in a reduction of both all-cause and cardiovascular disease mortality compared to physical inactivity. While controversial, a few limited studies have raised the concern that high volumes of aerobic exercise may be as bad for cardiovascular outcomes as no exercise at all. Researchers suggest that the possibility that too much exercise training could be harmful is worthy of investigation, but research results show that even for the very active, life-long endurance athletes, the benefits of exercise training outweigh the risks.

Tuesday, January 19, 2016

Aubrey de Grey of the SENS Research Foundation recently spoke on the future of rejuvenation biotechnology at a technology conference in Beijing. The Chinese language press have the text of his presentation - you'll need to use a tool such as Google Translate, though note that Chinese is one of those languages with a way to go yet in the quality of the automated translation.

This is the second time I came to Beijing, the first time I came to Beijing a decade ago, and I want to tell you the last time I came here, I was very disappointed, because few people heard my message. For I represent academia, and as a scholar I want to let many people know what I am talking about. Today we are here at the future forums, and earlier we have heard a lot of wonderful speech. Venture capitalists talked about a lot of big companies and big capital. Now we are in a good position to talk about control of aging, which is what we mean by rejuvenation biotechnology. Our technology in constant development and innovation in rejuvenation can help us achieve this vision, so that maybe in the future we can develop the ability to control the emergence of age-related human diseases, and and as a consequence improve the people's quality of life and well-being. As all human beings suffer the problems of aging, the problem may be the most serious in China, in the world, too, and so I believe that the issue of aging is a very difficult problem, is a very important issue, and is the human face put on a very grim reality. So today I want to discuss a topic of rejuvenation biotechnology, using biotechnology to achieve rejuvenation.

I do believe it will happen soon, and I will give you two reasons to make you believe as well. First and foremost we have to accept that the scientific community has accepted our view on rejuvenation biotechnology: we have published scientific papers and articles in top journals, and thus scientists have accepted that these researchers are leading scientists. Many researchers in different scientific fields have collaborated on this project. I can also point to our leading scientific advisers, who provide us with support and endorsement. Another way to make everyone believe that this is the fact, that I am not blindly optimistic, is that I can show you the work in progress. This image under the microscope is the number one killer in the world, the foam cells and damaged lipids that gather to block our blood vessels. With the continuous accumulation of damage and waste in blood vessels, macrophages continue to arrive and turn into more foam cells to make the problem worse. We have found a way to prevent this from happening, using bacterial enzymes that naturally consume these waste compounds, we modify them so that they can be effective in therapy. We have shown that using these bacteria, through genetic modification, it is possible to reduce the body's sterol content, which will improve healthy longevity.

We do not know how rapidly any of the advanced science needed will arrive, but it is likely that we can achieve the goals of rejuvenation biotechnology in 20-25 years to achieve, which would give us enough time to benefit. With time left in my last moment, I would like to talk entrepreneurial spirit: I have created this organization, the SENS Research Foundation, and I now have ten to twelve years of history working towards these goals in non-profits rather than the private sector so as to obtain the support of the scientific community. The science has made great progress, and now investors are interested - so you can get involved in this, and make a lot of profit. I think it is not the case that therapies will appear in twenty years, but rather that the first medical technology will be implemented in the next few years. People will realize that we can end aging as the technology appears, and will get involved. As things stand now worldwide, especially in China, the world's worst aging problem at the moment is that people have not yet begun to be involved.

Wednesday, January 20, 2016

Cellular quality control mechanisms such as autophagy are though to be an important part of the metabolic response to calorie restriction (CR), contributing to its ability to slow aging and lengthen life in most species and lineages tested. Here researchers dig into the biochemical details of the calorie restriction response in muscle tissue, and in this context it is interesting to note that calorie restriction has been shown to slow age-related loss of muscle mass and strength in mice:

It has been hypothesized that CR exerts its beneficial effects via a hormetic response that results in activation of protein chaperones, e.g. heat shock proteins (HSF), and autophagy, as well as in the inhibition of inflammation in rodents. However, the hormonal and molecular effects of long-term CR with adequate nutrition on stress-related factors have not been carefully evaluated in humans on long-term severe CR. In this study, we found that serum cortisol concentration, a major stress hormone, was significantly higher in the CR group than in sedentary or exercising subjects eating a Western diet and was notably inversely correlated with serum TNF-α levels. We also found that key stress-induced cytosolic chaperones and autophagic transcript and protein levels were significantly higher and inflammatory factors were lower in the skeletal muscle of CR individuals than in age-matched controls, providing evidence for a CR-induced enhancement of protein quality control and of the ability of cells to eliminate damaged proteins and organelles.

Chronic CR has consistently been shown to cause a dose-dependent moderate elevation (i.e., 30%-50% above baseline) of circulating corticosterone levels in both rats and mice. Data from a recent randomized clinical trial of 2-year mild CR in nonobese humans has shown a small, 7% transient increase of serum cortisol levels. Here, we show that serum cortisol concentration is ∼30% higher in humans practicing long-term severe CR than in age-matched control subjects. Our data suggest that the mechanism responsible for the sustained increase in serum cortisol concentrations induced by CR is likely related to CR itself, rather than changes in body composition, because the equally low body fat and leptin levels of the exercisers were not associated with high cortisol in the exercisers. Elevation of glucocorticoid levels is an essential adaptation required to cope with a variety of stressors, and in CR animals, high corticosterone level has been shown to play a role in inhibiting inflammation and cancer progression.

Whether the increased level of cortisol plays a direct role in upregulating HSPs is unclear. However, it is well known that CR increases HSF1 and HSP70 levels in rodents. Here, we show that long-term CR significantly upregulates transcripts along the HSF/HSP70 pathway and increases HSP70 and GRP78 protein levels in the human skeletal muscle. Because aging is associated with reduced protein folding capacity and ability to maintain homeostasis in response to stress, these data suggest that CR in humans prevents this decrease and may be involved in the slowing of age-dependent accumulation of damaged and dysfunctional proteins. We also found that chronic CR in humans is associated with lower inflammation.

Wednesday, January 20, 2016

Methods of preserving the brain for the long term immediately following death include cryonics, currently a long-standing but small industry, and plastination, a form of chemical fixation that has not yet progressed to the point of commercial availability for this purpose. Why preserve the brain? Because it is a favorable alternative the the oblivion of the grave, one that offers the possibility of a return to active life in a future in which advanced molecular nanotechnology and cellular medicine can be used to restore a preserved individual. In this age of rapid progress in molecular biochemistry more consideration is being given to proving that ideal preservation techniques do in fact preserve the structures thought to encode memory, as if that is not the case then the whole business is moot. Fortunately memory does appear to be preserved based on evidence to date, but the careful consideration continues:

Although most people usually focus on the brain cells when discussing brain preservation techniques, extracellular space is also worthy of consideration. In vivo, extracellular space makes up around 1/5th of overall brain volume, although this varies based on brain region, developmental stage, and surely many other factors. Over the past few months, researchers published two articles relevant to the preservation and importance of the extracellular space. As a very brief summary, one of the things that the authors show is that extracellular space is dramatically lower (less than 1%) following perfusion fixation than it is following their optimized chemical tissue fixation protocol, which involves varying the osmolarity of the buffer. And among other things, they show that cryofixation of tissue slices better preserves extracellular space as it occurs in vivo in comparison to conventional fixation procedures.

The mechanism for these findings is simple: fixation, as well as the ischemia that typically precedes it, causes a dramatic decrease in the number of extracellular ions, which causes water to enter cells and for them to expand. In particular, it appears that astrocytes expand preferentially during this process. One reason that this matters for people interested in brain preservation is that any information contained within or dependent upon the extracellular space is especially likely to be affected by most extant brain preservation procedures. For example, one extracellular structure proposed to play a role in memory is the perineuronal net. So it's worth asking the question: do perineuronal nets survive fixation? And evidence suggests that they do - indeed, some researchers thought that they were a fixation artifact!

Since water fluctuations are common in vivo, and animals often retain memories following ischemic events that presumably lead to dramatic local osmotic shifts of water, it is likely that most key elements of memory are encoded - or at least, encoded redundantly - by more stable structures than those which would be affected by extracellular water fluctuations. That said, it would be quite worthwhile to consider systematically what structures appear to hold information in the extracellular space, and evaluate whether they are preserved by any brain preservation procedure that purports to retain key elements of personal identity, such as memory.

Thursday, January 21, 2016

Many research groups are looking for protein levels and mechanisms that act as regulators or proximate causes of age-related reductions in stem cell activity. Here is one example, focused on tendon tissue:

Aged or degenerated tendons respond poorly to classical medicinal treatments, which often leads to rupture reoccurrence. Until now, several major factors contributing, directly, or indirectly, to tendon aging and degeneration were identified: disturbance of extracellular matrix turnover; decreasing cell numbers and metabolic activity; tenocyte dedifferentiation; and depletion or senescence of the local stem/progenitor cell pool. Tendon stem/progenitor cells (TSPCs) were first reported in 2007 as as plastic adherent cells that express classical stem cell markers while maintaining the expression of typical tendon-lineage genes. It was proposed that tendon healing is carried out mainly by such local tendon progenitor cells, which actively migrate to the wound site and engage in cell proliferation. However, TSPC features alter during tendon aging and degeneration. Aged TSPC display a profound self-renewal deficit accompanied with premature entry into senescence and substantial changes in their transcriptome. Furthermore these cells exhibit severely dysregulated cell-matrix interactions, motility and actin dynamics.

In the current study, we report for the first time that aged TSCP have dysregulated cell-cell interactions mediated by the ephrin family. By comparing young to aged TPSC we found that the expression of several ephrin members is significantly changed. Next, by carefully examining the role of two main candidates, namely the receptors EphA4 and EphB2, we could demonstrate that by activating their reverse signaling we can normalize several of the aged TSCP deficits, the migratory ability and actin turnover. However, only EphA4 stimulation improved aged TSPC cell proliferation to levels comparable to young TSPC. We propose that dysregulation in EphA4-triggered bi-directional signaling may contribute to the inferior and delayed tendon healing common for aged individuals, which will be the focus for upcoming investigation.

Thursday, January 21, 2016

Researchers here demonstrate the ability to grow neural networks, consisting of neurons linked by long axons, in the laboratory and transplant them into rats, where they integrate with brain tissue. This is a strategy that might in the future be employed to augment the natural plasticity of brain tissue, or repair damage in the central nervous system, as long axons don't to tend to regrow on their own:

Complex brain function derives from the activity of populations of neurons - discrete processing centers - connected by long fibrous projections known as axons. When these connections are damaged, by injury or diseases such as Parkinson's or Alzheimer's disease, they, unlike many other cells in the body, have very limited capacity to regenerate. Researchers have shown that lab-grown neural networks have the ability to replace lost axonal tracks in the brains of patients with severe head injuries, strokes or neurodegenerative diseases and can be safely delivered with minimal disruption to brain tissue.

Researchers have been working to grow replacement connections, referred to as micro-tissue engineered neural networks (micro-TENNS), in the lab and test their ability to "wire-in" to replace broken axon pathways when implanted in the brain. They have advanced the micro-TENNs to consist of discrete populations of mature cerebral cortical neurons spanned by long axonal projections within miniature hair-like structures. Preformed micro-TENNS can be delivered into the brains of rats to form new brain architecture that simultaneously replace neurons as well as long axonal projections. "The micro-TENNS formed synaptic connections to existing neural networks in the cerebral cortex and the thalamus - involved in sensory and motor processing - and maintained their axonal architecture for several weeks to structurally emulate long-distance axon connections."

In the latest paper, the research team report on a new, less invasive delivery method enabled by applying an ultra-thin coating to the micro-TENNs using a gel commonly found in food and biomedical products. This new biomaterial strategy allows the encapsulation of fully formed engineered neural networks for insertion into the brain without the use of a needle. "We searched for materials that could form a hard shell that would soften immediately following insertion to better match the mechanical properties of the native brain tissue." This, the team hypothesized, would minimize the body's reaction and improve the survival and integration of the neural networks. The additional coating was not detrimental to the number of surviving neurons, and the needleless method substantially reduces the implant footprint, suggesting that it would cause less damage and thus provide a more hospitable environment for implanted neurons to integrate with the brain's existing nervous system.

Friday, January 22, 2016

Hypertension, chronic high blood pressure, is largely a consequence of arterial stiffening, which in turn is caused by processes such as low-level accumulation of cross-links in the extracellular matrix, a form of metabolic waste that our biochemistry cannot effectively remove. One of the many harms done by hypertension is to cause a slow remodeling of portions of the heart, making it larger, weaker, and more prone to failure. The ideal solution to this problem is to remove the root cause - break the cross-links and repair the other forms of cell and tissue damage that degrade the elasticity of blood vessel walls. The medical research community is, as a rule, much more focused on proximate causes and their manipulation, however. So here, researchers identify genes and proteins necessary for the untoward growth and weakening of the heart in response to hypertension - the first step to a treatment that fails to address hypertension, but would diminish one of its consequences. This is the sort of outcome that tends to emerge from restricting the view to proximate causes; just as much time and effort goes into producing a therapy, but the therapy is limited in its scope, and the underlying problem continues on to cause numerous other issues:

Researchers have identified how two proteins, p38 gamma and p38 delta, control the growth of the heart and its adaptation to high blood pressure. The results not only increase our understanding of the mechanisms used by cardiac cells to grow and adapt, but could also help in the design of new strategies to treat heart failure caused by excessive growth of the heart. The heart adapts to the changing needs of each stage of life by adjusting its size. In this way the heart grows in line with the rest of our body, including during pregnancy, in a process called cardiac hypertrophy. However, excessive physical exercise, hypertension, and obesity can trigger excessive heart growth (pathological hypertrophy), a situation that can lead to a heart attack. Understanding the molecular processes that regulate heart function and growth is therefore of immense importance.

The researchers found that p38 gamma and p38 delta regulate the growth of the left ventricle, the largest and strongest heart chamber, responsible for pumping oxygenated blood to the body. The research team showed that the hearts of mice lacking these proteins are smaller than normal. These hearts, although they function normally, are incapable of responding to external stimuli, such as high blood pressure. The discovery advances understanding of the mechanisms through which heart cells grow and adapt. Moreover, "this new information could help in the design of new strategies to combat heart conditions caused by anomalous growth of heart muscle."

Friday, January 22, 2016

Aging is caused by a number of processes, each of which contributes its own form of cell and tissue damage to the bigger picture of breakage and decline. When shaping research strategy, it seems sensible to ask which of these processes is the most important cause of aging: there are limited funds for scientific and clinical development, and we'd like the research community to start at the top of the list. Is this a question that has a simple answer, however? The author of this open access paper would say no, pointing out that the processes and damage of aging interact with one another, and even in very simple models of interacting systems you cannot talk about significance of a single process in isolation, as interacting processes have synergies.

The background for this discussion is another question: can we obtain meaningful benefits to longevity by fixing just one of the forms of damage that cause aging? Insofar as there is a consensus at the moment, that consensus is "no." Even a perfect repair of one cause of aging will still leave medical conditions largely or completely caused by the others, conditions that will kill people on the same schedule as the smaller set of age-related diseases that are prevented or diminished by this narrow scope repair. Taking the other side, the author here proposes that the existence of interactions between forms of damage means that repair of one form of damage may indeed produce a large benefit - but whether this happens in reality is strongly dependent on details that we'll only learn in the near future by building and using rejuvenation therapies capable of this repair:

It becomes clearer and clearer that aging is a result of a significant number of causes and it would seem that counteracting one or several of them should not make a significant difference. Taken at face value, this suggests, for example, that free radicals and reactive oxygen species (ROS) do not play a significant role in aging and that the lifespan of organisms cannot be significantly extended. In this review, I point to the fact that the causes of aging synergize with each other and discuss the implications involved. One implication is that when two or more synergizing causes increase over time, the result of their action increases dramatically.

Here is a summary of what we have learned so far as a result of the analysis of aging and its mechanisms in yeast: during the replicative lifespan of yeasts some damage, such as protein aggregates and some mutations, accumulates and this potentially may lead to further damage. The damage accumulated during the replicative lifespan, but not due to mutations, is sufficient to eliminate the ability of the cells to reproduce but does not kill them in the literal sense of the word. In the subsequent period, as a result of further damage, aging accelerates, likely because the causes of aging, whose levels increase, synergize with each other and this finally leads to death. The synergizing causes likely include genomic changes and aggregates formation, as well as other forms of damage such as oxidative stress.

Due to the existence of synergistic interactions between the causes of aging, our perception of which causes are most important is influenced by a relativistic effect. Thus, to the observers investigating the toxicity of free radicals and/or their role in aging, they appear as the main cause, while the other causes appear insignificant, but the opposite appears to be the case for those that study other causes. Both are correct but also incorrect, specifically since the "other causes" are not insignificant! In reality, the processes are interdependent and it cannot be said that a given cause is responsible for 3% of aging, while another one for 33.3%. This undermines the arguments of those who suggest that the free radical theory of aging is dead or about to die, while certainly the free radicals and ROS are not the only important causes of aging. The same could be said for other theories, so such theories are still alive, at least for now. Since the causes of aging are synergizing, it is also concluded that none of them is the major one but many including free radicals, etc, play significant roles. It follows that health/lifespan might be significantly extended if we eliminate or even attenuate the increase of a few or even just one of the causes of aging.


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