Fight Aging!

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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Contents

• Blind Upon the Eve of Apotheosis
• The Hedonistic Imperative, Followed to the Ends of Paradise Engineering
• Adverse Interactions Between Natural Selection and the Modern Environment
• Exosomes From Induced Pluripotent Stem Cells Make Skin Cells More Resilient
• An Unconvincing Desire for Mortality
• Chimeric Antigen Receptor Therapy, but Using Natural Killer Cells
• Cleara Biotech Launches to Develop Senolytic Therapies Based on FOXO4-DRI
• Senolytics Reduce Age-Related Dysfunction and Extend Remaining Life Span by 36% Following Administration to Old Mice
• Endothelial Cell Dysfunction as the Early Manifestation of Small Vessel Disease
• More than You Wanted to Know About NAD+ in Metabolism and Aging
• A Life Lived is No Justification for a Death Unchosen
• Activation of the Anaphase Promoting Complex to Enhance Genomic Stability
• Upregulation of FGF21 to Prevent Visceral Fat Gain and Consequent Diabetes
• Arguing that Cytomegalovirus is Beneficial for Old Immune Systems
• Evidence to Show that Multivitamins Do Not Aid Cardiovascular Health

Blind Upon the Eve of Apotheosis
https://www.fightaging.org/archives/2018/07/blind-upon-the-eve-of-apotheosis/

Our present age of technology and accelerating progress is the first of its kind for our species. It commenced a few short centuries ago with subtle changes in wealth, agriculture, and life expectancy that compounded to form the foundations for the Industrial Revolution. It was a dramatic break with millennia in which stasis or the cyclic advance and retreat of applied knowledge - of civilization - were the norm. In our era, it is instead the case that progress today reliably creates the potential for greater and faster progress tomorrow. The most important consequence of this is arguably not that we now lead rich lives of greater wealth, capacity, and comfort, but that the technologies of tomorrow will radically transform our selves and our nature: these are the last decades of humanity as we know it. Human nature and the human condition as it has existed since the Great Leap Forward, some 50,000 years ago, will become malleable. We will be able to improve upon the human body and human mind. What comes next is something far greater than humanity, both for the billions of individuals who see the transformation from end to end and for our societies as a whole.

It has been argued that we have already changed ourselves greatly through technology. That the humans of Ur were far removed from the small and violently suspicious bands of humans who coexisted with their Neanderthal near relatives. That today's humans of internet and mobile phones are far removed from the humans of Ur and earlier cities. That technologies such as writing and global telecommunications, or even simply the size and density of population, leads to very different minds grown from the same genetic basis. On the face of it, this seems unlikely, however. Upon the eve of apotheosis, in a world linked by networks of communication and rapidly advancing technology, a glance at the activities of humanity finds any given populace worshipping civic idols and chieftains, in ways that are in essence little different from those of the ancient world, or reencting the politics of the greens and the blues of the Byzantine empire. Further, the past century has seen any number of small bands of humans brought into the modern era by neighboring peoples, with no signs of any fundamental difference in their human nature as a result of comparative isolation and lack of technology.

Past technological progress has not changed what it is to be human, the shape of our minds. What comes next will be very, very different in scope and outcome. It will start with some combination of a progressive reverse engineering of the brain, advanced biotechnology capable of altering and improving upon existing organ function, the development of interfaces between neural architecture and computing hardware, and software emulation of functional neural tissue. All of these lines of research are well established today, albeit in comparative infancy. They will converge into the ability to run minds in hardware and software, to alter the way in which minds function, to extend biological minds, and to move them into hardware, piece by piece. We presently forget 98% of everything we experience. That will go away in favor of perfect, controllable, configurable memory. Skills and knowledge will become commodities that can be purchased and installed. We will be able to feel exactly as we wish to feel at any given time. How we perceive the world will be mutable and subject to choice. How we think, the very fundamental basis of the mind, will also be mutable and subject to choice. We will merge with our machines, as Kurzweil puts it. The boundary between mind and computing device, between the individual and his or her tools, will blur.

Over the course of the 21st century, people will have access to an increasing array of options when it comes to enhancing the function of the mind and the body. The young of today will live to see all of that span, and more. Aging will soon become a treatable medical condition, its causes addressed by therapies that repair the molecular damage that accumulates in old tissues. The human genome will become fluid, the subject of any number of treatments that alter genes or gene expression in adult tissues in order to achieve specific benefits such as greater muscle mass or increased resistance to disease. Somewhere down the line, biotechnology and nanotechnology will merge to produce technologies such as artificial cells and cell-like machines, vastly more efficient at specific tasks than their biological counterparts. Biology will become an option, rather than the present mandate. People will be able to move to a more resilient vehicle for the brain than the present human body, and even the brain may be swapped out for better hardware, through a slow process of replacement and integration, one neuron at a time exchanged for a nanomachine.

Piece by piece, we will be able to choose physical immortality. Choose our physical forms. Choose exactly how our minds function. Choose how we think and feel. Choose exactly what being human is for each of us. A great branching in the diversity of minds and appearances will spring forth from our present uniformity in a matter of mere decades. The population may well expand greatly as well; minds in hardware and software can be copied. There are no limitations on the pace of reproduction in such a world, nor would such minds necessarily need to consume anywhere near the same resources as present humans. If we choose to believe that acceleration in technological development is, at root, largely a function of total human population and the degree to which people communicate with one another, then departing from our biological roots will enable the acceleration to continue far past its present limits.

That isn't just a matter of population, however. The pace of progress today bumps up against the limits imposed by organization of efforts, in that it takes a few years for humans to digest new information, talk to one another about it, decide on a course of action, gather together a group, raise funds, and start working. There is no necessary reason for any of these parts of the process to take more than a few seconds, however: consider a world in which human minds run far faster, because they run on something other than biological neurons, because they run hundreds of distinct streams of consciousness simultaneously, and because they are augmented by forms of artificial intelligence that take on some of the cognitive load for task assignment and decision making.

It is, frankly, hard to even speculate about the potential forms taken by society in such an environment. Technology clearly drives human organizational strategies and struggles, for all that the minds of prehistory, of Ur, and of our modern times are all the same. In the past, evolution of society was largely shaped by the ability to communicate over distances and by the size of the population. In the future it will be shaped to a far greater extent by the way in which intelligences think and feel, and the way in which their minds depart from the present standard for human nature. We struggle to model human action in the broadest sense of economic studies, and I suspect that this will be true for any society of minds, no matter how capable they are. The complexity of the group always exceeds the capabilities of any individual or research effort within that group. We can do little more than point out incentives and suggest trends that are likely to emerge from those incentives.

Nonetheless, the transition to what comes after humanity will come to pass, at some pace. Not as rapidly as some would like, in part because organizational matters will continue to happen slowly until minds are enhanced. Yet those of us who are young enough or fortunate enough to see the transition from end to end, perhaps with the aid of the first functional anti-aging therapeutics, will have the opportunity to become entities so capable, different, and vast in comparison to present humans that our ancestors would have called them gods or spirits. It will happen gradually, step by step, each such step forward a sensible choice to participate in an enhancement that brings benefits or a desired change, but in the end the sum of it will indeed be an apotheosis. Humans will become what they desire to become, leaving humanity as we presently understand it far behind. The present human condition is a seed, a childhood, and it will just as inevitably come to an end as we grow to reach our true potential.

The eyes of the world are by no means as closed to this future as was the case even a few short decades ago, when transhumanism was a niche vision. Posthumanity has been explored in fiction, discussion, and research far more extensively. Yet most people live in the here and the now, and act as though next year will be same as this year. It is a strange state of mind given that we are so evidently alive in a time of rapid change. Most of us have passed through the development of personal computing, the internet, and pervasive telecommunications, and have personal points of comparison for the enormous changes to habit and capabilities that have taken place. Equally, most of us squabble over politics, the blues and the greens again, save for retirement, and otherwise in thought and deed anticipate a life that has the same trajectory and span as that of our grandparents. Becoming gods is not on the agenda, not in the plan. It is still inevitable, however. Few will turn down longer lives, perfect memory, immunity to disease, the ability to run multiple streams of consciousness, and much more, when those capabilities exist. Scientists will build the basis for each incremental advance, entrepreneurs will bring it to the masses, and people will choose to better themselves.

Perhaps it will come slowly, perhaps rapidly. But insofar as there is godhood ahead, most will stumble into it without that ever being the intended goal. It is a strange thing to consider, this future of accidental deities, spawned from our largely blind society of people near entirely focused on unrelated minutiae. Does it even make much difference, we might ask, to stand with eyes open and see what is coming?

The Hedonistic Imperative, Followed to the Ends of Paradise Engineering
https://www.fightaging.org/archives/2018/07/the-hedonistic-imperative-followed-to-the-ends-of-paradise-engineering/

The two strongest urges are firstly to seek pleasure, in all its myriad forms, and secondly to evade suffering, in all its myriad forms. The primordial glass half full and glass half empty of the human condition. These are the two sides of the hedonistic imperative, and are perhaps the most important motivations guiding the development of technology. Technology, and I use the word in its broadest sense, can satisfy these urges either by helping to eliminate suffering or by helping to induce pleasure. Technology to reduce suffering has throughout history largely consisted of the vast and complex fields of medicine and agriculture. On the other side of the fence, for the induction of pleasure, we find intoxicants and pharmaceuticals of other classes, as well as, arguably, every technological development that can be turned to conquest and control. Not all pleasures are good in the moral sense, or perhaps it is better to say that given our deeper origins in an animal world that runs red in tooth and claw, many of the chemical incentives inherent to our biology are triggered only through selfish and damaging acts.

There are nonetheless many pleasures that can be attained without causing harm or resorting to advanced forms of technology. Completing challenging work, triggering the evolved response to pattern and surprise that is humor, simply being present in an attractive location, participating in the puzzle palace of human interactions, physical or otherwise, and so forth. Altering the operation of our brains to induce pleasure without the need to undertake much of that work was a fairly early innovation, however. The point of much of technological progress is to achieve better results with less effort, after all. The logical end of that line is wireheading or a life science equivalent yet to be designed: an augmentation in the brain, a button that you push, and the system causes you to feel pleasure whenever you want. There are numerous other alternatives in the same technological genre that seem plausible, such as always-on happiness, regardless of circumstances.

This sort of thing makes many people nervous, and, sadly, rarely for useful reasons. One doesn't have to look much further than the continued efforts to make mood-altering drugs illegal to see a panoply of bad motivations and perverse incentives exhibited front and center. Not every drug user becomes an addict, and self-destruction through addiction is clearly something that people do to themselves, only aided by the drug. A drug is an enabling technology, like a hammer, and neutral in and of itself. There remains considerable uncertainty today over who is more or less prone to addiction, and why, though there are plenty of addictive games against which you can test yourself in that way, such as those in which the makers gleefully exploit the effects of variable reinforcement on the human mind.

That said, I suspect that even the most self-controlled of individuals has sufficient self-doubt to be wary of the advent of implementations of wireheading that might be, say, a hundred times better, cheaper, and safer than today's most influential mood-altering drugs. What would you do in the presence of that potential option to substitute for the hedonic treadmill of work and reward? Little Heroes by Norman Spinrad is a worthy, albeit partial, fictional exploration of that question, and I recommend it. It is worth asking yourself "why not gain control of my mind in this way?" - and then follow your own answers to their logical ends. That exercise will probably reveal a great deal about how you view the world and your place in it.

Reliable, safe, on-demand pleasure (or confidence, or feelings of well-being, or happiness) achieved through technologies such as wireheading is a topic that has been comprehensively explored in fiction and philosophy, and is very slowly trickling into the real world via some forms of early, only weakly effective pharmaceutical products. There is little I can add to that library here that hasn't been said well many times over. What I will say is that to my eyes this is actually the less interesting and less consequential of the two sides of the hedonistic imperative. It is the elimination of suffering, not the gaining of pleasure, that, when taken to its conclusions, will lead to a world and a humanity changed so radically as to be near unrecognizable.

Paradise engineering is a catch-all term for the creation and large-scale use of technology to build a world that satisfies the hedonistic imperative. For me at least, pleasure on demand is a nebulous, potentially dangerous, and much less important goal when compared to the concrete list of forms of suffering that we might address, especially when given that for each of these pains and lacks we can envisage the necessary technologies and changes in some detail. The hedonic treadmill may well be inextricably tied to freedom in its purest sense: the freedom to make your own choices implies the freedom to make mistakes, and pleasure and its absence are an important part of the mental machinery by which we measure our use of time and effort. Suffering, however, is not necessary in this model. Thus I see the primary task of paradise engineers as being to take the list of suffering in some approximate order from greatest and most widespread harm to least and most localized harm, and work on solutions until such time as there is no more meaningful suffering. By this I mean solutions to the actual problems, the root cause of suffering, rather than any form of shortcut akin to wireheading or other forms of augmentation of feeling. Selectively blocking all unwanted physical pain is one response to the suffering caused by an incurable fatal degenerative disease, for example, but it isn't a good response.

It might surprise some that the greatest cause of human suffering is not the inhumanity with which all too many people treat one another, individually and collectively. Nor is it the related deficits in the organization of our societies: war, kleptocracy, repression, the enforced poverty that results when the bottom rungs of the ladder of growth are removed. The greatest cause of suffering receives the least attention. It is aging, the simple biological wear and tear of the body and the structures of the brain that support the mind. It affects everyone, and it causes drawn out pain, fear, and misery, alongside the loss of dignity, opportunity, and vigor - and ultimately the loss of the self as the mind decays. A staggering number of people are presently suffering in many ways because of aging. To the degree that we think of death as a loss and a form of suffering, then we should be prompted by the fact that aging is by far the greatest cause of death in our species.

This then, is the next goal for paradise engineering: to bring aging under medical control, and to reduce the cost of that control to the point at which everyone can live indefinitely in youthful health. It could be feasible within decades, given great enough support for the necessary research and development, as we all age for the same reasons, and identical mass therapies for billions could be produced with the greatest of economies of scale. Control of aging is not the first goal undertaken by paradise engineers, however, which is to say that paradise engineering has been taking place for some time. Many important incremental goals were achieved over the course of the past half century, for example: progress in agricultural technology sufficient to make famine impossible, save through human neglect and corruption; greater control over infectious disease; and many others.

After hunger and aging, there is still the other half of infectious disease to deal with, however. There are also the thousands of forms of internal failure of human biochemistry and biology unrelated to aging or infection. Ultimately the medical community seeks complete control over our molecular biochemistry, sufficient to eliminate all defects. At present a look to the future suggests that this goal will compete with the development of machine alternatives to biological systems, and humans will become hybrids of engineered, cultivated biology and artificial nanoscale machinery that will work with, enhance, or replace portions of our biology. Aging and disease will be banished, while malfunctions and breakages will be both far less common and cause only inconvenience when they do happen. We will have successfully defeated all of the most common sources of physical pain and dysfunction, either by remodeling the chassis of our biology, or by adding guards to protect it from harm.

Suffering is not only human, however. The natural world from which we evolved continues to be as bloody, terrible, and rife with disease as it ever was. Higher animal species are certainly just as capable of experiencing anguish and pain as are we humans, and the same is true far further down into the lower orders of life than we'd like to think is the case. We ourselves are responsible for inflicting great suffering upon animals as we harvest them for protein - an industry that is now entirely unnecessary given the technologies that exist today. We do not need to farm animals to live: the engineering of agriculture has seen to that. The future of paradise engineering could, were we so minded, start very soon with an end to the farming and harvesting of animals. That would be followed by a growing control over all wild animal populations, starting with the lesser numbers of larger species, in order to provide them with same absolute control of health and aging that will emerge in human medicine. Taken to its conclusions, this also means stepping in to remove the normal course of predator-prey relationships, as well as manage population size by controlling births in the absence of aging, disease, and predation.

Removing suffering from the animal world is a project of massive scope, as where is the line drawn? At what point is a lower species determined to be a form of biological machinery without the capacity to suffer? Ants, perhaps? Even with ants as a dividing line, consider the types of technology required, and the level of effort to distribute the net of medicine and control across every living thing in every ecosystem. Or consider for a moment the level of technological intervention required to ensure a sea full of fish that do not prey upon one another, and that are all individually maintained in good health indefinitely, able to have fulfilling lives insofar as it is possible for fish. Artificial general intelligences and robust molecular manufacturing technologies, creating self-replicating machinery to live alongside and inside every living individual in a vast network of oversight and enhancement might be the least of what is required.

At some point, and especially in the control of predators, the animal world will become so very managed that we will in essence be curating a park, creating animals for the sake of creating animals, simply because they existed in the past - the conservative impulse in human nature that sees us trying to turn back any number of tides in the changing world. It seems clear that the terrible and largely hidden, ignored suffering of the animal world must be addressed, but why should we follow this path of maintaining what is? What good comes from creating limited beings for our own amusement, when that same impulse could go towards creating intelligences with a capacity equal or greater than our own? Creating animals, lesser and limited entities that will be entirely dependent on us, to be used as little more than scenery, seems a form of evil in a world in which better choices are possible.

Given this, my suspicion is that when it comes to the animal kingdom, the distant future of paradise engineering will have much in common with the goals of past religious movements and today's environmentalist nihilists, those who preach ethical extinction as the best way to end suffering. Animals will slowly vanish, their patterns recorded, but no longer used. If animals are needed as a part of the world in order to make the human descendants of the era feel better, then that need can be filled through simulations, unfeeling machinery that plays the role well enough for our needs. The resources presently used by that part of a living biosphere will instead be directed to other projects.

That is the far future. Even now, however, we have the ability, the technological capacity, to eliminate more of the world's suffering than has already been tackled. All it would require is for people to make better choices. This hasn't happened because we are disorganized, because we are inhuman to one another and to animals, because evolved human nature produces harmful collective behaviors - the aforementioned war, kleptocracy, and so forth. Utopians of every stripe have had their say on how to fix these issues within the bounds of the human condition, but it seems quite clear that it cannot be done. The human mind, as presently constituted, results in behaviors and societies that will consistently sabotage the outcome of a paradise free from suffering.

Today human nature cannot be changed, but in the future we will become able to change ourselves, as well as to manufacture whatever nature we desire in the intelligences we create. Utopianism might be rescued by technology, by the ability to edit all of the fundamental aspects of human nature that we all presently take for granted. From a purely technical perspective, it seems feasible for a future society to engineer away the aspects of human nature that produce our failures. The urge to dominance, the urge to violence, the urge to cause pain and suffering and loss to others, as well as jealousy, poor impulse control, and many others. By the time that it is commonplace for organic brains to be augmented and replaced by other forms of processing machinery, I would imagine that the production of altered forms of human nature and human intelligence will be a going concern, alongside modeling and predicting the behavior of societies consisting of such modified human minds.

Unfortunately, I am skeptical that this technological capability can be successfully applied to solve the problem of human nature as it presently exists, even while it seems, from a purely technical point of view, possible to achieve the goal. Resources will always be limited at some level, whether atoms, energy, or computational power, as societies grow to match the bounds of usage. War, bad governance, and the like are the result of a race to the bottom based on violence and control of scarce resources. For so long as any section of society retains human-like nature sufficient to follow these historical patterns, then the rest will be driven to change or extinction, no matter how enlightened they are. To bypass this by changing everyone, imposing specific mental models on every living entity, would require a level of control and dictatorship that is hard to imagine coming to pass universally across the entire human polity - and that is quite beside the point that such an end is, in and of itself, just as malign as the behaviors it seeks to cure.

So: we can improve the state of lives, we can build a truly better world, but it will most likely always be flawed, marred by our own actions, just as is our world today. That is no reason to hold back, however, as there is so very much that might be improved even given that perfection is unattainable. Pain and anguish need not be our everyday companions, and need not exist throughout the animal kingdom. Suffering can be addressed, and every step we take in that direction is well worth the required effort.

Adverse Interactions Between Natural Selection and the Modern Environment
https://www.fightaging.org/archives/2018/07/adverse-interactions-between-natural-selection-and-the-modern-environment/

Our species evolved to perpetuate itself in a very different environment from the one we find ourselves in now. We are clearly far better off as individuals: lives are a good deal less nasty, brutish, and short than was the case for our distant ancestors. Technological progress has conquered a sizable slice of the death and disease of childhood and early adult life, to a degree varying by the wealth of any given region of the world. The worst half of infectious disease is controlled, but chronic age-related diseases remain poorly managed, and the incidence of these diseases rises inexorably as people live longer due to continued incremental improvements in medicine - but also as people become sedentary and overweight, the evolved human response to technologies of transport and abundant calories.

We might ask to what degree this situation can be considered a mismatch between environment and evolved adaptation. Is widespread age-related disease a problem that emerges with technology and its consequences because that technology has arrived over a short time frame, and thus previously evolved characteristics and biochemical mechanisms are square pegs faced with a suddenly round hole? We might think of our need for exercise to maintain health and function, coupled to a civilization in which ever fewer people are running down game animals or otherwise engaged in earnest physical activity day in and day out.

Alternatively, is this a preexisting problem that is now exacerbated by natural selection ongoing in the short time frame of modern technology, favoring harmful adaptations? What does a sudden, continual, unending abundance of calories do to a species that previously evolved through hundreds of thousands of years of feast and famine? What genes and traits are quickly selected? How might epigenetic inheritance based on calorie intake run awry? These and other, similar questions do not have good answers at this time, though there is certainly enough research to enable speculation. As is the case for deep investigations in the detailed progression of human aging in the natural state, full answers might never arrive, as the present situation will be swept away by the advent of practical rejuvenation therapies and the ethical imperative to use them.

The dark side of our genes - healthy ageing in modern times

Over the last four centuries human ecology, life styles, and life histories have dramatically changed. The transition to modernity also altered the major causes of human death. Infectious diseases prevalent in childhood have given way to chronic diseases associated with ageing. Naturally - as all of us must die - if some causes of death decrease others must increase in proportion. However, the increasing differences between the circumstances our genes have adapted to and our new environment also plays an important role.

Ageing is, in part, caused by the combined effect of many genes that are beneficial when young, but have adverse effects at older ages. Genes can influence a variety of traits and can also express themselves differently as we age (pleiotropy). The term antagonistic pleiotropy describes genes that can carry both beneficial and detrimental effects. Somewhat counter-intuitively evolution by natural selection can lead to antagonistic pleiotropy spreading in populations: The benefits received when young can outweigh the evolutionary disadvantages in old age. Some variants of the gene BRCA1 are, for example, beneficial to fertility. However, women who carry one of such variants of BRCA1 will - more likely than not - develop breast cancer by the age of 90.

In contrast, the evolutionary impact of contemporary life on human health is difficult to establish: evolutionary change often requires many generations to leave an unambiguous trace in our genome. The review found "suggestive but not yet overwhelming" evidence that natural selection, the engine of evolution, is changing course in our modern times. Several studies in pre- and post-industrial populations point, for example, to a selection toward an extended fertility period in women.

"We have to be cautious here, though. Changes in human biology are driven by two non-exclusive processes. The environment directly impacts how our genes are expressed: Bad nutrition in childhood can cause, for example, stunted growth. But the environment also shapes natural selection. Natural selection can make some genes more - and others less - frequent in the population over time: Lactose-intolerance in adults, for example. It's tempting to point to natural selection when we observe a particular change. However, particularly when the changes occurred recently, it is more likely that gene expression has changed, rather than that the genes themselves have adapted to a new environment."

The transition to modernity and chronic disease: mismatch and natural selection

The Industrial Revolution and the accompanying ecological, epidemiological, and demographic transitions - a combination that we call the transition to modernity (TTM) - have had a profound impact on human populations. Fundamental ecological changes driven by modernization include permanent improvements in nutrition and food security, a dramatic decline in exposure to pathogens and a global increase in exposure to air and water pollutants. Biological changes include shifts in our physiology, development, immunobiology, microbiota and life history traits and the age structures of our populations.

In the process, mismatches between our evolved capacities and our rapidly changing environment have emerged, with many consequences for health and disease. Previously evolved genetic effects mediated by antagonistic pleiotropy may now account for a substantial proportion of the increasing burden of non-communicable diseases, which are currently responsible for over 63% of the world's deaths. Of these deaths, 80% occur in low-income and middle-income countries, and half are in men and women of working age. Although important progress has been made in the past decade in stemming the rising death toll from noncommunicable diseases, they remain a substantial threat both to health and to global economic development.

If evolution in prior environments favoured alleles that are harmful to fitness in current environments, then selection should eventually either modify their effects or remove them from contemporary populations. Indeed, growing evidence suggests that the rates and sizes of recent phenotypic responses to mismatch can substantially alter the direction and intensity of natural selection for genes that contribute to important traits, such as age and size at first birth, body mass index (BMI), and age at menopause.

In this review, we focus on the impact of the ecological, epidemiological, and demographic changes driven by the TTM on human biology. We aim to answer two questions: how compelling is the evidence that once advantageous gene variants now contribute to the growing burden of non-communicable disease, and how compelling is the evidence that natural selection has started to improve survival and reproduction in humans living in recently changed environments? Our aim is to make clear the degree to which the TTM has revealed the ecological and evolutionary origins of much of the increasing burden of non-communicable diseases by changing both age structures and the leading causes of death. By informing our basic understanding of disease causes, this knowledge can help to guide the search for novel therapies.

Exosomes From Induced Pluripotent Stem Cells Make Skin Cells More Resilient
https://www.fightaging.org/archives/2018/07/exosomes-from-induced-pluripotent-stem-cells-make-skin-cells-more-resilient/

Research into exosome signaling has grown in recent years. Arguably the bulk of signaling between cells is transported via varieties of extracellular vesicle, collections of molecules packaged within a membrane. Exosomes are one such type of vesicle. An originating cell generates exosomes, releasing them to the environment, and other cells accept them as they arrive. The contents of an accepted exosome then go on to influence cell machinery and activities. The beneficial effects of most stem cell therapies are mediated by signaling rather than by any other actions of the transplanted cells, and thus in principle it should be possible to do away with the cells and base a therapy on the signals alone. In the near term that might be accomplished by harvesting exosomes from cell cultures, while in the long term manufacturing and delivering specific desired signal molecules directly will probably emerge as the dominant approach.

The research noted here is carried out in cell cultures only, but it is an interesting example of the degree of influence over cell behavior that might be obtained through delivery of exosomes. If cells in many tissue types can be encouraged to greater regeneration and greater resilience to adversity through exosomes harvested from stem cells, then this is enough, no doubt, to support a wide range of potential therapies. Juvena Therapeutics is one example of a company that is mining this sort of cell signaling to pull out therapeutics. In the years ahead a great many other similar ventures will arise.

At this point, even given two decades of experimentation with stem cell therapies, it remains something of an open question as how great of a benefit can be provided by regenerative therapies that work around underlying damage. "Putting cells back to work" might be the motto, but this happens without any deliberate attempt to repair the accumulation of damage that is present old tissues. How much of that damage will be fixed by telling cells to work harder? Certainly issues caused by too few active cells seem amenable to treatment via simple therapies that override cell instructions, but we know that at least some forms of molecular damage at the root of aging, such as persistent cross-links and a few varieties of metabolic waste, cannot be effectively repaired even by youthful and active cells.

Exosomes Derived from Human Induced Pluripotent Stem Cells Ameliorate the Aging of Skin Fibroblasts

Skin undergoes physiological changes as a consequence of the aging process. There are two basic types of skin aging, i.e., intrinsic and extrinsic aging. Intrinsic aging is genetically determined, which indicates that it occurs inevitably as time passes. Many studies have suggested epigenetic changes and post-translational mechanisms are more important pathways of intrinsic aging rather than genetic influence. On the other hand, extrinsic aging occurs by external factors such as smoking, air pollution, and unbalanced nutrition. Among them, UV exposure is the most important cause of extrinsic aging. Therefore, the skin damages induced by UV exposure is called "photoaging". Photoaging is characterized by irregular pigmentation, dryness, sallowness, roughness, premalignant lesions, and skin cancer. Intrinsic skin aging, in contrast, is characterized by a loss of elasticity and fine wrinkles rather than deep wrinkles due to photoaging.

Fibroblasts are the primary cell types constituting the dermis and are responsible for the synthesis of structural components such as procollagen and elastic fibers. Fibroblasts lose their capacities for proliferation and synthesis of collagen, the major extracellular matrix (ECM) constituent of the skin dermis, with aging. On the other hand, the expression of various types of matrix-degrading metalloproteinase (MMP) is upregulated in the aged fibroblasts. Age changes the number and proliferation of dermal fibroblasts, reduces collagen synthesis and repair, and accelerates degradation of the existing skin matrix by MMPs, thereby reducing the regenerative capacity of skin.

Stem cells have been widely used for skin regeneration. Recently, it has been demonstrated in several preclinical and clinical studies that the transplantation of mesenchymal stem cells (MSCs) contributes to wound repair and regeneration. However, paracrine actions of the transplanted stem cells are believed to play a crucial role in the therapeutic effects. Many studies have reported that stem cells secrete several cytokines which promote the proliferation of dermal fibroblasts and the synthesis of ECM molecules. In addition, there have been advances in exploring the roles of exosomes secreted from stem cells in these paracrine actions. Exosomes are small membrane lipid vesicles secreted by most cell types (30-120 nm in diameter).

Exosomes contain functional messenger RNAs (mRNAs) and microRNAs (miRNAs), as well as several proteins, that originate from the host cells. Several evidences have also been revealed that the presence of several classes of long noncoding RNAs (lncRNAs) in exosomes. As lncRNAs have the function to induce epigenetic modifications by binding to specific genomic loci and recruiting epigenetic regulators such as chromatin remodeling complexes, exosomes secreted from one cell may also induce epigenetic modifications in recipient cells.

We previously demonstrated the stimulatory effects of human induced pluripotent stem cell-conditioned medium (iPSC-CM) on the proliferation and migration of dermal fibroblasts. Herein, we hypothesized that the iPSCs-CM contained exosomes and the human induced pluripotent stem cells-derived exosomes (iPSC-Exo) played a key role in these effects of iPSC-CM. To address this hypothesis, we isolated exosomes from iPSC-CM and examined their effects on several cellular responses associated with skin aging, as well as the proliferation and migration in human dermal fibroblasts (HDFs).

To induce photoaging and natural senescence, HDFs were irradiated by UV and subcultured for over 30 passages, respectively. The expression level of certain mRNAs was evaluated by quantitative real-time PCR (qPCR). Senescence-associated-β-galactosidase (SA-β-Gal) activity was assessed as a marker of natural senescence. As a result, we found that exosomes derived from human iPSCs (iPSCs-Exo) stimulated the proliferation and migration of HDFs under normal conditions. Pretreatment with iPSCs-Exo inhibited the damages of HDFs and overexpression of matrix-degrading enzymes caused by UV irradiation. The iPSCs-Exo also increased the expression level of collagen type I in the photo-aged HDFs. In addition, we demonstrated that iPSCs-Exo significantly reduced the expression level of SA-β-Gal and matrix-degrading enzymes and restored the collagen type I expression in senescent HDFs. Taken together, it is anticipated that these results suggest a therapeutic potential of iPSCs-Exo for the treatment of skin aging.

An Unconvincing Desire for Mortality
https://www.fightaging.org/archives/2018/07/an-unconvincing-desire-for-mortality/

As progress towards actual, real, working rejuvenation therapies becomes ever harder to ignore, even for those without any great familiarity with the sciences, the positions espoused by those opposed to longevity is shifting. It is apparently easy to be opposed to, outraged with, up in arms about the prospect of longer human lives when longer human lives are not an option for the near future. Just as soon as rejuvenation becomes something that isn't just for the distant future elite, the tone changes. There are still all of the old inconsistencies and virtue signals, but the firm opposition becomes a good deal less firm.

Take a look at this short opinion piece, for example - the way in which it opens, tired lines about the terrible burden of living well for a long time that we've all seen before, and then the way it is steered to a new and more thoughtful close. That close is a claim to desire mortality, but not yet. "Not yet" is the first step on the road to agelessness. If "not yet" today, and tomorrow one is just as healthy and entertained, then will it be "not yet" tomorrow? If "not yet" then why not undergo the treatments that will make tomorrow just as healthy as today? And when will it ever stop? Based on the fact that most people choose not to suicide on any given day, it is my belief that the near future, in which rejuvenation therapies are highly effective, cheap, and widespread, will be populated by well-adjusted, exceptionally long-lived individuals of many varieties.

Many of those future ageless individuals will emerge from a past in which they thought themselves mortalists when mortality was the only option on the table. They aimed themselves at diminishment and death in the same way as their grandparents did. Then technology advanced, and they followed the crowd, followed the advice of their doctors, and turned out to live indefinitely in good health despite having nothing of the sort in mind at the outset. Our community works to promote progress towards rejuvenation therapies for these people just as much as those who presently desire a longer life. A death is just as tragic in either case, and there are no half measures here. Either we all win together, or we all lose together.

Memo to those seeking to live for ever: eternal life would be deathly dull

How long would you like to live? One hundred no longer seems too greedy. In 1983, the Queen sent 3,000 congratulatory telegrams to centenarians. By 2016 she was sending 14,500 cards. One in three children born that year are expected to make it to three figures. For many, that's not good enough. Maverick scientists such as Aubrey de Grey are trying to find a "cure" for senescence, while transhumanists are looking to avoid the problem of your body packing up by packing you up and sending it to something more durable, like a virtual reality.

It's long been fashionable to dismiss these longings as naive and foolish. Human beings are mortal animals. The wise embrace that, and with it the inevitability of their demise. For these sage souls, extreme longevity is a curse disguised as a gift. These realists understand that the nature of human experience is essentially one of transience and impermanence. Being aware of this does not diminish the experience but intensifies it. When we desire indefinite life we seem to be in denial of the essentially transient, impermanent nature of everything, especially of ourselves. To even imagine eternal life we have to assume that we are the kinds of creatures who could persist indefinitely. But contemporary philosophers, neuroscientists, psychologists, and the early Buddhists all agree that the self is in constant flux, lacking a permanent, unchanging essence. Put simply, there is no thing that could survive indefinitely.

Sensible and correct as the arguments against immortality are, I do wonder whether some of us are too keen to be reassured by these seemingly wise thoughts. Just as belief in an afterlife can help to remove the sting of death, so can convincing ourselves that it is not such a sting after all. On this, Aristotle was characteristically sensible, rejecting the arguments of both Plato and the Stoics that death was nothing to be regretted. The more we live life well, the more we "will be distressed at the thought of death". When you appreciate that "life is supremely worth living" you know what a grievous loss it is when that life comes to an end. Living for ever may be a terrible fate but living a lot longer in good health sounds like a wonderful one.

It is one thing to accept our mortality as a necessary part of being embodied beings who live in time. But it is quite another to romanticise death or consider it to be no bad thing at all. Immortality might be a foolish goal but a longer mortality certainly isn't. My attitude to death is therefore similar to Augustine's attitude towards chastity. Yes, I want to be mortal, but please - not yet.

Chimeric Antigen Receptor Therapy, but Using Natural Killer Cells
https://www.fightaging.org/archives/2018/07/chimeric-antigen-receptor-therapy-but-using-natural-killer-cells/

Adding chimeric antigen receptors to T cells (CAR-T), causing them to aggressively target cancer cells, has proven to be a fruitful approach to the treatment of cancer. Like most immunotherapies, it can result in potentially severe side-effects related to excessive immune activation, but it is also quite effective. Treatment of forms of leukemia in particular has produced good results in a large fraction of patients who have trialed the therapy. In the research reported here, scientists extend the chimeric antigen receptor approach to natural killer cells rather than T cells, noting that this may prove to be both safer and logistically easier to deploy to large numbers of patients.

Genetically engineered T cells that destroy cancer cells have proven to be promising options when other treatments fail. However, there's currently no one-size-fits-all CAR T, and each patient needs his own bespoke intervention. Now, researchers report that natural killer cells, grown from human induced pluripotent stem (IPS) cells and modified in a similar way to CAR-T cells, are effective against ovarian cancer in a mouse model. The result paves the way for developing an "off the shelf" immunotherapy that doesn't need to be personalized for each patient. Natural killer (NK) cells, which play an important role in tumor surveillance, offer a key advantage over T cells in that they kill some cancer cells without requiring tumor-specific cell-surface receptors, meaning they can work in many patients.

CAR-T cell therapies are built by harvesting a patient's T cells and genetically modifying them to produce so-called chimeric antigen receptors (CARs) that direct them to destroy cancer cells. Two such immunotherapies were approved last year. Unmodified NK cells isolated from peripheral blood or umbilical cord blood have also been shown to be effective against acute myelogenous leukemia in several clinical trials, and a few trials testing NK cells equipped with CARs in other forms of blood cancer have begun. But developing a means of deriving NK cells from stem cells would allow researchers to generate hundreds of thousands of doses that are standardized.

The team created the mouse models by transplanting human ovarian cancer cells into mice whose immune systems had been suppressed to prevent them from rejecting the human cells. The scientists then infused the CAR-NK cells into the animals, and for comparison, did the same for CAR-T cells. They noted that the mice treated with the iPSC-derived CAR-NK cells and those treated with CAR-T cells both had shrunken tumors after 21 days. The researchers were surprised to find that, compared to the mice treated with CAR NKs, the animals that had received the CAR-T cell treatment appeared to be in worse shape: they had damage in organs such as the liver, lungs, and kidneys and an increase in inflammatory cytokines. "The mice that got the CAR-T cells actually wound up getting sick, losing weight, and getting these toxicities, whereas the CAR-NK-cell-treated mice didn't."

Cleara Biotech Launches to Develop Senolytic Therapies Based on FOXO4-DRI
https://www.fightaging.org/archives/2018/07/cleara-biotech-launches-to-develop-senolytic-therapies-based-on-foxo4-dri/

The accumulation of senescent cells is thought to be one of the root causes of aging, and a growing body of evidence points to their direct contribution to numerous age-related conditions. Removing senescent cells is a narrow form of rejuvenation, capable of turning back measures of aging and age-related disease. Last year researchers published data on an approach to selective destruction of senescent cells based on interfering in the interaction between FOXO4 and p53. This pushes senescent cells into the form of programmed cell death known as apoptosis, while doing next to nothing to normal cells. The method of interference involves creating a safe but broken version of the FOXO4 protein, FOXO4-DRI, and introducing it into the body. A sizable fraction of senescent cells relying on the presence of working FOXO4 are destroyed as a result. The principal researcher involved in this work has now started a company with the assistance of Apollo Ventures to further develop this line of work into a viable senolytic therapy.

Cleara Biotech has raised seed funding to advance a program that reversed aspects of aging in mice. The modified FOXO4-p53 interfering peptide program made headlines last year when it restored the physical fitness, hair growth, and kidney function of mice. Peter de Keizer, Ph.D., and his collaborators achieved the improvements by targeting cells that had entered senescence, a state in which they stop dividing and start secreting different factors. Studies have linked these cells to an array of big diseases, attracting multiple research groups and powering Unity Biotech to an 85 million IPO. Among all these activities, Keizer's peptide stood out because it eliminated senescent cells without harming healthy tissues.

James Peyer, Ph.D., managing partner at aging-focused fund Apollo Ventures had been looking for a marker specific to senescent cells without success. Such specificity is vital if a drug is to treat chronic, age-related conditions such as kidney disease without causing intolerable side effects. When Peyer's fund saw Keizer's preliminary data, he teamed up with the senescence scientist and his collaborators. The result is Cleara. Cleara will spend the next year optimizing the peptide Keizer tested in mice in anticipation of moving into the clinic. This will entail designing multiple candidates with strengths, pharmacokinetic profiles, and other characteristics tailored to indications that Cleara may target.

Cleara is still zeroing in on indications, with Peyer noting that this is "one of the core challenges for a number of different drugs in this space, where you're presented with a cornucopia of options." But it has a broad idea of the areas it is going to target. One lead optimization strand will develop a candidate against a chronic condition, such as kidney disease, osteoarthritis, or COPD. The second strand will target an acute, life-threatening "rare or rare-ish" disease. This second strand will likely get into the clinic first - reflecting the higher tolerance for risk among patients with life-threatening diseases - and may ultimately target a type of cancer.

Senolytics Reduce Age-Related Dysfunction and Extend Remaining Life Span by 36% Following Administration to Old Mice
https://www.fightaging.org/archives/2018/07/senolytics-reduce-age-related-dysfunction-and-extend-remaining-life-span-by-36-following-administration-to-old-mice/

This paper isn't open access, but is important enough to stand out from the many publications on clearance of senescent cells emerging these days. While the evidence is compelling for senescent cells to be a root cause of aging, and removal of senescent cells via senolytic therapies to reverse aspects of aging, many of the fine details remain to be robustly established in the science and the implementations. Measures of senescent cell levels are not yet advanced enough for clinical implementations, for example, and the life span studies have so far involved animals genetically modified to suppress senescence rather than administration of senolytics to normal animals. That has now changed: in this study, researchers demonstrate that the senolytic mix of dasatinib and quercetin produces noteworthy results on the remaining life span of old mice.

Physical dysfunction and incapacity to respond to stresses become increasingly prevalent toward the end of life, with up to 45% of people over the age of 85 being frail. The cellular pathogenesis of age-related physical dysfunction has not been fully elucidated, and there are currently no root cause-directed, mechanism-based interventions for improving physical function in the elderly available for clinical application. Here we report a potential strategy for addressing this need: reducing senescent cell burden.

Senescent cell burden increases in multiple tissues with aging, at sites of pathology in multiple chronic diseases, and after radiation or chemotherapy. Senescent cells can secrete a range of proinflammatory cytokines, chemokines, proteases, and other factors; together, these are termed the senescence-associated secretory phenotype (SASP), which contributes to local and systemic dysfunction with aging and in a number of diseases.

Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan.

The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.

Endothelial Cell Dysfunction as the Early Manifestation of Small Vessel Disease
https://www.fightaging.org/archives/2018/07/endothelial-cell-dysfunction-as-the-early-manifestation-of-small-vessel-disease/

Cerebral small vessel disease is a form of age-related dysfunction in the smaller blood vessels of the brain, associated with damage to the white matter of the brain and the onset of dementia. It is thought that the increased blood pressure of hypertension and consequent physical stresses on blood vessel walls is the primary cause of small vessel disease, but here researchers provide evidence pointing towards specific forms of change in signaling generated by dysfunctional endothelial cells that form the blood-brain barrier in blood vessel walls. That signaling degrades some of the necessary supporting operations of cells in nearby brain tissue - a situation that sounds similar to the outcome of cellular senescence and the senescence-associated secretory phenotype, though that topic isn't mentioned at all in this paper. This endothelial cell signaling occurs prior to other aspects of small vessel disease, though itself must still be secondary to the underlying molecular damage of aging in and around blood vessel cells: senescence, cross-linking, and so forth.

Cerebral small vessel disease (SVD) affects arterioles in the brain, increasing risk of stroke and causing symptoms of dementia. Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause.

In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90α, which blocks oligodendroglial differentiation, contributing to impaired myelination: vascular tight junctions of the blood-brain barrier were impaired in SVD, and dysfunctional endothelial cells prevented oligodendrocyte precursors from maturing into myelinating cells.

Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single-nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD.

More than You Wanted to Know About NAD+ in Metabolism and Aging
https://www.fightaging.org/archives/2018/07/more-than-you-wanted-to-know-about-nad-in-metabolism-and-aging/

Manipulating levels of nicotinamide adenine dinucleotide (NAD+) so as to improve mitochondrial function in older individuals is a popular topic these days, particularly now that numerous groups are selling supplements alleged to raise NAD+ levels usefully. These might be thought of as a form of exercise mimetic drug, in the cases where they actually perform. Even given an intriguing early human trial, this is most likely a road to only minor benefits in the matter of aging. At 90, even the best of former athletes looks like a 90-year old, with a significant degree of dysfunction, and a high chance of failing to live to see 91. The research community can and must achieve better results than this class of intervention, by focusing on repair of underlying damage rather than compensatory adjustment of faltering cellular machinery.

In recent years, interest in nicotinamide adenine dinucleotide (NAD+) biology has significantly increased in many different fields of biomedical research. A number of new studies have revealed the importance of NAD+ biosynthesis for the pathophysiologies of aging and aging-related diseases. NAD+ is an essential component of cellular processes necessary to support various metabolic functions. The classic role of NAD+ is a co-enzyme that catalyzes cellular redox reactions, becoming reduced to NADH, in many fundamental metabolic processes.

There are five major precursors and intermediates to synthesize NAD+: tryptophan, nicotinamide, nicotinic acid, nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN). In mammals, a major pathway of NAD+ biosynthesis is the salvage pathway from nicotinamide. Nicotinamide is converted to NMN, a key NAD+ intermediate, by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this pathway. NMNATs then convert NMN into NAD+. NAMPT plays a critical role in regulating cellular NAD+ levels.

It is now becoming a consensus that NAD+ levels decline at cellular, tissue/organ, and organismal levels during the course of aging. Activities of NAD+-consuming enzymes are affected by this NAD+ decline, contributing to a broad range of age-associated pathophysiologies. Sirtuins are a family of NAD+-dependent deacetylases/deacylases which have central roles in translating NAD+ changes to the regulation of many regulatory proteins for metabolism, DNA repair, stress response, chromatin remodeling, circadian rhythm, and other cellular processes.

A significant cause for this age-associated NAD+ decline is the decrease in NAMPT-mediated NAD+ biosynthesis. It has been shown that the expression of Nampt at both mRNA and protein levels is reduced over age in a variety of tissues. This age-associated decrease in Nampt expression causes a reduction in NAD+ in those same tissues, affecting the activities of NAD+-dependent enzymes and redox reactions within the cell and leading to functional decline. Therefore, supplementation with NAD+ intermediates, such as NMN and NR, can effectively restore the NAD+ pool and cellular functions in aged animals.

A Life Lived is No Justification for a Death Unchosen
https://www.fightaging.org/archives/2018/07/a-life-lived-is-no-justification-for-a-death-unchosen/

Platitudes spoken after the death of elderly friend have a way of turning into justifications for that death. This is the flip side of the "fair innings" argument that is used fairly openly these days in rationed medical systems to direct resources away from providing treatments to the old. You have lived, now get along and die. Or perhaps it is a little of the old evolved conservatism in human nature, the urge to conformity: everyone else is dying, why not you? Or perhaps this is entwined with ageism, that older people are worth some fraction of a younger individual for whatever justification makes the everyone feel better about themselves. Even the older people go along with this, which is a shame. A death at any age is just as much a loss, and in this era of nascent rejuvenation biotechnology, members of the research and development community could be achieving far more than is currently the case to improve health and reduce mortality in old age.

You're probably familiar with the feeling of slight disappointment that you may have when a good thing - say, a nice trip - is over. Just as you say that it's too bad that the experience is already finished, someone will probably say that you had a good time nonetheless; an innocent, fitting expression to cheer you up a little bit. This phrase can be harmlessly used in a variety of circumstances, but there's one in which it really doesn't fit at all, yet people keep using it: when somebody dies of aging.

Death always has a profound impact on us all, and there's little or nothing that you can say to cheer up people who are losing their loved ones. Yet, we all feel that we must attempt to relieve their pain, and this kind of cliché has been repeated over and over for millennia; it's hard to give up on using it, as it's the only weapon, however ineffective, that we can use to sugarcoat the bitter notion that what happened will happen, in some form, to all of us. What I object against is how these set phrases are often used as more than mere uplifters; they become justifications for death. Just like people say "well, you had a good time" when your holiday is over, they say "well, she had a good life" when somebody dies, as if this made it any better; as a matter of fact, these two situations aren't even similar.

As a side note, you wouldn't say "well, he had a good life" in the case of someone who is dying before old age. You would say "oh, but he's so young!" Apparently, if a young person is dying, whether or not that person has had a good life thus far doesn't seem to make much of a difference. This betrays unintentional age-based discrimination: if you die young, that's a tragedy; if you die old, it's not so bad as it would have been had you died young. This double standard is fueled by the misconception that an old person wouldn't have much life left anyway, so it's not much of a loss if he or she dies. However, the remaining life of old people isn't short because they're old - it's short because they're not healthy enough to live a long time, and we aren't yet capable of fixing this.

"Well, she had a good life" is part of a plethora of other set phrases and coping mechanisms that, historically, have allowed humans to come to terms with mortality and allow the species to go on. However, they're just a hindrance now. It's true that rejuvenation is not here yet, and we're very far from being able to promise anyone that they will never die. However, rejuvenation science is in its infancy, and mindlessly perpetuating these coping mechanisms will only serve to delay its transition into adulthood. As we keep striving to bring aging to its knees, the time has perhaps come to find new, more rational ways to cope with the inevitable losses that will happen until that moment comes.

Activation of the Anaphase Promoting Complex to Enhance Genomic Stability
https://www.fightaging.org/archives/2018/07/activation-of-the-anaphase-promoting-complex-to-enhance-genomic-stability/

Does the accumulation of stochastic nuclear DNA damage over time contribute to all aspects of degenerative aging, or only contribute to cancer risk? That is an interesting question, and the answers lack strong proof in one direction or another. The current consensus is that mutational damage to nuclear DNA does indeed contribute to aging, most likely through expansion of such mutations into sizable fractions of a tissue when they occur in stem and progenitor cells. Thus there is some interest in the research community in finding ways to enhance the stability of the genome: better repair, or lower levels of damaging incidents. Given an efficient enough approach that only affects DNA damage and no other aging-related mechanism, it should be possible to use that to obtain strong proof or disproof of the role of nuclear DNA damage in aspects of aging other than cancer risk.

When does the aging process begin? How long can we live? Why do we age? These questions are highly debated with no distinct, definitive answers. Does aging begin when our skin starts to wrinkle, or when our hair commences to turn grey? Or perhaps aging begins after the completion of growth. Aging has also been defined as a shift in an organism's aging reality. The aging reality has been described as a mutually enslaved system of DNA and its environment in which signaling failures within this DNA environment occur over time.

The idea that aging is a random stochastic program is supported by many researchers in the field. The stochastic idea of aging gained traction when the free radical theory of aging was proposed. This theory states that aging occurs due to the natural wear and tear of cellular machinery and biological substances due to exposure to free radicals generated within the cell. Biological systems are constantly fighting a battle with its environment, both internally and externally, to ward off damage. The simple generation of mitochondrial-dependent energy and DNA replication expose cells to damage that must be repaired.

It now seems quite clear that cellular aging is largely dependent on the degree to which genomic instability has affected DNA-dependent processes. Many studies, from yeast to humans, have repeatedly shown that during aging, senescent cells that exit the cell cycle or cease to function harbor large accumulations of DNA mutation, rearrangements, and epigenetic alterations. There are numerous sources of DNA damage, both endogenous and exogenous, that the cell must deal with. It is thought that a somatic cell may receive as many as 100,000 lesions daily. It is not a coincidence that most age-dependent diseases, such as cancer, type II diabetes, and cardiopulmonary and neurodegenerative diseases are associated with increasingly elevated levels of genomic instability that occur over time.

Inside a cell, multiple antagonistic molecular networks are vying for available resources to respond to either stress or nutrients. It should be clear that the opposition of these pathways should not be all or none, as aspects of nutrient availability may be present even in an unfavorable environment. Thus, the question becomes how are nutrient and stress sensing networks regulated? What mediates the end of stress signaling when the stress is gone, or the stalling of the nutrient sensing pathways when the food source is used up? To answer these questions, it is important to identify components that connect stress and nutrient-sensing pathways. The Anaphase Promoting Complex (APC) has come to light as a potential link between the stress and nutrient sensing networks.

The APC is largely known for its role in cell cycle progression, but we and others have identified it as a central player in stress sensing and lifespan determination using the simple brewing yeast eukaryotic model system. Mitosis is a time during the cell cycle when DNA damage can become permanent and lead to further chromosome erosion and genomic instability. The APC is also required for replication-independent chromatin assembly and histone modifications. Considering that replication-independent chromatin assembly is required for DNA repair, we speculate that the APC may be involved in repair of DNA damage incurred during chromosome segregation.

We have reported that the yeast APC prolongs longevity (increased expression of only APC10 increased replicative lifespan), responds to stress, and interacts with multiple conserved stress response pathways. The positioning of the APC at the intersection point of the stress and nutrient sensing pathways confers importance upon this complex, as it may have the potential to protect the cells that come together to form the zygote from the aging process. The potential for aging likely begins for an individual as soon as the germ cells responsible for them are born. It is critical that the repair mechanisms within these cells are functioning optimally. As long as the APC is at its peak function, protection against cellular damage should be high. With continued proper function of the APC through the life of the germ cells and the subsequent offspring, increased healthspan may be possible.

Upregulation of FGF21 to Prevent Visceral Fat Gain and Consequent Diabetes
https://www.fightaging.org/archives/2018/07/upregulation-of-fgf21-to-prevent-visceral-fat-gain-and-consequent-diabetes/

Telling people to eat less doesn't work, as demonstrated by the vast number of overweight individuals with metabolic syndrome and type 2 diabetes. Both of those are preventable, reversible conditions, even in their later stages. All the patient has to do is eat less and lose the weight. Instead most people keep the weight, undergo largely palliative treatments that produce unpleasant side-effects, suffer many more medical complications with aging, and die younger than their peers. We don't live in a particularly rational world. Medical science may yet rescue the obese from themselves, however; certainly a very large amount of funding and effort goes into building potential treatments. Upregulation of FGF21 via gene therapy is an example of the type, a replication of one of the effects of calorie restriction that might have quite broad benefits in many organs, even for people of normal weight.

A research team has managed to cure obesity and type 2 diabetes in mice using gene therapy. A single administration of an adeno-associated viral vector (AAV) carrying the FGF21 (Fibroblast Growth Factor 21) gene, resulted in genetic manipulation of the liver, adipose tissue, or skeletal muscle to continuously produce the FGF21 protein. This protein is a hormone secreted naturally by several organs that acts on many tissues for the maintenance of correct energy metabolism. By inducing FGF21 production through gene therapy the animal lost weight and decreased insulin resistance, which causes the development of type 2 diabetes.

The therapy has been tested successfully in two different mouse models of obesity, induced either by diet or genetic mutations. In addition, the authors observed that when administered to healthy mice, the gene therapy promoted healthy ageing and prevented age-associated weight gain and insulin resistance. After treatment with AAV-FGF21, mice lost weight and reduced fat accumulation and inflammation in adipose tissue; fat content (steatosis), inflammation, and fibrosis of the liver were also reversed; this led to an increase in insulin sensitivity and in healthy ageing, without any adverse side effects.

The native FGF21 protein has a short half-life when administered using conventional procedures. For this reason, the pharmaceutical industry has developed FGF21 analogues/mimetics and has already conducted clinical trials. FGF21 analogues/mimetics, however, require periodic administration to mediate clinical benefits, but may raise immunological issues associated to the administration of exogenous proteins. The gene therapy vectors, however, induce the mice to produce for many years the same FGF21 hormone naturally produced by the body, after a single administration.

Arguing that Cytomegalovirus is Beneficial for Old Immune Systems
https://www.fightaging.org/archives/2018/07/arguing-that-cytomegalovirus-is-beneficial-for-old-immune-systems/

Researchers here make the intriguing argument that persistent cytomegalovirus (CMV) infection results in a better rather than worse immune system in old age, for at least some measures. This stands in opposition to the current consensus and broad range of evidence to show that much of the disarray of the aged immune system is due to CMV and similar latent viral infections. Too large a portion of the limited resources of the adaptive immune system becomes devoted to these foes, at a point in life when new T cells are created slowly, if at all. The thymus, where T cells mature, atrophies in later life, while the hematopoietic stem cell pool responsible for creating immune cells declines in function.

A number of potential immunotherapies work by provoking the immune system into greater activity; these are largely blunt tools, and can have serious side-effects. The argument in here is a similar one, perhaps, that the presence of CMV is provoking the immune system, thus making the immune response more effective in some ways than might otherwise have been the case. A caution here is that mouse and human adaptive immune systems are quite different in their dynamics in late life, and this may well be an important difference in this context. In old humans very few new T cells arrive from the thymus, and most are produced from replication in existing populations. In old mice, a much larger fraction of T cells emerge from the thymus. If the effects of CMV involve both firing up the immune system and causing too many cells to be specialized to attacking CMV rather than other tasks, then this could balance out to be a net benefit in mice and a net harm in humans.

Our immune system is at its peak when we're young, but after a certain age, it declines and it becomes more difficult for our bodies to fight off new infections. In search of a way to rejuvenate the immune system of older adults, scientists began researching cytomegalovirus, or CMV. The virus, which is usually contracted at a young age, affects more than half of all individuals. Because there is no cure, the virus is carried for life and is particularly prevalent in older adults. "CMV doesn't usually cause outward symptoms, but we still have to live with it every day since there's no cure. Our immune system always will be busy in the background dealing with this virus."

Researchers wondered how this lifelong virus ultimately affects the immune system. To study the effects of CVM, they infected mice with the virus. "We assumed it would make mice more vulnerable to other infections because it was using up resources and keeping the immune system busy. But that's not what happened. When infected with listeria, old mice carrying CMV proved to be tougher than old mice without CMV. We were completely surprised; we expected these mice to be worse off. But they had a more robust, effective response to the infection." Researchers are not certain how CMV strengthens the immune system - they are investigating that in a separate study - but they do believe they have gained new insight into the aging immune system.

For years, immunobiologists thought T-cells - the army of defenders that fights off infection - decreased in diversity as people aged, leaving older adults more susceptible to diseases. But when researchers examined the mice's T-cells, they found both groups of older mice had a decent supply of diverse T-cells. "Diversity is good. Different types of T-cells respond to different types of infections; the more diverse T-cells you have, the more likely you'll be able to fight off infections." The study shows that T-cells are almost as diverse in old mice as they are in young mice. The problem is diverse T-cells are not recruited to the battlefield in older mice unless they are infected with CMV. "It's as if CMV is issuing a signal that gets the best defenses out onto the field. This shows that the ability to generate a good immune response exists in old age - and CMV, or the body's response to CMV, can help harness that ability."

Evidence to Show that Multivitamins Do Not Aid Cardiovascular Health
https://www.fightaging.org/archives/2018/07/evidence-to-show-that-multivitamins-do-not-aid-cardiovascular-health/

Vitamins and related supplements are useful in the case of outright deficiency, but the scientific consensus is that they don't provide benefits when it comes to the progression of aging. In the case of antioxidants, they might even be modestly harmful. This data has proven to be a hard sell with the public, particularly given the existence of a very vocal marketplace of sellers willing to declare all sorts of beneficial outcomes to result from their products, regardless of the evidence. Nonetheless, it is hard to argue with the weight of evidence.

Taking multivitamin and mineral supplements does not prevent heart attacks, strokes, or cardiovascular death, according to a new analysis of 18 studies. The research team performed a "meta-analysis," putting together the results from randomized controlled trials and prospective cohort studies totaling more than 2 million participants and having an average of 12 years of follow-up. They found no association between taking multivitamin and mineral supplements and a lower risk of death from cardiovascular diseases.

"It has been exceptionally difficult to convince people, including nutritional researchers, to acknowledge that multivitamin and mineral supplements don't prevent cardiovascular diseases. I hope our study findings help decrease the hype around multivitamin and mineral supplements and encourage people to use proven methods to reduce their risk of cardiovascular diseases - such as eating more fruits and vegetables, exercising, and avoiding tobacco."

Controversy about the effectiveness of multivitamin and mineral supplements to prevent cardiovascular diseases has been going on for years, despite numerous well-conducted research studies suggesting they don't help. "Although multivitamin and mineral supplements taken in moderation rarely cause direct harm, we urge people to protect their heart health by understanding their individual risk for heart disease and stroke and working with a healthcare provider to create a plan that uses proven measures to reduce risk." The American Heart Association does not recommend using multivitamin or mineral supplements to prevent cardiovascular diseases.