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- The Potential Influence of Gut Microbes on the Progression of Sarcopenia
- Aging Research Half a Lifetime Ago: the Lost Decades of the 20th Century
- Vesicles from Young Cells Reverse Measures of Aging in Old Stem Cells
- Commercial Success Would Solve Most of the Challenges of the Cryonics Community
- Aubrey de Grey on Rejuvenation Research: How Big and How Near are the Benefits?
- Mitochondrial Transfer Partially Reverses Some Consequences of Oocyte Aging
- Evolution Discards the Old
- ALZFORUM Looks Back at 2017 in Alzheimer's Research
- Excess Fat Tissue Leaves Lasting Damage to Stem Cells, Even if Lost
- Laura Deming's Introductory Overview of Aging Research
- More on Efforts to Tissue Engineer Skin with Hair Follicles
- Viruses and Checkpoint Inhibitors Combine to Form an Effective Cancer Treatment
- A Call to Test Combinations of Drugs Shown to Slow Aging in Animal Studies
- Links Between Induced Pluripotency and Cellular Senescence
- MCP-1 as a Potential Biomarker of Biological Age
The Potential Influence of Gut Microbes on the Progression of Sarcopenia
Sarcopenia is the name given to the characteristic age-related loss of muscle mass and strength that affects every older adult, and eventually significantly contributes to outright frailty. For the past decade or more US researchers have been agitating to have sarcopenia officially defined as a medical condition, with no success yet. Indeed, this is a poster child for one of the ways in which the stifling effect of heavy regulation emerges in practice. For so long as the FDA doesn't consider sarcopenia a disease, then it becomes that much more challenging to raise funding for research and development of potential therapies; large commercial ventures won't consider it seriously, and in turn that lack of interest spreads back into earlier stages of research funding, for-profit and non-profit. The whole field slows down because someone's arbitrary boxes are not being checked.
There are many potential contributing causes to sarcopenia, all of which sound at least somewhat plausible and arrive accompanied by a fair amount of supporting evidence. Lower protein intake in older adults; defective processing of the amino acid leucine; sedentary behavior; chronic inflammation that disrupts the signaling and cell behavior needed for normal tissue maintenance; age-related decline in stem cell activity; infiltration of muscles by fat tissue; changes in mitochondrial dynamics that reduce energy output; blood vessel decline that reduces oxygenation; and loss of function neuromuscular junctions, to pick a few examples. The latest animal studies point firmly to stem cell decline as the primary cause, but there is a still quite a weight of research, collectively, for all of the other potential mechanisms. As in so many other areas of aging, the fastest path to assigning relative importance is probably to start fixing causes one by one and see what happens as a result.
In the paper noted here, researchers consider age-related changes in the gut microbiome as a way to make more sense of what has been reported of nutritional contributions to sarcopenia. In recent years the work of an increasing number of research groups has suggested that the bacteria of the gut are influential on natural variations in the pace of aging, perhaps to a degree that is in the same ballpark as exercise. Further, gut bacteria account for one portion of the many and varied mechanisms by which lowered calorie intake slows aging. The more compelling demonstrations are those in which transfer of gut bacteria from young to old animals extends life. Whether anything of significance to medicine arises from this is another matter entirely, however: consider how much time and effort has been spent on trying to reverse engineer exercise and calorie restriction, with little to show for it to date. The gut microbiome and its interaction with our biology is at least as complex, and possibly more so. The size of the potential benefits are just not that large in the grand scheme of things - perhaps a few additional years of life. There are better opportunities to chase with that same effort and funding, such as any of those in the SENS rejuvenation research portfolio.
Aging Gut Microbiota at the Cross-Road between Nutrition, Physical Frailty, and Sarcopenia: Is There a Gut-Muscle Axis?
Sarcopenia is a geriatric syndrome with a high prevalence in older individuals; its presence is estimated in up to 35% of hospital wards. Elderly individuals generally experience a decline of nutrient and energy intake with increasing age. This phenomenon is generally due to age-related loss of appetite, the so-called "anorexia of aging", whose physiopathology is only partly understood. It may also depend on increased energy requirements due to acute or chronic inflammation, leading to "disease-related malnutrition". Malnutrition and sarcopenia often overlap in older patients, so that one of the mainstays of sarcopenia prevention and treatment is promoting adequate nutrition. The prescription of adequate intakes of proteins, vitamin D, antioxidant nutrients, and long-chain polyunsaturated fatty acids has been particularly emphasized in this field, since these nutrients are able to counteract anabolic resistance, promote protein synthesis, and modulate inflammation, thereby preventing its detrimental consequences on muscle cells.
The human gut microbiota is composed of as much as 1014 bacteria, viruses, fungi, protozoa, and Archaea, with a gene pool 150 times larger than that of the host. It establishes a symbiotic relationship with the host, whereby individual environmental and genetic factors can shape its composition, while the host physiology is influenced and gets adapted to its presence. In healthy individuals, the gut microbiome generally includes between 1100 and 2000 bacterial taxa, most of which cannot be cultivated with traditional microbiological techniques.
Geographical location and diet are the major environmental factors explaining the interindividual differences in healthy gut microbiota composition. After the age of 65, gut microbiota resilience is generally reduced, so that its overall composition is more vulnerable to lifestyle changes, drug treatments such as antibiotics, and disease. As a result, species richness (i.e., the number of taxa that metagenomic analyses are able to identify) is reduced, and interindividual variability is enhanced. A lower number of species, decrease in the representation of taxa with purported health-promoting activity, and expansion of Anaerotruncus, Desulfovibrio, Coprobacillus and Gram-negative opportunistic pathogens are the most important changes that have been demonstrated in different clinical settings. These distinctive features of older persons' gut microbiome allow hypothesizing its involvement in the aging process with multiple mechanisms.
In a pioneering study on the ELDERMET cohort, it was demonstrated that the species richness of the fecal microbiota of older subjects is inversely related to physical performance. A secondary analysis of the same cohort has recently revealed that, in community dwellers, the presence of frailty, as measured through the Barthel Index (BI), is associated with a gut microbiome profile similar to that typical of nursing-home residents, with an increased representation of Anaerotruncus, Desulfovibrio, and Coprobacillus. These results are not merely speculative; they have important clinical correlates. For example, gut microbiota dysbiosis can be associated with a reduced survival in older individuals with frailty or disability. Moreover, the over-representation of opportunistic pathogens in the gut microbiota of frail multimorbid older patients may also increase the risk of developing infections.
However, these studies do not establish any cause-effect relationship between gut microbiota dysbiosis and physical frailty, due to their cross-sectional design. Several compounds produced or modified by the gut microbiota can enter systemic circulation and ultimately influence skeletal muscle cells. For example, a healthy gut microbiota is able to produce significant amounts of folate and vitamin B12, which may improve muscle anabolism. The most studied putative mediators of the effect of gut microbiota on skeletal muscle function are short chain fatty acids (SFCAs). These substances are generally derived from the bacterial metabolism of nutrients, such as proteins, which are introduced with diet. Their main host targets are skeletal muscle mitochondria.
The only intervention study carried out on older patients and targeted at exploring the effects of gut microbiota modifications on skeletal muscle outcomes involved the administration of prebiotics, i.e., substances promoting the overexpression of beneficial bacteria. In a randomized controlled trial, researchers enrolled 60 older patients who received treatment with a prebiotic formulation including fructooligosaccharides and inulin versus placebo for 13 weeks. Surprisingly, the treatment group experienced improvement in two outcomes of muscle function: exhaustion and handgrip strength. Thus, these data support the hypothesis of a modulation of muscle function by gut microbiota. Unfortunately, no other studies have explored this field to date.
The current state-of-the-art literature supports the hypothesis that gut microbiota may be involved in the onset and clinical course of sarcopenia. Since nutrition is one of the main determinants of gut microbiota composition, and is also involved in the pathogenesis of sarcopenia, the gut microbiota may be at the physiopathological cross-road between these two elements. Some key microbial taxa may have a relevant role in determining muscle structure and function by producing metabolic mediators that influence the host physiology after intestinal mucosa absorption. Glycine betaine, tryptophan, biliary acids, and SCFA, namely butyrate, are the most promising of these putative mediators.
Aging Research Half a Lifetime Ago: the Lost Decades of the 20th Century
We roughly know the recent history of longevity science, starting in the 1990s in a period in which the small scientific community interested in aging was defensive and self-policing, uninterested in any talk of treating aging as a medical condition. Young researchers were discouraged from thinking about intervention in the mechanisms of aging, or any hope of lengthening healthy human life span. Pushing that sort of viewpoint openly was career suicide. Established researchers in the field saw themselves as under siege by a tidal wave of pervasive and damaging nonsense generated by the anti-aging community of pills, potions, and outright lies, harming the prospects for building publicly funded research institutions to tackle specific age-related conditions, such as Alzheimer's disease.
Then came the work showing that single gene mutations could lengthen life in short-lived species. A rediscovery of the plasticity of longevity in response to environmental stress in worms, flies, and mice progressed from there onward. In particular there was ever greater interest and funding for calorie restriction research, mining the biochemistry of the mammalian response to low calorie intake, a part of the field put away and largely lost since the 1930s. Then the SENS rejuvenation research movement emerged just after 2000, and the thaw of a frozen research community started in earnest. Nothing proceeds rapidly in the sciences, even cultural change, and it was the late 2000s by the time that younger researchers could comfortably talk in public and publish papers about treating aging as a medical condition without career consequences. Nonetheless, that came to pass, and matters sped forward from there. Today, senolytic therapies capable of clearing senescent cells, one of the causes of aging, are under commercial development, and there is considerable excitement in the research community for this mode of intervention in the aging process. The thaw has completed, and the research community now confidently holds its own, unafraid of the anti-aging marketplace - which is just as full of nonsense and lies as it was thirty years ago.
What happened between the 1930s and the 1990s, however? Why was calorie restriction research abandoned? How did the understanding of aging progress over the 20th century? Looking back at history, we see so much of the past interest in aging and longevity as brief flashes, a few individuals undertaking it as a part of their broader research interests. Little in the way of a coherent whole emerges until our time; it is a collection of individuals, not a community. It is hard to understand the culture of the time from these few points of reference, the degree to which intervention in aging was or was not on the table as a point of interest for any particular group. Even the science fiction of the mid-20th century, usually illuminating as to the edges of scientific consideration, is unhelpful on this topic. The only assembled historical resource that I know of is Ilia Stambler's "A History of Life-Extensionism In The Twentieth Century", which actually provides much more information on a number of individuals who were at their peak of interest on the topic of aging in the late 1800s, versus what was going on between 1930 and 1950.
We can look back at a series of individual inquiries into aging across the span of very rapid technological progress in the decades to either side of 1900, leading up to, for example, the studies showing calorie restriction to slow aging and prolong healthy life in rats carried out in the 1930s. It all seems a logical progression of understanding and growth, leading somewhere. Yet after this, within the scientific community, it appears that the study of aging became ever more disconnected from practical thoughts of extending life. The closer researchers came to understanding the causes of aging, the more distanced they were from considering intervention in any organized way - the field turned to the treatment of age-related conditions, drawing an entirely artificial dividing line between aging and disease. I have no grasp on why this came to pass, at least in the first decades following the 1930s; after that, however, it is possible to draw connections and conclusions.
With the exception of the early establishment of amyloid aggregation by Alois Alzheimer, the causes of aging outlined in the SENS rejuvenation research proposals were all discovered, and those discoveries refined, in the thirty years between 1955 and 1985. The period between the 1960s and 1990s also encompasses the growth and success of the anti-aging marketplace outside the scientific community, probably spurred by the early scientific discoveries, but taking on a life of its own as people realized just how much profit could be made in this modern and more sophisticated incarnation of the old hoaxes regarding elixirs of life. For every group that approached anti-aging seriously, another ten were cheerfully selling nostrums and misrepresenting scientific discoveries - a trend that continues today.
Life extension was one of the tenets of the 1960s and 1970s culture propagated by people such as Timothy Leary, who wrote optimistically about scientific methods to dramatically extend human life span. There are probably people in the audience old enough and Californian enough to recall SMI2LE - Space Migration, Intelligence Increase, and Life Extension. The Age of Aquarius had its technological counterpart - now an overly optimistic retrofuture, only portions of which were attainable in the time span envisaged. But this movement was in no way a part of the small scientific community that studied aging, and the members of that research community rejected all of it, baby along with bathwater.
Thus to a very crude approximation, aging research in the latter half of the 20th century looks to have been steered by competing dynamics of commercially co-opted popular enthusiasm versus ivory tower rejection of that enthusiasm as a threat. There were never large numbers of thought leaders involved on either side, and the sums of money involved were never truly enormous, but this all happened in a period of growth and foundation and potential on either side of the fence. Could it have been different, and come to a better outcome for longevity science? Were those decades lost in terms of progress that could have occurred towards working healthy life extension technologies?
Everything boils down to economics in the end. It is reasonable to consider that progress only picked up in the frozen scientific community of the early 1990s because biotechnology had improved rapidly following the start of the computing revolution. Falling costs and greater capacity to generate results per unit expenditure mean fewer people must be asked for permission to perform any particular study. More exploration takes place by those with heretical views and useful curiosity. Nonetheless, we can imagine a very different world, one in which the institutional space race of the 1950s and on was instead a focus on biotechnology and aging. How much further might we be today, given massive investment on that front? It is hard to say. Could something like the Human Genome Project, for example, have been conducted at any price in the 1970s? Or any analogous feat of understanding? Drug discovery and cellular assessment were painfully slow and expensive processes back then; would it have been possible to uncover senolytic pharmaceuticals with any reliability?
But that is the root of any answer to the question of the degree to which the latter half of the 20th century was a series of lost decades in the matter of aging. We know that the scientific community retreated from engagement with the goal of extending human life, leaving that to the anti-aging marketplace, a community that did little of any great use for human longevity considering all of the effort expended, and generated much in the way of fraud, lies, and mistaken expectations along the way. A generation passed before the opportunity arose to change that state of affairs, but it is quite possible that the practical outcome might not have been all that different had it happened otherwise.
Vesicles from Young Cells Reverse Measures of Aging in Old Stem Cells
Much of the constant signaling that takes place between cells is carried via microvesicles and exosomes, membrane-bound packages of molecules. Researchers are finding that the contents of vesicles change in characteristic ways with advancing age, one of the many cellular reactions to rising levels of molecular damage and environmental stress. Some of these changes might be useful as a marker of cellular senescence, one of the more important changes in cell state associated with age. It should also be possible to use suitably formed vesicles to adjust cell behavior in situ, such as to spur greater regeneration. Perhaps these vesicles are harvested from young cells, or perhaps they might be manufactured directly. Many of the current class of widely used cell therapies might in theory be replaced by delivery of vesicles, as the cell therapies achieve their beneficial results via signaling, not other cell activities.
Another of the more important changes in cell state that occurs with age is the decline in stem cell activity. Stem cells are responsible for providing a supply of somatic cells for tissue maintenance and regeneration, and the progressive loss of that supply contributes to the gradual failure of tissue and organ function in later life. There is ample evidence to suggest that, at least in the stem cell populations most studied to date, such as those supporting skeletal muscle tissue, this is at least as much a problem of signaling as it is a problem of damage to the cells themselves. The stem cells react to the state of damage and behavior of other cells in the niche that supports them, as reflected in the signal molecules they receive. The current consensus in the scientific community is that this response to the damage of aging evolved to reduce cancer risk, one part of the current human life span as a balance between death by cancer versus death by slowly declining tissue function.
As research community interest in vesicle signaling picks up, we should expect to see more in the way of research results such as the one below, in which scientists find that delivery of vesicles from young niche cells can restore more youthful function to aged hematopoietic stem cells, the population resident in bone marrow and responsible for generating blood and immune cells. It seems plausible that we stand at the verge of an important shift in focus for the field of regenerative medicine, a change based on an improved understanding of how cells influence one another via signaling processes, and the identification of which of these signals are important determinants of the changes in regeneration and stem cell activity that occur over the course of aging.
Intercellular Transfer of Microvesicles from Young Mesenchymal Stromal Cells Rejuvenates Aged Murine Hematopoietic Stem Cells
Donor age is one of the major concerns in Bone Marrow Transplantation (BMT). Studies on murine system have demonstrated that aged marrow harbors increased pool of hematopoietic stem cells (HSCs) exhibiting myeloid bias and having compromised competitive repopulating ability. Aged HSCs also exhibit multiple epigenome and transcriptome changes. DNA damage, replication stress, and ribosomal stress have been shown to cause aging of HSCs. Age-associated changes in human HSCs were similar to those observed in mouse HSCs, suggesting that hematopoietic aging is an evolutionarily conserved process. A retrospective study done in BMT patients showed age as the only donor trait associated with their overall and disease-free survival.
Since donor age is such an important concern in BMT, it might be argued that the upper limit of donor age may be lowered. However, patients having an older individual as the sole matched donor could be denied access to this potentially life-saving treatment. To overcome this impediment, efforts are being made to rejuvenate aged HSCs to improve their performance. Here we report a novel finding that a brief exposure of aged HSCs to young mesenchymal stromal cells (MSCs) rejuvenates them via intercellular transfer of microvesicles (MVs) containing "youth signals". We also demonstrate that intercellular transfer of aged exosomes carrying negative regulators of autophagy causes aging of HSCs. Our data are relevant in both allogenic as well as autologous transplantations involving older individuals as donors and recipients, respectively.
Rejuvenation of aged HSCs prior to transplantation could expand the donor cohort and also help older individuals undergoing autologous stem cell therapy. Application of the MSCs as well as MVs in clinical BMT/SCT might be logistically straightforward, since they can be cryopreserved as "ready-to-use" reagents. Use of pharmacological compounds to rejuvenate aged stem cells in general, and aged HSCs in particular, is being pursued to gain clinical advantage. However, most pharmacological compounds could show off-target effects and they also regulate diverse processes and pathways. Therefore, use of clinical grade "cellular products" in manipulating HSCs, albeit expensive, would be a safer approach than the direct application of pharmacological tools on them.
Reduced autophagy is associated with aging, whereas stimulation of autophagy is speculated to have anti-aging effects. Aged HSCs having high autophagy levels are known to preserve their regenerative capacity. Here we provide a direct evidence for this hypothesis. We demonstrate that young MSCs transfer autophagy initiating mRNAs to the aged HSCs via intercellular transfer of MVs, leading to their rejuvenation. ATG-7 is a critical component of the autophagy pathway and has been shown to be essential for the maintenance of human CD34+ HSCs. Here we show that young MSCs and their MVs transfer Atg7 to aged HSCs.
FOXO3a has been linked to longevity in multiple population studies. FOXO3a is known to stimulate autophagy in primary mouse renal cells. Similarly, FOXO3a inhibition or depletion prevents autophagy induction by starvation in vivo in mouse muscle, confirming a strong link between transcription factors of the FOXO family and autophagy. We found that aged HSCs treated with young MVs show high levels of FOXO3. In the light of these reports, our data clearly demonstrate that direct transfer of MVs containing autophagy-inducing mRNAs seems to be one of the important mechanisms involved in rejuvenation of aged HSCs by young MSCs.
Myeloid bias of HSCs has been considered as a hallmark of their aging. This has been attributed to an accumulation of myeloid-biased HSCs in the aged marrow. In transplantation between old and young individuals, microenvironment-mediated myeloid skewing has been demonstrated. Here, we report a novel finding that myeloid bias of aged HSCs could also be a non-cell-autonomous process involving intercellular communication mechanisms. We demonstrate that aged MVs contain higher levels of Itga2b, which is a myeloid commitment marker, whereas young MVs contain higher levels of IL7r, which is a lymphoid commitment marker. Importantly, we show that partitioning of these mRNAs depends upon the levels of activated AKT in the stromal cells.
Thus, a continuous transfer of aged MVs containing Itga2b to the HSCs could impose a myeloid bias in them, and this coupled with their low levels of apoptosis, could lead to the accumulation of aged HSCs in the marrow. Our data strongly suggest that the lineage bias of HSCs could be dictated by the mRNA profile of the MVs transferred to them, which in turn depends on the signaling mechanisms prevailing in the stromal cells. This aspect needs further investigation. Nonetheless, our findings have certainly added a new dimension to the existing academic debate.
Commercial Success Would Solve Most of the Challenges of the Cryonics Community
Cryonics refers to the long-term storage of people at liquid nitrogen temperatures, starting as close to clinical death as possible, and involving cryoprotectant-induced vitrification of tissues rather than freezing. The goal is preservation of the fine structure of the brain, as that is where the data of the mind is encoded. Given a good enough preservation, a sufficient storage of the mind, then the possibility of later restoration exists, based on the advances in biotechnology and molecular nanotechnology foreseen for the coming century. Cryonics is thus an important service, albeit one that receives little attention and funding. Despite that thin profile, cryonics providers have nonetheless survived and evolved over more than four decades. Several hundred people are now preserved for the long term, and this option remains the only alternative to the grave for the countless others who will age to death prior to the advent of comprehensive rejuvenation therapies.
The primary challenges faced by the cryonics industry all relate to the small size of the community. It is largely non-profit, with only a few distinct organizations - the long-established non-profits Alcor and Cryonics Institute, and relative newcomers KrioRus, CryoSuisse, and some smaller groups in other countries that have yet to build a viable provider organization. Everyone knows everyone else. The resources available for operations, research, and expansion are small in scope. The number of people joining the community each year to contribute meaningfully in some way is similarly small. There have been instances in past years of the sort of cabin fever and clashes of personality that tend to occur in small, largely volunteer and non-profit communities. Anyone who has spent time in passionate movements knows how this goes when growth to the next stage doesn't materialize. People are people.
Cryonics is a long-term project, much more so than rejuvenation research. The framework of a rejuvenation toolkit should be largely sketched out, with first and second generation clinical applications available in all of its categories, twenty years from now, adding a significant number of years to health and life expectancy at 60 or 80. After that, it is a matter of filling in the spaces and incremental improvement, following the usual cycle of growth for a broad area of technology. For cryonics, on the other hand, one has to delve deeply into speculation on technological progress to, say, make the argument that it will be a plausible goal to reverse the cryopreservation of an individual in 2050 who was preserved using the methods of 2050. Maybe that could be achieved, maybe not. Repairing people preserved in the 20th century with no vitrification or partial vitrification and a fair load of ice crystals and fracture damage is a whole other story, however, something that will require mature molecular nanotechnology of the sort that may not emerge until much later in the century. But everything much past 2040 is very challenging to predict.
That cryonics is a long-term project puts a great deal of pressure on the community to engage younger members. There are enough of the prime of life folk at present to take over from the second generation leadership as needed in the years immediately ahead - the first generation who led in the 1970s and 1980s being retired, cryopreserved already, or more permanently dead and gone. But what comes afterwards? The longest standing cryonics organizations are 40 years old, give or take, and they may well have to continue for another century. There are many organizations, companies even, considerably older than that span of time. But how did they survive over generations? They did so through the size of their extended communities: workers, supporters, customers, patrons. Continuity of culture and commitment requires community, and when that community is small there is the very real risk of it sputtering out, as small communities have done since time immemorial.
The solution to all of this is growth. But how? The cryonics community has for four decades sought growth primarily through membership, through individuals signing up for the service of cryopreservation. This has been a very slow bootstrapping process. There are thousands of us, but not very many thousands, and most are entirely silent partners in this endeavor. That process will continue grinding away, but I don't think anyone should count on a sudden explosion of interest in the membership model of cryopreservation any time soon. If that was going to happen, it has had many opportunities to do so.
I would say that for growth in the community over the next twenty years, we should be looking more to customers than to supporters of other sorts. That growth could arrive from the array of technological spin-offs that can be produced from the methodologies of cryonics and related cryobiology. In particular indefinite tissue preservation via vitrification, something that is beginning to look plausible for whole organs. Reversible vitrification of large tissues such as whole organs is on the near horizon, a capability that would revolutionize the organ donation and transplantation industry. Members of the cryonics community are well aware of this, and efforts to find commercial growth have in fact been underway for years. This includes companies founded by community members, such as 21st Century Medicine and Arigos Biomedical. This, also, has proven to be a tough road - but I think it one with a better chance of opening up the cryonics industry to greater investment and attention than other approaches.
In a better world than ours, cryonics as an industry was implemented and sizable by the mid-20th century, soon after low enough temperatures could be reliably maintained indefinitely, and sufficient knowledge of cryoprotectants was established. It spread, replacing the funerary industry as the primary end of life choice. Instead of billions of graves and markers of individual extinction, billions of stored brains would be awaiting the chance to live again in a better, brighter future of limitless resources and expansion of humanity to the stars. This is still a goal that could be achieved in the years ahead, a way to dramatically reduce the number of people permanently lost to oblivion. First, however, the small, essential, and largely overlooked cryonics community needs to find its path to growth.
Aubrey de Grey on Rejuvenation Research: How Big and How Near are the Benefits?
Aubrey de Grey of the SENS Research Foundation was back again to present to rank and file Google employees recently as a part of the Talks at Google series. The SENS perspective on aging is easy to summarize at the high level: aging is caused by accumulated molecular damage in cells and tissues; here is the evidence-supported list of types of damage; here are a set of ways to repair that damage, all of which could be constructed in a decade or two given the funding. It is an engineer's view of aging as a harmful phenomenon that should be fixed, with the high priority given to that fix derived from the fact that aging causes more suffering and death, by far, than any other part of the human condition. That SENS is as much straightforward, logical engineering as scientific research probably explains why members of the software engineering community have, right from the start, made up a sizable fraction of those who helped to fund SENS research. It resonates: break down the problem to its roots, assemble the facts, assess them, act on them.Aubrey de Grey, PhD: "The Science of Curing Aging" | Talks at Google
Aubrey de Grey, Chief Science Officer, presents the SENS Research Foundation's current research into therapies that may add decades of healthy life for people who are adults today, as well as work that the Foundation has already spun out into successful startups. Dr. de Grey also explains how SRF's work fits within the context of the global anti-aging research effort and why it has gained broad expert support.
As de Grey points out in the talk here, if this is so straightforward, why does he have to tour the world canvassing support for the cause of rejuvenation research? There are two categories of challenge here. The first is that the bulk of the scientific community will not on their own initiative raise funds to work on most lines of rejuvenation research, at least not until it is obvious beyond refutation that a particular approach will work - which means animal studies showing significant, reliable life extension at a minimum. It is an exceeding conservative, risk-averse community. Look at senescent cell research before and after the 2011 demonstration of extended life in progeroid animals through destruction of senescent cells, for example. Before that point, there was next to no funding, and very few researchers made any effort to look into this area, despite the fact that decades of evidence strongly supported a role for cellular senescence as a cause of aging. The study itself was funded via philanthropy, rejected by the established funding institutions. In the few years afterwards, an avalanche of interest and funding arrived, leading to senolytic drug candidates and the present brace of startups bringing rejuvenation through senescent cell clearance to the clinic.
But that still leaves numerous lines of rejuvenation research that are just as promising, just as likely to produce sizable effects on health and reversal of aging, and yet the research community largely ignores them. Glucosepane cross-link breaking to reverse loss of tissue elasticity, for example. The philanthropy of the SENS Research Foundation and related groups is the only reason there is any significant progress in these areas - yet as soon as the first studies are in hand to show significant results on animal aging, exactly the same will occur there as did for senescent cell clearance. All it takes is sufficient funding to build the first technology demonstrations.
The second form of challenge is that the public at large is not engaged in any way with their future decline via aging. People react poorly to being directly challenged on aging as a source of pain, misery, and death. They deploy environmentalist and class envy arguments against deploying medicine to help turn back aging and lengthen life, while at the same time supporting causes such as cancer research or Alzheimer's research. Which is exactly the same thing under the hood! Few individuals argue for a halt to cancer research because too few people are dying and too many people are living longer, or because some people will get the treatments before others, and yet the average fellow in the street might well respond with concern on the topic of treating aging as a medical condition, exactly because there would be less suffering, less death, or because the third world will not immediately benefit.
All told, strange confusions and misapprehensions regarding aging and the potential to reverse aging are widespread out there. People mistakenly believe that therapies will be so expensive as to be restricted to the elite. Or that therapies will maintain people in a state of increasing decrepitude rather than making patients younger and healthier for longer. Or that resources will run out if people live even a little longer. This manifests in practice as a lack of readily available philanthropic funding at larger scales, needed to solve the first challenge noted above, the production of technology demonstrations to persuade the scientific community. We all have to work a lot harder than is the case for other, related causes in medicine to fund the early stage rejuvenation research needed to turn back the causes of aging. This is why we must conduct advocacy for the cause.
Mitochondrial Transfer Partially Reverses Some Consequences of Oocyte Aging
This is a most interesting technology demonstration for anyone interested in the various aspects of mitochondrial contributions to aging: transferring mitochondria from fat-derived cells into germline cells in an older mouse can reverse some of the consequences of aging in the germline, specifically loss of fertility in females. Mitochondria are the power plants of the cell, primarily responsible for generating chemical energy store molecules, though they have many other roles in fundamental cellular activities as well. There are a couple of different aspects to mitochondrial dysfunction in aging, and the research here is probably relevant to the one unconnected to SENS rejuvenation research: the general malaise that affects mitochondria throughout the body, probably a reaction to rising levels of other molecular damage, that changes mitochondrial dynamics and reduces available energy for cellular operations. The research results noted here raise many questions regarding the mechanisms involved in different rates of decline of mitochondrial function throughout the body.
The fertility of women decreases with maternal aging, resulting from various kinds of reasons including decreased follicle number, altered reproductive endocrinology, increased reproductive tract defects, decreased embryo quality, and impaired oocyte quality. Among the possibilities, decreased oocyte quality with maternal aging is the main reason because oocyte donation from young women could rescue the low live birth rate in elder women. With maternal aging, both the nuclear maturation and cytoplasmic quality are affected, and oocyte aneuploidy arising from chromosome segregation error increases dramatically. The obvious change in ooplasm with maternal aging is mitochondrial dysfunction.
It is well known that mitochondria function in energy production and apoptosis in cells. As the most prominent cell organelles in oocytes, mitochondria play pivotal functions and determine the developmental competence of oocytes. With advanced maternal age in women, the most common aberrations in mitochondrial structure are mitochondrial swelling and cristae disruption. Mitochondria are the main source of ATP through oxidative phosphorylation in mammalian oocytes. It is reported that reduced ATP content and metabolic level could be detected in aged oocytes, which would affect oocyte quality and embyogenesis. Mitochondrial malfunction is highly related with defects in spindle organization, cell cycle progress and chromosome segregation in oocytes of aged women and mice. Mitochondrial dysfunction is a major contributing factor for negative outcomes in IVF in general, especially in women of advanced maternal age. The findings reminded the researchers that mitochondria supplement or replacement in oocytes might be a possible strategy for infertility treatment in elder women.
The mitochondria replacement by transfer of heterologous ooplasm, germinal vesicle, spindle, polar body, or pronuclei has been tested in animals and humans to improve developmental potential of aged defective oocytes or to prevent trans-generational mitochondrial disease transmission, but clinical translation of these techniques requires further validation for their efficacy and safety. Especially, the compatibility between donor and recipient mitochondrial DNA and mitochondrial heteroplasmy are still a concern. Transfer of autologous mitochondria from cumulus and granulosa cells were tested for oocyte quality rescue, but it is worth noting that cumulus and granulosa cells age similarly to oocytes. We supposed that autologous adipose tissue-derived stem cell (ADSCs) might be an ideal mitochondrial source for rescuing oocyte quality and fertility. In our study, we found that supplement of autologous ADSC mitochondria could improve oocyte quality, embryogenesis, and fertility in aged mice. We propose that autologous ADSC mitochondria supplement may be a promising strategy for fertility retrieval in women with advanced reproductive age.
Evolution Discards the Old
One way of looking at evolution is to see yourself, the individual, as little more than a disposable short-term delivery system. The focus of evolution is propagation of the germline, and aging exists in its present unpleasant form because in 99.9% of all complex species there is no selection benefit in avoiding it. On the one hand, nature is red in tooth and claw, and the only system that survives in the wild is one that gets the job of replication done before a violent or diseased death. On the other hand, systems optimized for early life tend to fall apart and consume themselves in later life. The mammalian adaptive immune system is a good example, a limited capacity system that will eventually malfunction due to encountering and attempting to remember too many different pathogens regardless of all of the other issues of aging. Evolution led to that system because it works well enough to get by in early life, and because there is little selection pressure to avoid the inevitable crash later in life, when the chances of reproductive success are low.
Lastly, there appears to be a race to the bottom between long-lived and short-lived species. The reason why we see so few species succeeding in their own niche via a long-lived strategy of agelessness and continual replication, as is the case for some species of hydra, may be that aging species can adapt more rapidly to changing environments. Thus highly regenerative, ageless species of various sorts may arise over and again in larger numbers during long periods of environmental stability - it is hard to say from the fossil record whether or not this is the case - but are out-competed and swept away by aging species when the climate or ecology shifts rapidly enough over evolutionary time.
Many people would tell you that death - or rather, aging - wasn't around until we started reproducing sexually. There's no reason sexual recombination in itself would demand our death, however. In fact it clearly doesn't: we know of two species of worm which reproduce by splitting themselves lengthwise and fusing together, who are nonetheless no likelier to die in old age than in youth. The famously immortal Hydra is also capable of reproducing sexually (although it usually chooses budding instead). On the flip side, there are multiple organisms who produce eggs asexually, but aren't any safer from senescence than we are.
The rather disturbing truth about life and death is that our bodies are just disposable vessels for the replicators cushioned safe and snug within our germ cells. While a few organisms like the Hydra kept things simple by remaining as one with their germline, others built free-standing bodies of somatic cells with ever more complex machinery to house and propagate a germline that was reincarnated each generation inside a new (and hopefully improved) body. The resulting collections of meat and bone eventually became complex enough to totally obscure the germline itself, and conducted lives with apparent independence - humans in particular enjoyed millennia of ignorance about our fundamental irrelevance. But despite its obscurity, the consequences of its influence could hardly escape notice, for one simple reason: once the germline had abandoned the body, we were all condemned to death.
Key to this fate was the fact that you would, at some point, probably die anyway. Maybe you'd starve in a famine, or be eaten by the resident apex predator, or just freeze to death. But whatever the cause, you were always less likely to live two years than to live one. In this way, each individual's reproductive potential was concentrated at the beginning of his life, and declined at some rate after sexual maturity. The most crucial task was getting you to reproductive age at all, and consequently a lot of selection power had to be spent on birth and development. By contrast, ages that organisms were rarely capable of reaching would experience extraordinarily little selective pressure, the bottom of a genetic slump that began very soon after reproductive maturity. The problem wasn't just that beneficial alleles in old age weren't selected for; it was that alleles with damaging effects later in life could curry favor by increasing fitness at the ages of highest reproductive potential - an effect known as "antagonistic pleiotropy".
Exactly how bad a deal you, the body, get is dependent on your niche. How dangerous is it? How long are you likely to survive? If you're a wild mouse, your chances are around 10% in the first year. There's no sense in spending a long time on growth and development, and you'd better have lots and lots of children, because most of them will die. On the opposite end of the spectrum are organisms that live in relative safety. They may live on an island with no predators, such as a particular strain of opossum with unusually long life, or have an unusually reliable food source. Humans, for our part, didn't come out as bad as we could have. We're among the longer-lived species, and there's a good chance that apparently unrelated medical advances in the last century have been pushing us in the direction of a slower intrinsic aging rate.
ALZFORUM Looks Back at 2017 in Alzheimer's Research
ALZFORUM should be on your reading list if you have more than a passing interest in research into neurodegenerative conditions. It is a great example of what can be achieved in educational advocacy if any earnest institutional funding is devoted to the task. That investment in advocacy exists today because Alzheimer's disease research is by far the largest portion of the broader aging research community, measured by funding and volume of projects, and has been for some time. The situation is quite different for our area of interest, rejuvenation research to repair the causes of aging. Here, the scientific programs of our community are still bootstrapping towards success in the absence of any larger-scale institutional funding, powered almost entirely by philanthropy. There really is no comparison when it comes to funding infrastructure. Still, ALZFORUM turns out a quality of online advocacy and education that we can aspire to - and given the continued unremitting failure in clinical trials of potential Alzheimer's therapies, it has to be said that just having funding doesn't automatically make advocacy an easy goal.
Confronting failure in trying to stem symptomatic Alzheimer's disease (AD), the field's main thrust has turned toward retooling its drug trials for ever-earlier disease stages. To sustain enthusiasm among participants and sites, scientists were advised to focus on learning from failure rather than conveying a sense of nihilism, both in internal discussions and in speaking with reporters.
They got to practice a positive attitude when another setback hit home. Merck announced an end to the EPOCH mild to moderate AD trial of the BACE inhibitor verubecestat for lack of efficacy, and data released later indicated that the drug had nudged down amyloid plaques without a hint of benefit, even in the more mildly symptomatic participants. Even so, BACE inhibitors are very much alive and being evaluated to a collective tune of billions in funding. Researchers believe EPOCH treated people too late, when they'd had brain amyloid for years and neuron loss was well underway. The hope now rests on Phase 3 trials in people with mild AD. In trials of anti-amyloid antibodies, the place to go in 2017 was up. The A4 trial joined the trend in Alzheimer's immunotherapy when it quadrupled the solanezumab dose and extended treatment time to five years. Solanezumab had shown hints of efficacy in its negative Phase 3 trial, suggesting a higher dose might work.
Two different α-synuclein antibodies advanced to Phase 2. Researchers desperately want biomarkers for the next round of α-synuclein trials, and the race is on for PET tracers that will detect it. This work currently plays out on the Parkinson's disease (PD) front, but tracers and therapeutics for this protein will come in handy in Alzheimer's and dementia with Lewy bodies as well, as they will help scientists dissect the significant overlap of pathology and symptoms across the AD-PD spectrum.
Biomarkers will continue to be a research priority until they are solidly in place as routine features of AD diagnoses and trials, and 2017 saw strides toward that end. Researchers improved the standardization of cerebrospinal fluid (CSF) amyloid and tau measurement with automated CSF assays that vary less between runs and can predict clinical progression in cognitively normal people. Ultimately, clinicians prefer to use blood over CSF, and this year saw the first signs that this may be possible. Trialists all over the world seek a blood-based indicator of brain amyloid deposition to help them cut down on the number of expensive amyloid PET scans currently needed to recruit for secondary prevention trials.
Whatever doubt might have lingered out there about microglia's role in Alzheimer's was put to rest when scientists fingered a protective polymorphism near the gene for a major microglial transcription factor. Called PU.1, it controls myriad responses, including expression of known AD genes. This protective variant reduces PU.1 expression, lowers amyloidosis, and delays onset of AD. In a bizarre twist, 2017 ended on news that microglia not only help clear amyloid plaques, they may also help seed them. Some activated microglia spew protein bundles that power inflammatory cascades and also latch onto amyloid, driving plaque assembly.
The gradual sickening and eventual death of neurons defines neurodegenerative disease, but how exactly do disease-related proteins do this to neurons? A single theme did not emerge from this line of research in 2017; rather, it seems toxic proteins have an arsenal of weapons at their disposal. Tau appears to mess with all manner of cellular functions. Researchers implicated toxic tau variants in mitochondrial dysfunction, bungling synaptic vesicle release, disrupting the nucleus, compromising the epigenome. No one mechanism rose to the fore, however.
Vascular dementia research used to be a slow backwater relative to the flow of data every year on AD, but 2017 was different. Researchers made inroads into the physiology underlying this disease, for example by toppling a long-held dogma with their demonstration that the human brain does have a lymph system. The finding comes two years after a dural lymph system was discovered in mice. Continuing this year, the rodent studies reported that the dural lymph vessels drain cerebrospinal fluid from the brain into the blood stream. Besides the excitement about lymphatics, there was buzz about the regulation of blood flow in the brain. Researchers found that microinfarcts shut down local clearance of amyloid from the brain, at least in mice. These tiny, "silent" strokes are known to occur in people with AD, and the findings suggest they could hasten amyloid buildup by blocking clearance.
Excess Fat Tissue Leaves Lasting Damage to Stem Cells, Even if Lost
There is a fair amount of evidence from epidemiological studies to suggest that carrying excess visceral fat tissue will cause lasting damage to bodily systems even after that fat is lost. The longer it is there, and the more it there was, the worse off you are. You might recall a study that found lifetime maximum weight to be a better predictor of later age-related mortality than other measures, for example, implying that some forms of consequence linger even if the weight is lost. The study here identifies one possible mechanism to explain this sort of outcome; the authors find a lasting impact on the stem cell populations responsible for generating the cells of the immune system and other parts of the blood supply.
Obesity continues to weigh on the blood-forming stem cell compartment, altering the balance of the cell types produced there, even after the body sheds excess weight. Under the stress of obesity, hematopoietic stem cells (HSCs) begin to overexpress a regulatory gene that tilts blood production toward myeloid cells, and may even promote preleukemic fates. This shift in gene expression, which worsens over time, results in lasting dysregulation, even if HSCs are transplanted into a normal environment.
Although these findings come from a study that relied on a mouse model of obesity, they raise questions about the use of HSCs isolated from obese people in therapeutic transplant procedures. "Little is known about how obesity in marrow donors could affect the quality of the hematopoietic stem cell compartment. We want to better understand the molecular alterations in obesity to predict potential risks associated with the therapeutic use of stem cells isolated from obese donors."
The research team traced the dysregulation of the HSC compartment to altered expression of Gfi1, a transcription factor. "Mechanistically, we establish that the oxidative stress induced by obesity dysregulates the expression of the transcription factor Gfi1 and that increased Gfi1 expression is required for the abnormal HSC function induced by obesity. These results demonstrate that obesity produces durable changes in HSC function and phenotype and that elevation of Gfi1 expression in response to the oxidative environment is a key driver of the altered HSC properties observed in obesity."
Although the effects of chronic organismal stresses are still poorly understood, research is showing that age and environmental stresses can lessen the healthy diversity of cells in our blood-making machinery. "There is now an understanding that the blood stem cell compartment is made up of numerous cell subsets, Keeping this compartment healthy is essential to human health. This includes maintaining the diverse pool of blood-making stem cells needed to produce blood cells the body needs to function properly."
Laura Deming's Introductory Overview of Aging Research
Laura Deming runs the Longevity Fund, and has a research background in the study of aging. It seems likely that the fund will do well on the basis of having invested in Unity Biotechnology alone, even putting aside any other successes. The article here is a useful overview, with copious references, of the type of work presently taking place in the aging research community. It well illustrates that, aside from senescent cell clearance, nearly everything that counts as a major interest by funding and number of scientists involved is a form of tinkering with stress response biochemistry to modestly slow aging - not addressing root cause molecular damage by repairing it, but rather messing with metabolism to slow damage accumulation. Nowhere near as helpful.
Given what we know, where the data exists to compare outcomes between short-lived and long-lived species, the approach of altering metabolic processes to enhance beneficial stress response mechanisms is not going to move the needle all that far in humans. The results should be exercise-like and calorie-restriction-like in that they have worthwhile effects on long-term health, assuming that the cost of development and treatment is low, but they won't add much more to life expectancy than those two items are capable of achieving - which means perhaps the low end of five to ten years at best in our species, assuming life-long commitment to the intervention. Given that senescent cell clearance is a going concern, and other damage repair approaches such as cross-link breaking should follow in the years ahead, we can hope that the focus of the research community will shift as other approaches prove themselves much more cost-effective and successful.
As you get older, the chance that you will die goes up. As you get older, the chance that you will die from certain diseases also goes up. Why does this happen? A simple explanation would be that, like an old car, you accumulate damage in a random fashion. However, there are many simple things that we can do to make animals live longer. Why? We don't really know. Eating less makes mice live longer. Some genes, when mutated, make mice live longer. A few drugs, approved for human use, also make mice live longer. So what is the study of aging? I sum it up as the following: trying to figure out what kinds of damage accumulate with age, how to reverse that accumulation, and the search for switches that we could flip in human biology to increase lifespan.
In the 1930s, investigators wanted to do an experiment to see if stunted growth rates during the Great Depression might impact lifespan. They tested this in rats by feeding them less food than they would normally eat. To their surprise, this actually made the rats live longer! This was a seminal discovery. For the first time, we changed the environment of an animal to make it live longer than it normally would. Since then, investigators have tried to uncover how this works. While long-term human studies are sparse, investigators have run two caloric restriction experiments in monkeys, one of which showed promising results for an increase in survival.
In papers published in 1983-1993, investigators introduced the concept that a gene could control lifespan. Previously we'd known that caloric restriction could make animals live longer, but scientists found mutant genes that could make worms live longer. The first gene found encoded a protein that is similar to insulin-like growth factor and insulin receptors in humans. In mice, mutating members of both of those pathways can increase lifespan. One of the longest-lived mouse mutants we have today is a dwarf mouse. In one study, people with similar dwarf mutations seemed to suffer less age-related disease than their non-mutated relatives.
A paper published in the 70's showed that linking old and young female mice so that they share a bloodstream increased lifespan. Then, in 2011, a succession of papers came out showing that this procedure and others like it made mice better at remembering things, and improved heart and muscle function with age. These discoveries increased excitement and interest in the field, and lead to a wave of startups. Investigators in the field have proposed many possible causes for this phenomenon. Proteins, small vesicles, or cells in the young mouse cleaning the blood of the old mouse might all be part of the effect. Many companies are trying to figure out whether there is a special protein or molecule involved.
As you get old, so do your cells. But some of your cells get old in a way that is much worse than the others. If the cell refuses to die even when it stops working, and starts secreting signals to the immune system, we call that a 'senescent cell'. What happens when you get rid of these cells? Investigators found that getting rid of senescent cells in normal mice made them live a longer healthy lifespan. Knocking out senescent cells is tricky, because they don't have many unique identifiers. Companies are working to either find things empirically that kill senescent cells, or figure out specific mechanisms by which to try to destroy them.
Your body makes a lot of junk, on the molecular level, and cells need to clean this up. Just increasing the expression of one protein that helps to clean up this junk was enough to make mice live ~17% longer. Cells recycle old proteins and other molecules into a big vesicle, called a lysosome. It contains many proteins, and their job is to chop up old cell parts that it engulfs. Genes for proteins that do work in the lysosome are mutated in diseases such as Parkinson's. So improving this process has immediate relevance to neurodegenerative disease. As the lysosome gets older, more junk builds up in it that it cannot degrade. Finding ways to make more lysosomes, or help lysosomes degrade junk, may be interesting therapeutic avenues to pursue.
You may have heard mitochondria referred to as the 'powerhouses' of the cell. One concept that comes up when people talk about mitochondria is 'oxidative stress' - the idea that if molecules are very reactive, they are likely to interfere with a lot of other molecules in the cell that should be left to their own devices. Weirdly, the story has turned on its head over time. It's true that it is bad to pump an animal full of reactive oxygen species, and that you can make a mouse live longer by increasing the level of proteins that are supposed to clean up mitochondria. But you can also mutate things that should be helping the mitochondria, and end up increasing lifespan! It's counterintuitive, and one hypothesis is that a little bit of stress is good because it forces your cells to put up their defenses and ramp up production of molecules that neuter the reactive oxygen species. But we don't really know.
More on Efforts to Tissue Engineer Skin with Hair Follicles
Skin is one of the obvious initial targets for tissue engineering, as it is possible to grow in thin sheets without the need to solve the challenge of generating vascular networks to support larger, thicker tissue structures. Researchers have been making progress towards more complete, complex engineered skin, such as through the inclusion of functional hair follicles or sweat gland structures. The research noted here is an example of the type, though one should always be wary of publicity materials that claim researchers to be first to a specific goal in tissue engineering. It is more often the case that several different groups are in progress at at a similar stage for any given advance in this field. It is a very well funded and diverse area of research; few groups are the only ones working on their specific tissue type and methodological focus.
Researchers have cultured the first lab-grown skin tissue complete with hair follicles. This skin model, developed using stem cells from mice, more closely resembles natural hair than existing models. Although various methods of generating skin tissue in the lab have already been developed, their ability to imitate real skin falls short. While real skin consists of 20 or more cell types, these models only contain about five or six. Most notably, none of these existing skin tissues is capable of hair growth.
Researchers originally began using pluripotent stem cells from mice, which can develop into any type of cells in the body, to create organoids that model the inner ear. But the team discovered they were generating skin cells in addition to inner ear tissue, and their research shifted towards coaxing the cells into sprouting hair follicles. The team's recent research demonstrates that a single skin organoid unit developed in culture can give rise to both the epidermis (upper) and dermis (lower) layers of skin, which grow together in a process that allows hair follicles to form the same way as they would in a mouse's body.
While the researchers were unable to identify exactly which types of hairs developed on the surface of the organoid, they believe the skin grew a variety of hair follicle types similar to those present naturally on the coat of a mouse. The skin organoid itself consisted of three or four different types of dermal cells and four types of epidermal cells - a diverse combination that more closely mimics mouse skin than previously developed skin tissues. By observing the development of this more lifelike skin organoid, the researchers learned that the two layers of skin cells must grow together in a specific way in order for hair follicles to develop. As the epidermis grew in the culture medium, it began to take the rounded shape of a cyst. The dermal cells then wrapped themselves around these cysts. When this process was disrupted, hair follicles never appeared.
After discovering this recipe for lab-grown hair follicles, the researchers must now work to overcome a new roadblock in the study of in vitro hair development - physical limitations that prevent the hairs from shedding and regenerating. The shape of the tissue in culture causes the hair follicles to grow into the dermal cysts, leaving them with nowhere to shed. Nonetheless, the team thinks the mouse skin organoid technique could be used as a blueprint to generate human skin organoids.
Viruses and Checkpoint Inhibitors Combine to Form an Effective Cancer Treatment
Researchers here demonstrate a combination therapy that is far more effective in destroying a target cancer than either of its components alone. Effective synergies between therapies are discovered at a fairly low rate by the scientific community, which is in part a reflection of their rarity, but also a reflection of the fact that the regulatory system is not set up to encourage the commercial development of combination therapies. The number of trials for such efforts is small in comparison to single therapy tests. There isn't a good response to this observation beyond the usual calls for more freedom and more funding.
Immunotherapy, which helps the body's immune system attack cancer, has revolutionized treatment for cancers such as melanoma and leukemia. However, many other kinds of cancer remain resistant. A new study suggests that a combination of two immunotherapies (oncolytic viruses and checkpoint inhibitors) could be much more successful in treating breast cancer and possibly other cancers. "It was absolutely amazing to see that we could cure cancer in most of our mice, even in models that are normally very resistant to immunotherapy. We believe that the same mechanisms are at work in human cancers, but further research is needed to test this kind of therapy in humans."
The researchers studied three mouse models of triple negative breast cancer, and found that all were resistant to a checkpoint inhibitor which is commonly used to treat other kinds of cancer. They also found that while an oncolytic virus called Maraba could replicate inside these cancers and help the mouse's immune system recognize and attack the cancer, the virus alone had minimal impact on overall survival.
The researchers then tested the virus and checkpoint inhibitor together in models that mimic the metastatic spread of breast cancer after surgery, which is very common in patients. They found that this combination cured 60 to 90 percent of the mice, compared to zero for the checkpoint inhibitor alone and 20 to 30 percent for the virus alone. In these models, the virus was given before the surgery and the checkpoint inhibitor was given after. "When you infect a cancer cell with a virus, it raises a big red flag, which helps the immune system recognize and attack the cancer. But in some kinds of cancer this still isn't enough. We found that when you add a checkpoint inhibitor after the virus, this releases all the alarms and the immune system sends in the full army against the cancer." Ongoing clinical trials are testing oncolytic viruses (including Maraba) in combination with checkpoint inhibitors in people with cancer.
A Call to Test Combinations of Drugs Shown to Slow Aging in Animal Studies
I expect that little progress towards sizable human life extension will be achieved in the next few decades via pharmaceuticals that slow aging through triggering various stress response mechanisms. This includes calorie restriction mimetics, autophagy enhancers, exercise mimetics, and the like. It may well be the case that researchers come up with a few drugs that, if taken regularly for decades, reliably add a few years to life expectancy and improve health in old age to a degree that is in the same ballpark as the present results of exercise or eating a better diet. Is that worth billions in funding and decades of dedicated time from much of the research community, however? I think not, not when exercise and calorie restriction are free, and there is the much more promising field of rejuvenation research to focus on. Why tinker with slightly slowing the damage that causes aging when it is possible to work towards repair of that damage and thus reverse aging?
Still, the institutions focused on pharmaceutical recapture of stress responses are deeply entrenched, currently commandeering the majority of funding and attention. Even in failure, the work will continue out of sheer inertia. One would imagine that, in years ahead, researchers will start to try combinations of drugs that slow aging in mice and did not work out so well in humans, looking for synergies or additive effects. One would hope that at least some instead give up the strategy as a bad deal and turn their attention to rejuvenation research, but I expect that to be a slow and grudging process for much of the research community. The more support that we can give to organizations pushing the rejuvenation research agenda into clinical trials and proof of effectiveness, the better.
Aging is a complex multifactorial process, meaning that multiple pathways need to be targeted to effectively prevent or slow aging. A number of molecular pathways are well known for influencing aging, but only a few have been successfully targeted with individual drugs, and these drugs do not individually target all aging pathways. However, combinations of these drugs might have the potential of effectively broadening the scope of aging targets. There are a number of drug combinations that could be combined based on different but overlapping pharmacological activities. Since the number one criterion for selecting drugs should be based on known anti-aging effects, for example, in preclinical mouse studies, the number of drugs available to consider is markedly reduced. Three drugs with well-validated anti-aging effects in laboratory animals, rapamycin, acarbose, and SS31, are well suited to therapeutic multiplexing as a way to enhance healthy aging and stop the development of lesions associated with aging and physiological dysfunction based on interactive cellular mechanisms of each drug.
The concept of drug multiplexing to slow aging looks good on paper, but drug combinations have yet to be tested in any meaningful way. Historically, testing single drugs in mouse lifespan studies has provided useful information, but it is costly and time consuming. More importantly, lifespan studies are difficult to recapitulate in humans, making translation of the preclinical information challenging. And especially relevant is the fact that lifespan studies in mice are not well-suited to testing drug combinations that could more effectively target multiple factors involved in aging. Thus, new paradigms for testing therapeutics aimed at slowing aging are needed.
While the future for expanded use of drug combinations in treating various diseases and conditions, including aging, is highly promising the path toward eventual regulatory approval can be challenging and should be considered in any preclinical studies undertaken. The potential beneficial functional synergy gained from the logical and judicious use of rational drug combinations, such as rapamycin, acarbose, and SS31, is obviously complicated by the fact that different drugs with different metabolic, pharmacokinetic, and toxicity profiles are being superimposed on top of one another. Focusing not just on the benefits of combination products but also the potential liabilities early on can speed the development process.
In summary, the concept of drug multiplexing as a powerful platform to slow aging is promising but has not yet entered the mainstream of aging research. The combination of rapamycin, acarbose, and SS31, three drugs with individually documented anti-aging effects, is a logical approach designed to complement mechanisms of action of their molecular targets and robustly enhance a delay of aging and age-related disease not seen with mono-therapeutic approaches. Support for the preclinical investigation of this drug combination as well as other drug combinations is urgently needed to determine dosages, frequency of administration, and criteria for when to start administering the drugs, i.e. focus on treatment at older ages, or prevention at younger ages.
Links Between Induced Pluripotency and Cellular Senescence
Cellular senescence is one of the causes of aging. Lingering senescent cells produce the senescence-associated secretory phenotype, a damaging mix of secreted molecules that generate inflammation and tissue dysfunction. However, senescence is also an early defense against cancerous cells, especially those that gain the embryonic-like ability to replicate without limit and spawn many different cell types. Such cells are near all shut down and destroyed by the senescence process, at least in the earlier stages of life. Further, cellular senescence is also involved in tissue repair in a different, transient way. Wounds spur the temporary creation of senescent cells, which appear important in the coordination of healing.
Reprogramming normal cells into induced pluripotent stem cells is an important part of modern stem cell research, a basis for future regenerative therapies, and a potential way to produce arbitrary patient matched cell types to order. Yet it is in essence quite similar to the damage and mutation that produces rampaging cancer cells, freed from their restrictions. It also has more than a passing relation to the activities that take place during regeneration. Given this, we might not be too surprised to find links between cellular senescence and induced pluripotency. The paper here outlines some of these connections, and they are most interesting. This will probably have implications for a range of future efforts to control cellular activity in the body. For instance, inducing pluripotency in living animals has been tried, and at least in the short term shown to be beneficial - the contents of this paper put a novel spin on the sort of cautions that line of research might inspire.
Senescence is a cellular response to damage characterized by a stable cell cycle arrest and by the secretion of cytokines and other soluble factors with pleiotropic functions, collectively known as senescence-associated secretory phenotype or SASP. The primary role of senescence is thought to be the orchestration of tissue remodeling and repair. This has been demonstrated in a variety of settings, including tissue repair in the skin and liver. In general, senescent cells are efficiently cleared as part of a successful tissue repair process. However, upon severe or chronic damage, senescence-orchestrated tissue repair may fail and senescent cells may accumulate, contributing to disease and aging.
The power of cellular senescence in inducing tissue remodelling has been further extended to processes of cellular reprogramming in vivo. The transgenic expression of the four transcription factors abbreviated as OSKM (Oct4, Sox2, Klf4, and c-Myc) in adult mice induces dedifferentiation and cellular reprogramming within multiple tissues. However, in addition to reprogramming, the activation of OSKM also results in cellular damage and senescence. Therefore, OSKM induces two opposite cellular fates, namely senescence and reprogramming, that coexist in vivo in separate, but proximal, subsets of cells. Importantly, it has been demonstrated that senescence plays an active role in facilitating in vivo reprogramming through the paracrine action of the SASP, with interleukin-6 (IL6) as a critical mediator. Of note, IL6 plays an important role also during in vitro reprogramming. Moreover, the concept that senescence promotes cellular plasticity has been further extended to the activation of somatic stem/progenitor cells. In particular, the SASP can confer somatic stem/progenitor features onto proximal epithelial cells in several tissues.
The tumor suppressor genes p53, p21, Ink4a, and Arf act as cell-autonomous barriers for cellular reprogramming. These barriers are conceivably activated by cellular damages associated to reprogramming, most notably replication stress, which result in proliferation arrest and, consequently, inhibit reprogramming. At the same time, p53 and the genetic locus Ink4a/Arf also affect reprogramming, although in opposite directions, through cell extrinsic mechanisms. In the absence of p53, the induction of OSKM leads to exacerbated damage and senescence in tissues, which results in high levels of IL6 that further enhance reprogramming. The Ink4a/Arf locus plays a complex role in reprogramming: it promotes reprogramming through the paracrine influence of senescence, and, at the same time, it is a cell-autonomous barrier for reprogramming. In vivo, the absence of Ink4a/Arf severely impairs OSKM-senescence, IL6 levels are modestly increased, and reprogramming is very inefficient. Therefore, the positive cell-autonomous impact of Ink4a/Arf deficiency is completely obscured in vivo by the absence of senescence and IL6 secretion. The emerging picture is that tissue damage and senescence provide a tissue microenvironment that is critical for OSKM reprogramming in vivo.
MCP-1 as a Potential Biomarker of Biological Age
Researchers here add one more correlation between blood biochemistry and aging to the growing list. The greater the number of simple measures that can be associated with age-related decline, the more likely it is that researchers can find an algorithmic combination of those measures that quite accurately reflects biological age. At the moment epigenetic clocks based on assessment of DNA methylation patterns are leading the pack of potential biomarkers of aging because they are in effect a combined set of smaller measures, those being made by the cells themselves. Many specific DNA methylation changes are reactions to the cellular damage and dysfunction of aging. However, other approaches to combining measures of aging and cellular reactions may turn out to be better in the end. We shall see in the years ahead.
Generally agreed upon, robust, cheap, and reliable biomarkers of aging are important because they will greatly accelerate the pace of development in aging research. Currently the field lacks a good, rapid way to assess the outcome of a potential intervention to slow or reverse the aging process. The only widely accepted approach is to carry out life span studies, and that means that any sort of debate over viability or quality or strategy will drag on for years, and cost millions that might have been invested elsewhere. Mouse life span studies are not cheap. If the field is instead equipped with an assessment of biological age that can run immediately before and immediately after a treatment, then exploration and validation in aging research will become far more rapid and far less costly. The best approaches, most likely something along the lines of the SENS damage repair strategy, will win out more rapidly.
Aging is the major risk factor for numerous chronic diseases and is responsible for the bulk of healthcare costs. To address this healthcare crisis, there is a growing interest in identifying ways to therapeutically target aging in order to prevent, delay, or attenuate multiple age-related diseases simultaneously. A number of therapeutic strategies have emerged. However, a major barrier to clinical trials targeting aging is the prolonged time between intervention and clinical outcomes. For these studies, surrogate endpoints will dramatically improve the economy and timescale in which we can measure the effects of interventions on biological age.
Biological age is defined by the health or fitness of an individual, and lack of age-related diseases, irrespective of their chronological age. Biological age can be quite distinct from chronological age. For example, cancer survivors are biologically older than their chronological age due to exposure to genotoxic agents, while centenarians are frequently biologically younger than their chronological age. A biomarker of biological age in accessible bodily fluids or tissues would be extremely valuable for clinical trials testing antigeronic factors, but also potentially for triaging patients facing onerous therapeutic procedures. Hundreds of studies have aimed to discover age-related changes in circulating factors including metabolites, advanced glycation end-products, exosome content, miRNA, and inflammatory molecules, with varying success.
Here, we identified MCP-1/CCL2, a chemokine responsible for recruiting monocytes, as a potential biomarker of biological age. Circulating MCP-1 levels increased in an age-dependent manner in wild-type (WT) mice. That age-dependent increase was accelerated in Ercc1-/Δ and Bubr1H/H mouse models of progeria. Genetic and pharmacologic interventions that slow aging of Ercc1-/Δ and WT mice lowered serum MCP-1 levels significantly. Finally, in elderly humans with aortic stenosis, MCP-1 levels were significantly higher in frail individuals compared to nonfrail. These data support the conclusion that MCP-1 can be used as a measure of mammalian biological age that is responsive to interventions that extend healthy aging.