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Contents
The Burden of Somatic Mutation with Age
Back to Debating Limits to Human Life Span Again
More on the Debate Over the Classification of Aging as a Disease
Stem Cell Derived Extracellular Vesicles Reduce Epigenetic Age in Mice
Aubrey de Grey Establishes the Longevity Escape Velocity Foundation
A Subpopulation of Thymic Cells Can Restore Function to an Aged Thymus
Intermittent Hypoxia Doubles Nematode Life Span
Oxidative Stress and Inflammation in Aging Muscles
Repeating the Point that Metformin Just Doesn’t Look Good in Animal Studies
Relationships Between Strength Training and Aerobic Exercise and Late Life Mortality
Implicating Cellular Senescence in the Fibrosis and Inflammation of NASH
Theorizing a Role for Prelamin A in Aging
An Age of Metabolomics
Epigenetic Inheritance of Benefits Resulting from Parental Physical Fitness
Towards Direct Reprogramming of Heart Fibroblasts into Cardiomyocytes
The Burden of Somatic Mutation with Age
https://www.fightaging.org/archives/2022/10/the-burden-of-somatic-mutation-with-age/
Mutational damage occurs constantly to nuclear DNA throughout life. Little of that damage goes unrepaired, and little of the lasting breakage occurs in active parts of the genome. Where mutations go unrepaired in active parts of the genome, little of that occurs in important genes. Where it does occur in important genes, that only matters to the extent that (a) the mutation can spread, and (b) the mutation is potentially cancerous. Comparatively few cells in the body have the capacity to create many descendant cells through replication, as the Hayflick limit ensures that near all cells are limited in the number of times they can divide. The cell population of most tissues turns over with time, removing mutations.
Nonetheless, mutations in precursor cell and stem cell populations, responsible for generating new somatic cells to support a given tissue, can lead to patchwork patterns of those mutations spread throughout the tissue. This is known as somatic mosaicism, and it most likely makes some contribution to both cancer risk and altered tissue function with age.
Beyond this, a more recent suggestion is that double strand breaks, regardless of where in the genome they occur, can deplete cellular resources in ways that provoke epigenetic changes characteristic of aging. This work needs replication and greater support, but it would provide a convenient way to directly link mutation rate with contributions to degenerative aging, explaining many of the observations linking mutational burden with degree of aging. Otherwise, it is challenging to explain why a large fraction of age-related dysfunction should result from mutation, given that the vast majority of mutations don’t seem to have much of an effect on cell and tissue function.
Age-related somatic mutation burden in human tissues
There is now absolute consensus that somatic mutations accumulate with age in many if not all human tissues, independent of the method used for mutation evaluation. The mutation frequencies in human tissues and the increase with age are dependent on multiple factors, including environmental mutagens, such as exposure to sun and tobacco smoke.
Importantly, the accumulation rate of somatic mutations in humans differs significantly among different tissues. In this respect, the two extremes are germ tissue and colorectal crypts. The possible reasons are multiple, but the main one seems to be driven by the length of time needed for a cell or tissue type to function. This is likely why germ tissue has a very low somatic mutation burden and the expendable colonic crypts are tolerant for mutation accumulation. The intestinal epithelium is one of the most rapidly dividing regions of cells in the human body and mutations easily accumulate as replication errors. Also tissues exposed directly to high levels of exogenous genotoxicity harbor heavier mutation burdens, such as liver, skin, and lung.
Accumulation of somatic mutations will result in intra-tissue genetic heterogeneity, known as genome mosaicism. Thus far, the impact of genome mosaicism on the aging phenotype, other than cancer, remains unclear. Cancer risk increases exponentially as a function of age in both humans and animals through a mechanism of repeated cycles of somatic mutation (often in interaction with germline variants) and selection for a range of characteristics, including growth, tissue invasion, immune suppression, and metastasis. Accumulating somatic mutations are likely to play a role in the age-related increase in tumor incidence.
Elsewhere we proposed three possible general mechanisms for a functional impact of age-accumulated somatic mutations: (1) clonal expansion, (2) somatic evolution, and (3) mutational networking. The first two are based on clonal expansion of a mutation, either because of a selective advantage or genetic drift. They include hyperplastic or neoplastic disease, although mutations that occur early enough can have late-life effects on postmitotic tissues as well. The third possibility involves the actual adverse effects of high mutation burden on cell functioning, possibly through destabilization of gene regulatory networks. Genomes are robust and redundancy buffers them against mutations. However, when the mutation burden rises to very high levels, the functional organization of genomes in multiple regulatory sequences serving networks of extensively interacting genes will amplify the effects of mutations.
Back to Debating Limits to Human Life Span Again
https://www.fightaging.org/archives/2022/10/back-to-debating-limits-to-human-life-span-again/
While it is self-evident that longevity is limited in the practical sense, in that one or more degenerative processes of aging eventually make it so unlikely for survival to continue that everyone dies somewhere before age 120, that doesn’t mean that longevity is limited in any other sense. If we alter the consequences of the underlying processes of aging, by repairing the damage that they cause, by changing the process, and so forth, then longevity will increase. While the authors of today’s open access paper make generally sensible statements about the nature of aging, they seem far too skeptical that anything of practical use can be achieved in the near future in the field of rejuvenation research. They mount an argument from complexity, against the ability to increase maximum life span from any single intervention into processes of aging, that doesn’t seem at all sound to me.
If anything, the demonstrated network of interactions between processes of aging, and between processes and cellular metabolism, is an argument for addressing any one process to be broadly beneficial, eliminating harmful effects throughout cellular biochemistry and tissue function. That evolution has not produced this outcome in any given species is not an argument against the benefits of, for example, removing senescent cells from aging tissues. It is more an argument against the idea that evolutionary selection operates strongly on matters relating to later life. Species lifespan is most likely a consequence of evolutionary pressures operating on the early life environment, a byproduct of that tooth and nail competition, not a selected outcome.
Why Gilgamesh failed: the mechanistic basis of the limits to human lifespan
Thus far, geroscience has been remarkably successful in increasing our insight into aging and convincingly demonstrating that lifespan, at least mean lifespan, as well as healthspan, can be modulated, based on interventions targeting the molecular pathways first discovered in the worm. What it has not done, however, is demonstrate that the maximum lifespan of a vertebrate can be radically extended. The possibility of doing just that, however, is suggested by the large diversity of mortality curves across species.
Confidence in technological progress has now become so high that it has been argued that new medical interventions will soon emerge and radically increase human longevity. Such optimism is the driving force behind the very large sums of money recently donated by billionaires to new organizations active in geroscience. These include: the Methuselah Foundation, which has set up a series of prizes to demonstrate longevity extension in mice; the SENS Research Foundation, which has funded research into aging and rejuvenation; Calico, launched by Google, has engaged in multiple collaborations with academic and commercial researchers; Human Longevity, founded by Craig Venter of human genome fame, and largely focused on a concierge longevity service; and Altos Labs, a newcomer with 3 billion of funding.
Despite their impressive rosters and large cash flows, these organizations face great difficulty in achieving their lofty goals. Currently, there is little consensus as to the cause, or causes, of aging. Most would agree that aging is the result of damage, that is, deleterious changes, that are ultimately molecular in nature. Although preventative measures can be useful, a damage-repair approach, like the one advocated by the SENS Research Foundation and others, will be necessary
While in theory targeting cellular defense systems, including systems for DNA repair, detoxification, immune response and programmed cell death, to boost the quick removal of damage to biological macromolecules, protein aggregates, and senescent cells, should be feasible in the long term, singular causes of aging are conflicting with evolutionary theory. Indeed, if there would be one highly conserved central cause of aging, possibly going back in evolutionary time to the early replicators, multicellular organisms would fall prey to late-life adverse effects of mutations that accumulate in the germline due to the age-related decline in efficacy of natural selection. This would mean that, independent of any hypothetical central cause of aging, a host of additional adverse late-life effects have to be taken into account.
This would essentially mean that any fix of the limits to lifespan would require interventions at many choke points. Such multipoint targeting would also need to be fine-balanced so as to avoid side effects. Indeed, there are few if any gene regulatory pathways exclusively involved in somatic maintenance and it is this complexity that essentially rules out successful interventions aiming to exclusively extend maximum lifespan of a species. In essence, what needs to be done is to mimic evolution as to how this gave rise to extremely long-lived species, such as those mentioned above, but in real time. As this would involve possibly millions of genetic variants, this seems an impossible quest.
Based on the above, geroscientists should clearly distinguish between mean and maximum lifespan and not give the impression that their research can substantially increase the current limits to human lifespan. Their focus should be on improving life expectancy and healthspan, that is, bringing more people closer to the maximum lifespan possible for members of Homo sapiens and improving the quality of those years.
More on the Debate Over the Classification of Aging as a Disease
https://www.fightaging.org/archives/2022/10/more-on-the-debate-over-the-classification-of-aging-as-a-disease/
Whether or not aging is clearly listed as a disease in the International Classification of Diseases (ICD) maintained by the World Health Organization (WHO) only matters because medical research and development is heavily regulated. Since aging isn’t classified as a disease, there is no clear roadmap to obtaining regulatory approval to treat aging with a working rejuvenation therapy, and therefore no investor is willing to commit to funding that work. What happens instead is that the range of biotech companies presently working to produce age-slowing and rejuvenating therapies pick a specific age-related disease to start with, and progress through the regulatory system on that basis. After approval, it will then become something of a political battle of wills between regulators and physicians as to whether widespread off-label use emerges.
So it may or may not make all that much difference at the end of the day as to whether or not the WHO incorporated a clear definition for aging into the ICD-11 as a clearly defined disease. It is probably not going to greatly change the enormous costs imposed on medical development and provision of medical services by the FDA and similar regulatory organizations. Nonetheless, there are factions within the research community that are agitating hard for one outcome or the other, and factions within the WHO that are clearly far more concerned about appearances and ageism than about progress towards therapies that can reduce suffering in old age. It is a circus and probably a waste of effort.
The only thing that will change the behavior of the ponderous, uncaring, regulatory giants is competition. That competition will have to arise in other countries, those more willing to allow therapies, with more reasonably regulatory burdens. Medical tourism is at present disorganized and a small concern in the bigger picture, but when every human over the age of 40 is a potential customer, rather than only the few who are severely ill at any given time, that may well start to change. The existence of effective therapies that are substantially cheaper and more readily available, even given the cost of travel, will put considerable pressure on the regulators who currently act as a roadblock to the mass adoption of these therapies. That hasn’t happened yet for senolytics, or fecal microbiota transplantation, or other possibilities, but I think that it will as evidence from clinical trials accumulates.
The debate over whether aging is a disease rages on
Last year, over Canadian Thanksgiving weekend, Kiran Rabheru eagerly joined a call with officials from the World Health Organization (WHO). Word had spread of a change coming to the WHO’s International Classification of Diseases (ICD), a catalogue used to standardize disease diagnosis worldwide. In an upcoming revision, the plan was to replace the diagnosis of “senility,” a term considered outdated, with something more expansive: “old age.” The new phrasing would be filed under a diagnostic category containing “symptoms, signs, or clinical findings.” Crucially, the code associated with the diagnosis – a designation that is needed to register new drugs and therapies-included the word “pathological,” which could have been interpreted as suggesting that old age is a disease in itself.
Some researchers looked forward to the revision, seeing it as part of the path toward creating and distributing anti-aging therapies. But Rabheru, a professor at the University of Ottawa and a geriatric psychiatrist at the Ottawa Hospital, feared that these changes would only further ageism. If age alone were presumed to be a disease, that could lead to inadequate care from physicians, he says. Rather than pinpoint exactly what’s troubling a patient, a problem could simply be dismissed as a consequence of advanced years.
Rabheru became part of a group that secured the call with the catalogue team. Those on his side presented their arguments and, he says, were “very pleasantly surprised” by the response-a formal review followed by a retraction. On January 1, 2022, the 11th version of the ICD was released without the term “old age” – or language that suggests aging is a disease – in its contents. The decision wasn’t welcomed by everyone. “My question to the scientists and doctors who protested the inclusion of old age in their handbook is: What is so threatening?” David Sinclair says. “I would really love to know the motivation, besides just trying to maintain the status quo.” Sinclair is also concerned about ageism. But he argues that the best way to combat ageism is to tackle aging: facing the problem head-on by devising treatments to slow its progress. “The current view that aging is acceptable is ageism in itself.”
In the years leading up to the debut of ICD-11, a number of researchers argued that linking old age more directly to disease would help the field of longevity research overcome regulatory obstacles, paving the way for drugs designed specifically to treat aging. This issue, however, is seemingly becoming less of a concern as anti-aging research becomes more mainstream. The US Food and Drug Administration, for example, has said it doesn’t consider aging a disease. But in 2015, the agency made the surprising decision to greenlight the Targeting Aging with Metformin (TAME) study, a clinical trial that aims to show that aging can be targeted head-on, by testing whether the diabetes drug metformin can delay the development or progression of chronic diseases associated with aging.
Sinclair sees the WHO’s decision as a temporary setback. “Fortunately, the momentum is there from scientists, from the public, from investors. This is going to happen, and changes to some of the language in a document aren’t going to stop progress. Still, language is extremely important to how society views problems and potential solutions.”
Stem Cell Derived Extracellular Vesicles Reduce Epigenetic Age in Mice
https://www.fightaging.org/archives/2022/10/stem-cell-derived-extracellular-vesicles-reduce-epigenetic-age-in-mice/
As a strategy, the measurement of epigenetic age to assess the outcome of therapy intended to slow or reverse aging has its issues. Since it remains unknown as to how near all of the epigenetic marks on the genome are caused by the underlying processes of aging, it is quite possible that any given epigenetic clock will underestimate or overestimate the effects of a given approach to therapy, based on the choice and weighting of epigenetic marks used in the clock. It is suspected that the existing clocks are strongly influenced by only some of the mechanisms of aging.
Thus the assessment epigenetic age in a study of a potential treatment targeting aging should be considered exploratory at this time, a part of the ongoing and likely lengthy process of calibrating the clocks. It should be accompanied by a range of other measures of health and function.
Today’s open access paper, covering an extracellular vesicle based intervention, is an example of going about this in the right way, in which epigenetic age is only one of a number of measures of the impact of aging on the mice involved. The use of extracellular vesicles derived from cultured stem cells is a logical evolution of early stem cell therapies, in which the benefits are derived near entirely from the signaling produced by the transplanted cells. Delivery of vesicles is a logistically easier approach, with evidence suggesting that this can produce similar outcomes to stem cell therapies.
Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice
Extracellular vesicles (EVs), small vesicles that are released by virtually all cell types, with an innate ability to mediate the transmission of signaling molecules (proteins, small RNAs, and DNA) between cells are among the factors that are involved in the communication between cells. Stem cells have intrinsic regenerative effects that are not only mediated by the repopulation of damaged tissue. The releasing of regulatory molecules is also proposed as one of the most important mechanisms in stem cell therapies. More specifically, small EVs (sEVs) derived from multiple stem cells have demonstrated their capacity to promote tissue regeneration after several types of damage. Compared to stem cells, sEVs are more stable, have no risk of aneuploidy, have a lower chance of immune rejection, and can provide an alternative therapy for various diseases.
Here, we show that sEVs from young adipose-derived stem cells (ADSC-sEVs) improve several functions that are impaired in old mice. Old mice that received young ADSC-sEVs showed lower levels of frailty and improvements on physical condition tests, fur regeneration, and renal function. ADSC-sEVs induced proregenerative effects in muscle and kidney of aged mice, as well as a decrease in oxidative stress, inflammation, and senescence markers. Moreover, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and the metabolome of old mice treated with ADSC-sEVs changed from an old-like pattern to a youth-like one.
We observed a reduction of senescence in tissues and in vitro when sEVs were introduced; however, the mechanism of action remains unclear, as we did not find senolytic activity. They may probably act as senomorphics, molecules that suppress the senescent phenotype without the specific induction of apoptosis in senescent cells, probably through the inhibition of the senescence-associated secretory phenotype, as has been suggested recently.
We gained some insight into the microRNAs (miRNAs) contained in sEVs that might be responsible for the observed effects. We have explored miRNAs contained in young ADSC-sEVs and found that they are involved in several processes and pathways affected by aging, thus proposing miRNAs as possible mediators of the effects shown in mice. Taking into account our results and other preliminary studies, miR-214-3p may play a role in senescence. It is important to point out the debate on the relevance of miRNAs in the function of EVs, as recent studies have shown low levels of miRNAs in EVs, along with a limited delivery into target cells. More studies are needed to identify factors derived from stem cells that can assist tissue function and regeneration, as they could have an enormous impact on age-related pathologies, such as frailty or renal failure.
Aubrey de Grey Establishes the Longevity Escape Velocity Foundation
https://www.fightaging.org/archives/2022/10/aubrey-de-grey-establishes-the-longevity-escape-velocity-foundation/
Aubrey de Grey, co-founder of the Methuselah Foundation and later the SENS Research Foundation (SRF), funding the latter organization with 13M of his own resources to add to the donations of philanthropists, has over the past year separated from the SRF, for reasons that I intend to neither discuss nor have a public opinion on. Per his presentation at the recent Longevity Summit Dublin, he has now founded the Longevity Escape Velocity (LEV) Foundation in collaboration with the Ichor Life Sciences principals to continue to bring funding into the programs that he believes need to happen in order to unblock important lines of research and development leading to rejuvenation therapies.
It is quite clearly the case that we wouldn’t be as far advanced as we are today without the past twenty years of patient advocacy, agitation, education, outreach, and philanthropic funding of blocked and neglected research, without the efforts of the staff and leadership of the Methuselah Foundation, SENS Research Foundation, and their growing list of allies in the research community.
Details are somewhat sparse as to which specific programs will be undertaken by the LEV Foundation, but we should probably expect them to be much along the same lines as the work done at SRF over the past decade. Combining interventions appears to be an initial focus; it was always the case that the SENS approach to aging was envisaged as many different therapies targeting different forms of age-related damage. Meanwhile, many promising programs are roadblocked in the early stages by problematic financial and regulatory incentives, which can only be efficiently bypassed by philanthropic funding aimed at simply getting the job done: do the work, unblock the program, get it to a point at which it is interesting to entrepreneurs and biotech investors. That approach to progress at the SRF has led to a number of spin-out biotech companies working towards human rejuvenation, and more of the same lies in the future at the LEV Foundation.
The SRF (and Methuselah Foundation!) of course continue as they were: they are still conducting useful programs that advance specific areas of research relevant to human rejuvenation towards readiness for well-funded development. The Methuselah Foundation tends to focus much of its energy on projects relating to the tissue engineering of replacement organs, and running the Methuselah Fund for investment in biotech startups in the longevity industry, while the SRF has a broader remit connected to the fundamental biochemistry of aging, and the SENS vision of rejuvenation as repair of the underlying molecular damage that causes aging. Both are doing good work.
LEV Foundation
Longevity Escape Velocity (LEV) Foundation exists to proactively identify and address the most challenging obstacles on the path to the widespread availability of genuinely effective treatments to prevent and reverse human age-related disease.
Aubrey de Grey inspires at Longevity Summit Dublin 2022
Dr. Aubrey de Grey presented an overview of the projects LEV Foundation is already funding during his talk at Longevity Summit Dublin, video of which is available.
A Subpopulation of Thymic Cells Can Restore Function to an Aged Thymus
https://www.fightaging.org/archives/2022/10/a-subpopulation-of-thymic-cells-can-restore-function-to-an-aged-thymus/
You may recall that researchers have shown that endothelial progenitor cells can restore function to an atrophied thymus. Here, researchers identify a particular subset of functional cells in the thymus that can achieve the same result. The thymus loses active tissue with age, and this loss is a major contribution to the age-related decline of the immune system. The thymus is where thymocytes, created in the bone marrow, mature into new T cells of the adaptive immune system. Absent this supply of T cell reinforcements, the immune system becomes ever more crowded, year after year, with dysfunctional, broken cells. Restoring the aged thymus to enable production of T cells one more is an important goal for the rejuvenation research community.
Thymic atrophy and the progressive immune decline that accompanies it is a major health problem, chronically with age and acutely with immune injury. No solution has been defined. Here we demonstrate that one of the three mesenchymal cell subsets identified by single-cell analysis of human and mouse thymic stroma is a critical niche component for T lymphopoiesis. The Postn+ subset is located perivascularly in the cortical-medullary junction, medulla and subcapsular regions.
Cell depletion demonstrated that this cell population recruits T competent cells to the thymus and initiates T lymphopoiesis in vivo. This subset distinctively expresses the chemokine Ccl19 necessary for niche functions. It markedly declines with age and in the acute setting of hematopoietic stem cell transplant conditioning. When isolated and adoptively transferred, these cells durably engrafted the atrophic thymus, recruited early T progenitors, increased T cell neogenesis, expanded T cell receptor complexity and enhanced T cell response to vaccination. These data define a thymus lymphopoietic niche cell type that may be manipulated therapeutically to regenerate T lymphopoiesis.
Intermittent Hypoxia Doubles Nematode Life Span
https://www.fightaging.org/archives/2022/10/intermittent-hypoxia-doubles-nematode-life-span/
A number of interventions can produce a doubling or greater extension of life span in the nematode C. elegans. Nematode worms demonstrate the plasticity of longevity in short-lived animals, far greater than is the case in long-lived mammals such as our own species. Interventions that alter metabolism in ways that upregulate cellular stress responses, and in doing so produce greatly extended nematode longevity, might be expected to only improve long-term health and add a few years of life in humans. We only have to look at the practice of calorie restriction to see a direct comparison and illustration of this point. Thus while it is interesting to see in this preprint paper that the hypoxia response can be guided to produce a large effect on life span in nematodes, we should not expect that to imply that hypoxia mechanisms are of great worth as a basis for interventions to slow aging in humans.
Genetic activation of the hypoxia response robustly extends lifespan in C. elegans, while environmental hypoxia shows more limited benefit. Here we describe an intermittent hypoxia therapy (IHT) able to double the lifespan of wildtype worms. The lifespan extension observed in IHT does not require HIF-1 but is partially blocked by loss of DAF-16/FOXO. RNAseq analysis shows that IHT triggers a transcriptional state distinct from continuous hypoxia and affects down-stream genes of multiple longevity pathways.
We performed a temperature sensitive forward genetic screen to isolate mutants with delayed nuclear localization of DAF-16 in response to IHT and suppression of IHT longevity. One of these mutations mapped to the enzyme Inositol Polyphosphate MultiKinase (IPMK-1). ipmk-1 mutants, like daf-16 mutants, partially suppress the benefits of IHT, while other effectors of phosphatidyl inositol signaling pathways (PLCβ4, IPPK, Go/iα) more robustly suppress IHT longevity.
Oxidative Stress and Inflammation in Aging Muscles
https://www.fightaging.org/archives/2022/10/oxidative-stress-and-inflammation-in-aging-muscles/
With advancing age, muscle tissue loses mass and strength, leading to sarcopenia and frailty. A range of mechanisms are thought to contribute to this progressive degeneration, but researchers here suggest that the preventative focus for muscle aging should be placed on ways to reduce oxidative stress and chronic inflammation. These two aspects of aging go hand in hand, linked by a number of different mechanisms, such as the level of damage and altered behavior of mitochondria in cells. Both oxidative stress and inflammation change cell behavior for the worse, and in muscle tissue it may be that reduced activity in the stem cell populations responsible for generating new somatic cells to replace losses are of greatest importance.
With aging, the progressive loss of skeletal muscle will have negative effect on multiple physiological parameters, such as exercise, respiration, thermoregulation, and metabolic homeostasis. Accumulating evidence reveals that oxidative stress and inflammation are the main pathological characteristics of skeletal muscle during aging. Here, we focus on aging-related sarcopenia, summarize the relationship between aging and sarcopenia, and elaborate on aging-mediated oxidative stress and oxidative damage in skeletal muscle and its critical role in the occurrence and development of sarcopenia.
In addition, we discuss the production of excessive reactive oxygen species (ROS) in aging skeletal muscle, which reduces the ability of skeletal muscle satellite cells to participate in muscle regeneration, and analyze the potential molecular mechanism of ROS-mediated mitochondrial dysfunction in aging skeletal muscle. Furthermore, we have also paid extensive attention to the possibility and potential regulatory pathways of skeletal muscle aging and oxidative stress mediate inflammation. Finally, in response to the abnormal activity of oxidative stress and inflammation during aging, we summarize several potential antioxidant and anti-inflammatory strategies for the treatment of sarcopenia, which may provide beneficial help for improving sarcopenia during aging.
Repeating the Point that Metformin Just Doesn’t Look Good in Animal Studies
https://www.fightaging.org/archives/2022/10/repeating-the-point-that-metformin-just-doesnt-look-good-in-animal-studies/
Based on studies conducted in mice, metformin is a terrible candidate drug for the treatment of aging. It may well benefit metabolically abnormal individuals, such as diabetics, but results for aged, metabolically normal mice are all over the map. Further, the gold standard, rigorous Interventions Testing Program found no benefit in their assessment. If the goal is to modestly slow aging, then rapamycin is way and far better: robust, replicated results on health and life span in animal studies. But the goal should not be to modestly slow aging! It should be to produce rejuvenation! The sizable fraction of academia and industry that is focused on altering metabolism to provoke greater stress responses and modestly slow aging will, unfortunately, most likely do little to reduce the suffering and death of old age.
The animal study most often cited as evidence that metformin slows aging in lab mice is no such evidence at all. The investigators tested two doses of metformin in healthy, wild-type, nonobese mice. At the lower of the two tested doses, metformin increased the animals’ mean survival by a paltry 4-6%, and had no effect on maximum lifespan, meaning that the drug prevented a small number of deaths during and before middle age, but had no effect on aging. And when the mice were given the higher dose of metformin, it actually shortened the animals’ lives!
The best animal study to test metformin as a potential anti-aging drug was conducted as part of the National Institute on Aging (NIA)’s Interventions Testing Program: a rigorous, systematic effort to test conventional “messing with metabolism” anti-aging agents. ITP studies are designed with several features that make them a better test than the great majority of studies of whether a potential longevity therapeutic actually works (in mice!). First, each time the ITP tests a potential longevity therapeutic, the lifespan study is done not just once, but three times independently in parallel, with three separate cohorts of mice living out their lives at three independent research sites, cared for by three different groups of scientists. Second, ITP tests all candidate longevity therapeutics in a healthy, genetically-diverse mouse population, which better resembles the normal human population than the genetically homogenous mouse strains widely used in biomedical research.
When the ITP researchers put metformin to the test, the result was unambiguous. It did not extend the lives of the mice at any site. It did not even cause the modest reduction in early deaths seen in the previous, widely-cited study. Metformin simply has no effect at all on lifespan in normal, healthy mice.
Relationships Between Strength Training and Aerobic Exercise and Late Life Mortality
https://www.fightaging.org/archives/2022/10/relationships-between-strength-training-and-aerobic-exercise-and-late-life-mortality/
Both strength training and aerobic exercise independently correlate with improved health and reduced mortality in later life. Animal studies demonstrate causation, in that we’d expect both strength training and aerobic activity to produce the result of improved health and reduced mortality. It is reasonable to proceed on the believe that this will hold up in humans. Meanwhile, here is yet another epidemiological study that shows correlation in a human population, noteworthy for assessing the effects of both strength training and aerobic activity separately in the same study.
It is recommended that older adults (aged ≥65 years) participate in balance training, muscle-strengthening activities (MSAs; ≥2 days per week), and moderate to vigorous aerobic physical activity (MVPA; ≥150 minutes per week at moderate intensity, ≥75 minutes per week at vigorous intensity, or an equivalent combination). In this cohort study, we assessed self-reported leisure time physical activity and deaths among 1998-2018 National Health Interview Survey (NHIS) participants.
Leisure time MSA and MVPA were independently associated with lower all-cause mortality in this cohort study of 115,489 adults aged 65 years or older. During a mean follow-up of 7.9 years, 44,794 deaths occurred. Adjusting for MVPA, 2 to 3 and 4 to 6 MSA episodes per week (but not 7 to 28 episodes per week) were associated with a lower hazard of all-cause mortality, compared with fewer than 2 episodes. Adjusting for MSA, 10 to 149, 150 to 300, and more than 300 MVPA minutes per week were associated with a lower hazard of all-cause mortality vs less than 10 minutes per week. Combinations of MSA and MVPA had lower hazard estimates.
By using finer age and physical activity categories, a larger sample, and longer follow-up, we build on earlier studies and offer new insights for older adults and their health care professionals. First, the U-shaped dose-response between MSA and mortality, independent of aerobic physical activity, suggests that 2 to 6 episodes per week may be optimal. Second, the age-stratified associations indicate that current physical activity guidelines are important for all older adults, including those aged 85 years or older.
Implicating Cellular Senescence in the Fibrosis and Inflammation of NASH
https://www.fightaging.org/archives/2022/10/implicating-cellular-senescence-in-the-fibrosis-and-inflammation-of-nash/
Nonalcoholic steatohepatitis, NASH, is a condition characterized by chronic inflammation and fibrosis in the liver. Fibrosis is a malfunction of tissue maintenance, the deposition of excessive, scar-like collagen that disrupts tissue structure and function. Like all fibrotic diseases, means of effectively reversing the progression of NASH are presently lacking. NASH is a lifestyle condition, a consequence of fatty liver and obesity, but losing weight and otherwise changing lifestyle will not significantly reverse established fibrosis and loss of liver function. Where fibrosis and inflammation characterize a condition, we might by now expect senescent cells to be involved. Senescent cells secrete pro-growth, pro-inflammatory signals, and there is good evidence for cellular senescence to drive the progression of fibrosis in many tissues, including kidney, heart, and lungs. Thus why not the liver as well?
Cellular senescence is a state of irreversible cell cycle arrest and has been shown to play a key role in many diseases, including metabolic diseases. To investigate the potential contribution of hepatocyte cellular senescence to the metabolic derangements associated with non-alcoholic steatohepatitis (NASH), we treated human hepatocyte cell lines with the senescence-inducing drugs nutlin-3a, doxorubicin, and etoposide. The senescence-associated markers p16, p21, p53, and beta galactosidase were induced upon drug treatment, and this was associated with increased lipid storage, increased expression of lipid transporters and the development of hepatic steatosis.
Drug-induced senescence also led to increased glycogen content, and increased VLDL secretion from hepatocytes. Senescence was also associated with an increase in glucose and fatty acid oxidation capacity, while de novo lipogenesis was decreased. Surprisingly, cellular senescence caused an overall increase in insulin signaling in hepatocytes, with increased insulin-stimulated phosphorylation of insulin receptor, Akt, and MAPK. Together, these data indicate that hepatic senescence plays a causal role in the development of NASH pathogenesis, by modulating glucose and lipid metabolism, favoring steatosis. Our findings contribute to a better understanding of the mechanisms linking cellular senescence and fatty liver disease and support the development of new therapies targeting senescent cells for the treatment of NASH.
Theorizing a Role for Prelamin A in Aging
https://www.fightaging.org/archives/2022/10/theorizing-a-role-for-prelamin-a-in-aging/
Researchers here review the evidence for prelamin A to have a role in aging. This derives from research into the LMNA mutation that results in Hutchinson-Gilford progeria syndrome, as normal prelamin A has some commonalities with the mutated lamin A, called progerin, that produces pathology in that condition. As is always the case, the mechanisms look plausible, but the question remains open as to whether this does in fact produce a meaningful contribution to aging. The only way to find out is to downregulate prelamin A efficiently without affecting other mechanisms of aging, and see what happens.
Almost since the discovery that mutations in the LMNA gene, encoding the nuclear structure components lamin A and C, lead to Hutchinson-Gilford progeria syndrome, people have speculated that lamins may have a role in normal aging. The most common HPGS mutation creates a splice variant of lamin A, progerin, which promotes accelerated aging pathology. While some evidence exists that progerin accumulates with normal aging, an increasing body of work indicates that prelamin A, a precursor of lamin A prior to C-terminal proteolytic processing, accumulates with age and may be a driver of normal aging.
Prelamin A shares properties with progerin and is also linked to a rare progeroid disease, restrictive dermopathy. Here, we describe mechanisms underlying changes in prelamin A with aging and lay out the case that this unprocessed protein impacts normative aging. This is important since intervention strategies can be developed to modify this pathway as a means to extend healthspan and lifespan.
An Age of Metabolomics
https://www.fightaging.org/archives/2022/10/an-age-of-metabolomics/
Obtaining enormous amounts of data on the human metabolome now costs little. Databases of metabolomic data available for analysis have become vast, and continue to grow. Productive analysis trails far behind the production of data, unfortunately, as is true for all of the omics technologies. In this paper, researchers discuss the present state of metabolomic knowledge in the context of aging, and the path forward to producing useful understanding from this deluge of human data, contributing perhaps to the better development of treatments for aging.
Aging is a fundamental part of the human experience, and it has long been understood to be a crucial component of health and disease. Population estimates of mortality fundamentally incorporate and adjust for age, which is widely considered the most important predictor of mortality. Defining the biology that drives aging is challenging, but theories of aging have coalesced around several key hallmarks, ranging from cellular senescence and stem cell exhaustion to mitochondrial, proteostasis, and genomic dysfunction. As the world’s population ages, with one in six expected to be 60 or older by the end of 2030, understanding these physiological pathways and how to intervene in them will be critical to the prevention and management of the major drivers of morbidity and mortality.
In recent decades, technological advancements have opened up new possibilities for obtaining molecular data at a population scale. One of these technologies is metabolomics, which refers to the study of small molecules in the body. The Recon3D resource has mapped over 4,000 unique metabolites in a model of human metabolism, comprising over 13,000 metabolic reactions, and the Human Metabolome Database (HMDB) has annotated over 200,000 metabolites that may potentially be found in humans. Metabolites span a diversity of physiological processes, including the building blocks of the major macromolecules (e.g., amino acids, nucleic acids, carbohydrates, and fatty acids), functional nutrients (e.g., vitamins and cofactors), and compounds such as sex hormones, drug intermediates, and toxins. While this molecular diversity makes chemical identification more challenging, it also makes the metabolome an attractive dataset for application to many biomedical problems.
The decreasing cost and increasing scalability of metabolomics platforms have led to a proliferation of cohorts and biobanks adding metabolomics to their studies. For instance, the U.K. Biobank, one of the largest population cohorts to date, announced a project in 2018 to measure over 200 metabolites in half a million blood samples; the Trans-Omics for Precision Medicine (TOPMed) program has funded metabolomics collection in over 60,000 samples from diverse populations to pair with deep phenotyping and whole-genome sequencing data; and the Consortium of Metabolomics Studies (COMETS) has been working since 2014 to combine blood metabolomics data from dozens of cohorts worldwide for large-scale biomedical research. These studies represent a new era of population health research and molecular epidemiology that has enabled an unprecedented molecular view of aging processes with profound implications for precision health applications.
Epigenetic Inheritance of Benefits Resulting from Parental Physical Fitness
https://www.fightaging.org/archives/2022/10/epigenetic-inheritance-of-benefits-resulting-from-parental-physical-fitness/
Evolution has produced a system in which the epigenetics of offspring are adapted to the environment experienced by the parents, an effect presumably selected to produce greater fitness, in the same way as improved health in response to lower calorie intake is selected to produce greater fitness. Physically active parents produce an altered epigenetic landscape in offspring in comparison to those with worse health. This has been demonstrated in a number of species, with the research in mice noted here as one of many examples. Similar effects on the epigenetics of offspring no doubt exist in humans as well, but would be challenging to disentangle from the consequences of cultural transmission of lifestyle choices.
This study used mice to evaluate how their lifestyles – eating fatty foods vs. healthy and exercising vs. not – affected the metabolites of their offspring. Metabolites are substances made or used when the body breaks down food, drugs or chemicals, or its own fat or muscle tissue. “We have previously shown that maternal and paternal exercise improve health of offspring. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabolites has not yet been investigated.”
Researchers used targeted metabolomics – the study of metabolites – to determine the impact of maternal exercise, paternal exercise, and the combination of maternal and paternal exercise on the metabolite profile in offspring liver, skeletal muscle, and blood serum levels. This study found that all forms of parental exercise improved whole-body glucose metabolism in offspring as adults, and metabolomics profiling of offspring serum, muscle, and liver reveal that parental exercise results in extensive effects across all classes of metabolites in all of these offspring tissues.
Towards Direct Reprogramming of Heart Fibroblasts into Cardiomyocytes
https://www.fightaging.org/archives/2022/10/towards-direct-reprogramming-of-heart-fibroblasts-into-cardiomyocytes/
A promising approach to inducing regeneration from injury and age-related fibrosis in the heart is the reprogramming of fibroblast cells into heart muscle cells, cardiomyocytes. Like all such efforts, much of the work lies in establishing the recipe of regulatory signals needed to produce the desired outcome. The research results reported here are an illustrative example, representative of programs taking place in many laboratories, in which scientists are attempting to improve on the discovered forms of reprogramming in order to make them efficient enough to be useful as a basis for regenerative therapies.
Mammalian hearts have almost no ability to grow new heart muscle cells, called cardiomyocytes, after birth. Thus, dead tissue after an adult heart attack is not repaired with new cardiomyocytes. It is instead replaced with scar tissue that weakens the pumping power of the heart and often leads to heart failure. One promising strategy to remuscularize the injured heart is the direct cardiac reprogramming of heart fibroblast cells into cardiomyocytes.
Current cocktails for direct reprogramming of human fibroblasts suffer from low efficiency and insufficient production of functional cardiomyocytes. Researchers have now identified TBX20 as the most underexpressed factor when they compared cardiomyocytes induced from fibroblasts using a current reprogramming cocktail versus functional cardiomyocytes. The addition of TBX20 promoted cardiac reprogramming, as seen in activation of cardiac genes related to sarcomere structure, ion channels and heart contractions. A sarcomere is the smallest functional unit of striated muscle.
Mechanistically, the researchers found that TBX20 was bound to and activated cardiac gene enhancers. In detail, TBX20 primarily activated genes at late stage of reprogramming, enhancing calcium flux, contractility, and mitochondrial function in the induced-cardiomyocytes. Mitochondria are the energy source for heart muscle contractions. TBX20 appeared to help the mitochondria in the induced cardiomyocytes switch to an adult cardiomyocyte-like respiration.