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.

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.

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."

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.