Fight Aging!

The traditional view of the p53 tumor suppressor gene is that it is a representative mechanism in the evolved trade-off between suppression of cancer on the one hand and harmful buildup of senescent cells on the other. Specifically p53 is an important part of the machinery that induces cellular senescence in response to potentially cancerous mutational damage. A senescent cell ceases replication and secretes inflammatory signals in order to attract immune cells to destroy it and any other problem cells in the immediate vicinity. Unfortunately immune mediated clearance of senescent cells becomes less effective with advancing age, allowing a build up of a lingering senescent cell population. Their signaling is harmful to tissue structure and function.

So a lesser degree of p53 activity implies a lesser burden of cellular senescence in later life, and thus a slower pace of aging, but also a greater risk of cancer. More aggressive p53 activity impedes cancer, but then leads to greater cellular senescence and a shorter life span. This is an oversimplification of a more complicated picture, however. Once one starts to look into the biochemistry of diverse species, one finds all sorts of different variations on how p53-driven mechanisms relate to aging and cancer. For example, elephants have many copies of p53 and aggressive anti-cancer activity in general, but are nonetheless long-lived mammals. There is a great deal more to consider than just p53 when it comes to understanding the relevance of p53.

Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders

Usually, aging is a gradual process characterized (in humans and mouse models) by molecular biomarkers such as a decrease in leukocyte telomere length, decreased levels of IGF-1, and increased inflammation. Several molecular mechanisms have been purported to regulate aging and determine lifespan - many of which have been linked to p53 tumor suppressor activities. In low or high-stress conditions, p53 binds to several target genes - including those that encode PML, PAI-1, and DEC1 - which then induce cellular senescence. The link between aging and its ability to push cells to senescence is of particular interest to this study. In a senescent state, a damaged cell resists apoptosis and ceases to replicate. An accumulation of these cells triggers the aging process by creating a senescence-associated secretory phenotype (SASP) which creates a chronic inflammatory microenvironment. It has been shown that a programmed clearance of senescent cells delays aging phenotypes.

While p53 consensus sequences for most of these targets have been elucidated, few studies have explored regulatory mechanisms and structural features of p53 that could be implicated in organismal aging. Residual changes in the DNA-binding domain of several orthologs of p53 in Cetaceans have been linked to longevity. This supports findings that p53-mediated cellular senescence could be mediated directly by DNA binding. Additionally, there has been an extension exploration of the role of the mouse MDM2 gene in the aging process of mice. MDM2 is the most well-studied negative inhibitor of p53 tumor suppressive activity; disruption of the MDM2-p53 axis accelerates aging in some mice, suggesting the importance of the MDM2-p53 axis to the aging process.

However, p53's link to organismal aging may not be easily explainable just by the MDM2-p53 axis. MDM2 has only minor regulatory effects on the levels of p53 in the naked mole rat. And, interestingly, the naked mole rat lives an average of 30 years compared to an average of 2-4 years for most rodents. This is thought to be due in part to a hyperstable p53 - the source of this stability remains largely unknown. In another case, the African elephant despite being predisposed to cancer due to prolonged UV-radiation and large body mass lives comparably long lives and displays a significantly lower frequency of cancer when compared to humans. The unique presence of 20 copies of p53 in their genome is thought to be responsible for this.

This study seeks to elucidate, structurally and mechanistically, p53's roles in longevity. Through a relative evolutionary scoring (RES) algorithm, we quantify the level of evolutionary change in the residues of p53 across organisms of varying average lifespans in six taxonomic orders. Secondly, we used the PEPPI protein-protein interaction predictor to assess the likelihood of interaction between p53 - or p53-linked proteins - and known senescence-regulating proteins across organisms in the orders Primates and Perciformes. Our RES algorithm found variations in the alignments within and across orders, suggesting that mechanisms of p53-mediated regulation of longevity may vary. PEPPI results suggest that longer-lived species may have evolved to regulate induction and inhibition of cellular senescence better than their shorter-lived counterparts. With experimental verification, these predictions could help elucidate the mechanisms of p53-mediated cellular senescence, ultimately clarifying our understanding of p53's connection to aging in a multiple-species context.

Most of the present forms of assessment of biological age are based on immune cell characteristics in a blood sample. In this paper, researchers look at some of the differences in the biology of mice versus humans that may be relevant to the way in which we should think about animal data versus human data and the utility of various aging clocks. How much can one infer potential utility in humans based on data obtained from mice, and how does that vary by approach to biological age assessment?

Aging significantly impacts the hematopoietic system, reducing its regenerative capacity and ability to restore homeostasis after stress. Mouse models have been invaluable in studying this process due to their shorter lifespan and the ability to explore genetic, treatment, and environmental influences on aging. However, not all aspects of aging are mirrored between species. This review compares three key aging biomarkers in the hematopoietic systems of mice and humans: myeloid bias, telomere attrition, and epigenetic clocks.

Myeloid bias, marked by an increased fraction of myeloid cells and decreased lymphoid cells, is a significant aging marker in mice but is scarcely observed in humans after childhood. Conversely, telomere length is a robust aging biomarker in humans, whereas mice exhibit significantly different telomere dynamics, making telomere length less reliable in the murine system. Epigenetic clocks, based on DNA methylation changes at specific genomic regions, provide precise estimates of chronological age in both mice and humans. Notably, age-associated regions in mice and humans occur at homologous genomic locations. Epigenetic clocks, depending on the epigenetic signatures used, also capture aspects of biological aging, offering powerful tools to assess genetic and environmental impacts on aging.

Taken together, not all blood aging biomarkers are transferable between mice and humans. When using murine models to extrapolate human aging, it may be advantageous to focus on aging phenomena observed in both species. In conclusion, while mouse models offer significant insights, selecting appropriate biomarkers is crucial for translating findings to human aging.

Link: https://doi.org/10.1016/j.exphem.2024.104600

Researchers here exploit an interesting source of immunomodulatory proteins, parasitic worms that live in the mammalian intestine. The protein of interest inhibits TGF-β signaling, which in turn adjusts the innate immune cells known as macrophages into a more pro-regenerative state at a site of injury. This enables regeneration of injuries with a lesser degree of scarring. In skin, hair follicles regrow rather than being replaced by scar tissue, for example. Most of the approaches demonstrated to enhance regeneration in animal models should in principle have some application to the problem of reduced capacity for healing in older people, so it is worth keeping an eye on this part of the field of regenerative medicine.

The balance between scarring and successful tissue regeneration is strongly influenced by immune cells recruited to the wound site, and many researchers are interested in finding ways to boost the activity of immune cell types that promote regeneration while inhibiting the activity of immune cells that promote tissue scarring. Recent studies have suggested that molecules secreted by parasitic worms might modulate the host's immune system in ways that promote tissue regeneration.

In a new study, researchers investigated a protein called TGF-β mimic (TGM) that is produced by Heligmosomoides polygyrus, a parasitic roundworm that lives in the intestines of mice and other rodents. The researchers found that daily topical applications of TGM accelerated the closure of skin wounds in mice. Moreover, TGM treatment reduced the formation of scar tissue while enhancing skin regeneration. For example, unlike untreated animals, TGM-treated mice were able to form new hair follicles within the wounded region of the skin.

The researchers determined that TGM works by binding to a signaling protein, called the TGF-β receptor, that is found on the surface of many cell types in mice and humans, including immune cells. TGM treatment appears to stimulate the recruitment of immune cells known as macrophages into wounds and reprograms them to promote tissue regeneration.

Link: https://www.eurekalert.org/news-releases/1055270

A cell is a bag of molecules moving at incredible velocities, all running into one another countless times every second. Almost anything is possible in this high speed environment, albeit that some outcomes are highly unlikely in any given second. There are a lot of seconds and even more cells, however. Thus it is possible for fragments of mitochondrial DNA to somehow find their way into the cell nucleus and then somehow be incorporated into nuclear DNA. Evolution has made full use of this rare happenstance, as most of the original mitochondrial DNA, the genome of symbiotic bacteria that lived within the first eukaryotic cells, has shifted over evolutionary time: firstly forming viable genes in the nuclear genome, and then secondly the mitochondrial sequences deleted through forms of DNA damage.

Researchers here measure the occurrence of mitochondrial DNA inserts into the nuclear genome in human brain tissue. Interestingly, they find a correlation with mortality. This could be indicative that this sort of mutational damage is producing materially detrimental effects on tissue function; the arguments to be made here are similar to those for the role of somatic mosaicism in degenerative aging. Equally this may be a case in which greater age-related mitochondrial dysfunction produces a greater chance of mitochondrial DNA making its way into the nucleus. It is already known that aging is associated with inflammation driven by innate immune recognition of mislocalized mitochondrial DNA fragments in the cytosol. It seems sensible to hypothesize that more of this means more rare nuclear localization events.

Somatic nuclear mitochondrial DNA insertions are prevalent in the human brain and accumulate over time in fibroblasts

The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in nonhuman species. Here, we investigated numtogenesis dynamics in humans in 2 ways. First, we quantified Numts in 1,187 postmortem brain and blood samples from different individuals. Compared to circulating immune cells (n = 389), postmitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples, we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex (DLPFC) compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, an increase in the number of brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment (NCI) who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer.

Second, we tested the dynamic transfer of Numts using a repeated-measures whole-genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging. These longitudinal experiments revealed a gradual accumulation of 1 Numt every ~13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven by cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors.

Combined, our data documents spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human postmitotic tissues produces functionally relevant human Numts over timescales shorter than previously assumed.

Mitochondria must produce the chemical energy store molecule ATP in order for cells to function. The neurons lost in Parkinson's disease are particularly vulnerable on this front, and the state of their mitochondrial function is important in determining how vulnerable a patient is to the underlying protein aggregation mechanisms that drive cell dysfunction and death. Researchers here discuss a protein that is rate-limiting in the production of ATP via glycolysis in neurons, and show that even slightly upregulating its expression can be protective. One might think that this is an enhancement that could be generally beneficial to brain cells and brain function, given a safe means of upregulation, as the brain is usually running at the very edge of metabolic capacity even in youth.

The brain is a metabolically vulnerable organ suffering acute functional decline when fuel delivery is compromised. We previously showed that central nervous system nerve terminals rely on efficient activity-dependent up-regulation of ATP synthesis to sustain function and undergo abrupt synaptic collapse when this process fails. Reduced fuel delivery to the brain is correlated with aging and is an early predictor of eventual neurological dysfunction, suggesting that as fuel delivery becomes compromised, synaptic function becomes increasingly vulnerable to genetic metabolic lesions. Parkinson's disease (PD) has long-been thought to be, in part, driven by metabolic vulnerability of dopamine (DA) neurons of the substantia nigra pars compacta (SNc) as two of the earliest identified genetic drivers of PD, PARK2 and PARK6, when mutated, compromise the integrity of mitochondria.

Several recent discoveries point to a critical but unexpected outsized role of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) in protecting neurons against neurological impairment. PGK1, the first ATP-producing enzyme in glycolysis, catalyzes the sixth step in this 10-step enzymatic cascade. A chemical screen of a subset of FDA-approved drugs capable of suppressing cell death identified terazosin (TZ) as a weak (~4%) off-target activator of PGK1. TZ was subsequently shown to confer significant protection in numerous models of PD (mouse, rat, Drosophila, and human induced pluripotent stem cells), implying that contrary to expectations, PGK1 activity is a critical modulator of glycolytic throughput. Clinical use of TZ for treatment of benign prostate hyperplasia provided data for a retrospective analysis, which showed that prolonged use of TZ reduced the risk of developing PD by up to ~37% compared to tamsulosin, whose chemical structure differs significantly from TZ but has the same molecular target.

These data all predict that PGK1 activity is a crucial leverage point in neuronal bioenergetic control and that bioenergetic deficits, in turn, underpin many forms of PD. Here, we demonstrate that PGK1 is the rate-limiting enzyme in axonal glycolysis and that modest changes in PGK1 activity accelerate neuronal ATP production kinetics capable of reversing the synaptic deficit driven by the PARK20 mutation. We identified PARK7/DJ-1, the PD-associated molecular chaperone, as a necessary gene for PGK1 to up-regulate ATP production as loss of PARK7/DJ-1 itself led to deficits in neuronal glycolysis that impaired the ability of PGK1 up-regulation to provide protection. We showed that increasing PGK1 abundance in vivo offered strong protection against striatal DA axon dysfunction. These data strongly support the idea that PGK1 serves as a critical lever arm in controlling axonal bioenergetics.

Link: https://doi.org/10.1126/sciadv.adn6016

Early epigenetic clocks were insensitive to physical fitness, which didn't make much sense given the evident relationship between physical fitness and mortality risk in later life. Later, better epigenetic clocks have shown that physically fit individuals tend towards a lower biological age. To date, near all pharmacological interventions shown to adjust metabolism in ways that modestly slow aging, and for which human data exists, have failed to improve upon the effects of exercise. Exercise remains the low bar to beat for the longevity industry.

In this context, exercise is a powerful "geroprotector" that is well-recognized to extend the human health span. However, the relationship between physical fitness and biological age, based on the DNA methylation (DNAm) aging clock, is poorly understood. Most previous studies investigated the relationship between physical activity and DNAm aging clocks based on questionnaires and accelerometers using a molecular epidemiological approach. Theoretically, physical activity and fitness differ, with physical fitness considered the result of exercise, which is planned and regular physical activity. Considering that various health outcomes can be strongly associated with fitness, especially cardiorespiratory fitness (CRF), rather than with physical activity, CRF can be a stronger geroprotector than physical activity. Therefore, in the field of geroscience, it can be valuable to investigate the relationship between CRF and the DNAm aging clock and determine fitness reference values for delaying aging.

We attempted to determine the relationship between CRF and various lifestyle-related factors associated with biological aging based on DNAm aging clocks. We found that CRF was negatively related to epigenetic age acceleration, even after adjusting for confounders (chronological age, smoking, and alcohol consumption), and that maintenance of CRF above a reference value (i.e., 22.7 mL/kg/min) was associated with lower age acceleration. Collectively, these findings suggest that although the relative contribution of CRF to biological aging is relatively low when compared with lifestyle-related variables, such as smoking, the maintenance of CRF is associated with delayed biological aging in older males.

The central concern of exercise scientists is determining the causal relationship between CRF and biological aging. Several cross-sectional studies, including ours, have only demonstrated the relationship between physical activity, physical fitness, and biological aging; however, the causal relationship between them remains elusive. To prove a causal relationship, it is necessary to conduct longitudinal studies that track age-related changes in both CRF and DNAm aging clocks, as well as endurance exercise training intervention studies. In mouse studies, late-life exercise training could delay epigenetic aging of skeletal muscle. In humans, exercise training reportedly leads to epigenetic patterns toward a younger profile. Another study has reported that the number of subjects with higher baseline levels of epigenetic age acceleration decreased after exercise training

Link: https://doi.org/10.18632/aging.206031

Some years after first coming to the conclusion that treating aging as a medical condition is possible, a great idea, something that should be supported by vastly more research and development funding than is actually the case, one starts to lose touch with how most people think about aging, medical research, and medicine. Which is to say that it is in the background, not thought about that much at all, and aging is taken for granted. Not a big problem, just the state of things. It is akin to all of those people who don't think much about cancer medicine until they develop a cancer, and even then treat the state of medical capabilities as set in stone, a fixed state of the world to be guided through by a physician rather than a potentially adjustable, changeable field to learn, engage with, and try to improve on.

Most individuals with the capability to direct large sums of funding into research think this way. Wealth doesn't grant any particular capacity for vision or interest in aging and longevity. There is also, I think, a tendency in various non-profit and advocacy circles to conceive of billionaires as having a great deal more agency than is in fact the case when it comes to the ability to direct funds to causes. A billionaire is the figurehead of, figuratively, a small country with its various power blocks and interest groups. The billionaire is shaped by that as much as he or she shapes it in return. There is an intrinsic conservatism to very large aggregations of wealth and power; they are usually the last to the table when it comes to supporting novel directions. The exceptions are noteworthy and receive more than their share of media attention, but they are exceptions.

Peter Diamandis: "Stay Healthy, Anti-Aging Tech is Coming"

Billionaires sit on vast resources, but they don't seem to be ready to massively invest in longevity yet. But it shouldn't be just about the money. This is literally about life and death.

You're absolutely right, but that's just not the way they're viewing it. You could say that all of us put our money in three different buckets. There's a bucket for money that will be used to make more money. Another one is for money that will be used for family, enjoyment, vacations, and so on. And the last one is for helping people. Unfortunately, for most people, that last bucket is the smallest by orders of magnitude.

I think it's not just about philanthropy. It should also be driven by egoistic considerations. Maybe there's a place for a fourth bucket, where you help humanity, but you also help yourself. After all, today, death is pretty inescapable whether you're a billionaire or a construction worker. Even more so than, say, climate change.

It seems obvious to me. Why aren't people acting in their own self-interest? This thing should hit every bucket. I'm going to invest in longevity because it's going to help me, my family, and humanity, and it will also allow me to feel better, to have a happier life. And it's also a huge business opportunity, right? The only reason that's not hitting is that people don't believe it yet. We have been so indoctrinated about the inevitability of death!

I try to change it, by writing books about this. My mission is to help the public create a longevity mindset, which is based on the realization that the technology to enable us to extend the healthy human lifespan is coming online now, in the decade ahead. And if you believe that in the next ten years, we're going to significantly extend the human healthspan, and you can have access to it if you're in good health, then, logically, you'd want to do everything you can to remain in the best health possible. I want people to change the way they think about healthspan and longevity and what's possible for them. Because your mindset is the most powerful tool that you have. If you believe it, you're going to change your behavior.

Researchers here argue that the fine details of how and when amyloid-β is cleared from the brain matters greatly in the treatment of Alzheimer's disease. To make the point they use a form of antigen-binding protein known as an anticalin, a technology that produces similar outcomes to monoclonal antibodies but with fewer inflammatory side-effects. The researchers target forms of amyloid-β that arise prior to the formation of amyloid plaques, attacking the very earliest stages leading to pathology. It works in a mouse model of Alzheimer's disease, but it is worth bearing in mind that these models are very artificial and a great deal of what has worked in mice has failed in humans.

Until relatively recently, treatment strategies aiming at the scavenging of amyloid-β (Aβ) by passive immunization with antibodies have largely failed to show a significant deceleration of cognitive decline in clinical studies, in fact raising concerns about the amyloid hypothesis. Similar discouraging observations were made in Alzheimer's mouse models. There are several possible explanations for the general failure of these approaches, most prominently an inadequate timing of the therapeutic intervention after the brain has already undergone irreparable damage.

Moreover, anti-Aβ treatment at very early stages of development had positive outcomes in mouse models of amyloidosis. Thus, before Aβ plaque formation, the prevention of extracellular Aβ accumulation involving the use of γ-secretase inhibitors can effectively abolish neuronal hyperactivity. This is relevant because a variety of studies in mice and humans have established that neuronal hyperactivity is probably the earliest form of neuronal dysfunction in the diseased brain.

To untangle the conflicting results on the effectivity of Aβ removal obtained from previous mouse studies, we applied here an alternative approach based on the direct intracerebral application of Aβ-binding anticalins (Aβ-anticalins). Anticalins exhibit very high target affinities and, in contrast to antibodies, a low immunogenic potential. We demonstrate that an Aβ-anticalin can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages.

Link: https://doi.org/10.1038/s41467-024-50153-y

Immune clearance of senescence cells falters with age, becoming less efficient. This allows lingering senescent cells to accumulate, and their disruptive, inflammatory secretions contribute meaningfully to degenerative aging and age-related mortality. Greater knowledge of how exactly the immune system fails in its job may open novel avenues in the development of senolytic therapies to clear senescent cells - look at the work of Deciduous Therapeutics, for example. Here, researchers note that senescent cells appear to make use of immune checkpoints to fend off immune clearance. This area of biochemistry is well explored in connection with cancer immunology, and it may turn out to help in the context of senescent cells.

The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues.

Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8+ T cells and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8+ T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors.

Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.

Link: https://doi.org/10.1007/s10522-024-10114-w

How much of academia and industry is headed in the wrong direction in the matter of treating aging as a medical condition, working on projects that are unlikely to produce meaningful extension of human life span? I am largely in agreement with the author of today's open access paper, at least to the point of saying that a large fraction of projects cannot and will not move the needle on human life span, and that likely includes near everything commonly grouped under the heading of geroscience. That means calorie restriction mimetics, autophagy upregulation, small molecules that improve mitophagy, and so forth. These largely pharmacological approaches are unified in their inability to improve on the effects of exercise, where tested in humans, with very few exceptions (e.g. rapamycin).

I concur with the author's argument that the 1990s studies that launched the modern interest in treating aging and extending human life did not actually indicate the right way ahead. This has long been remarked upon, and coming to be taken for granted, in at least some parts of the longevity community. All of the early, low hanging fruit interventions that slowed aging in short-lived species make use of mechanisms related to the calorie restriction response, and do not meaningfully extend life in long-lived species. When it comes to surviving seasonal famine, only the short-lived species must evolve a sizable plasticity of life span. A season is a long time to a mouse, not so much to a human.

The greatest progress that has taken place towards viable treatments for aging did not build upon the early discoveries of single gene mutations that extended life in laboratory species, but happened as a result of a broadening of investment in the field into other lines of research. But in my view, unlike that of the author of the commentary, that expansion of research and development has in fact led to important approaches that seem quite likely to be useful. In particular those grouped under the Strategies for Engineered Negligible Senescence (SENS), or repair viewpoint of aging, in which one identifies specific fundamental, driving forms of cell and tissue damage and repair them. This stands in stark contrast to the geroscience viewpoint in which one adjusts metabolism to slow aging, i.e. slow the accumulation of cell and tissue damage.

Good scientists tend not to make good engineers (and possibly vice versa); the mindset needed is quite different. The scientific viewpoint is the drive for complete understanding, with only a grudging, reluctant forking of an ongoing research process into to the parallel process of using knowledge to build technology. The engineering viewpoint, on the other hand, is focused on making empirical progress in an environment of uncertainty and partial knowledge: take what is known right now and try to make something of it. It is fair to say that, from a modern materials science perspective, the ancient Romans did not know anywhere near enough about bridge building. But their engineers built great bridges because empirical discovery allows the development of a corpus of knowledge and practical expertise. That practicality can later be fleshed out by the scientists, and in fact tends to help the scientists a great deal. That is what is presently underway in the treatment of aging as a medical condition, and is largely why a growing longevity industry exists at all.

Calling the whole of the longevity industry into question because geroscience is the wrong direction is throwing the baby out with the bathwater.

Inflated expectations: the strange craze for translational research on aging

The emergence of Hevolution and the XPRIZE Healthspan is just the latest development in a remarkable phenomenon: a dramatic upsurge in activity in the private sector aimed at developing treatments for aging, fuelled by a heady optimism that the time is nigh. Other examples that involve massive funding to achieve practical outcomes in applied research on aging include the California Life Company (Calico), into which some US$2.5B has been invested; and Altos Labs, which in 2022 raised US$3B from investors.

Here we ask the question: what is the basis for this optimism? The last quarter of a century has seen a concerted effort by scientists to understand the fundamental biological mechanisms of aging, and much ground has been covered. How has this informed the recent upswell in commercial activity? We suggest that the latter is an anomaly arising in part from developments within the aging research field a decade ago that were, in some ways, counterproductive. These include the emergence of the so-called geroscience research agenda.

What seems to have happened is the following. Advances in research on the biology of aging that culminated in the 1990s yielded startling implications. It seemed possible not only to understand the fundamental mechanisms of aging, but also to slow them down. These promising prospects led to the aging field becoming bigger and better, thanks to increased funding and the influx of many good scientists. As a result, standards of research grew more rigorous, including critical reassessments of earlier findings. Such careful research over the past two decades has, regrettably, undermined a number of the reasons for earlier optimism. Disappointingly, caloric restriction in rhesus monkeys proved not to have the same remarkable effects as those seen in rodents. Growth hormone defects that extend lifespan in mice were found not to do so in humans.

With the dwindling likelihood that humans possess the plasticity in aging seen in shorter-lived animals, and the failure of existing theories of aging, how should one further pursue research? Here two possible approaches may be envisaged. On the one hand, scientists could renew their efforts to develop an effective theoretical framework with the capacity to explain diverse phenomena of aging. On the other hand, research could focus on translating existing theoretical claims and experimental observations into therapeutic trials - preclinical or clinical. The pursuit of this strategy in the early 2010s marked the emergence of the geroscience agenda.

In the past, this strategy of prioritizing translational research in the absence of a good understanding of the basic science has sometimes proved successful, aided by brute force and serendipity. There are, however, also numerous instances where such trial-and-error approaches failed, sometimes involving investment of billions of dollars. The reader may pick their own examples. Unquestionably, for translational research to yield useful, practical applications, at least some level of scientific understanding is required. At issue is judging when the time is ripe to move from basic to translational research, particularly where large investments of money and effort are involved. The oddest thing about the translational geroscience approach is its combination of pessimism about understanding aging, and optimism about translational research. Arguably, the inverse is more realistic.

Immunoglobulins are the molecules making up antibodies. Post-translational modification of immunoglobulin molecules changes their function, and is a complex aspect of this portion of the immune system, altering the character of immune responses. The post-translational modification of glycosylation has been shown to shift in characteristic ways in immunogloblins with age. Analysis of these changes has given rise to the GlycanAge clock for the measurement of biological age. Here, researchers review what is known of these age-related changes and their relevance to specific aspects of immune aging.

Immunoglobulin G (IgG) is an important serum glycoprotein and a major component of antibodies. Glycans on IgG affect the binding of IgG to the Fc receptor or complement C1q, which in turn affects the biological activity and biological function of IgG. Altered glycosylation patterns on IgG emerge as important biomarkers in the aging process and age-related diseases. Key aging-related alterations observed in IgG glycosylation include reductions in galactosylation and sialylation, alongside increases in agalactosylation, and bisecting GlcNAc.

Understanding the role of IgG glycosylation in aging-related diseases offers insights into disease mechanisms and provides opportunities for the development of diagnostic and therapeutic strategies. This review summarizes five aspects of IgG: an overview of IgG, IgG glycosylation, IgG glycosylation with inflammation mediation, IgG glycan changes with normal aging, as well as the relevance of IgG glycan changes to aging-related diseases. This review provides a reference for further investigation of the regulatory mechanisms of IgG glycosylation in aging-related diseases, as well as for evaluating the potential of IgG glycosylation changes as markers of aging and aging-related diseases.

Link: https://doi.org/10.3724/abbs.2024137

Some lower animals are effectively immortal, in that their risk of mortality doesn't appear to increase over time. This has been demonstrated for hydra, and some other marine species have an analogous, highly regenerative biology, such as a few jellyfish and the sea anemone species noted here. Notably, none of these animals have a sophisticated nervous system and brain. The evolution of neural tissue that can store complex data appears incompatible with a lack of degenerative aging built on constant, highly proficient regeneration and replacement of all portions of the body as needed.

While humans and most vertebrates can only regenerate parts of certain organs or limbs, other animal groups have far stronger regeneration mechanisms. This ability is made possible by pluripotent or multipotent stem cells, which can form (differentiate) almost all cell types of the body. The sea anemone Nematostella vectensis is also highly regenerative: it can reproduce asexually by budding and also shows no signs of ageing, which makes it an interesting subject for stem cell research. However, researchers have not yet been able to identify any stem cells in these animals.

"By combining single-cell gene expression analyses and transgenesis, we have now been able to identify a large population of cells in the sea anemone that form differentiated cells such as nerve cells and glandular cells and are therefore candidates for multipotent stem cells."

These potential stem cells express the evolutionarily highly conserved genes nanos and piwi, which enable the development of germ cells in all animals, including humans. By specifically mutating the nanos2 gene using the CRISPR gene scissors, the scientists were also able to prove that the gene is necessary for the formation of germ cells in sea anemones. It has also been shown in other animals that this gene is essential for the production of gametes. This proves that this gene function emerged around 600 million years ago and has been preserved to this day. In future studies, researchers now want to investigate which special properties of the sea anemone's stem cells are responsible for its potential immortality.

Link: https://medienportal.univie.ac.at/en/media/recent-press-releases/detailansicht-en/artikel/searching-old-stem-cells-that-stay-young-forever/

Epigenetic patterns of gene expression regulation change with age in distinct ways, and so it is possible to use machine learning to produce algorithmic combinations of this data that reflect chronological age and biological age. There are any number of such algorithms, and so there are many epigenetic clocks now, with more are being produced every year. These are now accompanied by clocks derived from other omics data, alongside clocks built from combinations of simple measures such as grip strength, gait speed, and so forth. It is commonly accepted, and evidence supports this hypothesis, that when a clock predicts an age higher than an individual's chronological age, this age acceleration is an indication of a greater burden of age-related damage and dysfunction.

None of this tells us how underlying damage and dysfunction produces the observed changes in clock data, for any of the clocks built from omics data. This is a problem, because absent this understanding one can't rely upon a clock to produce the right answer when it is used to assess the results of a potential rejuvenation therapy. For example, senolytic treatments clear senescent cells and reduce their impact on metabolism, but it is by no means a given that any given epigenetic clock is actually measuring that effect. Or perhaps the clock is overly reliant on that effect, and will therefore overestimate the benefit of removing senescent cells. Without, at minimum, calibrating a clock to the specific treatment in mouse life span studies one can't know.

Further, different tissues exhibit different patterns of omics data change with aging. Yet most clocks use blood samples, assessing biological age from immune cell populations. So how should researchers think about epigenetic and other omics clocks in the context of their work? Today's open access commentary is, I think, a useful summary of some of the present wisdom on this topic. Acceptance of the inherent limitations (for now, at least) and avoidance of generalizing results from blood markers given the large variance between tissues sounds like good advice.

Recalibrate concepts of epigenetic aging clocks in human health

First, epigenetic aging in human health should be viewed holistically. The relationship between epigenetic age and health outcomes is often viewed through a narrow lens. Blood epigenetic clocks are predominantly used due to their availability. However, as measured by these clocks, studies and trials frequently focus solely on blood, neglecting broader aging effects on the entire organism. This oversight can lead to exaggerated claims and misconceptions among the public. A younger biological age based on a buccal swab does not necessarily equate to a younger immune system or skeletal muscle composition.

Second, accept the limitations of epigenetic aging clocks. While efforts have been made to develop clocks independent of tissue or cell type, our study demonstrates that entirely eliminating the confounding effects of cell type in epigenetic age acceleration calculation is nearly impossible. Senescence at the cellular level manifests differently across cell types and states, making it challenging to devise a single clock applicable to all cell types. Although universal epigenetic aging marks may exist, modeling them accurately across cell types at the bulk tissue level is complicated by age-related changes in cell composition.

Third, contextualize when interpreting epigenetic aging results. The perception that an accelerated epigenetic age is always detrimental stems from a limited understanding of the clock mechanism. Contrary to this notion, multiple studies have documented beneficial outcomes in specific groups of cancer patients with accelerated epigenetic age. Immune responses play a pivotal role in cancer patient outcomes, and the connection between immune cell composition and epigenetic age established in our study sheds light on how epigenetic age acceleration affects these outcomes, especially in treatments like chemotherapy, radiation therapy, and immunotherapy that influence or rely on the immune system. Moreover, research has revealed significant daily oscillations in epigenetic age, mirroring changes in immune cell composition over the circadian rhythm.

Fourth, model epigenetic biomarkers on biological pathways to avoid black boxes. While direct modeling of DNA methylation changes with age enhances the predictability of biological age, it often obscures specific pathways captured by the algorithm, resulting in black boxes. To mitigate this, further efforts should focus on directly modeling aging and senescence-related pathways for novel biomarkers tracing age. Several markers exemplify the value of this approach. EpiTOC, for instance, functions as a mitotic clock, estimating stem cell divisions. It tracks age and correlates with increased cancer risk, offering insights into the association between cellular aging processes and cancer.

The thymus is necessary for the production of T cells of the adaptive immune system. Active thymic tissue diminishes with age to be replaced with fat, a process known as involution. This reduces the supply of new T cells and is an important contribution to the aging of the immune system. It may be that a better understanding of the fine details of the atrophy of the thymus with age may lead to new approaches to therapy. At present, the few groups working on rejuvenation of the thymus are largely focused on either delivering cells to the thymus or finding ways to upregulate the well-known regulatory pathway for thymic growth relating to the FOXN1 gene. There may be other ways forward.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons.

We applied single-cell and spatial transcriptomics, lineage-tracing, and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1.

Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.

Link: https://doi.org/10.1038/s41590-024-01915-9

Cancer, stroke, and other injuries to the brain have provided some insight into how the brain can restructure in response to damage. Provided that the damage progresses relatively slowly, as in the case of brain cancers, areas of the brain such as the neocortex can create new functional networks in order to maintain capabilities. When damage is fast, as in stroke, capabilities are lost. A few researchers see this as proof that it should be possible in principle to slowly and incrementally replace aged and damaged brain tissue with youthful tissue, given sufficiently advanced tissue engineering technology.

The focus of Jean Hébert's scientific work is the neocortex, the outer part of the brain that looks like a pile of extra-thick noodles and which houses most of our senses, reasoning, and memory. The neocortex is "arguably the most important part of who we are as individuals, as well as maybe the most complex structure in the world." There are two reasons Hébert believes the neocortex could be replaced, albeit only slowly. The first is evidence from rare cases of benign brain tumors, like a man described in the medical literature who developed a growth the size of an orange. Yet because it grew very slowly, the man's brain was able to adjust, shifting memories elsewhere, and his behavior and speech never seemed to change - even when the tumor was removed. That's proof, Hébert thinks, that replacing the neocortex little by little could be achieved "without losing the information encoded in it" such as a person's self-identity.

The second source of hope, he says, is experiments showing that fetal-stage cells can survive, and even function, when transplanted into the brains of adults. For instance, medical tests underway are showing that young neurons can integrate into the brains of people who have epilepsy and stop their seizures. "It was these two things together - the plastic nature of brains and the ability to add new tissue - that, to me, were like, 'Ah, now there has got to be a way.'"

One challenge ahead is how to manufacture the replacement brain bits, or what Hébert has called "facsimiles" of neocortical tissue. During a visit to his lab Hébert described plans to manually assemble chunks of youthful brain tissue using stem cells. These parts, he says, would not be fully developed, but instead be similar to what's found in a still-developing fetal brain. That way, upon transplant, they'd be able to finish maturing, integrate into your brain, and be "ready to absorb and learn your information." To design the youthful bits of neocortex, Hébert has been studying brains of aborted human fetuses 5 to 8 weeks of age. He's been measuring what cells are present, and in what numbers and locations, to try to guide the manufacture of similar structures in the lab.

Hébert's ideas appear to have gotten a huge endorsement from the US government. Hébert has proposed a $110 million project to ARPA-H to prove his ideas in monkeys and other animals, and that the government "didn't blink" at the figure. ARPA-H confirmed this week that it had hired Hébert as a program manager.

Link: https://www.technologyreview.com/2024/08/16/1096808/arpa-h-jean-hebert-wants-to-replace-your-brain/

Cerebrospinal fluid circulates in the brain. It is created in the choroid plexus and then drains from the brain via a range of pathways. One of the major drainage routes for cerebrospinal fluid is the glymphatic system, discovered and mapped by the research community only comparatively recently. The passage of cerebrospinal fluid from the brain is important as it allows for the removal of metabolic waste. Unfortunately, a reduced drainage of cerebrospinal fluid is a feature of aging, and thought to contribute meaningfully to the development of neurodegenerative conditions. Lost drainage capacity leads to the build up of metabolic waste that would otherwise be removed in a timely fashion. That in turn may contribute to, for example, the increasing overactivation of microglia in the brain and chronic inflammation of brain tissue.

Given the similarities between the glymphatic system and other fluid passage systems in the body, it is possible that existing small molecule drugs may be able to force aged glymphatic vessels into greater drainage capacity, overriding whatever environmental and signaling alterations are leading to tissue dysfunction. In today's research materials, this is the focus. The researchers better mapped the structure of glymphatic vessels, and found dysfunctional smooth muscle tissue that could act as a target for an existing mode of therapy known to provoke greater smooth muscle contractions. The result was, in mice, at least, a restoration of youthful glymphatic drainage capacity.

Cleaning up the aging brain

Alzheimer's, Parkinson's, and other neurological disorders can be seen as "dirty brain" diseases, where the brain struggles to clear out harmful waste. Aging is a key risk factor because, as we grow older, our brain's ability to remove toxic buildup slows down. However, new research in mice demonstrates that it's possible to reverse age-related effects and restore the brain's waste-clearing process.

Once laden with protein waste, cerebrospinal fluid (CSF) in the skull needs to make its way to the lymphatic system and, ultimately, to the kidneys, where it is processed along with the body's other waste. The new research combines advanced imaging and particle-tracking techniques to describe for the first time in detail the route by way of the cervical lymph vessels in the neck through which half of dirty CSF exits the brain.

Unlike the cardiovascular system, which has one big pump - the heart - fluid in the lymphatic system is instead transported by a network of tiny pumps. These microscopic pumps, called lymphangions, have valves to prevent backflow and are strung together, one after another, to form lymph vessels. The researchers found that as the mice aged, the frequency of contractions decreased, and the valves failed. As a result, the speed of dirty CSF flowing out of the brains of older mice was 63 percent slower compared to younger animals.

The team then set out to see if they could revive the lymphangions and identified a drug called prostaglandin F2α, a hormone-like compound commonly used medically to induce labor and known to aid smooth muscle contraction. The lymphangions are lined with smooth muscle cells, and when the researchers applied the drug to the cervical lymph vessels in older mice, the frequency of contractions and the flow of dirty CSF from the brain both increased, returning to a level of efficiency found in younger mice.

Restoration of cervical lymphatic vessel function in aging rescues cerebrospinal fluid drainage

Cervical lymphatic vessels (cLVs) have been shown to drain solutes and cerebrospinal fluid (CSF) from the brain. However, their hydrodynamical properties have never been evaluated in vivo. Here, we developed two-photon optical imaging with particle tracking in vivo of CSF tracers (2P-OPTIC) in superficial and deep cLVs of mice, characterizing their flow and showing that the major driver is intrinsic pumping by contraction of the lymphatic vessel wall.

Contraction frequency and flow velocity were reduced in aged mice, which coincided with a reduction in smooth muscle actin expression. Slowed flow in aged mice was rescued using topical application of prostaglandin F2α, a prostanoid that increases smooth muscle contractility, which restored lymphatic function in aged mice and enhanced central nervous system clearance. We show that cLVs are important regulators of CSF drainage and that restoring their function is an effective therapy for improving clearance in aging.

The accumulation of senescent cells is a significant contribution to age-related dysfunction and disease. These cells are created constantly in most tissues, and rapidly destroyed by programmed cell death or by the immune system. Unfortunately, in later life the immune system becomes ever less capable and as a result the burden of senescent cells grows. Senescent cells cease replication but secrete a pro-inflammatory mix of signals that, when maintained over the long term, causes structural change and loss of function. This picture may be more complicated in tissues with large non-diving cell populations, such as the brain or the heart, but it seems clear that senescent cells are still a contributing factor in the aging of these organs.

Adult cardiomyocytes in humans are terminally differentiated, i.e., they are post-mitotic/rarely dividing. Thus, telomere shortening/attrition due to repetitive cell division, a major mechanism of senescence in proliferating cells, termed replicative senescence, may not occur in cardiomyocytes. However, length-independent telomere damage, which may be caused by reactive oxygen species (ROS), induces senescence in terminally differentiated cardiomyocytes. Accumulating lines of evidence suggest that cardiomyocytes develop senescence during aging and in response to stresses such as ischemia/reperfusion and myocardial infarction (MI). β-adrenergic receptor stimulation and inflammation may also contribute to cardiomyocyte senescence during aging.

Senescent cardiomyocytes exhibit features of senescence commonly seen in other cell types, including enlarged cell size, DNA damage responses, senescence-associated β-galactosidase (SA-β-gal) activity, and the senescence-associated secretory phenotype (SASP). It should be noted that senescent cells are highly heterogeneous and their properties are dynamically altered. Thus, senescent cardiomyocytes may consist of multiple cell populations with distinct features. Furthermore, senescent cells in the heart can be either beneficial or detrimental depending on the cell types and conditions in which they are induced. Senescence in cardiac fibroblasts and endothelial cells may affect the heart differently from that in cardiomyocytes. Thus, conducting a deeper characterization of the gene expression profile in senescent cardiomyocytes and other cell types in the heart at the single-cell level is important.

There is a great interest in finding strategies to specifically eliminate senescent cells but not non-senescent cells, i.e., senolysis. Growing evidence supports the rationale of senolysis and its anti-aging effects. Since aging is a major risk factor for heart disease, senolysis could represent a promising intervention for the heart with senescent cardiomyocytes. Senolysis can be achieved using senolytic drugs (such as Navitoclax or Dasatinib and Quercetin), pharmacogenetic approaches (including the INK-ATTAC model), and immunogenetic interventions (CAR T cells or senolytic vaccination). Importantly, unlike regenerative and proliferative cells, cardiomyocytes are terminally differentiated. Thus, cardiomyocytes may not be replenished after senolysis. This raises the question of whether senolysis improves cardiac function despite the loss of cardiomyocytes. Although there have been reports suggesting that removal of cardiomyocytes by senolytics has salutary effects, thorough investigation into the mechanisms of cardiomyocyte senescence, especially the mechanisms through which cardiomyocytes develop and maintain the senescent state, is critical to identify or develop strategies for "safe" senolysis.

Link: https://doi.org/10.20517/jca.2024.06

Researchers here find a novel way to question the role of misfolded amyloid-β in the development of Alzheimer's disease. Evidence to date continues to suggest that the accumulation of amyloid-β in the aging brain is necessary to set the stage for later, more severe pathology driven by inflammation and tau aggregation. The failure of amyloid-β clearance to much modify the later disease state indicates that amyloid-β becomes less relevant as the condition progresses. But is it really the amyloid-β? Or is amyloid-β aggregation only coincident with the actual pathological mechanisms? A number of groups have proposed inflammation or infection driven models of Alzheimer's disease in which amyloid-β aggregation is a side-effect. Here researchers propose that amyloid-β aggregation allows other, potentially pathological molecules to aggregate alongside it.

In the brains of those who suffer from Alzheimer's, amyloids accumulate and build up into sticky plaque that disrupts brain functions and causes cognitive decline. The big unknown has been exactly how that occurs. According to the most widely adopted hypothesis, the amyloid beta buildup disrupts cell-to-cell communication and activates immune cells in a process that eventually destroys brain cells.

Researchers now present a new hypothesis, emphasizing a different role for amyloid beta, a simple protein that forms in all brains but normally dissolves out by natural processes. In experiments, they used cutting-edge analytical technologies to identify and measure the level of more than 8,000 proteins in human brains with Alzheimer's, as well as similar proteins in mice. Focusing on proteins whose levels increased most dramatically, they identified more than 20 proteins that co-accumulate with amyloid beta in both the human brains with Alzheimer's and the mice. As the research continues, they suspect they'll find more.

"Once we identified these new proteins, we wanted to know whether they were merely markers of Alzheimer's or if they could actually alter the disease's deadly pathology. To answer that, we focused on two proteins, midkine and pleiotrophin. Our research showed they accelerated amyloid aggregation both in the test tube and in mice. In other words, these additional proteins may play an important role in the process that leads to brain damage rather than the amyloid itself. This suggests they might be a basis for new therapies for this terrible brain affliction that's been frustratingly resistant to treatment over the years."

Link: https://news.emory.edu/stories/2024/08/hs_alzheimers_12_08_2024/story.html

The inside of a cell is a soup of molecules moving very rapidly; every molecule bumps into every other molecule in its region of the cell countless times every millisecond. Reactions occur. The DNA in the cell nucleus and its attendant handler proteins form a large and complex structure, but this is still a collection of rapidly moving molecules and thus subject to unintended reactions that damage it and break it. Hence there exists a complex collection of proteins in the cell nucleus that act in concert to detect DNA damage and repair DNA. Evolution, by necessity, has made this DNA repair machinery highly efficient. The mutations that we observe in older individuals make up only a tiny, tiny fraction of all of the potentially mutational DNA damage that takes place constantly in every cell in the body.

Mutational DNA damage is thought to be an important contributing factor in degenerative aging, leading to (a) the lethal threat of cancer and (b) somatic mosaicism in tissues, a disruptive influence on the correct function of tissues caused by the slow spread of mutations from stem cell and progenitor cell populations. While it is true that DNA repair machinery is highly efficient in all species, some lower organisms are dramatically more resilient than the average. Typically this was discovered as a result of their response to radiation damage. Some bacteria can survive radiation levels far in excess of the dose needed to kill other species, for example. Is there anything we can learn from these species that might be used to improve DNA repair efficiency in mammals, and thus reduce its contribution to aging?

Today's open access paper describes the discovery of a compact piece of the DNA repair machinery in a radiation-resistant bacteria that can be transplanted into other bacterial species to dramatically improve their DNA repair. The researchers feel that it should in principle be possible to introduce this protein into higher animals, but have not yet taken that step. Before we get too excited, it is worth noting that putting bacterial proteins, or indeed any foreign protein, into mammals is a project that comes accompanied by many obstacles. The immune system doesn't like foreign proteins, particularly bacterial, and the established system of regulators and investors is normally strongly opposed to introducing bacterial proteins as a part of therapy - or at least the burden of proof for safety is much higher, and thus development is slower and more expensive, which tends to discourage progress. Still, this is very interesting research, and we can speculate as to how we might best make use of it in human medicine.

Newly discovered protein stops DNA damage

The researchers found the protein - called DdrC (for DNA Damage Repair Protein C) - in a fairly common bacterium called Deinococcus radiodurans (D. radiodurans), which has the decidedly uncommon ability to survive conditions that damage DNA - for example, 5,000 to 10,000 times the radiation that would kill a regular human cell. DdrC scans for breaks along the DNA and when it detects one it snaps shut - like a mousetrap. This trapping action has two key functions: "It neutralizes it (the DNA damage), and prevents the break from getting damaged further. And it acts like a little molecular beacon. It tells the cell 'Hey, over here. There's damage. Come fix it.'"

Typically proteins form complicated networks that enable them to carry out a function. DdrC appears to be something of an outlier, in that it performs its function all on its own, without the need for other proteins. The team was curious whether the protein might function as a "plug-in" for other DNA repair systems. They tested this by adding it to a different bacterium: E. coli. "To our huge surprise, it actually made the bacterium over 40 times more resistant to UV radiation damage. This seems to be a rare example where you have one protein and it really is like a standalone machine."

In theory, this gene could be introduced into any organism - plants, animals, humans - and it should increase the DNA repair efficiency of that organism's cells. "The ability to rearrange and edit and manipulate DNA in specific ways is the holy grail in biotechnology. What if you had a scanning system such as DdrC which patrolled your cells and neutralized damage when it happened? This might form the basis of a potential cancer vaccine."

DdrC, a unique DNA repair factor from D. radiodurans, senses and stabilizes DNA breaks through a novel lesion-recognition mechanism

The bacterium Deinococcus radiodurans is known to survive high doses of DNA damaging agents. This resistance is the result of robust antioxidant systems which protect efficient DNA repair mechanisms that are unique to Deinococcus species. The protein DdrC has been identified as an important component of this repair machinery. DdrC is known to bind to DNA in vitro and has been shown to circularize and compact DNA fragments. The mechanism and biological relevance of this activity is poorly understood.

Here, we show that the DdrC homodimer is a lesion-sensing protein that binds to two single-strand (ss) or double-strand (ds) breaks. The immobilization of DNA breaks in pairs consequently leads to the circularization of linear DNA and the compaction of nicked DNA. The degree of compaction is directly proportional with the number of available nicks. Previously, the structure of the DdrC homodimer was solved in an unusual asymmetric conformation. Here, we solve the structure of DdrC under different crystallographic environments and confirm that the asymmetry is an endogenous feature of DdrC. We propose a dynamic structural mechanism where the asymmetry is necessary to trap a pair of lesions. We support this model with mutant disruption and computational modeling experiments.

This is not the only study to show evidence for points of transition in the progression of degenerative aging. You might recall a study of the gut microbiome published a few years ago that identified a transition into a less beneficial balance of microbial populations taking place in the mid-30s. Here, the points of rapid transition in omics data are identified as mid-40s and 60. This sort of data is interesting, but it should be replicated in larger populations before we get too fired about about interpreting it or speculating about the arrangement of mechanisms driving large and rapid shifts in metabolism at certain ages.

Aging is a complex process associated with nearly all diseases. Understanding the molecular changes underlying aging and identifying therapeutic targets for aging-related diseases are crucial for increasing healthspan. Although many studies have explored linear changes during aging, the prevalence of aging-related diseases and mortality risk accelerates after specific time points, indicating the importance of studying nonlinear molecular changes.

In this study, we performed comprehensive multi-omics profiling on a longitudinal human cohort of 108 participants, aged between 25 years and 75 years. The participants resided in California, United States, and were tracked for a median period of 1.7 years, with a maximum follow-up duration of 6.8 years. The analysis revealed consistent nonlinear patterns in molecular markers of aging, with substantial dysregulation occurring at two major periods occurring at approximately 44 years and 60 years of chronological age. Distinct molecules and functional pathways associated with these periods were also identified, such as immune regulation and carbohydrate metabolism that shifted during the 60-year transition and cardiovascular disease, lipid metabolism, and alcohol metabolism changes at the 40-year transition.

Overall, this research demonstrates that functions and risks of aging-related diseases change nonlinearly across the human lifespan and provides insights into the molecular and biological pathways involved in these changes.

Link: https://doi.org/10.1038/s43587-024-00692-2

Companies in the longevity industry that are working on ways to slow or reverse the age-related loss of muscle mass and strength that leads to sarcopenia have become attractive to the pharmaceutical industry and big investors of late. This is not because those entities have suddenly seen the light and now support the treatment of aging as a medical condition, but rather because their leadership is looking for ways to slow or reverse the muscle loss that attends the use of the suddenly popular GLP-1 receptor agonist drugs used for weight loss. How well are things going in the development of ways to slow or reverse sarcopenia, however? Not so well, perhaps, as here argued by the SENS Research Foundation staff, because researchers and developers are largely going about it the wrong way.

Suppose you were to take a group of people who were on the back end of current lifespans and give them an experimental drug to boost their muscle mass. Like most older people, they have lost a significant amount of the muscle they carried in midlife. By giving them our experimental muscle-building drug, we're hoping to restore their function, keeping them out of the nursing home and playing with their grandchildren. Excitingly, the drug seems to work. Over the course of a few months, the volunteers in our trial who receive our drug put on muscle mass, while people receiving the placebo continue to lose muscle. Mission accomplished, right?

Yet when the researchers test the volunteers on standardized tests of muscle strength and function, the newly-muscular elders are no stronger than when the trial started, and no better off than the people who were taking sugar pills. What's the drug? Actually, it's a lot of drugs. People have been trying to develop therapies to help aging people regain muscle mass and strength for decades now, and while a number of them have bulked up subjects' biceps, they have consistently failed to deliver on the functional outcomes that matter most.

As with other age-related diseases and disabilities, sarcopenia is a complex condition, driven by the collateral damage inflicted on multiple cellular and molecular structures by the processes that keep us alive. As these structural units are damaged or destroyed, we lose functional contribution to delivering muscle strength and power. To reverse this degenerative process, it isn't enough to simply add more of the dysfunctional muscle tissue aging people have. Instead, we need to develop rejuvenation biotechnologies capable of removing and repairing the range of cell and tissue damage that robs our muscles of their strength.

Link: https://www.sens.org/legs-of-iron-feet-of-clay/

Senescent cells most likely contribute meaningfully to all age-related conditions. Cells become senescent in response to damage, a toxic environment, the signals of other senescent cells, but most often because they reach the Hayflick limit on replication. Cellular senescence is useful in a number of contexts when senescent cells are present for a short period of time only, such as regeneration from injury and suppression of precancerous cells. Senescent cells secrete a mix of pro-growth, pro-inflammatory signals that attract the immune system to help to address these issues. The problem starts when senescent cells linger over time and steadily increase in number with advancing age. Their presence becomes disruptive to tissue structure and function.

In today's open access paper, the authors discuss the role of senescent cells in the vasculature in the development of cardiovascular disease. Interestingly, there has been little focus on cardiovascular disease to date on the part of the few groups involved in running clinical trials for first generation senolytic drugs, treatments capable of selectively destroying senescent cells. In fairness, when the possible set of age-related conditions to treat is "all of them," some conditions are going to be left behind. There are only so many researchers, only so much funding. But still, cardiovascular disease is the largest cause of human mortality. There is something to be said for starting at the top and working down.

Targeting vascular senescence in cardiovascular disease with aging

This review aimed to provide a brief summary of the effects of aging on cardiovascular disease through the accumulation of senescence, highlighting the crucial involvement of vascular cells in the progression of atherosclerosis and other cardiovascular diseases (CVDs). We also sought to describe the potential of senolytics to improve vascular function and reduce CVD in aging. Endothelial dysfunction occurs with aging and promotes reductions in nitric oxide (NO), increases in reactive oxygen species (ROS), a proinflammatory phenotype, and is associated with an increase in senescent cell accumulation. Understanding how endothelial cell (EC) senescence influences endothelial dysfunction, atherosclerosis, and CVD is important in the identification/design of novel effective therapeutics.

EC senescence is recognized as a contributing factor to endothelial dysfunction and is a major step in the development of atherosclerosis and other CVDs. Evidence suggests that genetic or pharmacological elimination of senescence, specifically in ECs, can attenuate vascular dysfunction and disease in aging through a reduction in the milieu of senescence-associated secretory phenotype (SASP) factors present in senescence. These findings have also improved our understanding of the endothelium's response to aging and how to combat endothelial dysfunction in this setting. Specifically, targeting endothelial cell senescence appears to be a promising strategy for maintaining endothelial functions and improving vascular health.

Preclinical evidence has shown the potential of senolytics for the treatment and prevention of CVD, leading to the investigation of senolytic therapy in the clinical setting. In a preliminary clinical trial investigating the effectiveness of senolytics, a treatment regimen involving a 3-day administration of dasatinib and quecertin (D&Q) per week for 3 weeks was implemented. This study was conducted on 14 patients with idiopathic pulmonary fibrosis and demonstrated high retention and completion rates, indicating the safety of this treatment. Although there were no significant improvements in pulmonary function, treatment with D&Q led to notable improvements in physical function, as evidenced by increases in 6-min walk distance and 4-min gait speed. Moreover, correlations were observed between enhanced physical function and a reduction in SASP factors.

Additionally, preliminary data from a phase 1 clinical trial involving patients with diabetic kidney disease revealed that senolytic therapy with D&Q reduced senescence burden in both adipose and epidermis tissue. This reduction was associated with a decrease in circulating cytokines and matrix metalloproteinases. In a 12-week pilot study of D&Q treatment on individuals with early-stage Alzheimer's disease (AD), there was no significant difference between neuroimaging endpoints and cognitive function. However, results indicated a reduction in cytokine and chemokine levels associated with senescence as well as a trending increase in Aβ42, a biomarker that is inversely related to Alzheimer's disease diagnosis. These studies show promise for the therapeutic potential of senolytic therapy in eliminating senescence, relieving SASP accumulation, and reducing inflammation, although more compounds with appropriate safety, tolerability, and feasibility need to be developed and investigated. Moreover, clinical trials using senolytic therapy in the context of atherosclerosis and cardiovascular disease should be conducted.

Currently, there is not enough research on the use and treatment of senolytic therapy in cardiovascular diseases in the clinical setting. It is unclear if senescent cell clearance, either systemically or in a cell-specific manner, will impact the cardiovascular system, specifically on health span in general. Furthermore, the long-term effects of senescent cell elimination, both systemic and tissue-specific, are not well known. More research must be conducted to answer these questions. While short-term clearance of senescent endothelial and vascular smooth muscle cells improved cardiovascular function and atherosclerosis in preclinical models, further studies are necessary to ensure that the elimination of this cell population has no adverse effects on systemic function, both long-term and short-term. Nevertheless, the potential of senolytics to transform age-related cardiovascular diseases and improve health span is an exciting frontier.

This paper captures a part of the present uncertainty over characterization of senescent cells, particularly in the aged immune system. There is some concern that present markers are not sufficiently selective for senescent immune cells, and that some of these possibly problematic populations are something else entirely. Immune system aging is already known to be complex, and there are certainly harmful populations that are not senescent: exhausted T cells, age-associated B cells, overly active microglia and macrophages, various small subpopulations that appear to be doing something counterproductive in a specific tissue, and so forth. The research community is perhaps more concerned with obtaining an accurate picture than with testing methods of clearance of subsets of the immune cell population in search of benefits.

In young and healthy individuals, damaged cells can enter a state of cellular senescence, which limits the spread of dysfunctional cells. These senescent cells produce a senescence-associated secretory phenotype (SASP) which attracts immune cells that may ultimately clear these senescent cells. Recent studies suggest that when the immune cells themselves become senescent, they fail to clear other senescent cells and drive senescence, and age-related dysfunction of other organs.

As we age, T cells may develop cellular senescence, similar to fibroblasts and other cell types in which the state of cellular senescence has been extensively investigated. But importantly, the cell surface markers frequently used to detect immunosenescent T cells, such as the loss of CD27 and CD28 expression or the upregulated KLRG-1 or Leu7 expression, or the exhaustion marker PD-1, do not accurately demarcate the population that is in a true state of senescence. Rather, they mark a heterogenous population of T cells, mostly but not exclusively consisting of senescent cells. Referring to this population as senescent T cells is, at best, an oversimplification and leads to a significant underestimation and misinterpretation of the actual number of senescent T cells in individual patients. Several hallmarks of cellular senescence, such as p16, p21, absence of proliferation, DNA-SCARS, telomere-associated foci (TAFs), senescence-associated heterochromatin foci (SAHFs), loss of LMNB1 and increased senescence-associated β-gal activity, should be included to accurately measure senescent T cells.

Future studies should investigate the functional properties of T cells that are in a state of cellular senescence in the different T cell differentiation stages. For a long time, research into T cell senescence has focused on late-stage differentiation stages, such as the CD28null population, the CD57+ TEMRA cells (the effector memory cells that re-express CD45RA), or the exhausted T cells. The question now arises whether earlier T cell differentiation stages can also become senescent. Knowledge on the functional consequences of accumulating senescent naïve or central memory T cells is lacking. It is essential to determine whether these subpopulations of senescent T cells increase in age-related diseases and actively contribute to pathology. Additionally, it is important to explore whether they secrete a SASP and how they differ functionally from non-senescent T cells of the same differentiation stage. These are critical open questions that require further investigation.

Link: https://doi.org/10.1111/acel.14300

Arterial stiffening is an important problem in aging, contributing to hypertension, cardiac remodeling, and other problems. The contributing factors are described in the paper noted here, with changes in the behavior of cells controlling constriction and dilation of vessels on the one hand, versus changes in the extracellular matrix that reduce tissue elasticity on the other hand. There remains comparatively little research and development aimed at repair of the aged extracellular matrix, but it is nonetheless important.

Arterial stiffness, a recognized marker of vascular health, reflects the elasticity and compliance of arteries. Central arterial stiffness, as measured by pulse wave velocity, is a predictor of cardiovascular events and mortality independent of traditional risk factors. Arterial stiffness is multifaceted, comprised of both active and passive stiffness. Aging is associated with increased arterial stiffness, caused by changes in active and passive arterial stiffness.

The active contribution to arterial stiffness, otherwise known as vascular tone, is regulated by vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). ECs, lining the inner surface of blood vessels, contribute towards vascular tone by releasing bioactive molecules that modulate vasoconstriction and vasodilation of VSMCs. Nitric oxide (NO), a key endothelium-derived vasodilator, is crucial for maintaining proper vessel function. EC dysfunction leads to impaired NO production, contributing towards augmented vasoconstriction, oxidative stress, and ultimately, cardiovascular diseases.

Passive stiffness encompasses extracellular matrix (ECM) structural proteins. Collagen and elastin are important structural proteins in ECM, contributing to mechanical properties of blood vessels. Collagen provides tensile strength, while elastin confers elasticity. The balanced interaction between collagen and elastin is vital for maintaining arterial integrity, allowing blood vessels to withstand mechanical stress. Arterial tissues from different anatomical regions on the aorta exhibit distinct mechanical properties and endothelial responses due to variations in structure, hemodynamics, and local microenvironments.

Link: https://doi.org/10.1038/s41598-024-68725-9

The goal of the cancer research community is, broadly, to find ways to selectively stress, kill, and halt the replication of cancer cells. Researchers have been earnestly engaged in this work for decades. Cells that are stressed and damaged tend to become senescent, even cancer cells. Senescent cells cease to replicate and begin to secrete pro-inflammatory molecules to attract the attention of the immune system. Driving cancerous cells into senescence has long been recognized as a goal in cancer research, alongside the related goal of killing the cancerous cells outright. Any suitably cytotoxic therapy will typically achieve both of those outcomes at the same time. So it is perhaps not surprising to find that the first senolytic drugs capable of selectively destroying senescent cells outside the context of cancer are repurposed chemotherapeutics.

It is now recognized that destroying cancer leaves a patient with a lingering burden of senescent cells, and these additional senescent cells are likely the reason why cancer survivors exhibit a reduced life span and increased burden of age-related disease. There is little debate over the question of whether it is a good idea to use senolytics to clear these errant cells after the cancer is banished: if senolytics are good for patients in the context of a normal age-related accumulation of senescent cells, then they should be good for cancer survivors as well. The debate is instead to be found over the question of whether and when it is a good idea to destroy senescent cells during cancer treatment, while the cancer is still in evidence. Will it help or harm efforts to remove the cancer? The answer may vary on a cancer by cancer and therapy by therapy basis.

Therapy-Induced Cellular Senescence: Potentiating Tumor Elimination or Driving Cancer Resistance and Recurrence?

Beyond its connection to aging, senescence has been recognized as a hallmark of cancer. Whether senescence is beneficial or detrimental to cancer initiation, progression, and/or treatment has remained controversial over the past few decades. On one hand, the induction of senescence can serve as a barrier against malignant transformation and excessive hyperproliferation due to reduced proliferative capacity. On the other, SnC accumulation may act as a driver of cancer progression and therapy resistance, primarily mediated by inflammatory factors in the senescence-associated secretory phenotype (SASP). Persistent senescence has been associated with promoting malignant transformation, accelerating tumor growth, inducing cancer stemness, facilitating distant metastasis, maintaining chronic inflammation, and dampening the anti-tumor immune response.

Confirming these deleterious effects, genetic elimination of senescent cells (SnCs) was shown to delay spontaneous tumorigenesis and decrease cancer-related mortality. Senolytic agents, drugs that selectively eliminate SnCs, have also demonstrated significant potential in improving cancer therapies. Nonetheless, our studies have identified opposing, apparently beneficial, effects of therapy induced senescence (TIS), where SnCs may serve as a vaccine to drive an adaptive immune response to inhibit tumor growth and boost radiation therapy. This work is built on pioneering studies revealing innate and adaptive immune recognition of SnCs leading to their elimination and tumor suppression, often described as senescence surveillance.

Over the past decade, a growing literature has appeared that further defines roles for host immunity in mediating the anti-tumor effects of SnCs, as reflected in recent reviews. Multiple studies have implicated the upregulation of inflammatory mediators including damage-associated molecular patterns (DAMPs), chemotactic factors and other cytokines, and antigen presentation machinery in the activation of both innate and adaptive immune responses, not only driving SnC elimination via immune surveillance but also potentiating broader immune responses. Such findings highlight the positive aspects of TIS, extending beyond growth suppression to significantly enhance anti-tumor immunity.

A factor underlying the apparent inconsistency may be that SnCs, including those formed by cancer therapies, can express immune checkpoint ligands that allow SnCs to evade surveillance and protect their microenvironment. Thereby, some benefits of immune checkpoint blockade (ICB) therapy in combination with genotoxic or targeted therapies may be mediated by overcoming immunosuppression driven by TIS and restoring immune surveillance.

This review examines cellular senescence in the context of cancer, highlighting the diverse roles of SnCs in the tumor microenvironment (TME) and arguing for a broad view of senescence and its functions. We will discuss how the interaction between SnCs and the immune system can lead to either beneficial or detrimental outcomes depending on the specific features of SnCs, particularly the SASP. We will then review SASP modulation and SnC elimination via senolytics. Such approaches may limit the adverse effects of senescence while amplifying its beneficial impact, which ultimately presents an alternative strategy to improve cancer therapies.

Parkinson's disease is driven by the spread of misfolded α-synuclein and the death of dopaminergic neurons that are vulnerable to the consequences of α-synuclein proteopathy. A fair amount of effort has gone into trying to understand why these neurons become dysfunctional and die, in search of ways to protect them from disease processes. The research noted here is an example of the type, in which scientists point to the evidence for lipid accumulation to take place in these neurons, driving them into a state of cellular senescence. The senescent state is inflammatory and disruptive to surrounding tissue; a growing presence of lingering senescent cells has been demonstrated to contribute to many age-related conditions.

Parkinson's disease (PD) is an age-related movement disorder caused by the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) of the midbrain, however, the underlying causes of this DA neuron loss in PD is unknown and there are currently no effective treatment options to prevent or slow neuronal loss or the progression of related symptoms. It has been shown that both environmental factors as well as genetic predispositions underpin PD development and recent research has revealed that lysosomal dysfunction and lipid accumulation are contributors to disease progression, where an age-related aggregation of alpha-synuclein as well as lipids have been found in PD patients.

We have recently discovered that artificial induction of lipid accumulation leads to cellular senescence of DA neurons, suggesting that lipid aggregation plays a crucial role in the pathology of PD by driving senescence in these vulnerable DA neurons. We propose that the expression of a cellular senescence phenotype in the most vulnerable neurons in PD can be triggered by lysosomal impairment and lipid aggregation. Importantly, we highlight additional data that perilipin (PLIN2) is significantly upregulated in senescent DA neurons, suggesting an overall enrichment of lipid droplets (LDs) in these cells.

These findings align with our previous results in dopaminergic neurons in highlighting a central role for lipid accumulation in the senescence of DA neurons. Importantly, general lipid droplet aggregation and global lysosomal impairment have been implicated in many neurodegenerative diseases including PD. Taken together, our data suggest a connection between age-related lysosomal impairment, lipid accumulation, and cellular senescence in DA neurons that in turn drives inflammaging in the midbrain and ultimately leads to neurodegeneration and PD.

Link: https://doi.org/10.18632/aging.206030

TDP-43 is the most recently discovered of the proteins known to be able to misfold or otherwise become altered in ways that encourage other molecules of the same protein to do the same. Like most of the other problem proteins, TDP-43 is involved in age-related neurodegeneration, and altered TPD-43 is commonly found in aged brains. As the study here makes clear, TDP-43 may be as important as the amyloid-β and tau of Alzheimer's disease. Finding ways to prevent pathological accumulation of the major varieties of altered proteins should be a priority for the research community.

A new type of degenerative brain disease, limbic-predominant age-related TDP-43 encephalopathy (LATE), was recognised just a decade or so ago, and remains relatively unknown. In the disease, the TDP-43 protein accumulates particularly in the limbic brain regions, which are also affected in the early stages of Alzheimer's disease. Accordingly, symptoms of LATE are similar to those of early Alzheimer's, but typically progress more slowly and are milder.

Researchers conducted the first study exploring the prevalence of LATE in a population-based Finnish autopsy dataset encompassing 300 Finns over the age of 85. LATE was found to be very common. Changes associated with the disease were identified in at least every second individual over the age of 85. The association between LATE and dementia was independent of other brain changes found in the study subjects. "The results suggest that LATE is, alongside Alzheimer's, one of the strongest determinants of dementia in the oldest old."

Link: https://www.helsinki.fi/en/news/brain/new-type-degenerative-brain-disease-underlying-dementia-very-common-among-oldest-old

The commensal microbiomes of the body, such as that of the gut and the oral cavity, change with age in detrimental ways. In part this is due the progressive age-related failure of the immune system to undertake its duties, such as removing problematic microbial species. Other mechanisms are likely involved, however, many of which are less direct. In today's open access paper, researchers focus on one such mechanism, a reduced production of immunoglobulin A antibodies. In mucous membranes, such as of the gut and the mouth, immunoglobulin A antibodies are produced in large amounts and their presence shapes the distribution of microbial populations via selective interactions with different forms of bacteria. With age, immunoglobulin A production in the gut decreases, and this allows the composition of the gut microbiome to shift in harmful ways.

The researchers provide evidence for this loss of immunogloblin A production to derive in part from the presence of senescent B cells in the lymph nodes of tissue close to the mucous membrane. The researchers extend earlier work on the gut microbiome to show that this mechanism likely operates on the oral microbiome as well. The more mechanisms of degenerative aging that are discovered to involve senescent cells, the more of a drive there should be to as rapidly as possible develop senolytic drugs for widespread use. This is true of both existing first generation senolytics such as the dasatinib and quercetin combination, and the much better approaches presently under development in the longevity industry.

B cell senescence promotes age-related changes in oral microbiota

Among various host-derived factors known to be involved in the regulation of commensal microbiota, immunoglobulin A (IgA), which is abundantly secreted on mucosal surfaces, is thought to play an important role. IgA is known to regulate the balance of the commensal microbiota by binding to bacteria and contributing to the promotion or elimination of bacterial colony formation, depending on the type of bacteria. Notably, dysbiosis of the gut microbiota stemming from IgA deficiency has been observed in both human and murine models, with implications for the development of autoimmune disorders through aberrant immune activation. IgA is secreted not only in the intestinal tract but also in other mucosal sites such as the oral cavity. While there is already evidence suggesting the involvement of IgA in the regulation of oral microbiota, the impact of IgA on age-related changes in oral microbiota and its mechanisms remain unclear.

Senescent cells also cause senescence-associated secretory phenotypes (SASP), in which the cells secrete a variety of pro-inflammatory factors into the extracellular fluid. Therefore, the accumulation of senescence-like cells, which is often seen with aging and/or obesity, ultimately leads to harmful side effects. Moreover, our recent studies have shown that age-associated cellular senescence of ileal germinal center (GC) B cells induced by commensal bacteria reduces IgA production and diversity, leading to gut dysbiosis. Based on these findings, we considered the possibility that similar mechanisms may operate in the oral immune system, contributing to abnormalities in the oral microbiota with aging.

Examination of p16-luc mice, wherein the expression of the senescent cell marker p16INK4a can be visualized, raised under specific pathogen-free (SPF) or germ-free (GF) conditions, indicated that, unlike ileal germinal center (GC) B cells, the accumulation of senescent cells in GC B cells of cervical lymph nodes increases with age regardless of the presence of commensal bacteria. Furthermore, longitudinal studies utilizing the same individual mice throughout their lifespan revealed concurrent age-related alterations in the composition of the oral microbiota and a decline in salivary IgA secretion. Further investigation unveiled that B cell senescence leads to reduced IgA secretion and alteration of the oral microbiota. These findings advance our understanding of the mechanism of age-associated changes in the oral microbiota and open up possibilities of their control.

The epidemiological study discussed here is noteworthy for its length. The results are consistent with many other studies, in that lifestyle choice and presence of chronic disease appear to be the major correlating factors with length of life. At the present time no therapies are yet proven in humans to beat lifestyle choices when it comes to effects on life expectancy - though it is certainly possible that some of the options on the table, such as early senolytic therapies, may turn out to do so.

To study possible determinants of longevity in a cohort of middle-aged men followed for 61 years until extinction using measurements taken at baseline and at years 31 or 61 of follow-up. In 1960, two rural cohorts including a total of 1712 men aged 40-59 years were enrolled within the Italian section of the Seven Countries Study of Cardiovascular Diseases, and measurements related to mainly cardiovascular risk factors, lifestyle behaviors, and chronic diseases were taken at year 0 and year 31 of follow-up (when only 390 could be examined). Multiple linear regression models were computed to relate personal characteristics with the length of survival in both dead men and survivors.

Baseline cardiovascular risk factors, smoking and dietary habits, and chronic diseases (taken at year 0 with men aged 40-59 years) were significant predictors of the length of survival both from year 0 to year 31 and from year 0 to year 61, but only chronic diseases were independent predictors for the period of 31 to 61 years. Significant predictors of survival using measurements taken at year 31 (age range 71 to 90 years) were only smoking and dietary habits and chronic diseases. In conclusion, during a lifetime of follow-up, the personal characteristics with continuous predictive power of survival were only lifestyle behaviors and major chronic diseases.

Link: https://doi.org/10.3390/jcdd11070221

Researchers have shown that extension of life via calorie restriction requires functional autophagy, the collection of cell maintenance processes responsible for recycling damaged proteins and structures. Similarly, researchers here note a novel autophagy regulator gene called MYTHOS that is present in species as far distant as humans and nematode worms, and which is required for a number of life-extending genetic interventions to work in nematodes. Further, MYTHOS expression is upregulated with age, suggesting it is a compensatory adaptation that attempts to combat rising levels of cellular dysfunction with greater housekeeping. MYTHOS itself may or may not be a basis for intervention, but it is yet another piece of evidence to support continued efforts to develop therapies that can improve the operation of autophagy in order to slow aging.

A general cause of cellular senescence and organism aging is the progressive accumulation of dysfunctional organelles and cellular damage. Impairment of proteostasis alters the protein quality control systems, leading to the accumulation of aberrant and dysfunctional macromolecules and is considered among the primary hallmarks of aging. All cells take advantage of an array of mechanisms to preserve the stability and functionality of their proteins or to remove them when they are irreversibly damaged. One of the most important cellular housekeeping and prosurvival pathways is macroautophagy, hereafter named autophagy, whose main action is to remove damaged proteins/organelles and generate molecules that sustain cellular core metabolism.

To identify uncharacterized factors that control aging and proteostasis, we screened our published transcriptomic profiles. We discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C. elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. We tested the long-lived glp-1 (which shows reduced proliferation of germline cells) and eat-2 (a genetic dietary restriction model) mutants. The findings that the absence of myt-1 completely blunted the life extension of glp-1 mutants and partially affected the longevity of eat-2 mutants suggest that myt-1 is mediating the response to germline signals and dietary cues, respectively.

Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging.

Link: https://doi.org/10.1172/JCI165814

Calorie restriction slows the progression of aging, and remains a benchmark yet to be beaten by pharmaceutical approaches to the manipulation of metabolism aimed at slowing down aging. Much of the beneficial response to calorie restriction is downstream of nutrient sensing, the complex package of cellular mechanisms that react to, for example, levels of essential amino acids that are only obtain via the diet. The most studied of these sensory systems of metabolic regulation is that targeting the essential amino acid methionine. Studies in rodents suggest that a sizable fraction of the calorie restriction response derives from methionine sensing, and promising results have been observed studies using low methionine diets without overall restriction of calories.

Low methionine diets are challenging to manage in day to day life, arguably harder than simply eating less, which might go some way towards explaining why they are not a popular option. A low methionine diet is a jigsaw puzzle lacking most of the pieces; near every lynchpin ingredient in a reasonable, balanced diet of any type is high in methionine. Low methionine medical diets do exist, however, and those who manufacture them for a few specialized uses would no doubt welcome evidence for their broader application to age-related conditions. Today's paper is an example of researchers gathering more supporting evidence for methionine restriction to be particularly applicable to a specific condition of interest, Alzheimer's disease in this case.

Systems genetics identifies methionine as a high risk factor for Alzheimer's disease

Recently researchers have found that amino acid homeostasis is disrupted in the serum and brain of patients with Alzheimer's disease (AD). Moreover, alterations in the levels of different amino acids in the physiological range have been linked to various pathological conditions, including neurological disorders. Longitudinal studies using mouse models of AD have also demonstrated abnormal essential amino acid levels. These findings suggest that dietary intervention may affect the progression of AD by regulating amino acids metabolism.

Methionine is a widely-used sulfur-containing amino acid that serves as a precursor for substances such as spermine, spermidine, and ethylene. It plays a pivotal role in various aspects of growth and development, including cell division, differentiation, apoptosis, homeostasis, and gene expression. Studies have shown that the methionine cycle is involved in the pathogenesis of AD. Methionine serves as a crucial methyl donor in certain methyltransferase reactions, providing methyl groups to various compounds. High methionine diet has been proven to induce AD-like symptoms. As a dietary intervention, methionine restriction has been reported to alleviate AD, but the molecular mechanisms remain unclear. Therefore, it is of great significance to explore the specific mechanisms, by which methionine is involved in the pathogenesis of AD.

This study utilized the data from BXD recombinant inbred (RI) mice to establish a correlation between the AD phenotype in mice and methionine level. Gene enrichment analysis indicated that the genes associated with the concentration of methionine in the midbrain are involved in the dopaminergic synaptic signaling pathway. Protein interaction network analysis revealed that glycogen synthase kinase 3 beta (GSK-3β) was a key regulator of the dopaminergic synaptic pathway and its expression level was significantly correlated with the AD phenotype. Finally, in vitro experiments demonstrated that methionine deprivation could reduce the expression of amyloid-β and phosphorylated tau, suggesting that lowering methionine levels in humans may be a preventive or therapeutic strategy for AD. In conclusion, our findings support that methionine is a high risk factor for AD. These findings predict potential regulatory network, theoretically supporting methionine restriction to prevent AD.

How well does an epigenetic clock measure biological age? The research community cares about whether an epigenetic clock can be trusted in the measure of biological age because being able to use clocks to assess potential rejuvenation therapies would greatly speed up research and development. This is an important question, but because of the way in which epigenetic clocks are constructed, using machine learning to fit algorithms to epigenetic data from populations at various ages, it is not obviously the case that researchers can quantify the risk that a specific clock is not a good measure of biological age. Here find a discussion of this issue and some thoughts on the way forward.

The primary assumption of aging clocks is that the deviation ∆ of predicted age from the chronological age C represents an accelerated or decelerated aging, that is, an increase or decrease in the biological age B. Since biological age cannot be measured directly, the epigenetic age estimated by the clocks is therefore considered a proxy measure of the biological age. However, before aging clocks could be integrated into clinical practice, these models should provide an estimate of uncertainty for their own predictions.

Uncertainty manifests itself in three ways: (i) Model choice uncertainty, part of a broader category known as epistemic uncertainty, represents how well a proposed model reflects the actual underlying process. (ii) Out-of-distribution (OOD) uncertainty, another type of epistemic uncertainty, emerges when the testing data are not represented in the training data distribution, leading to a high risk of model prediction failure (iii) Aleatoric uncertainty originates from data variations that cannot be reduced to zero by the model.

From the clinical perspective, epistemic uncertainty must be estimated to make reliable conclusions about whether to trust a model or not. Specifically, epistemic uncertainty resulting from the dataset shift should be scrutinized, considering the prevalence of batch effects in biological data. Dataset shift describes the case of OOD sampling where the testing population is under-represented within the training distribution. However, most popular DNA methylation aging clocks fail to meet this criterion because they are typically built using algorithms from the penalized multivariate linear regression (MLR) family. Such algorithms do not yield information on any of the uncertainties, except for the error between chronological and predicted ages in the training data.

In this work, we question the applicability of existing aging clock methodology for measuring rejuvenation by specifically examining prediction uncertainty. We present an analytical framework to consider rejuvenation predictions from the uncertainty perspective. Our analysis reveals that the DNA methylation profiles across reprogramming are poorly represented in the aging data used to train clock models, thus introducing high epistemic uncertainty in age estimations. Moreover, predictions of different published clocks are inconsistent, with some even suggesting zero or negative rejuvenation. While not questioning the possibility of age reversal, we show that the high clock uncertainty challenges the reliability of rejuvenation effects observed during in vitro reprogramming before pluripotency and throughout embryogenesis. Conversely, our method reveals a significant age increase after in vivo reprogramming. We recommend including uncertainty estimation in future aging clock models to avoid the risk of misinterpreting the results of biological age prediction.

Link: https://doi.org/10.1111/acel.14283

Researchers here provide animal model evidence for a novel approach to improve cognitive function in Alzheimer's disease. It is focused on neurons that maintain specific neural rhythms in the brain, necessary for the coordination of neural network activity that occurs during normal cognitive functions. These gamma waves appear to be important to memory functions, as well as many other aspects of brain health. They are observed to be disturbed in a number of neurological conditions. This approach is essentially compensatory, but the size of the effect is large, and therefore may be worth using even in an environment in which the brain is still being attacked by the underlying pathology of neurodegenerative conditions.

The molecule, DDL-920, works differently from recent FDA-approved drugs for Alzheimer's disease such as lecanemab and aducanumab, which remove harmful plaque that accumulates in the brains of Alzheimer's disease patients. While removing this plaque has been shown to slow the rate of cognitive decline, it does not restore the memory and cognitive impairments. "They leave behind a brain that is maybe without plaque, but all the pathological alterations in the circuits and the mechanisms in the neurons are not corrected."

Similar to a traffic signal, the brain fires off electric signals at different rhythms to start and stop various functions. Gamma oscillations are some of the highest-frequency rhythms and have been shown to orchestrate brain circuits underlying cognitive processes and working memory - the type of memory used to remember a phone number. Patients with early Alzheimer's disease symptoms such as mild cognitive impairment have been shown to have reduced gamma oscillations.

Researchers thought that perhaps there was a way to trigger these electrical rhythms from inside cells using a molecule. Specifically, they needed a compound to target certain fast-firing neurons, known as the paravalbumin interneurons, that are critical in generating gamma oscillations and therefore memory and cognitive functions. However, certain chemical receptors in these neurons that respond to the chemical messenger known as GABA work like brake pedals to reduce the gamma oscillations entrained by these neurons. Researchers identified the compound DDL-920 to antagonize these receptors, allowing the neurons to sustain more powerful gamma oscillations.

Alzheimer's disease model mice and wild-type mice underwent baseline cognitive testing in a Barnes maze - a circular platform surrounded by visual clues and containing one escape hole. The maze is used to measure how well rodents can learn and remember the location of the escape hole. After the initial tests, researchers orally administered DDL-920 to the Alzheimer's model mice twice daily for two weeks. Following treatment, the Alzheimer's disease model mice were able to recall the escape hole in the maze at similar rates as the wild-type mice. Additionally, the treated mice did not display any abnormal behavior, hyperactivity, or other visible side effects over the two-week period.

Link: https://www.uclahealth.org/news/release/molecule-restores-cognition-memory-alzheimers-disease-model

The Forever Healthy Foundation is the non-profit arm of Michael Greve's efforts to advance the state of the art in the treatment of aging as a medical condition, with a particular focus on the damage repair philosophy most notably advocated by proponents of the Strategies for Engineered Negligible Senescence (SENS). SENS is an scientific outline of the forms of cell and tissue damage that cause aging, alongside a roadmap for the development of therapies to control degenerative aging by repairing that damage. SENS was first developed and advocated by Aubrey de Grey and collaborators more than 20 years ago, and continues to be influential today.

The for-profit side of Michael Greve's activities is represented by Kizoo Technology Ventures, an investment fund that focuses on the small number of biotech startups that are developing therapies that seem plausibly capable of producing actual rejuvenation, actually repairing one or more forms of molecular damage relevant to the SENS view of aging.

The two sides meet at the Rejuvenation Startup Summit events, where companies present on their ongoing work, hosted by the Forever Healthy Foundation staff. This year, the Summit was held in May in Berlin, and the usual selection of high quality projects were presented. It seems clear that the most important therapies in the treatment of aging will be those that can reverse aging by repairing the damage that causes aging. Everything else is a sideshow, small gains, a lot of light and noise but little action. The Forever Healthy Foundation is slowly releasing videos from the 2024 Rejuvenation Startup Summit; a good selection are available now to peruse, with more to come.

I tidied up the transcript for my presentation as CEO of Repair Biotechnologies, and find that below, but I encourage you to look the other presentations. There were a great many very interesting technologies on exhibit, as described in my notes on the event posted earlier this year. Presenting companies with videos now posted include: Deciduous Therapeutics, with a promising one-time senolytic modulation of the immune system; Mogling Bio, developing improved versions of CASIN, a treatment that improves stem cell function in a lasting way following one round of therapy; Revel Pharmaceuticals, building ways to clear advanced glycation end-products from tissues; Nanotics, with a clever approach to very selective, rapid, effective clearance of problem signal molecules from the bloodstream that greatly improves upon existing approaches to achieve this goal; cellvie, working on the logistics needed to make mitochondrial replacement a viable and widespread option for rejuvenation; Intervene Immune; conducting human clinical trials of a growth hormone based approach to regrow lost thymus tissue; Rubedo Life Sciences, working on prodrug approaches to senolytics to clear senescent cells; and more.

Reason presents at the Rejuvenation Startup Summit 2024

As it says on the first slide here, we have achieved significant reductions in the burden of atherosclerotic plaque in mice and we intend to continue the way we started. With respect to the current standard of care for atherosclerosis, the big problem here, the thing that I'm going to beat you over the head with for five minutes or so, is that present treatments cannot greatly, rapidly, or reliably reduce the existing burden of plaque. But we can, and that is our value proposition.

Atherosclerosis is probably going to kill you if nobody does something about it. The rupture of fatty plaque that grows in blood vessels kills 27% of us directly via heart attack or stroke - and that is in a world in which everybody who can use statins is using statins. Further, that doesn't account for the people who are killed less directly by the reduced blood flow to the heart that leads to heart failure. In short, atherosclerosis is not a good thing and is the greatest single cause of of human mortality, greater even than than cancer. The more plaque you have, the bigger the problem: looking at this great data from a 2004 Dutch study, your mortality risk is five times greater if you have five or six plaques evident in imaging than somebody who doesn't have those plaques. You will notice the mortality risk is a very large range, by the way, as the type of plaque matters greatly; how much fat is in it, how much cholesterol is stuck in that plaque, how likely is it to rupture. Either way if your cardiologist can see five plaques in your major arteries you are not in a good place. You want to do something about it, but today what can you do about it? Not an awful lot.

Let me call your attention to two meta-analysis studies as good examples - there are any number of others we could look at - in which researchers looked over several dozen studies and thousands of patients. If you look at the numbers on the right, the percent atheroma volume is the percentage of the volume of the artery that's obstructed by the plaque. We are looking for percentage change in that in that number. You want it lower, but if after 18 months of statin therapy the outcome is a range of minus 5% to plus 3%, well, that is not a great form of treatment. The standard mean difference is even worse, as it is essentially zero! So if you take statins for 18 months then your existing plaque is still going to be there at the end of the day. But the plaque is the story! It is the most important part of this, because there are large studies that show that if you can produce a 1% reduction in your percent atheroma volume - just 1% - then the the reduction in cardiovascular event risk is much bigger, on the order of 20%. But that takes 18 months or thereabouts and only a subset of patients actually achieve that outcome no matter how low their blood cholesterol. There are people taking combinations of the modern PCSK9 inhibitors and statins and despite very low LDL cholesterol levels they have existing plaque and it's going to stay there.

Why am I pointing out this 1% figure? That leads us to the next slide, to make the point that in mice we can reduce plaque cross-sectional area in the aortic root by 17% over only 6 weeks of treatment. We look at a cross-sectional area at random in the body of the aortic root plaque to get that 17% figure, and if one assumes it will hold all the way through the slices of the plaque, then this is a 17% volume reduction, not just cross-sectional area. This is a big deal! The importance here is that we can reliably achieve this in mice, and we hope to be able to do the same in humans. You might ask how we achieve this outcome in mice, and the short answer is that use a LNP-mRNA gene therapy to make cells clear out localize deposits of excess free cholesterol - and I'm sure you you understand all the words in isolation but the context would probably help a little more. Excess free cholesterol is a feature of aging, and unfortunately it is also a feature of obesity - which is one of the reasons why a lot of the consequences of obesity appear similar to those of aging. Cholesterol is transported around the the body, it isn't really made or destroyed locally, and that complex transport system breaks down in ways that give rise to localized excesses of cholesterol. That localized excess overwhelms the cell's ability to make free cholesterol safe by esterifying it or incorporating it into cell membranes or attaching it to transport particles, and that free cholesterol is toxic. It is toxic in the liver particularly because the liver is the center of cholesterol metabolism; your liver function is greatly diminished and harmed by this this excess free cholesterol.

Now unfortunately this free cholesterol is undruggable. There is no "break down the cholesterol" mechanism operating throughout the human body, or even in liver cells, that you can adjust with a small molecule. You can't bind and sequester enough free cholesterol with something like a cyclodextrin to get rid of these excesses without killing the patient first - by removing too much cholesterol from cell membranes. In particular LDL cholesterol in the bloodstream, which is the target of lipid lowering therapies such as statins, has a tenuous relationship at best with a localized excess of cholesterol that might occur at some place in your body. You can lower LDL cholesterol in the bloodstream as much as you like and it won't really do that much to a localized excess of cholesterol.

That said there are human proteins that can act in conjunction to degrade excess free cholesterol. These proteins are just not expressed together in near all cells in our body. We took the best of these proteins, turned them into an optimized fusion protein, encoded that fusion protein in messenger RNA, and put the messenger RNA into a lipid nanoparticle that is targeted to the liver. We introduce the therapy via intravenous injection, it travels to the liver, it expresses our fusion protein in liver cells, and that clears out the excess free cholesterol in the liver. The liver is thereby restored to homeostasis and the result is systemic benefits throughout the body via removal of this age-related and obesity-related contribution to disease and dysfunction. It is not just atherosclerosis that is affected, but many other conditions as well.

We are heading in the direction of our our first human trials and our focus is on the rare genetic disease of homozygous familial hypercholesterolemia - that I will refer to HoFH from now on for the obvious reason that it is hard to say repeatedly. HoFH patients have enormous blood cholesterol levels, and over a lifetime that means that they exhibit accelerated atherosclerosis. Absent any sort of intervention these people die in their 30s - they are not not in good shape. There are very few HoFH patients, and this rare disease status means that the barriers are lower for FDA approval, and potentially fast track approval. This slide shows our timeline to clinical trials; note that I'm including our non-human primate studies in because I'm going to make a point about those in a moment. By late 2025 we are going to have efficacy data in a high fat diet model in cynomolgus macaques, but that runs in parallel with getting ready for the first clinical trial for HoFH in early 2026. Of course questions of time are essentially questions of money - all of this depends on raising a series A round this year, enabling licensing, GMP manufacture with a CDMO, IND-enabling studies, and all the rest of it. Everything is lined up, it just needs the funding and off we go. This timeline is 18 months to the IND submission, and you might feel that this is a long time - but this is in fact very fast in the world of biotech, as I'm sure many of you are aware.

But coming back to the non-human primate studies, here is why I wanted to mention our work there. It is an interesting aside there's a company called Verve Therapeutics, you might have heard of them because they recently ran into trouble with one of their clinical trials, but back in 2021 they were riding high because they had just gone public at a something approaching a $1 billion dollar valuation. At that time, the only data they had was in non-human primates. They had not conducted human trials at that point, and our therapy is objectively better than theirs - which is just a better a better statin, in brief. It lowers LDL cholesterol, and thus cannot possibly reverse plaque, just as is the case for all of the other LDL lowering technologies. As I said, we will be in this position about 15 months from now with a much better therapy, which is hopefully food for thought for those who might be thinking about investing in us.

I should say that while you know that atherosclerosis is why we are running this program, the starting point, it is not where we will will stop. This is a first-in-class therapy that's going to spawn half an industry's worth of further effort, research groups and companies tackling the many age-related conditions that are aggravated by free cholesterol pathology. This really should be a hallmark of aging, and I'm sure that as the hallmarks expand somebody will add it. We have demonstrated that we can reverse the liver fibrosis of metabolic dysfunction-associated steatohepatitis (MASH). We have also demonstrated over the course of that preclinical work that this form of therapy is likely relevant to type 2 diabetes as well, as we have demonstrated improved glucose tolerance and insulin levels following clearance of excess free cholesterol from the liver. Further, there are numerous neurodegenerative conditions in which the lipid metabolism of the brain is relevant. Patients and models exhibit cells with lipid droplets in the brain; there is clearly something going wrong in there, and we believe that excess cholesterol is probably relevant. Similarly I can point out a range of evidence in the cancer field, in immunology, in a number of other rare diseases, in which cholesterol metabolism runs off the rails in some part of the body, and where a therapy like ours could treat these conditions. This work will obviously be undertaken by an industry that will come after us, not by us - atherosclerosis is a very big problem in and of itself, but there is an even bigger pipeline here.

In the remaining 10 minutes I'm going to take you through a very brief tour of our results in atherosclerotic mice. This is the high level only, we have much more data, but the most important data is of course what happens to the plaque. We'll start with a really great picture of serum samples from a time series study. These LDLR-knockout mice are the model for HoFH, the human patients also have loss of function in the LDLR gene, meaning the liver can't take up cholesterol so the blood is filled with gunk: lots of cholesterol, lots of triglycerides. As the picture shows, when you pull serum from these mice it is actually opaque because it has so much so much stuff in there, unlike normal serum which is clear. In this time series study we injected the mice once with our therapy, and then sacrificed them at various time points afterwards. You can see that by 96 hours, a single injection of our of our therapy has essentially reversed the problem in the serum. The serum is back to being clear; we've removed the gunk, and that contributes to an impressive effect on the plaque.

Next up is the data showing 17% aortic root plaque reversal that I mentioned earlier. Just to fill in the details here, we took LDLR knockout mice and placed them on the a high fat diet for 16 weeks to make them severely atherosclerotic, and then gave them six weeks of weekly injections with our LNP-mRNA therapy. We used a very broad range of doses, from 0.25 mg/kg to 1.50 mg/kg. Those who know the mRNA space will know you you won't go far wrong by picking something between 0.5 mg/kg and 1.0 mg/kg - many therapies seem to resolve to that dose in the end, and perhaps there is some universal reason for that. In any case, we picked a range of doses and they all worked to reduce plaque, and when averaging across the groups we see the 17% reduction in plaque cross-sectional area. By the way, there is nothing stopping us from extending these study timelines - waiting a few weeks and introducing another six weeks of therapy with these mice. We haven't done that yet but in principle we should observe a greater regression of plaque.

Looking at further data, we took the mice and put them on a treadmill at study close, prior to sacrifice. Bear in mind that these are not mice that will win any prizes for exercise capacity because they are fat and sedentary, but all of the treated mice, at whatever dose, regained cardiovascular function to a very sizable degree versus the mice who were still impeded by the severe atherosclerosis that they were suffering. I want you to note that this is a very broad therapeutic window, with no side effects and yet benefits were observed at all doses tried.

Now we'll move over to the APOE knockout mice which are another accepted model for atherosclerosis in the general population. We conducted a study in which we compared our therapy with a statin. It starts the same way as before, put the mice on a lengthy high fat diet and then provide them with six weeks of treatment. In this case it was a single LNP-mRNA dose at 1.0 mg/kg alongside a reasonable 5.0 mg/kg daily dose of atorvastatin, a dosing level that will not provoke liver problems in the mice but should still provide a visible effect size on lipid metabolism. As the data shows, our therapy is not only much better than statins, but also synergizes with statins. It is important to note that all other treatments are complementary to ours, be that the Cyclarity approach, or statins, or PCSK9 inhibitors - they can all be used in conjunction. It is an enormous industry, there is room for everybody. Again, this six week treatment could be repeated. In principle you can keep going. You could take a break and conduct the treatment again for 6 weeks, and we would expect larger results on plaque composition and size.

An important point is we're not just removing lipids from the plaques and thereby stabilizing them, but we're also increasing the collagen content of the plaques. The lipids are effectively being replaced by collagen, and thus the result is a more fibrotic plaque which is stable and safer. Further, we're not replacing lipids with calcium - the plaque is not becoming calcified. I'm not going to present data on that topic, but I will say that in these models we do see a reversal of calcification in these plaques. You should probably take that with the grain of salt given that LDLR and APOE knockout models are not specifically models of calcification - if you put 100 of these mice on a lengthy high fat diet, you will maybe see 10 or 20 that have that exhibit a large degree of calcification in their plaques, not really enough to robustly draw conclusions.

I'll finish up by mentioning our team I think most of you know Bill Cherman and I, the co-founders. We come from a mixed investment and patient advocacy background in the longevity community. Morad Topors is a tremendously talented researcher who is here today so you should take the chance to talk to him - he has a very good background in cardiometabolic disease and is probably the world's leading expert at this point on clearing cholesterol for therapeutic effect. Bobby Khan, our CMO, is a very reputable, very well-known cardiovascular physician who has put drugs through the FDA and gives us good advice on our forthcoming forthcoming clinical program. Of course I really should mention that none of this would be possible without our very talented lab team, who in this picture are standing outside one of the two restaurants in Syracuse, New York that you have to go to if you go to Syracuse, New York. Now you know! If you're there go to this restaurant. Collectively this is now the world brain trust on clearing cholesterol for therapeutic effect, as that this program is only being conducted by us - nobody else has this, nobody else owns this, nobody else is working on this. We are the first-in-class approach to reversing cardiovascular disease.

Reprogramming is the process by which germline cells transform into embryonic stem cells of the early embryo, along the way resetting their epigenetic pattern from aged to youthful. This transformation is driven by the expression of the Yamanaka factors, Oct4, Sox2, Klf4, and c-Myc, or OSKM. In contrast, partial reprogramming involves exposing cells to the Yamanaka factors for long enough to provoke epigenetic rejuvenation, but not so long as to produce a change of state of somatic cells into what are known as induced pluripotent stem cells. Much of the early work on the implementation of partial reprogramming as a therapy is focused on the central nervous system. The results in mice are promising, but a long road remains in the matter of how to ensure the safety of reprogramming when used in human patients, the balancing act of avoiding the inadvertent generation of pluripotent cells while still generating enough epigenetic rejuvenation to be useful.

Age-associated neurodegenerative disorders represent significant challenges due to progressive neuronal decline and limited treatments. In aged mice, partial reprogramming, characterized by pulsed expression of reprogramming factors, has shown promise in improving function in various tissues, but its impact on the aging brain remains poorly understood. Here we investigated the impact of in vivo partial reprogramming on mature neurons in the dentate gyrus of young and aged mice.

Using two different approaches - a neuron-specific transgenic reprogrammable mouse model and neuron-specific targeted lentiviral delivery of OSKM reprogramming factors - we demonstrated that in vivo partial reprogramming of mature neurons in the dentate gyrus, a neurogenic niche in the adult mouse brain, can influence animal behavior, and ameliorate age-related decline in memory and learning. These findings underscore the potential of in vivo partial reprogramming as an important therapeutic intervention to rejuvenate the neurogenic niche and ameliorate cognitive decline associated with aging or neurodegeneration.

Link: https://doi.org/10.1101/2024.07.24.604939

The microbial populations of the gut are influential on health. The balance of these populations changes with age in harmful ways. The fungal component of the gut microbiome can be called the gut mycobiome, distinct from the many bacterial species that are usually the focus of research, but still interacting with the host and still potentially important. It has already been demonstrated that differences in the gut microbiome are exhibited in patients with a number of age-related conditions, such as Alzheimer's disease. Here, researchers show that the population of fungal species in the gut, the mycobiome, is notably different in long-lived individuals. The purpose of all of this research is to find reliable ways to alter the aged gut microbiome to improve health, building upon techniques such as delivery of probiotics in large amounts or fecal microbiota transplantation from young individuals.

Long-lived individuals have been extensively studied as a model to investigate the role of the gut microbiota in aging, but their gut fungi remain almost unexplored. Here, we recruited a community-dwelling cohort of 251 participants (24-108 years, including 47 centenarians) from Guangxi in China to characterize the gut mycobiome signatures. We found gut mycobiome markedly varied during aging and determined aging as a predominant factor driving these variations. For long-lived individuals, core taxa, including Penicillium and Aspergillus, were maintained and Candida enterotype was enriched when compared with old counterparts.

Individuals with this enterotype were more likely to possess Bacteroides enterotype enriched in young and centenarians. Moreover, the drivers from Candida enterotype were positively linked with the bacteria components dominated in Bacteroides enterotype. We also identified potentially beneficial yeasts-enriched features to differentiate long-lived individuals from others. Our findings suggest that the gut mycobiome develops with aging, and long-lived individuals possess unique fungal signatures.

Link: https://doi.org/10.1016/j.isci.2024.110412

Klotho is one of the few longevity-associated proteins that works in both directions: in animal models less of it than usual means worse health and a shorter live, more of it than usual means better health and a longer life. In humans researchers have observed correlations between klotho expression and late-life health. Klotho has a number of forms, the important one of which is α-klotho. α-klotho localizes to the cell membrane, where part is cut off to form the circulating α-klotho protein. This circulating protein appears to produce broad benefits via its interaction with cell receptors, including protection of kidney function and enhanced cognitive function.

Klotho is a great example of just how long it takes to figure out the biochemistry for one protein and its immediate interactions. The work is far from done, nearly 20 years since the effects on longevity were first discovered and published. How α-klotho works to produce improved tissue function is only understood in a very sketchy form, and there is every possibility that important aspects remain unknown. This is the case despite the fact that α-klotho is a topic of great interest, with many researchers working on it. For proteins that don't have this level of interest, little progress is made on similar time frames. So very much of cellular metabolism remains unknown at the detail level.

Today's open access paper on the relationship between AMPK and α-klotho is interesting because it has already been demonstrated that klotho expression increases AMPK expression. Thus there exists a bidirectional regulation between the two proteins and their effects on all of the processes that they subsequently influence. AMPK is one of the all-too-many proteins that appears to play a role in regulating all of the interesting core cellular processes relating to growth, regeneration, and maintenance. AMPK has long been a target of interest for researchers because it appears critical in the machinery responsible for the beneficial reactions to exercise and calorie restriction.

AMP-dependent kinase stimulates the expression of αKlotho

Renal transmembrane protein αKlotho has several important functions. On the one hand, it serves as a co-receptor for phosphaturic hormone fibroblast growth factor 23 (FGF23), which is mainly produced in bone. On the other hand, enzymatic cleavage of transmembrane αKlotho results in an extracellular form, called soluble Klotho (sKL), which exerts endocrine and paracrine effects in several tissues and organs. FGF23 exerts further effects in other organs including heart and is correlated with outcomes in kidney and cardiovascular disease.

The joint action of FGF23 and αKlotho in the kidney is pivotal for phosphate and vitamin D metabolism. Lack of either FGF23 or αKlotho results in massive phosphate and active vitamin D excess in mice, causing a phenotype of rapid aging with a plethora of aging-associated diseases that are reminiscent of human aging and affect almost all tissues and organs. Conversely, overexpression of αKlotho has powerful antiaging effects, expanding the life span by about 30% in mice. αKlotho has also been demonstrated to be highly beneficial in several acute and chronic disorders. Further putatively health-promoting effects of αKlotho may include the reduction in oxidative stress or anti-inflammatory effects to name a few.

AMP-dependent kinase (AMPK) is basically expressed in all cell types and consists of three subunits, α, β, γ. Physiologically, it is activated by increase in cellular AMP concentration, indicating lack of ATP and hence energy deficiency. In rough summary, AMPK reduces cellular processes consuming energy and induces pathways providing energy. Higher AMPK activity is associated with some remarkable health benefits. These may include the protection of the heart during ischemia, the reduction of microvascular disease in diabetes, or nephroprotection in insulin resistance. These beneficial effects are largely attributed to improvements in cell metabolism or stimulation of autophagy.

Given that both αKlotho and AMPK have beneficial effects in similar organs, we studied whether AMPK regulates αKlotho gene expression in Madin-Darby canine kidney cells, normal rat kidney 52E cells, and human kidney 2 cells. We measured αKlotho expression upon pharmacological manipulation or siRNA-mediated knockdown of AMPKα. AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) enhanced αKlotho expression, an effect reduced in the presence of AMPK inhibitor compound C or siRNA targeting AMPK catalytic subunits. Similarly, AMPK activators metformin and phenformin upregulated αKlotho transcripts. Taken together, our results suggest that AMPK is a powerful inducer of αKlotho and could thereby contribute to the development of future therapeutic interventions.

One of the noteworthy discoveries of recent years in the ongoing development of aging clocks was that there are sizable differences in epigenetic age when measured between different subtypes of immune cell in a blood sample. This is an important source of measure to measure variability. This has already led some assay providers, such as TruDiagnostic, to implement measures of "intrinsic epigenetic age" that just pick out the more invariant epigenetic marks or cell populations. Here, researchers put forward a modified clock built on the same principles of avoidance, the IntrinClock, that produces the same results from a blood sample regardless of immune cell subtype, and thus doesn't suffer from this problem. It seems plausible that something along these lines will have to be incorporated into present efforts to standardize to one aging clock.

Epigenetic clocks are age predictors that use machine-learning models trained on DNA CpG methylation values to predict chronological or biological age. Increases in predicted epigenetic age relative to chronological age (epigenetic age acceleration) are connected to aging-associated pathologies, and changes in epigenetic age are linked to canonical aging hallmarks. However, epigenetic clocks rely on training data from bulk tissues whose cellular composition changes with age.

Here, we found that human naive CD8+ T cells, which decrease in frequency during aging, exhibit an epigenetic age 15-20 years younger than effector memory CD8+ T cells from the same individual. Importantly, homogenous naive T cells isolated from individuals of different ages show a progressive increase in epigenetic age, indicating that current epigenetic clocks measure two independent variables, aging and immune cell composition. To isolate the age-associated cell intrinsic changes, we created an epigenetic clock, the IntrinClock, that did not change among 10 immune cell types tested. IntrinClock shows a robust predicted epigenetic age increase in a model of replicative senescence in vitro and age reversal during OSKM-mediated reprogramming.

Link: https://doi.org/10.1038/s42003-024-06609-4

Sepsis is an age-related problem, as the progressive incapacity of the immune system makes it ever more likely that an initiating infection can spiral out of control in this way. Sepsis can attack the kidney on the way to killing the patient. The paper here is focused on one particular fungal dietary supplement used in cases of acute kidney injury, but might be taken more generally as a look at the way in which improved mitochondrial function and adjustment of macrophage polarization towards a pro-regenerative phenotype are the mechanisms by which any protective (rather than pathogen-targeted) therapy should act in the case of sepsis-induced kidney dysfunction.

Sepsis-associated acute kidney injury (S-AKI) is among the most serious and common complications of sepsis. Although S-AKI has attracted widespread attention, the detailed pathophysiological mechanisms of S-AKI remain complicated and poorly understood. Extensive studies have reported various abnormal physiological processes in S-AKI, including impaired energy metabolism, excess oxidative stress, apoptosis and necrosis of renal tubular epithelial cells, impaired renal microcirculation, activation of inflammatory cells, and inflammatory storms. Moreover, because the kidneys are among the most energy-demanding organs in the body, energy metabolism is crucial for proper renal function.

Mitochondrial damage and dysfunction are highly involved in tubular cell injury or death in acute kidney injury. Therefore, maintaining the structural and functional integrity of the mitochondria may prevent tubular cell apoptosis, thereby facilitating renal recovery from acute kidney injury. Furthermore, the macrophage polarization state and production of inflammatory mediators markedly affect the progression of S-AKI. For example, the release of pro-inflammatory cytokines or excessive oxidative stress from M1 macrophages can exacerbate renal injury. Moreover, M2 macrophages releasing anti-inflammatory factors and growth factors have protective effects against kidney damage. Accordingly, renal mitochondria and macrophage polarization may be promising targets for the prevention and mitigation of S-AKI.

Cordyceps sinensis (CS) is a fungus with a long history of use in traditional Chinese medicine, owing to its anti-aging and anti-cancer properties. The active ingredients of CS include cordycepin, polysaccharides, sterols, and phenolic compounds. Because of its broad physiological effects, including antioxidant, anti-fibrotic, and anti-inflammatory activity, CS has been generally used for renal protection. In the present study, we first evaluated the protective and therapeutic effects of CS against LPS-induced AKI in mice via assays including histopathological staining, serum renal function indexes, and inflammatory cytokine analyses. We performed transcriptomic and proteomic assays on kidney tissues, revealing the molecular targets and pathways through which CS ameliorates S-AKI. We confirmed that CS protects the kidneys against S-AKI by synergistically reprogramming mitochondrial energy metabolism and macrophage polarization.

Link: https://doi.org/10.15212/AMM-2024-0018

I recently noticed an academic conference report covering the Longevity Med Summit held last year in Portugal. More organizers should put out commentary papers after the event; the only downside is that it takes far too long to move from writing to publication, as illustrated by the year-long delay here. It is good to see more events held in Europe these days, and more conferences setting out to explore a different part of the sizable space of research, industry, and clinics. I'm not going to comment on the conference series, but rather use it as an opportunity to note that all too much of the longevity field is focused on initiatives that are unlikely to make all that much difference.

Most companies develop small molecule drugs. Most small molecule drugs developed to target aging are in some way manipulating metabolism to slow aging, or compensate for some specific effect of aging. Most have most modest effect sizes, and only capture a small fraction of the results of the mutations or gene therapies that inspired them. Small molecule development has the advantages of being well-understood, involves lower costs, and offers a good amount of drug repurposing opportunities (again, lower costs), among others. It has the glaring disadvantage of turning out drugs that only modestly affect the target issue. The ever-more-costly machinery of the FDA spends most of its time attempting to tell the difference between marginally beneficial small molecules and useless small molecules.

Are we really all supporting this process of developing a longevity industry in order to call it a success to take an existing drug and repurpose it to gain a couple of years of additional life expectancy? That doesn't really change the big picture at all. It doesn't put a meaningful dent in the fundamental problem, that we are aging and dying. Yet it seems we might be doing just this, given the behavior of many of those involved. Setting aside the present fervor for reprogramming, the investment in marginal small molecule therapies - and number of companies involved in that work - outweighs the lesser number of groups working on potentially impressive approaches such as mitochondrial transplantation and advanced senolytics.

The Longevity Med Summit: insights on healthspan from cell to society

Translation of academic findings into practical applications within industry and clinical context is of the utmost importance within the field of longevity. The hallmarks of ageing have played a key role in paving the way for providing mechanisms for therapeutics to target and modify them for lowering biological age and enhancing longevity, attracting interest from academia, industry, and investors. Several speakers presented various data on the pharmacological and nutraceutical interventions currently under investigation in clinical trials, or in the pipeline.

Metformin and rapamycin, and its analogues (rapalogs), are among the most extensively studied longevity compounds, targeting AMPK and mTOR, respectively, as discussed by multiple speakers. Repurposing existing drugs has shown promise in combating ageing. These compounds exhibit a range of beneficial effects, including immunomodulation and alteration of cellular metabolism mechanisms, in both in vitro and in vivo models of healthy ageing. However, for their prescription solely for longevity purposes, further research is warranted to determine appropriate dosages and potential impacts on other bodily systems.

In addition to repurposing existing drugs, there are ongoing efforts to identify novel compounds and devise effective therapeutic regimes using machine learning and network pharmacology. Longevity and ageing research has necessitated a shift in disease research from reductionist to systems theory. Joao Pedro Magalhaes (University of Birmingham) discussed his research and the emergence of network pharmacology and in silico models, incorporating various disciplines such as systems biology, genomics, and proteomics, among others. By examining drug-network interactions through omics data analysis and network database retrieval, network pharmacology provides comprehensive insights into drug mechanisms and efficacy, making it particularly suitable for investigating longevity therapeutics.

A growing array of supplements, such as NAD+ and its precursors for cellular energy, calorie restriction mimetics for fasting-like effects, and other bioactives and nutraceuticals, are being explored for their potential anti-ageing benefits. These compounds target specific pathways or provide broad antioxidant and anti-inflammatory properties, which can alleviate age-related damage and promote overall health. Despite being promoted by numerous commercial entities, clinicians may exhibit hesitancy due to less stringent regulatory processes.

At the cellular level, senolytics are a class of drugs that aim to interfere with senescent cells. Several speakers outlined the process of cellular senescence and its contribution to unhealthy ageing via mechanisms including disrupting tissue functionality and limiting the regenerative potential of adult stem cells. The accumulation of senescent cells leads to an increase in biological age and increases the risk of disease. Senolytics hold promise in eliminating senescent cells, and in model organisms, they have shown potential to extend lifespan, enhance healthspan, and treat or even reverse age-related diseases.

Advancing to the systemic level, dysbiosis and chronic inflammation, recently recognised hallmarks of ageing, are interconnected and responsive to dietary interventions, as elucidated by Richard Siow (King's College London). Bioactive compounds in whole foods, potentially acting synergistically to mitigate age-related changes and enhance vitality pathways, are currently being investigated by commercial entities to isolate and validate them in vivo. Siow also emphasised the significant impact of dietary choices on rates of functional decline. With the emergence of longevity nutrition frontiers such as nutrigenomics, personalised nutritional regimens tailored to individuals' genetic profiles are now feasible, enhancing the effectiveness of interventions.

To promote longevity and lower biological age, pharmaceuticals, nutraceutical supplements, and other interventions should be considered as part of a comprehensive anti-ageing regimen that incorporates other complementary protocols. These may include adopting a healthful diet, engaging in regular exercise and resistance training, practising intermittent fasting, managing stress effectively, and optimising sleep patterns.

In mammals, females have two X chromosomes while males have one X chromosome and one Y chromosome. Other, lower species can and do have other differences in chromosomal DNA between the sexes. It is known that mammalian females typically live longer than males, but are the various aspects of this slowed aging driven by the presence of female gonads and hormonal signaling or by the presence of the additional X chromosome? There has been some discussion as to whether having only one X chromosome magnifies the effects of stochastic mutational damage, for example. To gain insight into this sort of question, researchers have engineered mice that mix and match male and female chromosomes versus male and female gonads. The research here is an example of what one can do given these animal models.

True sex differences exist in aging. Women live longer than men around the world; they also show resilience to cognitive decline and higher baseline function in typical aging in many populations, when dementia and its subsequent development are carefully excluded. Since cognition is a key manifestation of brain function eroded by aging, understanding sex differences and their causes are high value areas of investigation.

Whether female mice show better cognition in typical aging - and whether sex chromosomes or gonads influence sex difference in cognitive aging - remain largely unknown. To examine this, we utilized genetic mouse models of sex biology. The Four Core Genotype (FCG) model tests whether gonads or sex chromosomes contribute to a sex difference. The XY* model tests whether the X or Y chromosome contributes. We tested for cognitive aging and any accompanying sex differences in young and aged mice using the two-trial Y maze paradigm which measures spatial and working memory, a target of aging. As expected, aging decreased cognition in both sexes. While no sex differences were observed in young mice, female sex attenuated age-induced cognitive decline.

Link: https://doi.org/10.1101/2024.07.26.605328

An aging clock can be produced via machine learning from any sufficiently large set of biological data that changes with age. Researchers are creating a great many different aging clocks these days, even as there are efforts to standardize to a few generally accepted clocks. The push for standardization is conducted in order to better direct resources in the scientific community to passing the remaining hurdles that prevent clocks from being used to quantify the effectiveness of potential rejuvenation and age-slowing therapies. In principle the assembly of enough mouse and human data coupled with calibration studies for specific interventions could achieve this result for a large fraction of present research and development - but efforts applied to one clock are largely irrelevant to all of the others, so having a panoply of clocks and no consensus on the best is a hindrance.

Reactivation of retroelements in the human genome has been linked to aging. However, whether the epigenetic state of specific retroelements can predict chronological age remains unknown. We provide evidence that locus-specific retroelement DNA methylation can be used to create retroelement-based epigenetic clocks that accurately measure chronological age in the immune system, across human tissues, and pan-mammalian species.

We also developed a highly accurate retroelement epigenetic clock compatible with EPICv.2.0 data that was constructed from CpGs that did not overlap with existing first- and second-generation epigenetic clocks, suggesting a unique signal for epigenetic clocks not previously captured. We found retroelement-based epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV-1, and responsive to antiretroviral therapy. Our findings highlight the utility of retroelement-based biomarkers of aging and support a renewed emphasis on the role of retroelements in geroscience.

Link: https://doi.org/10.1111/acel.14288

Many species of bats depend absolutely upon hearing; without effective echolocation they cannot hunt prey or navigate. It is reasonable to suspect that evolution may have selected for resilience in hearing function in this species, whereas those mammals less dependent on hearing for survival, such as our own species, are stuck with an age-related decline in sensory hair cells of the inner ear and their connections to the brain. Is this the case, however? Someone has to do the legwork to find out. In today's open access paper, researchers pick a bat species and capture specimens in the wild to run epigenetic age and auditory function tests.

As is the case for any comparative biology of aging study, determining that a species is unusually resilient to aging in some way is just the first step on a long road. It is already well known that bats have an unusual metabolism in comparison to other mammals as a result of the energy demands of flight. Many bat species are exceptionally long-lived for their size, resistant to some of the damaging processes of aging. Given a specific finding such as a lack of age-related decline in hearing, researchers must then identify the meaningful biochemical differences in affected cell populations and tissues. That is a slow and expensive proposition. Following that comes the even harder exercise: how does one turn this knowledge into a viable therapy for humans? The field as a whole has yet to come to the point of successfully mining the biochemistry of a resilient species and building a therapy based upon an important identified difference.

Resistance to age-related hearing loss in the echolocating big brown bat (Eptesicus fuscus)

Hearing is essential for echolocating bats that rely extensively on their auditory systems to forage, navigate, and avoid obstacles. The evolution of echolocation in bats has been correlated with adaptations at all levels of auditory processing to enable active acoustic sensing of complex and dynamic environments. Consequently, echolocating species are exposed to intense self-generated sounds. Further, many species form high-density aggregations, where sonar sounds emitted by other individuals may be potentially damaging to the cochlea. The critical role of hearing in the fitness and survival of echolocating bats suggests that the evolution of this active sensing system may have introduced selective pressures to protect the auditory system from damage over a lifetime of exposure to sound.

The aging auditory system in most mammals shows a progressive loss of hearing sensitivity that begins with high-frequency deficits and extends to low frequencies over time. Although the etiology of age-related hearing loss (ARHL) is highly variable, depending on genetic, epigenetic, and environmental factors, its onset is generally correlated with senescent changes to the peripheral structures of the auditory system, including loss of inner and outer hair cells, loss of ribbon synapses and retraction of auditory nerve fibers (i.e., cochlear synaptopathy), and deterioration of the stria vascularis. The molecular mechanisms underlying ARHL are hypothesized to result from inter-related metabolic and physiological changes over the lifespan that lead to the accumulation of reactive oxygen species and increase susceptibility to cellular dysfunction.

We hypothesize that echolocation imposes selective pressures to preserve hearing function across the lifespan, especially in species that require echolocation-based active sensing for prey capture. Although bats are not immune to hearing loss, and indeed, some species appear vulnerable to ARHL, recent evidence indicates that species differences in echolocation behaviors may correlate with differential susceptibility to hearing loss. For example, echolocating bat species have shown evidence for resistance to noise-induced cochlear hair cell damage whereas non-echolocating visually dominant species were susceptible to acoustic overexposure and showed levels of hair cell loss comparable to that observed in mice.

In this study, we used DNA methylation to estimate the ages of wild-caught big brown bats (Eptesicus fuscus) and measured hearing sensitivity in young and aging bats using auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We found no evidence for hearing deficits in aging bats, demonstrated by comparable thresholds and similar ABR wave and DPOAE amplitudes across age groups. We additionally found no significant histological evidence for cochlear aging, with similar hair cell counts, afferent, and efferent innervation patterns in young and aging bats. Here we demonstrate that big brown bats show minimal evidence for age-related loss of peripheral hearing sensitivity and therefore represent informative models for investigating mechanisms that may preserve hearing function over a long lifetime.

The research noted here is interesting given the present impression of folate as a generally beneficial supplement. Like most aspects of the interaction between diet and cellular biochemistry, matters turn out to be more complex and situational. Nothing is simple! As it turns out, reduced folate in older animals reduces anabolic activity, and thus may be touching on some of the same mechanisms that produce benefits to health in response to a lower calorie intake.

Folate, or vitamin B9, is an essential dietary component used in the body to form red blood cells, as well as DNA, RNA, and proteins. It is especially vital for children, young adults and pregnant women because of its role in growth processes. Researchers wanted to explore its impact in lesser studied age groups. To simulate the effects in older adults, the researchers cut folate from the diets of animal models at an age corresponding roughly to human middle-age. A comparison group was raised the same but continued a typical diet inclusive of folate.

The researchers found the female folate-limited models were able to transition quicker between carbohydrate metabolism and fat metabolism across night and day compared to females on a typical diet. "When you sleep, your metabolism burns fat. And when you're awake and active, you're typically burning carbohydrates for quicker energy. As you get older, it takes longer to switch between these fat-burning and carbohydrate-burning states, but this metabolic plasticity seems to be better maintained in animal models on a folate-limited diet." The males on folate-limited diets had an overall increase in their metabolic rate during active periods, potentially helping them to maintain energy levels and physical activity. The folate-limited group maintained their weight and body fat into old age as opposed to the control group.

The research team began this work a few years ago by using methotrexate to reduce folate intake in yeast cells, then in the worm C. elegans. In both cases, cutting folate led the models to live longer. Looking forward, the team's next step will be to repeat the experiment in more genetically diverse models, simulating the genetic diversity of humans. The researchers will also expand their study of novel compounds to limit folate intake, which could later transition to clinical trials.

In 1998, the U.S. mandated that staple foods, particularly grains, be "enriched" or "fortified" with folic acid and other B vitamins following the refinement process. While helpful for some age groups, it might do more harm than good for older adults. As a result, this research opens a new avenue for developing drugs to limit dietary folate uptake for individuals who don't need as much, rather than cutting foods that contain folate or folic acid.

Link: https://agrilifetoday.tamu.edu/2024/08/01/reduction-in-folate-linked-to-healthier-aging-in-animal-models/

Parkinson's disease is driven by the spread of misfolded α-synuclein through the nervous system and brain. This is one of the few proteins in the body that can become altered in a way that causes other molecules of the same protein to also become altered, leading to solid aggregates and a surrounding biochemistry that is harmful to neurons. As misfolded α-synuclein moves from neuron to neuron, its spread causes disease symptoms. One option for treatment is to suppress the expression of α-synuclein, which slows progression of the altered form. While this seems a worse option in comparison to aiming at selective clearance of altered α-synuclein, there are many established approaches that might be used to downregulate the expression of a specific protein. The easier development path is often chosen, even given that it will lead to inferior therapies.

Antisense oligonucleotides (ASOs) are compounds that can be engineered to induce the target mRNA-specific degradation, which in turn decreases the levels of its corresponding protein. Even though they are not the only drugs that can control the expression of α-synuclein, ASOs have a crucial advantage over other approaches. "Currently, antibody drugs and vaccines targeting α-synuclein are under development, but their effects may not prevent the disease from progressing inside cells. In contrast, nucleic acid drugs like ASOs that specifically control intracellular levels of normal α-synuclein could offer higher safety and efficacy by both retaining the natural physiological functions of the protein while inhibiting the spread of pathogenic α-synuclein."

Considering that Parkinson's disease often emerges and then spreads out from specific regions in the brain, the researchers tested whether administering ASOs locally at diseased sites could be a sound treatment or preventive strategy. To this end, they injected ASOs directly into either the left or right striatum of mice brain and analyzed the spread of α-synuclein pathologies throughout various brain regions using the presence of Lewy body-like and Lewy neurite-like pathologies as indicators.

When ASOs were injected into the left striatum two weeks before inoculation of the mouse brain with disease-causing fibrils at the same site, a significant decrease of over 90% in Lewy pathology-like neuronal inclusion was observed. Compared to the control group, this pre-treatment effectively prevented the spread of abnormal fibrils-induced aggregate towards multiple regions of the brain. Even when ASOs were administered at the same time or even after inoculation with fibrillar α-synuclein, there was a notable inhibitory effect in the left striatum and other areas of the brain.

Link: https://www.tmd.ac.jp/english/press-release/20240607-1/

Our organs and bodily systems are all interconnected. Organ A relies on organ B in some way for many combinations of A and B and specific functions of those organs. Thus when an individual suffers from some form of age-related chronic disease, in which the function of one organ is particularly disrupted relative to all of the others, the whole body tends to suffer. This is one of the reasons why the research community observes correlations between the incidence of many different age-related diseases that occur in different organs.

As an example of this point, in today's open access paper researchers deploy epigenetic clocks to show that patients with chronic liver disease exhibit accelerated epigenetic aging in other tissues. The liver is the center of lipid metabolism in the body, and manages the blood-carried levels of many molecules that are important to the function of other organs. Separately, the liver also detoxifies a range of metabolic waste and foreign molecules that find their way into the digestive system and bloodstream. Faltering in these tasks has consequences.

Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease

Chronic liver disease (CLD) is a debilitating proinflammatory 'scarring' condition that often results in the development of age-associated comorbidities (especially physical frailty), leading to reduced quality of life and ultimately increased mortality. Increased systemic inflammation is recognized as a key driver of the aging phenotype, which increases the risk of multiple life-limiting diseases. The present study investigated whether CLD increases the rate of biological aging in skeletal muscle and in the immune system. These biological systems with known hallmark mechanisms of aging were also investigated to help explain the increased incidence of sarcopenia and reduced immunity in this patient population.

Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years). Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge, DunedinPACE, or Hannum epigenetic clocks, with no difference using the Horvath clock. The present findings provide the first evidence of increased biological aging in patients with CLD across these two biological systems utilizing epigenetic and immune phenotype-based measures. Clinically, the identification of a divergence of biological age from chronological age, or the presence of a negative aging trajectory, may highlight CLD patients at greatest risk of disease progression, allowing early therapeutic intervention, including medicines that directly modulate aging processes.

It has previously been reported that patients with CLD display hallmarks of aging, including reduced telomere length in liver tissue, hepatocytes, and leukocytes, and this telomere attrition is positively associated with mortality risk and hepatic fibrosis. In line with this, the present study identified greater epigenetic age acceleration in the skeletal muscle tissue of CLD patients, suggesting that epigenetic muscle aging may be a contributing factor to the development of muscle dysfunction, which has been reported in up to 70% of patients with CLD. Aging is also associated with a chronic increase in circulating proinflammatory cytokines and a decrease in the level of anti-inflammatory cytokines, a process referred to as 'inflammageing'.

Although the mechanisms that drive age-related epigenetic changes are not fully understood, elevated levels of circulating factors, including proinflammatory cytokines, such as TNFα, IL-6, and IL-12, may play a role in modulating epigenetic modifications of DNA. Similarly, increased adiposity, which is also strongly associated with chronic low-grade inflammation, has been reported to drive epigenetic age acceleration in other tissues, including the liver. Therefore, it is possible that alterations in circulating factors, such as increased levels of proinflammatory cytokines or ammonia following primary liver dysfunction, may drive epigenetic changes in secondary tissues, such as skeletal muscle, negatively impacting their aging trajectory. However, it will be important to elucidate key factors that drive epigenetic aging and those that become elevated secondary to age-associated changes in cellular function.

The balance of microbial populations that make up the gut microbiome is now known to change for the worse with age. Harmful inflammatory populations grow in number, while populations that produce beneficial metabolites shrink. A variety of strategies have been demonstrated to rejuvenate the gut microbiome by adjusting relative population sizes, and have produced evident benefits to health and longevity, in animal models at least. This is now widely appreciated in the research community, and many of the research groups that are focused on one specific age-related disease are presently working to understand (a) how the aging of the gut microbiome might contribute to their condition of interest, and (b) what to do about it.

Bone homeostasis in physiology depends on the balance between bone formation and resorption, and in pathology, this homeostasis is susceptible to disruption by different influences, especially under ageing condition. Gut microbiota has been recognized as a crucial factor in regulating host health. Numerous studies have demonstrated a significant association between gut microbiota and bone metabolism through host-microbiota crosstalk, and gut microbiota is even an important factor in the pathogenesis of bone metabolism-related diseases that cannot be ignored. This review explores the interplay between gut microbiota and bone metabolism.

Given the increasing recognition of the involvement of the gut microbiota in bone health, various investigations have explored the potential interventions in the gut microbiota for the treatment or prevention of bone diseases by inhibiting the inflammatory response in the senescent microenvironment or directly promoting the osteogenic process.

Probiotic therapy represents a feasible approach. Supplementation with Lactobacillus animalis has been documented to offer benefits in averting osteonecrosis of the femoral head via an extracellular vesicular mechanism. Lactobacillus helveticus HY7801 has demonstrated prophylactic and therapeutic properties in a murine arthritis model by increasing IL-10 expression in CD4+ T cells. Moreover, the administration of Bifidobacterium longum was found to suppress post-fracture weight reduction and lumbar spine bone density loss in a model of fractures in elderly female mice.

Fecal microbiota transplantation (FMT) involves transferring functional gut amicrobiota from the feces of a healthy individual into the gastrointestinal tract of a patient to restore normal intestinal function. This approach has demonstrated effectiveness in manageing systemic conditions like multiple sclerosis and cancer. While there is currently no research on the use of FMT for degenerative bone diseases, this paper highlights the substantial evidence linking intestinal dysbiosis to these conditions. Therefore, FMT has the potential to restore a healthy gut microbiota and may be a promising strategy for treating degenerative bone diseases.

Link: https://doi.org/10.3389/fendo.2024.1414350

Blood pressure is easily measured. Everyone is told by their physician and public health education materials that the high blood pressure of hypertension is a bad thing. Lifestyle change and low cost drugs can reduce blood pressure to normal levels in a majority of patients. So is hypertension a medical condition that is under control in the population at large? Apparently not. One can produce the therapies and propagate the information, but even so only a fraction of those who might benefit are in fact acting to eliminate the contributions made by hypertension to mortality and late life decline.

Uncontrolled hypertension is a major risk factor for stroke and myocardial infarction. Health providers should be aware that uncontrolled hypertension is one of the most common, serious and increasing conditions in their patients. Nationally, adults over the age of 18 include 249.2 million people of which 119.9 have hypertension. Myocardial infarction accounts for 25% of all deaths and stroke about 16.5%.

Hypertension has long been deemed "the silent killer" as most patients affected were unaware of their condition until its first presenting symptom was the myocardial infarction or stroke. Sudden cardiac death accounts for 50% of deaths from cardiovascular disease and is the first symptomatic event in ≥25% of cases. In addition, for 76% of stroke patients, the initial presenting symptom is the stroke itself.

Control of hypertension is effective and, at least in theory, is straightforward. Before the Hypertension Detection and Follow Up Program only about 50% of patients were aware of their hypertension, and of those, only 50% were actively treated. Of that group, only 50% received effective treatment. Thus, 1/8 of all patients were effectively treated. Today these figures are 54% aware of their hypertension, 40% actively treated, and 21% adequately controlled, respectively.

Link: https://doi.org/10.1016/j.amjmed.2024.07.005

Various planarian species exhibit highly proficient regeneration, capable of regrowing an entire body from fragments. This exceptional degree of regeneration is only exhibited in lower animals that lack a sophisticated nervous system. Researchers have made some inroads into identifying genes that are critical to this regenerative prowess, via the usual approach of disabling genes one by one to see what breaks in each case. A full understanding of the biochemistry involved remains a work in progress, as is true for the processes of tissue regeneration more generally.

In today's open access paper researchers report on their efforts to take a few of these planarian genes and introduce them into flies, to see if this transfer improves function in the context of age-related degeneration of tissues. We might say that fly aging is dominated by intestinal dysfunction in the same way that we'd say that human aging is dominated by cardiovascular dysfunction. It appears to be the critical path to most mortality. Therefore, researchers tend to first characterize intestinal function when investigating interventions that may affect aging in this species. Indeed, in this study researchers saw a slowing of intestinal aging as a result of the introduction of planarian regeneration-associated genes. This came at a cost, however, of disruption to the normal processes of regeneration.

Experiments in moving genes between species with an eye to effects on aging are becoming more common. As this study illustrates, researchers are still in the very early stages of this sort of work, and treat this approach as more a way to learn about gene functions rather than a viable path to therapies. Cellular biochemistry is highly complex, regeneration and tissue maintenance processes are equally complex, and changes rarely produce only one effect. Turning a foreign gene into the basis for an enhancement therapy remains an aspiration.

Highly regenerative species-specific genes improve age-associated features in the adult Drosophila midgut

While certain animals like planarians and hydras possess the remarkable ability to regenerate their entire body from a small fragment, other groups with more complex body structures, such as mammals and insects, exhibit a diminished regenerative potential and can only regenerate specific tissues and/or organs to a limited extent. Several cellular and molecular factors have been identified as determinants of regeneration capacity. Highly regenerative animals such as planarians and cnidarian polyps rely on pluripotent adult stem cells, called neoblasts and interstitial cells (i-cells), respectively. These stem cells migrate to the injury sites and contribute to the formation of a blastema, an undifferentiated cellular mass, enabling the restoration of amputated body structures. Some vertebrates like salamanders and fish, which do not possess adult pluripotent stem cells, can regenerate organs after injury by recruiting blastema cells through dedifferentiation and/or the activation of quiescent lineage-restricted stem cells. At the molecular level, the evolutionary conserved WNT signaling pathway promotes a wide range of regenerative events across species, including blastema formation in newts and Hydra.

In contrast to the conserved regulators of regeneration, several genes are specific to highly regenerative animal groups and species. For instance, the newt gene Prod1 regulates re-patterning during limb regeneration, and viropana family (viropana 1-5) is upregulated during lens regeneration. These species/group-specific genes might explain differences in regeneration capacity between species. Remarkably, ectopic expression of viropana 1-5 can enhance regeneration of the primordium of Drosophila eyes that maintain regenerative capacity during development. This finding raises the possibility that heterologous induction of regenerative genes may accelerate tissue regeneration, at least in developing animals, and potentially provide a cue for developing novel regenerative therapies.

Notably, given that basal metazoans such as Porifera, Ctenophore, Placozoa, and Cnidaria all exhibit robust regenerative abilities, it is conceivable that a common ancestor of all metazoans once possessed a high regenerative potential and independently lost genes related to high regenerative capacity in multiple phyla. Building upon this hypothesis, bioinformatics analysis has identified genes that are common among species with high regenerative abilities and absent in species with limited regenerative capacities. The highly regenerative species-specific JmjC domain-encoding genes (HRJDs) are a group of such genes (with typically two or three orthologs per species) characterized by their JmjC domain, yet their molecular functions remain unknown. Given their potential influence on the regenerative process, HRJDs may contribute to the high regeneration potential of highly regenerative animals. With this in mind, a question arises: what would happen if a low regenerative species, which has lost HRJDs, were to acquire them again?

Here, we express HRJDs in the fruit fly Drosophila melanogaster and evaluate their impact in vivo, especially by focusing on two epithelial tissues: developing wing discs and post-developmental adult midguts, both of which exhibit regeneration potential and can replenish damaged epithelial cells. In contrast to the predicted contribution of HRJDs in regeneration as observed in planarian, ectopic HRJD induction impedes regenerative responses and decreases organismal survival upon injury in Drosophila. Surprisingly, however, HRJD expression in the stem/progenitor population of the adult midguts extends organismal lifespan under the non-regenerative condition. Further investigations reveal that HRJDs enhance the proliferative activity of intestinal stem cells while keeping their differentiation fidelity in aged guts, ameliorating age-related decline in gut barrier functions. These findings provide evidence that genes specific to highly-regenerative animals can improve stem cell function as well as increase healthy lifespan upon heterologous expression in aging animals.

This popular science article touches on some of the research indicating that the protein Reelin may be an important protective factor in the aging brain. Alzheimer's disease reduces its production, which may contribute to the neurodegeneration and dementia produced by the underlying biochemistry of protein aggregation characteristic of the condition. As is often the case, the lynchpin for the assembly of accumulated scientific evidence emerges from the examination of an individual who bears a variant form of the protein and is thus protected from much of the consequences of Alzheimer's disease pathology.

A key protein that helps assemble the brain early in life also appears to protect the organ from Alzheimer's and other diseases of aging. A trio of studies published in the past year all suggest that the protein Reelin helps maintain thinking and memory in ailing brains, though precisely how it does this remains uncertain. The studies also show that when Reelin levels fall, neurons become more vulnerable. The research has inspired efforts to develop a drug that boosts Reelin or helps it function better, as a way to stave off cognitive decline.

Reelin became something of a scientific celebrity in 2023, thanks to a study of a man who should have developed Alzheimer's in middle age but didn't. The man was part of a large family that carries a very rare gene variant known as Paisa. Family members who inherit this variant are all but certain to develop Alzheimer's in middle age. But this man, despite having the variant, remained cognitively intact into his late 60s and wasn't diagnosed with dementia until he was in his 70s. After he died at 74, an autopsy revealed that the man's brain was riddled with sticky amyloid plaques, a hallmark of Alzheimer's. Scientists also found another sign of Alzheimer's - tangled fibers called tau, which can impair neurons. But oddly, these tangles were mostly absent in a brain region called the entorhinal cortex, which is involved in memory. That's important because this region is usually one of the first to be affected by Alzheimer's

The researchers studied the man's genome. And they found something that might explain why his brain had been protected. He carried a rare variant of the gene that makes the protein Reelin. A study in mice found that the variant enhances the protein's ability to reduce tau tangles. Another team published an analysis of the brains of 427 people. It found that those who maintained higher cognitive function as they aged tended to have more of a kind of neuron that produces Reelin.

A more recent study included a highly detailed analysis of post-mortem brains from 48 people. "The neurons that are most vulnerable to Alzheimer's neurodegeneration in the entorhinal cortex, they share one feature. They highly express Reelin." In other words, Alzheimer's appears to be selectively damaging the neurons that make Reelin, the protein needed to protect the brain from disease. As a result, Reelin levels decline and the brain becomes more vulnerable. The finding dovetails with what scientists learned from the man whose brain defied Alzheimer's. He had carried a variant of the Reelin gene that seemed to make the protein more potent. So that might have offset any Reelin deficiency caused by Alzheimer's.

Link: https://www.npr.org/sections/shots-health-news/2024/07/29/g-s1-13519/alzheimers-protein-reelin-brain-aging-amyloid-tau-memory

Researchers have known for a long time that removal of germline cells extends life in nematode worms. Since this discovery, research groups have been digging into the biochemistry of this species in order to try to understand why germline loss can trigger greater longevity. Here, researchers identify some of the important signaling involved, finding that it originates in the stem cell niche that normally hosts the germline cells. Targeting this signaling with various forms of therapy might form the basis for interventions that slow aging.

Reproduction and ageing tightly interact with each other. It has been shown in various organisms that the absence of germline significantly extends lifespan. Studies in the nematode Caenorhabditis elegans indicate that the somatic gonad generates an unknown signal to trigger a complex signalling network in other tissues to promote longevity when the germline is removed. Downstream of the somatic gonad-derived signal lies a complex genetic network. For example, daf-16/FOXO controls gonadal longevity. The biosynthesis of dafachronic acids (DAs) and the subsequent activation of the nuclear hormone receptor DAF-12/FXR is another critical pathway driving gonadal longevity. Intriguingly, the gonadal longevity signalling shares components with developmental timing machinery. In particular, the DA synthesis and DAF-12 activation are initiated at the end of germline development, implying that gonadal longevity could be from a checkpoint for germline integrity.

Despite the extensive understanding of the molecules controlling ageing upon germline ablation, the longevity signal from the somatic gonad remains poorly understood. Within the germline, the somatic gonad constitutes the niche of germ cells and regulates their development. It is the germline stem cells (GSCs) but not the oocytes or sperms that influence ageing. Therefore, we hypothesize that the gonadal longevity signal originates from the somatic gonadal cells neighbouring GSCs because these cells have intensive interactions with GSCs as their niche and should be the first to sense their absence.

In this study, we found that removing worm germline disrupts the cell adhesions between GSC and its niche, the distal tip cell (DTC), causing a significant transcriptomic change in DTC through the translocation of two GATA transcription factors, elt-3 and pqm-1, and the translocation of hmp-2/β-catenin. This, in turn, extends the lifespan of worms. Moreover, we further identified the TGF-β ligand, tig-2, as the cytokine from DTC upon germline ablation, which evokes the downstream longevity pathways throughout the body. Our findings thus reveal the origin of the longevity signalling in response to germline ablation, underscoring the interaction of stem cells and their niche in metazoan ageing.

Link: https://doi.org/10.1038/s44318-024-00185-3

The portions of adult human physiology that age most rapidly are the ovaries and the thymus/ Both are targets of interest for the research community. They represent not only ways to learn more about aging, by comparing these rapidly aging organs with those that sustain function further into old age, but also an easier point of intervention, in which rejuvenating or age-slowing therapies could in principle be deployed in mid-life or earlier and still produce benefits.

In today's open access paper, the authors discuss what is known of the role of cellular senescence in ovarian aging. The important question at the end of the day is whether senolytic drugs that selectively clear senescent cells are likely to produce an impact on fertility and menopause. As the researchers note, little has been published on this topic, and one might suspect that this is because the sort of unpublished exploratory work that happens behind the scenes has so far produced results that were not that promising.

On the one hand we might think, based on the evidence to date, that senescent cells start to accumulate in earnest throughout the body only after ovarian aging is well advanced, and thus do not play a major role in the ovaries. This point can certainly be argued, and the researchers here do so, pointing out lines of evidence that suggest that senescence occurs in the ovaries somewhat in advance of the rest of the body. On the other hand, even if senescent cells are harming the ovaries earlier in life than is the case in other organs, we might think that once the damage is done, there is no regenerative process that operates to restore lost ovarian function. Thus clearance of senescent cells after losses have occurred will do little to reverse ovarian aging. But this is all very much hand-waving and theorizing. More research is needed.

The role of cellular senescence in ovarian aging

The aging process differs from tissue to tissue. The primary feature of aging in most tissues is the accumulation of senescent cells. Cellular senescence is a state of permanent cell cycle arrest triggered in response to numerous stressors, aiming to inhibit the proliferation of aged and/or damaged cells. Despite this, senescent cells are metabolically active and secrete inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases. These factors are commonly referred to as the senescence-associated secretory phenotype (SASP). The SASP allows senescent cells to modulate pathways in neighboring and distant cells and tissues and has been widely used as a marker of cellular senescence. The SASP recruits immune cells, thereby creating a pro-inflammatory microenvironment in injured or aging tissues. The chronic accumulation of senescent cells with advancing age results in detrimental effects on health, increasing age-related diseases.

There is limited data on senescence cell accumulation and their function in the ovary. Although there is no well-defined panel of biomarkers for cellular senescence, some have been widely used in the ovary, including markers of pro-inflammatory stress, double-strand DNA breaks, and lipofuscin. Corresponding with reduced ovarian function, there is also a significant increase in markers related to senescence in the ovaries of mice between 3 and 12 months of age, along with the accumulation of lipofuscin aggregates. Similar accumulation of senescent cells in other organs is observed much later in life, around 18-20 months of age. Additionally, the ovarian transcriptomic profile indicates a positive regulation of genes related to pro-inflammatory stress and cell cycle inhibition, while genes involved in cell cycle progression were negatively regulated, which is characteristic of senescent cells. Increased SA-β-Gal and p21 levels were detected in the ovarian stroma of mice at 8-10 months of age, indicating senescent cell accumulation. Thus markers of senescence in ovarian tissue can be observed before 12 months of age in mice. Similar observations were made in human tissue. Expression of p21 was elevated in ovarian of middle-aged women (older than 37 years) compared to young controls (younger than 33 years). Other senescence and fibrosis related genes were also up-regulated in stromal cells of middle aged compared to younger women.

There are few studies using senolytics in young reproductive age mice available in the literature, which suggest that the compounds currently used have few beneficial systemic benefits at this age window. Even fewer studies evaluated the effects of senolytics in the ovary. These suggest that senolytics may prevent ovarian reserve loss, but cannot reverse the damage to the ovarian reserve after senescence is established. The activation of primordial follicles is an irreversible process, which means that the damage promoted by senescent cells in the ovarian reserve would not be able to be reverted by senolytics. This may indicate the direction for future studies, focusing on preventing accumulation of senescent cells in the ovaries in order to prevent declines in fertility. Additionally, the inflammation generated by senescent cells through the SASP itself can contribute to irreversible follicular activation. Therefore, it is possible that other senolytic compounds with greater efficacy in the ovary need to be tested. Compounds with senomorphic activity, i.e. able to decrease SASP secretion, may be considered to prevent the negative pro-inflammatory environment generated by senescent cells in the ovary. Therefore, the path to validating the use of senotherapies in female reproductive aging is still open. A better understanding of ovarian senescence biomarkers and the role of senescent cells on female fertility is still necessary in order to define how to promote targeted elimination of these cells without negative impact on other organs in young females.

Why did we evolve to suffer excess amyloid-β deposition in the brain in later life? Misfolded amyloid-β and its deposition into solid amyloid structures is the disruptive basis for Alzheimer's disease, slowly developing over decades. The antagonistic pleiotropy viewpoint states that aging is the consequence of processes that are selected over the course of evolutionary time because they are advantageous in youth, improving reproductive fitness in some way, but unfortunately also cause harm with age. The selection pressure exerted on young individuals is much stronger than that exerted on old individuals, so systems that act in this way are the inevitable outcome of natural selection. Amyloid-β acts as a component of the innate immune system, an antimicrobial peptide, and this benefit to younger individuals has been enough to maintain its presence despite the harms it causes in later life.

In Alzheimer's Disease (AD), amyloidogenic proteins (APs), such as β-amyloid (Aβ) and tau, may act as alarmins/damage-associated molecular patterns (DAMPs) to stimulate neuroinflammation and cell death. Indeed, recent evidence suggests that brain-specific type 2 immune networks may be important in modulating amyloidogenicity and brain homeostasis. Central to this, components of innate neuroimmune signaling, particularly type 2 components, assume distinctly specialized roles in regulating immune homeostasis and brain function.

Whereas balanced immune surveillance stems from normal type 2 brain immune function, appropriate microglial clearance of aggregated misfolded proteins and neurotrophic and synaptotrophic signaling, aberrant pro-inflammatory activity triggered by alarmins might disrupt this normal immune homeostasis with reduced microglial amyloid clearance, synaptic loss, and ultimately neurodegeneration. Furthermore, since increased inflammation may in turn cause neurodegeneration, it is predicted that AP aggregation and neuroinflammation could synergistically promote even more damage. The reasons for maintaining such adverse biological conditions which have not been weeded out during evolution remain unclear.

Here, we discuss these issues from a viewpoint of amyloidogenic evolvability (aEVO), a hypothetic view of an adaptation to environmental stress by AP aggregates. Speculatively, the interaction of AP aggregation and neuroinflammation for aEVO in reproduction, which is evolutionally beneficial, might become a co-activating relationship which promotes AD pathogenesis through antagonistic pleiotropy. If validated, simultaneously suppressing both AP aggregation and specific innate neuroinflammation could greatly increase therapeutic efficacy in AD. Overall, combining a better understanding of innate neuroimmunity in aging and disease with the aEVO hypothesis may help uncover novel mechanism of pathogenesis of AD, leading to improved diagnostics and treatments.

Link: https://doi.org/10.3389/fcell.2024.1430593

Ischemic stroke is an age-related condition, in which atherosclerotic plaque ruptures to block blood supply to a part of the brain for long enough to cause dysfunction, reperfusion injury, and cell death. If the harmed region of the brain is critical, the patient dies. Otherwise, the result is a lasting loss of function. Even given the brain's plasticity, that loss may never be fully restored. The aging of the vasculature is evidently critical to both the occurrence and severity of stroke. Researchers here review this topic and the mechanisms thought important in determining risk and severity of stroke.

In recent years, the intricate pathogenesis and potential interventions for ischemic stroke (IS) have been an intriguing area of research. Although there are some feasible treatments for IS, more effective treatments are still urgently needed. More and more evidence has indicated the vital roles of vascular aging in the pathology of IS with the involvement of oxidative stress and inflammatory response. Therefore, the identification of novel targets and the development of effective interventions that can modulate vascular aging by regulating oxidative stress and inflammatory response are worth continued research efforts. Only by unraveling the intricate pathogenesis and exploring more accurate targets can light be shed on how the risk of IS can be mitigated and the patient's quality of life improved with the innovation of more effective therapies.

Vascular aging is critically involved in the pathology of IS. Cellular senescence refers to a stress-induced, permanent cessation of the cell cycle, which leads to adverse functional and structural changes. Increased senescent cells in blood vessels tend to induce vascular aging within aging organisms, which brings about a gradual deterioration in oxidative stress and inflammatory response. This deterioration usually results in endothelial dysfunction and vascular remodeling, which increases the susceptibility and exacerbates the pathology of IS. Further uncovering the underlying mechanisms of vascular aging and IS holds significant implications for advancing our understanding and therapeutic strategies. In this review, we conclude that vascular aging is a multifaceted contributor to IS. It promotes endothelial dysfunction and drives vascular remodeling, which is marked by both oxidative stress and inflammatory response. These interconnected factors collectively amplify the susceptibility and pathological severity of IS.

Link: https://doi.org/10.1161/JAHA.123.033341

The results of the clinical trial in Parkinson's disease patients outlined in today's open access paper are interesting on a number of levels. Analysis of the gut microbiome in patients with Parkinson's disease and Alzheimer's disease has shown that many patients have a characteristically different balance of microbial populations. Some of the specific microbes involved are thought to be harmful. This suggests a contributing role for age-related dysbiosis of the gut microbiome in neurodegenerative conditions. This may be due to an increase in chronic inflammation, or due to other mechanisms that involve specific microbial species and their activities. It was certainly reasonable to test rejuvenation of the gut microbiome via fecal microbiota transplant from a younger individual as a treatment for Parkinson's disease.

Unfortunately, the intervention did not work in this case; it did not improve Parkinson's symptoms. The researchers offer some thought on why this be due to the specific protocol used. More discovery and optimization may be needed in order to produce a useful change in the gut microbiome. Equally, it could be the case that in Parkinson's disease specifically, a poor gut microbiome causes early harm but becomes irrelevant in later stages of the condition. This would occur via seeding of misfolded, pathological α-synuclein that replicates and spreads from the gut to the brain via the nervous system. By the time symptoms show up, misfolded α-synuclein is entrenched in the brain and the gut microbiome no longer matters. In this scenario, fixing the gut microbiome is closing the barn door after the horse has already left.

Fecal Microbiota Transplantation for Treatment of Parkinson Disease

Gut dysfunction is a prevalent, frequently premotor symptom in Parkinson disease (PD) and associated with faster progression. Gut microbiota (GMB) impacts PD pathology and symptoms, and GMB composition is linked to motor and nonmotor symptoms as well as disease progression. Interventions targeting GMB, such as fecal microbiota transplantation (FMT), have shown promising symptomatic and potentially neuroprotective effects in PD animal models. The underlying mechanisms are incompletely understood, but could involve changes in metabolism and immune activation. While several randomized clinical trials have suggested efficacy of probiotics for constipation in PD, with respect to FMT, only small and mostly uncontrolled studies are published suggesting safety and improvement of motor and nonmotor symptoms irrespective of the method of application. This study aimed to assess safety and symptomatic efficacy of FMT in PD.

In the FMT group in this randomized clinical trial, neither clinically meaningful improvement of PD symptoms vs placebo nor major safety concerns were observed. Donor FMT achieved a sustained GMB change close to what is observed between individuals. In the placebo group, dissimilarity remained somewhat higher than observed longitudinally in healthy individuals, indicating a persistent moderate alteration of GMB composition in the placebo group. However, the GMB alterations did not translate into observable clinical or biomarker improvements. This apparent futility or, for some readouts even worsening, is in contrast to previously published reports. Several studies showed improved motor function, increased striatal dopamine and serotonin, and reduced dopaminergic neuron loss, neuroinflammation, and gut inflammation in PD rodent models after FMT. Mostly uncontrolled or small clinical studies suggested safety of FMT in PD irrespective of the method of application and the potential for improvement of motor and nonmotor symptoms.

This negative trial may give important insights to design future improved and hopefully successful trials of this intervention. There is no consensus on many practical aspects of FMT, such as selection of donors and recipients, preparation of the fecal material (e.g., aerobic or anaerobic conditions, concentration of cryoprotectant, and transferred amount), pretreatment with antibiotics, and method of application (eg, upper vs lower gastrointestinal tract and single vs multiple dosing). Also, for clinical trials, there is no consensus about the best comparator (e.g., inert placebo vs autotransplant). Encouraging results from the probiotics field suggest that impact on motor and nonmotor PD symptoms through GMB manipulation is possible, however.

Epigenetic clocks to measure biological age that are derived from blood sample data (and therefore the epigenetic patterns of white blood cells) are here demonstrated to perform poorly in other cell types and tissue samples. This is known to be the case, and is an inevitable result given that (a) epigenetics differs between cell types, and (b) machine learning is used to derive an algorithm that matches up the data in hand to the epidemiological outcomes of interest. To produce a clock that performs well in multiple tissue types, one has to deliberately aim at that goal, incorporating epigenetic data obtained from all of those tissue types into the machine learning process. Some researchers have worked on this, as well as on the production of clocks that work in different species.

Epigenetic clocks are a common group of tools used to measure biological aging - the progressive deterioration of cells, tissues and organs. Epigenetic clocks have been trained almost exclusively using blood-based tissues but there is growing interest in estimating epigenetic age using less-invasive oral-based tissues (i.e., buccal or saliva) in both research and commercial settings. However, differentiated cell types across body tissues exhibit unique DNA methylation landscapes and age-related alterations to the DNA methylome. Applying epigenetic clocks derived from blood-based tissues to estimate epigenetic age of oral-based tissues may introduce biases.

We tested the within-person comparability of common epigenetic clocks across five tissue types: buccal epithelial, saliva, dry blood spots, buffy coat (i.e., leukocytes), and peripheral blood mononuclear cells. We tested 284 distinct tissue samples from 83 individuals aged 9-70 years. Overall, there were significant within-person differences in epigenetic clock estimates from oral-based versus blood-based tissues, with average differences of almost 30 years observed in some age clocks. In addition, most epigenetic clock estimates of blood-based tissues exhibited low correlation with estimates from oral-based tissues despite controlling for cellular proportions and other technical factors.

Our findings indicate that application of blood-derived epigenetic clocks in oral-based tissues may not yield comparable estimates of epigenetic age, highlighting the need for careful consideration of tissue type when estimating epigenetic age.

Link: https://doi.org/10.1101/2024.07.16.603774

The treatment of degenerative joint diseases has been one of the more promising uses for first generation stem cell therapies. These are comparatively simple procedures in which mesenchymal stem cells are harvested from fat and injected into a specific diseased joint. These cells can be safely transplanted from one individual to another, which brings the cost of manufacture down to a reasonable level for widespread use in older people.

MAG200 is a single injection of donor stem cells into the joint (an intra-articular injection). It's considered an 'off-the-shelf' therapy because it uses donor, or allogeneic, stem cells rather than the patient's own, the surgical harvesting of which is labor-intensive. Importantly, because the treatment uses mesenchymal stem cells - adult stem cells that can differentiate into other cell types - from adipose tissue or body fat, it doesn't trigger an immune response.

For the first-in-human Phase I/II trial of MAG200, the researchers randomized 40 participants with moderate knee osteoarthritis to receive either an intra-articular injection of the stem cell therapy or a placebo. All the participants had attempted to manage their osteoarthritis conservatively and had an average pain score of equal to or more than five on a scale of zero to 10. Measures of the impact of their osteoarthritis on function - performing the activities of daily living - were taken using a subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS). KOOS scores go from zero, indicating the worst possible knee symptoms, to 100, indicating no symptoms.

The primary efficacy objective of the study was clinically meaningful differences in pain (a decrease in pain score by two or more points) and function (an eight or more point increase in KOOS score) at 12 months. The researchers found that 75% of participants who'd received MAG200 exhibited clinically relevant and statistically significant improvement in pain and function, reporting improvement or complete recovery. There was sustained pain improvement of 58% at 12 months. MRI scans of the participants' knees indicated that, at 12 months, those who'd received MAG200 had improvements in cartilage volume and quality.

Link: https://newatlas.com/health-wellbeing/stem-cell-therapy-osteoarthritis-clinical-trial/

Considering a combination of robustness of data and size of effect, rapamycin is arguably the best of the small molecules known to slow aging to modestly extend life span in animal models. We could mount a good counterargument for the primacy of the dasatinib and quercetin combination, given its ability to dramatically reverse age-related conditions in animal models, but let us put that discussion to one side for the moment. An interesting and understudied question is the degree to which the known promising approaches to slowing aging combine with one another to produce larger benefits, or can be enhanced by the addition of other molecules. Certainly the work of Brian Kennedy, alongside the few others to test many combinations in vivo, suggests that combining any two promising small molecules is just as likely to produce a mutual sabotage of benefits as it is to produce a synergy of benefits.

This may go some way towards explaining why we see few published examples of successful synergies. Today's open access paper is a rarity, but an interesting one, as the researchers have found a drug that enhances the effect of rapamycin on life span in mice, producing more than a 30% gain in maximum life span in female mice, a sizable outcome that beats out near all other options other than inhibition of growth hormone signaling. Given a favorable safety profile, this approach will no doubt find its way into the expanding off-label use of rapamcyin for anti-aging purposes, as well as into the small number of clinical trials that are intended to further support this application of rapamycin.

A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

The insulin/IGF/mTORC1/Ras nutrient-sensing network is highly conserved in evolution and is implicated in the aetiology of many age-related diseases. There is therefore growing interest in the possibility of repurposing existing drugs with targets in this signalling network as geroprotectors to improve human health during ageing. One such example is inhibition of mTORC1 by rapamycin (sirolimus). Rapamycin robustly extends lifespan in multiple model organisms, ranging from worms and flies to mice, where rapamycin administration later in life at 600 days of age increases median and maximal lifespan in both sexes.

Reduced signalling through the phosphatidylinositol 3-kinase (PI3K) node of the nutrient-sensing network can extend lifespan in C. elegans and Drosophila, and was for long viewed as the primary route by which the anti-ageing effects of reduced upstream insulin/IGF signalling are mediated. However, Ras signalling plays a role in ageing in yeast, while in Drosophila the Ras-MEK-ERK pathway is as important a mediator as the PI3K pathway of the effects of reduced upstream insulin/Igf signalling on lifespan. Indirect inhibition of Ras in mice is associated with increased lifespan and enhanced motor function in old age. These findings suggest that inhibition of Ras pathway signalling may have an evolutionarily conserved, geroprotective effect.

Trametinib (also known as Mekinist) is a potent and highly specific small molecule inhibitor of MEK, and is an FDA-approved drug for the treatment of specific melanomas. Oral administration of trametinib increases Drosophila lifespan, even when started later in life. However, it is yet to be determined whether the lifespan-extending effects of trametinib are evolutionarily conserved. To examine whether trametinib is geroprotective in mice, we orally dosed female and male mice and assessed their ageing phenotypes.

In the present study, we investigated whether administration of trametinib alone or in combination with rapamycin can extend lifespan and improve health at old age in mice. We orally treated male and female mice with trametinib, or rapamycin, or with both drugs at the same doses as in the single drug treatments. We assessed their survival, fitness, brain metabolism, and organismal health. Single administration of trametinib or rapamycin significantly increased male and female mouse lifespan, while the combined treatment produced an additive further increase in both sexes. Additionally, the double combination of trametinib and rapamycin significantly reduced liver tumours in both sexes and spleen tumours in males at old age, and alleviated the age-related increased glucose uptake in the brain. Combination treatment also caused a marked reduction of age-related inflammation in brain, kidney, spleen, and muscle, accompanied by reduced levels of circulating pro-inflammatory cytokines.

As previously shown, intermittent rapamycin treatment extended lifespan in both sexes with an increase in median and maximum lifespan of 17.4% and 16.5% respectively in females and 16.6% and 18.3% respectively in males. Combined treatment caused a larger increase compared to the single treatment in both sexes, with median and maximum lifespan increased by 34.9% and 32.4%, respectively, in females and by 27.4% and 26.1%, respectively, in males.

Some fraction of the chronic inflammation of aging derives from maladaptive reactions of the innate immune system to forms of molecular damage. That chronic inflammation then drives changes in cell behavior that lead to tissue dysfunction and structural alteration. All of the common age-related diseases have a strong inflammatory component, and are are accelerated and made worse by greater systemic inflammatory signaling. This is also true of neurodegenerative conditions and the state of inflammation in the brain.

The complement system, best known as a key arm of innate immunity, has gained attention as a major player in healthy central nervous system (CNS) biology based on its contributions to normal neuronal development, but also for its involvement in inflammatory processes within the CNS. Studies have revealed dysregulation of complement activation in various neurodegenerative and inflammatory conditions, including Alzheimer's disease and multiple sclerosis. Interestingly, both beneficial and pathological activities of complement in the brain or spinal cord are majorly dependent on locally produced complement with limited involvement from the liver-derived circulating complement. This observation is in line with recent adjustments in our understanding of the complement system.

Initially, complement was thought to be a circulation- or vessel-operative system with only a simple role in mediating the detection and removal of bloodborne pathogens. Today, we acknowledge that the complement system is operative at different locations that span the vasculature, the extracellular space in tissues where it is critical in mediating protective tissue immunity, and within cells where it regulates basic cellular processes. The functional reach of complement allows it to directly modulate innate and adaptive immune responses and the behavior of non-immune cells, both during homeostasis and in response to danger-associated molecular patterns (DAMPs) and other noxious triggers. Furthermore, complement has emerged as a key mediator of tissue homeostasis, repair, and regeneration and as such is also involved in the molecular pathways underlying resolution of CNS inflammation and remyelination of neurons after myelin sheath loss, for example, in multiple sclerosis.

Here, we will give a condensed overview of the known sources and roles of complement components in normal CNS function, such as neuronal development and nerve pruning, as well as in disease pathologies contributing to neurodegenerative or neuroinflammatory pathogeneses, and processes that may aid in the resolution or repair of CNS tissue injury. We will conclude with a summary on emerging areas of new complement locations and activities that we suggest could be important in CNS pathologies, such as the intracellularly active complement system and its tight association with the control of single cell physiology and a potential connection between viral infections, complement, and neuroinflammation.

Link: https://doi.org/10.3389/fneur.2024.1396520

Alzheimer's disease is a slow condition, in which brain biochemistry changes for the worse over a span of many years prior to evident symptoms. Considerable progress has been made in the matter of finding markers that reflect those changes, a way to determine future risk of dementia. At some point these markers will be actionable in ways other than being a spur to change lifestyle for the better, doing so in the hopes of slowing down the progression of neurodegenerative processes. For now, however, at least there are some signposts on the way to cognitive decline.

Alzheimer's disease (AD) and related dementias feature a prolonged preclinical stage spanning decades, with the transition from midlife to late life marking the critical period for the onset and accumulation of pathological brain changes. Plasma biomarkers have shown great promise in becoming a cost-effective and noninvasive screening tool for AD pathology and neurodegeneration in symptomatic persons, but their presymptomatic trajectories are not well understood.

Using the well-established community-based Atherosclerosis Risk in Communities study, we characterized temporal changes in plasma biomarkers, identified factors associated with changes in plasma biomarkers over time, and evaluated the prospective associations of plasma biomarkers with late-life all-cause dementia. Analyses were conducted overall and stratified by demographics (sex, race), apolipoprotein E epsilon 4 (APOE ε4) allele status, and cognitive diagnosis.

In this retrospective analysis of prospectively collected plasma biomarkers from 1,525 adults from the Atherosclerosis Risk in Communities study, only Alzheimer disease (AD)-specific (Aβ42:Aβ40 ratio and p-Tau181) biomarkers in midlife demonstrated significant long-term associations with late-life dementia. In late life, each of the biomarkers and their change from midlife were significantly associated with incident all-cause dementia.

Link: https://doi.org/10.1001/jama.2024.6619

Walking speed is one of the long-standing simple biomarkers of aging, predating modern medicine. Measures of physical capacity correlate with the onset of frailty and increased risk of mortality. People become weaker and walk more slowly as they lose fitness and strength with the progression of aging. With the ongoing development of new measures of biological age, including epigenetic clocks and combinations of simple measures such as phenotypic age, researchers have some interest in comparing the new with the old.

In today's open access paper, researcher use the technique of Mendelian randomization to try to derive some indication of causation regarding walking speed and degenerative aging. They conclude that the data is supportive of a causal relationship between a faster walking pace and slower pace of aging. This fits well with current thought on the merits of mild physical activity on long-term health and mortality. The use of accelerometers in epidemiological studies has shown that even a modest level of activity in later life correlates with significant improvements versus being sedentary.

Effects of walking on epigenetic age acceleration: a Mendelian randomization study

Walking stands as the most prevalent physical activity in the daily lives of individuals and is closely associated with physical functioning and the aging process. Nonetheless, the precise cause-and-effect connection between walking and aging remains unexplored. The epigenetic clock emerges as the most promising biological indicator of aging, capable of mirroring the biological age of the human body and facilitating an investigation into the association between walking and aging. Our primary objective is to investigate the causal impact of walking with epigenetic age acceleration (EAA).

This represents the inaugural large-scale two-sample Mendelian randomization (MR) study uncovering the causal link between walking and epigenetic aging. Our results illuminate a consistent and significant causal association, indicating that increased walking speed correlates with the deceleration of epigenetic aging. Essentially, brisk walking appears to exert a beneficial influence on slowing down the aging process. Notably, this causal relationship persists uniformly across all four classical epigenetic clocks.

In contrast, alternate facets of walking, including walking duration and frequency over the past four weeks, did not exhibit resilient causality concerning accelerated epigenetic aging. Additionally, a comparative analysis using sedentary behavior revealed that leisurely sedentary behavior induced GrimAge EAA. While no conclusive causal link was identified in the analysis of sedentary behavior on the remaining three epigenetic clocks, the heightened correlation of GrimAge with behavioral lifestyle suggests a potential association between sedentary behavior and accelerated aging.

Every cell contains hundreds of mitochondria, actively generating adenosine triphosphate (ATP), a chemical energy store molecule used to power cell processes. Mitochondria are descended from symbiotic bacteria and retain many bacterial features, such as a circular genome, the mitochondrial DNA, and the ability to replicate and fuse together. Nonetheless, they have become cell components and are recycled by the quality control mechanism of mitophagy when damaged. In aged tissues, mitochondria become altered in size, activity, and ability to produce ATP for reasons that may have as much to do with epigenetic changes in the cell nucleus as they do with damage to mitochondrial DNA. It is thought that this mitochondrial dysfunction is an important contributing cause of degenerative aging.

Mitochondria are unique double-membrane organelles that came into existence due to the engulfment of alpha-proteobacterium by a eukaryotic progenitor cell in an endosymbiosis process, demonstrating evolutionary importance in the advancement of eukaryotic life. Mitochondria, apart from the nucleus, comprises its genome, metabolome, transcriptome, and proteome. Mitochondria have been considered a cellular powerhouse, responsible for approximately 95% of cellular ATP production. They are responsible for significantly contributing to the maintenance of cellular homeostasis by contributing to metabolic processes such as the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS).

Apart from regulating cellular energetics, mitochondria also play an essential role in intracellular calcium signaling, thermogenesis, apoptosis, generation of reactive oxygen species (ROS), and regulation of oxidative stress response. Any defect or deficit in mitochondrial number and function might be responsible for cellular damage. Mitochondrial dysfunction has been reported to be associated with aging and almost all chronic aging-associated diseases through reduced ATP production, alteration in the regulation of apoptosis, increased ROS production, and defective calcium signaling.

Accumulation of mutations in mitochondrial DNA (mtDNA) is the primary cause of mitochondrial anomalies, further contributing to aging and associated diseases. Here, we provide a detailed description of mitochondrial dysfunction, its implications in the aging process, the onset of aging-associated diseases, and potential therapeutic interventions targeting mitochondrial dysfunction to develop an effective strategy for treating age-related diseases.

Link: https://doi.org/10.3389/fphys.2024.1384966

The composition of the gut microbiome both changes with age and appears influential on the trajectory of aging. A microbiome with more inflammatory microbes and fewer beneficial microbes is harmful over the long term. Now that researchers can cheaply and accurately measure the relative abundance of microbial species present in the gut, they can ask questions about how exactly specific microbes are slowing or accelerating the onset and progression of specific age-related conditions. Here is an example of this sort of work applied to osteoporosis, the loss of bone density that occurs with age.

Osteoporosis (OP) constitutes a notable public health concern that significantly impacts the skeletal health of the global aging population. Its prevalence is steadily escalating, yet the intricacies of its diagnosis and treatment remain challenging. Recent investigations have illuminated a profound interlink between gut microbiota (GM) and bone metabolism, thereby opening new avenues for probing the causal relationship between GM and OP.

Employing Mendelian randomization (MR) as the investigative tool, this study delves into the causal rapport between 211 varieties of GM and OP. The data are culled from genome-wide association studies (GWAS) conducted by the MiBioGen consortium, in tandem with OP genetic data gleaned from the UK Biobank, BioBank Japan Project, and the FinnGen database.

The discernment emerged that the genus Coprococcus3 is inversely associated with OP, potentially serving as a deterrent against its onset. Additionally, 21 other gut microbial species exhibited a positive correlation with OP, potentially accentuating its proclivity and progression. Subsequent to rigorous scrutiny via heterogeneity and sensitivity analyses, these findings corroborate the causal nexus between GM and OP. Facilitated by MR, this study successfully elucidates the causal underpinning binding GM and OP, thereby endowing invaluable insights for deeper exploration into the pivotal role of GM in the pathogenesis of OP.

Link: https://doi.org/10.1097/MD.0000000000038861

It has taken some time for researchers involved in the study of the comparative biology of aging between species to start moving genes from long-lived species into short-lived species. This is now underway to some degree, however. One research group reported on the results of moving a naked mole-rat cancer resistance gene into mice not so long ago. In today's open access paper, a different set of researchers report on the results of moving the STING gene from a long-lived bat species into very much shorter-lived mice. STING is involved in innate immune sensing of pathogens and damage. Pathways involving STING are maladaptively triggered in later life, contributing to a rising level of chronic inflammation. That chronic inflammation is disruptive to tissue structure and function, contributing to age-related disease.

Bats are notoriously resilient to the consequences of viral infection, making them able to act as reservoirs of viral pathogens that can be spread to other species while apparently causing little to no harm to the bats themselves. It is thought that the mechanisms granting this form of resilience may also confer resistance to the inflammation that occurs in other mammals due to maladaptive innate immune reactions to forms of molecular damage characteristic of aging. The pathways for pathogen-driven and aging-drive inflammatory signaling are known to overlap, and STING is particularly implicated.

Myotis bat STING attenuates aging-related inflammation in female mice

Bats are also recognized as natural reservoir hosts for diverse highly pathogenic viruses, some of which have precipitated large-scale infectious diseases in humans, such as SARS-related coronaviruses and Ebola virus. Bats are also noted for their unparalleled longevity among mammals relative to their size, with those within the genus Myotis exhibiting the greatest longevity, living up to 40 years. However, the mechanisms underlying these unique characteristics, particularly their roles as viral reservoir hosts and long-lived animals, remain inadequately understood.

In recent years, research efforts have predominantly centered on unraveling the coexistence of bats and viruses. Our work, along with that of other researchers, has revealed that bats maintain a constitutively expressed interferon system, with a simultaneous dampening of stimulator of interferon gene (STING) expression and inflammatory response. These characteristics may enable early inhibition of viral replication or moderate the immune response upon viral infection. Notably, a low-level, overactive inflammatory response is also a hallmark of human aging, attributed to the senescence-associated secretory phenotype (SASP), which largely depends on the DNA-cGAS-STING pathway.

We previously identified a universal replacement of the serine 358 residue (a critical activation residue) in STING in bats, leading to attenuated downstream interferon responses and antiviral activity. In recent years, extensive research has explored the role of STING in the human aging process. Studies have shown that the cGAS-STING pathway acts as a driver of the senescence-associated secretory phenotype (SASP) in humans, and inhibiting cGAS-STING signaling may be a potential strategy for impeding neurodegenerative processes in old age. Consequently, we hypothesized that the uniquely dampened character of STING in bats may contribute to their relatively extended healthspan. In this study, we established a Myotis davidii bat STING (MdSTING)-knock-in mouse model and conducted a comprehensive comparative analysis of aging-related genotypes with wild-type (WT) mice over a 3-year period.

Blood transcriptomic analysis indicated a reduction in aging-related inflammation in female MdSTING mice, as evidenced by significantly lower levels of pro-inflammatory cytokines and chemokines, immunopathology, and neutrophil recruitment in aged female MdSTING mice compared to aged wild-type mice in vivo. These results indicated that MdSTING knock-in attenuates the aging-related inflammatory response and may also improve the healthspan in mice in a sex-dependent manner. Although the underlying mechanism awaits further study, this research has critical implications for bat longevity research, potentially contributing to our comprehension of healthy aging in humans.

Of the supplement compounds that have been shown to in some way improve mitochondrial function, urolithin A is probably the least well understood when it comes to how exactly it works. This is interesting, as a range of academic and industry groups are presently working on it or derivatives of it. A reasonable view of this class of approach to mitochondrial dysfunction in aging, which also includes MitoQ and vitamin B3 derivatives like nicotinamide riboside, is that the interventions likely produce much of their effect by improving the operation of the mitochondrial quality control processes of mitophagy. They may achieve this quite indirectly, as mitophagy is complex and appears strongly affected by changes in mitochondrial dynamics and function. Impaired mitophagy leading to damaged mitochondria and impaired mitochondrial function is a feature of aging. The primary objection to a focus on supplements to improve mitochondrial function is that, so far, exercise produces better results.

Urolithin A (UA) is a gut metabolite derived from ellagic acid. This systematic review assesses the potential geroprotective effect of UA in humans. In five studies including 250 healthy individuals, UA (10-1000 mg/day) for a duration ranging from 28 days to 4 months, showed a dose-dependent anti-inflammatory effect and upregulated some mitochondrial genes, markers of autophagy, and fatty acid oxidation. It did not affect mitochondrial maximal adenosine triphosphate production, biogenesis, dynamics, or gut microbiota composition. UA increased muscle strength and endurance, however, had no effect on anthropometrics, cardiovascular outcomes, and physical function.

There is very limited evidence on the effect of UA in human aging. UA showed some improvement in mitochondrial activity and autophagy. It decreased inflammatory markers and increased muscle strength and endurance. Taken together, current evidence does not support the beneficial effects of UA on physical function in healthy individuals. However, this conclusion should be considered in light of several limitations: small sample sizes, short intervention durations, and a wide participant age range (45-85 years), which includes both middle-aged and older individuals who may not be ideal candidates for geroprotection.

Link: https://doi.org/10.1016/j.arr.2024.102406

It is now understood that the past studies indicating that low levels of alcohol use were protective and modestly extended life were flawed. This has been the case for a few years now; the research noted here is just hammering home that point in a more robust way. The fundamental problem is that people can stop drinking for health reasons, and thus the cohort of abstainers tends to contain more sick individuals with a higher mortality risk than is the case for the moderate intake cohort. Problems of this nature, simple in hindsight but essentially ignored for years, bedevil many areas of epidemiological study. There were very similar issues in studies indicating a protective effect for being moderately overweight in later life, for example.

Studies linking moderate drinking to health benefits suffer from fundamental design flaws. The major issue: Those studies have generally focused on older adults and failed to account for people's lifetime drinking habits. So moderate drinkers were compared with "abstainer" and "occasional drinker" groups that included some older adults who had quit or cut down on drinking because they'd developed any number of health conditions. That makes people who continue to drink look much healthier by comparison. And in this case, he noted, looks are deceiving.

For the analysis, researchers identified 107 published studies that followed people over time and looked at the relationship between drinking habits and longevity. When the researchers combined all the data, it looked like light to moderate drinkers (that is, those who drank between one drink per week and two per day) had a 14% lower risk of dying during the study period compared with abstainers.

Things changed, however, when the investigators did a deeper dive. There were a handful of "higher quality" studies that included people who were relatively young at the outset (younger than 55, on average) and that made sure former and occasional drinkers were not considered "abstainers." In those studies, moderate drinking was not linked to a longer life. Instead, it was the "lower quality" studies (older participants, no distinction between former drinkers and lifelong abstainers) that did link moderate drinking to greater longevity.

Link: https://www.eurekalert.org/news-releases/1051741