Fight Aging!

The article that I'll point out today is primarily intended to explain to a layperson the recent history of partial reprogramming as an approach to the treatment of aging and age-related disease. The article clearly exists because the leadership at Altos Labs wants to attain a higher profile in the public eye. Altos was created in 2022 or thereabouts and funded with the immense sum of $3 billion, a sizable fraction of all biotech investment in that year. Thus the usual reason for increased publicity, meaning the desire to raise further funding from investors, seems less likely.

It is perhaps the case that there is some pressure behind the scenes to show results, particularly now that Life Biosciences has commenced a first human trial of a very narrowly focused use of partial reprogramming for optic nerve injury or degeneration. Biotech is a slow business, however, in which fifteen years between initial research and clinical approval is entirely normal. Nonetheless, one might imagine that more knowledgeable types might look back at the history of the Ellison Medical Foundation and Calico Life Sciences and express some concern that perhaps large amounts are once again being spent to, as yet, no evident good. This is of course all speculation, but we shall see.

Longevity Science Is Overhyped. But This Research Really Could Change Humanity

When a woman gets pregnant, she has been carrying her egg cells since birth. The sperm that joins with the egg to form a zygote might have been just a few months in the making, but it inherits markers of age from the man who produced it. It only follows that the zygote would also show signs of age - and at first it does. But then a mysterious metamorphosis begins: the cells of the zygote begin to reverse that damage, shaking off the metaphorical (epigenetic) dust that the parents accumulated on their DNA. After two weeks, the cells of the embryo are back to a kind of ground zero of youth. Recreating this rejuvenation is one of the newest and most promising developments in longevity research.

Over the past 20 years, they have learned how to trigger rejuvenation in the lab, achieving a series of breakthroughs that have made that future feel tantalizingly close. Scientists have taken skin cells from 90-year-olds and restored them to youth in a petri dish. They have rejuvenated diseased mice, turning their gray hair back to black and strengthening their muscles. Rejuvenation sounds just as sci-fi as any of the ideas coming out of the longevity field, and yet there's widespread agreement among scientists that the research has extraordinary potential. The most vehement disagreements are not over whether cellular aging can be reversed, but how far scientists can push it. Will it work in humans? Will its use be limited to targeted interventions that cure specific diseases? Or could it ever be safe enough to enable full-body rejuvenation - to help humans look and feel younger, or to stop them from aging in the first place?

Some of the answers to those questions are likely to come from Altos Labs, a secretive biotech company. With $3 billion in investment at its founding in 2022, Altos is thought to have been the single largest biotech start-up launch. A would-be Manhattan Project for longevity science, Altos is responsible for one of the biggest migrations of academics to industry in recent years, luring marquee names in the field with million-dollar salaries and the promise of near-unlimited funding. Among its competitors, Altos has earned a reputation as a black box.

In 2006, Shinya Yamanaka identified four unusual genes that are active in early embryonic development. He introduced them into the skin cells of older mice in a petri dish and watched and waited. Over the course of two weeks, the skin cells transformed, becoming something close to embryonic stem cells. The original Yamanaka factors are now considered just one of many potential ways that scientists could trigger rejuvenation. Altos and a handful of other start-up biotech companies are competing to find the safest version. Altos is conducting research on rejuvenation in the kidney, the heart, and the liver, which are often the first organs to fail as we age. The hope is that in fixing whatever organ is aging first, scientists could give someone a longer, healthier life, with everything essentially winding down at the same time, making for a mercifully brief period of decline.

Some varieties of hydra are immortal, in the sense that mortality rate and measures of function do not change over time. A hydra is in essence a sophisticated bundle of stem cells, somewhat analogous to an early embryo, capable of replacing any of its component parts. Are there aspects of hydra cellular biochemistry that could be introduced into more structured, sophisticated species to extend life? One view is that hydra-like strategies for longevity are incompatible with a central nervous system that retains information. Another view is that this point doesn't rule out all of the potentially interesting biochemistry in this species. Certainly, researchers have already started to move genes and other aspects of cellular biochemistry from long-lived species to short-lived species, such as from naked mole rats to mice, in order to test the bounds of the possible.

Hydra vulgaris ("Hydra") exhibits negligible senescence due to continuous self-renewal and stem cell cycling, contrasting sharply with short-lived, eutelic rotifers that exhibit rapid aging and fixed somatic cell numbers post-development. These organisms therefore represent extremes on the spectrum of invertebrate lifecycles and offer a unique opportunity to test whether patterns of gene expression associated with repressed senescence in Hydra can delay senescence in aging-prone animal models. We hypothesize that introducing Hydra-like gene expression profiles into rotifers (e.g., Brachionus manjavacas) via genetic manipulation will extend healthspan and reduce age-related mortality, providing proof-of-principle for effective manipulation of conserved anti-aging mechanisms.

While translation to humans remains highly speculative at this early stage, the rotifer-Hydra model provides a proof-of-principle framework for discovering targets potentially more relevant to mammalian aging than those from other invertebrate systems. If Brachionus manjavacas can, at least to some extent, exhibit more negligible senescence via transfer of relevant Hydra-like gene expression patterns, this would constitute the required proof-of-principle for the overall concept. It is a long leap from rotifers to geroprotective strategies for humans, but without the initial step from Hydra to rotifer, nothing else would likely be possible. Therefore, we posit that Hydra to rotifer, considered long term, is of relevance to the question of aging, senescence, and geroprotective strategies for humans.

Link: https://doi.org/10.18632/aging.206370

Lung fibrosis is challenging to treat and largely irreversible. There have been signs that clearance of senescent cells can improve the condition, but this has yet to move beyond early human safety trials. Here researchers take a more traditional approach to assessing and then tinkering with the expression of specific genes to produce a reduction in fibrosis in animal models. After finding that ID1 and ID3 exhibited elevated expression in some lung cells, they showed that reducing expression via a variety of means caused some degree of reversal of fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease in which scar tissue builds up in the lungs, making it increasingly difficult to breathe. Existing therapies can slow disease progression but do not stop or reverse it, and most patients survive only three to five years after diagnosis. The research combined analyses of human lung tissue and cells from patients with IPF with several experimental models in mice. The team found that ID1 and ID3 levels are elevated in diseased lung fibroblasts - cells that drive the formation of scar tissue.

When both proteins were inhibited, fibroblast activation was significantly reduced, limiting the processes that lead to pulmonary fibrosis. The researchers tested multiple strategies to block ID1 and ID3, including a small molecule drug and a targeted gene therapy approach. Across these approaches, inhibition of the proteins not only slowed disease progression but also reduced established pulmonary fibrosis in mice and improved lung function. The study also sheds light on how these proteins contribute to disease. ID1 and ID3 regulate fibroblast growth through cell cycle pathways and promote scarring through MEK/ERK signaling - key mechanisms underlying pulmonary fibrosis.

Link: https://www.eurekalert.org/news-releases/1125917

The blood industry is enormous, a long-standing component of the medical industry and one of the largest areas of focus for regulators. Blood is donated and sold in immense amounts, processed and separated into countless different fractions, and those fractions used in equally immense amounts. A sizable research and development community views the contents of human blood in much the same way as others view libraries of small molecules: a domain in which the focus is on discovery of potential new uses in medicine.

Since the modern resurrection of heterochronic parabiosis studies, in which an old mouse and young mouse have their circulatory systems linked, the role of alterations in blood contents with age has been a growing topic of interest. Evidence strongly suggests that old blood is harmful, while less robust evidence suggests that specific factors in young blood might be favorable. For example, one novel approach to therapy under development involves clearing circulating TGF-β while increasing circulating oxytocin, a little from both sides. There is, however, a great deal of ongoing research into many different approaches to improving health in old people by manipulating the circulating contents of the bloodstream.

Blood as the mirror and modulator of aging: mechanistic insights and rejuvenation strategies

Aging arises not only from intrinsic cellular decline but also from systemic alterations in circulating factors that govern tissue maintenance and regeneration. Recent multi-omics advances - including plasma proteomics, metabolomics, and single-cell immunomics - highlight blood as both a mirror and a modulator of organismal aging. Circulating proteins and metabolites reflect not only chronological and biological age but also organ-specific aging trajectories, serving as robust predictors of healthspan, longevity, and disease risk. Beyond their diagnostic value, blood-borne components actively dictate the tempo of aging by shaping immune remodeling, metabolic homeostasis, and interorgan communication.

Youthful circulation, defined as the blood-borne systemic environment of young individuals, promotes tissue homeostasis and regeneration and, when experimentally transferred via heterochronic parabiosis or young plasma transfer, induces transcriptomic, metabolic, and epigenetic rejuvenation across multiple tissues. Specific fractions - such as small extracellular vesicles, plasma proteins, and metabolites - restore mitochondrial function, suppress inflammation, and extend lifespan in animal models. Conversely, reducing pro-aging factors through plasma dilution or therapeutic plasma exchange mitigates age-associated decline and shows translational promise in neurodegenerative disease. Collectively, these insights position blood as a central regulatory axis of aging.

Human epidemiological data robustly indicates a trade-off between risk of cancer and risk of neurodegenerative conditions. Why is this the case? While all too little is understood of the precise details, at the high level it is thought that this is a reflection of the degree to which tissue maintenance activities decline with age. The less work undertaken by stem cells, the less cell replication in general, the lower the risk of a potentially cancerous combination of mutations occurring. But without that ongoing maintenance, the loss of tissue function accelerates, and neurodegenerative conditions are one of the more prominent outcomes. In essence one is forced to choose between cancer or regeneration. Not all species face that choice, of course. Some, like naked mole rats, can have their cake and eat it too; their cancer suppression mechanisms are so exceptionally effective that individuals can maintain youthful levels of regeneration and function well into late life without any downsides.

Neurodegeneration and cancer are fundamentally distinct disorders: one signifies gradual neuronal loss while the latter signifies uncontrolled cell growth and survival. However, emerging evidence explores an inverse association between these conditions, suggesting that they do not arise from independent biological processes. Understanding the context-dependent behaviour of major pathways (for example, p53, PI3K/AKT/mTOR, Wnt, and immune-stress signaling) remains pivotal in elucidating the relationship between these two diseases. Pathways promoting early-life fitness, tissue repair, and tumor suppression in dividing cells can become detrimental later in life for post-mitotic neurons.

Cross-species genomics studies reveal how evolution has repeatedly adapted these shared networks to balance cancer resistance with survival. Research on species exhibiting exceptional longevity and disease resistance, including naked mole rats and bowhead whales, shows that cancer resistance and longevity are not fixed traits but rather are controlled by precise regulatory mechanisms. In this review, we integrate insights from broad species genomics and multi-omic and single-cell studies to understand how evolutionarily conserved molecular crosstalks diverge at the interface of cancer and neurodegeneration.

Link: https://doi.org/10.3390/ijms27072989

Inflammation in the brain is thought to be important in the progression of neurodegenerative conditions, disruptive to cell and tissue function. Understanding why the other features of neurodegenerative disease activate chronic inflammation in the brain is a necessary first step on the long road to the development of therapies capable of selectively suppressing this harmful inflammation while only minimally interfering in the normal, necessary inflammatory response to pathogens and injury.

The protein called STING normally functions as part of the immune system's early-warning system. In the brains of people with Alzheimer's, the team discovered that STING undergoes a chemical modification known as S-nitrosylation (or SNO, a reaction involving sulfur, oxygen, and nitrogen) that promotes its overactivation. Blocking this chemical change to STING in a mouse model of the disease decreased neuroinflammation.

Over three decades ago researchers discovered the S-nitrosylation process, in which a molecule related to nitric oxide (NO) binds to a cysteine amino acid in proteins, producing "SNO" and thus regulates the protein's function. SNO, which can be triggered by aging, neuroinflammation, and environmental toxins such as air pollution and wildfire smoke, disrupts a variety of different proteins in the body.

In this new study, the team focused on the protein STING, which was previously linked to Alzheimer's inflammation. They pinpointed exactly where on STING an S-nitrosylation reaction occurred, homing in on one specific building block of the protein: cysteine 148. When cysteine 148 is S-nitrosylated, they discovered, STING clusters into larger complexes and triggers inflammation. The team found high levels of the chemically modified form of STING (called SNO-STING) in postmortem brain tissue from Alzheimer's patients, in human brain immune cells grown in the lab and exposed to Alzheimer's proteins, and in a mouse model of the disease.

In laboratory experiments, the team showed that the clumps of proteins found in the brain in Alzheimer's - including amyloid-beta and alpha-synuclein - can themselves trigger the S-nitrosylation reaction in STING. This finding suggests that inflammation occurs in a cycle: initial protein clumps, coupled with environmental influences and aging, could cause inflammation that generates NO, driving S-nitrosylation of STING, which in turn drives more inflammation.

The researchers then engineered a version of STING lacking cysteine 148 so it couldn't be S-nitrosylated. When this modified protein was introduced into a mouse model of Alzheimer's, brain immune cells showed significantly less inflammation, and critically, the connections between nerve cells (called synapses) were protected from degradation. This preservation of synapses is known to correlate with protection from the cognitive decline of dementia.

Link: https://www.scripps.edu/news-and-events/press-room/2026/20260423-lipton-alzheimers.html

Since the discovery that adult mice generate new neurons in the brain, and thus the brain is not wholly reliant upon structures and cells created during development, there has been considerable debate over whether or not this adult neurogenesis exists and is important in humans. This is in part a logistics problem: the human brain is inherently hard to study. It is in part a methodological problem, in that human neurogenesis appears to be different enough from mouse neurogenesis in its details to challenge researchers. Much of the debate of the past fifteen years has focused on whether the tools are working in the way that they are claimed to work, and whether human data actually reflects what those who present it think it reflects. Nonetheless, the present weight of data and scientific consensus support a role for neurogenesis in the maintenance of the aging brain.

So we come to the question of why some people exhibit molecular pathology characteristic of Alzheimer's disease, such as the generation of protein aggregates that can be visualized via imaging approaches, but do not suffer extensive cognitive decline as a result. There is a school of thought that suggests that these individuals have more efficient or greater levels of neurogenesis, capable of compensating for losses. Or that their neurogenic mechanisms are in some way more resistant to the damage of aging. This ties in to the high level concepts of cognitive resilience and cognitive reserve, created by clinicians and researchers seeking to describe the observed differences in the cognitive outcomes of neurodegeneration from individual to individual. Whether differences in neurogenesis are indeed important in this context remains an unanswered question; today's open access paper is an example of ongoing work aimed at developing better tools to obtain better data and thus come to a conclusion.

Not all Alzheimer's leads to dementia

Why do some people experience memory loss and cognitive decline as Alzheimer's builds up in their brain, while others stay mentally sharp? This question lies at the heart of new research into "cognitive resilience", a phenomenon that is gaining attention in neuroscience. "Around 30 percent of older adults who develop Alzheimer's disease never experience its symptoms. We really don't know why. That's a big mystery, and a very important one."

One possible explanation is that resilient brains are better at repairing themselves during Alzheimer's. This idea is linked to a process called adult neurogenesis, which refers to the birth of new neurons in the adult brain. It has been well-established in other animals, but its existence in humans has been debated for years. To study this, researchers used human brain tissue from the Netherlands Brain Bank, which collects and stores donated brain samples for research. They included brains from control donors with no brain pathology, Alzheimer's patients, and individuals with Alzheimer's pathology who remained resilient to developing dementia.

The team found what they were looking for: so-called "immature" neurons. These cells resemble young, not fully developed neurons. While the team had expected to find much more of these cells in the resilient group than in the Alzheimer's patients, the difference was not as big as expected. Instead, the team found that the key difference lies in how the immature neurons behave. "In resilient individuals, these cells seem to activate programs that help them survive and cope with damage. We also see lower signals related to inflammation and cell death."

Transcriptional profiles of immature neurons in aged human hippocampus track Alzheimer's pathology and cognitive resilience

An attractive approach to treating Alzheimer's disease (AD) could involve harnessing the brain's endogenous regenerative potential to restore function in the degenerating hippocampal network. This strategy presumes the occurrence of adult hippocampal neurogenesis (AHN) in the human brain and the functional integration of newly generated granule cell (GC) neurons into the hippocampal formation. Reconstructing the molecular and cellular signatures of immature hippocampal GC neurons may not only offer novel targets for brain repair and regeneration strategies in the AD human brain but also directly probe the question of whether human AHN contributes to a lifelong buildup of cognitive reserve. This reserve may, in turn, confer resilience to cognitive decline or AD-related dementia later in life.

Despite its therapeutic appeal, identifying and profiling putative neurogenic populations in the adult human brain has not been trivial; beyond reflecting technical roadblocks, this also hints at some potentially unique attributes of these cells. Although single-nucleus RNA sequencing (snRNA-seq)-based studies have identified cells with immature neuronal characteristics in the adult human hippocampus, methodological discrepancies have led to substantial debate in the field. Recently, we examined experimental and computational variables that may confound the results and conclusions of such approaches. Building on these insights, we here establish a refined experimental and computational framework aimed at reliably identifying neurogenic populations in the aged human brain, while minimizing biases inherent to marker-based preselection.

Our findings reveal that immature neuronal signatures persist into adulthood, with some of them potentially arising postnatally. Although these cells present some transcriptional similarities to their fetal counterparts, they also appear to have acquired unique features that may enable them to adapt to the complex adult niche microenvironment. Our findings suggest that the presence of these immature neuronal populations may actively contribute to maintaining homeostasis within the aged human hippocampus and to cognitive resilience in AD.

Researchers here show that fecal microbiota transplantation from young mice to old mice suppresses age-related increase in MDM2 expression and reduces risk of liver cancer. The balance of microbial populations making up the gut microbiome changes with age in ways that promote chronic inflammation and reduce the production of beneficial metabolites. Fecal microbiota transplantation is one of the few approaches that can make a permanent change to the composition of the gut microbiome, rejuvenating it when the donor is younger than the recipient. Numerous animal studies have shown improved health and extended live to result from this restoration of a youthful gut microbiome, and the work here is another example of the same, focused on the health of the liver.

Researchers collected fecal samples from eight young mice and transplanted them back into the same mice when they were older, a process called fecal microbiota transplantation, or FMT. The eight controls received sterilized fecal slurry, and a small group of similar young mice provided additional baseline data. None of the mice with the restored microbiome developed liver cancer by the end of the study, while liver cancer was found in 2 out of 8 aging controls. The mice with the restored microbiome also saw reduced inflammation and less liver damage.

At the conclusion of the in vivo study, the researchers conducted a comprehensive analysis of the liver tissue. They identified differences in MDM2, a gene already known to play a role in liver cancer. MDM2 protein levels were low in young mice, high in untreated older mice, and suppressed in treated older mice, making them more like young mice. "Restoring a more youthful microbiome can reverse several core features of aging at both the molecular and functional level, including inflammation, fibrosis, mitochondrial decline, telomere attrition, and DNA damage." The research grew out of an earlier cardiac study, which found that microbiome changes could improve heart function. When analyzing tissues at the end of that study, the team noticed an even more dramatic effect on the liver, which prompted deeper investigation.

Link: https://www.eurekalert.org/news-releases/1124997

Some evidence suggests that deubiquitylases are relevant to aging. These enzymes remove ubiquitin from proteins; recall that the decoration of a protein with ubiquitin enables it to be broken down into raw materials for further protein synthesis by a proteasome. Alongside autophagy, the ubiquitin-proteasome system is one of the important processes by which a cell maintains quality control and otherwise manages its contents. Managing which proteins are flagged by ubiquitin necessarily involves removal, not just addition, and thus the existence of deubiquitylases. Here, researchers provide evidence for rising levels of oxidative stress in the aging brain to impair the activity of deubiquitylases. As is usually the case in these matters, it is unknown as to the relative importance of this issue versus all of the other problems produced by age-related change in the operation of cellular biochemistry.

Among the cellular mechanisms governing proteostasis, the ubiquitin-proteasome system (UPS) plays a central role in signaling, stress responses, and protein degradation by attaching ubiquitin to lysine residues of specific target proteins. Within the UPS, ubiquitin ligases and deubiquitylases (DUBs) act antagonistically to modulate protein fate and signaling pathways dynamically. Altering DUB activity has been linked to lifespan in nematodes, and dysregulation of specific DUBs in humans leads to several neurodegenerative diseases, such as spinocerebellar ataxia and Parkinson's disease. However, a systematic understanding of how DUB functions is altered in the aging brain, the mechanisms driving these changes, and the consequences of altered DUB activity at the molecular level are still lacking.

Here we used activity-based proteomics to profile cysteine protease DUBs in aging mouse and killifish brains. We identified a subset of DUBs that progressively lose catalytic activity with age despite stable protein abundance. Mechanistically, oxidative stress impaired DUB function through thiol oxidation, whereas antioxidant treatment with N-acetylcysteine ethyl ester (NACET) restored activity in aging brains. In human induced pluripotent stem cell-derived neurons, global DUB inhibition and targeted inhibition of USP7, one of the most strongly age-affected DUBs, partially recapitulated ubiquitylation changes observed in aged brains. Temporal analysis in mice further revealed that DUB inhibition precedes proteasome decline during brain aging. Together, these findings identify redox-sensitive DUBs that lose activity with age and suggest impaired deubiquitylation as an early, potentially reversible driver of proteostasis decline in the aging brain.

Link: https://doi.org/10.1038/s41467-026-71921-y

You may recall the epidemiological study indicating that populations at moderate altitude exhibit better long term health and a lower risk of age-related disease. The authors of that study suggested that this is because a greater level of physical activity is involved in day to day activities in hilly regions, but this hypothesis is far from proven. Going beyond moderate elevation, we enter the realm of mild hypoxia as oxygen levels fall with increasing height above sea level. Interestingly, evidence suggests that intermittent mild hypoxia is beneficial, being one of the many forms of stress that cells react to with improved maintenance. Sustained mild hypoxia of the sort one achieves by living at a sufficiently high altitude is a different story, however.

In today's open access paper researchers report on a study of immune system characteristics and cell features in high altitude populations of the Tibetan plateau. Oxygen level is 20.9% at sea level. At 3500 meters, it is 13%. At 5000 meters it is 11%. There are small human populations living at around 5000 meters in Tibet, and their immune systems exhibit the downsides of a constant environment of mild hypoxia: greater chronic inflammation, and larger populations of various age-associated forms of T cell and B cell that are known to be harmful, for example. It is unknown as to the relative size of the contribution of altitude and its evident biochemical consequences versus socioeconomic factors to the comparatively low life expectancy in these high altitude populations, but these individuals certainly appear to exhibit accelerated immune aging, among other issues.

High altitude-mediated immune remodeling accelerates aging

High-altitude population (HAP) cohorts exhibit significantly reduced average lifespans compared to low-altitude population (LAP) cohorts, a pattern exemplified by Tibetans residing on the "Roof of the World," where life expectancy ranks much lower in China. As previously reported, populations chronically exposed to hypobaric hypoxia at high altitudes exhibit accelerated epigenetic aging, with the rate of epigenetic clock advancement positively correlating with residential altitude elevation. Notably, the Tuiwacun (TWC) (population of less than 160) in Tibet reports a median lifespan below 50 years, underscoring the proaging effects of high-altitude environments. While human diversity arises from molecular variations, these differences are not stochastic but rather reflect cellular adaptations to distinct environmental and lifestyle pressures, driving interpopulation heterogeneity.

High altitude mediates multifaceted physiological alterations that accelerate aging processes, driving organ functional decline, shifting in multidimensional aging-associated metrics, and ultimately elevating disease and mortality risks. Compared to LAP cohorts, HAP cohorts exhibit distinct gut microbiome profiles, genetic signatures, and transcriptional remodeling, reflecting evolutionary and environmental adaptations to chronic hypoxic stress. Long-term high-altitude residents may develop polycythemia to counteract hypobaric hypoxia; while this adaptation enhances oxygen-carrying capacity, it concurrently elevates blood viscosity, thereby increasing cardiac workload and thrombosis risk.

We present immune landscape characterization in human populations residing at 3656-meter (Lhasa) and 5070-meter (Tuiwacun) elevations on the Qinghai-Tibet Plateau, complemented by multiorgan single-cell RNA sequencing and spatially enhanced resolution omics sequencing (Stereo-seq) of mice under simulated 5000-meter hypoxic conditions. Comparative analysis revealed significantly elevated neutrophil proportions in high-altitude population (HAP) cohorts relative to low-altitude population cohorts. Notably, aging-associated immune cells (AICs) including exhausted T cells, age-associated B cells, and high-aging-score immune cells showed marked enrichment in HAP cohorts, a pattern conserved in mouse models. Stereo-seq analyses further identified coordinated niche interactions between AICs and aging-related intestinal epithelial cells, suggesting accelerated gut aging trajectories.

The company Seragon funded researchers to run a study of their combination therapy. The results claim a greater increase in life span than the effects of rapamycin treatment in aged mice. Neither Seragon nor the researchers reveal the identity of all of the combination components, but it includes a number of well-known supplements. In general, one should be skeptical regarding any initially published outcomes resulting from this sort of approach to slowing aging, given the evidence for many combinations of molecules that adjust metabolism to interfere with one another's benefits, and the further evidence from the very rigorous Interventions Testing Program to show that many molecules previously thought to slow aging in fact do not slow aging. In defense of Seragon, the researchers did use a relatively large number of mice in this study, 24 or 44 per group; that is always a pleasant surprise. Nonetheless, deciding to await further confirming evidence and more information on the components of the therapy is a sensible response to this paper.

Developing interventions to delay aging and improve lifespan and healthspan is a critical goal in aging research. Individual geroprotective compounds fail to address the complexity, interconnectedness, and dynamic nature of biological systems, limiting success in significantly extending lifespan and improving health. This study investigates the effects of SRN-901 - a novel oral combinatorial drug that consists of urolithin A, quercetin, nicotinamide riboside, alpha-lipoic acid, and Seragon's SRN-820 - on lifespan extension, frailty reduction, disease-related gene expression pathways, metabolic aging, and the proteome in 18-month-old mice fed a Western diet.

SRN-901-treated mice showed a significant increase of 33% in median remaining lifespan compared to placebo-treated mice. Cox proportional hazards analysis revealed a hazard ratio of 0.54, indicating that SRN-901 treatment was associated with a 46% reduction in the hazard of death. While rapamycin increased lifespan in adult mice, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) did not show significant differences in median lifespan compared to placebo. SRN-901 protected mice against increased frailty during aging, with baseline-normalized scores rising to 1.17 in treated mice and 1.57 in controls, corresponding to a 70% attenuation of frailty progression between pre-treatment (day 14) and post-treatment (day 128).

Transcriptomic analyses revealed that SRN-901 modulates gene expression across pathways implicated in aging biology, including inflammation, apoptosis, and DNA repair, as well as gene sets associated with neurodegenerative disorders, including Alzheimer's disease. Metabolic profiling revealed that SRN-901 was associated with attenuation of several age-related metabolic shifts, resulting in a blood metabolite profile that more closely resembled that of younger mice. The upregulation of glutathione metabolism and other longevity-related pathways underscores SRN-901's role in enhancing cellular defenses against oxidative stress and maintaining metabolic health.

Link: https://doi.org/10.2147/DDDT.S594895

In the matter of treating aging as a medical condition, emulating centenarians is not good enough; these survivors to advanced old age are still greatly impacted by aging, are frail and vulnerable, with high mortality rates. Nonetheless, the study of centenarian biochemistry might tell us something about which aspects of aging are more or less important than others. For example, see this review of what is known of the immune systems of centenarians. That there are noteworthy differences in immune aging in this population points to the importance of the age-related decline of immune function in degenerative aging, something that should be given significant attention by the research and development communities.

Immunosenescence refers to the gradual decline in immune efficacy linked to aging, resulting in heightened susceptibility to infections and an elevated risk of age-related diseases, such as cancer, neurodegenerative and autoimmune disorders, and cardiovascular diseases. This phenomenon plays a critical role in the aging process, significantly influencing the overall healthspan and lifespan. The implications of immunosenescence extend beyond mere susceptibility to disease; they encompass the complexities of inflammation, immune response, and the maintenance of health during the aging process, prompting extensive research into therapeutic interventions aimed at enhancing immune function in the elderly.

The study of immunosenescence in relation to centenarians has uncovered critical mechanisms underlying successful aging, including the management of chronic inflammation, known as inflammaging, and the maintenance of immune homeostasis. Centenarians often exhibit lower levels of chronic inflammation, which may contribute to their longevity and quality of life. Centenarian immune profiles are characterized by selective retention of naïve T cells, expansion of cytotoxic CD4+ and CD8+ subsets, tightly regulated inflammatory signaling, and systemic protective mechanisms such as enhanced oxidative-stress resistance, preserved epigenetic regulation, and extracellular vesicle-mediated T-cell modulation.

The connection between immunosenescence, age-related disorders, and the extraordinary health of centenarians has generated interest in elucidating the underlying mechanisms and formulating treatment approaches to enhance immunological function in the elderly. This narrative review examines the mechanisms and implications of immunosenescence as derived from studies of centenarians, contrasting the pathways of progressive immune decline versus the adaptive longevity observed in extreme aging.

Link: https://doi.org/10.1016/j.coi.2026.102777

Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that evolved to become components of the cell. Along the way most of the original mitochondrial genome migrated into the cell nucleus, leaving only a small remnant genome inside mitochondria. The primary task undertaken by mitochondria is the production of the chemical energy store molecule adenosine triphosphate (ATP), used to power cell activities. This is produced via energetic processes that also produce reactive oxygen species capable of damaging structures in the cell. Mitochondria, like all cell structures, are subject to replacement when damaged or dysfunctional. Mitochondria are recycled via the complex process of mitophagy, whereby a mitochondrion is conveyed to a lysosome to be disassembled into raw materials for protein synthesis. Mitochondria, like the ancestral bacteria they evolved from, make up lost numbers by replicating.

Unfortunately all of this glorious complexity runs awry with age. In old tissues, cells contain mitochondria characterized by altered morphology, impaired ATP production, increased reactive oxygen species production, and other dysfunctions, such as leakage of mitochondrial DNA fragments into the body of the cell where they trigger inflammatory reactions that evolved to combat infectious pathogens. Researchers are interested in trying to understand the causes of mitochondrial dysfunction with age, in a search for ways to address the issues. Much of it results from changes in gene expression in the cell nucleus, but it is a slow process to identify, one by one, important mechanisms that are impaired with age and then uncover possible ways to address each issue. Today's open access paper is an example of this sort of discovery, and since the findings point to choline supplementation as a way to address the problem, it seems likely to be only a minor contribution to overall mitochondrial dysfunction in our species. After all, choline supplementation is widely used and doesn't produce world-changing outcomes to health.

Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging

Mitochondrial dysfunction is clearly one of the best recognized hallmarks of aging, and in addition to causing cellular deterioration in late life, it blunts the efficacy of anti-aging interventions that rely on metabolic plasticity such as dietary restriction (DR) and DR mimetics. Despite extensive studies linking genetic impairments of mitochondrial homeostasis (e.g., altered fidelity of mitochondrial DNA synthesis, mitochondrial unfolded protein response (UPR), oxidative phosphorylation (OXPHOS) and others) to diseases and accelerated aging, it is less clear what endogenous processes instigate mitochondrial decline during normal aging. The identification of such "natural" drivers of mitochondrial aging is however crucial because they likely comprise suitable intervention targets towards restoration of mitochondrial integrity and organismal health in late life.

In this work, we combined omics, genetics, and functional analyses in C. elegans, with transcriptomics and metabolomics analysis in humans, and metabolic resilience tests in cell culture models to discover previously unrecognized interventions that improve mitochondrial health and metabolic plasticity during advanced aging. Our studies revealed a decline in phosphatidylcholine (PC) synthesis as a previously unappreciated, conserved driver of natural mitochondrial aging, which can be overcome by dietary supplements.

We initially used longitudinal proteomics analysis in wild type C. elegans and long-lived mitochondrial mutants, which was coupled to RNAi-mediated gene inactivation and longevity testing, to demonstrate that S-adenosylmethionine synthetase SAMS-1 is required for longevity maintenance in the context of mitochondrial impairments. Concurrently, we found SAMS-1 to be among the strongest downregulated proteins in old wild type nematodes in line with previous observations, and same strong and progressive downregulation with age was discovered for phosphoethanolamine N-methyltransferases PMT-1 and PMT-2, which utilize S-adenosylmethionine (SAM, the product of SAMS-1) in the nematode pathway of methylation-dependent PC synthesis.

We next explored the mechanistic basis of the longevity link between sams-1 gene inactivation and mitochondrial impairments, and discovered that knockdowns (KDs) of sams-1, pmt-1 and pmt-2 genes cause an early life increase of mitochondrial fragmentation and a decline of mitochondrial respiration that are comparable to structural and functional alterations of mitochondria observed during normal aging.

Importantly we could alleviate these defects by dietary provision of PC or choline (is converted to PC by the CDP-choline pathway) both in the KDs and also during WT aging. The impact of aging and the above gene knockdowns on the abundance of PC and its derivative lysophosphatidylcholine (LPC) were validated by lipidomics, and the restorative effect of choline supplementation was also detected in this case. While choline can enter several metabolic pathways once inside the cell, the collective evidence presented in this study suggests that the effects of choline provision on mitochondrial function are largely mediated through its conversion to PC.

Interestingly, we discovered by using the GTEx dataset (v8) and previously pre-processed gene expression data that levels of the human PMT-1/2 analog PEMT decline with age in several tissues and especially in organs showing overall highest PEMT expression. We followed up by analyzing the metabolomics data of the UK biobank cohort to discover that PC levels decline with age also in humans and especially in post-menopausal females known to be affected by mitochondrial insufficiency. This data indicates that aging-associated decrease of methylation-dependent PC synthesis is evolutionary conserved and may contribute to "natural" aging of mitochondria across species while other factors - such as the age-related upregulation of phospholipase activity, may also play a role in reducing PC levels with age.

Researchers here report a novel approach to improving mitochondrial function in aged muscle tissue, involving a reduction in the activity of the ghrelin receptor, either via gene knockout or by using an inverse agonist small molecule. It is interesting to note that while this improves muscle function, it fails to improve either muscle mass or longevity in the treated mice. One might expect to see enhanced mitochondrial function produce at least some effect on those parameters, but the data is the data.

Sarcopenia is characterized by age-related declines in muscle strength and mass, along with impaired physical function. It remains an unmet medical need, and there are no pharmacological interventions approved for this indication. The activation of growth hormone secretagogue receptor (GHSR)-1a, also known as ghrelin receptor, stimulates food intake and has acute anabolic effects. However, its impact on aging muscles remains uncertain. We examined the effects of GHSR-1a deletion on sarcopenia measurements (muscle mass, strength, and endurance) by comparing young and aged male GHSR-1a knockout (KO) and wildtype (WT) mice (6-, 24-, and 28-month-old).

Deletion of GHSR-1a improved muscle fatigue resistance, endurance, and muscle strength during aging without affecting muscle mass or longevity. Since muscle endurance is closely related to mitochondrial function, we examined mitochondrial biogenesis marker PGC-1α and mitophagy signaling via PINK1/p62 and found them improved in old mice with GHSR deletion. Proteomics analysis also revealed that mitochondrial components remain central for maintaining muscle mass and function.

We further investigated the effects of pharmacological inhibition of GHSR-1a by its inverse agonist, PF-5190457, in male WT mice. PF-5190457 mimicked the effects of GHSR-1a deletion, including improved endurance and increased markers of mitochondrial biogenesis (PGC-1α) and different mitophagy markers (LC3II and Bnip3). PF-5190457 also reduced body weight and adiposity, which were not observed with GHSR-1a deletion.

Link: https://doi.org/10.1111/acel.70472

The study of the comparative biology of aging, and comparative biology more generally, is alive and well. A sizable community of researchers consider that the study of differences between long-lived and short-lived species is a good path to a better understanding of aging that may ultimately inform the development of life-extending therapies. Whether there is biochemistry in long-lived species that can be directly transferred into humans for benefit remains an open question; it may be that nothing is that simple, but the example of employing naked mole-rat cGAS to improve DNA repair is a promising example of the sort of gene therapies that may become possible in the future. Is all of this research proceeding in an optimal way, however? Here, a researcher argues for a greater emphasis on holistic comparisons between species of specific organelle structures inside the cell, such as mitochondria, rather than continuing to proceed gene by gene and protein by protein.

The past decade has defined molecular hallmarks of aging, yet interventions that extend lifespan in short-lived organisms show limited and context-dependent translation to humans. Comparative studies of exceptional longevity remain largely genome-centric, although genomic instability alone cannot comprehensively explain aging-related pathologies. Many age-associated failures emerge at the level of cellular organelles whose stability underpins tissue function. The pathways that sustain these structures operate through proteomic, metabolic, and lipid networks that are insufficiently captured by genomic or transcriptomic analyses.

Notably, longer organismal lifespan increases the requirement for sustained organelle functionality and fidelity. This Perspective proposes that the next conceptual advance in geroscience will come from comparative organelle biology. Examining mammals with divergent lifespans, including species evolutionarily closer to humans, can reveal how long-lived lineages evolved organelle-level architecture and resilience mechanisms that support cellular function over decades. I introduce the Comparative Metabolic Longevity Cell Atlas (CMLCA), a cross-mammalian platform integrating standardized cellular systems, organelle-resolved multi-omics, and computational analysis to identify conserved features of resilience and inform next-generation strategies to improve human healthspan.

Link: https://doi.org/10.1038/s44321-026-00428-2