Fight Aging!

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 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

Naked mole-rats are an unusually long-lived mammalian species, of a similar size to mice but with a life span of decades rather than just a few years. This species also exhibits a near complete absence of cancer and very little age-related decline in function until very late in life. Investigations of their biochemistry have uncovered a range of interesting differences, such as senescent cells that are far more benign than their counterparts in other mammals, more efficient protein synthesis, more efficient DNA repair (such as an improved version of the cGAS protein), and more. That naked mole-rats live underground in oxygen poor environments, with a corresponding lack of predation, has prompted the evolution of greater longevity and the necessary co-evolution of the many features needed to support that longevity, such as improved cell resilience to common stresses.

In today's open access paper, researchers examine the gut microbiome in naked mole-rats. In mice and humans the composition of the gut microbiome changes with age, in ways that provoke greater inflammation and diminish the supply of beneficial metabolites. Animal studies have shown that restoring a youthful composition, such as via fecal microbiota transplantation from a young donor, improves health and extends life. Perhaps unsurprisingly, all things considered, the results in the paper here show that naked mole-rats exhibit very little change in the composition of the gut microbiome over a life span. Why this is the case is an interesting question, however. It perhaps argues for the hypothesis that changes in gut microbiome composition are downstream of the aging of the immune system, as it becomes ever less capable of suppressing populations of undesirable microbes.

The naked mole-rat microbiome is associated with healthy aging and social structure

The gut microbiome plays a pivotal role in health and disease, modulating digestion and xenobiotic processes, regulating metabolism, influencing epithelial development, and altering immune function. When the microbiome is dysregulated, as may occur during aging, it may contribute to myriad chronic diseases, such as cardiovascular disease, diabetes, and cognitive impairment. Similarly, therapeutic interventions that modify the microbiome with probiotics reportedly have been effective in the treatment of age-related cognitive impairment and sarcopenia and may even delay or abrogate the overall physiological declines that occur with advancing age.

Here, we investigate the naked mole-rat (NMR; Heterocephalus glaber) and its unique microbiome. These small (35-45 g) rodents are notable for both their unusual eusocial lifestyle and successful aging profile: breeding is monopolized by one female (the "queen") within a colony, with the result that although most NMRs remain in their natal colony, less than 1% of all individuals have the opportunity to reproduce over their exceptionally long lifespans (more than 40 years). In addition to their extraordinary longevity, NMRs show a lack of demographic aging, with no increased risk of dying in older animals, and well-maintained physiological, metabolomic, and biochemical function with advancing age. NMRs are also resistant to chronic age-associated diseases (e.g., cancer, neurodegeneration, and cardiovascular diseases). These atypical features suggest they are able to successfully retard, delay, or abrogate the functional declines that commonly accompany the aging process in other mammals.

Comparing fecal samples from NMR individuals over different social ranks and over a span of more than three decades. In contrast to a cohort of C57BL6/J mice, which showed extensive age-related changes, we found little difference in the microbiota of NMRs from different age cohorts. Only the archaea Methanomassiliicoccus intestinalis, which was present in the NMR gut but not the murine gut, showed an increased proportion with older age. Pregnant queens were found to have higher microbial diversity, potentially a consequence of their aggressive coprophagia. Overall, these findings provide a rich and dynamic picture of the NMR microbiome and starting points for future investigation.

Presently largely irreversible lung disease like idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease were one of the first conditions targeted for the development of senolytic therapies to clear senescent cells. A range of evidence supports a prominent role for an increased burden of senescent cells in airway and lung tissues in these conditions. Here, researchers discuss a more recent approach to senolytic therapy, employing a proteolysis-targeting chimera approach to make the cell break down one of the proteins involved in senescent cell survival. Senescent cells, unlike normal cells, are primed to undergo the programmed cell death of apoptosis. They are only held back from that fate by the activity of a few proteins, including BCLXL, which is the target here. When levels of BCLXL are dramatically reduced, senescent cells undergo apoptosis while normal cells are largely unaffected.

Ageing and cellular senescence significantly contribute to the progression of age-related diseases, particularly chronic obstructive pulmonary disease (COPD). Cellular senescence refers to the cessation of cell division in response to stress and damage. While senescent cells remain metabolically active, they secrete pro-inflammatory factors that drive disease progression. Senolytic therapies aim to selectively target and eliminate these senescent cells by inducing their apoptosis. This study examines the senolytic potential of BCLXL-PROTAC, a novel proteolysis-targeting chimera designed to degrade BCLXL, in small airway epithelial cells and fibroblasts from patients with COPD.

Treatment of COPD small airway epithelial cells and fibroblasts with BCLXL-PROTAC led to their apoptosis through the activation of caspase 3, along with a reduction in senescence markers such as p21CIP1, p16INK4a, and senescence-associated β-galactosidase. The effects of BCLXL-PROTAC were selective for senescent cells and did not affect non-COPD cells. The clearance of COPD small airway epithelial cells and fibroblasts by BCLXL-PROTAC was associated with an increase in the proliferation marker Ki67 and enhanced cell proliferation. Additionally, in precision-cut lung slices obtained from COPD patients, BCLXL-PROTAC significantly reduced p21CIP1 expression in the airway epithelium, validating its effectiveness in a more complex tissue environment.

These findings demonstrate that BCLXL-PROTAC is a potent and selective senolytic agent that may promote lung cell rejuvenation, supporting its potential as a novel therapeutic strategy for age-related diseases, including COPD.

Link: https://doi.org/10.1111/acel.70487

Senescent cells accumulate with age, but not all senescent populations are equal. Evidence suggests that some types of senescent cell cause more harm than others, and the research here is an example of this. Researchers find that a population of senescent macrophages in liver tissue acts as an important driver of chronic inflammation and dysfunction in liver aging and the metabolic liver disease associated with excess fat tissue that leads to cirrhosis and cancer. Senolytic therapies that selectively destroy the senescent macrophages reduce liver inflammation and liver dysfunction in mice, proving the point.

Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21+Trem2+ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling.

We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.

Link: https://doi.org/10.1038/s43587-026-01101-6

It is well established that long term exposure to forms of air pollution increases the risk of mortality and numerous age-related conditions. The mechanisms of interest revolve around increased systemic chronic inflammation that is provoked by the interaction of pollutants, such as fine particles, with airway and lung cells. Is this exposure and its consequences a form of accelerated aging? The question of whether one environmental factor or another accelerates aging forces us to consider how aging is defined and measured. Hitting people with hammers repeatedly will certainly increase mortality, and may even increase common measures of biological age, such as epigenetic clocks, but is it producing accelerated aging? One can debate the question, but clearly more biological data would be needed to actually answer it. Looking only at mortality or loss of function is insufficient, one has to also think about what is going on under the hood in the biochemistry of cells.

In today's open access paper, researchers correlate forms of air pollution, several different measures of biological age, and dementia risk. The greater the exposure to air pollution, the greater the increase in biological age measures and the greater the risk of dementia. Under the hood, there is more inflammation, a greater burden of senescent cells, and likely other features of aging to a greater degree. Biological age measures such as epigenetic clocks tend to obscure all of that, however. Senescent cell burden is perhaps a helpful way to think about the effects of exposure and whether those effects are in fact accelerating aging. Senescent cells accumulate with age, and the more there are the worse the outcome. They are a form of damage that negatively impacts tissue structure and function over time. We might consider any exposure that robustly increases senescent cell burden to be creating accelerated aging; consider obesity, for example, or chemotherapy. There are numerous other forms of aging-associated cell and tissue damage that we can measure, and to the degree that they are increased, we can suggest that this increase reflects an increased biological age.

Accelerated biological aging and brain structural alterations linking air pollution to dementia risk: a prospective cohort study

Air pollution is globally ubiquitous and has been identified as a risk factor for global disease burden. Limited epidemiological studies have linked air pollution to morphological brain alterations, with inconsistent findings, and most of them have focused only on a single type of regional brain region. Furthermore, although air pollution has been established as a risk factor for dementia, the underlying neurobiological mechanisms are poorly understood. Recent evidence suggests that air pollution may accelerate systemic biological aging.

Given that dementia is fundamentally an age-related neurodegenerative disorder, accelerated biological aging is a plausible, upstream mediator in the pathway from air pollution exposure to dementia. Since individuals age at different rates, quantifying biological aging rather than chronological age may reveal a more precise mechanistic link between exposure and health outcomes. Together, we propose a novel mechanistic hypothesis: exposure to air pollution may first accelerate systemic biological aging, which in turn drives the degeneration of specific brain structures, ultimately leading to the onset of dementia.

Therefore, using data from the UK Biobank, we aimed to: (1) examine the associations of long-term exposure to five air pollutants (PM2.5, PM10, PM2.5 absorbance, NO2, and NOx) with global gray/white matter volumes, 80 regional gray matter volumes, and incident dementia; (2) assess the association between biological age acceleration and both air pollution and incident dementia; and (3) investigate the mediating roles of biological aging acceleration and brain structure alterations underlying the air pollution-dementia association.

Cox proportional hazards regression models were used to evaluate the association between air pollution and incident dementia, while linear regression models were used to assess its associations with global and 80 regional brain structures. The mediating roles of biological aging acceleration (measured by Klemera-Doubal method Biological Age [KDM-BA] and PhenoAge) and brain structures in the air pollution-dementia association were evaluated using structural equation modeling (SEM).

Compared to participants with the lowest tertile of air pollution exposure, those in the highest exposure group had higher risks of dementia (Hazard ratio, HR: 1.141 for PM2.5; 1.09 for PM10; 1.09 for PM2.5 absorbance; 1.20 for NO2; and 1.14 for NOX). Air pollution exposure was inversely associated with global and several regional brain structural alterations. SEM revealed a consistent mediating pathway that integrates biological aging and brain structural alterations in the association between air pollution exposure and the risk of dementia.

Researchers here identify a common mechanism in the cellular responses to various forms of stress that appears to drive aspects of hematopoietic stem cell aging via impairment of mitochondrial function. Hematopoietic cells are responsible for generating immune cells and red blood cells. Aging produces alterations in the character and lineages of generated cells, contributing to dysfunction in the immune system and in platelet producing cells, among other issues. Suppressing some aspects of cellular stress responses, those that become maladaptive in the aged tissue environment, may prove to be useful as a basis for therapy. It nonetheless seems a poor alternative to instead repairing or otherwise addressing the forms of damage and dysfunction that provoke these excessive cell stress responses.

Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs.

The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death in HSCs but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.

Link: https://doi.org/10.1038/s41467-026-71060-4

In the context of Alzheimer's disease, the data for anti-amyloid immunotherapies, the most recent of which do effectively clear the aggregation of amyloid-β in the brain, is not compelling. Clinical trials and following studies show minimal to no benefit to patients even at earlier stages of the condition. There is some hope in the research and development community, where the amyloid cascade hypothesis remains dominant, that moving to even earlier deployment of these therapies might prevent the emergence of the condition, but the data obtained to date does not inspire optimism on this front. Other directions are much needed, perhaps restoration of cerebrospinal fluid drainage, for example, or more of a focus on chronic inflammation in brain tissue.

Alzheimer's disease is a neurodegenerative disorder and the most common cause of dementia. Aggregated amyloid-beta protein deposits are implicated in its pathogenesis. Amyloid-beta-targeting monoclonal antibodies (sometimes represented as Aβ-mAbs) are potentially disease-modifying for Alzheimer's disease: through the clearance of amyloid in the brain, they may slow cognitive and functional decline. In this meta-analysis we assess the clinical benefits and harms of amyloid-beta-targeting monoclonal antibodies aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab in people with mild cognitive impairment or mild dementia due to Alzheimer's disease.

The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action.

Link: https://doi.org/10.1002/14651858.CD016297