Fight Aging!

As 2025 winds to a close, it is time once again to look back at some of the aging and longevity research published in the past year. Matters do move forward, even in tough times. The research community continues to turn out interesting new papers, the XPRIZE Healthspan competition reached 100 participating teams, and the medical community continues to publicly wrestle with its instinctive resistance to treating aging as a medical condition, perhaps even making some progress towards adopting a better collective attitude to the challenge.

Yet we are closing in on the three year mark of an ongoing, terrible market for investment in biotechnology. This has impacted the longevity industry just as much as it has the rest of the human endeavor to develop new medical technologies. Funding has pulled back, and where it is available, it is largely only available for companies that have completed early clinical trials, representing only a small proportion of the industry as a whole. The preclinical side of the industry, which accounts for near all of the most promising projects relating to aging, age-related disease, and longevity, is slowed and diminished. Most companies lack the sizable funding needed to set up and conduct clinical trials no matter the merits of their potential therapies. It remains to be seen as to when matters will improve; investment funds cannot sit on the sidelines forever, but early signs of promise have repeatedly failed to blossom into a better market. Thus progress is much slower than is desired, even given the existence of a sizable faction that sees longevity medicine as the salvation for the pharmaceutical industry's financial woes.

A few notes from companies in the field follow, though admittedly following the industry is not my focus at the present time, and other organizations exist to undertake that task. Cyclarity Therapeutics started their first clinical trial of the ability to clear 7-ketocholesterol as a treatment for atherosclerosis, largely focused on safety, as is usually the case. Rubedo Therapeutics is one of the leading senolytics companies, and continues to make progress on a novel approach to killing senescent cells, focused on ferroptosis. Altos Labs, possessed of immense funding and a focus on reprogramming, is now expanding that focus to senotherapeutics; whether or not this is a good idea will likely remain unclear for some time. Another senolytics company, UNITY Biotechnologies, fell victim to the doleful market and ceased operations following a clinical trial that was not impressive enough for continued operations. Mitrix Bio is commencing a small initial trial of mitochondrial transfer in aged volunteers. Unlimited Bio is planning the similar small trial for VEGF gene therapy. Stealth Biotherapeutics received a rare disease approval for SS-31, though by this point we know less than we thought we did as to how this molecule primarily works to improve mitochondrial function. Lastly for now, well-funded and secretive cryonics company Until Labs is being more open about their work on reversible vitrification these days.

Moving on to interesting research, as was the case last year I'll restrict myself to work relevant to the Strategies for Engineered Negligible Senescence (SENS) categories of causative damage of aging, plus a few other topics that seem relevant to the endeavor of treating aging as a medical condition. I continue to favor SENS over the Hallmarks of Aging as a guide to areas and types of interventions. The rest of this post should be considered a sampling of the high points, and omits, for example, research into calorie restriction and its mimetics (and the same for exercise!), particularly the strong focus on induction of autophagy, as well as much of the present interest in proximate causes of immune aging and chronic inflammation, including efforts to suppress inflammatory signaling. These are interesting and relevant areas of research and development, but one has to draw the line somewhere.

Cell Loss / Atrophy

The atrophy of the thymus is particularly important to immune aging, as this small organ is where thymocytes generated in bone marrow mature into T cells of the adaptive immune system. A range of approaches to restore greater thymic activity in old age are under development at various stages, such as delivery of RANKL as a protein therapy or increased secretion of amphiregulin by regulatory T cells.

Damage and dysfunction in hematopoietic stem cells is another issue driving immune aging. This issue is multifaceted; for example, dysfunctional clusterin positive cells expand with age at the expense of other hematopoietic cells, but equally IL-10 signaling appears to be an important driver of dysfunction in the hematopoietic population, as does lysosomal dysfunction resulting from excessive acidification. Researchers are interested in finding novel ways to restore lost hematopoietic function. For example, RhoA inhibition improves function in aged hematopoietic stem cells. Delivery of new hematopoietic cells to replace those become damaged and dysfunctional is possible, given a robust source of patient-matched cells, and researchers recently developed a way to manufacture hematopoietic stem cells for this purpose.

Looking beyond the immune system, regenerative medicine aimed at restoring lost and damaged tissues continues to advance, in the lab and in the clinic. PDGF-BB protein therapy encourages nerve regrowth, while extensive work is conducted on cell therapies that might be developed to treat neurodegenerative conditions. This includes transplantation of neural stem cells, shown to improve recovery following stroke, and delivery of mesenchymal stem cell extracellular vesicles, shown to improve cognitive function in aged non-human primates. Alternatively, provoking greater neurogenesis is favored as a way to induce the creation of new neurons to replace those lost to damage and aging. Similar strategies may help regenerate a lost sense of smell. Axon regrowth is as necessary as the introduction of new cells, and ETBR inhibition encourages greater regeneration here.

A selection of other recent relevant work follows. Delivery of prostaglandin E2 improves stem cell function in aged muscle tissue. The engineering of thin patches of cardiac tissue for delivery to an injured heart continues to make slow progress. Thin patches of new cells are also in clinical trials for retinal degeneration. Alternative efforts aim to promote greater regenerative behavior on the part of existing cells in the heart, such as via CCNA2 upregulation. Degeneration of the tectorial membrane in the ear was noted as a novel cause of age-related hearing loss. Researchers identified targets for improving the regeneration of alveolar cells in the lung. Delivery of cysteine improves intestinal stem cell function. Adipose derived stem cell therapy was shown to encourage regrowth in bone fractures. 15-PGDH inhibition encourages cartilage growth, a goal that remains a challenge for the research community. Delivery of extracellular vesicles restores pancreatic beta cell function in aged mice. Finally, loss of capillary density in tissues seems an important feature of aging, and exercise can partially reverse this loss in muscle tissue.

Mutation and Other Damage to Nuclear DNA

You might recall evidence for repair of double strand breaks in nuclear DNA to cause the epigenetic changes characteristic of aging. More evidence on this front was published this year, showing that induced DNA damage leads to lasting epigenetic change in cells, and also in the brains of mouse models of Alzheimer's disease. Researchers have further proposed another novel way beyond double strand break repair in which mutational damage to nuclear DNA can provoke epigenetic changes characteristic of aging. This is an important area of study, still in need of a greater weight of evidence, but for there to be a strong link between random mutation and age-related epigenetic change is a compelling story.

Somatic moasicism is the spread of patterns of mutations through tissues due to their occurrence in the stem cell populations supporting that tissue. This seems one of the few ways in which specific mutations harmful to cell metabolism could induce noticable dysfunction in tissue - otherwise near all such harmful mutations occur in too few cells to matter, and in genes that are not even used by those cells. On this front, recent work suggests that somatic mosaicism can contribute to muscle aging. Random mutation of lamin A, the gene involved in the inherited condition progeria, may also contribute meaningfully to normal aging and age-related conditions such as chronic kidney disease, but here also a compelling weight of evidence has yet to be assembled.

Activation of transposable elements in the genome occurs with age. The ability of these remnants of ancient viral infections to stochastically alter the genome is likely an important mechanism of evolutionary change, but it may also provide a meaningful contribution to degenerative aging. While the relationship is clearly complex, supporting evidence continues to accumulate. Greater immune defense against human endogenous retrovirus K correlates with greater longevity in our species, for example. Treatment of HIV and hepatitis B with antiretroviral drugs shows some signs of being able to slow the onset of Alzheimer's disease, theorized to be because it suppresses transposable elements. Nonetheless, nothing is completely straightforward, and it appears that the activation of some transposable elements may be important in nerve regeneration.

In terms of what to do about DNA damage, a few potential options exist at an early stage of development, some more practical in the near term than others. Reprogramming to reset epigenetic changes is a prominent option. Researchers have shown that increased protein disulphide isomerase expression slows the accumulation of nuclear DNA damage. Naked mole rats exhibit extremely efficient DNA repair; transferring the naked mole rat version of cGAS into mice and flies improved DNA repair to slow aging.

Mitochondrial Dysfunction

Mitochondrial dysfunction is a feature of the age-related loss of function in every tissue. You'll find comprehensive reviews published on its role in aging every year, and the past year was no exception. Mitochondrial dysfunction isn't just a matter of reduced production of the chemical energy store molecule ATP. Mitochondria are tightly integrated into many cell functions, and these are also negatively impacted by mitochondrial dysfunction in aging.

In muscle aging mitochondrial dysfunction is clearly impactful, as muscles require a great deal of energy. Muscle also generates signals that affect other tissues, and thus we see that better mitochondrial function in muscle correlates with slower brain aging. The brain also requires a lot of energy, and mitochondrial dysfunction is thought to be important in the aging of many types of brain cell. Microglia exhibit age-related mitochondrial dysfunction, for example. Mitochondrial dysfunction is also linked to disrupted cholesterol metabolism in the aging brain. Looking beyond the brain, we might also consider mitochondrial dysfunction in the aging of ovaries via increased mitochondria-driven inflammation, intervertebral discs, and the aging of cartilage, and other tissues.

Mitochondrial DNA damage is one contribution to dysfunction. Increased levels of mitochondrial DNA damage prevent life extension produced by manipulation of insulin signaling in mice, indicating the importance of mitochondrial function to this aspect of the regulation of aging. That said, there is some debate over whether the primary animal model for mitochondrial DNA damage, the POLG loss of function mitochondrial mutator mice, are actually useful: an alternative approach to generate a high burden of similar mutations failed to produce mitochondrial dysfunction.

Researchers continue to explore novel and established classes of approach to improve mitochondrial function in aged tissues. Some cells in the body, such as the well protected oocytes, appear to resist the accumulation of mitochondrial DNA damage. Perhaps something might be learned from that biochemistry. SS-31 was finally approved by the FDA as elamipretide, through it remains unclear as to how it primarily functions to improve mitochondrial function. Exercise improves mitophagy but we need to do better than this. Inhibiting calcium uptake improves mitochondrial function and slows aging in nematode worms.

Transplantation of harvested mitochondria into old individuals has shown promise in animal studies, and the field is now attempting to build robust manufacturing approaches to generate the large numbers of mitochondria needed for therapies. Approaches to engineering those mitochondria before transplanting them is also an area of intense research. The use of drugs designed to stimulate mitochondrial G proteins shows promise to improve mitochondrial function. Additionally, mitochondrial electron transport chain complexes can join together to form supercomplexes, and inducing more supercomplex formation improves mitochondrial function to slow aging.

Increasing mitochondrial biogenesis can help in a range of contexts, achieved via approaches such as targeting PP2A-B55α or delivering molybdenum disulphide nanostructures into mitochondria. As an alternative point of focus, a range of efforts to improve the mitochondrial quality control processes of mitophagy exist, such as delivery of fluoropolymer nanoparticles and use of pulsed electromagnetic fields. Tuning the mitochondrial dynamics of fusion and fission to adjust important mitochondrial characteristics known to change with age, such as size, can also in principle be used to generate more efficient mitochondrial quality control.

Extracellular Matrix Damage

Far too little work is conducted on the aging of the extracellular matrix, and we remain fairly distant from any sizeable number of potential therapies based on manipulating or repairing the structures of the extracellar matrix. This remains the case even when including work on advanced glycation endproducts (AGEs), an important area of study in extracellular matrix aging, as AGEs contribute to aspects of aging such as muscle loss and frailty in older people. Some of this is via their impact on cell receptors, but a sizable fraction is thought to involve interactions with the extracellular matrix, such as formation of cross-links.

Still, new knowledge continues to arrive from those few labs focused on extracellular matrix aging. For example, we might note a recent review of heart tissue extracellular matrix aging that discusses the potential to use this understanding to improve cell therapies for heart regeneration. Chronic inflammation in heart tissue drives detrimental extracellular matrix remodeling, a mechanism and outcome that is seen in other tissues as well. Researchers have noted that isoDGR modifications to extracellular matrix molecules increase with age in lung tissue, and can be targeted for removal via immunotherapy. Researchers have shown benefits to extracellular matrix structure in degenerative disc disease by delivering just one matrix component into disc tissue. Researchers are also making progress on an artifical elastin that can be delivered to improve cell and tissue function.

Senescent Cells

The accumulation of senescent cells occurs in tissues throughout the body in later life, and is a contributing cause of many undesirable age-related changes, lost function, and subsequent disease. This is now an intensely studied aspect of the biology of aging. From just the past year, a selection of studies spans the breadth of the body in linking age-related declines to an increased burden of senescent cells: impaired production of saliva; the features of ovarian aging; forms of treatment-resistant epilepsy; muscle aging; benign prostate hyperplasia, where immune aging aggravages the behavior of senescent cells in the prostate; the aging of the lens of the eye; senescent macrophages inhibit vascularization in aged tissues; endothelial senescence contributes to atherosclerosis via a number of mechanisms; cardiovascular disease more generally, ever a popular topic; the secretions of senescent cells correlate with mild cognitive impairment; type 2 diabetes correlates with a greater burden of cellular senescence; senescence in osteoblasts contributes to osteoporosis; senescence is involved in a range of skeletal diseases; senescent microglia attack and destroy synapses; some fraction of the harms of obesity are caused by excess senescent cells; virus-induced senescence may cause lasting consequences following respiratory infection; senescence in oligodendrocyte precursor cells contributes to numerous aspects of brain aging; and senescent endothelial cells create a cascade of issues in aging skin/

For all the promise of clearing senescent cells and interest in progress in this field of development, particularly neurodegenerative conditions, it remains the case that clinical trials of established approaches to senotherapy continue to be small, producing promising results that could have been much more compelling were the trial larger. For example, this year results were publishd for a 12 patient trial of dasatinib and quercetin in mild cognitive impairment. Results also emerged for the UNITY Biotechnologies trial for macular edema, but were not good enough for the company to survive the present bad market, and it has since ceased operations.

While the trial landscape remains frustratingly small and slow, approaches to reduce the number or reduce the bad behavior of senescent cells continue to demonstrate their merits in animal studies. Examples from the past year include: reducing periodontal bone loss and treating periodontitis more generally; reducing surgery-induced neuroinflammation; improving the condition of degenerating intervertebral discs and consequent lower back pain; slowing progression of Alzheimer's disease; fisetin is still being used as a monotherapy to produce benefits in aged mice, yet we are still waiting on a human clinical trial of fisetin that actually publishes the results; and a senolytic prodrug reduced osteoathritis symptoms in mice.

Novel forms of senotherapy development in the laboratory include the use of ultrasound to make senescent cells alter their behavior in ways that make them more vulnerable to clearance by the immune system. Inducing elastin expression appears to reduce cellular senescence for reasons unrelated to its role in the extracellular matrix, and which have yet to be fully explored. A range of evidence suggests the burden of senescent cells is some degree dynamic, for example a study of the effects of exercise in obese individuals noted a small reduction in the burden of senescence over time. Similarly the OneSkin topical senotherapeutic is probably not meaningfully senolytic but instead acts on the pace of creation and clearance of senescent cells over time to reduce the level of of senescent cells. Pyrroloquinoline quinone is a senomorphic agent, reducing inflammatory signaling by senescent cells. β-hydroxybutyrate supplementation slows the accumulation of senescent cells. Injected 25-hydroxycholesterol is senolytic to senescent cells in the vasculature. Recombinant PDGF reduces the burden of senescent cells involved in intervertebral disc degeneration. The chemotherapeutic cabozantinib acts to reduce senescent cell inflammatory signaling. The body naturally clears dead cells, and the signaling used can in principle be repurposed to destroy any unwanted cell, such as senescent cells. Mesenchymal stem cell transplantation has been shown to have senomorphic effects, reducing inflammation. Urolithin A supplementation and the butyrate produced by gut microbes are also suggested to be senomorphic. Inhibiting the increased glycolysis used to power the energetic senescent cell metabolism turns out to be senolytic. Triggering ferropotosis rather than apoptosis can also kill senescent cells, an approach amenable to the construction of prodrugs activated by the high levels of β-galactosidase in senescent cells. Targeted delivery of existing senolytics to features of senescent cells is an ongoing project, attempting to reduce off-target effects of the strongest chemotherapeutic senolytics. For example, targeting the lipofuscin present in senescent cells.

There are so few examples of clearance of senescent cells failing to improve an age-related condition in animal models that new ones are worthy of note. This year, researchers showed that senolytic treatment failed to improve resistance to influenza in aged mice. On a separate but related topic, while reduced senescence appears beneficial to cardiovascular function, there is some concern that a well established population of senescent cells may be structurally important to atherosclerotic plaque, even as they make atherosclerosis worse. So there is more caution in developing the use of senolytics for cardiovascular disease than for other indications.

The biochemistry of senescence is an area of intense focus, as any new advance in understanding has the chance to act as the basis for therapies to clear senescent cells, prevent their creation, or suppress their bad behavior. For example GATA4 appears important in the senescence of stem cells. In particular, GATA4 is involved in the enlargement of cells on entering the senescent state, as is AP2A1. A clever study showed that this enlargement is essential for much of the harmful behavior of senescent cells, as sabotaging it dramatically reduces inflammatory secretions. m6A RNA modifications are associated with the senescent state. Surface markers distinct to senescent cells include LAMP1A. The Hippo pathway, already well-investigated in the context of regeneration has been connected to the induction of cellular senescence. ADAM19 knockdown reduces pro-inflammatory signaling by senescent cells. It appears that p62 and its interaction with autophagy has an important role in senescence in at least some cell types. HMGB1 is important in induction of bystander senescence in nearby cells. The behavior of senescent cells is different depending on the cell cycle phase in which senescence occurred. Senescent cells accumulate iron while resisting ferroptosis, potentially adding additional ways to provoke cell death by sabotaging that resistance. The CCND1-CDK6 complex seems important in driving senescent cell behavior, and is therefore a target for potential approaches to therapy.

The cancer research community continues to explore how to use senotherapeutics to best effect in the context of treating cancer. It is hard to tell in advance whether it will help or hinder cancer therapies in any specific case, though one sees examples such as evidence for senescent macrophages to accelerate tumor growth, while senolytic vaccines slow tumor growth in similar animal models.

One of the consequences of a strong focus on the biochemistry of senescence is a growing ability to reverse aspects of the normally irreversible senescent state. The question remains open as to whether this is a good idea in practice, as some senescent cells are senescent for good reasons, such as potentially cancerous DNA damage. Nonetheless, a variety of options have been explored. In just the last year: expression of the microRNA miR-302b reverses senescence to produce rejuvenation in mice; low frequency ultrasound reverses senescence; PURPL inhibition partially reverses the senescent state.

Better understanding how immune surveillance of senescent cells changes with age may help to fix the declining clearance of senescence cells in older individuals. A few examples of relevant research from the past year: SMARCA4 inhibitors enhance natural killer cell clearance of senescent cells, while senescent cells express GD3 to try to evade natural killer cells; researchers are considering various approaches to the development of senolytic vaccines to provoke immune clearance of senescent cells; γδ T cells are involved in clearance of senescent cells.

Intracellular and Extracellular Waste, Including Amyloids

There is a lot of new theorizing around the role of amyloid-β in Alzheimer's disease. For example that the problem is that production is stalled at an intermediate state, promoting dysfunction. Or the question of whether aggregates spread from neuron to neuron to cause dysfunction, or whether dysfunction in neurons induces aggregation. Or the degree to which amyloid-β aggregation is a consequence of persistent viral infection. Or that only some amyloid-β oligomers are the problem, not amyloid-β per se. Regardless, it is clearly the case that the aged brain is more vulnerable to amyloid-β than is the case in a young brain. There are many approaches to Alzheimer's disease that do not involve targeting amyloid-β, but none of those are yet producing compelling results in clinical trials either.

Protein aggregation isn't restricted to just the few well known culprits that exhibit excessive aggregation. Researchers have shown that hundreds of proteins transiently aggregate to some small degree in aging cells in the brain, it is a pervasive issue, and the collective contribution to dysfunction may be important. HAPLN2 aggregation may stand out as particularly problematic for its negative impact on microglia.

Promotion of autophagy to try to clear protein aggregates in the context of Alzheimer's disease and other conditions is a popular area of study. For example via upregulated KIF9 expression or UCP4A inhibition. Alternatively, researchers are also interested in ways to inhibit the formation of aggregates, such as via use of peptide amphiphiles. Researchers have found that aggregates need to be broken up to encourage clearance, and so enhancing this fragmentation is a new goal for drug development. Further novel approaches include enhancing greater export of amyloid-β through the blood-brain barrier and supplementing large amounts of arginine, which acts as a chaperone to reduce amyloid-β aggregation.

An different avenue is to improve the function of microglia, to either reduce their inflammatory behavior or increase their capacity to clear aggregates. TIM-3 inhibition or ADGRG1 upregulation in microglia encourages amyloid-β clearance, for example. Removing and recreating the whole population of microglia in the brain is thought to be promising, given the issues caused by dysfunctional microglia. Unfortunately this produces only transient reductions in amyloid-β in a mouse model of Alzheimer's disease.

Moving on from amyloid-β to α-synuclein, associated with Parkinson's disease, it was noted this year aggregates of misfolded α-synuclein appear to disrupt lipid metabolism in addition to the other harms caused, such as breaking down ATP needed for cell function, disruption of DNA repair, and increased DNA damage. New contrast PET scan approaches seem likely to be useful in distinguishing patents with aggregated α-synuclein. Increased air pollution is linked to increased α-synuclein aggregation. Researchers have suggested that specific mitochondrial dysfunction in Parkinson's disease contributes to α-synuclein aggregation, the opposite of the usual view of causation. Analogously, researchers have suggested that α-synuclein aggregation requires ubiquilin-2 to initiate the process, also indicating that upstream mechanisms may be a more important target than the α-synuclein itself.

Diminished flow of cerebrospinal fluid from the brain to the body is a waste clearance issue, as this flow acts to remove metabolic waste from the brain. The glymphatic system and cribriform plate are two well-described paths for cerebrospinal fluid to leave the brain. Efforts to clear amyloid in the brain do not improve glymphatic drainage, support for the arrow of caustion to be from drainage to the buildup of aggregates. Lost glymphatic function correlates with cognitive impairment, a result shown in several human studies. It also correlates with cerebral small vessel disease. Researchers demonstrated that VEGF-C gene therapy can restore some lost gymphatic system drainage of cerebrospinal fluid in animal models, most likely by promoting creation of new lymphatic vessels.

Tau protein becomes excessively phosphorylated and aggregates as a result in Alzheimer's disease and other tauopathies. Researchers have now shown that only one of the six isoforms of tau is important to pathology. Further, additional evidence has emerged for tau aggregation causes blood-brain barrier dysfunction. Returning to the question of a viral contribution to Alzheimer's disease, it was noted that viral proteins colocate with tau, potentially promoting its dysfunctional aggregation.

TDP-43 is another protein capable of forming aggregates linked to neurodegenerative conditions. TDP-43 aggregates have been shown to disrupt DNA repair mechanisms and cause leakage of the blood-brain barrier, among other issues. Researchers recently identified a possible approach to treating TDP-43 pathology by decorating it with a molecule that causes it to be sequestered into stress granules rather than forming aggregates. In addition upregulation of microRNA-126 touches on similar mechanisms to prevent TDP-43 pathology.

Transthyretin amyloidosis is arguably as important to cardiovascular aging as amyloid-β is to the aging of the brain, but this point is not as widely recognized. Transthyretin amyloidosis is increasingly shown to be prevalent in old people, but the very severe cases are still quite rare, and thus it remains treated as a rare disease, and only in fact treated in the most severe cases. So while a panoply of drugs exist to reduce this amyloid burden, they are not widely used.

Lipofuscin should probably not be a trailing last thought in this survey of recent research into metabolic waste and the harms that result from its aggregation with age, but there you have it. Lipofusin and what to do about lipofuscin are relatively poorly studied topics, and the literature is sparse in comparison to that for protein aggregates. Viable approaches to clearing out lipofuscin from long-lived cells such as neurons of the central nervous system have yet to be developed.

Reprogramming

Partial reprogramming or epigenetic reprogramming is the exposure of cells to Yamanaka factor expression for long enough to reset epigenetics to a youthful pattern, but not long enough to have any risk of inducing a change in cell state. This is a basis for potential rejuvenation therapies that may act to restore lost cell function in aged tissues. A great deal of funding is devoted to this area of research and development relative to the rest of the longevity industry. The near future of reprogramming may involve an emphasis on small molecule drugs capable of inducing Yamanaka factor expression, if only because whole-body delivery of gene therapies remains a challenge. The RepSox and tranylcypromine combination is currently a popular choice for studies, a combination also known as 2c to distinguish it from the 7c cocktail of which it is a part. Meanwhile, alternative approaches to reprogramming-like outcomes are being discovered. TOP2B is involved in maintaining DNA structure, and reducing its expression makes epigenetic patterns more youthful, improving health in aged mice.

The future will certainly involve an emphasis on separating desired epigenetic rejuvenation from undesirable dedifferentiation and loss of cell state, finding where in the complex web of regulating genes the dividing line between these two outcomes lies. Progress is already being made on this front. The activity of GSTA4 and its relationship with OCT expression is attracting attention as a potential point of focus.

The central nervous system is a focus for much of the presently ongoing work on reprogramming. This includes the prominant goal of treating Alzheimer's disease, but looks beyond that to other conditions as well. Reprogramming in retinal ganglion cells helps resist inflammation driven neurodegeneration, for example, while reprogramming targeted to the hypothalamus slows ovarian aging.

Gut Microbiome

The aging of the gut microbiome is a matter of shifting composition, changes in the relative proportions of different species and their activities, beneficial or harmful. This is notably different between sexes, and interestingly also between mitochondrial haplotypes. It is by now well established to correlate with and likely contribute to age-related disease. Some degree of this aging process may be driven by the use of antibiotics and other pharmaceuticals.

Researchers have presented evidence for changes in the gut microbiome to contribute to age-related conditions and shown correlations between gut microbiome composition and specific conditions in epidemiological studies. A brief survey of examples from the past year follows: effects of the gut microbiome on the development of sarcopenia, a popular area of study; gut microbiome changes correlate with loss of cognitive function and otherwise harm the brain, potentially via increased inflammatory signaling; specific features of the gut microbiome appear in Alzheimer's disease patients and similarly for Parkinson's disease; the gut microbiome causes issues that can be argued to contribute to the genomic instability and telomere erosion hallmarks of aging; phenylacetic acid produced by gut microbes is harmful to the vasculature; aging of the gut microbiome may contribute to forms of somatic mosaicism; some epidemiological data can offer support for causation in the relationship between gut microbiome and age-related diseases; the gut microbiome generates imidazole propionate to accelerate development of atherosclerosis; the aged gut microbiome accelerates the onset and progression of heart failure; the oral microbiome and gut microbiome interact in ways that change with age and might actually be important; evidence suggests a a bidirectional relationship between the gut microbiome and kidney dysfunction.

Nonetheless, there are aspects of aging where the gut microbiome may have a lesser impact. There appears to be little correlation between gut microbiome composition and age-related loss of bone density, for example, one modest reprieve for which we can all be appropriately thankful.

In terms of approaches to favorably change the aged gut microbiome, a few new results were published this year: doxifluridine treatment changes the behavior of microbes by affecting RNA splicing, with the effect of extending life in nematodes; fecal microbiota transplantation from young donors decreased measures of cardiovascular dysfunction in aged rats; separately, fecal microbiota transplantation from young to old rats improved memory function; separately again, fecal microbiota transplantation improves health in old mice; the old standby of calorie restriction improves the gut microbiome alongside slowing aging; and approaches to enhance production of specific beneficial metabolites could be useful, including mesaconic acid, 10-HSA, and colonic acid; increasing the presence of Bifidobacterium adolescentis reduces fibrosis in aging tissues;

Aging Clocks

Aging clocks are made using well established machine learning approaches to the analysis of any sufficiently large body of biological data derived from individuals of various ages. The result is an algorithm that is throught to reflect biological age, or some proxy for it. The world is now repleat with aging clocks of many varieties, and the research community continues to produce more at a fair pace. In just the last year clocks have been derived from data on immunosenescence; abdominal CT imagery; plasma metabolite levels; entropy in DNA methylation states; transcriptomics in microglia; the Healthspan Proteomics Score from UK Biobank proteomics data; clinical tests for sarcopenia assessment; a set of 25 other clinical measures; a different set of clinical measures; combined DNA methylation and inflammatory marker data; skeletal muscle transcriptomic data; and wearable device measurement of blood flow.

Clocks with outcomes other than a predicted age are also being created at a fair pace. Just this year: a clock that predicts intrinsic capacity rather than age, based on proteomics; a pace of aging clock built on clinical measures rather than omics data; several examples of further exploration of organ specific proteomic clocks that produce age assessments for individual organs rather than the individual as a whole.

Of course the list of caveats and challenges grows with time alongside the number of clocks: epigenetic clocks are typically trained on data from one tissue, and thus tend to produce different results by tissue type; even the mainstream clocks still need a lot more calibration against various long-standing interventions known to produce small changes in mortality. On this topic, you might recall that the Horvath clock appeared insensitive to exercise based on Finnish Twin Study data. It turns out that in this study exercise didn't appear to affect mortality. This is an unusual result, but it seems that the Horvath clock was not in error in this case.

Gathering more data on the relationship of clocks to as many different established metrics and outcomes as possible is an important project, and the only way to gain confidence in the value of any given clock. A few examples of this sort of work from the past year: showing that Cardiometabolic Index correlates with Klemera and Doubal accelerated biological age, as does mortality and risk of disease; researchers assessed the Organage clock in old blood samples; correlating insulin resistance with accelerated clock age; heat stress from hot weather accelerates epigentic age; assessing the effects of sedentary behavior and physical activity on aging clocks; a number of studies show reduced epigenetic age to correlate with degree of physical activity; therapeutic plasma exchange reduces epigenetic age in some clocks; GrimAge and GrimAge2 clocks are equivalent in predicting mortality; GLP-1 receptor agonists modestly reduce epigenetic age in obese individuals; accelerated epigenetic aging correlates with cognitive decline; greater epigenetic age correlates with osteoporosis risk; researches have applied clock algorithms to the longest-running epidemiological study, its participants born in the 1940s; assessing the reslationship between epigenetic age and frailty.

A Few Articles

• Request for Startups in the Rejuvenation Biotechnology Space, 2025 Edition
• Potential Roads for Upheaval Ahead in Medical Regulation in the US
• The Catalytic Antibody Work of Covalent Biosciences is Headed for the Public Domain
• Later Investors Eliminating the Ownership of Early Investors is an Ugly Reality in Longevity Biotech

Looking Ahead to 2026

It has become something of a dark year-end joke in the longevity industry to point out the signs of a bad market that has run its course, in expectation of an upturn in the year ahead ... and that we all remember saying exactly the same thing last year and the year before. That upturn has yet to arrive. It is the case that, insofar as there is such a thing, the average industry downturn only lasts a year. Present circumstances are clearly far from the average.

Still, the engines of creation continue. Scientists have not stopped in their pursuit of an understanding of aging and emplying that understanding in the production of interventions that can slow and reverse aging. If anything, this field continues to grow year over year. Acceptance of the ability to treat aging as a medical condition, even if we are still in the relatively early years of that project, is near universal. At some point, the engines of finance will start up again and efforts to implement these ideas as practical, accessible therapies will press forward at a better pace.

Mitochondrial uncoupling involves directing a greater fraction of the energetic activity of the electron transport chain in mitochondria to produce heat rather than the adenosine triphosphate (ATP) chemical energy store molecule needed to power cell operations. This uncoupling is how mammals maintain body temperature. Small molecules can be used to increase uncoupling. One of the effects of this approach is weight loss. Another is modestly slowed aging.

One of the earliest mitochondrial uncoupling drugs, 2,4-dinitrophenol (DNP), was inadvertently discovered a century ago, and used for a time for weight loss. DNP is too dangerous for present tastes, however; too much uncoupling is fatal, and the effective dose of DNP is a little too close to the lethal dose for comfort. The problem of how to avoid excessive uncoupling is the challenge facing any attempt to produce a safer mitochondrial uncoupler, but prompted by the prevalence of obesity and the financial success of existing weight loss drugs, the research community is returning to this line of work.

A new study focused on 'mitochondrial uncouplers'. These are molecules that make cells burn energy less efficiently, and release fuel as heat instead of converting it into energy the body can use. Compounds that induce mitochondrial uncoupling were first discovered around a century ago, however these early drugs were lethal poisons that induced overheating and death. During World War I, munitions workers in France lost weight, had high temperatures and some died. Scientists discovered this was caused by a chemical used at the factory, called 2,4-Dinitrophenol or DNP. It was briefly marketed in the 1930's as one of the first weight-loss drugs. It was remarkably effective but was eventually banned due to its severe toxic effects. The dose required for weight loss and the lethal dose are dangerously close.

In the new study, researchers created safer "mild" mitochondrial uncouplers by precisely adjusting the chemical structure of experimental molecules, allowing them to fine-tune how strongly the molecules boost cellular energy use. While some of the experimental drugs increased the activity of mitochondria without harming cells or disrupting their ability to produce ATP, others created the same risky uncoupling seen with the older, toxic compounds.

This discovery allowed the researchers to better understand why the safer molecules behave differently. The mild mitochondrial uncouplers slow the process to a level that cells can handle, protecting against adverse effects. Another advantage of mild mitochondrial uncouplers is that they reduce oxidative stress in the cell. This could improve metabolic health, provide anti-aging effects and protect against neurodegenerative diseases such as dementia. While the work is still at an early stage, the research offers a framework for designing a new generation of drugs that could induce mild mitochondrial uncoupling and harness the benefits without the dangers.

Link: https://www.uts.edu.au/news/2025/12/scientists-boost-cell-powerhouses-to-burn-more-calories

Reduced cerebral blood flow is an important component of loss of function in the aging brain. A number of different mechanisms contribute to this issue, including heart failure and thus a reduced ability to pump blood uphill to the brain, loss of capillary density with age, and various impairments in the small-scale regulation of blood flow via contraction and dilation of vessels. The research here focuses on mechanisms relevant to this latter vessel based control over blood flow, demonstrating a way in which these mechanisms can be manipulated to improve the flow of blood into the brain.

Brain capillaries are sensors of neural activity. When a brain region is active, capillary endothelial cells (ECs) sense neuron-derived mediators and elicit a local increase in blood flow (functional hyperemia) to support the rise in metabolic needs. This hyperemic response involves a rapid electrical component and a slower chemical component that involves Gαq PCR (GqPCR) activation by agonists released from neurons. The intravascular forces associated with hyperemia engage mechanosensitive Piezo1-mediated signaling that serves a mechano-feedback control function to facilitate the return of elevated blood flow to basal levels.

Whether GqPCR activity influences Piezo1 mechanosensitive signaling has not been explored, despite the potential significant implications of such crosstalk. Using patch-clamp electrophysiology and freshly isolated brain capillary ECs, we demonstrate that prostanoid or muscarinic GqPCR activation facilitates Piezo1 activity. Pharmacological studies revealed the involvement of Gαq and phospholipase C stimulation, as well as downstream phosphatidylinositol-4,5-bisphosphate (PIP2) hydrolysis in Piezo1 activation.

Exogenous application of nanomolar-to-micromolar PIP2 suppressed Piezo1 open probability. Brain capillary ECs from mouse models of Alzheimer's disease, cerebral small vessel disease, or Piezo1 gain-of-function mutation exhibited higher Piezo1 activity, that was corrected by exogenous ex vivo PIP2 application. We finally tested in vivo the hypothesis that systemic PIP2 administration restores functional hyperemia in EC-specific Piezo1 gain-of-function mutant mice suffering impaired blood flow. Our findings provide insights into Piezo1 channel regulation and how it affects neurovascular coupling and cerebral blood flow.

Link: https://doi.org/10.1073/pnas.2522750122

Control of hypertension is arguably one of the best success stories for small molecule drug development relevant to aging, emerging from an era prior to any meaningful attempt to address the root causes of age-related conditions. The results are about the best one could expect from this compensatory manipulation of cell behavior, in that the problem of high blood pressure can be made to go away in a sizable portion of patients, with an acceptable profile of side-effects. This is in large part an outcome that results from the nature of the regulation of blood pressure, in which multiple very different systems exhibit multiple very different avenues for changing their behavior. One can pick and choose from ways to target the kidney's regulation of blood volume, the dilation of vascular smooth muscle, or even heart rate if the goal is to reduce blood pressure.

Despite the present range of antihypertensive drugs, or perhaps because of it given that investment tends to cluster in areas in which success is already proven, research and development continues apace. Considerable funding and effort is devoted to building the foundations of incrementally better antihypertensive drugs, based on an improved understanding of the regulation of blood pressure and the various proteins involved in that complex process. Today's research materials are one example of many.

Yet still, none of this panoply of programs and therapies target the underlying causes of hypertension, the damage and dysfunction of aged tissues that gives rise to manifestations such a raised blood pressure. Those underlying causes continue to cause other harms, and aging progresses. If control by compensation is all that can be achieved, then that is what should be done. But far better approaches to age-related disease can be produced in principle, actual rejuvenation therapies that will treat age-related conditions by removing their causes.

Key protein ACE2 could protect against high blood pressure and diabetes

Researchers analysed nine key proteins in over 45,000 blood samples from the UK Biobank. ACE2 levels were increased in individuals with a diagnosis of high blood pressure or diabetes, both of which are risk factors for heart disease. The effect was seen particularly in females and was influenced by changes in genes that are associated with diabetes. Using a genetic analysis method called two-sample Mendelian randomisation, the researchers found evidence that these higher ACE2 levels may, in fact, be trying to protect against high blood pressure and type-2 diabetes. ACE2 breaks down angiotensin II, a compound that tightens blood vessels, and produces substances that relax blood vessels. In this way, the elevated levels of ACE2 seen in individuals with high blood pressure may be compensatory, by helping to relax constricted blood vessels.

ACE inhibitors are common drugs for treating high blood pressure and work by blocking the ACE1 protein which, in contrast to ACE2, makes angiotensin II. These findings could influence how ACE inhibitor drugs are used and by which patients, as it's likely that ACE2:ACE1 balance has a role in how successful ACE inhibitors are in treating blood pressure. Individuals with naturally altered levels of ACE2 may be better suited to certain ACE inhibitors, and this may lead to more tailored treatments based on blood ACE2 levels. Future research will explore whether increasing ACE2 activity or mimicking its effects could improve treatment for high blood pressure and diabetes. Previous preclinical studies of a common anti-diabetic drug, metformin, showed that it increases ACE2 expression as part of its action.

Circulating Cardiovascular Proteomic Associations With Genetics and Disease

To understand the relationships between circulating biomarkers and genetic variants, medications, anthropometric traits, lifestyle factors, imaging-derived measures, and diagnoses of cardiovascular disease, we undertook in-depth analyses of measures of 9 plasma proteins with a priori roles in genetic and structural cardiovascular disease or treatment pathways (ACE2, ACTA2, ACTN4, BAG3, BNP, CDKN1A, NOTCH1, NT-proBNP, and TNNI3) from the Pharma Proteomics Project of the UK Biobank cohort (over 45,000 participants sampled at recruitment).

We identified significant variability in circulating proteins with age, sex, ancestry, alcohol intake, smoking, and medication intake. Phenome-wide association studies highlighted the range of cardiovascular clinical features with relationships to protein levels. Genome-wide genetic association studies identified variants near GCKR, APOE, and SERPINA1, that modified multiple circulating protein levels (BAG3, CDKN1A, and NOTCH1). NT-proBNP and BNP levels associated with variants in BAG3. ACE2 levels were increased with a diagnosis of hypertension or diabetes, particularly in females, and were influenced by variants in genes associated with diabetes (HNF1A and HNF4A). Two-sample Mendelian randomization identified ACE2 as protective for systolic blood pressure and type-2 diabetes.

Researchers here take an interesting approach to reviewing the evolution of the field of aging research over the past century, employing machine learning approaches to process abstract summaries from the entire literature in search of meaningful patterns. Some of the findings are much as might be expected given the way in which top-down funding choices shape trends in research, while others are more subtle commentaries on the difference between the map and the territory, such as in the matter of the hallmarks of aging and its relationship with aging research as it actually exists.

Aging research has advanced significantly over the past century, from early studies on animal models to a current emphasis on clinical and translational applications. As research literature expands exponentially, traditional narrative reviews can no longer capture the field's complexity, highlighting the need for new, unbiased synthesis tools. Here, we leverage advanced natural language processing (NLP) and machine learning (ML) techniques to analyze 461,789 abstracts related to aging published between 1925 and 2023.

A central finding of our study is the marked evolution in research priorities over the past 50 years. Early decades were dominated by a focus on animal models and cellular mechanisms, which laid the groundwork for our mechanistic understanding of aging. In contrast, recent decades show a pronounced shift toward clinical research and healthcare applications, reflecting both technological advances and changing societal priorities as populations age. This transition is further underscored by a consolidation of research themes around a few dominant topics; most notably, those related to healthcare and clinics, and an intensive emphasis on neurodegenerative diseases where Alzheimer's disease (AD) and dementia have emerged as the most studied conditions in the aging field. The overwhelming dominance of AD and dementia research may not solely reflect emerging scientific trends but could also be partially driven by funding policies. For instance, agencies like the National Institute on Aging have historically allocated a substantial proportion of their research funding to Alzheimer's and related dementias, shaping the field's research priorities.

Our clustering analysis revealed distinct thematic groups that not only segregate clinical and basic biological research but also highlight specific tissue- and system-focused studies (e.g., those related to the central nervous system or skeletal muscle). Links between biology of aging clusters (such as oxidative stress and cellular senescence) and clinically oriented clusters remain sparse. This suggests that despite the overall growth in aging research, a significant gap persists between fundamental aging mechanisms and their translation to clinical settings.

Beyond these broad trends, a focused analysis on the biology of aging research literature uncovered distinct clusters corresponding to fundamental aging processes. When we compared these clusters with the well-established hallmarks of aging, we found that while some clusters align closely with these predefined categories, others do not clearly fit into them. This discrepancy suggests that the biology of aging contains more diversity than the classical hallmarks scheme alone might capture.

Link: https://doi.org/10.18632/aging.206340

Damaged and dying neurons in the brain release distinctive proteins that make their way into the bloodstream and can thus be measured. Researchers here note that by this metric, the death of neurons occurs throughout life, but increases with age. The pace of neuron death further increases in patients with neurodegenerative conditions, as might be expected. Interestingly, the established treatment of recombinant GM-CSF protein is shown to greatly reduce this age-related increase in neuron death. Recombinant protein therapies are notably costly and the effects of a single dose typically do not last long, but perhaps more attention given to this mechanism will lead to a more cost effective approach to therapy that can preserve neurons in the aging brain.

A new cross-sectional study of people of all ages has revealed that a protein released into the blood from dying brain neurons, called UCH-L1, and another protein released from damaged neurons, called NfL, are at low concentrations in the blood in early life and their levels are exponentially higher every year through age 85. Early life changes in this biomarker likely reflect a normal process of aging, but in later stages of life, increases in UCHL-1 are linked with poorer outcomes. This discovery could lead to earlier testing and new therapies for Alzheimer's disease (AD) and possibly for cognitive decline due to normal aging.

The drug sargramostim (also called Leukine), a synthetic form of the natural human protein GM-CSF, has been used for 30 years to treat a variety of conditions including cancer. It has also shown promise in its first clinical trial by improving blood biomarkers of brain pathology. The biomarker improvement lasted only as long as the drug was taken, yet memory improvement on one measure lasted longer. When people with AD were given sargramostim in the clinical trial, their blood levels of the UCH-L1 measure of neuronal cell death dropped by 40%, similar to levels seen in early life.

Sargramostim treatment led to improved scores on one of the cognitive tests performed, the Mini-Mental State Exam (MMSE), compared to those taking a placebo. Other cognitive tests showed no change. Whether the drug will reduce Alzheimer-associated neuronal damage only with continuous use is unclear and needs more study. At 45 days after treatment ended, the blood UCH-L1 concentration had returned to pre-treatment levels but the improvement in the MMSE measure of cognition was retained. More research will also be needed to determine if the drug can reduce normal age-associated neuron death and cognitive decline.

Link: https://news.cuanschutz.edu/news-stories/brain-neuron-death-occurs-throughout-life-and-increases-with-age-a-natural-human-protein-drug-may-halt-neuron-death-in-alzheimers-disease

As research into senescent cells continues to gather momentum over the years, links to specific conditions are spilling over from aging into other fields of medical research. Temporal lobe epilepsy isn't an age-related condition, but a number of the most unpleasant outcomes inflicted on the brain by aging, including stroke and brain cancer, can induce epilepsy in addition to all of the other attendant consequences. Interestingly, researchers have found that there is a clear correlation between an excessive burden of senescent cells in the brain and temporal lobe epilepsy. Senescent cells are by now well established to disrupt tissue structure and function via their inflammatory signaling when present in significant numbers over the long term. Typically this only happens in old age, but some other events such as infection, cancer therapies, and injury can result in a lasting excessive burden of senescent cells that emerges earlier in life.

Fortunately there is a low cost therapy that clears some fraction of lingering senescent cells, and has been shown to do so in early human trials, alongside a reasonable safety profile. This is the combination of dasatinib and quercetin. Unfortunately, there is little financial incentive for those organizations capable of conducting large scale clinical trials of dasatinib and quercetin to actually do so; low cost generic drugs and supplements are not a good source of revenue. Thus this approach to therapy remains stuck in the state of being available to the adventurous, prescribed by a small number of anti-aging physicians, and in much need of a far greater body of human clinical trial data than is likely to arrive any time soon.

Clearing the Brain of Aging Cells Could Aid Epilepsy and Reduce Seizures

Temporal lobe epilepsy (TLE) can be caused by several factors, including brain injuries from trauma or stroke, infections like meningitis, brain tumors, blood vessel malformations, and genetic syndromes. TLE is the most common type of drug-resistant epilepsy, affecting about 40% of patients with the condition. In one part of their study, the investigators looked at donated brain tissue in the lab that had been surgically removed from the temporal lobes of people. They found a five-fold elevation of senescent glia cells in human TLE cases compared to autopsy tissue from people without the disease. Glia cells support and protect neurons but do not produce electrical neuronal impulses.

Based on their human brain tissue investigation, the researchers suspected there could be an abundance of senescent cells in a mouse model that mimics TLE. Indeed, within two weeks of the initial injury that triggered TLE in the mice, the investigators found increases in cellular markers of senescence at both gene and protein levels. Treatment to remove the aging cells in mice resulted in a 50% reduction in these senescent cells, normalized their ability to navigate mazes, reduced seizures, and protected a third of animals from epilepsy altogether.

The drug treatment tested in the mice was a combination of dasatinib, a targeted therapy used to treat leukemia, and quercetin, a plant flavonoid found in fruits, vegetables, tea, and wine that can act as a powerful antioxidant and have anti-inflammatory properties. The combination of the two drugs has been widely used to kill senescent cells in a range of diseases modeled in animal studies.

Senescent Cell Clearance Ameliorates Temporal Lobe Epilepsy and Associated Spatial Memory Deficits in Mice

The pharmacological treatment of temporal lobe epilepsy (TLE), a disorder characterized by recurrent seizures and cognitive dysfunction, is limited to symptomatic control. Cellular senescence has been recently implicated in the development and progression of other neurodegenerative diseases, but its role in TLE is unstudied. We found a 5-fold elevation of senescent glia in human TLE cases as compared with controls. In a mouse model of TLE, we found increases in senescence markers at both the transcript and protein level and predominantly expressed in microglia, which developed within 2 weeks following induction of TLE. Senolytic treatment in mice produced a 50% reduction in senescent cells, rescued long-term potentiation deficits, normalized spatial memory impairments, reduced seizures, and protected a third of animals from epilepsy.

Researchers here demonstrate that a specific lactic acid bacteria species administered as a probiotic can improve immune function in aged mice by reducing chronic inflammation. Further work may isolate exactly which molecular interactions are involved, and thus move the research aim from a potential probiotic treatment to a potential small molecule drug or supplement, but for now the probiotic is the near term outcome.

Lactic acid bacteria (LABs) are present in various foods. Long-term administration of LABs to aged mice suppresses systemic and T cell-specific aging by inhibiting inflammasome activation. In particular, certain kefir-derived LAB strains, such as Lentilactobacillus kefiri DH5, exhibits anti-inflammatory activity. Notably, the potential effect of L. kefiri YRC2606, a strain isolated from kefir, on immunosenescence has not yet been evaluated.

We hypothesized that YRC2606 attenuates immunosenescence via IL-6/STAT3 suppression. Therefore, we examined changes in organ indices, cellular senescence, and age-associated chronic inflammation following the oral administration of YRC2606 to aged mice. YRC2606 treatment significantly increased the thymus index, reduced senescence marker expression in the spleen and kidney, and decreased proinflammatory cytokine levels in serum and tissues. Furthermore, phosphorylation of STAT3, a key mediator of inflammation and senescence, was notably suppressed in the YRC2606 group. The results of this study suggest that orally administered YRC2606 regulates immunosenescence by attenuating age-related chronic inflammation.

Link: https://doi.org/10.1016/j.jff.2025.107053

This research is chiefly interesting as a demonstration that liver cells can collectively influence immune function. Beyond the improvement in immune function attained in aged mice as a proof of concept, one might think that this should lead to further investigation as to how exactly aging in the liver can affect the aging of the immune system. It is unlikely that the specific signaling systems identified by the authors of this paper and used as a basis for therapy are the only relevant paths of communication. Thus other approaches likely exist.

Ageing erodes human immunity, in part by reshaping the T cell repertoire, leading to increased vulnerability to infection, malignancy, and vaccine failure. Attempts to rejuvenate immune function have yielded only modest results and are limited by toxicity or lack of clinical feasibility. Here we show that the liver can be transiently repurposed to restore age-diminished immune cues and improve T cell function in aged mice. These immune cues were found by performing multi-omic mapping across central and peripheral niches in young and aged animals, leading to the identification of Notch and Fms-like tyrosine kinase 3 ligand (FLT3L) pathways, together with interleukin-7 (IL-7) signalling, as declining with age.

Delivery of mRNAs encoding Delta-like ligand 1 (DLL1), FLT3L and IL-7 to hepatocytes expanded common lymphoid progenitors, boosted de novo thymopoiesis without affecting haematopoietic stem cell (HSC) composition, and replenished T cells while enhancing dendritic cell abundance and function. Treatment with these mRNAs improved peptide vaccine responses and restored antitumour immunity in aged mice by increasing tumour-specific CD8+ immune cell infiltration and clonal diversity and synergizing with immune checkpoint blockade. These effects were reversible after dosing ceased and did not breach self-tolerance, in contrast to the inflammatory and autoimmune liabilities of recombinant cytokine treatments. These findings underscore the promise of mRNA-based strategies for systemic immune modulation and highlight the potential of interventions aimed at preserving immune resilience in ageing populations.

Link: https://doi.org/10.1038/s41586-025-09873-4

If you are old enough, you may recall that the pineal gland received a great deal of quite unscientific attention from the early life extension community, decades ago, overlapping to some degree with its association in lineages of mystical thinking with the third eye. We live in a strange world populated by strange people. Scientifically, the pineal gland is a fairly important part of the endocrine system, and like all organs in the body, its normal function becomes disrupted by age. This has consequences, not all of which are fully mapped or understood. Are those consequences plausibly large enough for greater attention to be given to mechanisms of pineal gland aging specifically? The authors of today's open access paper would argue that this is the case.

This highlights one of the challenges inherent in engaging with aging as a phenomenon. The body is complex, and contains many different complex systems, organs, and tissue types. If the approach taken to aging is to run down the list of body parts one by one, then making meaningful progress in the matter of treating aging as a medical condition is going to take a long time. The alternative of focusing on underlying pathological mechanisms rather than tissues has a similar issue. Even today there are many portions of the body for which little has been said in the context of slowing aging or producing rejuvenation. If one looks at the major avenues of development for rejuvenation therapies, such as senolytics and partial reprogramming, one finds that most of the development end of the field is focused on just a few age-related conditions and a few organs.

That said, at this still relatively early stage in the development of the longevity industry it is unclear as to whether anyone should be concerned about the above points, versus maintaining a laser focus on forging ahead as fast as possible to the first rejuvenation therapies. But it is something to think about.

Pineal gland senescence: an emerging ageing-related pathology?

The pineal gland is a photo-neuroendocrine gland located in the midline of the brain outside the blood-brain barrier. It is part of the epithalamus, is attached to the third ventricle by a short stalk, and can weigh up to 180 grams. Its primary role is to receive information about the light-dark cycle from the environment, which it responds to through the production and secretion of melatonin. When it is light, the suprachiasmatic nucleus (SCN) secretes gamma-amino butyric acid (GABA), which in turn inhibits neurons in the paraventricular nucleus (PVN) of the hypothalamus. In darkness, the SCN secretes glutamate, which activates pathways from parvocellular pre-autonomic neurons of the PVN via the superior cervical ganglion to stimulate melatonin production by the pineal gland in response to noradrenaline.

The pineal gland may undergo ageing-related structural and morphological changes, including calcification, gliosis, cyst formation, and reduced density of β-adrenergic receptors, which are hypothesised to reduce melatonin secretion.

We hypothesise that pineal gland senescence may represent an ageing-related pathology as it describes a decline in function. This causes a reduction in the secretion of melatonin that may contribute to ageing-related sleep disorders as well as other physiological, cognitive, and psychiatric dysfunctions related to disturbances in circadian rhythm and melatonin concentrations. The current paper will describe the pathophysiology of the pineal gland and will discuss whether pineal gland senescence should be considered as a diagnostic entity.

The big advantage of aging clocks based on clinical biomarkers, such as the results of a complete blood count, or LDL cholesterol level, and so forth, is that one can at least theorize a little about what is going on under the hood when the clock output changes to indicate a higher or lower biological age. Each of the underlying biomarkers has meaning and a body of work attached to it, which is not the case for epigenetic clocks and barely the case for proteomic or transcriptomic clocks. Phenotypic age is the prototype of a widely used clinical biomarker clock. Others have been developed in recent years, and here find yet another recently published novel clinical biomarker clock.

Biological aging clocks offer valuable insights into age acceleration and disease development, making them a very powerful clinical tool for preventive medicine. However, the applicability of biological aging clocks in preventive clinical settings is closely linked to the effectiveness and efficiency of biomarker screening protocols, as well as their economic feasibility. To address this, we investigated the relationship between the performance of the regression model and the number of biomarkers utilized. Our aim was to unlock the full preventive potential of our biological aging clock.

We used a clinical cohort dataset from the Bumrungrad International Hospital in Bangkok, Thailand, encompassing 184,833 individuals and comprising 597,781 samples from 2000 to 2022. The total of 597,781 samples contained data on 174 clinical biochemistry biomarkers. Through expert consensus and iterative refinement, the biomarker set was refined to 51. Using an iterative approach, we systematically removed biomarkers with the least impact on predictive performance, ultimately narrowing the model down to six clinical biochemistry markers plus sex. These six biomarkers were creatinine, hemoglobin A1c (HbA1c), alanine aminotransferase (ALT), high-density lipoprotein (HDL), triglycerides, and albumin.

Based on only seven biomarkers, our clock accurately predicts both self-reported and physician-annotated ICD health data, indicating an increased hazard ratio. Importantly, the clock is robust even in the presence of acute infections or transient immune activation. To demonstrate the multi-ethnic generalizability of our biological age clock, we validated our approach using data from both the NHANES and UK Biobank cohorts. Our approach demonstrates the feasibility of a simple, robust, and interpretable clinical aging clock with potential for real-world implementation in personalized health monitoring and preventive care.

Link: https://doi.org/10.1038/s41598-025-27478-9

In recent years a number of different groups have generated aging clocks intended to assess distinct biological ages for different organs and systems in the body, OrganAge being one example. Data from large human populations suggests that different organs and systems can age at somewhat different rates. Here, researchers use UK Biobank data to generate a novel organ specific proteomic clock, producing similar data to the earlier OrganAge research program.

Organ-specific plasma protein signatures identified via proteomics profiling could be used to quantitatively track organ aging. However, the genetic determinants and molecular mechanisms underlying the organ-specific aging process remain poorly characterized. Here we integrated large-scale plasma proteomic and genomic data from 51,936 UK Biobank participants to uncover the genetic architectures underlying aging across 13 organs.

We identified 119 genetic loci associated with organ aging, including 27 shared across multiple organs, and prioritized 554 risk genes involved in organ-relevant biological pathways, such as T cell-mediated immunity in immune aging. Causal inference analyses indicated that accelerated heart and muscle aging increase the risk of heart failure, whereas kidney aging contributes to hypertension. Moreover, smoking initiation was positively linked to the aging of the lung, intestine, kidney, and stomach. These findings establish a genetic foundation for understanding organ-specific aging and provide insights for promoting healthy longevity.

Link: https://doi.org/10.1038/s41467-025-67223-4

As researchers note in today's materials, there is clear an association between periodontal disease and the progression of atherosclerosis. Atherosclerosis is universal in older humans, the growth of fatty lesions in blood vessel walls that ultimately impede circulating blood flow to a fatal degree or rupture to cause stroke and heart attack. The degree of atherosclerosis at a given age is highly variable across the human population, however. The degree to which atherogenic processes in any two individuals are driven by the same stimulus, such as increased LDL cholesterol levels or increased lipoprotein A levels or increased inflammation, can be very different. This makes it somewhat challenging to talk about how much of a problem any given atherogenic issue actually poses.

This is much the case for periodontitis and its contribution to atherosclerosis. One can demonstrate mechanisms that in principle allow periodontitis to make inflammatory diseases worse elsewhere in the body, primarily that bacteria and their inflammatory metabolites can leak into circulation via the injured gums. But it is a step from there to find good correlational data in human studies, let alone data that convincingly puts a number to the degree of risk produced by periodontitis. Still, avoiding chronic inflammation in later life is well established to be a beneficial goal for a wide range of reasons. Chronic inflammation is disruptive to tissue structure and function in many contexts, and wherever reasonable efforts can be taken to reduce sources of inflammation, the results should be worth it.

Gum disease may be linked to plaque buildup in arteries, higher risk of major CVD events

Although periodontal disease and atherosclerotic cardiovascular disease (ASCVD) share common risk factors, emerging data indicates there is an independent association between the two conditions. Potential biological mechanisms linking periodontal disease with poor cardiovascular outcomes include direct pathways such as bacteria in the blood and vascular infections, as well as indirect pathways such as chronic systemic inflammation.

Numerous studies have found that periodontal disease is associated with an increased risk of heart attack, stroke, atrial fibrillation, heart failure, peripheral artery disease, chronic kidney disease, and cardiac death. Although periodontal disease clearly contributes to chronic inflammation that is associated with ASCVD, a cause-and-effect relationship has not been confirmed. There is also no direct evidence that periodontal treatment will help prevent cardiovascular disease. However, treatments that reduce the lifetime exposure to inflammation appear to be beneficial to reducing the risk of developing ASCVD.

Periodontal Disease and Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association

Direct mechanisms of the association between periodontal disease and atherosclerotic cardiovascular disease (ASCVD) are thought to be through bacteremia and vascular infection. Dental plaque in periodontal disease contains multiple bacterial strains. Periodontal pockets, with manipulation of the tissue, can result in bleeding, which allows periodontal bacteria to enter systemic circulation. Once in the bloodstream, pathogens can trigger a systemic inflammatory response. This, along with increased vascular permeability, could lead to endothelial dysfunction. Endothelial dysfunction can be a sign of early subclinical atherosclerosis.

Bacteremia from chronic periodontal infections may increase the inflammatory burden that accelerates atherogenesis. Inflammation due to direct oral microbiome actions may affect systemic inflammation of blood vessel walls through two modes: direct invasion of bacteria through the diseased and inflamed periodontal tissues into the general circulation and phagocyte-mediated bacterial translocation. The oral microbiome thereby invades vascular tissues, which may experience acute inflammation, which, in the absence of complete resolution, could lead to chronic inflammation and ASCVD.

Researchers here identify FOXF2 as necessary to maintain function of the vascular endothelium that lines blood vessels and the blood-brain barrier that wraps blood vessels passing through the brain to protect the distinct environment of the brain from cells and molecules that would disrupt it. They hypothesize that reduced levels of FOXF2 or related dysfunction in the expression and activity of genes it influences, such as TIE2, are an important contribution to the vascular dysfunctions that make up cerebral small vessel disease.

Researchers have genetically modified mice so that only their endothelial cells lack the ability to produce certain proteins. Endothelial cells form the innermost lining of blood vessels and they are the site where small vessel disease often begins. By selectively switching off the Foxf2 gene - previously identified by the researchers as a stroke risk gene - these cells lack the corresponding protein, leading to impaired function of small cerebral vessels, especially disruption of the blood-brain barrier, which protects the brain from harmful influences.

Foxf2 is a transcription factor that activates many other genes - including, as researchers discovered, the gene Tie2 and its downstream components in the so-called Tie signaling pathway. In endothelial cells, activation of the Tie2 gene and proper functioning of the Tie2 pathway are crucial for maintaining vascular health. Without Tie2, for example, the risk of inflammatory reactions in the endothelial cells of larger vessels increases, which in turn promotes atherosclerosis and raises the risk of stroke and dementia.

The researchers tested a therapy targeting the impaired function of small cerebral vessels based on their new insights. The drug candidate AKB-9778 specifically activates Tie2. "I would love to announce that we are already preparing a clinical study to test this compound in patients. However, at the moment it is not easy to access the substance, as it is currently being evaluated in clinical trials for use in other conditions." The team is now searching for related compounds that could be developed for clinical testing in small vessel disease.

Link: https://www.lmu.de/en/newsroom/news-overview/news/stroke-and-dementia-combating-loss-of-function-in-small-vessels-of-the-brain-1313fe47.html

Research into the role of amyloid-β in Alzheimer's disease has shifted somewhat to focus on the surrounding biochemistry rather than the aggregates, now that clearing the aggregates via immunotherapies is an ongoing concern, and has shown less of a benefit to patients than hoped. As researchers note here, there is evidence for specific amyloid-β oligomers to be the most toxic consequence of having too much amyloid-β in general. Researchers have developed a drug that reduces levels of one of the problem oligomers, and this study is one of the early tests of its ability to help in an animal model of Alzheimer's disease.

One possible reason for the failure of early Alzheimer's disease (AD) clinical trials is that treatments were initiated after symptom onset, when pathology is already widespread. Another contributing factor, especially for amyloid-β (Aβ) targeting therapies, is that most treatments have selectively targeted monomeric or fibrillar forms of Aβ, which are not the most toxic species. Soluble amyloid-β oligomers (AβOs), which form prior to plaques, are widely regarded as the most toxic Aβ species.

One proposed mechanism by which early AβOs contribute to AD is by activation of immune cells. AβOs can activate glia in culture and in wild type rodent or primate brain following injection, but their role in initiating gliosis early in AD remains unclear. Since glial activation is among the primary events in AD, identifying molecules that trigger gliosis is critical for diagnostics and therapeutics.

In this study, we investigated early pathology in 5xFAD mice. Results showed distinct AβO subtypes differing in localization, morphology, and association with key AD hallmarks such as degenerating neurons, plaques, phosphorylated TDP-43 (pTDP-43), and activated immune cells. We report an AβO subtype that associates with the earliest degenerating neurons and activated immune cells and provide support for its role in early neuronal degeneration and astrogliosis. Furthermore, we validate the in vivo efficacy of NU-9, a drug-like compound recently shown to inhibit AβO accumulation in cultured hippocampal neurons. Oral NU-9 treatment significantly reduced ACU193+ AβOs on reactive astrocytes and rescued astrocyte glial fibrillary acidic protein (GFAP) levels, suggesting astrocyte-associated AβOs may induce reactive astrogliosis. We predict that neutralization of ACU193+ AβOs early in AD could slow or prevent disease progression.

Link: https://doi.org/10.1002/alz.70968

The innate immune system becomes increasingly inflammatory with age, in part due to damage and dysfunction in immune cells, in part a maladaptive reaction to a damaged environment. Chronic inflammation is disruptive to tissue structure and function. Macrophages make up a sizable fraction of the innate immune system, resident in tissues and involved in both tissue maintenance and defense against pathogens. A broad range of research is focused on better understanding and potentially manipulating macrophage behavior to obtain desired outcomes, such as a lower level of chronic inflammation in later life.

In today's open access paper, researchers focus on the macrophages resident in fat tissue. Visceral fat is a source of inflammation, and this is one of the reasons why being overweight is increasingly bad for health as life progresses into older age. This research illuminates one of the regulatory elements involved in increasing inflammatory behavior in macrophages in fat tissue, raising its profile as a potential target for anti-inflammatory therapies, and contributing to the bigger picture of inflammatory mechanisms in visceral fat tissue.

GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging

Older individuals have increased risk for infections and subsequent sepsis, in part owing to accumulating adiposity and a dysfunctional immune system. Gerotherapeutics that successfully improve the aged immune response are largely understudied. Our study reveals that the GDF3-SMAD2/3 axis may be a relevant pharmacologic target. GDF3 promotes the inflammatory phenotype of adipose tissue macrophages, contributing to the exacerbation of endotoxemia-induced inflammation in older, but not younger, organisms. GDF3 signals through SMAD2/3 and elicits proinflammatory responses in adipose tissue macrophages, diverging from their canonical immunoregulatory function.

Specifically, the chromatin landscape of adipose tissue macrophages shifts toward inflammation with age, increasing the accessibility of inflammation-associated genes. Our study demonstrates that Gdf3 deficiency can reverse the age-dependent changes in chromatin accessibility and transcription by restoring H3K27me3 levels in adipose tissue macrophages. Furthermore, genetic and pharmacological inhibition targeting the GDF3-SMAD2/3 axis protects against endotoxemia-induced inflammation and lethality in old mice.

The importance of visceral adipose tissue (VAT) in aging and inflammation is corroborated by studies that highlight the immunological role of VAT during metabolic challenge or infection in older organisms. Recent work indicates that B cells-derived IgG elevates macrophage expression of Tgfb, which promotes fibrosis and metabolic decline via SMAD2/3 in aged VAT. Our work builds on this model, providing additional evidence for the importance of B cell-macrophage crosstalk in VAT. We also provide evidence for the GDF3-SMAD2/3 axis regulating the phenotype of B cells. Although it remains unclear whether GDF3 acts synergistically with TGFβ-superfamily cytokines, our findings indicate that the mechanism governing inflammatory VAT microenvironment, driven by adipose tissue macrophages and B cells, may converge on SMAD2/3 signaling.

There is no good therapy for macular degeneration, a form of progressive blindness characterized by dysfunction and death of vital cells in the retina, and particularly for the "dry" form of the condition in which retinal blood vessels have not yet become dysfunctional. Cell therapies represent one possible form of restorative therapy, but it has proven challenging to deliver new retinal cells and have them survive to take over lost function. The publicity materials here report briefly on the state of one cell therapy program, in which researcher employed an engineered patch to support the delivered cells.

Researchers are launching a phase 2b clinical trial examining if stem cells bioengineered to replace failing cells in the retina damaged by macular degeneration could restore eyesight. The cells are attached to an implant - an ultra-thin patch, thinner than a strand of hair - which holds the cells in place. The clinical trial follows early research conducted on a small patient population that showed the implant was well-tolerated, stayed put in the eye and was successfully absorbed into the tissue of the retina. Additionally, 27% of patients had some improved vision.

Age-related macular degeneration affects the eye's macula, which is located in the center of the retina and is responsible for central vision. In advanced cases, the retinal pigment epithelium (RPE) cells, which line the macula and are key in helping the retina produce clear vision, become damaged or destroyed, which leads to vision loss. The retinal implant used in the clinical trial is derived from embryonic stem cells grown into RPE cells in a lab. During an outpatient surgical procedure, surgeons will implant a tiny layer of the lab-produced RPE cells into the retina. Patients will be monitored for at least one year to determine how the implant is tolerated and for any changes in vision. The trial is hoping to enroll 24 patients.

Link: https://news.keckmedicine.org/can-a-retinal-implant-reverse-macular-degeneration/

Senescence of β-cells in the pancreas appears to be an important component of all forms of diabetes, and thus diabetes becomes worse with age as the burden of cellular senescence increases for reasons relating to aging as well as reasons relating to diabetes. Here, researchers use extracellular vesicles derived from stem cell populations to treat aged mice and demonstrate a reduction in β-cell senescence and consequent improvement in function.

Targeting senescent pancreatic β-cells represents a promising therapeutic avenue for age-related diabetes; however, current anti-senescence strategies often compromise β-cell mass. In this study, human amniotic mesenchymal stem cell-derived small extracellular vesicles (hAMSC-sEVs) were identified as a novel intervention that can be used to effectively counteract cellular senescence and preserve β-cell integrity.

We aimed to systemically delineate the molecular mechanisms underlying hAMSC-sEV-mediated reversal of β-cell senescence in age-related diabetes. In oxidative stress-induced and naturally aged β-cell models, hAMSC-sEVs mitigated senescence-associated phenotypes, restored mitochondrial homeostasis, and enhanced insulin secretion capacity. In aged diabetic mice, administering these vesicles significantly ameliorated hyperglycemia, improved glucose tolerance, and reversed β-cell functional decline by reducing senescent β-cell populations, reinstating β-cell identity markers, and suppressing senescence-associated secretory phenotype (SASP) component production.

Mechanistic investigations revealed that the miR-21-5p-enriched hAMSC-sEVs directly target the interleukin (IL)-6 receptor α subunit (IL-6RA), thereby inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation and its subsequent nuclear translocation. This epigenetic modulation alleviated STAT3-mediated transcriptional repression of the mitochondrial calcium uniporter (MCU), rectifying age-related mitochondrial calcium mishandling and insulin secretion defects. Genetic ablation of MCU clearly established the central role of the miR-21-5p/IL-6RA/STAT3/MCU axis in this regulatory cascade.

Link: https://doi.org/10.1111/acel.70327

Cells become senescent constantly throughout life. A senescent cell ceases replication, increases in size, and generates disruptive inflammatory signaling. In youth those senescent cells that fail to undergo programmed cell death are removed by the immune system, but this clearance falters with advancing age. The result is a growing burden of senescent cells that disrupt tissue structure and function, contributing to age-related conditions. The research community is thus very interested in finding ways to selectively remove senescent cells, particularly given the evidence for rejuvenation to result from senescent cell clearance in aged mice.

The metabolism of senescent cells is very different from that of normal cells. Unlike normal cells they are primed to undergo programmed cell death, but held back by a range of mechanisms. Sabotage those mechanisms and a senescent cell dies, but a normal cell is largely unaffected. This is far from the only possible approach to the problem, and new approaches are discovered on a fairly regular basis. Today's open access paper focuses on the regulation of increased glycolysis as an energy source in senescent cells, analogous to the Warburg effect observed in cancer cells. A senescent cell has sizable energy needs, given its activities and size. If this regulation of glycolysis is sabotaged, the senescent cell can no longer support itself and dies.

Abrogation of aberrant glycolytic interactions eliminates senescent cells and alleviates aging-related dysfunctions

Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a non-cell autonomous manner.

This pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses pro-apoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes.

Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.

Researchers have developed many different approaches to selectively destroy senescent cells based on differences in their biochemistry. The use of prodrugs is one way to activate a cell-killing mechanism more specifically in senescent cells. Most such prodrugs make use of the fact that senescent cells express high levels of β-galactosidase, which removes galactose from molecules. A cell-killing molecule can be rendered inert by adding galactose to its structure, and is only activated to a large degree in senescent cells. Here, the cell-killing molecule acts to trigger ferroptosis in senescent cells, an approach analogous to the various ways that have been shown to trigger apoptosis in senescent cells. Senescent cells are primed for programmed cell death via apoptosis and ferroptosis. The mechanisms holding them back from that fate can be targeted fairly safely, as suppression of those preventative mechanisms will not cause cell death in a normal cell that is not primed for programmed cell death.

Accumulation of senescent cells is associated with aging and age-related diseases. However, current clearance therapies targeting senescent cells are often limited by low efficiency, poor specificity, and insufficient penetration. Here we develop a nano-platform composed of a probe (GD) that can be specifically activated by senescent cells, a photosensitizer (chlorin e6, Ce6), and a kininogen peptide (HK) for targeting ferritin, named HK-PCGC.

We show that upon entering senescent cells, GD is activated by high levels of β-galactosidase, releasing fluorescence to excite Ce6. Ce6 then generates reactive oxygen species to eliminate these cells. Additionally, we find that under the guidance of the peptide HK, our system degrades ferritin to trigger ferroptosis, further eliminating senescent cells. Collectively, we demonstrate that HK-PCGC can effectively eliminate senescent cells, reduce the senescence-associated secretory phenotype, and safely improve the physical fitness of aged mice. This study integrates senescent cell responsiveness, laser-free photodynamic therapy, and induction of ferroptosis, offering a potential approach for delaying aging.

Link: https://doi.org/10.1038/s41467-025-67364-6

Research is a highly specialized field of endeavor, and in the matter of aging most scientists maintain a narrow focus in their day to day work. One tissue or one layer of the mechanisms of aging is enough to keep a research group busy for years. Thus one sees papers such as the one noted here, in which researchers focus on the colon specifically, while touching on a range of areas of interest in cellular biochemistry, behavior, and what is known of the aging of complex systems such as the immune system and gut microbiome.

The colon is one of the gastrointestinal organs most profoundly affected by aging. Recent advances in our understanding of both colonic physiology and the general mechanisms of aging have significantly expanded our knowledge of the types and underlying processes of colonic aging. In this review, we summarize current insights into the cellular and molecular mechanisms that drive physiological aging of the human colon. We examine the unique structural and functional features of key components of the colon, including the epithelium, local immune system, microbiome, enteric neurons, and smooth muscle cells, and explore how aging affects each of these cell populations, ultimately impacting overall colonic function.

In the epithelium, increased mutational burden does not appear to be the primary driver of age-related dysfunction. Instead, dysregulation of signaling pathways such as EGF and Wnt is likely responsible for key phenotypic changes. Aged colonic neurons display protein misfolding and axonal dysfunction reminiscent of aging processes observed in the central nervous system. Similarly, smooth muscle cells exhibit impaired contractility, which is associated with disruptions in calcium homeostasis and deficits in cholinergic signaling. At the same time, age-related activation of the local immune system mirrors broader immunosenescence and may be further influenced by shifts in the gut microbiome, although a consistent aging-associated microbiome signature has yet to be identified.

These multifaceted changes, combined with the colon's inherent regional and cellular complexity and the challenges of modeling human colonic aging, continue to fascinate but also pose substantial obstacles for research. Emerging experimental models and clinical strategies offer promising avenues for improving the prevention and treatment of age-associated colonic dysfunction.

Link: https://doi.org/10.1016/j.mad.2025.112143

Lipofuscin is the name given to a mix of modified proteins, lipids, and other compounds that accumulate with age in long-lived cells. The accumulation of lipofuscin has long been considered a form of damage by a minority of researchers; removal of lipofuscin was an early call to action for the Strategies for Engineered Negligible Senescence, for example. There were even a few early, unsuccessful efforts to provide technology demonstrations of approaches to break down lipofuscin, or at least some of its components. Unfortunately, getting rid of lipofuscin isn't a straightforward task. Chemically it is diverse, a mess of many very different molecules, and thus ill suited as a target for the enzyme, antibody, and small molecule development that dominates the field of medical biotechnology. Getting rid of one specific molecule is feasible, getting rid of a hundred very different molecules is much less feasible. Lipofuscin has been largely left alone in favor of easier goals.

In today's open access paper, the authors restate some of the arguments for lipofuscin to be important in the onset and progression of age-related neurodegenerative conditions, and thus to be a therapeutic target worthy of greater attention on the part of the research and development community. This has all been said before! One of the challenges inherent to the development of rejuvenation therapies at this stage of the growth of the field is that there are far more potentially worthwhile areas of focus than there are research groups, companies, and funding to carry out the work. This will likely remain the case until the first generation of therapies to treat aging are approved, widely used in the clinic, and their existence a matter of fact for the average physician, researcher, and person in the street.

Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease

Lipofuscin, which has long been considered a passive byproduct of aging, is increasingly being recognized as a dynamic modulator of cellular homeostasis. Lipofuscin accumulation is indicative of lysosomal dysfunction and is closely related to redox imbalance and lipid peroxidation - critical pathways implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). Lipofuscin accumulation may contribute to and exacerbate amyloid-β accumulation and toxicity by interfering with autophagic clearance and promoting a highly oxidative environment.

In this review, we propose a reconsideration of lipofuscin from the "aging marker" or "autofluorescence pigment" to an active player in neurodegeneration and AD pathology. This paradigm shift opens new research directions and therapeutic possibilities. Targeting lipofuscin and its clearance may allow interference of upstream of amyloid plaque formation, preserving proteostasis, reducing oxidative damage, and ultimately slowing or preventing neurodegeneration.

We examine the potential interplay between lipofuscin accumulation, lysosomal dysfunction, lipid peroxidation and amyloid-β pathology in AD. We explore how lipofuscin may influence amyloid-β aggregation, clearance, and toxicity and propose mechanisms by which lipofuscin modulates AD progression. Importantly, we summarize evidence demonstrating that lipofuscin is released extracellularly upon neuronal death, thus preparing a highly oxidized environment that results in toxicity and a cascade of events leading to plaque formation and amyloid-β pathology.

Biological age as a concept is a measure of the burden of cell and tissue damage, and consequent dysfunction, that causes risk of mortality and disease. Over the past twenty years researchers have developed a range of approaches, starting with epigenetic clocks, that are attempts to produce a useful measure of biological age. There is considerable debate over the degree to which any of these approaches have succeeded, a debate that will only be settled by the accumulation of a great deal of human data. Ultimately, the real utility of a measure of biological age is the rapid assessment of potential rejuvenation therapies, to steer development towards better approaches that produce larger effects. At present it is unclear as to whether any of the approaches can be trusted to produce useful data given an entirely novel approach to the treatment of aging.

Numerous studies have analysed different aspects of biological age and developed clocks and models to assess biological age and measure the molecular changes due to biological ageing. Not only are there several generations of epigenetic clocks used to estimate biological age, but proteome-based clocks were developed, and metabolome- and microbiome-based clocks are being developed as well. Genomic studies have uncovered several genetic mechanisms that promote longevity, with a focus on protective mechanisms such as protective genetic variants and effective DNA repair systems.

Epigenomic changes that influence biological age are modified by diet and exercise and influenced by early life events. Age-related changes in blood proteome were identified, revealing non-linear and organ-specific alterations. Metabolomic profiles in blood plasma have identified age-related shifts in lipid metabolism and redox balance and demonstrated their application as biomarkers for ageing processes and health outcomes. Microbiomics has shown that the uniqueness and diversity of the gut microbiome reflect biological age and that this can also be measured by microbiome derived metabolites in plasma. In addition, multi-omics approaches have uncovered potential biomarkers that not only reflect the ageing processes but can also serve as targets for personalised interventions.

There are several limitations in selecting reliable biomarkers of ageing. First, there is a lack of consistently identified biomarkers, low methodological standardisation, and limited numbers of cohorts in ageing studies. Currently, ageing appears to be a non-linear process that does not progress at the same rate across all biological functions and organs. Comparisons of different clocks and omics data have shown poor correlation, suggesting that each clock or omics may represent a distinct ageing process. There is limited translation of DNA methylation and other biomarkers into clinical practice.

Furthermore, the definition of biological ageing is not yet clearly established within the community. Therefore, relying on only one type of data is unlikely to provide precise, specific, and reliable biomarkers. Ageing is a systems-level biological process, and only systems-level approaches are likely to lead to the development of reliable and interpretable predictions of biological age. Comparison of different omics data has also shown poor correlation between different molecular domains, indicating that each domain may reflect a different ageing process or organ. Moreover, it is clear that individuals and their organs age differently and at different rates.

Link: https://doi.org/10.1016/j.arr.2025.102988

The research community has achieved a growing ability to engineer bacteria to produce specific behaviors and outcomes. In the realm of cancer therapy, this includes altering the characteristics of bacteria to increase their ability to disrupt cancer cells by preferentially localizing to and colonizing tumor tissue. Techniques demonstrated in the laboratory include genetic engineering of bacteria manufacture or carry a payload of molecules capable of directly harming cancerous cells. The review noted here outlines the range of present approaches, including those that are progressing towards clinical use.

In contrast to conventional drugs, which accumulate through passive diffusion, live bacteria can actively penetrate deep into tumors, bypassing aggregation near blood vessels. The unique properties of the tumor microenvironment (TME) allow bacteria to preferentially replicate and colonize tumors. For example, Salmonella has been observed to localize to tumors at more than 10,000 times the density found in normal tissues. Live bacteria offer distinct advantages over traditional anticancer agents by amplifying antitumor effects through inherent tumor-targeting capabilities, potentially enhancing specific immune recognition. However, balancing the requirement for bacteria to evade host antimicrobial defenses while stimulating antitumor immunity within the TME remains a challenge.

Advances in synthetic biology allow the rational design of optimized oncolytic bacterial strains by attenuating virulence factors and integrating customizable therapeutic payloads, with several candidates already progressing into clinical evaluation. Fine-tuning the spatiotemporal control of bacterial therapeutic activity is essential for maximizing drug accumulation, improving resource efficiency, and reducing harm to healthy tissues. To this end, engineered oncolytic bacteria often utilize regulated gene expression systems, incorporating specific promoter elements, to allow for precise control of therapeutic payload delivery in vivo. Synthetic biology prioritizes rational and modular design, integrating programmable sensors, genetic circuits, and effectors to deliver precise, tunable, multilayer regulation of bacterial behaviors and therapeutic outputs.

Link: https://doi.org/10.1093/procel/pwaf085

In flexible, elastic tissues such as skin and blood vessel walls, large molecules of the extracellular matrix must be able to move relative to one another. When undesirable cross-links form between these molecules, tissue loses its elasticity and flexibility. Much of this undesirable cross-linking is the result of interactions with sugars, particularly via a class of compounds known as advanced glycation end-products, AGEs. In addition to the cross-linking, AGEs also provoke inflammation via interaction with the receptor for AGEs, RAGE. This is a well known harmful feature of the high-sugar, dysfunctional diabetic metabolism.

In the late 1990s and early 2000s, alagebrium was developed as a drug candidate on the basis of being able to break forms of AGE-induced cross-links found in arterial tissues, and thus reduce age-related arterial stiffening in preclinical studies in mice. In addition to breaking some forms of cross-link, alagebrium was also found to scavenge methylglyoxal, a particularly obnoxious precursor to AGEs and bad actor in diabetic metabolism. Sadly, the cross-links broken by alagebrium are prevalent in mice, but not in humans. Even more sadly, the failure of alagebrium to improve arterial stiffening in human clinical trials sabotaged any likelihood of further clinical trials in diabetic patients - so we have no idea whether alagebrium may or may not have improved the human diabetic metabolism to a sufficient degree to be useful.

The challenge with AGEs is that there are a lot of them, their chemistry is notably different from one to another, the catalog is incomplete, it is unclear whether the present consensus on which AGEs are important and which are not is correct, and this continues to be a relatively poorly studied part of the field. One of the consequences is a tendency for wheels to be reinvented. One might look at today's paper in which researchers use a novel mix of supplements in mice to try to reduce the aortic stiffening induced by methylglyoxal. That alagebrium improved aortic elasticity in mice, and failed to do so in humans, strongly suggests that the effort here is a dead end (or at least says little about the actual merits of the product undergoing testing), and no amount of skating over that point in the paper's discussion is going to change that reality.

Methylglyoxal-induced glycation stress promotes aortic stiffening: putative mechanistic roles of oxidative stress and cellular senescence

In this study, we investigated the impact of glycation stress on aortic stiffness in young and old mice, induced by advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH)-1, explored the potential molecular mechanisms involved, and evaluated the therapeutic potential of the glycation-lowering compound Gly-Low. We used a series of complementary in vivo, ex vivo, and in vitro experimental approaches to determine the causal role of MGO-induced glycation stress in aortic stiffening and the putative underlying mechanisms mediating this response, including excessive oxidative stress and cellular senescence. Additionally, we explored the therapeutic potential of Gly-Low, a cocktail consisting of the natural compounds nicotinamide, pyridoxine, thiamine, piperine, and alpha-lipoic acid, in mitigating aortic stiffening, oxidative stress, and cellular senescence mediated by MGO-induced glycation stress.

While MGO has previously been implicated in endothelial dysfunction, our results demonstrate that chronic MGO exposure significantly increases aortic stiffness in young mice. This effect was particularly pronounced in our pharmacological model of glycation stress, where young adult mice exhibited a marked increase in aortic stiffness after just two months of MGO exposure. Lastly, we also demonstrate the direct influence of glycation stress in mediating age-related aortic stiffening, which underscores the critical role of AGEs in promoting aortic stiffening with aging. Notably, our results also reveal the direct impact of MGO on aortic stiffening, supporting the notion that MGO-induced glycation stress can independently drive this pathology.

This paper is an example of work exploring how exactly mitochondrial dysfunction might contribute to age-related atrial fibrillation, the dysregulation of heart rhythm. It is possibly more helpful as an introduction to the roots of atrial fibrillation, meaning dysfunction in electrical connectivity and remodeling of structure in heart tissue, and how those two issues relate to one another. A perhaps surprisingly large fraction of atrial fibrillation can be at least temporarily corrected via minimally invasive surgical techniques, because in those cases the issue arises from inappropriate electrical signaling originating in small areas of the heart and connecting vessels, but once age-related changes in the heart become more widespread and severe, this stops being the case.

Atrial fibrillation (AF) is a common arrhythmia in clinical practice that often leads to severe complications such as heart failure, myocardial infarction, and stroke. It is associated with increased mortality and a significantly reduced quality of life. Current treatments for AF include risk factor control, medications for rate and rhythm control, and anticoagulation. For refractory cases, interventional procedures like cardiac radiofrequency ablation are used. However, these treatments have limitations, including adverse effects such as bleeding and a significant risk of AF recurrence. Further elucidating the mechanisms of AF development and identifying precise intervention targets are urgently needed.

The pathogenesis of AF has not been fully elucidated, but the core pathological basis for its development and maintenance primarily involves two major mechanisms: atrial electrical remodeling and structural remodeling. Electrical remodeling is mainly manifested as abnormal ion channel function in atrial myocytes, resulting in a shortening of action potential duration and increased dispersion of the effective refractory period. This creates a substrate for reentrant arrhythmias. Structural remodeling, on the other hand, involves morphological changes such as atrial fibrosis, myocardial hypertrophy, and dilation, which further promote the persistence and stabilization of AF.

Recent studies have confirmed that mitochondrial dysfunction is a central hub driving these remodeling processes. As the energy factories of the cell, mitochondria generate adenosine triphosphate (ATP) through oxidative phosphorylation, providing the necessary energy for sustained contraction, ion pump operation, and electrical signaling in cardiomyocytes. In the AF state, atrial myocytes are subjected to rapid, disorganized, high-frequency electrical excitation. The dramatic increase in energy demand leads to mitochondrial overload and accelerates mitochondrial senescence and damage.

Mitochondrial dysfunction affects intracellular ionic homeostasis and membrane excitability through dual disruptions of energy crisis (ATP insufficiency) and oxidative stress (reactive oxygen species burst). These disruptions directly impair cardiomyocyte ion channel function and expression, driving the onset and progression of AF. Mitophagy, a key mechanism for mitochondrial quality control, selectively removes damaged mitochondria to prevent reactive oxygen species accumulation and preserve the healthy mitochondrial network. However, chronic AF-related stress (e.g., calcium overload, sustained reactive oxygen species exposure) can impair mitophagy pathways, resulting in the accumulation of dysfunctional mitochondria.

This study combined bioinformatics analysis and experimental validation to uncover key genes and molecular networks underlying the interaction between mitophagy and ion channels in AF. The objective was to elucidate the molecular mechanisms underlying the "mitophagy defects -> ion channel dysfunction -> electrical remodeling" axis.

Link: https://doi.org/10.3389/fphys.2025.1687578

Researchers here mine human data and records from zoos to show that male castration and female sterilization increase life span in a very broad range of higher animals. Mechanisms are thought to be similar from species to species, even if the size of the effect on life span varies. In males, it appears largely connected with systemic effects of exposure to androgen hormones over a lifespan, while in females it appears largely connected to stresses resulting from reproduction. Thus in males only hormone level reduction increases life span, while in females any contraceptive approach that prevents reproduction increases life span.

Our results demonstrate that ongoing hormonal contraception and permanent methods of surgical sterilization increase vertebrate survivorship. The analysis of zoo records provides unparalleled insight into the taxonomic breadth of the lifespan response, with male castration, female surgical sterilization and ongoing female hormonal contraception linked to increased life expectancy across a broad range of species within the mammalian kingdom.

Life expectancy is increased by an average of 10-20% depending on the timing of treatment and environment the animal is exposed to, providing strong evidence for the presence of an intraspecific trade-off between adult reproduction and survival in vertebrates. Notably, however, we do not observe the very substantial, often more than 50% increases in lifespan that are observed in some invertebrate species after germ cell removal, particularly in species that are semelparous.

There is a wide species-level heterogeneity in the survival response to sterilization and contraception. What causes this remains to be determined. It has been widely hypothesized that male gonadal-specific hormone production (testosterone) contributes to shorter lifespans in males relative to females. In rodents, castration is associated with improvements in several domains of health in later life, in particular cognition and physical function. Thus, reducing male androgen signalling may broadly target multiple processes involved in the biology of ageing.

In females, increased life expectancy occurred with various contraceptive methods. Contraception reduced the risk of death from multiple causes, including infectious and non-infectious diseases. We hypothesize that the increased life expectancy in females arises from reduced allocation to reproduction and reproductive processes in adulthood, with contraception strongly reducing the direct and indirect costs of offspring production.

Link: https://doi.org/10.1038/s41586-025-09836-9

The axons that carry nerve impulses between neurons must be sheathed in myelin if they are to function. This structured myelin is built and maintained by a specialized population of cells called oligodendrocytes, which derive from a precursor population. Loss of myelin is a feature of severely disabling and ultimately fatal conditions such as multiple sclerosis. To a lesser degree, however, myelin loss also takes place with advancing age, and evidence suggests that this contributes to cognitive decline at the very least. Anything that disrupts the activity of oligodendrocytes will lead to loss of myelin, and the underlying damage that drives aging disrupts all cell populations in a variety of ways, to an increasing degree as the burden of damage rises over time.

The connection with aging is why it is worth keeping an eye on progress towards the development of therapies for multiple sclerosis. Therapies that treat demyelinating conditions may turn out be useful in older people as well. The details do matter, however. The targeted mechanisms must be applicable in both disease and aging, and it isn't always clear that this is the case. Today's open access paper is an example in which the researchers focus on multiple sclerosis patients and animal models of demyelination that have no relevance to aging. Thus the target they uncover does seem promising, but may or may not turn out to be useful outside the scope of multiple sclerosis.

The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation

Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination often fails in part due to the inhibition of OPC maturation into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA), generated by hyaluronidase activity, block OPC maturation and remyelination. Here, we aimed to identify which hyaluronidases are elevated in demyelinating lesions and to test if they influence OPC maturation and remyelination.

We find that the Cell Migration Inducing and hyaluronan binding Protein (CEMIP) is elevated in demyelinating lesions in mice with experimental autoimmune encephalomyelitis during peak disease when neuroinflammatory mediators, including tumor necrosis factor-α (TNFα), are at high levels. CEMIP expression is also elevated in demyelinated MS patient lesions. CEMIP is expressed by OPCs, and TNFα induces increased CEMIP expression by OPCs. Both increased CEMIP expression and HA fragments generated by CEMIP block OPC maturation into OLs. CEMIP-derived HA fragments also prevent remyelination in vivo.

This data indicates that CEMIP blocks remyelination by generating bioactive HA fragments that inhibit OPC maturation. CEMIP is therefore a potential target for therapies aimed at promoting remyelination.

Mitochondria retain a circular genome distinct from the DNA of the cell nucleus, a legacy of their distant evolutionary origins as symbiotic bacteria. Mitochondrial DNA damage is thought to contribute to the characteristic mitochondrial dysfunction of aging, although the relative contributions of mitochondrial DNA damage versus epigenetic changes in the nucleus that disrupt mitochondrial function remain up for debate. Researchers here provide evidence for a novel form of molecular damage to mitochondrial DNA to contribute to mitochondrial dysfunction. Once again, the question of relative contributions arises, always a challenge in everything associated with mechanisms of aging.

Mitochondrial DNA (mtDNA) is crucial for cellular energy production, metabolism, and signaling. Its dysfunction is implicated in various diseases, including mitochondrial disorders, neurodegeneration, and diabetes. mtDNA is susceptible to damage by endogenous and environmental factors; however, unlike nuclear DNA (nDNA), mtDNA lesions do not necessarily lead to an increased mutation load in mtDNA. Instead, mtDNA lesions have been implicated in innate immunity and inflammation.

Here, we report a type of mtDNA damage: glutathionylated DNA (GSH-DNA) adducts. These adducts are formed from abasic (AP) sites, key intermediates in base excision repair, or from alkylation DNA damage. Using mass spectrometry, we quantified the GSH-DNA lesion in both nDNA and mtDNA and found its significant accumulation in mtDNA of two different human cell lines, with levels one or two orders of magnitude higher than in nDNA.

The formation of GSH-DNA adducts is influenced by TFAM and polyamines, and their levels are regulated by repair enzymes AP endonuclease 1 (APE1) and tyrosyl-DNA phosphodiesterase 1 (TDP1). The accumulation of GSH-DNA adducts is associated with the downregulation of several ribosomal and complex I subunit proteins and the upregulation of proteins related to redox balance and mitochondrial dynamics. Molecular dynamics (MD) simulations revealed that the GSH-DNA lesion stabilizes the TFAM-DNA binding, suggesting shielding effects from mtDNA transactions.

Collectively, this study provides critical insights into the formation, regulation, and biological effects of GSH-DNA adducts in mtDNA. Our findings underscore the importance of understanding how these lesions may contribute to innate immunity and inflammation.

Link: https://doi.org/10.1073/pnas.2509312122

One can debate aspects of the way in which researchers here model what might happen if all of aging is controlled except random mutational damage to nuclear DNA, but the idea is an interesting one. Will random mutational damage to somatic cells be so much harder to eliminate than other aspects of aging that we should think ahead in this way? In tissues where cells are largely replaced, we might think that stem cell populations can at some point be repaired or replaced, and thus the mutational burden in tissues can be reduced over time via the influx of less damaged somatic cells created by the rejuvenated stem cell population. Most neurons in the central nervous system are long-lived, however, and are never replaced. We would have to postulate some very advanced technology to think that we will be able to address the stochastic mutational burden of vital cells in the brain, that damage different in every cell.

Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations.

Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median lifespan from a theoretical non-aging baseline of 430 years to 169 years. In contrast, proliferating tissues like liver maintain functionality for thousands of years through cellular replacement, effectively neutralizing mutation-driven decline.

Multi-organ integration predicts median lifespans of 134-170 years - approximately twice current human longevity. This substantial yet incomplete reduction indicates that somatic mutations significantly drive aging but cannot alone account for observed mortality, implying comparable contributions from other hallmarks.

Link: https://doi.org/10.1101/2025.11.23.689982

Alzheimer's disease is the most prominent of the tauopathies. This is a class of neurodegenerative conditions in which large enough amounts of tau protein become excessively altered by phosphorylation and aggregate into solid deposits, causing inflammation, loss of function, and cell death in the brain. The various isoforms of tau play an important role in maintaining the structure of axons that connect neurons, but aggregation would be problematic regardless of the normal function of tau.

Just as much of Alzheimer's research and development has long focused on trying to prevent, clear, or disarm misfolded amyloid-β and its toxic aggregates, a similar range of efforts is focused on finding ways to prevent, clear, or disarm hyperphosphorylated tau and its aggregates. Progress to date has been frustrating slow, just as it was for amyloid-β clearance via immunotherapy. Many of the possible paths forward appear challenging to implement well.

Today's research materials present an example of the type, an approach that potentially allows dramatic reduction in overall tau levels. Yet tau is important to axonal function, one can't just get rid of it, which presents developers with the much harder goal of achieving a balancing act with dose and outcome. Even then it tends to be the case that therapies that treat a condition in which a protein becomes altered into a toxic form by reducing overall expression of that protein tend to have unpleasant side-effects.

Novel discovery reveals how brain protein OTULIN controls tau expression and could transform Alzheimer's treatment

The research team initially hypothesized that inhibiting the enzyme activity of the OTULIN protein would enhance tau clearance through cellular garbage disposal systems. However, when they completely knocked out the OTULIN gene in neurons, tau disappeared entirely - not because it was being degraded faster, but because it wasn't being made at all. "This was a paradigm shift in our thinking. We found that OTULIN deficiency causes tau messenger RNA to vanish, along with massive changes in how the cell processes RNA and controls gene expression."

The study used neurons derived from a patient with late-onset sporadic Alzheimer's disease, which showed elevated levels of both OTULIN protein and phosphorylated tau compared to healthy control neurons. This correlation suggested OTULIN might be contributing to disease progression. "OTULIN could serve as a novel drug target, but our findings suggest we need to modulate its activity carefully rather than eliminate it completely. Complete loss causes widespread changes in cellular RNA metabolism that could have unintended consequences."

The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons

The degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system and autophagy, which are impaired in Alzheimer's disease (AD) and related dementias (ADRD), causing tau aggregation. Protein ubiquitination, with its linkage specificity determines the fate of proteins, which can be either protein degradative or stabilizing signals. While the linear M1-linked ubiquitination on protein aggregates serves as a signaling hub that recruits various ubiquitin-binding proteins for the coordinated actions of protein aggregate turnover and inflammatory nuclear factor-kappa B (NF-κB) activation, the deubiquitinase OTULIN counteracts the M1-linked ubiquitin signaling. However, the exact role of OTULIN in neurons and tau aggregates clearance in AD are unknown.

Based on our quantitative bulk RNA sequencing analysis of human induced pluripotent stem cell-derived neurons (iPSNs) from an individual with late-onset sporadic AD (sAD2.1), a downregulation of the ubiquitin ligase activating factors (MAGE-A2/MAGE-A2B/MAGE-H1) and OTULIN long noncoding RNA (OTULIN lncRNA) was observed compared to healthy control iPSNs. The downregulated OTULIN lncRNA is concurrently associated with increased levels of OTULIN protein and phosphorylated tau.

Inhibiting the deubiquitinase activity of OTULIN with a small molecule UC495 reduced the phosphorylated tau in iPSNs and SH-SY5Y cells, whereas the CRISPR-Cas9-mediated OTULIN gene knockout (KO) in sAD2.1 iPSNs decreased both the total and phosphorylated tau levels. CRISPR-Cas9-mediated OTULIN KO in SH-SY5Y resulted in a complete loss of tau at both mRNA and protein levels, and increased levels of polyubiquitinated proteins, which are being degraded by the proteasome. In addition, SH-SY5Y OTULIN KO cells showed downregulation of various genes associated with inflammation, autophagy, ubiquitin-proteasome system, and the linear ubiquitin assembly complex that consequently may prevent development of an autoinflammation in the absence of OTULIN gene in neurons.

Together, our results suggest, for the first time, a noncanonical role for OTULIN in regulating gene expression and RNA metabolism, which may have a significant pathogenic role in exacerbating tau aggregation in neurons. Thus, OTULIN could be a novel potential therapeutic target for AD and ADRD.

Like the gut microbiome, the composition of the oral microbiome changes with age. Some of these changes have been shown to correlate with health status, but research into this part of the commensal microbiome is nowhere near as advanced as is the case for the gut microbiome. It is unclear as to the degree to which the oral microbiome is causing issues in aging, even where mechanisms are known to exist, such as leakage of bacteria and bacterial products associated with gingivitis into the bloodstream. It is also unclear as to whether the classes of strategy shown to rejuvenate the composition of the gut microbiome can work effectively for the oral microbiome.

Evidence indicates that the composition of the oral microbiome changes with age, although findings on diversity are inconsistent, with reports of both increases and decreases in older adults. These shifts are influenced by factors such as diet, oral hygiene, and immune function. Unhealthy aging, including conditions like frailty, neurodegenerative diseases, and sarcopenia, is associated with distinct oral dysbiosis. Potential mechanisms linking the oral microbiome to aging include chronic inflammation and immunosenescence.

Although research on the oral microbiome is still in its early stage compared to that on the gut microbiome, existing studies still indicate a link between the oral microbiome and aging. The purpose of this review is to explore whether the oral microbiome, which serves as a common gateway for the microbiota of the respiratory and digestive systems, should be considered a target for predicting and delaying aging. We focus primarily on the changes in the oral microbiome during healthy aging, the characteristics of the oral microbiome in unhealthy aging states such as frailty and age-related diseases and the possible mechanisms underlying the association between the oral microbiome and aging. Finally, we summarize the current research findings and provide possible directions for microbiome-based aging interventions.

Link: https://doi.org/10.1080/20002297.2025.2589648

The balance of microbial populations making up the gut microbiome changes with age in ways that are detrimental to health. Microbes generating necessary metabolites diminish in number, while microbes that provoke chronic inflammation grow in number. Further, researchers have established that is a tendency towards a distinctly different gut microbiome composition in some age-related conditions, such as Alzheimer's disease. Whether this difference over and above the more usual age-related changes acts to contribute directly to Alzheimer's disease, or is a side-effect of a dysregulated immune system or other aspect of aged metabolism, remains to be concretely determined. Here, researchers focus on microglia, the innate immune cells of the brain. Dysfunctional, inflammatory microglia are thought to be involved in neurodegenerative conditions, and one can argue for a connection to the gut microbiome.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that can be caused by multiple factors, such as abnormal amyloid-beta (Aβ) deposition, pathological changes in Tau protein, lipid metabolism disorders, and oxidative stress. For decades, research into AD has been dominated by the amyloid cascade hypothesis. However, amyloid-beta (Aβ) clearance alone slows progression by only 35%. This compels increasing attention to peripheral factors in AD pathophysiology, redirecting the field from a brain-centric, amyloid-focused model toward a systemic perspective that emphasizes peripheral-central interactions.

It is now increasingly recognized that chronic, low-grade systemic inflammation, a condition often termed "inflammaging," acts as a critical driver of neuroinflammation and accelerates neurodegenerative processes. Within this framework, the gastrointestinal tract, which harbors the body's largest immune cell population and the vast metabolic capacity of the gut microbiome, emerges as a pivotal hub for originating peripheral signals that shape brain health and disease. This article reviews the direct and indirect effects of gut microbiota and its derivatives on microglia, explores their role in the pathogenesis of AD, and discusses therapeutic strategies based on gut microbiota. Although existing studies have shown the potential of these interventions, further research is needed to completely understand their application in the treatment of AD.

Link: https://doi.org/10.3389/fragi.2025.1704047

Clearly change must occur constantly in the adult brain. However we suppose information to be encoded in physical structures of the brain, the information content of a brain evidently changes over time, as illustrated by the processes of memory and learning, and thus the structure of the brain must also change. Nonetheless, if one backtracks to the early 1990s, the consensus at the time was that new neurons were not created in the adult brain. Any change in the brain's information content was thought to be a matter of rearranging axonal connections between neurons or to involve alterations in other, smaller-scale structures such as dendritic spines. Then it was persuasively demonstrated that the creation of new neurons does in fact occur in adult mice.

In the grand scheme of progress in the life sciences, that something occurred thirty years ago makes it a relatively recent realization. Follow up and debate are still very much in progress. Over the past decade, a debate in the scientific literature occurred over whether the limited human data in fact supported the existence of adult neurogenesis in our own species. Matters appear to have settled to a consensus that human adult neurogenesis does occur. Nonetheless, it remains the case that most of the data for adult neurogenesis is (a) obtained from studies in mice, and (b) focused on the hippocampus, an important region for the function of memory.

Today's open access paper is a brief and readable review on the question of aging and neurogenesis in the hippocampus. Neurogenesis is interesting in this context because, as shown in mice, it declines with age. This is thought to contribute to loss of memory function, and there is a sizable contingent of researchers engaged in trying to boost neurogenesis as a possible basis for future therapies. As this review makes clear, however, after nearly thirty years of work on this topic there are still looming gaps in knowledge everywhere you look.

Extent and activity of adult hippocampal neurogenesis

There is strong evidence for human hippocampal neurogenesis occurring well into adulthood, albeit at a steadily decreasing rate, but we lack a cohesive scientific discourse surrounding its physiological role, particularly the relationship between neurogenic extent and activity. Research emphasis is generally on the former, relying on the assumption that the number of newborn neurons sufficiently explains any functional implications. This approach ignores the reality that individual neurons vary drastically in activity, even in otherwise identical cell populations. This review focuses on the relationship between the extent of neurogenesis and activity of the newborn neurons themselves, with a particular emphasis on how we might use this information to inform future studies.

Adult hippocampal neurogenesis is the process by which new neurons are generated in the dentate gyrus of the hippocampus in the adult brain. The generation of new neurons is a hierarchical, activity-dependent process that starts with radial glia-like precursors that quickly transition to progenitors before eventual differentiation into neuroblasts. This immature neuronal population matures and migrates a short distance from the subgranular zone of the dentate gyrus to the granular layer, where it integrates into pre-existing circuits.

Newly generated neurons progress through dynamic stages important for their normal functioning, finally resulting in behavioral modulation with their integration into hippocampal circuitry. This complex process is regulated by various factors that can increase or decrease neurogenesis, leading to alterations in both the number and function of newly generated neurons. For example, aging is a major physiological factor that contributes to the decline of adult hippocampal neurogenesis by pushing the neural stem cell pool into a quiescent stage and reducing the ability of neural stem cells to proliferate.

Even if the neural stem cells produce new neurons, aging impairs the survival and integration of these newborn neurons into existing circuits. Indeed, aging disrupts the dentate gyrus microenvironment by reducing synaptic density and compromising vascularization, ultimately creating a less supportive niche for neurogenesis. The dentate gyrus plays a critical role in pattern separation and episodic memory, and age-related reductions in hippocampal neurogenesis have been directly linked to cognitive decline; studies show that diminished neurogenesis contributes to impairments in spatial learning, memory precision, and cognitive flexibility, all hallmark features of age-related cognitive decline.

In nematode worms, SKN-1 is a known longevity-related gene, and researchers here explore its role in the lysosomal enlargement that occurs with aging. Lysosomes are necessary for the cellular maintenance processes of autophagy to function. Lysosomes carry out the last step in the recycling of damaged and excess proteins machinery and structures in the cell, which is to break down those materials into components that can be reused. It has been observed that lysosomes become larger in cells in aged tissues, but this is apparently a compensatory behavior rather than a form of dysfunction. It is an attempt to maintain lysosomal function and thus the health of the cell in the face of the damage of aging.

Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes.

Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.

Link: https://doi.org/10.1371/journal.pbio.3003540

Researchers here build an aging clock based on the expression levels of three microRNAs as a proof of principle that microRNA clocks are viable. This should not be a surprise; if the past twenty years of work on aging clocks have taught us anything, it is that any sufficiently complex body of data that changes with age can be used as the basis for a clock. Clocks are now relatively easily produced. The much harder challenge is to take any given clock and amass sufficient human data to (a) demonstrate that it is usefully measuring biological age or something closely related to biological age, and (b) understand its quirks and limitations to the point at which one can trust the use of that clock in the assessment of potential rejuvenation therapies, in order to guide and accelerate progress in the field.

The extension of human longevity has intensified the search for biomarkers that capture not only chronological age but also biological aging and functional healthspan. Among molecular candidates, microRNAs (miRNAs) have emerged as promising regulators and indicators of aging-related processes. In this pilot study, we explored whether selected circulating miRNAs could serve as potential biomarkers of biological age and lifestyle-associated aging dynamics.

Based on current literature, we focused on three miRNAs - miR-24, miR-21, and miR-155 - previously linked to inflammation, senescence, and metabolic regulation. Capillary blood samples from a heterogeneous adult cohort were analyzed using quantitative PCR. Values were integrated into a composite "miRNA-3Age" model through multivariate regression analysis to estimate biological age. Associations between lifestyle variables (diet, exercise, stress, and smoking) and miRNA-based biological age were examined.

The miRNA-3Age model predicted biological age with moderate correlation to chronological age and revealed variability consistent with individual health profiles. Participants with favorable lifestyle factors (e.g., frequent consumption of fish, whole grains, and green tea; regular exercise) tended to exhibit lower miRNA-3Age estimates, whereas stress and smoking were associated with higher predicted biological age. The miRNA-3Age model provides a preliminary step toward a scalable, lifestyle-sensitive aging metric that warrants validation in diverse populations.

Link: https://doi.org/10.3389/fnut.2025.1659730

Reprogramming involves exposing cells to expression of one or more of the Yamanaka factors, c-Myc, Oct4, Sox2, and KLF4. This slowly alters cell state in a small fraction of exposed somatic cells, and these cells transform to become induced pluripotent stem cells, essentially the same as embryonic stem cells. This recapitulates some of the processes involved in embryogenesis. More rapidly and reliably than this change of state, a cell exposed to Yamanaka factor expression also exhibits rejuvenation of nuclear DNA structure and patterns of gene expression, leading to a restoration of youthful function. This cannot fix everything in an aged cell, such as mutational DNA damage, but it has a sizable enough effect on cells, and in mice, that partial reprogramming as a basis for rejuvenation therapies has become a popular area of development.

Can reprogramming of cell state be efficiently separated from reprogramming of nuclear structure? If we want reliable rejuvenation therapies, it seems likely that progress must be made on this front. Researchers are investigating the regulation of reprogramming downstream of the Yamanaka factors, but this is a painfully slow process. Still, every incremental advance in tracing the interactions of proteins might be the one that disentangles rejuvenation from state change, unleashing a much more efficient approach than offered by the present options capable of triggering reprogramming.

Most of the longevity industry now consists of reprogramming initiatives if measuring by investment size. Related to that, we might argue that most of the work carried out on reprogramming as a basis for rejuvenation therapies is in fact conducted outside academia at this point. In the long run this work will become just as visible as academic efforts, but for now it is dark matter. Thus to find ongoing indications of progress on picking apart the systems of regulation that produce rejuvenation in response to Yamanaka factor expression, one must keep up with the publication of academic papers - such as today's example.

Conserved Master Regulators Orchestrate Cellular Reprogramming-Induced Rejuvenation

Partial somatic cell reprogramming has been proposed as a rejuvenation strategy, yet the regulatory architecture orchestrating age reversal remains unclear. What molecular systems allow partial relaxation of identity to restore youthful regulatory function while avoiding dedifferentiation? Previous work has identified chromatin regulators as central to this process. DNA methyltransferases Tet1 and Tet2 may be required for reprogramming-induced rejuvenation, and reprogramming-induced rejuvenated cells exhibit restored nucleosome regularity and recalibrated histone modification balance. However, identifying genes that change during rejuvenation does not reveal which factors actively drive the process versus those that respond as downstream consequences. Distinguishing upstream regulators from effector genes requires network-level analysis that can infer causal regulatory relationships.

Here, we performed gene regulatory network reconstruction across several independent systems to identify master regulators that coordinate reprogramming-induced rejuvenation (RIR). In mouse mesenchymal stem cells, mouse adipocytes, and human fibroblasts undergoing partial reprogramming, we identified genes showing opposite expression dynamics during aging and reprogramming. This approach revealed regulators governing rejuvenation rather than developmental programs. Despite divergent overall network architectures, nine transcription factors converged as master regulators across all three systems, including Ezh2, Parp1, and Brca1. These regulators undergo coordinated reorganization during reprogramming, characterized by broader target engagement and enhanced regulatory coherence.

We further demonstrated that direct perturbation of Ezh2 bidirectionally modulates transcriptomic age. Notably, overexpression of a catalytically inactive Ezh2 mutant achieved rejuvenation, suggesting mechanisms distinct from canonical H3K27me3-mediated regulation are involved in RIR. Our findings reveal that cellular rejuvenation is orchestrated by conserved master regulators whose network coordination can be targeted independently of the reprogramming process.

Senescent cells grow in number with age, lingering to cause harm via inflammatory secretions. This is a problem in every tissue. Here researchers focus on the endothelial lining of blood vessels, and demonstrate that a strategy to reduce the pace at which endothelial cells enter a senescent state can slow the development of vascular stiffness and atherosclerosis in a mouse model of these cardiovascular issues. There are many different ways in which one might go about making cells more resistant to stress-induced senescence, and here the approach is to improve cell defenses against oxidative molecules.

Terazosin (TZ), a well-known antagonist of the α1-adrenergic receptor (α1-AR), has demonstrated protective effects on vascular endothelial cells (ECs) and reduced vascular stiffness in clinical studies. Endothelial dysfunction and oxidative stress are central drivers of cardiometabolic diseases such as diabetes, where sustained reactive oxygen species burden accelerates EC senescence and barrier failure. These findings suggest its potential role in combating vascular aging and atherosclerosis; however, the underlying mechanisms remain partially understood.

In this study, we investigated whether TZ can prevent atherosclerosis in ApoE-/- mice fed a high-cholesterol diet and aimed to elucidate the mechanisms involved. Our results showed that TZ significantly reduced plaque size, EC senescence, vascular permeability, and reactive oxygen species (ROS) levels, effectively inhibiting atherosclerosis independently of α1-AR signaling.

In cultured primary human umbilical vein ECs (HUVECs), TZ inhibited EC senescence via the Pgk1/Hsp90 pathway. It enhanced the interaction between Hsp90 and the antioxidant enzyme peroxiredoxin 1 (Prdx1), leading to lower reactive oxygen species levels - a key driver of cellular senescence. These findings were confirmed in atherosclerotic ApoE-/- mice.

Furthermore, senescent ECs exhibited increased levels of vascular endothelial growth factor A (VEGFA) and decreased levels of angiostatin, contributing to higher vascular permeability and exacerbating atherosclerosis. TZ effectively reversed these changes.

Overall, our study demonstrates that TZ primarily alleviates EC senescence and atherosclerosis through the Pgk1/Hsp90/Prdx1 pathway, highlighting Pgk1 activation as a strategy that may also mitigate endothelial dysfunction and oxidative stress in broader cardiometabolic contexts (e.g., diabetes), suggesting that TZ is a promising senomorphic agent for treating vascular aging and that Pgk1-targeted interventions could have implications beyond atherosclerosis.

Link: https://doi.org/10.1186/s12933-025-02976-2

The aging of the extracellular matrix is not as well studied as is the case for cell biochemistry. There are likely many important changes that take place in the extracellular matrix over a lifetime that meaningfully affect cell function in aged tissues, but have yet to be discovered and understood. One example is outlined here, a matrix protein that declines with age but seems necessary to maintain the normal function of muscle stem cells. Declining muscle stem cell function is one of the important contributions to the characteristic loss of muscle mass and strength that occurs with age.

Skeletal muscle regeneration occurs through the finely timed activation of resident muscle stem cells (MuSC). Following injury, MuSC exit quiescence, undergo myogenic commitment, and regenerate the muscle. This process is coordinated by tissue microenvironment cues, however the underlying mechanisms regulating MuSC function are still poorly understood.

Here, we demonstrate that the extracellular matrix protein Tenascin-C (TnC) promotes MuSC self-renewal and function. Mice lacking TnC exhibit reduced number of MuSC, and defects in MuSC self-renewal, myogenic commitment, and repair. We show that fibro-adipogenic progenitors are the primary cellular source of TnC during regeneration, and that MuSC respond through the surface receptor Annexin A2. We further demonstrate that TnC declines during aging, leading to impaired MuSC function. Aged MuSC exposed to soluble TnC show a rescued ability to both migrate and self-renew in vitro.

Overall, our results highlight the pivotal role of TnC during muscle repair in healthy and aging muscle.

Link: https://doi.org/10.1038/s42003-025-09189-z

Even in this age of single cell sequencing, a great deal of the categorization and counting of cells is still accomplished via assessment of cell surface proteins. The ability to cheaply create and manufacture novel antibodies that selectively bind to specific proteins naturally led to technologies such as flow cytometry that can separate and count cells that express a specific surface protein, or high versus low levels of that surface protein. The large number of proteins with names that start with "CD" for cluster of differentiation are so named because researchers have spent a lot of time looking for ways to distinguish different populations of immune cells with very different behaviors.

Recognizing specific surface markers is also an important foundation for the development of cell killing technologies and immunotherapies. Thus the cancer research field is very interested in categorizing cells by their markers. Similarly, now that the research community recognizes that senescent cells accumulate with age and are harmful, an important contribution to age-relaed loss of function and disease, there is interest in distinct markers of senescence. Firstly, senescent cells are not uniform, and it may be useful to distinguish their types. Secondly, cell killing technologies that are highly selective for senescent cells are very much a desirable goal. Thirdly, the well established approaches to assess the burden of senescence in tissues are likely suboptimal in a number of ways.

The exploration of markers of senescence is a work in progress, with ongoing debate over the merits of one approach over another, particularly when it comes to the immune system. To come full circle, cellular senescence in the immune system appears important to immune system aging - but so are a range of other issues. The immune system is very complex, and far from fully mapped. There is a great deal of room for improvement to the present state of knowledge, and today's open access paper is an example of this sort of ongoing work on the topic of immune cell senescence and how to best identify this state.

Re-evaluating CD57 as a marker of T cell senescence: implications for immune ageing and differentiation

Ageing is accompanied by a decline in immune function, associated with susceptibility to infections and malignancies, and reduced vaccine efficacy. These immunological changes, affect multiple components of the immune system, particularly T lymphocytes, which exhibit altered subset distributions and accumulate senescent features.

CD57, a surface glycoprotein expressed on T cells, has emerged as a potential marker of terminal differentiation and senescence used for immunomonitoring in infection or cancer contexts. However, the use of CD57 as a marker of T cell senescence remains unclear. To investigate this, we analyzed CD57 expression on CD8+ and CD4+ T cells in healthy donors from two independent cohorts, considering cellular differentiation, age, cytomegalovirus status, and other senescence markers.

Our findings reinforce the association between CD57 expression, T cell differentiation, and cytomegalovirus seropositivity, but not with chronological age. Although CD57 is associated with altered proliferation and survival in all T cell differentiation subsets, it does not fully align with a senescent phenotype. Therefore, we propose that CD57 may be better appreciated as a marker of immunological age. Moreover, the interpretation of CD57 expression must account for cytomegalovirus serostatus to avoid misleading conclusions, especially in oncology and ageing research.

Given the ability to accurately map the microbial species and relative population sizes of the gut microbiome via 16S rRNA sequencing, researchers are generating an enormous amount of data linking specific characteristics of the gut microbiome to specific medical conditions, including the changes that take place with age. Here, researchers use data from patients with fibrosis in the lungs to mount an argument for Bifidobacterium adolescentis to be a beneficial species, and then test this proposal in aged mice. Increasing the presence of Bifidobacterium adolescentis in the gut microbiome of mice proves capable of attenuating fibrosis in the lung, making it a potentially interesting intervention. At present many forms of lung fibrosis are hard to treat and largely irreversible.

The global burden of pulmonary fibrosis is increasing. Recent studies have shown that some pulmonary fibrotic lesions caused by COVID-19 infection may persist for a long time. Emerging evidence suggested a critical association between gut microbiota and pulmonary fibrosis. In this study, the clinical follow-up data from post-COVID-19 patients indicated that those with higher CT image scores were older, had a significantly lower Blautia and Bifidobacterium to Streptococcus ratio (B/S index).

We examined whether Bifidobacterium adolescentis could attenuate bleomycin-induced pulmonary fibrosis in mice, with particular attention in the aging mice. Aging mice exhibited more severe pulmonary fibrosis after bleomycin induction, while the intervention of B. adolescentis attenuated the degree of pulmonary fibrosis in aging mice to a state similar to that of young mice. B. adolescentis alleviated inflammatory responses by enhancing the gut barrier, and reduced fibrotic marker expression (TGF-β, IL-17, α-SMA, Collagen I, Collagen III) by modulating PPAR and Th17 signaling pathways. Furthermore, B. adolescentis stabilized gut microbiota and increased the abundance of Bifidobacterium, Turicibacter, and norank_f_Desulfovibrionaceae, thereby suppressed the prostaglandin E2 (PGE2) and affected collagen deposition.

In conclusion, B. adolescentis alleviates pulmonary fibrosis through the gut-lung axis by regulating PGE2/PPAR/Th17 signaling, providing a promising therapeutic approach for pulmonary fibrosis management.

Link: https://doi.org/10.1038/s41538-025-00613-6

Excess weight is a risk factor for Alzheimer's disease, but nowhere near as strongly as, say, for type 2 diabetes. It is likely not as straightforward a relationship in terms of the underlying biochemistry. Here, researchers note that obesity correlates with low levels of choline in blood samples, and low levels of choline in turn are established in animal studies to worsen age-related inflammation and progression of neurodegeneration. The researchers propose that low choline contributes to the metabolic consequences of obesity, but note that it is unclear as to whether obesity causes low choline. As is usually the case when looking at human data, correlations are easily established, but finding definitive evidence of causation is challenging.

Here, we demonstrate a relationship between early-life obesity, insulin resistance, circulating choline, and inflammation, emphasizing their potential as risk factors for disorders such as Alzheimer's disease (AD). Choline levels were lower in obese participants compared to those with a healthy body mass index (BMI). Importantly, several metabolic indicators were elevated in the obese group, and body composition markers (BMI and %Body Fat) and insulin sensitivity markers (insulin levels and HOMA-IR) were negatively correlated as well as associated with choline levels.

Obese participants also exhibited dysregulated inflammatory profiles; 11 cytokines were elevated. Additionally, levels of aldolase B and sorbitol dehydrogenase - liver enzymes involved in sugar metabolism - were higher in obese individuals and negatively correlated with choline levels, paralleling our previous findings in AD mice on a choline-deficient diet. Evidence of neuronal axonal damage was observed in obese participants; as plasma NfL was elevated and inversely correlated with choline levels, this relationship was validated in independent mild cognitive impairment (MCI) and AD cohorts.

Collectively, these findings support the idea that low circulating choline levels may contribute to the metabolic and inflammatory dysfunctions associated with obesity and may increase the risk of neurodegenerative diseases.

Link: https://doi.org/10.14336/AD.2025.1207

The glymphatic system parallels blood vessels where they enter the brain, providing a path for drainage of cerebrospinal fluid from the brain into the body. The other well described path is through channels in the cribriform plate bone. These drainage routes become dysfunctional with age, allowing metabolic waste to build up in the brain, and thus contributing to the dysfunctional environment that causes pathology and neurodegeneration.

An approach to measure drainage of cerebrospinal fluid through the glymphatic system via magnetic resonance imaging was developed relatively recently, known by the unwieldy name of diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). DTI-ALPs has been having its time in the sun over the past few years, with numerous research groups working to expand the body of data for this measurement in various patient populations. Today's open access paper is an example of this sort of work, focused on patients with cerebral small vessel disease.

Cerebral small vessel disease, also known as microangiopathy, emerges from a combination of endothelial dysfunction in microvessels, a loss of microvessel density that impairs blood flow, and other issues that affect the integrity and function of the smallest vessels that support brain tissue. It is worth considering that the aspects of aging that harm the vasculature likely also harm the near neighbor glymphatic system. That patients with cerebral small vessel disease also exhibit impaired glymphatic drainage of cerebrospinal fluid doesn't necessarily mean that one condition causes the other. They may both be emergent properties of the cell and tissue damage of aging, and likely each makes the other worse in a variety of different ways.

Glymphatic system impairment in cerebral small vessel disease: associations with perivascular space volume and cognition

Cerebral small vessel disease (CSVD) is a progressive cerebrovascular disease characterized by diverse clinical manifestations, especially neurocognitive dysfunction, a primary contributor to vascular cognitive impairment. The glymphatic system, a brain waste clearance system first described in 2012, facilitates the exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). In this process, CSF enters the brain parenchyma via para-arterial perivascular spaces, passes through astrocytic aquaporin-4 (AQP4) water channels, and mixes with ISF before being cleared along perivenous routes, thereby promoting the removal of metabolic waste.

Recent evidence suggests that impaired glymphatic function may represent a final common pathway in the pathogenesis of dementia and has been increasingly implicated in the pathophysiology of CSVD. However, the relationship between glymphatic dysfunction and CSVD is likely bidirectional and multifactorial. On one hand, CSVD-related pathologies, such as endothelial dysfunction, blood-brain barrier disruption, and reduced arterial pulsatility, may impair glymphatic flow by compromising perivascular pumping mechanisms and fluid transport. On the other hand, impaired glymphatic clearance may exacerbate CSVD by allowing the accumulation of neurotoxic waste products, such as amyloid-β and tau proteins, and pro-inflammatory molecules within perivascular spaces, further damaging vascular integrity and promoting white matter injury.

We enrolled 120 CSVD patients [52 with no cognitive impairment (CSVD-NCI) and 68 with mild cognitive impairment (CSVD-MCI)] and 40 healthy controls. Glymphatic function was assessed using the left ALPS index derived from diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). Group comparisons in the ALPS index and perivascular space (PVS) volume fraction (VF), and correlations among glymphatic function, perivascular burden, and cognition were analyzed.

Compared to healthy controls, CSVD patients showed decreased ALPS index and increased PVS VF in basal ganglia, caudate, putamen, and hippocampus, with more pronounced alterations in the left hemisphere. The ALPS index was inversely correlated with PVS VF in the basal ganglia (r = -0.232), thalamus (r = -0.213), caudate (r = -0.221), and putamen (r = -0.210) in CSVD. Furthermore, a lower ALPS index was associated with poorer performance in global cognition (r = 0.312), executive function (r = 0.242), processing speed (r = 0.264), and visuospatial function (r = 0.272). Finally, the ALPS index partially mediated the association between putamen-PVS VF and global cognitive function, especially in the left hemisphere. Our findings demonstrate that impaired glymphatic function was associated with enlarged basal ganglia PVS, especially in the putamen, and worse cognitive performance, highlighting its potential role in disease progression and cognitive decline in CSVD.

Much of the benefit of stem cell therapies results from the signals released by those cells in the short time they survive in the body following transplantation. Much of that signaling is carried by extracellular vesicles, membrane-wrapped packages of molecules. Extracellular vesicle therapies can in principle become considerably less costly than stem cell therapies, because manufacture can be centralized, and because extracellular vesicles are much more readily stored and transported, but we are not there yet. Thus while extracellular vesicle therapy is certainly available to those with the time and patience to navigate the medical tourism space, or find suppliers and a cooperative physician inside the US, the schedule of 36 doses over 18 months used in this study is beyond the financial reach of most individuals at the present time. Still, it is quite interesting to see that the researchers demonstrated improvement in cognitive function in the aged monkeys assessed in the study.

Aging humans and non-human primates both exhibit a similar pattern of cognitive decline beginning in middle age that is characterized by progressive impairments in rule learning, executive function, and working and recognition memory-functions often associated with dysfunction of prefrontal and medial temporal lobe regions. The heterogeneity and inter-subject variability in aging and age-related cognitive impairments present challenges for developing effective therapeutics and can be attributed to differing degrees of cortical white matter (WM) damage and alterations to local and long-range prefrontal and temporal networks.

A promising therapeutic that has been shown to be efficacious in mitigating WM damage and improving cognitive function in rodent models is mesenchymal cell-derived extracellular vesicles (MSC-EVs). In the present study, late middle-aged rhesus monkeys were systemically administered monkey-derived MSC-EVs every 2 weeks for 18 months. We demonstrate that MSC-EV treatment improves spatial working memory and decreases the frequency of perseverative responses with largely no effects on recognition memory. These cognitive improvements were associated with increases in MRI diffusion measures of WM structural integrity over time as well as preservation of inter-network functional connectivity as measured by resting-state functional MRI.

These findings suggest that MSC-EV treatment can slow or reverse age-related cognitive decline while strengthening WM integrity and improving functional connectivity in late middle-aged rhesus monkeys.

Link: https://doi.org/10.1007/s11357-025-01992-0

Researchers here describe an indirect method of inducing greater resistance to damage and regeneration following a heart attack via modulation of macrophage behavior. Macrophages are innate immune cells resident in tissues that play an important role in regeneration and response to injury. The approach taken here is to grant macrophages better control over internally mislocalized DNA, escaped from either the nucleus or mitochondria into the cytosol. This provokes mechanisms intended to react to the presence of infectious pathogens, and is a cause of inflammatory signaling in aged and stressed cells. The better protected macrophages engage in a pattern of behavior that aids tissue regeneration and resilience following the injury of a heart attack.

Noncoding RNAs (ncRNAs) are increasingly recognized as promising therapeutic candidates. Here, we report the development of therapeutic Y RNA 1 (TY1), a synthetic ncRNA bioinspired by a naturally occurring human small Y RNA with immunomodulatory properties. TY1 up-regulates three-prime DNA exonuclease 1 (TREX1), an exonuclease that rapidly degrades cytosolic DNA.

In preclinical models of myocardial infarction (MI) induced by ischemia-reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed to either TY1 or Trex1 overexpression. Inhibition of Trex1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for Trex1, TY1 attenuated DNA damage in the post-MI heart.

The key beneficial effects appear to be mediated by extracellular vesicles secreted by TY1-conditioned macrophages. This previously undescribed mechanism - pharmacological upregulation of Trex1 in macrophages - establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity.

Link: https://doi.org/10.1126/scitranslmed.adp1338

A number of distinct cellular processes are labeled as forms of autophagy. These are ways in which a cell identifies unwanted structures and molecules, conveys those unwanted structures and molecules to a lysosome, and there breaks down the unwanted structures and molecules into raw materials. Autophagy is necessary for cell function, and has attracted attention in the aging research space for a number of reasons. Firstly the efficiency of autophagy appears to decline with age, secondly a number of ways to alter metabolism to modestly slow aging, such as calorie restriction and mTOR inhibition, appear to primarily function via increased efficiency of autophagy, and thirdly a few strategies to directly and selectively improve the efficiency of autophagy, such as LAMP2A upregulation, have also been shown to slow aging.

Today the focus is on chaperone mediated autophagy, in which unwanted proteins bind to a chaperone protein such as HSC70 that in turn binds to features such as LAMP2A on the surface of a lysosome, allowing the unwanted protein to be engulfed and then broken down. A pair of recently published papers from a team that has been working on LAMP2A for twenty years or so caught my attention. The work implicates an age-related decline in the efficiency of chaperone mediated autophagy in the aging of muscle tissue. The researchers show that maintaining efficient chaperone mediated autophagy in later life, achieved via upregulation of LAMP2A in a genetically engineered mouse lineage, can slow the age-related loss of muscle mass and strength. This approach likely works via helping to maintain muscle stem cell function into later life.

Age-related decline of chaperone-mediated autophagy in skeletal muscle leads to progressive myopathy

Chaperone-mediated autophagy (CMA) contributes to proteostasis maintenance by selectively degrading a subset of proteins in lysosomes. CMA declines with age in most tissues, including skeletal muscle. However, the role of CMA in skeletal muscle and the consequences of its decline remain poorly understood. Here we demonstrate that CMA regulates skeletal muscle function. We show that CMA is upregulated in skeletal muscle in response to starvation, exercise, and tissue repair, but declines in ageing and obesity.

Using a muscle-specific CMA-deficient mouse model, we show that CMA loss leads to progressive myopathy, including reduced muscle force and degenerative myofibre features. Comparative proteomic analyses reveal CMA-dependent changes in the mitochondrial proteome and identify the sarcoplasmic-endoplasmic reticulum Ca2+-ATPase (SERCA) as a CMA substrate. Impaired SERCA turnover in CMA-deficient skeletal muscle is associated with defective calcium (Ca2+) storage and dysregulated Ca2+ dynamics. We confirm that CMA is also downregulated with age in human skeletal muscle. Remarkably, genetic upregulation of CMA activity in old mice partially ameliorates skeletal muscle ageing phenotypes. Together, our work highlights the contribution of CMA to skeletal muscle homoeostasis and myofibre integrity.

Chaperone-mediated autophagy sustains muscle stem cell regenerative functions but declines with age

Proteostasis supports stemness, and its loss correlates with the functional decline of diverse stem cell types. Chaperone-mediated autophagy (CMA) is a selective autophagy pathway implicated in proteostasis, but whether it plays a role in muscle stem cell (MuSC) function is unclear. Here we show that CMA is necessary for MuSC regenerative capacity throughout life. Genetic loss of CMA in young MuSCs, or failure of CMA in aged MuSCs, causes proliferative impairment resulting in defective skeletal muscle regeneration.

Using comparative proteomics to identify CMA substrates, we find that actin cytoskeleton organization and glycolytic metabolism are key processes altered in aged murine and human MuSCs. CMA reactivation and glycolysis enhancement restore the proliferative capacity of aged mouse and human MuSCs, and improve their regenerative ability. Overall, our results show that CMA is a decisive stem cell-fate regulator, with implications in fostering muscle regeneration in old age.

As a brief introduction to the way in which the statistical tools used by policy makers exhibit important disconnections from reality, one can start with the quality-adjusted life year (QALY) and value of statistical life (VSL). Sadly we live in a world in which medicine is ever more centralized and regulated, with an ever greater fraction of decisions made by regulators based on statistics rather than by the individual patient based on their preferences. The paper here is an interesting glance at the relationship between the value of QALY and the VSL as used in practice, in this course of arguing that the value of QALY used in policy decisions should change with age (and other circumstances) because the VSL changes with age (and other circumstances).

In the healthcare sector, cost-benefit analysis (CBA) using measures such as the value of statistical life (VSL) and quality-adjusted life years (QALY) is commonly employed to guide policy interventions and the efficient allocation of healthcare resources. The VSL is calculated based on willingness to pay for mortality risk reduction and is widely used in CBA to evaluate the economic benefits of a policy. The QALY, which considers both quality of life (QoL) and life expectancy, equates one QALY to one year of life in perfect health (QoL = 1).

The VSL and QALY are considered to be closely related, and research on their relationship has been active in recent years. This measure allows for cross-sectional comparisons of different healthcare policies and is widely used in many countries as a standard metric for public health policies and resource allocation decisions. By employing QALY-based CBA, policymakers can quantitatively assess the effectiveness of healthcare interventions based on scientific evidence, thereby facilitating informed decision-making. For instance, the UK's National Institute for Health and Care Excellence (NICE) uses QALY to assess pharmaceutical and medical technologies, providing guidelines for the effective use of limited healthcare resources.

However, the QALY has several limitations. For example, it applies uniformly across different age groups, despite significant differences in health status and life expectancy between younger and older individuals. The current QALY-based CBA may not adequately account for age-specific differences, potentially leading to biased results. Additionally, QALY values are often derived based on practices from other countries without fully considering regional characteristics such as population, economic conditions, and age distribution.

This study aims to present a QALY metric that considers age-specific health status (QoL) and life expectancy by deriving QALY from VSL. We model the VSL-based QALY and demonstrate its effectiveness through a scenario and policy evaluation analysis. In this study, we focus our analysis on the monetary value of a QALY that arises solely from life extension without incorporating QoL improvements and present the results of VSL, QALY, and policy cost reduction, using socioeconomic data from Japan.

Link: https://doi.org/10.1038/s41598-025-29794-6

Stressing cancer cells to induce a senescent state is a secondary goal of cancer therapy, after inducing cell death, as senescence brings a halt to replication. Senescent cell burden is an important component of degenerative aging, and so clearance of the senescent cells created by treatment following the completion of cancer therapy should be beneficial to patients. There is a complex relationship between the presence of senescent cells and the ability of a cancer to grow, however. Senescent cells draw the attention of the immune system, but also secrete signals that can help to support the growth of cancerous cells. There is some debate over whether one should expect clearance of senescent cells during cancer treatment to help or hinder the goal of eliminating the cancer. Here, researchers provide animal model data to suggest that removing senescent cells hinders cancer growth to some degree.

Immunologically mediated clearance of senescent cells has been demonstrated in several model systems. Given increasing evidence for these cells promoting tumor pathology and immune escape, we sought to examine whether a vaccine against senescent cells can lead to tumor regression. A senolytic dendritic cell (DC) immunotherapy ("SenoVax") was created by pulsing DC with cell lysate from senescent fibroblasts, producing DCs that expressed co-stimulatory molecules, stimulated T cell proliferation, and expressed the senescence antigen p16.

SenoVax induced prophylactic and therapeutic tumor regression in Lewis Lung Carcinoma (LLC) primary and metastatic murine tumor models. T cell proliferative and cytokine recall responses towards senescent cells but not to control stromal cell pulsed DCs were detected in vaccinated mice. Additionally, reduction in senescence associated biomarkers IL-11, IL-6, IL-23 receptor, and YLK-40 were observed. Adoptive transfer experiments revealed a role for CD8+ T cells in transplanting protection.

When SenoVax was administered in combination with anti-PD-L1 or anti-CTLA-4 antibodies, the data showed synergistic effects in reducing tumor growth. SenoVax also demonstrated reduction of glioma, pancreatic cancer, and breast cancer cell growth. No significant activation of complement or induction of autoantibodies was observed. The data provide mechanistic support for advancement of senolytic immunotherapy as a novel form of cancer therapy.

Link: https://doi.org/10.1186/s12967-025-07393-3

Cells become senescent constantly throughout life, in tissues throughout the body, for a variety of reasons. Some senescence is a response to damage or stress or inflammatory signaling, some cells become senescent to help coordinate regeneration following injury, but most senescence is the result of cells reaching the Hayflick limit on replication. A senescent cell ceases to replicate, becomes larger, primes itself for programmed cell death, and secretes a potent mix of pro-growth, pro-inflammatory signals that attract the attention of the immune system.

In youth, senescent cells are efficiently removed by the immune system. In later life, this process slows as damage and stress increases, leading to the accumulation of senescent cells over time. Senescent cell signaling sustained over the long term by this growing, lingering population becomes increasingly disruptive to tissue structure and function, an important contribution to degenerative aging.

The research community is engaged in finding ways to selectively destroy senescent cells, reverse the normally irreversible senescent state, or shut down senescent cell signaling. A range of programs are scattered across the length of the slow and expensive path that leads towards clinical trials and eventual regulatory approval. At the same time, researchers continue to expand on the presently understanding of how exactly senescent cells cause harm to their host tissues. Today's open access paper is an example of this sort of work, focused on skin aging. As is usually the case in biology, nothing is direct and simple.

Endothelial senescence drives intrinsic skin aging via the neuroimmune CGRP-mast cell axis in mice

Endothelial cells (ECs), lining the inner surfaces of blood vessels, are particularly vulnerable to senescence, a state of irreversible cell cycle arrest triggered by telomere dysfunction, oxidative stress, and chronic inflammation. Senescent ECs secrete a senescence-associated secretory phenotype (SASP), a pro-inflammatory mix of cytokines, chemokines, and matrix-degrading enzymes that disrupt tissue homeostasis and propagate senescence. Although EC senescence has been implicated in age-related pathologies such as neurodegeneration, metabolic disorders, and pulmonary dysfunction, its contribution to skin aging remains poorly understood.

Skin aging is classified into two distinct types: extrinsic aging, driven primarily by environmental stressors such as ultraviolet (UV) radiation and pollution, and intrinsic (chronological) aging, mediated largely by genetic, metabolic, and vascular factors. While extrinsic aging manifests as epidermal hyperplasia, elastosis, and pigmentation, intrinsic aging is characterized by dermal thinning, collagen degradation, and impaired wound healing. Given the high vascular density within the dermis, microvascular dysfunction may contribute significantly to intrinsic skin aging by disrupting tissue homeostasis. However, the precise molecular mechanisms underlying the relationship between vascular dysfunction and intrinsic skin aging remain unknown.

Here we show that EC senescence contributes to intrinsic skin aging through immune dysregulation. Using an EC-specific senescent mouse model, we observe mast cell activation driven by the neuropeptide calcitonin gene-related peptide (CGRP), independent of traditional immunoglobulin E mediated pathways. Senescent ECs secreted pro-inflammatory SASP factors, activating dermal neurons to produce CGRP, leading to mast cell degranulation and subsequent skin aging phenotypes. Pharmacological stabilization of mast cells or inhibition of the EC-SASP-CGRP pathway significantly attenuate dermal thinning, collagen degradation, and delayed wound healing, which are hallmarks of intrinsic skin aging. These findings identify vascular senescence as an upstream regulator of skin aging through a neuroimmune mechanism and suggest potential therapeutic targets for age-related skin deterioration.

Vaccination for the herpes zoster virus that causes shingles is generally done after age 50. Evidence from widely used vaccines suggests that many forms of vaccination produce long-term trained immunity effects, which include increased resistance to unrelated pathogens, and a reduction in innate immune system inflammatory signaling in older individuals. Insofar as vaccination is connected with reduced incidence of an inflammatory disease, this may well be the important mechanism. Equally, in the case of Alzheimer's disease, some evidence suggests that persistent viral infection may be an important contributing factor in the onset and progression of this condition for other reasons. None of this is completely cut and dried - there are contradictory findings and clinical trial outcomes. But on balance, the evidence leans towards a protective effect of vaccination.

Clinical and subclinical reactivations of the neurotropic herpesvirus (the varicella zoster virus) that causes chickenpox and shingles may constitute a chronic immune stressor that drives inflammatory pathways in both the peripheral and central nervous system, interfering with neuroimmune homeostasis in older age. The varicella zoster virus has also recently been linked to amyloid deposition and aggregation of tau proteins, as well as cerebrovascular disease that resembles the patterns commonly seen in Alzheimer's disease. Reducing clinical and subclinical reactivations of the virus through herpes zoster (HZ) vaccination might thus have a beneficial impact on the development or progression of dementia, as well as neuroimmune health and cognitive reserve in older age more broadly.

Moreover, it is possible that HZ vaccination, and potentially vaccinations in older age more generally, act on the dementia disease process through a pathogen-independent immune mechanism. Such an effect might counteract immunosenescence and would add to the growing body of evidence suggesting that vaccines frequently have broader health benefits beyond their intended target.

Using natural experiments, we have previously reported that live-attenuated HZ vaccination appears to have prevented or delayed dementia diagnoses in both Wales and Australia. Here, we find that HZ vaccination also reduces mild cognitive impairment diagnoses and, among patients living with dementia, deaths due to dementia. Exploratory analyses suggest that the effects are not driven by a specific dementia type. Our approach takes advantage of the fact that individuals who had their eightieth birthday just after the start date of the HZ vaccination program in Wales were eligible for the vaccine for 1 year, whereas those who had their eightieth birthday just before were ineligible and remained ineligible for life. The key strength of our natural experiments is that these comparison groups should be similar in all characteristics except for a minute difference in age. Our findings suggest that live-attenuated HZ vaccination prevents or delays mild cognitive impairment and dementia and slows the disease course among those already living with dementia.

Link: https://doi.org/10.1016/j.cell.2025.11.007

TDP-43 is one of the few proteins known to form persistent aggregates in the aging brain. When this aggregation becomes excessive it is a cause of neurodegenerative conditions, notably ALS and LATE, but it is worth remembering that every aged brain exhibits some degree of this problem. Here, researchers show that TDP-43 is involved in regulating a form of DNA repair, and depletion of the functional TDP-43 protein by aggregation leads to increased DNA damage and consequent dysfunction in cells.

TDP43 is an RNA-binding/DNA-binding protein increasingly recognized for its role in neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As characterized by its aberrant nuclear export and cytoplasmic aggregation, TDP43 proteinopathy is a hallmark feature in over 95% of ALS/FTD cases, leading to detrimental cytosolic aggregates and a reduction in nuclear functionality in neurons.

Building on our prior work linking TDP43 proteinopathy to the accumulation of DNA double-strand breaks (DSBs) in neurons, the present investigation uncovers a novel regulatory relationship between TDP43 and DNA mismatch repair (MMR) gene expression. Here, we show that TDP43 depletion or overexpression directly affects the expression of key MMR genes. Alterations include changes in MLH1, MSH2, MSH3, MSH6, and PMS2 levels across various primary cell lines, independent of their proliferative status. Our results specifically establish that TDP43 selectively influences the expression of MLH1 and MSH6 by influencing their alternative transcript splicing patterns and stability.

We furthermore find that aberrant MMR gene expression is linked to TDP43 proteinopathy in two distinct ALS mouse models and in post-mortem brain and spinal cord tissues of ALS patients. Notably, MMR depletion resulted in the partial rescue of TDP43 proteinopathy-induced DNA damage and signaling. Moreover, bioinformatics analysis of the TCGA cancer database reveals significant associations between TDP43 expression, MMR gene expression, and mutational burden across multiple cancers. Collectively, our findings implicate TDP43 as a critical regulator of the MMR pathway and unveil its broad impact on the etiology of both neurodegenerative and neoplastic pathologies.

Link: https://doi.org/10.1093/nar/gkaf920

Since around the time at which the goal of extending life through improvements in medical technology became a respectable goal, let us say somewhere a little after 2010, perhaps around the time that the first demonstration of clearing senescent cells in mice was conducted, the official message from the academic research community to the public and politicians has been that the goal of the field is to extend healthspan, but not lifespan. Extending the healthy period of life is great, but extending overall lifespan is shady and disavowed. Why did the prominent figures of aging research so enthusiastically embrace this public messaging?

Today's open access paper provides one view on that question, but I don't think that it touches closely enough on what seems the actual answer. It seems quite clear to those of us who lived through that period of time that this messaging was a way to distance the dominant factions in academia, who are ever sensitive to any threat that might impact their perceived status and thus ability to raise funds, from the growing voices of patient advocates and a minority faction of researchers who had started to achieve some success in talking up radical life extension and the medical control of aging, while funding research into technologies to repair cell and tissue damage thought to cause aging. The "healthspan but not lifespan" messaging was a rush to conservatism undertaken in fear of reduced funding from conservative institutions. This is, after all, what happened in the field of aging research following the anti-aging advocacy and birth of the supplement industry in the 1970s. The leaders of the field disavowed any attempt to intervene in aging. It was an exclusion of those not following the orthodoxy, and a rebranding and message intended to distinguish the orthodox form the newcomers, all conducted to protect existing status and sources of funding.

But make your own mind up! One could also argue, much as is done in the paper here, that it was a reaction to the data obtained from decades of efforts to treat age-related diseases. Since those efforts did not in fact target causes of aging, they produced very little gain in life span, but heroic efforts in development and clinical practice had managed to incrementally extend healthspan. It takes enormous effort to coax a failing machine into continued function if repair is off the table, but it can be achieved to some degree. Still, some researchers may have felt that this outcome represented the bounds of the possible, and thus the newcomers who aimed to extend life span by changing the strategy to medicine to one of repairing causative damage were mistaken.

Against "Extending Healthspan but Not Lifespan" as a Goal for Biogerontology

Extending human healthspan is of course highly desirable. However, within the biogerontology field one increasingly encounters this view that our goal should be to extend healthspan but not lifespan. This view has been stated explicitly, for example by Jay Olshansky, who argued that "life extension should no longer be the primary goal of medicine when applied to people older than 65 years of age. The principal outcome and most important metric of success should be the extension of healthspan." From some perspectives, this is a strange position to take. What is wrong with extending lifespan? We suggest that this anomaly has arisen from conflation of the goals of two distinct disciplines, namely geriatric medicine, that addresses the health needs of older adults, and biogerontology, the study of the biology of aging.

A challenge for geriatricians is that all of their patients will inevitably die from the condition that ails them, namely the process of senescence (aging). Faced with this, laudable and inspiring goals for geriatric medicine were set out in the early 1980s in a vision that accepts the harsh fact that, as in most animal species, there exists an upper ceiling for human longevity. Thanks to improvements in public health during the last century or so, an increasing proportion of the population are living longer lives, coming closer to the longevity ceiling. This is reflected in an increasing rectangularization of population survival curves. It was argued that the goal of late-life medicine should be to reduce the proportion of later life in poor health: "The rectangularization of the survival curve may be followed by rectangularization of the morbidity curve and by compression of morbidity."

By contrast, the vision of biogerontology is very different. Central to it is the possibility of decelerating or even reversing the aging process as a whole, or in its greater part. That this is feasible is suggested by the existence of numerous interventions that extend both healthspan and lifespan in animal models, particularly rodents. In terms of medical applications, the main, ultimate goal of biogerontologists is much the same as that of most of medical research: to alleviate illness, reduce disease burden, and save lives. Anti-aging treatments will always reduce disease, and may extend lifespan, but whether they increase healthspan and compress morbidity is to a large extent a matter of chance. For a biogerontologist to say that their goal is to increase healthspan but not lifespan is as strange as for a practitioner of any other medical specialism (say, oncology) to say it.

The arguments for healthspan rather than lifespan originated in the field of geriatrics, in which they are cogent, but were subsequently imported into biogerontology, where they are not. Possibly this partly reflects efforts by biogerontologists to align themselves with the agenda of the broader and better funded biomedical field, particularly as part of the geroscience agenda. In the end, medical interventions that save lives and postpone death may or may not cause an expansion of morbidity. Whether they do or not, such interventions are beneficial to the patient, and a good thing. The prospect of a doctor denying a patient a life-saving treatment on grounds that they will remain alive for an extended period in poor health is not part of any ethical reality. We advocate that biogerontologists frankly state their goals of understanding and intervening in aging, to make any gains possible in terms of improvements to late-life health and saving of lives (i.e. life extension).

In discussions of aging, references to klotho usually mean α-klotho, a transmembrane protein, and specifically the fragment of α-klotho that projects beyond the cell membrane and is shed to circulate in the body, also known as soluble α-klotho. Soluble α-klotho interacts with cell receptors to produce beneficial changes in cell function in a range of tissues. Klotho has long been of interest to researchers because increased expression of α-klotho slows aging, whereas reduced expression accelerates aging. Past research has focused on beneficial effects resulting from soluble α-klotho in the kidney and brain. Improved function in these organs might be enough to explain systemic benefits throughout the body, but as shown here soluble α-klotho likely has direct effects on cells in other tissues as well.

We investigate the effects of α-Klotho, an anti-aging hormone, on cell proliferation across three tissues with varying regenerative capacities in the context of aging. Using young and old wild-type mice, alongside old heterozygous Klotho-deficient mice, we administered soluble α-Klotho (sKL) daily for 10 weeks to elucidate the impact of α-Klotho deficiency and its supplementation. Our investigation spanned three organs: the small intestine, the kidney, and the heart.

We measured cell cycle markers (BrdU, Ki-67, and phospho-histone-3), Sirtuin-1, DNA-damage response pathways (gamma-H2Ax, ATM, CHK2), and the aging phenotypes. Supplementation of sKL significantly enhances proliferative markers and attenuates many aging changes. Mechanistic studies show that sKL acts through the Sirt1-CHK2 pathway to promote cell proliferation. In summary, Klotho deficiency exacerbated aging phenotypes, reduced regenerative capacity, and impaired cellular proliferation. Supplementation with sKL effectively counters these age-related declines across multiple tissues by enhancing cellular proliferation and attenuating aging phenotypes through the Sirt1-CHK2 signaling pathway.

Link: https://doi.org/10.1038/s41514-025-00286-1

Myelin is a protein that forms an insulating sheath around the axons that connect neurons, enabling the effective transmission of nerve impulses. It is essential for the normal function of the nervous system and brain, and thus demyelinating diseases such as multiple sclerosis that cause extensive loss of myelin are particularly debilitating. A lesser but still significant loss of myelin integrity occurs with aging, and thus forms of therapy that encourage myelin formation that are under development as potential treatments for multiple sclerosis may eventually find more widespread use in the aging population. Myelin is maintained by a population of specialized cells called oligodendrocytes, and all aspects of aging that degrade cell function in the brain and nervous system thus contribute to a progressive loss of myelin integrity. The example here for cardiovascular disease is likely connected to a number of mechanisms, from reduced blood flow to the brain to the inflammation and high burden of cell and tissue damage that contributes to both cardiovascular and nervous system degeneration.

A new study applied a novel multivariate approach to brain assessment using 12 separate metrics. The researchers compared test results and MRI scans of 43 patients with coronary artery disease (CAD) to those of 36 healthy individuals. All participants were over age 50. The multivariate approach of bundling individual white matter metrics into one overarching metric provides advantages over past studies. It allows the researchers to simplify complex aspects of brain health into a single metric that can be compared to the same metric in healthy controls.

The researchers found that individuals with CAD had widespread structural changes in their white matter compared to their healthy counterparts. The changes were particularly noticeable in the parts of the brain fed by the middle cerebral artery and anterior cerebral artery. Both regions are key for cognitive and motor functions.

The researchers found that the changes were mainly linked to reduced myelin content - the fatty coating that insulates nerve fibers and allows signals to travel quickly through the brain. Myelin loss can slow communication between brain cells and is often an early sign of cognitive aging. Interestingly, participants with higher measures of myelin integrity performed better on tests of processing speed, a key aspect of thinking and attention. However, no significant differences were observed between groups in overall cognitive scores, suggesting that brain changes may precede noticeable symptoms.

Link: https://www.concordia.ca/news/stories/2025/11/25/concordia-researchers-identify-key-marker-linking-coronary-artery-disease-to-cognitive-decline.html

Evolution produces species that exhibit stochastic metabolic variation from individual to individual. Any species or subpopulation of a given species lacking this individual variation might be more successful in a specific ecological niche, but would vanish due to competition the moment that niche changed in any way. And change is a feature of the world we live in. Given a long enough time scale, everything shifts in character. The species we see today are the descendants of the survivors of change, that survival enabled by individual metabolic variation within the species.

This adds to the growing list of complexities faced by any group attempting to find ways to adjust metabolism in order to slow aging. What works in one person may not work in the same way, or anywhere near as well, in another. We can see how this will likely turn out in the long run by looking at the past few decades of preventative clinical practice in cardiovascular disease. Individual variation in cholesterol metabolism has complicated attempts to reduce cardiovascular disease by lowering circulating LDL cholesterol. People exhibit a high degree of variance in the relationship between LDL cholesterol, other circulating atherogenic factors such as Lp(a), the pace at which atherosclerotic plaque grows in blood vessels with age, and the structure of that plaque. Most people presenting with a first heart attack or stroke do not have elevated LDL cholesterol, and it seems likely that only a subset of the population is benefiting meaningfully from LDL lowering drugs.

Today's open access paper notes that one can take a set of genetically identical nematode worms, raise them in identical ways, and still find that this population naturally produces stochastic differences in metabolism during development. These differences then affect the degree to which age-slowing interventions that attempt to alter metabolism into a more favorable state actually manage to achieve a slowing of aging.

The efficacy of longevity interventions in Caenorhabditis elegans is determined by the early life activity of RNA splicing factors

Geroscience aims to target the aging process to extend healthspan. However, even isogenic individuals show heterogeneity in natural aging rate and responsiveness to pro-longevity interventions, limiting translational potential. Using RNAseq analysis of young, isogenic, subpopulations of Caenorhabditis elegans selected solely on the basis of the splicing pattern of an in vivo minigene reporter that is predictive of future life expectancy, we find a strong correlation in young animals between predicted life span and alternative splicing of messenger RNAs related to lipid metabolism.

The activity of two RNA splicing factors, Reversed Polarity-1 (REPO-1) and Splicing Factor 1 (SFA-1), early in life is necessary for C. elegans response to specific longevity interventions and leads to context-specific changes to fat content that is mirrored by knockdown of their direct target POD-2/ACC1. Moreover, POD-2/ACC1 is required for the same longevity interventions as REPO-1/SFA-1. In addition, early inhibition of REPO-1 renders animals refractory to late onset suppression of the TORC1 pathway. Together, we propose that splicing factor activity establishes a cellular landscape early in life that enables responsiveness to specific longevity interventions and may explain variance in efficacy between individuals.

Collagen supplementation has an interesting history, and as is often the case in these matters there is all too much hype and marketing in relation to the amount of actual data. But even looking at only the clinical trials, it seems likely that collagen supplementation can produce small beneficial results in a number of aspects of aging and age-related conditions. Here, researchers demonstrate in cells, worms, mice, and a human clinical trial that one can supplement the amino acids used in the production of collagen, in the right ratio, in order to produce these benefits. The human dose used was 8400 mg glycine, 1700 mg proline, and 1700 mg hydroxyproline, taken daily for six months. The biological age measure used was TruAge, a DNA methylation clock.

Collagen supplementation has gained attention with increasing claims regarding its beneficial effects on healthy aging based on clinical observations and lifespan extension in pre-clinical models; however, how and which part of an ingested collagen promotes healthy longevity is unknown. Here, we identified the minimal required unit of ingested collagen, which consists of the proper ratio of three glycine to one proline to one hydroxyproline that was sufficient to increase the healthspan and lifespan of C. elegans, as well as collagen homeostasis in human fibroblasts in vitro.

Supplementation in 20-month-old mice improved grip strength and prevented age-related fat accumulation. In a clinical observational trial (ISRCTN93189645), oral supplementation in humans demonstrated improved skin features within three months and a reduction in biological age by 1.4 years within 6 months. Thus, a ratio of three amino acids elicits evolutionarily conserved health benefits from ingested collagens.

Link: https://doi.org/10.1038/s41514-025-00280-7

Sizable regeneration of damaged or lost cartilage remains impossible in practice, but also a highly desirable goal given the prevalence of osteoarthritis. The best that has been achieved to date in clinical practice results from one specific implementation of stem cell therapy, Cartistem. Other stem cell therapies haven't done as well in this context. You may recall that inhibition of 15-PGDH was shown to improve muscle function in old mice. That work has since moved on to initial clinical trials of a small molecule drug, developed by Epirium Bio. Here, researchers show that the same approach can produce some degree of cartilage regrowth, also in old mice.

Blocking the function of 15-PGDH with a small molecule results in an increase in old animals' muscle mass and endurance. Conversely, expressing 15-PGDH in young mice causes their muscles to shrink and weaken. 15-PGDH has also been implicated in the regeneration of bone, nerve, and blood cells. In each of these tissues, regeneration is due to increases in the proliferation and specialization of tissue-specific stem cells.

Osteoarthritis occurs when a joint is stressed by aging, injury, or obesity. The chondrocytes begin to release pro-inflammatory molecules and to break down collagen, which is the primary structural protein of cartilage. When collagen is lost, the cartilage thins and softens; the accompanying inflammation causes the joint swelling and pain that are hallmarks of the disease. Under normal circumstances, articular cartilage rarely regenerates. Although some populations of putative stem or progenitor cells capable of generating cartilage have been identified in bone, attempts to identify similar populations of cells in the articular cartilage have been unsuccessful.

When researchers compared the amount of 15-PGDH in the knee cartilage in young versus old mice, they saw that, as in other tissues, levels increased about two-fold with age. They next experimented with injecting old animals with a small molecule drug that inhibits 15-PGDH activity - first into the abdomen, which affects the entire body, then directly into the joint. In each case, the knee cartilage, which was markedly thinner and less functional in older animals as compared with younger mice, thickened across the joint surface. Further experiments confirmed that the chondrocytes in the joint were generating hyaline, or articular, cartilage, rather than less-functional fibrocartilage. Similar results were observed in animals with knee injuries.

Link: https://med.stanford.edu/news/all-news/2025/11/joint-cartilage-aging.html

One of the most interesting areas of research into aging at the moment is the question of whether detrimental epigenetic changes that occur in cells throughout the body with age, altering cell behavior for the worse, are caused by the operation of DNA repair processes in response to stochastic damage to nuclear DNA. The concept and animal study evidence are recent enough that it should be considered speculative, and any of the details published to date subject to revision.

If true, however, this relationship in which DNA repair causes epigenetic aging would neatly resolve a range of challenges in the understanding of the role of nuclear DNA damage in aging. For example that mutational damage to nuclear DNA doesn't appear to cause enough harm to cell function to explain the major changes that occur with age. Most nuclear DNA damage occurs in somatic cells with few cell divisions remaining, limiting the spread of the mutation, and occurs in gene sequences that don't much matter or are not even used.

Somatic mosiacism, the spread of mutations over time from stem cell populations out into the tissues they support via the vector of daughter somatic cells, can somewhat salvage this situation by amplifying a tiny number of mutations into widespread existence. However, present investigations of the role of clonal hematopoiesis of indeterminate potential, the name given to somatic mosaicism in hematopoietic cells and the immune system, suggest that it isn't harmful enough to explain very much of aging. It raises risks, it isn't driving degeneration.

Today's open access paper is a recent exploration of epigenetic change induced by DNA damage, employing a mouse model generated a few years ago. Here, this model is crossbred with an Alzheimer's disease model in order to look at relevance to that condition. Cynically, one should assume that this choice of direction in research is driven as much by the funding incentives as the reasonable scientific rationale for the relevance of a mechanism of aging to any specific age-related condition, as work on Alzheimer's disease represents a sizable fraction of all public funding for aging research. Still, all significant new work on this issue of DNA repair and epigenetic change is welcome.

DNA Break-Induced Epigenetic Alterations Promote Plaque Formation and Behavioral Deficits in an Alzheimer's Disease Mouse Model

The dramatic increase in human longevity over recent decades has contributed to a rising prevalence of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE (Inducible Changes to the Epigenome) model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift.

We hypothesized that DNA damage induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess amyloid-β pathology and neuroinflammatory markers.

Our findings reveal that DNA damage-induced epigenetic changes significantly affect cognitive behavior and alters amyloid-β plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage-induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.

Butyrate is one of the better known metabolites generated by microbial populations within the gut microbiome, a product of the fermentation of dietary fiber. Butyrate has been shown to produce beneficial effects in a range of tissues, such as via increased BDNF signaling to improve brain and muscle health. Production of butyrate declines with age, a consequence of harmful shifts in the composition of the gut microbiome that take place with age. Here, researchers show that butyrate is senomorphic, in that is reduces the number of cells entering a senescent state. This sort of effect is thought to be beneficial over time, as it allows the normal mechanisms of senescent cell clearance, impaired with age but still operating, to catch up and reduce the age-related burden of senescence.

Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs).

Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial reactive oxygen species (ROS) accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB.

Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.

Link: https://doi.org/10.1111/acel.70257

Scar tissue is formed by excess deposition of extracellular matrix molecules such as collagen. It obstructs complete healing. In aged tissues, fibrosis is a form of inappropriate scarring and consequent loss of function produced by the disruption of normal tissue maintenance. Researchers here provide evidence for scarring following injury to be driven by a subpopulation of monocytes and macrophages, types of myeloid immune cell. The pro-fibrotic behavior of these cells is triggered by mechanical cues. Mechanosensing is a complex set of regulatory pathways by which cells react to the mechanical properties of the surrounding environment, such as degree of tissue stiffness or mechanical stresses placed upon the tissue. These regulatory pathways can be manipulated via drugs and genetic engineering, just like others, and this opens the door to a novel approach to reducing scar formation following injury.

In response to injury, a variety of different cells are recruited to sites of injury to facilitate healing. Recent studies have examined the importance of the heterogeneity of tissue resident fibroblasts and mechanical signalling pathways in healing and fibrosis. However, tissue repair and the inflammatory response also involves blood cells that are recruited from the circulation.

Here we identify mechanoresponsive myeloid subpopulations present in scar and unwounded skin. We then modulate these subpopulations by manipulating mechanical strain in vivo and in vitro and find that specifically targeting myeloid mechanical signalling is sufficient to reduce the pro-fibrotic myeloid subpopulations and restore the native, anti-inflammatory subpopulations.

In addition, myeloid-specific mechanotransduction ablation also downregulates downstream pro-fibrotic fibroblast transcriptional profiles, reducing scar formation. As inflammatory cells circulate and home to injury sites during the initial healing phases in all organs, focusing on mechanoresponsive myeloid subpopulations may generate additional directions for systemic immunomodulatory therapies to target fibrosis and other diseases across other internal organ systems.

Link: https://doi.org/10.1038/s41551-025-01479-5

On the one hand there is a modest amount of evidence for GLP-1 receptor agonist drugs to produce beneficial effects on an aged metabolism that are unconnected to weight loss. On the other hand, when Big Pharma has a very successful drug, it will attempt to use that drug for every condition it can that is associated with a sizable market, whether or not the expected effects are marginal. So it isn't necessarily indicative of support for these non-weight-loss mechanisms that leads the clinical trial of a weight loss drug for patients with Alzheimer's disease. Cynically, it is that Alzheimer's is an enormous market.

The present state of regulation makes it more cost-effective for companies to push existing drugs into new marginal uses than it is to develop new drugs that are actually effective for that new use. At times, it seems that the entire world cares nothing for how well a drug, a supplement, any intervention actually works at its given task. Effect sizes are boring, a dead letter. Drugs that do relatively little and only marginally slow progression of a condition are marketed aggressively and have huge sales. Big Pharma is far from the only culprit in this matter, of course. Just look at the supplement industry.

That a weight loss drug produces weight loss but at the same time fails to slow Alzheimer's disease might be taken as another data point to illustrate that the relationship between obesity and Alzheimer's disease is very different in character to, say, the robust and very direct relationship between obesity and type 2 diabetes. Yes, being overweight appears to be a risk factor that plays into Alzheimer's disease, but it isn't as strong a relationship, indicating a great deal more complexity and variation from individual to individual in the mechanisms involved.

Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer's disease progression

Novo Nordisk today announced the top-line results from the 2-year primary analysis of evoke and evoke+ phase 3 trials in early-stage symptomatic Alzheimer's disease. The two trials were randomised, double-blinded, enrolled a total of 3,808 adults and evaluated the efficacy and safety of oral semaglutide compared to placebo on top of standard of care. The decision to pursue an Alzheimer's disease indication with semaglutide was based on real-world evidence studies, pre-clinical models as well as post-hoc analyses from diabetes and obesity trials.

The evoke and evoke+ trials did not confirm superiority of semaglutide versus placebo in the reduction of progression of Alzheimer's disease, as measured by the change in Clinical Dementia Rating - Sum of Boxes (CDR-SB) score compared to baseline. While treatment with semaglutide resulted in improvement of Alzheimer's disease-related biomarkers in both trials, this did not translate into a delay of disease progression.

The chemistry of molecules in solution is dynamic and complex, such as the spontaneous liquid-liquid phase separation in which a solution divides into regions of greater and lesser concentrations to form droplets. This process is important in the formation of protein aggregates involved in neurodegenerative disease. Here, researchers show that the α-synuclein that misfolds and aggregates to cause Parkinson's disease does not undergo liquid-liquid phase separation on its own, but rather is dragged into the liquid-liquid phase separation and droplet formation of another protein, UBQLN2. This suggests possible novel targets to interfere in this chemistry.

Some neurodegenerative disease-associated proteins form liquid droplets via liquid-liquid phase separation (LLPS). Over time, these droplets transition from a highly labile liquid state to a hydrogel state, and eventually to a solid-like condensate, via self-interaction and oligomerization of the proteins within, thereby leading to the formation of amyloid fibrils. Recently, α-synuclein (α-syn) has been reported to be one such protein. However, the precise molecular events involved in the early stages of α-syn aggregation remain controversial.

In this study, we show that α-syn aggregation is promoted by droplets formed by ubiquilin-2 (UBQLN2), rather than by α-syn LLPS itself. During the liquid-gel/solid transition of UBQLN2 droplets, α-syn within the droplets transforms into pathogenic fibrils both in vitro and in cells. Immunohistochemistry of brain sections from sporadic Parkinson's disease patients revealed UBQLN2 in substantia nigra Lewy bodies, implicating UBQLN2 in α-syn aggregation in vivo. Furthermore, the small molecule 1,2,3,6-tetra-O-benzoyl-muco-inositol (SO286) inhibited both UBQLN2 self-association and its interaction with α-syn by binding to the STI1 domain, thereby suppressing α-syn aggregation.

These findings demonstrate that UBQLN2 droplets catalyze α-syn fibrillization and suggest that small molecules targeting fibril-catalyzing proteins such as UBQLN2 may represent a promising therapeutic approach for neurodegenerative diseases.

Link: https://doi.org/10.1038/s44318-025-00591-1

Brown fat, or adipose tissue, is responsible for generating heat to maintain body temperature. Research has shown its presence and activity to be beneficial in the context of aging, in that the presence of more brown adipose improves long-term health. However, like all tissues, brown adipose tissue becomes dysfunctional with age. Here, researchers investigate what appears to be an important mechanisms in this process, in which brown fat adipocyte cells and macrophage cells of the innate immune system interact in ways that provoke inflammation and dysfunction.

Loss of brown adipose tissue (BAT) activity observed during ageing, obesity, and living at thermoneutrality is associated with lipid accumulation, fibrosis, and tissue inflammation in BAT. The mechanisms that promote this degenerative process of BAT remain largely enigmatic. Here, we show that an imbalance between sympathetic activation and mitochondrial energy handling causes BAT degeneration, which leads to impaired energy expenditure and systemic metabolic disturbances.

Mechanistically, we demonstrate that brown adipocytes secrete adenosine triphosphate (ATP) in response to imbalanced thermogenic activation, which activates the P2X4 and P2X7 receptors of BAT-resident macrophages. Notably, mice lacking activity of these purinergic receptors in myeloid cells are protected against BAT inflammation, thermogenic dysfunction, and systemic metabolic disturbances under conditions of imbalanced BAT activation, thermoneutrality, or overnutrition. These results highlight the relevance of extracellular ATP released by brown adipocytes as a paracrine signal for myeloid cells to initiate BAT degeneration.

Link: https://doi.org/10.1038/s44319-025-00642-y

Stem cells exist in order to minimize the number of cells capable of unrestricted replication; most cells in the body are limited in the number of times that they can divide. This limit serves to reduce the risk of cancer - and other severe disruptions that could result from unlimited replication of a malfunctioning cell - to an acceptably low level to enable evolutionary success. Stem cells provide a supply of daughter somatic cells to replace those that are lost over time, due to limited somatic cell replication. In actuality, stem cells spend much of their time in a state of quiescence, without replicating. This is necessary to preserve their function and minimize damage over the course of a lifetime. When forced into excessive activity, stem cells risk a state of exhaustion, becoming dysfunctional and displaying harmful alterations in behavior.

Hematopoietic stem cells reside in the bone marrow and are responsible for generating immune cells and red blood cells. The dysfunctions that arise with aging in this cell population, such as a growing bias towards the production of myeloid cells at the expense of lymphoid cells, appear similar to the dysfunctions that arise when hematopoietic stem cells are forced into exhaustion by excessive replication. In today's open access paper, researchers explore the relevance to hematopoietic stem cell aging of IL-10 signaling intended to bring an end to an acute episode of inflammation, such as in response to an infection that is now defeated. Hematopoietic stem cells must be ever ready to produce large numbers of immune cells to help defend the body, but at the same time they must also return to quiescence when that danger is passed. The chronic inflammation of aging may well sabotage this balance, driving ever greater dysfunction in the production of immune cells.

Impaired IL-10 Receptor Signaling Leads to Inflammation Induced Exhaustion in Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) are maintained in quiescence, which protects this pool from the damaging effects of excessive proliferation. Quiescence is tightly regulated by intrinsic programs, including FoxO3a, p53, and cyclin-dependent kinase inhibitors, and by extrinsic cues such as TGF-beta and Notch. Under homeostatic conditions, HSCs remain largely dormant but can rapidly activate in response to inflammatory stimuli, such as infection, to support emergency hematopoiesis. A timely return to quiescence after activation is essential to prevent stem cell exhaustion, which occurs if cycling persists.

Many hallmarks of stem cell exhaustion, including impaired regenerative capacity, expansion of phenotypic HSCs with reduced function, increased inflammatory signaling, and a shift toward myeloid-biased differentiation, mirror features of aged hematopoiesis. Aging is associated with chronic, low-grade inflammation that stresses the HSC pool, driving both functional decline and selective pressure for clones that resist inflammation-induced exhaustion.

Although much is known about maintaining HSC quiescence under steady-state conditions, the signals that govern the return to quiescence after inflammatory activation remain poorly defined. In other cell types IL-10 is an anti-inflammatory cytokine that restrains excessive immune activation by suppressing responses downstream of Toll-like receptor (TLR) stimulation. We identify IL-10 receptor (IL-10R) signaling as critical for returning HSCs to quiescence. IL-10R blockade prolongs HSC cycling and sustains activated transcriptional programs after acute inflammation. With chronic exposure, blockade increases cumulative divisions and accelerates aging hallmarks, including myeloid bias, loss of polarity, and functional defects, under conditions that do not otherwise exhaust HSCs when IL-10R signaling is intact. Our findings identify IL-10R signaling as a key coordinator of post inflammatory return to quiescence and suggest that modulating this axis could preserve HSCs and shape clonal hematopoiesis.

Age-related loss of function in hematopoietic stem cells resident in the bone marrow is an important component of immune system aging, and thus important to aging as a whole. There is a tendency to think of cells only in terms of chemistry, but some of that chemistry is linked to structure, mechanical forces, and the physical properties of surrounding tissues. Researchers here find that RhoA, a key protein in a cell's response to mechanical stimulus, is important in loss of function in aged hematopoietic stem cells. It is something of an open question as to how much of this importance is driven by changes in the mechanical properties of surrounding tissues versus epigenetic changes inside the cell that affect its structure, but RhoA inhibition clearly restores some degree of lost hematopoietic function regardless of the precise details.

Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. Mechanical forces trigger multiple signaling pathways that converge in the activation of RhoA, which is a small RhoGTPase that can cycle between an active (RhoA-GTP) and an inactive (RhoA-GDP) status. RhoA is a key regulator of mechanotransduction regardless of whether the activating mechanical stimulus is cell extrinsic, as occurs in cells responding to alterations of substrate stiffness, or cell intrinsic, such as, for example, when the cell nucleus acts as a mechanosensor of genomic changes.

Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons.

Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lymphoid/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function.

Link: https://doi.org/10.1038/s43587-025-01014-w

It is well established that excess visceral fat is harmful to health. The primary mechanism is likely that this tissue provokes chronic inflammation in a variety of ways, from increased cellular senescence to mimicking the signaling produced by infected cells. It is also well established that muscle tissue is protective in later life, however here the underlying mechanisms are less well understood. Muscle tissue is just as metabolically active as visceral fat, and generates a variety of signal molecules that alter the behavior of cells throughout the body, particularly following exercise. Cataloging these signals and their effects is an active area of ongoing research.

Researchers have found that a specific body profile - higher muscle mass combined with a lower visceral fat to muscle ratio - tracks with a younger brain age. Brain age is the computational estimation of chronological age from a structural MRI scan of the brain. Muscle mass, as tracked by body MRI, can be a surrogate marker for various interventions to reduce frailty and improve brain health, and brain age predicted by structural brain images can lend insight to Alzheimer's disease risk factors, such as muscle loss.

For the ongoing study, 1,164 healthy individuals (52% women) were examined with whole-body MRI. The mean chronological age of the participants was 55.17 years. The researchers combined MRI imaging with T1-weighted sequences, a technique that produces images where fat appears bright and fluid appears dark. This allows for optimal imaging of muscle, fat and brain tissue. A machine learning algorithm was used to quantify total normalized muscle volume, visceral fat (hidden belly fat), subcutaneous fat (fat under the skin) and brain age.

The researchers found that a higher visceral fat to muscle ratio was associated with higher brain age, while subcutaneous fat showed no significant association with brain age. Building muscle and reducing visceral fat are actionable goals. Whole-body MRI and brain-age estimates provide objective endpoints to design and monitor interventions, including programs or therapies under study that lower visceral fat while preserving muscle.

Link: https://www.rsna.org/media/press/2025/2614

Lysosomes are a vital component in the recycling systems of the cell, organelles that break down harmful or unwanted molecules in order to provide raw materials for manufacture of new molecules. As is the case for all cell components, lysosomes become dysfunctional with age. The buildup of persistent metabolic waste, such as lipofuscin, that cells struggle to break down is implicated in age-related lysosomal dysfunction in long-lived cells, such as neurons. Sweeping epigenetic and transcriptomic changes that alter the production of proteins occur with age in all cells, and it is likely that a subset of these changes contributes meaningfully to impaired lysosomal function.

Today's open access paper is interesting not just for the connection between specific forms of lysosomal dysfunction and hematopoietic stem cell aging, and thus the aging of the immune system, but also because the researchers involved found that a vacuolar ATPase inhibitor can reverse this dysfunction. Vacuolar ATPases are responsible for acidifying lysosomes, among other activities, and the specific issue identified in aged hematopoietic stem cells is that their lysosomes are overly acidic. When lysosomes cease to function efficiently, as appears to happen in this circumstance, the whole cell suffers because harmful molecules are not cleared and recycled in good time. As the researchers point out, this includes mislocalized DNA from mitochondria that can trigger inflammatory pathways. Restoring lysosomal function in aged cells reduces inflammatory signaling and improves cell health.

Scientists Reverse Aging in Blood Stem Cells by Targeting Lysosomal Dysfunction

Lysosomes are specialized structures that act as the cell's recycling system, breaking down proteins, nucleic acids, carbohydrates, and lipids. Lysosomes accumulate and degrade waste, and eventually recycle it to be reused in biosynthetic processes. Lysosomes can also store nutrients to be released when needed. Lysosomes are recognized as pivotal for regulating metabolism in the cell, both catabolism (breaking down complex molecules to simple ones) and anabolism (building complex molecules from simpler ones).

As people age, hematopoietic stem cells (HSCs) become defective and lose their ability to renew and repair the blood system, decreasing the body's ability to fight infections as seen in older adults. Another example is a condition called clonal hematopoiesis; this asymptomatic condition is considered a premalignant state that increases the risk of developing blood cancers and other inflammatory disorders. Its prevalence increases significantly with age.

Researchers discovered that lysosomes in aged HSCs become hyper-acidic, depleted, damaged, and abnormally activated, disrupting the cells' metabolic and epigenetic stability. Using single-cell transcriptomics and stringent functional assays, the researchers found that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor restored lysosomal integrity and blood-forming stem cell function. The old stem cells started acting young and healthy once more. Old stem cells regained their regenerative potential and ability to be transplanted and to produce more healthy stem cells and blood that is balanced in immune cells; they renewed their metabolism and mitochondrial function, improved their epigenome, reduced their inflammation, and stopped sending out "inflammation" signals that can cause damage in the body.

Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells

Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging - beyond their passive mediation of autophagy - is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs' in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.

As you might be aware, the genetic differences present in Down syndrome patients produce a dramatic acceleration of amyloid-β aggregation, tau aggregation, and the other pathologies of Alzheimer's disease. Researchers here describe the discovery of a variant in the gene CSF2RB in a subset of Down syndrome patients that resist loss of cognitive function, and show that it improves the function of microglia. Microglia are innate immune cells resident in the brain. Increased inflammation and dysfunction in this cell population is strongly implicated in neurodegenerative conditions such as Alzheimer's disease. When equipped with the variant CSF2RB, microglia are less inflammatory and more capable when exposed to Alzheimer's-related protein aggregates - which may be enough to explain the resilience of patients with this gene variant.

Alzheimer's disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer's disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience.

Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4 to 10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence.

Thus CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies.

Link: https://doi.org/10.1038/s41593-025-02117-8

Researchers here point out that inflammatory bowel disease can produce intestinal dysfunction that is in ways similar to the intestinal dysfunction that occurs in aging, but the underlying mechanisms are quite different. It is a good example of the way in which forms of cell and tissue damage can produce dysfunction that appears superficially similar to aging, even when the damage is not the same as occurs during aging. This is true for DNA repair deficiencies that lead to excessive DNA damage, far more than occurs with aging, for example, or for the excessive accumulation of broken lamin A in progeria that doesn't occur to a large degree in normal aging.

Inflammatory bowel disease (IBD) and physiological gut aging present with overlapping clinical features, including impaired barrier functioning, decreased nutrient absorption, and intestinal frailty. Emerging evidence indicates that even young IBD patients can exhibit gut phenotypes akin to those seen with aging. However, the two processes differ substantially in their underlying mechanisms.

Gut aging is characterized by low-grade, chronic inflammation, and gradual cellular senescence, whereas IBD involves persistent immune activation, cyclical tissue damage, and accelerated degenerative changes. This review systematically contrasts physiological gut aging and IBD-associated accelerated gut aging across several dimensions: cellular senescence and programmed cell death, immune cell remodeling, alterations in gut microbiota, changes in mesenteric adipose tissue, and the evolving role of the appendix.

By integrating current advances in basic and translational research, this article highlights both the shared and distinct pathways driving gut dysfunction in aging and IBD, and underscores the importance of early recognition and targeted intervention for premature gut aging in clinical practice.

Link: https://doi.org/10.5582/bst.2025.01279