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