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.
View the full article at FightAging
