Fight Aging!

An archly conservative viewpoint links establishment academia ("this thing you are doing has not yet been proven beyond all doubt to work") to the thought leadership of Big Pharma ("this thing you are doing has not yet been proven beyond all doubt to generate profit"). Both sides look at the billions in funding devoted to the growing longevity industry, and the decades of painstaking scientific work that set the foundation for that industry, and see an ongoing test in progress, as yet unfinished and the result undetermined. Can aging in fact be slowed or reversed in a practical way in humans as it can in laboratory species?

There are those who determinedly take a wait and see approach, wanting the concrete answer. Obviously a great many other people, scientists, entrepreneurs, patients, and patient advocates, are less conservative than this, otherwise there would be no longevity industry. Many lines of work that lead to potential rejuvenation therapies are highly promising, and the only remaining question is how much additional life they can provide to members of our own species. The future is ever uncertain, but one doesn't win victories by refraining from participation.

Today's open access review, being a very broad survey of everything that might fall into the purview of the diverse longevity industry, lumps together a range of very different approaches under one heading. I think this a mistake, a category error that is becoming common. At the very least one should not be placing NAD+ upregulation (unreliable animal data, small effect size, long history of failed human trials for a range of conditions) into equivalence to senolytics to clear senescent cells (reliable and extensive animal data, large effect size for reversal of age-related conditions, mixed data from only a few early human trials). These are very different classes of therapy with very different supporting evidence, and emerge from very different philosophies of development.

Geroprotective Effects of Drugs Modulating Metabolic Pathways: Perspectives of Pharmacology in Anti-Aging Therapy

Aging is the strongest risk factor for chronic diseases such as cardiovascular diseases, cancer, diabetes, and neurodegenerative disorders. Advances in geroscience indicate that pharmacological modulation of conserved molecular pathways may extend healthspan and delay multimorbidity. This review focused on molecular pathways implicated in aging, pharmacological interventions targeting these pathways, and their preclinical and clinical evaluation. Particular emphasis was placed on translational evidence, including human biomarker studies and randomized clinical trials, and on the distinction between biomarker modulation and clinically meaningful outcomes.

Repurposed drugs such as metformin and rapamycin have among the most extensive preclinical and translational evidence, although clinical evidence for broadly applicable geroprotection remains limited. Statins, SGLT2 inhibitors, GLP-1 receptor agonists, and menopausal hormone therapy have established disease-specific or cardiometabolic benefits that may have indirect relevance to geroprotection, but direct effects on biological aging and healthspan remain unproven. Other candidates, including senolytics, NAD+ precursors, taurine, and epigenetic reprogramming approaches, are at different stages of translational development, with evidence ranging from promising preclinical findings to early human studies.

Across interventions, a substantial gap remains between mechanistic plausibility and clinically validated geroprotection. Geroprotective pharmacology represents a promising but incompletely validated approach to extending healthspan. Major uncertainties include the absence of universally accepted biomarkers and clinical endpoints of biological aging, heterogeneity in treatment response, optimal timing and duration of interventions, and long-term safety. Future research should prioritize adequately powered randomized clinical trials integrating standardized measures of biological aging with clinically meaningful outcomes, alongside biomarker-guided patient selection, appropriate treatment timing, and careful assessment of long-term safety.

Mitochondrial transplantation as a form of therapy to improve mitochondrial function in aged tissues has barely started as a going concern, and only a few patients have been treated in early studies conducted to date. Yet once the protocols for manufacture and quality control become widely known, availability will likely spread quickly through the medical tourism community, made up of clinics with staff already experienced in the similar techniques used in the provision of stem cell therapies and exosome therapies. Certainly, the research community has already moved on to debating how to improve delivery of mitochondria via a range of potential approaches, and that there will soon enough be an industry hungry for such improvements is assumed to be the case.

Despite the central role of mitochondrial dysfunction in disease progression, current therapeutic strategies remain largely indirect and insufficient for restoring damaged mitochondrial networks. Mitochondrial transplantation introduces a conceptually distinct approach by directly supplying healthy mitochondria to injured cells, shifting mitochondrial medicine from molecular modulation toward organelle replacement and laying the foundation for organelle-level therapy. The concept of mitochondrial transplantation is supported not only by therapeutic need but also by the natural biology of intercellular mitochondrial transfer. Early studies demonstrated that mitochondria or mitochondrial DNA can move between mammalian cells and rescue aerobic respiration in cells with nonfunctional mitochondria.

However, endogenous mitochondrial transfer is spatially restricted, context-dependent, and difficult to control therapeutically. Therefore, the clinical translation of mitochondrial transplantation requires engineered systems that can reproduce the protective and selective features of natural transfer while enabling scalable, stable, and targetable delivery. Early mitochondrial transplantation studies largely relied on the direct administration of isolated free mitochondria; however, this approach was limited by the rapid loss of mitochondrial activity in the extracellular environment, immune-mediated clearance, and inefficient delivery to target tissues. Free mitochondria are intrinsically fragile once removed from the intracellular environment. During isolation, storage, circulation, and uptake, mitochondria are exposed to mechanical stress, osmotic fluctuation, calcium overload, oxidative damage, and extracellular stress, all of which can compromise membrane potential and respiratory competence.

To overcome the limitations of free mitochondrial administration, engineered delivery has become a central determinant of mitochondrial transplantation efficacy. Collectively, recent advances have shifted mitochondrial transplantation from the simple administration of isolated organelles toward carrier-assisted and target-oriented delivery systems. These strategies can be broadly categorized into surface-engineered mitochondria, cell-mediated mitochondrial transport, vesicle-encapsulated mitochondrial delivery, and cell-type-targeted mitochondrial transplantation.

Link: https://doi.org/10.1016/j.scib.2026.08.058

It is well known that electromagnetic fields affect cellular biochemistry, but the interactions are complex enough that electromagnetic therapies have yet to emerge in any robust way. It remains challenging to replicate and explain benefits arising in some studies from even long-standing forms of electromagnetic therapy, such as the use of pulsed electromagnetic field devices. While in principle carefully sculpted electromagnetic fields can enhance or impede specific biochemical reactions occurring in cells, in practice this line of development remains largely unexplored. Here, by shielding flies with and without mutations affecting mitochondrial function from the natural geomagnetic field, reducing field strength to a very low level, researchers show that the geomagnetic field meaningfully affects mitochondrial function, and thus longevity. The effects are clearly complex and circumstantial, however, far from straightforward.

Modulation of magnetic field strength may be a potential therapeutic strategy, particularly in the context of ageing and neurodegenerative disease. Research on magnetic fields (MFs) has been motivated by diverse factors, including interplanetary space travel, emissions from medical equipment, and the mechanisms underlying magnetoreception in migratory birds. The biochemistry of hypomagnetic field (HMFs; <5 μT) exposure has focused on healthy model organisms, leaving their therapeutic potential unexplored.

We investigated the effects of HMF exposure in a neurodegenerative disease model. The Pink1 loss-of-function model recapitulates key features of early-onset Parkinson's disease, including mitochondrial dysfunction, locomotor impairment, dopaminergic neuron degeneration, and reduced lifespan. A benchtop shielding apparatus was used to generate a uniform internal field of 5 nT, to effectively remove Earth's geomagnetic field (GMF; 25-60 μT). Wild-type (WT) and Pink1 knockout D. melanogaster were exposed to HMF and assessed for survival, locomotor performance, mitochondrial respirometry and reactive oxygen species production.

HMF exposure increased lifespan in Pink1⁻ D. melanogaster by 20%, with a paradoxical reduction in climbing ability. WT D. melanogaster had decreased lifespan and improved locomotor performance under HMF. Nitrogen-vacancy (NV) centre quantum diamond sensors, were used to detect elevated superoxide levels following HMF exposure. High-resolution respirometry showed increased mitochondrial complex II activity under HMF conditions. In conclusion, hypomagnetic fields modulate mitochondrial physiology and reactive oxygen species production in D. melanogaster. This highlights the potential of HMF exposure as a novel, non-invasive approach for modulating mitochondrial dysfunction in neurodegenerative disease.

Link: https://doi.org/10.18632/aging.206424

Of the many varied approaches to mimic some of the beneficial metabolic response to calorie restriction, mTOR inhibition is arguably the most well studied. Countless animal studies have been conducted, and early clinical trials for novel mTOR inhibitors have taken place. The mTOR inhibitor rapamycin is a generic, low cost drug now used by a growing number of people for its potential to slow aging. That potential remains to be proven in humans, but in mice rapamycin produces a reliable 10% to 20% increase in life span. Like calorie restriction, mTOR inhibitors appear to produce their benefits as a consequence of the increased operation or efficiency of autophagy, a collection of maintenance processes that recycle damaged proteins and structures in the cell. Near all forms of stress response converge on autophagy, which acts to improve cell function and resilience.

Today's open access review is a short deep dive into the biochemistry of mTOR, the role of mTOR in aging, and ability of mTOR inhibitors to modestly slow aging. If there is a single point that the authors would like you to take away with you, it is that mTOR is not a straightforward target. Optimal mTOR inhibition is context and tissue dependent, and there is probably room to improve on the sort of pharmacological mTOR inhibition conducted to date via rapamycin and similar small molecule drugs. Nonetheless, there is still a compelling argument to be made that rapamcyin is a cost-effective treatment for aging, blunt as it is, and modest as the effects are. A small benefit for a trivial cost is still a win. That argument still needs to be resolved with human data, however, and movement towards that goal is painfully slow. Low cost drugs have few champions willing to underwrite the huge expense of formal human trials.

mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes

Protein kinases are tightly regulated enzymes that ensure signaling fidelity through precise spatial and temporal control of their activity. Protein kinases constitute one of the largest and most functionally important enzyme families. They regulate virtually all major biological processes by transferring phosphate groups from adenosine triphosphate (ATP) to serine, threonine, or tyrosine residues. This reversible post-translational modification propagates intracellular signaling through phosphorylation cascades, whereas phosphatases terminate signaling by removing phosphate groups from target proteins.

Among phosphatidylinositol 3-kinase-related kinases (PIKKs), mechanistic target of rapamycin (mTOR) occupies a central position in aging biology owing to its role in coordinating nutrient sensing, metabolism, and stress adaptation. mTOR is a multidomain serine/threonine kinase that integrates environmental and intracellular signals to regulate metabolism, growth, autophagy, and cell survival. It assembles into two functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which differ in molecular composition, upstream regulation, and downstream signaling outputs.

Rather than functioning as a linear signaling pathway, mTOR acts as a dynamic signaling hub that coordinates anabolic and catabolic processes in response to nutrient availability, energy status, and cellular stress. Dysregulated or persistent mTOR activation is associated with reduced metabolic flexibility, impaired stress adaptation, and accelerated aging, whereas context-dependent modulation of mTORC1 and mTORC2 supports cellular homeostasis and organismal resilience. Consequently, mTOR has become one of the principal molecular targets in geroscience and a promising focus for interventions aimed at promoting healthy aging.

This review provides an integrative analysis of the molecular architecture and biological functions of mTOR signaling, with particular emphasis on the emerging role of mTORC2 in aging and longevity. It examines mechanistic, genetic, experimental, and translational evidence linking mTOR signaling to lifespan regulation and critically evaluates current geroprotective interventions that modulate this pathway. Finally, the review discusses the therapeutic opportunities, biological trade-offs, and remaining translational challenges of targeting mTOR signaling to improve healthspan and healthy aging.

Later stages of Alzheimer's disease and other tauopathies are characterized by the aggregation of altered tau protein, and a toxic surrounding biochemistry that provokes inflammation and destroys neurons. So far little headway has been made towards therapies that can halt tau pathology, by clearing harmful tau or preventing its formation. Given the several decade span of intense effort devoted to the clearance of amyloid-β in the brain before success ultimately emerged, we might expect that much more remains to be accomplished in order to reach the same point for tau. Unfortunately, many discoveries in the neurodegenerative field are approaches that cannot be curative, and this is the case here. The peptide discussed can only reduce tau pathology in mouse models of tauopathy, not eliminate it.

Neurodegenerative disorders such as Alzheimer's disease (AD), Corticobasal Degeneration (CBD), and Progressive Supranuclear Palsy (PSP) are characterized by tau aggregation, neuroinflammation, and progressive cognitive decline. Although metabolic dysregulation and neuropeptide imbalance have been linked to these disorders, the functional consequences of this imbalance and its reversal remain poorly understood. Our previous work identified chromogranin A (CgA), the gene encoding a pro-hormone for several metabolic peptides, as a key regulator of tau pathology.

Here, we investigate Catestatin (CST), a CgA-derived peptide, for its role in modulating tauopathy. We report marked reductions in CST levels and an increase in Pancreastatin (PST) in the hippocampus and cortex of AD brains, as well as in the frontal cortex of CBD and the basal ganglia of PSP. CST-supplementation in cortical neuronal cultures and organotypic slice cultures (OTSC) reduced Tau phosphorylation and aggregation. In vivo, CST administration to PS19 tauopathy mice decreased pathological Tau species, attenuated gliosis, improved cognitive function, and reduced amyloid burden and neuroinflammation in 5xFAD mice.

Mechanistically, CST reduced epinephrine levels in PS19 and 5xFAD mice, suppressed Protein Kinase A hyperactivation in PS19 and OTSC, and revealed a link between CST deficiency, adrenergic stress signaling, tauopathy-mediated neurodegeneration, and the therapeutic potential of CST supplement.

Link: https://doi.org/10.1016/j.ymthe.2026.09.022

Researchers here provide an initial proof of concept demonstration of a novel foundation for replacing lost visual capacity in cases of retinal degeneration, without addressing the underlying pathology that causes loss of function in photoreceptor cells. Recall that direct stimulation of retinal cells by grid electrodes implanted in the retina has been used to produces a poor substitute for actual vision, but a substitute that allows blind people at least some capacity to navigate and even read. Here, researchers introduce light sensitive nanoparticles into the retina that can in principle provide the basis for a more refined artificial substitute for normal vision. Based on the results of the electrode grids, one would expect the result to be a view of the world painted in glowing shades of phosphenes at various intensities.

The possibility to electrically stimulate living tissue creates new opportunities for therapeutic applications. Interfaces between biology and nanomaterials open an array of possibilities for non-genetic modulation of bioelectric activity with subcellular spatiotemporal control. Nanoparticles (NPs) have shown to be able to build tight interfaces with both intra- and extracellular membranes. Importantly, light can trigger electrochemical or photothermal effects at the semiconductor NP/cellular interface acting as a leadless electrophysiological modulator.

Here, drawing inspiration from photosynthesis, we develop hollow-sphere graphitic carbon nitride nanoparticles (hg-C3N4 NPs) that can modulate biological activity from subcellular processes to whole-tissue function. The homogeneous hg-C3N4 NPs show responsiveness to light via both photoelectrochemical and photothermal mechanisms and can be spontaneously internalized with excellent cytocompatibility.

We demonstrate that hg-C3N4 nanoparticles can be safely delivered and elicit measurable cortical and behavioural light responses in a model of advanced retinal degeneration. The application of hg-C3N4 NPs to porcine retinal tissue ex vivo confirms their modulation capability to directly activate retinal ganglion cell activity under light-emitting diode photostimulation.

Link: https://doi.org/10.1038/s41551-026-01773-w

PD-L1 found on the surface of cells is a well known immune checkpoint protein. When it binds to the receptor PD-1 found on the surface of T cells and B cells, it acts to suppress immune activity. This is a necessary brake to avoid runaway immune reactions, but because it is also abused by cancer cells to shield them from the immune system, the cancer research community has given a great deal of attention to this and other forms of immune checkpoint. Checkpoint inhibitors such as antibodies for PD-L1 are a well established class of drug intended to enable the immune system to better attack cancerous cells.

In today's open access paper, researchers report on the results of delivering a PD-L1 antibody directly into the brains of Alzheimer's disease model mice. Past research has suggested that the more usual intravenous delivery outside the brain can help improve clearance of protein aggregates in the brain by immune cells, but the mechanism would have to be fairly indirect. The immune systems of body and brain are quite distinct from one another, separated by the blood-brain barrier, and in normal circumstances only small numbers of immune cells from the body can enter the brain. Would a more direct targeting of brain cells produce a larger effect?

While the authors of today's paper view checkpoint inhibition in terms of enabling greater clearance of protein aggregates by a more active population of immune cells, it seems plausible that clearance of senescent cells in the brain is equally important. Like cancerous cells, senescent cells in aged tissues have been found to employ immune checkpoint activation to preserve themselves from clearance by the immune system. Senescent cells are clearly detrimental to the aging brain, a major contribution to disruptive chronic inflammation. It is plausible that checkpoint inhibition could reduce the burden of senescent cells in an aging brain. Alas, the researchers here restrict themselves to measuring only some functional aspects of brain cell populations, so whether or not this is the case in the present study is unclear.

Targeting glial PD-1/PD-L1 restores microglial homeostasis and reduces neuronal hyperactivity in an Alzheimer's disease model

Immunotherapy targeting the immune checkpoint pathway, particularly the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis, has emerged as a promising strategy for treating Alzheimer's disease (AD). Previous studies have suggested that the systemic administration of anti-PD-L1 antibody reduces amyloid-β burden and improves cognitive outcomes in AD mouse models, primarily by activating peripheral immune responses and promoting the recruitment of monocyte-derived macrophages (MDMs) into the brain. However, these studies have primarily focused on peripheral immune cells.

Unlike the systemic approaches, our study emphasizes the direct modulation of PD-1/PD-L1 signaling within the brain and its implications for glial and neuronal functions. Microglia, the brain's intrinsic immune cells, are central to maintaining neuronal homeostasis; they monitor neuronal activities and modulate synaptic functions. In AD, microglia often exhibit a dysfunctional state characterized by impaired phagocytosis, reduced motility, and altered gene expression. Astrocytes also play a vital role in maintaining brain homeostasis by modulating neuronal activities, thereby regulating synaptic transmission and supporting microglial function. PD-L1 expressed on astrocytes has been implicated in neuroimmune interactions, but its specific role in AD has not been fully investigated.

Increased PD-1 and PD-L1 levels in microglia and astrocytes show features analogous to their sustained expression in exhausted peripheral immune cells during chronic infections and tumors, in which they help suppress heightened immune responses. In AD, such upregulation of PD-1/PD-L1 may contribute to glial dysfunction, with potential consequences for immune surveillance and neuronal modulation. Consequently, targeting glial PD-1/PD-L1 signaling directly within the brain could provide a promising strategy to restore glial and neuronal function.

In this study, we investigated the effects of direct intracortical anti-PD-L1 administration on microglial function, neuronal activity, and amyloid-β pathology in a 5xFAD mouse model using real-time in vivo two-photon microscopy. Seven days after the intracortical injection, the anti-PD-L1 treatment effectively rescued microglial process motility and restored spontaneous neuronal calcium activity, while reducing amyloid-β plaque burden and increasing plaque-associated microglia. Furthermore, astrocyte-specific PD-L1 knockdown showed effects similar to those resulting from the inhibition of the glial PD-1/PD-L1 pathway. Collectively, our findings suggest that brain-intrinsic glial PD-1/PD-L1 modulation reduces amyloid-β pathology along with restoring functional interactions among microglia, astrocytes, and neurons.

Researchers here provide a proof of concept for the use of Raman spectroscopy to non-invasively measure the burden of senescent cells in an imaged tissue. This works because Raman imaging can provide distinct signatures of different molecules via scattering of photons. Provided the field of imaging is sufficiently constrained, it is possible to produce results that measure differing abundances of specific molecules in different cells. Senescent cells exhibit a range of upregulated and downregulated proteins and other molecules, so in principle creating a system to assess the presence of senescent cells is just a matter of putting in the work to construct and validate a specific implementation.

Aging and tissue repair involve heterogeneous remodeling across transcriptional, biochemical, and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how these states co-evolve. Here we present RamanOmics, a multimodal framework integrating label-free hyperspectral Raman imaging with single-nucleus RNA sequencing and spatial transcriptomics to link biochemical states with transcriptional programs at single-cell spatial resolution.

Applied to young and old mouse lung and skin, RamanOmics reveals tissue-specific programs: lung senescent cells are enriched for extracellular matrix remodeling and transforming growth factor-β signaling, whereas skin senescence is dominated by epidermal differentiation genes (Krt10, Lor, and Sbsn). Across tissues, we identified a conserved lipid-linked Raman signature marking p21+ senescent cells and developed a machine learning-derived, multimodal barcode enabling nondestructive senescence identification in situ. In a mouse wound-healing model, RamanOmics reveals reactivation of epidermal differentiation genes (Krt10, Lor and Sbsn) in senescent cells, alongside increased lipid-associated Raman signatures.

Taken together, RamanOmics provides a tissue-agnostic framework for scalable, multimodal profiling of cellular states.

Link: https://doi.org/10.1038/s43587-026-01219-7

One of the more interesting new concepts in aging research is that repeated activation of the DNA damage response may cause epigenetic changes in the management of nuclear DNA structure that are characteristic of aging. It neatly explains how stochastic DNA damage to unused DNA sequences can possible contribute to aging. It also frames partial epigenetic reprogramming as a true rejuvenation therapy, one of the reasons why there is a great deal of funding for that line of work. Is it actually the case, however? The mechanistic evidence to date is suggestive, but as usual the question is less whether the mechanism exists and more whether it provides a meaningful contribution to degenerative aging. Maybe those epigenetic changes are largely the result of other processes, for example. Here, a researcher discusses the evidence to date, and proposes tests that one might consider running in order to provide a better set of answers regarding the contribution of the DNA damage response to aging than presently exist.

Aging is multi-causal, yet its molecular hallmarks may converge on a few upstream integrating nodes. We advance the hypothesis that chronic, largely mutation-independent overactivation of the DNA damage response (DDR) is one such node, dysregulating the cell's intact guardian pathways - the tumor-suppressor networks and their negative regulators - to induce senescence, deplete stem-cell pools, and drive inflammaging. Unlike cancer, where mutations inactivate these guardians, aging more often reflects functional dysregulation of wild-type pathways, either chronically overactivated (p53, p16INK4a) or epigenetically silenced (SIRT1, FOXO3, NRF2, Klotho). That the very programs guarding against cancer can, when chronically engaged, come to drive aging we term the guardian paradox.

We organize 16 candidate axes - which we term the aging axis - across three evidence tiers, mapped onto the hallmarks of aging, outlining for each a conceptual diagnostic signature and an illustrative restoration strategy, with all numeric biomarker bands and vector details as non-clinical placeholders. We set this DDR-integrator hypothesis against mitochondria-, proteostasis-, and reprogramming-first models and pre-specify longitudinal, mediation, and head-to-head tests that could support, demote, or refute it. No integrated human interventional data yet exist; we therefore present a falsifiable research agenda, not a therapeutic protocol.

Link: https://doi.org/10.18632/aging.206416

Type 1 conventional dendritic cells are a subclass of dendritic cell known to be an important component of the immune response to pathogens and cancerous cells, particularly focused on stimulating the activity of cytotoxic T cells. The cancer research community, as is often the case when it comes to specific components of the immune system, has led the way in generating a better understanding of these cells, and so much of the present literature is focused on their role in cancer. Generally speaking, patients with more type 1 conventional dendritic cells tends to exhibit better outcomes, because the cancer will be more aggressively attacked by the immune system. Unfortunately, the population of type 1 conventional dendritic cells declines with age.

Today's open access paper assembles existing data to provide a coherent viewpoint on the interconnected mechanisms leading to the age-related loss of type 1 conventional dendritic cells, and proposes a readily available solution, albeit one involving cell therapy. A number of interventions assessed by the cancer research community have been shown to somewhat restore dendritic cell function, but none of them are sufficient because they each only address once small part of the overall cause of the loss of type 1 conventional dendritic cells. The authors of today's paper propose that an existing approach to the ex vivo production of type 1 conventional dendritic cells for anti-cancer cell therapy will solve the problem by providing cells that were not exposed to the specific changes in an aged biochemistry that form the root cause of the issue.

A proposed convergent molecular chain linking senescence, cancer, and chronic infection to a correctable failure of dendritic cell instruction

Three convergent phenomena in biomedical research have lacked a unified mechanistic explanation: the dendritic cell dysfunction of aging, the immune evasion of cancer, and the tolerogenic bias of chronic infection. In each setting, the specific cell responsible for instructing effector immunity, the type 1 conventional dendritic cell (cDC1), is numerically depleted, functionally silent, or both, leading to loss of its bioactive IL-12p70 output.

The cDC1 is defined at the lineage level by its dependence on the transcription factor IRF8, which is required for cDC1 specification, survival, and the capacity to produce IL-12p70. The IRF8 locus is regulated by a BATF3-dependent enhancer architecture that has been shown to operate as a bistable switch with no stable intermediate state: a committed cDC1 is either IRF8-high and surveillance-competent or IRF8-low and tolerogenic. The switch does not sit between these states. This architectural property is central to understanding why partial interventions have produced only partial results.

We propose that aging, cancer, and chronic infection converge on a single molecular chain that forces this switch into the off position. The chain has four steps, each of which is individually established in the published literature. Senescence-associated secretory phenotype (SASP) cytokines activate STAT3 in hematopoietic progenitors; STAT3 recruits DNMT1 and EZH2 to the IRF8 locus; dual DNA methylation and histone methylation installs a bistable silencing state with no stable intermediate; IL-12 transcription and cDC1 instruction collapse.

Any correction that leaves the upstream SASP intact and attempts to unlock IRF8 in situ must overcome both DNA methylation and H3K27me3 on a bistable locus whose low-affinity enhancer architecture is biased toward the off state. Pharmacological attempts to do this, DNMT inhibitors, EZH2 inhibitors, JAK/STAT3 inhibitors, IL-6 blockade, have produced partial restoration of dendritic-cell function in preclinical settings but not durable correction. The logic of the chain explains why: each of these interventions targets a single node while the remaining nodes continue to reinforce silencing.

An alternative approach bypasses the architecture rather than unlocking it. A cDC1 manufactured ex vivo in a STAT3-free environment, with IFN-γ priming and TLR3 engagement, is never exposed to the sustained STAT3 signal required for DNMT and EZH2 recruitment. Its IRF8 locus is not methylated because the conditions that drive methylation are absent from the bioreactor. The α-type-1 polarized dendritic cell (α-DC1) protocol developed in the early 2000s produces precisely such a cell. The α-DC1 protocol has been evaluated clinically, most directly in recurrent malignant glioma, within a broader body of dendritic-cell vaccine trials in melanoma and other solid tumors. The clinical data in these trials are consistent with the framework. Interpreted within the framework presented here, the α-DC1 functions as a replacement instructor for a cell population whose native equivalents have been silenced.

Suppression of cancer is a necessary component of species longevity, and finding out how exactly cancer incidence is in some cases dramatically reduced is one of the primary goals for the field of comparative biology. Here, researchers survey known cancer-associated sequences across the genomes of long-lived and short-lived species, and see that sequences are more conserved in long-lived species. Patterns of epigenetic modifications to the genome at these locations also exhibit differences in long-lived species. Thus one component of reduced cancer risk in these species involves specific sequence differences in oncogenes and related genes, and different expression of oncogenes in circumstances relevant to induction of cancer.

Recently, accumulated evidence has shown that longer-lived species, such as naked mole rats, elephants, and some bat species display enhanced resistance to cancer. In this study, we identify genomic sites in 58 mammalian species that are homologous to human cancer-associated regions and compare their evolutionary dynamics to those of cancer-unrelated sites. By contrasting mutation rates in longer-lived versus shorter-lived species, we evaluate whether evolutionary constraint at these loci correlates with lifespan or body size. Because epigenetic modifications are intimately linked to oncogenesis, and synonymous changes can affect tumorigenesis by perturbing m6A deposition, we also examine the distribution of 5mC and m6A marks at cancer-associated versus unrelated sites across the two lifespan groups.

While overall evolutionary rates at cancer-associated loci do not differ significantly between long-lived and short-lived species, cancer-associated sites show greater evolutionary conservation relative to non-cancer sites within long-lived mammals but not within short-lived mammals. Furthermore, long-lived species exhibit a pronounced enrichment of m6A at cancer-associated loci (based on m6A modification sites derived exclusively from male samples) despite lower global m6A levels. Notably, tumor suppressor genes in long-lived mammals harbor proportionally more m6A-modified transcripts, suggesting a potential association between messenger RNA methylation and post-transcriptional regulation at cancer-relevant loci. Together, these results suggest that enhanced sequence conservation at cancer loci, coupled with targeted mRNA modification, may be part of a multilayered molecular strategy that reduces cancer risk in long-lived mammals.

Link: https://doi.org/10.1038/s41467-026-76479-3

Here find a small slice of programmed aging consideration focused on some of the changes in cognitive function that take place in later life. The researchers argue that a shift in focus to integration of information, characterized by a loss of precision in episodic memory, is adaptive and selected for in older individuals. It is an interesting point of view, though given the tools the research community has today it would be challenging to determine whether any specific age-related alteration in neural circuitry and cognitive function in the brain is adaptive change versus change that is a response to damage and loss of function.

Prevailing theories of cognitive aging depict late life as a period of compensatory decline - an effort to preserve performance despite progressive neural deterioration. We propose instead that aging represents a continuation of development: a genetically conserved, adaptive reorganization of memory systems that parallels the brain's earlier-life transitions. Drawing on convergent molecular, network, behavioral, and comparative evidence, we argue that the well-documented decline in episodic-memory precision reflects a deliberate recalibration of plasticity from hippocampal to cortical circuits, favoring semantic integration and schematic stability over rapid encoding of novel details.

This shift, we suggest, is not a workaround for loss but an evolved optimization suited to the cognitive ecology of late life, when accumulated knowledge, social insight, and intergenerational teaching become primary adaptive functions. The resulting semantic mode of cognition supports narrative coherence, emotional regulation, and wisdom, distinguishing normal aging from pathological derailments such as Alzheimer's disease. We outline testable predictions across longitudinal, neuroimaging, and computational domains and reinterpret constructs like cognitive reserve as expressions of this developmental reallocation. By reframing aging as purposeful maturation rather than compensation, the adaptive-aging hypothesis positions late-life cognition as a distinct, evolutionarily honed phase of human development.

Link: https://doi.org/10.1177/17456916261469175

It is well understood in the aging research community that the lack of a useful, consensus measure of biological age or pace of biological aging is a considerable hindrance to progress. If researchers could quickly measure the pace of aging or the state of aging in a robust way, then discovery and optimization of interventions would proceed a great deal more rapidly. At present, too many suboptimal lines of research are maintained despite the likely lack of effectiveness at the end of the day, and the discovery of new approaches to slow aging and extend life is a slow and expensive process; even in mice, life span studies take years to run.

There are a great many age-related changes in health, biochemistry, and physical function that can be measured, and many of those have their advocates. The "just measure grip strength and get on with it already" faction is a sizable one. Various aging clocks produce decent correlations with age-related mortality and morbidity. And so forth. But the challenge with all of the existing options is that we have no idea as whether then can be trusted to accurately reflect the effects of any new class of intervention. Maybe they will overstate the outcome. Maybe they will understate it. The only way to find out is to calibrate assays against interventions in long-running and expensive studies. And so development remains stuck in the slow lane.

In today's open access paper, researchers propose one possible way forward to an incrementally better situation. The idea is to look through the existing high quality studies of slowed aging in mice conducted by the Interventions Testing Program, and find common biochemical and metabolic measures that appear in mice exhibiting slowed aging. This seems relevant to the classes of therapy that slow aging by provoking cellular stress responses, repair and maintenance and defense activities that improve cell function: calorie restriction, calorie restriction mimetics, and the like. It seems tough to argue that metrics uncovered via these studies could then be applied to completely different approaches to therapy that do not touch on these shared stress response systems, such as senolytics or stem cell therapies, however.

Aging rate indicators and the search for anti-aging drugs

Evidence that drugs, diets, and single-gene mutations can slow aging and extend the healthy lifespan of mammals has begun to convert biogerontology from an observational science into one based on interventions that could provide people with additional years of healthy, productive life. However, the research and development of anti-aging drugs is hampered by the lack of instantaneous and continuous measures of the rate of aging itself. This article presents recent work on anti-aging drugs that are effective in mice, provides evidence for candidate "aging rate indicators" (ARIs), and outlines a roadmap for translating these into clinical research to slow aging in humans.

Thus far, 14 agents or combinations have significantly increased the lifespan of mice in studies conducted under the Interventions Testing Program (ITP) of the National Institute on Aging, often when initiated in late adulthood. Recent evidence suggests that many, perhaps all, interventions that slow aging in mice induce common, shared changes in physiological status and molecular pathways. We have proposed 12 such mechanisms as candidate ARIs, i.e., measurable outcomes that reflect a slow-aging state and that could discriminate between normal mice (and perhaps humans) and those exposed to effective anti-aging interventions - thereby accelerating research.

Research priorities now include testing the robustness of these ARIs, extending them to include plasma constituents, elucidating the mechanisms through which diverse interventions alter them, uncovering the links between the ARIs and late-life diseases, and extending research to dogs, non-human primates, and humans. The growing recognition of the legitimacy and promise of evidence-based interventions resulting from aging biology should elevate this field to a level of urgency and respect comparable to that of current research on individual age-related conditions.

Researchers have started on the long process of transferring promising genes from long-lived species into short-lived species, one by one, with each such transfer as a test of how important that specific difference is to the progression of aging and species longevity. Differences in the presence of hyaluronan in the extracellular matrix are thought to improve the health and resilience of long-lived naked-mole rats, and so researchers generated a mouse lineage that manufactures naked mole rat hyaluronan. The result is improved healthspan, and so now researchers are beginning to assess this novel lineage of mice more deeply. Here, for example, researchers show that this alteration to hyaluronan doesn't have any effect on age-related hearing loss.

Approximately one in three adults aged 65-74 years reports hearing difficulty, including age-related hearing loss (AHL, presbycusis). The C57BL/6 mouse is widely used in preclinical AHL research because it develops AHL relatively early. Calorie restriction (CR) attenuates AHL and improves healthspan and longevity in this strain. A recently developed transgenic C57BL/6 mouse expressing naked mole-rat hyaluronan synthase 2 (nmrHas2), which produces very high molecular mass hyaluronan (vHMM-HA), also exhibits improved healthspan, reduced inflammaging, and increased longevity. Therefore, we evaluated nmrHas2 mice for evidence of alleviated AHL.

The goal of this experiment was to determine whether ubiquitous expression of the nmrHas2 transgene, including within the cochleae, attenuated AHL. Our results indicate that a genetic intervention that had previously been shown to improve healthspan, reduce inflammaging, and increase longevity in C57BL/6 mice did not attenuate AHL, i.e., these outcomes were decoupled in nmrHas2 mice, which contrasts with outcomes following CR. This points to differences in the mechanisms of action of these two interventions, at least within the cochleae.

Link: https://doi.org/10.3389/fragi.2026.1936677

Many approaches to modestly slow aging in short-lived species involve a mild mitochondrial dysfunction that that somewhat increases the level of reactive oxygen species generated in the course of producing adenosine triphosphate (ATP) to power the cell. Reactive oxygen species react with and damage molecular machinery throughout the cell, damage that needs to be repaired. The cell reacts with an increase in repair and maintenance activities that address oxidative damage and other forms of damage, producing a net benefit to function. Here, researchers investigate one portion of how this response is regulated, looking at the metabolism of nematode worms.

The reactive oxygen species superoxide is generated by mitochondria during the process of producing energy. While superoxide can cause oxidative damage to the cell, we and others have shown that a mild increase in mitochondrial superoxide extends longevity in multiple model organisms. To elucidate the molecular mechanisms involved, we identified transcriptional changes in mitochondrial superoxide dismutase deletion mutants (sod-2 worms) using RNA sequencing. sod-2 mutants exhibit a number of changes in nuclear gene expression resulting from elevated mitochondrial superoxide suggesting that mitochondria-to-nucleus signaling is contributing to their longevity.

Gene ontology enrichment analysis demonstrated that genes involved in innate immunity and cuticle formation are significantly upregulated in sod-2 worms. To identify kinases involved in this lifespan-extending pathway, we completed a targeted RNA interference screen to examine the contribution of selected kinases to sod-2 longevity. From this screen, we found 25 kinases which are required for the long lifespan of sod-2 mutants including mak-2, which has a role in a kinase signaling pathway involved in axon regeneration. Disruption of mak-2 specifically reduces sod-2 lifespan but not wild-type longevity and also decreases resistance to multiple exogenous stressors. In examining other genes that act with mak-2 in established signaling pathways, we identified a SEK-3/PMK-3/MAK-2/CEBP-1 signaling pathway that is specifically required for sod-2 longevity but not wild-type lifespan.

Combined these results suggest a novel role for kinases with established roles in axon regeneration in promoting longevity through a mitochondria-to-nucleus signaling pathway.

Link: https://doi.org/10.1016/j.redox.2026.104385

The cGAS protein is a sensor for mislocalized DNA in the cell cytoplasm, and responds by triggering STING, a regulator of the inflammatory response to damage and dysfunction. The cGAS-STING interaction produces some fraction of the maladaptive chronic inflammation characteristic of aging, as, among other reasons, mitochondrial dysfunction tends to spill mitochondrial DNA fragments into the cell cytoplasm. Nothing in the cell has only one purpose, however, and cGAS is also involved in the regulation of the DNA damage response in the cell nucleus. It is known to inhibit homologous recombination of double strand breaks, for example.

An examination of cGAS in different species suggests that different variants can aid or hinder late life health via their actions in either the DNA repair context or the chronic inflammation context. Introducing naked mole rat cGAS into mice improves DNA repair and reduces the impact of aging, and a rare lineage of humans exhibits a variant form of cGAS that reduces cGAS-STING activation, and thus late life inflammation.

cGAS does serve a useful purpose, despite producing a maladaptive contribution to degenerative aging. This is demonstrated in today's open access paper, in which disabling cGAS entirely in killifish does not extend life. Benefits are provided by removing its maladaptive activity, and harms are caused by removing its helpful activity. This is characteristic of interventions in the regulation of inflammation: chronic inflammation is harmful, but the normal short term inflammatory response serves a necessary purpose in tissue maintenance, and both run through the same regulatory pathways, making it challenging to intervene in a selective way.

Loss of killifish cGAS attenuates age-related signatures but does not affect organismal life span

A major source of inflammaging stems from chronic activation of the nucleic acid-sensing innate immune pathway cGAS/STING. Cytosolic DNA fragments arising from DNA damage, mitochondrial dysfunction, or infection bind cGAS to stimulate production of 2'3'-cGAMP (cGAMP). Subsequently, cGAMP activates STING, triggering the type I interferon response and inflammatory cytokine production. While this pathway is important for host defense, its chronic stimulation promotes age-related pathology. The cGAS-STING pathway also plays a central role in cellular senescence. Cytosolic DNA in these cells is detected by cGAS, triggering the senescence-associated secretory phenotype (SASP), whose persistence fosters chronic inflammation. Hence, limiting cGAS/STING pathway activity may improve late-life health.

Despite its importance in age-related disease, the effect of cGAS/STING on lifespan itself remains unknown. Here, we elucidated the role of cGAS in the short-lived African turquoise killifish Nothobranchius furzeri, a vertebrate model of aging. In this work, we used CRISPR-engineering to knock out killifish cGAS to examine its impact on senescence and aging. We hypothesized that cGAS loss would improve health and extend life. Although cGAS deficiency reduced senescence markers, attenuated age-related transcriptional changes, and maintained higher proliferative capacity with age, lifespan was unchanged, indicating that cGAS is not limiting for organismal longevity.

Researchers here take a very broad tour of the established literature on the comparative biology of aging in long lived species of all sorts, picking from those that can live more than 250 years, whether plant or animal, and comparing reported differences in biochemistry both between species and between individuals of the same species. It seems just as interesting to ask which mechanisms are important in individual variation in pace of aging in a long-lived species as to ask why the species is long-lived in the first place. The usual challenges exist, in that one can identify differences in biochemistry that seem reasonably likely to contribute to differences in longevity, but establishing the relative importance of each contribution is near impossible without some form of intervention that sabotages or enhances one mechanism in isolation of all of the others.

Certain molecular processes shape the lifespan of each species and each individual. Deciphering these processes, which underlie the diversity in lifespan across and within species can help us better understand how they evolved and why. Such knowledge may inform the design of effective strategies towards increasing human and other species' healthspan and lifespan. Here, we consider 101 species that live past 250 years, including the longest-living beings on Earth. Among these species, 90 are plants and only 11 are animals. Some barely reach an age of 250 years, while others live for up to 80,000 years. Few, such as the freshwater planarian and the Turritopsis dohrnii jellyfish, are considered potentially immortal. None of these species are mammals; indeed, no known mammal lives for over 250 years.

We surveyed the genetic, transcriptional, proteomic, metabolomic, regeneration-, stress-, and cancer-related components of intraspecific and interspecific lifespan variation, across these species. We examined whether the mechanisms regulating intraspecific lifespan variation across these species are the same or different from mechanisms regulating interspecific lifespan variation. We identified several similarities: both types of variation include mechanisms related to DNA maintenance, stemness, and stress management. Such mechanisms are also typical of early developmental stages and germ cells. Nonetheless, caution should be exercised when attempting to draw robust conclusions based on available data, given the lack of in-depth molecular studies on the healthspan and lifespan across thousands of individuals and species, the methodological variation across published studies, and our partial understanding of the interplay between physiology and the environment across species.

Link: https://doi.org/10.18632/aging.206419

Rationing of sugar in the United Kingdom in the years immediately following the Second World War forms a natural experiment in the long term effects of changes in human nutrition that can be explored in great detail given the establishment of the UK Biobank. Researchers here show that lower sugar intake in early life correlates with improved later life health, reduced biological age measures, and reduced mortality. A number of other natural experiments around the time of the Second World War have been used to explore the effects of calorie restriction in early life, but this particular episode of rationing is a way to separate lower sugar intake from overall calorie restriction; it is interesting to see positive results.

Excessive intake of free or added sugars is strongly linked to childhood dental caries and is also associated with higher risks of incident obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), obesity-related cancers, and dementia in adulthood. Britain's post-World War II sugar rationing provides a unique natural experiment. Unlike famine, rationing constrained access to added sugars without broad caloric deprivation, offering a rare opportunity to isolate the long-term impact of early-life sugar reduction to determine the impact on a variety of ageing-related outcomes.

Exposure to sugar rationing during the first 1,000 days of life is associated with a 9% lower incidence of hallmark-related disease, with a hazard ratio of 0.91, and a 19% lower risk of all-cause mortality. Mediation analysis indicates that the survival association is statistically mediated, by approximately 60%, through differences in incident hallmark-related disease. Rationed individuals show 1.0-1.2-year younger biological ages across multiple clocks and lower organ ages, particularly in the lung, heart, and liver. Proteomic profiling identifies 47 altered proteins, with enrichment of adenosine monophosphate-activated protein kinase (AMPK) and longevity pathways and suppression of mechanistic target of rapamycin (mTOR) signaling.

Link: https://doi.org/10.1038/s41467-026-76257-1

A range of gene therapies are presently available in the medical tourism community of clinics outside the US and Europe, largely originating with a small number of companies such as BioViva Sciences and Triple Helix Science. These gene therapies tend to involve intramuscular (targeting muscle) or intranasal (targeting the brain) delivery of a modern adeno-associated virus (AAV) vector, such as AAV8 or AAV9. While AAV therapies have exhibited a concerning risk of life-threatening immune response when injected systemically at high doses, lower doses used in conjunction with local delivery appear to be relatively safe. The genes delivered by these gene therapies include follistatin for muscle growth, VEGF for vascular growth, and some well-known genes hoped to improve the state of the aging body and brain such as telomerase, SIRT1, and so forth. One can argue that perhaps the largest body of direct and practical experience in the implementation of gene therapies is now this community, outside the regulated medical community, and publishing relatively little of the data on what works that they have accumulated.

So it is interesting to see the Triple Helix folk here reporting on their experience in the use of grip strength as a biomarker of aging to assess the results of gene therapies intended to improve function. One of the largest challenges in the matter of measuring aging is the uncertainty over whether any given biomarker that appears to work well in normal aging will then continue to work well when a patient receives some form of regenerative or anti-aging therapy. The best way to stress test a biomarker is to gather data on how it actually performs given a range of different types of regenerative or anti-aging therapy. Until recent years, the range of available interventions known to reliably affect aging has been quite narrow, essentially diet and exercise and first generation stem cell therapies, with newcomers like senolytics and mTOR inhibitors starting be used widely enough for data to emerge. Now, AAV gene therapies can provide a dozen or more very different effects to assess.

Grip strength as a systems biomarker of aging: neuromuscular junction constraints and biomarker decoupling in gene therapy

Grip strength occupies a privileged position among biomarkers of biological aging. Meta-analyses encompassing hundreds of thousands of participants consistently demonstrate that grip strength predicts all-cause mortality with effect sizes comparable to established risk factors such as systolic blood pressure. This predictive relationship persists across age groups, ethnicities, and disease states, extending beyond mortality to encompass cognitive decline, disability onset, hospitalization risk and quality of life measures. Yet the mechanistic basis for this remarkable predictive breadth remains incompletely understood. The dominant interpretation treats grip strength as a convenient proxy for overall muscle mass or general frailty. We argue this view is incomplete and increasingly problematic. When grip strength remains predictive after statistical adjustment for lean mass - while lean mass alone loses significance - something beyond simple muscularity must be at work.

This interpretive challenge becomes urgent as longevity medicine enters a new era. Longevity gene therapies are being explored in early translational and compassionate-use settings and include follistatin for muscle enhancement, klotho for multi-system protection, FOXO3 for stress resistance, hTERT for telomere extension, SIRT1 for metabolic regulation, PGC-1α for mitochondrial biogenesis, VEGF for vascular function, and FGF21 for metabolic health. These therapies represent a fundamental shift from observational aging assessment to interventional aging modification.

The central question this article addresses is: How should clinicians interpret grip strength changes in patients receiving longevity gene therapies? We propose that grip strength predicts mortality because it integrates information from multiple aging systems. We highlight the neuromuscular junction (NMJ) as a particularly critical and often-overlooked rate-limiting factor, noting that age-related strength loss (∼2.5-4% annually) outpaces mass loss (∼0.6-1% annually) by two-to fivefold - a disparity attributable in large part to NMJ deterioration. Critically, we argue that follistatin's anabolic efficacy is contingent on intact NMJ integrity, with denervated muscle fibers exhibiting a blunted net anabolic response despite elevated follistatin expression - creating a therapeutic paradox wherein mass gains can occur without proportional functional improvement. We provide a conceptual analysis of how each therapy may influence grip strength, predict decoupling risk based on the breadth of systems affected, outline plausible timing windows for intervention, and propose a heuristic framework for clinical interpretation.

Senescent cells accumulate with age, likely largely because the aging of the immune system slows down the clearance of senescent cells, but the relative importance of different contributions to the growing burden of senescence in aging tissues is an area of ongoing discussion. Senescent cells secrete inflammatory signals that are disruptive to tissue structure and function when sustained over the long term. Separately, cells throughout the body accumulate mutations over the course of aging. Much of this has little to no effect, occurring in cells with few replications remaining, or in genes not used by the cell. However, a growing burden of mutation in stem cell populations spreads slowly into the tissues they support via the daughter somatic cells generated to replace those cells lost to the Hayflick limit; this somatic mosaicism is thought to produce a meaningful disruption of function, as well as set the stage for rare cancer-inducing mutations to prosper. All distinct causes of aging are thought to interact with one another, to make one another worse, which is one of the reasons why degenerative aging is not a linear process, but cellular senescence and somatic mutation are somewhat challenging to reason about in this respect. Nonetheless, researchers here make the attempt.

Cellular senescence is widely recognized as a driver of age-related phenotypes, intrinsically linked to other aging hallmarks such as telomere dysfunction, chronic inflammation, and stem cell exhaustion. Differently, the potential interplay of somatic mutations (as distinct from the broader concept of genome instability) with the other hallmarks of aging is still unprobed, and the contribution of an altered DNA sequence to aging needs deeper understanding. More broadly, our discussion of cellular senescence and somatic mutations illustrates the wider challenge of biogerontology in distinguishing driver from passenger mechanisms of aging.

Cellular senescence and mutation accumulation are distinct events, and it is presently unclear how these pathways relate to each other. Notably, among the limited evidence connecting the two paradigms, an important discovery is that they can functionally converge when mutations cause oncogene activation and consequent cellular senescence. In addition, although senescent cells are mitotically arrested and thus immune to replication errors, they may still accumulate mutations due to increased production of genotoxic reactive oxygen species and the reactivation of retrotransposons, which can cause insertional mutagenesis. The observation that senescent cells repress several DNA repair genes and have decreased repair efficiency upon irradiation, combined with their resistance to apoptosis, provide the bases for mutation accumulation in these cells.

Defining the interplay between cellular senescence and mutations remains a significant challenge, with a limited number of dedicated studies in the literature, because both processes derive from DNA damage and are difficult to disentangle. Such analyses are further complicated by the low abundance of senescent cells in aged tissues and by the impossibility of expanding these arrested cells. Therefore, elucidating this relationship represents a largely unexplored area of research in the field, one that will refine our understanding of the aging network.

Link: https://doi.org/10.18632/aging.206414

Researchers here suggest yet another possible use for retinal imaging, in this case an assessment of the burden imposed on the central nervous system by atrial fibrillation in its early stages. The retina is a window into the health of the central nervous system; many of the pathologies of the aging brain also take place in the retina. Retinal imaging is a relatively low cost procedure, and machine learning techniques make it feasible to reliably categorize features in the retina that change with aging and disease.

Atrial fibrillation, one of the most common heart conditions causing an irregular heart rhythm, affects millions of people worldwide and significantly increases the risk of stroke and heart failure. Detecting it early, before symptoms arise, remains a major clinical challenge. In this study, we explored whether the retina could offer clues about a person's cardiac health. Because the retina shares structural and vascular similarities with the brain and heart, changes visible on routine eye scans may reflect broader changes occurring elsewhere in the body.

Using eye imaging data from over 90,000 individuals across two large independent datasets, we found that people with atrial fibrillation show measurable thinning of specific inner retinal layers, the ganglion cell and inner plexiform layer, and the inner nuclear layer, compared to those without atrial fibrillation. Crucially, individuals with a thinner retina at baseline were significantly more likely to develop atrial fibrillation in the future, even before any cardiac diagnosis had been made, underlining the difficulty of establishing the diagnosis. These findings suggest that standard, non-invasive retinal scans which are widely used both in eye clinics and community settings, could potentially help identify individuals at elevated cardiac risk, potentially enabling earlier intervention and improved outcomes.

Link: https://doi.org/10.1371/journal.pdig.0001661

Like many age-related conditions, atherosclerosis is accelerated by the chronic inflammation of aging. An atherosclerotic plaque is an inflammatory environment, in which macrophage cells are overwhelmed by excess cholesterol and toxic derivatives of cholesterol. Macrophages attempt to remove cholesterol from the plaque, returning it to the bloodstream attached to HDL particles, and otherwise repair the damage. Inflammatory signaling both attracts macrophages to the plaque and hinders macrophage repair efforts, overall making it more likely that the macrophages will die and add their mass to the growing plaque. Further, it distorts the behavior of cells close to the plaque, which can also act to accelerate plaque growth, such as via the transformation of smooth muscle cells into more macrophages.

Thus there are good reasons to try anti-inflammatory strategies in the context of atherosclerosis, and a range of studies exist in which varieties of anti-inflammatory therapy were assessed for their ability to affect atherosclerotic plaque. In general, results were little more effective than drugs that statins that lower cholesterol bound to LDL particles in the bloodstream, which is to say that treatments only modestly slow plaque growth and modestly reduce the risk of a plaque rupture leading to heart attack or stroke. This is interesting, and perhaps suggests that researchers have not yet found the right inflammatory signals or regulatory mechanisms to target. The research community remains interested in further exploration of novel anti-inflammatory strategies, in search of better outcomes.

Targeting Inflammation in Atherosclerosis: Mechanistic Rationale, Clinical Trials, and Regulatory Considerations

Atherosclerosis remains the leading cause of global mortality, most commonly manifesting as ischemic heart disease, stroke, and peripheral arterial disease. Although age-adjusted cardiovascular mortality has declined in many developed nations, the global burden of atherosclerotic disease continues to rise due to population aging and growth. This narrative review examines the evolving understanding of atherosclerosis, which has shifted from a predominantly lipid-centric model to a chronic inflammatory disease.

Atherosclerosis is initiated by the retention and modification of apolipoprotein B-containing lipoproteins within the arterial wall and propagated by innate and adaptive immune responses. Central to this process is activation of the NLRP3 inflammasome and downstream IL-1β-IL-6 signaling and pyroptotic cell death, which amplify vascular inflammation and promote plaque progression and instability. Clinical evidence demonstrates that targeting inflammation, independent of lipid lowering, reduces cardiovascular events, as exemplified by agents such as canakinumab and colchicine. Consequently, the therapeutic landscape is rapidly evolving, with ongoing efforts to refine cytokine-targeted approaches (e.g., IL-6 inhibition), develop selective NLRP3 inhibitors, and advance innovative modalities including cell-based interventions. These strategies aim to provide more durable, precise, and potentially disease-modifying or even curative approaches. However, challenges related to safety, the high cost of biologic agents, and optimal patient selection have limited widespread implementation.

A major barrier remains the lack of sensitive and specific biomarkers to identify patients with active vascular inflammation, complicating trial design and therapeutic targeting. In addition to circulating markers such as high-sensitivity C-reactive protein (hsCRP) and IL-6, emerging insights highlight the liver as a central hub linking inflammation and thrombosis through complement and coagulation pathways, offering potential avenues for developing novel biomarkers. Despite promising advances, clinical translation faces persistent challenges, including increased infection risk, inadequate biomarkers for patient selection, cost constraints, and regulatory and payer requirements for hard clinical endpoints.

Every tissue in the body exchanges signals with every other tissue. Every tissue is dependent on specialized functions that are conducted elsewhere in the body. Thus in the matter of neurodegenerative disease, it is possible to focus too much on the brain, where the damage is taking place. Other organs and biological systems in the body do make a contribution to the onset and progression of neurodegenerative conditions. The brain requires a functioning circulatory system, a kidney to clear out metabolic waste, a lymphatic system to drain cerebrospinal fluid, and so forth. The functions of the brain are disrupted by chronic inflammatory signaling originating in other parts of the body, or by unwanted metabolites originating in the gut microbiota. The list continues; it is a long one. Thinking about neurodegeneration in this way naturally leads one to a view of medicine that looks very much like that of the longevity industry, as illustrated here.

Alzheimer's disease is a progressive neurodegenerative condition characterised by amyloid-β and phospho-tau pathology, causing synaptic and neuronal loss that leads to decline in memory, cognition, and ability to perform daily tasks. The exact causal mechanisms of neurodegenerative conditions such as Alzheimer's disease remain unclear, and the pathophysiological changes in the brain and body during the prodromal stage are not well understood. Significant changes in the physiopathology of body systems occur before and after the onset of these conditions. Several studies suggest that Alzheimer's disease progression involves complex, multi-scale interactions across genetic, metabolic, proteomic, and physiological domains. However, current approaches are limited in their ability to capture and interpret the complex interactions and interconnections among these dynamics.

This systemic framing is supported by recent large-scale plasma proteomic studies of dementia cohorts, which identify circulating protein signatures associated with neurodegeneration and shared across distinct neurodegenerative conditions. Such peripheral signatures are difficult to reconcile with a brain-focused model alone, but follow naturally if the underlying pathology reflects a common breakdown in cellular clearance and energy regulation, expressed throughout the body. The fact that these signatures are detectable in blood is significant in itself. It places markers of the proposed systemic dysfunction within reach of routine, longitudinal measurement. This opens the possibility of tracking cellular dysregulation across the lifespan and identifying the critical time points, or windows of opportunity, at which interventions are more likely to alter the disease trajectory.

The case for a systemic view of neurodegenerative conditions such as Alzheimer's disease is reinforced by recent therapeutic trials. Anti-amyloid monoclonal antibodies achieve substantial amyloid clearance; however, they yield only modest slowing of clinical decline. If amyloid were the principal driver of disease, effective clearance would be expected to produce a correspondingly significant clinical benefit. This gap between biological target engagement and clinical outcome, together with the limited effect on long-term disease trajectory, instead suggests that amyloid is one component of a broader, multifactorial process, and that effective disease modification may require strategies that address underlying systemic dysfunction rather than targeting a single downstream target.

Link: https://doi.org/10.1038/s43856-026-01831-z

Researchers here process data from a longitudinal study of several thousand people to show that better cardiovascular heath in the early 40s correlates with better outcomes in later old age. There are many reasons to put in the effort to maintain a better state of physical fitness, and that it meaningfully slows the pace of degenerative aging is one of them. In some metrics, such as odds of surviving until age 90, the spread of outcomes between least fit and most fit is sizable - a 6-fold increase in survival. It is food for thought for an age of sedentary comfort.

We examined how low cardiovascular risk in early midlife is associated with frailty, quality of life, happiness, and well-being in old age. At mean age of 42 years, five low-risk factors (non-smoking, BMI < 25 kg/m2, systolic blood pressure < 140 mmHg, total cholesterol < 6.0 mmol/L, one-hour post-load glucose < 9.0 mmol/L) were measured among 2,690 healthy men. Phenotypic frailty, health-related quality of life (HRQoL, RAND-36), psychological wellbeing, and feeling of happiness (a Cantril ladder-type 10 cm visual analogue scale) were assessed in 2007 at a mean age of 79 years. Mortality was retrieved from national registers through 31 January 2025 (2,524 men died).

At baseline, 59 men had zero, 422 one, 855 two, 832 three, 417 four and 105 five low-risk factors. The proportion reaching 90 years increased accordingly: 6.8%, 14.2%, 18.3%, 26.7%, 36.6%, and 41.9%. At mean age of 79 years (n = 907, response rate 63% and similar in baseline groups), compared to those with no low-risk factors in midlife, men with five factors had less frailty (2.2% vs. 24.5%), reported greater happiness (8.0 vs. 7.5), higher psychological wellbeing (55.1% vs. 39.0%), and better HRQoL in several domains. Thus low cardiovascular risk in early midlife was associated with greater longevity, less frailty, better quality of life, and higher levels of happiness and well-being in old age.

Link: https://doi.org/10.1093/eurjpc/zwag429

The major neurodegenerative conditions are characterized by pathology deriving from a small number of misfolded or otherwise altered proteins. Amyloid-β misfolding and aggregation is thought to be the initiating event in Alzheimer's disease, which leads to the spread of altered forms of tau protein that cause the real damage. α-synuclein, once misfolded, spreads from cell to cell through the nervous system like a prion, encouraging other molecules of α-synuclein to also misfold in the same way. Once in the brain, α-syncuclein pathology gives rise to Parkinson's disease. In recent years, researchers have connected the spread of misfolded TDP-43 in the brain to a number of conditions such as frontotemporal dementia. All of these pathologies exist in aged brains to some degree, overlapping and driving dysfunction, and eventually that dysfunction will rise to the level of a named neurodegenerative condition, absent some other form of mortality cutting that process short.

As the past few decades of efforts to develop anti-amyloid therapies for Alzheimer's disease had demonstrated, the biochemistry of protein aggregates and their pathology is enormously complex and remains incompletely understood, even for amyloid-β, even after years of enormous funding for research and development. Amyloid-β clearance took decades to achieve, but does not produce the sizable benefits hoped for in patients, and the reasons why this is the case are yet to be established. It seems likely that the road ahead will be similarly challenging for the development of ways to target other common protein aggregates in the brain. With that in mind, today's open access paper is a tour of the state of development of therapies targeting tau protein aggregation in the aging brain; very different from past anti-amyloid therapy development at the detail level, but quite similar in many ways at the high level.

Therapeutic Targeting of Tauopathies: From Druggable Biology to Precision Intervention

Tauopathies comprise a group of neurodegenerative disorders caused by abnormal tau pathology, including Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), etc. Despite the wide spectrum of tau-related diseases, therapeutic strategies directly targeting pathological tau remain relatively underdeveloped, and no broadly effective clinical treatment has yet to be established.

Most current tau-directed therapeutic approaches have been designed around the tau pathological cascade. Microtubule-associated protein tau (MAPT) mutations and other disease-associated processes can promote abnormal post-translational modifications (PTMs) of tau, with hyperphosphorylation being the most characteristic. Aberrantly modified tau loses microtubule-binding and stabilizing functions, aggregates into neurofibrillary tangles (NFTs), and ultimately contributes to neuronal dysfunction and degeneration. Based on the pathological mechanism, existing therapeutic strategies can be broadly classified into three categories: (1) reducing overall tau levels at both the RNA and protein levels, (2) regulating tau modifications, and (3) interfering with tau aggregation.

However, these approaches have not achieved satisfactory clinical outcomes, probably due to the complexity of tau pathology. Pathological tau can also spread between neurons, thereby facilitating the propagation of neurodegeneration. In addition, tau interacts with other pathogenic proteins, such as amyloid-β (Aβ) and α-synuclein (α-syn), creating mutually reinforcing pathological cycles that accelerate disease progression. Furthermore, tau exhibits remarkable isoform diversity, beyond abnormalities in protein structure and total amount, an imbalance in tau isoform ratios can itself drive disease development.

In this review, we summarize recent advances focusing on these challenges. Emerging therapeutic strategies are not only targeting more precise molecular sites, but are also placing greater emphasis on co-pathogenic proteins and the broader pathological processes involved in tauopathies. Moreover, by deepening our understanding of tau pathological mechanisms, we propose several potential therapeutic targets that may offer new directions for future drug development and therapeutic strategies for tau-related diseases.

The research community is in the early stages of development of therapies for age-related neurodegeneration based on reprogramming the supporting glial cells of the brain to provoke transformation into neurons. A supply of new neurons can restore lost function, integrating into existing neural circuits. As noted here, however, much of this research and development has been conducted in young mice. In old mice, a combination of chronic inflammation and changes in glial cells acts to reduce the efficiency of reprogramming. Attempts to build therapies based on generating new neurons from glial cells will have to address these issues.

Reprogramming resident glia into neurons holds great therapeutic promise for neurodegenerative diseases across the central nervous system, yet these strategies have been developed largely in young animals. Because aging is the primary risk factor for neurodegeneration, whether glia-to-neuron reprogramming remains effective in aged tissue is a critical unanswered question. Here, using the retina as an accessible part of the central nervous system, we show that aging is a major barrier to glia-to-neuron reprogramming in vivo.

Across three transcription factor-based strategies, aged Müller glia exhibit consistently reduced neurogenesis. Single-cell transcriptomics reveal that aged glia fail to activate progenitor programs and instead adopt reactive and inflammatory states. Concurrently, the aged retina mounts an exacerbated neuroimmune response to injury. Immunomodulation with dexamethasone partially restores neurogenesis. Thus, aging imposes both glial-intrinsic and microenvironmental barriers to neuronal regeneration that can be partially overcome by immunomodulation.

Link: https://doi.org/10.1073/pnas.2612369123

Atherosclerosis, the growth of fatty plaques in blood vessel walls, is the largest cause of human mortality. Unstable plaques rupture to block blood vessels to cause a heart attack or stroke, while the narrowing of arteries by plaque contributes to heart failure, dementia, and other conditions. A plaque is in essence a growing macrophage graveyard. Macrophage cells of the innate immune system constantly arrive from the bloodstream, drawn to the plaque, and attempt to repair it. The macrophages are instead overwhelmed by the toxic plaque environment, become inflammatory to call in more macrophages, and die to add their mass to the plaque. The largest plaques also distort the biochemistry of the smooth muscle surrounding blood vessels, and smooth muscle cells transform into macrophages to further accelerate the process of plaque growth - almost a cancer-like mechanism of growth.

Atherosclerosis, the fundamental pathological basis of most cardiovascular diseases which remain the leading cause of global mortality, is driven by both lipid accumulation and dynamic cellular reprogramming within the vessel wall. Central to this process is the remarkable phenotypic plasticity of vascular smooth muscle cells (VSMCs). Far from being terminally differentiated, VSMCs undergo profound transitions from a contractile state to diverse states, including synthetic, macrophage-like, foam cell-like, and fibroblast-like states, which critically influence plaque formation, stability, and rupture.

This review synthesizes the multilayered molecular mechanisms governing VSMC plasticity, encompassing transcriptional networks, epigenetic reprogramming, and microenvironmental cues. Moreover, this review highlights recent breakthroughs enabled by single-cell omics and lineage tracing, that have revealed unprecedented heterogeneity and clonal expansion of VSMCs within atherosclerotic lesions. Furthermore, we explore the translational potential of targeting VSMC plasticity, and discuss emerging strategies, including phenotype-specific modulation, immunotherapy, nanomedicine, and senotherapeutics.

Finally, we outline future directions focused on dynamic regulatory networks, spatial pathophysiology, and the integration of aging biology to advance precision medicine in atherosclerosis. In summary, VSMC phenotypic plasticity is a core mechanism underlying the initiation and progression of atherosclerosis. Precise modulation of this process holds promise for overcoming current therapeutic limitations and driving a paradigm shift toward mechanism-guided personalized therapy for cardiovascular diseases.

Link: https://doi.org/10.31083/RCM50363

PD-L1 and PD-L2 are components of immune checkpoints, widely expressed in tissues throughout the body. They act by binding to the PD-1 receptor on immune cells to suppress immune activation, and are part of the panoply of biochemical interactions that provide self-tolerance to prevent the immune system from inappropriately attacking healthy cells. Autoimmunity is a breakdown of these mechanisms. Cancerous cells abuse the strategies by which normal somatic cells are shielded from immune cell attention, and thus most research into immune checkpoints has taken place in the cancer research community. Inhibition of checkpoint interactions to unleash the immune system now forms the foundation for a number of cancer therapies, albeit that most work has focused on PD-1 and PD-L1 rather than on PD-L2.

In today's open access paper, researchers show that PD-L2 is generated by senescent cells in aged tissues, allowing these cells to shield themselves from the immune system. In youth senescent cells are generated constantly, in response to stress, damage, or cells reaching the Hayflick limit on replication. Senescent cells secrete inflammatory signals that attract the immune system, and are promptly destroyed after serving this purpose. Senescence helps reduce cancer risk, and is involved in the coordination of wound healing. Clearance of senescent cells becomes inefficient with age, however, and a growing population of lingering senescent cells contributes to chronic inflammation. It seems that PD-L2 contributes to this growing burden of senescent cells in later life.

PD-L2 inhibition seems a plausible basis for senolytic therapies that allow the immune system to destroy senescent cells. It seems likely that many of the same caveats apply here as for the use of checkpoint inhibitors in cancer therapy. Broad checkpoint inhibition can cause meaningful damage to normal tissues, as immune checkpoints do serve a useful, necessary purpose in the regulation of immune activity. Checkpoint inhibition is one of the many classes of therapy that can become a great deal safer, more effective, and more useful when narrowly targeted to specific cells. There are now ways to do this for senescent cells, such as PROTACs that only activate inside senescent cells, so it will be interesting to see what emerges from this line of research.

Blocking a Protein May Reduce Buildup of Harmful Aging Cells

A team has identified a protein that may hide aging cells from the body's immune system, allowing them to build up and contribute to age-related health problems. The findings suggest that the protein, called PD-L2, could serve as a target for treatments designed to remove harmful aging cells or as a blood marker that helps researchers track them. These harmful aging cells, called senescent cells, become damaged and stop dividing but do not die. The cells remain in tissues and release substances that promote inflammation and interfere with the function of nearby cells. Their buildup has been linked to age-related health problems.

Investigators found that in laboratory mice, removing or blocking PD-L2 reduced the number of aging cells and levels of the inflammatory substances they produce. The mice were better able to process sugar and could grip objects with greater strength. Investigators also found that human aging cells produced more PD-L2 than younger cells, and levels of the protein increased in some human tissues with age. "If we can find a way to block this protein, we may be able to help the immune system get rid of these cells and potentially improve health problems linked with aging."

Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction

Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.

Damage to nuclear DNA occurs constantly, and near all of it is immediately repaired. A tiny fraction lingers, however, and over time a burden of mutational damage builds up in tissues throughout the body. It is an open question as to how large a component of degenerative aging is a direct result of this damage, under normal circumstances. High rates of mutation in individuals with disabled DNA repair mechanisms shorten life span and accelerate the onset of age-related conditions, sometimes dramatically, but that doesn't necessarily mean the DNA damage is important in aging at levels exhibited in normal individuals. The best approach to firm data is to find a way to suppress or repair mutations without affecting other mechanisms, but the life-extending interventions that are known to slow the accumulation of DNA damage also have many other beneficial effects on metabolism. As reported here, for example, calorie restriction slows the pace at which the burden of DNA damage grows over time. Calorie restriction also improves cell function and health in numerous other ways, however, producing sweeping changes in the operation of cells and systems throughout the body that are unrelated to DNA damage.

Past studies in animals have shown that a large reduction in the number of calories they consume, called caloric restriction, extends their lifespans and slows aspects of aging. But whether caloric restriction also slows the rate at which mutations occur with age had not been investigated across the genome, the complete set of genetic material present in every cell. A new study has shown that caloric restriction reduced the level of mutations across several tissues in mice that were fed 30 percent fewer calories than they would have ingested if allowed to eat freely.

The study analyzed the effect of caloric restriction on different types of genetic changes. They found that to varying degrees across tissues, it dialed down the level of substitution mutations, in which one DNA letter is swapped for another, and insertion and deletion mutations, in which one or more DNA letters are added to or missing from the genome. The study results also showed that the impact of caloric restriction varies across tissues and cell types, as well as across the genome. For example, liver cells showed a greater reduction in mutation burdens with caloric restriction than kidney or brain cells.

Surprisingly, in liver and kidney cells, the reduction in the number of mutations from caloric restriction was greatest in the least-active regions of the genome, which contain either no genes or genes not being used by a given cell. One possible explanation is that if caloric restriction reduces DNA damage across the genome, active regions of the genome would not benefit as much because those regions already repair DNA damage frequently.

Link: https://nyulangone.org/news/feeding-mice-fewer-calories-reduces-dna-mutations

Sports medicine is somewhat focused on specific functional aspects of health, and so it was probably inevitable that factions in that community found the measures of life span and even health span to be lacking. Here, for example, a researcher proposes movement span as a useful concept, the period of life in which one is capable of navigating the world easily - the inverse of physical frailty, more or less. Interestingly, life span and health span in nematode worm studies of aging and longevity are already in practice forms of movement span, as manual or automated measures of worm movement is how researchers assess that the worms remain healthy and alive.

How we conceptualize aging shapes how we measure it, how we respond to it, and ultimately how we experience it. For much of the past century, longevity served as the dominant metric of successful aging. As population health science matured, researchers and clinicians began emphasizing not merely how long people live but also how well they live, giving rise to the concept of health span, which redirected attention from mortality to morbidity. Yet even health span fails to capture something more immediate and experientially salient: the degree to which an individual can move through the world with ease, confidence, and adaptive capacity.

This opinion proposes movement span as a third, conceptually distinct dimension of aging, addressing the trajectory of functional movement capacity over the life course. Movement span is not reducible to either life span or health span, though it is deeply related to both. Its decline may precede the onset of diagnosable chronic disease or may be driven instead by patterns of reduced demand on the sensorimotor system. Understanding movement span has significant implications for how clinicians assess patients, how public health frameworks are constructed, and how individuals respond to their own aging.

Link: https://doi.org/10.1016/j.jshs.2026.101150

A great deal of advocacy for the development of therapies to slow and reverse aging has moved on from a focus on reducing suffering. That the majority of the arguments now focus on economic productivity and reduced entitlement costs reflects a broad and possibly quite correct cynicism about what motivates the politicians, wealthy political influencers, and bureaucrats who collectively control the largest flows of funding and support in our societies. Private funding for research and development focused on longevity remains very motivated by the potential reduced suffering, and indeed the potential to reduce one's own personal suffering in the years ahead. However, the longevity industry of the recent past, and for the near future, exists in a state of tension as it attempts to make the transition from a privately supported new venture to an established field supported by the full panoply of state controlled medical systems - to be as openly and comprehensively backed by governments as cancer research and development.

Most advocates these days appear to believe that the way to make this happen is to exploit the high level of anxiety in the ruling classes of much of the world that centers around the demographic transition to ever increasing numbers of older people, and the costs of old age. The governments of the world have largely chosen to exert a great deal of control over the development and provision of medicine, to the point of it becoming an expense for them, a burden much akin to the mess that was made of pension entitlements, the creation of large enough promises of future expenditure to financially ruin the systems created to manage them. Treatments for aging are a deus ex machina that will save the system, or that is the hope being pushed into government circles by advocates attempting to achieve greater support for the development of longevity therapeutics. The realpolitik always seems somewhat shabby in full daylight when it departs utterly from the considerations of what aging does to an individual, physically and mentally. The true reason to build therapies to treat aging is because this offers the strong possibility of a very sizable reduction in human suffering and death, not because it can prop up dysfunction systems of governance.

The longevity dividend: Why governments and markets must catch up

'How much' often matters less than 'how fast'. Financial systems might comfortably accommodate a decade increase in life expectancy if it emerges gradually over half a century, but could they accommodate the same increase within 5 years? Economies are built to absorb gradual change and are much less comfortable with discontinuities. Human longevity may be approaching that kind of discontinuity. The latest scientific advances point to the emergence of what we have termed 'system-level' therapeutics capable of bringing about rapid, non-linear changes in both healthspan and lifespan trajectories, challenging the incremental paradigms that underpin current economic and demographic forecasting models. If they do, governments, healthcare systems, insurers and pension funds will have to respond to a break with history, not a continuation of it.

Public debate often treats longevity as a cost curve. That is only half the ledger. In an era of demographic ageing and stagnant economic growth forecasts, one overlooked truth is emerging: longevity science may be the most powerful economic productivity lever of all time. Governments spend billions annually on education, digital transformation and industrial innovation - all in the name of boosting national productivity. Yet few acknowledge that the single largest drag on workforce participation is declining health in midlife and beyond due to ageing. In the United States, the direct costs of chronic health conditions total around $1.1 trillion - equivalent to 5.8% of US gross domestic product (GDP). When indirect costs of lost economic productivity are included, the total costs of chronic diseases in the United States increase to $3.7 trillion - in other words, they equate to almost 20% of the US GDP.

The economic argument for longevity research is clear: targeting the root causes of ageing is not just a healthcare imperative, it is set to become a non-negotiable economic strategy. Governments should treat it as such, allocating funding accordingly and incentivising translational research, clinical trials, and public-private partnerships in this field. In the 20th century, public investment in antibiotics and vaccines changed the world. In the 21st century, ageing biology has the potential to do the same.

Sarcopenia is the name given to severe age-related loss of muscle mass and strength. This loss occurs steadily throughout later life. The present state of research into this condition is representative of aging more generally, in that while a range of quite different mechanisms all have strong supporting evidence for a meaningful contribution to sarcopenia, their relative importance to one another is unclear, how they connect to one another at the detail level is unclear, which are largely causes and which are largely consequences of one another, and their relationship to the known underlying forms of cell and tissue damage that drive aging is unclear. See the evidence for loss of muscle stem cell function to be the primary cause of sarcopenia, and surrounding discussions on that topic, for example. Here, researchers point instead to disruption of lactate metabolism in both liver and muscle tissue as the primary cause of sarcopenia; the involvement of the liver a reminder that no one tissue stands alone in the matter of aging. All organs communicate with one another and are interdependent in many different ways.

Sarcopenia is a progressive disease characterized by age-related decline in skeletal muscle force and mass. The fundamental molecular pathogenesis of sarcopenia has not yet been elucidated. Here, we show that the accumulation of lactate and intracellular acidification, lactic acidosis, in skeletal muscle owing to impaired liver-skeletal muscle lactate metabolism is the fundamental cause of sarcopenia. Systemic lactate tolerance decreased in aged mice owing to the impaired lactate processing capacity in the liver, which caused lactic acidosis in skeletal muscle.

Furthermore, pharmacological activation of hypoxia-inducible factor (HIF) or liver-specific activation of HIF1α improved age-associated impairment in lactate tolerance, lactic acidosis in skeletal muscle, and sarcopenia. Mechanistically, the decreased nicotinamide adenine dinucleotide level was the cause of dysregulated skeletal muscle functions due to lactic acidosis. Using mouse models, our results show lactic acidosis in skeletal muscle as a key molecular pathogenesis of sarcopenia and highlight HIF1α in the liver as a pharmacological target for sarcopenia.

Link: https://doi.org/10.1126/sciadv.aeb4011

Normal cell metabolism, particularly the activities of mitochondria, generates oxidizing molecules that react with proteins to disrupt their function. This damage occurs constantly, and is repaired constantly. Cells remove damaged proteins, undo oxidative changes, and make use of antioxidant enzymes such as SOD1 to prevent damage from occurring in the first place. With age, oxidation increases and becomes an important component of cell dysfunction. Here, researchers note that SOD1 itself can become oxidized and harmful, and discuss the importance of antioxidants disabled by oxidization in the growth of age-related oxidative stress in cells. The specific focus is on skin aging, but the points have relevance to all tissues.

As the body's primary barrier against environmental insults, the skin is continually exposed to oxidative stress, which may contribute to progressive proteotoxic stress. Excess reactive oxygen species (ROS) can overwhelm cellular protein-quality-control systems, promoting the accumulation of damaged and misfolded proteins, proteome instability, and eventual protein homeostasis (proteostasis) collapse. Superoxide dismutase 1 (SOD1), a Cu/Zn-dependent cytosolic antioxidant enzyme and key component of cellular defense against superoxide radicals, is itself vulnerable to oxidative modification. ROS-mediated post-translational oxidation of SOD1 may promote its misfolding and the formation of toxic protein species, potentially establishing a self-amplifying cycle of superoxide accumulation, further protein damage, and impaired cellular homeostasis.

In cutaneous cell types, including dermal fibroblasts and epidermal cells, these processes may be especially relevant to age-associated declines in proteostatic capacity and skin aging. This review distinguishes established skin-specific evidence from hypotheses extrapolated from other systems and synthesizes current evidence on the interplay among ROS-induced protein damage, proteostasis failure, SOD1 dysfunction, and cutaneous aging. We highlight the bidirectional relationship between proteostasis collapse and mitochondrial dysfunction, which may establish a self-reinforcing cycle of oxidative stress, cellular senescence, and chronic low-grade inflammation. These interconnected processes may converge to promote extracellular-matrix remodeling and tissue dysfunction, contributing to wrinkles, reduced elasticity, and impaired barrier function.

Link: https://doi.org/10.1016/j.arr.2026.103351

A few species of hydra are immortal in their normal environmental conditions, meaning that function does not decline over time and mortality risk does not increase over time. Researchers spent a good deal of time taking care of hundreds of hydra some years ago to demonstrate that this is the case. Hydra are lower animals, essentially a bundle of stem cells capable of regenerating and replacing any part of their bodies, somewhat analogous to an ambulatory embryo. It is an open question as to whether anything we can learn from their biochemistry can be useful in human medicine.

In today's open access paper, researchers report on the employment of telomerase by hydra. Telomeres are repeated sequences at the end of chromosomes that shorten with each cell replication, creating a clock that leads to cell death when telomeres are too short. In most species, somatic cells are limited in this way in order to minimize the risk of cancer, while stem cells employ telomerase to maintain long telomeres while delivering a supply of new daughter somatic cells to replace losses. The body is just a temporary vehicle for an immortal population of germline stem cells, in one view. Hydra are obvious very different in terms of the balance between stem cell behavior versus somatic cell behavior in individuals.

Telomerase expression and activity in the immortal cnidarian Hydra

Most living eumetazoan animals are mortal. A fundamental mechanism underlying cellular and organismal aging in many species is the progressive shortening of telomeres - protective nucleoprotein structures at chromosome ends. The finite replicative lifespan of somatic cells is linked to telomere attrition. The discovery of telomerase, a ribonucleoprotein complex with reverse transcriptase activity that synthesizes telomeric repeats, provided a molecular explanation for the unlimited proliferative potential of germlines, stem cells, and most cancer cells. In humans, telomerase is not expressed in most somatic tissues and is active primarily in germ cells, stem cells, and certain rapidly renewing tissues such as blood or intestinal epithelium.

Comparative studies indicate that telomere dynamics correlate with lifespan, with slower shortening rates in long-lived species. Recent cross-species analyses, however, reveal a more complex picture, suggesting that the relationship between telomere maintenance strategies (telomerase activity vs. alternative lengthening) and longevity is not strictly deterministic. Nevertheless, it remains a prevailing hypothesis that biologically immortal organisms must possess robust mechanisms for telomere maintenance. Supporting this, sustained telomerase activity in somatic tissues has been documented in non-senescent invertebrate models such as planarians and long-lived bivalves.

Importantly, several taxa, including some hydras, planarians, and rotifers, have been reported to exhibit negligible or undetectable senescence. In this study, we characterized the telomerase of Hydra vulgaris. The expression pattern of the telomerase catalytic subunit (hyTERT) mRNA correlates with regions exhibiting high proliferative potential and remains unchanged during budding or regeneration. These findings were further corroborated by measurements of telomerase activity. Our data suggest that telomerase may play a role in the immortality of Hydra.

Persistent infections such as cytomegalovirus and other herpesviruses most likely accelerate aging, primarily via harmful effects on the immune system that lead to earlier immunosenescence and chronic inflammation than would otherwise be the case. A range of mechanistic and epidemiological research broadly supports this hypothesis. It remains challenging to completely clear persistent viral infections, however. If a strong antiviral therapy existed, epidemiological data would likely prove the point one way or another within five to ten years, as effects on aging would become apparent in older populations. As it stands, the present relatively weak antiviral therapies show some evidence for positive effects on late life risk of mortality and age-related disease, but not in all studies.

Asymptomatic infections are traditionally considered harmless, reflecting effective immune control and the absence of clinical disease. Yet growing evidence shows that these silent encounters with microbes are far from being immunologically neutral. Throughout life, humans are challenged by a remarkably broad spectrum of viruses and bacteria, including latent pathogens that persist, fluctuate, or periodically reactivate without producing significant symptoms. From an evolutionary standpoint, this represents a fundamental trade-off. Long-lived hosts benefit from maintaining diverse commensal, latent, and low-grade persistent microbes that enhance immune readiness, promote cross-protective immunity, and reduce vulnerability to severe infections. However, this adaptive advantage is counterbalanced by the continuous burden of chronic, almost undetectable immune activation and inflammation, and by the energetic cost of sustaining such mechanisms of surveillance.

In this regard, retroviral integrations provide a striking illustration of how persistent viral presence has shaped the evolution of complex organisms by introducing new regulatory elements, immune modulators, and developmental programs. These ancient viral imprints demonstrate that clinically-silent host-microbe interactions can exert long-term selective pressures and influence species-specific biological trajectories. At the individual level, repeated asymptomatic infections trigger transient waves of immune activation, endothelial perturbation, mitochondrial stress, and complement engagement. Although each episode is mild and self-limited, their cumulative burden generates micro-damage that accelerates immunosenescence, perturbs metabolic and vascular homeostasis, and contributes to the progressive rise in systemic inflammation characteristic of aging.

Link: https://doi.org/10.1016/j.arr.2026.103340

Cells become senescent constantly throughout life in response to various forms of damage and stress, ceasing replication and generating a potent mix of inflammatory signals. In youth, these cells are promptly cleared by the immune system, but with advancing age they begin to linger and accumulate. The inflammatory signaling becomes disruptive to tissue structure and function when sustained over the long term, and this is an important contribution to degenerative aging. Here, researchers show that macrophage cells in the kidney express increasing amounts of the P2RX7 receptor on the cell surface as they progress towards becoming senescent, and blocking this receptor with a suitable antagonist small molecule reduces macrophage senescence and improves kidney function.

Macrophage senescence is a pathological feature in aging or diseased kidneys. However, the role of senescent macrophages in kidney injury and aging has not been fully elucidated yet. We integrated the analysis of single-cell RNA sequencing datasets and the adoptively transfusion of pretreated bone marrow-derived macrophages to investigate the role of renal macrophage senescence in kidney injury. Here, we portrayed the senescence trajectory along multiple time points in infiltrating macrophages, and observed the persistent increase of macrophage-expressed purinergic receptor P2RX7 along the senescence trajectory in injured kidneys of septic mice.

Importantly, our discovered small-molecule P2RX7 antagonist strikingly improved kidney function and pathological damage, as well as mitigated macrophage senescence in septic and aging mice. Mechanistically, P2RX7 antagonist could promote the wound healing, migration, and proliferation capacity of senescent reparative macrophages, thus exerting anti-inflammatory effects and repairing kidney tissues. Together, our findings illustrate the crucial participation of senescent macrophages in septic kidney injury, and offer novel therapeutic strategy via intervening P2RX7 against immunosenescence-associated kidney injury and aging.

Link: https://doi.org/10.7150/ijbs.138299

Despite considerable and growing effort put towards the development of novel means to slow and reverse aging over the past thirty years, the longest lived laboratory mice remain those lineages first established in the 1990s with mutations that disable growth hormone metabolism, such as via knockout of growth hormone or growth hormone receptor genes. These mice are small and vulnerable to cold, but live as much as 70% longer than their unmodified peers.

It seems likely that this has little relevance to human aging, as Laron syndrome is the analogous human inherited condition, usually caused by a growth hormone receptor loss of function mutation. Laron syndrome patients may have a lower incidence of some age-related conditions, but do not appear to live meaningfully longer than the rest of the human population. One of the most important lessons of the past thirty years of study of calorie restriction and growth hormone metabolism in the context of aging is that these interventions produce much larger effects in short-lived species than in long-lived species.

Nonetheless, disruption of growth hormone metabolism remains an active area of study. You might recall a paper published five years ago or so in which researchers showed that disruption of growth hormone metabolism starting in adult life, at six months of age in mice, still produced a slowing of aging. Here, the same team repeats the same effort starting at twelve months of age, mid-life for mice. The size of effect on life span is much the same in male mice when starting at this later age, but worse in female mice. In either case, the extension of life span is modest in comparison to life-long disruption of growth hormone metabolism, less than 10%. Like the existence of Laron syndrome, this argues against putting meaningful effort into attempts to build human therapies based on this mechanism.

Midlife Growth Hormone Receptor Ablation Extends Healthy Lifespan and Induces Sex-Specific Hepatic Transcriptional Changes at Single-Cell Resolution

Suppression of growth hormone (GH) signaling is known to be effective to extend lifespan in mammals, yet most models rely on congenital disruption of the GH/insulin-like growth factor-1 (IGF-1) axis. Whether modulation of this pathway later in life can still influence aging and the underlying cellular mechanisms remains incompletely understood. To address this, we ablated the growth hormone receptor (Ghr) at 12-months of age in mice (12mGHRKO), using a tamoxifen-inducible model.

This midlife Ghr disruption produced the expected endocrine signature of GH resistance, including reduced circulating IGF-1 and elevated GH levels. Importantly, lifespan was significantly extended in both sexes without major effects on somatic growth. Despite increased adiposity, male 12mGHRKO mice exhibited improved insulin sensitivity and protection against age-related deterioration of neuromuscular performance and bone microarchitecture. Single-nucleus RNA sequencing (snRNA-seq) of liver tissue identified a reduction of B-cells in both sexes and a dimorphic transcriptional remodeling, including a shift toward feminized gene expression in male hepatocytes, marked by reduced male-biased gene expression and increased female-biased transcriptional programs, consistent with impaired pulsatile GH-STAT5 signaling.

Together, these findings demonstrate that suppression of GH signaling initiated in middle age is sufficient to reshape hepatic transcriptional programs and promote healthy longevity, supporting the GH/IGF-1 axis as a promising target for gerotherapeutic interventions.

Researchers here run a much larger than usual mouse study to show a ~10% slowing of aging, depending on how one slices the data, in mice genetically engineered to exhibit a growth hormone mutation that changes the interaction of circulating growth hormone with the growth hormone receptor on cell surfaces. Growth hormone is switched from a receptor agonist (binds with and activates the receptor) to a receptor antagonist (binds with the receptor without activating it, blocking other molecules from activating it). This extension of life is entirely expected given all of the long-lived mouse lineages in which growth hormone metabolism is in some way sabotaged. This specific form of sabotage had not been tested rigorously, however. While interesting, it is worth noting that humans with Laron syndrome, an inherited dysfunction of growth hormone metabolism analogous to many of the mouse models exhibiting longevity, do not appear to live meaningfully longer than the rest of the human population.

Interventions that disrupt growth hormone (GH) action are recognized as some of the most potent methods for extending lifespan. Accordingly, GH receptor antagonists (GHA) represent potential therapeutics to improve healthspan. Somavert (Pegvisomant for injection), used for treating patients with acromegaly, is currently the only FDA approved GHA. This drug was based on our laboratory's early 1990s discovery that mutating a codon for a conserved glycine - at position 119 in bovine GH or 120 in human GH - to a variety of amino acids, including lysine, ultimately converted GH from an agonist to antagonist. Since Pegvisomant has poor affinity to rodent GHR, it has not been tested for its ability to extend lifespan in rodents.

To address this gap, we evaluated survival in GHA transgenic mice, a mouse line that played a crucial role in the discovery and development of Pegvisomant and has been maintained in our lab since 1991. While a prior study with several limitations failed to detect lifespan extension in GHA mice, our current study addressing these limitations shows that both median and maximal lifespan were significantly increased in male and female GHA mice, with maximal lifespan extended by 186 and 265 days, respectively. Analysis of an independent cohort of 2-year-old mice revealed that GHA males and females were less frail with enhanced grip strength despite increased adiposity. These findings demonstrate for the first time that GH antagonism can improve health and extend lifespan.

Link: https://doi.org/10.1111/acel.70697

Researchers have been working towards practical approaches to inhibiting RUNX2 activity as a way to slow age-related loss of bone mineral density. Bone extracellular matrix is constantly remodeled throughout life, created by osteoblast cells and destroyed by osteoclast cells. In youth these activities are balanced, but with advancing age osteoclast activity comes to dominate. Many drugs have been deployed in attempts to improve osteoblast activity or suppress osteoclast activity, but researchers continue to try to create incrementally better approaches. RUNX2 inhibition acts by increasing osteoblast activity. Here, a novel RUNX2 inhibitor emerging from the cancer research community is demonstrated to slow loss of bone mineral density in mice.

Osteoporosis is a metabolic bone disorder characterised by low bone mass, structural deterioration, and increased fracture risk. Current therapies are limited. Antiresorptives such as bisphosphonates and denosumab reduce fracture risk but long-term use carries risks of atypical femoral fractures and osteonecrosis of the jaw. Anabolic agents, including parathyroid hormone (PTH) derivatives and analogues, namely teriparatide and abaloparatide, are effective but require daily injection. Romosozumab offers monthly dosing but has cardiovascular safety concerns. Hormone replacement therapy also reduces fracture risk but its association with breast, ovarian, and uterine cancer risk limits patient uptake. Thus, new treatments with few side effects and broader applicability remain a clinical priority.

We recently evaluated the small molecule RUNX2 antagonist CADD522 in several preclinical cancer models. RUNX2 is critical for in utero skeletogenesis and cancer metastasis. Unexpectedly, CADD522 reduced cancer-induced bone disease, suggesting potential utility in osteoporosis. Here, we investigated whether RUNX2 inhibition could protect against post-menopausal bone loss. In an ovariectomy-induced mouse model, CADD522 (25 mg/kg, three times weekly for eight weeks) enhanced bone formation, preserved trabecular microarchitecture and reduced marrow and peripheral adiposity. Cross-species pharmacokinetic and toxicological studies demonstrated oral bioavailability, favourable short-term tolerability, and target engagement despite rapid systemic clearance, while cellular thermal shift assays confirmed direct engagement of RUNX2.

Together, these findings identify RUNX2 inhibition as a therapeutic strategy that simultaneously improves skeletal integrity and metabolic homeostasis, supporting further development of CADD522 for osteoporosis and other RUNX2-driven diseases.

Link: https://doi.org/10.1038/s44386-026-00076-z

The immune systems of the body and brain are distinct and separate, or at least largely separate, influencing one another via signaling. The blood-brain barrier keeps the vast majority of immune cells in the body out of the brain, and vice versa. A few channels have been discovered in recent years whereby a small number of adaptive immune cells, such as T cells, enter the brain in the normal course of events. Additionally, the blood-brain barrier becomes dysfunctional and leaky with age, allowing a wide range of unwanted cells into the brain, T cells included.

Increasing inflammatory activity in the innate immune cells of the brain known as microglia is a growing focus of research interest in the context of aging and neurodegenerative conditions. While some of of this maladaptive behavior arises from reactions to local conditions and internal age-related damage, some is driven by interactions with the body's immune system. Along the way, attention has also turned to the entry of T cells into the brain, and their potential role in provoking inflammatory neurodegeneration. In today's open access paper, for example, researchers demonstrate that dendritic cells encourage T cells to enter the brain to cause problems. Removing the dendritic cells in mice reduces the impact of T cells on the aging of the brain and progression of neurodegeneration.

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration

Tauopathies are a group of neurodegenerative diseases, including Alzheimer's disease and certain forms of frontotemporal dementia, defined by the intracellular aggregation of hyperphosphorylated tau protein, which tightly correlates with neuronal dysfunction and death. Tauopathy is accompanied by increased reactive microglia and astrocytes and increased T cells in the brain, particularly CD8+ cytotoxic T lymphocytes. We previously found that depleting T cells significantly ameliorated tau-mediated neurodegeneration in p.Pro301Ser (P301S) tau transgenic mice expressing human APOE4 (TE4), supporting an active role for T cells in driving tau-mediated neurodegeneration.

Clonally expanded CD8+ T cells constituted a majority of the infiltrating CD3+ T cells (~60-70%) in TE4 brain. Conventional type 1 dendritic cell (cDC1s) are specialized antigen-presenting cells (APCs) that perform antigen cross-presentation, a process that involves presenting exogenously derived antigens on major histocompatibility complex class I (MHC-I) molecules to prime CD8+ T cells. During T cell priming, naive CD8+ T cells receive antigenic, co-stimulatory and cytokine signals from APCs, driving their differentiation into effector cells that subsequently migrate to peripheral tissues to execute their immune functions.

Here, we investigated the role of cDC1s in tau-mediated neurodegeneration by genetically ablating cDC1s or disrupting their antigen cross-presentation capacity in TE4 mice. Both interventions markedly protected against neurodegeneration and selectively reduced CD8+ T cell accumulation in the brain. Importantly, we found that cDC1-dependent antigen cross-presentation of a brain-derived antigen occurs outside central nervous system tissues, highlighting peripheral antigen presentation as a potential therapeutic target for tauopathies, including Alzheimer's disease.

Atherosclerosis is the largest cause of human mortality, producing stroke and heart attack when fatty plaques obstructing arteries rupture. There is accordingly a great deal of research aimed at influencing the course of the condition. Reversal of plaque growth to clear arteries and remove potentially unstable plaques remains a challenge, and few approaches have been shown to achieve this goal with any reliability even in animal studies. Conversely, many different approaches have been shown to slow the development of atherosclerosis in high fat diet mouse models of the condition. The example here is a demonstration of the degree to which maladaptive fat tissue metabolism contributes to the environment of inflammation and cell stress that accelerates the growth of atherosclerotic plaque. Unfortunately, like so many other approaches, reducing inflammation (via many different means) has not been shown to significantly regress established plaque in and of itself.

Adipocyte dysfunction is closely associated with oxidative stress and chronic inflammation, which contribute to systemic metabolic disturbances and atherosclerosis. We previously identified the NKA (Na/K-ATPase) α1 subunit as a signal transducer that activates Src-family kinases and promotes oxidative stress and inflammation in various cell types, including adipocytes and macrophages. NaKtide, a peptide inhibitor of NKA signaling, has been shown to reduce systemic oxidative stress and inflammation in vivo. In this study, we investigated the role of adipocyte-specific NKA signaling in atherosclerosis.

Adipocyte-specific NaKtide was delivered to Apoe-/- mice using a lentiviral vector under the adiponectin promoter. The mice were then fed a Western diet for 12 weeks to induce atherosclerosis and then assessed for atherosclerotic plaque burden in the aortic arch and at the level of the aortic sinus. Inflammatory and oxidative stress markers were analyzed in adipose tissue and plasma. Adipocyte-specific NaKtide reduced atherosclerotic plaque area by 67% in the aortic arch and by 48% in the aortic sinus. CD68+ macrophage content and α-SMA+ smooth muscle cell content in the aortic sinus were decreased by 45% and 53%, respectively. These vascular improvements were accompanied by dampened adipose tissue inflammation and oxidative stress, improved glucose tolerance, and reduced systemic inflammation.

These findings highlight a critical contributing role for adipocyte NKA signaling in atherosclerosis, suggesting an important endocrine and paracrine influence of adipose tissue on large artery atherogenesis and supporting the therapeutic potential of targeting NKA in cardiometabolic disease.

Link: https://doi.org/10.1161/ATVBAHA.126.325070

Aging is a complex stochastic process of damage accumulation, shaped at the detail level by choices made, environments encountered, and the responses and interactions of countless cells. As the paper here notes, this gives rise to a sizable variance between individuals, even those with the same genetics or similar lifestyles. The research and medical community largely react to this variance with a drive towards developing personalized medicine, but the underlying mechanisms of aging are the same from individual to individual, even if outcomes vary. A therapy that addresses one underlying mechanism in one tissue will tend to produce differing levels of benefit from person to person, but in principle it should always produce benefit. Undergoing some degree of repair should always result in better outcomes than not undergoing repair.

Most human omic studies remain cross-sectional, despite growing evidence that transcriptomic and metabolomic states are temporally dynamic. Cross-sectional designs are limited in their capacity to separate stable interindividual differences from within-participant change and may obscure the degree to which molecular aging varies between individuals. Longitudinal multiomic studies address this gap but are challenging to implement. To address these challenges, we established the MultiMuTHER study within the deeply phenotyped TwinsUK cohort. MultiMuTHER includes repeated whole-blood RNA sequencing and serum metabolomic profiling at three or more time points over up to 8 years in 335 females. We used this resource to ask four questions: which genes and metabolites change over time; how much individual trajectories diverge from population-level trends; to what extent multiomic trajectories are shaped by intrinsic factors including host genetics and cell type composition as well as extrinsic elements such as circadian timing, seasonality, and environmental exposures; and whether transcriptomic and metabolomic changes are coordinated across omic layers.

We identified 5,061 genes and 181 metabolites whose levels changed over time, with participants displaying distinct longitudinal trajectories, sometimes opposite to population-level trends. Longitudinal changes in gene expression exhibited marked cell type specificity, with different patterns in the adaptive versus innate immune compartments. Longitudinally variable genes were enriched for functional categories relevant to aging, including cardiometabolic and neurodegenerative disorders. Gene expression and metabolite levels showed strong context-specificity, with 25% of genes and 24% of metabolites associated with seasonality, and 26 and 39%, respectively, associated with circadian variation.

Our findings show molecular aging to be a dynamic, context-dependent, and highly individualized process. Longitudinal multiomic profiling revealed molecular changes shared across the population and trajectories that diverged between individuals, while highlighting the influence of cell type composition, host genetics, biological rhythms, environmental exposures, and cross-omic connectivity. This study, along with the MultiMuTHER resource, provides a framework for understanding biological aging as a set of interacting molecular trajectories, with utility for future precision medicine efforts.

Link: https://doi.org/10.1126/science.aed6452

Every field of specialist knowledge consists of a series of concentric circles, the greatest knowledge at the center, the scientists advancing the state of the art, and the least knowledge at the outskirts, the public at large. In between we find lesser scientists, patient advocates, laypeople with a strong interest in the field, and so forth - various gradations of knowledge. The members of any given ring engage in an educational dialog with the next ring out, and themselves learn from the education efforts of the more knowledgeable neighboring inner ring. The more distant any two rings are, the less they tend to engage with one another directly.

Thus we end up with the edifice of public messaging, simplifications of scientific knowledge intended for people who will never spend much time delving into a field, and largely constructed by those who are not the most knowledgeable specialists in the field. Some of these simplifications are better than others, depending on the incentives of those creating them. It seems a necessary evil, given the way the world works. We all have the freedom to pursue a greater understanding in the aspects of life and technology that we consider important, but far from enough time to become a polymath. Some shortcuts are necessary in the service of doing some good in the world.

An aging essential 8: closing the gap between geroscience and the public it serves

Longevity medicine has reached an uncomfortable milestone: more clinically credible than at any prior point, and simultaneously more publicly confused. Senolytics, partial epigenetic reprogramming, and GLP-1 metabolic agents have entered human trials within a single decade. Alongside that progress, biological age tests, longevity clinics, and consumer wearables have scaled well ahead of any shared standard governing what they measure or what a person should do with the result. The field has begun to describe this as an implementation gap, in which biological age products and clinics operate ahead of validated standards and regulatory frameworks. The remedies under active discussion are directed at research and clinical infrastructure: standardizing what longevity clinics measure, how they are structured, and which biomarkers and outcomes should count. Few of them address the layer that ordinary people actually encounter, which is a number on an application, a panel of biomarkers, or a clinic promising rejuvenation, with no common framework against which any of it can be read.

The commercial layer is already substantial. Direct to consumer epigenetic age tests are now sold online, longevity clinics offering biological age panels have opened in many cities, and consumer wearables report readiness, recovery, and pace of aging scores derived from proprietary and largely undisclosed algorithms. None of these products share a common scale, none is obliged to demonstrate that its output responds to intervention, and a person who buys two of them may receive two different biological ages with no means of reconciling them. This is the environment into which any public facing instrument would arrive, and it is why such an instrument is worth building and not merely describing.

Cardiovascular medicine encountered a comparable problem and resolved it not with a new therapeutic but with a communication instrument: Life's Essential 8, which distilled a contested risk landscape into eight components scored from 0 to 100, and which has since been shown to track biological aging itself. This perspective argues that geroscience has assembled much of the material for an equivalent instrument, even while the field continues to disagree about foundational questions. Expert panels have converged on which biomarkers are worth tracking as outcomes in aging intervention trials, and have concluded that no single biomarker suffices, which leaves a composite as the only viable path. What has not happened is the translation of that research-level agreement into a public-facing instrument.

Aging clocks built using machine learning techniques applied to biological data are colloquially said to measure biological age, or at least aspire to measure biological age. Biological age is nebulous and debated at the detail level, but a rigorous definition is the increase over time in risk of mortality from intrinsic causes. A greater mortality risk implies a greater biological age, regardless of chronological age. Regarding clocks, it would be more accurate to say that they may measure some reflection of biological age, or factors that correlate with biological age, and it is actually far from clear that any given clock does this in a useful way. The lengthy review and discussion noted here is a good one, and digs into many of the subtle issues in how aging clocks are presently presented.

Biological age (BA) has been proposed as a complementary construct to chronological age (CA) for quantifying interindividual heterogeneity in aging trajectories. Biological aging clocks (BACs) integrate molecular, clinical and multi-omics biomarkers to estimate aging-related phenotypes beyond CA. This narrative review critically examines the biological foundations, statistical methodologies, interpretative challenges and translational applications of BACs. We discuss the mechanistic basis of BACs development within the frameworks of the hallmarks and domains of aging, emphasizing the roles of age-related methylome remodeling, immunosenescence, and chronic low-grade inflammation.

BACs are classified into three major generations according to their training objectives: first-generation clocks optimized to predict CA, second-generation clocks designed to estimate morbidity and mortality risk, and third-generation clocks developed to quantify the pace of aging from longitudinal biomarker changes. We also review multi-omics and artificial intelligence-based approaches that aim to capture the multidimensional nature of aging. Important limitations remain regarding biological specificity, causal interpretation, reverse causation, confounding, generalizability and clinical applicability of BACs. Current evidence suggests that BACs represent distinct operationalizations of biological aging instead of interchangeable measures of a single construct. Future advances will require longitudinal, mechanistic, and diverse population-based studies to improve interpretability, reproducibility, and translational utility.

Link: https://doi.org/10.1016/j.ric.2026.100053

The accumulation of senescent cells is an important contribution to degenerative aging; the inflammatory secretions of senescent cells actively degrade tissue structure and function. Animal studies have shown that selective destruction of senescent cells produces a meaningful degree of rejuvenation in old animals, alongside reversal of the pathology and progression of many age-related conditions. Senescent cells exhibit a sizable number of metabolic differences from normal cells, and researchers continue to explore these differences in search of novel ways to selectively destroy senescent cells. Here find an example of a novel finding, in which researchers explore the increased glycolysis that supports senescent cell energy metabolism and find a way to sabotage it.

Aging is a complex biological process, which is affected by several factors, lifestyle, diet, genetic or epigenetic factors, environmental stress, and metabolisms. Among others, several reports observed increased glycolysis in senescent cells (SnCs) and individual aging, whose causal effects or biological mechanisms have been unclear. Recently, we identified phosphoglycerate mutase 1 (PGAM1)-checkpoint kinase 1 (Chk1) binding as a booster for glycolytic metabolism and cell viability in SnCs.

Secretory phenotype of inflammatory factors, known as senescence associated secretory phenotype (SASP), is one of prominent properties in SnCs, which accelerates chronic inflammation and aging-relevant dysfunctions in tissues. Inhibition of PGAM1-Chk1 binding removes SnCs and suppresses SASP, alleviating organ damage and pulmonary fibrosis in vivo. Thus, PGAM1-Chk1 interaction represents a target for senolysis to preserve resilience in aging.

Link: https://doi.org/10.70401/Geromedicine.2026.0034

Without careful study design, studies in which the use of GLP-1 receptor agonists such as semaglutide lowered calorie intake significantly via suppression of appetite might be expected to teach us little that we did not already know. Reducing calorie intake without compromising minimum necessary levels of essential nutrients slows aging and extends life, whether achieved via limiting food availability or by limiting appetite. Researchers know this, and they know a great deal about the fine details of the metabolic response to reduced nutrient availability. The effects of reduced calorie intake readily overpowers the effects of other mechanisms that may or may not be operating as a result of GLP-1 receptor agonism, particularly in short-lived species. One has to look more carefully to see any more interesting outcomes that lie outside the normal effects of calorie restriction.

Reported in today's open access paper, researchers conducted a study in mice in which (a) GLP-1 receptor agonism reduced calorie intake by a quarter when started in late life, and (b) the mice lived ~15% longer. That falls in line with the results of many calorie restriction studies conducted in aged mice over the past twenty years. Indeed, the researchers conducted their own calorie restriction study with a reduced calorie intake matched to the results of their GLP-1 receptor agonist study, and found the outcomes in health to be very similar. There are a few differences, however. Why do those differences exist? GLP-1 receptor agonism affects some aspects of metabolism that calorie restriction does not, and vice versa. Most notably, calorie restricted mice are hungry for much of the time, while mice treated with GLP-1 receptor agonists are not. The signaling associated with the hunger response has its own effects on metabolism distinct from those resulting directly from sensing of nutrient levels in cells.

Late-life semaglutide treatment slows ageing and extends lifespan in female mice

Preclinical studies in disease mouse models and clinical studies have revealed pleiotropic beneficial effects of GLP-1R activation, including improved glucose and weight control, and reduced cardiovascular, renal, hepatic, and neurodegenerative disease burden. We found that GLP-1R activation late in life improved physiological function and extended lifespan in an ageing mouse model (20-month-old female C57BL/6) treated with a defined semaglutide regimen that reduced food intake by 24%. Female mice were selected to minimize confounding effects of male aggression and injury, consistent with previous long-term ageing studies. Within the end points monitored in the study, we did not observe adverse effects attributable to semaglutide. While GLP-1 medicines are widely used clinically, whether GLP-1R activation modulates ageing trajectories and lifespan in humans will require long-term clinical studies designed to evaluate ageing-related outcomes in older populations.

Our findings establish that GLP-1R activation late in life alleviates broadly ageing-associated decline and phenocopies the molecular and physiological benefits of calorie restriction. In aged female C57BL/6 mice, semaglutide treatment extended lifespan, improved physiological function, reduced hallmarks of ageing (such as stem cell attrition, inflammation, cellular senescence, genomic instability, mitochondrial dysfunction, and loss of proteostasis) and modulated the genetic regulators of ageing and nutrient sensors in the same manner as calorie restriction. The restoration of neural stem cells and neurogenesis in aged mice was particularly marked, considering the emerging evidence that GLP-1 medicines have beneficial effects on neurodegeneration.

Direct comparison of semaglutide treatment with matched calorie restriction further showed comparable effects across several aspects of ageing-associated physiological decline, consistent with the idea that GLP-1 medicines can act as calorie restriction mimetics. As ageing is the biggest risk factor for numerous chronic diseases and calorie restriction slows ageing and ameliorates a broad spectrum of ageing-associated diseases, our findings raise the possibility that GLP-1 medicines may influence a wide array of seemingly unrelated diseases by slowing ageing.

Past research has noted that socioeconomic status is a part of a web of correlations that include wealth, intelligence, education, lifestyle choices, and longevity. Untangling all of that to make definitive pronouncements on what exactly drives the observed variation in human life span has proven challenging. It is a reasonable assumption, based on animal studies, that lifestyle choices and consequent degree of physical fitness are the primary factor determining late life survival, however. Here, researchers take a more subtle approach to data analysis and conclude that socioeconomic and demographic status has very little influence on individual longevity. This is much as we might expect if lifestyle choice related to fitness is the primary influence, as will continue to be the case until the first therapies targeting mechanisms of aging become used far more widely.

Against the backdrop of descriptive, causal, and theoretical work on mortality, the explosion of rich microdata has enabled a new predictive perspective. In this study, we apply this perspective to ask: Can observable sociodemographic characteristics - such as education, income, race, and marital status - predict individual-level lifespan? This question tests the limits of social determinism. If lifespan is highly predictable, it would suggest that one's lifespan is tightly structured by systemic forces ("demography is destiny"). Low predictability would imply that, despite large and well-documented between-group mortality disparities, most lifespan variation remains unexplained by major social or economic factors. This distinction matters for how we think about lifespan inequality: Is mortality governed more by structural inequalities or by stochastic individual variation?

Using U.S. Census data linked to administrative death records, we assess how well early-adulthood social, economic, and demographic characteristics predict individual lifespan in a cohort of men born in 1910 and observed through their deaths between 1975 and 2005 (N = 121,000). Despite large group-level disparities, we find that sociodemographic characteristics measured in early adulthood explain less than two percent of the overall variation in individual lifespan. These findings reaffirm a central demographic regularity: variance in life expectancy between groups is small compared to variation in lifespan within groups. This highlights the fundamentally nondeterministic nature of how structural inequality shapes individual mortality.

Link: https://doi.org/10.1111/padr.70065

Screening compound libraries for effects on aging in short-lived species has grown to become a significant area of interest in the aging research community. As a general rule, discoveries are modest in effect size, and largely take the form of novel ways to influence the beneficial maintenance and repair activities (such as autophagy) triggered by calorie restriction, heat, cold, and other forms of stress. These responses have a much larger effect on life span in short-lived species than in long-lived species, so in the long run are not all that interesting. Nonetheless, considerable effort has been made to find ways to make this screening process more efficient and automated. Research equipment has been constructed to house tens of thousands of nematode worms and use machine learning analysis of imagery to report on measures of health. Many of the techniques involved have been attempted in mouse studies to at least some degree. Here find an example of the state of the art in this type of work.

We describe the development and implementation of an integrated, high-throughput platform to evaluate the effects of small molecules on longevity across yeast, nematodes, flies, killifish, and mice. By utilizing miniaturized, automated assays with longitudinal imaging and machine learning-based death detection, we screened over 400 compounds and evaluated thousands of drug-dose conditions. This effort represents a first-of-its-kind screening campaign of this magnitude, testing conditions at a scale comparable to the entire existing literature for several of these models.

In S. cerevisiae, a miniaturized PI/flow cytometry chronological lifespan assay enables scalable screening and identifies key assay confounders, while in C. elegans and D. melanogaster, compact imaging platforms coupled to object detection models provide a no-transfer, high-throughput survival scoring, and capture compound-, diet-, and sex-dependent effects. In killifish, we develop an in-house drug-pellet formulation for standardized oral delivery in large cohorts, and in mice we combine longitudinal lifespan studies with home-cage activity monitoring to assess late-life interventions.

Across five evolutionarily distant models, we observed that consistent lifespan extension across species was achieved for only a subset of compounds, reflecting the challenge of identifying truly conserved geroprotectors. This result supports prior observations that most reported interventions in aging literature are model-specific or context-dependent. Nevertheless, a substantial number of compounds, including baicalein, doxycycline, forskolin, metformin, resveratrol, and rifampicin, displayed significant positive effects in multiple species, suggesting a tractable space of conserved pharmacological regulators of longevity.

Link: https://doi.org/10.1016/j.celrep.2026.117897

At the high level, without delving into specific mechanisms, the consensus view on aging is that it exists in the shadow of natural selection. The selection pressure that drives the spread of changes in genes, systems, biology in general in any given species operates most strongly on early life reproductive success. This inevitably gives rise to systems that perform well initially, but which fall apart later. Expenditure of resources on long-term maintenance loses out to expenditure of resources on short-term reproductive fitness. Aging is a near universal side-effect of evolutionary competition, a race to the bottom that exists because early life reproductive success wins out over repeated reproductive success for a longer period of time.

That a given aspect of an individual's biochemistry can be beneficial in early life and harmful in later life is known as antagonistic pleiotropy. There are many examples at all scales, ranging from the structure and behavior of the adaptive immune system and its limited capacity for memory, to the well-known trade-off between developmental growth and later risk of age-related disease, to activities of specific proteins such VGLL3. There is a great deal of literature on this topic. Today's open access paper thus treads familiar ground in discussing aging as a side-effect of evolutionary pressures, attempting a modestly different framing of the situation.

Living Beyond Our Evolutionary Warranty: Why Non-Communicable Diseases May Be The Inevitable Costs of an Extended Lifespan

Despite decades of research, age-related non-communicable diseases (NCDs) remain prevalent even in populations with healthcare access. The conventional explanation invokes "evolutionary mismatch": modern lifestyles clash with ancestral biology. Yet a paradox persists: even individuals maintaining optimal health behaviours eventually develop NCDs. Hunter-gatherers living in ancestral conditions show moderate signs of atherosclerosis, metabolic dysfunction, and immune senescence past age 60-70. This raises the question, "Why are NCDs so difficult to prevent?"

We hereby propose an alternative framework where many NCDs represent not preventable consequences of modern lifestyle, but rather inevitable costs of adaptive mechanisms that were never "designed" to operate over 70 to 90-year lifespans. This "Adaptive Cost Hypothesis" (ACH) reframes NCDs as manifestations of evolutionary trade-offs largely, though not absolutely, between early-life fitness advantages and late-life pathology-trade-offs subject to sharply attenuated selection because they occur long after reproductive success. Late-life pathology is intrinsic to epigenetically programmed adaptive responses, manifesting even under matched environmental conditions. This is not mismatch. It is the inevitable cost of adaptive mechanisms operating beyond their evolved design duration.

One of the goals of the Dog Aging Project is to better establish that the characteristics of aging in dogs are close enough to the characteristics of aging in humans to make the results of interventions on dog life span relevant to the development of human medicine. Thus the paper here, in which researchers establish that comorbidity, the presence of multiple age-related conditions in the same individual, has much the same relationship with aging and mortality in dogs as it does in people. To have an age-related disease is to have a significant degree of dysfunction in some organ or tissue. The greater the burden of underlying cell and tissue damage resulting from aging, the more likely it is that multiple age-related conditions will emerge. Further, significant dysfunction in any one organ or tissue will tend to generate issues in other organs or tissues; everything connections everything else in our biology.

Multimorbidity, the presence of two or more conditions, is associated with a higher risk of death as individuals age. However, modeling multimorbidity in laboratory animals is difficult, if not impossible, because specific conditions are seldom individually diagnosed and treated in these settings. Because of their shared environment, physiology, and genetic diversity, and because they are medically managed as individuals, companion dogs have potential to serve as a translational multimorbidity model. Yet it is unknown how diagnoses accumulate over time, how these diagnoses are associated with mortality, and which multimorbid condition combinations are the most prevalent and hazardous.

Utilizing owner-reported data from over 50,000 dogs in the Dog Aging Project (DAP), we assessed how multimorbidities develop, learned which are the most prevalent, and evaluated their impact on survival. Like in humans, we show that the accumulation of conditions is associated with an increased risk of death in dogs. We also present data suggesting that future reported condition rates vary depending on the conditions a dog's owner already has reported. Not surprisingly, our analysis reveals that the overall canine aging process appears to be the driving factor behind disease development, more so than other covariates. Through classifying multimorbidities, we found that almost all either exhibit a synergistic effect or are driven by a single, predominant condition. In both cases, osteoarthritis, overweight, and cancer were highly prevalent throughout.

This analysis expands on previously conducted DAP work and further highlights the usefulness of the companion dog as a translational model for human aging.

Link: https://doi.org/10.1007/s11357-026-02342-4

In recent years, researchers have been gathering as much data as possible on the behavior of aging clocks of various sorts. The study here is an example of the type, in which multiple proteomic clocks were assessed in large epidemiological study populations. As one might expect, where there is age acceleration, meaning a higher clock age than chronological age, this correlates with a greater risk of age-related disease and mortality. Though as noted, clocks don't improve all that much on lifestyle indicators when it comes to the quality of the correlation. This sort of study helps to build a foundation of data as a reference for further exploration of clock behavior in response to interventions thought to affect the pace or state of degenerative aging.

Assessment of biological aging using proteomic clocks may enhance risk prediction and elucidate the molecular links between aging and chronic diseases. Here, among 17,473 participants of the European Prospective Investigation into Cancer and Nutrition, we examined associations of plasma SomaScan-based proteomic clocks, including organ-specific clocks, with risk factors, 24 incident chronic diseases and all-cause mortality, over up to 28 years of follow-up. Replication was conducted in the Whitehall II study.

We show that the global age gap, an age acceleration score combining proteomic clocks, was associated with smoking, alcohol consumption, physical inactivity and higher risk of mortality, cardiovascular diseases, dementia and cancers of the liver, upper aero-digestive tract, lung and kidney. Lung, kidney and stomach cancers were more strongly associated with related organ-specific age gaps. Predictive performance of proteomic clocks for mortality was comparable to that of classical lifestyle risk factors. In summary, proteomic clocks appear promising biomarkers of generalized age-related disease risk.

Link: https://doi.org/10.1038/s43587-026-01163-6

There are a good many affordable interventions that may well produce enough of an effect on aging to justify widespread use. At the more compelling end of the spectrum, based on a relatively large effect size in animal data and very limited supporting human data, we might consider the senolytic combination of dasatinib and quercetin, stem cell and exosome therapies, and fecal microbiota transplantation from a young donor to an old recipient. Somewhere in the middle lies rapamycin and some bisphosphonate therapies for osteoporosis. At the less compelling end of the list, based on an expectation of smaller positive outcomes and very mixed data for any effect on aging, we find widely used interventions such as hyperbaric oxygen therapy.

But we don't know with reasonable certainty for any of these interventions that it is in fact useful in the matter of aging, as that reasonable certainty requires at least a few fairly large clinical trials, summing to a patient population of high hundreds to low thousands at minimum. Interventions that only slow aging would also require those trials to last a long time, at least five years, in order to generate a meaning signal from incidence of age-related death and disease.

The challenge faced by all affordable interventions, capable of being readily implemented by most clinics, is that no-one has much of a motivation to fund a clinical program that would provide confidence in their ability to slow or reverse aging in specific ways. Regulators in the wealthier parts of the world, in collaboration with large pharmaceutical companies, have made the process of running a responsible clinical trial so very expensive that only a small fraction of the space of all possible therapies can possibly make enough of a profit to justify the investment. Anything that is hard to patent, and thereby obtain some degree of monopoly on the market, is not interesting to investors. Outside of the pharmaceutical and biotech industries, there is only limited funding for clinical trials from other sources, such as academia.

So we have the situation in which therapies potentially applicable to aging can exist in the market for decades without any sufficiently rigorous attempt being made to determine (a) whether they can treat aging, and (b) how good they are at treating aging. What can be done about this?

A variety of initiatives have been underway for some time, to some degree. Some groups want to reduce the cost of medical regulation. Thirty years of very aggressive lobbying, patient advocacy, and activism on this front have yielded just about nothing. Less than nothing, really, as the cost of putting a drug through the FDA regulatory system has more than doubled in recent decades, and the pace at which new drugs are approved keeps falling. It remains to be seen as to whether the present green shoots in the US regulatory system, such as Right to Try laws, will make any difference, but so far rhetoric from inside the system about accelerated approvals and reducing costs remains rhetoric.

A subset of those interested in reducing the cost of regulation are specifically engaged with the question of how to make clinical trials cost less. This is a complicated topic, and little progress has been made for many of the same reasons that regulation is expensive in the first place. Those in charge have little short term incentive to reduce the costs of the system; bureaucrats use it to diffuse blame for failures, while large pharmaceutical companies use the high cost of development as a moat to defend against upstart competitors. Everyone involves recognizes the flaws in the system, and no-one does anything about it because it is not in their immediate interest to do so.

Some groups devote themselves to making therapies available outside the major regulatory systems, via medical tourism. This has been relatively successful in the provision of therapies, albeit to a comparatively small number of people relative to those that could be reached if treatments were available in heavily regulated regions, but it has absolutely failed to generate an environment in which hard, reliable data on the efficacy of such therapies results. The medical tourism field is a black box; one roughly knows what therapies are available, but that is about it. Everything else is hidden, unavailable. First generation stem cell therapies have been widely used for more than 20 years, and we still know relatively little about efficacy in most use cases.

Some groups are trying to build systems and communities for self-experimentation and medical tourism participants that are specifically designed to yield higher quality data that might form the basis for synthetic clinical trials. So far this has not generated any meaningful success. It is a hard problem. All of the incentives are for patients and clinics not to share, and if one is paying enough to change those incentives, one is back to effectively running a less well organized form of expensive clinical trial.

Overall the problem of proving that an affordable therapy is or is not worthwhile as a treatment for degenerative aging is a challenging mess. For my part, I suspect that producing good data on low-cost interventions is going to require, at least at the outset, for the first dozen or so interventions, a community of dedicated, wealthy philanthropists who care more about this topic than they do about being wealthy. To my eyes, philanthropic support of clinical trials is the only short-term practical approach to bring change that might demolish the present set of perverse incentives, or at least lead to a few of the most interesting of the affordable potential interventions for aging being proven and quantified in clinical trials.

Exosomes are one category of extracellular vesicle secreted by cells, a membrane-wrapped package of molecules, one complex component of the extensive, incompletely mapped communication that takes place constantly between cells. Exosome therapies are conceptually similar to stem cell therapies, an attempt to favorably adjust the behavior of native cells via signaling. While the first exosome therapies are widely available via medical tourism, with a few organizations in the early stages of sponsoring clinical trials to allow use in more regulated regions, the research community is assessing approaches that involve engineering the contents or surface features of exosomes harvested from young donor blood, tissues, or stem cells. The example here is tested in a mouse model of Alzheimer's disease, producing favorable results.

In this study, the rabies virus glycoprotein-targeting peptide (RVG-29) was conjugated to the surface of young plasma-derived exosomes (EXOs) to construct RVG-engineered EXOs (RVG-EXOs). RVG-EXOs exhibit enhanced blood-brain barrier penetration and neuron targeting, thus offering an efficient delivery system for targeted Alzheimer's disease (AD) therapy. RVG-EXOs treatment markedly improved multiple cognitive behaviors in 3xTg AD mice, including spatial learning, working memory, and novel object recognition. RVG-EXOs effectively alleviated AD pathology by promoting amyloid-β clearance, suppressing Tau hyperphosphorylation, and preserving synaptic integrity and neuronal survival.

Mechanistic studies revealed that RVG-EXOs activates the autophagy pathway by inhibiting RPTOR expression, providing a molecular basis for the neuroprotective effects of young plasma exosomes. Single-cell RNA sequencing revealed that RVG-EXOs remodeled brain cellular landscape: increased neurons, rebalanced inhibitory/excitatory neurons, strengthened Ptn-Sdc3 neuroprotection, and attenuated APP-CD74 signaling, which suppressed disease-associated microglia (DAM) and promoted homeostatic microglia.

Link: https://doi.org/10.1016/j.bioactmat.2026.08.008

Some aspects of cognitive function exhibit marked declines relatively early in later life, by middle age. Here, researchers show that episodic and associative memory recall, meaning the ability to correctly link together and place in context specific individual memories, shows a sizable decline in 50-something participants versus their 20-something counterparts. The fine details of the storage of memories are understood to be fairly dynamic over time; accessing memory can change storage, as can mechanisms of aging operating on the organization of neural networks. Even outside the context of aging, memory is far from perfect even in the best of circumstances. We forget most of our personal histories quite quickly, retaining perhaps 2% of the past according to early research into memory and forgetting. There is a great deal of room for improvement.

Episodic memory is the ability to bind elements of an experience into coherent associations. This ability declines with age, often producing errors that can interfere with daily life. Memory distortions might arise from unstable hippocampal representations that cannot be maintained across encoding, storage, and later retrieval. However, whether aging disrupts the temporal continuity of these representations across memory phases has not been directly tested.

Here, adults aged 20-74 completed functional magnetic resonance imaging (fMRI) scanning during an associative memory task involving face-object and face-scene pairings, followed by post-encoding rest and a cued retrieval test. Using multivoxel correlation structure analyses, we quantified hippocampal pattern similarity across each memory stage. Increasing age was associated with increased category errors and reduced representational similarity across all transitions. Higher encoding-retrieval similarity predicted better associative accuracy in younger adults and was less predictive in middle-aged and diminished in older adults.

Uniquely among older adults, greater cross-phase similarity predicted elevated category-level binding errors, suggesting a shift from selective reactivation to misbinding with age. Baseline hippocampal organization and encoding-specific connectivity supported accurate reinstatement only in younger adults. Thus aging disrupts hippocampal stability, possibly representing a core mechanism of age-related decline in associative memory across the adult lifespan.

Link: https://doi.org/10.1093/cercor/bhag114

Many of the more sophisticated forms of medicine, including gene therapies and immunotherapies, are challenging to deliver to the brain. At the very least there are far fewer practical options for delivery, and it is possible that none of that that exist fit a given desired use case. The blood-brain barrier stands in the way of intravenous injection as a path for most approaches, blocking passage of most cells and molecules from circulation to brain tissue. While direct injection into the brain or into reservoirs of cerebrospinal fluid can be achieved, they are sufficiently invasive and challenging to rule out commonplace use.

The brain is made up of many different cell types, and more sophisticated approaches will want specificity to regions or cell types. Small molecules can readily pass everywhere in the body, but are a poor tool if the goal is to engineer selective activity in a given cell type. That selectivity is readily achievable via any form of gene therapy in which expression is keyed to a promoter only active in the cell type of interest. But gene therapies with that capability are largely very hard to get into the brain, or have other characteristics that present hurdles. Forms of AAV viral vectors now exist that can pass the blood-brain barrier, but AAV is restricted in size of payload, and payload size is required for promoter-driven selectivity, ability to turn off the therapy at any point, and other add-ons.

So it is always interesting to see people trying new approaches. Today's open access paper presents a way to selectively deliver antibodies via intravenous injection, through the blood-brain barrier, and into astrocytes in the brain. The astrocytes are reprogrammed into neurons that integrate into existing neural networks and reverse loss of cognitive function. The treatment is focused on Alzheimer's disease, and given the artificiality of the mouse models of this condition, it is always good to wait for a while before becoming too excited by any claimed advance. All too many approaches improve the mice, but do not work well in the human condition. More generally, a feasible approach to deliver antibodies to degrade a specific protein in a specific set of brain cells is quite an interesting technology, however.

Reverse the progression of Alzheimer's disease through Nano-ERASER-based adult neuroregeneration

The irreversible loss of neurons in key cognitive circuits highlights a central therapeutic challenge: neurodegeneration in Alzheimer's disease (AD) outpaces the brain's intrinsic capacity for repair. Astrocyte-to-neuron (AtN) reprogramming has recently emerged as an appealing regenerative strategy because astrocytes, which are abundant, regionally distributed, and proliferative, represent an endogenous cellular reservoir from which new neurons might be generated in situ. Among the molecular targets proposed to induce AtN conversion, polypyrimidine tract-binding protein 1 (PTBP1) has attracted particular attention. PTBP1 is an RNA-binding protein that maintains non-neuronal splicing programs; its downregulation is a hallmark of neuronal differentiation during development. Early studies reported that suppressing PTBP1 in astrocytes or other glia could initiate neuronal transcriptional programs and produce cells resembling functional neurons in models of Parkinson's disease and retinal injury, sparking strong enthusiasm for PTBP1 as a single-factor reprogramming node. However, subsequent lineage-tracing studies yielded conflicting results, suggesting that PTBP1 depletion alone may be insufficient to drive genuine AtN conversion in the adult mammalian brain, raising concerns that some reported conversions reflected viral promoter leakage into pre-existing neurons.

A major technical hurdle in translating PTBP1-based reprogramming for therapeutic use is precise, efficient, and cell-type-selective delivery of the reprogramming agent to astrocytes in vivo while avoiding off-target perturbation of neurons and other cell types. Conventional PTBP1 knockdown methods, including viral shRNA, CRISPR, and antisense oligonucleotides, struggle to achieve astrocyte-restricted suppression without off-target effects on neurons, microglia, or peripheral tissues.

Recently, our group developed a Nano-ERASER system that can downregulate a specific protein by intracellular delivery of its corresponding antibodies via proteasome-mediated degradation, achieving Trim-Away in adult animals and in a disease model for the first time. Thus, we designed a Nano-ERASER-based Trim-Away platform to (1) effectively deliver anti-PTBP1 antibodies (aPTBP1) into astrocytes in the adult brain and (2) trigger rapid intracellular degradation of endogenous PTBP1 via TRIM21-mediated proteasomal clearance. The Trim-Away mechanism depletes target proteins directly at the protein level, bypassing limitations of transcriptional or RNA-targeting approaches and offering temporally precise control over protein levels. By combining blood-brain barrier (BBB)-targeting ligands with a polymer nanocarrier engineered for efficient endosomal escape and intracellular antibody release, the system aims to achieve transient, localized PTBP1 depletion in astrocytes while minimizing exposure to neurons and peripheral tissues. In doing so, it provides a rigorous platform to test whether transient PTBP1 ablation at the protein level is sufficient to engage neuronal splicing programs and promote astrocyte conversion in adult mammalian brain regions relevant to AD pathology.

Treatment with our new system significantly improves cognition, learning, and memory, demonstrating true functional reversal of AD-associated deficits in the 5XFAD mouse model of AD. By resolving the long-standing controversy surrounding PTBP1 reprogramming and establishing a translational biomaterials-based platform for in situ neuronal regeneration, this work introduces a transformative therapeutic paradigm aimed not only at slowing AD but at rebuilding the neuronal circuitry it destroys.

Researchers here suggest that increased ERBB4 expression in neurons is an important driving mechanism in the onset and progression of Alzheimer's disease. One has to be cautious with such findings, even given the effort made by the researchers to show that human data is compatible with the hypothesis, because the mouse models of Alzheimer's disease in which these sorts of discovery are made are very artificial. Mice do not normal exhibit anything like Alzheimer's disease, so the models induce forms of dysfunction that result in something resembling Alzheimer's in humans. The model embodies assumptions about relevant mechanisms that may not be correct, and this is one of the reasons why progress towards therapies has been slow and painful.

Single-nucleus RNA-sequencing analysis identified the emergence of early-responsive excitatory neurons (EREN), characterized by expression of ectopic Erb-B2 receptor tyrosine kinase 4 (Erbb4), as one of the earliest major alterations in Alzheimer's disease (AD) mouse models. Selective Erbb4 deletion in AD excitatory neurons abrogated abnormal neuronal network activities and synapse loss, as well as reactive gliosis, amyloid plaque deposition and cognitive deficits. Conversely, Erbb4 overexpression in wild-type excitatory neurons recapitulated these core AD-like phenotypes without amyloid plaques.

Mechanistically, these effects required mammalian target of rapamycin (mTOR) signalling downstream of ERBB4. Subsequent transcriptomic analyses showed that excitatory neuronal Erbb4 is both necessary and sufficient to induce EREN and reactive gliosis. Directed mediation analysis of human AD transcriptomic data further support a model in which excitatory neuronal ERBB4 contributes to a pathogenic cascade that links amyloid pathology to tau propagation and cognitive decline. These findings identify aberrant Erbb4 expression in excitatory neurons as an early driver of AD pathophysiology and a potential therapeutic target across neurodegenerative diseases.

Link: https://doi.org/10.1038/s41586-026-10964-z

This is far from the only study to indicate that the children of long-lived individuals tend also to be long-lived. The open question is the degree to which this is genetic versus cultural transmission. The construction of very large population databases over the past few decades has produced evidence for genetics to play only a small role in life expectancy for the vast majority of people. Similarly the weight of evidence for lifestyle choice, particularly physical fitness, to be the presently dominant influence on life expectancy is compelling. Against that background, the hypothesis that centenarians are centenarians because they have favorable gene variants that might form the basis for age-slowing therapies faces an uphill battle.

Centenarian lifespan extension is frequently accompanied by delayed onset of aging-associated diseases. Understanding the transgenerational patterns of this phenomenon is crucial for informing investigations of genetic and environmental factors that promote healthy aging. Three independent longitudinal cohorts were studied: LonGenity (2008-2024; New York City area), the New England Centenarian Study (NECS; 1995-2024; throughout the US), and the UK Biobank (2006-2022; throughout the UK). Participants were selected from the 3 studies based on their parental lifespan. Centenarians' offspring had at least 1 parent who reached age 100 years and were compared with control offspring of parents with shorter lifespans.

Differences in age at death and age at onset of 4 age-associated morbidities - cardiovascular disease (CVD), cancer, hypertension, and stroke - were evaluated within study cohorts using Cox proportional hazards regression modeling, estimating hazard ratios (HRs) and delays in expected age of incidence. Combined, centenarians' offspring and control participants numbered 480 in LonGenity (median enrollment age, 74 years [range, 65-94 years]; 262 women [55%]; 245 offspring of centenarians [51%]), 1566 in NECS (median enrollment age, 71 years [range, 39-100 years]; 923 women [59%]; 1082 offspring of centenarians [69%]), and 1984 in the UK Biobank (median enrollment age, 65 years [range, 42-71 years]; 1006 women [51%]; 992 offspring of centenarians [50%]).

Meta-analyses identified consistently reduced hazards in centenarian offspring for death, CVD, and hypertension, with aggregate HR estimates of 0.58 for death, 0.67 for CVD, and 0.68 for hypertension, and delays of 3.12 years for death and 5.21 years for hypertension. Stroke hazards were reduced only in LonGenity (HR, 0.27) and NECS (HR, 0.41). No significant associations with cancer were identified.

Link: https://doi.org/10.1001/jamanetworkopen.2026.30964

Senescent cells accumulate with age in tissues throughout the body, disrupting tissue structure and function with inflammatory secretions. The growing burden of senescent cells is an important contributing cause of degenerative aging. A cell becomes senescent in response to damage induced by some form of stress, or more often when a somatic cell reaches the Hayflick limit on cellular replication. In youth senescent cells are efficiently cleared by the immune system, but immune system aging allows senescent cells to linger and grow in number. Immune cells themselves are prone to reaching the Hayflick limit and entering replicative senescence because they respond to a variety of issues with greater replication to multiply their efforts.

Research into neurodegenerative conditions and the state of the aging brain has increasingly focused on maladaptive behavior on the part of microglia, innate immune cells resident in the central nervous system that are analogous to macrophages elsewhere in the body. Microglia do not just attack pathogens and malfunctioning cells, but also participate in normal tissue maintenance and aid in maintenance of neural circuits. When microglia become too inflammatory, whether or not this includes entering a senescent state, the brain suffers. Inflammatory microglia appear to be an important component of neurodegenerative conditions and age-related deterioration in cognitive function. As today's open access paper shows, senescent microglia are clearly harmful in specific ways.

Senescent microglia with shortened telomeres secrete soluble DLK1 to induce aging-associated hypomyelination and neuronal dysfunction

Critical shortening of telomeres by the end replication problem induces cell-cycle arrest and causes the cell to enter replicative senescence. Glial cells in the brain (e.g., microglia, astrocytes, and oligodendrocytes) retain proliferative capabilities after development and become more proliferative in response to damage to the central nervous system (CNS) and other stressors. Thus, glial cells are under heavy replicative stress, and telomere shortening is detected in the white matter, whereas telomere length in the gray matter remains relatively unchanged.

Glial senescence has been suggested to transform the brain from normal aging to pathological aging and to drive the buildup and spread of AD pathologies. Microglia are the resident macrophages in the CNS responsible for immune surveillance and innate immune responses to damage and pathogenic species. Microglia are susceptible to increased replicative stress associated with the reactivation of the proliferative program in response to neurodegenerative pathologies, including tauopathy and amyloid beta (Aβ) accumulation.

Here, we report direct evidence that senescent microglia exert detrimental influences on other cell types through an altered secretion profile. We investigated the brains of telomere-shortened mice and observed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single-nucleus RNA sequencing (snRNA-seq) revealed accelerated glial aging and elevated microglial senescence pathways. In a senescence model of human induced pluripotent stem cell (iPSC)-derived microglia, delta-like non-canonical Notch ligand 1 (DLK1) was identified as a novel senescence-associated ligand. Soluble DLK1 (sDLK1) was increased in the cerebrospinal fluid of telomere-shortened and naturally aged mice, and this increase was eliminated by microglial depletion.

In vivo elevation of sDLK1 caused hypomyelination and blocked oligodendrocyte lineage progression, and these effects demonstrate the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.

Long-lived bats are extreme outliers in the normal mammalian relationships between species body size, metabolic rate, and life span. They are small, have a high metabolic rate, and unlike near all other mammals with those characteristics, many bat species are long-lived. But bat species do exhibit a very wide range of life spans; near neighbor species can have very different paces of aging. Researchers here sequence the genomes of a number of different bat species in search of insight into the mechanisms driving longevity in bats. As is usually the case, the distant end goal of this sort of comparative biology of aging research is to find potential approaches to the development of longevity therapies. That is a long road, and little progress has been made beyond investigation. Only in recent years have the first speculative transfers of genes from long-lived species to short-lived species occurred, for example.

The genus Myotis is one of the largest clades of bats, and it exhibits some of the most extreme variation in lifespans among mammals, alongside unique adaptations to viral tolerance and immune defence. Here, to study the evolution of these phenotypes, we generated cell lines and near-complete genome assemblies for eight closely related Myotis species. Using genome-wide screens of positive selection, analyses of structural variation and functional experiments in primary cells, we identify patterns of adaptation contributing to longevity, cancer resistance, and viral interactions.

We demonstrate distinct modes of adaptation to DNA and RNA viruses compared with all other mammals, with bats exhibiting genome-wide over-representation of positive selection for DNA-virus-interacting proteins and elevated rates of copy-number variation for RNA-virus-interacting proteins. Characterization of Myotis-specific duplications of the key immune factor EIF2AK2 (also known as PKR) reveals multiple ancient segregating trans-species copy-number polymorphisms. We show that the recurrent evolution of longevity seen in Myotis is associated with positive selection in cancer pathways, and demonstrate a unique response to DNA damage in primary cells of the long-lived Myotis lucifugus. Together, our results suggest that bats' remarkable longevity and immunity are linked through pleiotropic adaptations to viruses and ageing-related disease.

Link: https://doi.org/10.1038/s41586-026-10932-7

Clonal hemotopoiesis is the emergence of patterns of potentially problematic mutations occurring in hematopoietic stem cells that then spread over time throughout the immune system, as these stem cells are the source of all immune cells. It is the most well studied form of the somatic mosaicism that occurs in all tissues, the spread of mutations originating in stem cell populations, with some correlational evidence for it to contribute to the development of other age-related conditions. Here researchers note that clonal hematopoiesis associates with idiopathic pulmonary fibrosis, an age related condition with causes that are poorly understood. The immune system is clearly important to health, but equally the research community is some way from fully understanding how exactly disruptive mutations cause downstream problems in tissues.

Clonal hematopoiesis (CH), defined as expanded somatic blood cell clones in persons without other hematological abnormalities, is also age related. CH at variant allele frequencies (VAF) ≥2% is associated with greater risk of chronic diseases, such as coronary heart disease or chronic obstructive pulmonary disease (COPD). Commonly mutated genes (e.g., DNMT3A and TET2) epigenetically control gene expression and are important regulators of disease-related immune responses. Given these shared risk factors, we hypothesized that incidence of CH is associated with idiopathic pulmonary fibrosis (IPF) progression.

DNA was extracted from whole blood after written informed consent was obtained from 123 patients with IPF. Clinical data, available at sampling and within 12 months after blood collection, was used to assign progression (n = 89) as follows: (a) ≥10% absolute forced vital capacity (FVC) 12-month decline alone; (b) ≥5% absolute FVC 12-month decline and radiologic progression; or (c) 12-month radiologic progression alone. CH-defining somatic mutations were analyzed with a targeted sequencing panel (ASXL1, CALR, CBL, DNMT3A, JAK2, MPL, PPM1D, SF3B1, SRSF2, TET2, TP53, U2AF2, and ZRSR2).

CH mutations were present in 38% of patients with IPF (overall median VAF = 6.2%). Significantly more CH-mutated patients were characterized as rapid progressors (53% vs. 25%) and had a greater 12-month loss in FVC compared with those without CH (280 vs. 90 mL).

Link: https://doi.org/10.1172/jci.insight.198458

The most common metabolic diseases, such as type 2 diabetes or fatty liver disease leading to metabolic dysfunction-associated steatohepatitis (MASH), a fibrotic condition of the liver, are consequences of the dysfunctional state of metabolism that results from being overweight and sedentary. These conditions are rare in thin, fit people, even in later life when the damage of aging makes metabolism more vulnerable and inflammatory. Excess visceral fat tissue is known to promote the accumulation of senescent cells. While cells become senescent throughout life, in youth they are promptly cleared by the immune system. That clearance falters with age, allowing senescent cells to linger and accumulate. The metabolic dysfunction produced as a consequence of being overweight accelerates this process.

In today's open access paper researchers review what is known of the bidirectional relationship between metabolic dysfunction and the burden of senescent cells. Metabolic dysfunction promotes senescence, and in turn the inflammatory secretions of senescent cells further disrupt the operation of metabolically active tissues such as the liver. While a fair number of companies are presently developing senolytic drugs capable of clearing a meaningful fraction of senescent cells from the body, and while cheap first generation senolytic treatments, such as the dasatinib and quercetin combination, are readily available for anyone willing to put in a little effort to obtain them, metabolic disease is fairly low on the research and development communities' priority list. It seems unlikely that clinical trials will take place any time soon, but an increasing number of people are choosing to use senolytics off-label, an option that unfortunately generates very little solid data on whether or not a therapy is effective in any given use case.

Metabolically Active but Dysfunctional: The Impact of Senescent Cells and SASP

Cellular senescence and its secretory phenotype (SASP) have emerged as important contributors to chronic inflammation and metabolic dysfunction across multiple tissues. In adipose tissue, a combination of telomere attrition, oxidative stress, and pro-inflammatory signals pushes preadipocytes and mature adipocytes into premature senescence. These senescent adipocytes secrete a complex SASP, rich in cytokines, chemokines, and matrix-remodeling enzymes, that perpetuates local "metaflammation," impairs insulin signaling, and promotes systemic lipotoxicity.

In the liver, hepatocyte and stellate cell senescence similarly contribute to the progression of steatosis to MASH and cirrhosis, as SASP factors drive fibrosis, immune cell infiltration, and metabolic reprogramming. In the pancreas and skeletal muscle, senescence undermines β-cell function and glucose uptake, respectively, further exacerbating insulin resistance and hyperglycemia. Collectively, the cumulative burden of senescence and chronic SASP underscores a feed-forward cycle: metabolic stress induces senescence, and persistent SASP amplifies tissue dysfunction and accelerates disease progression.

Despite the protective role that acute, transient senescence can play in wound healing and tumor suppression, the accumulation of senescent cells in aged or obese individuals creates a pathogenic SASP milieu, often termed "inflammaging", that underlies obesity, type 2 diabetes, MASLD/MASH, and related cardiometabolic disorders. In rodent models, reducing senescent-cell marker burden has been associated with improved metabolic parameters, reduced fibrosis, and improved insulin sensitivity. These findings suggest translational potential for senotherapy in metabolic disease, although whether it can delay or reverse disease onset in humans remains to be established.

The research community remains very interested in finding novel ways to promote muscle growth with minimal side effects. Therapies that inhibit myostatin or upregulate follistatin signaling are under development, and follistatin gene therapies have been available via medical tourism for some years. But most of the research community is focused on pharmacology, the use of small molecules to influence muscle metabolism. As an example of this type of work, researchers here report on a small molecule that mimics adiponectin signaling to promote muscle growth in rats.

Skeletal muscle atrophy is a hallmark of ageing and chronic diseases, yet effective pharmacotherapies remain unavailable. Adiponectin signalling through receptors AdipoR1 and AdipoR2 regulates skeletal muscle metabolism, regeneration and oxidative capacity, but the therapeutic use of adiponectin is limited by its large size and complex multimeric structure. Small-molecule AdipoR agonists, therefore, represent an attractive therapeutic strategy.

Here, we report the discovery and pharmacological characterization of medicarpin, a previously described osteogenic phytoalexin and its water-soluble sodium salt (Med), as dual AdipoR1/R2 agonists, and demonstrate the efficacy of Med in vitro and in rodent models of skeletal muscle atrophy. Med enhanced myogenic differentiation, evidenced by increasing myotube formation and expression of MyoD, myogenin and MyHC. Med also enhanced oxidative capacity by increasing fatty acid oxidation and Med-treated cells showed elevated oxidative fibre markers.

Oral administration of Med significantly attenuated muscle atrophy in both rat models, evidenced by improved muscle morphology, suppressed atrogenes, enhanced myogenic markers and increased muscle adiponectin expression and corresponding downstream signalling. Med markedly improved muscle function, including grip strength, wire hanging, rotarod performance, and toe-spread ability of denervated limbs.

Link: https://doi.org/10.1002/jcsm.70364

Parkinson's disease and Lewy body dementia are synucleinopathies, characterized by the spread of misfolded α-synuclein through the central nervous system. The presence of misfolded α-synuclein provokes harmful changes in cell behavior and ultimately cell death in important populations of neurons. Researchers here explore differences in the vulnerability of different parts of the brain to the pathology produced by misfolded α-synuclein. They conclude that more complex parts of the brain, characterized by increased mitochondrial activity and greater connectivity between neurons, are more fragile in the face of the pathological mechanisms of syncleinopathy.

A total of 89 patients with dementia with Lewy bodies and 89 matched controls underwent T1-weighted brain MRI. Scans were processed to generate surface-based cortical thickness maps. Regional cortical thickness estimates, after slice-by-slice manual correction, were mapped to gene expression data from healthy postmortem human brains to identify transcriptomic signatures associated with decreased thickness in dementia with Lewy bodies. We assessed whether genes whose expression was increased with regional thinning converged onto established Parkinson's disease- and Alzheimer's disease-related pathways and identified genes uniquely implicated in dementia with Lewy bodies. Spatial annotation mapping was then used to test whether patterns of cortical thinning overlapped with in vivo neurotransmitter system distributions and whether the observed thickness pattern was constrained by large-scale structural connectivity, consistent with a network-based propagation process.

Cortical thinning predominated in regions that, in the healthy brain, show higher expression of genes involved in mitochondrial function and synaptic transmission. The transcriptomic profile associated with thinning significantly overlapped with genes belonging to Parkinson's disease and Alzheimer's disease pathways, supporting shared pathogenic mechanisms across Lewy body- and Alzheimer-type neurodegeneration. However, 90 genes associated with cortical thinning did not overlap with Parkinson's disease or Alzheimer's disease pathways and were enriched for GABAergic signalling. Spatial mapping analyses showed that regions with greatest thickness reductions colocalized with GABAA, serotoninergic 5-HT1A, 5-HT1B, 5-HT4, and dopaminergic D2 receptor distributions, and that the thickness pattern followed structural connectivity.

In conclusion, MRI-derived cortical thickness changes in dementia with Lewy bodies reflect selective molecular and network vulnerabilities rather than a non-specific degenerative process. Mitochondrial and synaptic genes, together with a distinct GABAergic association and connectivity constraints, delineate mechanisms explaining why some cortical territories are more affected in dementia with Lewy bodies.

Link: https://doi.org/10.1186/s12929-026-01267-6

Atherosclerosis is universal; everyone develops fatty atherosclerotic plaques in their arteries at some point, and to some degree. Plaques narrow blood vessels to impede blood flow, and rupture of unstable plaque causes heart attack, stroke, and embolism. It is the largest cause of human mortality, and at present the best that the medical community can do is to slow down plaque growth. Established therapies based on reducing the amount of cholesterol carried outward from the liver on low-density lipoprotein (LDL) particles produce something like a 15% mortality risk reduction at best, and do not regress plaque to any meaningful degree. Interestingly, the drivers of atherosclerosis are sufficiently complex and varied for there to be a few lucky people who exhibit 10% or more plaque regression in response to some combination of lifestyle change and medication. The flip side of that point is the majority of people who show up in a hospital in the immediate aftermath of a first heart attack or stroke do not in fact exhibit elevated LDL cholesterol, and probably benefit very little from the relentless clinical focus on LDL cholesterol.

It isn't all that easy to assess the degree of plaque present in the early stages of atherosclerosis. Imaging approaches have improved greatly over the past ten to fifteen years, but still struggle to distinguish small amounts of plaque. Little to no assessment takes place in the early stages of the condition. Many people have no idea as to whether or not they are in a high risk group until it is far too late. Simple risk factors are well understood, such as chronic inflammation, being overweight, suffering metabolic disease, and so forth. But as the discovery and continued research into the role of Lp(a) in atherosclerosis risk illustrates, there is a great deal yet to be catalogued of how exactly specific differences in metabolism yield differences in the pace at which atherosclerotic lesions emerge. It remains largely a mystery as to why any given person exhibits a given degree of atherosclerosis.

It does seem plausible that differences in atherosclerosis risk, onset, and progression, could correlate usefully well from specific differences in the configuration of the immune system, some of which are more likely (but not guaranteed) to exist in overweight, chronically inflamed, or metabolically dysfunctional people. Fundamentally, an atherosclerotic lesion is a consequence of macrophage dysfunction. Macrophages are innate immune cells responsible for clearing up excess cholesterol in blood vessel walls, and otherwise repairing damage. A lesion is a macrophage graveyard, perpetually calling in more macrophages, driving them into an inflammatory state, and killing them with its toxic mix of excess cholesterol and other lipids. Macrophages do not operate in a vacuum, however, and are strongly influenced by the activities of cells in other immune compartments. There is plenty of evidence for T cells of the adaptive immune system to affect plaque growth in animal studies, for example.

CD8+ effector memory and regulatory T cell dynamics predict subclinical atherosclerotic plaque formation in healthy aging

Age-related structural and functional changes in the arterial wall promote endothelial dysfunction and accelerate atherosclerosis development. Importantly, this process begins long before clinical symptoms appear. During this silent phase, early vascular damage and subclinical atherosclerotic plaque (SAP) formation may already occur but remain undetected. Detecting such early alterations is therefore crucial for improving prevention and enabling timely intervention. Immunological mechanisms and inflammation are increasingly recognized as central drivers of atherogenesis. T cells play a pivotal role in maintaining chronic vascular inflammation. Both CD4+ and CD8+ T-cell subsets modulate plaque biology through pro- and anti-inflammatory effects, whereas regulatory T cells (Tregs) exert protective effects by limiting immune activation and stabilizing plaque. Reduced Treg activity has been linked to accelerated vascular damage. In addition, a broad network of mediators, including cytokines such as Interleukin (I)L-1β, IL-6, IL-18, and tumor necrosis factor-alpha (TNF-α), contributes to endothelial activation, arterial remodeling, and plaque progression. Together with circulating proteins such as growth differentiation factor-15 (GDF-15) and osteoprotegerin (OPG), these immune-related pathways form a complex regulatory network that may provide early insight into emerging vascular vulnerability.

Previous cross-sectional work in a carefully characterized cohort of healthy, medication-free older adults with high cardiorespiratory fitness demonstrated that SAP were accompanied by distinct cellular and molecular immune signatures. Individuals with SAP exhibited hallmarks of immunosenescence, including reduced proportions of naïve CD4+ T cells, expansion of differentiated subsets such as CD4+ and CD8+ central memory cells, elevated inflammatory mediators, molecular features of cellular senescence, and alterations within Treg subpopulations. These findings underscored the pivotal role of immune system alterations in early plaque formation and suggested that immunological profiling may help identify individuals at increased vascular risk before clinical manifestation.

In a three-year longitudinal study, 49 healthy older adults (63.8 ± 3.8 years) underwent carotid ultrasound, T cell phenotyping, serum protein profiling, body composition assessment, and fitness testing at baseline and follow-up. At follow-up, participants were classified as no SAP, new SAP or persistent SAP. We analyzed baseline determinants and within-person changes to predict incident plaque formation. New SAP occurred in 30.3% of those initially plaque-free. At baseline, lower frequencies of CD8+ effector memory (EM) T cells and higher frequencies of CD8+ effector memory re-expressing CD45RA (EMRA) T cells and regulatory T cells (Tregs) were associated with higher odds of new SAP. Over time, expansion of CD8+ EM T cells was the most consistently associated independent variable of new SAP, accompanied by declines in Tregs and in the Treg/Teff ratio. Vascular cell adhesion molecule-1 (VCAM-1) at baseline was an additional independent predictor. Increases in visceral fat and declines in VO2peak were linked to new SAP, but immune markers were more robust than metabolic variables or serum cytokines.

Oligodendrocytes resident in the brain are responsible for maintaining the insulating myelin sheaths around axons that are required for the effective transmission of electrical impulses between neurons. Loss of myelin integrity is the cause of a number of debilitating conditions, but also occurs to some degree with aging. It has been an open question as to how large a contribution this makes to age-related cognitive decline. Researchers here provide evidence for age-related changes in oligodendrocyte behavior and myelin structures to be more complicated than the simple concept of reduced remyelination and loss of myelin integrity, and to correlate with meaningful differences in the trajectory of cognitive decline in mice.

The underlying mechanisms driving cognitive decline in aging remain unclear. Learning in humans in youth and adulthood is associated with increased central nervous system (CNS) myelin, the insulating membrane produced by oligodendrocytes that surrounds neuronal axons to facilitate rapid electrical impulse conduction and provide metabolic support. Furthermore, it is now well established that, in mice, learning requires an increase in oligodendrocytes through de novo generation. Cognitive impairment in aged mice and non-human primates is associated with reduced oligodendrocytes and myelin; however, the white matter pathologies driving human cognitive decline remain unclear. Indeed, although magnetic resonance imaging studies associate white matter abnormalities with cognitive decline in aged humans, the underpinning oligodendrocyte and myelin changes are unknown.

Here we uncover a role for oligodendrocytes in explaining the variance of cognitive decline with aging. By investigating neuropathological and transcriptomic changes in human white matter associated with individual rates of cognitive decline in aging, we find that worse cognitive trajectories unexpectedly associate with smaller myelinated axon size, thicker myelin and more oligodendrocytes with downregulation of NRF2. Aged oligodendrocyte-specific NRF2-knockout mice showed attenuated cognitive improvement over time and mirrored the white matter pathology of human cognitive decline in aging. These findings place the oligodendrocyte as a contributor to cognitive decline and highlight the NRF2 pathway as a therapeutic target to preserve cognition in human aging.

Link: https://doi.org/10.1038/s41591-026-04608-y

Blood tests to assess Alzheimer's disease risk and progression exist, for example based on the presence of circulating varieties of tau protein, but there is a great deal of room for improvement. Researchers here provide evidence for an approach to the measurement of very small amounts of misfolded amyloid-β in blood to work reasonably well in patients. The amyloid cascade hypothesis continues to steer much of the field of research and development for Alzheimer's disease; misfolded amyloid-β spreads slowly in the brain over years, and eventually causes sufficient dysfunction to promote a subsequent disease stage characterized by a feedback loop between chronic inflammation and tau aggregation. Tracking this growth in misfolded amyloid-β make sense as an approach to assessing risk and progression of the early stages of Alzheimer's disease.

A hallmark of Alzheimer's disease (AD) pathophysiology is the misfolding and aggregation of β-amyloid (Aβ) protein in the brain, which results in tau pathology, neuroinflammation, synaptic loss, neurodegeneration, and cognitive decline. The misfolded Aβ aggregates, or "seeds", range from small, soluble oligomers to large, insoluble fibrils that have a rich β-sheet secondary structure and are generally stable. Because of its specific structure, Aβ seeds corrupt natively folded Aβ and promote the aggregation and formation of pathogenic assemblies, which is a process similar to prion-like aggregation. Such a process follows a secondary nucleation mechanism in which new aggregates generate at a rate dependent on the concentration of existing seeds.

Based on this seeding nucleation mechanism, protein misfolding cyclic amplification (PMCA) has been developed to amplify trace amounts of misfolded proteins to a detectable level in biological samples. It uses repeated cycles of incubation and amplification for seed multiplication. However, the application of these techniques to AD diagnosis is relatively limited. In the present study, we detected plasma Aβ aggregation seeding activity using a real-time sonication-based PMCA method. A total of 549 participants were recruited between December 2020 and May 2024. Plasma Aβ aggregation seeding activity was measured using a real-time sonication-based protein misfolding cyclic amplification assay. The diagnostic performance of plasma Aβ aggregation seeding activity as a biomarker was assessed.

In the validation stage, plasma Aβ aggregation seeding activity exhibited high diagnostic accuracy with optimal cutoff values of 42.91 for distinguishing AD from cognitively unimpaired (area under the curve [AUC] = 0.93), 42.02 for AD from non-AD dementia, and 43.24 for mild cognitive impairment due to AD from non-AD dementia. Plasma Aβ seeding activity significantly correlated with cognitive functions (Mini-Mental State Examination [MMSE] scores: rs = -0.68; Clinical Dementia Rating [CDR] scores: rs = 0.71).

These findings indicate that plasma Aβ aggregation seeding activity could serve as a promising minimally invasive biomarker for identifying both AD and MCI due to AD. This biomarker potentially facilitates early detection and differential diagnosis of AD at different clinical stages.

Link: https://doi.org/10.1097/CM9.0000000000004142