Fight Aging!

Cells become senescent in response to stress and damage, in response to tissue injury, but most commonly upon reaching the Hayflick limit to replication. A senescent cell ceases to replicate, grows in size, and generates a potent mix of pro-growth, pro-inflammatory signals. Senescent cells are created throughout life in tissues throughout the body, but an established population of lingering senescent cells only begins to accumulate in later life. In youth, the immune system efficiently clears senescent cells, allowing senescence to be a beneficial state in the coordination of regeneration and in drawing the attention of the immune system to potentially cancerous cells. In later life, the immune system falters in this task. An established population of senescent cells that generates signaling constantly, even in relatively small numbers compared to the overall count of cells in a tissue, is highly disruptive to tissue structure and function.

To what degree is the age-related failure of immune clearance of senescent cells a consequence of harmful changes in the immune system versus harmful changes in the senescent cells themselves? This is an interesting and unresolved question, though there is at least some degree of evidence for contributions from both sides. Today's open access paper from a research group with a long history of work on the cellular maintenance processes of autophagy provides evidence for a loss of capacity in chaperone-mediated autophagy in aged senescent cells to induce a loss of chaperone-mediated autophagy in aged innate immune cells, which contributes to the inability of the immune system to efficiently clear senescent cells. In chaperone-mediated autophagy, an target unwanted or damaged protein is bound by a chaperone protein, and that chaperone protein facilitates the entry of the target into a lysosome for disassembly. It is a complex business, and so it seems likely there will be many possible targets for future drug candidates intended to improve this form of autophagy in senescent cells or immune cells.

Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells

Here we focus on the role of chaperone-mediated autophagy (CMA) during establishment, maintenance, and immune resolution of senescence in the aging context. CMA selectively degrades in lysosomes proteins containing a KFERQ-like motif, recognized by the cytosolic chaperone heat shock cognate protein of 71 kDa (HSC70). Substrate delivery to the CMA receptor, the lysosome-associated membrane protein 2A (LAMP2A), triggers its multimerization into a translocation complex for substrate entry into the lysosomal lumen. CMA declines with age in most tissues, and its malfunction is linked to neurodegenerative conditions, metabolic syndrome of aging, and atherosclerosis.

Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic, and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells.

Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.

Functional connectivity is a measure of neuronal activity over time in different parts of the brain, assessed using MRI to detect the increased blood flow that accompanies increased neuronal activity. Researchers here demonstrate that changes in functional connectivity observed in Alzheimer's disease patients differ from age-related changes observed in individuals without dementia. As is the case for many measures of aging, there is some debate within the scientific community with regard to whether any specific change is dysfunction or an adaptive, compensatory reaction to dysfunction. This will likely remain the case until effective rejuvenation therapies or effective treatments for specific neurodegenerative conditions such as Alzheimer's exist, can be used in sizable patient populations, and the results measured.

Aging and Alzheimer's disease (AD) are both associated with changes in functional brain networks - groups of regions that typically communicate with one another and support cognition. However, the precise nature of these changes - their spatio-temporal dynamics and whether they reflect compensatory adaptations, pathological disruptions, or both - remains a topic of active debate. Functional connectivity (FC), the temporal synchrony of activity between brain regions, may be a mechanism facilitating the spread of pathology, a system affected by pathology, or an interplay of both.

Here, in two independent cohorts (BioFINDER-2, N = 973; Alzheimer's Disease Neuroimaging Initiative, N = 129), we show that functional connectivity changes associated with aging and AD are strongly aligned with separate fundamental axes of hierarchical brain communication. Early accumulation of AD pathology and subsequent cognitive decline are both linked to functional change along the sensory-association axis. Meanwhile, age-related functional changes occur along the representation-executive axis consistently throughout the adult lifespan. These findings together suggest that both AD and aging alter major but orthogonal functional pathways in the brain.

Link: https://doi.org/10.1038/s41593-026-02402-0

A great deal of drug discovery starts by screening compounds from the vast libraries of molecules that exist. The libraries are too large to screen everything (and even then the scope of the libraries is only a sampling of the space of the possible). Thus even unbiased screening starts with some hypothesis to cut down the number of molecules being screened to a tractable number for the time and budget at hand. Here, researchers discuss the use of existing transcriptomic data to guide drug screening approaches intended to uncover geroprotective compounds that adjust metabolism to modestly slow aging. Based on results to date, this side of aging research seems unlikely to produce exciting outcomes, as near all of what has been discovered in this way triggers the same array of known beneficial stress responses, and thus doesn't improve on the present state of the art.

To date, invertebrate-based screens have identified hundreds of life span-extending compounds. However, relatively few have been validated across multiple species, and most of the geroprotectors belong to extensively studied classes like mechanistic target of rapamycin (mTOR) inhibitors, AMPK activators, or histone deacetylase (HDAC) inhibitors. Because these pathways regulate broad cellular processes, direct pharmacological modulation of their core components may produce pleiotropic effects. This reliance on a limited set of well-studied targets and drug classes underscores the need for unbiased tools that can prioritize diverse candidate geroprotectors.

Currently, several strategies have been developed to identify small-molecule geroprotectors, ranging from unbiased screening to transcriptomic-based drug prediction. The latter, which infers the geroprotective effects of drugs based on drug-induced transcriptomic changes, is an emerging method and has gained traction thanks to availability of large-scale transcriptomic resources. Several methodologies have been developed within this framework. One widely used strategy is the "reversal approach," which identifies drugs that counteract aging-associated gene expression changes. This approach has led to discoveries such as oridonin, an AKT inhibitor extending life span in yeast and mice. However, the reversal approach assumes that all age-related changes are detrimental despite evidence that some may be adaptive.

Another strategy, the "mimic approach," matches drug-induced transcriptomic profiles to those of known antiaging interventions. This method has been applied to identify compounds like allantoin and rilmenidine, which extend life span in Caenorhabditis elegans. However, this method tends to rediscover drugs similar to known interventions, limiting its capacity to reveal novel mechanisms.

Here, we used C. elegans and mice to explore transcriptomic strategies for geroprotector discovery. Applying transcriptomic clocks and coexpression network analysis, we found that many aging-associated changes in C. elegans are adaptive - some transcriptomic changes that resemble aging may contribute to longevity. We identified conserved coexpression modules associated with life span: "aging modules" enriched in translation and mitochondrial genes and "longevity modules" enriched in stress response genes, including daf-16 targets. Several of these longevity-associated modules are preserved in specific mouse tissues and are associated with mouse health span. Last, we conducted a small-scale screen and identify seven novel geroprotectors using the module gene expressions as our transcriptomic signatures. Our findings demonstrate that expression profiles of conserved aging-related processes can serve as predictive signatures for finding effective geroprotective compounds.

Link: https://doi.org/10.1126/sciadv.aee3657

A reduced intake of calories triggers protective responses to low nutrient availability, dramatically altering the operation of cellular metabolism. For so long as adequate levels micronutrients are still ingested, this response to calorie restriction is beneficial. The cell maintenance processes of autophagy operate more efficiently, for example, and this improved autophagy is thought to be the primary mechanism by which calorie restriction improves health and slows aging. This response to calorie restriction is triggered by a variety of independent sensors that assess the availability of various components of the diet, where essential amino acids are one of the more important components in this respect. Researchers have assessed the metabolic response to diets low in the essential amino acid methionine, and found it to produce broadly similar effects to overall calorie restriction in laboratory animals.

The authors of today's open access paper argue that methionine restriction is likely misnamed, as: (a) low methionine diets are also low in the non-essential amino acid cysteine; (b) in a low cysteine environment, methionine is consumed to produce cysteine, meaning one can't really distinguish between the effects of low methionine and low cysteine easily; (c) given a suitably engineered animal, with the methionine to cysteine pathway disabled, one can show that in fact the important metabolic response occurs as a result of low cysteine levels and not as a result of low methionine levels.

Cysteine reduction rather than methionine restriction promotes immunometabolic fitness to confer survival benefit in aging

Cysteine is a dietary non-essential yet biochemically irreplaceable amino acid. Methionine, the other sole proteinogenic sulfur amino acid (SAA), lacks a thiol group and hence cannot form complexes with metals, including disulfide bond formation, nucleophilic catalysis, and redox signaling. Typically, cysteine and methionine contents are high in animal-based diets, while plant-based vegetarian foods are lower in SAA. It is now recognized that cysteine is essential for organismal metabolism through pleiotropic effects, including regulation of coenzyme A (CoA) and glutathione (GSH)-mediated redox balance. Creation of forced cysteine depletion by deletion of cystathionine γ-lyase (CTH) and feeding a cysteine-free diet causes rapid, progressive 30% weight loss. In addition, cysteine depletion induces activation of central nervous system nuclei that control sympathetic nervous system (SNS)-derived norepinephrine, which causes rapid adipose tissue browning and thermogenesis through β3-adrenergic receptors.

However, an important underappreciated issue is that methionine restriction (MR) is erroneously called MR because this diet also lacks cystine. Interestingly, it has been well established that an 80% reduction of methionine content (in a diet with 0% cystine) in adult rats resulted in robust 40% increases in median and maximum lifespan. Additional independent studies confirmed that MR, which in fact lacks both methionine and cysteine, robustly enhances lifespan in mice despite an increase in food intake, without restriction of calories. Moreover, using methionine-and cysteine-titrated diets in wild-type mice, the anti-adiposity effects of SAA restriction have been linked to cysteine restriction.

When dietary cystine is eliminated, host redirects substrates from methionine cycle and generates cysteine via CTH in transsulfuration pathway, leaving it unclear which SAA controls aging. Here, we show that selective cysteine restriction in Caenorhabditis elegans enhanced lifespan and stress survival independently of methionine. Notably, cysteine-free diets (methionine-replete or restricted) in Cth-deficient mice induced pro-metabolic effects, whereas MR with normal cysteine was ineffective. Sustained 70% cysteine reduction in aged CTH knockout mice reprogrammed the immunometabolic axis, conferring healthspan benefits. Thus, lowering cysteine while keeping the methionine pool intact enhances healthy lifespan.

Dental follicle stem cells can be used as a basis for regenerative cell therapy in the treatment of periodontitis, the prevalent form of gum disease, and a condition that becomes more common with age. Researchers here note that IGFBP5 expression is reduced in senescent dental follicle stem cells, and find that increased expression of IGFBP5 reduces the pace at which these cells become senescent. Cellular senescence in the cultured cells used in cell therapy is a problem that the regenerative medicine community is becoming increasingly aware of, and various efforts have been made in various contexts to try to mitigate the issue. Here, researchers employ this new knowledge regarding the role of IGFBP5 to design a better cell therapy to promote periodontal regeneration, and carry out a proof of principle study in a rat model of periodontitis.

The improvement of health and the delay of aging represent pivotal goals in medical research. Bone aging contributes to various age-related disorders, including periodontitis. Dental follicle stem cells (DFSCs) serve as ideal seed cells for periodontal regenerative therapy. Insulin-like growth factor binding protein 5 (IGFBP5) has been reported to exert complex and context-dependent effects. However, its role in DFSC senescence remains undefined. In this study, we observed a significant decrease in IGFBP5 expression in DFSCs undergoing replicative or H2O2-induced senescence.

Functional experiments demonstrated that IGFBP5 overexpression alleviated cellular senescence and enhanced osteogenic potential, a process linked to the modulation of non-canonical Wnt signaling. WNT5B was then identified as a potential downstream regulator involved in mediating the pro-osteogenic effects of IGFBP5. To translate these findings clinically, we developed Gel-vHA@oe-DFSC, a nanoparticle-embedded hydrogel system for cell delivery, which enhanced the therapeutic efficacy of DFSCs and promoted periodontal regeneration in a rat model. Collectively, our study reveals a novel function of IGFBP5 in mitigating DFSC senescence and presents a promising strategy for combating periodontal bone loss.

Link: https://doi.org/10.1038/s41368-026-00463-2

Cancers are primarily age-related conditions for a range of reasons, such as the decline of the immune system's ability to find and destroy cancerous cells, a rising burden of senescent cells providing a more hospitable environment for cancerous growth, and the fact that the cells of older people have a greater burden of somatic mutations than younger people. The interesting part of this paper is that normal cells in cancer patients exhibit a higher burden of somatic mutations than normal cells in healthy individuals, thus suggesting that random mutational damage, and particularly that occurring in stem cells that can spread out into tissues over time to form the patterned outcome over overlapping mutations known as somatic mosaicism, raises the odds of a cancerous combination of mutations occurring.

Self-renewing normal tissues generate several somatic mutations at each division. Previous studies have reported that cancer cells have more mutations than their normal counterparts. It is not obvious why dramatic differences in mutational burdens between normal tissues and cancers should exist. To fully understand human tumorigenesis, the increase in mutational burden across cancers will have to be understood. In this study, we provided a systematic comparison of mutational burdens in normal and cancer cells from 5 different organs, revealing a 4-fold increase in mutational burden in cancerous versus noncancerous cells.

Three proposed hypotheses could account for the increased mutational burdens in cancer: the classical hypothesis, in which driver gene mutations explain the higher mutational burden; the catastrophic hypothesis, in which extreme mutational events lead to large-scale genomic alterations; and the tail hypothesis, in which differences in baseline mutation rates among individuals account for the differences. Testing through orthogonal observations showed that the observed medians and distributions of mutational burdens in cancers could be explained by the hypotheses to various degrees of significance, and only the tail hypothesis could easily explain the increase in median mutational burdens in the normal tissues of patients with cancer compared with the normal tissues of noncancer patients.

Overall, this study characterizes an increased mutational burden across multiple types of cancer compared with normal tissue and provides insights into the contributing factors. A tenable hypothesis proposed in this study involving fundamental differences in baseline mutation rates among individuals could have implications for cancer prevention strategies.

Link: https://doi.org/10.1158/0008-5472.CAN-26-0117

The tissues of the mammalian body span a broad range of regenerative capacity, from the highly regenerative liver to the minimal regenerative capabilities of the brain and the heart. We might speculate that the evolutionary road to a reduced capability of regeneration in the central nervous system results need to retain structure that stores memory. The heart incorporates a complex electrical system, and the need to retain the structure of this system may also place constraints on the level of regeneration that can take place following injury. Heart damage, such as that resulting from a heart attack and consequent transient loss of blood supply to regions of the heart, heals poorly, and is typically characterized by fibrosis that is disruptive to heart tissue structure and function. It sets the patient on a downward course towards mortality.

Here, researchers investigate one small part of the regulatory system that determines heart cell activities following injury. They uncover a possible way to improve mitochondrial function and reduce the formation of fibrotic structures in injured heart tissue. Notably, they also demonstrate that it is insufficient to enhance the replication of heart muscle cells if the goal is improved function. More than only this is needed. Regeneration is a complex time and space dependent interplay between multiple cell types in injured tissue; it should not be surprising to find a lack of very straightforward single protein interventions that can improve matters.

A metabolic-epigenetic switch governs multicellular cardiac repair following succinate dehydrogenase inhibition

The adult mammalian heart exhibits only a negligible capacity for regeneration following injury. Metabolic reprogramming has emerged as a promising strategy to enhance regenerative capacity in the adult heart. Succinate dehydrogenase (SDH), a protein complex which links the tricarboxylic acid (TCA) cycle and electron transport chain, has been extensively studied in ischemia-reperfusion injury, where malonate reduces succinate accumulation, mitochondrial reactive oxygen species and tissue injury following reperfusion across multiple mammalian models. Moreover, mutations in SDH drive profound metabolic reprogramming in multiple cancers characterized by enhanced glycolysis and Warburg-like metabolic states. Therefore, we hypothesized that transient SDH inhibition could metabolically reprogram the adult heart toward a more regenerative state.

We previously demonstrated that transient pharmacological inhibition of SDH with malonate promotes regeneration after myocardial infarction. Here, we integrate single-nucleus RNA sequencing and ATAC-seq to reveal multicellular transcriptional and epigenetic reprogramming underlying this response. Cell-specific deletion of the Sdhb subunit of SDH dissected contributions of SDH inhibition; cardiomyocyte-specific Sdhb deletion transiently increased cardiomyocyte proliferation but did not improve post-myocardial infarction function, whereas myofibroblast-specific Sdhb deletion suppressed myofibroblast activation and fibrosis and improved cardiac function.

SDH inhibition promoted reductive mitochondrial metabolism and remodeled H3K4me3-marked and H3K27me3-marked chromatin states in cardiomyocytes and fibroblasts. Integration of CUT&RUN, chromatin accessibility and transcriptional profiling identified regulatory targets linking metabolic and epigenetic remodeling to regenerative responses. Together, these findings establish SDH as a multicellular regulator of cardiac regeneration and define distinct cell-specific mechanisms contributing to the regenerative effects of transient pharmacological SDH inhibition.

Any sufficiently complex set of biological data that changes with age can be used as the basis for an aging clock. Well established machine learning techniques can identify patterns and find optimal correlations between algorithmic combinations of measurements taken from the data and outcomes of interest, such as age, mortality risk, risk of age-related disease, and so forth. For all that we are now many years into the development of aging clocks as a technology, it still remains to determine how best to use them to accelerate research and development of therapies to treat aging. In principle, a rapid measure of the state of aging should allow better progress towards rejuvenation therapies. In practice, it is impossible to trust that any given clock will react in the right way to efforts to treat aging, and the only sure way to find out is to run long and expensive life span studies. Until this core challenge is solved, clocks cannot add much to the pace of development.

Biological aging clocks offer estimations of aging and dementia, yet scalability is limited. We introduce a large-scale, cross-national speech clock derived from 2928 individuals across five Latin American countries, spanning healthy controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-language/language-dominant frontotemporal dementia (nldFTD/ldFTD). Multimodal acoustic and linguistic features were trained with supervised models to estimate chronological age, generating speech age gaps (SAGs) as cross-sectional markers of deviations from chronological age, with positive values interpreted as relatively older-appearing speech profiles.

SAGs differentiated diagnostic groups (HCs < patient groups, with AD < nldFTD < ldFTD). This pattern was associated with clinical/cognitive domains. SAGs correlated with phosphorylated tau (p-Tau217) in AD and social exposome in HCs and AD. Brain clocks (structural/functional/combined) were associated with SAG in AD, nldFTD, and ldFTD. Epigenetic age correlated with SAGs in HCs and AD across Hannum, Retroclock, and OMICmAge, whereas ldFTD associations were limited to Retroclock and OMICmAge. These results indicate that SAGs capture cross-sectional multilevel aging-related variation and may offer a scalable, culturally adaptable, low-cost biomarker candidate for research in underrepresented global settings.

Link: https://doi.org/10.1126/sciadv.aef9864

Added to the growing list of specific ways in which the gut microbiome can contribute to degenerative aging, researchers here note that indole produced by gut microbiobes provokes a chain of events that worsens the maladaptive inflammatory immune response to the damage of an ischemic stroke, increasing the overall harm done. Like many of these recent single metabolite discoveries, there is a single point of intervention that may be used to reduce the impact of indole on the immune system, and thereby improve stroke outcomes.

The gut microbiota modulates systemic immunity and neurological diseases, yet the underlying mechanisms remain unclear. Here, we identify the enrichment of indole-producing Escherichia coli being associated with worse outcomes in mice and patients with ischemic stroke. Microbial indole triggers an aryl hydrocarbon receptor (AHR)-dependent response in dendritic cells (DCs). DC-specific AHR deletion improves stroke outcomes and preserves intestinal conventional type 1 DCs. AHR deletion also promotes immunoregulatory and migratory transcriptional signatures and enhances CCR7-dependent migration in vitro.

Pharmacological AHR inhibition favors gut-derived DC accumulation in the meninges, accompanied by increased regulatory T cells (Tregs) and reduced neuroinflammation, while Treg depletion abolishes the neuroprotection conferred by AHR inhibition. Detrimental effects of indole-producing Escherichia coli, indole administration, and microbiota transplantation from patients with stroke are attenuated in DC-specific AHR-deficient mice. These findings define a microbiota-AHR axis that programs intestinal immune responses before brain injury and highlight microbial tryptophan metabolism as a tractable therapeutic target.

Link: https://doi.org/10.1016/j.cell.2026.09.013

Cancer survivors who underwent chemotherapy or radiotherapy in the course of putting their cancer into remission have been shown to exhibit an increased burden of senescent cells relative to healthy peers. This is thought to explain the observed reduction in life expectancy and increased odds of unrelated cancers in cancer survivors. In general, these individuals are aging more rapidly than would be the case with a lesser burden of senescent cells, as these errant cells generate inflammatory signaling that is disruptive to tissue structure and function throughout the body.

Evidence suggests that interventions like exercise that upregulate the cellular maintenance processes of autophagy can reduce the pace at which cells become senescent, and perhaps help to spur greater immune mediated clearance of lingering senescent cells over time. This is one of the mechanisms by which exercise can improve late life health and reduce mortality risk, though of course it is challenging to identify the relative importance of the many and varied plausible mechanisms at work. Exercise changes a great deal of the operation of cellular biochemistry for the better.

Cancer survivors make a good natural experiment: how well exercise works to improve health in these individuals provides a point of comparison with the extensive data on the aged population in general, one that might help pinpoint the importance of cellular senescence in human aging. Today's open access paper is a report of such a study conducted in cancer survivors, and one might compare the results with any number of similarly structured studies conducted in similarly aged people without cancer.

Exercise slows biological aging in breast cancer survivors: secondary analysis of a randomized trial

Sedentary breast cancer survivors within 5 years of diagnosis were randomized to a remotely delivered exercise intervention or a contact-matched health and wellness condition. Whole blood samples and cognitive assessments were obtained at baseline, 6, and 12 months. Epigenetic ages and differential methylation were calculated. A subsample of 124 participants with complete data was analyzed.

The Exercise arm showed slower epigenetic aging than the Health and Wellness arm over the 12-month study, according to GrimAge2 and DNAmFitAge clocks. Changes in epigenetic aging were significantly correlated with alterations in attention and self-reported cognition, with faster epigenetic aging associated with greater cognitive decline. Furthermore, genome-wide analysis of the blood epigenome identified differentially methylated CpG sites, some mapping to genes enriched for brain-derived neurotrophic factor (BDNF) signaling pathways.

The first human application of partial epigenetic reprogramming of aged tissues, using adeno-associated viral (AAV) vectors, was not in fact the first patient dosed in the recently launched Life Biosciences clinical trial for optic neuropathy. Instead, a few older and entrepreneurial individuals in the longevity community made use of the AAV gene therapy experience accumulated in recent years by organizations in the more reputable end of the medical tourism industry (e.g. Triple Helix Science in particular, but also BioViva and others with lower profiles) in order to responsibly manufacture and use reprogramming therapy. The medical tourism community tends not to generate formally published and peer-reviewed data, sadly, but in this case some of those involved may choose to share data further along the line, given enough time to see results.

AAV is something of a special case among modes of advanced therapy. Many of the good AAV serotypes with well defined behavior are in the public domain, there is broad, ongoing industry experience in manufacture and use in clinical trials to draw upon, and manufacture is relatively straightforward. Other forms of gene therapy vector remain locked down by patent holders, or are much harder to work with safely, or have relatively little of a manufacturing and development community. That will change over time. That AAV gene therapy is now more democratized, more accessible, and spreading into the medical tourism community is a preview of how things will be in the future for a much larger range of advanced medicine: both more accessible, but at the same point in time robust data on effects and effectiveness will be harder to uncover.

Kenneth Scott was born in 1942 and Helga Sands was born in 1938. Their KHL Foundation works with scientists, physicians, and biotechnology developers to help develop and adapt promising rejuvenation technologies for practical human application, beginning with the generation that needs them now. To this end a small number of people have received an experimental 11-gene therapy containing reprogramming factors OCT4, SOX2, and KLF4 (OSK) developed through a Triple Helix Science initiative. One of those recipients, Christine Scott, received the treatment on March 11, 2026. The therapy was administered submucosally with cognitive function as its principal target. Expression of the OSK components is controlled through a doxycycline activation regimen.

The underlying gene-therapy initiative is led by Patrick Sewell, MD, and Triple Helix Science. KHL is supporting the initiative, including through the participation and monitoring of Christine Scott, who in prior years had experienced substantial cognitive and neurological decline following a severe adverse reaction attributed to ciprofloxacin. To the best knowledge of Sewell, Scott, and Sands, these treatments represent the first administrations of OSK to humans. KHL has identified no publicly documented earlier human OSK administration and is continuing to assemble and review the treatment chronology before making an unqualified worldwide-first claim.

"This is not an announcement that we have proved that OSK reverses cognitive decline. It is an announcement that human application has begun. Now we can monitor what actually happens, learn from it and adapt. Gene therapy is becoming increasingly practical. I've already seen the cost of the technology fall dramatically. The next challenge is moving credible science into responsible human application and learning from what happens."

Link: https://khlfoundation.com/resources-center/madrid-2026-press-release/

AMPK is the target of a range of interventions known to modestly slow aging in short-lived species. Like much of the complex array of evolved machinery that responds to various forms of cellular stress with improved maintenance, repair of damage, and a consequent slowing of aging, AMPK is involved in the regulation of energy metabolism. Many of these interventions, such as metformin, are far from robust. The animal data is mixed. One might argue that this is in part because the effects on the behavior of AMPK are indirect, as researchers do in this paper. Still, their direct approach to activating AMPK still produces only a modest effect on life span, and does so in species known to be far more receptive to life extension via metabolic alteration than is the case for humans. One wouldn't expect great things to emerge from attempting this in our species.

AMP-activated protein kinase (AMPK) is a fundamental sensor of metabolic status and stress, which is universal throughout eukaryotes. AMPK plays a central role in energy homeostasis and is therefore an attractive therapeutic target in health and disease. AMPK consists of a heterotrimer, with a catalytic α subunit and regulatory β and γ subunits, and displays strong evolutionary conservation across eukaryotes, as evident from sequence alignments between the human, fly, worm, and yeast orthologues. Maximal kinase activity of AMPK requires phosphorylation of a conserved threonine in the α subunit.

Many studies utilise pharmacological targeting of AMPK, for instance by the anti-diabetic drug metformin, which activates AMPK indirectly by altering the cellular AMP/ADP:ATP ratio. To overcome the complexity and non-specificity of metformin, studies with direct AMPK activators are essential to fully appreciate the therapeutic potential of AMPK in health and ageing. Here, we apply the direct AMPK activator compound 991 in yeast, worms, flies and mice to investigate its potential pro-longevity effects. We demonstrate that direct activation of AMPK with the compound 991 extends lifespan in Drosophila melanogaster, Caenorhabditis elegans, and Schizosaccharomyces pombe. In mice, 991 treatment induces a pro-longevity proteomic profile, highlighting the potential for translation to mammals. Overall, our study provides important proof-of-principle for AMPK as a pharmacological target with longevity benefits.

Link: https://doi.org/10.1111/acel.70721

Hundreds of mitochondria in every cell work to produce adenosine triphosphate (ATP), a chemical energy store molecule needed to power cell activities. Mitochondria evolved from symbiotic bacteria, and are now fully integrated as components of the cell, with much of their original DNA moved into the cell nucleus. Mitochondria become dysfunctional with age, reducing their production of ATP, increasing oxidative byproducts, and causing maladaptive inflammatory reactions. This is an important contribution to the disruption of cell and tissue function that takes place in aged tissues.

Unfortunately, mitochondrial dysfunction, while well established and readily measured, is also enormously complex and incompletely understood. Many different contributing mechanisms are plausible, but it is a challenge to determine which of them are more or less important than the others. So far, attempts to improve mitochondrial function in older individuals via pharmacology and supplements have struggled to improve on the effects of exercise, suggesting that the mechanisms targeted are not those with the largest effects on function, or at least are not in and of themselves sufficient to improve function.

In today's open access paper, researchers outline one of the many contributing issues to mitochondrial dysfunction. Their focus is on muscle tissue, but much of the underlying problem generalizes to other tissues. The structure of the inner mitochondrial membrane relies upon the presence of cardiolipin, but cardiolipin production declines with age. This triggers changes in mitochondrial function that muscle tissue reacts to with remodeling of the distribution of fiber type in additional to any other issues that arise. Experiments in a mouse lineage engineered to lack cardiolipin suggests that replacing lost cardiolipin can help to restore function, but one would want to see that same study repeated in aged mice before taking it at face value.

Mitochondrial membrane lipid cardiolipin controls fiber-type adaptations in aging muscle via estrogen-related receptor γ

Skeletal muscle is composed of fiber types that span a continuum of contractile and metabolic properties, enabling the tissue to meet diverse functional demands. Along this spectrum, slow-twitch (type I) fibers show high mitochondrial oxidative capacity, whereas fast-twitch fibers comprise both oxidative (type IIa) and glycolytic (type IIx and IIb) subtypes that rely differently on oxidative versus glycolytic metabolism for force generation. Diminished mitochondrial function disrupts systemic energy homeostasis and is a hallmark of myopathies and aging. Yet, seemingly paradoxically, myopathies and aging also lead to selective atrophy of glycolytic fibers and a shift toward oxidative metabolism. The timing and mechanisms driving this fiber-type-specific shift remain unclear. Whether diminished mitochondrial function has a causal role in eliciting adaptive measures or is merely a marker of age- and disease-related decline is unknown.

Mitochondrial function is heavily shaped by the inner mitochondrial membrane (IMM), which coordinates cellular and organismal homeostasis by modulating macronutrient exchange, bioenergetic capacity, fusion and fission, and interactions with other organelles. The IMM's distinct curvature is conferred by a unique lipid composition, most notably the phospholipid cardiolipin (CL). Here we show that synthesis of cardiolipin causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle.

By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell-autonomously orchestrate fiber-type adaptations in aging and myopathies.

The immune system of the brain and body are distinct from one another, separated by the blood-brain barrier that lines blood vessels passing through the central nervous system. In health and youth, only small numbers of immune cells from the body pass in the brain, but this number increases considerably with advancing age and the presence of neurodegenerative disease. The blood-brain barrier leaks, and immune cells from the body finding their way into the brain in ever greater numbers are thought to maladaptively promote inflammation, causing dysfunction and damage in brain tissue. Here, researchers find an approach to slowing down this passage of immune cells into the brain, producing benefits in a mouse model of neurodegeneration.

CXCR3 is a well-defined chemokine receptor expressed by T cells, predominantly on activated T helper 1 (Th1)-polarized CD4+ and cytotoxic CD8+ T cells. Its canonical chemokine ligands, CXCL9, CXCL10, and CXCL11, are induced by interferon gamma (IFNγ) and are abundant during chronic inflammation. Upon homing to tissues, activated T cells amplify immune responses by secreting chemokines and cytokines such as IFNγ to facilitate cellular damage. In peripheral tissues, CXCR3-ligand interactions orchestrate T cell recruitment and infiltration into tissues, and some lines of evidence suggest a role in neuroinflammatory conditions.

We hypothesized that the CXCR3 axis is an important chemotactic gradient for brain-infiltrating T cells in tauopathy, thereby linking peripheral immune activation to tau-driven brain injury. To address this, we established an acute model of brain T cell infiltration via stereotaxic injections of recombinant IFNγ into the hippocampus. Using this model allowed us to confirm that antibody-mediated blockade of CXCR3 and genetic deletion of Cxcr3 or Cxcl10 prevented brain T cell infiltration. This confirmed that acute central nervous system injection of IFNγ could result in brain T cell infiltration and a putative role for CXCL10 and CXCR3 in this infiltration.

In a mouse model of tauopathy and neurodegeneration, chronic systemic anti-CXCR3 treatment markedly reduced parenchymal CD4+ and CD8+ T cell accumulation, attenuated neurodegeneration, and improved aspects of cognition. CXCR3 blockade decreased microglial major histocompatibility complex (MHC)-II expression without broadly suppressing classical disease-associated inflammatory phenotypes. Single-cell RNA sequencing and flow cytometry further revealed a reduction in the proportion of activated CD4+ T cell populations and elevated CD8+ T cell terminal exhaustion in the brain.

Link: https://doi.org/10.1016/j.neuron.2026.08.030

Researchers here discuss the chronic inflammation of aging as a contribution to the bidirectional relationship between the loss of bone mineral density leading to osteoporosis and neurodegenerative pathology leading to cognitive impairment. As they point out, the best interpretation of the correlation between these two aspects of aging is that underlying processes contribute to both forms of degenerative aging. The chronic inflammatory signaling characteristic of aging is one of the best candidate mechanisms, given what is known of its effects on bone tissue and brain tissue at the detail level.

This review consolidates existing evidence into an integrative immunopathological framework in which inflammaging - the chronic, low-grade, sterile systemic inflammatory state driven by senescent cells and their senescence-associated secretory phenotype (SASP) - is examined as a shared upstream driver that concurrently reconfigures skeletal remodeling and central neuroimmune dynamics through the bone-brain axis. Meta-analytical evidence indicates that osteoporosis is associated with a substantially elevated risk of cognitive impairment (odds ratio = 2.01), and that cognitive impairment carries a reciprocally increased risk of osteoporosis (risk ratio = 1.56) - with Alzheimer's disease conferring a particularly high risk (risk ratio = 1.70). This bidirectional association is best interpreted as the shared output of multiple interlocking aging mechanisms rather than as a direct causal relationship between the two conditions.

At the molecular level, persistently elevated SASP-derived cytokines (IL-6, IL-1β, TNF-α) engage RANKL-dependent osteoclastogenesis in bone and prime microglial neuroinflammation in the central nervous system. Chronic NF-κB signaling and NLRP3 inflammasome activation, amplified in preclinical models by mitochondrial DNA release via the cGAS-STING axis, sustain this dual pathological output. Within the bone-brain axis, bone-derived endocrine signaling is remodeled during aging: osteocalcin (OCN) secretion declines, while osteocyte-derived sclerostin (SOST) rises and may antagonize Wnt/β-catenin signaling in both compartments. Blood-brain barrier disruption and peripheral immune-cell infiltration further amplify central neuroinflammation.

Candidate bone-brain dual-targeting interventions - senolytics (dasatinib plus quercetin), NLRP3 inhibitors, cGAS-STING blockade, GLP-1 receptor agonists, and microbiota-targeted strategies - are discussed with explicit reference to current evidence level, safety concerns, and translational limitations, rather than as established co-therapies. Dual-endpoint randomized trials enriched for elevated inflammaging biomarkers are needed before any of these agents can be positioned for clinical use in bone-brain comorbidity.

Link: https://doi.org/10.3389/fimmu.2026.1874465