Fight Aging!

An important goal in the research community is to build a robust measure of biological age, the burden of age-related damage and dysfunction contributing to disease and mortality, that can be used to rapidly assess the quality of any potential intervention to slow or reverse aging. One of the reasons why the longevity field moves slowly is that, in the absence of a robust measure of biological age, it takes a long time to assess any given therapy by running life span studies in mice, and repeating such studies in humans is infeasible. So there is relatively little drive to compare, contrast, and optimize approaches shown to slow or reverse aging in laboratory species. One might hope that a robust measure of biological age would speed up the research community's efforts to build a basis for greater human longevity.

There are obviously a great many existing biomarkers of aging, some of which are very straightforward to measure. Grip strength is a popular one, and today's open access paper advocates for imaging of the degree of fat infiltration into muscle tissue. The issue is that these measures are not known to be robust. Either their relationship with outcomes in aging varies greatly from individual to individual, or they cannot be trusted to accurately reflect effects on outcomes produced by interventions. Any measure of aging can be calibrated against any specific form of treatment for aging, to determine whether or not it is helpful in that case, but then one is back to needing long-running, expensive studies to make progress. It doesn't help the bigger picture because it doesn't accelerate the field.

Myosteatosis: an emerging biomarker of aging

Adipose tissue infiltration into skeletal muscle (i.e., myosteatosis) has emerged as an independent contributor to metabolic disorders and declines in skeletal muscle function with age. It remains unclear whether myosteatosis is a marker of aging or simply a consequence of disease or disuse. This review summarizes evidence from population-based epidemiologic studies that utilized non-invasive imaging to measure myosteatosis and to evaluate age-related changes among community-dwelling middle aged and older adults.

Myosteatosis consistently increased with age, independent of weight change, and the burden of myosteatosis was greater among women, and non-White racial and Hispanic ethnic groups after accounting for physical activity levels, chronic disease burden, and overall body size. Myosteatosis accumulation is not uniform throughout the body and is differentially associated with clinically meaningful age-related outcomes, including changes to gait, balance, muscle strength, and physical function. Hormonal, cellular, genetic, and lifestyle differences comprise the biological pathways that may lead to age-related increases in myosteatosis.

Future work in diverse populations using standardized imaging methodologies could include longitudinal measures of biological markers to better understand the biological precursors that accompany the phenotypic change. In conclusion, while myosteatosis does not accumulate uniformly with age across sex, race, or anatomical location, evidence from several well-characterized epidemiologic studies supports myosteatosis as a potential marker of aging, independent of weight change, body size, activity level, or chronic disease burden.

Any sufficiently complex biological data that changes with age can be used to construct an aging clock. Here, researchers report on a clock derived from images of the nuclei of hematopoietic stem cells. Nuclear DNA exhibits structural changes in response to circumstances, regulated by epigenetic decorations to DNA and its supporting proteins, as regions unfold or are compacted. The structure of DNA determines which gene sequences are exposed to translation machinery, and thus whether or not a given gene is expressed. Some of these structural changes are characteristic of aging, and thus machine learning approaches should be able to visualize age-related differences in imaging.

The functional decline of the hematopoietic system during aging affects organismal function and contributes to reduced healthspan. Quantifying hematopoietic aging holds great scientific and clinical relevance. Alterations in chromatin architecture are a well-established hallmark of aging that encode rich and informative signatures of the aging process, yet they remain largely unexplored as quantitative markers.

Here, we present an interpretable deep learning approach based on convolutional neural networks, ChromAgeNet, that learns changes in the spatial features of chromatin architecture upon aging of hematopoietic stem cells (HSCs). We trained our algorithm on 3D microscope images of DAPI-stained HSC nuclei to discriminate between young and aged murine HSCs, achieving an area under the receiver operating characteristic curve (AUROC) of 0.77 ± 0.03. This approach outperforms classical machine learning models trained on handcrafted chromatin features from the same dataset. We then applied explainable artificial intelligence techniques, identifying chromatin entropy, peripheral heterochromatin, and chromatin condensates as predictive markers.

As a proof of concept, we evaluated the potential of our model as a phenotypic screening tool for aged HSCs treated with epigenetic drugs to detect rejuvenation. Altogether, we demonstrate that changes in chromatin organization can be modeled via machine learning to predict age-associated chromatin states in the hematopoietic compartment. Our developed framework, ChromAgeNet, serves as an interpretable algorithm to unravel the intricate relationship between chromatin changes and stem cell aging, and advance high-throughput drug screening for rejuvenation therapies.

Link: https://doi.org/10.1111/acel.70656

The antimicrobial drug K21 acts via disruption of bacterial membranes, but is also known to produce improved wound healing, which suggests the involvement of mechanisms other than antimicrobial activity. Here, K21 is shown to favorably modulate macrophage activity, in that exposure improves the operation of the mitochondrial quality control processes of mitophagy in macrophages, which in turn improves mitochondrial function. Delivery of K21 to nematode worms resulted in longer life spans, as one might expect from any intervention that improves mitochondrial function without meaningful side effects.

Here, we sought to use single-cell RNA-seq to explore the diversity of the innate immune response and to understand its potential to be reprogrammed by antimicrobial therapy. Antimicrobials primarily target specific aspects of the pathogen's lifecycle to inhibit its spread, yet few drugs can effectively control viruses, bacteria, and other pathogens, including fungi, while improving cellular health. The only possible way to achieve this is to alter the host immune repertoire to effectively inhibit pathogenic survival. We chose to study the antimicrobial compound K21, a quaternary ammonium silane compound that not only exhibits broad-spectrum effects against viruses, bacteria, and fungi but also demonstrates potent wound healing activity.

As macrophages and macrophage polarization orchestrate the phases of wound-healing, shifting from pro-inflammatory signaling that combats infection to pro-regenerative signaling that recruits fibroblasts and keratinocytes to repair the epithelial tissue, we reasoned that K21 might operate by modulating macrophage properties, classes, and/or dynamics. We chose to examine the effects of K21 on monocyte-derived macrophages from human peripheral blood monocytes (PBMCs) because of their technical accessibility, their ability to be isolated in a relatively naïve state and co-cultured with other cell types, and their controllable M1/M2 polarization.

We found that supplementing cytokine and cell-surface marker profiling with scRNA-seq transcriptomic analysis provides unparalleled resolution of macrophage diversity and plasticity, allowing us to demonstrate how treatment with K21 remodels the macrophage repertoire both inside and outside the cell. We show that a key aspect of K21 treatment is the induction of mitochondrial fission and autophagy (mitophagy). We turned to the distantly related model system C. elegans to examine whether the mechanism used by K21 is used systemically in vivo and evolutionarily conserved. K21 induced DRP-1-mediated mitochondrial fission and mitophagy in vivo without impairing viability, development, or fertility; indeed, it reprogrammed metabolic gene expression and extended lifespan in these nematodes, consistent with its effects observed in mammalian cells.

Link: https://doi.org/10.26508/lsa.202603852

Aging clocks have yet to fulfill their promise, which is to produce a robust measure of biological aging that can be used to rapidly assess the results of potential therapies to slow or reverse the progression of aging, such as via repair of underlying cell and tissue damage that causes aging. This is because these clocks are produced by machine learning approaches applied to data from a patient population, such as omics data, that changes with age. Exactly why any specific combinations of measures identified in this way, such as the state of DNA methylation at scores of specific CpG sites on the nuclear genome in the case of epigenetic clocks, can predict age or mortality risk is a mystery. There is no way at present to connect a given CpG site or protein expression level or feature in imaging data to what is known of mechanisms of aging. Thus a clock cannot be trusted to assess a new approach to treating aging without calibrating it against that approach in slow, expensive life span studies. Which defeats the point of the exercise.

One of the ways in which researchers approach this challenge is to gathering as much data as possible for as many clocks as possible, in a search for patterns and understanding that will allow clocks to be better trusted. Prospective memory is the ability to remember to follow through on a previously made plan. Like all forms of memory function, it declines with age as the mechanisms of aging produce progressively greater neurodegeneration in brain tissue. In today's open access paper, researchers report on correlations in existing data between epigenetic age acceleration measured in the 40s and prospective memory dysfunction a decade later. The study wasn't large enough and the approach used to assess memory dysfunction was not robust enough to detect correlations at a given age between epigenetic age acceleration and memory function at that time. This suggests that early midlife is an important foundation for later health.

Linking epigenetic age acceleration to self-reported daily memory lapses: evidence from the National Study of Daily Experiences

DNA methylation algorithms, such as DunedinPACE, are increasingly used to study the mechanisms of aging and to identify associations with risk factors in adult development and aging. Growing evidence suggests that an increased pace of epigenetic aging is associated with cognitive impairment and dementia, but the correlation between epigenetic aging and subjective cognitive complaints (eg, forgetting a name or forgetting to take your medication), an early marker of dementia risk, remains unexplored.

Using data from The National Study of Daily Experiences (NSDE) and Midlife in the United States (MIDUS; N = 232), we examined the relationship between epigenetic aging rate (ie, DunedinPACE) and self-reported daily memory lapses (ie, occurrence, irritation, interference) in midlife and older adults. We found no significant main effects of the rate of epigenetic aging on self-reported memory lapses; however, a significant chronological age interaction indicates that among the comparatively younger adults in the sample (age 40-49), faster than average rates of aging (ie, higher DunedinPACE) were associated with more prospective memory lapses approximately a decade later as well as greater reports of prospective memory lapse irritation and interference. Additionally, for respondents in their forties, a higher DunedinPACE was associated with both greater prospective memory lapse irritation and interference.

These results suggest that early midlife may be a sensitive period during which the rate of epigenetic aging is more influential on cognitive health outcomes.

First generation stem cell therapies have become widespread; they are readily accessed in medical tourism clinics, and are also available for a range of issues in more regulated parts of the world. Initially it was hoped that transplanted cells would engraft and survive to assist tissues in repair and regeneration, but it has become clear that this is not how the therapies produce benefits. Rather it is a matter of signals generated by the transplanted cells in the short time they survive that beneficially alter the behavior of native cells. Unfortunately, while effects such as months-long suppression of chronic inflammation are fairly reliable, other hoped for improvements such as the stimulation of greater regeneration or regression of disease remain highly unreliable outcomes. One might ask where the field goes from here, and the consensus seems to be (a) attempts to make the generation of stem cells for transplantation much more robust and the outcomes more reliable, and (b) moving away from cells to instead manufacturing secretome or extracellular vesicle therapies derived from stem cell cultures.

Mesenchymal stem/stromal cells (MSCs) continue to drive innovation in regenerative medicine, yet the field is undergoing a critical evolution from the early concept of cellular engraftment to complex paracrine-mediated tissue repair. While MSCs were initially thought to repair tissues via direct engraftment and differentiation, accumulating evidence demonstrates that functional recovery relies predominantly on paracrine effects rather than direct cellular replacement. Through paracrine signaling, MSCs secrete a rich array of bioactive molecules - including cytokines, chemokines, growth factors, and extracellular vesicles (EVs) - that stimulate tissue regeneration, promote angiogenesis, and modulate inflammation, apoptosis, and fibrosis.

Despite these biological advantages and their ability to be expanded ex vivo for therapeutic use, the clinical outcomes of MSC-based interventions remain highly variable across different disease models. While MSCs have demonstrated promising regenerative capacity, their efficacy in complex organ regeneration and chronic inflammatory diseases is often inconsistent. Differences in tissue source, donor characteristics, manufacturing protocols, and the host disease microenvironment collectively influence therapeutic efficacy

To bridge this translational gap, a systematic reassessment of MSC therapies is urgently needed. Beyond the biological characteristics and general applications of MSCs, this review provides a critical, translational perspective on overcoming current clinical bottlenecks. It is our perspective that overcoming present limitations demands a strategic pivot towards precise cell-free MSC-EV therapies and advanced bioengineering strategies.

Link: https://doi.org/10.1016/j.scib.2026.09.057

The commensal microbes of the gut microbiome generate a range of metabolites that are beneficial or necessary to cell function. Levels of a number of these metabolites have been shown to decline with age as the composition of the gut microbiome changes for the worse. Overall the gut microbiome clearly makes a meaningful contribution to health and longevity, as demonstrated by the sizeable benefits resulting from providing a young microbiome to an old animal, but it isn't clear as to how much of these effects derive from changes in the production of any specific metabolite.

Metabolites produced by gut bacteria are taken up by the host and have a direct impact on its health. However, to our knowledge, no studies have investigated the effects of gut bacterial metabolites on the lifespan of the host using gnotobiotic animals colonized with gut bacteria deficient in biosynthetic genes involved in the production of specific metabolites.

Polyamines, such as putrescine and spermidine, are among the most important metabolites of gut bacteria. Previous studies have shown that increasing polyamines in the colon of mice extends their lifespan and biological functions. In this study, we produced gnotobiotic flies colonized with Escherichia coli, in which polyamine biosynthetic genes were deleted or complemented. Gnotobiotic flies were fed a polyamine-free diet, and the effects of metabolites derived solely from gut bacteria on the lifespan of the host were analyzed.

The results showed that polyamines derived from gut bacteria significantly prolonged the lifespan of the flies. Furthermore, the expression of TotM and Halo was suppressed in flies monocolonized with polyamine-producing E. coli compared with those monocolonized with mutant bacteria incapable of producing polyamines.

Link: https://doi.org/10.1128/mbio.01484-26

The effects of calorie restriction and even larger effects of growth hormone receptor knockout on the lifespan of mice have proven to be hard to beat. In large part, this is because (a) aging is the result of a number of very different causes, (b) producing comprehensive rejuvenation will require a number of very different therapies applied in combination, and (c) next to no-one is assessing the results of combination therapies targeting the root causes of aging. One of the other consequences of aging having multiple distinct (but interacting) causes is that it is in principle possible to make good progress on treating a cause of aging without producing an appreciable gain in healthspan or lifespan, or without reversing a given class of age-related disease, because that particular cause is not the limiting cause. If dysfunction results from several different mechanisms, then removing one of them may or may not help, and may or may not help in a sizable way, because the other mechanisms are still sufficient on their own to cause dysfunction. Nonetheless, all of the mechanisms will have to be dealt with to remove that dysfunction.

We can see examples in the development of rejuvenation therapies from recent years that illustrate the range of possible outcomes. Firstly, senolytics to clear senescent cells are very good at reversing age-related conditions in mice, but don't extend life to the same degree as calorie restriction, indicating a strong contribution to age-related disease, but a complex relationship with other aspects of degenerative aging - and those other aspects are enough in and of themselves to produce mortality. Secondly, clearance of amyloid-β aggregates is in principle a good idea, as that protein aggregation can cause pathology in the aging brain, but that clearance does little for patients in later stages of Alzheimer's disease, because other mechanisms become dominant in driving disease progression. With this in mind, today's opinion piece argues for a greater weight to be placed on the assessment of the ability of individual therapies to achieve their stated goal in reduction of specific forms of age-related cell and tissue damage, rather than effects on healthspan or lifespan, and for a greater focus on funding the assessment of therapies in combination, rather than individually.

When Lifespan, Healthspan, and their Surrogates are the Wrong Metrics for the Aging/Longevity Field

Aging is multifactorial. It is several diverse and distinct molecular subproblems. Very effective treatment of aging will clearly require the intelligent combination of several elements (several separate therapeutic interventions). Lifespan and healthspan extension are the ultimate result of very effective comprehensive treatment of adult biological aging pathology. They are the obvious outcome metrics for any final or somewhat comprehensive solution to aging. However, that does not make them, or their surrogates, the right metrics for testing individual interventions or for tracking progress of the field.

To illustrate the essence of the claim about how to evaluate individual interventions, consider a simpler imaginary system in which their are only two subproblems that limit functional lifespan. Pretend that a boat must ferry cargo across a body of water but suffers from 2 main problems: (1) Its hull is old and develops small holes regularly due to direct exposure to the corrosive water, and if uncorrected these holes slowly expand. (2) It must travel over some kelp some of which extends from the bottom close enough to the surface to become tangled in the boats propeller or rudder.

Now consider three interventions: A. Repair/patch the holes in the hull periodically. B. Remove the kelp strands from the propeller periodically. C. Replace the containers that the cargo is carried in with lighter-weight containers such that the boat rides higher in the water, causing both less of the hull to be exposed directly to the water causing fewer holes to develop and causing the propeller and rudder to ride higher where it encounters fewer kelp strands causing fewer to become tangled. Imagine the following: Studies of the effect of intervention C alone show that it extends the useful life of the boat vs. no intervention. Studies of the effect of intervention A alone and separate studies of intervention B alone show that neither alone increases the useful life of the boat vs. no therapy at all. Should we conclude that interventions A and B have no value? No, of course not. The monotherapy studies of A or B alone each left the unaddressed subproblem to eventually worsen to the point of ending the boat's useful life.

Multiple things go wrong in aging. Multiple interventions will eventually be required to do the best job possible at mitigating all these problems to the best extent possible. All that matters is: what is the best overall combination of interventions (for each person at each time). How important each intervention is depends almost entirely on how well it helps the ultimate endpoint of interest within the overall suite of interventions and hardly at all on how well it works with respect to the ultimate endpoint when used by itself, a way in which no one will use it in the long run. Some people want lifespan extension from monotherapy use to demonstrate relevance. This is misguided.

Why is the APOEε2 variant of the APOE gene associated with a lower risk of Alzheimer's disease and slightly longer life expectancy? Past research has investigated the role of APOE in cholesterol metabolism and inflammation in microglia, the innate immune cells of the brain implicated in neurodegenerative conditions. Here, researchers focus instead on pericytes and their role in maintaining the blood-brain barrier. The barrier prevents unwanted molecules and cells from entering the brain, but becomes leaky with age. This leakage of the blood-brain barrier generates inflammation and damage in the brain, and is thought to be an early inciting event in the onset of neurodegenerative conditions.

Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer's disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity.

To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation.

Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated lipid droplet accumulation in APOE3 and APOE4 pericytes.

Link: https://doi.org/10.1093/brain/awag311

Given a wildly successful drug, the standard pharmaceutical industry playbook is to push as hard as possible to find new uses for that drug, an effort that will tend to increase publication on the topic in the academic literature. The drive to classify GLP-1 receptor agonists as an anti-aging drug rather than a weight loss drug is an example of this behavior. While, yes, there are a few interesting preclinical studies suggesting interesting biology going on in the brain at doses too low to cause weight loss, for the most part we are discussing an attempt to find additional anti-aging effects of a drug that makes patients engage in calorie restriction, the most robust anti-aging intervention known to date.

Calorie restriction produces sweeping, incompletely understood, beneficial changes to the operation of metabolism throughout the body, changes that, in preclinical studies in mice, outweigh every pharmacological approach demonstrated to date to slow aging - and most of that pharmacology merely mimics portions of the response to calorie restriction. It seems unlikely that one can analyze the human GLP-1 receptor agonist study data obtained to date and responsibly claim that GLP-1 receptor agonism is doing something meaningfully more for aging than only reducing calorie intake. Maybe it is, maybe it isn't - but this is trying to find a tree in the forest.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events, all-cause mortality, and systemic inflammation in randomized controlled trials, with effect sizes exceeding those predicted from glycemic and weight-related improvements alone. The convergence of these findings with a maturing body of evidence linking metabolic dysfunction to accelerated epigenetic aging has prompted renewed interest in GLP-1 RAs as candidate gerotherapeutic agents. The present review synthesizes contemporary preclinical, mechanistic, and clinical evidence relevant to this question.

The SELECT trial demonstrated a 19% reduction in all-cause mortality (hazard ratio [HR] 0.81) in patients with obesity without diabetes, the FLOW trial demonstrated a 24% reduction in the primary kidney composite endpoint (HR 0.76), and the first randomized evidence of GLP-1 RA modulation of validated DNA methylation clocks was reported in 2025, with significant deceleration of DunedinPACE, PCGrimAge, and PhenoAge over 32 weeks of semaglutide therapy. Mechanistic studies have identified convergent pathways involving the hypothalamic GLP-1 receptor, AMPK/SIRT1 signaling, and microbiome-derived short-chain fatty acid production. The aggregate evidence supports the framing of GLP-1 RAs as a candidate class of geroprotective therapeutics, although definitive trials with prespecified epigenetic aging endpoints, durability follow-up, body-composition assessment, prespecified sex-stratified analyses, and adequate representation of diverse populations remain to be conducted.

Link: https://doi.org/10.1016/j.exger.2026.113325

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