Fight Aging!

Atherosclerosis is the development of fatty plaques that narrow blood vessels and eventually rupture to cause a stroke or heart attack, the most common cause of human mortality. Atherosclerotic plaque is a consequence of a runaway process of failure in the behavior of cells responsible for clearing excess cholesterol from blood vessel walls. Cholesterol is needed by every cell in the body, but largely only manufactured in the liver. A complex system of transport particles moves cholesterol to and from the liver via the bloodstream. Macrophages in the blood vessel walls clean up excess cholesterol and move it back into the bloodstream, but as aging progresses these macrophages become ever more vulnerable to being overwhelmed by localized cholesterol excess. Eventually, a plaque forms as an area of inflammation and toxic cholesterol and cholesterol derivatives, drawing in macrophages to be killed, adding their mass to the plaque.

As you may know, I founded Repair Biotechnologies with Bill Cherman back in 2018 that has since been developing a means to regress atherosclerotic plaque. The biggest challenge for present cardiovascular medicine is that the primary strategy of lowering circulating LDL cholesterol via lifestyle, statins, PCSK9 inhibition, and other more recently developed methods only slows plaque growth and very slowly over years somewhat stabilizes the most unstable plaques. It does not produce sizable or reliable regression of plaque, and this is why atherosclerosis remains the single largest cause of human mortality: 27% of all deaths are via heart attack and stroke, and other varieties of cardiovascular disease caused by obstructive plaque may contribute meaningfully to the demise of another 10-15% of our species. Here I'll point out a recent interview and update on our progress and explanation of our lead drug and how it works.

Developing a Drug To Reverse Heart Disease

So let's get straight into the lead candidate. REP-0003, can you give us the quick, layman's version on how that works?

Firstly, it's actually REP-0004 now that is the lead candidate. We updated the sequence, but these two drugs are both very similar. They are lipid nanoparticles that encapsulate messenger RNA (mRNA) and then deliver it directly to the liver and nowhere else in the body. It goes to the liver via the normal mechanisms of lipid nanoparticle delivery. The particles are sized to pass through the blood vessel walls for glands like the liver, and the liver is the usual destination for things that are injected intravenously anyway.

Secondly, there's a ligand on the surface that only interacts with receptors present on hepatocytes in the liver, so that then delivers the mRNA into the cells through the receptor-mediated endocytosis; the mRNA escapes the endosome into the cell, where it is processed into a fusion protein. That fusion protein is just a selection of human proteins that are not normally expressed together in any cell. When acting together they very selectively break down only excess intracellular free cholesterol. By free cholesterol, I mean unmodified cholesterol.

This produces a variety of benefits to your liver, because excess free cholesterol serves no useful purpose and is toxic if you have too much of it inside a cell. Normally, a cell will attempt to take that free cholesterol and keep just a little bit of it, and the rest of it gets esterified into lipid droplets or put into the cell membrane or handed off in some way. But, if you get fat or you get old, in both cases, this process stops working as well, and you have too much free cholesterol inside your cells. I should emphasize this really isn't just a problem of obesity. You can have thin people with excessive intracellular free cholesterol in their liver and elsewhere in their bodies.

Now, when you reduce free cholesterol in the liver, the organ kicks it back into working properly. It also makes the liver feel like it's in a cholesterol deficit, even if it isn't. So, it will try to pull as much cholesterol back from the rest of the body as it can. Various mechanisms of homeostasis will dial up reverse cholesterol transport, and drag back free cholesterol from the rest of the body to the liver, where it then gets intercepted by our fusion protein and broken down. This feedback loop operates for the few days that the protein is present in the body as a result of an mRNA therapy, and the outcome is a draining of excess free cholesterol everywhere, not just the liver. That reduces inflammation. It improves tissue function throughout the body, outside the brain at least, as the brain has its own fairly distinct cholesterol metabolism.

The two outcomes of greatest interest at the moment are, firstly, a dramatic regression of atherosclerotic plaque very rapidly, and secondly, a reversal of liver disease, such as metabolic dysfunction-associated steatohepatitis. You also get a reduction in fibrosis. It happens very rapidly and dramatically, and that is how the drug works.

How receptive has the FDA been to this approach?

They like it. The FDA looked at our materials for the pre-IND and said, "Yes, we agree. Go do this." No, they didn't note any meaningful objections, just the usual small feedback. They granted us an orphan drug designation for treatment of the accelerated atherosclerosis that characterizes the rare disease of homozygous familial hypercholesterolemia, and they don't hand that out like candy. The FDA has to really be interested in what you're doing for that to happen. We were granted orphan drug designation mid last year, and right now we're applying to the Rare Disease Evidence Principles (RDEP) program, which is a new next-level addition to the orphan drug designation. This was announced late last year, and right now nobody really knows, including the FDA, how this program will work out in detail. In principle, it should speed the path to approval for these rare disease therapies where it's somewhat more difficult to organize trials than for a more common condition. The FDA is going to rely more on preclinical evidence and post-approval assessment of the drug than on trials. We'll see how it develops.

This interview was conducted a few months ago at this point, and Repair Biotechnologies has since been granted eligibility for the Rare Disease Evidence Principles program.

It remains an open question as to whether anything discovered about the roots of individual variation in life expectancy within a species will give rise to usefully effective interventions to treat aging. Some researchers hold up the passage of late life aging in centenarians as a goal to aim for - but centenarians, while having evaded death for longer than most, are nonetheless greatly impacted by degenerative aging and exhibit significant dysfunction and mortality rates. We must aim higher, to create therapies that produce results that do not happen naturally in old people, such as comprehensive clearance of senescent cells in aged tissues, replacement of damaged mitochondria with functional mitochondria, and so forth. Actual repair of dysfunction, not just slowing it down a little.

Ageing is an inevitable, yet highly heterogeneous process shaped by genetic, epigenetic, and environmental influences. While most individuals experience progressive functional decline, a minority exhibits accelerated degeneration due to rare pathogenic mutations, whereas others achieve exceptional healthy longevity. This continuum - from progeroid syndromes to centenarians - provides a unique framework to examine how deleterious and protective genetic variants differentially modulate conserved biological pathways. Genetic models of accelerated ageing reveal mechanisms driving premature functional deterioration, whereas studies of exceptionally long-lived individuals highlight variants associated with resilience, stress adaptation, and preserved homeostasis. Together, these extremes define a genetic dichotomy that informs, but does not deterministically predict, ageing trajectories.

This review critically highlights current evidence on genetic factors and molecular mechanisms that regulate human ageing across this spectrum. Beyond established hallmarks such as cellular senescence and chronic inflammation, we discuss emerging pathways implicated in successful ageing, including hypoxic adaptation, transcriptional and chromatin regulation, autophagy, and metabolic reprogramming. We further evaluate epigenetic clocks as quantitative tools for assessing biological ageing, emphasising their strengths, limitations, and context dependence. Throughout, we distinguish between genetic associations, mechanistic findings, and preclinical evidence, explicitly addressing gaps, biases, and translational uncertainty.

Link: https://doi.org/10.1016/j.arr.2026.103176

Epidemiological evidence is strong for particulate air pollution to contribute to dementia risk. The primary underlying mechanism is thought to be increased systemic chronic inflammation via the interaction of pollutants with lung and airway tissue. Dementia is an age-related condition, however, and thus regardless of efforts to reduce air pollution, the incidence of dementia is increasing as the population undergoes demographic aging, where the proportion of old people grows over time. Demographic aging changes nothing of the moral and ethical arguments centered around prevention of suffering and death for developing means to effectively treat aging as a medical condition, but it does make the economic motivation more pressing. Suffering age-related disease and loss of function is expensive, both in terms of direct costs and opportunity costs. Sadly, the powers that be seem much more motivated by economic concerns rather than by ethical and moral concerns.

Air pollution was recently recognised as one of the 12 major modifiable risk factors for dementia. Although China's clean air policies have substantially reduced fine particulate matter (PM2.5) concentrations since 2013, the implications for dementia-associated mortality remain unclear in the context of an ageing population. In this health impact assessment study, we integrated exposure data, population data, exposure-response association data, and mortality information from multiple sources, to estimate PM2.5-attributable dementia deaths in China from 2000 to 2024.

From 2000 to 2013, PM2·5-attributable dementia deaths increased from 55,668 to 106,571. From 2013 to 2024, despite substantial declines in population-weighted PM2.5 concentration, PM2.5-attributable dementia deaths dramatically increased from 106,571 to 171,420, with population ageing as the dominant driver of increasing dementia deaths, contributing approximately 67,000 PM2.5-attributable dementia deaths, with reductions in PM2.5 exposure avoiding approximately 11,000 deaths during this period.

Link: https://doi.org/10.1016/j.lanhl.2026.100841

One of the defining features of the field of aging research is the lack of consensus at the detail level regarding what exactly aging is, why it happens, how it happens, how best to measure it, and how best to treat aging as a medical condition. Thus a fair amount of the scientific debate in the field is either implicitly or explicitly arguing over the definition of the field in some way, not just reporting data or proposing programs. The past three decades have been characterized by the development of overarching taxonomies of the manifestations and mechanisms of aging that attempt to provide answers to pressing questions for scientists such as "what should we study in order to improve our understanding of aging" and "how should we proceed towards the development of therapies for aging".

Initially the Strategies for Engineered Negligible Senescence (SENS) emerged from scientific outsiders as both a proposed description of root causes of aging and a call to action to do something about these causes from a humanitarian perspective. Later, the Hallmarks of Aging and Pillars of Aging emerged from scientific insiders, descriptions of manifestations of aging with no attached ethical imperative, the Hallmarks in particular coming to dominate discussions of the taxonomy of mechanisms of aging. The Hallmarks, for better or worse, are now treated much like a checklist for planning out future research aimed at understanding or treating aging. How these shifts within a field occur, how a field of scientific endeavor describes itself, is of course a well studied topic in and of itself. Thus one can find commentary such as today's open access paper on the transformation of the aging research field in recent decades.

The Hallmarks of Aging: Paradigms and Scientific Progress

Aging matters. Many lives are at stake. In this work, we have examined in detail what is probably the most influential conceptual framework in contemporary geroscience, analyzing the Hallmarks through philosophical tools that had also already been partially invoked in the literature of the field itself.

In Kuhnian terms, the dominant model in contemporary geroscience understands aging as the accumulation of molecular and cellular damage, and the Hallmarks represent its most characteristic exemplar: the canonical structure through which normal science operates, defining what counts as valid evidence, what types of intervention are considered pertinent, and what problems are considered solvable. From a Lakatosian perspective, this same process can be interpreted as the consolidation of a theoretical core based on the same ontology, surrounded by a protective belt of alternative models and classifications - such as the Strategies for Negligible Senescence, SENS - in the debate, and which allow the empirical horizon to be expanded without questioning their fundamental assumptions.

From Laudan's approach, this process can be understood as a reorganization of the problem-space of the field, where the consolidation of the framework has not eliminated the open empirical or conceptual problems, but has restructured them within a more coherent methodological environment. From Kitcher's view, its success can be explained in more contextual than purely theoretical terms, as a result of its organizational capacity and its diffusion as a common reference. Finally, following Galison's ideas, the Hallmarks can be understood as a pragmatic device that harmonizes methods, data, and scientific communities, functioning as a stabilized trading zone in which collaboration can continue even in the absence of full theoretical convergence.

This reading also connects with a concern that is increasingly visible in the recent debate: the problem of consensus in the biology of aging. Faced with the persistence of disagreements on fundamental questions, our analysis suggests that the role of the Hallmarks in this context may have been greater than has usually been recognized. Rather than resolving the disagreement, they have contributed to structuring the field by allowing its practical coordination despite the absence of theoretical consensus, and we believe we have offered sufficient reasons to justify this interpretation. This structuring function becomes especially clear when one considers the recent catalogue of 100 open questions in research in the field. What is significant is not only the magnitude of the issues identified, but the fact that many of them are formulated within the conceptual space that the Hallmarks have helped to stabilize. Returning to Laudan, this can be interpreted as evidence of how a framework contributes to defining which problems are considered scientifically relevant.

The expression of genes from nuclear DNA is determined by the structure of nuclear DNA, meaning which regions are spooled and inaccessible versus which regions are unspooled and accessible to transcription machinery. This is visible as the structure of chromatin in the cell nucleus, where chromatin is the name given to the complex structures formed by nuclear DNA and its supporting molecules such as histones. Epigenetic mechanisms control DNA structure by adding and removing decorations to DNA and histones, and this control changes with age in ways that are ultimately detrimental. A range of potential approaches to treatments for aging revolve around the question of whether there are safe enough, effective enough ways to change this epigenetic landscape to make the structure of DNA more youthful in nature, and thus gene expression and cell behavior also more youthful in nature. The most well developed example is partial reprogramming, but it is not the only one.

Aging is associated with detrimental changes in chromatin structure and gene expression, contributing to inflammation, metabolic decline, and tissue dysfunction. SIRT6, a histone deacetylase, plays a key role in maintaining chromatin integrity and promoting longevity. Our multi-omics approach, combining ATAC-seq, methylome, and RNA-seq shows that aging leads to increased chromatin accessibility in the male murine liver, accompanied by upregulation of inflammation and downregulation of metabolic pathways.

Remarkably, SIRT6 overexpression reverses these changes in chromatin structure, reducing inflammation and enhancing metabolic function. Notably, ETS family members and liver-enriched transcription factors are enriched in regions with increased and reduced accessibility during aging, respectively. ChIP-seq shows that H3K9ac, but not H3K56ac, is associated with increased accessibility during aging, and that SIRT6 can reverse this effect. Furthermore, AAV-mediated SIRT6 overexpression in aged male mice demonstrates that SIRT6 not only slows age-related chromatin changes but can also reverse them, rejuvenating chromatin accessibility to a youthful state.

Link: https://doi.org/10.1038/s41467-026-73115-y

Researchers here report on a recent conference focused on bringing the viewpoint of the physics community to the study of aging. This is largely a matter of building models of aging for a variety of purposes, such as breaking down aging into different conceptual components to make more sense of the observed, somewhat confusing range of outcomes in different species, better predicting which classes of intervention may be most effective in the treatment of aging, or better understanding which aspects of cellular biochemistry are more versus less important in aging.

The first session focused on applying physics laws to understand the aging process, work on how to model three aging patterns - exponentially rising death with late slowdown, exponentially rising disease incidence with late decline, and linear decline of physiological function with age. The saturating removal (SR) model equation has damage production that rises with time (due to accumulating damage producing units) and damage removal process that saturates at high damage plus noise. This equation can explain all three aging patterns.

Furthermore, the model can analyze the shape of the survival curve to tell if geroprotective interventions act on damage production (survival scaling) or damage removal/threshold (survival steepening). Based on the SR model, longevity interventions act by reducing the damage production rate and/or increasing the damage removal rate, both of which are inherently age-dependent processes in this model. He theorized that interventions that prevent damage production will lead to scaling of both lifespan and sickspan, which leads to scaling of the lifespan curves, while interventions that increase damage removal rate can compress the sickspan, leading to the steepening of the survival curve.

Mathematical models can "find simplicity in complexity" when studying the highly intricate process of aging. By integrating diverse data and enabling in silico experiments, such models offer powerful tools to understand aging mechanisms. Researchers presented work on developing new computational tools such as the multi-scale aging model, which integrates nutrient signalling, metabolism, damage accumulation, and growth, enabling exploration of metabolic changes as the cell ages and becomes exposed to stress and protein damage. As the cell gets older, the timing and pattern of normal metabolic states change, so-called metabolic phases. By accounting for these altered patterns, the model can help guide metabolic interventions for lifespan control, by identifying points where interventions might have different effects depending on when they occur in the cell's life.

Link: https://doi.org/10.18632/aging.206378

The gut microbiome is made of thousands of microbial species, many of which conduct activities necessary to health. Our tissues have evolved to at least somewhat rely upon the molecules produced by many of these species as they process the food we eat. Unwanted species are also present, generating harmful products that trigger inflammation and tissue dysfunction. With age, the size of harmful microbial populations increase at the expense of the size of helpful microbial populations. Our health suffers as a result. Animal studies have demonstrated that restoring a more youthful composition to the gut microbiome of an old animal, such as via fecal microbiota transplantation from a young donor, can improve health and lengthen life.

The study of communication between cells has moved on from considering only single secreted molecules, one at a time, to incorporate an attempt to understand the role of extracellular vesicles. These vesicles are membrane-wrapped packages containing many different molecules. The scientific community presently categorizes vesicles by size, such as exosomes versus microvesicles. Cataloguing their contents and the factors determining size and contents is a work in progress at the earliest stage; all too little is mapped out. Vesicles are generated and taken by cells constantly. Just as this happens between our own cells, we might expect vesicles to be an important form of communication between the gut microbiome and our cells. Some of that communication will be detrimental to tissue function, as illustrated in today's open access paper.

Gut Luminal Exosomes in Young and Old Mice: Multi-Omic Characteristics and Regulation of Gut Permeability

Aging is a multifaceted process impacting physiological, genomic, metabolic, and immune functions. This study investigates the role of luminal fecal exosomes (LFEs) in age-associated metabolic dysfunction. We analyzed LFEs from the intestines of young (3-month) and old (24-month) male and female C57BL/6 mice to characterize age-related differences in exosomal proteomic and microRNA cargos. To explore interactions between LFEs and the gut microbiome, naïve young mice were gavage fed with LFEs from old donors, followed by 16S rRNA sequencing. Gut permeability in vitro and in vivo and systemic metabolic effects were assessed.

Bioinformatic analyses identified specific proteins and microRNAs linked to insulin resistance and barrier dysfunction. Heatmaps and principal component analysis revealed distinct differences in LFE profiles between young and old mice. Notably, LFEs from old mice impaired gut barrier integrity and metabolic function in young recipients, with reciprocal effects noted in older mice when receiving LFEs from young mice. Multi-omics profiling, including proteomics and microRNA sequencing, identified age-dependent and gender-related changes in LFE cargo, encompassing host- and microbiome-derived proteins and microRNAs. These age-specific profiles were associated with pathways implicated in cancer, neurobehavioral changes, and metabolic dysfunction.

Our findings highlight that LFEs from old mice are enriched with proteins and microRNAs involved in insulin resistance and gut barrier disruption. Together, these findings identify gut luminal exosomes as age-dependent mediators of microbiome-host communication that contribute to intestinal barrier dysfunction and metabolic decline.

Cyclarity Therapeutics has been processing safety data from a phase 1 safety trial of a cyclodextrin drug to bind 7-ketocholesterol, a toxic form of oxidized cholesterol that contributes to a range of conditions. The company is initially focused on atherosclerosis, the formation of fatty plaques that obstruct blood vessels and ultimately rupture to cause a stroke or heart attack. It is thought that 7-ketocholesterol may be a significant factor in the toxic environment of atherosclerotic plaques, alongside other forms of cholesterol that are also harmful to cell function in larger amounts. Recall that atherosclerosis progresses in its later stages because macrophages are called to the plaque to attempt to repair it, are overwhelmed by the plaque environment, become inflammatory, and die, adding their mass to the plaque. The field is searching for better ways to take the stress off macrophage cells and thus tip the balance towards at least a slower growth of plaque over time.

Data from a study offers the first clinical evidence that 7-ketocholesterol (7KC), a root cause of atherosclerosis, can be safely targeted and removed from the human body, marking a pivotal milestone toward moving cardiovascular treatments from managing arterial damage to achieving true plaque reversal. Results of the phase 1 trial evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of UDP-003. UDP-003 is the first clinical-stage therapeutic discovered using Cyclarity's proprietary drug discovery AI Platform which engineers cyclodextrin molecules to reverse disease and protect against future accumulation of harmful molecules and aging pathologies. These engineered cyclodextrins precisely attract and encapsulate hydrophobic molecules such as forms of cholesterol, rendering them dissolvable in water and thus destined to be purged from the bloodstream.

Most cardiovascular drugs, including statins, anti-inflammatories, and RNA-based therapies, work systemically throughout the body to alter how cholesterol, inflammation, and gene expression are regulated. In contrast, Cyclarity's UDP-003 binds directly to 7KC, a root cause of plaque buildup, then facilitates urinary excretion of it. Much like removing rust from metal, this approach directly targets a key source of damage within plaque with the goal of reversing and preventing atherosclerosis, a primary underlying cause of cardiovascular disease, and does so locally within the plaque to reduce risks of unintended systemic effects.

7KC is considered a biologically active driver of cardiovascular disease, contributing to inflammation, cell death, and plaque instability and has emerged as an important target in emerging therapies aimed at treating the disease at its root. In addition to cardiovascular disease, 7KC is implicated in Alzheimer's disease, metabolic dysfunction-associated steatohepatitis (MASH), and other age-related conditions. Cyclarity is currently enrolling patients with acute coronary syndrome (ACS) into the efficacy cohort of the ongoing Phase 1 trial, which includes pre- and post-treatment coronary CT angiography (CCTA) to assess plaque changes.

Link: https://cyclaritytx.com/cyclarity-unveils-first-ever-clinical-data-demonstrating-excretion-of-oxidized-cholesterol/

As aging emerges from the accumulation of a relatively small number of underlying forms of damage and dysfunction, we might expect even very different aspects of aging to correlate with one another. Maybe not a very tight correlation if the two aspects are far removed from one another in terms of the connection of proximate causes and their interactions, but ultimately they arise from the same roots. Here, researchers rely on the interconnected nature of aging in order to make use of retinal aging to assess bone aging. The researchers use an aging clock derived from retinal imagery and show that greater predicted age correlates with greater loss of bone mineral density and risk of fracture resulting from the progression of osteoporosis.

Osteoporosis is a common condition that weakens bones and raises the risk of fractures, especially in older adults. However, many individuals are not diagnosed until after a fracture occurs, in part because the standard diagnostic test, Dual-energy X-ray Absorptiometry (DEXA), is not always readily accessible. We therefore investigated whether retinal photographs, taken from the back of the eye, could help identify people at higher risk of osteoporosis. This possibility arises from the idea that the retina may reflect the body's overall biological aging.

Hence, we used an artificial intelligence-derived age marker, RetiAGE, to estimate retinal biological age and test the association between retinal age and osteoporosis. In the Singapore study of 1,965 older adults, older retinal biological age was associated with lower bone mineral density (BMD), lower BMD T-scores, and higher fracture risk scores. In the UK Biobank study of 43,938 participants, older retinal biological age also predicted a higher risk of developing osteoporosis over time, even after accounting for major risk factors. These findings suggest that retinal biological aging may reflect broader aging processes related to skeletal health. Retinal imaging may therefore provide a simple, non-invasive, and accessible way to support opportunistic screening for osteoporosis risk.

Link: https://doi.org/10.1371/journal.pdig.0001360

Ken Scott and Helga Sands have been features of the longevity industry conference circuit for about as long as there has been a longevity industry; I first met Ken at at the big Undoing Aging conference in Berlin in 2019, just before COVID started up, and he became one of the early investors in Repair Biotechnologies, the company I co-founded with Bill Cherman. Ken is an enthusiastic self-experimenter for personal gain in health and very much an advocate for something better than the present medical regulatory system, particularly when it comes to the long span of years that it takes for therapies to move from laboratory to clinic. Ken is now in his 80s and not one to be patient; there is a powerful argument there for some form of improvement in terms of the right to try and the primacy of patient choice when considering any balance of risk versus reward in access to new medical technologies.

Ken and Helga recently launched the KHL Foundation, a medical tourism concern that seeks to expand the availability of gene therapies that are already deployed or under development. These are relatively safe approaches to gene therapy that have emerged from the efforts of Bioviva and competitors such as Triple Helix, alongside newer developers such as Unlimited Bio and others. These companies are largely focused on the use of local injections of viral vectors, as that minimizes the potential for adverse immune reactions, and on a few genes and proteins known to robustly produce benefits in animal models: klotho, follistatin, telomerase, and so forth. This seems a growing market, and I expect it to continue to expand in much the same way that the stem cell industry expanded, for better or worse. Few companies will publish data, it will be hard to distinguish high quality versus low quality clinics, but over time a few companies will take what has been learned, pay the regulatory costs, and bring the best approaches to clinics in the US and Europe. Meanwhile, for anyone who doesn't want to wait, there is medical tourism.

KHL Foundation

The KHL Foundation, founded by Kenneth Scott (b. 1942) and Helga Sands (b. 1938), is dedicated to making proven rejuvenation therapies available now for people over 60 who refuse to age on schedule. We founded the KHL Foundation because we believe that people over 60 deserve access to the best scientifically grounded rejuvenation therapies available today, not ten or twenty years from now. We test therapies on ourselves. We partner with trusted clinicians. We share results openly. And we move with the insouciance of youth, because we know how precious time is.

The Rejuvenation Cocktail delivers three carefully selected gene therapies that target the core mechanisms of aging. Each gene enhances one of the pillars of vitality - muscle, mind, and metabolism - to restore youthful performance and resilience. Results are designed to be long lasting, with effects that will persist for 15 to 20 years. Klotho is often called the longevity gene. It supports neuronal health, maintains vascular flexibility, and reduces inflammation. Follistatin suppresses myostatin and activin - both limit muscle growth. Increasing its levels enhances muscle regeneration. Sirtuin 1 is a master regulator of mitochondrial function and cellular energy. The treatment includes same day intramuscular injections of follistatin gene therapy and intranasal application under local anesthetic of klotho and sirtuin 1 gene therapies.

The composition of the gut microbiome changes in detrimental ways with age, leading to increased production of inflammatory metabolites and reduced production of beneficial metabolites. There is ample evidence for this to contribute to aspects of aging. Rejuvenation of the composition of the gut microbiome via various approaches has been shown in animal studies to improve health and extend life span. A human trial has started for fecal microbiota transplantation from young donors to old patients, but it will take a few years for data to be published. The study noted here describes a quite different approach to the problem, which is the use of ultrasound to bias the gut microbiome composition; it used only a small number of mice, and it is entirely unclear as to how ultrasound might produce this outcome. So: interesting, but more research needed.

This study employed a natural ageing mouse model to investigate whether noninvasive low-intensity pulsed ultrasound (LIPUS), a therapeutic ultrasound, delivered to the abdomen, could alleviate age-related muscle deterioration and whether its effects were linked to gut microbiota modulation. C57BL/6 mice were maintained until 92 weeks of age, after which abdominal LIPUS stimulation was administered for 8 weeks. At 100 weeks, both forelimb and hind limb grip strength were assessed prior to euthanasia.

Naturally aged mice exhibited sarcopenia-like characteristics, including impaired muscle performance, reduced myofiber diameter and decreased muscle weight (n = 6). Age-related renal impairment promoted the accumulation of advanced glycation end products (AGEs) in skeletal muscle, triggering pro-inflammatory signalling cascades characterized by elevated COX-2, phosphorylated NF-κB, NLRP3, IL-1β, and Caspase-1 (n = 5-6). LIPUS treatment significantly improved muscle strength (forelimb and hind limb grip strength, n = 6) and muscle mass (n = 6), while suppressing inflammatory mediators (n = 5-6).

Gut microbiota analysis showed that LIPUS increased microbial diversity (n = 5-6) and altered taxonomic composition, enriching anti-inflammatory taxa such as Lactobacillus, Bifidobacterium, Faecalibaculum and Coriobacteriaceae_UCG_002 (n = 6). Correlation analysis indicated that these LIPUS-enriched taxa were positively associated with enhanced muscle performance. These data suggest that LIPUS mitigates sarcopenia in naturally aged mice by restoring muscle integrity and attenuating inflammation, possibly via gut microbiota regulation.

Link: https://doi.org/10.1002/jcsm.70291

Age-associated B cells are a problematic subset of the B cell population of immune cells that emerges in later life. In recent years researchers have uncovered various ways in which these cells contribute to the pathology of specific age-related conditions. The existence of age-associated B calls makes clearance of B cells an interesting topic; there are ways to destroy the entire B cell population in the body, which then reconstitutes itself within a few weeks minus any senescent or age-associated or other problem B cells. Unfortunately there doesn't appear to be any meaningful effort underway to bring such immune clearance approaches to the clinic. Studies so far remain preclinical, meaning assessments in animal models of age-related disease, and looking over correlations in human data. That said, one strong focus that may give rise to clinical efforts is the contribution of age-associated B cells to autoimmune conditions.

Age-associated B cells (ABC) are a unique subset of antigen-experienced B cells that were first identified in old female mice. ABC have both physiological and pathological roles in humans and they are important in the progression of some immune disorders, chronic infections, and even in the aging process. These cells are differentiated from other B cell subsets by the expression of transcription factors T-bet and surface markers such as CD11c+, CD21/CD35-, CD23-.

ABCs are heterogeneous cell populations that are involved in the development of autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis by producing inflammatory cytokines and autoantibodies, antigen-presenting to T cell, and developing a specific humoral response and memory. Discovering the exact function of ABCs and their related regulatory factors can be effective in introducing them as therapeutic targets and diagnostic biomarkers. In this manuscript, we aimed to explain the role of these cells and their function in autoimmune diseases so that by reviewing past studies, a new window can be opened towards a better therapy approach of mentioned autoimmune diseases, in the future.

Link: https://doi.org/10.1186/s12979-026-00564-w

The immune system declines with age, and this causes more than just a progressive failure to adequately defend against infectious pathogens. The immune system is deeply involved in normal tissue function, maintenance, and regeneration. It is also responsible for destroying senescent and potentially cancerous cells throughout the body. Thus immune decline both degrades tissue function and increases the risk of cancer. Researchers tend to bucket aspects of immune aging into two broad categories, immunosenescence and inflammaging. Immunosenescence is the loss of capacity, while inflammation is a continual overactivation of the immune system, placing it in a state of chronic, unresolved inflammatory signaling.

There are obviously sex differences in the pace and structure of degenerative aging. In our species, women live longer but suffer greater disability. Given that the immune system touches on so much of heath and tissue function, we might expect to find a catalog of specific differences in immune system aging between the sexes. This is indeed the case. Today's open access paper provides a tour of what is known on this topic. It is possible that comparisons between the sexes might teach us useful things about aging, but equally the causes of aging are the same from individual to individual. The differences lie in the way in which damage spirals out into interacting webs of dysfunction and further damage. A therapy that targets an underlying cause of aging should be useful to all older individuals, though it is certainly possible that it will be more useful for some categories of individual than for others.

The problem with one-size-fits-all medicine: Biological sex and the aging immune system

The immune system can be divided into two categories: innate and adaptive. Innate immune cells (e.g., neutrophils, macrophages, and dendritic cells [DCs]) release cytokines and pro-inflammatory mediators that coordinate the immune response and protect the host. By contrast, the adaptive immune system provides a targeted and long-term defense against pathogens. While innate responses are rapid and general, adaptive immunity is slower and highly specific.

Like other biological systems, the immune system undergoes age-related functional decline. Indeed, the latest hallmarks of aging recognized by the field now include chronic inflammation as a distinct hallmark, recognizing its crucial role in aging phenotypes. Changes in the immune system can both promote or restrain aging across multiple organs. Two main characteristics of immune aging are 'immunosenescence' and 'inflammaging'. Together, these processes promote the development of age-associated diseases (e.g., atherosclerosis, dementia, osteoarthritis). Understanding hallmarks of immune aging is critical, as they influence both life span and healthspan.

In addition to shared age-related changes, sex differences further shape immune aging. Sex differences lead to divergent patterns of life span and healthspan between males and females. Overall, females tend to live longer than males, yet experience more age-related and immune-related diseases, whereas males are more likely to develop severe outcomes from infections. This discrepancy, in which females outlive males but spend more years in poor health, is referred to as the 'morbidity-mortality' paradox. One potential driver of sex differences in disease susceptibility and health outcomes is maternal-fetal microchimerism, which has been shown to modulate the immune system. However, sex differences in disease susceptibility and health outcomes are thought to be mainly driven by the effect of sex chromosomes (XX versus XY) and/or sex hormones on the immune system.

Indeed, the X chromosome contains many immune genes, some of which escape X inactivation with aging, contributing to stronger immune responses in females. By contrast, the Y chromosome encodes relatively few immune genes, which contributes to sex differences in immune system robustness. Reflecting this difference in copy number, females generally produce more cytokines than males regardless of age. Sex-steroid receptors are expressed broadly in immune cells, though absolute levels vary. Estrogens exert both pro-inflammatory and anti-inflammatory effects, depending on concentrations, whereas androgens suppress immune activity.

With aging, females maintain adaptive immune responses more effectively than males, suggesting that the female immune system has higher baseline activity, with stronger expression of adaptive versus innate immune pathways. Conversely, aging males rely more heavily on innate immunity, which may partly explain heightened innate responses but poorer outcomes following infections and vaccinations. This sex difference may be due to overall higher levels of testosterone in males, which has been shown to have important impacts the immune system over time. However, while stronger immune responses provide protection in females, they also increase autoimmunity risk with age. Sex differences in immune aging highlight how differences in both adaptive and innate immunity shape lifelong susceptibility to infections and age-related diseases, emphasizing the importance of sex as a biological variable in both immunological research and clinical care.

Far too little research into infectious disease and the development of vaccines and other approaches to therapy employs old animals. It is accepted that infectious disease becomes worse with age and treatments become less effective, and then left to the smaller aging research community to see if anything can be done about it. Here, for example, is an example of research in which scientists attempt to build an incrementally better picture as to what exactly is going wrong in the aging immune system, in the specific context of a single infectious disease, tuberculosis. Matters move slowly.

Aging profoundly impairs immune competence, a phenomenon termed immunosenescence, rendering older adults (≥60 years) highly vulnerable to infectious diseases such as tuberculosis (TB). Clinically, older adults exhibit reduced vaccine effectiveness alongside heightened susceptibility to TB, with epidemiological data indicating 2-3 times higher TB incidence and up to four times higher mortality than younger patients. Despite this growing burden, current TB research predominantly employs young adult mouse models (6-8 weeks old, equivalent to ~18-year-old humans), which do not adequately capture the immune landscape of older hosts. Evidence from studies suggests that old mice exhibit higher bacterial burden, delayed CD4+ T cell responses, and altered immune activation compared to younger counterparts. However, the impact of immunosenescence on bacterial clearance dynamics, immune cell phenotypes, and host responses during TB treatment remain largely unexplored.

Here, we monitored the immunopathology, frequency, and functionality of immune cells across extreme age groups of C57BL/6 mice following low aerosol dose infection (100-120 cfu) with TB and treatment with rifampicin and isoniazid (RIF-INH). Up to 6 weeks post infection, mycobacterial load in tissues (lung, spleen, and liver) of old (17-19 months old) and aged (31 months old) C57BL/6 mice was similar to that of young (2-4 month old) mice. However, at two weeks post-treatment, older mice showed a slower rate of TB clearance in the lungs. TB-infected old mice had higher splenic T-follicular cytotoxic (TFC)-like cells, and proteomic analysis of flow-sorted CD4+CD44+ T cells revealed deregulated mitochondrial proteins (4-hydroxy-2-oxoglutarate aldolase, aspartate aminotransferase, and prostaglandin E synthase), suggesting impaired mitochondrial function.

Collectively, these findings suggest that age-associated immune alterations may disrupt immunometabolic pathways, thereby contributing to the delayed TB clearance. Targeting immunometabolic dysfunction therefore represents a promising strategy to enhance TB treatment efficacy and reduce disease burden in older populations.

Link: https://doi.org/10.18632/aging.206374

Given access to a large body of biological data from people of various ages, creating an aging clock from that data is fairly straightforward and costs relatively little in time and funding. Thus clocks are proliferating, a new one published by an academic research group every few months. Most will vanish into obscurity. The problem is not the lack of a perfect clock for any given situation, but the lack of understanding as to how any given clock will react to a novel potential approach to slowing or reversing aging. The real potential value of clocks is not risk estimation for patients, but rather the rapid assessment of potential therapies to treat aging. But that latter use is challenging when one can't trust that a clock will in fact react appropriately and correctly judge the degree to which aging has been slowed or reversed.

Identifying individuals at risk of dementia is essential for prevention and targeted disease-modifying strategies. We investigated whether mid-life metabolomic ageing is associated with incident dementia and its age of onset and assessed joint associations and interactions with APOE genotype and dementia polygenic scores. In the UK Biobank, plasma metabolites were quantified at baseline. Metabolomic age (MileAge) delta reflects the difference between metabolite-predicted and chronological age. Dementia was identified via health records.

Amongst 223,496 participants, 3,976 developed dementia. A higher MileAge delta was associated with higher hazards of all-cause, unspecified and vascular dementia (hazard ratio, HR = 1.61) and earlier onset. Key metabolites were lipids, lipoproteins, and amino acids. MileAge delta and genetic risk were jointly associated with dementia. Individuals with a high MileAge delta and two APOE ε4 alleles had a 10.30-fold higher all-cause dementia risk. Thus metabolomic ageing and genetic risk likely represent independent biological pathways contributing to dementia risk.

Link: https://doi.org/10.1002/alz.71280