Fight Aging!

The innate immune system becomes increasingly inflammatory with age, in part due to damage and dysfunction in immune cells, in part a maladaptive reaction to a damaged environment. Chronic inflammation is disruptive to tissue structure and function. Macrophages make up a sizable fraction of the innate immune system, resident in tissues and involved in both tissue maintenance and defense against pathogens. A broad range of research is focused on better understanding and potentially manipulating macrophage behavior to obtain desired outcomes, such as a lower level of chronic inflammation in later life.

In today's open access paper, researchers focus on the macrophages resident in fat tissue. Visceral fat is a source of inflammation, and this is one of the reasons why being overweight is increasingly bad for health as life progresses into older age. This research illuminates one of the regulatory elements involved in increasing inflammatory behavior in macrophages in fat tissue, raising its profile as a potential target for anti-inflammatory therapies, and contributing to the bigger picture of inflammatory mechanisms in visceral fat tissue.

GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging

Older individuals have increased risk for infections and subsequent sepsis, in part owing to accumulating adiposity and a dysfunctional immune system. Gerotherapeutics that successfully improve the aged immune response are largely understudied. Our study reveals that the GDF3-SMAD2/3 axis may be a relevant pharmacologic target. GDF3 promotes the inflammatory phenotype of adipose tissue macrophages, contributing to the exacerbation of endotoxemia-induced inflammation in older, but not younger, organisms. GDF3 signals through SMAD2/3 and elicits proinflammatory responses in adipose tissue macrophages, diverging from their canonical immunoregulatory function.

Specifically, the chromatin landscape of adipose tissue macrophages shifts toward inflammation with age, increasing the accessibility of inflammation-associated genes. Our study demonstrates that Gdf3 deficiency can reverse the age-dependent changes in chromatin accessibility and transcription by restoring H3K27me3 levels in adipose tissue macrophages. Furthermore, genetic and pharmacological inhibition targeting the GDF3-SMAD2/3 axis protects against endotoxemia-induced inflammation and lethality in old mice.

The importance of visceral adipose tissue (VAT) in aging and inflammation is corroborated by studies that highlight the immunological role of VAT during metabolic challenge or infection in older organisms. Recent work indicates that B cells-derived IgG elevates macrophage expression of Tgfb, which promotes fibrosis and metabolic decline via SMAD2/3 in aged VAT. Our work builds on this model, providing additional evidence for the importance of B cell-macrophage crosstalk in VAT. We also provide evidence for the GDF3-SMAD2/3 axis regulating the phenotype of B cells. Although it remains unclear whether GDF3 acts synergistically with TGFβ-superfamily cytokines, our findings indicate that the mechanism governing inflammatory VAT microenvironment, driven by adipose tissue macrophages and B cells, may converge on SMAD2/3 signaling.

There is no good therapy for macular degeneration, a form of progressive blindness characterized by dysfunction and death of vital cells in the retina, and particularly for the "dry" form of the condition in which retinal blood vessels have not yet become dysfunctional. Cell therapies represent one possible form of restorative therapy, but it has proven challenging to deliver new retinal cells and have them survive to take over lost function. The publicity materials here report briefly on the state of one cell therapy program, in which researcher employed an engineered patch to support the delivered cells.

Researchers are launching a phase 2b clinical trial examining if stem cells bioengineered to replace failing cells in the retina damaged by macular degeneration could restore eyesight. The cells are attached to an implant - an ultra-thin patch, thinner than a strand of hair - which holds the cells in place. The clinical trial follows early research conducted on a small patient population that showed the implant was well-tolerated, stayed put in the eye and was successfully absorbed into the tissue of the retina. Additionally, 27% of patients had some improved vision.

Age-related macular degeneration affects the eye's macula, which is located in the center of the retina and is responsible for central vision. In advanced cases, the retinal pigment epithelium (RPE) cells, which line the macula and are key in helping the retina produce clear vision, become damaged or destroyed, which leads to vision loss. The retinal implant used in the clinical trial is derived from embryonic stem cells grown into RPE cells in a lab. During an outpatient surgical procedure, surgeons will implant a tiny layer of the lab-produced RPE cells into the retina. Patients will be monitored for at least one year to determine how the implant is tolerated and for any changes in vision. The trial is hoping to enroll 24 patients.

Link: https://news.keckmedicine.org/can-a-retinal-implant-reverse-macular-degeneration/

Senescence of β-cells in the pancreas appears to be an important component of all forms of diabetes, and thus diabetes becomes worse with age as the burden of cellular senescence increases for reasons relating to aging as well as reasons relating to diabetes. Here, researchers use extracellular vesicles derived from stem cell populations to treat aged mice and demonstrate a reduction in β-cell senescence and consequent improvement in function.

Targeting senescent pancreatic β-cells represents a promising therapeutic avenue for age-related diabetes; however, current anti-senescence strategies often compromise β-cell mass. In this study, human amniotic mesenchymal stem cell-derived small extracellular vesicles (hAMSC-sEVs) were identified as a novel intervention that can be used to effectively counteract cellular senescence and preserve β-cell integrity.

We aimed to systemically delineate the molecular mechanisms underlying hAMSC-sEV-mediated reversal of β-cell senescence in age-related diabetes. In oxidative stress-induced and naturally aged β-cell models, hAMSC-sEVs mitigated senescence-associated phenotypes, restored mitochondrial homeostasis, and enhanced insulin secretion capacity. In aged diabetic mice, administering these vesicles significantly ameliorated hyperglycemia, improved glucose tolerance, and reversed β-cell functional decline by reducing senescent β-cell populations, reinstating β-cell identity markers, and suppressing senescence-associated secretory phenotype (SASP) component production.

Mechanistic investigations revealed that the miR-21-5p-enriched hAMSC-sEVs directly target the interleukin (IL)-6 receptor α subunit (IL-6RA), thereby inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation and its subsequent nuclear translocation. This epigenetic modulation alleviated STAT3-mediated transcriptional repression of the mitochondrial calcium uniporter (MCU), rectifying age-related mitochondrial calcium mishandling and insulin secretion defects. Genetic ablation of MCU clearly established the central role of the miR-21-5p/IL-6RA/STAT3/MCU axis in this regulatory cascade.

Link: https://doi.org/10.1111/acel.70327

Cells become senescent constantly throughout life. A senescent cell ceases replication, increases in size, and generates disruptive inflammatory signaling. In youth those senescent cells that fail to undergo programmed cell death are removed by the immune system, but this clearance falters with advancing age. The result is a growing burden of senescent cells that disrupt tissue structure and function, contributing to age-related conditions. The research community is thus very interested in finding ways to selectively remove senescent cells, particularly given the evidence for rejuvenation to result from senescent cell clearance in aged mice.

The metabolism of senescent cells is very different from that of normal cells. Unlike normal cells they are primed to undergo programmed cell death, but held back by a range of mechanisms. Sabotage those mechanisms and a senescent cell dies, but a normal cell is largely unaffected. This is far from the only possible approach to the problem, and new approaches are discovered on a fairly regular basis. Today's open access paper focuses on the regulation of increased glycolysis as an energy source in senescent cells, analogous to the Warburg effect observed in cancer cells. A senescent cell has sizable energy needs, given its activities and size. If this regulation of glycolysis is sabotaged, the senescent cell can no longer support itself and dies.

Abrogation of aberrant glycolytic interactions eliminates senescent cells and alleviates aging-related dysfunctions

Cellular senescence is deeply involved in physiological homeostasis, development, tissue repair, aging, and diseases. Senescent cells (SnCs) accumulate in aged tissues and exert deleterious effects by secreting proinflammatory molecules that contribute to chronic inflammation and aging-related diseases. We revealed that an aberrant interaction between glycolytic PGAM1 and Chk1 kinase is augmented in SnCs associated with increased glycolysis, whose byproduct, lactate, promotes this binding in a non-cell autonomous manner.

This pseudo-Warburg effect of SnCs with enhanced PPP (pentose phosphate pathway) activity is maintained by HIF-2α phosphorylation by Chk1 and subsequent upregulation of glycolytic enzymes, creating a vicious cycle reprogramming the glycolytic pathway in SnCs. HIF-2α also activates FoxM1 expression, which transcriptionally suppresses pro-apoptotic profiles, including BIM, and upregulates DNA repair machineries in SnCs. FoxM1 thus supports the genomic integrity and survival capacity of SnCs during their glycolytic changes.

Chemical abrogation of PGAM1-Chk1 binding reverts these phenotypes and eliminates SnCs through senolysis. Inhibition of the PGAM1-Chk1 interaction improves physiological parameters during aging and inhibits lung fibrosis in mouse models. Our study highlights a novel pathway contributing to the metabolic reprogramming of SnCs and how the use of a new senolytic molecule that targets the PGAM-Chk1 interaction creates a specific vulnerability of those cells to potentially fight age-related diseases.

Researchers have developed many different approaches to selectively destroy senescent cells based on differences in their biochemistry. The use of prodrugs is one way to activate a cell-killing mechanism more specifically in senescent cells. Most such prodrugs make use of the fact that senescent cells express high levels of β-galactosidase, which removes galactose from molecules. A cell-killing molecule can be rendered inert by adding galactose to its structure, and is only activated to a large degree in senescent cells. Here, the cell-killing molecule acts to trigger ferroptosis in senescent cells, an approach analogous to the various ways that have been shown to trigger apoptosis in senescent cells. Senescent cells are primed for programmed cell death via apoptosis and ferroptosis. The mechanisms holding them back from that fate can be targeted fairly safely, as suppression of those preventative mechanisms will not cause cell death in a normal cell that is not primed for programmed cell death.

Accumulation of senescent cells is associated with aging and age-related diseases. However, current clearance therapies targeting senescent cells are often limited by low efficiency, poor specificity, and insufficient penetration. Here we develop a nano-platform composed of a probe (GD) that can be specifically activated by senescent cells, a photosensitizer (chlorin e6, Ce6), and a kininogen peptide (HK) for targeting ferritin, named HK-PCGC.

We show that upon entering senescent cells, GD is activated by high levels of β-galactosidase, releasing fluorescence to excite Ce6. Ce6 then generates reactive oxygen species to eliminate these cells. Additionally, we find that under the guidance of the peptide HK, our system degrades ferritin to trigger ferroptosis, further eliminating senescent cells. Collectively, we demonstrate that HK-PCGC can effectively eliminate senescent cells, reduce the senescence-associated secretory phenotype, and safely improve the physical fitness of aged mice. This study integrates senescent cell responsiveness, laser-free photodynamic therapy, and induction of ferroptosis, offering a potential approach for delaying aging.

Link: https://doi.org/10.1038/s41467-025-67364-6

Research is a highly specialized field of endeavor, and in the matter of aging most scientists maintain a narrow focus in their day to day work. One tissue or one layer of the mechanisms of aging is enough to keep a research group busy for years. Thus one sees papers such as the one noted here, in which researchers focus on the colon specifically, while touching on a range of areas of interest in cellular biochemistry, behavior, and what is known of the aging of complex systems such as the immune system and gut microbiome.

The colon is one of the gastrointestinal organs most profoundly affected by aging. Recent advances in our understanding of both colonic physiology and the general mechanisms of aging have significantly expanded our knowledge of the types and underlying processes of colonic aging. In this review, we summarize current insights into the cellular and molecular mechanisms that drive physiological aging of the human colon. We examine the unique structural and functional features of key components of the colon, including the epithelium, local immune system, microbiome, enteric neurons, and smooth muscle cells, and explore how aging affects each of these cell populations, ultimately impacting overall colonic function.

In the epithelium, increased mutational burden does not appear to be the primary driver of age-related dysfunction. Instead, dysregulation of signaling pathways such as EGF and Wnt is likely responsible for key phenotypic changes. Aged colonic neurons display protein misfolding and axonal dysfunction reminiscent of aging processes observed in the central nervous system. Similarly, smooth muscle cells exhibit impaired contractility, which is associated with disruptions in calcium homeostasis and deficits in cholinergic signaling. At the same time, age-related activation of the local immune system mirrors broader immunosenescence and may be further influenced by shifts in the gut microbiome, although a consistent aging-associated microbiome signature has yet to be identified.

These multifaceted changes, combined with the colon's inherent regional and cellular complexity and the challenges of modeling human colonic aging, continue to fascinate but also pose substantial obstacles for research. Emerging experimental models and clinical strategies offer promising avenues for improving the prevention and treatment of age-associated colonic dysfunction.

Link: https://doi.org/10.1016/j.mad.2025.112143

Lipofuscin is the name given to a mix of modified proteins, lipids, and other compounds that accumulate with age in long-lived cells. The accumulation of lipofuscin has long been considered a form of damage by a minority of researchers; removal of lipofuscin was an early call to action for the Strategies for Engineered Negligible Senescence, for example. There were even a few early, unsuccessful efforts to provide technology demonstrations of approaches to break down lipofuscin, or at least some of its components. Unfortunately, getting rid of lipofuscin isn't a straightforward task. Chemically it is diverse, a mess of many very different molecules, and thus ill suited as a target for the enzyme, antibody, and small molecule development that dominates the field of medical biotechnology. Getting rid of one specific molecule is feasible, getting rid of a hundred very different molecules is much less feasible. Lipofuscin has been largely left alone in favor of easier goals.

In today's open access paper, the authors restate some of the arguments for lipofuscin to be important in the onset and progression of age-related neurodegenerative conditions, and thus to be a therapeutic target worthy of greater attention on the part of the research and development community. This has all been said before! One of the challenges inherent to the development of rejuvenation therapies at this stage of the growth of the field is that there are far more potentially worthwhile areas of focus than there are research groups, companies, and funding to carry out the work. This will likely remain the case until the first generation of therapies to treat aging are approved, widely used in the clinic, and their existence a matter of fact for the average physician, researcher, and person in the street.

Lipofuscin accumulation in aging and neurodegeneration: a potential "timebomb" overlooked in Alzheimer's disease

Lipofuscin, which has long been considered a passive byproduct of aging, is increasingly being recognized as a dynamic modulator of cellular homeostasis. Lipofuscin accumulation is indicative of lysosomal dysfunction and is closely related to redox imbalance and lipid peroxidation - critical pathways implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). Lipofuscin accumulation may contribute to and exacerbate amyloid-β accumulation and toxicity by interfering with autophagic clearance and promoting a highly oxidative environment.

In this review, we propose a reconsideration of lipofuscin from the "aging marker" or "autofluorescence pigment" to an active player in neurodegeneration and AD pathology. This paradigm shift opens new research directions and therapeutic possibilities. Targeting lipofuscin and its clearance may allow interference of upstream of amyloid plaque formation, preserving proteostasis, reducing oxidative damage, and ultimately slowing or preventing neurodegeneration.

We examine the potential interplay between lipofuscin accumulation, lysosomal dysfunction, lipid peroxidation and amyloid-β pathology in AD. We explore how lipofuscin may influence amyloid-β aggregation, clearance, and toxicity and propose mechanisms by which lipofuscin modulates AD progression. Importantly, we summarize evidence demonstrating that lipofuscin is released extracellularly upon neuronal death, thus preparing a highly oxidized environment that results in toxicity and a cascade of events leading to plaque formation and amyloid-β pathology.

Biological age as a concept is a measure of the burden of cell and tissue damage, and consequent dysfunction, that causes risk of mortality and disease. Over the past twenty years researchers have developed a range of approaches, starting with epigenetic clocks, that are attempts to produce a useful measure of biological age. There is considerable debate over the degree to which any of these approaches have succeeded, a debate that will only be settled by the accumulation of a great deal of human data. Ultimately, the real utility of a measure of biological age is the rapid assessment of potential rejuvenation therapies, to steer development towards better approaches that produce larger effects. At present it is unclear as to whether any of the approaches can be trusted to produce useful data given an entirely novel approach to the treatment of aging.

Numerous studies have analysed different aspects of biological age and developed clocks and models to assess biological age and measure the molecular changes due to biological ageing. Not only are there several generations of epigenetic clocks used to estimate biological age, but proteome-based clocks were developed, and metabolome- and microbiome-based clocks are being developed as well. Genomic studies have uncovered several genetic mechanisms that promote longevity, with a focus on protective mechanisms such as protective genetic variants and effective DNA repair systems.

Epigenomic changes that influence biological age are modified by diet and exercise and influenced by early life events. Age-related changes in blood proteome were identified, revealing non-linear and organ-specific alterations. Metabolomic profiles in blood plasma have identified age-related shifts in lipid metabolism and redox balance and demonstrated their application as biomarkers for ageing processes and health outcomes. Microbiomics has shown that the uniqueness and diversity of the gut microbiome reflect biological age and that this can also be measured by microbiome derived metabolites in plasma. In addition, multi-omics approaches have uncovered potential biomarkers that not only reflect the ageing processes but can also serve as targets for personalised interventions.

There are several limitations in selecting reliable biomarkers of ageing. First, there is a lack of consistently identified biomarkers, low methodological standardisation, and limited numbers of cohorts in ageing studies. Currently, ageing appears to be a non-linear process that does not progress at the same rate across all biological functions and organs. Comparisons of different clocks and omics data have shown poor correlation, suggesting that each clock or omics may represent a distinct ageing process. There is limited translation of DNA methylation and other biomarkers into clinical practice.

Furthermore, the definition of biological ageing is not yet clearly established within the community. Therefore, relying on only one type of data is unlikely to provide precise, specific, and reliable biomarkers. Ageing is a systems-level biological process, and only systems-level approaches are likely to lead to the development of reliable and interpretable predictions of biological age. Comparison of different omics data has also shown poor correlation between different molecular domains, indicating that each domain may reflect a different ageing process or organ. Moreover, it is clear that individuals and their organs age differently and at different rates.

Link: https://doi.org/10.1016/j.arr.2025.102988

The research community has achieved a growing ability to engineer bacteria to produce specific behaviors and outcomes. In the realm of cancer therapy, this includes altering the characteristics of bacteria to increase their ability to disrupt cancer cells by preferentially localizing to and colonizing tumor tissue. Techniques demonstrated in the laboratory include genetic engineering of bacteria manufacture or carry a payload of molecules capable of directly harming cancerous cells. The review noted here outlines the range of present approaches, including those that are progressing towards clinical use.

In contrast to conventional drugs, which accumulate through passive diffusion, live bacteria can actively penetrate deep into tumors, bypassing aggregation near blood vessels. The unique properties of the tumor microenvironment (TME) allow bacteria to preferentially replicate and colonize tumors. For example, Salmonella has been observed to localize to tumors at more than 10,000 times the density found in normal tissues. Live bacteria offer distinct advantages over traditional anticancer agents by amplifying antitumor effects through inherent tumor-targeting capabilities, potentially enhancing specific immune recognition. However, balancing the requirement for bacteria to evade host antimicrobial defenses while stimulating antitumor immunity within the TME remains a challenge.

Advances in synthetic biology allow the rational design of optimized oncolytic bacterial strains by attenuating virulence factors and integrating customizable therapeutic payloads, with several candidates already progressing into clinical evaluation. Fine-tuning the spatiotemporal control of bacterial therapeutic activity is essential for maximizing drug accumulation, improving resource efficiency, and reducing harm to healthy tissues. To this end, engineered oncolytic bacteria often utilize regulated gene expression systems, incorporating specific promoter elements, to allow for precise control of therapeutic payload delivery in vivo. Synthetic biology prioritizes rational and modular design, integrating programmable sensors, genetic circuits, and effectors to deliver precise, tunable, multilayer regulation of bacterial behaviors and therapeutic outputs.

Link: https://doi.org/10.1093/procel/pwaf085

In flexible, elastic tissues such as skin and blood vessel walls, large molecules of the extracellular matrix must be able to move relative to one another. When undesirable cross-links form between these molecules, tissue loses its elasticity and flexibility. Much of this undesirable cross-linking is the result of interactions with sugars, particularly via a class of compounds known as advanced glycation end-products, AGEs. In addition to the cross-linking, AGEs also provoke inflammation via interaction with the receptor for AGEs, RAGE. This is a well known harmful feature of the high-sugar, dysfunctional diabetic metabolism.

In the late 1990s and early 2000s, alagebrium was developed as a drug candidate on the basis of being able to break forms of AGE-induced cross-links found in arterial tissues, and thus reduce age-related arterial stiffening in preclinical studies in mice. In addition to breaking some forms of cross-link, alagebrium was also found to scavenge methylglyoxal, a particularly obnoxious precursor to AGEs and bad actor in diabetic metabolism. Sadly, the cross-links broken by alagebrium are prevalent in mice, but not in humans. Even more sadly, the failure of alagebrium to improve arterial stiffening in human clinical trials sabotaged any likelihood of further clinical trials in diabetic patients - so we have no idea whether alagebrium may or may not have improved the human diabetic metabolism to a sufficient degree to be useful.

The challenge with AGEs is that there are a lot of them, their chemistry is notably different from one to another, the catalog is incomplete, it is unclear whether the present consensus on which AGEs are important and which are not is correct, and this continues to be a relatively poorly studied part of the field. One of the consequences is a tendency for wheels to be reinvented. One might look at today's paper in which researchers use a novel mix of supplements in mice to try to reduce the aortic stiffening induced by methylglyoxal. That alagebrium improved aortic elasticity in mice, and failed to do so in humans, strongly suggests that the effort here is a dead end (or at least says little about the actual merits of the product undergoing testing), and no amount of skating over that point in the paper's discussion is going to change that reality.

Methylglyoxal-induced glycation stress promotes aortic stiffening: putative mechanistic roles of oxidative stress and cellular senescence

In this study, we investigated the impact of glycation stress on aortic stiffness in young and old mice, induced by advanced glycation end-product (AGE) precursor methylglyoxal (MGO) and its non-crosslinking AGE MGO-derived hydroimidazolone (MGH)-1, explored the potential molecular mechanisms involved, and evaluated the therapeutic potential of the glycation-lowering compound Gly-Low. We used a series of complementary in vivo, ex vivo, and in vitro experimental approaches to determine the causal role of MGO-induced glycation stress in aortic stiffening and the putative underlying mechanisms mediating this response, including excessive oxidative stress and cellular senescence. Additionally, we explored the therapeutic potential of Gly-Low, a cocktail consisting of the natural compounds nicotinamide, pyridoxine, thiamine, piperine, and alpha-lipoic acid, in mitigating aortic stiffening, oxidative stress, and cellular senescence mediated by MGO-induced glycation stress.

While MGO has previously been implicated in endothelial dysfunction, our results demonstrate that chronic MGO exposure significantly increases aortic stiffness in young mice. This effect was particularly pronounced in our pharmacological model of glycation stress, where young adult mice exhibited a marked increase in aortic stiffness after just two months of MGO exposure. Lastly, we also demonstrate the direct influence of glycation stress in mediating age-related aortic stiffening, which underscores the critical role of AGEs in promoting aortic stiffening with aging. Notably, our results also reveal the direct impact of MGO on aortic stiffening, supporting the notion that MGO-induced glycation stress can independently drive this pathology.

This paper is an example of work exploring how exactly mitochondrial dysfunction might contribute to age-related atrial fibrillation, the dysregulation of heart rhythm. It is possibly more helpful as an introduction to the roots of atrial fibrillation, meaning dysfunction in electrical connectivity and remodeling of structure in heart tissue, and how those two issues relate to one another. A perhaps surprisingly large fraction of atrial fibrillation can be at least temporarily corrected via minimally invasive surgical techniques, because in those cases the issue arises from inappropriate electrical signaling originating in small areas of the heart and connecting vessels, but once age-related changes in the heart become more widespread and severe, this stops being the case.

Atrial fibrillation (AF) is a common arrhythmia in clinical practice that often leads to severe complications such as heart failure, myocardial infarction, and stroke. It is associated with increased mortality and a significantly reduced quality of life. Current treatments for AF include risk factor control, medications for rate and rhythm control, and anticoagulation. For refractory cases, interventional procedures like cardiac radiofrequency ablation are used. However, these treatments have limitations, including adverse effects such as bleeding and a significant risk of AF recurrence. Further elucidating the mechanisms of AF development and identifying precise intervention targets are urgently needed.

The pathogenesis of AF has not been fully elucidated, but the core pathological basis for its development and maintenance primarily involves two major mechanisms: atrial electrical remodeling and structural remodeling. Electrical remodeling is mainly manifested as abnormal ion channel function in atrial myocytes, resulting in a shortening of action potential duration and increased dispersion of the effective refractory period. This creates a substrate for reentrant arrhythmias. Structural remodeling, on the other hand, involves morphological changes such as atrial fibrosis, myocardial hypertrophy, and dilation, which further promote the persistence and stabilization of AF.

Recent studies have confirmed that mitochondrial dysfunction is a central hub driving these remodeling processes. As the energy factories of the cell, mitochondria generate adenosine triphosphate (ATP) through oxidative phosphorylation, providing the necessary energy for sustained contraction, ion pump operation, and electrical signaling in cardiomyocytes. In the AF state, atrial myocytes are subjected to rapid, disorganized, high-frequency electrical excitation. The dramatic increase in energy demand leads to mitochondrial overload and accelerates mitochondrial senescence and damage.

Mitochondrial dysfunction affects intracellular ionic homeostasis and membrane excitability through dual disruptions of energy crisis (ATP insufficiency) and oxidative stress (reactive oxygen species burst). These disruptions directly impair cardiomyocyte ion channel function and expression, driving the onset and progression of AF. Mitophagy, a key mechanism for mitochondrial quality control, selectively removes damaged mitochondria to prevent reactive oxygen species accumulation and preserve the healthy mitochondrial network. However, chronic AF-related stress (e.g., calcium overload, sustained reactive oxygen species exposure) can impair mitophagy pathways, resulting in the accumulation of dysfunctional mitochondria.

This study combined bioinformatics analysis and experimental validation to uncover key genes and molecular networks underlying the interaction between mitophagy and ion channels in AF. The objective was to elucidate the molecular mechanisms underlying the "mitophagy defects -> ion channel dysfunction -> electrical remodeling" axis.

Link: https://doi.org/10.3389/fphys.2025.1687578

Researchers here mine human data and records from zoos to show that male castration and female sterilization increase life span in a very broad range of higher animals. Mechanisms are thought to be similar from species to species, even if the size of the effect on life span varies. In males, it appears largely connected with systemic effects of exposure to androgen hormones over a lifespan, while in females it appears largely connected to stresses resulting from reproduction. Thus in males only hormone level reduction increases life span, while in females any contraceptive approach that prevents reproduction increases life span.

Our results demonstrate that ongoing hormonal contraception and permanent methods of surgical sterilization increase vertebrate survivorship. The analysis of zoo records provides unparalleled insight into the taxonomic breadth of the lifespan response, with male castration, female surgical sterilization and ongoing female hormonal contraception linked to increased life expectancy across a broad range of species within the mammalian kingdom.

Life expectancy is increased by an average of 10-20% depending on the timing of treatment and environment the animal is exposed to, providing strong evidence for the presence of an intraspecific trade-off between adult reproduction and survival in vertebrates. Notably, however, we do not observe the very substantial, often more than 50% increases in lifespan that are observed in some invertebrate species after germ cell removal, particularly in species that are semelparous.

There is a wide species-level heterogeneity in the survival response to sterilization and contraception. What causes this remains to be determined. It has been widely hypothesized that male gonadal-specific hormone production (testosterone) contributes to shorter lifespans in males relative to females. In rodents, castration is associated with improvements in several domains of health in later life, in particular cognition and physical function. Thus, reducing male androgen signalling may broadly target multiple processes involved in the biology of ageing.

In females, increased life expectancy occurred with various contraceptive methods. Contraception reduced the risk of death from multiple causes, including infectious and non-infectious diseases. We hypothesize that the increased life expectancy in females arises from reduced allocation to reproduction and reproductive processes in adulthood, with contraception strongly reducing the direct and indirect costs of offspring production.

Link: https://doi.org/10.1038/s41586-025-09836-9

The axons that carry nerve impulses between neurons must be sheathed in myelin if they are to function. This structured myelin is built and maintained by a specialized population of cells called oligodendrocytes, which derive from a precursor population. Loss of myelin is a feature of severely disabling and ultimately fatal conditions such as multiple sclerosis. To a lesser degree, however, myelin loss also takes place with advancing age, and evidence suggests that this contributes to cognitive decline at the very least. Anything that disrupts the activity of oligodendrocytes will lead to loss of myelin, and the underlying damage that drives aging disrupts all cell populations in a variety of ways, to an increasing degree as the burden of damage rises over time.

The connection with aging is why it is worth keeping an eye on progress towards the development of therapies for multiple sclerosis. Therapies that treat demyelinating conditions may turn out be useful in older people as well. The details do matter, however. The targeted mechanisms must be applicable in both disease and aging, and it isn't always clear that this is the case. Today's open access paper is an example in which the researchers focus on multiple sclerosis patients and animal models of demyelination that have no relevance to aging. Thus the target they uncover does seem promising, but may or may not turn out to be useful outside the scope of multiple sclerosis.

The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation

Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination often fails in part due to the inhibition of OPC maturation into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA), generated by hyaluronidase activity, block OPC maturation and remyelination. Here, we aimed to identify which hyaluronidases are elevated in demyelinating lesions and to test if they influence OPC maturation and remyelination.

We find that the Cell Migration Inducing and hyaluronan binding Protein (CEMIP) is elevated in demyelinating lesions in mice with experimental autoimmune encephalomyelitis during peak disease when neuroinflammatory mediators, including tumor necrosis factor-α (TNFα), are at high levels. CEMIP expression is also elevated in demyelinated MS patient lesions. CEMIP is expressed by OPCs, and TNFα induces increased CEMIP expression by OPCs. Both increased CEMIP expression and HA fragments generated by CEMIP block OPC maturation into OLs. CEMIP-derived HA fragments also prevent remyelination in vivo.

This data indicates that CEMIP blocks remyelination by generating bioactive HA fragments that inhibit OPC maturation. CEMIP is therefore a potential target for therapies aimed at promoting remyelination.

Mitochondria retain a circular genome distinct from the DNA of the cell nucleus, a legacy of their distant evolutionary origins as symbiotic bacteria. Mitochondrial DNA damage is thought to contribute to the characteristic mitochondrial dysfunction of aging, although the relative contributions of mitochondrial DNA damage versus epigenetic changes in the nucleus that disrupt mitochondrial function remain up for debate. Researchers here provide evidence for a novel form of molecular damage to mitochondrial DNA to contribute to mitochondrial dysfunction. Once again, the question of relative contributions arises, always a challenge in everything associated with mechanisms of aging.

Mitochondrial DNA (mtDNA) is crucial for cellular energy production, metabolism, and signaling. Its dysfunction is implicated in various diseases, including mitochondrial disorders, neurodegeneration, and diabetes. mtDNA is susceptible to damage by endogenous and environmental factors; however, unlike nuclear DNA (nDNA), mtDNA lesions do not necessarily lead to an increased mutation load in mtDNA. Instead, mtDNA lesions have been implicated in innate immunity and inflammation.

Here, we report a type of mtDNA damage: glutathionylated DNA (GSH-DNA) adducts. These adducts are formed from abasic (AP) sites, key intermediates in base excision repair, or from alkylation DNA damage. Using mass spectrometry, we quantified the GSH-DNA lesion in both nDNA and mtDNA and found its significant accumulation in mtDNA of two different human cell lines, with levels one or two orders of magnitude higher than in nDNA.

The formation of GSH-DNA adducts is influenced by TFAM and polyamines, and their levels are regulated by repair enzymes AP endonuclease 1 (APE1) and tyrosyl-DNA phosphodiesterase 1 (TDP1). The accumulation of GSH-DNA adducts is associated with the downregulation of several ribosomal and complex I subunit proteins and the upregulation of proteins related to redox balance and mitochondrial dynamics. Molecular dynamics (MD) simulations revealed that the GSH-DNA lesion stabilizes the TFAM-DNA binding, suggesting shielding effects from mtDNA transactions.

Collectively, this study provides critical insights into the formation, regulation, and biological effects of GSH-DNA adducts in mtDNA. Our findings underscore the importance of understanding how these lesions may contribute to innate immunity and inflammation.

Link: https://doi.org/10.1073/pnas.2509312122

One can debate aspects of the way in which researchers here model what might happen if all of aging is controlled except random mutational damage to nuclear DNA, but the idea is an interesting one. Will random mutational damage to somatic cells be so much harder to eliminate than other aspects of aging that we should think ahead in this way? In tissues where cells are largely replaced, we might think that stem cell populations can at some point be repaired or replaced, and thus the mutational burden in tissues can be reduced over time via the influx of less damaged somatic cells created by the rejuvenated stem cell population. Most neurons in the central nervous system are long-lived, however, and are never replaced. We would have to postulate some very advanced technology to think that we will be able to address the stochastic mutational burden of vital cells in the brain, that damage different in every cell.

Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations.

Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median lifespan from a theoretical non-aging baseline of 430 years to 169 years. In contrast, proliferating tissues like liver maintain functionality for thousands of years through cellular replacement, effectively neutralizing mutation-driven decline.

Multi-organ integration predicts median lifespans of 134-170 years - approximately twice current human longevity. This substantial yet incomplete reduction indicates that somatic mutations significantly drive aging but cannot alone account for observed mortality, implying comparable contributions from other hallmarks.

Link: https://doi.org/10.1101/2025.11.23.689982