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- Type 2 Diabetes Accelerates Age-Related Disease
- Inhibition of Mitochondrial Calcium Uptake Slows Aging
- Evidence for Amyotrophic Lateral Sclerosis to be an Autoimmune Condition
- Loss of Coordination of Gene Expression as a Biomarker of Aging
- Delving into the Dysfunction of Aging Neurons Involved in Impairment of Spatial Memory
- A Novel Approach to a Near Universal Cancer Therapy
- Mitochondrial Driven Inflammation in the Aging of the Ovaries
- Diet, the Gut Microbiome, and Aging
- CHGA Variants Correlate with Longevity
- Helicobacter Pylori Infection Correlates with Risk of Abdominal Aortic Aneurysm
- High Cysteine Intake Boosts Intestinal Stem Cell Function
- Extracellular Vesicles in Obese Individuals Increase the Aggregation of Amyloid-β in the Brain
- Inhibition of IL-33 Expression in Cartilage to Treat Osteoarthritis
- FDA Approval for Mitochondrial Therapeutic Elamipretide, Formerly SS-31
- PP2A-B55α as a Target to Improve Mitochondrial Function
Type 2 Diabetes Accelerates Age-Related Disease
https://www.fightaging.org/archives/2025/10/type-2-diabetes-accelerates-age-related-disease/
Type 2 diabetes is near entirely a condition caused by the presence of excess visceral fat tissue, by being overweight or obese. Even in relatively late stages, type 2 diabetes can be reversed by low calorie diets and the consequent loss of that excess visceral fat. Visceral fat is metabolically active, and directly provokes chronic inflammation through a range of mechanisms, such as by mimicking the signaling of cells infected by pathogens. Excess visceral fat also disrupts insulin metabolism and control of blood glucose. The abnormal, sugar-rich diabetic metabolism also directly provokes inflammation, such as via the interaction between molecules altered by sugars known as advanced glycation endproducts (AGEs) and the receptor for AGEs (RAGE) on cell surfaces.
However it is caused, unresolved inflammatory signaling is disruptive to tissue function and structure, changing the behavior of cells for the worse. This chronic inflammation accelerates the onset and progression of all of the common fatal age-related conditions. That outcome is well established, both the mechanisms and the epidemiology demonstrating correlations between inflammation and age-related diseases.
Today's research materials add to the existing mountain of epidemiological data that aims to quantify the harms done by type 2 diabetes. As one might expect, patients with type 2 diabetes have significantly worse outcomes in long-term health. Sadly we live in an era in which obesity is prevalent, for reasons that have yet to be concretely determined. Many factors may contribute, from lesser degrees of exercise to refined dietary components that were not common a century ago to microplastics in the environment. Whatever the hierarchy of causes, the outcome is clearly harmful to health, medical costs, and life expectancy.
Type 2 diabetes may accelerate development of multiple chronic diseases, particularly in the early stages
Type 2 diabetes (T2D) is projected to become the biggest epidemic disease in the world, affecting an estimated 1.3 billion people by 2050. T2D frequently occurs with other chronic conditions, such as high blood pressure, heart failure, chronic kidney disease, and depression, contributing substantially to the global burden of multimorbidity. Researchers explored how T2D influenced the rate of chronic disease development in 502,368 UK Biobank participants. The average age of the participants at enrollment was 58 years, and around 46% were men. Researchers used health records to track health outcomes over 15 years on average.
To calculate the pace of chronic disease development, researchers used multistate models to compare transition rates between groups with equivalent total disease. For example, they compared how long it took someone with T2D and one additional chronic condition to acquire a third condition, versus how long it took someone with two non-T2D chronic conditions to develop another condition. This approach isolates the role of T2D by ensuring both groups start with the same total number of chronic conditions.
Individuals with T2D consistently experienced higher transition rates (more rapid progression) between multiple disease stages. For example, for individuals with two chronic conditions, those with T2D as one of them progressed to a third condition at a rate of 5.7% per year, compared to 3.5% per year for those with two non-T2D conditions. This corresponds to people with T2D continuously facing a 60% higher risk of a new disease being diagnosed compared to those without T2D.
The role of type 2 diabetes in shaping multimorbidity progression: evidence from the UK Biobank cohort
We analyzed data from the UK Biobank, a prospective population-based cohort study (n=502,368, median age 58 years [range 37-73], 46% male at baseline) with a median follow-up 15.3 year. 9.5% of participants were diagnosed with T2D over the period. We counted the current number of morbidities (among 80 long-term chronic conditions) identified through hospital admission records using ICD-10 diagnosis codes.
The total follow-up time was 7.5 million person-years (PY), of which 0.33 million PY was in T2D. Individuals with T2D consistently experienced higher transition rates between morbidity transition stages. For example, the transition rate from 2 to 3 morbidities was 3.48 per 100 PY without the presence of T2D, compared to 5.68 per 100 PY once T2D was present (rate ratio=1.6). The disproportion of transition rates was most pronounced in early disease stages. Further, the transition rates were consistently influenced by T2D status and age, with younger individuals with T2D showing the most accelerated progression.
Inhibition of Mitochondrial Calcium Uptake Slows Aging
https://www.fightaging.org/archives/2025/10/inhibition-of-mitochondrial-calcium-uptake-slows-aging/
Methods of both modestly impairing and modestly improving mitochondrial function have been shown to slow aging in short-lived species such as flies and nematodes, albeit for different reasons. Every cell contains hundreds of mitochondria that undertake the energetic process of producing adenosine triphosphate (ATP), a chemical energy store molecule used to power cell operations. The chemistry of ATP manufacture produces damaging oxidative molecules as a side-effect, but that flux of oxidative molecules is also a signal that a cell reacts to with increased maintenance, such as an increase in autophagy to clear out damaged proteins and structures. Better mitochondrial function is directly helpful to the cell, but modestly worse mitochondrial function can inspire a sufficient increase in cell maintenance to still come out ahead. Better cell function throughout the body tends to translate to improved health and slowed aging.
In today's open access paper, researchers report on their assessment of one of the many approaches to modestly impair mitochondrial function, by impeding the uptake of calcium ions through the mitochondrial membrane. As is the case for a number of such approaches, this adjustment increases the production of oxidative molecules in mitochondria, causing the cell to react with improved maintenance. Interestingly, this harms survival in early life, which explains why evolution has not provided species with mitochondria altered in this way to slow aging and improve overall life span.
Enhancing Late-Life Survival and Mobility via Mitohormesis by Reducing Mitochondrial Calcium Levels
Mitochondrial calcium (Ca2+) homeostasis plays a critical role in aging and cellular fitness. In the search for novel antiaging approaches, we explored how genetic and pharmacological inhibition of mitochondrial Ca2+ uptake influences the lifespan and health of Caenorhabditis elegans. Using live-cell imaging, we demonstrate that RNA interference-mediated knockdown of mcu-1, the nematode ortholog of the mitochondrial Ca2+ uniporter (MCU), reduces mitochondrial Ca2+ levels, thereby extending lifespan and preserving motility during aging, while compromising early-life survival.
This longevity benefit requires intervention before day 14 and coincides with a transient increase in reactive oxygen species (ROS), which activates pathways involving pmk-1, daf-16, and skn-1, orthologs of human p38 mitogen-activated protein kinase (p38 MAPK), forkhead box O (FOXO), and nuclear factor erythroid 2-related factor 2 (NRF2), respectively. This pathway promotes antioxidant defense mechanisms and preserves mitochondrial structure and function during aging, maintaining larger, more interconnected mitochondria and restoring the oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) ratio and oxygen consumption rates to youthful levels.
Pharmacological inhibition of mitochondrial Ca2+ uptake using the MCU inhibitor mitoxantrone mirrors the effects of mcu-1 knockdown, extending lifespan and improving fitness in aged nematodes. In human foreskin fibroblasts, short-term mitoxantrone treatment also transiently elevates ROS production and induces enhanced expression and activity of antioxidant defense enzymes, underscoring the translational relevance of findings from nematodes to human cells. Our findings suggest that modulation of mitochondrial Ca2+ uptake induces mitohormesis through ROS-mediated signaling, promoting improved longevity and healthspan in nematodes, with possible implications for healthy aging in humans.
Evidence for Amyotrophic Lateral Sclerosis to be an Autoimmune Condition
https://www.fightaging.org/archives/2025/10/evidence-for-amyotrophic-lateral-sclerosis-to-be-an-autoimmune-condition/
Amyotrophic lateral sclerosis (ALS) is a somewhat age-related disease in that it tends to show up in later life, with fewer than 10% of cases occurring under the age of 40. The relationship between age and risk of ALS is not a clear progression of increasing risk after age 40, however. Most patients with ALS start to exhibit the condition in their 40s or 50s, and the risk declines at older ages. The reasons for this remain obscure, as the research community has struggled to identify the cause of the condition, or even why it progresses very rapidly in some patients versus more slowly in others.
There has long been a strong suspicion than ALS is an autoimmune disease, based on the relationship with age and other aspects of its epidemiology, even lacking firm mechanistic proof of that suspicion. Today's research materials offer a first step towards that firm proof. Researchers provide a mechanism by which the immune system malfunctions to attack motor neurons, and aspects of this mechanism can explain the difference between patients whose disease proves fatal within a couple of years and those who live on for a decade or more.
As this and the relatively recent discovery of type 4 diabetes indicates, we might suspect that a great deal of poorly characterized, quite varied, and poorly understood autoimmunity occurs in later life as the immune system finds ways to malfunction in response to the damage and dysfunction of aging. Only when the onset of a form of autoimmunity occurs relatively early in later life and the outcome is quite characteristic across much of the patient population do we see a lot of attention given to the problem. And even there, as ALS demonstrates, it can take a long time to make progress. Meanwhile the suspected autoimmunities of later old age are obscured by other health issues, and receive comparatively little attention from the research community.
ALS appears to be an autoimmune disease
Around 5,000 Americans are diagnosed with amyotrophic lateral sclerosis (ALS) each year. About half of patients die within 14 to 18 months of being diagnosed, usually due to breathing failure. The exact cause of ALS has long been unknown. Now, scientists have uncovered evidence that ALS may be an autoimmune disease. The researchers discovered that inflammatory immune cells, called CD4+ T cells, mistakenly target a specific protein (called C9orf72), which is expressed in neurons. This kind of "self-attack" is the defining feature of autoimmune disease.
By examining T cell responses in ALS patients, the researchers were surprised to find two distinct patient groups. One group had shorter predicted survival times. Their inflammatory CD4+ T cells were quick to release inflammatory mediators when they recognized C9orf72 proteins. The second patient group also had harmful inflammatory CD4+ T cells, but they also had higher numbers of different T cells, anti-inflammatory CD4+ T cells. This second group also had significantly longer projected survival times. This suggests that the anti-inflammatory CD4+ T cells may reduce harmful autoimmune responses and slow the progression of ALS.
Autoimmune response to C9orf72 protein in amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a progressive loss of motor neurons. Neuroinflammation is apparent in affected tissues, including increased T cell infiltration and activation of microglia, particularly in the spinal cord. Autoimmune responses are thought to have a key role in ALS pathology, and it is hypothesized that T cells contribute to the rapid loss of neurons during disease progression. However, until now there has been no reported target for such an autoimmune response.
Here we show that ALS is associated with recognition of the C9orf72 antigen, and we map the specific epitopes that are recognized. We show that these responses are mediated by CD4+ T cells that preferentially release IL-5 and IL-10, and that IL-10-mediated T cell responses are significantly greater in donors who have a longer predicted survival time. Our results reinforce the previous hypothesis that neuroinflammation has an important role in ALS disease progression, possibly because of a disrupted balance of inflammatory and counter-inflammatory T cell responses. These findings highlight the potential of therapeutic strategies aimed at enhancing regulatory T cells, and identify a key target for antigen-specific T cell responses that could enable precision therapeutics in ALS.
Loss of Coordination of Gene Expression as a Biomarker of Aging
https://www.fightaging.org/archives/2025/10/loss-of-coordination-of-gene-expression-as-a-biomarker-of-aging/
A number of lines of research indicate that coordination of gene expression within and between cells deteriorates with age. If any two genes are tightly correlated in the expression levels in youth, that correlation tends to decline in strength with age. On the one hand there is increased noise in the distribution of behaviors from cell to cell in response to the same environmental circumstances. Further, where systems of regulation interact with one another, those interactions drift out of synchronization, such as the loss of coordination between central and peripheral circadian clocks. We can hypothesize on how these changes might arise from a stochastic distribution across cell populations of the well known forms of damage associated with aging, including mutations in nuclear DNA, mitochondrial dysfunction, and cellular senescence. But clear chains of cause and effect are at present challenging to establish in the complexity of the biochemistry of a single cell, never mind in tissues and organisms made up of countless such cells.
Nonetheless, measures of loss of coordination of gene expression might prove to be useful biomarkers of aging. This is the conclusion of today's open access paper on the topic. Many age-related changes are visible and interesting in large study populations, but are too varied in their behavior and relationships with the rest of biology to use effectively as biomarkers for individuals. Telomere length measured in immune cells from a blood sample is a good example. The researchers involved in the study noted here conclude that loss of coordination in gene expression is not like this, and does in fact correlate well with other measures of aging on an individual basis. They go on to speculate on whether this loss of coordination is pathological, a cause of age-related dysfunction. Are specific aspects of age-related changes in gene expression meaningfully harmful in and of themselves, or are they a reaction to other harms that do not in and of themselves cause much further damage? That is an ongoing debate, and it won't be settled here.
Personalized transcriptional network analysis links age-related loss of gene coordination to individual biological aging
Aging is characterized by widespread dysregulation across various biological levels, including a decline in gene-to-gene transcriptional coordination. This decline leads to reconfigured interrelations within gene transcriptional networks, which warrants study to better understand the biological system disorders in the aging process. However, the gene pair coordinated expression relationships (CERs) in past analyses were estimated using correlation coefficients across a bulk of samples, capturing only population-level trends. Changes in CERs within individuals during aging remain unclear. Especially since such an analysis cannot determine whether two genes are coordinated in a single individual, it is difficult to connect the gene coordination to personalized biological functioning and health status, thus limiting its potential as an indicator or biomarker of an individual's biological aging or even disease risk. Therefore, a study focusing on gene-to-gene transcriptional coordination at an individual-specific level is urgently needed to gain deeper insights into its biological significance in aging and even age-related outcomes.
To systematically explore the individual-level gene-gene expression coordination dynamics during aging, we constructed 15,933 personalized transcriptional networks in 26 tissues from 967 donors (ranged from 20 to 80 years old), sourced from the Genotype-Tissue Expression (GTEx) project. We revealed that the loss of gene coordination is positively correlated to an individual's senescence-related molecular traits (e.g., senescence-associated secretory phenotype (SASP) and immune cell infiltration) and biological functioning processes (e.g., reactive oxidative species (ROS) and oxidative phosphorylation). Notably, we provided evidence showing that age-related CER loss has the potential to serve as an indicator of an individual's biological aging and health status. Moreover, we found that gene-to-gene relationship loss during aging leads to disrupted gene expression coordination in key pathways, such as proteolysis, which are closely related to longevity and healthy aging. Further analysis indicated that the aging-related CER loss may be pathogenic in a gene dosage-dependent manner.
Delving into the Dysfunction of Aging Neurons Involved in Impairment of Spatial Memory
https://www.fightaging.org/archives/2025/10/delving-into-the-dysfunction-of-aging-neurons-involved-in-impairment-of-spatial-memory/
There are many layers to aging research. There is the function of tissue, the behavior of cells, the pattern of expression of genes, the profile of circulating molecules of various classes. Typically one research program is focused on one layer (and often only in one organ, or a single function of a tissue), with only occasional excursions into another layer (or other organs, or other functions). There are the usual reasons for this, such as different skills and knowledge being required, different expensive equipment being required, the tendency for researchers to specialize into ever narrower niches, and the eternal pressure to do more with less that exists in academia. It does mean that much of the literature is siloed into layers that talk little to one another, and integration of these layers into a bigger picture of cause and effect lags behind.
Today's open access paper reports on altered behaviors in neurons involved in spatial memory in the aged mouse brain, and connects these changes to the age-related loss of spatial memory. Different forms of memory involve different neural networks and different regions of the brain, and so can be distinctly affected by aging even if the underlying damage and dysfunction contributing to aging is more or less evenly spread across tissues. This research attempts to link two layers of aging in some of the specific neurons involved in spatial memory, the layer of cell behavior and the layer of gene expression. The intent is to provide a foundation for later efforts to find ways to restore these cells to a more youthful pattern of behavior.
Spatial coding dysfunction and network instability in the aging medial entorhinal cortex
Across mammalian species, neural systems in the medial temporal lobe, including the medial entorhinal cortex (MEC) and hippocampus (HPC), are required for spatial memory. The MEC contains grid cells that fire periodically during environmental traversals and have firing fields that hexagonally tile physical space in rodents, non-human primates, and humans. This firing is proposed to provide a map of space that can support path integration. Head direction-, border-, speed-, and object vector-tuned cells have also been identified in MEC, providing information regarding an animal's movement through the environment and sensory features likely relevant to navigation. Additionally, MEC neurons can change their firing rates or shift where their firing fields are active, phenomena collectively referred to as 'remapping'. MEC remapping events often occur in response to changes in task demands and environmental features, potentially facilitating the differentiation of distinct contexts. Such remapping in MEC grid cells is likely complemented by place cells and goal-vector cells in the reciprocally connected HPC, which can also exhibit context-dependent remapping. Collectively, this network of functional cell types across MEC and HPC may provide the necessary neural substrates for an animal to navigate to goals in novel and familiar environments.
Several lines of evidence suggest that MEC-HPC circuit dysfunction contributes to aged spatial memory deficits. It is unclear how aging impacts the quality or stability of tuning to navigational variables across MEC functional cell types, however. The integrity and flexibility of population-level spatial maps in the aged MEC also remain unknown. Since the HPC and MEC are reciprocally connected, one possibility is that spatial coding dysfunction in these regions might interdependently contribute to spatial memory decline in aging. Eventually, rejuvenating aged spatial cognition dependent on MEC-HPC networks will also require a more precise understanding of the molecular mechanisms that drive cellular and circuit dysfunction.
Here, we combined in vivo silicon probe recordings with neuronal bulk sequencing in MEC in the same mice, complemented by single-nucleus RNA sequencing (snRNA-seq), to identify neural and molecular substrates of aged spatial memory function. Advanced electrophysiologic tools permitted the simultaneous recording of hundreds of neurons per day from each mouse. As a result, we could robustly analyze age effects on MEC spatial coding at the animal level. Moreover, we interrogated how aging altered single neuron firing patterns and population-level spatial coding phenomena. Using a virtual-reality (VR) task with two dynamically interleaved contexts and another with invariant cues, we demonstrated how aging impacts the flexibility and stability of MEC spatial coding at both these levels. Finally, by correlating key spatial coding metrics with the expression of neuronal genes differentially expressed across age groups, we identified potential molecular drivers of aging-mediated spatial cognitive decline in MEC.
A Novel Approach to a Near Universal Cancer Therapy
https://www.fightaging.org/archives/2025/10/a-novel-approach-to-a-near-universal-cancer-therapy/
The most important lines of cancer research are those that might lead to therapies that can be applied to many (or even all) types of cancer with little adjustment of delivery or payload. This requires a mechanism that is present in most or all cancers, and which is essential to the cancer, such that cancer cells cannot just evolve away from using it in response to treatment. At present only a few areas of focus offer this potential, such as interference in telomere lengthening. Here, researchers describe a novel approach that seems to have a broad potential to treat the majority of cancers. It involves the delivery of a molecule that encourages T cells to bind to specific surface molecules that are characteristic of cancer cells, but which normally bind poorly and have thus been ignored as a possible target in the past.
Bispecific antibodies and chimeric antigen receptor T cells (CAR T) potently reduce tumor burden in B cell-related malignancies. Both trigger T cell-mediated killing of cancer cells by targeting a cell-surface cancer antigen using modified antibodies. However, applying this therapeutic strategy to the majority of cancer types, particularly solid cancers, is limited by a lack of safe targetable protein antigens.
Many cell-surface cancer antigens are not proteins but rather complex carbohydrates and are termed "tumor-associated carbohydrate antigens" (TACAs). Two well-described TACAs are β1,6GlcNAc-branched N-glycans and the Tn antigen, the latter an abnormally truncated O-glycan. As both markers and drivers of diverse cancers, β1,6-branching and Tn antigen provide excellent targets for antigen-specific immunotherapies. However, anti-glycan antibodies typically have affinities 1,000-100,000-fold lower than antibodies to peptide antigens. This is due to higher flexibility of glycans than peptides, absence of T cell help to B cells from lack of major histocompatibility complex (MHC) presentation of pure glycans, and attachment of glycans to a vast array of different proteins/lipids resulting in a non-uniform antigen.
The inability to generate an antibody to β1,6-branching and effective antibodies to pure Tn antigen has prevented effective targeting of these well-established tumor-associated antigens. To address this issue, we envisioned a class of immunotherapeutics that utilize sugar-binding proteins (lectins) that have well-established specificity, rather than antibodies, to target glycan antigens. We have termed this "glycan-dependent T cell recruiter" (GlyTR, pronounced "glitter"). GlyTR bispecific proteins fuse a carbohydrate-recognition domain (CRD) from a lectin to a single-chain variable fragment (scFv) from an antibody targeting CD3. Lectins utilize high binding avidity (velcro-like binding) to achieve specificity for glycan targets. This is in distinction to antibodies, where high affinity (key-lock binding) achieves specificity.
We developed GlyTR1 and GlyTR2 to bind immunosuppressive β1,6GlcNAc-branched N-glycans or multiple TACAs, respectively. GlyTR1 and GlyTR2 overcome immunosuppressive mechanisms in the tumor microenvironment and trigger target-density-dependent T cell-mediated pan-cancer killing, yet they lack toxicity in mice with human-like TACA expression. Thus density-dependent lectin binding to TACAs provides highly potent and safe pan-cancer immunotherapeutics.
Mitochondrial Driven Inflammation in the Aging of the Ovaries
https://www.fightaging.org/archives/2025/10/mitochondrial-driven-inflammation-in-the-aging-of-the-ovaries/
Hundreds of mitochondria are present in every cell, responsible for generating chemical energy store molecules to power cell processes. Mitochondria are the descendants of ancient symbiotic bacteria, still replicate like bacteria, and retain a remnant genome. With age mitochondria become dysfunctional for reasons relating to damage to mitochondrial DNA and changes in the expression of mitochondrial genes in the cell nucleus. This dysfunction is known to contribute to the chronic inflammation of aging via its interaction with innate immune mechanisms, making rejuvenation of mitochondria an important goal in the treatment of aging. While this paper is focused on the aging of the ovaries, most of the discussion of mechanisms is relevant to the rest of the body as well, as mitochondrial dysfunction occurs in all tissues with age.
Ovarian ageing is a key factor in the decline of female fertility. It is primarily characterised by diminished oocyte quality, follicular depletion, and dysregulated hormone levels. In recent years, mitochondria-driven inflammation has emerged as a potential mechanism in ovarian ageing. Mitochondrial dysfunction results in the accumulation of reactive oxygen species (ROS) and the release of mitochondrial DNA (mtDNA), as well as the leakage of mitochondrial components and metabolites into the cytosol or extracellular space. These elements act as damage-associated molecular patterns (DAMPs), activating inflammasomes like NLRP3, thereby initiating and amplifying innate immune responses and contributing to sustained inflammation.
The differential regulation of these signals under physiological versus pathological ageing conditions is particularly poorly characterised. Moreover, existing therapeutic strategies often target isolated pathways. For instance, antioxidant treatments may reduce ROS accumulation but have limited effects on the broader signalling networks involved in ovarian ageing. From a clinical translation perspective, several challenges remain, including insufficient drug targeting, unclear optimal timing of intervention, and limited understanding of long-term safety. For example, during the activation of primordial follicles, augmented mitochondrial biogenesis contributes to the preservation of oocyte energy balance. Conversely, the follicular atresia phase is closely associated with excessive activation of inflammatory signalling, and moderate inhibition of the NLRP3 inflammasome has demonstrated efficacy in retarding granulosa cell apoptosis and decelerating the atresia process. However, current therapeutic strategies lack the precision to temporally regulate these dynamic changes.
Diet, the Gut Microbiome, and Aging
https://www.fightaging.org/archives/2025/10/diet-the-gut-microbiome-and-aging/
Researchers can now accurately measure the composition of the gut microbiome, and how the distribution of different microbial species changes for the worse in association with age and disease. Studies have been conducted to map specific changes in the gut microbiome to specific diseases and outcomes. Another ongoing project is to link these relatively new findings with the established body of work covering the effects of diet on long-term health. Diet evidently has considerable influence over the composition of the gut microbiome, but there is a great deal of room to understand at the detail level how diet, disease, aging, and the gut microbiome interact with one another.
The interplay between diet, gut microbiota, and aging represents a dynamic and modifiable system with profound implications for human health. Aging is accompanied by notable shifts in gut microbial composition, including reduced diversity and the loss of beneficial taxa, which contribute to systemic inflammation, impaired immunity, and metabolic dysfunction. However, dietary patterns, especially those rich in fiber, polyphenols, and healthy fats, can reshape the microbiota, enhance production of beneficial metabolites, like short-chain fatty acids, and mitigate age-related decline. The Mediterranean, plant-based, and other nutrient-rich diets have shown promise in promoting microbial profiles associated with reduced frailty, preserved cognition, and improved metabolic health.
Importantly, the gut microbiota functions not just as a target but also as a mediator, translating dietary inputs into molecular signals that influence host aging processes. Emerging evidence supports the potential of microbiota-targeted dietary interventions such as prebiotics, probiotics, and precision nutrition to promote healthy aging. Nonetheless, translating these findings into real-world solutions requires deeper mechanistic insights and broader clinical validation. By recognizing the gut microbiota as a key interface between nutrition and aging, future strategies may more effectively support longevity and functional health across the lifespan.
CHGA Variants Correlate with Longevity
https://www.fightaging.org/archives/2025/10/chga-variants-correlate-with-longevity/
The search for genetic determinants of longevity in humans has, on the whole, not gone well. Only a very small number of widespread gene variants (such as those in the APOE gene) manage to show effects on life span in multiple study populations, and their effect sizes are largely much smaller than those attributed to exercise. The modern existence of large genetic databases has, if anything, pushed down the estimate of the degree to which genetic variation contributes to longevity. The study of the genetics of extremely long-lived individuals has been underway a while and has not produced data to support a credible set of longevity genes. We are left with a picture of thousands of relevant genes, with every single variant exerting a situational, small contribution, and collectively their influence on longevity far outweighed by the effects of lifestyle choices. Nonetheless, researchers continue to produce studies such as the one noted here, and as for any such study, based on past outcomes we should expect there to be low odds of the results replicating in a different study population.
Aging, age-related diseases, and longevity are interconnected processes influenced by shared molecular and genetic mechanisms. In this study, we investigated the role of genetic variation in the Chromogranin A (CHGA) gene, which encodes a multifunctional precursor of regulatory peptides, in human longevity and age-related traits. Using a case-control design with two age cohorts (older adults: 65-85 years; long-lived: 86-107 years), we analysed nine selected CHGA single nucleotide polymorphisms (SNPs) for associations with survival to advanced age and relevant clinical parameters.
Five SNPs (rs9658628, rs9658631, rs9658634, rs7159323, and rs7610) were significantly associated with longevity. In the older adult cohort, the 5′-UTR rs9658628-A allele was associated to reduced odds of reaching advanced age and correlated with increased insulin resistance, type 2 diabetes, and lower cognitive performance, traits typically linked to higher mortality risk. Paradoxically, this allele was also associated with a lower risk of cardiovascular disease, suggesting pleiotropic effects potentially mediated by its regulatory effects on CHGA expression across different tissues. Functional annotation supported rs9658628 as an expression quantitative trait locus (eQTL) for CHGA and neighboring genes (ITPK1, FBLN5 genes in particular) in relevant tissues. Additionally, the 3′-UTR rs7610-T allele was associated with both increased diastolic blood pressure and enhanced survival, highlighting the complexity of blood pressure regulation in aging.
These findings suggest that genetic variations in CHGA exert a complex and multifactorial influence on pathways related to metabolism, cognition, and vascular health, with possible consequences for longevity. This intricate pattern could be due to the multiple, sometimes opposing, functions of CHGA and its active fragments. The biological rationale and potential clinical implications of these associations call for further investigation and independent confirmation.
Helicobacter Pylori Infection Correlates with Risk of Abdominal Aortic Aneurysm
https://www.fightaging.org/archives/2025/10/helicobacter-pylori-infection-correlates-with-risk-of-abdominal-aortic-aneurysm/
The H. pylori bacterium is famously associated with stomach ulcers; a researcher gave himself stomach ulcers by drinking a mix containing H. pylori to prove the point, in one of the more widely publicized self-experiments of recent history. Here, researchers review the evidence for H. pylori infection to correlate with the risk of suffering an aneurysm of the abdominal aorta. An aneurysm is a weakened blood vessel wall that forms a bulge at risk of rupture. In a major vessel such a rupture is frequently fatal. Inflammatory signaling is thought to be involved in the formation of an aneurysm, so one can consider that the persistent presence of a pathogen such as H. pylori may contribute via their effects on the inflammatory environment. There may be other mechanisms involved, however.
Abdominal aortic aneurysm (AAA) is a condition of considerable clinical importance, characterized by the dilation and weakening of the abdominal aorta. While several risk factors have been identified, recent studies have suggested a potential link between Helicobacter pylori infection (HPI) and the development of AAA. Abdominal aortic aneurysms pose a significant public health challenge, particularly among the elderly population. The prevalence of AAA increases with age, affecting a total of 35.12 million individuals, and its rupture can lead to catastrophic outcomes, including massive internal hemorrhage and mortality. Identifying modifiable risk factors is crucial for prevention and early intervention. Traditionally associated with gastric ulcers and gastritis, H. pylori is a bacterium that colonizes the gastric mucosa. However, recent investigations have explored its potential involvement in other systemic conditions, including cardiovascular diseases. It is hypothesized that chronic inflammation induced by H. pylori infection may contribute to the pathogenesis of AAA.
This study aims to quantify the association between Helicobacter pylori (H. pylori) infection and AAA development through a systematic review and meta-analysis, emphasizing numerical results for clarity. Following PRISMA guidelines, PubMed, SCOPUS, Medline, and Embase searches were conducted. Data extraction and quality assessment were performed using standardized tool. Among the 8 selected studies, H. pylori infection exhibited a statistically significant overall risk ratio of 1.54 for AAA development. Subgroup and sensitivity analyses were conducted to address high heterogeneity, revealing consistent results. These findings underscore the importance of further research to elucidate underlying mechanisms and inform preventive strategies and interventions aimed at mitigating the risk of AAA in individuals with H. pylori infection.
High Cysteine Intake Boosts Intestinal Stem Cell Function
https://www.fightaging.org/archives/2025/10/high-cysteine-intake-boosts-intestinal-stem-cell-function/
There is a sizable literature of animal studies in which researchers increase or decrease intake of one specific dietary amino acid and observe the outcomes. Despite this, there are a lot of gaps and contradictory results in the understanding of the long term effects of increased intake of specific single amino acids, even for the smaller number of essential amino acids. Here, researchers find that increased cysteine intake can improve intestinal stem cell function in mice, and thus promote tissue health in the small intestine. While the context of the research is injury, such as the consequences of radiotherapy, this may be able to somewhat compensate for the loss of intestinal stem cell function that occurs with age.
A fundamental question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine is maintained by rapidly renewing LGR5+ intestinal stem cells (ISCs) that respond to macronutrient changes such as fasting regimens and obesogenic diets, yet how specific amino acids control ISC function during homeostasis and injury remains unclear.
Here we demonstrate that dietary cysteine, a semi-essential amino acid, enhances ISC-mediated intestinal regeneration following injury. Cysteine contributes to coenzyme A (CoA) biosynthesis in intestinal epithelial cells, which promotes expansion of intraepithelial CD8αβ+ T cells and their production of interleukin-22 (IL-22). This enhanced IL-22 signalling directly augments ISC reparative capacity after injury. The mechanistic involvement of the pathway in driving the effects of cysteine is demonstrated by several findings: CoA supplementation recapitulates cysteine effects, epithelial-specific loss of the cystine transporter SLC7A11 blocks the response, and mice with CD8αβ+ T cells lacking IL-22 or a depletion of CD8αβ+ T cells fail to show enhanced regeneration despite cysteine treatment.
These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.
Extracellular Vesicles in Obese Individuals Increase the Aggregation of Amyloid-β in the Brain
https://www.fightaging.org/archives/2025/10/extracellular-vesicles-in-obese-individuals-increase-the-aggregation-of-amyloid-%ce%b2-in-the-brain/
Researchers here outline a mechanism by which excess fat tissue may accelerate the onset and progression of Alzheimer's disease, by affecting the content of extracellular vesicles passing into the brain, that in turn increase the aggregation of misfolded amyloid-β that is characteristic of the early stages of the condition. Excess visceral fat also contributes to chronic inflammation via a range of different mechanisms, and Alzheimer's disease is clearly an inflammatory condition. As is usually the case, determining which mechanisms of disease are more or less important than the others is challenging. It is unclear how much weight to assign to this new discovery.
Obesity is a major modifiable risk factor for Alzheimer's disease (AD), but the mechanistic link between peripheral metabolic dysfunction and AD progression remains unclear. Adipose-derived extracellular vesicles (EVs) may penetrate the brain and alter lipid homeostasis, contributing to neurodegeneration. We isolated exosome-enriched EVs from subcutaneous and visceral fat of lean and obese individuals, followed by lipidomic profiling. An in vitro amyloid-β (Aβ) aggregation assay using purified Aβ40 and Aβ42 peptides was performed under lipid environments mimicking physiological and pathological states.
Our study shows that EVs from obese adipose tissue carry specific lipid species that modulate Aβ40 and Aβ42 aggregation in a lipid-type- and concentration-dependent manner. These findings provide compelling molecular evidence linking peripheral lipid imbalance to Aβ aggregation, suggesting that metabolic dysfunction associated with obesity may contribute to central amyloid pathology via adipose-derived EV lipids. Further in vivo validation is warranted to substantiate this proposed link. These findings support lipid-targeted strategies as potential therapeutics for neurodegenerative diseases.
Inhibition of IL-33 Expression in Cartilage to Treat Osteoarthritis
https://www.fightaging.org/archives/2025/10/inhibition-of-il-33-expression-in-cartilage-to-treat-osteoarthritis/
Here, researchers link increased expression of IL-33 to increased cellular senescence and dysfunction in cartilage tissue in joints and the consequent progression of osteoarthritis. Using small interfering RNA to reduce IL-33 expression, the researchers demonstrate a slowing of the progression of this destructive condition in an animal model. Regeneration of damaged cartilage remains a preferred goal, but progress on that front is slow, and research and development tends to focus more on available approaches than on approaches that require an uncertain amount of work to realize.
Osteoarthritis (OA) imposes a substantial health and economic burden globally. Currently, there is a lack of disease-modifying osteoarthritis drugs (DMOADs). This study aimed to elucidate the relationship between chondrocyte senescence and OA progression, as well as to develop an effective small interfering RNA (siRNA) nanodelivery platform for OA treatment. We engineered neutrophil membrane-coated, siIL33-loaded nanoparticles (NM-NP-siIL33) for OA management. The therapeutic efficacy of NM-NP-siIL33 was evaluated through both in vitro and in vivo experiments.
Our findings revealed that IL-33 expression was significantly upregulated in damaged articular cartilage in both young and aged mice following anterior cruciate ligament transection (ACLT) surgery. In vitro experiments demonstrated that IL-33 promotes chondrocyte senescence by inhibiting cellular autophagy via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Additional in vivo studies showed that NM-NP-siIL33 effectively delivered siIL33 to target cells within OA tissues, thereby mitigating the degradation of articular cartilage. Our results suggest that IL-33 plays a critical role in OA progression by accelerating chondrocyte senescence. Furthermore, NM-NP-siIL33 represents a promising therapeutic strategy for managing OA.
FDA Approval for Mitochondrial Therapeutic Elamipretide, Formerly SS-31
https://www.fightaging.org/archives/2025/10/fda-approval-for-mitochondrial-therapeutic-elamipretide-formerly-ss-31/
Elamipretide, originally known as SS-31, is a mitochondrially targeted small molecule originally thought to be an antioxidant akin to plastiquinones (such as visomitin / SkQ1 which is approved for use in Russia), but which may primarily function through other mechanisms to improve mitochondrial function. As we should all know by now, mitochondrial function declines with age, and compensatory therapies that improve function may be at least modestly useful in a range of age-related conditions. So far, however, the available options (such as mitoQ and vitamin B3 derivatives like nicotinamide riboside) largely compare unfavorably to the benefits of exercise on mitochondrial function.
The recent FDA approval of elamipretide is for the treatment of a rare disease, as is often the case for new therapies with broad potential, as it is faster and easier to obtain approvals in rare disease indications. An approved therapy can be prescribed off-label for other uses, but it remains to be seen as to whether the community of anti-aging physicians develops a favorable view of elamipretide based on results in their patients, and whether the company is willing to manufacture enough of the drug for off-label use at this stage.
Stealth BioTherapeutics Inc. (the "Company" or "Stealth"), a commercial-stage biotechnology company focused on the discovery, development and commercialization of novel therapies for diseases involving mitochondrial dysfunction, today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to FORZINITY™ (elamipretide HCl) to improve muscle strength in adult and pediatric patients with Barth syndrome weighing at least 30 kilograms (kg) (approximately 66 pounds). Barth syndrome is a life-limiting pediatric mitochondrial cardioskeletal disease that affects approximately 150 individuals in the United States.
"The approval of FORZINITY, the first treatment option for Barth syndrome and the first FDA-approved mitochondria-targeted therapeutic, is a pivotal victory for the Barth syndrome community and offers hope for expedited regulatory attention to other ultra-rare diseases. We appreciate the FDA's close engagement in recent months and are grateful to the trial participants, caregivers, advocates, researchers and healthcare providers who persevered in partnership with us over this decade-long journey. We plan to continue providing expanded access to children weighing less than 30 kilograms who are currently receiving treatment or require emergency access, while we work with the FDA to generate data needed to expand the indication to include these children. We are committed to the continued development of therapies to treat all patients with Barth syndrome and other devastating diseases of mitochondrial dysfunction."
The approval of FORZINITY is supported by the efficacy and safety data from the TAZPOWER clinical trial. During the open-label portion of the TAZPOWER trial, knee extensor muscle strength improved from study baseline. The most common adverse reactions were injection site reactions which can be treated with oral antihistamines or topical corticosteroids. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial.
PP2A-B55α as a Target to Improve Mitochondrial Function
https://www.fightaging.org/archives/2025/10/pp2a-b55%ce%b1-as-a-target-to-improve-mitochondrial-function/
Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that are primarily responsible for generating adenosine triphosphate (ATP), a chemical energy store molecule used to power the cell. Mitochondrial function declines with age, negatively impacting health, and thus researchers are interested in finding ways to either enhance function to compensate for this decline or find ways to prevent and reverse the loss of mitochondrial activity. Most currently available approaches fail to much improve on the effects of exercise on this front, and appear to largely work by improving quality control mechanisms that have evolved to remove damaged mitochondria. Here, researchers report on a novel target to improve mitochondrial function in older individuals, one that improves both quality control and generation of new mitochondria.
Mitochondrial homeostasis relies on a tight balance between mitochondrial biogenesis and degradation. Although mitophagy is one of the main pathways involved in the clearance of damaged or old mitochondria, its coordination with mitochondrial biogenesis is poorly characterized. Here, by unbiased approaches including last-generation liquid chromatography coupled to mass spectrometry and transcriptomics, we identify the protein phosphatase PP2A-B55α/PPP2R2A as a Parkin-dependent regulator of mitochondrial number.
Upon mitochondrial damage, PP2A-B55α determines the amplitude of mitophagy induction and execution by regulating both early and late mitophagy events. A few minutes after the damage, ULK1 is released from the inhibitory regulation of PP2A-B55α, whereas 2 to 4 hours later, PP2A-B55α promotes the nuclear translocation of TFEB, the master regulator of autophagy and lysosome genes, to support mitophagy execution. Moreover, PP2A-B55α controls a transcriptional program of mitochondrial biogenesis by stabilizing the Parkin substrate and PGC-1α inhibitor PARIS.
PP2A-B55α targeting rescues neurodegenerative phenotypes in a fly model of Parkinson's disease, thus suggesting potential therapeutic application.
View the full article at FightAging
