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- Chronic Inflammation and Differences in Frailty Between the Sexes
- Recent Progress Towards Measures of the Burden of Cellular Senescence
- Exercise Can Partially Reverse the Age-Related Loss of Muscle Tissue Capillary Density
- Exploring Alternative Splicing as a Determinant of Species Life Span
- Increased FMO3 Expression to Generate More TMAO is a Part of Harmful Adipose Tissue Aging
- Canagliflozin Reduces Pathology in the Aging Mouse Brain for Male Mice Only
- Physical Fitness Correlates with a Slower Onset of Chronic Diseases of Aging
- Physical Activity Correlates with Improved Benefits from Calorie Restriction in Humans
- A Discussion of the Impact of the Gut Microbiome on Aging
- Towards Engineered Mitochondria for Therapy
- Reviewing the Development of Senolytic Therapies for Neurodegenerative Conditions
- Reviewing the Ongoing Move from Stem Cell Therapies to Exosome Therapies
- Lower Circulating BDNF Level Correlates with Greater Cognitive Decline
- Potential Targets to Enhance the Regenerative Capacity of Alveolar Type 2 Cells in the Lungs
- Visceral Fat Correlates with Progression of Atherosclerosis
Chronic Inflammation and Differences in Frailty Between the Sexes
https://www.fightaging.org/archives/2025/10/chronic-inflammation-and-differences-in-frailty-between-the-sexes/
We are all well aware of the differences in life expectancy between women and men. The underlying reasons for the female advantage in longevity are much debated, but since similar sex differences exist across many species, it is likely to have deep roots in evolutionary biology and the complex interactions between reproductive fitness, mating strategies, and biochemistry. More prosaic explanations invoking the consequences of cultural and lifestyle choices that differ characteristically between sexes seem unlikely to be correct.
The situation is more complex than just a matter of life span, however. While living longer, women in late life exhibit a greater burden of disease and dysfunction than equivalently aged men. This seems a paradox, as reliability theory suggests that failing complex machine will have a shorter life span. Yet the data is the data. The research community spends a fair amount of time and effort attempting to find an explanation for sex based disparities in late life health that can explain all of the observed outcomes. Today's open access paper is an example of the process of gathering yet more data that might help researchers to better understand what is going on under the hood.
Inflammaging and the sex-frailty paradox
During aging, the immune cell functionality gradually decreases, resulting in a phenomenon known as "immunosenescence", which undermines both the innate and adaptive immune systems, leading to an increased incidence of disease and infection. Immunosenescence is the basis of inflammaging, a phenomenon that occurs during aging and consists of a chronic and persistent state of low-grade inflammation characterized mainly by the production of components of the innate immune response. The theory posits that excessive stimulation of pro-inflammatory pathways and an ineffective anti-inflammatory response are a driving force behind the development of frailty and age-related diseases.
Specifically, frailty reflects a state of increased vulnerability to stressors, a consequence of the gradual decline in the individual's homeostasis and functional reserves. A sex-associated divergence in frailty and mortality, termed the "sex-frailty paradox", is widely known. This consists of the observation that women, while generally living longer than men, often show higher rates of frailty reflecting a worse health status. This could be due to the fact that men tend to suffer from more malignant conditions (e.g. stroke and ischaemic heart disease), while women mainly from "life-threatening" chronic conditions associated with greater morbidity (e.g. fractures, constipation, depression, and headaches).
Research on sex-specific differences in frailty and its contributing factors suggests that these disparities are probably the result of the complex interplay between biological, psychosocial, and behavioural factors which differ between women and men. Interestingly, some studies have shown a different association between certain inflammatory markers and frailty in women and men. We studied 452 subjects (315 women and 137 men) stratifying them by age (≤ 80, 81-99 and ≥ 100 years) and sex. A 47-item frailty index was calculated. Plasma concentrations of inflammatory markers were analysed by next-generation ELISA.
Women aged ≤ 80 years were less frail while those aged ≥ 100 years were more frail than their male counterparts. Interestingly, the 81-99-year-old group showed similar frailty degree between females and males. The observed differences in frailty index values between women and men in the three age groups paralleled the peculiar associations of biomarker concentrations. This finding was in agreement with the concentrations of IL-10 and TNF-α, which were higher in men aged ≤ 80 years, and with the concentrations of IL-6 and soluble TREM1, which were higher in men aged ≤ 80 as well as in men aged 81-99 years than in women peers. This data may support the fact that immune-senescence is accelerated in men compared to women, resulting in a greater decrease in B lymphocytes and naïve T lymphocytes and a greater increase of memory T lymphocytes and natural killer cells. This alteration of immune cell function results in elevated levels of pro-inflammatory as well as anti-inflammatory cytokines, the so-called inflammaging, and in immune system dysfunction, which may underlie reduced longevity in men.
Recent Progress Towards Measures of the Burden of Cellular Senescence
https://www.fightaging.org/archives/2025/10/recent-progress-towards-measures-of-the-burden-of-cellular-senescence/
Cells become senescent constantly, ceasing to replicate and generating inflammatory signaling. This occurs when cells reach the Hayflick limit on replication, and in response to damage, injury, and toxicity. Senescence helps to draw the attention of the immune system to where it is needed, and in youth senescent cells are efficiently destroyed by immune cells once that task is accomplished. With age, however, the immune system becomes progressively less efficient while the environment becomes more damaged. As a consequence a burden of lingering senescent cells grows over time, and their contribution to the chronic inflammation of aging disrupts tissue structure and function.
Usefully measuring the burden of senescence in older people in a low-cost, non-invasive way remains a work in progress. In principle different tissues may be burdened to different degrees, and only looking at immune cells in a blood sample can be misleading with regarding to the situation in other organs and systems. Nonetheless, blood samples are largely what the research community aims to work with when building assays; it is what the medical community is geared to focus on, and data from blood samples is largely what one finds in epidemiological databases.
In today's open access paper, researchers report on the results of applying a number of approaches to deriving a score for the burden of cellular senescence based on gene expression data to the data from a large epidemiological study. While some of these assessments can be conducted in multiple tissues, the study gene expression data is from blood samples only, so the usual caveats apply as to whether this is representative of the whole body. Nonetheless, the researchers do find correlations with other metrics of health and aging, suggesting that there is value in these efforts to produce practical measures of the burden of cellular senescence.
Gene expression composite scores of cellular senescence predict aging health outcomes in the Health and Retirement Study
Cellular senescence is one of the molecular/cellular-level hallmarks of aging that accumulates with advancing age and plays an important pathogenic role in a number of adverse health outcomes. In response to damage, senescent cells stop proliferating and enter into a generally irreversible state of growth arrest. However, senescent cells are still metabolically active; they release a wide range of pro-inflammatory cytokines, chemokines, proteases, growth factors, and other bioactive molecules to the local microenvironment. Such proinflammatory secretion is termed Senescence-Associated Secretory Phenotype (SASP), and is thought to mediate downstream aging outcomes.
Recent work has suggested a more comprehensive approach to capturing the entire effect of cellular senescence rather than solely relying on SASP. In addition to SASP, other key aspects of cellular senescence include cell cycle arrest (CCA) and macromolecular damage (MD). To profile these distinct aspects of cellular senescence, researchers developed three lists of genes that are involved in the canonical senescence pathway (CSP), senescence initiating pathway (SIP), and senescence response pathway (SRP) to respectively represent CCA, MD, and SASP. These gene lists were tested and validated in two independent RNA sequencing datasets, and were associated with senescence in previous studies based on various cell and tissue types in human and mouse brains. Another gene list reflecting intracellular changes specific to senescent immune cells, termed SenMayo, was also recently developed. SenMayo includes genes involved in CCA, MD, and SASP, and thus has the potential to measure cellular senescence comprehensively.
Using RNA sequencing data from the U.S. representative Health and Retirement Study (HRS) sample (N = 3,580), we examine how CSP, SIP, SRP, and SenMayo relate to sociobehavioral factors and aging-related outcomes. Results show that senescence scores generally increase with age except for CSP. Higher scores are observed in women and individuals with class II obesity. All scores, except for CSP, are associated with accelerated epigenetic aging, physiological dysregulation, multimorbidity, cognitive decline, and 6-year mortality. These associations largely persist after adjustment for the pace of aging clock DunedinPACE. Our findings suggest that cellular senescence gene expression composite scores capture meaningful variation in aging-related health and complement existing epigenetic aging biomarkers.
Exercise Can Partially Reverse the Age-Related Loss of Muscle Tissue Capillary Density
https://www.fightaging.org/archives/2025/10/exercise-can-partially-reverse-the-age-related-loss-of-muscle-tissue-capillary-density/
Every tissue is supported by countless capillaries, the smallest vessels in the branching vascular network. Take a square cross-section of tissue a millimeter in each dimension and one finds hundreds of capillaries passing through it. This intricate branching network of vessels must be constantly maintained, but unfortunately the processes of maintenance decline with age, as is the case for all complex systems in the body. The resulting progressive loss of capillary density reduces the supply of oxygen and nutrients, and this is thought to provide a meaningful contribution to loss of tissue function and the onset of age-related disease.
What can be done about this? Manipulating some of the regulators and participants at various stages of angiogenesis seems promising. Angiogenesis is a multi-step process wherein a new branch from an existing blood vessel is constructed. It is an example of one of the better understood mechanisms involved in the maintenance of our biology, as it is extensively studied and the research community has a good understanding of how it works, but there is still room for exploration at the detail level. Studies have shown that upregulation of VEGF, an important signal in angiogenesis, can lead to greater angiogenesis. VEGF is involved in the creation of pathological, leaky blood vessels in macular degeneration, but no such issue is seen in the animal studies in which circulating VEGF is increased. Alternatively, strategies to mobilize hematopoietic progenitor cells from the bone marrow into circulation, such as CXCL12 upregulation, used when harvesting hematopoietic cells from a donor for transplantation, also promote angiogenesis.
Today's open access paper focuses on the more prosaic intervention of exercise. There is evidence for late life exercise to partially reverse loss of capillary density in muscle tissue. Exercise is in general beneficial for systems throughout the body, so this is perhaps not surprising. Relatively few of the manifestations of aging are completely immune to treatment via lifestyle choice, even though the degree of reversal that can be achieved is much smaller than desired.
The role of exercise induced capillarization adaptations in skeletal muscle aging: a systematic review
Skeletal muscle aging is often accompanied by capillary rarefaction, which limits the effective delivery and distribution of hormones, nutrients, and growth factors within skeletal muscle. Furthermore, exercise is widely regarded as having the potential to improve microcirculation and delay skeletal muscle aging. This review aims to explore exercise-induced improvements in capillarization and related adaptations to mitigate the adverse changes that occur during the aging process of skeletal muscle.
Studies have shown that older adults still possess the capacity to improve skeletal muscle capillarization through exercise. Moderate-intensity aerobic exercise not only significantly enhances the level of capillarization but also induces effects that can be maintained even after cessation of training. Capillarization adaptations induced by resistance training exhibit marked inter-individual variability, which is primarily determined by each individual's baseline level of capillarization, thereby resulting in distinct patterns of adaptation. The studies also revealed that the regulation of capillarization depends on the synergistic action of VEGF and eNOS, and that different types of exercise may elicit adaptations through distinct molecular pathways.
In conclusion: during the aging process, exercise-induced improvements in capillarization can enhance nutrient delivery, metabolic efficiency, and regenerative capacity in skeletal muscle. To some extent, these adaptations help suppress degenerative changes in muscle function and provide a targeted foundation for anti-aging intervention strategies.
Exploring Alternative Splicing as a Determinant of Species Life Span
https://www.fightaging.org/archives/2025/10/exploring-alternative-splicing-as-a-determinant-of-species-life-span/
A gene coding for a protein consists of multiple exon and intron sequences of DNA. During gene expression, the full DNA sequence of exons and introns is first transcribed into a RNA sequence, the primary transcript. That primary transcript undergoes a series of alterations that include RNA splicing. This splicing process removes the introns and stitches together the remaining exons to form a messenger RNA molecule. That messenger RNA is then used as a template by a ribosome manufacture many copies of the protein that it encodes.
Interestingly, many genes can undergo alternative splicing to produce several different messenger RNAs and proteins. A specific intron is not always excluded, a specific exon is not always retained. In some cases this is normal and expected, in other cases it has the look of an error that produces toxic proteins. The landscape of alternative splicing across all of the proteins encoded in the genome shifts with age, altering the balance of proteins produced via gene expression. Some research groups consider this to be a component of degenerative aging and a potential target for therapies to slow aging.
Species life span and the aging of individuals are related but may be driven by distinct mechanisms. Learning more about the determinants of species life span may or may not yield insights that are relevant to making individuals of any given species life longer. Differences in the regulation of alternative splicing may be important in determining species life span, but the research community is still at the early stages of gathering data to shed more light on this question. Today's open access paper is an example of this sort of exploration.
The Implications of Alternative Splicing Regulation for Maximum Lifespan
Alternative splicing (AS) is a post-transcriptional or co-transcriptional regulatory mechanism by which a single gene generates multiple distinct mature transcript isoforms, leading to protein diversity in higher eukaryotes. Up to 95% of multi-exon human genes undergo AS, often exhibiting tissue- or cell-type dependent regulation and dynamically controlled in distinct cellular processes. The association between AS and the intertwined realms of aging and longevity remains unclear. Age-associated splicing changes have been reported in different experimental systems, albeit in a piecemeal fashion, and alterations in certain splicing factor expressions in the spleen have been linked to differences in lifespan. These initial findings hint that splicing regulation might impact lifespan, but a comprehensive comparative analysis of maximum lifespan (MLS) as a species trait across species with widely varying maximum lifespans has not yet been conducted.
In this study, we systematically investigated MLS-associated AS events across multiple mammalian species spanning a broad range of maximum lifespans to uncover potential links between splicing and lifespan regulation. Our results suggest alternative splicing as an important factor correlated with both the evolved differences in mammalian lifespan and the human aging, and show potential molecular mechanisms (e.g., RNA processing, neural regulation, intrinsically disordered proteins, RNA-binding protein regulators) underlying these effects. Remarkably, nearly half of the highly conserved alternative splicing events show a significant association with maximum lifespan in at least one tissue. While many of these splicing associations are consistent across different tissues, the effects in the brain stand out as particularly distinct. Although the precise functions of many of these brain-specific events are unclear, previous studies have suggested a critical role for AS in regulating neuronal longevity and animal survival.
These findings suggest alternative splicing as a distinct, transcription-independent axis of lifespan regulation, offering new insights into the molecular basis of longevity.
Increased FMO3 Expression to Generate More TMAO is a Part of Harmful Adipose Tissue Aging
https://www.fightaging.org/archives/2025/10/increased-fmo3-expression-to-generate-more-tmao-is-a-part-of-harmful-adipose-tissue-aging/
A number of lines of research indicate that fat tissue becomes actively harmful to other tissues with advancing age via forms of signaling. Much of this work is focused on the role of excess visceral fat tissue in long-term health. Visceral fat acts to increase the burden of senescent cells, which then promote inflammation throughout the body via inflammatory signaling, but fat cells can also act to directly generate pro-inflammatory signaling in other ways, such as via mimicking the signaling generated by infected cells. These are not the only mechanisms, and nor do fat cells act in isolation to cause issues in the aging body.
Researchers here produce evidence to show that fat cells mediate a problematic relationship between the gut microbiome and various the age-related cardiometabolic diseases with a strong inflammatory component, such as type 2 diabetes and atherosclerosis. With age, changes in the composition of the gut microbiome ensure that bacteria in the gut increasingly generate trimethylamine. Meanwhile other aspects of aging ensure that fat cells throughout the body increasingly express FMO3, converting that trimethylamine into trimethylamine-N-oxide (TMAO). TMAO is well established to promote inflammation, at this point a fairly well studied contribution to the inflammation of aging.
Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing
White adipose tissue (WAT) acts as an endocrine organ to maintain systemic energy and glucose homeostasis. Transcriptomic and proteomic analyses indicate that WAT is the first tissue showing functional decline in ageing. WAT is composed of diverse cell populations, including mature white adipocytes that produce bioactive adipokines to communicate and coordinate with the neighboring cells and distal metabolic tissues in control of systemic metabolism under varying nutritional and environmental conditions. Ageing alters composition and functionality as well as the interaction of the adipocytes and the WAT-resident cells.
Gut microbiota control host metabolism by generating an array of metabolites targeting to multiple metabolic tissues. Flavin-containing monooxygenase 3 (FMO3), a xenobiotic metabolizing enzyme primarily expressed in the liver, converts gut microbiota-produced trimethylamine (TMA) from its nutrient precursors (such as choline, L-carnitine, and betaine) into trimethylamine-N-oxide (TMAO) via hepatic FMO3. Early human and animal studies showed the important role of this microbiota-host axis in cardiometabolic health. In rodent models, knockdown of hepatic FMO3 using anti-sense oligonucleotides or global deletion of FMO3 improves hepatic insulin resistance, hyperlipidemia, obesity and atherosclerosis. Dietary treatment with TMAO promotes inflammation in visceral WAT (vWAT) by upregulating the expression of pro-inflammatory cytokines.
Although the liver is considered the main site for TMAO production via FMO3, we here demonstrate that adipocyte FMO3 is the contributor to the elevated TMAO level in ageing. We found that FMO3 and TMAO are abundantly expressed in mature adipocytes of WAT, and their levels are induced in humans and rodents with ageing via a p53-dependent pathway. Adipocyte-specific deletion of FMO3 protects against ageing- or obesity-induced functional decline of WAT, accompanied by improvement of glucose, lipid homeostasis and energy balance in mouse models. Adipocyte FMO3-derived TMAO acts as an autocrine and paracrine factor to trigger inflammasome activation and subsequent IL-1β production in mature adipocytes and adipose tissue-resident macrophages. Our proteomics analysis identifies numerous TMAO-binding proteins that participate in inflammatory pathways, particularly inflammasome activation. In summary, our study uncovers how aged adipocytes convert gut microbiota-derived metabolite to elicit adipose tissue dysfunction and systemic dysmetabolism in ageing.
Canagliflozin Reduces Pathology in the Aging Mouse Brain for Male Mice Only
https://www.fightaging.org/archives/2025/10/canagliflozin-reduces-pathology-in-the-aging-mouse-brain-for-male-mice-only/
Researchers have found that a number of antidiabetic drugs act to modestly slow aging in mice, albeit often differently by sex, while some effects are more reliable than others. Insulin metabolism was one of the first aspects of cell biochemistry to be well studied in the context of effects on aging, and drugs that affect insulin metabolism in the environment of the dysfunction of type 2 diabetes were thus thought likely to have at least some small effect on aging. The effect is indeed small and unreliable in some of the more studied drugs, such as metformin. Here, researchers assess the outcome of treatment with the antidiabetic drug canagliflozin in a mouse model of Alzheimer's disease, focusing on measures of brain aging and pathology, finding it to produce useful benefits in male mice only.
Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice.
In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose control improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.
Physical Fitness Correlates with a Slower Onset of Chronic Diseases of Aging
https://www.fightaging.org/archives/2025/10/physical-fitness-correlates-with-a-slower-onset-of-chronic-diseases-of-aging/
A sizable body of epidemiological evidence links physical fitness to improved health, greater longevity, and slowed aging in later life. Use it or lose it, as they say. Here researchers quantify the degree to which physical fitness can slow the onset of the chronic diseases of aging. Obviously one can't escape degenerative aging via exercise, but given that maintaining fitness has one of the larger presently available effects on the long-term trajectory of health, why not make the effort?
Cardiorespiratory fitness (CRF) has been linked to lower risk of individual chronic diseases, but little is known about the CRF in relation to multimorbidity. Thus the authors here investigated the association between CRF and multimorbidity risk and explored differences in the trajectories of chronic disease accumulation at varying levels of CRF. The study included 38,348 adults from the UK Biobank (mean age 55.21 ± 8.15 years) who were followed for up to 15 years to detect the incidence of 59 common chronic diseases. CRF was estimated using a 6-minute submaximal exercise test and tertiled as low, moderate, and high (after standardization by age and sex). Multimorbidity was defined as the presence of 2 or more chronic diseases.
During the follow-up (median 11.57 years), 15,368 (40.08%) participants developed multimorbidity. The risk of multimorbidity was 21% lower in participants with high compared to low CRF (hazard ratio, HR: 0.79). The median time to multimorbidity onset was 1.27 years later for those with high compared to low CRF. Moreover, participants with high CRF experienced a significantly slower annual rate of chronic disease accumulation (β = -0.043). Thus high CRF is associated with lower multimorbidity risk, delayed onset of multimorbidity, and significantly slower accumulation of chronic diseases. The findings highlight the importance of CRF for healthy longevity.
Physical Activity Correlates with Improved Benefits from Calorie Restriction in Humans
https://www.fightaging.org/archives/2025/10/physical-activity-correlates-with-improved-benefits-from-calorie-restriction-in-humans/
The CALERIE study of human calorie restriction was conducted some years ago. Participants aimed at 25% calorie restriction and achieved a ~12% reduction in calorie intake over a span of two years. A number of papers have been published on the positive results for participant heath, and researchers continue to produce new analyzes of the data. Here, researchers show that participants who conducted more physical activity while calorie restricted exhibit modestly better outcomes in a number of measures of health known to change favorably with the practice of calorie restriction.
It is unclear how physical activity energy expenditure (PAEE) influences calorie restriction (CR)-induced benefits in individuals without obesity. We examined associations between PAEE and healthspan markers and physical activity (PA) time during prolonged CR. In Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) 2, participants without obesity were randomized to 25% CR or ad libitum control. This post-hoc analysis included baseline and 24-month data from participants in both groups who demonstrated CR. PAEE was calculated from total and resting energy expenditure. Outcomes included grip strength, aerobic capacity, glucose, insulin, blood lipids, and self-reported PA time.
Overall, 136 participants (97 females; average age 38.6 years; average BMI 25.3) who showed CR were analyzed. A smaller decrease in PAEE was associated with improved grip strength, homeostatic model assessment of insulin resistance, and high-density lipoprotein-cholesterol. PAEE change was not associated with aerobic capacity, low-density lipoprotein-cholesterol, triglycerides, glucose, or insulin. A smaller PAEE decline was associated with greater PA time. For some blood lipids, change in PAEE interacted with baseline BMI class: in participants who were overweight, higher PAEE was associated with lower triglyceride and triglyceride to high-density lipoprotein-cholesterol ratio, whereas in participants who were normal weight, it was related to increased total-cholesterol.
In conclusion, a smaller reduction in PAEE during CR was associated with small improvements in several healthspan markers and greater PA time. Maintaining PAEE during CR may enhance healthspan in individuals without obesity.
A Discussion of the Impact of the Gut Microbiome on Aging
https://www.fightaging.org/archives/2025/10/a-discussion-of-the-impact-of-the-gut-microbiome-on-aging/
The composition of the gut microbiome is influential on health, perhaps to a similar degree as diet and exercise choices. This composition changes with age in ways that are detrimental to long-term health, reducing the supply of metabolites necessary for tissue function while increasing the number of microbes capable of provoking chronic inflammatory signaling. Altering the composition of the gut microbiome in lasting ways, such as via flagellin immunization or fecal microbiota transplantation, has been shown to produce benefits to health and longevity in animal studies. Bringing these or related techniques to wider human use remains to be achieved, however, and the presently available approaches of diet and probiotics to adjust the balance of populations in the gut microbiome are not as effective as desired.
The gut microbiome is a salient contributor to human health, with considerable evidence also supporting it as a marker and mediator of healthy aging. The gut microbiome undergoes compositional and functional changes throughout the human lifespan. Studies in model organisms have demonstrated that the gut microbiome affects aging and longevity through metabolic activities that modulate host immunity. This modulation is also present in the centenarian gut microbiomes, with unique characteristics that plausibly contribute to longevity, including increased microbial and metabolic diversity, enriched beneficial taxa like Akkermansia and Christensenellaceae, and enhanced gut homeostasis.
Mechanistically, the gut microbiome orchestrates the aging process through various pathways. These pathways change with age, with age-related gut dysbiosis reciprocally promoting inflammaging through the decreased production of anti-inflammatory short-chain fatty acids and declined gut barrier integrity. The worsened inflammation amplifies neuroinflammatory responses, triggering cognitive decline through the gut-brain axis. Furthermore, gut dysbiosis also negatively affect muscle mass and function, which in turn exacerbate frailty in the elderly.
Some intriguing questions remain open for investigation. First, the human aging process is composed of nonlinear waves in molecular changes, with approximately 44 and 60 years of age being the two critical periods characterized by the highest number of dysregulated molecules and microbes. These two chronological ages are therefore of research interest, warranting further investigation into strategies based on gut microbiome modulation that could mitigate dysregulation to slow down or, at the very least, alleviate the aging process and reduce disease risk in later life. Second, some microbially derived metabolites, such as phenylacetylglutamine, accelerate host cellular senescence. Identifying gut microbes driving these metabolic processes and targeting them through dietary interventions to reduce the substrates fueling these pathways could provide internal benefits to the aging process.
Towards Engineered Mitochondria for Therapy
https://www.fightaging.org/archives/2025/10/towards-engineered-mitochondria-for-therapy/
Cells can take up mitochondria from the surrounding environment, and researchers have demonstrated in mice that intravenous delivery of mitochondria allows some degree of replacement of the native populations in cells. This improves function when native mitochondria are dysfunctional, as occurs with age. At present, delivery of mitochondria as a therapy to restore mitochondrial function in older people is a work in progress. A few companies are working on the challenge, which largely involves developing the techniques needed to reliably manufacture mitochondria at scale. In this paper, researchers look beyond that effort to the next step in the road, which is to engineer the delivered mitochondria to be more efficient and more resilient, or to act as factories for therapeutic molecules, or to have some other desired capability.
Conventional mitochondrial transplantation (MT), a therapeutic process involving the isolation and delivery of healthy exogenous mitochondria to damaged cells or organs to restore bioenergetics and promote repair, typically relies on the direct injection or infusion of isolated, unmodified mitochondria. Inspired by cell surface engineering, we propose nanoengineered mitochondria, which are biohybrid systems formed by integrating synthetic nanomaterials or biomolecules with isolated mitochondria to confer new functionalities.
This emerging strategy operates at the interface of bioengineering and mitochondrial biology and aims to overcome the limitations of conventional MT. These tailored nanobiohybrid systems have the potential to improve mitochondrial quality, boost metabolic activity, and reduce oxidative stress. Moreover, these systems can enhance the targeting efficiency and motility of mitochondria, which is achieved through mitochondrial ligand-receptor recognition (e.g., triphenylphosphonium cation (TPP+)-modified nanoparticles and mitochondrial membrane potentials), stimulus-responsive navigation (e.g., pH/ROS-sensitive polymers guiding mitochondria to inflammatory sites), and external field-driven propulsion (e.g., magnetically steered nanocapsules). This mini-review therefore focuses specifically on the emerging of nanoengineered mitochondria, moving beyond the scope of earlier reviews that centered primarily on conventional transplantation. We envision nanoengineered mitochondria as a next-generation platform for precise anti-aging interventions.
Reviewing the Development of Senolytic Therapies for Neurodegenerative Conditions
https://www.fightaging.org/archives/2025/10/reviewing-the-development-of-senolytic-therapies-for-neurodegenerative-conditions/
Senescent cells accumulate with age in tissues throughout the body, generating sustained pro-inflammatory signaling that is increasingly disruptive to tissue structure and function. This is an important contribution to degenerative aging, as illustrated by the many animal studies in which senolytic therapies that selectively destroy senescent cells produce significant reversal of aspects of aging and age-related disease. Here, researchers review the evidence for senolytic therapies to effectively treat neurodegenerative conditions by removing the harms done by senescent cells in the brain.
The cellular phenomenon of aging is irreversible and is characterized by the arrest of cell division and induction of growth. It is believed that this mechanism contributes to age-related illnesses, such as neurodegenerative diseases, as well as the ageing process itself. The ability of aging cells in the brain to release pro-inflammatory chemicals like cytokines and chemokines is a factor that contributes to the deterioration of neurons and the advancement of neurodegenerative disorders. The accumulation of β-amyloid and tau proteins seen in Alzheimer's disease (AD), coupled with the clustering of senescent microglia and astrocytes in the brain, worsens neuroinflammation. Similarly, the accumulation of senescent dopaminergic neurons and microglia has been accompanied by the pathogenesis of Lewy bodies and the neuroinflammatory response in individuals with Parkinson's disease (PD).
Current research has looked at the possibility of alleviating the symptoms of neurodegenerative diseases by using senolytics, which are pharmaceuticals or chemical compounds that selectively remove aged cells. In animal models of AD and PD, senolytic therapy has been demonstrated to enhance cognitive function and decrease neuroinflammation in both diseases. Despite the promising potential of targeting cellular senescence, several challenges remain. Further research is needed to better understand the complex interplay between senescent cells and the surrounding microenvironment in the brain. Additionally, the long-term safety and efficacy of senolytic therapies need to be carefully evaluated in clinical trials.
Reviewing the Ongoing Move from Stem Cell Therapies to Exosome Therapies
https://www.fightaging.org/archives/2025/10/reviewing-the-ongoing-move-from-stem-cell-therapies-to-exosome-therapies/
The medical tourism industry has adopted the therapeutic use of exosomes derived from stem cells in much the same way as it adopted the use of stem cell therapies. Transplanted stem cells produce benefits via signaling, and most signaling is carried via extracellular vesicles such as exosomes. From a logistics point of view, exosomes are more easily stored, transported, and used, while all of the tools needed to harvest exosomes from stem cell cultures already existed. Meanwhile, the regulated medical industry lags years behind, given the large costs and lengthy development programs required to satisfy regulatory requirements for manufacturing consistency and data on outcomes. Lack of consistency is certainly a long-standing issue in stem cell therapies, and will likely continue to be an issue for exosome therapies. This may simply be an inherent characteristic of material sourced from donors, and will continue to exist until such time as standardized universal cell lines are a going concern.
Stem cell-derived exosomes have broad application prospects in different medical fields, and are increasingly being considered a replacement for mesenchymal stromal cells (MSCs) therapy. Adipose-derived stem cells (ADSCs) are an efficient and high-quality source of stem cell exosomes because ADSCs can be easily obtained from autologous adipose tissue and there are only minor ethical concerns, also ADSCs shown multipotent differentiation potential, self-renewal potential, low immunogenicity, and high proliferation rate.
Exosomes derived from ADSCs have the function of promoting tissue regeneration through activation or inhibition of multiple signaling pathways (such as Wnt/β-catenin, PI3K/Akt), and immunomodulation, angiogenesis, cell migration, proliferation and differentiation, and tissue remodeling. This review presents the current state of knowledge on ADSCs exosomes and summarizes the use of ADSCs exosomes in stem cell-free therapies for the treatment of diabetes mellitus, cardiovascular, wound healing, neurodegenerative, skeletal, respiratory diseases, and skin aging and other conditions, thus providing novel insights into the clinical applications of MSC-derived exosomes in disease management.
Lower Circulating BDNF Level Correlates with Greater Cognitive Decline
https://www.fightaging.org/archives/2025/10/lower-circulating-bdnf-level-correlates-with-greater-cognitive-decline/
A range of research suggests that an increase in the circulating levels of BDNF is beneficial to the function of the brain (and likely muscle tissue as well). This is one of the ways in which alterations to the diet and gut microbiome composition can affect the brain, as microbial production of butyrate via fermentation of dietary fiber acts to increase BDNF expression. The research community has an interest in finding other ways to increase BDNF levels more directly, and that is a work in progress. Meanwhile, researchers continue to produce evidence to support that goal, such as the data noted here.
Brain Derived Neurotrophic Factor (BDNF) plays a crucial role in supporting neuronal survival, promoting neurogenesis, and enhancing synaptic plasticity, all of which are vital for cognitive health. The aim of this study was to investigate the relationship between BDNF levels and cognitive impairment in the elderly population. This was a cross-sectional study involving older adults at a social service care. Cognitive function was assessed using the Montreal Cognitive Assessment-Indonesian Version (MoCA-INA). BDNF levels were measured in peripheral blood samples using the Enzyme-Linked Immunosorbent Assay.
Of the 88 participants with a median age of 69.5 years, 71 (80.7%) had cognitive impairment. The median MoCA-INA score was 15.0. The most affected cognitive domain was abstraction, absolute number of patients 87 patients (98.9%). The mean BDNF level was 1.55 (±0.62) ng/mL with 50 (56.8%) patients having normal level. A weak positive correlation was found between BDNF level and performance in the visuospatial-executive (r = 0.232) and abstraction domains (r = 0.249). BDNF levels were significantly lower in those with cognitive impairment compared to those with normal cognitive function.
In conclusion, we observed a correlation between BDNF levels and cognitive function, particularly in the visuospatial-executive and abstraction domains, highlighting the potential role of BDNF in cognitive decline in aging.
Potential Targets to Enhance the Regenerative Capacity of Alveolar Type 2 Cells in the Lungs
https://www.fightaging.org/archives/2025/10/potential-targets-to-enhance-the-regenerative-capacity-of-alveolar-type-2-cells-in-the-lungs/
Researchers here report on potential targets to enhance the regenerative capacity of alveolar type 2 cells, a population necessary for regeneration in lung tissue, but which falters in this duty in the context of progressive and age-related lung disease. Compensating for poorly understood mechanisms of damage and disease that direct alveolar type 2 cells away from regenerative activity can in principle be achieved by overriding the regulatory system that controls this aspect of cell behavior, provided enough is understood of how that regulatory system works. This approach to therapy doesn't fix the underlying issues, but may well prove to be beneficial enough to pursue. There are numerous examples in the present practice of medicine of compensatory approaches that succeed in producing benefits for patients.
When a person's lungs are damaged, that organ's survival depends on a small but powerful set of cells that must choose whether to repair the tissue or fight infection. "We were surprised to find that these specialized cells cannot do both jobs at once. Some commit to rebuilding, while others focus on defense. That division of labor is essential - and by uncovering the switch that controls it, we can start thinking about how to restore balance when it breaks down in disease."
The new research centers on alveolar type 2 (AT2) cells, which play a dual role in the lung. These cube-shaped cells secrete surfactant proteins that keep air sacs open, but they also act as reserve stem cells capable of regenerating alveolar type 1 (AT1) cells - the paper-thin cells that form the surface for gas exchange. This regenerative capacity makes AT2 cells essential for lung repair after injury. For decades, scientists have known that these cells often fail to regenerate properly in lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and severe viral infections like COVID-19. What remained unclear was how AT2 cells lose their stem cell capacity.
Using single-cell sequencing, imaging and preclinical injury models, the team mapped the developmental "life history" of AT2 cells. They found that newly formed AT2 cells stay flexible for about one to two weeks after birth before "locking in" to their specialized identity. That timing is controlled by a molecular circuit involving three key regulators called PRC2, C/EBPα, and DLK1. The researchers showed that one of them, C/EBPα, acts like a clamp that suppresses stem cell activity. In adult lungs, AT2 cells must release this clamp after injury to regenerate. The discoveries could guide the development of therapies to fix AT2 cells that are broken in disease. Drugs that target C/EBPα, for example, may restore repair programs or reduce scarring in pulmonary fibrosis.
Visceral Fat Correlates with Progression of Atherosclerosis
https://www.fightaging.org/archives/2025/10/visceral-fat-correlates-with-progression-of-atherosclerosis/
The more visceral fat that is present in the body, the greater the burden of atherosclerotic plaque narrowing and weakening major blood vessels. This isn't just for those people who are very overweight, but the data shows that any degree of excess visceral fat correlates with a relative degree of acceleration of atherosclerosis: the more fat the worse the outcome. Visceral fat also contributes to other age-related conditions, with the most likely link being promotion of chronic inflammation via a number of different mechanisms. Visceral fat tissue promotes a greater burden of cellular senescence, fat cells produce signaling that mimics infected cells, and so forth.
Visceral fat (VAT), a type of fat stored in the abdomen, and buildup of fat within the liver are known to increase type 2 diabetes, high blood pressure, and heart disease risk. This study aims to see how these types of fat affect artery health. Participants in the Canadian Alliance of Healthy Hearts and Minds (CAHHM) cohort study (n = 6760; average age = 57.1; 54.9% female) underwent MRI for VAT volume, hepatic fat fraction (HFF), and carotid atherosclerosis assessed by carotid wall volume (CWV). Regression models were used to assess the associations of VAT and HF with carotid atherosclerosis, separately in males and females, controlling for other cardiovascular risk factors. Associations of VAT and proton-density hepatic fat fraction (PDFF) with ultrasound-measured carotid-intima media thickness (CIMT) were also assessed in the UK Biobank (UKB; n = 26,547; average age = 54.7; 51.9% female).
In CAHHM, we show that a 1 standard deviation higher VAT volume is associated with a 6.16 mm^3 higher CWV, but there is no association between HFF and CWV. In the UK Biobank cohort, a 1 standard deviation higher VAT volume is associated with a 0.016 ± 0.009 mm higher CIMT, and a 1 standard deviation higher PDFF is associated with a 0.012 ± 0.010 mm higher CIMT. After adjustment for CV risk factors, these associations are attenuated. A pooled analyses of CAHHM and UKB support a direct, positive association of VAT and HFF with subclinical atherosclerosis in both sexes, albeit slightly weaker for hepatic fat. Thus visceral fat, and to a lesser extent, hepatic fat, are associated with increased carotid atherosclerosis.
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