Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,please visit:https://www.fightaging.org/newsletter/
Longevity Industry Consulting Services
Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/
- Chronological Age Doesn't Correlate Well with Cognitive Decline
- Early Life Intestinal Injury in Fruit Flies Delays Intestinal Aging and Mortality
- Measuring the Quality of Death
- Senescent Macrophages Accelerate Tumor Growth
- Sestrin 1 is Required for Calorie Restriction to Extend Life in Nematode Worms
- Improving Mitochondrial Function in Chondrocytes to Improve Cartilage Regeneration
- Mesenchymal Progenitor Cells with Modified FOXO3 Improve Health in Aged Monkeys
- ADGRG1 in Microglia Facilitates Clearance of Amyloid in the Aging Brain
- Potential Therapeutic Approaches to Cerebral Small Vessel Disease
- Hypertension Allows Harmful Immune Cell Infiltration of the Brain
- How Age-Related Fat Infiltration of Muscle Harms Regeneration
- Mitochondrial Dysfunction in the Aging of Muscle Tissue
- Antiviral Treatment Fails to Slow the Progression of Early Stage Alzheimer's Disease
- Modest Amounts of Fast Walking Reduce Mortality in Older People
- Targeting Cellular Senescence to Treat Age-Related Diseases
Chronological Age Doesn't Correlate Well with Cognitive Decline
https://www.fightaging.org/archives/2025/08/chronological-age-doesnt-correlate-well-with-cognitive-decline/
In today's open access paper, researchers report on correlations between phenotypic age and cognitive function in older adults. Phenotypic age is an aging clock that uses a small number of blood chemistry measures as its inputs, such as portions of a complete blood count, creatine, C-reactive protein, and so forth. The big advantage of this approach over epigenetic clocks is that one can look at what changed following an intervention and theorize a little about what that means. Did C-reactive protein levels go down in the course of a reduction in phenotypic age, for example? That indicates positive effects on the chronic inflammation characteristic of later life. This sort of reasoning remains impossible for epigenetic clocks at the present time. One can see what changed, which CpG sites on the genome are differently methylated in the sample, but there is no connection from there to the rest of our biochemistry. It is a dead end.
The most interesting outcome reported in today's study is that chronological age fails to correlate with cognitive function. We might take this as hopeful. Cognitive decline is not inevitable in a normal human life span, even given the universal operation of mechanisms of degenerative aging, and even given the paucity of interventions to slow aging beyond exercise and lifestyle choice. Accelerated phenotypic age does correlate with a decline in cognitive function in the study population, and we might take this as the usual cautionary tale about taking better care of one's long-term health. The data suggests that these differences are largely a matter of exercise and physical fitness.
Aging acceleration, not chronological age, is associated with cognitive performance in older adults: A cross-sectional study on the protective role of physical activity
Cognitive decline in older adults is a growing public health concern, and traditional measures such as chronological age are insufficient for accurately assessing cognitive function. Phenotypic age (PhenoAge) and phenotypic age acceleration (PhenoAgeAccel), which reflect biological age and aging acceleration, may be better predictors of cognitive decline. Additionally, physical activity (PA) has been recognized for its protective effects on aging and cognitive health. This study explored the role of PhenoAge and PhenoAgeAccel in cognitive performance and investigated whether PA moderates this relationship.
We used data from the National Health and Nutrition Examination Survey, which analyzed 1,298 participants aged 60 years and older. PhenoAge was calculated using 10 biomarkers, and PhenoAgeAccel was derived as the difference between chronological age and PhenoAge. Cognitive performance was assessed using the Digit Symbol Substitution Test. The relationship between PhenoAge, PhenoAgeAccel, and low cognitive performance was analyzed using weighted logistic regression models. Subgroup and sensitivity analyses were conducted, and the interactions between PhenoAgeAccel and PA were evaluated.
Both PhenoAge and PhenoAgeAccel scores were significantly associated with low cognitive performance. The highest quartiles of PhenoAge (odds ratio = 3.22) and PhenoAgeAccel (odds ratio = 2.31) were associated with higher odds of low cognitive performance. By contrast, chronological age did not show a significant relationship with cognitive performance. PA was found to moderate the association between PhenoAgeAccel and cognitive performance. Higher levels of PA attenuated the impact of PhenoAgeAccel on cognitive decline. Receiver operating characteristic curve analysis showed that PhenoAge (area under the curve [AUC] = 0.562), PhenoAgeAccel (AUC = 0.589), and chronological age (AUC = 0.513) were significantly different. In conclusion, PhenoAgeAccel and PA are significant predictors of cognitive decline, with PA offering a protective effect against the impact of accelerated aging on cognition.
Early Life Intestinal Injury in Fruit Flies Delays Intestinal Aging and Mortality
https://www.fightaging.org/archives/2025/08/early-life-intestinal-injury-in-fruit-flies-delays-intestinal-aging-and-mortality/
Fruit flies are used as a model of intestinal aging primarily because this aspect of aging drives mortality in that species. We can say that flies die from intestinal dysfunction in the same way that we can say that humans die from cardiovascular dysfunction; it isn't the whole story by any means, but it is a sizable chunk of the story and the most common cause of mortality. So whenever one reads research materials on the topic of the aging of intestinal tissue, it is reasonable to expect fruit flies to be involved in that work at some point.
In today's open access paper, researchers present an interesting finding regarding mechanisms of intestinal tissue maintenance and aging. Because enterocyte cells in the intestinal epithelium do not turn over all that rapidly, an early life injury that provokes greater turnover for a time has the side-effect of making a fly more resilient to later age-related damage and dysfunction. The intervention doesn't have to be injury, as fasting also provokes greater turnover of enterocytes. Anything that allows some degree of replacement of enterocytes in adult life will lead to a long-term resilience to age-related intestinal dysfunction.
Age mosaic of gut epithelial cells prevents aging
Similar age-related structural and functional declines have been reported in the aging mammalian and Drosophila intestines. The Drosophila midgut epithelium has emerged as a model system for the study of aging genetically, and contributes to the understanding of the mechanisms of mammalian intestinal aging. The Drosophila midgut epithelium is a monolayer tissue composed of self-renewing intestinal stem cells (ISCs) that divide asymmetrically to give rise to enteroblasts (EBs) that differentiate into absorptive polypoid enterocytes (ECs) or enteroendocrine progenitor cells that give rise to a pair of enteroendocrine cells (EECs). In old flies, the midgut epithelium exhibits hyperplasia and barrier disruption, which associates with fly death.
However, it is still unclear how to limit hyperplasia to extend lifespan. Here, we show that early midgut injury prevents the abrupt onset of aging hyperplasia and extends lifespan in flies. Daily transcriptome profiling and lineage tracing analysis show that the abrupt onset of aging hyperplasia is due to the collective turnover of developmentally generated "old" enterocytes (ECs). Early injury introduces new ECs into the old EC population, forming the epithelial age mosaic. Age mosaic avoids collective EC turnover and facilitates septate junction formation, thereby improving the epithelial barrier and extending lifespan. Furthermore, we found that intermittent time-restricted feeding benefits health by creating an EC age mosaic. Our findings suggest that age mosaic may become a therapeutic approach to reverse aging.
Measuring the Quality of Death
https://www.fightaging.org/archives/2025/08/measuring-the-quality-of-death/
Medicine is the collective, warring, practical implementation of some of our most fundamental, important views on the human condition. What do we think can and should be done about the existence of suffering? What is the purpose of life? What do we do about death and its consequences? The development and provision of medical services inevitably requires these questions to be answered at some point by most of the people involved. Why start a career in medicine or medical development? Why continue it? What to focus on? Where does meaning arise in this life choice?
Medicine is largely a response to suffering. But it cannot only be a response to suffering, because there are two paths to alleviating suffering, as we all know. The first path requires no medicine in its simplest implementations, and is to bring as quick as possible an end to the life of the suffering individual. Medicine exists because this is rarely an individual's first impulse. Few indeed follow that path down to the nihilist's logical conclusion that all entities capable of suffering should be prevented from coming into being or persuaded into destruction. Faced with situations in which an end to life is the rational choice because there is no other option, emotions ranging from dissatisfaction to rage drive the creation of individual and collective initiatives to find another option.
Nonetheless, death happens regardless. Medicine cannot yet prevent people from dying in all too many scenarios, largely those associated with aging. Even though the medical community has come around to trying to do something about aging, it remains the case that someone, somewhere, at any given time is thinking about how to make inevitable death less terrible. This is the sort of thing that medical communities do when they cannot yet solve the problem. They chew on it, measure it, try to do something, anything that can be done now to reduce the suffering associated with the intractable problem, even if that means considering the paths that none of us like to consider.
Measuring and monitoring the quality of dying in the UN Decade of Healthy Ageing
To monitor and evaluate the UN Decade of Healthy Ageing (2021-30), the World Health Organization has proposed a set of indicators of healthy ageing, based on functional ability and intrinsic capacity of older people. Functional ability is defined as the health-related attributes that enable people to be and to do what they have reason to value. This definition could include individuals who are dying; however, specific indicators for this stage have yet to be developed. Mortality rates and life expectancy are important outcome indicators used to assess health-care system performance, with health-care interventions typically aimed at reducing avoidable mortality. Nonetheless, death is inevitable, and the importance of how we die has been widely recognised, for example, by the Lancet Commission on the Value of Death. The period preceding death forms a part of the ageing trajectory and requires targeted actions to ensure that it is lived with the highest level of health and dignity. Dying well constitutes an integral component of healthy ageing.
Measuring the quality of dying can guide care and support for individuals who are dying and their families, inform clinical decision making, shape health and care delivery, support policy development and evaluation, facilitate comparisons across institutions and countries, and track changes over time across settings where people are dying and where end-of-life care should be accessible to them. However, in attempting to identify such measures, numerous questions arise. How should a good death be defined? Who should report on the quality of dying? Over what timeframe should the evaluation occur? Which descriptors should be used? Should the assessment be performed prospectively or retrospectively? How do we take account of widely varying contexts, individual preferences, and sociocultural diversities? How can measurement and monitoring be implemented worldwide?
This article explores these challenges, identifying potentially measurable indicators and ambiguities in their use, and offers recommendations towards a practical measurement framework. We aimed to define a concise, meaningful, and pragmatic set of indicators that could be collected and applied universally across countries and over time. We define a logic model of candidate variables at different conceptual levels and describe an empirical exercise for prioritising and operationalising these variables for measurement.
Senescent Macrophages Accelerate Tumor Growth
https://www.fightaging.org/archives/2025/08/senescent-macrophages-accelerate-tumor-growth/
The innate immune cells known as macrophages are found in tissues throughout the body, and their activities are important in tissue maintenance and regeneration. Macrophages can adopt different packages of behavior in response to circumstances. There are a number of ways to define these behaviors, but researchers usually refer to (a) M1 macrophages that are inflammatory and aggressive, focused on destroying pathogens and errant cells, versus (b) M2 macrophages that are anti-inflammatory and more focused on tissue maintenance. This split of activities becomes particularly important in aged, damaged, or cancerous tissue. Cancers are known to reprogram and subvert immune cells in order to fuel growth, and the macrophages present in cancerous tissue, known as tumor-associated macrophages, are front and center in that process.
In today's open access paper, the authors discuss how cellular senescence in tumor-associated macrophages is particularly important in determining how these macrophages accelerate tumor growth. One of the useful activities undertaken by senescent cells in normal tissue is to coordinate regeneration from injury, and the senescence-associated secretory phenotype (SASP) generated by senescent cells is as much pro-growth as it is pro-inflammatory. A tumor evolves to encourage macrophage senescence, which in turn supports unchecked replication of tumor cells.
The research community is very interested in the application of senotherapeutics to cancer. Indeed, many successful chemotherapeutic drugs of past years have turned out to be senotherapeutic in the light of more recent knowledge. That these drugs are capable of destroying senescent cells or changing their behavior explains their success. Separately, researchers are also very interested in manipulating tumor-associated macrophages to make tumors less aggressive, such as via attempts to force M2 macrophages in tumor tissue to adopt an M1 state, or otherwise stop supporting cancer growth in favor of attacking cancerous cells. These two areas of research interest dovetail well with one another.
Senescent macrophages in cancer: roles in tumor progression and treatment opportunities
Macrophages play critical roles in the tumor microenvironment (TME), where they influence tumor progression through their remarkable plasticity and environmental adaptability. Typically, pro-inflammatory M1 macrophages (classically activated macrophages) are found in healthy tissues; in contrast, the macrophages in the TME predominantly adopt a pro-tumorigenic M2 (alternatively activated macrophages) phenotype, which facilitates tumor progression via extracellular matrix remodeling, angiogenesis, and immune suppression. Consequently, tumor-associated macrophages (TAMs) are central to promoting tumor growth, invasion, and metastasis through paracrine signaling and other mechanisms.
The role of cellular senescence in tumor development, particularly the effects of senescent macrophages in the TME, has garnered increasing attention. Cellular senescence was initially considered a tumor-suppressive mechanism. However, senescence paradoxically promotes tumor progression, particularly via senescent macrophages. Senescent macrophages, after exposure to specific intrinsic and extrinsic stimuli, undergo cellular aging. These cells are typically characterized by upregulation of p16 Inhibitor of Cyclin-Dependent Kinase 4a (p16INK4a) and distinct features associated with the senescence-associated secretory phenotype (SASP). Through intrinsic senescence, therapeutic interventions, or external stimuli, senescent macrophages exhibit functional impairments including chronic inflammation, decreased antigen presentation, and impaired phagocytosis. These changes foster an immunosuppressive environment conducive to tumor growth.
Key in this process is the SASP, comprising cytokines, chemokines, proteases, and growth factors that disrupt the immune environment and enhance tumorigenesis. Notably, IL-6 is a prominent SASP factor contributing to a pro-inflammatory, tumor-promoting milieu. Emerging evidence highlighting that senescent macrophages exacerbate tumor progression through SASP secretion and immune dysregulation has underscored the importance of understanding their mechanisms. Therapeutic strategies targeting senescent macrophages, including senolytics, senomorphics, and senoreverters, as well as immunotherapies such as Chimeric Antigen Receptor T-cell (CAR-T) cells, offer promising avenues for halting tumor growth and reversing the harmful effects of the aging TME. Future research is expected to focus on optimizing these treatments and elucidating the interactions between senescent macrophages and tumor cells to improve clinical outcomes.
Sestrin 1 is Required for Calorie Restriction to Extend Life in Nematode Worms
https://www.fightaging.org/archives/2025/08/sestrin-1-is-required-for-calorie-restriction-to-extend-life-in-nematode-worms/
A common approach taken by researchers when investigating how a specific aspect of cellular biochemistry functions is to disable genes one by one to observe whether they are necessary or not. This isn't exactly straightforward, as cells typically have several ways of achieving a given goal, and removing one of those ways may or may not appear to do anything, depending on how exactly the researcher chooses to measure the outcome. This is the curse of engaging with complex systems. Nonetheless, sometimes one does find that one gene is critical, and that usually helps to advance the understanding of how the biochemistry of interest functions.
Today's open access paper is an example of this sort of research applied to calorie restriction, an incremental advance in the understanding of how beneficial effects result from a lowered calorie intake. Calorie restriction induces the activation of cell maintenance processes to produce improved resilience, health, and longevity. This response to starvation evolved very early in the history of life on earth, and is thus remarkably similar in organisms ranging from yeast to worms to mice to humans. In all of these species, it produces sweeping changes to the operation of cellular biochemistry, making it a challenge to pick out the controlling mechanisms and important outcomes. Over the years, researchers have established that autophagy is required for calorie restriction to extend life, and have identified some important regulatory genes, such as mTOR.
There is much left to discover. But it seems plausible that this sizable focus of research, and the development of calorie restriction mimetic drugs that follows, will be only a footnote to the future extension of the healthy human life span. Calorie restriction has nowhere near the same effect on longevity in long-lived species as it does in short-lived species. Calorie restricted mice can live as much as 40% longer, but humans probably gain only a few years in the same circumstances. Why this is the case remains an open question, but it may be that long-lived species are long-lived because they already possess most of the metabolic improvements induced by the practice of calorie restriction in short-lived species.
Sesn-1 is required for lifespan extension during caloric deprivation in C. elegans through inhibition of mTORC1 and activation of autophagy
Sestrins were identified two decades ago as stress-responsive proteins that play an important role in regulating cellular homeostasis. Vertebrate genomes showcase three Sestrin genes (SESN1-3), while invertebrates feature just one. Numerous stressors, ranging from hypoxia and oxidative stress to DNA damage and nutrient deprivation, induce Sestrin expression in mammalian cells. The orchestration behind this expression involves several transcription factors, notably p53, FOXO, ATF4, and NRF2. Highlighting evolutionary conservation, the same signalling pathways trigger the activation of dSesn in D. melanogaster. Consequently, Sestrins play pivotal roles in the regulation of cellular viability under various stress conditions, such as hypoxia, oxidative stress, DNA damage, and glucose deprivation.
Earlier research from our team established Sestrins as antioxidant proteins that play a critical role in inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) kinase. mTORC1 is an intricate environmental sensor that integrates signals from nutrients, growth factors, and stresses to regulate cell fate decisions. Remarkably, mTORC1 plays a key role in lifespan and aging regulation across various species. Application of specific mTORC1 inhibitors, like rapamycin, has been shown to enhance lifespan in different organisms from yeast to mice. Similarly, caloric restriction (CR), a well-documented longevity enhancer across many species, also represses mTORC1 activity, further cementing the role of this kinase in aging control.
This study aimed to elucidate the influence of the sesn-1 gene on lifespan modulation during caloric restriction (CR) in the nematode model organism C. elegans. Our findings reveal that sesn-1 mediates lifespan extension under CR, primarily through the repression of mTORC1 kinase and activation of autophagy. Moreover, we identified an essential role for sesn-1 in enhancing stress resilience in nematodes, particularly in the context of nutrient sensing. Further investigations demonstrated sesn-1's interaction with the GATOR2 protein complex, its role in maintaining muscle integrity and a potential synergy between sesn-1 and the FOXO pathway. Overall, our research underscores the profound implications of Sestrins in aging and stress resistance, shedding light on possible therapeutic avenues for prevention and treatment of age-associated disorders.
Improving Mitochondrial Function in Chondrocytes to Improve Cartilage Regeneration
https://www.fightaging.org/archives/2025/08/improving-mitochondrial-function-in-chondrocytes-to-improve-cartilage-regeneration/
Cartilage is a poorly regenerative tissue, one of the reasons why cartilage damage is a feature of aging and persistent consequences of joint injury. Nonetheless, cartilage is formed during development so in principle there must exist programs of regeneration that might be activated via suitable forms of therapy. Here, researchers use a targeted nanoparticle approach to deliver a therapeutic cargo into chondrocytes in damaged cartilage tissue. This caused an improvement in both mitochondrial function and capacity for regeneration.
Treating osteoarthritis (OA) presents a significant challenge due to the fact that conventional intra-articular injections only achieve superficial penetration and uncontrolled drug release. Here, amino-modified cationic mesoporous silica nanoparticles were covalently conjugated with cartilage-targeted peptides to form a Trojan horse-like architecture for enveloping the prochondrogenic fucoidan.
The hydrogel microsphere, consisting of photocurable gelatin methacryloyl (GelMA) and chondroitin sulfate methacryloyl (ChSMA), were fabricated using a microfluidic platform for cargo delivery. The cationic targeting nanoparticle-hydrogel microsphere@fucoidan (CTNM@FU) possess three-step programmable characteristics that enable responsive transport toward injured cartilage, effective penetration of the cartilage extracellular matrix and selective entry into chondrocytes, escape from lysosomes, and release of bio-activators.
The impaired cartilage metabolism was significantly reversed upon co-culturing with CTNM@FU. Intra-articular administration of CTNM@FU not only mitigated cartilage degeneration but also expedited de novo cartilage formation. Mechanistically, CTNM@FU protected cartilage by activating SIRT3, enhancing mitochondrial energy and countering aging. Collectively, a spatiotemporally guided strategy enables more precise treatments for degenerative joint disorders.
Mesenchymal Progenitor Cells with Modified FOXO3 Improve Health in Aged Monkeys
https://www.fightaging.org/archives/2025/08/mesenchymal-progenitor-cells-with-modified-foxo3-improve-health-in-aged-monkeys/
A number of variants of the FOXO3 gene are associated with greater longevity, which researchers believe may be due to an altered distribution of different forms of the FOXO3 protein. Here, researchers note a study in which a human pluripotent cell line was engineered with a favorably altered FOXO3 sequence and differentiated into mesenchymal progenitor cells. These cells were injected into aged monkeys, producing an across the board improvement in measures of health and function. This is much as one would expect from a good stem cell therapy repeated over time, but it is unclear as to whether the mechanisms involved go beyond a suppression of age-related chronic inflammation. Generally, transplanted cells die quickly. Beneficial effects are derived from the signals that they produce, favorably altering the behavior of native cells for a time. The most reliable outcome is reduced inflammation.
FOXO3 is a well-established regulator of longevity, stress resistance, and stem-cell maintenance. In a pioneering effort to reprogram aging-related genetic circuits, researchers introduced two phospho-null mutations (S253A and S315A) to eliminate phosphorylation sites into the FOXO3 locus, generating engineered human embryonic stem cells that, upon mesenchymal differentiation, gave rise to progenitor cells with enhanced stress resilience and self-renewal capacity - designated as senescence-resistant cells (SRCs).
Administering SRCs intravenously to aged cynomolgus monkeys over a 44-week period led to a cascade of restorative changes. Compared to wild-type mesenchymal cells, SRCs more effectively reversed age-related changes across the brain, immune system, bone, skin, and reproductive tissues. Multi-modal assessments-behavioral, histological, transcriptomic, and methylomic-consistently indicated biological age reversal.
Notably, SRC-treated monkeys exhibited improved cognitive function, restored cortical architecture, and enhanced hippocampal connectivity. Bone density increased, periodontal degeneration was mitigated, and immune cell transcriptional profiles shifted toward a youthful state. At the molecular level, transcriptomic aging clocks showed an average reversal of 3.34 years with SRCs, while DNA methylation clocks corroborated these effects in multiple tissues. Furthermore, the authors observed the restoration of reproductive system health. In both male and female monkeys, SRC treatment reduced senescent markers, enhanced germ cell preservation, and reversed transcriptional aging clock across ovaries and testes. Single-cell transcriptomics revealed that oocytes, granulosa cells, and testicular germ cells responded particularly well, rejuvenating by up to 5-6 years.
ADGRG1 in Microglia Facilitates Clearance of Amyloid in the Aging Brain
https://www.fightaging.org/archives/2025/08/adgrg1-in-microglia-facilitates-clearance-of-amyloid-in-the-aging-brain/
Specific receptors on the surface of immune cells enable these cells to ingest and clear specific forms of metabolic waste. Receptors are proteins that are produced via the usual mechanisms of gene expression. The amount produced can change with age and circumstances, as epigenetic regulation of gene expression changes, and this will affect the ability of immune cells to act against specific targets. Researchers here report on the ability of the innate immune cells known as microglia to clear excess amyloid-β from the brain, and show that it is dependent on expression of the ADGRG1 receptor. In severe Alzheimer's disease, microglia lack sufficient ADGRG1 to effectively clear plaque. Whether this is a contributing cause of Alzheimer's disease rather than a side-effect remains to be demonstrated conclusively, but this is far from the only data suggesting that microglial dysfunction is important in neurodegenerative conditions.
In Alzheimer's disease, proteins like amyloid beta form clumps, known as plaques, that damage the brain. But in some people, immune cells called microglia break down these proteins before they can cause harm. This leads to fewer and smaller clumps - and much milder symptoms. Researchers identified a protein called ADGRG1 that enables microglia to gobble up and digest plaques. When the researchers removed this protein, which is a kind of receptor, from mice, their microglia barely nibbled on the plaques. This led to the rapid buildup of plaques, neurodegeneration and problems with learning and memory.
When the researchers reanalyzed a prior study of gene expression in the human brain, they found that individuals who died while exhibiting mild Alzheimer's had microglia with lots of these receptors, and mild cognitive impairment - implying that the microglia ate well and kept the disease in check. But in those who died of severe Alzheimer's, the microglia had very few of the receptors, and the plaques proliferated. ADGRG1 is part of a large family of receptors, called G protein-coupled receptors, that are routinely targeted in drug development. This bodes well for a rapid translation of the discovery into new therapies.
Potential Therapeutic Approaches to Cerebral Small Vessel Disease
https://www.fightaging.org/archives/2025/08/potential-therapeutic-approaches-to-cerebral-small-vessel-disease/
Cerebral small vessel disease is the term given to a noteworthy level of dysfunction in the small blood vessels of the brain, a big tent category that includes endothelial dysfunction, blood-brain barrier leakage, stiffening of vessels, and the damage left by minor vessel rupture. Clinicians diagnose small vessel disease in the brain typically as a result of scans in hypertensive patients who had a stroke or exhibit cognitive dysfunction and for whom imaging shows a sizable burden of hyperintensity lesions, small volumes of dead and damaged brain tissue resulting from the rupture of small vessels.
Cerebral small vessel disease (cSVD) is a common cause of stroke and dementia. Ageing, hypertension, hyperglycaemia, and smoking make up the biggest risk factors for cSVD. They individually or collectively increase the levels of reactive oxygen species, pro-inflammatory cytokines and matrix metalloproteinases, decrease the bioavailability of nitric oxide, and, in the process, compromise the structural integrity and function of the vascular endothelium, blood-brain barrier, and brain parenchyma. These then appear as white matter hyperintensities, enlarged perivascular spaces, cerebral microbleeds, and atrophy in cerebral imaging.
As there is currently no curative therapy for cSVD, prevention or delay of cSVD remains of particular importance to preserve quality of life for as long as possible. Bearing that in mind, this review explores whether drugs used for other neurovascular conditions may prevent neuroinflammation and oxidative damage and effectively maintain endothelial function and blood-brain barrier integrity. It also examines whether potential benefits may be extended to cSVD. The list of drugs includes anti-anginal drugs, acetylcholine esterase inhibitors, β-hydroxy β-methylglutaryl-CoA reductase inhibitors, lithium drugs, phosphodiesterase inhibitors, oral antihyperglycaemic drugs, and tetracycline antibiotics. This review discusses the mechanisms of action of these agents and critically evaluates preclinical, translational, and clinical research pertaining to cSVD.
Hypertension Allows Harmful Immune Cell Infiltration of the Brain
https://www.fightaging.org/archives/2025/08/hypertension-allows-harmful-immune-cell-infiltration-of-the-brain/
The high blood pressure of hypertension is harmful to tissues throughout the body. Pressure damage directly damages tissue structure, disrupts tissue function, and alters cell behaviors for the worse. This is particularly harmful to the brain, as brain tissue has only a limited capacity for regeneration following rupture of small blood vessels and consequent cell death. More subtly, increased pressure disrupts the normal operation of the blood-brain barrier that lines blood vessels passing through the brain. This allows leakage of inappropriate cells and molecules into the brain to provoke persistent inflammation, an important contribution to neurodegenerative conditions.
Hypertension increases the risk for cognitive impairment and promotes vascular and renal inflammation. We tested if immune cell infiltration occurs in the brain during hypertension and if it is associated with cognitive impairment. Male C57Bl/6 mice were administered angiotensin II or aldosterone as an experimental model of hypertension. This increased blood pressure and promoted blood-brain barrier dysfunction, leukocyte accumulation in the brain, and impairment of working memory.
When co-administered with angiotensin II, the antihypertensive medication hydralazine prevented the development of these changes. In a separate cohort of mice in which angiotensin II-induced changes were first established, intervention with hydralazine lowered blood pressure but did not reverse brain inflammation or cognitive impairment. Finally, angiotensin II infusion altered the transcriptomic profile of the whole brain, as well as specifically within the hippocampus, and co-treatment with hydralazine modulated these changes.
In conclusion, experimental hypertension leads to brain inflammation and was associated with impaired working memory. Cognitive impairment that develops during hypertension can be inhibited, but not readily reversed, by anti-hypertensive therapy.
How Age-Related Fat Infiltration of Muscle Harms Regeneration
https://www.fightaging.org/archives/2025/08/how-age-related-fat-infiltration-of-muscle-harms-regeneration/
It is well known that the formation of fat deposits within muscle tissue is a feature of aging, and is also associated with a variety of muscle disorders. Here, researchers explore how exactly this infiltration of fat into muscle harms muscle function, with a focus on regenerative capacity. At present physical activity is the most reliable approach to prevent or reduce fat infiltration of muscle tissue, but it seems likely that at least some of the growing number of weight loss drugs in development, many of which improve upon GLP-1 receptor agonists by neither reducing calorie intake nor causing loss of muscle mass, will also be effective.
Adipose tissue acts as an energy storage as well as an endocrine organ. However, different fat depots, such as subcutaneous (SAT), visceral (VAT), and intramuscular adipose tissue (IMAT), have stark metabolic and phenotypic differences. IMAT, the accumulation of adipocytes between individual myofibers within skeletal muscle, is a pathological hallmark of muscular dystrophies, but it is also present in a spectrum of metabolic disorders, including diabetes, obesity, and sarcopenia. The progressive infiltration of IMAT within muscle tissue has been closely associated with loss of muscle mass, metabolic dysfunction, disease progression, and impairment of patient mobility.
The cellular origin of IMAT is a population of stem cells located in the muscle interstitium, called fibro-adipogenic progenitors (FAPs). In a healthy muscle, FAPs are critical in maintaining muscle mass during homeostasis and playing a central role in muscle regeneration. FAPs secrete pro-myogenic factors to aid the cellular origin of muscle fibers, muscle stem cells (MuSCs), in their differentiation process toward myofibers. With age and disease, however, FAPs can also differentiate into either adipocytes, leading to IMAT formation or myofibroblasts, giving rise to fibrosis.
To understand the influence of IMAT on skeletal muscle, we created a conditional mouse model, termed mFATBLOCK that blocked IMAT formation by deleting peroxisome proliferator-activated receptor gamma (Pparγ) from FAPs. This deletion had no effect under normal conditions but successfully prevented IMAT accumulation after an adipogenic injury. Mechanistically, our data argues that IMAT acts as a physical barrier and prevents new nascent myofiber formation during early regeneration, as well as myofiber hypertrophy during the later regenerative phase. Consequently, this results in a functionally weakened muscle that has both fewer and smaller myofibers.
Mitochondrial Dysfunction in the Aging of Muscle Tissue
https://www.fightaging.org/archives/2025/08/mitochondrial-dysfunction-in-the-aging-of-muscle-tissue/
Every cell contains hundreds of mitochondria, the descendants of ancient symbiotic bacteria that have their own DNA, replicate to maintain their numbers, and are responsible for generating the chemical energy store molecule adenosine triphosphate (ATP) to power the cell. Mitochondria, like all cell structures, are constantly damaged. Damaged and dysfunctional mitochondria are removed via the cell maintenance process of mitophagy. With age, this quality control falters, while the expression of genes necessary for mitochondrial function change for the worse. Mitochondrial DNA becomes damaged in ways that further degrade function. As a result, cell and tissue function also becomes disrupted, contributing to the many manifestations of degenerative aging. The focus here is on muscle tissue, but analogous stories can be told for any tissue in the aging body.
As the global population trends toward aging, the number of individuals suffering from age-related debilitating diseases is increasing. With advancing age, skeletal muscle undergoes progressive oxidative stress infiltration, coupled with detrimental factors such as impaired protein synthesis and mitochondrial DNA (mtDNA) mutations, culminating in mitochondrial dysfunction. Muscle stem cells (MuSCs), essential for skeletal muscle regeneration, also experience functional decline during this process, leading to irreversible damage to muscle integrity in older adults.
A critical contributing factor is the loss of mitochondrial metabolism and function in MuSCs within skeletal muscle. The mitochondrial quality control system plays a pivotal role as a modulator, counteracting aging-associated abnormalities in energy metabolism and redox imbalance. Mitochondria meet functional demands through processes such as fission, fusion, and mitophagy. The significance of mitochondrial morphology and dynamics in the mechanisms of muscle regeneration has been consistently emphasized. In this review, we provide a comprehensive summary of recent advances in understanding the mechanisms of aging-related mitochondrial dysfunction and its role in hindering skeletal muscle regeneration. Additionally, we present novel insights into therapeutic approaches for treating aging-related myopathies.
Antiviral Treatment Fails to Slow the Progression of Early Stage Alzheimer's Disease
https://www.fightaging.org/archives/2025/08/antiviral-treatment-fails-to-slow-the-progression-of-early-stage-alzheimers-disease/
The evidence for persistent viral infection by herpesviruses and others to be a significant cause of Alzheimer's disease is mixed and contradictory. There are clear and well understood mechanisms by which persistent infection can in principle contribute to neurodegeneration, but only some epidemiological data supports the a role for viral infection in Alzheimer's disease. It may be that the contribution is small, or emerges very slowly over a long time, or it may be that only a subset of patients exhibit the necessary biochemistry for persistent infection to play a major role in neurodegenerative disease. Once clinical trials start to show that no beneficial effect results from antiviral treatment, however, further investigations will likely slow to a minimal level of effort.
Various studies have found connections between herpes infections and Alzheimer's, including an autopsy study that found HSV1 DNA was often associated with amyloid plaques in the brains of people diagnosed with Alzheimer's. Additional studies have found that people treated for herpes infections were less likely to be later diagnosed with Alzheimer's than HSV-positive people who received no antiviral treatment. This raised hopes that herpes treatments could slow progression of Alzheimer's symptoms among patients. But the first clinical trial to test that theory has found that a common antiviral for herpes simplex infections, valacyclovir, does not change the course of the disease for patients in the early stages of Alzheimer's.
The trial included 120 adults, age 71 on average, all diagnosed with early Alzheimer's disease or mild cognitive impairment with imaging or blood tests that indicated Alzheimer's pathology. All participants had antibodies revealing past herpes infections (mostly HSV1, some HSV2). The participants were randomly assigned to take daily pills containing either valacyclovir or a placebo. The researchers measured the patients' memory functions and imaged the brain to look for amyloid and tau deposits associated with Alzheimer's and other structural changes. After 18 months, the researchers found that patients taking the placebo performed slightly better on cognitive tests than the valacyclovir group, but no other measures were significantly different.
"Our trial suggests antivirals that target herpes are not effective in treating early Alzheimer's and cannot be recommended to treat such patients with evidence of prior HSV infection. We do not know if long-term antiviral medication treatment following herpes infection can prevent Alzheimer's because prospective controlled trials have not been conducted."
Modest Amounts of Fast Walking Reduce Mortality in Older People
https://www.fightaging.org/archives/2025/08/modest-amounts-of-fast-walking-reduce-mortality-in-older-people/
The introduction of cheap accelerometers via the mobile phone industry had the side-effect of allowing the research community to accurately assess the effects of varying low levels of physical activity on long-term health. Self-reporting is particularly inaccurate in this range of exertion, and thus the use of accelerometers in studies enabled a much more accurate determination of the lower end of the dose-response curve for exercise. The results demonstrated that even small amounts of exercise are very much better than no exercise. Double the small amount of exercise is better yet. The paper here is an example of this sort of dose-response gradient at lower levels of exercise, focused on fast walking in older people.
While the health benefits of daily walking are well-established, limited research has investigated effects of factors such as walking pace on mortality. Data from the Southern Community Cohort Study were used, including information from nearly 85,000 predominantly low-income and Black individuals recruited during 2002-2009 across 12 southeastern US states. Participants provided baseline information on daily walking pace and time, demographic information, lifestyle factors, and health status. Mortality data were collected until December 31, 2022.
Over a median follow-up of 16.7 years, 26,862 deaths occurred. Significant associations were found between all-cause mortality and daily fast walking time. Fast walking as little as 15 minutes a day was associated a nearly 20% reduction in total mortality (hazard ratio, HR: 0.81), while only a 4% reduction in mortality (HR: 0.96) was found in association with more than three hours of daily slow walking. Fast walking was independently associated with reduced mortality, regardless of the leisure-time physical activity levels. The inverse association was more pronounced for mortality due to cardiovascular diseases than cancers. Participants with baseline comorbidities had larger risk reductions compared to their generally healthy counterparts, although all individuals benefited from fast walking.
Targeting Cellular Senescence to Treat Age-Related Diseases
https://www.fightaging.org/archives/2025/08/targeting-cellular-senescence-to-treat-age-related-diseases/
Senescent cells accumulate with age and contribute to degenerative aging by provoking inflammation and disrupting tissue structure and function. Targeting cellular senescence for the treatment of age-related disease is presently in the slow, optimistic phase of research and development that comes after the initial hype has died down, but before a large number of attempts have been made at definitive, sizable clinical trials. This can last for years. The clinical development of new therapies is a very slow business. It has been something like fifteen years since the first flush of real excitement about senescent cells as a mechanism of aging captured the research community, and while a dozen or more life science companies are developing drugs to destroy or alter the behavior of senescent cells in patients, only a few small clinical trials have been conducted to date.
With the intensification of global aging, the incidence of age-related diseases (including cardiovascular, neurodegenerative, and musculoskeletal disorders) has been on the rise, and cellular senescence is identified as the core driving mechanism. Cellular senescence is characterized by irreversible cell cycle arrest, which is caused by telomere shortening, imbalance in DNA damage repair, and mitochondrial dysfunction, accompanied by the activation of the senescence-associated secretory phenotype (SASP).
In this situation, proinflammatory factors and matrix-degrading enzymes can be released, thereby disrupting tissue homeostasis. This disruption of tissue homeostasis induced by cellular senescence manifests as characteristic pathogenic mechanisms in distinct disease contexts. In cardiovascular diseases, senescence of cardiomyocytes and endothelial cells can exacerbate cardiac remodeling. In neurodegenerative diseases, senescence of glial cells can lead to neuroinflammation, while in musculoskeletal diseases, it can result in the degradation of cartilage matrix and imbalance of bone homeostasis.
This senescence-mediated dysregulation across diverse organ systems has spurred the development of intervention strategies. Interventional strategies include regular exercise, caloric restriction, senolytic drugs (such as the combination of dasatinib and quercetin), and senomorphic therapies. However, the tissue-specific regulatory mechanisms of cellular senescence, in vivo monitoring, and safety-related clinical translational research still require in-depth investigation.
View the full article at FightAging
