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Fight Aging! Newsletter, July 20th 2025


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Posted Today, 10:59 AM


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/

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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/

Contents

Transplanted Neural Stem Cells Induce Remyelination in the Brains of Mice
https://www.fightaging.org/archives/2025/07/transplanted-neural-stem-cells-induce-remyelination-in-the-brains-of-mice/

The axonal connections between neurons are sheathed in myelin, which acts as an insulator to enable the propagation of electrical impulses along the axon. Like all molecular structures in the body and brain, myelin sheathing is subject to ongoing damage and must continually be maintained in order to prevent dysfunction in the nervous system. A population of cells known as oligodendrocytes undertakes this task. Conditions in which excessive loss of myelin occurs, such as the autoimmune condition multiple sclerosis, are particularly debilitating. But a lesser degree of myelin damage occurs to everyone in old age, in part due to reduced oligodendrocyte function, and this damage contributes to cognitive impairment.

Thus it is interesting to keep an eye on that part of the research community focused on dymelinating conditions such as multiple sclerosis. It is plausible that future therapies capable of achieving at least some degree of remyelination in patients with severe demyelination could also help to restore meylin loss in aged individuals - it all depends on the fine details. Therapies that compensate for damage and dysfunction by increasing oligodendrocyte activity will probably be effective in both aged individuals and patients with multiple sclerosis, while curative therapies that directly address the autoimmune causes of multiple sclerosis will likely be of little use in aged individuals.

Delivering neural stem cells into the brain has been tested as a therapy of many forms of neurodegeneration, at least in animal models. Bringing this sort of therapy into human trials has progressed very slowly indeed over recent decades, with ongoing programs of research and development largely focused on Parkinson's disease while the state of the art advanced from fetal cells to embryonic stem cells to induced pluripotent stem cells. Today's open access paper is an example of the more broad application of neural stem cells in animal models, in which the transplanted cells induce remyelination to repair severe damage to myelin sheathing in the brain.

Remyelination of chronic demyelinated lesions with directly induced neural stem cells

The limited ability of central nervous system (CNS) progenitor cells to differentiate into oligodendrocytes limits the repair of demyelinating lesions and contributes to the disability of people with progressive multiple sclerosis (PMS). Neural stem cell (NSC) transplantation has emerged as a safe therapeutic approach in people with PMS, where it holds the promise of healing the injured CNS. However, the mechanisms by which NSC grafts could promote CNS remyelination need to be carefully assessed before their widespread clinical adoption.

In this study, we used directly induced NSCs (iNSCs) as a novel transplantation source to boost remyelination in the CNS. Using a mouse model of focal lysophosphatidylcholine (LPC)-induced demyelination, we found that mouse iNSCs promote remyelination by enhancing endogenous oligodendrocyte progenitor cells differentiation and by directly differentiating into mature oligodendrocytes. Transplantation of mouse iNSCs in LPC-lesioned Olig1 knockout mice, which exhibits impaired remyelination, confirmed the direct remyelinating ability of grafts and the formation of new exogenous myelin sheaths. We also demonstrated that the xenotransplantation of human iNSCs (hiNSCs) is safe in mice, with hiNSCs persisting long-term in demyelinating lesions where they can produce graft-derived human myelin.

Our findings support the use of NSC therapies to enhance remyelination in chronic demyelinating disorders, such as PMS.

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Preclinical Studies of Means to Slow and Reverse Aging are More Haphazard than is Desired
https://www.fightaging.org/archives/2025/07/preclinical-studies-of-means-to-slow-and-reverse-aging-are-more-haphazard-than-is-desired/

Any life scientist who has written a meta-analysis or systematic review of preclinical or clinical studies is likely capable of complaining at length and in detail about the lack of standardization, the myriad ways in which small differences in study design can sabotage any attempt at comparison, the critical details missing from published study methods, the misleading interpretations and summaries observed in the abstracts of a sizable minority of papers, and so forth. From some perspectives the literature is a mess, as you might expect when thousands of people with little incentive to conform to any one viewpoint set forth to pursue their own ideas about how to run a study.

Paper-length complaints about this situation can be found in the literature. You might recall a recent discussion of the harms done by non-standard controls in life span studies, for example. In today's preprint, researchers work through a database of preclinical studies in order and outline all of the problems that they encountered in trying to build any sort of broader body of understanding from a field in which every scientific group takes a different approach when it comes to assessing the effects of interventions on aging. Beyond standardization, rigor is clearly also an issue.

Reporting quality, effect sizes, and biases for aging interventions: a methodological appraisal of the DrugAge database

There is increasing interest in interventions targeting the aging process. The "geroscience hypothesis" posits that a shared pathophysiology of aging shapes most chronic diseases and interventions targeting aging will confer larger health benefits than those targeting any individual disease. Research into such anti-aging interventions has grown substantially, including trials repurposing commonly used drugs such as metformin. Given the possible substantial health benefits of slowing aging, the quality of preclinical studies in this area may be especially important. However, alongside the challenges translating results from one species to another, model organism studies have a long history of shortcomings and design flaws.

Here, we systematically analyzed 667 studies from DrugAge, a curated database of preclinical experiments investigating the effects of interventions on aging and lifespan in non-human animals. We aimed to evaluate the quality of reporting and methodological rigor of this literature, assess the distribution of observed effect sizes, and probe for the presence of diverse biases. We also investigated how these features changed over time. We found significant shortcomings in reporting of crucial design features such as randomization and blinding, as well as large variation in reporting quality and effects across species. Non-mammal findings typically did not translate to mammals. For 36 compounds with both mammal and non-mammal experiments, only eight showed a significant lifespan increase in both non-mammals and mammals; the number of experiments and sample sizes for these results were limited. These results are exploratory, and the numbers are small, but they raise hesitation about the direct translation of these results to more complex organisms such as humans.

Furthermore, previous work has suggested that some interventions may have different effects if started late in an organism's lifespan rather than early, and there is significant interest in discovering interventions that slow aging in older adults. In our assessment, we found that most preclinical experiments started the anti-aging intervention early in the organism's lifespan, often prior to sexual maturity, when key senescence mechanisms may lack relevance. Although we did not find a significant difference in the effect of interventions between early and late start experiments, the sparsity of late start results makes this comparison uncertain. Our study clearly highlights the paucity of late start experiments in the literature, a deficit of evidence that needs to be remedied.

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Senescent Microglia Elevate the Destruction of Synapses to a Pathological Level
https://www.fightaging.org/archives/2025/07/senescent-microglia-elevate-the-destruction-of-synapses-to-a-pathological-level/

The neurons of the brain form intricate, shifting networks of synaptic connections. Synapses are constantly created and destroyed in regions important to memory and learning, and supporting cell populations of the brain aid in this process. Microglia, for example, are innate immune cells of the central nervous system, analogous to macrophages elsewhere in the body. Ingesting and destroying unwanted synapses is one of the tasks undertaken by this cell population. In recent years, researchers have focused on dysfunction in microglia as an important contribution to pathology in inflammatory neurodegenerative conditions. Microglia become more inflammatory, change their behavior in other ways, and a fraction of these cells become senescent. Senescent cells cease to replicate, further alter their behavior, and generate a potent mix of pro-inflammatory and pro-growth signaling.

In today's open access paper, researchers investigate how senescent microglia might contribute to the known pathologies observed in inflammatory neurodegenerative conditions. The scientists demonstrate in mice that the presence of senescent microglia causes an increased pace of destruction of synapses. Some destruction is necessary to adjust neural networks, but too much destruction causes cognitive dysfunction, an outcome characteristic of brain inflammation. It is possible to clear microglia generally, using CSF1R inhibitors, or selectively destroy only senescent cells in the brain using some of the first generation senolytics - the dasatinib and quercetin combination passes the blood-brain barrier. This approach to treatment will likely be beneficial, but progress towards clinical use in this context is slow.

Senescent Microglia Mediate Neuroinflammation-Induced Cognitive Dysfunction by Selective Elimination of Excitatory Synapses in the Hippocampal CA1

Microglia-mediated neuroinflammation has been shown to exert an important effect on the progression of a growing number of neurodegenerative disorders. Prolonged exposure to detrimental stimuli leads to a state of progressive activation and aging-related features in microglia (also termed as senescent microglia). However, the mechanisms by which senescent microglia contribute to neuroinflammation-induced cognitive dysfunction remain to be elucidated.

Here, we developed a mouse model of neuroinflammation induced by lipopolysaccharides at 0.5 mg/kg for 7 consecutive days. To evaluate cognitive function, C57BL/6J mice were employed and subjected to a series of behavioral assessments, including the open field, Y-maze, and novel object recognition tests. Employing single-cell RNA sequencing technology, we have delved into the differential expressions of RNA within microglia. Furthermore, to investigate anatomic and physiological alterations of pyramidal neurons, we utilized Golgi staining and whole-cell patch-clamp recordings, respectively. Validation of our results in protein expression was performed using western blotting and immunofluorescence.

We specifically identified senescent microglia with a high expression of p16INK4a and observed that microglia in the hippocampal CA1 region of the model exhibited signatures of elevated phagocytosis and senescence. A senolytic by ABT-737 treatment alleviated the production of senescence-associated secretory phenotypes, the accumulation of senescent microglia, and the microglial hyperphagocytosis of excitatory synapses following LPS exposures. This treatment also restored reduced excitatory synaptic transmission, impaired long-term potentiation, and cognitive function in the model. These results indicate that reducing senescent microglia may potentially serve as a therapeutic approach to prevent neuroinflammation-related cognitive dysfunction.

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Psilocybin as a Geroprotective Drug
https://www.fightaging.org/archives/2025/07/psilocybin-as-a-geroprotective-drug/

Psilocybin is a plant derived hallucinogen with a long history of use and shorter history of prohibition that suppressed earnest efforts to research its biochemistry. Efforts to guide psilocybin from the state of prohibition into a form of therapy for neurological conditions have been underway for some years now, however. Increased interest in this compound in research and funding circles, alongside the ability to run studies on psilocybin without censure, inevitably leads to new discoveries. In today's open access paper, for example, researchers provide evidence to suggest that psilocybin acts to slow aging.

Mice given monthly doses of psilocybin starting in late life exhibit at 10-15% increase in overall median life span. The researchers conducted cells studies that suggest that psilocybin touches on a few well-studied pathways known to influence mammalian life span, and reduces the burden of cellular senescence. Treated versus untreated mice exhibited a similar body weight, so the animal study results don't appear to be the result of inadvertent calorie restriction. All in all, this is quite interesting, but a great deal more work is needed in order to dig into the mechanisms involved. Additionally, one should bear in mind that most mechanisms shown to slow aging have much larger effects in short-lived species than in long-lived species such as our own.

Psilocybin treatment extends cellular lifespan and improves survival of aged mice

To date, more than 150 clinical studies with psilocybin have been completed or are ongoing for various clinical indications, including psychiatric (anxiety, depression, addiction), neurodegenerative (Alzheimer's), pain, and more. Human studies have demonstrated that a single-dose of psilocybin can improve debilitating physical and psychological symptoms - with durable effects (up to ~5 years). Despite considerable clinical evidence supporting the therapeutic benefits of psilocybin, the molecular mechanisms responsible for these impacts remain enigmatic. Studies with psilocybin have predominantly focused on neurological impacts and/or behavioral outcomes; few studies have evaluated alternative or systemic mechanisms which may also contribute to its beneficial effects.

The "psilocybin-telomere hypothesis" postulates that psilocybin interventions may quantifiably impact telomere length, which offers a potential explanation for its efficacy across a wide range of clinical indications. This hypothesis is based on a large corpus of studies linking mental health to biological aging markers. However, no prior studies have experimentally investigated the direct impact of psilocybin on biological aging.

To evaluate the impact of psilocybin on cellular aging, we employed an in vitro model of replicative senescence. Cells were serially passaged with media containing psilocin or vehicle until they reached replicative senescence. Psilocin treatment (10 μM) resulted in a 29% extension of cellular lifespan. Results were more striking using a higher dose of psilocin in the same cell type (100 μM treatment led to a 57% extension in cellular lifespan). Results were more striking using a higher dose of psilocin in the same cell type (100 μM treatment led to a 57% extension in cellular lifespan. Telomere length was preserved in psilocin-treated age-matched cells. This data suggest that psilocin impacts signaling pathways associated with cellular aging.

To evaluate the impact of psilocybin on longevity in vivo, aged (19 month) female mice were treated with vehicle or psilocybin once/month for 10 months. Mice were initially given a low-dose (5 mg/kg) for the first treatment followed monthly high-dose (15 mg/kg) treatment for a total of 10 treatments. We elected to utilize 19-month old mice, which is roughly equivalent to 60-65 human years, in order to evaluate its therapeutic potential as a clinically-relevant anti-aging intervention. Notably, psilocybin treated mice demonstrated significantly higher survival (80%), compared to vehicle (50%). Although not quantitatively measured, psilocybin-treated mice exhibited phenotypic improvements in overall fur quality, including hair growth and reductions in white hair compared to vehicle-treated mice. In summary, we provide the first experimental evidence demonstrating that psilocybin treatment can enhance survival in aged mice.

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A Conservative View of Rapamycin
https://www.fightaging.org/archives/2025/07/a-conservative-view-of-rapamycin/

The dominant view of the regulation of medicine within academia and government is more or less that (a) people should not have the right to choose their own risks and make their own mistakes, (b) the role of regulators is to remove as much risk as possible, and © that the high cost of medicine and slow pace of introduction of new drugs is a better problem to have than greater freedom for patients. This is the background against which one can find papers such as today's open access discussion of rapamycin and the state of its use as a means to improve late life health and modestly slow degenerative aging.

Rapamycin has long been approved for use as an immunosuppressive drug, but of late has attracted far more attention for its ability to upregulate autophagy, slow aging, and extend life in animal studies. This has led to a significant degree of off-label prescription of rapamycin by physicians. Physicians have the discretion to prescribe any approved drug for any use that is defensible, but this only happens when there is a body of work to suggest that the novel use could be safe and useful.

Thus rapamycin is in the nebulous state occupied by many drugs that are prescribed off-label: animal studies indicate that it could be used in a novel way at a novel dose, in this case to slow aging at lower doses than its established immunosuppressive use, but little to no concrete human data exists to confirm that new use. That data is unlikely to emerge any time soon because clinical trials are expensive and genetic drugs cannot produce enough revenue to justify that cost. Meanwhile, a good fraction of academics and regulators are appalled by off-label use, as one might expect given their views on freedom, risk, and the purpose of regulators.

Rapamycin for longevity: the pros, the cons, and future perspectives

Rapamycin, an antibiotic discovered in the 1970s, has become a critical tool in biomedical research. Initially recognized for its potent antifungal and immunosuppressive properties, rapamycin has recently gained significant attention for anti-aging therapy and seizure treatment via mTOR pathway inhibition. The mechanistic target of the rapamycin (mTOR) pathway is an evolutionarily conserved metabolic signaling cascade that regulates cell division, growth, and survival. There is growing evidence that mTOR pathway activity accelerates aging and the development of age-related diseases including cancer, atherosclerosis, diabetes, and declining immune function. Therefore physicians and "biohackers" are using mTOR inhibition via rapamycin (and rapamycin analogs) off-label for prevention of age-related conditions despite not being widely recognized as a treatment by the broader clinical community.

As rapamycin gains popularity for its anti-aging potential, online longevity clinics have emerged offering access to the drug with minimal medical oversight. This semi-regulated availability raises ethical concerns regarding patient safety, misinformation, and the potential for serious harm. This is best illustrated by the widely publicized case of tech entrepreneur Bryan Johnson, who undertook an elaborate self-directed anti-aging regimen involving rapamycin, metformin, and over 100 daily supplements. Despite extensive physiological tracking, Johnson ultimately discontinued rapamycin and expressed regret over its use citing side effects such as elevated blood glucose, susceptibility to infection, and impaired healing. This case highlights the risks of bypassing peer-reviewed science in favor of anecdotal "biohacking" culture. Clinical literature has long documented rapamycin-associated toxicities that mirror the complaints reported by Johnson and others. The use of such a powerful immunosuppressant outside established indications, especially in otherwise healthy individuals, demands stronger ethical scrutiny and public education.

Lastly, while the FDA does not recognize aging as a disease, there is growing interest in approving therapeutics that enhance healthspan, or delay aging-related decline. However, FDA approvals are structured around specific, diagnosable indications, rather than generalized syndromes. Should rapamycin or related compounds demonstrate efficacy, they would be approved for specific indications (e.g., Alzheimer's) rather than aging per se under the current approval standards. Nonetheless, even within this evolving framework, it is important to note that most off-label prescribing-despite it being common clinical practice-rarely achieves FDA approval, as only about 30% of off-label prescribing is supported by adequate scientific evidence despite any clinically observed positive outcomes. These regulatory and evidentiary constraints must be considered when evaluating rapamycin's future clinical and research trajectory.

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Towards Therapies to Restore a More Youthful Gut Microbiome
https://www.fightaging.org/archives/2025/07/towards-therapies-to-restore-a-more-youthful-gut-microbiome/

It is by now well understood in the research community that the balance of microbial populations making up the gut microbiome changes with age in ways that promote tissue dysfunction and chronic inflammation. Animal studies of varied approaches to the restoration of a more youthful gut microbiome have produced extended life and improved long-term health, demonstrating that an altered gut microbiome is likely an important component of degenerative aging. That said, the fine details of those alterations remain to be fully mapped and understood. Similarly, effective and deterministic approaches to the recreation of a youthful gut microbiome have yet to be created. While fecal microbiota transplantation from a young donor to an old recipient works to rejuvenate the gut microbiome, it is far from deterministic. The direction taken by the research and development community will likely involve greatly expanding the capabilities of the probiotics industry to culture well-defined artificial microbiomes of thousands of species, given to patients in enteric-coated capsules for oral adminstration.

The human gut microbiome, a densely populated and diverse microbial community, exists in symbiotic harmony with the host and within itself, continually adapting and realigning in response to the host's environment and lifestyle across the lifespan. However, disruptions in the gut microbiome, driven by intrinsic or extrinsic elements, can disrupt microbial homeostasis, leading to a state of "dysbiosis," which can induce or exacerbate the onset of different age-related diseases (ARDs) through multidirectional communication axes involving host intestinal, cardiometabolic, immune, and/or neurocognitive health.

Recent research demonstrates the potential of microbiome-targeting therapeutics to promote healthy aging by preventing/ameliorating ARDs. Thus, a precise understanding of natural and environmentally induced microbiome alterations, including disease-specific taxa and their metabolic functions, is crucial for developing personalized therapies for older adults. Aging-associated changes in the gut microbiome may serve as primary determinants of late-life health. In this context, novel and emergent strategies to optimize the microbiome for therapeutic purposes could extend healthspan and lifespan, while reducing global healthcare costs.

To this end, we herein present a perspective on emerging research wherein we deliberate the topical concept of targeting the gut microbiome and dysbiosis as a potential therapeutic target for ARDs. Sequentially, we summarize and deliberate recent advances pertaining to the incipient potential of microbiome-based therapeutics to promote healthy aging and longevity. Finally, we introduce and propose the term "biome-aging" to denote the concept of such aging-associated microbiome transformations during different stages of our lifespan. In introducing biome-aging, we emphasize how cumulative changes in the gut environment - from shifts in barrier integrity and nutrient absorption to the effects of polypharmacy - progressively remodel microbial communities. This dynamic favors a decrease in beneficial microbes, an upsurge in pathobionts, and heightened inflammatory responses at both the local and systemic levels. By defining biome-aging, we underscore the importance of preserving a balanced gut ecosystem in older adults and open new possibilities for mitigating health risks tied to accelerated or pathological aging.

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Altered ANGPTL4 Expression in the Context of Aging
https://www.fightaging.org/archives/2025/07/altered-angptl4-expression-in-the-context-of-aging/

One of the default modes of life science research focused on age-related diseases is a protein by protein consideration of potential targets of interest, investigating the biochemistry of a relatively small number of specific proteins that are both fairly well understood and involved in mechanisms relevant to aging and disease. Fashions and levels of interest in specific proteins change over time; as a given protein attracts greater attention from the scientific community, researchers shift their priorities in order to incrementally expand that understanding, while at the same time exploring ways to alter protein expression levels or interfere in or enhance specific interactions with other proteins. The output of this process is a body of knowledge and some number of potential therapies, most of which of which never make it into further development, let alone clinical use.

The angiopoietin-like protein 4 (ANGPTL4), also known as fasting-induced adipose factor, is a secreted glycoprotein that belongs to the ANGPTL protein family. Due to its expression in various cell types and tissues and its interactions with other proteins, ANGPTL4 plays diverse roles within its family, exhibiting a wider range of molecular functions. For instance, ANGPTL4 is intricately involved in modulating central energy metabolism and enhancing exercise endurance, while also acting as a pivotal mediator in the interaction between gut microbiota and host lipid metabolism.

The expression of ANGPTL4 is directly controlled by aging-related signaling pathways. Its excessive activation accelerates the aging process by triggering mechanisms like heightened oxidative stress, epithelial-mesenchymal transition (EMT) and fibrosis, abnormal lipid accumulation, and cellular arrest, thereby advancing the development of age-related diseases. Given the pivotal roles of ANGPTL4 and its associated molecules in organ fibrosis and cancer advancement, targeting ANGPTL4 emerges as a promising therapeutic approach. However, the intricate and sometimes conflicting functions of the two cleavage fragments of ANGPTL4, namely N-terminal fragment (nANGPTL4) and C-terminal fragment (cANGPTL4), in different chronic diseases - exerting inhibitory or stimulatory effects depending on the disease stage - have posed challenges to the progress of ANGPTL4 antibody therapy.

This review provides an overview of the biological mechanisms of ANGPTL4, its dual impact on fibrosis and tumorigenesis, and highlights its recent advancements as a potential biomarker in age-related diseases and inflammation-related conditions. ANGPTL4 is a high-potential but complex target, requiring mechanism-driven strategies for safe clinical translation.

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Cytomegalovirus Specific T Cell Populations are Associated with Adverse Outcomes in Aging
https://www.fightaging.org/archives/2025/07/cytomegalovirus-specific-t-cell-populations-are-associated-with-adverse-outcomes-in-aging/

In individuals with normal immune function, cytomegalovirus infection goes unnoticed and produces no immediately evident ill effects. It is very prevalent in the human population. By the time old age is reached, something like 90% of individuals test positive for persistent cytomegalovirus presence. Like other herpesviruses, cytomegalovirus cannot be cleared by the immune system and lurks in the body for the remainder of life. Unfortunately, it appears that the presence of cytomegalovirus does cause harm over time in older individuals, provoking the aged immune system into an ever greater focus on this one virus at the expense of retaining capacity to address other threats, one part of the bigger picture of age-related immune dysfunction. It is one that could perhaps be addressed by a suitably selective destruction of immune cells with specific molecular markers, using well established gene therapy tools, but little work has taken place on this sort of approach to therapy.

Cytomegalovirus (CMV) infection is one of the most common infections in humans, and CMV antigens are the major drivers of repetitive T-cell stimulation as a part of a well-adapted immune response in immunocompetent individuals. With higher age, the recurrent clonal expansion of CMV-specific T cells results in high frequencies of CMV-specific effector T cells. Further on, CMV seropositivity has been linked to an increased risk of developing cardiovascular diseases (CVD). Here we investigated the frequency and phenotype of CMV-specific T cells in the circulation of a population cohort of 650 individuals focusing on the age group over 60 years.

We add to previous knowledge by showing that the frequency of CMV-specific CD8+ T cells is associated with the total percentage and absolute counts of CD8+ and CD4+CD8+ double-positive T cells within leukocytes, and further with systolic blood pressure (SBP) and history of CVD. An investigation into the differentiation status of CMV-specific T cells revealed an association of higher age and increased frequencies of both effector memory (TEM) and CD27-expressing terminally differentiated effector re-expressing CD45RA (TEMRA) cells. In contrast, higher CMV-IgG titers were found to be associated with TEM and CD27- TEMRA cell frequencies. SBP significantly correlated with CMV-specific effector CD8+ T cells, which was mostly reflected by CD27- TEMRA cells.

In conclusion, within the circulating CMV-specific T cell population, different effector T-cell subtypes were associated with age, serostatus, and SBP. This suggests that it is not age or infection per se that render CMV-positive individuals susceptible to CVD, but rather the cellular immune response to CMV. Detailed immunophenotyping may identify individuals whose immune systems are strongly influenced by the response to CMV, leading to health consequences and impairing healthy aging.

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Loss of STING Signaling Dysregulates Lipid Metabolism
https://www.fightaging.org/archives/2025/07/loss-of-sting-signaling-dysregulates-lipid-metabolism/

The STING protein is a point of convergence for a range of molecular sensors in a cell that detect damage or infection. Triggering STING activity produces an inflammatory response. Unfortunately, cell dysfunctions characteristic of aging produce issues such as the escape of fragments of mitochondrial and nuclear DNA into the cell cytosol, where they trigger sensors evolved to detect infectious agents, and thus activate STING. This contributes to the chronic inflammation of aging. For this and other reasons, researchers are considering STING inhibition as a potential form of therapy for a range of inflammatory age-related conditions. This approach has the obvious downside of also inhibiting necessary, short-term inflammatory responses, just like existing immunosuppressive therapies - but as researchers note here, STING inhibition may also produce other, less obvious harmful side effects.

The Stimulator of Interferon Genes (STING) pathway is pivotal in innate immunity, facilitating the detection of cytosolic DNA and initiating type I interferon-dependent responses. In addition to its immunological roles, STING has been increasingly associated with metabolic regulation, since research indicates that its inhibition can diminish inflammation, lipid accumulation, and tissue damage in obesity and other metabolic disorders. The findings have prompted a suggestion of STING inhibition as a viable treatment approach for metabolic illness. Nonetheless, the physiological function of STING in lipid homeostasis under normal settings remains largely unexplored, as does the impact of its absence on metabolism throughout various life stages in the absence of disease. This information deficit is crucial, particularly in light of the increasing interest in the long-term pharmacological suppression of STING.

o examine the function of STING in lipid metabolism during physiological, non-pathological conditions throughout the lifespan, we assessed wild type (WT) and STING knockout (STINGKO) mice at various ages and discovered that STING deficiency results in a consistent increase in body weight, independent of alterations in locomotor activity or food consumption. STINGKO mice exhibited markedly increased circulation levels of triglycerides and total cholesterol. Histological and morphological analysis demonstrated augmented fat accumulation in adipose and hepatic tissues, despite the lack of nutritional or genetic metabolic stress. These findings indicate a crucial function for STING in the control of lipid homeostasis across the lifespan, and caution against the prolonged use of STING inhibitors, as chronic STING suppression may lead to detrimental metabolic effects.

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Better Lifestyle Choices Correlate with a Lower Burden of White Matter Damage in the Brain
https://www.fightaging.org/archives/2025/07/better-lifestyle-choices-correlate-with-a-lower-burden-of-white-matter-damage-in-the-brain/

A great deal of funding and effort goes into attempts to quantify the effects of lifestyle choices on long-term health, incidence of disease, and age-related mortality. Perhaps more than is useful, given what we know about the limits of the possible. Exercise improves the quality of later life, but you can't exercise your way out of being physically aged and ultimately dying from age-related disease. Animal studies demonstrate that some forms of treatment, such as senolytics, can achieve degrees of delay or reversal of aspects of aging beyond that of any lifestyle choice. Research attention might be better focused on that sort of exploration. Further, one might argue that more data on the benefits of a better lifestyle is not actionable: it doesn't instruct us to do anything that we didn't already know that we should be doing. Still, today's open access paper is representative of a sizable body of work and ongoing effort on the part of the scientific community.

The American Heart Association introduced Life's Essential 8 (LE8) as a comprehensive set of eight metrics that reflect health behaviours that support cardiovascular health (CVH), with the aim to help older individuals maintain CVH and live longer and healthier. These eight measures are categorized into two major areas: health behaviours (eating healthier foods, being more active, quitting tobacco, getting healthy sleep) and health factors (managing weight, controlling cholesterol, managing blood glucose, managing blood pressure). Beyond its association with CVH, LE8 is increasingly recognized for its impact on neurological health. Recent studies linked higher LE8 scores with neuroimaging markers of better brain health.

This cross-sectional study utilized data from the UK Biobank. Regional fractional anisotropy measures from diffusion tensor imaging (DTI) data were used to predict white matter brain age via random forest regression. The white matter brain age gap (BAG) was calculated by subtracting chronological age from predicted brain age. As compared to other neuroimaging markers like brain volume and white matter hyperintensities, white matter BAG is more sensitive to early and subtle change in WM integrity. The analysis included 18,817 participants (mean age 55.45). Higher LE8 scores were associated with a lower white matter BAG, indicating delayed brain ageing. The effect was more pronounced in non-APOE4 carriers (124 days younger per 10-point increase) compared to APOE4 carriers (84 days younger per 10-point increase). Potential interaction between APOE4 and LE8 on brain ageing was observed for some age and sex groups but with only borderline significance, further investigation in larger and more targeted studies is needed to validate the finding.

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Reviewing Cellular Senescence in Skeletal Disease
https://www.fightaging.org/archives/2025/07/reviewing-cellular-senescence-in-skeletal-disease/

The evidence is compelling for the age-related accumulation of senescent cells to be an important driving mechanism of degenerative conditions in bone tissue. As for many other age-related conditions, animal study data suggests that clearance of senescent cells via the use of senolytic therapies is a promising form of treatment for age-related dysfunction in bone tissue. Human data is arriving only slowly, and initially only in small clinical trials more focused on safety than efficacy. Few trials are being conducted for the first generation, low-cost senolytics such as the dasatinib and quercetin combination, because there is no financial incentive for the industry to pay for this work, while the clinical development of novel senolytics is proceeding at the usual glacial pace.

Cellular senescence and other age-related mechanisms synergistically lead to impaired bone cell function, facilitating the onset and progression of bone diseases, such as osteoporosis (OP), intervertebral disc degeneration (IVDD), and osteoarthritis (OA). Cellular senescence is a particular cellular state characterized by irreversible arrest of the cell cycle and the emergence of a distinctive senescence-associated secretory phenotype (SASP), which is one of the key mechanisms in the development and progression of skeletal diseases. In addition, other age-related mechanisms occur in the skeletal system that synergistically contribute to the development of bone diseases. For example, the impaired intercellular crosstalk leads to an abnormal accumulation of senescence phenotypes in the bone marrow, the generation of a disturbed microenvironment promotes senescence in the skeletal system.

The elderly population has a high prevalence of age-related bone diseases. Particularly in elderly individuals (aged 65 and above), age-related bone diseases represent the leading cause of disability worldwide. The associated pain and limited mobility lead to a decrease in quality of life, posing a significant healthcare burden to the government. Prospects for the development of drugs targeting skeletal aging diseases are currently not optimistic, largely owing to a lack of understanding of the cellular senescence and other age-related mechanisms that lead to bone dysfunction during aging. In this review, we summarize the current understanding of cellular senescence and other age-related mechanisms in the pathogenesis of bone diseases, highlighting the diversity of the mechanisms involved in cellular senescence within different skeletal aging microenvironments. Moreover, we provide an overview of therapeutic approaches involving selective elimination or the reversion of cellular senescence.

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A Form of PDGF Suppresses Cellular Senescence in Intervertebral Disc Degeneration
https://www.fightaging.org/archives/2025/07/a-form-of-pdgf-suppresses-cellular-senescence-in-intervertebral-disc-degeneration/

Senescent cells generate inflammatory signaling that is disruptive to tissue structure and function when sustained for the long term. The lingering presence of senescent cells is considered a driving mechanism for many inflammatory conditions, including intervertebral disc degeneration. Here, researchers demonstrate in cell models that recombinant PDGF can be used to suppress the markers of the presence of cellular senescence, though it remains to be seen as to whether it achieves this outcome by destroying senescent cells, reprogramming them, or preventing their creation.

Low back pain (LBP), ranked as the first cause of years lived with disability, is a prevalent condition. Although the etiology of LBP is multifactorial, a major contributor of LBP is intervertebral disc (IVD) degeneration. The IVD consists of three compartments: the gelatinous nucleus pulposus (NP), fibrous annulus fibrosus (AF), and cartilaginous endplate.

Cellular senescence, triggered by normal cells in response to various intrinsic and extrinsic stressors, is a fundamental mechanism underlying age-related chronic diseases. Senescent cells are featured by irreversible growth arrest and acquire a senescent-associated secretory phenotype (SASP) and the secretion of pro-inflammatory cytokines, chemokines, and tissue-damaging proteases. In the IVD, it has been well established that the number of senescent cells increases with aging and IVD degeneration.

Previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptosis, anti-inflammation, and pro-anabolism. However, its impact on IVD cell senescence remains elusive. PDGF is a major constituent of platelet rich plasma (PRP), which is widely used in the clinical setting for tissue regeneration and repair. It can be made of a homodimer of A, B, C, and D polypeptide chains, or an AB heterodimer. Among these, PDGF-AB and -BB are the predominant forms in PRPs. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 days and changes of transcriptome profiling were examined through mRNA sequencing.

PDGF-AB/BB treatment resulted in downregulation of gene clusters related to neurogenesis and response to mechanical stimulus in AF cells while the downregulated genes in NP cells were mainly associated with metabolic pathways. In both NP and AF cells, PDGF-AB and BB treatment upregulated the expression of genes involved in cell cycle regulation, mesenchymal cell differentiation, and response to reduced oxygen levels, while downregulating the expression of genes related to the SASP, including oxidative stress, reactive oxygen species (ROS), and mitochondrial dysfunction. The rhPDGF-AB/BB treatment mitigated the senescence progression through increased cell population in the S phase, reduced SA-β-Gal activity, and decreased expression of senescence related regulators including P21, P16, IL6, and NF-κB. Our findings reveal a novel anti-senescence role of PDGF in the IVD, making it a promising potential candidate to delay aging-induced IVD degeneration.

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ACBP Expression Contributes to Degenerative Aging
https://www.fightaging.org/archives/2025/07/acbp-expression-contributes-to-degenerative-aging/

Researchers here provide evidence for expression of the hormone ACBP to be detrimental, an accelerator of degenerative aging. Knocking down ACBP improves kidney and heart resilience in a number of circumstances, while circulating ACBP levels correlate with aspects of aging and age-related loss of function. At the present time therapies to reduce circulating levels of a given protein (such as monoclonal antibodies or forms of gene therapy targeted to the cells expressing the protein) are relatively expensive, though given a broadly beneficial use case one might imagine that costs will fall commensurate with the scale of use.

The tissue hormone acyl coenzyme A-binding protein (ACBP, encoded by the gene diazepam-binding inhibitor, DBI) has been implicated in various facets of pathological aging. Here, we show that ACBP plasma concentrations are elevated in (close-to-)centenarians (mean ± SD age 99.5 ± 4.5 y) commensurate with their health deterioration, correlating with a reduced glomerular filtration rate and a surge in senescence-associated cytokines. ACBP neutralization by means of a monoclonal antibody (mAb) improved health span in a strain of progeroid mice.

In a mouse model of chronic kidney injury induced by cisplatin, anti-ACBP mAb administration counteracted both histopathological and functional signs of organ failure. ACBP inhibition also prevented the senescence of tubular epithelial cells and glomerular podocytes induced by cisplatin or doxorubicin, respectively, as measurable by the immunohistochemical detection of cyclin-dependent kinase inhibitor 1A (CDKN1A, best known as p21). Senescence was also prevented by anti-ACBP monoclonal antibody treatment in additional mouse models of accelerated aging. This applied to liver damage induced by a combination of high-fat diet and carbon tetrachloride, where hepatic cells become senescent.

Moreover, administration of anti-ACBP monoclonal antibody prevented natural and doxorubicin-accelerated cardiomyocyte senescence. We performed single-nucleus RNA sequencing to study the transcriptome of hearts that had been exposed to doxorubicin and/or anti-ACBP in vivo. In cardiomyocytes, doxorubicin caused an anti-ACBP-reversible dysregulation of mRNAs coding for cardioprotective proteins involved in autophagy, fatty acid oxidation, mitochondrial homeostasis, and oxidative phosphorylation. Altogether, these findings plead in favor of a broad age-promoting effect of ACBP across different organ systems.

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GrimAge and GrimAge2 Clocks Perform Similarly in Predicting Mortality
https://www.fightaging.org/archives/2025/07/grimage-and-grimage2-clocks-perform-similarly-in-predicting-mortality/

Researchers here demonstrate that the GrimAge and GrimAge2 epigenetic clocks beat out other clocks while performing more or less equivalently to one another when it comes to predicting mortality in a novel study population. The higher a patient's epigenetic age relative to their chronological age, the higher the risk of future mortality. Epigenetic clock results are not actionable, however. Since researchers do not yet understand how the specific epigenetic marks incorporated into the clock algorithm correlate with mechanisms of age-related dysfunction and disease, they cannot describe why a result is bad or good, nor inform any action taken in response. So at the present time it doesn't matter what an epigentic clock result looks like - one should seek to improve one's health in the same ways regardless.

Epigenetic clocks have been widely applied to assess biological ageing, with Age Acceleration (AA) serving as a key metric linked to adverse health outcomes, including mortality. However, the comparative predictive value of AAs derived from different epigenetic clocks for mortality risk has not been systematically evaluated. In this retrospective cohort study based on 1,942 NHANES participants (median age 65 years; 944 women), we examined the associations between AAs from multiple epigenetic clocks and the risks of all-cause, cancer-specific, and cardiac mortality.

Restricted cubic spline models were used to assess the shape of these associations, and Cox proportional hazards regression was employed to quantify risk estimates. Model performance was compared using the Akaike Information Criterion (AIC) and concordance index (C-index).

Our findings revealed that only GrimAge AA and GrimAge2 AA demonstrated approximately linear and positive associations with all three mortality outcomes. Both were significantly associated with increased risks of death, and these associations were consistent across most subgroups. GrimAge and GrimAge2 AAs showed very similar performance in predicting all-cause, cancer, and cardiac mortality, with only small differences in AIC values and C-index scores. These findings suggest that both GrimAge and GrimAge2 are effective epigenetic biomarkers for mortality risk prediction and may be valuable tools in future ageing-related research.

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Protein Misfolding is Pervasive in the Aging Brain
https://www.fightaging.org/archives/2025/07/protein-misfolding-is-pervasive-in-the-aging-brain/

After a protein is created in the cell, it must be folded into the right conformation in order to function correctly. A complex set of mechanisms is focused on (a) achieving correct folding and (b) removing misfolded proteins when the process fails. Research into protein misfolding is weighted heavily to the consideration of the comparatively few proteins that form solid aggregates when misfolded, largely because this is an evident and measurable form of pathology that is demonstrably a cause of pathology in conditions such as Alzheimer's disease and the varied forms of amyloidosis. What about all of the other misfolded proteins, however, those that remain soluble? Researchers here point out that hundreds of different misfolded proteins can be found in the aged rat brain, and we might reasonably think that their collective role in neurodegeneration is significant.

Many studies have found that the proteostasis network, which functions to keep proteins properly folded, is impaired with age, suggesting that there may be many proteins that incur structural alterations with age. Here, we have used limited proteolysis mass spectrometry (LiP-MS) to identify proteins that vary in structure in the hippocampus of aged rats with or without cognitive impairment, which we have defined as CASC proteins.

We identified 215 CASC proteins in the CA1 hippocampal region. Research in aging, dementia, and neurodegenerative disease has long made a connection between these disease processes and protein misfolding; however, emphasis has historically been paid to proteins that form amyloids or other insoluble aggregates. We have focused on the soluble fraction of the hippocampal proteome and used a methodology that can sensitively detect subtle changes in protein structure. The results enable us to conclude that protein misfolding is perhaps a more pervasive feature in cognitive decline than previously appreciated and that many of these misfolded forms persist as soluble species.

This finding suggests that there may be previously unidentified avenues for potential therapeutic targets and diagnostic biomarkers for cognitive decline than the small subset of amyloid-forming proteins frequently studied. Of course, these interventions would need to be conformation specific, creating additional opportunities and challenges.

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