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Fight Aging! Newsletter, September 1st 2025


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Posted Today, 11:45 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 to the newsletter,please visit:https://www.fightaging.org/newsletter/.To unsubscribe, send email or reply to this email at newsletter@fightaging.org with "unsubscribe" in the subject or body.

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Contents

UCP4A Knockdown in Muscles Removes Protein Aggregates to Extend Life in Flies
https://www.fightaging.org/archives/2025/08/ucp4a-knockdown-in-muscles-removes-protein-aggregates-to-extend-life-in-flies/

Cellular metabolism is a complex web of connections. For any well known protein that regulates metabolism in ways relevant to aging that can be affected directly by various small molecules, gene therapies, or mutations, there are probably a score of other ways to indirectly affect its expression and activity. The mTOR pathway is well researched, as suppression of mTOR activity is a part of the response to low nutrient levels that adjusts cellular biochemistry in favor of conservation and increased maintenance, such as via an upregulation of autophagy. This tends to slow aging. Even though mTOR and its proximate biochemistry is a relatively well researched area of molecular biology, researchers continue to find new links to other aging-related areas of interest.

In today's open access paper, the authors draw a connection between mild suppression of mitochondrial activity and mTOR activity via a convoluted chain of interactions centered around an uncoupling protein. Mitochondria are the power plants of the cell, producing the chemical energy store molecule adenosine triphosphate (ATP) in an energetic process that produces damaging free radicals as a side-effect. A mild suppression of this mitochondrial activity (whether achieved via mutation, uncoupling, or other approaches) can slow aging in laboratory species, and the resulting changes include reduced mTOR activity. That in turn upregulates autophagy and helps to clear out damaged structures and protein aggregates that can harm cell function. A better understanding of how mitochondria instruct the rest of the cell to improve its function might lead to better ways to artificially induce this behavior.

The mitochondrial aspartate transporter Ucp4a regulates muscle aging and animal lifespan in Drosophila melanogaster

Mitochondria are subcellular organelles that utilize an electron transport chain (ETC) to produce cellular energy and also synthesize numerous metabolites that efflux to the cytosol. Mild knockdown of mitochondrial ETC proteins prolongs lifespan, a phenomenon that has been observed in diverse organisms including C. elegans, Drosophila, and mice. In mammalian cells, ETC perturbation or mitochondrial distress represses the mechanistic target of rapamycin complex 1 (mTORC1) pathway through activation of the transcription factor ATF4. Studies in Drosophila muscle have found ETC perturbation to repress systemic insulin signaling through expression of ImpL2, an inhibitor of Drosophila insulin-like peptides (Dilps). Repression of either mTORC1 or insulin signaling is established to extend lifespan; however, the mechanisms underlying this mitochondrial-distress-mediated life extension are not yet completely understood.

Aspartate (asp), a proteogenic amino acid, is synthesized in the mitochondrial matrix from glutamate and oxaloacetic acid (OAA), a tricarboxylic acid (TCA) cycle metabolite. Of note, asp synthesis requires integral mitochondrial function. In mammalian cells, treatment with an ETC inhibitor depletes asp due to impairment of NADH flux, which is required for integrity of the TCA cycle. Perturbation of asp synthesis impairs cell proliferation, and in endothelial cells impairs the cytosolic mTORC1 pathway.

Here we show that in flies mutation in uncoupling protein 4a (Ucp4a), which encodes a mitochondrial aspartate transporter, can extend lifespan without restricting feeding. Remarkably, the life-extension effect of Ucp4a mutation is specifically due to knockdown of Ucp4a in muscles; knockdown in other tissues was not effective in life-extension. We find that protein aggregates, a characteristic of muscle aging, are reduced by Ucp4a knockdown in muscles. Consistently, Ucp4a mutants and lines with Ucp4a knockdown in muscle maintain healthier muscle than control flies, as suggested by observation of enhanced locomotor activity in aged flies.

Aspartate (Asp) is converted to asparagine (Asn) by the asparagine synthetase (ASNS) enzyme in the cytosol, suggesting that Ucp4a knockdown is likely to reduce cytosolic Asn. This reduction might be a signal that relates to inhibition of the mTORC1 pathway. This possibility is supported by a recent finding that inhibition of glutaminolysis, which is required for asp synthesis, activates the ATF4-mediated pathway to suppress mTORC1 activity through expression of the mTORC1 negative regulators Sestrin2 and Redd1. Ultimately, asp reduction-mediated lifespan extension might require inhibition of the mTORC1 pathway. Further confirmatory research remains required.

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Cabozantinib is a Senotherapeutic that Slows Osteoporosis
https://www.fightaging.org/archives/2025/08/cabozantinib-is-a-senotherapeutic-that-slows-osteoporosis/

The development of cancer is strongly affected by the presence of senescent cells. Cellular senescence is a tool of cancer suppression in the earliest stages at which cancers emerge from cell damage, attempting to halt replication in damaged cells as well as call in the immune system via inflammatory signaling to destroy potentially cancerous cells. Senescent cells are also involved in wound healing and coordination of regeneration, however, and this capacity can be subverted by an established tumor to support its growth. Once a cancer is established, the accumulation of senescent cells in and around tumor tissue creates a more favorable environment for plaque growth via growth factor signaling.

Because of this connection between senescent cells and cancer, many successful chemotherapeutic drugs that were developed before the modern understanding of the relevance of senenscent cells to cancer and aging are turning out to be successful precisely because they kill senescent cells or suppress the pro-inflammatory, pro-growth signaling of senescent cells. The early senolytic drugs demonstrated to selectively kill senescent cells and reverse aspects of aging were all repurposed chemotherapeutics. Researchers continue to identify ever more compounds in the long list of approved and potential chemotherapeutics established over past decades as senotherapeutics that could be repurposed to treat age-related diseases by destroying or suppressing the activities of senescent cells.

Cabozantinib, an Anti-Aging Agent, Prevents Bone Loss in Estrogen-Deficient Mice by Suppressing Senescence-Associated Secretory Phenotype Factors

As the cellular micro-environment changes with age, senescent cells begin to secrete senescence-associated secretory phenotypes (SASPs) factors. These include pro-inflammatory cytokines [e.g., interleukin (IL)-1α, IL-1β, IL-6, and IL8], chemokines [e.g., C-C motif ligand 1 (CCL1), CCL2, and CCL5], proteases (e.g., matrix metalloprotease and serine protease), and growth factors (e.g., PDGF). SASP factors exhibit dual roles: they contribute to tissue regeneration, tumor suppression, and immunosurveillance, but can promote inflammation, tissue damage, and cancer progression. Consequently, extensive research has focused on anti-aging strategies that target senescent cells.

Bone homeostasis is maintained by a delicate balance between bone-forming osteoblasts and bone-resorbing osteoclasts. With aging, particularly post-menopause, this balance is disrupted, leading to impaired bone formation and increased resorption, thereby increasing the risk of osteoporosis and fractures. In aging bone, mesenchymal stem cells are more likely to differentiate into adipocytes rather than osteoblasts. Moreover, SASP factors such as tumor necrosis factor-alpha (TNFα), IL1α, IL1β, IL6, and CCL2 are secreted by senescent cells, fostering a pro-inflammatory microenvironment within bone tissue. TNFα, IL1α, and IL6 specifically impair osteoblast differentiation and enhance osteoclastic bone resorption. These findings highlight the importance of therapeutic strategies targeting senescent cells (senolytics) or modulating SASP activity (senomorphics) to prevent age-related osteoporosis.

In this study, we screened cabozantinib, a tyrosine kinase inhibitor approved for medullary thyroid cancer, for its anti-aging effects in bone-related cells, specifically osteoblasts and osteoclasts. Cabozantinib demonstrated the ability to activate osteoblasts and inhibit osteoclasts by suppressing the secretion of SASP factors from these cells. Additionally, it prevented bone loss in estrogen-deficient, ovariectomized mice. Our findings indicate that targeting senescent osteoblastic and osteoclastic cells using cabozantinib could be a potential therapeutic approach for treating age-related osteoporosis.

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Menopause Accelerates Aging
https://www.fightaging.org/archives/2025/08/menopause-accelerates-aging/

It is well known that the health of women and aspects of aging worsen in many ways after menopause. The biochemistry of menopause and its role in aging is not as easily researched as it might be, as mice do not naturally exhibit menopause. Menopause can certainly be induced by chemical or surgical means in mice, but these models are all artificial and come with caveats as to the interpretation of results. It was thought that only a few larger mammals exhibit menopause, and this remains the consensus, but in recent years researchers have provided evidence to suggest that most large mammals do in fact undergo menopause. Identifying that this is the case has not been an area of focus, as large mammals are not often used in fundamental research into mechanisms of aging for reasons of cost and time.

In today's open access paper, researchers use an aging clock to assess biological age in women at various stages of menopause. The usual concerns apply for the use of clocks, as to whether they are in fact a good representation of of the accumulated damage and dysfunction of aging in any novel specific context. The only way to determine whether this is the case is to accumulate as much data as possible in many contexts, so researchers here use a well-established clock, one for which there is plenty of existing data to support its ability to measure something useful in this context. Setting that aside, the results are much as one would expect, and show that both entering menopause and undergoing earlier menopause both correlate with an increased biological age.

Menopausal status, transition, and age at menopause with accelerated biological aging across multiple organ systems: findings from two cohort studies

This study aimed to investigate the associations between menopausal factors and both comprehensive and organ-specific biological aging, as well as the modifying role of reproductive history. This study included 37,244 women from the China Multi-Ethnic Cohort (CMEC) and 140,479 from the UK Biobank (UKB). Menopausal factors included menopausal status, menopausal transition, and age at menopause. Comprehensive and organ-specific biological ages (BAs) were calculated using the Klemera-Doubal method and clinical biomarkers and have been shown to predict age-related health outcomes. Multiple linear regression and change-to-change models were applied, with stratified analyses based on reproductive history.

Compared with pre-menopausal women, those who were peri-menopausal or post-menopausal or had undergone hysterectomy or oophorectomy exhibited greater acceleration in comprehensive, liver, metabolic, and kidney BA. In longitudinal change-to-change models, women undergoing menopausal transition showed greater increases in comprehensive BA (CMEC: β = 1.33; UKB: β = 2.60), as well as liver, metabolic, and kidney BAs compared to those remaining pre-menopausal. Earlier age at menopause was associated with accelerated comprehensive BA in UKB (earlier than 40 years: β = 0.69; 40-44 years: β = 0.24). Across organ-specific BAs, liver BA showed the strongest associations with menopausal factors. Reproductive history like age at live birth and number of live births emerged as potential modifiers of these associations.

Menopause, particularly the menopausal transition, was associated with accelerated comprehensive and organ-specific biological aging, with liver aging being most affected. These findings underscore the menopausal transition as a critical window for interventions to enhance women's health and longevity.

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More on the Lower Age-Related Inflammation in Hunter-Gatherer Populations
https://www.fightaging.org/archives/2025/08/more-on-the-lower-age-related-inflammation-in-hunter-gatherer-populations/

Inflammaging is the age-related tendency of the immune system to slip into chronic inflammation in the absence of any external provocation such as injury or infection. Research into this phenomenon has produced a list of many different contributing mechanisms: the growing burden of senescent cells that produce pro-inflammatory signaling; excess visceral fat tissue that encourages the creation of senescent cells and provides pro-inflammatory signaling of its own; mitochondrial dysfunction that leads to mitochondrial DNA fragments escaping into the cell cytosol to maladaptively trigger mechanisms evolved to sense the presence of foreign DNA; and so forth. The resulting continual, unresolved inflammation is disruptive to tissue structure and function, an important contribution to age-related disease and mortality.

Over the past decade or so, researchers have shown that a number of hunter-gatherer populations exhibit much lower degrees of age-related dysfunction and disease than is the case in the populations of wealthy regions: a slower onset of neurodegeneration, and lower incidence of cardiovascular disease, for example. Hunter-gatherers undertake a great deal of physical activity relative to wealthier populations, and their diet is somewhat different. Today's research materials is a companion to a recent publication on the failure of chronic inflammation to greatly increase with age in Tsimane hunter-gatherers. Here, the same researchers compare the Tsimane and Moseten, near neighbor groups with differing degrees of adoption of modernity. Their data supports the consensus position that some of modernity, particularly the processed dietary options and lack of physical activity, are not so good for us.

Inflammaging is minimal among forager-horticulturalists in the Bolivian Amazon

An increase in chronic systemic inflammation in later life, termed inflammaging, is implicated in health risk. However, it is unclear whether inflammaging develops in all human populations, or if it is the product of environmental mismatch. We assessed inflammaging in Tsimane forager-horticulturalists of the Bolivian Amazon, using serum cytokines in a primarily cross-sectional sample (1,134 samples from n = 714 individuals, age 39-94, 51.3% female).

IL-6 was positively associated with age (β = 0.013). However, other pro-inflammatory markers, including IL-1β and TNF-α, did not increase with age (β = -0.005 and β = -0.001, respectively). We then compared the Moseten, a neighbouring population that has experienced greater market integration (423 samples from n = 380 individuals, age 39-85, 48.2% female). The Moseten also showed a positive age association for IL-6 that attenuated at later ages (age β = 0.025; age2 β = -0.001). Further, IL-1β and TNF-α were both positively associated with age (β = 0.021 and β = 0.011, respectively).

Our results demonstrate minimal inflammaging in the Tsimane, highlighting variation across populations in this age-related process. They also suggest that inflammaging is exacerbated by lifestyle shifts.

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An Example of DNA Repair Deficiency Accelerating Muscle Aging
https://www.fightaging.org/archives/2025/08/an-example-of-dna-repair-deficiency-accelerating-muscle-aging/

Randomly occurring mutations to nuclear DNA accumulate with age. While DNA repair machinery in the cell nucleus has evolved to be highly efficient, nonetheless some fraction of the damage accumulated via radiation and molecular interactions slips through. There is considerable debate over the degree to which the accumulation of mutations contributes to degenerative aging, and which effects are important. Clearly mutation burden increases risk of cancer, that conclusion is solid and well supported: the more mutations, the more likely it is that a cancerous combination of mutations will occur. Going beyond this, matters become less clear, however.

The current consensus on this subject is that mutations occurring in stem cell populations is important, as these mutations can spread throughout a tissue via the daughter cells created by mutated stem cells. One sees patchy waves of mutational combinations arising with age in tissues throughout the body, a phenomenon called somatic mosaicism. There is at least some correlational evidence to link somatic mosaicism with a few age-related conditions, but it is by no means a foregone conclusion that it does provide an important contribution to general metabolic dysfunction.

Many varieties of malfunction in DNA repair produce both an accelerated accumulation of mutations and the appearance of accelerated aging. It is important to note that one can argue over whether this is in fact accelerated aging, versus just an excessive accumulation of a form of damage that plays a lesser role (or even possibly insignificant role, yet to be robustly determined either way) in normal aging. It is possible that researchers will ultimately learn little of importance from DNA repair deficiencies, for all that the research community makes a great deal of use of this phenomenon in animal models in order to obtain support for theories of aging relating to DNA damage.

One final thought on DNA damage is the more recent work suggesting that the damage is important insofar as it produces double strand breaks, as repeated repair of these breaks acts to alter epigenetic marks and the structure of DNA regardless of the location of this damage in the genome. This model dispenses of the idea that random breakage in gene sequences, largely only important where it is spread though somatic mosaicism, is collectively causing metabolic dysfunction. Instead, the repeated act of repair causes the epigenetic changes to gene expression that are characteristic of aging in all cells throughout the body. This also is work in need of confirmation and further exploration.

Induced somatic mutation accumulation during skeletal muscle regeneration reduces muscle strength

Aging is linked to reduced tissue function and regeneration, with genomic instability, marked by accumulating somatic mutation, being a key hallmark. These mutations, arising from replication errors or DNA repair defects, are not inherited but lead to tissue mosaicism. Although genome instability and DNA damage have been characterized in aging, the functional role of somatic mutation accumulation in age-related tissue decline and age-related diseases beyond cancer remains less explored.

Whole-genome sequencing (WGS) studies have shown that somatic mutations accumulate with age in human skeletal muscle progenitor cells and other tissues, with similar observations in most tumor types. Differentiated cells often carry even higher mutation loads, highlighting the underestimated extent of age-related somatic mutagenesis. Although we previously showed that high mutation burden impairs satellite cell (SC) function in vitro, in vivo evidence for the role of somatic mutations in muscle tissue function remains limited.

Aged human cells, including SCs, show structural genetic variations such as chromosomal aberrations, single-nucleotide variants (SNVs), and short insertions/deletions (InDels). To model this, we generated muscle somatic mutator (MSM) mice by deleting the DNA repair genes Msh2 and Blm specifically in SCs. This allowed us to assess how elevated DNA damage and somatic mutations affect muscle regeneration following injury. These mice exhibited impaired muscle regeneration, characterized by smaller muscle fibers, reduced muscle mass gain, and decreased grip strength. Importantly, similar muscle deficits were observed in a second mouse model where somatic mutations were elevated with less substantial DNA damage. These findings provide evidence that the accumulation of somatic mutations can potentially compromise the function of somatic cells, contributing to the aging phenotype in skeletal muscle.

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Application of Keratin Repairs Tooth Enamel
https://www.fightaging.org/archives/2025/08/application-of-keratin-repairs-tooth-enamel/

While modern dentistry offers a range of good-enough approaches to damaged teeth, regeneration of lost enamel remains a much desired capability. Here, researchers show that the application of keratin to damaged tooth enamel provokes the formation of an enamel-like replacement structure. This is quite interesting, and simple enough in implementation that it could emerge as a widespread option in the near future.

Scientists discovered that keratin, a protein found in hair, skin and wool, can repair tooth enamel and stop early stages of decay. Keratin forms a dense mineral layer that protects the tooth and seals off exposed nerve channels that cause sensitivity, offering both structural and symptomatic relief. The treatment could be delivered through a toothpaste for daily use or as a professionally applied gel, similar to nail varnish, for more targeted repair. The team is already exploring pathways for clinical application and believes that keratin-based enamel regeneration could be made available to the public within the next two to three years.

In their study, the scientists extracted keratin from wool. They discovered that when keratin is applied to the tooth surface and comes into contact with the minerals naturally present in saliva, it forms a highly organised, crystal-like scaffold that mimics the structure and function of natural enamel. Over time, this scaffold continues to attract calcium and phosphate ions, leading to the growth of a protective enamel-like coating around the tooth. This marks a significant step forward in regenerative dentistry.

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Reviewing What is Known of Mitochondrial Sirtuins in Aging
https://www.fightaging.org/archives/2025/08/reviewing-what-is-known-of-mitochondrial-sirtuins-in-aging/

The sirtuin family of proteins has attracted research interest for its involvement in mechanisms that may influence the pace of aging. While the overhyped work on the effects of sirtuin 1 on aging unraveled to produce no practical applications, sirtuin 3, sirtuin 4, and sirtuin 5 are localized in the mitochondria and there is a range of more convincing evidence to suggest that they can be manipulated to meaningfully adjust mitochondrial function in later life.

Sirtuins, colloquially termed "longevity proteins," are central regulators in the intricate molecular networks of aging. These proteins function as nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases or adenosine diphosphate (ADP)-ribosyltransferases, operating within multiple cellular regulatory pathways crucial to the aging process. The mammalian sirtuin family comprises seven members (SIRT1-7), with SIRT3, SIRT4, and SIRT5 specifically localized to the mitochondria.

These mitochondrial sirtuins have garnered significant scientific interest due to their potential roles in aging and age-associated disorders, primarily through their involvement in maintaining mitochondrial function and energy metabolism. Through the regulation of mitochondrial metabolism, stress response pathways, and other cellular processes, these proteins contribute to the maintenance of mitochondrial integrity and function, thereby supporting overall cellular homeostasis.

The diverse actions of mitochondrial sirtuins contribute to delaying age-related functional decline in various organs and extending lifespan in model organisms, positioning them as central players in the complex biology of aging. Given their critical roles in regulating aging, a systematic review of SIRT3, SIRT4, and SIRT5 functions in aging and age-related diseases is warranted. This review aims to provide a comprehensive overview of the current understanding of mitochondrial sirtuins, focusing on their involvement in various aging processes and their roles in age-related pathologies.

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HAPLN2 Forms Aggregates to Provoke Microglial Inflammation in the Aging Brain
https://www.fightaging.org/archives/2025/08/hapln2-forms-aggregates-to-provoke-microglial-inflammation-in-the-aging-brain/

A small number of proteins in the body and brain are known to become misfolded or altered in ways that provoke the formation of extensive, harmful protein aggregates. Neurodegenerative conditions in particular are strongly linked to the aggregates of specific proteins, such as amyloid-β, tau, and α-synuclein. Researchers continue to discover new proteins that produce aggregates capable of contributing significantly to forms of age-related disease, however. That TDP-43 aggregates to cause a prominent form of dementia is a comparatively recent discovery, for example. Further, research makes clear that many more proteins, potentially hundreds, can produce aggregates as a result of dysfunction in protein quality control mechanisms. Thus we should probably expect that the present body of knowledge is incomplete with regard to which proteins and aggregates are important in age-related disease.

Protein aggregation is a hallmark of neurodegenerative diseases and is also observed in the brains of elderly individuals without such conditions, suggesting that aging drives the accumulation of protein aggregates. However, the comprehensive understanding of age-dependent protein aggregates involved in brain aging remains unclear. Here, we investigated proteins that become sarkosyl-insoluble with age and identified hyaluronan and proteoglycan link protein 2 (HAPLN2), a hyaluronic acid-binding protein of the extracellular matrix at the nodes of Ranvier, as an age-dependent aggregating protein in mouse brains.

Elevated hyaluronic acid levels and impaired microglial function reduced the clearance of HAPLN2, leading to its accumulation. HAPLN2 oligomers induced microglial inflammatory responses both in vitro and in vivo. Furthermore, age-associated HAPLN2 aggregation was also observed in the human cerebellum. These findings suggest that HAPLN2 aggregation results from age-related decline in brain homeostasis and may exacerbate the brain environment by activating microglia. This study provides new insights into the mechanisms underlying cerebellar aging and highlights the role of HAPLN2 in age-associated changes in the brain.

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FTL1 Inhibition in Neurons Slows Brain Aging in Mice
https://www.fightaging.org/archives/2025/08/ftl1-inhibition-in-neurons-slows-brain-aging-in-mice/

Changes in the expression of countless genes takes place with aging. Some of these changes are adaptive, attempts to resist the damaged environment or compensate for other impaired functions. Many are maladaptive and actively cause harm. Researchers here identify a specific maladaptive change in expression in neurons in the brains of aged mice, an increase in FTL1 that appears to produce a range of harm that contributes to loss of cognitive function.

Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that impairs cognition. Using transcriptomic and mass spectrometry approaches, we detect an increase in neuronal FTL1 in the hippocampus of aged mice, the levels of which correlate with cognitive decline.

Mimicking an age-related increase in neuronal FTL1 in young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting neuronal FTL1 in the hippocampi of aged mice improves synaptic-related molecular changes and cognitive impairments. Using neuronal nuclei RNA sequencing, we detect changes in metabolic processes, such as ATP synthesis, and boosting these metabolic functions through NADH supplementation mitigated pro-aging effects of neuronal FTL1 on cognition. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation.

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Data Suggests Taurine Does Not Decline with Age in Primates
https://www.fightaging.org/archives/2025/08/data-suggests-taurine-does-not-decline-with-age-in-primates/

A study from a few years ago showed that circulating taurine levels declined with age in mice, and taurine supplementation extended healthy life span. That sparked some interest in the research community in corroborating those findings. Here, researchers show that matters relating to taurine and taurine supplementation are not straightforward, as in their data sets taurine from blood samples does not decline with age, and is not straightforwardly associated with age-related issues. It remains the case that conducting a study in people with low taurine levels would be comparatively simple to carry out, albeit expensive as is the case for any clinical trial, but the choice of what to assess as an outcome is now more complex than it was.

Taurine recently gained popularity as dietary supplement due to recent research that found supplementation with taurine improved multiple age-related traits and extended lifespan in model organisms (worms and mice). However, there is no solid clinical data that shows its supplementation benefits humans.

In a new study, researchers measured taurine concentration in longitudinally collected blood from participants in the Baltimore Longitudinal Study of Aging (aged 26-100), rhesus monkeys (aged 3-32 years) and mice (aged 9-27 months). Taurine concentrations increased with age in all groups, except in male mice in which taurine remained unchanged. Similar age-related changes in taurine concentrations were observed in two cross-sectional studies of geographically distinct human populations, the Balearic Islands Study of Aging (aged 20-85) from the Balearic region of Mallorca, and the Predictive Medicine Research cohort (aged 20-68) from Atlanta, Georgia, as well as in the cross-sectional arm of the Study of Longitudinal Aging in Mice.

Researchers also found that the relation between taurine and muscle strength or body weight was inconsistent. For example, analyses of gross motor function highlight the limitations of considering solely circulating taurine changes as indicative of biological aging, as comparatively low motor function performance can be associated either with high or low concentrations of taurine, whereas in other cases, no relation at all is found between these variables.

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Exerkines and Myokines in the Context of Muscle Aging
https://www.fightaging.org/archives/2025/08/exerkines-and-myokines-in-the-context-of-muscle-aging/

Muscle tissue is metabolically active and does produce effects on the rest of the body via signaling. Myokines are signal molecules produced my muscle tissue, while exerkines are signal molecules produced during exercise, and which induce improvements in tissue function, both in muscle and in other organs. This signaling is incompletely mapped and its effects in detail are not well understood outside of a few specific signals that have attracted research attention in past years. The broader topic of how muscle, and muscle use in exercise, influences function in the rest of the body is an area of interest for ongoing research. Researchers would like to produce exercise mimetic drugs, for example, analogous to calorie restriction mimetic drugs, that induce some of the signaling changes induced by exercise. A greater understanding of those signals helps.

Sarcopenia is an unavoidable condition that affects the majority of older adults in their later years. Exercise has been extensively researched as an effective intervention for sarcopenia. In particular, the release of exerkines and myokines during physical activity has beneficial effects on the body, which, as mediators, offer a novel therapeutic strategy for elucidating how exercise enhances skeletal muscle mass and function.

In this review article, we summarize how exerkines exert protective effects on aging skeletal muscle mainly through the following mechanisms: (1) mediating energy diversion to skeletal muscle, ensuring more energy supply to the muscle; (2) enhancing the activity of skeletal muscle satellite cells to promote muscle repair and regeneration; (3) upregulating the expression of genes associated with muscle regeneration and, at the same time, inhibiting the expression of those genes that contribute to the atrophy of skeletal muscle; and (4) improving the function of the neuromuscular junction to improve the neural control of skeletal muscle. These combined effects constitute the protective mechanism of myokines on aging skeletal muscle.

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Metabolic Syndrome Correlates with Increased Risk of Parkinson's Disease
https://www.fightaging.org/archives/2025/08/metabolic-syndrome-correlates-with-increased-risk-of-parkinsons-disease/

Metabolic syndrome is a consequence of excess fat tissue, being overweight. It is the precursor to type 2 diabetes, and produces the same sort of harmful contributions to age-related conditions via increased chronic inflammation and a range of other mechanisms relating to the disruption of normal metabolism. It should not be surprising to see that metabolic syndrome increases the risk of a neurodegenerative condition like Parkinson's disease, as this class of age-related conditions are well known to involve inflammation in brain tissue.

Metabolic syndrome is defined as having three or more of the following risk factors: excess belly fat, high blood pressure, high blood sugar, higher than normal triglycerides, which are a type of fat found in the blood, and low high-density lipoprotein (HDL) cholesterol, or "good" cholesterol. The study involved 467,200 people with an average age of 57; of those 38% had metabolic syndrome. The participants were followed for a median of 15 years. During that time, 3,222 people developed Parkinson's disease. For people without metabolic syndrome, the incidence rate for Parkinson's was 4.87 cases per 10,000 person-years, compared to 5.21 cases per 10,000 person-years for people who had metabolic syndrome. Person-years represent both the number of people in the study and the amount of time each person spends in the study.

After adjusting for age, smoking status, physical activity, and genes that increase the risk of Parkinson's disease, researchers found that people with metabolic syndrome were about 40% more likely to develop Parkinson's disease than people without the syndrome. The researchers also conducted a meta-analysis of all studies on this topic and confirmed the finding that people with metabolic syndrome have an increased risk of Parkinson's disease. Combining the current study with eight previous studies, the researchers found that people with metabolic syndrome were 29% more likely to develop Parkinson's disease than people without the syndrome.

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Progerin Expression May Play a Role in Chronic Kidney Disease
https://www.fightaging.org/archives/2025/08/progerin-expression-may-play-a-role-in-chronic-kidney-disease/

Progerin is a truncated form of lamin A, a protein needed to ensure the cell nucleus has a normal structure. In patients with Hutchinson-Gilford progeria syndrome, lamin A mutation leads to a large amounts of progerin, widespread cell dysfunction, the appearance of accelerated aging, and early mortality. In normal aging, progerin is expressed to some degree in some cells, and may or may not be significant; as in all potential contributing mechanisms of aging, it is very hard to assign the degree to which that mechanism is important relative to all of the other ongoing issues. Here, researchers provide evidence for somatic mutations in lamin A that occur in stem cells or progenitor cells, and that thus then expand out into somatic cells in tissue, to arise in chronic kidney disease and contribute to the pathology of that condition.

Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the protein responsible for the premature aging disease Hutchinson-Gilford progeria syndrome, steadily recurring in vascular smooth muscle cells of patients with CKD. Notably, the most common progeria-causing mutation, LMNA c.1824C>T, was identified as a somatic mutation in CKD arteries.

Clusters of proliferative progerin-expressing cells in CKD arteries and in vivo lineage-tracing in mice revealed clonal expansion capacity of mutant cells. Mosaic progerin expression contributed to genomic damage, endoplasmic reticulum stress and senescence in CKD arteries and resulted in vascular aging phenotypes in vivo. These findings suggest that certain somatic mutations may be clonally expanded in the arterial wall, contributing to the disease-related functional decline of the tissue.

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CISD2 Slows the Age-Related Dysfunction of Heart Muscle
https://www.fightaging.org/archives/2025/08/cisd2-slows-the-age-related-dysfunction-of-heart-muscle/

Increased CISD2 expression has been shown to slow aging in mice, and is one of the few longevity-inducing genes robustly identified to date. Increased expression improves liver function, reduces senescent cell inflammatory signaling in skin, and generates a range of other beneficial effects along the way. CISD2 produces numerous changes in aspects of metabolism, including mitochondrial function and calcium transport. Understanding which of these effects are more versus less important, and how exactly they induce improved long-term health, remains a work in progress. Expect to see many more papers akin to the one noted here, a deep dive into the effects of CISD2 expression in one specific tissue.

Age-associated atrial myopathy results in structural remodeling and a disturbance of atrial conductance. Atrial myopathy often precedes atrial fibrillation (AF) and can facilitate AF progression. However, the molecular mechanism linking aging to atrial deterioration remains elusive. CDGSH iron-sulfur domain-containing protein 2 (CISD2) is a mammalian pro-longevity gene. We used Cisd2 knockout (Cisd2KO) and Cisd2 transgenic (Cisd2TG) mice to investigate pathophysiological mechanisms underlying age-related atrial myopathy.

Four findings are pinpointed. Firstly, in both humans and mice, the level of atrial CISD2 declines during natural aging; this correlates with age-associated damage, namely degeneration of intercalated discs, mitochondriaps://en.wikipedia.org/wiki/Mitochondrion">mitochondria, sarcoplasmic reticulum (SR) and myofibrils. Secondly, in Cisd2KO and naturally aged wild-type mice, Cisd2 deficiency causes atrial electrical dysfunction and structural deterioration; conversely, sustained Cisd2 levels protect Cisd2TG mice against age-related atrial myopathy. Thirdly, Cisd2 plays a vital role in maintaining Ca2+ homeostasis in atrial cardiomyocytes. Cisd2 deficiency disrupts Ca2+ regulation, leading to elevated cytosolic Ca2+, reduced SR Ca2+, impaired store-operated calcium entry, and mitochondrial Ca2+ overload; these compromise mitochondrial function and attenuate antioxidant capability. Finally, transcriptomic analysis reveals that Cisd2 protects the atrium from metabolic reprogramming and preserves into old age a transcriptomic profile resembling a youthful pattern, thereby safeguarding the atrium from age-related injury.

This study highlights Cisd2's crucial role in preventing atrial aging and underscores the therapeutic potential of targeting Cisd2 when combating age-associated atrial dysfunction, which may lead to the development of strategies for improving cardiac health in aging populations.

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Mesaconic Acid as a Beneficial Metabolite Generated in the Gut Microbiome of Centenarians
https://www.fightaging.org/archives/2025/08/mesaconic-acid-as-a-beneficial-metabolite-generated-in-the-gut-microbiome-of-centenarians/

A good deal of research interest is now focused on the composition of the gut microbiome as either (a) a contributing factor in degenerative aging, due to changes that take place with age or (b) a factor in determining natural variations in human life span. For example, a number of research groups have mapped the composition of gut microbiomes in very long-lived individuals. The study here goes a little beyond a map of species and relative population sizes to identify a metabolite produced by microbes that appears to be protective in older individuals, based on results in mice.

The gut microbiota of centenarians plays a vital role in promoting healthy longevity. We performed a cross-sectional study of 224 people from Jiaoling, China, which is globally recognised for the longevity of its residents. Compared with younger people, centenarians showed significantly increased alpha-diversity//en.wikipedia.org/wiki/Alpha_diversity">alpha-diversity, enrichment of the beneficial bacteria Lactobacillus, Akkermansia, and Christensenella, and increased redox capacity in the gut microbiota. Serum metabolomics of centenarians showed significant enrichment of antioxidant metabolites, including L-ascorbic acid 2-sulphate and lipoic acid.

Finally, we isolated and screened a strain of Lactobacillus plantarum 124 (LP124) with a good antioxidant effect on the gut microbiota of centenarians. Animal experiments further verified that mesaconic acid from LP124 regulates the gut microbiota, is anti-inflammatory, relieves oxidative stress, maintains the intestinal barrier. LP124 derived from the gut microbiota of centenarians and its metabolite mesaconic acid, have a significant positive effect on health and longevity.

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