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- GFI1 Inhibition as an Approach to Reduce T Cell Exhaustion
- Reviewing the Role of Inflammasomes in Aging
- Semaglutide Modestly Reduces Epigenetic Age in Overweight Individuals
- R-Loop DNA Provokes Chronic Inflammation via cGAS/STING
- Immunosenescence Framed as a Treatable Condition
- Effects of Young Serum Factors on a Skin Tissue Model
- A Bidirectional Relationship Between Aging and Fibrotic Liver Disease
- Urolithin A as a Treatment for Neurodegenerative Conditions
- Regulating the DNA Damage Response as a Treatment for Synucleinopathies
- Arguing for Exercise to Slow Muscle Aging via Improved Mitophagy
- Immune Aging as a Contribution to Type 2 Diabetes Risk
- The Relevance of Long-Lived Molecules to Aging Remains Speculative
- SkeletAge, a Skeletal Muscle Transcriptomic Aging Clock
- Towards Tissue Engineered Patches for a Ruptured Myocardium
- Calorie Restriction is Protective in the Context of Chronic Kidney Disease
GFI1 Inhibition as an Approach to Reduce T Cell Exhaustion
https://www.fightaging.org/archives/2025/08/gfi1-inhibition-as-an-approach-to-reduce-t-cell-exhaustion/
When continually stimulated, as occurs in persistent viral infections and cancer, T cells of the adaptive immune system become exhausted. This state is characterized by an inability to attack and kill pathogens and harmful cells. As with any other aspect of the immune system, however, exhaustion is not a well-defined and simple binary state, but rather a broad category that contains many different subtypes of exhausted cell, degrees of exhaustion, and distinct biochemistries contributing to exhaustion. Cellular biochemistry is complicated at every level.
Researchers want to find effective ways to reprogram T cells to exit exhaustion or resist the onset of exhaustion. This seems possible in principle, and a number of technology demonstrations exist to demonstrate that at least some manipulation of T cell exhaustion can be accomplished. Turning those initial research results into useful therapies is very different matter, of course. Today's research materials report on new discovery that may help to make exhaustion less of a problem in cancer and persistent infection. The researchers have identified GFI1 as a regulator of the degree to which exhaustion prevents T cells from generating a useful response to pathogens and cancerous cells, and GFI1 inhibitors may prove to be a useful class of drug.
Reinvigorating exhausted T cells in cancer and chronic viral infections
Killer immune cells destroy cancer cells and cells infected by virus. However, in chronic viral infection and cancer, the killer cells often lapse into "exhausted" CD8+ T cells that no longer can stem disease. Exhausted CD8+ T cells are a complex population of subsets composed of progenitor cells and "effector-like" or "terminally exhausted" cells. Effector-like cells still retain some killer ability.
Researchers used mice infected with a chronic virus to describe four subsets in the population, including a previously under-described Ly108+CX3CR1+ subset that expresses low levels of Gfi1, while other established subsets have high expression. This Ly108+CX3CR1+ subset is transitory and develops to terminally exhausted cells and effector-like cells, which retain some tumor killing ability. This process depends on low levels of Gfi1.
"Considering Gfi1 downregulation is associated with the active differentiation of CD8+ T cell progenitors, we argue that transient and intermittent inhibition of Gfi1 with lysine-specific histone demethylase may facilitate the differentiation of progenitors to Ly108+CX3CR1+ cells and then to effector-like cells, thereby improving the control of chronic infections and tumors/"
Gfi1 controls the formation of effector-like CD8+ T cells during chronic infection and cancer
During chronic infection and tumor progression, CD8+ T cells lose their effector functions and become exhausted. These exhausted CD8+ T cells are heterogeneous and comprised of progenitors that give rise to effector-like or terminally-exhausted cells. The precise cues and mechanisms directing subset formation are incompletely understood. Here, we show that growth factor independent-1 (Gfi1) is dynamically regulated in exhausted CD8+ T cells.
During chronic LCMV Clone 13 infection, a previously under-described Ly108+CX3CR1+ subset expresses low levels of Gfi1 while other established subsets have high expression. Ly108+CX3CR1+ cells possess distinct chromatin profiles and represent a transitory subset that develops to effector-like and terminally-exhausted cells, a process dependent on Gfi1. Similarly, Gfi1 in tumor-infiltrating CD8+ T cells is required for the formation of terminally differentiated cells and endogenous as well as anti-CTLA-4-induced anti-tumor responses. Taken together, Gfi1 is a key regulator of the subset formation of exhausted CD8+ T cells.
Reviewing the Role of Inflammasomes in Aging
https://www.fightaging.org/archives/2025/08/reviewing-the-role-of-inflammasomes-in-aging/
Constant, unresolved inflammatory signaling is a feature of aging. It occurs in absence of the usual provocations of infection and injury, and is disruptive to tissue structure and function. Normal, short-term inflammation is useful and necessary, but long-term inflammation is harmful. It changes cell behavior for the worse, causes the normal processes of tissue maintenance to run awry, degrades the effectiveness of the immune system, encourages growth of cancers, and contributes to the onset and progression of all of the common fatal diseases of aging.
Much of this unwanted inflammation of aging is caused by the reaction of inflammasomes to the molecular damage present in an aged cell. Inflammasomes are protein complexes that evolved to react to the presence of molecules characteristic of infectious agents such as viruses by inducing inflammatory signaling that will then be amplified by the immune system. Unfortunately, this means that they will also react to age-related cell dysfunction that leads to the escape of fragments of nuclear DNA from the nucleus and mitochondrial DNA from mitochondria into the body of the cell. Analogous maladaptive activation of inflammasomes also takes place as a result of other dysfunctions that occur in aged cells.
Researchers are interested in targeting inflammasomes to prevent this induction of inflammation in aged tissues. The challenge here is that, so far, it appears that distinguishing between unwanted activation and desirable activation will be challenging. Efforts to suppress inflammatory signaling will not just suppress the harmful chronic inflammation, but also suppress useful short-term inflammation, further impairing immune function. It remains to be seen as to whether there are clever ways around this problem; one or two possible paths forward have been found in recent years, but these approaches may or may not work out. It is too early to say.
Potential Role of Inflammasomes in Aging
Inflammaging is a term used to describe the physiological changes in the immune system associated with aging that play a significant role in the onset and progression of complex aging-related diseases. These changes affect various conditions, including skin aging, cardiovascular disease, neurodegenerative disease, periodontal disease, and other chronic illnesses. Molecular and cellular mechanisms linking aging and chronic inflammation have been studied extensively, focusing on increased cytokine expression related to inflammasomes and their sustained activation in inflammatory diseases.
Inflammasomes are protein complexes observed within the cell cytoplasm, serving as critical molecular platforms that induce inflammatory responses. Inflammasomes recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), leading to the secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β and IL-18, as well as the initiation of pyroptosis, a form of cell death. The activation of inflammasomes involves various sensors, including nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptor (NLR) proteins, pyrin, absent in melanoma 2 (AIM2), and gamma-interferon-inducible protein Ifi-16 (IFI16). These sensors activate the protease enzyme caspase-1, which cleaves pro-IL-1β and pro-IL-18, generating mature IL-1β and IL-18. Furthermore, inflammasome activation leads to the cleavage of gasdermin-D, resulting in N-terminal fragments that form pores in the cell membrane. This process induces pyroptosis while releasing various DAMPs and cytokines.
Inflammasomes play a fundamental role in enhancing innate immune responses and promoting pathogen clearance and tissue repair. However, their activation can be context-dependent, and excessive activation may exacerbate inflammatory conditions. Conversely, insufficient cytokine activation could contribute to chronic inflammation. Therefore, the precise regulation of inflammasome activity is essential for maintaining physiological homeostasis.
The targeting of inflammasomes offers a promising avenue for mitigating inflammaging and age-related diseases. Given the distinct yet overlapping roles of various inflammasome sensors, the development of selective and broad-spectrum inflammasome inhibitors is critical. While many studies have focused on NLRP3 inhibition, the involvement of other inflammasomes in inflammaging suggests that a more comprehensive approach is necessary. Each inflammasome sensor responds to different activation signals, meaning that a single-target strategy may be insufficient to fully mitigate chronic inflammation and its systemic effects in aging. Further research is needed to determine how targeting multiple inflammasomes simultaneously could impact the inflammaging process and whether dual or multi-inflammasome inhibition can provide synergistic benefits without compromising immune surveillance.
Semaglutide Modestly Reduces Epigenetic Age in Overweight Individuals
https://www.fightaging.org/archives/2025/08/semaglutide-modestly-reduces-epigenetic-age-in-overweight-individuals/
There is some debate over whether GLP-1 receptor agonist drugs such as semaglutide can affect mechanisms relevant to aging independently of weight loss. GLP-1 receptors are present in many organs, including the brain, so it is not unreasonable to think that other outcomes may result from GLP-1 receptor agonism over and above reduced appetite and calorie intake. But do those outcomes slow aging to a meaningful degree in comparison to the effects of weight loss? That is where we should be appropriately skeptical.
Compelling mechanistic and epidemiological data indicates that excess visceral fat tissue accelerates aging, such as via the increased accumulation of senescent cells and the induction of a harmful diabetic metabolism. The effect size is fairly large. Losing weight should reduce biological age, so any data on GLP-1 receptor agonist drug use and biological age in overweight populations, as is the case in today's open access paper, cannot be used to argue that there is something other than weight loss going on - the weight loss effects get in the way.
The most compelling evidence for GLP-1 receptor agonists to affect pace of aging independently of loss of visceral fat tissue comes from a study in mice using low doses of the drug exenatide, too low to cause weight loss. The researchers nonetheless noted effects on aging, and their evidence suggests that this is specifically due to GLP-1 receptor agonism in the hypothalamus, and downstream effects from there. Recall that the hypothalamus is influential on many aspects of metabolism, and research has suggested that changes in hypothalamic function do affect pace of aging.
Semaglutide Slows Epigenetic Aging in People with HIV-associated lipohypertrophy: Evidence from a Randomized Controlled Trial
People with HIV (PWH) represent a unique population exhibiting accelerated biological aging, characterized by premature onset of age-related conditions, persistent low-grade inflammation, and metabolic dysfunction, even when HIV replication is effectively suppressed by antiretroviral therapy. A common metabolic complication in this population is HIV-associated lipohypertrophy, defined by excessive accumulation of visceral and ectopic adipose tissue, which further exacerbates aging processes. Within the geroscience framework, the accelerated-aging phenotype in PWH provides an ideal clinical model to evaluate candidate geroprotective therapies.
In a completed phase 2b, randomised, double-blind, placebo-controlled trial (semaglutide n = 45; placebo n = 39), we tested whether once-weekly semaglutide can slow epigenetic aging in people with HIV-associated lipohypertrophy, a population marked by visceral adiposity (average BMI = 32.86) and accelerated epigenetic age. Using paired peripheral-blood methylomes collected at baseline and 32 weeks, we conducted a post-hoc analysis spanning 17 DNA-methylation clocks.
After adjustment for sex, BMI, hsCRP, and sCD163, semaglutide significantly decreased epigenetic aging: PCGrimAge (-3.1 years), GrimAge V1 (-1.4 years), GrimAge V2 (-2.3 years), PhenoAge (-4.9 years), and DunedinPACE (-0.09 units, ≈9 % slower pace). Semaglutide also lowered the multi-omic OMICmAge clock (-2.2 years) and the transposable element-focused RetroAge clock (-2.2 years). Eleven organ-system clocks showed concordant decreased with semaglutide, most prominently inflammation, brain and heart, whereas an Intrinsic Capacity epigenetic clock was unchanged. These findings provide, to our knowledge, the first clinical-trial evidence that semaglutide modulates validated epigenetic biomarkers of aging, justifying further evaluation of GLP-1 receptor agonists for health-span extension.
R-Loop DNA Provokes Chronic Inflammation via cGAS/STING
https://www.fightaging.org/archives/2025/08/r-loop-dna-provokes-chronic-inflammation-via-cgas-sting/
Stretches of nuclear DNA can adopt a broad range of transient structural forms, guided by the complex feedback loops of epigenetic marks, decorating molecules added to and removed from DNA. Epigenetics as a form of control over gene expression is all a matter of structure: which regions are packaged up and inaccessible, which are accessible. Other processes can also have their effects on local structure of the DNA, however. Some of the resulting structural forms can be problematic, and might be thought of as damage or dysfunction or an unwanted side-effect of those processes operating on DNA. This is all fairly well described by the scientific community, with an established nomenclature for different structural features.
In this context, an R-loop is a structure in which a length of double-stranded nuclear DNA has a RNA sequence stuck to it, perhaps the consequence of a failure of transcription, the first step of gene expression. In today's open access paper, researchers provide evidence for R-loops to result in leakage of nuclear DNA fragments from the nucleus into the cytosol. This triggers inflammatory signaling via the cGAS/STING system that evolved to detect inappropriately localized nucleic acids, such as that belonging to viruses and bacteria. Unfortunately, forms of cell damage related to aging and disease will result in mislocalized fragments of the cell's own nucleic acids, generating a maladaptive inflammatory reaction on the part of cGAS/STING that further contributes to the progression of aging and disease.
Targeted Inhibition of cGAS/STING signaling induced by aberrant R-Loops in the nucleus pulposus to alleviate cellular senescence and intervertebral disc degeneration
Intervertebral disc degeneration (IVDD) is a significant contributor to chronic low back pain and disability worldwide, yet effective treatment options remain limited. Through integrative analysis of single-cell RNA-seq data from intervertebral discs (IVDs), we have firstly uncovered that the aberrant accumulation of R-Loops - a type of triple-stranded nucleic acid structure - can result in the cytoplasmic accumulation of double-stranded DNA (dsDNA) and activate cGAS/STING signaling and induce cellular senescence in nucleus pulposus cells (NPCs) during IVDD. Restoring the R-Loop state significantly mitigated both the activation of the cGAS/STING pathway and NPC senescence. Additionally, we identified ERCC5 as a critical regulator of the R-Loop state and cellular senescence.
Thus, we developed an NPC-targeting nano-delivery platform (CTP-PEG-PAMAM) to deliver small interfering RNA for ERCC5 (si-Ercc5) to the NP region of the IVDD. This approach aims to modulate the abnormal R-Loop state and inhibit the activation of cGAS/STING signaling in NPCs for IVDD treatment. CTP-PEG-PAMAM demonstrated excellent targeting capability towards NPCs and NP tissue, and achieved effective silencing of the Ercc5 gene without causing systemic organ complications. Both in vitro and in vivo experiments revealed that CTP-PEG-PAMAM-siERCC5 significantly inhibited cGAS/STING signaling activated by aberrant R-Loops, alleviated cellular senescence and promoting cell proliferation, thereby delayed IVDD in a puncture-induced rat model.
In conclusion, the ERCC5-R-Loop-cGAS/STING axis in NPCs represents a promising therapeutic target for delaying IVDD, and the designed CTP-PEG-PAMAM/siRNA complex holds great potential for clinical application in the treatment of IVDD.
Immunosenescence Framed as a Treatable Condition
https://www.fightaging.org/archives/2025/08/immunosenescence-framed-as-a-treatable-condition/
Immunosenescence is the name given to the age-related decline in the capacity of the immune system to carry out its duties: defend against pathogens; destroy senescent and cancerous cells; participate in normal tissue maintenance. Inflammaging, a chronic inflammatory stage characteristic of aging that arises from maladaptive reactions to damage, the presence of senescent cells, and other causes, is considered by some researchers to be an aspect of immunosenescence, while others think of it as a distinct phenotype. Both immunosenescence and inflammaging are important contributions to degenerative aging. Infectious disease and cancer are far more dangerous for the old precisely because the immune system is diminished in capacity, while the chronic inflammation of aging contributes to all of the common age-related diseases.
The research and development communities are well aware of the damage done by immune aging, and many projects have aimed and continue to aim at producing therapies that can improve immune function in older individuals. Among the more promising approaches are the various ways to restore a more youthful capacity of hematopoietic stem cell populations to generate functional immune cells in the right proportions, or regrow the atrophied thymus to restore a youthful supply of new T cells of the adaptive immune system, or selectively destroy one or more of the small, dysfunctional subpopulations of immune cells that cause harm in the aging body. It is a very interesting, active area of development, but it remains to be seen as to how rapidly viable therapies can be introduced into widespread clinical use.
Immunosenescence: signaling pathways, diseases and therapeutic targets
Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels.
Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials.
In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.
Effects of Young Serum Factors on a Skin Tissue Model
https://www.fightaging.org/archives/2025/08/effects-of-young-serum-factors-on-a-skin-tissue-model/
Researchers continue to search for circulating factors present in young blood fractions that might produce beneficial effects on cells in aged tissues. Transfusion of blood fractions from young donors to aged recipients has failed to produce compelling data, but it remains possible that specific factors could be manufactured and delivered in larger amounts to produce benefits. The paper here is one example of many early stage discovery projects presently taking place, in which researchers produce in vitro cell and tissue models to cost-effectively assess the effects of varied young blood fractions and specific factors. Their data suggests that factors from young blood fractions could produce benefits by altering the behavior of immune cells derived from the bone marrow that are present in tissues throughout the body.
Aging is a complex process that significantly contributes to age-related diseases and poses significant challenges for effective interventions, with few holistic anti-aging approaches successfully reversing its signs. Heterochronic parabiosis studies illuminated the potential for rejuvenation through blood-borne factors, yet the specific drivers including underlying mechanisms remain largely unknown and until today insights have not been successfully translated to humans.
In this study, we were able to recreate rejuvenation of the human skin via systemic factors using a microphysiological system including a 3D skin model and a 3D bone marrow model. Addition of young human serum in comparison to aged human serum resulted in an improvement of proliferation and a reduction of the biological age as measured by methylation-based age clocks in the skin tissue. Interestingly, this effect was only visible in the presence of bone marrow-derived cells.
Further investigation of the bone marrow model revealed changes in the cell population in response to young versus aged human serum treatment. Using proteome analysis, we identified 55 potential systemic rejuvenating proteins produced by bone marrow-derived cells. For seven of these proteins, we were able to verify a rejuvenating effect on human skin cells using hallmarks of aging assays, supporting their role as systemic factors rejuvenating human skin tissue.
A Bidirectional Relationship Between Aging and Fibrotic Liver Disease
https://www.fightaging.org/archives/2025/08/a-bidirectional-relationship-between-aging-and-fibrotic-liver-disease/
Metabolic dysfunction-associated steatohepatitis (MASH) follows a fatty liver, largely a consequence of obesity, but made worse by aging, in which fat-induced dysfunction of liver tissue maintenance leads to an increasing burden of fibrosis and loss of function. In fibrosis, the normal mechanisms of tissue maintenance run awry and excessive collagen is deposited to form scar-like structures that disrupt tissue function. At present fibrosis is largely irreversible, despite some potentially promising lines of research and development.
In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging.
In conclusion, there is a close bidirectional relationship between MASLD/MASH and aging. After aging, the prevalence, severity, and mortality of MASLD/MASH all increase. At the same time, MASLD/MASH can exacerbate liver aging, leading to the senescence of liver cells and affecting the normal functions of the liver. However, the detailed mechanisms by which aging contributes to the development of MASLD/MASH and why aging is exacerbated by this disease remain unclear. Moreover, the causal relationship between the two is not explained in detail, which one comes first and which one comes next. Future studies should further explore the specific mechanisms of this relationship and develop targeted preventive and therapeutic strategies to mitigate the impact of liver disease on the aging process and delay the progression of liver disease in the elderly population.
Urolithin A as a Treatment for Neurodegenerative Conditions
https://www.fightaging.org/archives/2025/08/urolithin-a-as-a-treatment-for-neurodegenerative-conditions/
Urolithin A is one of a number of molecules regulated as supplements that is known to modestly improve mitochondrial function. A number of companies are working on deriving drugs from modified forms of urolithin A, while the research community is more focused on trying to understand how exactly it improves mitochondrial function. The effect size is not large, as is the case for better understood approaches to improve mitochondrial function in aged tissues, such as the various ways to increase NAD+ in mitochondria, and delivery of forms of mitochondrially targeted antioxidant. These various molecules tend to produce results that are smaller than those resulting from greater exercise and greater physical fitness, where there is data to compare directly, and have collectively failed to move the needle on diseases in a range of clinical trials. Nonetheless, there remains considerable interest in all of these approaches, largely because they cost little and are immediately available for use.
Urolithin A (UA) is a natural compound produced through a multi-step metabolic process by gut microbiota, derived from dietary precursors such as ellagitannins (ETs) and ellagic acid (EA). These polyphenols are abundant in foods like pomegranates, berries, and tea. Extensive preclinical research highlights UA's diverse biological effects, including anti-inflammatory, antioxidant, anti-senescence, anti-apoptotic, and promoting mitophagy. Randomized clinical studies further validate UA's ability to upregulate proteins linked to mitophagy and oxidative phosphorylation (OXPHOS) in muscle tissue while reducing plasma inflammatory markers, such as C-reactive protein (CRP).
Regarding safety, clinical trials have confirmed UA's tolerability at doses up to 1000 mg daily, with no serious adverse effects reported in interventions lasting up to four months. Notably, UA is the first compound shown in human trials to induce mitochondrial-related gene expression without significant side effects. The U.S. FDA has granted UA Generally Recognized as Safe status as a food additive.
UA has been extensively investigated in preclinical models of various central nervous system (CNS) disorders. This review systematically integrates preclinical evidence for UA's therapeutic potential in CNS disorders and elucidates its biosynthesis, pharmacokinetic properties, key bioactivities, and recent clinical trials involving UA. Although clinical trials targeting UA treatment for CNS disorders have not yet been initiated, multiple clinical trials have demonstrated that UA possesses favorable safety and pharmacokinetic profiles and have validated some of the biological effects observed in in preclinical studies. Importantly, this review provides an in-depth analysis of the challenges encountered in the clinical translation of UA for the treatment of CNS disorders.
Regulating the DNA Damage Response as a Treatment for Synucleinopathies
https://www.fightaging.org/archives/2025/08/regulating-the-dna-damage-response-as-a-treatment-for-synucleinopathies/
Synucleinopathies are neurodegenerative conditions characterized by the aggregation of misfolded α-synuclein, a form of protein aggregation that drives much of the pathology of these diseases. The most prominent synucleinopathy is Parkinson's disease, but it may well be that α-synuclein plays a role in the aging of the brain more generally. Synucleinopathies are exaggerated versions of a damaging process that operates to some degree in every older person. Here, researchers suggest that aspects of DNA damage and DNA repair play a noteworthy role in synucleinopathies - altered in some way by the presence of α-synuclein aggregates, and in turn driving a significant fraction of the chronic inflammation of brain tissue that is a feature of these and other neurodegenerative conditions. Modulating the DNA repair process can help, at least in animal models of α-synuclein aggregation.
Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression remain incompletely understood, emerging evidence suggests that the buildup of nuclear DNA damage, especially DNA double-strand breaks (DDSBs), plays a key role in contributing neurodegeneration, promoting senescence and neuroinflammation. Despite the pathogenic role for DDSB in neurodegenerative disease, targeting DNA repair mechanisms in PD is largely unexplored as a therapeutic approach.
Ataxia telangiectasia mutated (ATM), a key kinase in the DNA damage response (DDR), plays a crucial role in neurodegeneration. In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy. Four-month-old C57BL/6J mice were unilaterally injected with either an empty AAV1/2 vector (control) or AAV1/2 expressing human A53T α-synuclein to the substantia nigra, followed by daily AZD1390 treatment for six weeks.
In AZD1390-treated α-synuclein mice, we observed a significant reduction in the protein level of γ-H2AX, a DDSB marker, along with downregulation of senescence-associated markers, such as p53, Cdkn1a, and NF-κB, suggesting improved genomic integrity and attenuation of cellular senescence, indicating enhanced genomic stability and reduced cellular aging. AZD1390 also significantly dampened neuroinflammatory responses, evidenced by decreased expression of key pro-inflammatory cytokines and chemokines. Interestingly, mice treated with AZD1390 showed significant improvements in behavioral asymmetry and motor deficits, indicating functional recovery. Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy.
Arguing for Exercise to Slow Muscle Aging via Improved Mitophagy
https://www.fightaging.org/archives/2025/08/arguing-for-exercise-to-slow-muscle-aging-via-improved-mitophagy/
The hundreds of mitochondria present in every cell are responsible for generating the chemical energy store molecule adenosine triphosphate to power cell processes. Dysfunction in the mitochondrial population is characteristic of aging and thought to be a meaningful contribution to loss of tissue function. This dysfunction arises in part because the quality control mechanisms that cull damaged mitochondria become less effective. When functioning correctly, the processes of mitophagy identify and flag damaged mitochondria, which are then conducted to a lysosome, engulfed, and broken down. The remaining mitochondria replicate to make up their numbers. Many interventions known to modestly slow aging or aspects of aging, exercise included, improve the operation of mitophagy and consequently improve mitochondrial function. How much of the overall benefit arises from improved mitophagy versus other mechanisms is a hard question to answer, however.
Sarcopenia is a syndrome associated with aging, characterized by a progressive decline in skeletal muscle mass and function. Its onset compromises the health and longevity of older adults by increasing susceptibility to falls, fractures, and various comorbid conditions, thereby diminishing quality of life and capacity for independent living. Accumulating evidence indicates that moderate-intensity aerobic exercise is an effective strategy for promoting overall health in older adults and exerts a beneficial effect that mitigates age-related sarcopenia. However, the underlying molecular mechanisms through which exercise can confer these protective effects remain incompletely understood.
In this study, we established a naturally aging mouse model to investigate the effects of a 16-week treadmill-based aerobic exercise regimen on skeletal muscle physiology. Results showed that aerobic exercise mitigated age-related declines in muscle mass and function, enhanced markers associated with protein synthesis, reduced oxidative stress, and modulated the expression of genes and proteins implicated in mitochondrial quality control. Notably, a single session of aerobic exercise acutely elevated circulating levels of β-hydroxybutyrate (β-HB) and upregulated the expression of BDH1, HCAR2, and PPARG in the skeletal muscle, suggesting a possible role of β-HB-related signaling in exercise-induced muscle adaptations. However, although these findings support the beneficial effects of aerobic exercise on skeletal muscle aging, further investigation is warranted to elucidate the causal relationships and to characterize the chronic signaling mechanisms involved.
Immune Aging as a Contribution to Type 2 Diabetes Risk
https://www.fightaging.org/archives/2025/08/immune-aging-as-a-contribution-to-type-2-diabetes-risk/
People who do not put on a lot of excess weight, and the excess visceral fat tissue that goes with it, are very unlikely to develop type 2 diabetes. It is a metabolic disease in which the primary, addressable cause is the presence of too much visceral fat. Adoption of a low calorie diet and undergoing the consequent weight loss is a curative strategy, and can reverse the course of type 2 diabetes even in late stages of the condition. With all that said, typically, overweight people develop type 2 diabetes later in life. It takes a great deal of visceral fat tissue to push someone into type 2 diabetes in earlier adulthood. So clearly the mechanisms and dysfunctions of degenerative aging do play a role. Here, researchers focus specifically on the aging of the immune system and its interaction with the metabolic dysfunction that leads to type 2 diabetes.
Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR), inflammation, and dysregulation in glucose metabolism. The disease is spreading globally, partly due to aging, which can damage the immune system and speed up the progression of the metabolic disorder. This review primarily delves into the triggers for T2D within the framework of the ominous octet, which emphasizes 8 principal factors that contribute to high blood glucose and associated metabolic disorders. The octet includes impaired insulin secretion, diminished incretin effect, increased lipolysis, heightened hepatic glucose production (HGP), neurotransmitter dysfunction, augmented renal glucose reabsorption, reduced glucose uptake in muscle, and inflammation-driven IR in adipose tissue (AT).
We further discuss the interplay of hyperinsulinemia, mitochondrial dysfunction (MD), and endoplasmic reticulum (ER) stress with immune aging in driving disease progression affecting each component of the octet. MD and ER stress can result in defects in insulin signaling, ultimately leading to pancreatic β-cell death. Chronic inflammation associated with aging, also known as inflammaging, especially affects older adults by worsening IR and glucose regulation, which creates a continuous sequence of metabolic problems. Thus, the "ominous octet" framework provides fundamental knowledge to develop personalized treatment approaches that target metabolic dysfunction together with ER stress, MD, and immune system imbalances. These strategies show promising potential to improve treatments for T2D and may lead to better health outcomes for older adults dealing with this condition.
The Relevance of Long-Lived Molecules to Aging Remains Speculative
https://www.fightaging.org/archives/2025/08/the-relevance-of-long-lived-molecules-to-aging-remains-speculative/
Some long-lived proteins (such as components of nuclear pore structures) in some long-lived cells (such as neurons) may never be replaced across a normal life span, or at the very least have lifetimes of years. That suggests that damage to these molecules may be important in aging and age-related disease. Some research has taken place on this topic, but as noted here, issues of measurement ensure that damage to long-lived molecules remains a more speculative contribution to degenerative aging. It may be important relative to other mechanisms, or it may not.
Neurons, unlike most other cell types, do not divide and are not replaced over an organism's lifetime. This lack of turnover necessitates robust mechanisms to maintain cellular integrity and function across prolonged periods of time, up to many decades. One key aspect of neuronal longevity is protein homeostasis, or proteostasis, which involves the balance between protein synthesis, folding, and degradation. Advances in metabolic labeling techniques have provided unexpected insights into protein turnover rates in neurons, and identified long-lived proteins (LLPs) in the brain. In addition to proteins, recent studies assessing the longevity of RNA have led to the identification of long-lived RNAs (LLRs) in the brain, challenging the prevailing consensus that RNA molecules are unstable.
Investigating the mechanisms underlying the long-term maintenance of these long-lived molecules - and the consequences of their dysfunction during brain aging or in the pathogenesis of age-related disease - is crucial to understanding their pathophysiological roles. However, due to limitations in measurement sensitivity and the lack of tools to selectively manipulate long-lived molecules, current proposals regarding their roles in brain aging remain largely speculative. In this opinion article, we discuss recent developments in characterizing LLPs and LLRs, as well as advances in emerging technologies to detect long-lived molecules in the brain. We also examine the mechanisms underlying the maintenance of long-lived molecules and these molecules' potential physiological roles. We finally delineate future directions to improve current understanding of the biological roles of long-lived molecules in brain aging and longevity.
SkeletAge, a Skeletal Muscle Transcriptomic Aging Clock
https://www.fightaging.org/archives/2025/08/skeletage-a-skeletal-muscle-transcriptomic-aging-clock/
Aging clocks can be manufactured using machine learning techniques from any sufficiently complex set of biological data obtained from people of different ages. An algorithm is found that maps age-related changes in the data to chronological age, on average. When that algorithm is applied to an individual not in the data set, the predicted age is called a biological age. Higher biological ages predicted by a clock usually correlate fairly well to risk of disease and mortality. Given the relatively low cost involved in creating clocks, new clocks are being produced at a rapid pace. It remains to be seen as to which of the many clocks created over the past decade or so prove to be useful enough in some context to be broadly adopted.
Identifying the set of genes that regulate baseline healthy aging - aging that is not confounded by illness - is critical to understating aging biology. Machine learning-based age-estimators (such as epigenetic clocks) offer a robust method for capturing biomarkers that strongly correlate with age. In principle, we can use these estimators to find novel targets for aging research, which can then be used for developing drugs that can extend the healthspan. However, methylation-based clocks do not provide direct mechanistic insight into aging, limiting their utility for drug discovery.
Here, we describe a method for building tissue-specific bulk RNA-seq-based age-estimators that can be used to identify the ageprint. The ageprint is a set of genes that drive baseline healthy aging in a tissue-specific, developmentally-linked fashion. Using our age estimator, SkeletAge, we narrowed down the ageprint of human skeletal muscles to 128 genes, of which 26 genes have never been studied in the context of aging or aging-associated phenotypes. The ageprint of skeletal muscles can be linked to known phenotypes of skeletal muscle aging and development, which further supports our hypothesis that the ageprint genes drive (healthy) aging along the growth-development-aging axis, which is separate from (biological) aging that takes place due to illness or stochastic damage. Lastly, we show that using our method, we can find druggable targets for aging research and use the ageprint to accurately assess the effect of therapeutic interventions, which can further accelerate the discovery of longevity-enhancing drugs.
Towards Tissue Engineered Patches for a Ruptured Myocardium
https://www.fightaging.org/archives/2025/08/towards-tissue-engineered-patches-for-a-ruptured-myocardium/
In the near term, the field of tissue engineering aims to produce artificial tissue structures that can support cells and integrate with native tissue when implanted into an injury, promoting regeneration that would not otherwise have taken place. In the longer term, the goal is to produce entirely artificial, fully functional organs - but first things first. Producing large sections of pseudo-tissue that can reliably promote regeneration is still a work in progress, with many projects at varying stages of development. As this paper makes clear, the fine details involved in sufficiently replicating tissue structural properties can be a challenge.
Myocardial Infarction (MI) occurs when blood flow to the heart is restricted, causing cardiomyocyte death, scar tissue formation, and myocardial remodeling. These changes reduce the heart's efficiency, increasing the mechanical load on surrounding tissue and causing the infarcted region to thin. In severe cases, this leads to myocardial rupture, which requires immediate surgical intervention. Here, cardiac patches made from biological (bovine pericardium), synthetic materials (polytetrafluoroethylene or polyester fiber) are implanted to stabilize the heart. However, these materials do not degrade, contract, or integrate into the myocardium. Furthermore, these patches undergo undesirable biological interactions such as calcification, thrombosis, and inflammation. These drawbacks hinder the application of cardiac patches in pediatric patients, impairing long-term recovery and safety in many cases.
An ideal cardiac patch would be implantable, easy to handle surgically and provide short-term mechanical support while promoting biological regeneration of the damaged myocardium. Such a patch would fully integrate with native tissue, degrade in a controlled manner, and avoid triggering an immune response or other adverse effect. Tissue-engineered cardiac patches, or engineered heart tissues (EHTs), offer a potential solution to these challenges. Previous research has shown that large, clinically relevant cardiac tissues can be fabricated and engrafted onto animal hearts, where they maintain their structural and electrical properties, undergo vascularization, and improve cardiac function. However, tissue-engineered cardiac patches are primarily applied to the epicardial surface of the heart, and few examples of intraventricular implantation exist.
In this work, we developed an implantable, intraventricular cardiac patch by reinforcing EHTs with 3D-printed polycaprolactone (PCL) materials. A key challenge in designing intraventricular cardiac patches is balancing the biological compatibility of soft materials with the mechanical robustness required for implantation. To address this, we utilized volumetric 3D printing (VP) to fabricate a porous PCL metamaterial that could be infiltrated with a cell-laden hydrogel and provide tunable mechanical properties that match the myocardium. We combined our metamaterial with a hydrogel-infiltrated melt-electrowritten (MEW) mesh, which reduces permeability and enables patch implantation via suturing. This multi-material design enabled the patch to be implanted in an acute large animal trial, where it withstood intraventricular pressure, prevented bleeding, and enabled hemodynamic restabilization (partial restoration of blood pressure and heart rate), demonstrating its potential for myocardial defect repair.
Calorie Restriction is Protective in the Context of Chronic Kidney Disease
https://www.fightaging.org/archives/2025/08/calorie-restriction-is-protective-in-the-context-of-chronic-kidney-disease/
The practice of calorie restriction involves eating fewer calories while still obtaining at least adequate levels of micronutrients. Mild calorie restriction might be a 10% reduction from recommended calorie levels, but as much as 40% is possible given sufficient diligence and attention to the details. Calorie restriction induces sweeping metabolic changes that collectively act to improve cell and tissue function. The present consensus is that the most important of these changes is enhanced autophagy. Autophagy is a collection of maintenance processes responsible for recycling damaged proteins and structures in the cell. In near all species assessed to date, calorie restriction slows aging and improves health.
Diet influences disease progression, yet the effects of fasting on acute kidney injury (AKI) and its transition to chronic kidney disease (CKD) remain unclear. This study evaluated fasting-mimicking diet (FMD) cycles versus ad libitum feeding in murine models of AKI and CKD induced by aristolochic acid or folic acid.
FMD significantly reduced serum creatinine, kidney injury, and maladaptive repair marker expression, and promoted faster recovery. It also lowered renal cytokines and pro-fibrotic genes, reduced CCL2 levels, and decreased monocyte recruitment while favoring protective monocyte phenotypes. Cycles of caloric restriction yielded similar nephroprotection. Initiating FMD at the peak of AKI enhanced repair and attenuated inflammation.
Inhibition of CCR2 abolished FMD's protective effects, implicating the CCL2/CCR2 axis in mediating its benefits. However, broader anti-inflammatory actions may also contribute, and reduced CCL2 may reflect downstream effects. These findings highlight the potential of dietary interventions to modulate kidney injury and inflammation in AKI and CKD.
View the full article at FightAging
