Izumi Yanatori, Tasuku Hirayama, Raku Son ...
· The EMBO journal
· Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. [email protected].
· pubmed
Iron accumulation is a conserved hallmark of cellular as well as organismal aging, yet its mechanistic role in senescence remains largely elusive. Here we show that the accumulation of ferrous iron (Fe
Iron accumulation is a conserved hallmark of cellular as well as organismal aging, yet its mechanistic role in senescence remains largely elusive. Here we show that the accumulation of ferrous iron (Fe
Longevity Relevance Analysis
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The paper demonstrates that lysosomal sequestration of ferrous iron, mediated by cholesterol shielding, drives cellular senescence while conferring resistance to ferroptosis. This work is highly relevant because it identifies a specific mechanistic link between a conserved hallmark of aging (iron accumulation) and the cellular state of senescence, offering a potential target for interventions aimed at delaying the functional decline associated with aging rather than merely treating downstream symptoms.
Zecheng Liu, Guoxing Zhu, Yuhan Zeng ...
· Microbiology spectrum
· Center for Environment and Health in Water Source Area of South-to-North Water Diversion, School of Public Health, Hubei University of Medicine, Shiyan, Hubei, China.
· pubmed
Atp12 is known as a chaperone for mitochondrial ATP synthase assembly, yet its functions and mechanisms in regulating mitochondrial and cellular aging remain elusive. In this study, we demonstrate that Atp12 plays a critical role in regulating mitochondrial dynamics and chronolog...
Atp12 is known as a chaperone for mitochondrial ATP synthase assembly, yet its functions and mechanisms in regulating mitochondrial and cellular aging remain elusive. In this study, we demonstrate that Atp12 plays a critical role in regulating mitochondrial dynamics and chronological lifespan (CLS) in the fission yeast
Longevity Relevance Analysis
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Atp12 regulates mitochondrial fusion and chronological lifespan in fission yeast through the interaction with Fzo1. This paper is relevant because it identifies a specific molecular mechanism (Atp12/Fzo1 interaction) governing mitochondrial dynamics that directly influences chronological lifespan, a fundamental model for studying cellular aging and the root causes of senescence.
Amit K Dey, Bradley Olinger, Mozhgan Boroumand, ★ Rafael de Cabo ...
· Nature aging
· Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
· pubmed
Assessing and validating circulating biomarkers is essential for developing preclinical measures of biological aging in mice. However, comprehensive serum proteomics are limited by technical challenges and low sample volumes. Here we present a quantitative nanoparticle-based enri...
Assessing and validating circulating biomarkers is essential for developing preclinical measures of biological aging in mice. However, comprehensive serum proteomics are limited by technical challenges and low sample volumes. Here we present a quantitative nanoparticle-based enrichment workflow coupled with data-independent acquisition mass spectrometry for deep proteomic profiling of low-volume mouse serum. This approach increased proteomic coverage by 3-6-fold with median coefficient of variation <10%. In 30 mice aged 12, 24 and 30 months, we uncovered 3,992 protein groups from 20 µl of serum and revealed age- and sex-specific changes, and capturing senescence-associated circulating proteins. With 1 µl additional serum,the proximity extension assay quantified 43 cytokines not detected by mass spectrometry. Comparison with plasma proteomics from the Baltimore Longitudinal Study of Aging identified conserved age-associated circulating proteins, several of which were linked to frailty in humans, notably COL6A3. These results establish a scalable approach for discovering aging biomarkers in sample-limited mouse studies with translational relevance to human health.
Longevity Relevance Analysis
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The paper demonstrates that a nanoparticle-based enrichment workflow coupled with data-independent acquisition mass spectrometry can achieve deep proteomic profiling of low-volume mouse serum, identifying age- and sex-specific changes and conserved human aging biomarkers. This is relevant because it provides a scalable, high-sensitivity technical method for discovering circulating biomarkers of biological aging in preclinical models, which is essential for validating interventions that target the root causes of aging, although the study itself is primarily methodological and cross-sectional rather than demonstrating a lifespan-extending intervention.
Chisaka Kuehnemann, Samantha T Jezak, Bronwyn A Mogck ...
· Cell
· Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
· pubmed
When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such responses are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here, we show that senescent cells increase import and membr...
When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such responses are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here, we show that senescent cells increase import and membrane levels of multiple polyunsaturated fatty acids (PUFAs), but a specific intermediate PUFA, dihomo-gamma-linolenic acid (DGLA, 20:3ω-6), is reduced. Exogenous repletion of DGLA instead results in cell death by ferroptosis. Senescent cells manifest additional features associated with ferroptosis, including labile iron and expression of lipoxygenases as well as low-level membrane peroxidation. Oral DGLA supplementation lowers markers of senescence in aged mice and improves age-related functional outcomes. Finally, obese humans with lowered DGLA desaturation rates have lower markers of adipose tissue senescence. Together, our data implicate shifts in PUFA metabolism as a driver of decisions between senescence and ferroptosis.
Longevity Relevance Analysis
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The paper claims that the specific reduction of the polyunsaturated fatty acid DGLA in senescent cells drives the cellular decision toward senescence rather than ferroptosis, and that restoring DGLA levels can reverse senescence markers and improve age-related functional outcomes. This is highly relevant to longevity research because it identifies a specific metabolic mechanism (PUFA desaturation) that acts as a switch between two distinct cell fates, offering a potential therapeutic target to prevent or reverse cellular senescence, a core driver of biological aging, rather than merely treating downstream symptoms.
Xiaoming Huang, Yanfang Yang, Feng Huang ...
· Catechin
· Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
· pubmed
Epigallocatechin gallate (EGCG), a major tea polyphenol, has been proposed to promote healthy aging, but population-level evidence and underlying mechanisms remain unclear. We analyzed 10,977 participants from the National Health and Nutrition Examination Survey (NHANES) and cond...
Epigallocatechin gallate (EGCG), a major tea polyphenol, has been proposed to promote healthy aging, but population-level evidence and underlying mechanisms remain unclear. We analyzed 10,977 participants from the National Health and Nutrition Examination Survey (NHANES) and conducted mechanistic studies in Caenorhabditis elegans and AML12 hepatocytes. Compared with non-consumers, both lower and higher EGCG intake categories were associated with lower PhenoAge acceleration, lower all-cause mortality, and higher estimated residual life expectancy. In C. elegans, EGCG supplementation extended lifespan and health span. Transcriptomics revealed upregulation of peroxisome-related genes. EGCG enhanced peroxisome biogenesis, as shown by increased peroxisome abundance, elevated prx-5 and prx-19 mRNA levels, and increases in PRX-5 and PRX-19 proteins. This increase in peroxisome capacity was accompanied by enhanced peroxisomal fatty acid β-oxidation, with increased mRNA levels of acox-1.2, acox-3, and dhs-28, increased ACOX-3 protein, and reduced very long-chain fatty acids (VLCFAs). Lipidomics showed enhanced processing of VLCFAs and accumulation of shorter-chain intermediates. Knockdown of prx-5, acox-1.2, or dhs-28 abolished EGCG-induced lifespan and health span benefits. In doxorubicin-induced senescent AML12 hepatocytes, EGCG reduced the proportion of SA-β-gal-positive cells and decreased p21 and p16 protein levels, while increasing peroxisome abundance and peroxisome-related proteins, including the biogenesis factors PEX5 and PEX19, the membrane transporters ABCD1 and PMP70, and the β-oxidation enzymes ACOX1, HSD17B4, EHHADH, and ACAA1. Conversely, the anti-senescent effects of EGCG were attenuated by Pex5 or Acox1 knockdown. Collectively, dietary EGCG intake is associated with slower biological aging, while experimental findings support peroxisome biogenesis and peroxisomal fatty acid β-oxidation in EGCG-mediated anti-aging effects.
Longevity Relevance Analysis
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The paper claims that dietary EGCG extends lifespan and delays biological aging by activating peroxisome biogenesis and enhancing peroxisomal fatty acid β-oxidation. This is relevant because it identifies a specific cellular mechanism (peroxisome function) through which a common dietary compound may mitigate aging processes, supported by both large-scale epidemiological data and mechanistic validation in model organisms.
Ke Cheng, Yaru Wang, Yueyuan Pan ...
· Heterochromatin
· Stem Cell Research Center, Shantou University Medical College, Shantou, China.
· pubmed
Chromatin stability and nuclear architectural integrity constitute the primary defense against cellular senescence. Their collapse precipitates genomic disarray, epigenetic misregulation, and functional decline in stem cells. Although TOP2A is conventionally known for resolving D...
Chromatin stability and nuclear architectural integrity constitute the primary defense against cellular senescence. Their collapse precipitates genomic disarray, epigenetic misregulation, and functional decline in stem cells. Although TOP2A is conventionally known for resolving DNA topological stress, its role in aging remains largely unexplored. Here, we found that TOP2A expression progressively decreased in senescent mesenchymal stem cells (MSCs), and its depletion initiated a catastrophic nuclear remodeling process characterized by the loss of Lamin B1, heterochromatin erosion, and senescence-associated phenotypes. Mechanistically, TOP2A directly regulated the expression of Lamin B1 to maintain nuclear architecture. TOP2A depletion set off a domino effect involving nuclear membrane rupture, loss of heterochromatin-associated factors (H3K9me3, KAP1, and LAP2), deterioration of cellular functions and acceleration of senescence. Notably, overexpression of TOP2A restored Lamin B1 levels, mitigated nuclear protein loss, preserved nuclear integrity, and counteracted cellular senescence. The in vivo relevance of these findings was further underscored by TOP2A inhibitor-induced brain aging in murine models. Our study establishes TOP2A as a novel modulator of cellular senescence, which stabilizes heterochromatin and nuclear structure, and provides new perspectives for targeting chromatin-based mechanisms in aging.
Longevity Relevance Analysis
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TOP2A maintains heterochromatin stability and counteracts cellular senescence by directly sustaining LMNB1 expression. This paper is relevant because it identifies a specific molecular mechanism (TOP2A-LMNB1 axis) that preserves nuclear architecture and prevents the chromatin collapse associated with the aging process, offering a potential target for interventions aimed at delaying senescence.
A Kafka, L Becker, H Hauner ...
· Herz
· School of Medicine and Health, Technical University of Munich, Munich, Germany.
· pubmed
Age is the strongest risk factor for cardiovascular disease, yet biological aging is increasingly recognized as a modifiable process. Animal studies over the past few decades have demonstrated that genetic, pharmacological, and dietary interventions can extend the healthspan and ...
Age is the strongest risk factor for cardiovascular disease, yet biological aging is increasingly recognized as a modifiable process. Animal studies over the past few decades have demonstrated that genetic, pharmacological, and dietary interventions can extend the healthspan and lifespan of animals by targeting conserved mechanisms of aging. Examining whether lifespan-extending interventions work in humans is challenging due to the long lifespan of our species. However, the development of biomarkers of biological aging or "aging clocks" has allowed for human trials where the rate of biological aging can be estimated. These surrogate markers now enable the first generation of human geroscience trials, in which interventions such as caloric restriction, rapamycin, taurine, plasma exchange, or nutritional strategies are evaluated for their ability to slow biological aging. Particularly relevant for cardiology are recently developed organ- and cell-specific aging clocks that estimate the biological age of the heart, vasculature, and cardiovascular cell types. These biomarkers may be suitable for improving cardiovascular risk prediction and providing surrogate outcomes for trials targeting cardiovascular aging. Together, these advances suggest that slowing biological aging could complement established cardiovascular prevention and treatment strategies in the future.
Longevity Relevance Analysis
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The paper posits that biological aging is a modifiable risk factor for cardiovascular disease and that organ-specific aging clocks can serve as surrogate endpoints for geroscience trials. This is a review article summarizing existing concepts in geroscience and cardiovascular aging rather than presenting novel experimental data or a breakthrough mechanism, making it a solid but limited contribution to the field.
Hironobu Ikehata, Masayuki Yamamoto
· Mutagenesis
· Department of Medical Biochemistry, Tohoku University Graduate School of Medicine.
· pubmed
Our body is continuously exposed to endogenous and exogenous sources of oxidative stress arising from physiological metabolism and environmental factors such as ultraviolet (UV) radiation. These stresses generate reactive oxygen species (ROS) that can induce genotoxicity through ...
Our body is continuously exposed to endogenous and exogenous sources of oxidative stress arising from physiological metabolism and environmental factors such as ultraviolet (UV) radiation. These stresses generate reactive oxygen species (ROS) that can induce genotoxicity through oxidative DNA damage. To evaluate the contribution of NRF2, which is a master transcription factor regulating cellular antioxidant responses, to the suppression of oxidative stress-induced genotoxicity in the skin, we examined Nrf2-deficient mice regarding mutagenic responses to two separate biological situations: acute UVB exposures and the chronic process of aging. Analyses were performed using transgenic mice carrying the bacterial lacZ gene as a mutational reporter. No significant differences were detected between Nrf2-deficient and wild-type mice in mutagenicity, induced mutation spectrum, and mutation distribution within the reporter gene after acute UVB exposure, whereas the dose-response kinetics of UVB-induced mutation in the phase called "mutation induction suppression" (MIS) differed significantly between genotypes, with a more pronounced MIS response observed in the Nrf2-/- epidermis. Little contribution of ROS to genotoxicity was observed after the acute exposure. Notably, however, the age-dependent accumulation of mutations was significantly elevated in the Nrf2-deficient epidermis compared to the wild-type. These findings indicate that NRF2 plays a protective role for the skin, not by directly preventing genotoxicity, but by promoting tissue recovery after acute UVB damage and, more importantly, by suppressing the genotoxic effects of physiologically produced ROS in a chronic aging process.
Longevity Relevance Analysis
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NRF2 suppresses age-dependent mutation accumulation in skin epidermis by mitigating chronic oxidative stress rather than preventing acute UVB-induced genotoxicity. This study provides mechanistic evidence that NRF2 is a critical regulator of the mutational burden associated with the aging process, identifying it as a potential target for interventions aimed at slowing the accumulation of somatic mutations that drive age-related decline.
Yang Yu, Yuying Bai, Taihu Wan ...
· Ageing research reviews
· Department of Hepatobiliary and Pancreatic Surgery，China-Japan Union Hospital of Jilin University，Jilin University, Changchun, 130000, China. Electronic address: [email protected].
· pubmed
The major characteristics of cellular senescence are stable cell-cycle arrest, accumulation of DNA damage responses, mitochondrial dysfunction, metabolic remodeling, and the release of pro-inflammatory senescence-associated secretory phenotype (SASP) factors. Redox imbalance play...
The major characteristics of cellular senescence are stable cell-cycle arrest, accumulation of DNA damage responses, mitochondrial dysfunction, metabolic remodeling, and the release of pro-inflammatory senescence-associated secretory phenotype (SASP) factors. Redox imbalance plays a significant role in the initiation and maintenance of senescence, and the mammalian thioredoxin system-comprising cytosolic Trx-1, mitochondrial Trx-2, thioredoxin reductases (TrxR1, TrxR2), and the inhibitor TXNIP-is at a key juncture between oxidative stress, cellular ageing, and age-related diseases. Evidence was identified through a structured literature search of PubMed, Web of Science, and Scopus from inception to July 2026 using predefined search terms and eligibility criteria. Primary experimental studies in mammalian cells, tissues, or animal models that directly measured senescence markers were prioritised. Reviews, non-mammalian studies, and studies reporting only general oxidative-stress endpoints were included only when they provided essential mechanistic context and are clearly labelled as such. This review focuses primarily on mammalian mechanisms linking the thioredoxin system to senescence initiation, senescence maintenance, inflammaging, tissue dysfunction, and translational geroscience. We distinguish isoform-specific and context-dependent effects of Trx-1, Trx-2, TrxR, and TXNIP. We also discuss therapeutic strategies targeting the thioredoxin system, including redox modulation, isoform-selective inhibitors, senomorphic approaches, and disease-specific interventions. Overall, the thioredoxin system is a significant molecular link between redox homeostasis, cellular senescence, ageing biology, and age-related pathology, and a candidate target for future geroscience interventions, although direct evidence in aged mammals remains limited.
Longevity Relevance Analysis
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The thioredoxin system acts as a critical molecular link between redox homeostasis and cellular senescence, representing a viable target for geroscience interventions. This review synthesizes existing evidence on how manipulating this specific redox pathway could influence the initiation and maintenance of senescence, offering a mechanistic framework for potential anti-aging therapies, though it remains a descriptive summary rather than a primary breakthrough.
Larissa Traxler, Lukas Karbacher, Oliver Borgogno ...
· Fibroblasts
· Department of Neurosciences, University of California San Diego, La Jolla, California, USA.
· pubmed
Biological aging drives cellular dysfunction and human disease, yet studying human aging dynamics remains challenging due to limited experimental platforms. Here we show that long-term post-mitotic culture of human fibroblasts recapitulates and accelerates features of in vivo agi...
Biological aging drives cellular dysfunction and human disease, yet studying human aging dynamics remains challenging due to limited experimental platforms. Here we show that long-term post-mitotic culture of human fibroblasts recapitulates and accelerates features of in vivo aging. Longitudinal paired transcriptomic and epigenetic analyses of four female fibroblast lines revealed that in vitro aging reflects key signatures of in vivo primary fibroblast aging. Direct neuronal conversion of in vitro-aged fibroblasts preserved biological age, enabling pseudo-longitudinal modeling of neuronal aging through direct reprogramming. Single-cell transcriptomics of in vitro-aging fibroblasts revealed a time-dependent increase in age-heterogeneity, consistent with the previously reported age-associated heterogeneity driven by the variable loss of transcriptional programs in vivo. Using this accelerated aging platform, we evaluated anti-aging compounds: Metformin broadly attenuated transcriptomic and epigenetic aging, while Rapamycin showed limited efficacy. These findings align with pre-clinical evidence, providing a platform to evaluate and predict therapeutic anti-aging compound efficacy at molecular resolution. This system advances our understanding of aging mechanisms and facilitates the development of interventions against age-related diseases.
Longevity Relevance Analysis
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Long-term post-mitotic culture of human fibroblasts recapitulates in vivo aging signatures and enables the evaluation of anti-aging compounds like Metformin. This is relevant because it provides a scalable, human-specific platform to test interventions against the root causes of aging, although the use of fibroblasts and the limited efficacy of Rapamycin suggest it is a solid but incremental advance in aging research tools rather than a major breakthrough.
Satomi Miwa, Olena Kucheryavenko, Kristin Herrmann ...
· Longevity
· Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
· pubmed
Efforts to extend longevity and healthspan have benefited from the use of in vitro systems, short-lived model organisms and computational approaches, but translation to humans depends on demonstrating efficacy and safety in mammalian in vivo models. However, rigorously controlled...
Efforts to extend longevity and healthspan have benefited from the use of in vitro systems, short-lived model organisms and computational approaches, but translation to humans depends on demonstrating efficacy and safety in mammalian in vivo models. However, rigorously controlled rodent lifespan studies are slow, costly and low-throughput. Hormesis, the induction of adaptive stress response pathways by low-level toxic or metabolic challenges, provides a mechanistic means for improved resilience, but testing hormetic dose-response relationships in mammals is logistically challenging. Regulatory long-term toxicity studies, mandated for chemical authorisation, routinely generate lifespan and chronic toxicity data from large cohorts across multiple dose groups and therefore represent an underused resource for detecting unexpected survival benefits. We mined a random subset of the German Federal Institute for Risk Assessment (BfR) electronic archive for long-term rodent pesticide studies in ≥ 50 animals per dose and sex. From qualifying studies with 154 substances, we identified 27 substances (18% of entries) that significantly increased survival at study termination (≥ 10%, p < 0.05). Fifteen publicly disclosable substances were examined further; roughly half perturbed mitochondrial oxygen consumption rates in mammalian cells, and bromoxynil acted as a mitochondrial uncoupler. Back-translation to Caenorhabditis elegans showed bromoxynil improved multiple healthspan indicators without compromising organismal health. Regulatory toxicity archives can thus be repurposed to identify candidate compounds, targets and mechanisms for mammalian healthy ageing research, complement conventional screening pipelines, align with 3Rs by maximising existing data, and supply high-quality datasets for AI-driven prioritisation of interventions for rigorous preclinical follow-up.
Longevity Relevance Analysis
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The paper claims that mining existing regulatory rodent toxicity archives can identify candidate compounds with hormetic longevity effects, specifically highlighting bromoxynil as a mitochondrial uncoupler that improves healthspan in C. elegans. This is relevant because it proposes a novel, high-throughput method for discovering mammalian longevity agents by repurposing existing safety data, thereby bypassing the need for new, costly lifespan studies for initial screening.
Wenlong Wang, Kai Pan, Andy X Li ...
· Advanced healthcare materials
· Medical College, Qingdao University, Qingdao, China.
· pubmed
Mesenchymal stem cells (MSCs) are widely used to modulate immune responses and promote tissue regeneration, but cellular senescence significantly impairs their therapeutic potential. MSCs undergo senescence characterized by an enlarged morphology, reduced proliferative capacity, ...
Mesenchymal stem cells (MSCs) are widely used to modulate immune responses and promote tissue regeneration, but cellular senescence significantly impairs their therapeutic potential. MSCs undergo senescence characterized by an enlarged morphology, reduced proliferative capacity, and altered expression of genes related to the cytoskeleton. This study revealed that the mechanical microenvironment critically regulates MSC aging. Culturing senescent MSCs on high-stiffness extracellular matrix (ECM) hydrogels reverses key aspects of the senescent phenotype, including the restoration of normal morphology, improved cytoskeletal integrity, and enhanced proliferation. This mechanical rescue is accompanied by genetic reprogramming and activation of the PI3K-AKT signaling pathway. The inhibition of PI3K-Akt with LY294002 abolished these rejuvenating effects. These findings demonstrate that the mechanical microenvironment can reprogram senescent MSCs through PI3K-AKT-mediated mechanotransduction, offering a novel strategy to restore stem cell function in aging and regenerative medicine.
Longevity Relevance Analysis
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Culturing senescent mesenchymal stem cells on high-stiffness extracellular matrix hydrogels reverses key aspects of the senescent phenotype via PI3K-AKT signaling. This is relevant because it identifies a specific mechanotransduction pathway that can reverse cellular senescence, a fundamental hallmark of aging, offering a potential strategy to restore stem cell function in aged tissues.
Bhat, A. S., Kokko, H.
· ecology
· Johannes Gutenberg University, Mainz, Germany
· biorxiv
Most organisms become increasingly likely to die as they grow older, a phenomenon known as demographic senescence. We develop a general mathematical framework for modelling senescence in which individuals are viewed as comprising a fixed number of interacting intra-organismal sub...
Most organisms become increasingly likely to die as they grow older, a phenomenon known as demographic senescence. We develop a general mathematical framework for modelling senescence in which individuals are viewed as comprising a fixed number of interacting intra-organismal sub-systems, each characterised by stochastic failure and repair rates. In many organisms, `failure begets failure' because sub-systems are typically interdependent. We use diffusion approximations to derive an expression for population-level mortality curves in this setting, and demonstrate that greater interdependence leads to faster rates of senescence. Since individuals who die can no longer age, observed cohorts become increasingly composed of `lucky' individuals that avoided death by (stochastically) taking paths in failure space associated with lower mortality despite no intrinsic differences in their quality. Selective disappearance of `unlucky' individuals generates deviations of population-level measurements from individual-level trajectories, causing late-life mortality plateaus. We show that while these deviations must always exist, they may often be too small to detect, either because the failure accumulation process is stereotyped or because detection requires unreasonably large cohort sizes. We provide necessary and asymptotically sufficient conditions for Gompertz-Makeham mortality in our framework, with falsifiable predictions in terms of a scaling law for mortality near complete failure. We also show that the simplest null model in our framework leads to exact Gompertz-Makeham curves. Our work establishes a general framework for modelling demographic senescence and selective disappearance from biological first principles, and provides concrete predictions for when Gompertz-Makeham mortality emerges in such models.
Longevity Relevance Analysis
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The paper demonstrates that stochastic failure accumulation in interdependent sub-systems naturally generates Gompertz-Makeham mortality curves and late-life mortality plateaus through selective disappearance. This is relevant because it provides a fundamental mathematical framework for understanding the root causes of demographic senescence and the emergence of mortality patterns, rather than focusing on symptomatic treatments or social aspects of aging.
Shi-Ying Li, Qi Peng, Hui Cai ...
· Journal of advanced research
· Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Key Laboratory of Medical Electrophysiology of Ministry of Education School of Pharmacy Southwest Medical University, Luzhou, Sichuan 646000, China.
· pubmed
Cellular senescence contributes to age-related tissue dysfunction and is closely linked to metabolic remodeling and mitochondrial redox imbalance. However, senotherapeutic strategies with defined molecular targets and functionally validated downstream mechanisms remain limited.
Cellular senescence contributes to age-related tissue dysfunction and is closely linked to metabolic remodeling and mitochondrial redox imbalance. However, senotherapeutic strategies with defined molecular targets and functionally validated downstream mechanisms remain limited.
Longevity Relevance Analysis
(3)
Ziyu glycoside I suppresses cellular senescence and ameliorates age-related functional decline by stabilizing LDHA and restoring lactate output. This paper is relevant because it identifies a specific molecular mechanism (LDHA stabilization) and a potential senotherapeutic agent that targets the root cause of aging (cellular senescence) rather than just treating downstream symptoms.
YuJuan Zhou, Xinshu Wang, Jiyuan Zhang ...
· Sirtuin 1
· State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
· pubmed
The deacetylase SIRT1 is a critical regulator of cellular senescence, and the excessive accumulation of senescent cells can further drive the onset of organismal aging. SIRT1 activity is tightly governed by posttranslational modifications, including ubiquitination. While ubiquiti...
The deacetylase SIRT1 is a critical regulator of cellular senescence, and the excessive accumulation of senescent cells can further drive the onset of organismal aging. SIRT1 activity is tightly governed by posttranslational modifications, including ubiquitination. While ubiquitination has been well documented to control SIRT1 protein stability, the precise regulatory pathway underlying SIRT1 activity remains poorly understood. Here, we identify the deubiquitinase USP25 as a central regulator of cellular senescence. Specifically, USP25 deficiency in mice mitigates age-related phenotypes and improves overall physiological function. Mechanistically, USP25 directly interacts with SIRT1 and mediates its deubiquitylation via K63-linked polyubiquitination, specifically targeting SIRT1 lysine residues K506 and K513, which ultimately suppresses SIRT1 deacetylase activity. Reduced SIRT1 deacetylase activity, in turn, increases P53 or PGC1α acetylation, which further increases the transcriptional activation of downstream target genes and consequently accelerates cellular senescence. Furthermore, we developed a cell-penetrating peptide, pSirt1-4, that efficiently disrupts the USP25-SIRT1 interaction, increases SIRT1 deacetylase activity, and attenuates cellular senescence. Collectively, our findings establish USP25 as a critical regulator of aging and highlight the USP25-SIRT1 axis as a promising therapeutic target for treating senescence-related diseases.
Longevity Relevance Analysis
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The paper claims that disrupting the USP25-SIRT1 interaction via a novel peptide activates SIRT1 deacetylase activity, thereby suppressing cellular senescence and mitigating age-related phenotypes in mice. This is relevant to longevity research as it identifies a specific molecular mechanism (USP25-mediated deubiquitination) regulating SIRT1, a known longevity gene, and proposes a direct therapeutic intervention to reduce senescent cell burden, which is a root cause of aging.
Anna Reale, Dario Di Bari, Katsiaryna Karpach ...
· Experimental gerontology
· Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy. Electronic address: [email protected].
· pubmed
Quantifying biological aging and predicting age-related functional decline are increasingly important for reducing the health and socioeconomic burden of population aging. DNA methylation is one of the most extensively studied epigenetic features of aging and underlies epigenetic...
Quantifying biological aging and predicting age-related functional decline are increasingly important for reducing the health and socioeconomic burden of population aging. DNA methylation is one of the most extensively studied epigenetic features of aging and underlies epigenetic clocks, promising quantitative biomarkers of biological age. However, the molecular processes driving age-associated DNA methylation changes and the biological signals captured by these clocks remain unclear. A major unresolved issue is the contribution of oxidized 5-methylcytosine (5mC) derivatives to epigenetic remodeling during aging. These derivatives, including 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine, are generated through TET-mediated oxidation of 5mC. Although they can act as intermediates of DNA demethylation, they may also represent epigenetic signals with regulatory functions distinct from 5mC. This review summarizes current evidence on oxidized 5mC derivatives in mammalian aging, focusing on 5hmC. Aging is associated with context-dependent changes in global 5hmC levels and genome-wide distribution. Age-associated differentially hydroxymethylated regions occur in genes, regulatory elements, repetitive sequences and transposable elements. 5hmC and 5mC changes often show distinct genomic distributions, suggesting partially independent epigenetic processes. 5hmC may regulate transcriptional stability, cellular identity, inflammation and tissue vulnerability. Understanding the TET/5hmC pathway may improve interpretation of epigenetic aging and support 5hmC-based clocks and healthy-aging strategies.
Longevity Relevance Analysis
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The paper reviews evidence that 5-hydroxymethylcytosine (5hmC) undergoes distinct, context-dependent changes during aging that are partially independent of 5mC, suggesting it captures unique biological signals for epigenetic clocks. This is relevant because it addresses the fundamental molecular mechanisms of epigenetic aging and proposes 5hmC as a potential biomarker for biological age, which is central to understanding and potentially intervening in the aging process, though as a review it offers no new experimental data or direct interventions.
Takafumi Ogawa, Masaki Mizunuma
· Journal of biochemistry
· Unit of Biotechnology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
· pubmed
SKN-1, a Cap'n'Collar transcription factor in Caenorhabditis elegans, is a well-established regulator of oxidative stress responses and xenobiotic detoxification. Over the past two decades, the late Dr. T. Keith Blackwell (1957-2025) and colleagues made seminal contributions to d...
SKN-1, a Cap'n'Collar transcription factor in Caenorhabditis elegans, is a well-established regulator of oxidative stress responses and xenobiotic detoxification. Over the past two decades, the late Dr. T. Keith Blackwell (1957-2025) and colleagues made seminal contributions to defining its biological functions and regulatory mechanisms. Owing to its robust conservation with mammalian Nrf family proteins, SKN-1 research has yielded fundamental insights into how nutrient and stress signals modulate metabolism, proteostasis, and aging. Recently, the discovery that distinct SKN-1 isoforms execute unique physiological roles has further refined this field. In this review, we summarize how SKN-1 regulates longevity, particularly through the mTOR nutrient-sensing pathway, discuss recent advances in isoform-specific regulation, and highlight critical questions for future research.
Longevity Relevance Analysis
(3)
Distinct SKN-1 isoforms regulate C. elegans longevity through specific interactions with the mTOR nutrient-sensing pathway. This review synthesizes existing knowledge on how isoform-specific regulation of the Nrf2 homolog SKN-1 modulates aging via mTOR signaling, providing a mechanistic framework for understanding conserved longevity pathways, though as a review it offers no new experimental data or breakthroughs.
Wenyu Zhang, Koichiro Kako, Hiroaki Daitoku ...
· Bioscience, biotechnology, and biochemistry
· Doctoral Program in Life and Agricultural Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan.
· pubmed
Protein arginine methyltransferase 7 (PRMT-7) contributes approximately 30% of total protein arginine monomethylation in Caenorhabditis elegans. Loss of prmt-7 extended lifespan without affecting brood size. However, prmt-7 mutants showed reduced heat-stress resistance, and trans...
Protein arginine methyltransferase 7 (PRMT-7) contributes approximately 30% of total protein arginine monomethylation in Caenorhabditis elegans. Loss of prmt-7 extended lifespan without affecting brood size. However, prmt-7 mutants showed reduced heat-stress resistance, and transient heat stress did not further extend their lifespan, suggesting distinct roles for PRMT-7 in longevity and heat-stress adaptation.
Longevity Relevance Analysis
(3)
Loss of PRMT-7 extends lifespan in C. elegans while simultaneously impairing heat-stress resistance, indicating that the molecular pathways governing longevity and stress adaptation are distinct. This study contributes to the understanding of the genetic and epigenetic mechanisms underlying aging by identifying a specific methyltransferase that influences lifespan independently of general stress resilience, offering a new target for investigating the root causes of aging.
Justin T Millares-Cangiani, Juan D Rayo Parra, Zachary Grand ...
· Mechanisms of ageing and development
· Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8(th) Street AHC2, Miami, FL 33199, USA.
· pubmed
Cellular senescence is a biological process characterized by stable cell cycle arrest that contributes to tumor suppression and tissue remodeling but can also promote aging-associated dysfunction when senescent cells persist and accumulate. Senescent cells influence neighboring a...
Cellular senescence is a biological process characterized by stable cell cycle arrest that contributes to tumor suppression and tissue remodeling but can also promote aging-associated dysfunction when senescent cells persist and accumulate. Senescent cells influence neighboring and distant tissues through the senescence-associated secretory phenotype (SASP), of which extracellular vesicles (EVs) are an increasingly recognized component. This review examines how microRNAs (miRNAs) carried by EVs regulate senescence and ageing. miRNAs are key post-transcriptional regulators of senescence, particularly within the p53/p21
Longevity Relevance Analysis
(3)
The paper reviews how microRNA-loaded extracellular vesicles mediate the senescence-associated secretory phenotype (SASP) to propagate aging signals. This is relevant because it addresses the mechanism of senescent cell accumulation and its systemic effects, which are considered root causes of aging, though as a review article it provides a synthesis of existing knowledge rather than a novel breakthrough.
Zhe Li, Ying Li, Lei Sui ...
· Ageing research reviews
· State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China; Department of Stomatology, Air Force Medical Center, Beijing, 100142, China. Electronic address: [email protected].
· pubmed
Bone marrow macrophages (BMMs) coordinate skeletal remodelling, haematopoietic niche function, immune surveillance, and tissue repair. Whether a persistent senescent state in BMMs is a causal driver of skeletal ageing, however, remains unresolved. The central challenge is both de...
Bone marrow macrophages (BMMs) coordinate skeletal remodelling, haematopoietic niche function, immune surveillance, and tissue repair. Whether a persistent senescent state in BMMs is a causal driver of skeletal ageing, however, remains unresolved. The central challenge is both definitional and causal: macrophages may be quiescent, terminally differentiated, chronically activated, tolerant, or metabolically dysfunctional, whereas commonly used senescence markers-including p16
Longevity Relevance Analysis
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The paper investigates whether a persistent senescent state in bone marrow macrophages is a causal driver of skeletal aging and systemic consequences. This is relevant to longevity research because it addresses the cellular mechanisms of aging (senescence) and their role in tissue degeneration, rather than merely treating the symptoms of osteoporosis or bone loss.
Toros, A., Pettersson, M. E., Fuentes-Pardo, A. P. ...
· evolutionary biology
· University of Uppsala
· biorxiv
Insights into the genetic basis of lifespan evolution can link evolutionary theory with an understanding of health, disease and adaptation. We leverage the power of >200 generations of experimental evolution in a seed beetle to unveil the genomic architecture of lifespan evolutio...
Insights into the genetic basis of lifespan evolution can link evolutionary theory with an understanding of health, disease and adaptation. We leverage the power of >200 generations of experimental evolution in a seed beetle to unveil the genomic architecture of lifespan evolution. Replicated populations evolved under regimes favoring either a short or long life, resulting in a near doubling of lifespan. Whole genome re-sequencing revealed that short- and long-lived lines were strongly differentiated (global FST = 0.41) and more than 700 genes showed consistent signs of divergent selection. Remarkably, short- and long-lived lines were consistently divergent in a large number of regions harboring copy-number variants (CNVs), involving >600 genes. The evolution of a long life involved many distinct biological processes, such as DNA fidelity, mitotic integrity, reproduction, metabolism, immunity and stress response. A pedigree-based genome scan for quantitative trait loci (QTLs) uncovered several QTLs with large effects on lifespan, but the genetic basis of a long life was dominated by a very large number of regions with medium and small effects. The genome-wide spatial association with QTL effects was, if anything, stronger for CNVs than for sequence variants. The genetic effects of QTLs on lifespan were positively correlated overall between the sexes, but four regions showed pronounced sex-differences. Our results show that structural variants play a significant role in the evolution of an extended lifespan and the highly polygenic genomic architecture is to some extent sex-specific, consistent with differences in physiology and life history tradeoffs between the sexes.
Longevity Relevance Analysis
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The paper demonstrates that structural variants, particularly copy-number variants, and sex-specific genetic effects play a significant role in the evolutionary adaptation of lifespan. This is relevant because it identifies specific genomic mechanisms (CNVs) and sex-specific trade-offs that drive the evolution of longevity, providing a foundational understanding of the genetic architecture necessary for extending lifespan.
Kurbaj, J. M., Ataei, R., Simon, A. F.
· neuroscience
· University of Western Ontario
· biorxiv
Neuroligins are conserved postsynaptic adhesion proteins involved in synaptic function and behaviour. In Drosophila melanogaster, Neuroligin 3 (Nlg3) regulates social behaviour, sleep and synaptic architecture. We now report, through analysis of publicly available transcriptomics...
Neuroligins are conserved postsynaptic adhesion proteins involved in synaptic function and behaviour. In Drosophila melanogaster, Neuroligin 3 (Nlg3) regulates social behaviour, sleep and synaptic architecture. We now report, through analysis of publicly available transcriptomics data, confirmed with RT-qPCR data, that loss-of-function of the nlg3 gene downregulates the expression of longevity-associated genes foxo, hsp70s, and hsp68. Graded genetic manipulation of the Drosophila melanogaster neuroligin 3 (nlg3) gene indeed modulates both social spacing and lifespan. Specifically, reduced nlg3 expression (via heterozygous deletion, or transposable-element insertion) extends lifespan in both sexes, while overexpression or complete deletion shortens it. In contrast, overexpression or complete loss of nlg3 leads the flies to be further apart (increased social distance, or social space), as does RNAi knockdown, while heterozygous reduction of nlg3 expression either lowers or does not alter the flies social space. This work identifies a previously unrecognized link between a conserved synaptic gene, social behaviour, and organismal longevity.
Longevity Relevance Analysis
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The paper claims that graded genetic manipulation of the neuroligin 3 (nlg3) gene in Drosophila modulates organismal lifespan, with reduced expression extending life and overexpression or complete deletion shortening it. This is relevant because it identifies a conserved synaptic protein as a regulator of longevity, suggesting a potential mechanistic link between synaptic function, social behavior, and aging pathways (such as FOXO and heat shock proteins), although the findings are limited to a model organism and represent an incremental step in understanding the genetic architecture of lifespan rather than a direct intervention for human aging.
Qingxia Huang, Yongjie Wang, Karina Farias ...
· Cardiovascular research
· Department of Pharmacology, Weill Cornell Medicine, New York, NY 10021.
· pubmed
Cardiomyocyte senescence is a hallmark of cardiac aging and closely associated with diastolic dysfunction and heart failure in older adults. Strategies to effectively delay or reverse cardiomyocyte senescence in the aged heart remain limited. We investigated whether NAD+ replenis...
Cardiomyocyte senescence is a hallmark of cardiac aging and closely associated with diastolic dysfunction and heart failure in older adults. Strategies to effectively delay or reverse cardiomyocyte senescence in the aged heart remain limited. We investigated whether NAD+ replenishment regulates cardiomyocyte senescence and cardiac function in aging.
Longevity Relevance Analysis
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NAD+ replenishment reduces cardiomyocyte senescence and improves diastolic function in the aged male heart. This study addresses a fundamental mechanism of aging (NAD+ decline and cellular senescence) rather than merely treating symptoms, demonstrating that restoring metabolic precursors can mitigate specific age-related cardiac dysfunction.
Angela Falvino, Roberto Bonanni, Calogero Asaro ...
· Musculoskeletal Diseases
· Department of Systems Medicine, "Tor Vergata" University of Rome, Rome, Italy.
· pubmed
Aging is an important risk factor for musculoskeletal disorders such as osteoarthritis, osteoporosis, and sarcopenia. Cellular senescence contributes to age-related tissue deterioration by promoting functional alterations and a pro-inflammatory environment, making senotherapeutic...
Aging is an important risk factor for musculoskeletal disorders such as osteoarthritis, osteoporosis, and sarcopenia. Cellular senescence contributes to age-related tissue deterioration by promoting functional alterations and a pro-inflammatory environment, making senotherapeutics promising strategies to selectively eliminate senescent cells or limit their deleterious effects. Our systematic review synthesized the available preclinical evidence on the efficacy of senotherapeutics in murine models of osteoarthritis, osteoporosis, and sarcopenia, analyzing structural and functional outcomes and the main molecular mechanisms involved in the regulation of cellular senescence. A literature search was conducted in the MEDLINE, Scopus, and Web of Science databases according to PRISMA guidelines, while the methodological quality of the included studies was assessed using the SYRCLE RoB tool. 26 experimental studies were included, of which 15 involved osteoarthritis models, 6 osteoporosis models, and 5 sarcopenic models. Overall, senotherapeutics demonstrated protective effects on musculoskeletal tissues by reducing inflammation and improving the evaluated outcomes through the modulation of pathways associated with cellular senescence. However, the heterogeneity of experimental models, therapeutic protocols, and outcome measures limits the possibility of drawing definitive conclusions. Further studies will be necessary to clarify the molecular mechanisms involved, optimize therapeutic strategies, and promote the translation of experimental evidence into clinical practice.
Longevity Relevance Analysis
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Senotherapeutics demonstrate protective effects on musculoskeletal tissues in murine models by reducing inflammation and modulating cellular senescence pathways. This systematic review synthesizes preclinical evidence supporting the hypothesis that targeting cellular senescence—a fundamental hallmark of aging—can mitigate age-related musculoskeletal disorders, thereby addressing a root cause of aging rather than merely treating symptoms.
Björn Schumacher
· Caloric Restriction
· Institute for Genome Stability in Aging and Disease, Medical Faculty, University Hospital of Cologne, University of Cologne, Cologne, Germany; Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. Electronic address: [email protected].
· pubmed
In this issue of Cell, Grońska-Pęski et al. examine how calorie restriction (CR) affects DNA mutation rates. While CR lowers the accumulation of mutations, this effect does not scale with the degree of lifespan extension. Their work raises important new questions about how CR imp...
In this issue of Cell, Grońska-Pęski et al. examine how calorie restriction (CR) affects DNA mutation rates. While CR lowers the accumulation of mutations, this effect does not scale with the degree of lifespan extension. Their work raises important new questions about how CR impacts the causal mechanisms of aging.
Longevity Relevance Analysis
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Calorie restriction reduces the accumulation of DNA mutations without a corresponding proportional increase in lifespan, suggesting that mutation rate is not the primary causal driver of the lifespan extension observed under CR. This is relevant because it challenges the "mutation accumulation" theory of aging and helps delineate the specific mechanisms by which caloric restriction extends healthspan, distinguishing between DNA damage reduction and other metabolic or signaling pathways.
Franziska Meiners, Daniel Palmer, Roberto A Avelar ...
· Cellular Reprogramming
· Institute for Biostatistics and Informatics in Medicine and Ageing Research, University Medical Center Rostock, Rostock 18057, Mecklenburg-Vorpommern, Germany.
· pubmed
Partial reprogramming by cyclic expression of Yamanaka factors has been proposed as a rejuvenation strategy, yet evaluating tissue-specific responses and potential risks remains challenging. Here, we reanalyzed RNA-seq data from the liver, kidney, and spleen of aged mice subjecte...
Partial reprogramming by cyclic expression of Yamanaka factors has been proposed as a rejuvenation strategy, yet evaluating tissue-specific responses and potential risks remains challenging. Here, we reanalyzed RNA-seq data from the liver, kidney, and spleen of aged mice subjected to seven months of partial reprogramming. We used the Adverse Outcome Pathway (AOP) framework to estimate adverse and beneficial signatures, assessed functional changes via gene set enrichment analysis and deconvoluted bulk RNA-seq data to estimate differences in cell type proportion. In the liver and kidney, partial reprogramming suppressed age-activated immune and inflammatory processes, while activating age-suppressed metabolic and catabolic pathways. In the spleen, cell cycle, DNA replication, and DNA damage response programs were prominent, indicative of increased proliferative activity, and cell type deconvolution showed increased proportions of megakaryocyte-erythroid progenitor cells and decreased proportions of natural killer cells, while AOPs flagged a potential risk of sustained genomic and proliferative stress. Based on the existing AOP framework, we did not find any enriched Key Events in the kidney (reprogrammed vs. old). In the liver, AOP analysis identified pathways regulated in opposition to liver steatosis, indicated by activation of nuclear receptor signaling (
Longevity Relevance Analysis
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The paper claims that partial reprogramming via cyclic Yamanaka factor expression reverses age-associated transcriptional signatures in liver and kidney while inducing proliferative stress in the spleen. This is relevant because it directly evaluates the efficacy and safety profile of a leading candidate intervention for biological rejuvenation, providing critical tissue-specific data on the balance between rejuvenation and carcinogenic risk.
Lim, S., Pickering, A. M.
· molecular biology
· The University of Texas Health Science Center at Houston
· biorxiv
Aging alters protein abundance throughout the body, but whether proteomic aging signatures are shared across organs, and how they are represented in RNA, remains unclear. Plasma proteomics does not measure protein abundance directly within individual organs. Here, we developed or...
Aging alters protein abundance throughout the body, but whether proteomic aging signatures are shared across organs, and how they are represented in RNA, remains unclear. Plasma proteomics does not measure protein abundance directly within individual organs. Here, we developed organ-specific proteomic aging clocks for eight mouse organs. The clocks retained age associations across independent cohorts but transferred poorly between organs of the same mice, indicating predominantly organ-specific aging signatures. This organ specificity extended to RNA. Applied to the transcriptomes of the genes encoding each clock's protein features, with protein-derived weights unchanged, the scores retained age associations in independent transcriptomic cohorts, with stronger associations in the corresponding organs. The strength of age associations across molecular layers also differed by organ: in paired analysis, protein scores tracked age more strongly than RNA scores in brain and skeletal muscle, with no statistically detectable difference in kidney, liver or lung, suggesting a greater post-transcriptional contribution to proteomic aging in brain and muscle. In spatial transcriptomes, protein-derived RNA scores rose with age within tissue niches, usually without detectable changes in relative niche abundance. In the brain, white matter and glia-enriched microdomains showed elevated proteomic scores compared to other regions since young age. Together, these findings support organ-specific regulation of proteomic aging and identify molecular remodeling within persistent tissue compartments.
Longevity Relevance Analysis
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The paper demonstrates that proteomic aging signatures are predominantly organ-specific and that protein levels track age more strongly than RNA in brain and muscle, indicating significant post-transcriptional regulation of aging. This is relevant to longevity research as it provides a detailed molecular map of how aging manifests differently across tissues, which is essential for developing targeted interventions that address the specific mechanisms of aging in different organs rather than relying on a single systemic biomarker.
Jin Li, Zhen-He Wang, Jia-Xin Pan ...
· Cognitive Dysfunction
· Department of Basic Innovation Research, Beijing Hospital, National Center or Gerontology; National Clinical Research Center for Gerontology; The Key Laboratory of Geriatrics of NHC; Beijing Key Laboratory of Aging Mechanism and Intervention Research on Aging-Related Diseases; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
· pubmed
Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here...
Oxidative stress is a hallmark of aging and a key driver of neurodegenerative diseases. While much attention has been given to oxidative damage of macromolecules, the functional consequences of oxidizing the abundant nucleotide triphosphate (NTP) pool remain largely unknown. Here, we identify oxidized GTP (8-oxoGTP)-a major product of NTP oxidation-not as a mere marker of damage, but as an endogenous signaling molecule that drives microglial activation and neuroinflammation. 8-oxoGTP accumulated in the aging mouse brain, and its elevation was sufficient to induce synaptic dysfunction, tau hyperphosphorylation, neuronal loss, and cognitive decline. Mechanistically, 8-oxoGTP functioned as a potent activator of heterotrimeric G proteins, binding more strongly to Gα subunits than GTP itself, triggering Src kinase/MAPK/Akt/NF-κB signaling in microglia, leading to pro-inflammatory cytokine production, reactive oxygen species generation, and neurotoxicity. Pharmacological inhibition of Src family kinases rescued the neuroinflammatory and cognitive phenotypes induced by 8-oxoGTP. Our findings reveal a previously unrecognized mechanism linking nucleotide oxidation to age-associated neurodegenerative processes.
Longevity Relevance Analysis
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The paper claims that 8-oxoGTP acts as an endogenous signaling molecule that drives microglial activation and neuroinflammation, thereby accelerating cognitive decline. This is relevant to longevity research because it identifies a specific molecular mechanism linking oxidative stress (a root cause of aging) to neurodegeneration, offering a potential therapeutic target to mitigate age-related brain dysfunction rather than just treating downstream symptoms.
Qingxu Song, Xiaoxue Du, Wenbo Dong ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Department of Spine Surgery, The First Hospital of Jilin University, Changchun, People's Republic of China.
· pubmed
Senolytic vaccines hold promise for eliminating senescent cells, but their efficacy is limited by poor seno-antigen immunogenicity and age-related dendritic cell (DC) dysfunction. Here, we engineered an active biomaterial-enabled bi-adjuvant senolytic nanovaccine (CK5-GC-NV) by c...
Senolytic vaccines hold promise for eliminating senescent cells, but their efficacy is limited by poor seno-antigen immunogenicity and age-related dendritic cell (DC) dysfunction. Here, we engineered an active biomaterial-enabled bi-adjuvant senolytic nanovaccine (CK5-GC-NV) by co-assembling CpG oligodeoxynucleotide with a fusion protein of the seno-antigen Gpnmb and a cationic spider silk protein variant (CK5). Beyond antigen delivery, the CK5 scaffold acts as an intrinsic senomodulator associated with the downregulation of mitotic kinases Aurka/b and a concomitant decrease in senescence-associated PI3K/AKT phosphorylation in DCs. This intervention attenuates aged DC phenotypes, restores antigen cross-presentation, and synergizes with CpG to elicit potent cytotoxic T-lymphocyte responses against senescent targets. Across multiple aging mouse models, CK5-GC-NV immunization orchestrated targeted clearance of Gpnmb
Longevity Relevance Analysis
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The paper claims that a bi-adjuvant nanovaccine using a spider silk protein scaffold can reverse dendritic cell senescence and enhance the immune clearance of senescent cells. This is relevant because it addresses a fundamental barrier to senolytic therapies—age-related immune dysfunction—by targeting the root cause of aging (senescent cell accumulation) rather than just treating downstream metabolic symptoms.
Jiangtian Chen, Fernando G Noriega, ★ Marc Tatar
· Juvenile Hormones
· Department of Evolution, Ecology and Organismal Biology, and The Brown Center on the Biology of Aging, Brown University, Providence, RI 02912, USA.
· pubmed
Insulin-like signaling modulates aging and lifespan in insects. Here, we discuss a novel view of this control: insulin hormone in the adult regulates the production of the sesquiterpenoid juvenile hormone (JH) that in turn acts as the systemic regulator of aging and lifespan. Wor...
Insulin-like signaling modulates aging and lifespan in insects. Here, we discuss a novel view of this control: insulin hormone in the adult regulates the production of the sesquiterpenoid juvenile hormone (JH) that in turn acts as the systemic regulator of aging and lifespan. Work in Drosophila establishes that insulin signaling is allatotropic - it stimulates the production and secretion of JH from the corpora allata. JH then exerts systemic effects on adult survival through its control of specific proteins, translation and proteostasis. The interdependent functions of insulin and JH allow reproduction and longevity to be coupled in many insects or decoupled in social insects with long-lived queens and in some long-lived genetic mutants of Drosophila. Features of these insulin-regulated life history syndromes are also found in the nematode Caenorhabditis elegans. Recognizing the systemic role of JH in aging provides grounds to search for analogous systems in mammals that might modulate human lifespan.
Longevity Relevance Analysis
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The paper proposes that insulin-like signaling regulates aging in insects primarily by stimulating the production of juvenile hormone (JH), which acts as the systemic regulator of lifespan. This is relevant because it identifies a specific hormonal mechanism (insulin-JH axis) that couples reproduction and longevity, offering a comparative framework for identifying analogous systemic regulators of mammalian aging.