Rebecca Sereda, Kristen Lindenau, Antonio Diaz, ★ Guido Kroemer, ★ Ana Maria Cuervo ...
· Nature aging
· Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
· pubmed
Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent ...
Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms.
Longevity Relevance Analysis
(6)
The paper claims that age-related decline in chaperone-mediated autophagy (CMA) impairs macrophage clearance of senescent cells, and that pharmacological CMA activation reduces senescent cell burden and disease severity in aged mice. This is highly relevant to longevity research because it identifies a specific molecular mechanism (CMA decline) that drives the persistence of senescent cells, a known root cause of aging, and demonstrates that targeting this pathway can reverse age-related pathology, offering a potential strategy for extending healthspan.
Meiling Lai, Fengge Xu, Yingxia Xu ...
· Longevity
· Institute of Advanced Biotechnology, Institute of Homeostatic Medicine, and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
· pubmed
Canine models are invaluable for translational geroscience, but natural sex-associated immune aging remains under investigated. Here, we characterize the age-associated hematologic and serum cytokine profiles in a controlled cross-sectional cohort of 80 intact laboratory Beagles ...
Canine models are invaluable for translational geroscience, but natural sex-associated immune aging remains under investigated. Here, we characterize the age-associated hematologic and serum cytokine profiles in a controlled cross-sectional cohort of 80 intact laboratory Beagles spanning 1 to 11 years of age. Canine immune aging is heterogeneous and non-linear. While several absolute leukocyte counts declined with age before rising again in geriatric dogs, serum cytokines exhibited distinct, sex-stratified patterns. Although more cytokines varied significantly with age in males than in females, formal age-by-sex interactions did not remain significant after false discovery rate correction. To explore short-term geroprotective responses, we evaluated 24 young beagles following a 90-day intervention with rapamycin, canagliflozin, or dietary restriction. Rapamycin was associated with the broadest endpoint cytokine response. Canagliflozin showed narrower cytokine differences alongside descriptive body-weight reduction, whereas dietary restriction reduced body weight without altering measured immune endpoints. Given the small group sizes and endpoint-only cytokine measurements, these intervention findings remain exploratory and hypothesis-generating. Together, our findings describe stage-specific hematologic changes and sex-stratified cytokine patterns across the canine lifespan and provide a basis for future longitudinal studies.
Longevity Relevance Analysis
(3)
The paper characterizes sex-stratified immune aging patterns in Beagles and evaluates short-term cytokine responses to rapamycin, canagliflozin, and dietary restriction. This is relevant to longevity research as it provides baseline immunological data for a key translational animal model and offers preliminary evidence on how specific geroprotective interventions modulate the immune system, although the findings are limited by small sample sizes and cross-sectional design.
Hitesha Trivedi, Suraj Tripathi, Jalay Thacker ...
· British journal of clinical pharmacology
· Department of Pharmacology, Zydus Medical College and Hospital, Dahod, India.
· pubmed
Cellular senescence, a key feature of ageing, involves irreversible cell cycle arrest and the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP) factors, which contribute to tissue degeneration and age-related diseases. Targeting senescent cells with s...
Cellular senescence, a key feature of ageing, involves irreversible cell cycle arrest and the secretion of pro-inflammatory senescence-associated secretory phenotype (SASP) factors, which contribute to tissue degeneration and age-related diseases. Targeting senescent cells with senolytics, senomorphics and anti-ageing therapies marks a major shift in translational geroscience, with the potential to delay or reverse age-related conditions. A systematic review and narrative synthesis was conducted in accordance with PRISMA 2020 guidelines. Eligible human clinical studies evaluating pharmacological interventions targeting cellular senescence were included, comprising randomized and nonrandomized clinical trials and pilot studies reporting clinical, functional or senescence-associated outcomes. Data on study characteristics, interventions, efficacy, safety and senescence-associated biomarkers were extracted and synthesized qualitatively. Six completed clinical studies were included in the evidence synthesis, with one additional ongoing clinical trial identified separately. Senolytic interventions, particularly dasatinib plus quercetin, showed preliminary improvements in selected functional outcomes and reductions in senescence-associated biomarkers, while senomorphic and mTOR-targeting interventions demonstrated effects on selected tissue and immune-related outcomes. Reported adverse events were generally mild or manageable, but small sample sizes and short follow-up limited assessment of uncommon and long-term safety risks. Current evidence suggests that pharmacological targeting of cellular senescence is feasible and may produce measurable biological and functional effects in humans, but evidence remains insufficient to establish clinical efficacy or long-term safety. Senolytic and senomorphic strategies should therefore be considered investigational rather than established therapies. Larger, adequately powered randomized trials with standardized senescence biomarkers, clinically meaningful outcomes, longer follow-up and systematic safety assessment are needed.
Longevity Relevance Analysis
(3)
The paper claims that pharmacological targeting of cellular senescence via senolytics and senomorphics is feasible and produces measurable biological effects in humans, though current evidence is insufficient to establish clinical efficacy. This is relevant because it synthesizes the limited human clinical data on interventions designed to remove or suppress senescent cells, a core mechanism of aging, providing a necessary baseline for the field's transition from preclinical to translational medicine.
Hyun-Ji Cho, Sung Jin Ryu, Byung Ju Kim ...
· Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
· Department of New Biology, DGIST, Daegu 42988, Republic of Korea; Well Aging Research Center, DGIST, Daegu 42988, Republic of Korea. Electronic address: [email protected].
· pubmed
Receptor tyrosine kinases are critical regulators of cell survival, mediating responses to environmental changes and maintaining biological responsiveness. However, despite growing interest in developing senolytics that target survival factors in senescent cells as a promising st...
Receptor tyrosine kinases are critical regulators of cell survival, mediating responses to environmental changes and maintaining biological responsiveness. However, despite growing interest in developing senolytics that target survival factors in senescent cells as a promising strategy to overcome age-related diseases, the therapeutic potential of RTKs in senescence remains largely unexplored. In this study, we aimed to identify senolytic compounds that modulate RTK signaling and ameliorate age-related phenotypes by selectively inducing senescent cell death. Using a drug screening approach, we identified sunitinib, a multi-targeted RTK inhibitor that effectively suppresses PDGFR activation and induces apoptosis specifically in senescent HDFs (sHDFs) by activating caspase-9, -3, and -7. Moreover, in a mouse model of bleomycin-induced lung fibrosis in which senescent cells accumulate in the tissue, sunitinib reduced senescent cells and suppressed SASP expression. These findings, together with the observed increase in PDGFRβ phosphorylation in aged cells, led us to hypothesize that modulating PDGFRβ activity could induce senolysis. Indeed, knockdown of PDGFRβ expression sensitized senescent cells to cell death, with minimal effects on non-senescent HDFs (nsHDFs). At the mechanistic level, PDGFRβ and its downstream pathways, including the JAK2-STAT3 pathway, contributed to the senolytic response to sunitinib. Notably, sunitinib-induced JAK1 phosphorylation contributed to resistance to sunitinib in nsHDFs. Our findings suggest that sunitinib is a promising senolytic agent and that targeting PDGFRβ may represent a previously unknown approach to senolytics. Therefore, our study may provide a potential therapeutic strategy for age-related diseases associated with chronic inflammation.
Longevity Relevance Analysis
(4)
Sunitinib induces senolysis in senescent cells by modulating PDGFRβ signaling, thereby reducing senescent cell burden and SASP expression in a lung fibrosis model. This paper is relevant because it identifies a specific receptor tyrosine kinase pathway (PDGFRβ) as a target for senolytic therapy, offering a mechanistic strategy to clear senescent cells, which is a core driver of aging and age-related pathologies.
Che, A., Shah, P., Tanner, K. T. ...
· bioinformatics
· Robert N. Butler Columbia Aging Center, Mailman School of Public Health, Columbia University
· biorxiv
DE-SWAN is a commonly used method to study how large ensembles of omics biomarkers change across the life course. It has been used to demonstrate apparent repeated accelerations and decelerations of aging rates across the life course, including 2-3 peaks of aging-related changes....
DE-SWAN is a commonly used method to study how large ensembles of omics biomarkers change across the life course. It has been used to demonstrate apparent repeated accelerations and decelerations of aging rates across the life course, including 2-3 peaks of aging-related changes. This result contradicts what is expected based on the demography of aging and known biological mechanisms. Here, we use simulations to study the robustness of DE-SWAN to the age distribution of the study sample and to choice of window size. We show that under many realistic scenarios, DE-SWAN is highly sensitive to factors unrelated to the underlying rates of change in aging biology. This calls into question the results of previous analyses that have attributed DE-SWAN peaks to acceleration and deceleration of aging. We conclude that the method is unreliable for studying rates of change across the life course under most circumstances.
Longevity Relevance Analysis
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The paper claims that the DE-SWAN method for analyzing biomarker trajectories is highly sensitive to sample age distribution and window size, rendering previous conclusions about aging acceleration unreliable. This is relevant because it corrects a significant methodological error in the field of aging biology, preventing the misinterpretation of biomarker data as evidence for specific aging dynamics, though it does not propose a new intervention or mechanism for lifespan extension.
Antoine M Dujon, Nikita Stepanskyy, Jordan Meliani ...
· Journal of evolutionary biology
· School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, Australia.
· pubmed
The freshwater cnidarian Hydra vulgaris has been shown to exhibit extremely low rates of senescence when maintained under laboratory conditions, with a potential maximum lifespan extending to hundreds or even thousands of years. A congeneric species, H. oligactis, which undergoes...
The freshwater cnidarian Hydra vulgaris has been shown to exhibit extremely low rates of senescence when maintained under laboratory conditions, with a potential maximum lifespan extending to hundreds or even thousands of years. A congeneric species, H. oligactis, which undergoes senescence following sexual reproduction, has also been suggested (based on anecdotal evidence) to display negligible senescence during its asexual phase, similar to H. vulgaris. However, a proper evaluation of age-dependent mortality patterns in asexual H. oligactis is lacking. Here we analyzed age-dependent mortality and reproductive patterns in H. oligactis individuals derived from parental polyps collected from a pond in Southern France. Throughout their lifespan, experimental animals were maintained in the laboratory under two feeding regimes: high food availability (five feedings per week) and low food availability (three feedings per week). We recorded asexual reproduction and spontaneous tumours and used Bayesian Weibull survival models to relate food treatment, reproductive investment and tumour development to survival rates. Our results provide clear evidence of actuarial senescence in H. oligactis: mortality rates increased substantially over time, with a maximum observed lifespan of approximately two years. Survival was higher in the low-food group, indicating a dietary restriction effect in this non-bilaterian species. Asexual reproduction rate was positively associated to survival probability, while tumour development significantly reduced it. These findings show that H. oligactis, contrary to its congener H. vulgaris, undergoes senescence in the asexual stage, revealing previously unrecognized diversity in aging patterns within the genus Hydra.
Longevity Relevance Analysis
(3)
The paper demonstrates that the asexual phase of *Hydra oligactis* undergoes significant actuarial senescence with a maximum lifespan of approximately two years, contrasting with the negligible senescence of *Hydra vulgaris*. This finding is relevant to longevity research as it identifies specific biological boundaries and mechanisms (such as the impact of dietary restriction and tumor development) that distinguish senescent from non-senescent lineages within the same genus, providing a comparative model for understanding the evolution of aging.
Mengyang Chang, Kaixue Zhang, Junwei Wang ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· School of Chemistry and Chemical Biology, Eastern Institute of Technology, Ningbo, Zhejiang, People's Republic of China.
· pubmed
Senescence-associated β-galactosidase (SA-β-gal) is widely used to target senescent cells, but its activity in non-senescent tissues can limit selectivity. Here, we developed a light-enzyme AND-gate strategy in which an o-nitrobenzyl photocage blocks β-galactoside cleavage until ...
Senescence-associated β-galactosidase (SA-β-gal) is widely used to target senescent cells, but its activity in non-senescent tissues can limit selectivity. Here, we developed a light-enzyme AND-gate strategy in which an o-nitrobenzyl photocage blocks β-galactoside cleavage until 390 nm irradiation. The strategy was evaluated using a fluorescent probe (LS-C), a doxorubicin prodrug (LS-D), and an ARV-771-based PROTAC (LS-A). LS-C exhibited dual-trigger-dependent fluorescence activation, while LS-D preferentially induced apoptosis and LS-A promoted BRD4 degradation in senescent cells following light activation. Across multiple senescence models, LS-D and LS-A showed higher senolytic indices than their corresponding parent compounds. In senescent lung cancer patient-derived organoids, LS-D combined with light increased organoid death, whereas either treatment alone had minimal effects. These results provide proof-of-concept evidence for sequential light-enzyme AND-gating as a strategy for controlling payload activation in senescent cells under the tested in vitro and ex vivo conditions.
Longevity Relevance Analysis
(3)
The paper demonstrates that a light- and enzyme-triggered AND-gate prodrug strategy can selectively activate senolytic payloads in senescent cells, improving selectivity over non-senescent tissues. This is relevant to longevity research as it addresses the challenge of selectively eliminating senescent cells (a root cause of aging) with higher precision, potentially reducing the off-target toxicity that limits current senolytic therapies.
Hao-Lin Zhang, Yue Wang, Caizhu Wang ...
· Oocytes
· College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China.
· pubmed
Aging represents a major contributor to the deterioration of female fertility, with oocyte quality being the central determinant of ovarian aging, a key factor underlying infertility. Although several natural compounds with anti-aging activity have been documented, highly effecti...
Aging represents a major contributor to the deterioration of female fertility, with oocyte quality being the central determinant of ovarian aging, a key factor underlying infertility. Although several natural compounds with anti-aging activity have been documented, highly effective strategies to reverse ovarian aging remain elusive. Here, we report that the peptide elamipretide preserves ovarian function and sustains female fertility during maternal aging. We found that elamipretide administration increases litter size in aged mice and ameliorates oocyte quality decline. Metabolomic and transcriptomic profiling revealed substantial restoration of multiple biological processes in aged oocytes after elamipretide injection. Elamipretide improved both nuclear and cytoplasmic maturation of aged oocytes, accompanied by enhanced cytoskeletal dynamics, mitochondrial metabolism, and organelle reorganization. Mechanistically, elamipretide alleviated age-associated oocyte maturation defects through synergistic activation of the vitamin B6-VEGF axis. Furthermore, elamipretide significantly promoted maturation, fertilization, and cleavage of aged human oocytes. Elamipretide treatment also rescued the developmental competence of porcine oocytes under oxidative damage. Collectively, this study identifies a novel peptide therapeutic candidate for aging-related infertility, showing that elamipretide restores the quality of aged oocytes for fertility by coordinately boosting nuclear and cytoplasmic maturation via activation of the VEGF signaling pathway.
Longevity Relevance Analysis
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Elamipretide restores oocyte quality and fertility in aged mice and human oocytes by activating the vitamin B6-VEGF axis to improve mitochondrial metabolism and cytoskeletal dynamics. This is relevant because it targets the fundamental cellular mechanisms of aging (mitochondrial dysfunction and metabolic decline) to reverse a specific age-related physiological deficit, rather than merely treating the symptom of infertility.
Myrthe Klaver, Lotte Sophie Steeneken, Naomi Veeningen ...
· The EMBO journal
· European Research Institute for the Biology of Ageing (ERIBA), University of Groningen (RUG), University Medical Center Groningen (UMCG), Groningen, Netherlands.
· pubmed
Cellular senescence has undergone a remarkable conceptual evolution since its discovery in 1961. Initially described by Hayflick and Moorhead as the finite proliferative lifespan of cultured human cells, senescence was first viewed as a consequence of cellular aging. The identifi...
Cellular senescence has undergone a remarkable conceptual evolution since its discovery in 1961. Initially described by Hayflick and Moorhead as the finite proliferative lifespan of cultured human cells, senescence was first viewed as a consequence of cellular aging. The identification of telomere shortening, senescence biomarkers, and oncogene- and damage-induced senescence subsequently established its molecular basis and role as a tumor-suppressive stress response. The discovery of the senescence-associated secretory phenotype (SASP) further transformed the field by revealing that senescent cells actively communicate with and remodel their tissue environment. Genetic mouse models later demonstrated causal roles for senescent cells in tissue repair, aging, and age-related disease, while senotherapeutics established senescence as a therapeutic target. Here, we trace the major conceptual transitions that shaped the field, from replicative endpoint to stress-response program, regulator of tissue homeostasis, driver of chronic pathology, and clinically actionable process. We discuss the discoveries, controversies, and technological advances underlying these transitions and how emerging single-cell technologies, precision biomarkers, and targeted interventions are shaping the next era of senescence research.
Longevity Relevance Analysis
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This review traces the conceptual evolution of cellular senescence from a replicative endpoint to a clinically actionable driver of aging and disease. It is relevant because it synthesizes the foundational understanding of senescence as a root cause of aging and outlines the emerging therapeutic strategies (senotherapeutics) aimed at bypassing or mitigating this fundamental aging mechanism, though as a review, it does not present new primary data.
Lixiao Liu, Jing Qu, Guang-Hui Liu ...
· Trends in endocrinology and metabolism: TEM
· Beijing Key Laboratory of Intelligent Governance and Application of Biological Big Data, China National Center for Bioinformation and Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
· pubmed
Ferro-aging links age-associated iron dyshomeostasis to chronic lipid peroxidation and progressive functional decline across human and nonhuman primate tissues. Vitamin C extends beyond its antioxidant activity by directly inhibiting ACSL4, limiting polyunsaturated fatty acid inc...
Ferro-aging links age-associated iron dyshomeostasis to chronic lipid peroxidation and progressive functional decline across human and nonhuman primate tissues. Vitamin C extends beyond its antioxidant activity by directly inhibiting ACSL4, limiting polyunsaturated fatty acid incorporation into membrane phospholipids and thereby reducing lipid peroxidation and ferro-aging-associated phenotypes.
Longevity Relevance Analysis
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Vitamin C extends its longevity benefits by directly inhibiting ACSL4 to limit polyunsaturated fatty acid incorporation into membranes, thereby reducing lipid peroxidation and ferro-aging phenotypes. This paper is relevant because it proposes a specific molecular mechanism (ACSL4 inhibition) by which a common nutrient mitigates a fundamental driver of aging (iron-dependent lipid peroxidation), offering a potential pathway for lifespan extension rather than just symptom management.
Olova, N. N., Zhou, T., Boner, W. ...
· developmental biology
· University of Edinburgh
· biorxiv
Environmental conditions experienced early in life have profound consequences for vertebrate health, yet the molecular pathways linking developmental stress to aging and reduced lifespan remain poorly understood. Through a novel highly accurate epigenetic clock, developed from RR...
Environmental conditions experienced early in life have profound consequences for vertebrate health, yet the molecular pathways linking developmental stress to aging and reduced lifespan remain poorly understood. Through a novel highly accurate epigenetic clock, developed from RRBS-based blood DNA methylation profiles, we show that experimental lifespan-reducing early-life stress rapidly accelerates epigenetic age in zebra finch chicks (Taeniopygia guttata). Corticosterone-treated 29-day-old chicks share differentially methylated loci with non-treated aged birds and cluster with 6-month-old birds. The transcriptional repressor ZBTB16 emerges as an epigenetically top age-correlated gene and is strongest affected by corticosterone. Elevated developmental corticosterone causes rapid epigenetic remodelling of metabolic pathways well-established in aging and longevity. Our results demonstrate epigenetic rewiring of the aging trajectory through conserved stress-survival mechanisms immediately following elevated early-life stress exposure.
Longevity Relevance Analysis
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Early-life stress exposure epigenetically rewires metabolic pathways associated with aging, accelerating biological age in zebra finches. This study provides mechanistic insight into how developmental stressors influence the aging trajectory via conserved epigenetic mechanisms, contributing to the understanding of the root causes of accelerated aging rather than just treating symptoms.
Bao Wang, Luzhang Ji, Qian Bian
· Matrix Attachment Region Binding Proteins
· Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200125, China.
· pubmed
Precise three-dimensional (3D) genome organization is crucial for regulating gene expression during development, yet its role in age-related transcriptional changes and physiological decline remains elusive. Here, we show that aging reshapes chromatin architecture and gene regula...
Precise three-dimensional (3D) genome organization is crucial for regulating gene expression during development, yet its role in age-related transcriptional changes and physiological decline remains elusive. Here, we show that aging reshapes chromatin architecture and gene regulation in murine naive CD4
Longevity Relevance Analysis
(3)
Aging-associated deficiency of the chromatin organizer SATB1 drives the remodeling of 3D genome architecture and transcriptional programs in naive CD4+ T cells. This paper is relevant because it identifies a specific molecular mechanism (SATB1 loss) underlying age-related changes in immune cell gene regulation, contributing to the understanding of the fundamental biological processes of aging rather than just treating symptoms.
Simpson, D. J., Crofts, S. J., Mavrommatis, C. ...
· epidemiology
· Mayo Clinic, Rochester MN
· medrxiv
Cellular senescence is a central hallmark of aging, yet its measurement in humans remains invasive, low-throughput and tissue-specific, precluding population-scale study. We developed Methylation-associated Gene Expression (MaGE) predictors: whole-blood DNA methylation proxies of...
Cellular senescence is a central hallmark of aging, yet its measurement in humans remains invasive, low-throughput and tissue-specific, precluding population-scale study. We developed Methylation-associated Gene Expression (MaGE) predictors: whole-blood DNA methylation proxies of p14ARF, p16INK4A and p21CIP1 expression, plus a composite score, providing the first scalable measure of senescence-marker expression. Deployed across Generation Scotland (n=18,859), MaGE yielded 45 Bonferroni-significant associations spanning 18 incident diseases and all-cause mortality. The two strongest associations recapitulated the established tissue specificity of p21CIP1 and p16INK4A activation, with MaGE-p21 associating with incident alcoholic liver disease and MaGE-p16 with pulmonary fibrosis. In a separate study, MaGE tracked disease severity and treatment response in Crohn's disease. MaGE is a scalable, interpretable biomarker of senescence that enables its study at population scale and offers a route to patient stratification in senolytic trials.
Longevity Relevance Analysis
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The paper claims that whole-blood DNA methylation can serve as a scalable, non-invasive proxy for cellular senescence marker expression, enabling population-scale study of aging mechanisms. This is relevant because it addresses the critical bottleneck of measuring a core hallmark of aging (senescence) in humans without invasive biopsies, thereby facilitating the identification of senescence-associated diseases and the stratification of patients for potential senolytic interventions.
A Doğa Yücel, Adrian Molière, ★ Vadim N Gladyshev
· Aging
· Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
· pubmed
Ageing has been described through many theoretical frameworks, yet its mechanistic basis remains unresolved. Here we propose that ageing reflects progressive decanalization of mammalian cell identity, driven by erosion of a regulatory grammar written during development. Extending...
Ageing has been described through many theoretical frameworks, yet its mechanistic basis remains unresolved. Here we propose that ageing reflects progressive decanalization of mammalian cell identity, driven by erosion of a regulatory grammar written during development. Extending Waddington's epigenetic landscape, development canalizes cell fates through globally coordinated chromatin programs that establish identity constraints across multiple timescales. Subsequently, these constraints can only be maintained through local mechanisms with limited fidelity. The asymmetry between high-fidelity writing and imperfect maintenance generates predictable drift that accumulates with biological time. Antagonistic chromatin pathways, particularly polycomb repressive complex 2 (PRC2)-mediated repression opposed by H3K4/36 methylation and RNA polymerase II binding, enforce identity boundaries through mutual constraint. With age, this balance erodes. Consistent with this framework, the vast majority of age-associated DNA methylation gain in somatic mitotic tissues occurs at PRC2-bound low-methylated regions, indicating that these domains function as conserved coordinates of slow-layer drift. This model explains cross-tissue ageing signatures, developmental timing-to-lifespan correlations and robustness of pan-mammalian epigenetic ageing clocks. It provides testable predictions for interventions that stabilize architecture to preserve cellular identity and function.
Longevity Relevance Analysis
(4)
The paper proposes that aging is driven by the progressive decanalization of cell identity due to the erosion of a developmental regulatory grammar, specifically predicting that age-associated DNA methylation gains occur at PRC2-bound regions. This is relevant because it offers a mechanistic framework for the root cause of aging (loss of epigenetic identity) rather than treating symptoms, though it is primarily a theoretical model with limited direct experimental validation in this abstract.
Xiaofang Zhang, Tao Tao, Wanyi Liu ...
· Mitochondrion
· The Second Affiliated Hospital of Guangdong Medical University, School of Ocean and Tropical Medicine, Guangdong Medical University, Zhanjiang 524023, China; Hospital of Stomatology, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
· pubmed
Mitochondria and their biomacromolecular complexes-such as the electron transport chain (ETC), mitochondrial permeability transition pore (mPTP), and protein quality control systems-play pivotal roles in aging and age-related diseases. This review integrates recent insights into ...
Mitochondria and their biomacromolecular complexes-such as the electron transport chain (ETC), mitochondrial permeability transition pore (mPTP), and protein quality control systems-play pivotal roles in aging and age-related diseases. This review integrates recent insights into how structural and functional disruptions of these complexes drive cellular senescence and systemic decline. We outline the architecture of mitochondrial assemblies (e.g., oxidative phosphorylation (OXPHOS) complexes, mtDNA-protein interactions) essential for energy production and organelle stability. Age-related alterations in stoichiometry, conformational states (e.g., mPTP opening), and post-translational modifications (e.g., SIRT3-mediated acetylation) compromise mitochondrial integrity, fueling metabolic dysfunction and chronic inflammation ("inflammaging"). Therapeutic strategies include small-molecule stabilizers of ETC supercomplexes, peptide-based mPTP inhibitors, and CRISPR-mediated correction of mtDNA-protein mismatches. Tissue-specific models (e.g., Complex I in skin aging, Bcl-2 protein imbalance in ovarian aging) exemplify the clinical relevance. We also categorize nine age-associated diseases-neurodegenerative, cardiovascular, and cancer types-based on their dependence on distinct mitochondrial complexes, such as ATP synthase in cancer resistance and the TIM/TOM import machinery in Alzheimer's disease. By linking structural findings (e.g., cryo-EM studies) with therapeutic innovation, this review offers a framework for targeting mitochondrial complexes to mitigate aging and its related pathologies.
Longevity Relevance Analysis
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This review synthesizes structural and functional insights into mitochondrial complexes to propose therapeutic strategies for mitigating aging and age-related pathologies. While the paper addresses the root causes of aging by targeting mitochondrial dysfunction, it is a review article that integrates existing knowledge rather than presenting novel experimental data or a major breakthrough, resulting in a solid but limited impact on the field.
Fabian Finger, Mikkel Frost, Shinya Watanabe ...
· Nature aging
· Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. [email protected].
· pubmed
Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthes...
Aging paradoxically leads to both a decline in skeletal muscle mitochondrial function and a shift in muscle composition that favors fibers rich in mitochondria. Yet the biological rationale and mechanism underlying this phenomenon remain largely unknown. Here we show that synthesis of the mitochondrial membrane lipid, cardiolipin, causally links mitochondrial dysfunction to fiber-type adaptations in aging mouse and human skeletal muscle. By mimicking the aging decline of skeletal muscle cardiolipin levels in young mice using inducible tissue-specific cardiolipin synthase 1 (Crls1) deletion, we could reproduce key aging hallmarks, including the shift from glycolytic to oxidative fibers. This shift is mediated by mitochondria-to-nucleus signaling through the nuclear receptor, estrogen-related receptor γ, which promotes reactive oxygen species-sensitive glucose uptake and enhanced glycolytic rerouting to sustain antioxidant defenses. Restoring Crls1 expression in adult Crls1 knockout mice reestablishes cardiolipin levels, initiates reversal of muscle atrophy and fully rescues premature mortality. These findings reveal how changes in a mitochondrial membrane lipid cell autonomously orchestrate fiber-type adaptations in aging and myopathies.
Longevity Relevance Analysis
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The paper claims that the decline in the mitochondrial membrane lipid cardiolipin causally drives the shift from glycolytic to oxidative muscle fibers in aging via estrogen-related receptor γ signaling. This is relevant to longevity research because it identifies a specific, cell-autonomous molecular mechanism linking mitochondrial lipid metabolism to age-related muscle phenotypes, offering a potential target for interventions that could preserve muscle function and metabolic health during aging.
Lu, Y. R. R., Shen, H., Kajderowicz, K. ...
· genetics
· Whitehead Institute for Biomedical Research
· biorxiv
Aging is a complex phenomenon, yet therapeutic discovery has largely relied on testing individual hypothesis-driven targets. Here, we performed a genome-scale open reading frame (ORF) screen for oxidative-stress resistance in retinal pigment epithelium (RPE) cells, which are vuln...
Aging is a complex phenomenon, yet therapeutic discovery has largely relied on testing individual hypothesis-driven targets. Here, we performed a genome-scale open reading frame (ORF) screen for oxidative-stress resistance in retinal pigment epithelium (RPE) cells, which are vulnerable to oxidative damage during aging. The screen identified nine protective ORFs including antioxidant factors and an epithelial-to-mesenchymal transition regulator. Notably, we also identified three factors that reduce transcriptomic age including the cardiac transcription factor NKX2-5. NKX2-5 conferred robust oxidative resilience in vitro and in vivo. Domain dissection revealed that its homeodomain is dispensable for resilience, enabling development of NKX2-5{Delta}HD, which retained protective activity without detectable toxicity over 14 months. In middle-aged mice, subretinal NKX2-5{Delta}HD restored visual and electrophysiological function, and its systemic delivery improved grip strength and reduced frailty in late-aged mice. These findings highlight the value of unbiased, genome-scale gain-of-function screening, as resilience factors normally expressed in other contexts can be reengineered as potential therapeutics for age-related decline in other tissues.
Longevity Relevance Analysis
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The paper claims that a reengineered variant of the cardiac transcription factor NKX2-5 (lacking its homeodomain) can restore visual function in aged mice and improve systemic frailty markers. This is relevant to longevity research because it identifies a specific, unbiasedly discovered genetic factor that confers oxidative resilience and reverses age-related functional decline in multiple tissues, offering a potential therapeutic strategy to bypass the physiological consequences of aging rather than just treating isolated symptoms.
Hirotaka Iijima, Kandarp M Dave, Kai Wang ...
· Nature aging
· Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute at Spaulding, Charlestown, MA, USA. [email protected].
· pubmed
Extracellular vesicles (EVs) have been proposed to be mediators of the health-promoting effects of exercise throughout the body, but how EVs communicate these beneficial signals to recipient cells remains unknown. Here we interrogated these mechanisms using articular cartilage as...
Extracellular vesicles (EVs) have been proposed to be mediators of the health-promoting effects of exercise throughout the body, but how EVs communicate these beneficial signals to recipient cells remains unknown. Here we interrogated these mechanisms using articular cartilage as a model. Network propagation of EV microRNA perturbations on a cartilage-specific network identified microRNA-29 as an exercise-responsive regulator of cellular aging. Consistent with this prediction, a 3-month aerobic exercise intervention in older adults increased microRNA-29 levels in EVs relative to baseline EVs. In vitro studies revealed that these exercise-primed EVs epigenetically de-repressed the KL gene, which encodes the longevity-associated protein α-Klotho, and restored a more youthful chondrocyte phenotype. EVs engineered to express microRNA-29 recapitulated these anabolic effects in a KL-dependent manner. Intra-articular administration of exercise-primed EVs into aged mice enhanced cartilage health, thereby confirming physiological and potentially translational relevance. These findings elucidate mechanisms by which exercise transduces beneficial signals in EVs to promote health in distal tissues through regulation of KL.
Longevity Relevance Analysis
(4)
Exercise-primed extracellular vesicles carrying microRNA-29 restore youthful chondrocyte phenotypes by epigenetically de-repressing the longevity-associated gene KL (α-Klotho). This paper is relevant because it identifies a specific molecular mechanism (miR-29/KL axis) by which exercise mitigates cellular aging in cartilage, offering a potential translational pathway to combat age-related joint degeneration rather than just treating symptoms.
Jingyi Xu, Jinghui Yang, Wentao Sun ...
· Biochimica et biophysica acta. General subjects
· Laboratory of Intensive Care, The Affiliated Hospital of Yangzhou University, Yangzhou, China; Laboratory for Prevention and Translation of Geriatric Diseases, The Affiliated Hospital of Yangzhou University, Yangzhou, China.
· pubmed
Activation of specific calcium regulators, along with their downstream intracellular calcium signaling pathways has been established as a hallmark feature of cellular senescence. Nevertheless, alternations in intracellular free calcium concentration and the functional consequence...
Activation of specific calcium regulators, along with their downstream intracellular calcium signaling pathways has been established as a hallmark feature of cellular senescence. Nevertheless, alternations in intracellular free calcium concentration and the functional consequences thereof during cellular senescence and age-related diseases remain incompletely understood, particularly in fibroblasts. In this study, we measured intracellular calcium levels during senescence and observed a significant increase. Subsequently, chelation of intracellular calcium accumulation induced by senescence stimuli effectively delayed not only calcium elevation, but also reactive oxygen species (ROS) accumulation, DNA damage and fibroblast senescence. In vivo experiments demonstrated that intraperitoneal administration of the calcium chelator BAPTA-AM (BAPTA) markedly alleviated the pulmonary fibrosis phenotypes, as evidenced by attenuated loss of body weight, reduced infiltration of inflammatory cells, decreased collagen deposition and diminished expression of both fibrosis and senescence markers. Notably, transcriptomic analysis of fibrotic lung tissues revealed that BAPTA treatment significantly suppressed the senescence associated secretory phenotype (SASP). Collectively, our findings indicate that restriction of the intracellular calcium accumulation upon senescence triggers can mitigate fibroblast senescence and ameliorate pulmonary fibrosis, thereby highlighting the therapeutic potential of calcium chelators in age-associated pathologies.
Longevity Relevance Analysis
(4)
The paper claims that chelating intracellular calcium accumulation delays fibroblast senescence and alleviates pulmonary fibrosis. This is relevant because it identifies a specific intracellular signaling mechanism (calcium homeostasis) as a driver of cellular senescence, a core hallmark of aging, and demonstrates that modulating this pathway can mitigate age-related tissue pathology, offering a potential therapeutic target for age-associated diseases.
Xu, B., Ji, S., Lin, Z. ...
· systems biology
· Faculty of Life and Health Sciences, Shenzhen University of Advanced Technology
· biorxiv
Aging is often characterized statically as molecular profiles, but how these profiles may affect the capacity of systems to respond to the external environment remains elusive. We perturbed young and aged mice via transient sleep deprivation and profiled transcriptomes from six o...
Aging is often characterized statically as molecular profiles, but how these profiles may affect the capacity of systems to respond to the external environment remains elusive. We perturbed young and aged mice via transient sleep deprivation and profiled transcriptomes from six organs immediately after stress and following recovery. The same perturbation induced complex temporal dynamics for each gene in an organ- and age- dependent manner. A shape parameter distinguished genes that recovered toward control expression from those that continued to drift away during recovery. Transcriptomic vector fields were inferred from these transitions using neural ordinary differential equations, revealing distinct stability regimes across organ systems. Interestingly, that of testis from the young mice contained a separatrix bounding the region within which perturbed state can return toward control. These findings establish transient perturbation and recovery as a framework for probing age-dependent transcriptomic stability and identifying boundaries that determine whether a perturbed system can return.
Longevity Relevance Analysis
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The paper claims that transient stress and recovery dynamics reveal a separatrix in transcriptomic landscapes that defines the boundary between systems capable of returning to homeostasis and those that drift away, providing a dynamic framework for assessing age-dependent physiological resilience. This is relevant because it moves beyond static molecular aging markers to characterize the functional stability and recovery capacity of organ systems, offering a mechanistic basis for understanding how aging erodes the body's ability to maintain homeostasis.
Sergio Gordillo-García, Jesus Fernandez-Abascal, Blanca Hernando-Rodríguez ...
· Cell reports
· Andalusian Centre for Developmental Biology, Consejo Superior de Investigaciones Científicas/Junta de Andalucía/Universidad Pablo de Olavide, Seville, Spain; Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.
· pubmed
The mitochondrial prohibitin (PHB) complex is essential for mitochondrial homeostasis, yet its depletion produces opposite effects on lifespan: shortening it in wild-type C. elegans but extending it in insulin/IGF-1 receptor daf-2 mutants, which show an attenuated mitochondrial u...
The mitochondrial prohibitin (PHB) complex is essential for mitochondrial homeostasis, yet its depletion produces opposite effects on lifespan: shortening it in wild-type C. elegans but extending it in insulin/IGF-1 receptor daf-2 mutants, which show an attenuated mitochondrial unfolded protein response (UPR
Longevity Relevance Analysis
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USP-48 enables insulin-mediated longevity by modulating the mitochondrial stress response, specifically the UPRmt, in C. elegans. This paper is relevant because it identifies a specific molecular mechanism (USP-48) that links the insulin/IGF-1 signaling pathway to mitochondrial homeostasis and lifespan regulation, providing a potential target for understanding how nutrient sensing controls aging.
Weihan Huai, Li-Fang Ng, Jasinda H Lee ...
· Longevity
· Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.
· pubmed
Currently, no generalizable tools exist for predicting the impact of interventions on aging using gene expression changes. Here, we build a model for predicting potential geroprotectors by deconstructing the aging transcriptome into coexpression modules and identifying those modu...
Currently, no generalizable tools exist for predicting the impact of interventions on aging using gene expression changes. Here, we build a model for predicting potential geroprotectors by deconstructing the aging transcriptome into coexpression modules and identifying those modulated by life span-extending interventions in
Longevity Relevance Analysis
(3)
The paper claims that deconstructing the aging transcriptome into coexpression modules allows for the prediction of geroprotective compounds. This is relevant because it aims to identify interventions that modulate conserved longevity-associated modules to extend lifespan, addressing the root causes of aging rather than just treating symptoms, though the abstract suggests a computational modeling approach that likely represents a solid but incremental advance in drug discovery methodology rather than a major breakthrough.