Musi, N., Wang, C.-P., MacCarthy, D. ...
· geriatric medicine
· Cedars-Sinai Health Sciences University
· medrxiv
Importance: Preclinical and human observational studies suggest that metformin may decrease age-related pathology, including frailty. Objective: Determine whether metformin reduces frailty progression and biological age in older adults with glucose intolerance, a population at in...
Importance: Preclinical and human observational studies suggest that metformin may decrease age-related pathology, including frailty. Objective: Determine whether metformin reduces frailty progression and biological age in older adults with glucose intolerance, a population at increased risk of becoming frail. Design, Setting and Participants: Randomized, double-blind, placebo-controlled trial of metformin in 145 non-frail or pre-frail older adults. Participants (72 +/-5 years, 48% female, 94% White, 35% Hispanic) were randomized to metformin vs. placebo for two years. Main Outcomes and Measures: Effect on frailty was primarily determined using generalized estimating equations by change in the Fried frailty phenotype score (based on weight loss, exhaustion, physical activity, gait speed, and grip strength). Because metformin can cause significant weight loss, effects on the Fried score were assessed with and without the weight loss criterion. Frailty also was assessed by change in the frailty index (composite of 95 deficits). Biological age was estimated by DNA methylation-based epigenetic clocks in blood. Results: Metformin led to a non-linear response in the Fried score rate of change, with an upward trajectory in year 1 (0.72 +/-0.22 per year vs. placebo, p=0.0011) and stabilization in year 2 (-0.33 +/-0.17 per year vs. placebo, p=0.056). Metformin led to more weight loss than placebo (-5.7 +/-5.2 vs. -2.3 +/-5.4 kg, p=0.0002); thus, when assessing effect on Fried score without the weight loss criterion, no difference was observed, indicating that weight loss in year 1 accounted for the change in Fried score. Notably, metformin caused a steady improvement in the frailty index (-0.006 +/-0.0026 per year vs. placebo, p=0.0222) that persisted with covariates adjustment including body mass index. Metformin reduced biological age estimated by PC-Horvath2 (-0.40 +/-0.16 per year, p=0.014) and PC-Hannum (-0.33 +/-0.16 per year, p=0.047) clocks. Metformin was well tolerated. Conclusions and Relevance: Metformin halts the progression of the deficit accumulation frailty index and reduces biological age, suggesting potential benefit for extending healthspan. Trial Registration: ClinicalTrials.gov: NCT02570672.
Longevity Relevance Analysis
(3)
Metformin treatment reduces biological age as measured by DNA methylation clocks and improves a deficit-accumulation frailty index in older adults with glucose intolerance. The paper is relevant because it directly measures biological age and healthspan metrics rather than just treating a specific age-related disease symptom, although the findings are incremental and limited to a specific pre-frail population.
Qian Zhang, Yuedan Zhu, Yi Chen ...
· Science signaling
· West China Centre of Excellence for Pancreatitis and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
· pubmed
Aging impairs intestinal stem cell (ISC) function, disrupting epithelial homeostasis and regenerative repair. Loss of ISC quiescence promotes intestinal dysfunction and contributes to organismal aging. Here, we report an epitranscriptomic mechanism through which a decrease in ade...
Aging impairs intestinal stem cell (ISC) function, disrupting epithelial homeostasis and regenerative repair. Loss of ISC quiescence promotes intestinal dysfunction and contributes to organismal aging. Here, we report an epitranscriptomic mechanism through which a decrease in adenosine-to-inosine (A-to-I) RNA editing by the adenosine deaminase ADAR in ISCs during aging disrupts a conserved signaling axis that maintains ISC quiescence. In
Longevity Relevance Analysis
(3)
A reduction in ADAR-mediated A-to-I RNA editing disrupts Pumilio-mediated inhibition of MAPK signaling, leading to the loss of intestinal stem cell quiescence and driving organismal aging. This paper identifies a specific epitranscriptomic mechanism linking RNA editing to stem cell maintenance, offering a potential target for modulating aging-related tissue dysfunction.
Xiaojuan Zhong, Weixin Lv, Xueer Li ...
· Biogerontology
· Aging and Vascular Diseases, Human Aging Research Institute (HARI) and School of Life Science, Nanchang University, and Jiangxi Province Key Laboratory of Aging and Disease, Nanchang, 330031, Jiangxi, China.
· pubmed
Endothelial senescence is a critical contributor to vascular aging and age-related vasculopathies. Our previous work identified AGGF1 as a regulator of cell cycle progression and anti-inflammatory signaling. However, whether AGGF1 modulates endothelial senescence remains unclear....
Endothelial senescence is a critical contributor to vascular aging and age-related vasculopathies. Our previous work identified AGGF1 as a regulator of cell cycle progression and anti-inflammatory signaling. However, whether AGGF1 modulates endothelial senescence remains unclear. Here, we demonstrate that AGGF1 is downregulated in both replicative and DOX-induced senescent HUVECs. AGGF1 knockdown accelerated cellular senescence as evidenced by senescence markers, including increased SA-β-gal activity, enhanced formation of γH2AX foci, elevated IL-6 levels, and impaired proliferation, whereas AGGF1 overexpression prevented DOX- and MMC-induced senescence using adenovirus and lentivirus-mediated gene manipulation. To investigate the underlying mechanisms, we performed RNA sequencing, small-molecule drug intervention, transmission electron microscopy (TEM), and other imaging techniques in subsequent experiments. Transcriptomic and functional analyses revealed that AGGF1 transcriptionally upregulates TGFB3, which is associated with TAK1 activation and AMPK phosphorylation, ultimately inhibiting excessive mitochondrial fragmentation and suppressing cellular senescence. This signaling module reduced DRP1 expression and attenuated its activating phosphorylation at Ser616. TEM results further confirmed that AGGF1 overexpression significantly reduced mitochondrial fragmentation in cells. Additionally, this proposed association was supported by pharmacological inhibition (Takinib, Compound C) and TGFB3 knockdown, which abrogated AGGF1-mediated protection. Collectively, we identified that AGGF1 is critical for regulating a proposed TGFB3-TAK1-AMPK regulatory module, which delays endothelial senescence partially through maintenance of mitochondrial morphology. Our study provides evidence that AGGF1 plays an important role in metabolic control and cellular senescence.
Longevity Relevance Analysis
(2)
AGGF1 delays endothelial senescence by upregulating TGFB3 to activate the TAK1-AMPK axis, thereby maintaining mitochondrial morphology and reducing DRP1-mediated fragmentation. This study provides incremental mechanistic detail on a specific signaling pathway in endothelial cell aging, which is a fundamental process in vascular aging, but represents a standard molecular biology characterization rather than a transformative discovery or novel therapeutic intervention.
Jian Yin, Yizhou Gao, Yaobin Jing ...
· Protein & cell
· State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
· pubmed
Cellular senescence is accompanied by profound lysosomal alterations, yet whether lysosome-associated factors actively drive aging remains unclear. Through a focused CRISPR/Cas9 screen in human mesenchymal progenitor cells (hMPCs), we identified N-acetylglucosamine-1-phosphotrans...
Cellular senescence is accompanied by profound lysosomal alterations, yet whether lysosome-associated factors actively drive aging remains unclear. Through a focused CRISPR/Cas9 screen in human mesenchymal progenitor cells (hMPCs), we identified N-acetylglucosamine-1-phosphotransferase subunits alpha and beta (GNPTAB), an enzyme responsible for lysosomal hydrolase targeting, as a potent regulator of cellular senescence. Genetic ablation of GNPTAB attenuated senescence, whereas its overexpression accelerated senescence. This pro-senescent function occurred independently of GNPTAB's canonical enzymatic role. Instead, GNPTAB binds to the innate immune adaptor stimulator of interferon genes (STING) via a specific interface (E1119), leading to activation of STING and its downstream TANK-binding kinase 1 (TBK1), as well as pro-inflammatory gene expression. A STING-binding-deficient GNPTAB mutant (E1119A) preserved canonical lysosomal functions but failed to induce senescence, while STING depletion abolished GNPTAB-driven senescence. Together, these findings uncover a new signaling pathway wherein GNPTAB engages STING to facilitate its activation, nominating this interface as a potential target for mitigating age-related cellular dysfunction.
Longevity Relevance Analysis
(3)
The study identifies a non-canonical mechanism where GNPTAB activates STING to drive cellular senescence, suggesting that targeting this specific protein-protein interface could mitigate age-related cellular dysfunction. This work is relevant because it addresses a root cause of aging (cellular senescence) rather than just treating symptoms, but the impact is limited as it represents an incremental mechanistic discovery within the existing STING-senescence paradigm rather than a transformative breakthrough.
Jérôme Salignon, Maria Tsiokou, Patricia Marqués ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Department of Medicine Huddinge, Karolinska Institute, Huddinge, Sweden.
· pubmed
With the growing burden of age-related diseases, understanding and modulating the aging process has become a priority. Transcriptomic aging clocks (TACs) can track biological age but remain limited by platform dependence, tissue specificity, or restricted accessibility. To addres...
With the growing burden of age-related diseases, understanding and modulating the aging process has become a priority. Transcriptomic aging clocks (TACs) can track biological age but remain limited by platform dependence, tissue specificity, or restricted accessibility. To address this, we developed Pasta, a robust and broadly applicable human TAC, built using a novel 'age-shift' learning framework. Pasta accurately predicted relative age across diverse tissues and data types, including bulk and single-cell RNA-Seq as well as microarray data. Its predictions aligned with senescent and stem-like cellular states and relied on model coefficients enriched for p53 and DNA damage response pathways. Pasta's age scores correlated with tumor grade and patient survival in several cancer types, indicating potential clinical relevance. Applied to over three million transcriptomes from the Connectivity Map L1000 dataset, Pasta identified both established and previously unrecognized age-modulatory compounds and genetic perturbations, highlighting mitochondrial translation and mRNA splicing as key determinants of cellular propensity for aging and rejuvenation, respectively. Experimental validation confirmed pralatrexate as a potent senescence inducer and piperlongumine as a rejuvenating agent in human cells. Together, these findings establish Pasta as a versatile and accessible tool for aging research and therapeutic discovery.
Longevity Relevance Analysis
(3)
The study develops and validates a versatile transcriptomic aging clock (Pasta) that identifies specific genetic and chemical determinants of cellular aging and rejuvenation, including the experimental validation of pralatrexate and piperlongumine as modulators of senescence and rejuvenation. This work provides a robust, platform-independent tool for mapping the molecular landscape of aging and discovering potential interventions, thereby contributing to the fundamental understanding of aging mechanisms and the identification of therapeutic targets.
Xunshan Ren, Huangming Zhuang, Junming Zhu ...
· Journal of advanced research
· Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, China; Central Laboratory of Renmin Hospital of Wuhan University, Wuhan, China.
· pubmed
An increase in the number of senescent cells with advancing age is a major predisposing factor for aging-related osteoarthritis (OA). However, effective intervention strategies targeting cellular senescence have yet to be developed. Increasing evidence suggests that rising epigen...
An increase in the number of senescent cells with advancing age is a major predisposing factor for aging-related osteoarthritis (OA). However, effective intervention strategies targeting cellular senescence have yet to be developed. Increasing evidence suggests that rising epigenetic entropy, specifically the detachment of heterochromatin from the nuclear envelope, is a driver of cellular senescence.
Longevity Relevance Analysis
(2)
Bioorthogonal epigenetic anchoring of heterochromatin to the nuclear lamina reverses senescence and osteoarthritis. This study presents an incremental mechanistic advance in understanding epigenetic entropy as a driver of senescence, but the specific therapeutic application to osteoarthritis limits its broad impact on fundamental longevity research compared to interventions targeting core aging hallmarks directly.
Shiye Ke, Huijun Yang, Weifeng Lu ...
· Experimental gerontology
· Department of Endocrinology and Metabolic Diseases, The Eighth Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518033, Guangdong Province, China; Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, Guangdong Province, China; Biological Laboratory of Hetao Cooperation Zone, the Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518033, Guangdong Province, China.
· pubmed
Vascular aging profoundly impacts on cardiovascular disease. Sirtuin 3 (SIRT3) is a key regulator of metabolic homeostasis whose expression declines with age; however, the mechanisms linking SIRT3 deficiency to age-associated vascular impairment remain unclear. Here, we investiga...
Vascular aging profoundly impacts on cardiovascular disease. Sirtuin 3 (SIRT3) is a key regulator of metabolic homeostasis whose expression declines with age; however, the mechanisms linking SIRT3 deficiency to age-associated vascular impairment remain unclear. Here, we investigated whether SIRT3 deficiency drives age-associated vascular impairment by inducing mitochondrial dysfunction and initiating endothelial-to-mesenchymal transition (EndMT).
Longevity Relevance Analysis
(2)
SIRT3 deficiency drives age-associated vascular impairment by inducing mitochondrial dysfunction and endothelial-to-mesenchymal transition. This study provides mechanistic insight into a specific pathway of vascular aging, representing a standard incremental advance in the field of geroscience rather than a transformative breakthrough.
Mariah F Calubag, Ismail Ademi, Cara L Green ...
· Nature aging
· Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
· pubmed
Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is suf...
Dietary protein is a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction are mediated by reduced intake of dietary branched-chain amino acids (leucine, valine and isoleucine) and restriction of the branched-chain amino acids is sufficient to extend healthspan and lifespan in mice. Here we find that valine restriction (Val-R) improves metabolic health in C57BL/6J mice, promotes leanness and glycemic control across ages, and reduces frailty, cancer prevalence and senescent cell burden in both sexes while increasing median male lifespan by 23%. Assessing gene relationships across tissues, we identified a liver gene module enriched in mitochondrial pathways and increased mitochondrial respiration in Val-R-fed male mice. Our results demonstrate that Val-R improves multiple aspects of healthspan in mice of both sexes, extends lifespan in male mice and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.
Longevity Relevance Analysis
(3)
Dietary restriction of valine extends median male lifespan and improves healthspan metrics in mice. The study provides mechanistic insights into how specific amino acid restriction influences metabolic health and aging, contributing to the broader field of nutritional interventions for longevity.
Yue Kong, Qiuyan Zhang, Jianzhong Zhang ...
· Experimental gerontology
· School of Pharmacy, Shandong Medical and Pharmaceutical University, Yantai, 264003, China.
· pubmed
Cellular senescence is a central driver of organismal ageing and related pathologies, primarily promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Unlike senolytics, which aim to eliminate senescent cells, senomorph...
Cellular senescence is a central driver of organismal ageing and related pathologies, primarily promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Unlike senolytics, which aim to eliminate senescent cells, senomorphic agents offer a complementary therapeutic strategy by modulating the SASP without clearing the cells, thereby preserving their potential physiological functions. This review systematically elucidates the multi-target mechanisms of senomorphic agents, including the inhibition of key signaling pathways such as NF-κB, mTOR, JAK/STAT, and cGAS-STING. We classify them into three major categories: "old drugs with new uses" and metabolic modulators (e.g., metformin), natural products and their derivatives (e.g., urolithin A), and designed targeted synthetic inhibitors (e.g., ruxolitinib). Furthermore, we review their translational potential in neurodegenerative diseases, cardiovascular ageing, and osteoarthritis, highlighting the advantages of drug repurposing and synergistic therapy with senolytics. Finally, we discuss current challenges-such as the lack of specific biomarkers and targeted delivery systems-and future directions, including precision senotherapy and integrated intervention strategies. This review demonstrates that by 'taming' the senescent microenvironment rather than eliminating cells, senomorphic agents offer a promising strategy for achieving healthy ageing, yet clinical translation remains hindered by the lack of specific biomarkers, tissue-specific delivery systems, and long-term safety data. Here, we summarize current advances and critically analyze the barriers that must be overcome to move senomorphic agents from preclinical models to clinical practice.
Longevity Relevance Analysis
(3)
Senomorphic agents modulate the senescence-associated secretory phenotype (SASP) to mitigate chronic inflammation and tissue dysfunction associated with aging. This review is relevant because it addresses cellular senescence, a fundamental hallmark of aging, by evaluating strategies to alter the aging process rather than merely treating specific age-related pathologies.
Daniel Barnett, Caroline Booraem, Anna G Orr ...
· Molecular cell
· Helen and Robert Appel Alzheimer's Disease Research Institute, Weill Cornell Medicine, New York, NY, USA; Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA; Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY, USA.
· pubmed
Mitochondrial reactive oxygen species (mtROS) have been implicated in aging and disease for decades and are typically viewed as a unitary, non-specific oxidative burden on cells and tissues. However, recent studies have identified at least eleven individual sources of mitochondri...
Mitochondrial reactive oxygen species (mtROS) have been implicated in aging and disease for decades and are typically viewed as a unitary, non-specific oxidative burden on cells and tissues. However, recent studies have identified at least eleven individual sources of mitochondrial ROS (ISOMRs) and revealed that ISOMRs have distinct, dynamic, and often reversible roles in diverse physiological and pathological processes, including neurodegenerative diseases, immune and metabolic dysregulation, and ischemia-reperfusion injury. This review describes the upstream molecular events that control ISOMR activity, recently developed tools for studying mtROS in general and ISOMRs more specifically, and the evolving perspectives on ISOMR roles in context-specific cell signaling. Future studies to define predictive principles of ISOMR regulation are necessary to open frontiers of redox biology and identify therapeutic strategies for selective modulation of ISOMR-dependent mechanisms in aging and disease.
Longevity Relevance Analysis
(2)
The paper argues that mitochondrial reactive oxygen species are not a uniform oxidative burden but consist of distinct sources with specific, context-dependent signaling roles, challenging the traditional "free radical theory of aging." This review is relevant because it addresses the root cause of aging by refining the mechanistic understanding of mitochondrial dysfunction, a primary hallmark of aging, although as a review summarizing existing knowledge rather than presenting new experimental data, its direct impact on extending lifespan is limited.
Mia Simons Weston, Marta Dominguez Prieto, Nicoleta Moisoi
· Cellular signalling
· Leicester School of Pharmacy, Leicester Institute for Pharmaceutical and Health Innovations, Faculty of Health Sciences, De Montfort University, The Gateway, Hawthorn Building, Leicester LE1 9BH, UK.
· pubmed
Cellular senescence is a hallmark of ageing and age-related disease and is closely associated with mitochondrial dysfunction and the accumulation of DNA damage. However, the contribution of mitochondria-nucleus communication, mitochondrial quality control (mtQC) and stress signal...
Cellular senescence is a hallmark of ageing and age-related disease and is closely associated with mitochondrial dysfunction and the accumulation of DNA damage. However, the contribution of mitochondria-nucleus communication, mitochondrial quality control (mtQC) and stress signalling to senescence remains incompletely understood. Here, we investigated the interplay between mtQC pathways and cellular stress responses in DNA damage-induced senescence using mouse embryonic fibroblasts (MEFs). MEFs deficient in the mitochondrial protease HtrA2 (proteostasis), the transcription factor Chop (integrated stress response; ISR) or the mitophagy regulator Pink1 were exposed to three mechanistically distinct DNA-damaging agents: bleomycin, etoposide and doxorubicin. Senescence was characterised using multiple complementary markers, including the proportion of high senescence-associated β-galactosidase-positive cells, nuclear size, total and nuclear p21 abundance, and transcriptional analysis of p16, p21 and genes associated with cell-cycle regulation and stress signalling. Mitochondrial dysfunction through mtQC impairment enhanced sensitivity to senescence with HtrA2 and Pink1 loss promoting increased senescence under DNA damage. Although DNA damage response (DDR) was activated as seen by changes in p21 homeostasis, this did not always correlate with senescence levels, which indicates that DDR alone cannot account for all senescence characteristics. The ISR played a modulatory role in the senescence induction, with Chop loss of function reducing senescence induction following DNA damage despite DDR activation. The different DNA damaging drugs produced different senescence outcomes, thus highlighting the importance of the stressor context in addition to the cellular homeostasis mechanisms in the overall senescence profile. This approach allowed, for the first time, to identify senescence subtypes dependent of mtQC and ISR integrity in the context of genotoxic stress.
Longevity Relevance Analysis
(2)
Impairment of mitochondrial quality control (HtrA2, Pink1) or the integrated stress response (Chop) modulates the induction of cellular senescence following genotoxic stress. This paper provides incremental mechanistic insight into how specific mitochondrial and stress signaling pathways influence senescence, a hallmark of aging, but does not propose novel interventions or demonstrate lifespan extension.
Roberta Di Pietro, Rosa Mancinelli, Gianna Impicciatore ...
· Satellite Cells, Skeletal Muscle
· Department of Medicine and Aging Sciences, "G. d''Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100, Chieti, Italy.
· pubmed
Satellite cells (SCs) are essential for skeletal muscle regeneration, but their function declines with aging, often associated with increased pro-apoptotic signaling. This study investigated the impact of in vitro serum starvation-as a model of acute microenvironmental and nutrie...
Satellite cells (SCs) are essential for skeletal muscle regeneration, but their function declines with aging, often associated with increased pro-apoptotic signaling. This study investigated the impact of in vitro serum starvation-as a model of acute microenvironmental and nutrient stress-on the apoptosis and differentiation potential of human SCs from young and aged donors. SCs were isolated from the Vastus Lateralis of young and aged subjects and cultured in serum-free medium for up to 72 h. We assessed apoptosis through Annexin V/PI staining, TUNEL assays, and caspase activity measurements, while transcriptional profiles were analyzed via RT-PCR. Aged SCs displayed a significantly higher susceptibility to stress-induced apoptosis compared to young controls, marked by the early upregulation of CASP9 and FOXO1. While typical nucleosomal DNA fragmentation was absent, we observed the activation of caspase-3 after 72 h of starvation. In aged cells, activated caspase-3 co-localized with myogenin and extranuclear DNA at sites of nuclear remodeling. Notably, treatment with a pan-caspase inhibitor (z-VAD-fmk) prevented the formation of micronuclei and myotubes, further highlighting a non-apoptotic role for these enzymes. Aged SCs also showed a distinct cell cycle profile characterized by an enlarged G0/G1 phase and altered expression of CDK and CCNB1 genes. Our findings suggest that in human aged SCs, caspase enzymes serve a dual role: mediating a heightened stress response and facilitating the nuclear remodeling necessary for myogenic differentiation. These results clarify how intrinsic aging shapes the response of muscle stem cells under severe environmental and metabolic resource deprivation.
Longevity Relevance Analysis
(2)
The study demonstrates that caspase-3 facilitates nuclear remodeling and myogenic differentiation in aged human satellite cells under stress, rather than solely mediating apoptosis. This work is relevant to longevity as it elucidates a fundamental mechanism of stem cell exhaustion and tissue regeneration decline with age, specifically addressing the intrinsic aging of muscle stem cells. However, the findings are largely descriptive and incremental, offering limited immediate translational potential for lifespan extension or broad therapeutic intervention compared to more transformative mechanistic studies.
Mihalas, B. P., Lin, D., Bustamante, S. ...
· cell biology
· University of New South Wales
· biorxiv
The age-related decline in oocyte nicotinamide adenine dinucleotide (NAD) is associated with reduced developmental potential and female infertility. Despite the extraordinary longevity of the female germline, the mechanism for maintaining oocyte NAD remains unresolved. Here, we u...
The age-related decline in oocyte nicotinamide adenine dinucleotide (NAD) is associated with reduced developmental potential and female infertility. Despite the extraordinary longevity of the female germline, the mechanism for maintaining oocyte NAD remains unresolved. Here, we used stable isotope tracing to identify a new mechanism for shared, intercellular NAD biosynthesis, whereby somatic-germline metabolic coupling between the oocyte and its surrounding cumulus cells is critical to maintain oocyte NAD homeostasis. We show that this coupling deteriorates with reproductive aging, identifying altered NAD metabolism in cumulus cells from mice and women of advancing reproductive age. This cumulus-oocyte metabolic coupling of NAD biosynthesis contributes to protection against the age-related increases in oocyte reactive oxygen species (ROS). In intact complexes, restoring NAD through supplementation with the precursor nicotinamide mononucleotide (NMN) increased glutathione, reduced ROS and improved mitochondrial membrane potential in oocytes from aged mice and in oocytes exposed to oxidative insult. Importantly, the ability of NMN to resolve elevated ROS depends on the presence of cumulus cells. Together, this new model of somatic-germline metabolic coupling of NAD biosynthesis places an age-related deterioration in cumulus cell-mediated metabolic support as a key driver of impaired oocyte NAD levels and redox dysregulation with aging.
Longevity Relevance Analysis
(3)
The study identifies that age-related deterioration of somatic-germline metabolic coupling for NAD biosynthesis is a root cause of oocyte redox dysregulation and infertility, proposing that restoring this coupling via NMN can mitigate specific aging phenotypes in the germline. This work is relevant because it elucidates a fundamental mechanism of cellular aging (metabolic coupling failure) rather than merely treating symptoms, although its impact is limited by its specific focus on reproductive biology rather than whole-organism lifespan extension.
Piotr Paweł Chmielewski
· Cellular Senescence
· Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 6a Chałubińskiego Street, 50-368, Wrocław, Poland. piotr.chmielewski@umw.edu.pl.
· pubmed
Cellular senescence is a context-dependent cellular state characterised by persistent cell-cycle arrest, epigenetic remodelling, metabolic reprogramming and acquisition of a senescence-associated secretory phenotype. Transient senescence contributes to embryogenesis, tissue repai...
Cellular senescence is a context-dependent cellular state characterised by persistent cell-cycle arrest, epigenetic remodelling, metabolic reprogramming and acquisition of a senescence-associated secretory phenotype. Transient senescence contributes to embryogenesis, tissue repair and tumour suppression, whereas persistent senescent cell populations accumulate with advancing age across multiple tissues, in part owing to declining immune-mediated clearance and intrinsic resistance to apoptosis, thereby promoting chronic systemic inflammation, tissue fibrosis, stem-cell dysfunction and propagation of secondary senescence. Experimental genetic and pharmacological evidence supports a contributory and in several contexts causal role for senescent cells in cardiovascular, metabolic, musculoskeletal, fibrotic and neurodegenerative disorders. These findings have accelerated the development of senotherapeutic strategies, including senolytics, senomorphics and immune-mediated clearance approaches, with early clinical studies showing preliminary evidence of functional benefit in idiopathic pulmonary fibrosis and diabetic kidney disease. However, clinical translation remains constrained by senescence heterogeneity, limited biomarker specificity and unresolved long-term safety concerns. Improved molecular, spatial and functional resolution of senescent states will be essential for developing biomarker-guided and tissue-specific interventions that preserve the beneficial functions of transient senescence while limiting its chronic deleterious effects.
Longevity Relevance Analysis
(3)
This review establishes the causal link between cellular senescence and multiple age-related pathologies, highlighting the potential of senotherapeutics to target root causes of aging. The paper is relevant because it focuses on senotherapeutic interventions aimed at removing senescent cells, a fundamental mechanism of aging, rather than merely treating downstream symptoms. However, as a review summarizing existing evidence and acknowledging significant translational hurdles such as biomarker specificity and safety, it represents a solid synthesis of the field rather than a surprising new discovery or major breakthrough.
Chong Yang, Keiyo Takubo, Toshio Suda
· Experimental hematology
· State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, China; Tianjin Institutes of Health Science, China.
· pubmed
Hematopoietic stem cell (HSC) aging is often described as a gradual loss of stem cell fitness that culminates in impaired blood production, immune dysfunction, and increased susceptibility to hematologic disease. However, recent work suggests that this view is too simple. Rather ...
Hematopoietic stem cell (HSC) aging is often described as a gradual loss of stem cell fitness that culminates in impaired blood production, immune dysfunction, and increased susceptibility to hematologic disease. However, recent work suggests that this view is too simple. Rather than a uniform decline, aging appears to remodel the HSC compartment into metabolically and functionally distinct states, including maladaptive trajectories as well as surprisingly resilient subsets. In this review, we argue that HSC aging is best understood through the interplay of mitochondrial regulation, metabolic uncoupling, and niche-derived stress, with particular emphasis on how recent findings revise several longstanding assumptions in the field (Box 1).
Longevity Relevance Analysis
(3)
This review proposes that metabolic uncoupling and mitochondrial resilience are key mechanisms driving heterogeneous aging trajectories in hematopoietic stem cells, challenging the uniform decline model. The paper is relevant as it addresses fundamental cellular aging mechanisms in stem cells, which are central to longevity research, but as a review article offering a conceptual framework rather than novel experimental data, its direct scientific impact is limited to synthesizing existing knowledge.
Nathan R Zemke, Seoyeon Lee, Sainath Mamde ...
· Hippocampus
· Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
· pubmed
Changes in gene expression have been observed in the aging human brain, but our understanding of the underlying regulatory mechanisms remains limited. To unravel these complexities, we analyzed single-nucleus gene expression, chromatin accessibility, DNA methylation, and three-di...
Changes in gene expression have been observed in the aging human brain, but our understanding of the underlying regulatory mechanisms remains limited. To unravel these complexities, we analyzed single-nucleus gene expression, chromatin accessibility, DNA methylation, and three-dimensional (3D) chromatin architecture from human hippocampal tissues spanning the adult lifespan. We identified both linear and nonlinear dynamic gene regulatory programs during aging. Between the ages of 50 to 75, embryonic yolk sac-derived microglia were depleted and replaced by cells resembling peripheral blood monocyte-derived microglia. Hippocampal astrocytes decreased substantially with age, including those regulating synaptic transmission. Across cell types, 3D genome architecture underwent global erosion. Our analysis provides insights for how altered gene regulatory programs promote cell type-specific aging phenotypes in the human brain.
Longevity Relevance Analysis
(2)
The study characterizes age-related changes in the human hippocampus, including microglial replacement and 3D genome erosion, providing descriptive insights into the regulatory mechanisms of brain aging. This work is relevant as it maps fundamental epigenetic and architectural shifts associated with aging, though it is primarily observational and incremental rather than offering a novel intervention or solving root causes.
Sergio Pandolfi, Charlye Ghezzi, Geir Björklund ...
· NAD
· High Master School of Oxygen-Ozone Therapy, Section Neurosurgery, University of Pavia, Pavia, Italy.
· pubmed
This study examines the biological and clinical relevance of NAD⁺ supplementation using a combined review and mathematical modelling approach. NAD⁺ plays a central role in cellular energy metabolism, redox balance, and signaling pathways linked to aging, neurodegeneration, and me...
This study examines the biological and clinical relevance of NAD⁺ supplementation using a combined review and mathematical modelling approach. NAD⁺ plays a central role in cellular energy metabolism, redox balance, and signaling pathways linked to aging, neurodegeneration, and metabolic health. Current evidence shows that oral NAD⁺ precursors such as nicotinamide riboside and nicotinamide mononucleotide can increase circulating NAD⁺ levels, although their clinical benefits remain variable and context-dependent. Intravenous NAD⁺ administration is less well characterized and lacks robust clinical validation. The modelling framework presented here highlights that NAD⁺ responses are nonlinear and influenced by factors such as dose, age, metabolic state, and route of administration. Rather than following a simple dose-response relationship, NAD⁺ supplementation appears to operate within a complex regulatory system involving feedback mechanisms and biological saturation. Overall, these findings emphasize the need for cautious interpretation of current data and for well-designed clinical studies to define effective and safe therapeutic strategies.
Longevity Relevance Analysis
(2)
The paper proposes that NAD⁺ supplementation responses are nonlinear and governed by complex feedback mechanisms rather than simple dose-response relationships, highlighting the need for cautious clinical interpretation. This is a relevant review and modeling study addressing the mechanistic basis of a major longevity intervention, but it represents an incremental synthesis of existing knowledge rather than a transformative discovery.
Morozova, T., Polster, A., Axelson-Fisk, M.
· systems biology
· Chalmers University of Technology
· biorxiv
Aging reflects both stochastic fluctuation and biological regulation. We present a Markov chain framework for epigenetic aging that extends noise-driven models by adding a state-dependent bias term representing regulatory constraint. Using DNA methylation data from mice, rats, an...
Aging reflects both stochastic fluctuation and biological regulation. We present a Markov chain framework for epigenetic aging that extends noise-driven models by adding a state-dependent bias term representing regulatory constraint. Using DNA methylation data from mice, rats, and bats, we show that empirical epigenetic aging is characterized by a progressive restriction of the accessible state space. We demonstrate that a stochastic model incorporating state-dependent regulatory bias successfully reproduces this constraint, whereas standard noise-driven models fail to capture it. Subsequently, the results indicate that a regression-based drift model can be used to predict future trajectories and achieve lower mean, covariance, and state-increment dependence errors than the biased model. The pattern of state loss is consistent with discrete bifurcation events, suggesting resilience declines stepwise rather than continuously. This implies that the solution space for intervention narrows irreversibly at each transition, making intervention timing critical
Longevity Relevance Analysis
(2)
The paper proposes a mathematical model suggesting that epigenetic aging is constrained by regulatory bias leading to discrete state-space reductions, but it remains a theoretical framework without experimental validation of the proposed mechanism or demonstration of lifespan extension. This work offers a descriptive statistical model rather than a mechanistic solution to the root causes of aging, limiting its immediate impact on longevity research.
Krogsaeter, E. K., McKetney, J., Lishi Li, L. ...
· neuroscience
· University of California San Francisco
· biorxiv
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease and promotes neuronal dysfunction through incompletely understood mechanisms. Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic APOE3 and APOE4 hu...
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease and promotes neuronal dysfunction through incompletely understood mechanisms. Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic APOE3 and APOE4 human iPSC-derived neurons and found that APOE4 fundamentally impairs neuronal proteome renewal. Although transcriptional changes were modest, APOE4 disrupted ribosome occupancy, altered translational dynamics, and uncoupled protein abundance from transcript levels. Proteome-wide turnover measurements revealed a global extension of protein half-lives and widespread accumulation of long-lived proteins. Functional proteomic analyses demonstrated concurrent lysosomal and proteasomal impairments associated with reduced proteasome activity and increased association of APOE with neuronal proteasomes. Longitudinal proteomics further showed that protein accumulation emerges during neuronal maturation and precedes a senescence-like cellular stress state. Together, these findings identify impaired proteome renewal as a central mechanism underlying neuronal vulnerability to APOE4 and establish defective proteostasis as an early pathogenic event in Alzheimer's disease.
Longevity Relevance Analysis
(3)
APOE4 impairs neuronal proteostasis by extending protein half-lives and uncoupling translation from abundance, leading to the accumulation of long-lived proteins that precede senescence. This paper is relevant because it identifies defective proteome renewal and proteostasis collapse as an early, root-cause mechanism of neuronal vulnerability in aging, rather than merely describing downstream pathology.
Seon Pyo Hong, Cheolhwa Jin, Myung Jin Yang ...
· Cell
· Center for Vascular Research, Institute for Basic Science, Daejeon 34141, Republic of Korea. Electronic address: sp_hong@ibs.ac.kr.
· pubmed
Meningeal (dural) lymphatics are essential for cerebrospinal fluid (CSF) clearance to cervical lymph nodes, yet the precise pathway is incompletely understood. Using a multifaceted approach in mice, we examined tracer dynamics and the CSF outflow pathway from the subarachnoid spa...
Meningeal (dural) lymphatics are essential for cerebrospinal fluid (CSF) clearance to cervical lymph nodes, yet the precise pathway is incompletely understood. Using a multifaceted approach in mice, we examined tracer dynamics and the CSF outflow pathway from the subarachnoid space (SAS) to the nasal mucosa and identified a discrete arachnoid region surrounding the olfactory bulbs with abundant fenestrations. Similar arachnoid fenestrations were found in cynomolgus monkeys. Fluorescent tracers in the SAS passed through arachnoid fenestrations into dural lymphatics, which traversed the cribriform plate foramina, joined the nasal lymphatics, and drained to the cervical lymph nodes. In aged mice, the known reduction in CSF outflow was accompanied by lymphatic atrophy in the olfactory dura and nasal mucosa and by fewer arachnoid fenestrations and smaller cribriform plate foramina. Importantly, the lymphatics and CSF clearance were restored to normal by intranasal delivery of vascular endothelial growth factor-C (VEGF-C), thereby documenting the reversibility of the aging-related impairment in CSF clearance.
Longevity Relevance Analysis
(3)
The study identifies arachnoid fenestrations as a critical pathway for CSF clearance and demonstrates that aging-related impairment in this pathway can be reversed by intranasal VEGF-C delivery. This is relevant to longevity research as it addresses the glymphatic system's role in clearing neurotoxic waste, a root cause of neurodegeneration, and offers a potential therapeutic intervention to restore youthful clearance mechanisms.
Aditya Barve, Preeti Dabas, Adam Cornwell ...
· Anemia, Sickle Cell
· Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA.
· pubmed
Sickle cell disease (SCD) is a blood disorder affecting millions worldwide. Emerging evidence reveals that SCD pathophysiology increases the risk of myeloid malignancies and hematopoietic stem cell (HSC) dysfunction, likely because of chronic stress on bone marrow. To investigate...
Sickle cell disease (SCD) is a blood disorder affecting millions worldwide. Emerging evidence reveals that SCD pathophysiology increases the risk of myeloid malignancies and hematopoietic stem cell (HSC) dysfunction, likely because of chronic stress on bone marrow. To investigate this further, we interrogated bone marrow hematopoietic stem and progenitor cells (HSPCs) from mice and individuals with SCD and observed molecular signatures of chronic cellular stress including oxidative stress, DNA damage, and hallmarks of senescence. Consistent with these findings, SCD HSPCs displayed transcriptomic dysregulation of senescence-associated molecular programs and diminished mitogen response with prolonged cell cycle kinetics during time-lapse live cell imaging. SCD mice displayed a marked loss of immunophenotypic bone marrow HSPCs by flow cytometry and functional blood repopulating HSPCs in transplantation studies, whereas human SCD bone marrow HSPCs exhibited poor ex vivo hematopoietic colony-forming ability, and these phenotypes were reversed after senescence-targeting therapy with either ABT-263 (navitoclax) or the combination of dasatinib and quercetin. Thus, treatment with senescence-targeting therapy improves bone marrow HSPC function in vivo in mice and ex vivo in cells from individuals with SCD and could represent a possible strategy to improve HSPC health, promote manufacture of high-quality bespoke clinical products, and potentially enhance the safety of potentially curative gene therapies using autologous HSPCs from individuals with SCD.
Longevity Relevance Analysis
(3)
Targeting senescent hematopoietic stem and progenitor cells with senolytics (ABT-263, dasatinib/quercetin) restores their function in models of sickle cell disease, demonstrating that clearing senescent cells can reverse specific stem cell deficits associated with chronic physiological stress. This paper is relevant because it investigates cellular senescence—a fundamental hallmark of aging—as a driver of stem cell dysfunction, although its primary focus is on a specific genetic blood disorder rather than general aging or lifespan extension.
Hisashi Kanemaru, Steven Luong, Yuta Yamamoto ...
· Immunotherapy
· Department of Surgery, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
· pubmed
Chronic inflammation increases with age and contributes to cancer progression and therapeutic resistance, yet the mechanisms underlying this process remain incompletely understood. Here, we identify an increased frequency of pro-inflammatory myeloid cells in aged mice and humans,...
Chronic inflammation increases with age and contributes to cancer progression and therapeutic resistance, yet the mechanisms underlying this process remain incompletely understood. Here, we identify an increased frequency of pro-inflammatory myeloid cells in aged mice and humans, characterized by elevated production of IL-1α, IL-1β, IL-6, and TNF-α. These cells are enriched in the breast tumor microenvironment and are associated with accelerated tumor progression. Using heterochronic parabiosis and bone marrow chimeras, we show that age-associated myeloid cell inflammatory activation is suppressed by non-bone marrow-derived circulating factors present in young hosts. Integrative analyses identify thymulin, a thymus-derived peptide that declines with age, as a mediator that suppresses pro-inflammatory cytokine production by inhibiting NF-κB signaling. Furthermore, thymulin enhances antitumor T-cell immunity, improves tumor control and survival, and sensitizes tumors to anti-PD-L1 therapy in an age-dependent manner. Together, these findings uncover a thymus-myeloid cell regulatory axis linking aging, inflammation, and cancer immunity, and suggest thymulin as a potential strategy to improve cancer immunotherapy in older individuals.
Longevity Relevance Analysis
(3)
Thymulin, a thymus-derived peptide that declines with age, suppresses age-associated myeloid inflammation by inhibiting NF-κB signaling, thereby enhancing cancer immunotherapy efficacy in older individuals. This paper is relevant because it identifies a specific circulating factor linked to the thymus that drives inflammaging, addressing a root mechanism of age-related immune decline rather than merely treating a downstream symptom.
Roman Franěk, Radek Šindelka, Aarón Torres-Martínez ...
· BMC biology
· Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Zatisi 728/II, University of South Bohemia in Ceske Budejovice, 389 25, Vodnany, Czech Republic. franek@frov.jcu.cz.
· pubmed
Reproductive aging in vertebrates is commonly interpreted as a gradual decline; however, whether aging of the male gonad proceeds linearly or is characterized by periods of accelerated remodeling remains unclear. The turquoise killifish (Nothobranchius furzeri), a short-lived ver...
Reproductive aging in vertebrates is commonly interpreted as a gradual decline; however, whether aging of the male gonad proceeds linearly or is characterized by periods of accelerated remodeling remains unclear. The turquoise killifish (Nothobranchius furzeri), a short-lived vertebrate, enables lifespan-wide resolution of both rapid germline establishment and subsequent aging within months.
Longevity Relevance Analysis
(2)
The study characterizes the temporal dynamics of testicular aging in a short-lived vertebrate model, providing descriptive baseline data on germline remodeling rather than identifying novel mechanisms for lifespan extension. This work offers incremental insight into the biology of aging in a specific tissue but does not address root causes of aging or propose interventions to bypass age-related decline.
Chung-Ho E Lau, Elena Chekmeneva, Rui Pinto ...
· GeroScience
· Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
· pubmed
Understanding the links between metabolism, ageing, and age-related phenotypes may clarify the role of ageing in disease onset and improve risk prediction. We conducted a cross-cohort assessment of biological age using broad-spectrum LC-MS metabolomics of 3,686 plasma samples in ...
Understanding the links between metabolism, ageing, and age-related phenotypes may clarify the role of ageing in disease onset and improve risk prediction. We conducted a cross-cohort assessment of biological age using broad-spectrum LC-MS metabolomics of 3,686 plasma samples in 2,295 participants, aged 20-89, from the UK Airwave study (N = 960) and the Irish Longitudinal Study of Ageing (N = 1,335). The nucleoside N
Longevity Relevance Analysis
(2)
The study develops and validates a metabolomic biomarker for biological age and demonstrates its association with frailty and cognitive function. This represents an incremental advance in biomarker development rather than a breakthrough in understanding or intervening in the root causes of aging.
Syeda Ayesha Ali, Pengfei Qiang, Xiaojun Zhou ...
· Hyaluronan Receptors
· College of Bioengineering, Henan University of Technology, 100 Lianhua Street, High-Tech Zone, Zhengzhou, 450001, China.
· pubmed
Aging is characterized by a progressive decline in cellular and tissue function, shaped in part by disruptions in communication between the extracellular matrix (ECM) and intracellular signaling networks. The cell surface receptor CD44 functions as a molecular hub, integrating si...
Aging is characterized by a progressive decline in cellular and tissue function, shaped in part by disruptions in communication between the extracellular matrix (ECM) and intracellular signaling networks. The cell surface receptor CD44 functions as a molecular hub, integrating signals from a remodeled ECM to regulate core aging programs including senescence, inflammation, and metabolic balance. This review synthesizes evidence that CD44, through its structural domains, isoform diversity, and proteolytic processing, integrates extracellular cues to modulate key pathways such as STAT3, NF-κB, and the class III PI3K complex. Mechanistically, HA-fragment engagement of CD44 activates the CD44-STAT3 axis in vascular tissue, suppressing autophagic flux and promoting endothelial senescence. Concurrently, ECM-derived ligand binding to CD44 drives NF-κB signaling that amplifies chronic inflammation in a tissue and context-dependent manner, contributing to inflammaging. Functional outcomes are context-dependent, shaped by isoform switching and γ-secretase-mediated release of CD44-ICD, which may drive degeneration or support repair and proteostasis. Emerging single-cell and spatial transcriptomics reveal spatiotemporal CD44 dysregulation across vasculature, brain, adipose tissue, kidney, and liver. This review establishes CD44 as a mechanistic link connecting ECM remodeling to nuclear responses in aging and outlines therapeutic strategies including ligand competition, antibody blockade, and γ-secretase modulation to mitigate age-related pathology and extend health span. These insights provide a coherent framework for understanding aging biology and guiding future translational interventions targeting CD44 signaling pathways effectively.
Longevity Relevance Analysis
(2)
This review proposes that CD44 acts as a mechanistic hub integrating extracellular matrix signals to regulate aging-related pathways like senescence and inflammation, offering a framework for therapeutic intervention. The paper is relevant because it addresses fundamental mechanisms of aging (inflammaging, autophagy, tissue homeostasis) rather than just treating specific age-related diseases, but as a review of existing knowledge with incremental mechanistic synthesis, its immediate scientific impact is limited.
Spiros Palikyras, Vassiliki Varamogiani-Mamatsi, Yajie Zhu ...
· Nature aging
· Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
· pubmed
Senescence, the endpoint of normal cells' replicative lifespan, is accompanied by a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences and ...
Senescence, the endpoint of normal cells' replicative lifespan, is accompanied by a complex sequence of molecular events. One such event is the dramatic reorganization of CTCF into senescence-induced clusters (SICCs). However, the molecular determinants, genomic consequences and functional purpose of SICCs remain unknown. Here we combine three-dimensional genomics, super-resolution imaging, DNA tracing and functional assays with modeling to dissect SICC emergence. We find that, on senescence entry, cells repurpose SRRM2-a key component of nuclear speckles-and BANF1-a 'molecular glue' for chromosomes-to cluster CTCF and rewire genome architecture. This CTCF-centric reorganization in reference to nuclear speckles helps instruct the senescence splicing program, because disruption of SICCs almost fully reverts alternative splicing patterns and delays senescence onset. We therefore uncover a paradigm whereby human cells translate changes in nuclear biochemistry into architectural changes directing splicing choices to commit to the fate of senescence.
Longevity Relevance Analysis
(2)
Senescent cells repurpose SRRM2 and BANF1 to cluster CTCF on nuclear speckles, thereby instructing an alternative splicing program that drives the commitment to cellular senescence. This paper is relevant because it elucidates a fundamental mechanistic driver of cellular senescence, a key hallmark of aging, by linking nuclear architecture to splicing regulation; however, the impact is limited as it describes a specific molecular pathway within a known aging process rather than offering a novel therapeutic intervention or a paradigm-shifting discovery that bypasses aging.
Vivek Pandey, Rahul Sachdeva, Sanda Despa
· GeroScience
· Department of Physical Medicine and Rehabilitation, University of Kentucky, 2050 Versailles Road, Lexington, KY, 40504, USA. vivek.pandey@uky.edu.
· pubmed
Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are now recognized as integral components of the proteostasis network that preserves cellular and tissue function across the lifespan. With aging, increasing oxidative load, metabolic imbalanc...
Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are now recognized as integral components of the proteostasis network that preserves cellular and tissue function across the lifespan. With aging, increasing oxidative load, metabolic imbalance, and Ca
Longevity Relevance Analysis
(2)
The paper proposes that the PERK pathway exhibits a paradoxical role in aging by driving both cellular senescence and neurodegeneration through endoplasmic reticulum stress, suggesting that modulating this specific UPR branch could mitigate age-related proteostasis decline. This work is relevant as it addresses the root cause of aging by focusing on proteostasis network failure and ER stress, which are fundamental hallmarks of aging, rather than merely treating downstream symptoms.