Alberto J Espay, Andrea Sturchio, Alberto Imarisio ...
· BioEssays : news and reviews in molecular, cellular and developmental biology
· James J. and Joan A. Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, Ohio, USA.
· pubmed
Protein aggregation is a normal response to age-related exposures. According to the thermodynamic hypothesis of protein folding, soluble proteins precipitate into amyloids (pathology) under supersaturated conditions through a process similar to crystallization. This soluble-to-in...
Protein aggregation is a normal response to age-related exposures. According to the thermodynamic hypothesis of protein folding, soluble proteins precipitate into amyloids (pathology) under supersaturated conditions through a process similar to crystallization. This soluble-to-insoluble phase transition occurs via nucleation and may be catalyzed by ectopic surfaces such as lipid nanoparticles, microbes, or chemical pollutants. The increasing prevalence of these exposures with age correlates with the rising incidence of pathology over the lifespan. However, the formation of amyloid fibrils does not inherently cause neurodegeneration. Neurodegeneration emerges when the levels of functional monomeric proteins, from which amyloids form, fall below a critical threshold. The preservation of monomeric proteins may explain neurological resilience, regardless of the extent of amyloid deposition. This biophysical framework challenges the traditional clinicopathological view that considers amyloids intrinsically toxic, despite the absence of a known mechanism of toxicity. Instead, it suggests that chronic exposures driving persistent nucleation consume monomeric proteins as they aggregate. In normal aging, replacement matches loss; in accelerated aging, it does not. A biophysical approach to neurodegenerative diseases has important therapeutic implications, refocusing treatment strategies from removing pathology to restoring monomeric protein homeostasis above the threshold needed to sustain normal brain function.
Longevity Relevance Analysis
(5)
The paper claims that preserving monomeric proteins above a critical threshold is essential for maintaining normal brain function and preventing neurodegeneration. This research addresses the underlying mechanisms of aging-related protein aggregation and its implications for therapeutic strategies, which is directly relevant to longevity and age-related diseases.
Miaomiao Du, Yujia Wang, Xinyuan Wang ...
· Aging cell
· Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, People's Republic of China.
· pubmed
Aging is the greatest risk factor for learning and memory disorders; dementia prevalence significantly increases with age due to numerous molecular changes in the body. Although research has consistently shown that aging leads to learning and memory impairments, the molecular mec...
Aging is the greatest risk factor for learning and memory disorders; dementia prevalence significantly increases with age due to numerous molecular changes in the body. Although research has consistently shown that aging leads to learning and memory impairments, the molecular mechanisms linking aging to these cognitive deficits remain incompletely understood. Previous studies have revealed that complement C3 levels increase with age in humans, monkeys, and mice; elevated C3 expression is also observed in the brains of dementia patients. These data suggest that C3 plays critical roles in initiating learning and memory impairments. To investigate whether C3 contributes to these deficits during aging, we developed a transgenic mouse model with elevated C3 expression to simulate age-related increases. Mice with increased C3 expression showed impaired learning and memory, along with synaptic loss, neuronal loss, and astrocytosis. Quantitative polymerase chain reaction microarray and cellular assays revealed that C3 elevation may impair cognitive functions by affecting insulin signaling pathways. Notably, antibody therapy targeting complement C3 in SAMP8 mice, which naturally exhibit increased brain C3 levels, alleviated their learning and memory deficits. These findings suggest that age-related complement C3 elevation drives memory impairments and associated neuropathologies; targeting complement C3 may alleviate these deficits.
Longevity Relevance Analysis
(4)
Elevated complement C3 levels contribute to age-related memory impairments and associated neuropathologies. The paper addresses a molecular mechanism linked to cognitive decline in aging, which is relevant to understanding and potentially mitigating age-related diseases.
Vazquez Ramos, G. J. A.
· neuroscience
· Morehouse School of Medicine
· biorxiv
Background: The pineal gland secretes melatonin but paradoxically calcifies more than any other intracranial structure, forming hydroxyapatite "brain-sand" (corpora arenacea) that correlates with reduced melatonin output, sleep disruption and heightened neuro-degenerative risk. W...
Background: The pineal gland secretes melatonin but paradoxically calcifies more than any other intracranial structure, forming hydroxyapatite "brain-sand" (corpora arenacea) that correlates with reduced melatonin output, sleep disruption and heightened neuro-degenerative risk. Whether this mineralization is a passive dystrophic event or an active, bone-like process remains unclear. Methods: Analyzed RNA-seq datasets from pineal glands of six vertebrate species-calcifiers Homo sapiens, Rattus norvegicus and Capra hircus, versus non-calcifiers Mus musculus, Gallus gallus and Danio rerio. Species-specific transcripts were mapped to human orthologues, merged, and filtered. Phylogenetically informed differential expression testing used Brownian-motion and Pagel's lamda phylogenetic generalized least-squares models, calibrated on a TimeTree divergence phylogeny. Genes significant in both models (|logtwoFC| > 1; FDR < 0.05; lamda < 0.7) were assigned to functional pathways and visualized by PCA, heat-mapping and volcano plots. Results: Calcifying species segregated cleanly from non-calcifiers on the first two principal components, reflecting a shared 103-gene "calcifier module". Top up-regulated transcripts included developmental morphogens (GLI4, IQCE, NOTCH4), epigenetic regulators (SETD1A, ZNF274, ATF7IP), inflammatory mediators (CSF2RB), and quality-control factors (GABARAPL2, RHOT2). Every leading candidate exhibited minimal phylogenetic signal (lamda to 0), indicating that differential expression tracks the calcified phenotype rather than shared ancestry. Conversely, only three genes (RMI2, RASL11B, GPR18) formed a non-calcifier module, suggesting potential protective roles that are down-regulated during mineralization. Conclusions: Pineal calcification is not a passive by-product of aging but a regulated, lineage- restricted program that redeploys Hedgehog, Notch and chromatin-remodeling pathways classically required for skeletal ossification. The ten-gene core signature identified offers a molecular foothold for mechanistic dissection and therapeutic targeting aimed at preserving pineal function and circadian health. Significance This is the first phylogenetically controlled transcriptomic survey to link pineal "brain-sand" formation to specific developmental and inflammatory gene networks, revealing convergent evolution of calcification programs across divergent mammalian lineages.
Longevity Relevance Analysis
(4)
Pineal calcification is a regulated process linked to specific developmental and inflammatory gene networks. The study addresses the mechanisms underlying pineal gland calcification, which may have implications for circadian health and neurodegenerative risks associated with aging.
Juan Liu, Qingru Song, Chen Li ...
· Cell proliferation
· Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China.
· pubmed
Aging is characterised by progressive structural and functional changes in the liver, with the extracellular matrix (ECM) playing a key role in modulating these changes. Our study presents a comprehensive proteomic analysis of the liver ECM across different age stages, uncovering...
Aging is characterised by progressive structural and functional changes in the liver, with the extracellular matrix (ECM) playing a key role in modulating these changes. Our study presents a comprehensive proteomic analysis of the liver ECM across different age stages, uncovering significant age-related changes. Through the identification of 158 ECM proteins in decellularised rat liver scaffolds, we reveal the intricate relationship between ECM composition and liver maturation, as well as the decrease in regenerative capacity. Lumican was identified as a critical regulator with heightened expression in neonatal livers, which is associated with enhanced hepatocyte proliferation and maintenance of stem cell characteristics. Temporal expression analysis distinguished four distinct clusters of ECM proteins, each reflecting the liver's functional evolution from early development to old age. Early developmental stages were marked by proteins essential for liver growth, while adulthood was characterised by a robust ECM supporting metabolic functions. Middle age showed a regulatory shift towards protease balance, and later life was associated with haemostasis-related processes. Our findings underscore the multifaceted role of the ECM in liver health and aging, offering potential opportunities for therapeutic intervention to counteract age-induced liver dysfunction. This study provides a foundational understanding of ECM dynamics in liver aging and sets the stage for the development of innovative strategies to mitigate the effects of age-related liver decline.
Longevity Relevance Analysis
(4)
The study identifies age-dependent changes in the liver's extracellular matrix and highlights Lumican's role in liver regeneration. This research is relevant as it explores the underlying mechanisms of aging in the liver, potentially offering insights into therapeutic targets for age-related liver dysfunction.
Jing Lu, Hongyan Wang, Haiyu Zhang ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China.
· pubmed
Cardiac fibrosis, a key pathological feature of cardiac remodeling, is a major contributor to mortality in older patients with heart failure. The underlying mechanisms are complex, involving alterations in intercellular communication and chronic inflammation. This study investiga...
Cardiac fibrosis, a key pathological feature of cardiac remodeling, is a major contributor to mortality in older patients with heart failure. The underlying mechanisms are complex, involving alterations in intercellular communication and chronic inflammation. This study investigates the role of indole-3-propionic acid (IPA) in aging-related myocardial fibrosis and its regulatory effects on autophagy through palmitoyl-protein thioesterase 1 (PPT1). Here, plasma levels of IPA, a tryptophan-derived metabolite, are found to be reduced in older patients with heart failure, and this reduction is associated with deteriorating cardiac function. Notably, IPA supplementation significantly attenuated aging-related myocardial fibrosis. PPT1, a lysosomal enzyme involved in autophagy, is upregulated in macrophages during aging. IPA reversed aging-induced increase in PPT1 expression. Using PPT1
Longevity Relevance Analysis
(4)
Indole-3-propionic acid supplementation can attenuate aging-related myocardial fibrosis by regulating macrophage autophagy through PPT1 inhibition. This study addresses a mechanism related to aging and its impact on cardiac health, which is crucial for understanding and potentially mitigating age-related diseases.
Nicolas P Tessier, Lise M Hardy, Florence Mauger ...
· Aging cell
· Laboratory for Genomics, Foundation Jean Dausset-CEPH, Paris, France.
· pubmed
Plasma circulating cell-free nucleic acids (ccfNAs) provide an exceptional source of information about an individual's health, yet their biology in healthy individuals during aging remains poorly understood. Here, we present the first integrative multiparametric analysis of the m...
Plasma circulating cell-free nucleic acids (ccfNAs) provide an exceptional source of information about an individual's health, yet their biology in healthy individuals during aging remains poorly understood. Here, we present the first integrative multiparametric analysis of the major types of plasma ccfNAs, including nuclear (ccfnDNA) and mitochondrial (ccfmtDNA) DNA, as well as ribosomal (ccfrRNA), messenger (ccfmRNA) and micro-RNA (ccfmiRNA) in 139 healthy donors aged 19-66 years. We focused on quantity, integrity, and DNA methylation using an optimized experimental workflow that combines highly sensitive analytical methods with the detection of highly repetitive DNA and highly abundant RNA sequences, thereby reducing the required amount of ccfNAs per analysis. We showed a highly significant increase in ccfnDNA levels during aging (p < 0.001), associated with a decrease in its integrity (p < 0.05), while no significant changes were detected in ccfmtDNA levels and ccfDNA methylation. Moreover, a significant increase in ccfmRNA and ccfrRNA (p < 0.05), as well as miR-483-5p (p < 0.001) levels was detected during aging, but without any changes in ccfRNA integrity. Finally, we also showed that ccfDNA and ccfRNA levels were correlated (p < 0.001), and a similar pattern was observed for ccfmtDNA and ccfRNA levels, suggesting a possible common release, maintenance, and/or clearance mechanism. Therefore, our study provides an optimized workflow for the global analysis of ccfNAs, enhances the understanding of their biology during aging, and identifies several potential ccfNA-based biomarkers of aging.
Longevity Relevance Analysis
(4)
The study identifies significant changes in circulating cell-free nucleic acids during aging, suggesting potential biomarkers for aging. The research focuses on understanding biological changes associated with aging, which is directly relevant to longevity research.
Hong Guo-Parke, Oisin Cappa, Dermot A Linden ...
· American journal of respiratory cell and molecular biology
· Queen's University Belfast, Wellcome Wolfson Institute for Experimental Medicine, Belfast, United Kingdom of Great Britain and Northern Ireland.
· pubmed
Cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The mechanisms of senescence in the bronchial epithelium, however, remain largely unknown. This study aimed to elucidate whether cellular senescence in COPD epithelial cel...
Cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The mechanisms of senescence in the bronchial epithelium, however, remain largely unknown. This study aimed to elucidate whether cellular senescence in COPD epithelial cells contributes to the pathogenesis of the disease and investigated the potential molecular mechanisms involved. Single cell RNA sequencing was performed on well differentiated primary bronchial epithelial cells from COPD and healthy subjects. We evaluated the abundance and distribution of senescence markers in key epithelial differentiated subtypes and senescence-associated secretory phenotype involved in airway epithelial dysfunction. The effects of interferon pathway inhibitors on cellular senescence were also investigated. There was increased expression of cellular senescence genes in the COPD cohort, which was predominantly in basal and club cells. Enhanced expression of cellular senescence markers, p16 and p21, was observed in COPD cultures, which was histologically confirmed in the lung tissue of COPD patients. There was also a notable increase in IFN-β and IFN-γ. Senescence associated secretory phenotype productions were increased in COPD and was attenuated by JAK-STAT or cGAS-STING pathway inhibitors (baricitinib or C-176). These inhibitors also effectively suppressed expression of senescence markers. COPD bronchial epithelium displays a senescence driven phenotype which is mediated by type I/II interferons. Inhibition of JAK-STAT or STING-cGAS interferon pathways may represent targets to alleviate cellular senescence and chronic inflammation in COPD.
Longevity Relevance Analysis
(4)
The study claims that cellular senescence in bronchial epithelium contributes to the pathogenesis of COPD and that targeting interferon pathways may alleviate this senescence. This research is relevant as it explores the mechanisms of cellular senescence, which is a key aspect of aging and age-related diseases, potentially offering insights into therapeutic strategies that address the root causes of aging-related pathologies.
Minsol Jeon, Da-Eun Kim, So Young Choi ...
· Cell communication and signaling : CCS
· Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 02841, Republic of Korea.
· pubmed
The autophagy-lysosomal pathway is a cellular degradation mechanism that regulates protein quality by eliminating aggregates and maintaining normal protein function. It has been reported that aging itself reduces lysosomal proteolytic activity in age-related neurodegenerative dis...
The autophagy-lysosomal pathway is a cellular degradation mechanism that regulates protein quality by eliminating aggregates and maintaining normal protein function. It has been reported that aging itself reduces lysosomal proteolytic activity in age-related neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Reduction in lysosomal function may underlie the accumulation of protein aggregates such as amyloid beta (Aβ), tau, and α-synuclein. Some of these protein aggregates may cause additional lysosomal dysfunction and create a vicious cycle leading to a gradual increase in protein aggregation. In this study, liposome-based lysosomal pH-modulating particles (LPPs), containing a liquid solution to adjust lysosomal pH, have been developed to restore lysosomal function. The results demonstrate that acidic LPPs effectively restore lysosomal function by recovering lysosomal pH and facilitating the removal of protein aggregates. These findings demonstrated that acidic LPPs could effectively recover the abnormal lysosomal function via restoration of lysosomal pH and enhance the clearance of protein aggregates. Furthermore, the simultaneous introduction of Cathepsin B (CTSB) proteins and acidic LPP revealed a synergistic effect, promoting lysosomal pH recovery and enhancing aggregates removal. These findings suggest a novel strategy for improving lysosomal clearance activity in proteinopathies.
Longevity Relevance Analysis
(4)
The study claims that acidic liposome-based particles can restore lysosomal function and enhance the clearance of protein aggregates associated with neurodegenerative diseases. This research is relevant as it addresses the underlying lysosomal dysfunction linked to aging and age-related diseases, potentially offering a strategy to mitigate the effects of aging on cellular degradation mechanisms.
Mutz, J., Gilchrist, L., Allegrini, A. G. ...
· epidemiology
· King\'s College London
· medrxiv
Background: Individuals with mental and behavioural disorders face increased risk of age-related diseases and premature mortality. Accelerated biological ageing may contribute to this disparity. We investigated differences in metabolomic ageing between individuals with and withou...
Background: Individuals with mental and behavioural disorders face increased risk of age-related diseases and premature mortality. Accelerated biological ageing may contribute to this disparity. We investigated differences in metabolomic ageing between individuals with and without mental disorders. Methods: The UK Biobank is a community-based health study of middle-aged and older adults. Mental disorders were identified from hospital inpatient, primary care, death registry and self-reported physician diagnosis data. Plasma metabolites were profiled using the Nightingale Health platform. We examined differences in MileAge delta, the difference between metabolite-predicted and chronological age, across broad ICD-10 diagnostic groups and for 45 individual diagnoses. We further investigated sex-specific associations and tested whether polygenic scores for mental disorders were associated with MileAge delta. Results: Amongst 225,212 participants (54% female; mean age = 56.97 years), 38,524 had at least one mental disorder diagnosis preceding baseline. Substance use, psychotic, affective and neurotic disorders were associated with a metabolite-predicted age exceeding chronological age. In contrast, obsessive-compulsive and eating disorders were associated with a younger MileAge, particularly in females. Associations were generally stronger in males, with several diagnoses showing sex-specific patterns. Higher genetic liability to major depression, autism and ADHD was associated with a MileAge exceeding chronological age, whereas psychosis, tobacco use disorder, obsessive-compulsive disorder and anorexia nervosa polygenic scores were associated with a younger MileAge. Conclusions: Metabolomic ageing varies across mental disorders, with direction and strength of association differing by diagnosis and sex. These findings highlight the heterogeneity of biological ageing across mental disorders and contribute to our understanding of the biological processes linking mental disorders to excess morbidity and premature mortality.
Longevity Relevance Analysis
(4)
Metabolomic ageing varies across mental disorders, with associations differing by diagnosis and sex. This paper is relevant as it explores biological ageing mechanisms linked to mental disorders, contributing to understanding the relationship between mental health and age-related diseases.
Xianhong Zhang, Yue Gao, Siyu Zhang ...
· Cell communication and signaling : CCS
· State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institutes of Biomedical Sciences, School of Life Sciences, Inner Mongolia University, Hohhot, 010070, China.
· pubmed
Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellula...
Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.
Longevity Relevance Analysis
(4)
Mitochondrial dysfunction plays a critical role in aging and age-related diseases, and targeting it may delay senescence. The paper addresses the underlying mechanisms of aging, specifically mitochondrial dysfunction and its relationship with chronic inflammation and cellular senescence, which are central to longevity research.
Birong Jiang, Hongwei Zhang, Qixia Xu ...
· Aging cell
· School of Pharmacy, Institute of Aging Medicine, Binzhou Medical University, Yantai, Shandong, China.
· pubmed
Cellular senescence is an aging-related mechanism characterized by cell cycle arrest, macromolecular alterations, and a senescence-associated secretory phenotype (SASP). Recent preclinical trials established that senolytic drugs, which target survival mechanisms of senescent cell...
Cellular senescence is an aging-related mechanism characterized by cell cycle arrest, macromolecular alterations, and a senescence-associated secretory phenotype (SASP). Recent preclinical trials established that senolytic drugs, which target survival mechanisms of senescent cells, can effectively intervene in age-related pathologies. In contrast, senomorphic agents inhibiting SASP expression while preserving the survival of senescent cells have received relatively less attention, with potential benefits hitherto underexplored. By revisiting a previously screened natural product library, which enabled the discovery of procyanidin C1 (PCC1), we noticed pyrroloquinoline quinone (PQQ), a redox cofactor that displayed remarkable potential in serving as a senomorphic agent. In vitro data suggested that PQQ downregulated the full spectrum expression of the SASP, a capacity observed in several stromal cell lines. Proteomics data supported that PQQ directly targets the intracellular protein HSPA8, interference with which disturbs downstream signaling and expression of the SASP. PQQ restrains cancer cell malignancy conferred by senescent stromal cells in culture while reducing drug resistance when combined with chemotherapy in anticancer regimens. In preclinical trials, PQQ alleviates pathological symptoms by preventing organ degeneration in naturally aged mice while reserving senescent cells in the tissue microenvironment. Together, our study supports the feasibility of exploiting a redox-active quinone molecule with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing proof-of-concept evidence for future exploration of natural antioxidant agents to delay aging and ameliorate age-related conditions. Prospective efforts are warranted to determine long-term outcomes and the potential of PQQ for the intervention of geriatric syndromes in clinical settings.
Longevity Relevance Analysis
(4)
Pyrroloquinoline quinone (PQQ) acts as a senomorphic agent that downregulates the senescence-associated secretory phenotype (SASP) while preserving senescent cells. This paper is relevant as it explores a potential intervention targeting the mechanisms of cellular senescence, which is a root cause of aging and age-related diseases.
Chenghui Yu, Xingxing Qiu, Si Tao ...
· Biogerontology
· Department of Hematology, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, China.
· pubmed
This study investigates the impact of dietary restriction (DR) on gene expression in hematopoietic stem cells (HSCs) derived from aged mice. RNA sequencing (RNA-seq) data were obtained from sorted HSCs, followed by weighted gene co-expression network analysis (WGCNA) to identify ...
This study investigates the impact of dietary restriction (DR) on gene expression in hematopoietic stem cells (HSCs) derived from aged mice. RNA sequencing (RNA-seq) data were obtained from sorted HSCs, followed by weighted gene co-expression network analysis (WGCNA) to identify differentially expressed genes (DEGs) and key transcriptional modules. Principal component analysis (PCA) and heatmaps revealed significant differences between the groups, highlighting a predominant upregulation of gene expression during aging and a more suppressive gene expression profile under DR. Functional enrichment analysis indicated that the aging process in HSCs is characterized by enhanced expression of genes associated with inflammatory responses and DNA damage, whereas DR significantly reduced gene expression related to immune responses, protein quality control, and cellular stress responses. Additionally, our analysis identified key transcription factors (TFs), such as Gata2, Klf16, and Runx3, which likely mediate the gene expression changes observed under DR. These TFs are implicated in critical processes, including signal transduction, transcriptional regulation, and cellular responses to DNA damage. Furthermore, machine learning algorithms identified Gnptg as a key hub gene associated with programmed cell death (PCD) in HSC aging with its gene products maintaining lysosomal homeostasis. DR reduced lysosomal numbers and preserved lysosomal membrane integrity in aging HSCs, suggesting that lysosomal dysfunction contributes to HSC aging. Overall, DR induces a distinct transcriptional landscape in aged HSCs, suggesting a protective role by reducing harmful gene expression linked to inflammation, DNA damage, apoptosis, and stress responses, thereby maintaining HSC function during aging.
Longevity Relevance Analysis
(4)
Dietary restriction alters the transcriptional profiles of hematopoietic stem cells in aged female mice, suggesting a protective role against aging-related dysfunction. The study addresses the underlying mechanisms of aging by exploring how dietary interventions can influence stem cell function, which is crucial for longevity research.
Danai Koftori, Charandeep Kaur, Laura Mora Bitria ...
· PLoS biology
· Department of Infectious Disease, Imperial College London, London, United Kingdom.
· pubmed
T stem cell-like memory cells (TSCM cells) are considered to be essential for the maintenance of immune memory. The TSCM population has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single po...
T stem cell-like memory cells (TSCM cells) are considered to be essential for the maintenance of immune memory. The TSCM population has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed. We show that the human TSCM population consists of two distinct cell subpopulations which can be distinguished by the level of their CD95 expression (CD95int and CD95hi). Crucially, using long-term in vivo labelling of human volunteers, we establish that these are distinct populations rather than transient states of the same population. These two subpopulations have different functional profiles ex vivo, different transcriptional patterns, and different tissue distributions. They also have significantly different TREC content indicating different division histories and we find that the frequency of CD95hi TSCM increases with age. Most importantly, CD95hi and CD95int TSCM cells also have very different dynamics in vivo with CD95hi cells showing considerably higher proliferation but significantly reduced clonal longevity compared with CD95int TSCM. While both TSCM subpopulations exhibit considerable multipotency, no single population of TSCM cells has both the properties of self-renewal and clonal longevity. Instead, the "stemness" of the TSCM population is generated by the complementary dynamic properties of the two subpopulations: CD95int TSCM which have the property of clonal longevity and CD95hi TSCM which have the properties of expansion and self-renewal. We suggest that together, these two populations function as a stem cell population.
Longevity Relevance Analysis
(4)
The paper claims that two distinct subpopulations of T stem cell-like memory cells exhibit complementary roles in self-renewal and clonal longevity. This research is relevant as it explores the mechanisms of immune memory maintenance, which could have implications for understanding aging and longevity at the cellular level.
Brigos-Barril, E., Vasallo, C., Farre, X. ...
· genetic and genomic medicine
· Hospital Universitari Institut Pere Mata (HUIPM), Institut d\'Investigacio Sanitaria Pere Virgili (IISPV-CERCA), Universitat Rovira i Virgili (URV), Reus, Catal
· medrxiv
The persistence of genetic variants that increase susceptibility to complex diseases poses an evolutionary paradox: despite their detrimental health effects, these variants are not eliminated by natural selection. Life-history theory proposes that trade-offs and pleiotropic effec...
The persistence of genetic variants that increase susceptibility to complex diseases poses an evolutionary paradox: despite their detrimental health effects, these variants are not eliminated by natural selection. Life-history theory proposes that trade-offs and pleiotropic effects across fitness components may explain the evolutionary maintenance of disease-associated alleles. We hypothesize that certain disease-risk alleles might segregate in the population because they confer reproductive advantages, even at the expense of late-life costs on health and longevity. Leveraging genome-wide association studies, we investigated genetic correlations and pleiotropic relationships between 62 complex diseases, longevity, and fertility. In our study, we estimated fertility by meta-analyzing complementary measures of offspring number and used parental lifespan as a proxy for longevity. We found that 85% of diseases showed negative genetic correlations with longevity, whereas 87% of diseases with significant correlations showed positive associations with fertility. Moreover, most disease-risk variants were associated with reduced longevity, even after accounting for socioeconomic confounders. Fertility-increasing alleles exhibited evolutionary signals consistent with adaptive selection despite having pleiotropic effects on disease-risk. Finally, we compared the number of offspring among individuals with high genetic risk of disease and found that, for most diseases, affected individuals had more offspring than disease-free individuals. However, for early-onset conditions, non-affected individuals exhibited higher fertility, highlighting the reproductive cost of early-onset diseases. These findings support the Antagonistic Pleiotropy theory, showing that alleles that enhance early-life reproductive success can persist despite late-life health costs. By uncovering these evolutionary trade-offs between reproduction, longevity, and disease risk, our study shows how Darwinian selection continues to shape contemporary patterns of human disease susceptibility. Understanding these evolutionary trade-offs can inform public health approaches and help anticipate unintended consequences of targeting disease-related genetic pathways.
Longevity Relevance Analysis
(4)
The paper claims that certain disease-risk alleles persist in the population due to their reproductive advantages despite their negative effects on longevity. This research is relevant as it explores the evolutionary trade-offs between fertility, longevity, and disease, contributing to our understanding of the underlying mechanisms of aging and healthspan.
Edward R Ivimey-Cook, Zahida Sultanova, Alexei A Maklakov
· Aging cell
· School of Biodiversity, One Health, and Veterinary Medicine, University of Glasgow, Glasgow, UK.
· pubmed
Dietary restriction (DR) robustly increases lifespan across taxa. However, in humans, long-term DR is difficult to maintain, leading to the search for compounds that regulate metabolism and increase lifespan without reducing caloric intake. The magnitude of lifespan extension fro...
Dietary restriction (DR) robustly increases lifespan across taxa. However, in humans, long-term DR is difficult to maintain, leading to the search for compounds that regulate metabolism and increase lifespan without reducing caloric intake. The magnitude of lifespan extension from two such compounds, rapamycin and metformin, remains inconclusive, particularly in vertebrates. Here, we conducted a meta-analysis comparing lifespan extension conferred by rapamycin and metformin to DR-mediated lifespan extension across vertebrates. We assessed whether these effects were sex- and, when considering DR, treatment-specific. In total, we analysed 911 effect sizes from 167 papers covering eight different vertebrate species. We find that DR robustly extends lifespan across log-response means and medians and, importantly, rapamycin-but not metformin-produced a significant lifespan extension. We also observed no consistent effect of sex across all treatments and log-response measures. Furthermore, we found that the effect of DR was robust to differences in the type of DR methodology used. However, high heterogeneity and significant publication bias influenced results across all treatments. Additionally, results were sensitive to how lifespan was reported, although some consistent patterns still emerged. Overall, this study suggests that rapamycin and DR confer comparable lifespan extension across a broad range of vertebrates.
Longevity Relevance Analysis
(5)
Rapamycin, but not metformin, significantly extends lifespan in vertebrates, comparable to dietary restriction. The paper is relevant as it investigates compounds that may mimic the effects of dietary restriction, a key area in longevity research focused on lifespan extension and the underlying mechanisms of aging.
Living animals reach their end-of-life through a stereotypic set of fascinating but poorly understood processes. The discovery, first in flies and later in nematodes and zebrafish, of the "Smurf phenotype" is a central tool for picking this complex "lock of biology", that one of ...
Living animals reach their end-of-life through a stereotypic set of fascinating but poorly understood processes. The discovery, first in flies and later in nematodes and zebrafish, of the "Smurf phenotype" is a central tool for picking this complex "lock of biology", that one of ageing. Using the Smurfs, we have shown an evolutionarily conserved end-of-life transition across Drosophilids, nematodes and zebrafish. This tool has been key to identify the discontinuous nature of ageing and predict impending death from natural causes as well as from environmental stresses. This phenotype allowed us to discover that ageing is made up of two successive phases : a first phase where individuals are healthy and have no risk of mortality, but show an age-dependent and increasing risk of entering a second phase, characterized by the so-called hallmarks of ageing and a high risk of death. Here, we test whether these two consecutive phases of ageing separated by the Smurf transition are a conserved feature of ageing in the mammals using Mus musculus as a model. We performed a longitudinal longevity study using both males and females from two different mouse genetic backgrounds and by integrating physiological, metabolic and molecular measurements with the life history of approximately 150 mice. We show the existence of a phenotypic signature typical of the last phase of life, observable at any chronological age. Validating the two-phase ageing model in a mammalian organism allows better characterized the high risk of imminent death and would extend its implications to a broader range of species for ageing research.
Longevity Relevance Analysis
(4)
The paper claims that there are two consecutive phases of ageing in mammals, characterized by a phenotypic signature that indicates a high risk of imminent death. This research is relevant as it seeks to understand the fundamental processes of ageing and the transition to end-of-life, which could inform strategies for longevity and age-related health improvements.
Wuzhe Fan, Tao Zheng, Mingsong Mao ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Key Laboratory of Biorheological Science and Technology, Ministry of Education College of Bioengineering, Chongqing University, Chongqing, 400044, China.
· pubmed
Traditional biomaterial design often prioritizes empirical knowledge over disease mechanisms and pathological dynamics, resulting in imprecise solutions in complex clinical conditions. Age-related osteoporosis (A-OP) is a disease associated with aging, characterized by a dysfunct...
Traditional biomaterial design often prioritizes empirical knowledge over disease mechanisms and pathological dynamics, resulting in imprecise solutions in complex clinical conditions. Age-related osteoporosis (A-OP) is a disease associated with aging, characterized by a dysfunctional pathological microenvironment that hinders the osseointegration of conventional titanium implants. To develop a targeted titanium implant for A-OP, rat single-cell transcriptomics is integrated with human serum-derived transcriptome data to investigate dynamic changes in skeletal stem cells (SSCs) during aging, which guided the implant design. These findings reveal that hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) within SSCs interact via a feedback loop: HSCs undergo premature senescence, leading to depletion of HSCs and secondary senescence of MSCs. Senescent MSCs exhibit adipogenic bias, perpetuating the pathological cycle of A-OP. Using core genes identified in the transcriptome analyses, resveratrol is selected and utilized it and a GelMA-chitosan hydrogel to decorate titanium implants for localized delivery. In the A-OP microenvironment, the hydrogel enables sustained responsive release of resveratrol, which reverses MSC senescence and redirects differentiation from adipogenic to osteogenic lineages, thereby breaking the pathological cycle. This multi-omics-driven implant design enhances precision and offers a novel methodology for biomaterial development.
Longevity Relevance Analysis
(4)
The paper claims that a titanium implant designed with a GelMA-chitosan hydrogel can reverse MSC senescence and promote osteogenic differentiation in the context of age-related osteoporosis. This research is relevant as it addresses the underlying mechanisms of aging-related bone degeneration and proposes a novel approach to improve outcomes in age-related diseases.
Garrod-Ketchely, C., Callender, L. A., Schroth, J. ...
· immunology
· QMUL
· biorxiv
Ageing is associated with significant immune changes, with unhealthy ageing characterised by chronic inflammation and immune dysregulation. Here we identify a population of CD8 TEMRA cells during unhealthy ageing, which exhibit features of premature senescence and are regulated i...
Ageing is associated with significant immune changes, with unhealthy ageing characterised by chronic inflammation and immune dysregulation. Here we identify a population of CD8 TEMRA cells during unhealthy ageing, which exhibit features of premature senescence and are regulated in part by TGF{beta}. These cells show impaired cytotoxic function and altered migratory behaviour, including an increased presence in tissues. TGF{beta} plays a pivotal role in modulating their phenotype by inducing CD103 expression and downregulating KLRG1, causing these cells to resemble tissue-resident memory cells. This disruption to receptor recycling leads to defective degranulation potentially altering the capacity of these cells to mount an effective immune response. Overall, these findings suggest that TEMRA cells in the context of unhealthy ageing are a pathogenic T cell subset that accumulate in tissues where they are unable to exert an effector function.
Longevity Relevance Analysis
(4)
The paper identifies a pathogenic subset of CD8 TEMRA cells in unhealthy ageing that exhibit features of premature senescence and impaired immune function. This research is relevant as it explores the immune changes associated with unhealthy ageing, potentially addressing underlying mechanisms that contribute to age-related diseases.
Eleanor L S Conole, Josephine A Robertson, Hannah M Smith ...
· Nature reviews. Neurology
· Department of Biochemistry, University of Oxford, Oxford, UK.
· pubmed
Ageing has profound effects on the human brain across the lifespan. Cognitive testing and brain imaging are currently used to monitor healthy and pathological brain ageing. However, peripheral markers of cognitive function, cognitive ageing and neurological disease could provide ...
Ageing has profound effects on the human brain across the lifespan. Cognitive testing and brain imaging are currently used to monitor healthy and pathological brain ageing. However, peripheral markers of cognitive function, cognitive ageing and neurological disease could provide a valuable, minimally invasive approach to tracking these processes longitudinally. In this Review, we introduce the concept of DNA methylation-based biomarkers and present current evidence of their potential to address the challenge of monitoring brain ageing and stratifying the risk of neurological disease. We focus on epigenetic clocks, which can be applied across multiple tissues and organs to estimate biological ageing, as well as on blood-based epigenetic scores (EpiScores) that can directly track brain-based phenotypes, such as cognitive function, and risk factors for neurological diseases, such as lifestyle behaviours and proteomic markers of inflammation. We discuss the associations between these epigenetic biomarkers and multiple measures of cognitive health, including cognitive test data, brain MRI measures and dementia.
Longevity Relevance Analysis
(4)
The paper discusses the potential of DNA methylation-based biomarkers to monitor brain ageing and neurological disease risk. This research is relevant as it explores biological markers that could help in understanding and potentially mitigating the effects of aging on brain health.
Adiv A Johnson, Maxim N Shokhirev
· Aging
· Tally Health, New York, NY, USA. [email protected].
· pubmed
Aging biomarkers that predict age given methylomic data are referred to as epigenetic aging clocks. While the earliest, first-generation clocks were exclusively trained to predict chronological age, more recent next-generation models have been explicitly trained to associate with...
Aging biomarkers that predict age given methylomic data are referred to as epigenetic aging clocks. While the earliest, first-generation clocks were exclusively trained to predict chronological age, more recent next-generation models have been explicitly trained to associate with health, lifestyle, and/or age-related outcomes. Although these next-generation models have been trained using distinct approaches and techniques, existing evidence indicates that they associate with a greater number of health and disease signals than first-generation clocks. Moreover, they are often more predictive of age-related outcomes and appear more responsive to interventions. In this work, we provide definitions for first- versus next-generation clocks and discuss the potential merits of further dividing next-generation clocks into sub-categories. In addition, we summarize existing next-generation epigenetic aging clocks, including how they were trained and how they can be accessed. Given the relative value of interventional data over observational data, we comprehensively tabulate existing literature documenting the ability of an intervention to influence at least one epigenetic aging clock. While we acknowledge that the decision to a use a specific clock is ultimately dependent on the research application and goal, current evidence suggests that next-generation models should be generally prioritized for health-oriented association and interventional studies.
Longevity Relevance Analysis
(4)
Next-generation epigenetic aging clocks are more predictive of age-related outcomes and responsive to interventions compared to first-generation clocks. The paper is relevant as it discusses advancements in aging biomarkers that can potentially lead to better understanding and interventions in the aging process.
Jieyu Wu, Victoria R Yarmey, Olivia Jiaming Yang ...
· Nature neuroscience
· Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA.
· pubmed
The nervous system is primarily composed of neurons and glia, and the communication between them has profound roles in regulating the development and function of the brain. Neuron-glia signal transduction is known to be mediated by secreted signals through ligand-receptor interac...
The nervous system is primarily composed of neurons and glia, and the communication between them has profound roles in regulating the development and function of the brain. Neuron-glia signal transduction is known to be mediated by secreted signals through ligand-receptor interactions on the cell membrane. Here we show a new mechanism for neuron-glia signal transduction, wherein neurons transmit proteins to glia through extracellular vesicles, activating glial signaling pathways. We find that in the amphid sensory organ of Caenorhabditis elegans, different sensory neurons exhibit varying aging rates. This discrepancy in aging is governed by the cross-talk between neurons and glia. We demonstrate that early aged neurons can transmit heat shock proteins to glia via extracellular vesicles. These neuronal heat shock proteins activate the glial IRE1-XBP1 pathway, leading to the transcriptional regulation of chondroitin synthases to protect glia-embedded neurons from aging-associated functional decline. Therefore, our studies unveil a new mechanism for neuron-glia communication in the nervous system and provide new insights into our understanding of brain aging.
Longevity Relevance Analysis
(4)
Neurons transmit heat shock proteins to glia via extracellular vesicles, activating glial signaling pathways that protect against aging-associated functional decline. This study explores a novel mechanism of neuron-glia communication that could provide insights into the biological processes underlying aging and potential interventions to mitigate age-related decline.
Lei Zhang, Kai Xiang, Jinlong Li ...
· ACS nano
· School of Pharmacy, Wannan Medical College, Wuhu 241002, China.
· pubmed
Osteoarthritis (OA) is a classic age-related disorder, and its progression is positively associated with the number of senescent cells in the synovium of the joint. Senolytics have been used to slow or reverse the aging process, which is currently limited by off-target toxicity. ...
Osteoarthritis (OA) is a classic age-related disorder, and its progression is positively associated with the number of senescent cells in the synovium of the joint. Senolytics have been used to slow or reverse the aging process, which is currently limited by off-target toxicity. Therapeutic efficacy can be achieved by enhancing the immune-mediated clearance of senescent cells. However, the surveillance of senescent cells by the immune system is often hindered by immunosuppressive factors within the inflammatory microenvironment. Herein, we constructed photoactivatable exosenolytics based on microphage-derived exosomes adorned with the gripper ligand aPD-L1 and aging cell-targeting ligands, encapsulating with a photosensitizer and NKG2D ligand activator for the precise antiaging treatment of OA. Exosenolytic-mediated photodynamic therapy can induce the recruitment of natural killer (NK) cells, enhance the gripping effect of NK cells to senescent fibroblast-like synoviocytes, and strengthen the immune system for clearance of senescent synovial cells by activating the cGAS-STING pathway. Importantly, exosenolytics selectively accumulated in senescent fibroblast-like synoviocytes in the inflamed joints of OA mice and effectively suppressed synovial inflammation and progression of OA. Exosenolytics employ an immunological conversion strategy to remodel the senescent immune microenvironment, offering a promising approach for aging immunotherapy.
Longevity Relevance Analysis
(4)
The paper claims that photoactivatable exosenolytics can enhance the immune-mediated clearance of senescent cells in osteoarthritis. This research addresses the root cause of aging by targeting senescent cells, which are implicated in age-related diseases, thus contributing to the field of longevity.
Yuan Liu, Shiyang He, Kawon Pyo ...
· Cell Proliferation
· Department of Biochemistry, University of California, Riverside, 3401 Watkins Drive, Boyce Hall, Riverside, CA, USA.
· pubmed
Cellular quiescence is a state of reversible proliferative arrest that plays essential roles in development, resistance to stress, aging, and longevity of organisms. Here we report that rapid depletion of RNase MRP, a deeply conserved RNA-based enzyme required for rRNA biosynthes...
Cellular quiescence is a state of reversible proliferative arrest that plays essential roles in development, resistance to stress, aging, and longevity of organisms. Here we report that rapid depletion of RNase MRP, a deeply conserved RNA-based enzyme required for rRNA biosynthesis, induces a long-term yet reversible proliferative arrest in human cells. Severely compromised biogenesis of rRNAs along with acute transcriptional reprogramming precede a gradual decline of the critical cellular functions. Unexpectedly, many arresting cells show increased levels of histone mRNAs, which accumulate locally in the cytoplasm, and S-phase DNA amount. The ensuing proliferative arrest is entered from multiple stages of the cell cycle and can last for several weeks with uncompromised cell viability. Strikingly, restoring expression of RNase MRP leads to a complete reversal of the arrested state with resumed cell proliferation at the speed of control cells. We suggest that targeting rRNA biogenesis may provide a general strategy for rapid induction of a reversible proliferative arrest, with implications for understanding and manipulating cellular quiescence.
Longevity Relevance Analysis
(4)
Rapid depletion of RNase MRP induces a long-term yet reversible proliferative arrest in human cells. The study explores mechanisms of cellular quiescence, which are directly linked to aging and longevity, suggesting potential strategies for manipulating these processes.
Caihong Gu, Ting Guo, Xiaobing Chen ...
· Mitochondria
· Department of Critical Care Medicine, The First Affiliated Hospital of Kangda College of Nanjing Medical University, The Affiliated Lianyungang Hospital of Xuzhou Medical University, Lianyungang Clinical College of Nanjing Medical University, Lianyungang, 222000, Jiangsu, PR China.
· pubmed
The benefits of senolytic therapy have been known in a series of age-related diseases, whereas its potential roles in global cerebral ischemic (GCI) brain injury remain unexplored. In current study, we aim to investigate the effects of combined senolytics Dasatinib plus Quercetin...
The benefits of senolytic therapy have been known in a series of age-related diseases, whereas its potential roles in global cerebral ischemic (GCI) brain injury remain unexplored. In current study, we aim to investigate the effects of combined senolytics Dasatinib plus Quercetin (D&Q) treatment in GCI and the underlying mechanisms in a mouse model. We firstly report that 12-week post-GCI D&Q treatment effectively eliminated cellular senescence of astrocytes and microglia in the hippocampus of mice brain, followed by decreased release of the potent inflammatory senescence-associated secretory phenotypes (SASP). Further mechanistic analysis suggested that D&Q administration can effectively regulate mitochondrial function as a critical downstream target. D&Q treatment inhibited GCI-induced mitochondrial fragmentation and maintained mitochondrial integrity. Subsequently, D&Q treatment improved the mitochondrial metabolic function by enhancing mitochondrial cytochrome c oxidase (CCO) activity and ATP production. Moreover, D&Q treatment reversed the decline of mitochondrial antioxidant enzyme SOD2 and reduced the ROS accumulation and suppressed oxidative damage to cellular protein structure. Further investigation indicated D&Q treatment protected the hippocampal neurons after GCI by mitigating the dendritic injury and neuronal apoptotic signaling. Extensive behavioral tests assessed the functional outcomes and showed that D&Q treatment effectively preserved hippocampus-dependent spatial reference memory and recognition memory, and mitigated GCI-induced anxiety and depression levels. Taken together, our study provides leading evidence for the neuroprotective roles of the senolytics D&Q in GCI model and identifies regulation of mitochondrial functions could be the key underlying mechanism. These findings offer novel insights into the potential clinical applications of senolytic agents in therapy.
Longevity Relevance Analysis
(4)
The paper claims that senolytic treatment with Dasatinib and Quercetin improves cognitive recovery and mitigates brain injury by targeting mitochondrial function. The study addresses the role of senolytics in alleviating cellular senescence, which is a key aspect of aging and age-related diseases, thus contributing to the understanding of potential therapeutic strategies for longevity.
Karina A Cicali, Angie K Torres, Cheril Tapia-Rojas
· Neural regeneration research
· Laboratory of Neurobiology of Aging, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile.
· pubmed
Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfuncti...
Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfunction of mitochondria, particularly those located at synapses. Synaptic mitochondria are specialized organelles that produce the energy required for synaptic transmission but are also important for calcium homeostasis at these sites. In contrast, non-synaptic mitochondria primarily involve cellular metabolism and long-term energy supply. Both pools of mitochondria differ in their form, proteome, functionality, and cellular role. The proper functioning of synaptic mitochondria depends on processes such as mitochondrial dynamics, transport, and quality control. However, synaptic mitochondria are particularly vulnerable to age-associated damage, characterized by oxidative stress, impaired energy production, and calcium dysregulation. These changes compromise synaptic transmission, reducing synaptic activity and cognitive decline during aging. In the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, the decline of synaptic mitochondrial function is even more pronounced. These diseases are marked by pathological protein accumulation, disrupted mitochondrial dynamics, and heightened oxidative stress, accelerating synaptic dysfunction and neuronal loss. Due to their specialized role and location, synaptic mitochondria are among the first organelles to exhibit dysfunction, underscoring their critical role in disease progression. This review delves into the main differences at structural and functional levels between synaptic and nonsynaptic mitochondria, emphasizing the vulnerability of synaptic mitochondria to the aging process and neurodegeneration. These approaches highlight the potential of targeting synaptic mitochondria to mitigate age-associated cognitive impairment and synaptic degeneration. This review emphasizes the distinct vulnerabilities of hippocampal synaptic mitochondria, highlighting their essential role in sustaining brain function throughout life and their promise as therapeutic targets for safeguarding the cognitive capacities of people of advanced age.
Longevity Relevance Analysis
(4)
The paper claims that targeting synaptic mitochondria could mitigate age-associated cognitive impairment and synaptic degeneration. This research is relevant as it addresses the functional decline of synaptic mitochondria, which is a critical factor in the aging process and neurodegenerative diseases, potentially offering insights into interventions that could impact longevity and cognitive health.
Jiajin Chen, Sicheng Li, Shichen Bu ...
· GeroScience
· Institute of Cardiovascular Diseases, Xiamen Cardiovascular Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2999 Jinshan Road, Xiamen, 361006, Fujian, China. [email protected].
· pubmed
Older adults with established cardiovascular diseases (CVD) are at elevated risk of heart failure (HF). Frailty, a hallmark of multi-system aging, may contribute to HF development through inflammation. However, population-based evidence remains scarce. Leveraging data from 49,530...
Older adults with established cardiovascular diseases (CVD) are at elevated risk of heart failure (HF). Frailty, a hallmark of multi-system aging, may contribute to HF development through inflammation. However, population-based evidence remains scarce. Leveraging data from 49,530 CVD patients in the UK Biobank, frailty was measured by five components: weight loss, exhaustion, low physical activity, slow walking speed, and low grip strength. We employed Cox regression models to assess the association between frailty and incident HF, and conducted mediation analyses to evaluate mediating roles of 15 inflammatory markers in this association. Furthermore, we constructed a polygenic risk score (PRS) for HF risk based on the Global Biobank Meta-analysis Initiative (N = 1,020,441), and evaluated the joint association and interaction between frailty and PRS in relation to incident HF. During a median follow-up of 13.3 years, 6293 participants developed HF. Compared to robust individuals, pre-frail (hazard ratio (HR) = 1.31 [95% CI: 1.23-1.40]) or frail (HR = 1.80 [1.64-1.98]) participants had a higher risk of HF, and the potential causality was suggested by Mendelian randomization. Such relationship was partially mediated by inflammatory markers, including interleukin-6, tumor necrosis factor-α, and C-reactive protein. Moreover, individuals with both frailty and high PRS had the greatest risk of HF (HR = 4.35 [3.74-5.06]), with a relative excess risk due to interaction of 1.39, accounting for 32% of total risk. Frailty interacts with PRS to enhance risk stratification of HF. Inflammation may mediate the frailty-HF association, suggesting the potential of anti-inflammatory interventions to mitigate HF risk in frail CVD patients.
Longevity Relevance Analysis
(5)
Frailty and polygenic risk score interact to enhance the risk of heart failure in cardiovascular patients, with inflammation mediating this association. The study addresses the underlying mechanisms linking frailty and heart failure, which are critical for understanding age-related diseases and potential interventions targeting the root causes of aging.
Payet, A., Guillou, E., Bernat-Fabre, S. ...
· cell biology
· RESTORE Research Center
· biorxiv
Aging involves a progressive decline in physiological functions, often marked by the onset of a \"frailty point\" just before survival rates decrease rapidly. Here, we investigate how the Mediator subunit Med19 modulates this transition in Drosophila. We find that upregulating Me...
Aging involves a progressive decline in physiological functions, often marked by the onset of a \"frailty point\" just before survival rates decrease rapidly. Here, we investigate how the Mediator subunit Med19 modulates this transition in Drosophila. We find that upregulating Med19 extends the median lifespan by nearly 90% and postpones the onset of accelerated mortality, suggesting that Med19 helps preserve the resilience phase of aging. In contrast, Med19 downregulation sharply reduces both median and maximum lifespan, advancing the frailty threshold. We show that Med19 knockdown increases fly vulnerability to environmental insults such as oxidative and genotoxic challenges whereas Med19 upregulation helps them resist these stresses, underscoring Med19\'s protective role in maintaining genomic integrity. We link these phenotypes to altered stress response pathways at the cellular level: Med19 depleted cells show a compensatory upregulation of genes involved in iron-sulfur cluster biogenesis, glutathione metabolism, and DNA damage repair. At the cellular level, Med19 depletion triggers a \"loser\" phenotype in cell competition assays, activating the JNK pathway and undergoing apoptosis, highlighting a form of \"cellular frailty\" that parallels organismal frailty. Finally, we found that the Med19 protein level naturally decreases with age and showed that restoring Med19 expression in aged flies increases fitness and delays the onset of frailty even in older, \"frail\" individuals, underscoring its significance as an aging regulator. Altogether, our findings establish Med19 as a crucial mediator of lifespan and stress resilience, suggesting it acts as a rheostat that modulates the transition from healthy aging to frailty in Drosophila.
Longevity Relevance Analysis
(5)
Upregulating Med19 extends median lifespan in Drosophila by preventing cellular and organismal frailty. The paper addresses the mechanisms underlying aging and lifespan extension, focusing on a specific protein that influences the transition from healthy aging to frailty, which is central to longevity research.
Kristian E Markon, Frank D Mann, Colin D Freilich ...
· Aging
· University of Minnesota, Minneapolis, Minnesota, United States of America.
· pubmed
Measurement of aging is critical to understanding its causes and developing interventions, but little consensus exists on what components such measurements should include or how they perform in predicting mortality. The aim of this study was to identify factors of aging among a c...
Measurement of aging is critical to understanding its causes and developing interventions, but little consensus exists on what components such measurements should include or how they perform in predicting mortality. The aim of this study was to identify factors of aging among a comprehensive set of indicators, and to evaluate their relative performance in predicting mortality. Measurements on 34 clinical, survey, and neuroimaging variables, along with epigenetic age markers, were obtained from two waves (2004-2021) of the Midlife in the United States (MIDUS) study. Mortality data was also available on 11875 participants, including 1908 twins. Factor analyses were used to identify aging factors, and these were used to predict mortality as of 2022. Twin data were used to model predictors of mortality within families. Factor analyses identified 9 major dimensions of aging: frailty, cognition, adiposity, glucose, blood pressure, inflammation, lipids, adaptive functioning, and neurological functioning. The strongest predictors of survival among the aging dimensions were cognition, adaptive functioning, and inflammation, and among the epigenetic markers, the decline-predictive markers (GrimAge and DunedinPACE). When entered in joint prediction models, cognition remained a significant predictor of mortality, but the epigenetic markers did not. Cognition, adaptive functioning, and inflammation remained significant predictors of mortality within twin pairs as well. Aging is a multidimensional construct, with cognition, adaptive functioning, and inflammation being the strongest predictors of survival among the aging dimensions examined. Their association with mortality is observed within families, suggesting that early developmental factors cannot entirely account for their association with survival. Interventions and assessments should prioritize cognition in measures of aging quality, along with adaptive functioning and inflammation.
Longevity Relevance Analysis
(4)
Cognition, adaptive functioning, and inflammation are identified as significant predictors of mortality among aging dimensions. The paper is relevant as it explores multidimensional aspects of aging and their relationship to mortality, contributing to the understanding of aging's root causes and potential interventions.
Lukacsovich, D., Young, J., Gomez, L. ...
· genetic and genomic medicine
· University of Miami
· medrxiv
Aging is the strongest risk factor for Alzheimer's disease (AD), yet the molecular mechanisms linking aging to AD remain poorly understood. DNA methylation (DNAm) is an epigenetic modification that plays a critical role in gene regulation and has been implicated in both aging and...
Aging is the strongest risk factor for Alzheimer's disease (AD), yet the molecular mechanisms linking aging to AD remain poorly understood. DNA methylation (DNAm) is an epigenetic modification that plays a critical role in gene regulation and has been implicated in both aging and AD. In this study, we performed a meta analysis of DNAm profiles in the prefrontal cortex using two large, independent postmortem brain cohorts, the Religious Orders Study and Memory and Aging Project (ROSMAP) and Brains for Dementia Research (BDR), to identify DNAm differences associated with aging in late life. We identified 3264 CpGs significantly associated with aging, the majority of which were hypermethylated and enriched in promoter regions and CpG islands. These aging associated DNAm changes were significantly overrepresented in genes involved in immune regulation and metabolic pathways. When compared with AD associated DNAm changes, we found a significant overlap, with nearly all CpGs and differentially methylated regions (DMRs) that were associated with both aging and AD Braak stage displaying concordant directionality. This supports the hypothesis that aging and AD are interconnected at the molecular level. Further integrative analyses indicated that a number of these DNAm variants may have functional relevance in AD. By integrating blood DNAm data, we identified multiple CpGs that showed significant brain to blood correlations and were involved in both aging and AD pathogenesis. Colocalization analyses with genomewide association study (GWAS) data revealed shared genetic regulation of DNAm and dementia at several AD risk loci. Out of sample validation using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrated that, among 334 CpGs showing concordant DNAm changes in aging and AD, baseline DNAm levels at cg10752406 in the AZU1 promoter were significantly associated with AD progression at a 5% false discovery rate, even after adjusting for age, sex, APOE {varepsilon}4 allele status, years of education, and baseline MMSE. Notably, this CpG also showed a strong brain blood DNAm correlation, further supporting its potential as a peripheral biomarker for AD. Our study provides valuable insights into the epigenetic landscape of aging and its implications for AD, suggesting that aging related epigenetic modifications may provide a viable source of biomarkers for AD.
Longevity Relevance Analysis
(4)
The study identifies DNA methylation changes associated with aging that overlap with those in Alzheimer's disease, suggesting potential biomarkers for AD. The paper is relevant as it explores the molecular mechanisms linking aging to Alzheimer's disease, which could contribute to understanding the root causes of age-related cognitive decline.
Ayala-Hernandez, M. G., Torales, A. B., Tan, H. C. ...
· biochemistry
· University of California Davis
· biorxiv
Mutations in mitochondrial complex I can cause severe metabolic disease. Although no treatments are available for complex I deficiencies, chronic hypoxia improves lifespan and function in a mouse model of the severe mitochondrial disease Leigh syndrome caused by mutation of compl...
Mutations in mitochondrial complex I can cause severe metabolic disease. Although no treatments are available for complex I deficiencies, chronic hypoxia improves lifespan and function in a mouse model of the severe mitochondrial disease Leigh syndrome caused by mutation of complex I subunit NDUFS4. To understand the molecular mechanism of NDUFS4 mutant pathophysiology and hypoxia rescue, we investigated the structure of complex I in respiratory supercomplexes isolated from NDUFS4 mutant mice. We identified complex I assembly intermediates bound to complex III2, proving the cooperative assembly model. Further, an accumulated complex I intermediate is structurally consistent with pathological oxygen-dependent reverse electron transfer, revealing unanticipated pathophysiology and hypoxia rescue mechanisms. Thus, the build-up of toxic intermediates and not simply decreases in complex I levels underlie mitochondrial disease.
Longevity Relevance Analysis
(4)
The paper claims that the accumulation of toxic intermediates, rather than simply decreased complex I levels, underlies mitochondrial disease pathophysiology. This research is relevant as it explores the molecular mechanisms of mitochondrial dysfunction, which is a significant contributor to aging and age-related diseases, potentially leading to insights that could inform longevity interventions.
Rimsha Abaidullah, Shaukat Ali, Muhammad Summer ...
· Cell biochemistry and biophysics
· Medical Toxicology and Biochemistry Laboratory, Department of Zoology, Government College University, Lahore, 54000, Pakistan.
· pubmed
Aging as a complex process is marked by physiological and functional deterioration, making the individual vulnerable to age-related diseases. Different organs experience unique aging processes that lead to conditions such as cardiovascular, cancer, metabolic, and musculoskeletal ...
Aging as a complex process is marked by physiological and functional deterioration, making the individual vulnerable to age-related diseases. Different organs experience unique aging processes that lead to conditions such as cardiovascular, cancer, metabolic, and musculoskeletal disorders. Understanding of these processes is essential to formulate effective interventions. To this end, plant-derived bio-actives are effective antiaging agents due to their specific mechanism of action. Phytochemicals in these plants possess antioxidant, anti-inflammatory, and senolytic activities that qualify them as good candidates for antiaging interventions. These molecules are also reported to act on important aging pathways such as immunomodulation, control of inflammation, reduction of oxidative stress, and senescence. The current review emphasizes the organ-specific mechanisms of aging and the role of certain plant constituents that have shown promising antiaging activity. By overviewing the natural interventions against aging mechanisms, this review provides a foundation for future research focused on using natural antiaging interventions involving phytochemicals.
Longevity Relevance Analysis
(4)
The paper claims that plant-derived bio-actives can effectively target organ-specific aging mechanisms and serve as potential antiaging interventions. This research is relevant as it explores the underlying mechanisms of aging and proposes natural therapeutics that could contribute to longevity and the mitigation of age-related diseases.
Hansknecht, A., Mankarious, M., Baranda, M. V. ...
· cell biology
· Helmholtz Institute For Biomedical Engineering, Uniklinik Aachen
· biorxiv
Epigenetic regulatory mechanisms, which include histone modifications and DNA methylation, play a central role in development and aging. Dimethylation of H3K36, deposited mainly by the histone methyltransferase NSD1, occurs predominantly in intergenic regions and recruits the DNA...
Epigenetic regulatory mechanisms, which include histone modifications and DNA methylation, play a central role in development and aging. Dimethylation of H3K36, deposited mainly by the histone methyltransferase NSD1, occurs predominantly in intergenic regions and recruits the DNA methyltransferase DNMT3A to facilitate DNA methylation. Haploinsufficiency of NSD1 results in the overgrowth disorder Sotos syndrome in vivo, which is associated with aberrant DNA methylation signatures and an enhanced epigenetic age. To understand the mechanisms by which NSD1 may regulate development, differentiation and diseases, we generated human iPSC lines deficient in functional NSD1 (NSD1-KO). NSD1-KO cells exhibit a substrate-specific decrease in proliferation, reduced H3K36me2 levels and extensive DNA hypomethylation. Notably, the loss of functional NSD1 altered the differentiation potential of iPSCs, with aberrant endodermal and mesodermal lineage commitment. Further analysis revealed that NSD1 might drive endodermal differentiation by regulating the expression of an endodermal lncRNA HIDEN by mechanisms independent of the regulation of DNA methylation. Our NSD1-KO iPSC lines partially recapitulate the DNA methylation defects associated with NSD1-related disorders. Additionally, we uncovered a novel mechanism by which NSD1 may regulate endodermal differentiation of human iPSCs.
Longevity Relevance Analysis
(4)
NSD1 regulates H3K36me2-mediated DNA methylation and influences the differentiation of human iPSCs. The study explores epigenetic mechanisms that could be linked to developmental processes and aging, suggesting a potential role in understanding the root causes of aging and differentiation.
Domenica Berardi, Gillian Farrell, Abdullah AlSultan ...
· Aging cell
· Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.
· pubmed
The relationship between in vitro senescence cell induction and intracellular biomolecular dysregulation is still poorly understood. In this study, we have found that a range of metabolic subphenotypes exists and is dependent on the induction method that is used. To develop under...
The relationship between in vitro senescence cell induction and intracellular biomolecular dysregulation is still poorly understood. In this study, we have found that a range of metabolic subphenotypes exists and is dependent on the induction method that is used. To develop understanding of these subphenotypes, we developed and employed a novel bioanalytical pipeline integrating untargeted metabolomics, label-free proteomics, and stable isotope tracing alongside cellular deformability measurements and established senescence biomarkers. Initially, standard senescent markers indicated all induction methods were consistent by showing elevated SA-β-Gal expression, p21 levels, and γH2AX DNA damage markers alongside a decrease in Ki67 and an increase in shape, volume, and deformability. However, when probed at the metabolic and protein levels, all senescence models indicated both shared and unique biomolecular responses. A metabolic shift toward reductive pathways (driven by serine and taurine rewiring) and impaired proteostasis was an observed shared response. These findings suggest that targeting metabolic redox circuits, alongside serine and taurine metabolic processes, presents novel therapeutic strategies for addressing senescence and aging. But importantly, alongside this general shift, we found that significant metabolic and proteomic heterogeneity also exists across different senescence induction methods. This demonstrates that the method of senescence induction significantly influences cell metabolic and proteomic profiles. Critically, methods of senescence induction are not interchangeable, and careful consideration is needed when choosing between different induction methods and when comparing cellular phenotypes across different in vitro senescence experiments.
Longevity Relevance Analysis
(4)
The paper claims that different methods of senescence cell induction lead to distinct metabolic and proteomic profiles, suggesting that targeting specific metabolic pathways may offer therapeutic strategies for addressing senescence and aging. This research is relevant as it explores the underlying mechanisms of cellular senescence, which is a key factor in the aging process and age-related diseases, potentially contributing to strategies for longevity and lifespan extension.
David Furman, Johan Auwerx, Anne-Laure Bulteau ...
· Nature aging
· Stanford 1000 Immunomes Project, Stanford School of Medicine, Stanford, CA, USA. [email protected].
· pubmed
Accumulating evidence indicates that biological aging can be accelerated by environmental exposures, collectively called the 'exposome'. The skin, as the largest and most exposed organ, can be viewed as a 'window' for the deep exploration of the exposome and its effects on system...
Accumulating evidence indicates that biological aging can be accelerated by environmental exposures, collectively called the 'exposome'. The skin, as the largest and most exposed organ, can be viewed as a 'window' for the deep exploration of the exposome and its effects on systemic aging. The complex interplay across hallmarks of aging in the skin and systemic biological aging suggests that physiological processes associated with skin aging influence, and are influenced by, systemic hallmarks of aging. This bidirectional relationship provides potential avenues for the prevention of accelerated biological aging and the identification of therapeutic targets. We provide a review of the interactions between skin exposure, aging hallmarks in the skin and associated systemic changes, and their implications in treatment and disease. We also discuss key questions that need to be addressed to maintain skin and overall health, highlighting the need for the development of precise biomarkers and advanced skin models.
Longevity Relevance Analysis
(4)
The paper discusses the bidirectional relationship between skin aging and systemic biological aging, suggesting that understanding these interactions could lead to therapeutic targets for preventing accelerated aging. This research is relevant as it explores the underlying mechanisms of aging and potential interventions, rather than merely addressing symptoms of age-related diseases.
Qianglan Lu, Chengwei Ye, Wei Mao ...
· ACS nano
· Department of Gastric and Hernia Surgery, Nanjing Drum Tower Hospital, College of Engineering and Applied Sciences, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing 210023, China.
· pubmed
Idiopathic pulmonary fibrosis (IPF) remains an age-related, fatal, incurable, epithelial-driven fibrotic lung disease despite the availability of approved antifibrotic drugs. The medical need for effective antipulmonary fibrotic therapies is thus very high. A promising therapeuti...
Idiopathic pulmonary fibrosis (IPF) remains an age-related, fatal, incurable, epithelial-driven fibrotic lung disease despite the availability of approved antifibrotic drugs. The medical need for effective antipulmonary fibrotic therapies is thus very high. A promising therapeutic intervention for IPF is to target key cellular senescence processes in alveolar type 2 (AT2) cells. Herein, we introduce an inhalable gene-editable nanoplatform, comprising a CRISPR-Cas9 gene-editing system linked to a core FePt diatomic catalyst, encapsulated within a biocompatible hyaluronic acid (HA) surface layer (FePtR@HA). The FePt diatomic site facilitates H
Longevity Relevance Analysis
(4)
The paper claims that an inhalable gene-editable nanoplatform can target senescent alveolar type 2 cells to mitigate idiopathic pulmonary fibrosis. This research addresses a key aspect of cellular senescence, which is a fundamental process associated with aging and age-related diseases, thus contributing to the understanding of potential interventions in longevity.
Abel Anwar, Tianchen Li, Yi Shen
· ACS applied materials & interfaces
· School of Chemical and Biomolecular Engineering, The University of Sydney, PNR Building, Darlington, NSW 2008, Australia.
· pubmed
The ability of biomolecular condensates to reversibly dissolve and reform is crucial for maintaining cellular stability and functions. In the context of cell physiology and disease, they can serve as a metastable phase mediating the liquid-to-solid transition of disease proteins ...
The ability of biomolecular condensates to reversibly dissolve and reform is crucial for maintaining cellular stability and functions. In the context of cell physiology and disease, they can serve as a metastable phase mediating the liquid-to-solid transition of disease proteins or rapidly assemble/disassemble as a mechanism for stress response. However, as metabolic rates decline with aging, the protein-rich condensates persist longer, therefore increasing the propensity of undergoing irreversible liquid-to-solid transitions. Temperature, as a physical stimulus, plays a key role in controlling the condensate formation, dissolution, and material properties. In this study, we explore how the reversibility of short peptide biomolecular condensates (z-FF) can be modulated by a temperature change. Our findings reveal that aged condensates exhibit reduced responsiveness to external temperature stimuli. By using thermal cycling experiments to simulate repeated heat stress, we found that the time taken for irreversible fiber formation could be delayed up to 4.7-fold compared to that of condensates without thermal cycles. We also found that the dissolution rate of condensates progressively slows as they age but remains more stable with thermal cycles. Importantly, our results indicate that continuous cycles of liquid-liquid phase separation and dissolution act as a reset mechanism, preserving the biomolecular condensates from further liquid-to-solid transition. These findings provide valuable insights into how aging impacts condensate behavior and highlight potential strategies to preserve cellular function through controlled phase transitions.
Longevity Relevance Analysis
(4)
The paper claims that thermal cycling can delay the irreversible liquid-to-solid transition of peptide condensates in aged cells. This research is relevant as it explores mechanisms that could preserve cellular function and mitigate the effects of aging on biomolecular condensates, potentially addressing root causes of cellular aging.
Lewis, C., Levis, H., Holbrook, J. ...
· bioengineering
· University of Utah Department of Biomedical Engineering, Salt Lake City, UT
· biorxiv
Senescence has been shown to contribute to the progression of aging related diseases including degenerative disc disease (DDD). However, the mechanisms regulating senescence in the intervertebral disc (IVD) and other tissues/diseases remain poorly understood. Recently, in a CRISP...
Senescence has been shown to contribute to the progression of aging related diseases including degenerative disc disease (DDD). However, the mechanisms regulating senescence in the intervertebral disc (IVD) and other tissues/diseases remain poorly understood. Recently, in a CRISPRa genome-wide screen, our lab identified a previously uncharacterized zinc finger protein, ZNF865 (BLST), that regulates a wide array of genes related to protein processing, cell senescence and DNA damage repair. Here, we demonstrate that ZNF865 expression is correlated with age and disease state in human patient IVD samples and mouse IVD. Utilizing CRISPR-guided gene modulation, we show that ZNF865 is necessary for healthy cell function and is a critical protein in regulating senescence and DNA damage in intervertebral disc cells, with implications for a wide range of tissues and organs. We also demonstrate that downregulation of ZNF865 induces senescence and upregulation mitigates senescence and DNA damage in human nucleus pulposus (NP) cells. Importantly, upregulation of ZNF865 shifts the chromatin landscape and gene expression profile of human degenerative NP cells towards a healthy cell phenotype. Collectively, our findings establish ZNF865 as a novel modulator of genome stability and senescence and as a potential therapeutic target for mediating senescence/DNA damage in senescence related diseases and disorders.
Longevity Relevance Analysis
(4)
ZNF865 regulates cell senescence and DNA damage in intervertebral disc cells, with potential implications for aging-related diseases. The paper addresses mechanisms of senescence and DNA damage, which are central to understanding and potentially mitigating the root causes of aging.
Dalgarno, A., Evans, S. A., Kelsey, M. M. G. ...
· genomics
· Brown University
· biorxiv
Cellular senescence is a stable form of cell cycle arrest that contributes to aging and age-associated diseases through the secretion of inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). While senescence is driven by transcriptional ...
Cellular senescence is a stable form of cell cycle arrest that contributes to aging and age-associated diseases through the secretion of inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). While senescence is driven by transcriptional and epigenetic changes, the contribution of higher-order genome organization remains poorly defined. Here, we present the highest-resolution Hi-C maps (~3 kb) to date of proliferating, quiescent, and replicative senescent (RS) human fibroblasts, enabling a comprehensive analysis of 3D genome architecture during senescence. Our analyses reveal widespread senescence-associated remodeling of chromatin architecture, including extensive compartment and subcompartment switching toward transcriptionally active states, and a dramatic increase in unique chromatin loops. These structural features correlate with local DNA hypomethylation and are largely independent of canonical CTCF binding. The altered 3D genome landscape supports expression of SASP genes, inflammation-related pathways, and neuronal gene signatures consistent with age-associated epigenetic drift. We further demonstrate that architectural changes at multiple levels, including compartments, subcompartments, and loops, facilitate the derepression of LINE-1 retrotransposons, linking 3D chromatin structure to activation of proinflammatory transposable elements. Interestingly, quiescent cells, commonly used as senescence controls, exhibited substantial overlap in inflammatory gene expression with senescent cells, raising important considerations for experimental design. Structural analysis of cell cycle genes showed distinct chromatin configurations in senescence versus quiescence, despite similar transcriptional repression. Together, our results establish a high-resolution framework for understanding how genome architecture contributes to the senescent state.
Longevity Relevance Analysis
(5)
The paper claims that senescence-associated chromatin rewiring facilitates the activation of proinflammatory transposable elements and supports the expression of SASP genes. This research is relevant as it addresses the underlying mechanisms of cellular senescence, which is a key contributor to aging and age-related diseases, potentially offering insights into the root causes of these conditions.
Hanpei Miao, Sian Liu, Zehua Wang ...
· NPJ digital medicine
· The Tenth Affiliated Hospital, The First School of Clinical Medicine, Southern Medical University, Dongguan, 523059, China.
· pubmed
Reproductive aging impacts women's health through fertility decline, disease susceptibility, and systemic aging. This study explores the retinal age gap-the difference between predicted retinal age and chronological age-as a novel biomarker for reproductive aging. By developing a...
Reproductive aging impacts women's health through fertility decline, disease susceptibility, and systemic aging. This study explores the retinal age gap-the difference between predicted retinal age and chronological age-as a novel biomarker for reproductive aging. By developing a Swin-Transformer-based dual-channel transfer learning model with data from 1294 healthy women, we examined associations between the retinal age gap and Anti-Müllerian Hormone (AMH), a key marker of ovarian reserve. Findings revealed a negative association between the retinal age gap and AMH levels, particularly among women aged 40-50. Lower AMH levels correlated with earlier reproductive aging milestones, emphasizing the predictive value of retinal aging. Genetic data from genome-wide association studies further supported these associations and enhanced AMH prediction through multimodal modeling. These findings highlight the retinal age gap as a promising, non-invasive biomarker for reproductive aging and its potential role in disease prediction and personalized health interventions in women.
Longevity Relevance Analysis
(4)
The study claims that the retinal age gap can serve as a novel biomarker for reproductive aging in women. This research is relevant as it explores a potential non-invasive method to assess reproductive aging, which is a significant aspect of women's health and longevity.
McGovern, S. E., Meng, G., Marlin, M. N. ...
· molecular biology
· Purdue University
· biorxiv
Alterations in biological rhythms are a common feature of aging, and disruption of circadian rhythms can exacerbate age-associated pathologies. The retina is critical for detecting light for both vision and for transmitting time-of-day information to the brain, synchronizing rhyt...
Alterations in biological rhythms are a common feature of aging, and disruption of circadian rhythms can exacerbate age-associated pathologies. The retina is critical for detecting light for both vision and for transmitting time-of-day information to the brain, synchronizing rhythms throughout the body. Disruption of circadian rhythms by manipulating the molecular clock leads to premature retinal degeneration in flies and mice, and gene expression rhythms are disrupted in models of age-associated ocular disease. Despite this, it is unknown how or why the gene expression rhythms of the retina change with age. Here, we show that ~70% of the Drosophila transcriptome is rhythmically expressed throughout the diurnal cycle, with ~40% of genes showing altered rhythms with age. These transcriptome-wide changes in aging photoreceptors are accompanied by shifts in the rhythmic patterns of RNA Polymerase II (Pol II) occupancy, histone H3 lysine 4 (H3K4) methylation, and chromatin accessibility, without major changes in occupancy of the circadian clock transcription factors Clock (Clk) and Cycle (Cyc). Instead, aging decreases genome-wide levels of several different histone methyl marks including H3K4 methylation, whose relative levels across the day correlate with the phase of rhythmic gene expression. Moreover, individual knockdown of the three H3K4 methyltransferases in young photoreceptors results in massive disruptions to rhythmic gene expression that resemble those observed during aging. We conclude that there are broad epigenetic shifts in the aging retina, including decreased histone methylation, that contribute to changes in biological rhythms even in the presence of a robust molecular circadian clock.
Longevity Relevance Analysis
(4)
The paper claims that broad epigenetic shifts in the aging Drosophila retina contribute to altered rhythmic gene expression. This research is relevant as it explores the underlying mechanisms of aging at the epigenetic level, which could provide insights into the root causes of age-related changes in biological rhythms and potentially inform strategies for lifespan extension.
Bean, L. A., Thomas, C., Villa, J. F. ...
· physiology
· Indiana University School of Medicine
· biorxiv
Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is d...
Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. The composition of the soleus muscle was unaffected and myofiber caliber was reduced comparably in type I, IIa, and IIx fibers. Muscle contractile function declined in Klotho-deficient mice, as evidenced by reduced absolute twitch and torque, and decreased rates of contraction and relaxation. RNA-sequencing analysis identified increased transcriptional expression of synaptic and fetal sarcomeric genes, which prompted us to test effects on muscle innervation. Klotho-deficiency induced morphological remodeling of the neuromuscular junction, myofiber denervation, and a functional loss of motor units. Loss of motor units correlated with absolute torque. Collectively, our findings have uncovered a novel mechanism through which Klotho-deficiency leads to alterations to the muscle synapse affecting motor unit connectivity that likely influences muscle wasting and weakness.
Longevity Relevance Analysis
(4)
Klotho deficiency leads to muscle wasting and weakness through impaired motor unit connectivity. The study addresses a potential mechanistic link between Klotho and muscle health, which is relevant to understanding aging and age-related decline in physical function.
Carrilho, B. d. S., Silva, A. D., Sant Anna, A. M. K. ...
· neuroscience
· D\'Or Institute for Research and Education
· biorxiv
Aging is modulated by nutrient-sensing pathways that integrate metabolic and hormonal cues to regulate growth, stress resilience, and lifespan. Caloric restriction (CR), a well-established intervention, extends longevity in diverse species primarily through inhibition of the TOR ...
Aging is modulated by nutrient-sensing pathways that integrate metabolic and hormonal cues to regulate growth, stress resilience, and lifespan. Caloric restriction (CR), a well-established intervention, extends longevity in diverse species primarily through inhibition of the TOR signaling pathway. Lysergic acid diethylamide (LSD), a classic serotonergic psychedelic with emerging therapeutic applications, remains largely unexplored in the context of aging. Here, we show that LSD treatment significantly extends lifespan in Caenorhabditis elegans and reduces age-associated lipofuscin accumulation, indicative of delayed cellular aging. LSD reproduces several CR-like phenotypes, including decreased reproductive output and increased nuclear localization of the transcription factor PHA-4/FOXA, without affecting food intake. Moreover, LSD treatment reduces lipid stores and downregulates global protein synthesis, both hallmark signatures of TOR inhibition. These findings establish LSD as a modulator of evolutionarily conserved longevity pathways and suggest that psychedelic signaling can mimic a caloric restriction-like metabolic state, paving the way for the development of novel geroprotective strategies.
Longevity Relevance Analysis
(4)
Lysergic acid diethylamide (LSD) treatment extends lifespan in Caenorhabditis elegans by mimicking caloric restriction-like metabolic states. The paper is relevant as it explores a potential intervention that targets longevity pathways and aging mechanisms, contributing to the understanding of lifespan extension.
Marinelli, S., Rossi, C., Pieroni, L. ...
· neuroscience
· Consiglio Nazionale delle Ricerche
· biorxiv
Biological aging and sex interact to shape systemic metabolism, yet their role in chronic pain resolution remains unexplored. We hypothesized that metabolic resilience, the ability to flexibly switch fuel sources and maintain energy homeostasis, rules successful recovery from ner...
Biological aging and sex interact to shape systemic metabolism, yet their role in chronic pain resolution remains unexplored. We hypothesized that metabolic resilience, the ability to flexibly switch fuel sources and maintain energy homeostasis, rules successful recovery from nerve injury in a sex-dependent manner during aging. In 12-month-old male and female mice, corresponding to the perimenopausal phase in females and the onset of hormonal decline in both sexes, we induced sciatic nerve chronic constriction injury and performed multi-omics profiling during Wallerian degeneration, a phase known to trigger long-term neurobiological remodeling. Aging females exhibited early activation of fatty acid oxidation, increased resting energy expenditure, upregulation of mitochondrial redox enzymes and circulating progesterone and corticosterone. Proteomic and metabolomic analysis revealed pentose phosphate pathway enrichment and gluconeogenesis, supporting redox balance and metabolic flexibility. Conversely, males displayed persistent glycolytic reliance, long-chain acylcarnitine accumulation, suppression of adiponectin and PPARgamma, indicating metabolic inflexibility. Longitudinal behavioral analysis revealed that aging females recovered earlier and more fully than aging males, reversing the pattern previously shown in our adult mouse study, where females developed persistent pain and males recovered rapidly. These patterns highlight a non-linear, sex-specific interaction between biological aging and injury response, where hormonal decline reprograms the metabolic trajectory and reshapes pain outcomes. Metabolic resilience governs sex-specific recovery following nerve injury by directing early systemic adaptations that precede and predict long-term pain trajectories. These results define mechanistically anchored, sex- and age-specific biomarkers, and propose preclinical targets for timely, personalized interventions in age-associated neuropathic pain.
Longevity Relevance Analysis
(4)
Metabolic resilience governs sex-specific recovery following nerve injury by directing early systemic adaptations that precede and predict long-term pain trajectories. The study explores the interaction between biological aging, sex, and metabolic processes, which are crucial for understanding the mechanisms underlying age-related pain and potential interventions, thus addressing root causes of aging-related issues.
Lu, R. J., Chen, S., Kim, M. ...
· immunology
· USC
· biorxiv
Aging is a complex process characterized by a progressive decline in physiological functions driven by both biological and environmental factors, with notable differences between sexes. Immune function is strongly influenced by biological sex, affecting both innate and adaptive i...
Aging is a complex process characterized by a progressive decline in physiological functions driven by both biological and environmental factors, with notable differences between sexes. Immune function is strongly influenced by biological sex, affecting both innate and adaptive immune responses, including macrophage behavior. In this study, we investigated the effects of age and sex on the immune cell composition within the peritoneal cavity niche and identified macrophages as the most affected cell type. Macrophages, as central components of the innate immune system, play critical roles in maintaining tissue homeostasis and responding to infections. Here, we find that aging induces sex-specific remodeling of peritoneal macrophage transcriptomic and epigenomic landscapes. Consistently, peritoneal macrophages undergo sex-specific functional remodeling with aging (i.e. female-specific phagocytic decline and metabolic rewiring). Modulation of gonadal hormone signaling showed that changes in circulating estrogen levels likely contribute to aspects of female-specific macrophage age-related changes. Importantly, multi-omic analysis identified candidate transcription factors whose sex-specific age-regulated expression may drive aspects of sex-specific \'omic\' remodeling with aging. Specifically, Irf2 downregulation in female macrophages recapitulates distinct transcriptomic and metabolic aspects of macrophage female aging phenotypes. These findings suggest that female-specific age-related functional remodeling arises through hormone-dependent and -independent mechanisms in peritoneal macrophages.
Longevity Relevance Analysis
(4)
The paper claims that aging induces sex-specific remodeling of peritoneal macrophages, influenced by hormonal changes. This research is relevant as it explores the biological mechanisms underlying aging and immune function, particularly in females, which could contribute to understanding age-related changes and potential interventions.
Goldman-Pham, R., Alter, M. P., Bao, R. ...
· epidemiology
· Department of Medicine, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec Canada
· medrxiv
Background: Early-life growth adversity is important to later-life health, but precision assess-ment in adulthood is challenging. We evaluated whether the difference between attained and genotype-predicted adult height ("height-GaP") would associate with prospectively ascertained...
Background: Early-life growth adversity is important to later-life health, but precision assess-ment in adulthood is challenging. We evaluated whether the difference between attained and genotype-predicted adult height ("height-GaP") would associate with prospectively ascertained early-life growth adversity and later-life all-cause and cardiovascular mortality. Methods: Data were first analyzed from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UKBiobank. Genotype-predicted height was calculated using a multi-ancestry polygenic height score. Height-GaP was calculated as the difference between measured and gen-otype-predicted adult height. Early-life growth conditions were ascertained prospectively via standardized procedures (ALSPAC) and mortality via death register (UKBiobank). Regression models adjusted for age, sex, genotype-predicted height and genetic ancestry. Analyses were replicated in the Dunedin Multidisciplinary Health and Development Study (DMHDS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Findings: Among 4,582 ALSPAC participants (median [IQR] age: 24[18-25] years at height-GaP assessment), lower gestational age at birth, greater pre- and post-natal deprivation indices, tobacco smoke exposure and less breastfeeding were associated with larger adult height-GaP deficit (p<0.01). Among 483,385 UKBiobank participants (mean+-SD age: 56+-8 years at height-GaP assessment), height-GaP deficit was associated with death from all-causes (adjusted hazard ratio comparing highest-to-lowest height-GaP deficit quartile [aHR]:1.25 95%CI:1.21-1.29), ath-erosclerotic cardiovascular disease (aHR:1.33 95%CI:1.24-1.43) and coronary heart disease (aHR:1.68 95%CI:1.52-1.86). Early- and later-life height-GaP associations replicated in DMHDS and MESA. Interpretation: This study introduces a simple index of early-life growth adversity deployable in adulthood to investigate the developmental origins of longevity and improve health equity across the life course.
Longevity Relevance Analysis
(4)
The paper claims that early-life growth adversity, as quantified by the height-GaP index, is associated with increased mortality risk in adulthood. This research is relevant as it explores the developmental origins of health disparities and longevity, potentially addressing root causes of aging-related health issues.
Maria Lastra Cagigas, Andrius Masedunskas, Yao Lin ...
· Aging cell
· Charles Perkins Centre, The University of Sydney, Sydney, Australia.
· pubmed
Prediabetes, characterized by impaired fasting glucose and/or glucose tolerance, is associated with organ damage, increased mortality, and accelerated aging, even before diabetes onset. Severe short-term energy restriction while maintaining essential nutrient intake is among the ...
Prediabetes, characterized by impaired fasting glucose and/or glucose tolerance, is associated with organ damage, increased mortality, and accelerated aging, even before diabetes onset. Severe short-term energy restriction while maintaining essential nutrient intake is among the most effective strategies for weight loss, metabolic health improvement, and delaying type 2 diabetes progression. Extracellular vesicles contribute to these metabolic benefits; however, the impact of energy-restriction-induced weight loss on the extracellular vesicle proteome remains incompletely understood. This study employed targeted and untargeted proteomics to investigate the effect of an 8-week severely energy-restricted diet on the plasma proteome in adults with prediabetes from Sydney, Australia, as part of the PREVIEW study. Circulating extracellular vesicles were enriched in plasma using an immunoaffinity-based protocol. A total of 44 participants who achieved at least a 12% weight loss and provided informed consent were included in the study. Paired changes in over 2000 proteins between baseline and week 8 were analyzed. Following the intervention, multiple proteins associated with inflammation and senescence were significantly reduced, reversing the increase commonly associated with aging. The decline in inflammatory and senescence markers may have been mediated by extracellular vesicles, as indicated by significantly lower circulating levels of several vesicular markers. Additionally, several markers of protein synthesis downstream of mTORC1 and protein degradation were significantly reduced in vesicle-enriched plasma, suggesting decreased intercellular secretion and/or trafficking. Overall, this study identifies a diet-induced proteomic signature suggestive of reduced inflammation, lower senescence, and enhanced vesicle-associated proteostasis, potentially conferring health benefits beyond glycemic control.
Longevity Relevance Analysis
(4)
Short-term severe energy restriction can reduce inflammation and senescence markers in adults with prediabetes. The study addresses mechanisms that may contribute to reversing aging signatures, which is directly relevant to longevity research.
Li, J., Wang, T., Lu, W. ...
· cell biology
· University of Pennsylvania
· biorxiv
Lysosomal pH is frequently elevated in age-dependent neurodegenerations like Age-related Macular Degeneration (AMD), Alzheimer\'s Disease (AD), and Parkinson\'s Disease (PD). Tools that restore lysosomal pH to an optimal acidic range could enhance enzymatic degradation and reduce...
Lysosomal pH is frequently elevated in age-dependent neurodegenerations like Age-related Macular Degeneration (AMD), Alzheimer\'s Disease (AD), and Parkinson\'s Disease (PD). Tools that restore lysosomal pH to an optimal acidic range could enhance enzymatic degradation and reduce waste accumulation. Acidic nanoparticles offer a promising strategy for restoring lysosomal function, but accurate tracking of organelle delivery and long-term retention is needed to optimize dosage. To improve detection and enhance delivery, nanoparticles were synthesized from Poly(D,L-lactide-co-glycolide) (PLGA) polymers covalently linked to the fluorescent Cyanine3 amine (Cy3) probe. Nanoparticle concentration and loading times were optimized to achieve >90% delivery to lysosomes in cultured induced pluripotent stem cell-derived retinal pigment epithelial (iPS-RPE) cells. Uptake was heterogeneous, varying between adjacent cells. Once loaded into lysosomes, the nanoparticles were stably retained, with no detectable changes in concentration, distribution, or size for at least 28 days. iPS-RPE cells internalized more nanoparticles than the ARPE-19 cell line or mouse optic nerve head astrocyte cultures. Functionally, PLGA nanoparticles restored an acidic pH and cathepsin D levels in compromised lysosomes. In summary, Cy3-PLGA nanoparticles enabled improved tracking and long-term delivery to lysosomes, supporting future in vivo applications to restore lysosomal pH in aging and degenerating tissues.
Longevity Relevance Analysis
(4)
The paper claims that Cy3-PLGA nanoparticles can restore acidic pH levels in lysosomes of retinal pigment epithelial cells and astrocytes. This research addresses a root cause of aging-related neurodegenerative diseases by focusing on lysosomal dysfunction, which is a significant aspect of cellular aging and degeneration.
Rathore, D.
· molecular biology
· Indian Institute of Sciences
· biorxiv
Genomic instability is a hallmark of ageing, driven by the accumulation of DNA lesions and the decline of high-fidelity repair pathways such as homologous recombination (HR) and classical nonhomologous end joining (c-NHEJ). We hypothesised that ageing cells increasingly rely on m...
Genomic instability is a hallmark of ageing, driven by the accumulation of DNA lesions and the decline of high-fidelity repair pathways such as homologous recombination (HR) and classical nonhomologous end joining (c-NHEJ). We hypothesised that ageing cells increasingly rely on microhomology-mediated end joining (MMEJ), an inherently error-prone repair pathway, whose role in ageing remains poorly characterised. Here, we present the first systematic, tissue-wide analysis of MMEJ activity across eight rat organs using an in vitro assay with defined 10 to 16 nt microhomology substrates and cell-free extracts from rats of different ages. Our results reveal age-associated and tissue-specific reprogramming of MMEJ: activity increased in the testes and liver, newly emerged in kidneys and lungs, and declined in immune tissues such as the spleen and thymus. Strikingly, aged brain extracts exhibited latent MMEJ activity. Repair efficiency was further modulated by microhomology length in a tissue-dependent manner. These functional shifts correlated with altered expression of key MMEJ effectors, including XRCC1, PARP1, Ligase III, and notably FEN1, whose upregulation in aged lungs mirrored robust MMEJ activation. Together, our findings uncover dynamic remodelling of MMEJ during ageing, implicating it in age-related genomic instability and highlighting potential therapeutic targets to mitigate mutation burden in ageing tissues.
Longevity Relevance Analysis
(4)
The paper claims that ageing cells increasingly rely on microhomology-mediated end joining (MMEJ) for DNA repair, which is linked to age-related genomic instability. This research is relevant as it explores the mechanisms of DNA repair in the context of ageing, potentially addressing root causes of genomic instability associated with aging.
Chengchi Huang, Hong Tian, Wei Li
· GeroScience
· Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX, 77030, USA.
· pubmed
Recent studies reported that anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) alleviate choroidal neovascularization (CNV) in young but not aged animals. We recently developed a disease-targeted anti-angiogenic therapy against secretogranin III (Scg3), wh...
Recent studies reported that anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) alleviate choroidal neovascularization (CNV) in young but not aged animals. We recently developed a disease-targeted anti-angiogenic therapy against secretogranin III (Scg3), which selectively binds to diseased but not healthy vessels in young mice. Herein, using a unique in vivo ligand binding assay, we predicted and confirmed that Scg3 selectively binds CNV vessels in both young and aged mice. In contrast, VEGF with minimal increased binding to CNV vessels exhibited an age-dependent decline in binding to both CNV and healthy vessels with negligible binding in aged mice. Based on these binding activity patterns, we further predicted and confirmed that a humanized anti-Scg3 antibody effectively alleviated laser-induced CNV in both young and aged mice, whereas the anti-VEGF drug aflibercept was effective only in young mice. These findings suggest that enhanced binding of Scg3 to CNV vessels in both age groups provides a molecular basis for an age-independent anti-Scg3 therapy, offering potential to address anti-VEGF resistance in clinical treatment of wet age-related macular degeneration with CNV.
Longevity Relevance Analysis
(4)
The study claims that a humanized anti-Scg3 antibody can effectively treat choroidal neovascularization in both young and aged mice, unlike traditional anti-VEGF therapies. This research is relevant as it addresses a specific mechanism of age-related disease (choroidal neovascularization) and proposes a novel therapeutic approach that could potentially overcome age-related treatment resistance, contributing to the understanding of aging-related pathologies.
Marc Tatar, Wenjing Zheng, Shweta Yadav ...
· PLoS genetics
· Department of Ecology, Evolution and Organismal Biology, The Center for the Biology of Aging, Brown University, Providence, Rhode Island, United States of America.
· pubmed
Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan across many species. Multiple mechanisms are proposed for how this altered signaling slows aging. To elaborate these causes, we recently developed a series of Drosophila insulin-like receptor (...
Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan across many species. Multiple mechanisms are proposed for how this altered signaling slows aging. To elaborate these causes, we recently developed a series of Drosophila insulin-like receptor (dInr) mutants with single amino acid substitutions that extend lifespan but differentially affect insulin sensitivity, growth and reproduction. Transheterozygotes of canonical dInr mutants (Type I) extend longevity and are insulin-resistant, small and weakly fecund. In contrast, a dominant mutation (dInr353, Type II) within the Kinase Insert Domain (KID) robustly extends longevity but is insulin-sensitive, full-sized, and highly fecund. We applied transcriptome and metabolome analyses to explore how dInr353 slows aging without insulin resistance. Type I and II mutants overlap in many pathways but also produce distinct transcriptomic profiles that include differences in innate immune and reproductive functions. In metabolomic analyses, the KID mutant dInr353 reprograms methionine metabolism in a way that phenocopies dietary methionine restriction, in contrast to canonical mutants which are characterized by upregulation of the transsulfuration pathway. Because abrogation of S-adenosylhomocysteine hydrolase blocks the longevity benefit conferred by dInr353, we conclude the methionine cycle reprogramming of Type II is sufficient to slow aging. Metabolomic analysis further revealed the Type II mutant is metabolically flexible: unlike aged wildtype, aged dInr353 adults can reroute methionine toward the transsulfuration pathway, while Type I mutant flies upregulate the transsulfuration pathway continuously from young age. Altered insulin/insulin growth factor signaling has the potential to slow aging without the complications of insulin resistance by modulating methionine cycle dynamics.
Longevity Relevance Analysis
(4)
The paper claims that a specific Drosophila insulin-like receptor mutant can extend lifespan by remodeling methionine metabolism without inducing insulin resistance. This research is relevant as it explores mechanisms that could potentially slow aging, addressing root causes rather than merely treating symptoms of age-related decline.
Zhai, T., Mazzucato, P., Ricciardi, C. ...
· epidemiology
· Harvard T.H. Chan School of Public Health
· medrxiv
Rare genetic DNA repair deficiency syndromes can lead to immunodeficiency, neurological disorders, and cancer. In the general population, inter-individual variation in DNA repair capacity (DRC) influences susceptibility to cancer and several age-related diseases. Genome wide asso...
Rare genetic DNA repair deficiency syndromes can lead to immunodeficiency, neurological disorders, and cancer. In the general population, inter-individual variation in DNA repair capacity (DRC) influences susceptibility to cancer and several age-related diseases. Genome wide association studies and functional analyses show that defects in multiple DNA repair pathways jointly increase disease risk, but previous technologies did not permit comprehensive analyses of DNA repair in populations. To overcome these limitations, we used fluorescence multiplex host cell reactivation (FM-HCR) assays that directly quantify DRC across six major DNA repair pathways. We assessed DRC in phytohemagglutinin-stimulated primary lymphocytes from 56 healthy individuals and validated assay reproducibility in 10 individuals with up to five independent blood draws. We furthermore developed generalized analytical pipelines for systematically adjusting for batch effects and both experimental and biological confounders. Our results reveal significant inter-individual variation in DRC for each of 10 reporter assays that measure the efficiency of distinct repair processes. Our data also demonstrate that correlations between the activities of different DNA repair pathways are relatively weak. This finding suggests that each pathway may independently influence susceptibility to the health effects of DNA damage. We furthermore developed a pipeline for analyzing comet repair kinetics and related our new functional data to previously reported comet assay data for the same individuals. Our pioneering analysis underscores the sensitivity of FM-HCR assays for detecting subtle biological differences between individuals and establishes standardized methodologies for population studies. Our findings and open source analytical tools advance precision medicine by enabling comprehensive exploration of genetic, demographic, clinical, and lifestyle factors and supporting targeted interventions to enhance DNA repair and maintain genomic integrity, thereby promoting personalized healthcare and disease prevention.
Longevity Relevance Analysis
(4)
The paper claims that inter-individual variation in DNA repair capacity significantly influences susceptibility to age-related diseases. This research is relevant as it addresses the underlying mechanisms of DNA repair, which is a critical factor in aging and longevity, potentially leading to targeted interventions for enhancing genomic integrity and promoting healthier aging.
Chenyu Zhu, Tingting Huang, Jiaqi Fu ...
· mSystems
· Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, Guangdong, China.
· pubmed
Hydrogen peroxide (H
Hydrogen peroxide (H
Longevity Relevance Analysis
(4)
The paper claims that global m6A RNA and whole 5mC DNA methylation contribute to cell replicative and premature senescence induced by oxidative stress. This research is relevant as it explores molecular mechanisms that may underlie aging processes and cellular senescence, which are critical factors in longevity and age-related diseases.
Sophie Guyonnet, Claudie Hooper, Heike A Bischoff-Ferrari ...
· GeroScience
· IHU HealthAge, Gérontopôle, Department of Geriatrics, CHU Toulouse, Toulouse, France.
· pubmed
HealthAge was devised by a conglomerate of research groups in Toulouse, France, with the combined goal of narrowing the lifespan-healthspan gap through novel translational bench-to-bedside research studies. HealthAge comprises the "INStitute for Prevention" "healthy aging" and "m...
HealthAge was devised by a conglomerate of research groups in Toulouse, France, with the combined goal of narrowing the lifespan-healthspan gap through novel translational bench-to-bedside research studies. HealthAge comprises the "INStitute for Prevention" "healthy aging" and "medicine Rejuvenative" (INSPIRE) human translational, outbred SWISS mice and African turquoise killifish (GRZ strain) cohorts in which aging is studied based on the concept of intrinsic capacity (IC). In this narrative review, we describe the three INSPIRE aging models (human cohort, n = 1109, age range 20 -102 years old with mean age ± standard deviation, 62.4 ± 19.0 years and 61.9% female; outbred SWISS mice, n = 1576 and African Turquoise killifish, n = 300) and explain how IC is assessed at the clinical (in humans) and biological level over time. HealthAge strives to elucidate the underlying biology of IC and to identify biomarkers of IC declines and novel gero-therapeutics using the clinical and biological data and biospecimens collected prospectively in the three species. The data sharing policy will foster scientific discovery through new multi-disciplinary collaborations. Thus, HealthAge will promote healthy aging using a unique translational platform based on IC phenotyping with the ultimate goal of preventing loss of human independence and alleviating health costs associated with an aging population.
Longevity Relevance Analysis
(4)
The paper aims to explore intrinsic capacity changes across species to identify biomarkers and gero-therapeutics for healthy aging. This research is relevant as it addresses the underlying biology of aging and seeks to narrow the lifespan-healthspan gap, which is central to longevity studies.
Zink, M. E., Zhen, L., McHaney, J. R. ...
· neuroscience
· University of Pittsburgh
· biorxiv
Middle age represents a critical period of accelerated brain changes and provides a window for early detection and intervention in age-related neurological decline. Hearing loss is a key early marker of such decline and is linked to numerous comorbidities in older adults. Yet, ~1...
Middle age represents a critical period of accelerated brain changes and provides a window for early detection and intervention in age-related neurological decline. Hearing loss is a key early marker of such decline and is linked to numerous comorbidities in older adults. Yet, ~10% of middle-aged individuals who report hearing difficulties show normal audiograms. Cochlear neural degeneration (CND) could contribute to these hidden hearing deficits, though its role remains unclear due to a lack of objective diagnostics and uncertainty regarding its perceptual outcomes. Here, we employed a cross-species design to examine neural and behavioral signatures of CND. We measured envelope following responses (EFRs) - neural ensemble responses to sound originating from the peripheral auditory pathway - in young and middle-aged adults with normal audiograms and compared these responses to young and middle-aged Mongolian gerbils, where CND was histologically confirmed. We observed near identical changes in EFRs across species that were associated with CND. Behavioral assessments revealed age-related speech-in-noise deficits under challenging conditions, while pupil-indexed listening effort increased with age even when behavioral performance was matched. Together, these results demonstrate that CND contributes to speech perception difficulties and elevated listening effort in midlife, which may ultimately lead to listening fatigue and social withdrawal.
Longevity Relevance Analysis
(4)
Cochlear neural degeneration contributes to speech perception difficulties and increased listening effort in middle-aged adults. This paper is relevant as it explores underlying mechanisms of auditory processing decline in midlife, which is crucial for understanding age-related neurological changes and potential interventions.
Xicong Tang, Hongyu Qiu
· Mitochondria
· Cardiovascular Translational Research Center, College of Medicine-Phoenix, University of Arizona, Phoenix, United States.
· pubmed
The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.
The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.
Longevity Relevance Analysis
(4)
Blocking arginase-II could help maintain cardiac youthfulness. The paper addresses a specific enzyme's role in cardiac aging, which is directly related to the mechanisms of aging and potential interventions for longevity.
Zhihai Huang, Yulan Zhang, Peibin Zou ...
· Myelin Sheath
· Institute for Cerebrovascular and Neuroregeneration Research (ICNR), Department of Neurology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71103, USA.
· pubmed
Myelin is a multilamellar membrane that surrounds axons in the vertebrate nervous system. Properly functioning myelin is essential for the rapid conduction of nerve impulses, and it metabolically supports axonal integrity. Emerging evidence indicates that myelin is also involved ...
Myelin is a multilamellar membrane that surrounds axons in the vertebrate nervous system. Properly functioning myelin is essential for the rapid conduction of nerve impulses, and it metabolically supports axonal integrity. Emerging evidence indicates that myelin is also involved in various aspects of cognition, with adaptive myelination playing a critical role in memory consolidation and motor learning. However, these physiological processes can be disrupted in various diseases. Understanding the mechanisms underlying myelin pathology is therefore essential for the development of targeted therapies for associated medical conditions. This review provides a comprehensive overview of the role of myelin in neural function, with a particular focus on adaptive myelination in cognition. We also highlight myelin dysfunction and the underlying mechanisms in the aging brain, as well as in diverse brain disorders and neurological conditions, including neurodegenerative diseases, psychiatric conditions, brain injuries, chemotherapy-related cognitive impairment, and neurological symptoms associated with COVID-19. Furthermore, we discuss the therapeutic potential of recently identified pro-myelinating compounds in aging-associated cognitive decline and brain disorders, as well as the future of remyelination therapies. Current evidence suggests that restoring functional myelin may serve as a therapeutic strategy for various medical conditions associated with myelin dysfunction.
Longevity Relevance Analysis
(4)
Restoring functional myelin may serve as a therapeutic strategy for various medical conditions associated with myelin dysfunction. The paper addresses myelin dysfunction in the aging brain and its implications for cognitive decline, which is directly relevant to understanding and potentially mitigating age-related cognitive decline.
Gupta, N., Sinks, M., Hubbard, E. J. A.
· cell biology
· NYU Grossman School of Medicine
· biorxiv
A decline in tissue renewal and repair due to changes in tissue stem cells is a hallmark of aging. Many stem cell pools are maintained by interaction with morphologically complex local niches. Using the C. elegans hermaphrodite germline stem cell system, we analyzed age-related c...
A decline in tissue renewal and repair due to changes in tissue stem cells is a hallmark of aging. Many stem cell pools are maintained by interaction with morphologically complex local niches. Using the C. elegans hermaphrodite germline stem cell system, we analyzed age-related changes in the morphology of the niche, the distal tip cell (DTC), and identified a molecular mechanism that promotes a subset of these changes. We found that a long-lived daf-2 mutant exhibits a daf-16-dependent decline in number and length of long DTC processes. Surprisingly, the tissue requirement for daf-16(+) is non-autonomous and is independent of the longevity requirement: daf-16(+) in body wall muscle is both necessary and sufficient. We also determined that pre-formed DTC processes deteriorate prematurely when the underlying germline differentiates. We propose a reciprocal DTC-germline interaction model and speculate a mechanism by which reducing daf-2 activity prevents stem cell exhaustion. These studies establish the C. elegans DTC as a powerful in vivo model for understanding age-related changes in cellular morphology and their consequences in stem cell systems.
Longevity Relevance Analysis
(4)
The paper proposes a reciprocal DTC-germline interaction model that suggests reducing daf-2 activity can prevent stem cell exhaustion. This research is relevant as it explores the mechanisms underlying age-related changes in stem cell niches, contributing to our understanding of aging and potential interventions.
Susan F Cheng, Wan Lin Yue, Kwun Kei Ng ...
· Brain
· Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, Singapore.
· pubmed
Brain age has emerged as a powerful tool to understand neuroanatomical aging and its link to health outcomes like cognition. However, there remains a lack of studies investigating the rate of brain aging and its relationship to cognition. Furthermore, most brain age models are tr...
Brain age has emerged as a powerful tool to understand neuroanatomical aging and its link to health outcomes like cognition. However, there remains a lack of studies investigating the rate of brain aging and its relationship to cognition. Furthermore, most brain age models are trained and tested on cross-sectional data from primarily Caucasian, adult participants. It is thus unclear how well these models generalize to non-Caucasian participants, especially children. Here, we tested a previously published deep learning model on Singaporean elderly participants (55-88 years old) and children (4-11 years old). We found that the model directly generalized to the elderly participants, but model finetuning was necessary for children. After finetuning, we found that the rate of change in brain age gap was associated with future executive function performance in both elderly participants and children. We further found that lateral ventricles and frontal areas contributed to brain age prediction in elderly participants, while white matter and posterior brain regions were more important in predicting brain age of children. Taken together, our results suggest that there is potential for generalizing brain age models to diverse populations. Moreover, the longitudinal change in brain age gap reflects developing and aging processes in the brain, relating to future cognitive function.
Longevity Relevance Analysis
(4)
The study claims that the rate of change in brain age gap is associated with future executive function performance in both elderly participants and children. This research is relevant as it explores the relationship between brain aging and cognitive function, contributing to our understanding of aging processes and their implications for longevity and cognitive health.
Sonam Fathima Mehak, Apoorva Bettagere Shivakumar, Feyba Jijimon ...
· Aging cell
· Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
· pubmed
Remembering familiar versus novel stimuli is fundamental to survival, but it is compromised in several neurodegenerative disorders where aging is a key factor. Although the components of the extracellular matrix (ECM) have been suggested to be implicated in memory maintenance, th...
Remembering familiar versus novel stimuli is fundamental to survival, but it is compromised in several neurodegenerative disorders where aging is a key factor. Although the components of the extracellular matrix (ECM) have been suggested to be implicated in memory maintenance, the mechanistic and behavioral roles of ECM during the aging process remain unclear. Here, we employed an accelerated mouse model of aging to elucidate the causal link between ECM dynamics and recognition memory during aging. Aged mice exhibited impaired social and non-social recognition memory, accompanied by increased intensity of perineuronal nets (PNNs), specialized ECM structures in the hippocampal dorsal CA2 (dCA2). A reduction in the power of theta oscillations (3-7 Hz) in the dCA2 of aged mice was also observed. Notably, selective degradation of PNNs in the dCA2 using chondroitinase ABC (ChABC) rescued recognition memory deficits and restored theta oscillations. Together, our findings identify abnormal PNN in the CA2 as a critical factor for age-related deficits in hippocampal-dependent recognition memory and network rhythmicity. These insights raise the possibility that targeting CA2 PNNs could facilitate the development of diagnostic and therapeutic strategies to address age-associated cognitive frailty.
Longevity Relevance Analysis
(4)
Selective degradation of perineuronal nets in the CA2 region of the hippocampus can restore recognition memory and theta oscillations in aged mice. This research addresses the mechanistic role of the extracellular matrix in age-related cognitive decline, which is directly relevant to understanding and potentially mitigating the effects of aging on memory and cognition.
Dhanekula, A. S., Harrison, B., Pharaoh, G. ...
· cell biology
· University of Washington
· biorxiv
This study investigated the role of mitochondrial function in aortic aging. As the aorta ages, it becomes stiffer and less compliant, increasing the risk of aneurysmal disease, hypertension, and diastolic dysfunction. Given the role of mitochondrial dysfunction in non-age related...
This study investigated the role of mitochondrial function in aortic aging. As the aorta ages, it becomes stiffer and less compliant, increasing the risk of aneurysmal disease, hypertension, and diastolic dysfunction. Given the role of mitochondrial dysfunction in non-age related aortopathies and as a hallmark of aging, we investigated its contribution to the aging aorta. Both male and female young (5-6 month) and aged (24-25 month) C57Bl/6J mice received mitochondrial-targeted peptide elamipretide (ELAM; SS-31) for 8 weeks. ELAM restored complex II-linked respiration in aged mice to values seen in young mice, while also improving relative phosphorylative flux. ELAM treatment also reduced inflammatory MMP9 expression and elastin breaks in aged mice. Bulk RNAseq analysis revealed that ELAM treatment significantly affected the aortic transcriptome in an age-dependent manner, reducing the expression of senescent and associated pro-inflammatory genes. Mitochondrial dysfunction thus drives aortic aging and is a potential therapeutic target for future study.
Longevity Relevance Analysis
(5)
Mitochondrial dysfunction drives age-related degeneration of the thoracic aorta. This study addresses a root cause of aging by investigating mitochondrial function and its therapeutic potential in a key age-related vascular condition, contributing to the understanding of aging mechanisms.
Jayarathne, H. S., Manchanayake, D. H., Chimienti, N. ...
· neuroscience
· Wayne State University
· biorxiv
Aging is the strongest risk factor for cognitive decline and Alzheimer\'s disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulne...
Aging is the strongest risk factor for cognitive decline and Alzheimer\'s disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana\'s potential to combat brain aging and AD through sex-specific mechanisms.
Longevity Relevance Analysis
(4)
Canagliflozin treatment reprograms brain aging and improves cognitive function in male mice while revealing sex-specific mechanisms. The study addresses the modulation of brain aging and Alzheimer's-like pathology, which are central to understanding and potentially mitigating the root causes of age-related cognitive decline.
De Man, R., Cai, Z., Doddaballapur, P. ...
· physiology
· Yale
· biorxiv
The geroscience hypothesis suggests that understanding underlying ageing mechanisms will enable us to delay aging and lessen age-related disability and diseases. While hallmarks of ageing list multiple contributing factors, role of mechanics has only been recently recognized and ...
The geroscience hypothesis suggests that understanding underlying ageing mechanisms will enable us to delay aging and lessen age-related disability and diseases. While hallmarks of ageing list multiple contributing factors, role of mechanics has only been recently recognized and increasingly appreciated. Here, we use mouse models of ageing to investigate changes in mechanics of the proximal pulmonary artery, lung and right ventricle function in ageing. We found an age-related decline in the capacity to store energy and increased circumferential stiffness of the proximal pulmonary artery with age that associated with a reorientation of collagen towards the circumferential direction, decreased exercise ability, and decreased function of the lung and right ventricle. The observed compromised mechanics in proximal pulmonary artery is consistent across multiple mouse models of accelerated ageing. Further, transcriptional changes in proximal pulmonary artery indicate that aging is associated with senescence of perivascular macrophages, adventitial fibroblasts, and medial smooth muscle cells. Older pulmonary arteries increase expression of genes associated with ECM turnover (including genes in the TGF{beta} pathway) and increased intercellular signaling amongst perivascular macrophages, fibroblasts and smooth muscle cells. Our results provide promising biomarkers of ageing for diagnosis and potential pathways and molecular targets for targeting anti-ageing therapies.
Longevity Relevance Analysis
(4)
The paper claims that proximal pulmonary artery stiffening serves as a biomarker of cardiopulmonary aging. This research is relevant as it investigates underlying mechanisms of aging and identifies potential biomarkers and molecular targets for anti-aging therapies.
Chen, X., Wang, S., Torres, M. ...
· cell biology
· University of Virginia School of Medicine
· biorxiv
Mitochondrial quality control is essential for maintaining cellular energy homeostasis, particularly in brown adipocytes where dynamic mitochondrial remodeling supports thermogenesis. Although the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and aut...
Mitochondrial quality control is essential for maintaining cellular energy homeostasis, particularly in brown adipocytes where dynamic mitochondrial remodeling supports thermogenesis. Although the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) pathway and autophagy are two major proteostatic systems, how these pathways intersect to regulate mitochondrial integrity in metabolically active tissues remains poorly understood. Here, using adipocyte-specific genetic mouse models combined with high-resolution 2D and 3D ultrastructural imaging technologies, we reveal an unexpected synergy between SEL1L-HRD1 ERAD and autophagy in maintaining mitochondrial structure and function in brown adipocytes. Loss of ERAD alone triggers compensatory autophagy, whereas combined deletion of both pathways (double knockout, DKO) results in severe mitochondrial abnormalities, including the accumulation of hyperfused megamitochondria penetrated by ER tubules, even under basal room temperature conditions. These phenotypes are absent in mice lacking either pathway individually or in SEL1L-IRE1 DKO, highlighting the pathway-specific coordination between ERAD and autophagy. Mechanistically, dual loss of ERAD and autophagy induces ER expansion, excessive ER-mitochondria contact, upregulation of mitochondria-associated membrane (MAM) tethering proteins, impaired calcium transfer, and defective mitochondrial turnover. As a result, DKO adipocytes accumulate dysfunctional mitochondria, exhibit respiratory deficits, and fail to sustain thermogenesis. Collectively, our study uncovers a cooperative and previously unrecognized mechanism of mitochondrial surveillance, emphasizing the critical role of ERAD-autophagy crosstalk in preserving mitochondrial integrity and thermogenic capacity in brown fat.
Longevity Relevance Analysis
(4)
The paper claims that the synergistic interaction between ERAD and autophagy is crucial for maintaining mitochondrial integrity and thermogenic capacity in brown adipocytes. This research is relevant as it explores mechanisms that could influence cellular energy homeostasis and mitochondrial function, which are critical factors in the aging process and longevity.
Alexandru, A. C., Hormazabal, G. V., Matsui, H. ...
· immunology
· Buck Institute for Research on Aging
· biorxiv
Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated {beta}-galactosidase (SA-{beta}Gal) activity is a well establis...
Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated {beta}-galactosidase (SA-{beta}Gal) activity is a well established senescence marker, its functional significance and the precise cellular subsets affected within the T cell compartment remain unclear. Here, we identify and characterize a previously unrecognized subset of naive CD4 and CD8 T cells displaying high SA-{beta}Gal activity that significantly increases with age. Despite exhibiting hallmark features of senescence such as DNA damage, nuclear envelope disruption, loss of heterochromatin, and pronounced dysregulation of autophagy and lysosomal pathways, these SA-{beta}Gal-high naive T cells notably lack the canonical senescence marker p21CIP1 and retain robust proliferative capacity upon activation. Remarkably, naive CD4 SA-{beta}Gal-high T cells acquire cytotoxic properties including NK-like features, granzyme secretion, and the ability to induce paracrine DNA damage in endothelial cells. Mechanistically, we demonstrate that impaired autophagic flux contributes significantly to this phenotype. Our findings address critical knowledge gaps regarding the nature and functional plasticity of senescence-like states in naive T cells, highlighting a novel link between lysosomal-autophagic dysfunction, cellular stress adaptation, and inflammaging. Understanding this unique T cell population provides important insights into immune aging and offers potential targets to mitigate age-associated immune dysfunction and chronic inflammation.
Longevity Relevance Analysis
(5)
The paper identifies a novel subset of naive T cells with high SA-βGal activity that exhibits features of senescence while retaining proliferative capacity, linking immune aging to cellular stress adaptation. This research is relevant as it addresses mechanisms underlying immune aging and offers insights into potential interventions for age-related immune dysfunction.
Liu, Z., Jia, X., Gao, W. ...
· epidemiology
· Zhejiang University School of Medicine
· medrxiv
Proteomics enables systematic elucidation of the biological mechanisms underlying health states including frailty. Here, through a large-scale proteome-wide association study (PWAS) encompassing 2,911 plasma proteins in 50,506 UK Biobank participants, we identified 1,339 proteins...
Proteomics enables systematic elucidation of the biological mechanisms underlying health states including frailty. Here, through a large-scale proteome-wide association study (PWAS) encompassing 2,911 plasma proteins in 50,506 UK Biobank participants, we identified 1,339 proteins significantly associated with frailty, revealing novel functional modules implicated in frailty pathogenesis, particularly the one characterized by the collagen-containing extracellular matrix and vesicle lumen pathways. Replication analyses in an independent external cohort (TwinGene study) confirmed partial but consistent associations at both protein and pathway levels, supporting the reliability of these findings. Mendelian randomization analyses supported causal associations of 50 proteins with frailty. Protein-protein interaction network and expression quantitative trait loci analyses revealed MMP1 and LGALS8 serving as hub proteins. Moreover, we developed a novel proteome-based frailty measure, termed as Proteomic Frailty Score (PFS), which demonstrated robust predictive performance (C-index > 0.7) for 198 (30.2% = 198/655) incident diseases across 13 categories and broad responsiveness to 85 modifiable risk factors. Incorporating PFS into a conventional risk factors model significantly improved the predictive performance for 510 (77.9% = 510/655) incident diseases. Longitudinal analyses with three assessments (n~1000) revealed an accelerated progression of the PFS with advancing age and increasing baseline frailty severity. To facilitate public use, we further created a publicly accessible online tool for PFS calculation (https://zipoa.shinyapps.io/frailty/). Finally, we observed a biphasic pattern of frailty-associated proteomic dysregulation across lifespan, with peak transitions occurring at approximately ages 50 and 63, implicating distinct biological pathways. Together, we establish PFS as a robust biomarker of biological aging while identifying critical windows and molecular targets for interventions against frailty progression.
Longevity Relevance Analysis
(5)
The paper establishes a novel Proteomic Frailty Score (PFS) as a biomarker of biological aging and identifies critical pathways for interventions against frailty progression. The study addresses the biological mechanisms underlying frailty, which is a significant aspect of aging and longevity research, aiming to provide insights into interventions that could mitigate age-related decline.
Hyeonuk Jeon, Siyeon Lee, Yumin Kim ...
· npj aging
· Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.
· pubmed
Senescence is the gradual process of aging in tissues and cells, and a primary cause of aging-associated diseases. Among them, intestinal stem cells (ISCs) experience exhaustion during aging, leading to reduced regenerative capacity in the intestinal crypt, which impairs intestin...
Senescence is the gradual process of aging in tissues and cells, and a primary cause of aging-associated diseases. Among them, intestinal stem cells (ISCs) experience exhaustion during aging, leading to reduced regenerative capacity in the intestinal crypt, which impairs intestinal function and contributes to systemic health issues. Given the critical role ISCs play in maintaining intestinal homeostasis, preventing their senescence is essential for preserving intestinal function. Among the various strategies proposed to slow cellular senescence, regular exercise has emerged as one of the most well-known and widely accepted interventions. Here, we examined how exercise affects the small intestine in an aging mouse model. Using single-cell RNA sequencing, we found that signaling pathways and gene expression related to DNA replication and cell cycle progression were upregulated in ISCs. Additionally, genes promoting ribosome biogenesis showed increased expression in both ISCs and transit amplifying cells. Exercise also recovered Wnt signaling inhibition, potentially influencing ISC differentiation. Furthermore, exercise increased Reg3g expression in Paneth cells and improved gut barrier function, contrasting with findings from a diet-induced obese mouse model. This suggests that regular exercise helps inhibit the aging of ISCs in multiple ways, contributing to the maintenance of intestinal homeostasis.
Longevity Relevance Analysis
(4)
Regular exercise alters transcriptional profiles in intestinal stem cells, potentially inhibiting their senescence and maintaining intestinal homeostasis. The study addresses the root causes of aging by exploring how exercise can mitigate cellular senescence in a critical tissue, thus contributing to the understanding of longevity and age-related health.