Zhao, K., Xie, H., Fonzo, G. A. ...
· neuroscience
· Stanford University
· biorxiv
As populations age, identifying the neurobiological basis of cognitive resilience is critical for delaying or preventing Alzheimers disease (AD). While most older adults experience memory decline, a subset known as superagers (SA) maintains youthful memory into late life, offerin...
As populations age, identifying the neurobiological basis of cognitive resilience is critical for delaying or preventing Alzheimers disease (AD). While most older adults experience memory decline, a subset known as superagers (SA) maintains youthful memory into late life, offering a unique window into protective mechanisms against neurodegeneration. Here, we identified a functional connectivity (FC) signature, termed Alzheimer\'s-resilient connectome (ARC), that robustly differentiates SA from age-matched patients with AD. Using resting-state fMRI in a discovery cohort (N = 290), we identified ARC derived from machine learning classifiers that distinguished SA from AD with high accuracy (AUC = 0.85), and validated the replicability of the ARC in an independent replication cohort (N = 143). ARC involved prefrontal, temporal and insular networks and was strongly associated with brain age. When applied to cognitively unimpaired (CU) adults (discovery cohort: N = 818 and replication cohort: N = 497), ARC-based subtyping revealed SA-like and AD-like subgroups with similar baseline cognitive performance but markedly divergent longitudinal trajectories. SA-like CU individuals showed slower cognitive decline, reduced amyloid-{beta} accumulation, and lower risk of conversion to mild cognitive impairment and AD, reinforcing the ARC signature as a potential early indicator of resilience. Genome-wide association analysis identified CLYBL and FRMD6 as novel genetic modulators associated with these divergent aging phenotypes. Together, our findings position ARC as a sensitive and generalizable biomarker of resilience, enabling early risk stratification and precision prevention for AD.
Longevity Relevance Analysis
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The paper claims that the Alzheimer's-resilient connectome (ARC) can serve as an early biomarker for cognitive resilience against Alzheimer's disease. This research is relevant as it explores neurobiological mechanisms that could contribute to delaying or preventing age-related cognitive decline, addressing root causes of aging and neurodegeneration.
Sophie Dürauer, Hyun-Seo Kang, Christian Wiebeler ...
· Ubiquitin
· Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
· pubmed
The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslinks (DPCs). To understand how SPRTN's promiscuous protease activity is confined to cleavage of crosslinked proteins, we reconstitute the repair of DPCs including their modification w...
The DNA-dependent protease SPRTN maintains genome stability by degrading toxic DNA-protein crosslinks (DPCs). To understand how SPRTN's promiscuous protease activity is confined to cleavage of crosslinked proteins, we reconstitute the repair of DPCs including their modification with SUMO and ubiquitin chains in vitro. We discover that DPC ubiquitylation strongly activates SPRTN independently of SPRTN's known ubiquitin-binding domains. Using protein structure prediction, MD simulations and NMR spectroscopy we reveal that ubiquitin binds to SPRTN's protease domain, promoting an open, active conformation. Replacing key interfacial residues prevents allosteric activation of SPRTN by ubiquitin, leading to genomic instability and cell cycle defects in cells expressing truncated SPRTN variants that cause premature aging and liver cancer in Ruijs-Aalfs syndrome patients. Collectively, our results reveal a ubiquitin-dependent regulatory mechanism that ensures SPRTN activity is deployed precisely when and where it is needed.
Longevity Relevance Analysis
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The paper claims that ubiquitin activates the SPRTN protease, which is crucial for maintaining genome stability and preventing premature aging and cancer. This research is relevant as it addresses mechanisms that contribute to genomic stability, a key factor in aging and age-related diseases.
Yidan Pang, Siyuan Zhu, Peng Ding ...
· MedComm
· Department of Orthopaedics Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China.
· pubmed
Obesity and aging are major risk factors for diseases such as Type 2 diabetes mellitus, dementia, and osteoporosis. High-fat diet (HFD) consumption is one of the most important factors contributing to obesity. To elucidate and provide resources on how long-term HFD to aging (LHA)...
Obesity and aging are major risk factors for diseases such as Type 2 diabetes mellitus, dementia, and osteoporosis. High-fat diet (HFD) consumption is one of the most important factors contributing to obesity. To elucidate and provide resources on how long-term HFD to aging (LHA) affects the bone marrow and solid organs, we established an LHA mice model and demonstrated that LHA caused a shift from osteogenesis to adipogenesis in the bone marrow microenvironment. Single-cell transcriptomics of bone marrow cells highlighted LHA-driven perturbations in immune cell populations with distinct metabolic adaptations to LHA. We demonstrated that bone marrow macrophages of the LHA group upregulated Chil3 and Fabp4, which are associated with inflammatory response and regulation of adipocytes. Moreover, we identified the Ptn-Sdc3 axis and Cxcl12-Cxcr4 axis between bone marrow macrophages and brain epithelial cells as possible candidates for crosstalk between bone marrow and brain in LHA mice. Our findings indicated the bone marrow microenvironment as a central hub of LHA-induced pathology, where adipogenic reprogramming and myeloid cell dysfunction collectively drive skeletal and systematic inflammation. This resource highlights therapeutic opportunities targeting bone marrow to mitigate obesity-accelerated aging.
Longevity Relevance Analysis
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Long-term high-fat diet consumption shifts the bone marrow microenvironment from osteogenesis to adipogenesis, impacting aging-related inflammation. This study addresses the underlying mechanisms of aging and obesity, linking metabolic changes in the bone marrow to broader implications for age-related diseases.
Chenke Jiang, Yihong Gan, Shengyu Chen ...
· Aging clinical and experimental research
· School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China.
· pubmed
Observational studies have shown that physical activity and sedentary behavior are associated with aging. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between genetic...
Observational studies have shown that physical activity and sedentary behavior are associated with aging. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between genetically predicted physical activity, sedentary behavior, and aging.
Longevity Relevance Analysis
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The paper claims to assess the genetic correlation and causal relationships between genetically predicted physical activity, sedentary behavior, and aging. This research is relevant as it explores the underlying causal mechanisms linking lifestyle factors to aging, which could inform strategies for longevity and age-related health improvements.
Critchlow, A. J., Hiam, D., O'Bryan, S. ...
· endocrinology
· Deakin University
· medrxiv
Whether and how ovarian hormone fluctuations mediate the skeletal muscle response to ageing in females remains to be elucidated. We examined a tightly controlled, cross-sectional cohort of 96 females between 18-80 years of age to map the functional and molecular trajectory of mus...
Whether and how ovarian hormone fluctuations mediate the skeletal muscle response to ageing in females remains to be elucidated. We examined a tightly controlled, cross-sectional cohort of 96 females between 18-80 years of age to map the functional and molecular trajectory of muscle ageing and determine its relationship with female sex hormones. Across every decade, we quantified body composition using dual-energy x-ray absorptiometry, muscle morphology using peripheral quantitative computed tomography and voluntary and evoked muscle strength. Circulating sex hormone concentrations were measured with gas chromatography mass spectrometry and immunoassays. Morphology and gene expression of vastus lateralis muscle samples were assessed with immunohistochemical staining and RNA sequencing, respectively. After adjusting for the relevant variables, age was negatively associated with muscle mass, strength, and muscle fibre size, and positively associated with hybrid type I/II fibre prevalence and fibrosis. We found 37 unique patterns of gene expression across individual decades of age. Immune signalling, cellular adhesion, and extracellular matrix organisation pathways were the most upregulated with age, while mitochondrial function pathways were the most downregulated. Independently of age, circulating oestradiol and progesterone, but not testosterone, concentrations were positively associated with lean mass and negatively associated with hybrid muscle fibres across the lifespan. Oestrogen receptor binding sites were significantly enriched in upregulated genes in pre- versus post-menopausal muscle, suggesting a reduction in the translation of oestrogen target genes after menopause. The effects of sex hormone fluctuations across the female lifespan should therefore be considered in the development of therapies to mitigate age-related muscle wasting.
Longevity Relevance Analysis
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The paper claims that fluctuations in female sex hormones significantly influence muscle mass and function across the lifespan. This research is relevant as it addresses the biological mechanisms underlying age-related muscle deterioration in females, which is a critical aspect of aging and longevity.
STOLZ, A., XUAN, C., FREITAS, C. ...
· cell biology
· INSERM UMR1287, Universite Paris Saclay, Gustave Roussy Cancer Center, 94805 Villejuif, France
· biorxiv
Chronic inflammation that accompanies aging impairs the function of hematopoietic stem cells (HSCs) and promotes expansion of TET2-mutated cells, leading to clonal hematopoiesis of indeterminate potential (CHIP). The molecular mechanisms underlying these processes are still uncle...
Chronic inflammation that accompanies aging impairs the function of hematopoietic stem cells (HSCs) and promotes expansion of TET2-mutated cells, leading to clonal hematopoiesis of indeterminate potential (CHIP). The molecular mechanisms underlying these processes are still unclear. We recently showed that age and stresses like irradiation reduce the heterochromatin mark H3K9me3, leading to the epigenetic derepression of transposable elements such as LINE-1/L1, and L1-induced HSC functional changes through DNA damage and transcriptomic alterations. However, the impact of TEs on the clonal expansion of Tet2-/- HSCs upon chronic inflammation is unknown. Here we show that in wild type (WT) HSC, chronic inflammation induced by repeated low doses of lipopolysaccharide (LPS) triggers H3K9me3 loss at L1. We further show that L1s are involved in LPS-induced DNA damage and reduction of HSC clonogenicity. In contrast, Tet2-/- HSCs resist LPS-induced L1 epigenetic derepression and associated DNA damage. As a result, WT HSCs show decreased competitiveness against Tet2-/- HSCs upon chronic inflammation. These findings identify epigenetic control of L1s as a key mediator of inflammation-induced HSC dysfunction and clonal expansion of Tet2-mutant cells.
Longevity Relevance Analysis
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The paper claims that Tet2-deficient HSCs resist L1-induced DNA damage during chronic inflammation, leading to their clonal expansion. This research is relevant as it explores the underlying mechanisms of hematopoietic stem cell dysfunction in the context of chronic inflammation and aging, potentially addressing root causes of age-related clonal expansion and its implications for longevity.
Nguyen, T. D., Khan, Y. Z., Hossen, F. ...
· cell biology
· University of Illinois Chicago
· biorxiv
As the innermost lining of blood vessels, endothelial cells (ECs) regulate blood flow, maintain vascular tone, and limit inflammation for vessel health. EC-derived nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), is a vasodilator essential for improving...
As the innermost lining of blood vessels, endothelial cells (ECs) regulate blood flow, maintain vascular tone, and limit inflammation for vessel health. EC-derived nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), is a vasodilator essential for improving blood flow and vascular homeostasis. The RhoA/ROCK pathway regulates eNOS levels, where overactivation decreases eNOS expression and downstream NO production. As such, RhoA/ROCK hyperactivity and increased pMLC have been identified as major contributors to age-associated vasoconstriction and hypertension. Intriguingly, recent studies identify Sun1, a key component of the linker of nucleoskeleton and cytoskeleton (LINC) complex, as a major regulator of RhoA/ROCK activity. Moreover, endothelial aging deteriorates nuclear pore complexes (NPCs) (i.e. nucleoporin [Nup93]) and impairs nucleocytoplasmic transport, thereby insinuating a role for nuclear envelope components in vessel homeostasis. Here, we show that targeted loss of endothelial Nup93 in adult mice significantly reduces eNOS expression and NO bioavailability for consequent defects in NO-dependent vasodilatory responses. In vitro knockdown of Nup93 in primary human ECs also decreases both eNOS expression and NO production. Mechanistically, we find that loss of Nup93 significantly reduces endothelial Sun1 levels for a concomitant increase in RhoA activity. Indeed, restoring Sun1 protein levels in Nup93-deficient ECs mitigates RhoA activity to rescue both eNOS expression and NO production. Taken together, we demonstrate endothelial Nup93, through Sun1 stabilization, as a novel regulator of eNOS-NO signaling and vessel reactivity, contributing to the growing importance of nuclear membrane components in EC and vascular biology.
Longevity Relevance Analysis
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Endothelial Nup93 regulates eNOS expression and NO production through Sun1 stabilization, impacting vascular function. The study addresses mechanisms underlying endothelial aging and vascular health, which are critical for longevity and age-related vascular diseases.
The maintenance of mitochondrial proteins homeostasis, which is essential for proper cell function, is affected in pathophysiological ageing, yet several underlying mechanisms remain unexplored. We show that in normal and accelerated ageing cells, POLG1, the enzyme responsible fo...
The maintenance of mitochondrial proteins homeostasis, which is essential for proper cell function, is affected in pathophysiological ageing, yet several underlying mechanisms remain unexplored. We show that in normal and accelerated ageing cells, POLG1, the enzyme responsible for mitochondrial DNA replication, is degraded by the protease cathepsin B, which is overexpressed, escapes from lysosomes, and is stabilized by the chaperone activity of another protease, HTRA3. This degradation is in part counteracted by RAC1, a small GTPase also stabilized by HTRA3. POLG1 depletion, that occurs in progeroid Cockayne syndrome and senescent cells, is linked respectively to impairment or downregulation of the CSB protein, which promote cellular senescence. Our experiments in engineered cells, demonstrate that senescence itself, and not the absence of CSB, triggers the accumulation of cathepsin B and HTRA3, leading to POLG1 degradation. In summary, we uncover a complex, multi-step process that controls the degradation of POLG1 in mitochondria, a process that is activated by cell senescence and becomes more pronounced in Cockayne syndrome cells, providing new insight in the regulation of mitochondrial proteostasis in ageing and progeroid disorders.
Longevity Relevance Analysis
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The paper claims that the protease-chaperone HTRA3 stabilizes cathepsin B, leading to the degradation of POLG1 in the context of cellular senescence and mitochondrial dysfunction. This research is relevant as it explores mechanisms underlying mitochondrial protein homeostasis and degradation processes that contribute to aging and age-related disorders, potentially offering insights into the root causes of cellular senescence.
Luciana Yamamoto de Almeida, Catharine Dietrich, Ashleigh S Hanner ...
· Aging cell
· Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, Maryland, USA.
· pubmed
Large-scale bone defects require complex surgical procedures to repair, but full restoration of the bone is not guaranteed due to the significant tissue loss involved. In contrast, fractures can frequently be treated with conservative techniques. Particularly, ribs have a remarka...
Large-scale bone defects require complex surgical procedures to repair, but full restoration of the bone is not guaranteed due to the significant tissue loss involved. In contrast, fractures can frequently be treated with conservative techniques. Particularly, ribs have a remarkable ability to spontaneously regenerate large-scale bone defects. However, we show here that skeletal maturity and age are associated with a decrease in the regenerative potential of human ribs. To investigate skeletal maturity and age-related cellular and transcriptional changes during large-scale bone regeneration, we used a mouse model that mimics the regenerative clinical features of human ribs. Unlike immature mice, mature mice lose the ability to regenerate after rib resection, and instead of bone, the resected rib space is repaired with abundant fibronectin cells. In addition, bone repair in mature mice presents reduced immune cell infiltration, which coincides with decreased levels of circulatory pro-inflammatory factors. To address the role of cell-cell communication and test whether skeletal maturity and age-related changes in immune cells and circulatory factors influence bone regeneration, we used immunodeficient mouse strains and performed heterochronic parabiosis. In immature mice, defective immune cell function altered callus composition rather than inhibiting bone regeneration. Remarkably, under parabiosis, a systemic pro-regenerative response is triggered exclusively in resected immature mice and is capable of partially rescuing bone regeneration in mature mice otherwise unable to regenerate spontaneously. Collectively, these findings suggest that therapeutic strategies focused on identifying pro-regenerative immune factors are promising for supporting the regeneration of large bone defects.
Longevity Relevance Analysis
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The paper claims that age-related changes in immune cells and circulatory factors impair bone regeneration, suggesting that targeting these factors could enhance regenerative capacity in older individuals. This research is relevant as it addresses the mechanisms underlying age-related decline in regenerative potential, which is a key aspect of longevity and aging.
Douglas M Ruden
· Epigenomics
· C. S. Mott Center for Human Growth and Development, Institute for Environmental Health Sciences, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI, USA.
· pubmed
Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcri...
Aging is a complex biological process involving coordinated changes across multiple molecular systems. Traditional reductionist approaches, while valuable, are insufficient to capture the full scope of aging's systemic nature. Multiomics - integrating data from genomics, transcriptomics, epigenomics, proteomics, and metabolomics - provides a comprehensive framework to study aging as an interconnected network. In this Perspective, I explore how multiomic strategies, particularly those leveraging epigenomic and single-cell data, are reshaping our understanding of aging biology. Epigenetic alterations, including DNA methylation and histone modifications, are not only hallmarks but also powerful biomarkers of biological age. I discuss advances in multiomic aging clocks, cross-tissue atlases, and single-cell spatial technologies that decode aging at unprecedented resolution. I also build on a prior review I wrote with colleagues, Epigenomics. 2023;15(14):741-754, which introduced the concept of pathological epigenetic events that are reversible (PEERs) - epigenetic alterations linked to early-life exposures that predispose to aging and disease but may be therapeutically modifiable. This Perspective examines how PEERs and multiomics intersect to inform biomarkers, geroprotective interventions, and personalized aging medicine. Finally, I highlight integration challenges, ethical concerns, and the need for standardization to accelerate clinical translation. Together, these insights position multiomics as a central pillar in the future of aging research.
Longevity Relevance Analysis
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The paper claims that multiomics can reshape our understanding of aging biology and inform biomarkers and interventions. This research is relevant as it addresses the systemic nature of aging and explores potential therapeutic avenues to modify epigenetic alterations linked to aging and disease.
Korcari, A., Tauc, H., Duggan, J. ...
· immunology
· Genentech
· biorxiv
Aging is associated with a decline in the regenerative capacity of many tissues. Central to this decline is a complex interplay between inflammation and stem cell function. How these two processes are linked and influence regenerative capacity remains unclear. Here, we undertake ...
Aging is associated with a decline in the regenerative capacity of many tissues. Central to this decline is a complex interplay between inflammation and stem cell function. How these two processes are linked and influence regenerative capacity remains unclear. Here, we undertake a comprehensive assessment of age-related changes in the mouse colon at single-cell resolution. A survey of immune and epithelial compartments revealed a hyperactivated inflammatory state in the colon of old mice characterized by the induction of an interferon {gamma} (IFN{gamma}) response signature in immune cells. This does not result in increased inflammation under homeostasis, but triggers a disproportionate inflammatory response, disrupting regeneration after challenge with the enteropathogen Citrobacter rodentium. Colons of old mice exhibit higher production of IFN{gamma} by T and innate lymphoid cells (ILCs) that are associated with reduced Lgr5+ stem cells and decreased epithelial proliferation. Interestingly, we find aged intestinal epithelial cells to be hypersensitive to IFN{gamma} signaling, inducing a regeneration-associated fetal-like gene expression signature that, in turn, renders these cells more sensitive to IFN{gamma}-induced apoptosis. Our findings reveal an age-related imbalance in the interaction between the immune and epithelial compartments in the colon, priming the system for excessive inflammatory responses and the emergence of a hypersensitive epithelial cell state thus derailing proper repair of the intestinal epithelium after injury.
Longevity Relevance Analysis
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The paper claims that maladaptive inflammatory signaling in old mice impairs colonic regeneration by promoting a sustained fetal-like epithelial state. This research is relevant as it addresses the underlying mechanisms of aging and how inflammation affects regenerative capacity, which is crucial for understanding age-related decline in tissue function.
Nusrat Jan, Shazia Sofi, Aijaz Ahmad Mir ...
· Molecular and cellular biochemistry
· Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, 190006, India.
· pubmed
Aging and cancer are interconnected processes resulting from irreversible dysfunctions, primarily caused by stress-induced DNA and cellular damage. While aging is characterized by the accumulation of senescent cells (SnCs), cancer development is linked to a progressive decline in...
Aging and cancer are interconnected processes resulting from irreversible dysfunctions, primarily caused by stress-induced DNA and cellular damage. While aging is characterized by the accumulation of senescent cells (SnCs), cancer development is linked to a progressive decline in the ability of cells to undergo senescence and apoptosis. Both processes serve as crucial tumor suppressor mechanisms in early life but may contribute to aging-related pathologies over time. Cellular senescence and apoptosis are stress responses that play vital roles in maintaining tissue homeostasis. In aging, SnCs accumulate in tissues due to dysregulated apoptotic pathways, while in cancer, reduced senescence and apoptosis enable uncontrolled proliferation. Recent findings suggest that several anticancer drugs, including classical apoptosis inducers, can also promote senescence, highlighting the potential for pro-senescence strategies in cancer therapy. Understanding the mechanistic pathways and biomarkers of these processes can provide insight into their interplay and their impact on disease progression. Exploring the balance between cellular senescence and apoptosis may lead to novel therapeutic approaches for both aging and cancer. Targeting these mechanisms could help develop anti-aging and anticancer treatments with minimized adverse effects, offering promising avenues for future research and clinical applications.
Longevity Relevance Analysis
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The paper suggests that understanding the balance between cellular senescence and apoptosis can lead to novel therapeutic approaches for aging and cancer. This research is relevant as it addresses mechanisms that could potentially target the root causes of aging and age-related diseases rather than merely treating symptoms.
Dieu-Huong Hoang, Jessica Bouvière, Johanna Galvis ...
· EMBO reports
· Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du Muscle, Université Claude Bernard Lyon 1, Inserm U1315, CNRS 5261, Lyon, France.
· pubmed
Muscle regeneration is impaired with aging, due to both intrinsic defects of muscle stem cells (MuSCs) and alterations of their niche. Here, we monitor the cells constituting the MuSC niche over time in young and old regenerating mouse muscle. Aging alters the expansion of all ni...
Muscle regeneration is impaired with aging, due to both intrinsic defects of muscle stem cells (MuSCs) and alterations of their niche. Here, we monitor the cells constituting the MuSC niche over time in young and old regenerating mouse muscle. Aging alters the expansion of all niche cells, with prominent phenotypes in macrophages that show impaired resolution of inflammation. RNA sequencing of FACS-isolated mononucleated cells uncovers specific profiles and kinetics of genes and molecular pathways in old versus young muscle cells, indicating that each cell type responds to aging in a specific manner. Moreover, we show that macrophages have an altered expression of Selenoprotein P (Sepp1). Macrophage-specific deletion of Sepp1 is sufficient to impair the acquisition of their restorative profile and causes inefficient skeletal muscle regeneration. When transplanted in aged mice, bone marrow from young WT mice, but not Sepp1-KOs, restores muscle regeneration. This work provides a unique resource to study MuSC niche aging, reveals that niche cell aging is asynchronous and establishes the antioxidant Selenoprotein P as a driver of age-related decline of muscle regeneration.
Longevity Relevance Analysis
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Macrophage-specific deletion of Selenoprotein P impairs muscle regeneration in aged mice. This paper addresses the mechanisms of muscle regeneration impairment due to aging, focusing on the role of macrophages and their altered functions, which is directly related to understanding and potentially mitigating age-related decline in muscle health.
Lihuan Guan, Lei Feng, Anderson Li Yang Khoo ...
· European journal of epidemiology
· Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
· pubmed
The global population is ageing rapidly. While genetics, lifestyle, and environment are known contributors to healthspan, most insights are drawn from Western cohorts, leaving Asian populations underrepresented despite unique biological, lifestyle, and cultural factors. The SG90 ...
The global population is ageing rapidly. While genetics, lifestyle, and environment are known contributors to healthspan, most insights are drawn from Western cohorts, leaving Asian populations underrepresented despite unique biological, lifestyle, and cultural factors. The SG90 cohort study aimed to fill knowledge gaps in healthy ageing by identifying modifiable medical, biological, lifestyle, psychological, behavioural, and social factors that contribute to longevity in the oldest-old. The study recruited 1,158 participants aged 85 and above from the Singapore Chinese Health Study (SCHS) and Singapore Longitudinal Aging Study (SLAS) between 2015 and 2021. Data collection involved face-to-face interviews to obtain sociodemographic, lifestyle, sleep, functional status, quality of life, medical conditions and healthcare economics information, along with clinical assessments covering physical examinations, anthropometry, physical performance, cognition, and mental health. Biospecimens, including blood, saliva, stool, urine, toenails, hair, and skin tape strips were collected to support extensive multi-omic and cellular analyses. Participants, primarily female (64.5%) and Chinese (97.5%) with a median age of 87 years [interquartile range (IQR): 86-89], were mostly non-smokers (72.1%) and infrequent alcohol consumers (94.9%), with 66.5% exercising regularly. Functional assessments indicate high independence, with median Basic activities of daily living (BADL) and Instrumental ADL (IADL) scores of 20 (IQR: 19-20) and 14 (IQR: 11-16), respectively. 36% of participants rated their self-reported health as good to excellent. The SG90 cohort study offers a comprehensive clinical and biological data resource on healthy ageing among Asia's oldest-old, laying a foundation for targeted interventions to promote healthy longevity and quality of life.
Longevity Relevance Analysis
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The SG90 cohort study identifies various factors contributing to healthy ageing in the oldest-old population in Singapore. This research addresses knowledge gaps in longevity by focusing on an underrepresented demographic, potentially leading to targeted interventions for promoting healthy ageing.
Li, M., Song, Z., Reed, E. ...
· molecular biology
· Boston University
· biorxiv
Background. Age is one of the major risk factors for a wide range of diseases. Nevertheless, some individuals can better cope with these changes and become centenarians. We hypothesize that their blood transcriptome may provide insights into the mechanisms contributing to healthy...
Background. Age is one of the major risk factors for a wide range of diseases. Nevertheless, some individuals can better cope with these changes and become centenarians. We hypothesize that their blood transcriptome may provide insights into the mechanisms contributing to healthy aging, as well as enable the discovery of candidate therapeutic targets. The Long-Life Family Study (LLFS), which includes participants from families enriched with long-lived individuals, serves as a valuable dataset for achieving these objectives. Methods. To identify transcripts associated with age, we analyzed the association between age at blood draw and 16,284 RNAseq-based blood transcriptomic data from 2,167 LLFS participants with ages ranging from 18 to 107. We used linear mixed-effect models controlling for familial relatedness and adjusted for genetic, socioeconomic, and technical confounders. We validated results in a dataset of 20,884 RNAseq-based blood transcriptomic data from 434 participants of the Integrative Longevity Omics Study, and compared findings to a published reference aging signature. We integrated the results by building a transcriptomic aging clock. We also identified transcripts associated with mortality risk using a Cox-proportional hazard model. Results. We identified 4,227 transcripts increasing and 4,044 transcripts decreasing with age. Age-associated expression patterns were significantly replicated in external datasets, with high correlation (R = 0.78 - 0.94). Enrichment analysis revealed age-related upregulation of inflammatory and senescence-related pathways (e.g., IFN-{gamma} response, TNF-/NF-{kappa}B signaling), and downregulation of MYC and Wnt/{beta}-catenin targets, among others. WGCNA identified co-expression modules reflecting inflammation, immune signaling, and decreased protein synthesis. We also identified 314 transcripts significantly associated with mortality risk and found that pro-survival gene sets included NK cell-mediated cytotoxicity and GPCR signaling. A subset of transcripts showed age associations unique to longevity-enriched cohorts and not present in non-longevity populations, implicating IL6-Jak-Stat3, mitotic spindle, and p53 pathways. Finally, transcriptomic age (delta-age) was strongly associated with increased mortality (HR = 1.108, p = 3.33e-18), with significant survival differences between delta-age groups. Conclusions. This study identified robust transcriptomic signatures of aging and mortality in a longevity-enriched population, highlighting key biological pathways such as immune modulation, inflammation, and senescence. Age-associated expression profiles that are unique to long-lived individuals may represent resilience mechanisms distinct from general aging trends. Transcriptomic age acceleration is a strong predictor of mortality, reinforcing its utility as a molecular biomarker of biological aging.
Longevity Relevance Analysis
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The study identifies transcriptomic signatures associated with aging and mortality, suggesting potential biological pathways that contribute to healthy aging and longevity. The research focuses on understanding the molecular mechanisms of aging and resilience in long-lived individuals, which is directly relevant to longevity research.
Sadoughi, B., Petersen, R., Patterson, S. K. ...
· genomics
· Vanderbilt University
· biorxiv
Age and early life adversity (ELA) are both key determinants of health, but whether they target similar physiological mechanisms across the body is unknown due to limited multi-tissue datasets from well-characterized cohorts. We generated DNA methylation (DNAm) profiles across 14...
Age and early life adversity (ELA) are both key determinants of health, but whether they target similar physiological mechanisms across the body is unknown due to limited multi-tissue datasets from well-characterized cohorts. We generated DNA methylation (DNAm) profiles across 14 tissues in 237 semi-free ranging rhesus macaques, with records of naturally occurring ELA. We show that age-associated DNAm variation is predominantly tissue-dependent, yet tissue-specific epigenetic clocks reveal that the pace of epigenetic aging is relatively consistent within individuals. ELA effects on loci are adversity-dependent, but a given ELA has a coordinated impact across tissues. Finally, ELA targeted many of the same loci as age, but the direction of these effects varied, indicating that ELA does not uniformly contribute to accelerated age in the epigenome. ELA thus imprints a coordinated, tissue-spanning epigenetic signature that is both distinct from and intertwined with age-related change, advancing our understanding of how early environments sculpt the molecular foundations of aging and disease.
Longevity Relevance Analysis
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The paper claims that early life adversity and age shape a coordinated epigenetic signature across tissues, influencing the molecular foundations of aging and disease. This research is relevant as it explores the underlying mechanisms of aging and how early environmental factors can affect epigenetic changes related to health outcomes.
Jantrapirom, S., Sangphukieo, A., U-on, N. ...
· neuroscience
· Faculty of Medicine, ChiangMai University
· biorxiv
Targeting Endoplasmic Reticulum Oxidoreductase 1 Alpha (ERO1A) offers therapeutic potential for ER stress-related conditions, including motor neurone diseases and congenital muscle disorders. However, selective ERO1A inhibitors remain unavailable. Here, we developed a multi-modal...
Targeting Endoplasmic Reticulum Oxidoreductase 1 Alpha (ERO1A) offers therapeutic potential for ER stress-related conditions, including motor neurone diseases and congenital muscle disorders. However, selective ERO1A inhibitors remain unavailable. Here, we developed a multi-modal discovery pipeline combining molecular docking with in vitro and in vivo assays, screening 401,824 natural products from the COCONUT database. We identified two compounds, S88 and geniposide, that inhibited ERO1A in vitro, reduced tunicamycin-induced ER stress markers in human neurons, and improved locomotion and neuromuscular junctions in UBQLN2ALS Drosophila. S88 maintained efficacy in late-stage disease and extended lifespan in a D-galactose aging model. In fly brains, S88 selectively reduced phosphorylated eIF2a; without lowering its downstream effector ATF4, suggesting engagement of alternative mechanisms preserving ATF4 homeostasis. These findings highlight S88 as a promising lead for treating ER stress-associated neuromuscular disorders and demonstrate the utility of this integrative discovery pipeline for identifying bioactive natural compounds with disease-modifying potential.
Longevity Relevance Analysis
(4)
The paper claims that the pyrazolopyridine alkaloid S88 mitigates neuronal ER stress and extends lifespan in a D-galactose aging model. This research addresses a potential therapeutic approach to a root cause of aging-related decline by targeting ER stress, which is implicated in various age-related diseases.
Wanting Jiang, Xing Wang, Lijuan Mao
· Journal of Alzheimer's disease : JAD
· School of Athletic Performance, Shanghai University of Sport, Shanghai, China.
· pubmed
Cognitive decline is age-specific or related to dementia and Alzheimer's disease (AD), which poses great concern to older adults. Exercise contributes to cognitive gains, with aerobic exercise (AE) being the most commonly studied type. However, other types, such as resistance exe...
Cognitive decline is age-specific or related to dementia and Alzheimer's disease (AD), which poses great concern to older adults. Exercise contributes to cognitive gains, with aerobic exercise (AE) being the most commonly studied type. However, other types, such as resistance exercise (RE), have received less attention in exercise-cognition research. This narrative review aims to synthesize evidence addressing the effects of RE, including the influence of its various parameters on cognitive function in older adults. It also examines the adaptations of neurotrophic factors, brain structure, and brain function in response to RE and explores the relationship between these adaptive responses and cognitive function. A comprehensive search of PubMed databases was conducted up to Jan 2025, identifying 41 randomized controlled trials for inclusion. RE may effectively improve executive function, memory function, and global cognition in older adults with and without cognitive impairment. However, optimal exercise parameters, such as intensity, frequency, and length, remain to be established. Evidence suggests that RE may elevate peripheral insulin-like growth factor 1 levels, increase gray matter thickness, mitigate hippocampal atrophy, and enhance brain activation, all of which appear to contribute to cognitive improvements. Collectively, these studies advance our understanding of the potential role of RE in promoting cognitive and brain health during aging.
Longevity Relevance Analysis
(4)
Resistance exercise may improve cognitive function in older adults through various neurobiological adaptations. The paper is relevant as it explores the potential of resistance exercise to enhance cognitive health, which is a critical aspect of longevity and aging research.
Bahr, L., Amrit, F. R., Silvia, P. E. ...
· genetics
· University of Pittsburgh School of Medicine
· biorxiv
Reproduction and immunity are fundamental, energy intensive processes that often compete for resources, leading to trade-offs observed across diverse species. Lipid metabolism plays a crucial role in integrating these processes, particularly during stressful conditions such as pa...
Reproduction and immunity are fundamental, energy intensive processes that often compete for resources, leading to trade-offs observed across diverse species. Lipid metabolism plays a crucial role in integrating these processes, particularly during stressful conditions such as pathogenic infections. Yet the molecular mechanisms governing this integration remain poorly understood. TCER-1, the C. elegans homolog of mammalian TCERG1, suppresses immunity and promotes fertility, especially upon maternal infection. Here, we show that TCER-1 regulates two conserved lysosomal lipases, lipl-1 and lipl-2, to balance reproduction, immunity and lifespan. Using transcriptomic, lipidomic, and molecular-genetic analyses, we demonstrate that while both lipl-1 and lipl-2 mediate infection-induced lipid remodeling, lipl-1 enhances immunity and catalyzes the accumulation of ceramide species linked to stress response and longevity, whereas, lipl-2 unexpectedly does not. Both lipases contribute towards fertility outcomes, but lipl-2 is especially critical for maintaining embryonic-eggshell integrity during maternal infection and aging. Strikingly, expression of human lysosomal acid lipase (LAL), the ortholog of lipl genes, rescues the immune defects triggered by lipl-l loss and enhances immune resilience. Together, these findings uncover functionally distinct roles for lipl-1 and lipl-2 in modulating lipid species that shape immune fitness, healthspan and reproductive health, and suggest a potentially conserved mechanism by which lipid metabolism links fertility and immunity.
Longevity Relevance Analysis
(4)
TCER-1 regulates distinct lysosomal lipases that modulate lipid metabolism, impacting immunity, fertility, and longevity. The study explores the molecular mechanisms linking lipid metabolism to longevity and healthspan, which is directly relevant to understanding aging processes.
Guoqing Pan, Yi Zhang, Ju-Jiao Kang ...
· npj aging
· Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.
· pubmed
Given the growing global elderly population and the accelerating decrease in grey matter volume (GMV) with age, understanding healthy brain aging is increasingly important. This study investigates whether variations in modifiable traits can account for differences in GMV and whet...
Given the growing global elderly population and the accelerating decrease in grey matter volume (GMV) with age, understanding healthy brain aging is increasingly important. This study investigates whether variations in modifiable traits can account for differences in GMV and whether these traits can inform strategies to mitigate risks of future brain disorders. We identified 66 traits significantly associated with total GMV. Further, we examined the joint contributions of different domain traits to the GMV variance, finding that blood biomarkers and physical measurements accounted for the largest proportion of GMV variance. Some traits mediated the relationship between the genetic risk for brain disorders and GMV. Moreover, the identified traits divided the population into two subgroups, with significant differences in GMV and incidences of brain disorders. Our findings underscore the importance of modifiable traits in supporting healthy brain aging and reducing the risk of brain disorders, suggesting potential targets for intervention.
Longevity Relevance Analysis
(4)
Modifiable traits can significantly influence grey matter volume in mid-to-late adulthood. The study addresses factors that may mitigate risks of brain disorders, which is pertinent to understanding healthy aging and longevity.
Pei Lin Li, Jie Tang, Xiao Tong Li ...
· Osteoarthritis
· Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing 100850, P.R. China.
· pubmed
Osteoarthritis (OA) is a challenging degenerative joint disease with limited treatment options. Subchondral bone plays a critical role in maintaining joint homeostasis and influencing OA progression. Here, we investigated the role of senescence in mesenchyme-derived stem/progenit...
Osteoarthritis (OA) is a challenging degenerative joint disease with limited treatment options. Subchondral bone plays a critical role in maintaining joint homeostasis and influencing OA progression. Here, we investigated the role of senescence in mesenchyme-derived stem/progenitor cells (MDSPCs) during OA progression, aiming to identify potential therapeutic targets. Histopathological evaluations and bioinformatic analyses of OA samples from both humans and mice revealed that EGFR
Longevity Relevance Analysis
(4)
The paper identifies senescent mesenchyme-derived stem/progenitor cells as critical for osteoarthritis progression and potential therapeutic targets. This research addresses the role of cellular senescence in a degenerative disease, linking it to aging processes and potential interventions that could impact longevity.
Huang, Q., Wang, Y., Farias, K. ...
· pharmacology and toxicology
· Weill Cornell Medicine
· biorxiv
Cardiomyocyte senescence, characterized by elevated cell cycle inhibitor expression, persistent DNA damage response, and mitochondrial dysfunction, contributes to myocardial stiffness and the progression of heart failure with preserved ejection fraction (HFpEF), the most common f...
Cardiomyocyte senescence, characterized by elevated cell cycle inhibitor expression, persistent DNA damage response, and mitochondrial dysfunction, contributes to myocardial stiffness and the progression of heart failure with preserved ejection fraction (HFpEF), the most common form of heart failure affecting individuals over 65. In this study, we investigated the role of NAD metabolism in cardiomyocyte senescence and cardiac function. Aged mice exhibited reduced cardiac NAD levels, impaired NAD biosynthesis and mobilization, and increased consumption, leading to suppressed SIRT1/6 activity and accumulation of senescent cardiomyocytes. This was accompanied by diastolic dysfunction consistent with HFpEF. In senescent AC16 cardiomyocytes, NAD depletion promoted senescence, which was reversed by the NAD precursors nicotinamide riboside (NR) and dihydronicotinamide riboside (NRH). In aged mice, two months of NR or NRH treatment improved diastolic function and reduced cardiomyocyte senescence. While NR primarily activated SIRT1 to suppress cell cycle arrest markers, NRH more robustly activated both SIRT1 and SIRT6, enhancing DNA damage repair. Acetylated H2AX, a SIRT6 substrate elevated in aged hearts and senescent cells, was selectively deacetylated by NRH. These findings identify NAD availability as a critical regulator of cardiac senescence and support NAD precursors, particularly NRH, as promising senescence-reducing therapies for treating aging-associated HFpEF.
Longevity Relevance Analysis
(4)
NAD⁺ replenishment mitigates cardiomyocyte senescence and improves heart function in aged mice. This study addresses the underlying mechanisms of aging-related cardiac dysfunction, specifically targeting cellular senescence, which is a key aspect of the aging process.
Pablo-Reina Gonzalez, Muhammet Ay, Monica Langley ...
· Toxicological sciences : an official journal of the Society of Toxicology
· Dept of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
· pubmed
Astrocytes, the most abundant glial cells in the central nervous system, play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood-brain barrier integrity. However, these cells can undergo senescence, a cellular state characterized by irreversible g...
Astrocytes, the most abundant glial cells in the central nervous system, play essential roles in maintaining neuronal homeostasis, synaptic regulation, and blood-brain barrier integrity. However, these cells can undergo senescence, a cellular state characterized by irreversible growth arrest and the secretion of proinflammatory factors, in response to aging, and pathological stressors, contributing to synaptic dysfunction and neurodegenerative diseases. This review examines the molecular mechanisms driving astrocytic senescence, including oxidative stress, DNA damage, and inflammatory signaling pathways such as NF-κB and the senescence-associated secretory phenotype (SASP). A particular focus is placed on the diverse array of known chemical inducers of astrocyte senescence such as pesticides and heavy metals, which provide critical insights into the processes governing cellular aging in the brain. By analyzing the effects of these inducers, we highlight their implications for neurodegenerative disease progression and brain aging. Understanding astrocytic senescence offers new insights into age-related neuropathology and presents promising avenues for targeted therapies in neurodegenerative disorders induced by environmental toxicants.
Longevity Relevance Analysis
(4)
The paper claims that astrocytic senescence driven by neurotoxicants contributes to neurodegeneration and brain aging. This research is relevant as it explores the underlying mechanisms of cellular aging in the brain, which could lead to potential interventions targeting the root causes of age-related neurodegenerative diseases.
Gopal, S., Chaturbedi, A., Ramachandrula, T. V. ...
· developmental biology
· Cornell University
· biorxiv
The nuclear hormone receptor NHR-49, a homolog of mammalian PPAR and HNF4, is a key transcriptional regulator of nutrition sensing and fatty acid metabolism in Caenorhabditis elegans. Here we uncovered a new function of NHR-49 in reproduction - controlling oocyte activation and o...
The nuclear hormone receptor NHR-49, a homolog of mammalian PPAR and HNF4, is a key transcriptional regulator of nutrition sensing and fatty acid metabolism in Caenorhabditis elegans. Here we uncovered a new function of NHR-49 in reproduction - controlling oocyte activation and ovulation. Loss of NHR-49 causes inappropriate oocyte activation and laying of unfertilized oocytes in the absence of sperm, resulting in rapid loss of yolk and stored fat, and drastically shortening of lifespan. We further demonstrated that prevention of yolk transfer into the oocytes largely restore fat storage and partially rescue lifespan in the nhr-49 mutants. Additionally, NHR-49 appears to couple germline proliferation to nutritional status, as evidenced by its requirement for starvation-induced reduction in germline proliferation. Mechanistically, we showed that NHR-49 primarily acts in somatic cells, rather than the germline itself, to regulate oocyte activation and ovulation. We further demonstrated that NHR-49 binds to the promoter of GSA-1 and may stimulate its expression. GSA-1 encodes a G-protein coupled receptor known to act in the gonadal sheath cells to couple sperm sensing and oocyte activation. Our findings therefore suggest a model whereby NHR-49 regulates the expression of GSA-1, which in turn regulates oocyte activation in response to sperm signal. Overall, our findings suggest a mechanistic link between nutrition sensing and fertility and point to regulated retention of reproductive resources to be critical for maintaining longevity.
Longevity Relevance Analysis
(4)
NHR-49 regulates oocyte activation and ovulation in C. elegans, linking fertility regulation to resource allocation and longevity. The study explores a mechanistic connection between nutrition sensing, reproductive resource management, and lifespan, which is pertinent to understanding the biological underpinnings of aging.
Gotz, M., Hayman, D. J., Adams, G. ...
· physiology
· University of Sheffield
· biorxiv
Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway) is pro-longevity. Activat...
Stress response pathways are emerging as conserved modulators of lifespan. The prevailing hypothesis is that activation of stress responsive pathways, including the amino acid deprivation arm of the integrated stress response (ISR; the GCN2-ATF4 pathway) is pro-longevity. Activation of ATF4 orthologs extends lifespan in Saccharomyces cerevisiae (yeast) and Caenorhabditis elegans, but its role in other longer-lived organisms remains unclear. We comprehensively tested the role of the GCN2-ATF4 pathway in the fly (Drosophila melanogaster) for the first time. We used conditional genetic manipulation of dGCN2 and its downstream effector Drosophila ATF4 (crc; dATF4). In contrast to previous studies, we show that overexpression of dGCN2 and dATF4 significantly reduces lifespan, while knockdown (in vivo RNAi) of dATF4 extends lifespan. We confirmed dATF4 activity was successfully modulated using a fluorescent dATF4 activation reporter. Borrelidin, a tRNA synthetase inhibitor, significantly reduced lifespan in a both dATF4 and diet-dependent manner, independent of microbial load, showing our modulation of dATF4 altered nutrient to ISR signalling. We further conducted long-read RNA sequencing and found that our manipulation of dATF4 changed global transcription in opposite directions, including known ATF4 target genes. Enrichment analysis revealed that dATF4 overexpression may drive metabolic stress, while dATF4 knockdown upregulates proteostasis and DNA repair pathways. Our work reveals that ATF4 exhibits a dual, dose- and context-dependent role in ageing. Chronic dATF4 activation is detrimental in flies, while chronic suppression is pro-longevity. The GCN2-ATF4 pathway thus qualifies as a modifiable control of lifespan with cross-species relevance.
Longevity Relevance Analysis
(4)
Chronic suppression of dATF4 extends lifespan in Drosophila, while its overexpression reduces lifespan. The paper investigates the role of the GCN2-ATF4 pathway in lifespan modulation, addressing fundamental mechanisms of aging rather than merely treating age-related diseases.
Onder Albayram, Natalia Oleinik, Besim Ogretmen
· Aging cell
· Department of Pathology and Laboratory Medicine, ER-AL Neurovascular Protection Laboratory, Medical University of South Carolina, Charleston, South Carolina, USA.
· pubmed
The misclassification of functional genomic loci as pseudogenes has long obscured critical regulators of cellular homeostasis, particularly in aging-related pathways. One such locus, originally annotated as RPL29P31, encodes a 17-kDa protein now redefined as PERMIT (Protein that ...
The misclassification of functional genomic loci as pseudogenes has long obscured critical regulators of cellular homeostasis, particularly in aging-related pathways. One such locus, originally annotated as RPL29P31, encodes a 17-kDa protein now redefined as PERMIT (Protein that Mediates ER-Mitochondria Trafficking). Through rigorous experimental validation-including antibody development, gene editing, lipidomics, and translational models-p17/PERMIT has emerged as a previously unrecognized mitochondrial trafficking chaperone. Under aging or injury-induced stress, p17 mediates the ER-to-mitochondria translocation of Ceramide Synthase 1 (CerS1), facilitating localized C18-ceramide synthesis and autophagosome recruitment to initiate mitophagy. Loss of p17 impairs mitochondrial quality control, accelerating neurodegeneration, and sensorimotor decline in both injury and aging models. This Perspective highlights p17 as a paradigm-shifting discovery at the intersection of lipid signaling, mitochondrial biology, and genome reannotation, and calls for a broader reassessment of the "noncoding" genome in aging research. We summarize a rigorous multi-platform validation pipeline-including gene editing, antibody generation, lipidomics, proteomics, and functional rescue assays-that reclassified p17 as a bona fide mitochondrial trafficking protein. Positioned at the intersection of lipid metabolism, organelle dynamics, and genome reannotation, p17 exemplifies a growing class of overlooked proteins emerging from loci historically labeled as pseudogenes, urging a systematic reevaluation of the "noncoding" genome in aging research.
Longevity Relevance Analysis
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The paper claims that p17/PERMIT is a mitochondrial trafficking protein that plays a crucial role in mediating cellular homeostasis and mitophagy, linking aging and neurodegeneration. This research addresses a fundamental aspect of aging by exploring the role of previously misclassified genomic loci in mitochondrial function and cellular quality control, which are critical for understanding the mechanisms of aging and potential interventions.
Shchukina, I., Rodriguez-Hernandez, C., Ruiz, H. S. ...
· immunology
· Washington University in St. Louis
· biorxiv
Aging profoundly reshapes the immune cell landscape, with particularly strong effects on CD8+ T cells, including a marked decline in naive cells and the emergence of age-associated GZMK+ CD8+ T cells (TAA cells). Although TAA cells make up a significant fraction of the aged CD8+ ...
Aging profoundly reshapes the immune cell landscape, with particularly strong effects on CD8+ T cells, including a marked decline in naive cells and the emergence of age-associated GZMK+ CD8+ T cells (TAA cells). Although TAA cells make up a significant fraction of the aged CD8+ T cell compartment, the pathway underlying their development remains unknown. In this study, we demonstrate that TAA cell development is cell-extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a novel TNFdAU/+ mouse model, we show that systemic low-grade inflammation, characteristic of inflammaging, accelerates CD8+ T cell aging and promotes early accumulation of TAA cells. Through detailed analysis of TAA cell heterogeneity, we identified a progenitor subpopulation enriched in the aged adipose tissue. Using heterochronic transplantation, we show that adipose tissue acts as a functional niche, supporting progenitor maintenance and driving the conversion of young CD8+ T cells into the aged phenotype. Taken together, our findings reveal how aging of non-lymphoid tissues orchestrates the reorganization of the CD8+ T cell compartment and highlight adipose tissue as a promising target for therapeutic strategies aimed at modulating immune aging.
Longevity Relevance Analysis
(5)
The paper claims that systemic low-grade inflammation in aged non-lymphoid tissues drives the development of age-associated CD8+ T cells. This research is relevant as it addresses the mechanisms of immune aging, which is a fundamental aspect of the aging process and could inform strategies for longevity and age-related disease interventions.
Mekulu, K., Aqlan, F., Yang, H.
· health informatics
· Pennsylvania State University
· medrxiv
Early detection of cognitive impairment in assisted living is hindered by time intensive tools like MMSE and MoCA. We present a 60-second voice based screening model that analyzes picture descriptions to estimate dementia risk. Using transcripts from the DementiaBank corpus, our ...
Early detection of cognitive impairment in assisted living is hindered by time intensive tools like MMSE and MoCA. We present a 60-second voice based screening model that analyzes picture descriptions to estimate dementia risk. Using transcripts from the DementiaBank corpus, our model integrates traditional linguistic features (pause rate, pronoun use, syntactic complexity) with latent semantic dimensions extracted from language model embeddings. These semantic axes, interpretable constructs like "Drift & Hesitation" or "Over detailed Narration", consistently emerged as top predictors and may represent novel linguistic biomarkers of early decline. The final ElasticNet classifier is sparse, interpretable, and outperforms known non deep learning baselines (AUC = 0.858), exceeding MMSE. Its simplicity enables deployment in mobile apps or in-room monitors, offering scalable, low burden screening for early dementia. This work supports a shift toward linguistically grounded, tech enabled cognitive care in aging populations.
Longevity Relevance Analysis
(4)
The paper claims that a 60-second voice-based screening model can effectively estimate dementia risk using linguistic features. This research is relevant as it addresses early detection of cognitive impairment, which is a significant concern in aging populations and could lead to improved cognitive care strategies.
Bravo, J. I., Tewelde, E., King, C. D. ...
· genomics
· University of Southern California
· biorxiv
During aging and cellular senescence, repetitive elements are frequently transcriptionally derepressed across species and cell types. Among these, the most abundant repeats by copy number in the human genome are Alu retrotransposons. Though Alu elements are often studied for thei...
During aging and cellular senescence, repetitive elements are frequently transcriptionally derepressed across species and cell types. Among these, the most abundant repeats by copy number in the human genome are Alu retrotransposons. Though Alu elements are often studied for their mutagenic potential, there is increasing appreciation for their contributions to other biological functions, including pro-inflammatory signaling and mitochondrial dysfunction. However, a comprehensive analysis of Alu-driven molecular changes remains to be conducted, and Alu\'s potential contributions to aging features remain incompletely characterized. Here, we show that overexpression of an AluJb transposon in human primary IMR-90 fibroblasts leads to large-scale alterations across the transcriptome, cellular proteome, and secretome. Functional genomics analyses reveal alterations in aging/senescence pathways, broadly, and mitochondrial metabolism, proteostasis, cell cycle, and extracellular matrix pathways, more specifically. Our results demonstrate that Alu transcriptional upregulation is sufficient to drive widespread disruptions to cellular homeostasis that mirror aging-associated alterations.
Longevity Relevance Analysis
(4)
Overexpression of an Alu transposon in human fibroblasts disrupts aging-associated pathways. The paper addresses the role of Alu retrotransposons in aging, suggesting that their transcriptional upregulation can drive changes that mirror aging processes, thus contributing to understanding the root causes of aging.
Alan Kavšek, Jérôme Salignon, Lluís Millan-Ariño ...
· Caenorhabditis elegans
· Integrated Cardio Metabolic Centre (ICMC) and Division of Biosciences and Nutrition, Department of Medicine, Karolinska Institute, Huddinge, Sweden.
· pubmed
The nuclear chromatin landscape changes with age. Here, we investigate whether chromatin alterations distinguish also animals with unusual aging rates, focusing on Caenorhabditis elegans with reduced insulin/IGF-like signaling (IIS), i.e., daf-2 mutants. In these animals, enhance...
The nuclear chromatin landscape changes with age. Here, we investigate whether chromatin alterations distinguish also animals with unusual aging rates, focusing on Caenorhabditis elegans with reduced insulin/IGF-like signaling (IIS), i.e., daf-2 mutants. In these animals, enhancer regions that close with age tend to open and become transcriptionally active. We identify LIN-39 as a transcription factor (TF) binding these regions and being required for the longevity of daf-2 mutants. LIN-39 acts during late development in hermaphrodite-specific VC motor neurons - at a time when these undergo maturation. LIN-39-mediated longevity requires DAF-16/FOXO, suggesting cooperation of both TFs in VC neurons to open enhancers. Our findings argue that longevity of daf-2 mutant hermaphrodites relies on a signal emitted by properly matured VC neurons, and due to its essential role in this maturation process LIN-39 becomes a rare example of a development-specific lifespan determinant.
Longevity Relevance Analysis
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LIN-39 is identified as a transcription factor that is essential for the longevity of daf-2 mutants in C. elegans. This paper is relevant as it explores the mechanisms underlying longevity and aging, specifically how developmental factors influence lifespan through insulin signaling pathways.
Brittany Intzandt, Safa Sanami, Julia Huck ...
· The journals of gerontology. Series A, Biological sciences and medical sciences
· BrainLab, Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto Canada.
· pubmed
Cerebral blood flow (CBF) declines consistently in aging and this decline is a critical component of several late life diseases. Understanding why this occurs in normal aging, prior to pathological changes, is crucial. Physical activity (PA) is a powerful preventative tool to imp...
Cerebral blood flow (CBF) declines consistently in aging and this decline is a critical component of several late life diseases. Understanding why this occurs in normal aging, prior to pathological changes, is crucial. Physical activity (PA) is a powerful preventative tool to improve vascular health and preserves CBF in both sexes, though females may benefit most throughout the lifespan. There is currently limited knowledge however about what intensity is needed to derive benefit, and if there are sex differences in this relationship with intensity. Here, CBF and PA were investigated according to sex and age. A total of 573 participants aged 36 to 90 years were included from the Human Connectome Lifespan Aging. Linear and quadratic regressions were utilized to investigate relationships among CBF and PA intensities in each of the four groups. Vigorous PA in middle aged males was related to greater CBF (p < 0.05). Older females showed benefit at all intensities (p < 0.05). Middle aged females were least sensitive to the effects of PA. In all groups except older males, hippocampal CBF was only dependent on vigorous PA (p < 0.05). These results highlight the sex-specific relationship between CBF and PA, and the importance of tailoring recommendations to sex and lifespan stage including addressing and updating current public health guidelines to maximize adoption and benefit, specific to brain health.
Longevity Relevance Analysis
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The paper claims that sex-specific differences exist in the relationship between physical activity intensity and cerebral blood flow across different age groups. This research is relevant as it explores the underlying mechanisms of brain health in aging, which is crucial for developing targeted interventions to promote longevity and mitigate age-related cognitive decline.
Shoma Ishikawa, Björn Schumacher
· Annual review of genetics
· 1Institute for Genome Stability in Aging and Disease and Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne and University Hospital of Cologne, Cologne, Germany; email: [email protected], [email protected].
· pubmed
The faithful transmission of genomic DNA over succeeding generations is an essential prerequisite for species maintenance. The germplasm theory by August Weismann has been foundational for the current understanding of heredity; it proposed that genetic inheritance is exclusively ...
The faithful transmission of genomic DNA over succeeding generations is an essential prerequisite for species maintenance. The germplasm theory by August Weismann has been foundational for the current understanding of heredity; it proposed that genetic inheritance is exclusively mediated by germ cells while they are protecting heritable germline genomes from the phylogenetic influences of an individual's life history. However, recent studies on the inheritance of epigenetic variation have challenged the traditional dogma of heredity and opened new perspectives on molecular mechanisms of inheritance. This review highlights the current knowledge about heritable memories of the ancestral lifestyle and discusses emerging frontiers in soma-germline circuits with a focus on the control of the integrity of heritable genomes as well as their implications for somatic and reproductive aging.
Longevity Relevance Analysis
(4)
The paper discusses the implications of somatic and reproductive aging in relation to the integrity of heritable genomes. This research is relevant as it explores the molecular mechanisms of inheritance and their potential impact on aging processes, which could contribute to understanding the root causes of aging.
Yidan Liu, Xiuxing Liu, Jianjie Lv ...
· Receptors, Adiponectin
· State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou 510060, China.
· pubmed
Aging induces substantial structural and functional decline in the retina, yet the molecular drivers of this process remain elusive. In this study, we used heterochronic parabiosis (HP) combined with single-cell RNA sequencing to generate comprehensive transcriptomic profiles of ...
Aging induces substantial structural and functional decline in the retina, yet the molecular drivers of this process remain elusive. In this study, we used heterochronic parabiosis (HP) combined with single-cell RNA sequencing to generate comprehensive transcriptomic profiles of murine retinas from young, aged, and HP pairs, aiming to identify antiaging targets. Our analysis revealed extensive transcriptional alterations across retinal cell types with aging. HP experiments demonstrated that systemic factors from young mice rejuvenated aged retinas and alleviated senescent phenotypes, while aged blood accelerated aging in young mice. Integrative analysis pinpointed adiponectin receptor 1 (AdipoR1) and the downstream adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway as central to the molecular mechanisms underlying retinal rejuvenation. Treatment with the AdipoR1 agonist AdipoRon reversed retinal aging. Mechanistically, AdipoR1-AMPK activation promoted mitochondrial function, contributing to the restoration of youthful cellular phenotypes. Together, our study identifies AdipoR1 as a therapeutic target for retinal aging and provides insights into the molecular programs driving retinal rejuvenation.
Longevity Relevance Analysis
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The study identifies AdipoR1 as a key target for reversing retinal aging through the activation of the AMPK signaling pathway. This research is relevant as it addresses the molecular mechanisms of aging and proposes a potential therapeutic target for rejuvenating aged retinal cells, contributing to the understanding of aging processes.
Valentin J A Barthet, Scott W Lowe
· Genes & development
· Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
· pubmed
Cellular senescence plays a dual role in tissue biology by promoting tumor suppression and wound healing when transient but driving inflammation, fibrosis, and age-related disease when persistent. The growing recognition that senescent cell clearance can reverse these pathologies...
Cellular senescence plays a dual role in tissue biology by promoting tumor suppression and wound healing when transient but driving inflammation, fibrosis, and age-related disease when persistent. The growing recognition that senescent cell clearance can reverse these pathologies has catalyzed efforts to develop therapeutics that preferentially kill senescent cells (also known as "senolytics"). However, clinical translation from bench to bedside remains challenging due to senescent state heterogeneity, limited biomarkers, off-target toxicities, and the frailty of aged patients. Small molecule senolytics, although promising, often lack defined mechanisms of action and pose safety concerns that may constrain their use in older adults. Emerging precision approaches, including those that exploit surface markers and leverage engineered immune therapies, offer a rational and potentially more selective path forward. Here we highlight recent advances in senescence profiling and targeted clearance strategies, emphasizing the need for therapies designed with both biological complexity and the needs of aging populations in mind.
Longevity Relevance Analysis
(5)
The paper discusses the development of precision senolytics aimed at selectively targeting and clearing senescent cells to mitigate age-related diseases. This research is relevant as it addresses the underlying mechanisms of aging and seeks to develop therapies that could potentially extend healthspan by targeting cellular senescence.
Enzo Scifo, Sarah Morsy, Ting Liu ...
· The EMBO journal
· Translational Biogerontology Lab, German Center for Neurodegenerative Diseases (DZNE), Venusberg-Campus 1/99, 53127, Bonn, Germany.
· pubmed
Aging is associated with the accumulation of molecular damage, functional decline, increasing disease prevalence, and ultimately mortality. Although our system-wide understanding of aging has significantly progressed at the genomic and transcriptomic levels, the availability of l...
Aging is associated with the accumulation of molecular damage, functional decline, increasing disease prevalence, and ultimately mortality. Although our system-wide understanding of aging has significantly progressed at the genomic and transcriptomic levels, the availability of large-scale proteomic datasets remains limited. To address this gap, we have conducted an unbiased quantitative proteomic analysis in male C57BL/6J mice, examining eight key organs (brain, heart, lung, liver, kidney, spleen, skeletal muscle, and testis) across six life stages (3, 5, 8, 14, 20, and 26-month-old animals). Our results reveal age-associated organ-specific as well as systemic proteomic alterations, with the earliest and most extensive changes observed in the kidney and spleen, followed by liver and lung, while the proteomic profiles of brain, heart, testis, and skeletal muscle remain more stable. Isolation of the non-blood-associated proteome allowed us to identify organ-specific aging processes, including oxidative phosphorylation in the kidney and lipid metabolism in the liver, alongside shared aging signatures. Trajectory and network analyses further reveal key protein hubs linked to age-related proteomic shifts. These results provide a system-level resource of protein changes during aging in mice, and identify potential molecular regulators of age-related decline.
Longevity Relevance Analysis
(5)
The paper identifies organ-specific proteomic alterations associated with aging in mice. This research contributes to understanding the molecular mechanisms of aging, which is essential for developing interventions aimed at longevity and age-related decline.
Ryan G Walker, Tomohiro Kato, Laura Ben Driss ...
· Growth Differentiation Factors
· Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
· pubmed
Circulating Growth Differentiation Factors 11 and 8 (GDF11/8) exist in both latent and active forms, and it is unclear if specific forms can predict disease outcomes. Our data suggest that a dual-specific aptamer selectively binds GDF11/8 after prodomain activation. In 11,609 pat...
Circulating Growth Differentiation Factors 11 and 8 (GDF11/8) exist in both latent and active forms, and it is unclear if specific forms can predict disease outcomes. Our data suggest that a dual-specific aptamer selectively binds GDF11/8 after prodomain activation. In 11,609 patients at risk for future cardiovascular events, low dual-specific aptamer-detected GDF11/8 levels strongly predicted adverse outcomes, including cardiovascular events (HR = 0.43, p = 9.1 × 10⁻⁶³) and all-cause mortality (HR = 0.33, p = 4.8 × 10⁻⁴⁰). Use of selective aptamers suggested that results observed with the dual-specific aptamer for cardiovascular and mortality risk replicated with a GDF8 aptamer although with a smaller effect size. In a second cohort of 4110 individuals (ARIC), low dual-specific aptamer-detected GDF11/8 levels also predicted increased 8 year dementia risk (HR = 0.66, p = 0.00148). Our findings reveal that activation of GDF11/8 may be a factor in future aging-related cardiovascular and cognitive decline.
Longevity Relevance Analysis
(4)
Low levels of activated GDF11/8 predict adverse cardiovascular events and mortality in humans. The study addresses biomarkers that may indicate underlying mechanisms of aging-related decline, linking them to cardiovascular and cognitive outcomes.
Ki Yun Park, Abraham Z Snyder, Manu S Goyal ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, 63110, USA.
· pubmed
Cerebral glucose metabolism (CMRGlc) systematically decreases with advancing age. We sought to identify correlates of decreased CMRGlc in the spectral properties of fMRI signals imaged in the task-free state. Lifespan resting-state fMRI data acquired in 455 healthy adults (ages 1...
Cerebral glucose metabolism (CMRGlc) systematically decreases with advancing age. We sought to identify correlates of decreased CMRGlc in the spectral properties of fMRI signals imaged in the task-free state. Lifespan resting-state fMRI data acquired in 455 healthy adults (ages 18-87 years) and cerebral metabolic data acquired in a separate cohort of 94 healthy adults (ages 25-45 years, 65-85 years) were analyzed. The spectral properties of the fMRI data were characterized in terms of the relative predominance of slow versus fast activity using the spectral slope (SS) measure. We found that the relative proportion of fast activity increases with advancing age (SS flattening) across most cortical regions. The regional distribution of spectral slope was topographically correlated with CMRGlc in young adults. Notably, whereas most older adults maintain a youthful pattern of SS topography, a distinct subset of older adults significantly diverged from the youthful pattern. This subset of older adults also diverged from the youthful pattern of CMRGlc metabolism. This divergent pattern was associated with T2-weighted signal changes in frontal lobe white matter, an independent marker of small vessel disease. These findings suggest that BOLD signal spectral slope flattening may represent a biomarker of age-associated neurometabolic pathology.
Longevity Relevance Analysis
(4)
The paper claims that BOLD signal spectral slope flattening may serve as a biomarker for age-associated neurometabolic pathology. This research is relevant as it explores the underlying mechanisms of aging and identifies potential biomarkers that could contribute to understanding age-related changes in brain function.
Amelia Farinas, Jarod Rutledge, Veronica Augustina Bot ...
· Nature medicine
· Graduate Program in Neuroscience, Stanford University, Stanford, CA, USA.
· pubmed
The brain barrier system, including the choroid plexus, meninges and brain vasculature, regulates substrate transport and maintains differential protein concentrations between blood and cerebrospinal fluid (CSF). Aging and neurodegeneration disrupt brain barrier function, but pro...
The brain barrier system, including the choroid plexus, meninges and brain vasculature, regulates substrate transport and maintains differential protein concentrations between blood and cerebrospinal fluid (CSF). Aging and neurodegeneration disrupt brain barrier function, but proteomic studies of the effects on blood-CSF protein balance are limited. Here we used SomaScan proteomics to characterize paired CSF and plasma samples from 2,171 healthy or cognitively impaired older individuals from multiple cohorts, including the Global Neurodegeneration Proteomics Consortium. We identified proteins with correlated CSF and plasma levels that are produced primarily outside the brain and are enriched for structural domains that may enable their transport across brain barriers. CSF to plasma ratios of 848 proteins increased with aging in healthy control individuals, including complement and coagulation proteins, chemokines and proteins linked to neurodegeneration, whereas 64 protein ratios decreased with age, suggesting substrate-specific barrier regulation. Notably, elevated CSF to plasma ratios of peripherally derived or vascular-associated proteins, including DCUN1D1, MFGE8 and VEGFA, were associated with preserved cognitive function. Genome-wide association studies identified genetic loci associated with CSF to plasma ratios of 241 proteins, many of which have known disease associations, including FCN2, the collagen-like domain of which may facilitate blood-CSF transport. Overall, this work provides molecular insight into the human brain barrier system and its disruption with age and disease, with implications for the development of brain-permeable therapeutics.
Longevity Relevance Analysis
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The paper claims that aging disrupts the cerebrospinal fluid-plasma protein balance, which is associated with cognitive impairment and may inform the development of brain-permeable therapeutics. This research is relevant as it explores the molecular mechanisms underlying aging and cognitive decline, potentially addressing root causes rather than just symptoms.
Willian R Gomes, Shan Hama, Giorgio Napolitani ...
· Blood advances
· University of Sao Paulo, Brazil.
· pubmed
Pathogenic germline variants causing excessive telomere shortening may result in bone marrow failure, hematopoietic malignancy, and extramedullary complications, such as pulmonary fibrosis, liver cirrhosis, and solid tumors. Patients with short telomeres also develop immunodefici...
Pathogenic germline variants causing excessive telomere shortening may result in bone marrow failure, hematopoietic malignancy, and extramedullary complications, such as pulmonary fibrosis, liver cirrhosis, and solid tumors. Patients with short telomeres also develop immunodeficiency with low CD4+ T cells and impaired general immunosurveillance, particularly against solid neoplasms. We investigated a broad spectrum of lymphocyte subsets and myeloid immune cells from human patients with telomere biology disorders (TBDs) and matched healthy volunteers to understand further how the immune system is affected by telomere dysfunction. We employed mass cytometry (CyTOF) for deep-immunophenotyping peripheral blood mononuclear cells (PBMCs), followed by high-dimensional data analysis. Cytokines, chemokines, and growth factors were assessed in serum. Our results showed profound immune alterations in TBD beyond those observed in aging, with low naïve lymphocytes and thymic hypofunction. We further observed that T helper subsets were markedly skewed, with an inverted TH2/TH1 ratio and low TH17 and TH17.1 levels. T cell activation and exhaustion markers were upregulated, whereas circulating mucosal-associated invariant T (MAIT) cells were significantly decreased and overactivated. Several serum cytokine levels were positively correlated with telomere length and blood counts, suggesting an association with marrow function. In aggregate, these findings suggest a pro-inflammatory profile in TBDs. Our data provide new details on how TBD affects immune cells, particularly lymphocytes, which may contribute to the clinical phenotypes.
Longevity Relevance Analysis
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The paper claims that telomere biology disorders lead to profound immune alterations characterized by a pro-inflammatory profile. This research is relevant as it explores the underlying mechanisms of telomere dysfunction, which is a critical aspect of aging and age-related diseases, potentially contributing to our understanding of longevity and immune system aging.
Tan Ma, Lulin Tan, Chenghao Shen ...
· Environmental science & technology
· Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China.
· pubmed
Dibutyl phthalate (DBP), a common plastic additive, is employed extensively to enhance the flexibility of various polymeric materials despite its known toxicity to multiple organ systems. Our previous study found that maternal DBP exposure caused early puberty in male offspring, ...
Dibutyl phthalate (DBP), a common plastic additive, is employed extensively to enhance the flexibility of various polymeric materials despite its known toxicity to multiple organ systems. Our previous study found that maternal DBP exposure caused early puberty in male offspring, but the effect on male brain aging was unclear. In this study, pregnant mice were orally administered corn oil (control) or varying doses of DBP via gavage from gestational day 12. The results demonstrated that prenatal DBP exposure induced premature aging in the hippocampus and hypothalamus of male offspring during adolescence and led to a cognitive decline in adulthood. In vitro analyses further showed that monobutyl phthalate (MBP), the principal DBP metabolite, promotes senescence in both HT22 hippocampal and GT1-7 GnRH neuronal cells by activating NF-κB signaling. Notably, the pharmacological inhibition of NF-κB using BAY 11-7082 significantly mitigated this senescence. This study provides the first evidence linking maternal DBP exposure to accelerated brain aging and precocious puberty in offspring, establishing a foundation for investigating DBP's role in aging-related toxicity.
Longevity Relevance Analysis
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Maternal exposure to dibutyl phthalate (DBP) induces premature aging in the hippocampus and hypothalamus of male offspring. This study is relevant as it explores the impact of environmental toxins on the biological mechanisms of aging, potentially contributing to our understanding of the root causes of age-related cognitive decline.
Jose Alberto Santiago-de-la-Cruz, Nadia Alejandra Rivero-Segura, Juan Carlos Gomez-Verjan
· Journal of cheminformatics
· Dirección de Investigación, Instituto Nacional de Geriatría, Mexico City, 10200, México.
· pubmed
Age-related diseases and syndromes result in poor quality of life and adverse outcomes, representing a challenge to healthcare systems worldwide. Several pharmacological interventions have been proposed to target the aging process to slow its adverse effects. The so-called geropr...
Age-related diseases and syndromes result in poor quality of life and adverse outcomes, representing a challenge to healthcare systems worldwide. Several pharmacological interventions have been proposed to target the aging process to slow its adverse effects. The so-called geroprotectors have been proposed as novel molecules that could maintain the organism's homeostasis, targeting specific aspects linked to the hallmarks of aging and delaying the adverse outcomes associated with age. On the other hand, machine learning (ML) is revolutionising drug design by making the process faster, cheaper, and more efficient.
Longevity Relevance Analysis
(4)
The paper claims that machine learning screening can identify natural product candidates that may act as geroprotectors. This research is relevant as it addresses potential interventions targeting the aging process directly, rather than merely treating age-related diseases.
Changli Zhang, Martha Elena Diaz-Hernandez, Takanori Fukunaga ...
· Cellular Senescence
· Department of Orthopaedics, Emory University School of Medicine, Atlanta, United States.
· pubmed
Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. While previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through a...
Accumulation of senescent cells is closely linked with intervertebral disc (IVD) degeneration, a prevalent age-dependent chronic disorder causing low back pain. While previous studies have highlighted that platelet-derived growth factor (PDGF) mitigated IVD degeneration through anti-apoptotic and pro-anabolic effects, its impact on IVD cell senescence remains elusive. In this study, human NP and AF cells derived from aged, degenerated IVDs were treated with recombinant human (rh) PDGF-AB/BB for 5 d. Transcriptome profiling by mRNA sequencing revealed that NP and AF cells responded to the treatment in similar yet distinct ways. The effects of PDGF-AB and BB on human IVD cells were comparable. Specifically, rhPDGF-AB/BB treatment downregulated genes related to neurogenesis and mechanical stimulus response in AF cells, while in NP cells, metabolic pathways were predominantly suppressed. In both NP and AF cells, rhPDGF-AB/BB treatment upregulated genes involved in cell cycle regulation and response to reduced oxygen levels, while downregulating genes related to senescence-associated phenotype, including oxidative stress, reactive oxygen species (ROS), and mitochondria dysfunction. Network analysis revealed that PDGFRA and IL6 were the top hub genes in treated NP cells. Furthermore, in irradiation-induced senescent NP cells, PDGFRA gene expression was significantly reduced compared to non-irradiated cells. However, rhPDGF-AB/BB treatment increased PDGFRA expression and mitigated the senescence progression through increased cell population in the S phase, reduced SA-β-Gal activity, and decreased expression of senescence-related regulators. Our findings reveal a novel anti-senescence role of PDGF in the IVD, making it a promising potential candidate to delay aging-induced IVD degeneration.
Longevity Relevance Analysis
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The paper claims that PDGF-AB/BB treatment mitigates cellular senescence in intervertebral disc cells, potentially delaying aging-induced degeneration. The research addresses a mechanism related to cellular senescence, which is a fundamental aspect of aging and age-related diseases, making it relevant to longevity research.
Guillem Santamaria, Cristina Iglesias, Sascha Jung ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, 6 Avenue du Swing, Esch-Belval Esch-sur-Alzette, 4367, Luxembourg.
· pubmed
The increase in life expectancy has caused a rise in age-related brain disorders. Although brain rejuvenation is a promising strategy to counteract brain functional decline, systematic discovery methods for efficient interventions are lacking. A computational platform based on a ...
The increase in life expectancy has caused a rise in age-related brain disorders. Although brain rejuvenation is a promising strategy to counteract brain functional decline, systematic discovery methods for efficient interventions are lacking. A computational platform based on a transcriptional brain aging clock capable of detecting age- and neurodegeneration-related changes is developed. Applied to neurodegeneration-positive samples, it reveals that neurodegenerative disease presence and severity significantly increase predicted age. By screening 43840 transcriptional profiles of chemical and genetic perturbations, it identifies 453 unique rejuvenating interventions, several of which are known to extend lifespan in animal models. Additionally, the identified interventions include drugs already used to treat neurological disorders, Alzheimer's disease among them. A combination of compounds predicted by the platform reduced anxiety, improved memory, and rejuvenated the brain cortex transcriptome in aged mice. These results demonstrate the platform's ability to identify brain-rejuvenating interventions, offering potential treatments for neurodegenerative diseases.
Longevity Relevance Analysis
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The paper claims that a machine-learning platform can identify rejuvenating interventions that improve brain function and counteract neurodegeneration. This research is relevant as it addresses potential interventions that could mitigate age-related brain decline, aligning with the goal of extending healthy lifespan by targeting the underlying mechanisms of aging.
Feng, B., Yang, R., Wang, G. R. ...
· genetic and genomic medicine
· St. Jude Children\'s Research Hospital
· medrxiv
Objective: To assess the causal effects of leukocyte telomere length (TL) and epigenetic age acceleration (EAA) on healthspan. Methods: We performed two-sample Mendelian randomization (MR) analyses in accordance with STROBE-MR guidelines. Genetic instrumental variables (IVs) for ...
Objective: To assess the causal effects of leukocyte telomere length (TL) and epigenetic age acceleration (EAA) on healthspan. Methods: We performed two-sample Mendelian randomization (MR) analyses in accordance with STROBE-MR guidelines. Genetic instrumental variables (IVs) for TL and four EAA biomarkers (Hannum, GrimAge, PhenoAge, and intrinsic EAA) were derived from published genome-wide association study (GWAS) summary statistics involving up to 472,174 individuals for TL and approximately 35,000 individuals for each EAA biomarker. GWAS summary statistics for healthspan, defined as age at first diagnosis of any of eight major chronic conditions or death, were obtained from the UK Biobank (N=300,477 unrelated European-ancestry participants). The primary MR estimates were obtained using the inverse-variance weighted (IVW) method, complemented by various sensitivity analyses to assess pleiotropy, instrument heterogeneity, and robustness of causal inference. The strength of the IVs was evaluated using F-statistics, and causal directionality was validated using Steiger filtering. Results: Genetically predicted longer TL was causally associated with extended healthspan (IVW {beta} =0.106; 95% CI: 0.053 -- 0.159; p=6.9E-5). The association was robust across multiple sensitivity analyses, with no indication of directional pleiotropy (MR-Egger intercept p=0.47), no influential outliers identified by MR-PRESSO, and consistent causal direction confirmed by Steiger tests. In contrast, none of the four EAA biomarkers demonstrated convincing causal effects on health span (all IVW p - values >0.05), and results were inconsistent across sensitivity analyses, suggesting their role as correlates rather than causal determinants of healthy longevity. Conclusions: This MR study provides robust evidence supporting a causal role of genetically determined telomere length in extending healthspan, while no such effect was observed for four commonly studied EAA biomarkers. These findings underscore the central role of telomere biology in healthy aging and indicate that telomere maintenance may represent a promising target for interventions aimed at delaying the onset of age-related diseases.
Longevity Relevance Analysis
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Genetically predicted longer telomere length causally influences healthspan, while epigenetic aging acceleration does not. The study addresses the biological mechanisms underlying aging by focusing on telomere length as a potential target for interventions aimed at extending healthspan, which is central to longevity research.
Sujan Chatterjee, Sayan Ghosh, Zachary Sin ...
· Aging cell
· Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas, Nevada, USA.
· pubmed
Age-related macular degeneration (AMD), a leading cause of vision loss affecting retinal pigment epithelial (RPE) cells, remains largely unexplained by current genome-wide association studies (GWAS) risk variants. Our research on Cryba1, encoding βA3/A1-crystallin protein, reveal...
Age-related macular degeneration (AMD), a leading cause of vision loss affecting retinal pigment epithelial (RPE) cells, remains largely unexplained by current genome-wide association studies (GWAS) risk variants. Our research on Cryba1, encoding βA3/A1-crystallin protein, reveals its crucial role in RPE cell function via a novel epigenetic mechanism, also evident in human atrophic AMD samples. Loss of Cryba1 in mouse RPE cells triggers epigenetic changes by reducing histone deacetylase 3 (HDAC3) activity through two mechanisms. First, Cryba1 depletion reduces inositol polyphosphate multikinase (IPMK) expression, which potentially reduces inositol hexakisphosphate (InsP6) generation since IPMK's kinase activity is essential for producing InsP4 and InsP5 as precursors to InsP6. Since InsP4, InsP5, or InsP6 is crucial for HDAC3's interaction with the corepressor's DAD domains, reduced IPMK expression in Cryba1-depleted cells likely diminishes the HDAC3-DAD interaction, leading to a reduction in HDAC3's activity. Second, reduced βA3/A1 protein in Cryba1-deficient cells impairs HDAC3's interaction with casein kinase 2 (CK2), resulting in decreased HDAC3 phosphorylation. Collectively, this increases H3K27 acetylation at the RET promoter region, likely enhancing the transcription of RET, a receptor tyrosine kinase critical for cell survival. Although RET is transcriptionally increased, Cryba1 loss disrupts its protein maturation, causing immature RET protein accumulation. This triggers age-dependent endoplasmic reticulum (ER) stress, potentially contributing to the pathogenesis of AMD. Interestingly, although Cryba1 is not identified as an AMD-linked variant in current GWAS, its loss may be linked to AMD mechanisms. These findings underscore the potential of gene-agnostic and epigenetic therapeutic strategies for treating AMD.
Longevity Relevance Analysis
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The paper claims that loss of Cryba1 in retinal pigment epithelial cells leads to epigenetic changes that may contribute to age-related macular degeneration (AMD). This research addresses underlying mechanisms of aging-related diseases, specifically focusing on epigenetic regulation and its implications for AMD, which is a significant age-related condition.
Mavrommatis, C., Belsky, D., Ying, K. ...
· epidemiology
· University of Edinburgh
· medrxiv
Epigenetic Clocks have been trained to predict chronological age, healthspan and lifespan. Such clocks are often analysed in relation to disease outcomes - typically using small datasets and a limited number of clocks. Here, we present the first large-scale (n=18,849), unbiased c...
Epigenetic Clocks have been trained to predict chronological age, healthspan and lifespan. Such clocks are often analysed in relation to disease outcomes - typically using small datasets and a limited number of clocks. Here, we present the first large-scale (n=18,849), unbiased comparison of 14 widely used clocks as predictors of 174 incident disease outcomes and all-cause mortality. Second-generation clocks significantly outperformed first-generation clocks, which have limited applications in disease settings. Of the 176 Bonferroni significant (P<0.05/174) associations, there were 27 diseases (including primary lung cancer and diabetes) where the hazard ratio for the clock exceeded the clock's association with all-cause mortality. Furthermore, there were 35 instances where adding a clock to a null classification model with traditional risk factors increased the classification accuracy by >1% with an AUCfull > 0.80. Second-generation epigenetic clocks show promise for disease risk prediction, particularly in relation to respiratory and liver-based conditions.
Longevity Relevance Analysis
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Second-generation epigenetic clocks can predict disease outcomes and all-cause mortality more effectively than first-generation clocks. The study addresses the predictive capabilities of epigenetic clocks in relation to disease outcomes, which is relevant to understanding aging and its associated diseases.
Senile osteoporosis (SOP) primarily arises from an imbalance between bone formation and bone resorption. The tightly regulated coupling between osteoblasts and osteoclasts limits the therapeutic efficacy of conventional anti-resorptive agents and anabolic agents. Anti-aging thera...
Senile osteoporosis (SOP) primarily arises from an imbalance between bone formation and bone resorption. The tightly regulated coupling between osteoblasts and osteoclasts limits the therapeutic efficacy of conventional anti-resorptive agents and anabolic agents. Anti-aging therapy offers a potential strategy to modify the senescent phenotype of bone-associated cells, restore cellular function, and re-establish homeostasis between bone resorption and formation. Calcium-based nanoparticles can effectively deliver therapeutic agents to target sites while simultaneously supplying exogenous calcium. Moreover, restored osteoblast function enhances the cellular capacity to process supplemented exogenous calcium ions, ultimately increasing bone density and further alleviating osteoporosis. In this context, a dual-functional calcium carbonate nanoparticle is engineered. This nanoparticle facilitates the complexation of nicotinamide mononucleotide, enabling targeted delivery to osteoblasts, reversing osteoblast senescence, and restoring their osteogenic function. Simultaneously, through calcium supplementation, the nanoparticle promotes osteoblast differentiation and mineralization. In vitro and in vivo studies have demonstrated the promising therapeutic efficacy of this nanoparticle in treating SOP, providing critical insights for the future development of integrated anti-senescence therapies and calcium supplementation strategies.
Longevity Relevance Analysis
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The paper claims that dual-functional calcium carbonate nanoparticles can reverse osteoblast senescence and enhance calcium supplementation to alleviate senile osteoporosis. This research addresses the underlying mechanisms of aging-related bone density loss, focusing on restoring cellular function rather than merely treating symptoms.
Yiming Hao, Beibei Yu, Mingze Qin ...
· Nature aging
· Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
· pubmed
Antler blastema progenitor cells (ABPCs) are a distinct population of skeletal mesenchymal stem cells found in regenerating deer antlers, with strong stemness and renewal capacity in vitro. Stem cell-derived extracellular vesicles (EVs) are emerging as potential therapeutic candi...
Antler blastema progenitor cells (ABPCs) are a distinct population of skeletal mesenchymal stem cells found in regenerating deer antlers, with strong stemness and renewal capacity in vitro. Stem cell-derived extracellular vesicles (EVs) are emerging as potential therapeutic candidates that can mediate donor cells' beneficial effects. Here, we tested the effects of ABPC-derived EVs (EVs
Longevity Relevance Analysis
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ABPC-derived extracellular vesicles can reverse bone loss and mitigate aging-related phenotypes in mice and macaques. The study addresses potential mechanisms for rejuvenation and regeneration, which are central to longevity research.
Glebov, O. O., Du, F., Wan, Q.
· neuroscience
· Qingdao University
· biorxiv
Physiological impact of fever in the brain remains poorly understood. Here, we demonstrate that induction of fever by yeast injection in rats (N=9) and by whole-body hyperthermia in mice (N=7) triggers structural synaptic enhancement in the prefrontal cortex involving AMPA-type g...
Physiological impact of fever in the brain remains poorly understood. Here, we demonstrate that induction of fever by yeast injection in rats (N=9) and by whole-body hyperthermia in mice (N=7) triggers structural synaptic enhancement in the prefrontal cortex involving AMPA-type glutamate receptor signalling and protein translation (N=6). Repeated fever induction in juvenile rats (N=9) results in synaptic strengthening that persists into adulthood, mitigating learning deficits and synaptic loss in a D-galactose model of accelerated aging (N=11). Our results show how common environmental conditions may shape brain function in the long-term via synaptic plasticity, warranting further exploration of thermal treatment for cognitive protection in aging.
Longevity Relevance Analysis
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Induction of fever enhances synaptic strength and mitigates learning deficits in an accelerated aging model. The study explores how physiological responses, like fever, can influence long-term brain function and potentially offer insights into cognitive protection mechanisms in aging, addressing root causes of age-related cognitive decline.
Kanglun Yu, Sagar Vyavahare, Dima W Alhamad ...
· JCI insight
· Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, United States of America.
· pubmed
The aryl hydrocarbon receptor (AhR) is proposed to mediate the frailty-promoting effects of the tryptophan metabolite kynurenine (Kyn), which increases with age in mice and humans. The goal of the current study was to test whether administration of pharmacological AhR inhibitors,...
The aryl hydrocarbon receptor (AhR) is proposed to mediate the frailty-promoting effects of the tryptophan metabolite kynurenine (Kyn), which increases with age in mice and humans. The goal of the current study was to test whether administration of pharmacological AhR inhibitors, BAY2416964 and CH-223191, could abrogate musculoskeletal decline in aging mice. Female C57BL/6 mice (18 months old) were treated with vehicle (VEH) or BAY2416964 (30 mg/kg) via daily oral gavage 5 days/week for 8 weeks. A second AhR antagonist, CH-223191, was administered to 16-month-old male and female C57BL/6 mice via intraperitoneal injections (3.3 mg/kg) 3 days/week for 12 weeks. While grip strength declined over time in VEH-treated mice, BAY2416964 preserved grip strength in part by improving integrity of neuromuscular junctions, an effect replicated during in vitro studies with siRNA against AhR. Cortical bone mass was also greater in BAY2416964- than VEH-treated mice. Similarly, CH-223191 treatment improved cortical bone and showed beneficial effects in skeletal muscle, including reducing oxidative stress as compared to VEH-treated animals. Transcriptomic and proteomic data from BAY2416964-treated mice supported a positive impact of BAY2416964 on molecular targets that affect neuromuscular junction function. Taken together, these data support AhR as a therapeutic target for improving musculoskeletal health during aging.
Longevity Relevance Analysis
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Inhibition of AhR improves musculoskeletal health in aging mice. The study addresses a potential therapeutic target for enhancing bone and muscle function, which are critical aspects of aging and frailty, thus contributing to the understanding of mechanisms that could mitigate age-related decline.
Lei Zhang, Bernhard Ross, Yi Du ...
· Music
· State Key Laboratory of Cognitive Science and Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
· pubmed
During cognitive tasks, older adults often show increased frontoparietal neural activity and functional connectivity. Cognitive reserve accrued from positive life choices like long-term musical training can provide additional neural resources to help cope with the effect of aging...
During cognitive tasks, older adults often show increased frontoparietal neural activity and functional connectivity. Cognitive reserve accrued from positive life choices like long-term musical training can provide additional neural resources to help cope with the effect of aging. However, the relationship between cognitive reserve and upregulated neural activity in older adults remains poorly understood. In this study, we measured brain activity using functional magnetic resonance imaging during a speech-in-noise task and assessed whether cognitive reserve accumulated from long-term musical training bolsters or holds back age-related increase in neural activity. Older musicians exhibited less upregulation of task-induced functional connectivity than older non-musicians in auditory dorsal regions, which predicted better behavioral performance in older musicians. Furthermore, older musicians demonstrated more youth-like spatial patterns of functional connectivity, as compared to older non-musicians. Our findings show that cognitive reserve accrued through long-term music training holds back age-related neural recruitment during speech-in-noise perception and enlighten the intricate interplay between cognitive reserve and age-related upregulated activity during cognitive tasks.
Longevity Relevance Analysis
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Long-term musical training can reduce age-related increases in neural activity during speech-in-noise tasks in older adults. The study explores cognitive reserve mechanisms that may mitigate age-related cognitive decline, aligning with longevity research focused on enhancing cognitive function and resilience against aging effects.
Bowen Xu, Alexander Hull, Olivia N M Hill ...
· Longevity
· Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, United Kingdom.
· pubmed
Attenuating protein synthesis promotes longevity in multiple species. However, numerous studies indicate that aging drives a decrease in protein synthetic capacity. These observations hint at potential, unexplored benefits of stimulating protein synthesis in old age. In this work...
Attenuating protein synthesis promotes longevity in multiple species. However, numerous studies indicate that aging drives a decrease in protein synthetic capacity. These observations hint at potential, unexplored benefits of stimulating protein synthesis in old age. In this work, we focus on Maf1, a repressor of protein synthesis genes transcribed by RNA Polymerase (Pol) III, such as the 5S rRNA and tRNAs, and its role in aging. We show that the knockdown of Maf1 extends lifespan in Drosophila. Maf1 limits longevity specifically from adult neurons in both female and male fruit flies. In older females, adult neuron-specific knockdown of Maf1 improves neuromuscular function as well as the function of a distal organ, the gut. We find that the extension of female lifespan upon Maf1 knockdown requires Pol III initiation on the 5S rRNA. Indeed, reducing neuronal Maf1 activity rescues the age-related decline in 5S expression and protein synthesis in the brain of female flies. Hence, our findings show that stimulating neuronal protein synthesis can promote healthy aging.
Longevity Relevance Analysis
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Knockdown of Maf1 in neurons extends lifespan in Drosophila by preventing the age-related decline in 5S rRNA and enhancing protein synthesis. This research addresses a mechanism related to aging and longevity, focusing on the role of protein synthesis in promoting healthy aging rather than merely treating age-related symptoms.
Siyu Li, Songming Tang, Haocheng Ma ...
· DNA Methylation
· School of Mathematical Sciences and LPMC, Nankai University, Tianjin, 300071, China.
· pubmed
Accurately quantifying biological age is crucial for understanding the mechanisms of aging and developing effective interventions. Molecular aging clocks, particularly epigenetic clocks that use DNA methylation data to estimate biological age, have become essential tools in this ...
Accurately quantifying biological age is crucial for understanding the mechanisms of aging and developing effective interventions. Molecular aging clocks, particularly epigenetic clocks that use DNA methylation data to estimate biological age, have become essential tools in this area of research. However, the lack of a comprehensive, publicly accessible database with uniformly formatted DNA methylation datasets across various ages and tissues complicates the investigation of epigenetic clocks. Researchers face significant challenges in locating relevant datasets, accessing key information from raw data, and managing inconsistent data formats and metadata annotations. Additionally, there is a lack of dedicated resources for aging-related differentially methylated sites (DMSs, also named differentially methylated positions or differentially methylated cytosines) and regions (DMRs), which hinders progress in understanding the epigenetic mechanisms of aging. To address these challenges, we developed MethAgingDB, a comprehensive DNA methylation database for aging biology. MethAgingDB includes 93 datasets, with 11474 profiles from 13 distinct human tissues and 1361 profiles from 9 distinct mouse tissues. The database provides preprocessed DNA methylation data in a consistent matrix format, along with tissue-specific DMSs and DMRs, gene-centric aging insights, and an extensive collection of epigenetic clocks. Together, MethAgingDB is expected to streamline aging-related epigenetic research and support the development of robust, biologically informed aging biomarkers.
Longevity Relevance Analysis
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The paper presents MethAgingDB, a comprehensive DNA methylation database aimed at facilitating research on biological aging. This work is relevant as it addresses the challenges in studying the epigenetic mechanisms of aging, which are crucial for understanding and potentially intervening in the aging process.
Luciele Guerra Minuzzi, Helena Batatinha, Christopher Weyh ...
· Killer Cells, Natural
· Exercise and Immunometabolism Research Group, Postgraduation Program in Movement Sciences, Department of Physical Education, São Paulo State University (UNESP), 305 Roberto Simonsen, Presidente Prudente, 19060-900, Brazil. [email protected].
· pubmed
Aging is associated with immune dysfunction, but long-term endurance training may confer protective effects on immune cell function. This study investigates how natural killer (NK) cell phenotypes, functional markers, and metabolism differ between endurance-trained and untrained ...
Aging is associated with immune dysfunction, but long-term endurance training may confer protective effects on immune cell function. This study investigates how natural killer (NK) cell phenotypes, functional markers, and metabolism differ between endurance-trained and untrained older adults. Ex vivo expanded NK cells from endurance-trained (63.6 ± 2.1 years) and untrained (64.3 ± 3.3 years) males were exposed to adrenergic blockade (propranolol; 0-200 ng/mL) or mTOR inhibition (rapamycin; 10-100 ng/mL), both with or without PMA-induced inflammatory stimulation. Flow cytometry assessed NK subsets, activation (CD38, CD57, CD107a, NKG2D), senescence (KLRG1), and inhibitory markers (PD-1, LAG-3, TIM-3, NKG2A). Seahorse analysis measured metabolic parameters. Trained participants displayed healthier immune profiles (lower NLR, SII) and higher effector NK cells with lower cytotoxic subsets. Propranolol at 100 ng/mL blunted PMA-driven increases in CD57, CD107a, and NKG2D, while potentiating regulatory markers KLRG1, LAG-3, and PD-1 in the trained group, indicating stronger immunoregulation. With rapamycin, trained NK cells preserved NKG2D and CD107a at 10 ng/mL, maintaining cytotoxicity and degranulation. In contrast, at 100 ng/mL rapamycin plus PMA, trained NK cells shifted toward an effector phenotype with higher CD57 and CD107a, yet a blunted PMA-increased LAG-3 and TIM-3, suggesting resistance to exhaustion. PD-1 and KLRG1 remained elevated, reflecting balanced immune control. Mitochondrial analysis revealed that trained NK cells exhibited higher basal and maximal OCR, greater spare respiratory capacity, and OCR/ECAR ratio, reflecting superior metabolic fitness. These findings indicate that endurance-trained older adults have NK cells with greater functional adaptability, reduced senescence, and enhanced metabolism under inflammatory and pharmacological stress.
Longevity Relevance Analysis
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Endurance-trained older adults exhibit improved functional and metabolic responses of natural killer cells under adrenergic blockade and mTOR inhibition. This study addresses the impact of endurance training on immune function in aging, which is crucial for understanding mechanisms that could mitigate age-related immune dysfunction and promote healthier aging.
de Witte, A., Matthijs, A., Parrell, B. ...
· neuroscience
· KU Leuven
· biorxiv
Aging is frequently perceived negatively due to its association with the decline of various brain and bodily functions. While it is evident that motor abilities deteriorate with age, it is incorrect to assume that all aspects of movement execution are equally affected. The cerebe...
Aging is frequently perceived negatively due to its association with the decline of various brain and bodily functions. While it is evident that motor abilities deteriorate with age, it is incorrect to assume that all aspects of movement execution are equally affected. The cerebellum, a brain region that is closely involved in motor control among other functions, undergoes clear structural changes with aging. While several studies suggest that cerebellar degeneration causes age related motor control deficits, other studies suggest that the cerebellum might act as a motor reserve and compensate for its structural degeneration, leaving cerebellar motor function intact despite cerebellar degeneration. The present study aims at thoroughly investigating the impact of age on cerebellar function across an array of tasks and domains. We investigated cerebellar motor and cognitive functions across the lifespan by examining 50 young adults (20 to 35 years), 80 older adults (55 to 70 years), and 30 older old adults (over 80 years). Participants completed a test battery comprising seven motor control tasks and one cognitive task, each designed to probe cerebellar function through different paradigms. This multi task approach allowed for a comprehensive evaluation of performance patterns, providing a balanced perspective on cerebellar function across the different age groups. In addition, we analyzed outcomes from the same tasks that, while related to movement, were not specifically linked to cerebellar function. Structural magnetic resonance imaging was also conducted to assess whether cerebellar atrophy was present in the older and older old groups compared to the young. Our results revealed that, despite age-related cerebellar degeneration, cerebellar functions in older adults remained intact compared to young adults, even in adults above 80 years old. In contrast, the sensorimotor measures that were not directly linked to cerebellar function exhibited a clear pattern of decline in older adults, and were further deteriorated in the older-old adults compared to the older adults. These findings indicate that cerebellar motor control functions remain largely preserved with age, providing compelling evidence that the cerebellum possesses a remarkable degree of functional resilience and redundancy. This suggests that cerebellar circuits may be uniquely equipped to preserve function despite structural degeneration.
Longevity Relevance Analysis
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The paper claims that cerebellar functions remain largely preserved in older adults despite structural degeneration. This research is relevant as it explores the resilience of brain functions in aging, contributing to the understanding of longevity and the potential for maintaining cognitive and motor abilities in older populations.
Krystyna Mazan-Mamczarz, Dimitrios Tsitsipatis, Bennett G Childs ...
· Nature aging
· Laboratory of Genetics and Genomics, National Institute on Aging (NIA) Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA.
· pubmed
Growing evidence suggests that the induction of cellular senescence in vascular cells is causally linked to the etiology of cardiovascular diseases. To investigate systematically the heterogeneity of senescent vascular cells in atherosclerosis, we used a high-fat diet and PCSK9 o...
Growing evidence suggests that the induction of cellular senescence in vascular cells is causally linked to the etiology of cardiovascular diseases. To investigate systematically the heterogeneity of senescent vascular cells in atherosclerosis, we used a high-fat diet and PCSK9 overexpression to induce atherosclerosis in a senescence reporter mouse model (p16-tdTomato
Longevity Relevance Analysis
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The paper claims to systematically investigate the heterogeneity of senescent vascular cells in atherosclerosis. This research is relevant as it addresses cellular senescence, a key mechanism implicated in aging and age-related diseases, potentially contributing to understanding and mitigating the root causes of cardiovascular aging.
Dan Wu, Chen Yan, Linhui Han ...
· Journal of nanobiotechnology
· Department of Orthopedic Surgery, Changzheng Hospital, Navy Medical University, Shanghai, 200003, China.
· pubmed
Intervertebral disc degeneration (IVDD) is a significant contributor to chronic low back pain and disability worldwide, yet effective treatment options remain limited. Through integrative analysis of single-cell RNA-seq data from intervertebral discs (IVDs), we have firstly uncov...
Intervertebral disc degeneration (IVDD) is a significant contributor to chronic low back pain and disability worldwide, yet effective treatment options remain limited. Through integrative analysis of single-cell RNA-seq data from intervertebral discs (IVDs), we have firstly uncovered that the aberrant accumulation of R-Loops-a type of triple-stranded nucleic acid structure-can result in the cytoplasmic accumulation of double-stranded DNA (dsDNA) and activate cGAS/STING signaling and induce cellular senescence in nucleus pulposus cells (NPCs) during IVDD. Restoring the R-Loop state significantly mitigated both the activation of the cGAS/STING pathway and NPC senescence. Additionally, we identified ERCC5 as a critical regulator of the R-Loop state and cellular senescence. Thus, we developed an NPC-targeting nano-delivery platform (CTP-PEG-PAMAM) to deliver si-Ercc5 to the NP region of the IVDD. This approach aims to modulate the abnormal R-Loop state and inhibit the activation of cGAS/STING signaling in NPCs for IVDD treatment. CTP-PEG-PAMAM demonstrated excellent targeting capability towards NPCs and NP tissue, and achieved effective silencing of the Ercc5 gene without causing systemic organ complications. Both in vitro and in vivo experiments revealed that CTP-PEG-PAMAM-siERCC5 significantly inhibited cGAS/STING signaling activated by aberrant R-Loops, alleviated cellular senescence and promoting cell proliferation, thereby delayed IVDD in a puncture-induced rat model. In conclusion, the ERCC5-R-Loop-cGAS/STING axis in NPCs represents a promising therapeutic target for delaying IVDD, and the designed CTP-PEG-PAMAM/siRNA complex holds great potential for clinical application in the treatment of IVDD.
Longevity Relevance Analysis
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The paper claims that targeting the ERCC5-R-Loop-cGAS/STING axis can alleviate cellular senescence and intervertebral disc degeneration. This research addresses a mechanism related to cellular senescence, which is a key factor in aging and age-related diseases, thus contributing to the understanding of longevity.
Hernan Hernandez, Hernando Santamaria-Garcia, Sebastian Moguilner ...
· Nature medicine
· Latin American Brain Health Institute (BrainLat), Universidad Adolfo Ibañez, Santiago de Chile, Chile.
· pubmed
Protective and risk factors can drive healthy or accelerated aging, with distinct environments modulating their effects. The impact of the exposome-the combined physical and social exposures experienced throughout life-on accelerated aging remains unknown. We assessed delayed and...
Protective and risk factors can drive healthy or accelerated aging, with distinct environments modulating their effects. The impact of the exposome-the combined physical and social exposures experienced throughout life-on accelerated aging remains unknown. We assessed delayed and accelerated aging in 161,981 participants from 40 countries (45.09% female; mean age, 67.06; s.d., 9.85) by measuring biobehavioral age gaps (BBAGs), defined as the difference between estimated age from protective and risk factors and chronological age, in cross-sectional and longitudinal designs. BBAGs predicted chronological age, followed by regional and exposomal factor analyses, linked to accelerated aging. Europe led in healthy aging, while Egypt and South Africa showed the greatest acceleration; Asia and Latin America fell in between (Cliff's delta (δd) = 0.15-0.52; all P < 0.0001). Accelerated aging was more evident in eastern and southern Europe; globally, it was also associated with lower income (δd = 0.48-0.56, P < 1 × 10
Longevity Relevance Analysis
(4)
The paper claims that the exposome influences biobehavioral age gaps, which can predict accelerated aging across diverse populations. This research is relevant as it explores environmental factors affecting aging, potentially addressing root causes of accelerated aging rather than merely treating symptoms.
Haijun He, Ruixue Ai, Evandro Fei Fang ...
· npj aging
· Department of Physiology, Medical School, National and Kapodistrian University of Athens, 157 27, Athens, Greece.
· pubmed
The Rab3 protein family is composed of a series of small GTP-binding proteins, including Rab3a, Rab3b, Rab3c, and Rab3d, termed Rab3s. They play crucial roles in health, including in brain function, such as through the regulation of synaptic transmission and neuronal activities. ...
The Rab3 protein family is composed of a series of small GTP-binding proteins, including Rab3a, Rab3b, Rab3c, and Rab3d, termed Rab3s. They play crucial roles in health, including in brain function, such as through the regulation of synaptic transmission and neuronal activities. In the high-energy-demanding and high-traffic neurons, the Rab3s regulate essential cellular processes, including trafficking of synaptic vesicles and lysosomal positioning, which are pivotal for the maintenance of synaptic integrity and neuronal physiology. Emerging findings suggest that alterations in Rab3s expression are associated with age-related neurodegenerative pathologies, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, among others. Here, we provide an overview of how Rab3s dysregulation disrupts neuronal homeostasis, contributing to impaired autophagy, synaptic dysfunction, and eventually leading to neuronal death. We highlight emerging questions on how Rab3s safeguards the brain and how their dysfunction contributes to the different neurodegenerative diseases. We propose fine-tuning the Rab3s signaling directly or indirectly, such as via targeting their upstream protein AMPK, holding therapeutic potential.
Longevity Relevance Analysis
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The paper claims that dysregulation of Rab3 proteins contributes to neurodegeneration and suggests targeting their signaling pathways for therapeutic potential. The relevance lies in its focus on understanding molecular pathways that underlie age-related neurodegeneration, which could inform strategies for addressing the root causes of aging-related cognitive decline.