A G Newman, J Sharif, P Bessa ...
· Heterochromatin
· Institute of Cell and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. andrew.newman@pm.me.
· pubmed
In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs result...
In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs result in a chronic inflammatory environment characterized by neurodegeneration and cognitive decline in mice. We identify distinct roles for HP1 proteins to ERV silencing where HP1γ is necessary and sufficient for H4K20me3 deposition and HP1β deficiency causes aberrant DNA methylation. Combined loss of HP1β and HP1γ results in loss of DNA methylation at ERVK elements. Progressive ERV de-repression in HP1β/γ DKO mice is followed by stimulation of the integrated stress response, an increase of Complement 3+ reactive astrocytes and phagocytic microglia. This chronic inflammatory state coincides with age-dependent reductions in dendrite complexity and cognition. Our results demonstrate the importance of preventing loss of epigenetic maintenance that is necessary for protection of postmitotic neuronal genomes.
Longevity Relevance Analysis
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The paper claims that loss of heterochromatin maintenance and de-repression of endogenous retroviruses lead to chronic inflammation and cognitive decline in aging neurons. This research addresses the underlying mechanisms of aging-related cognitive decline, focusing on epigenetic maintenance as a potential target for interventions in age-related diseases.
Valentin Flietner, Bernd Heidergott, Frank den Hollander ...
· Aging
· PwC, Bernhard-Wicki-Strasse 8, 80636, Munich, Germany.
· pubmed
In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modelling of network evolutio...
In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modelling of network evolution with Poisson processes is universal and can be derived from fundamental principles. Second, with the help of two simplifying approximations, which we refer to as mean-field assumption and homogeneity assumption, we provide an analytical derivation of Gompertz law under generic and biologically relevant conditions. Third, we identify for which network parameters Gompertz law is accurate, express the parameters in Gompertz law as a function of the network parameters, and illustrate our computations with simulations and analytic approximations. Our paper is the first to offer a full mathematical explanation of Gompertz law and its limitations based on network theory.
Longevity Relevance Analysis
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The paper presents a mathematical model that explains Gompertz law in the context of aging and mortality through network theory. This work is relevant as it addresses fundamental aspects of aging and mortality, potentially contributing to a deeper understanding of the biological processes underlying aging.
Stephen B Kritchevsky, Steven R Cummings
· JAMA
· Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, and the Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest University of School of Medicine, Winston-Salem, North Carolina.
· pubmed
The incidence of stroke, heart failure, dementia, many cancers, coronary artery disease, and physical disability rise exponentially with age. Geroscience is a relatively new discipline that aims to define and modify aging-related biologic pathways, slow age-related disability, pr...
The incidence of stroke, heart failure, dementia, many cancers, coronary artery disease, and physical disability rise exponentially with age. Geroscience is a relatively new discipline that aims to define and modify aging-related biologic pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival.
Longevity Relevance Analysis
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The paper discusses the potential to define and modify aging-related biologic pathways to prevent age-related diseases. This research is relevant as it addresses the root causes of aging and aims to extend healthspan and lifespan.
Amin Haghani, Ake T Lu, Qi Yan ...
· GeroScience
· Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. ahaghani@altoslabs.com.
· pubmed
Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigeneti...
Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.
Longevity Relevance Analysis
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EnsembleAge demonstrates that integrating multiple epigenetic clocks can improve the assessment of biological aging and intervention effects. This paper is relevant as it addresses the root causes of aging by providing a robust tool for identifying and validating interventions that modulate biological aging.
Mishra, M., Kim, H.-H., Youm, Y.-H. ...
· physiology
· Yale School of Medicine
· biorxiv
Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower ...
Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.
Longevity Relevance Analysis
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The paper claims that complement C3 deactivation is a metabolically regulated checkpoint that reduces inflammaging and can extend healthspan. This research is relevant as it addresses a potential mechanism underlying aging and healthspan extension through immunometabolic pathways, rather than merely treating age-related diseases.
Peng Li, Yi Yang, Xiang Qin ...
· Research (Washington, D.C.)
· Department of Anesthesiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
· pubmed
This perspective critically examines the paradigm-shifting findings regarding cellular senescence's dual role in tissue biology, particularly focusing on its unexpected regenerative potential in hair growth. While cellular senescence has traditionally been viewed as a detrimental...
This perspective critically examines the paradigm-shifting findings regarding cellular senescence's dual role in tissue biology, particularly focusing on its unexpected regenerative potential in hair growth. While cellular senescence has traditionally been viewed as a detrimental process associated with aging and tissue dysfunction, research has revealed its surprising beneficial effects on tissue regeneration. We analyze the groundbreaking discovery that senescent melanocytes can stimulate hair follicle stem cells through the osteopontin-CD44 signaling pathway, challenging the conventional understanding of senescence. This perspective also evaluates the implications of this finding for both basic research and therapeutic applications, suggesting that cellular senescence represents a complex, context-dependent phenomenon rather than a uniformly detrimental process. We discuss how this new perspective necessitates a more nuanced approach to senescence-targeted therapies and opens novel therapeutic possibilities for hair loss treatment. This analysis underscores the importance of understanding senescent cell heterogeneity and their diverse functions in tissue homeostasis, which could lead to more precise therapeutic strategies in regenerative medicine.
Longevity Relevance Analysis
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Senescent melanocytes can stimulate hair follicle stem cells through the osteopontin-CD44 signaling pathway. This research challenges the traditional view of cellular senescence as solely detrimental and suggests that understanding its dual role could lead to novel therapeutic strategies in regenerative medicine, directly addressing mechanisms related to aging.
Xiaoli Li, Yuecong Chen, Zhuoyi Gao ...
· Aging cell
· National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China.
· pubmed
Aging is a process of gradual decline in physical and cognitive function and is a major risk factor for mortality. Despite the increasing number of relevant studies, the mechanisms regulating the aging process have not been fully elucidated. Genetic factors have long been recogni...
Aging is a process of gradual decline in physical and cognitive function and is a major risk factor for mortality. Despite the increasing number of relevant studies, the mechanisms regulating the aging process have not been fully elucidated. Genetic factors have long been recognized as key factors in controlling the rate of aging. Testes-specific protease 50 (TSP50) has been shown to be involved in the regulation of embryonic development and intestinal homeostasis, but its role in the regulation of aging remains unclear. Here, we showed that TSP50 expression was reduced in the hippocampus of both aged humans and mice. TSP50 deficiency in neural stem cells (NSCs) drove accelerated aging in mice, characterized by exacerbated age-related cognitive impairments and significantly elevated neuroinflammation. Notably, aged mice with NSCs-specific knockout of TSP50 exhibited impaired intestinal mucosal barriers, dysbiosis of gut microbiota, and a marked reduction in the production of short-chain fatty acids (SCFAs). Restoring gut microbial ecology using fecal microbiota transplantation (FMT) and overexpressing TSP50 successfully alleviated aging-associated cognitive decline and neuroinflammation. Taken together, our study suggests that TSP50 plays a critical role in the aging process and identifies gut microbiota as a pivotal mediator of TSP50's influence on age-related cognitive decline and neuroinflammation. These findings highlight the potential therapeutic value of targeting TSP50 and gut microbiota for aging, offering insights into aging mechanisms and interventions for aging-related neurodegenerative diseases.
Longevity Relevance Analysis
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TSP50 regulates aging-related cognitive decline and neuroinflammation through its influence on gut microbiota. The paper addresses mechanisms underlying aging and suggests potential therapeutic targets, aligning with the goal of understanding and intervening in the aging process.
Jongsun Lee, Bora Lee, Hyein Lee ...
· Ribosomes
· Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yuseong-gu, Daejeon 34141, South Korea.
· pubmed
Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here...
Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is indispensable for longevity in the nematode
Longevity Relevance Analysis
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Pelota promotes longevity and protects against age-related pathological phenotypes across species. The study addresses the role of ribosome-associated quality control in aging, focusing on a mechanism that could potentially mitigate age-related decline, thus contributing to the understanding of longevity and aging processes.