Patrick Lacolley, Stéphane Avril, Tamás Gáll ...
· Cardiovascular research
· Université de Lorraine, Inserm, DCAC, Nancy, France.
· pubmed
Vascular aging is considered now to be the first factor of multiorgan aging in what is called "the vascular theory of aging". Clinical understanding of vascular aging has long been limited to arterial hypertension and arterial stiffness. The effects of age on arterial mechanical ...
Vascular aging is considered now to be the first factor of multiorgan aging in what is called "the vascular theory of aging". Clinical understanding of vascular aging has long been limited to arterial hypertension and arterial stiffness. The effects of age on arterial mechanical properties have always been difficult to interpret for reasons linked to the non-linear behaviour of the stiffness/pressure function and the complex interactions between vascular cells and the matrix. Even new methodologies for decoding aging at the single-cell level are equally difficult to interpret. This objectives of this review are: (i) to introduce new computational approaches in biomechanics and mechanobiology; (ii) to revisit the role of oxidative stress and cellular senescence; (iii) to summarize some of the main molecular, cellular and mechanistic contributions to vascular aging; (iv) to present the latest human studies of accelerated arterial aging with particular reference to cognitive impairment and functional decline; (v) to propose some future directions for research related to vascular aging.
Longevity Relevance Analysis
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The paper discusses the mechanobiological and oxidative stress contributions to vascular aging and proposes future research directions. It is relevant as it addresses the underlying mechanisms of vascular aging, which is a critical aspect of the broader understanding of aging and longevity.
Tianhao Wu, Yingqian You, Yuhan Zhou ...
· The journals of gerontology. Series A, Biological sciences and medical sciences
· Department of Occupational and Environmental Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
· pubmed
Both mosaic loss of the Y chromosome (mLOY) and frailty are related to human aging. However, their relationship and the potential mediating effect of mLOY on the association between frailty and mortality risk remain understudied. A total of 8947 middle-aged and older male adults ...
Both mosaic loss of the Y chromosome (mLOY) and frailty are related to human aging. However, their relationship and the potential mediating effect of mLOY on the association between frailty and mortality risk remain understudied. A total of 8947 middle-aged and older male adults from the Dongfeng-Tongji cohort were included in this study. Causes of death were tracked till the end of year 2018. Frailty index (FI) was calculated by 34 deficits and categorized into three groups: robust (FI ≤ 0.10), prefrail (0.10< FI < 0.25), and frail (FI ≥ 0.25). mLOY was estimated by genotyping data and presented as the proportion of leukocytes with mLOY. Cox proportional hazards regressions were used to assess the associations of mLOY with risk of mortality. Mediation effects of mLOY were estimated under a counterfactual-based framework. In this prospective study, the prevalence of prefrail and frail participants were 50.2% and 29.0%, respectively. Compared to the robust participants, frail males exhibited significantly increased level of mLOY [β (95%CI) =1.15 (0.62, 1.68)]. Frailty and mLOY showed significant associations with increased mortality risks, and mLOY may mediate a separate 27.3%, 53.9%, and 23.5% of the association of frailty with the risks of death from all causes, cancer, and other causes. These relationships were confined to males aged ≥65 years. These findings unveiled the relationships of frailty with mLOY and the mediation role of mLOY in the frailty-mortality association among older males aged ≥65 years. Our results highlighted the importance of mLOY during male aging.
Longevity Relevance Analysis
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The study claims that mosaic loss of the Y chromosome (mLOY) mediates the relationship between frailty and mortality risk in older males. This research is relevant as it explores the biological mechanisms underlying aging and mortality, specifically focusing on genetic factors that may contribute to frailty and longevity.
Steven B Wells, Daniel B Rainbow, Michal Mark ...
· Nature immunology
· Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA.
· pubmed
The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from...
The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.
Longevity Relevance Analysis
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The paper claims to identify tissue-specific signatures of immune homeostasis that change with age. This research is relevant as it explores the effects of aging on immune cell function, which is a critical aspect of understanding the biological mechanisms of aging and potential interventions for age-related decline in immune function.
Shun-Ming Ting, Xiurong Zhao, Guanghua Sun ...
· The Journal of neuroscience : the official journal of the Society for Neuroscience
· Department of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, TX, 77030, USA.
· pubmed
After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore...
After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore, aged MΦ become overactivated in response to stroke, enhancing secondary brain injury. In this study, we demonstrated that by reversing the age-related dysfunctions in MΦ through activating the retinoid x receptor (RXR), the recovery after stroke in the aged brain could be improved. Using RNA sequencing, we compared the transcriptomes between MΦ isolated from the brains of young and aged male mice. We observed higher levels of pro-inflammatory genes and lower levels of phagocytosis-facilitating genes (
Longevity Relevance Analysis
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The paper claims that activating the retinoid x receptor (RXR) can reverse age-related dysfunctions in microglia and improve post-stroke recovery in aged brains. This research is relevant as it addresses the underlying mechanisms of aging-related decline in immune function, specifically in the context of stroke recovery, which aligns with the goal of understanding and potentially mitigating age-associated diseases.
Xiaoyue Luo, Jiong Zhang, Johan Tolö ...
· Neural regeneration research
· Department of Neurology, University Medical Center Go.ttingen, Go.ttingen, Germany.
· pubmed
Aging is characterized by a decreased autophagic activity contributing to the intracellular deposition of damaged organelles and macromolecules. Autophagy is particularly challenging in neurons since autophagic vesicles are formed at the axonal tip and must be transported to the ...
Aging is characterized by a decreased autophagic activity contributing to the intracellular deposition of damaged organelles and macromolecules. Autophagy is particularly challenging in neurons since autophagic vesicles are formed at the axonal tip and must be transported to the soma where final degradation occurs. Here, we examined if axonal transport of autophagic vesicles is altered during aging. We employed two-photon microscopy for in vivo imaging in the optic nerve of young and aged rats. In old animals (> 18 months old), retrograde autophagic vesicle transport was significantly reduced with regard to motility and velocity. While activation of autophagy was decreased, expression of key proteins of the autophagy-lysosomal pathway including p62 and procathepsin D and the number of autophagolysosomes was increased. Maturation of autophagic vesicles was shifted to more distal regions of the axon and axonal lysosomal clearing was impaired. In a pull-down assay, the protein binding between dynein and dynactin was decreased by half, which could explain the retrograde axonal transport effects. Taken together, retrograde axonal autophagic vesicle transport in vivo is diminished during aging accompanied by decreased autophagy activation, alterations of the lysosomal pathway, and a reduced dynein-dynactin binding.
Longevity Relevance Analysis
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The paper claims that retrograde axonal transport of autophagic vesicles is diminished during aging due to decreased dynein-dynactin protein interaction. This research is relevant as it addresses the mechanisms of autophagy and axonal transport in neurons, which are critical processes that can influence the aging process and age-related neurodegenerative diseases.
Boyang Zheng, Weijie Zhang, Gongwang Yu ...
· Nature communications
· Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
· pubmed
Aging is a series of adverse changes over time that increases mortality risk. Several hypotheses have been proposed to explain aging, including Leslie Orgel's Error-Catastrophe Theory, which asserts that translation errors erode the translational machinery, become self-amplifying...
Aging is a series of adverse changes over time that increases mortality risk. Several hypotheses have been proposed to explain aging, including Leslie Orgel's Error-Catastrophe Theory, which asserts that translation errors erode the translational machinery, become self-amplifying, and eventually lead to death. Evidence for the theory is scarce, especially regarding intra-specific fidelity-longevity correlations. Here, we demonstrate that the correlation can be hidden by the constrained evolution of translational fidelity, but remains detectable in long-lived samples. Measuring the lifespan and translational fidelity of a panel of BY × RM yeast recombinant haploid progenies, we validate the fidelity-longevity correlation. QTL analyses reveal that both fidelity and longevity are most strongly associated with a locus encoding vacuolar protein sorting-associated protein 70(VPS70). Replacing VPS70 in BY by its RM allele reduces translation error by ~8.0% and extends lifespan by ~8.9% through a vacuole-dependent mechanism. Our results support the impact of translational fidelity on intra-specific longevity variation.
Longevity Relevance Analysis
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The paper claims that translational fidelity is genetically linked to longevity, demonstrating a correlation between translation error rates and lifespan in yeast. This research is relevant as it explores a potential root cause of aging by investigating the genetic factors that influence longevity through translational fidelity.
Ciarchi, M., Simons, B. D., Rulands, S.
· cell biology
· Ludwig-Maximilian-Universitity Munich
· biorxiv
Aging involves processes spanning orders of magnitude in time, from fast events that occur at the molecular scale to the slow decrease of physiological function. Whether and how fast molecular events lead to the slow progression of aging, and what ultimately sets the timescale of...
Aging involves processes spanning orders of magnitude in time, from fast events that occur at the molecular scale to the slow decrease of physiological function. Whether and how fast molecular events lead to the slow progression of aging, and what ultimately sets the timescale of aging, is not understood. Here, by focusing on dynamic changes in DNA methylation, we show how aging phenomena on long timescales emerge from the kinetics of fast molecular processes, providing a bridge between temporal scales. By combining DNA methylation sequencing data across a range of timescales with a statistical modeling-based approach, we show that DNA methylation aging is governed by a three-fold hierarchy of processes that dominate on distinct timescales: individual stochastic events in which enzymes interact with the DNA and with each other (milliseconds); the convergence of molecular concentrations to steady states (days to months); and stochastic transitions between these steady states (years to decades). Our findings provide a unified picture of how DNA methylation aging arises across temporal scales.
Longevity Relevance Analysis
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The paper claims that DNA methylation aging is governed by a three-fold hierarchy of processes across distinct timescales. This research is relevant as it addresses the underlying mechanisms of aging at the molecular level, potentially contributing to our understanding of the root causes of aging and informing future interventions in longevity.
Torsak Tippairote, Pruettithada Hoonkaew, Aunchisa Suksawang ...
· Biogerontology
· School of Health Sciences, Sukhothai Thammathirat Open University, Pak Kret District, Nonthaburi, 11120, Thailand. [email protected].
· pubmed
Aging is increasingly understood not as the passive accumulation of molecular damage, but as the cumulative cost of unresolved physiological adaptation under bioenergetic constraint. This review introduces Exposure-Related Malnutrition (ERM) as a mechanistically grounded and clin...
Aging is increasingly understood not as the passive accumulation of molecular damage, but as the cumulative cost of unresolved physiological adaptation under bioenergetic constraint. This review introduces Exposure-Related Malnutrition (ERM) as a mechanistically grounded and clinically actionable phenotype of early maladaptation. ERM arises from sustained metabolic strain during chronic stress exposure and manifests not through overt weight loss or nutrient deficiency, but through subtle, multisystem declines in physical, cognitive, and regenerative capacity. These include fatigue, impaired recovery, cognitive slowing, immune dysregulation, chronic pain, anabolic resistance, and reproductive decline-features often missed by classical malnutrition criteria. We propose a unifying framework-Respond → Adapt → Resolve-to model the trajectory of stress response and resolution, emphasizing the critical role of bioenergetic availability in shaping divergent outcomes. When metabolic substrates are insufficient, resolution fails and the system defaults to a trade-off state, prioritizing immediate survival over long-term maintenance. ERM represents this inflection point: a reversible, energy-constrained condition that precedes frailty and chronic disease. We review interconnected mechanisms-including neuroendocrine activation, immune reprogramming, skeletal muscle catabolism, translational suppression, and mitochondrial distress-that create a self-perpetuating loop of maladaptive adaptation. We map ERM onto key hallmarks of aging, propose a multidimensional staging model, and outline clinical strategies to detect and reverse ERM using dynamic biomarkers, functional assessments, and circadian-aligned lifestyle interventions. By reframing aging as a failure of adaptive resolution, this framework offers a novel lens to extend healthspan-via early detection of metabolic compromise and restoration of resilience before functional decline becomes irreversible.
Longevity Relevance Analysis
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The paper proposes that Exposure-Related Malnutrition (ERM) is a bioenergetic phenotype of aging that can be detected and potentially reversed to extend healthspan. This research is relevant as it addresses the underlying mechanisms of aging and offers a framework for early detection and intervention, which could contribute to longevity and improved health outcomes.
Yishu Wang, Jianmei Huang, Sixiong Lin ...
· Bone research
· Department of Biochemistry, Homeostatic Medicine Institute School of Medicine Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, China.
· pubmed
The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-relate...
The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-related osteoporosis. Vinculin loss severely impaired osteocyte adhesion and dendrite formation. Deleting vinculin using the mouse 10-kb Dmp1-Cre transgenic mice causes dramatic bone loss in the weight-bearing long bones and spine, but not in the skull, in both young and aged mice by impairing osteoblast formation and function without markedly affecting bone resorption. Vinculin loss impairs the anabolic response of skeleton to mechanical loading in mice. Vinculin knockdown increases, while vinculin overexpression decreases, sclerostin expression in osteocytes without impacting expression of Mef2c, a major transcriptional regulator of the Sost gene, which encodes sclerostin. Vinculin interacts with Mef2c and retains the latter in the cytoplasm. Thus, vinculin loss enhances Mef2c nuclear translocation and binding to the Sost enhancer ECR5 to promote sclerostin expression in osteocytes and reduces bone formation. Consistent with this notion, deleting Sost expression in osteocytes reverses the osteopenic phenotypes caused by vinculin loss in mice. Finally, we find that estrogen is a novel regulator of vinculin expression in osteocytes and that vinculin-deficient mice are resistant to ovariectomy-induced bone loss. Thus, we demonstrate a novel mechanism through which vinculin inhibits the Mef2c-driven sclerostin expression in osteocytes to promote bone formation.
Longevity Relevance Analysis
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The paper claims that vinculin regulates sclerostin expression in osteocytes, influencing bone formation and mass. This research is relevant as it addresses mechanisms underlying bone loss associated with aging, potentially offering insights into interventions that could mitigate age-related osteoporosis.
Oghogho P Ebeigbe, Volha Mezhnina, Artem Astafev ...
· Cell reports
· Center for Gene Regulation in Health and Disease (GRHD), Cleveland State University, Cleveland, OH 44115, USA; Department of Biological Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA.
· pubmed
Calorie restriction (CR) improves health and longevity. CR induces a periodic fasting cycle in mammals; our study compares CR with unanticipated fasting (F), when the food is unexpectedly withheld. F induces hepatic steatosis, whereas CR reduces it; surprisingly, the difference i...
Calorie restriction (CR) improves health and longevity. CR induces a periodic fasting cycle in mammals; our study compares CR with unanticipated fasting (F), when the food is unexpectedly withheld. F induces hepatic steatosis, whereas CR reduces it; surprisingly, the difference is not due to hepatic β-oxidation. Liver transcriptome analysis identifies fatty acid transporters (Slc27a1 and Slc27a2), triglyceride (TAG) synthesis (Gpat4), and lipid storage (Plin2 and Cidec) genes to be upregulated only in F, in agreement with hepatic steatosis. The circadian clock and anticipated fasting contribute to preventing fasting-associated hepatic steatosis in CR. Mechanistically, the Slc27a1, Plin2, and Cidec genes are upregulated, and liver TAGs accumulate in circadian clock mutant mice on CR or if wild-type CR mice miss their anticipated meal. The results highlight the similarities and differences between F and CR, suggesting that circadian clock-dependent gating of transcriptional response to fasting controls lipid homeostasis and prevents hepatic steatosis.
Longevity Relevance Analysis
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The study claims that circadian clocks and anticipated fasting prevent fasting-associated hepatic steatosis in calorie restriction. This research is relevant as it explores mechanisms that may influence metabolic health and longevity through the regulation of lipid homeostasis, which is a key factor in aging and age-related diseases.
Peijie Luo, Miao Yu, Shuncong Zhang ...
· Biogerontology
· Spinal Surgery Department, The Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
· pubmed
Cytoskeleton-Associated Protein 4 (CKAP4) is a multifunctional protein implicated in diverse cellular processes, including cytoskeletal organization, signal transduction, and extracellular matrix remodeling. Recent studies have highlighted the dual role of CKAP4 in regulating cel...
Cytoskeleton-Associated Protein 4 (CKAP4) is a multifunctional protein implicated in diverse cellular processes, including cytoskeletal organization, signal transduction, and extracellular matrix remodeling. Recent studies have highlighted the dual role of CKAP4 in regulating cell growth and aging. On one hand, CKAP4 can promote cell proliferation and survival by activating signaling pathways such as PI3K/Akt, thereby delaying cellular senescence under physiological conditions. On the other hand, under chronic stress or pathological stimuli, CKAP4 may induce cell cycle arrest and accelerate aging by interacting with ligands such as antiproliferative factor (APF) and Dickkopf-1 (DKK1), leading to the upregulation of cell cycle inhibitors and the suppression of autophagy. Moreover, CKAP4 has emerged as a key mediator linking extracellular matrix remodeling to inflammatory responses, which are closely associated with age-related diseases. This review comprehensively summarizes the current understanding of CKAP4's molecular mechanisms in cell longevity and aging, discusses its involvement in inflammation and tissue homeostasis, and explores its potential as a therapeutic target for aging-related disorders.
Longevity Relevance Analysis
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CKAP4 plays a dual role in regulating cell growth and aging, influencing both proliferation and senescence. The paper is relevant as it discusses molecular mechanisms that could potentially address the root causes of aging and age-related diseases.
Haruhisa Kawasaki, Toshihiko Sato, Norio Ishida
· Biogerontology
· Institute for Chronobiology, Foundation for Advancement of International Science (FAIS), 3-24-16 Kasuga, Tsukuba, Ibaraki, 305-0812, Japan.
· pubmed
Cannabidiol (CBD), a non-psychoactive cannabinoid, has been studied for its various health-promoting effects recently. This study investigates the effects of dietary CBD to the circadian clock of Drosophila melanogaster as a model animal and its many physiological effect to flies...
Cannabidiol (CBD), a non-psychoactive cannabinoid, has been studied for its various health-promoting effects recently. This study investigates the effects of dietary CBD to the circadian clock of Drosophila melanogaster as a model animal and its many physiological effect to flies. We showed that CBD extended the period of locomotor activity in a dose-dependent manner, suggesting its influence on the circadian clock. Additionally, CBD improved sleep quality and extended lifespan under starvation conditions. The study also revealed enhanced rhythmicity in Close Proximity (CP) rhythm and increased eggs reproduction with dietary CBD supplementation. Furthermor, CBD attenuates age-related motor dysfunction in wild-type and Parkinson's disease (PD) model in Drosophila. These findings strongly suggest that appropriate amount of CBD affects the circadian rhythms, sleep, life span, CP rhythm, egg reproduction and motor function of Drosophila melanogaster, and providing a basic data for exploring its potential applications in managing circadian-related disorders in other animals.
Longevity Relevance Analysis
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Cannabidiol (CBD) extends lifespan and improves various physiological functions in Drosophila melanogaster. The study investigates the effects of CBD on circadian rhythms and lifespan, which are directly related to aging and longevity research.
Emily R Lowry, Tulsi Patel, Jonathon A Costa ...
· Nature neuroscience
· Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
· pubmed
Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resi...
Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by reexpression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral reexpression of ISL1 and LHX3 selectively in postnatal motor neurons reactivates aspects of their youthful gene expression program and alleviates key disease-relevant phenotypes in the SOD1
Longevity Relevance Analysis
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The paper claims that reexpression of embryonic motor neuron factors ISL1 and LHX3 in postnatal motor neurons can reactivate youthful gene expression and alleviate ALS symptoms. This research is relevant as it explores mechanisms to restore youthful characteristics in neurons, potentially addressing the underlying causes of neurodegeneration associated with aging.
Stefan Stamenkovic, Franca Schmid, Gokce Gurler ...
· Nature neuroscience
· Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
· pubmed
The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or a consequence remains debatable. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in c...
The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or a consequence remains debatable. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in cortical layer 6 and the corpus callosum. We identified sparse, wide-reaching venules, termed principal cortical venules, which exclusively drain deep tissues and resemble the vasculature at the human cortex and U-fiber interface. Aging led to selective constriction and rarefaction of capillaries in deep branches of principal cortical venules. This resulted in mild hypoperfusion that was associated with microgliosis, astrogliosis and demyelination in deep tissues, but not the upper cortex. Induction of comparable hypoperfusion in adult mice using carotid artery stenosis triggered a similar tissue pathology specific to layer 6 and the corpus callosum. Thus, impaired capillary-venous drainage is a contributor to hypoperfusion and a potential therapeutic target for preserving blood flow to white matter during aging.
Longevity Relevance Analysis
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Impaired capillary-venous drainage contributes to hypoperfusion and tissue pathology in aging white matter. The study addresses a potential root cause of cognitive decline associated with aging, focusing on the mechanisms of blood flow impairment in the brain, which is relevant to longevity research.
Kim, C., Ofria, L. D., Kshirsagar, A. ...
· bioengineering
· The University of Texas at Austin
· biorxiv
Aging is increasingly recognized as a systemic process, yet the mechanisms by which senescent cells signal from peripheral tissues accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to ...
Aging is increasingly recognized as a systemic process, yet the mechanisms by which senescent cells signal from peripheral tissues accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to investigate how peripheral aging signals reshape brain tissue architecture. We combined spatially resolved optical fiber-based interferometry nanoindentation with transcriptomic and immunofluorescence profiling, demonstrating that bone-derived senescence-associated secretory phenotype (SASP) factors induce a biphasic mechanical response, early global tissue softening, followed by the emergence of discrete hyper-stiff microdomains. This spatially heterogeneous biomechanical remodeling was accompanied by upregulation of extracellular matrix (ECM), inflammatory, and senescence pathways, and suppression of neurodevelopmental and synaptic gene networks. Our results reveal that chronic paracrine SASP exposure from senescent osteocytes drives localized ECM reorganization and mechanical vulnerability in human brain tissue, providing mechanistic insight into how peripheral cellular senescence may contribute to regional brain fragility during aging.
Longevity Relevance Analysis
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Chronic exposure to senescent osteocyte secretome induces biomechanical vulnerability and ECM remodeling in human brain organoids. This study addresses the mechanisms by which peripheral cellular senescence contributes to brain aging, aligning with the investigation of root causes of aging.
Barny, L. A., Garcia, S. K., Houcek, A. J. ...
· biochemistry
· Vanderbilt University
· biorxiv
Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their post-mitotic and long-lived nature a...
Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their post-mitotic and long-lived nature and thus represent a unique cell type to understand the dynamics of proteostasis throughout development, maturation, and aging. Here, we utilized a dual-species co-culture model of human excitatory neurons and mouse glia to investigate cell type-specific, age-related changes in the proteostasis network using data-independent acquisition (DIA) LC-MS/MS proteomics. We quantified branch-specific unfolded protein response (UPR) activation by monitoring curated effector proteins downstream of the ATF6, IRE1/XBP1s, and PERK pathways, enabling a comprehensive, unbiased evaluation of UPR dynamics during neuronal aging. Species-specific analysis revealed that aging neurons largely preserved proteostasis, although they showed some signs of collapse, primarily in ER-to-Golgi transport mechanisms. However, these changes were accompanied by upregulation of proteostasis-related machinery and activation of the ATF6 branch, as well as maintenance of the XBP1s and PERK branches of the UPR with age. In contrast, glia exhibited broad downregulation of proteostasis factors and UPR components, independent of neuronal presence. Furthermore, we quantified stimulus-specific modulation of select UPR branches in aged neurons exposed to pharmacologic ER stressors. These findings highlight distinct, cell-type-specific stress adaptations during aging and provide a valuable proteomic resource for dissecting proteostasis and UPR regulation in the aging brain.
Longevity Relevance Analysis
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The paper claims that aging neurons maintain proteostasis despite some collapse, while glia show downregulation of proteostasis factors. This research is relevant as it explores the mechanisms of proteostasis and the unfolded protein response in aging, which are critical for understanding the biological processes underlying aging and potential interventions.
Robert G Leija, José Pablo Vázquez-Medina, George A Brooks
· American journal of physiology. Endocrinology and metabolism
· Exercise Physiology, Department of Integrative Biology, University of California, Berkeley, CA 94720-3140.
· pubmed
Resting and maximal exercise respiratory rates (V̇O
Resting and maximal exercise respiratory rates (V̇O
Longevity Relevance Analysis
(4)
The paper claims that the resilience of the mitochondrial reticulum plays a crucial role in the aging process. This research is relevant as it addresses mitochondrial function, which is a key factor in the aging process and could provide insights into potential interventions for longevity.
Watrous, J. D., Tiwari, S., Long, T. ...
· biochemistry
· Sapient Bioanalytics, LLC
· biorxiv
Mass spectrometry (MS)-based metabolomics is a key technology for the interrogation of exogenous and endogenous small molecule mediators that influence human health and disease. To date, however, low throughput of MS systems have largely precluded large-scale metabolomics studies...
Mass spectrometry (MS)-based metabolomics is a key technology for the interrogation of exogenous and endogenous small molecule mediators that influence human health and disease. To date, however, low throughput of MS systems have largely precluded large-scale metabolomics studies of human populations, limiting power to discover physiological roles of metabolites. Here, we introduce a fully automated rapid liquid chromatography-mass spectrometry (rLC-MS) system coupled to an AI-enabled computational pipeline that enables high-throughput, reproducible, non-targeted metabolite measurements across tens of thousands of samples. This system captures thousands of polar, amphipathic and nonpolar (lipid) metabolites in a human plasma sample in 53 seconds of analytical time, enabling analysis of greater than 1,000 samples per day per instrument. To demonstrate the discovery power of the rLC-MS platform, a subset of samples from Sapient\'s DynamiQ biorepository -- comprised of 62,039 total plasma samples collected longitudinally from 11,045 individuals -- were selected for deep analysis by rLC-MS to capture a rich, dynamic landscape of chemical variation that reflects both physiological processes and environmental influences. 26,042 plasma samples with matched real-world data (RWD) were chosen for the study, representing 6,935 individuals with diverse demographic backgrounds and disease profiles. Unbiased exploratory analysis revealed human metabotypes that correlate with heterogenous disease phenotypes, including key sub-populations of cardiometabolic and other human diseases. Moreover, a metabolic aging clock machine learning model trained on healthy individuals in this dataset accurately predicted accelerated aging in various chronic diseases, with dynamic reversal of metabolic aging following definitive therapy. These data demonstrate that the rLC-MS platform enables prediction of clinically relevant physiological states from plasma metabolomics at scale in human populations.
Longevity Relevance Analysis
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The paper claims that the rLC-MS platform can predict clinically relevant physiological states from plasma metabolomics at scale in human populations. This research is relevant as it explores metabolic aging and its correlation with chronic diseases, potentially addressing underlying mechanisms of aging rather than merely treating symptoms.
Ogg, M., Coon, W. G.
· neurology
· Johns Hopkins University Applied Physics Laboratory
· medrxiv
Biological age estimation, derived from physiological signatures such as brain activity, is emerging as a valuable biomarker for health and well-being. Discrepancies between biological and chronological age have been linked to multiple physical, mental, and cognitive health outco...
Biological age estimation, derived from physiological signatures such as brain activity, is emerging as a valuable biomarker for health and well-being. Discrepancies between biological and chronological age have been linked to multiple physical, mental, and cognitive health outcomes. However, current approaches primarily focus on MRI-based measurements, which are costly, challenging to obtain, and contraindicated for certain populations. This study explores polysomnographic (PSG) sleep signals, which capture activity from multiple physiological systems, as an accessible alternative for biological age prediction. Sleep serves as an ideal platform for age prediction due to its standardized data collection protocols, abundant public data resources, and the presence of well-documented age-related changes in sleep architecture. Additionally, the proliferation of consumer sleep monitoring tools offers potential for widespread application and longitudinal analysis. We trained transformer-based neural network models on over 10,000 nights of PSG data and performed rigorous internal and external validation. Our best models achieved age predictions with an absolute error of 5-10 years from just a single physiological time series input and were especially accurate with respect to certain stages of sleep (specifically, N2). Electroencephalography (EEG) signals were essential for capturing sleep architecture changes that correlate with age, while electrocardiogram (ECG) signals, although less accurate overall, tended to overestimate age in association with health conditions such as elevated blood pressure, higher body mass index, and sleep apnea. Despite strong performance, generalization beyond the training dataset remains a challenge (age prediction errors increase between internal validation and external data by at least 3 to 5 years). These findings show that noninvasive sleep-derived electrophysiological signals, particularly EEG, can rival MRI-based age prediction models in accuracy-while offering lower cost, greater accessibility, and broader applicability.
Longevity Relevance Analysis
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The paper claims that transformer models can accurately predict biological age from sleep physiology data. This research is relevant as it explores noninvasive methods for biological age estimation, which could contribute to understanding aging processes and improving health outcomes related to aging.
Eun-Ha Kim, Ho Bin Jang, Se-Mi Kim ...
· B-Lymphocytes
· Center for Virus Research Resource, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
· pubmed
Aging significantly influences host immune responses to viral infections, including Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), which is associated with high mortality in elderly patients. Despite its high fatality rate and pandemic potential, effective therapies r...
Aging significantly influences host immune responses to viral infections, including Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), which is associated with high mortality in elderly patients. Despite its high fatality rate and pandemic potential, effective therapies remain unavailable, and the age-dependent mechanisms underlying SFTSV pathogenesis are not fully understood. To address this gap, we employed a ferret model (an immunocompetent animal model that mimics human SFTSV infections) and performed multi-tissue single-cell RNA sequencing and histopathological analyses. Our results reveal that, upon SFTSV infection, aged ferrets experience extensive decrease of critical immune cells (particularly B and T cells) due to infection-induced cell death and excessive hemophagocytosis in hematopoietic organs, whereas young-adult ferrets rapidly clear the virus with minimal lymphocyte changes. Notably, aged ferrets display marked immune dysregulation, characterized by non-specific activation of T-bet ⁺ age-associated memory B cells (T-bet+ ABCs) and the proliferation of defective plasmablasts (MKI67 ⁺ PB1), which serve as major viral reservoirs and drive systemic viral dissemination. Comparative analysis further demonstrated that the MKI67 ⁺ PB1 subset dominates SFTSV⁺ cells in both aged ferrets and human fatal cases, exhibiting the highest per-cell viral UMI counts. Moreover, monocytes and macrophages in aged ferrets exhibit heightened inflammatory gene expression, contributing to the hyper-inflammatory state observed during infection. Collectively, these insights underscore the critical role of dysregulated memory B cell responses and hyper-inflammation in age-dependent SFTSV pathogenesis, highlighting potential targets for interventions in elderly populations.
Longevity Relevance Analysis
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Aged ferrets exhibit immune dysregulation and B cell dysfunction that contribute to severe outcomes in SFTSV infection. The paper addresses age-related immune mechanisms that could inform interventions targeting the aging process and its effects on viral infections, making it relevant to longevity research.
Kirsten C Sadler, Mekayla A Storer, N Sumru Bayin
· The FEBS journal
· Program in Biology and Center for Genomics and Systems Biology, NYU Abu Dhabi, UAE.
· pubmed
A strong regenerative capacity is a hallmark of youth. From the tadpole's tail to the mammalian brain, young animals of many species can repair or regrow damaged tissues more effectively than older animals. Here, we take a broad perspective on ageing, inclusive of the transition ...
A strong regenerative capacity is a hallmark of youth. From the tadpole's tail to the mammalian brain, young animals of many species can repair or regrow damaged tissues more effectively than older animals. Here, we take a broad perspective on ageing, inclusive of the transition from the developmental processes of embryogenesis through maturation to adulthood, as well as the processes that occur as an animal reaches the end of its lifespan. In some cases, the loss of regenerative capacity occurs once development is complete, and in others it occurs in the latter part of the animal's life. Regardless, the loss of regenerative capacity is caused by a failure to activate genes required for successful regeneration. This, in part, can be attributed to restructuring of the epigenome.
Longevity Relevance Analysis
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The paper claims that the loss of regenerative capacity with age is due to epigenomic restructuring that prevents the activation of necessary genes for regeneration. This research addresses the underlying mechanisms of aging and regeneration, which are crucial for understanding longevity and potential lifespan extension.
Ryo Murayama, Kenichi Horisawa, Shizuka Miura ...
· Aging cell
· Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
· pubmed
Aging causes significant changes in gene expression and metabolic function of cells in various organs. Although it is known that liver regeneration is delayed by aging, the effects of aging on changes in gene expression and metabolic functions in liver regeneration need further i...
Aging causes significant changes in gene expression and metabolic function of cells in various organs. Although it is known that liver regeneration is delayed by aging, the effects of aging on changes in gene expression and metabolic functions in liver regeneration need further investigation. In this study, we comprehensively analyzed changes in gene expression and metabolic function by liver regeneration in young and old mice to examine the effects of aging on these changes. During the process of liver regeneration, the gene expression profiles of hepatocytes from young and old mice changed significantly in a stepwise manner while each remained close together. After the completion of liver regeneration, the genes with aging-specific expression patterns in old mouse hepatocytes changed to expression levels close to those in young mouse hepatocytes. In contrast to the results of these transcriptome analyses, the aging-specific changes in metabolic state detected in old mouse livers were found to be largely maintained after the completion of liver regeneration. These results demonstrated that the gene expression state in the liver of old mice is flexibly altered by liver regeneration, whereas their metabolic state is robust. This finding helps to elucidate the relationship between aging and liver regeneration and to determine the basis of the increased incidence of liver disease with aging.
Longevity Relevance Analysis
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The paper claims that liver regeneration alters gene expression in old mice, but their metabolic state remains unchanged. This research is relevant as it explores the relationship between aging and liver regeneration, contributing to understanding the biological mechanisms underlying age-related changes and potential interventions.
Yifan Xiang, Vineeta Tanwar, Parminder Singh ...
· Menarche
· The Buck Institute for Research on Aging, Novato, United States.
· pubmed
Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antag...
Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited.
Longevity Relevance Analysis
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Early menarche and childbirth are linked to accelerated aging-related outcomes and age-related diseases. This paper explores the relationship between reproductive factors and aging, contributing to the understanding of the biological mechanisms underlying aging and potential interventions.
Evgeniia Bakaleinikova
· Aging
· Western Governors University, Millcreek, UT, USA. [email protected].
· pubmed
Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms drivin...
Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms driving these phenomena remain elusive. Here, a unifying hypothesis is proposed: that the progressive reactivation of human endogenous retroviruses (HERVs), combined with latent viral infections acquired during life, imposes an escalating burden on the epigenetic regulatory system. This "virome pressure" demands continuous silencing via DNA methylation, histone deacetylation, and NAD⁺-dependent pathways. With age, these silencing mechanisms deteriorate, leading to HERV reactivation, disruption of key mitochondrial quality control genes, and activation of innate immune responses. This is likened to a molecular peat bog, a simmering threat buried beneath the surface, where silencing mechanisms struggle to contain viral elements until pressure builds and erupts as the organism ages. This model integrates virology, epigenetics, and mitochondrial biology to offer novel insights into the aging process and suggests new targets for therapeutic intervention research.
Longevity Relevance Analysis
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The paper proposes that reactivation of endogenous retroviruses and latent viral infections contributes to epigenetic drift and mitophagy failure in aging. This research addresses potential root causes of aging by linking viral reactivation to epigenetic and mitochondrial dysfunction, which are critical factors in the aging process.
Boyang Li, Shaowei Wang, Bilal Kerman ...
· Aging cell
· Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
· pubmed
Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism...
Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia(iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.
Longevity Relevance Analysis
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Dysregulated cholesterol metabolism in microglia drives cellular senescence in Alzheimer's disease. The paper addresses a potential root cause of aging-related pathology by linking cholesterol dysregulation in microglia to cellular senescence, which is a significant aspect of aging and age-related diseases.
Anyu Zeng, Hailong Liu, Shuling He ...
· DNA Methylation
· Department of Bone and Soft Tissue Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510080, P. R. China.
· pubmed
Skeletal muscle stem cells (MuSCs) have strong regenerative abilities, but as we age, their ability to regenerate decreases, leading to a decline in muscle function. Although the methylation reprogramming of super-enhancers (SEs) plays a pivotal role in regulating gene expression...
Skeletal muscle stem cells (MuSCs) have strong regenerative abilities, but as we age, their ability to regenerate decreases, leading to a decline in muscle function. Although the methylation reprogramming of super-enhancers (SEs) plays a pivotal role in regulating gene expression associated with the aging process, our understanding of the molecular diversity of stem cells during aging remains limited. This study aimed to identify the methylation profile of SEs in MuSCs and explore potential therapeutic molecular targets associated with aging.
Longevity Relevance Analysis
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The paper claims to identify the methylation profile of super-enhancers in skeletal muscle stem cells and explore therapeutic targets related to aging. This research is relevant as it addresses the molecular mechanisms underlying the decline in regenerative abilities of muscle stem cells with age, which is a fundamental aspect of the aging process.
Athanasios Siametis, George A Garinis
· BioEssays : news and reviews in molecular, cellular and developmental biology
· Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece.
· pubmed
Persistent genomic instability compromises cellular viability while also triggers non-cell-autonomous responses that drive dysfunction across tissues, contributing to aging. Recent evidence suggests that DNA damage activates secretory programs, including the release of inflammato...
Persistent genomic instability compromises cellular viability while also triggers non-cell-autonomous responses that drive dysfunction across tissues, contributing to aging. Recent evidence suggests that DNA damage activates secretory programs, including the release of inflammatory cytokines, damage-associated molecular patterns, and extracellular vesicles, that reshape immune homeostasis, stem cell function, and metabolic balance. Although these responses may initially support tissue integrity and organismal survival, their chronic activation has been associated with tissue degenerative changes and systemic decline. Here, we discuss how nuclear DNA damage responses trigger the activation of cytoplasmic sensing pathways, promote secretory phenotypes, and affect organismal physiology. Targeting DNA damage-driven mechanisms may help buffer harmful systemic responses while preserving regeneration and immune surveillance, offering new ways to delay aging-related decline.
Longevity Relevance Analysis
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Chronic activation of DNA damage responses leads to systemic decline and may be targeted to delay aging-related degeneration. The paper addresses the root causes of aging by exploring how DNA damage contributes to systemic dysfunction, which is central to longevity research.
Miras Moreno, S., Torres, A., Ruiz, J. ...
· epidemiology
· University of Almeria
· medrxiv
Cardiorespiratory fitness (CRF) is a strong predictor of mortality and non-communicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified CRF associated metabolomics (n=30,010) and proteomics (n=4,235) signatures in UK Bioba...
Cardiorespiratory fitness (CRF) is a strong predictor of mortality and non-communicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified CRF associated metabolomics (n=30,010) and proteomics (n=4,235) signatures in UK Biobank participants. These signatures were validated in an independent sample of UK participants with data on metabolomics (n=198,871) and proteomics (n=29,961) to investigate prospective associations with all-cause mortality and non-communicable diseases. Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed two novel metabolic CRF signatures, one metabolomic and one proteomic, that robustly reflect CRF levels (R2: 0.49-0.60). Over an average of 9 years of follow-up, we observed 27,659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic CRF signature was strongly associated with a 34-39% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (89-91%), cardiovascular disease (35-39%), and colorectal cancer (32-54%). Additionally, the proteomic CRF signature was associated with a 17% lower risk of all-cause mortality, and with a 22-39% lower risk of type 2 diabetes and cardiovascular disease. Together, these findings suggest that circulating metabolites and proteins can capture the physiological imprint of CRF and may serve as indirect biomarkers for predicting mortality and non-communicable disease risk.
Longevity Relevance Analysis
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The paper claims that specific metabolomic and proteomic signatures associated with cardiorespiratory fitness can predict all-cause mortality and non-communicable disease risk. This research is relevant as it explores the molecular mechanisms underlying cardiorespiratory fitness, which is a significant factor in longevity and age-related health outcomes.
Leite, J. A., Ergun, Z., Stylianakis, E. ...
· immunology
· University Medical Center Mainz
· biorxiv
Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the contex...
Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the context of age-related inflammation remains poorly understood. Here we demonstrate that age-related changes in the microbiota promote impaired Treg cell function, resulting in the differentiation of inflammatory T cells. In agreement, we find that aged germ-free (GF) mice exhibited a more balanced immune profile, where the Treg cells are functional and pro-inflammatory mediators are reduced, suggesting that microbial exposure is essential for the establishment of inflammaging. Furthermore, we show that the use of old microbiota in young animals was sufficient to induce pro-inflammatory T cell responses and impaired mucosal Treg cell proliferation, while young microbiota restored Treg cell function in old animals. Mechanistically, we show that exposure to aged microbiota was associated with sustained TNF signaling, elevated oxidative stress, DNA damage, and increased expression of senescence markers such as {gamma}H2AX and p16 in Treg cells. These findings uncover a microbiota-TNF- dependent mechanism by which age-associated microbial dysbiosis drives Treg cell dysfunction and promotes immune aging, highlighting the therapeutic potential of microbiota-targeted strategies to restore immune homeostasis in the elderly.
Longevity Relevance Analysis
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Age-related changes in the microbiota impair Treg cell function through TNF signaling, contributing to immune aging. This paper is relevant as it addresses a potential root cause of aging by exploring the microbiota's role in immune dysfunction, which could lead to therapeutic strategies for restoring immune homeostasis in the elderly.
Maxim N Shokhirev, Adiv A Johnson
· GeroScience
· Tally Health, New York, NY, USA. [email protected].
· pubmed
Using 100 technical replicate samples from two adult buccal cohorts, we compared technical methylation variability and signal strength between the Infinium MethylationEPIC v2.0 array and the Twist Human Methylome Panel across 753,648 shared CpGs. Twist methylation sequencing show...
Using 100 technical replicate samples from two adult buccal cohorts, we compared technical methylation variability and signal strength between the Infinium MethylationEPIC v2.0 array and the Twist Human Methylome Panel across 753,648 shared CpGs. Twist methylation sequencing showed skewed methylation distributions and fewer highly correlated CpGs than MethylationEPIC arrays. Variance analysis revealed a skew toward higher signal strength in MethylationEPIC datasets, with a subset of CpGs showing high signal strength in both methylation sequencing and array datasets. Despite these biases, four principal component (PC) trained epigenetic clocks (pcHorvath1, pcHorvath2, pcHannum, and pcDNAm PhenoAge) were robust across both technologies, even with missing data. While pcHannum and pcDNAm PhenoAge were similarly reproducible with mean absolute replicate difference (MRD) values ranging from 1.014 years to 1.194 years, pcHorvath1 was more reproducible in arrays (MRD = 0.459 years) than methylation sequencing (MRD = 2.320 years) and pcHorvath2 was more reproducible in methylation sequencing (MRD = 0.760 years) than arrays (MRD = 1.011 years). Furthermore, original non-PC versions of these clocks were less reproducible in Twist datasets and, as an example of this, MRD for uncorrected clocks went as high as 15.498 years in arrays and as high as 20.180 years in methylation sequencing. Obvious differences in age prediction were also observed in original clocks compared to their PC-trained versions across both technologies (with a mean absolute difference ranging from 4.492 years to 46.724 years). This underscores the need for careful selection of epigenetic clocks and technology-specific adjustments when optimizing for accuracy and reproducibility.
Longevity Relevance Analysis
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The paper demonstrates that different epigenetic clocks exhibit varying levels of reproducibility across methylation technologies, highlighting the importance of technology-specific adjustments for accurate age prediction. This research is relevant as it addresses the measurement of biological age, which is a key factor in understanding the aging process and potential interventions for lifespan extension.
Wan-Hsuan Lu, Sophie Guyonnet, Jérémy Raffin ...
· Aging cell
· IHU HealthAge, Toulouse, France.
· pubmed
Evidence connecting skin aging to functional decline and systemic aging biomarkers is lacking. This study investigated how skin-aging biomechanics were associated with changes in intrinsic capacity (IC), a marker of healthy aging. We also explored their links with biological agin...
Evidence connecting skin aging to functional decline and systemic aging biomarkers is lacking. This study investigated how skin-aging biomechanics were associated with changes in intrinsic capacity (IC), a marker of healthy aging. We also explored their links with biological aging clocks (epigenetic and inflammatory clocks) and potential moderating effects on the skin-IC relationship. Baseline skin elasticity and viscoelasticity were measured in 441 INSPIRE-T participants aged 20 to 93 (59.9% women) using Cutometer parameters. IC was evaluated over 3 years as a five-domain score covering cognition, locomotion, psychology, vitality, and sensory (a higher score indicated better). Biological aging was measured at baseline using six epigenetic clocks (Horvath pan-tissue, Horvath skin & blood, Hannum, PhenoAge, GrimAge, and DunedinPACE) and inflammatory clock (iAge). Poor skin elasticity and viscoelasticity in older adults were associated with lower baseline IC after controlling for demographic, medical, and lifestyle factors. Longitudinally, older men with a higher viscoelastic ratio (R6) experienced a faster decline in IC (a standardized coefficient [95% CI] ranged from -0.37 [-0.72, -0.03] at age 62 to -1.32 [-1.91, -0.73] at age 93). Accelerated iAge was associated with reduced skin elasticity (R2, R5, R7). Moreover, the association between parameters related to elastic recovery (R5, R7) and baseline IC became more pronounced as accelerated iAge increased. This is the first study demonstrating the association between skin-aging biomechanics and IC. Poor skin elasticity was associated with higher systemic inflammation. Therefore, skin biomechanical properties may reflect overall functional aging, with inflammation serving as a common underlying factor.
Longevity Relevance Analysis
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The paper claims that poor skin biomechanical properties are associated with lower intrinsic capacity and higher systemic inflammation in older adults. This research is relevant as it explores the connections between skin aging, functional decline, and biological aging markers, contributing to the understanding of aging mechanisms.
Andrea Castegnaro, Alexander Dior, Neil Burgess ...
· Psychology and aging
· Institute of Cognitive Neuroscience, University College London.
· pubmed
Navigational skills are essential for interacting with our environment, supported by multiple types of spatial representations. We investigated age-related differences in spatial memory using a virtual reality task that manipulated viewpoints between the encoding and retrieval of...
Navigational skills are essential for interacting with our environment, supported by multiple types of spatial representations. We investigated age-related differences in spatial memory using a virtual reality task that manipulated viewpoints between the encoding and retrieval of one or four-object locations. The task investigates compensatory mechanisms in aging, specifically how spatial updating via self-motion affects spatial memory. We tested 21 young adults (ages 19-36) and 23 older adults (ages 63-80). The task involved three movement conditions: same-viewpoint condition, where participants walked away and returned to the same viewpoint; shifted-viewpoint (walking) condition where participants walked to a different viewpoint, enabling continuous updates of their egocentric representations through self-motion; and shifted-viewpoint (teleport) condition where participants teleported to the other viewpoint, involving both a virtual translation and rotation of the participant's view. Retrieval was tested by asking participants to place each object at its previously seen location. Average displacement error was affected by age group, object configuration, and movement condition, with an interaction between age and movement condition. Differences in movement conditions were primarily driven by older participants, who were most accurate from the same viewpoint. In shifted-viewpoint conditions, teleportation-where self-motion cues were absent-led to significantly greater errors than walking in the older group. Our results highlight the role of spatial updating in supporting spatial memory and suggest that age-related decline in allocentric representations can be mitigated by continuous updating of egocentric representations by self-motion. We speculate that the use of spatial updating might be impaired early in the progression to Alzheimer's dementia due to entorhinal cortical pathology. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
Longevity Relevance Analysis
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The paper claims that spatial updating via self-motion can mitigate age-related decline in allocentric spatial memory. This research is relevant as it explores cognitive mechanisms that could potentially address aspects of aging and their implications for conditions like Alzheimer's disease.
Raymond Laboy, Marjana Ndoci, Shamsh Tabrez Syed ...
· Hexokinase
· Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany.
· pubmed
The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in
The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in
Longevity Relevance Analysis
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Hexokinase regulates Mondo-mediated longevity through the pentose phosphate pathway and organellar dynamics. The paper addresses mechanisms that may influence longevity pathways, which is directly related to understanding and potentially mitigating the aging process.
Yuko Maejima, Shoko Yokota, Megumi Yamachi ...
· Aging cell
· Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan.
· pubmed
While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation...
While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation on improving age-related decline of neural function. Comparing young (9 weeks) and aged (> 45 weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs-CRP, and decreased OXT-positive neurons in the hypothalamus. Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten-eleven translocation (TET) family mRNA expression, decreased 5-hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10 μg/day) for 10 days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT-positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression. Directly confirming a role for OXTR signaling, TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) null mice, compared with age-matched WT mice. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.
Longevity Relevance Analysis
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Oxytocin supplementation can reverse age-related declines in neural function by enhancing demethylation through TET enzyme expression. The study addresses the mechanisms of aging and suggests a potential intervention to mitigate age-related decline, making it relevant to longevity research.
The MULTI Study, , O'Toole, C. K., Song, Z. ...
· health informatics
· Columbia University
· medrxiv
Optimal sleep plays a vital role in promoting healthy aging and enhancing longevity. This study proposes a Sleep Chart to assess the relationship between sleep duration and 23 biological aging clocks across 17 organ systems or tissues and 3 omics data types (imaging, proteomics, ...
Optimal sleep plays a vital role in promoting healthy aging and enhancing longevity. This study proposes a Sleep Chart to assess the relationship between sleep duration and 23 biological aging clocks across 17 organ systems or tissues and 3 omics data types (imaging, proteomics, and metabolomics). First, a systemic, U-shaped pattern shows that both short (<6 hours) and long (>8 hours) sleep duration are linked to elevated biological age gaps (BAGs) across 9 brain and body systems and 3 omics types, with optimal sleep time varying by organ and sex ([6.4-7.8] hours). Furthermore, short and long sleep duration, compared to a normal sleep duration ([6-8] hours), are consistently linked to increased risk of systemic diseases beyond the brain and all-cause mortality, with evidence from genetic correlations and time to incident disease predictions, such as migraine, depression, and diabetes. Finally, short and long sleep duration are associated with late-life depression via distinct pathways: long sleep may contribute indirectly through biological aging processes, while short sleep shows a more direct link. Although our Mendelian randomization does not show strong causal effects from disease to sleep disturbances, it does not fully rule out the possibility that sleep disturbances may, in part, reflect underlying disease burden. Our findings suggest that the U-shaped relationship is likely driven by modifiable sleep disturbances rather than genetic predisposition, highlighting the potential of sleep optimization to support healthy aging, lower disease risk, and extend longevity. An interactive web portal is available to explore the Sleep Chart at: https://labs-laboratory.com/sleepchart.
Longevity Relevance Analysis
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The study identifies a U-shaped relationship between sleep duration and biological aging clocks across various organ systems, suggesting that optimizing sleep can support healthy aging and lower disease risk. The paper is relevant as it explores modifiable factors that may influence biological aging and longevity, rather than merely addressing symptoms of age-related diseases.
Ying Huang, Zhenxing Zhou, Mengjia Huan ...
· Aging cell
· The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, P. R. China.
· pubmed
Antioxidant decline is crucial to driving age-related macular degeneration (AMD). Ferroptosis, a regulated cell death mediated by iron-dependent hydroxyl radical-catalyzed phospholipid peroxidation through the Fenton reaction, is implicated in various chronic degenerative disease...
Antioxidant decline is crucial to driving age-related macular degeneration (AMD). Ferroptosis, a regulated cell death mediated by iron-dependent hydroxyl radical-catalyzed phospholipid peroxidation through the Fenton reaction, is implicated in various chronic degenerative diseases. Here, we show that superoxide activates ferroptosis in retinal pigment epithelium (RPE) cells via the Haber-Weiss reaction, thereby contributing to dry AMD. We silenced manganese superoxide dismutase (MnSOD/SOD2) in RPE cells and exposed the cells to blue light to induce ferroptosis by increasing superoxide anions. Additionally, MnSOD deficiency triggered the Hsp70-linked ubiquitin-dependent degradation of GPX4, further aggravating ferroptosis. We validated blue light-induced ferroptosis in the RPE layer as a driver of the dry AMD phenotype in Sod2
Longevity Relevance Analysis
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Superoxide activates ferroptosis in retinal pigment epithelium cells, contributing to age-related macular degeneration. The study addresses a mechanism related to oxidative stress and cell death in the context of aging, which is relevant to understanding and potentially mitigating age-related diseases.
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. [email protected].
· 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.
Saptashwa Datta, Jen-Chieh Yu, Yi-Hsiang Lin ...
· Machine Learning
· Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
· pubmed
Aging is a natural phenomenon characterized by the loss of normal morphology and physiological functioning of the body, causing wrinkles on the skin, loss of hair, and compromised immune systems. Peptide therapies have emerged as a promising approach in aging studies because of t...
Aging is a natural phenomenon characterized by the loss of normal morphology and physiological functioning of the body, causing wrinkles on the skin, loss of hair, and compromised immune systems. Peptide therapies have emerged as a promising approach in aging studies because of their excellent tolerability, low immunogenicity, and high specificity. Computational methods can significantly expedite wet lab-based anti-aging peptide discovery by predicting potential candidates with high specificity and efficacy. We propose AAGP, an anti-aging peptide predictor based on diverse physicochemical and compositional features. Two datasets were constructed, both shared anti-aging peptides as positives, with the first using antimicrobial peptides as negatives and the second using random peptides as negatives. Peptides were encoded using 4,305 features, followed by adaptive feature selection with a heuristic algorithm on both datasets. Nine machine learning models were used for cross-validation and independent tests. AAGP achieves reasonably accurate prediction performance, with MCCs of 0.692 and 0.580 and AUCs of 0.963 and 0.808 on the two independent test datasets, respectively. Our feature importance analysis shows that physicochemical features are more crucial for the first dataset, whereas compositional features hold greater importance for the second. The source code of AAGP is available at https://github.com/saptawtf/AAGP .
Longevity Relevance Analysis
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The paper claims to present AAGP, a machine learning-based predictor for identifying anti-aging peptides. The research is relevant as it focuses on computational methods to discover peptides that may directly influence aging processes, rather than merely addressing age-related symptoms.
Jing-Yu Chang, Kuei-Ru Chou, Yu-Ling Chang ...
· Journal of physical activity & health
· Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
· pubmed
Cognitive frailty, defined by the coexistence of physical frailty and mild cognitive impairment, can be reversed through targeted interventions. This meta-analysis evaluated the efficacy of physical activity interventions on cognitive function and well-being in older adults with ...
Cognitive frailty, defined by the coexistence of physical frailty and mild cognitive impairment, can be reversed through targeted interventions. This meta-analysis evaluated the efficacy of physical activity interventions on cognitive function and well-being in older adults with frailty.
Longevity Relevance Analysis
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Physical activity interventions can improve cognitive function and well-being in older adults with cognitive frailty. This paper addresses cognitive frailty, which is a significant aspect of aging and seeks to improve the quality of life in older adults, thus contributing to longevity research.
Bo Ma, Yuanxin Miao, Yan Xu ...
· NPJ science of food
· School of Food and Biology, Jingchu University of Technology, Jingmen, PR China.
· pubmed
This study evaluated the in vitro and in vivo antioxidant activities of puerarin (PUE) and β-lactoglobulin (β-lg). The results of the in vitro antioxidant assay revealed that the DPPH and ABTS radical scavenging rates of the PUE/β-lg complex were generally superior to those of fr...
This study evaluated the in vitro and in vivo antioxidant activities of puerarin (PUE) and β-lactoglobulin (β-lg). The results of the in vitro antioxidant assay revealed that the DPPH and ABTS radical scavenging rates of the PUE/β-lg complex were generally superior to those of free PUE within the tested experimental concentration range. The in vivo antioxidant activity assay, using Caenorhabditis elegans (C. elegans) as a model organism, showed that the PUE/β-lg complex significantly increased the superoxide dismutase (SOD) activity and reduced glutathione (GSH) content in C. elegans, and also increased the mean lifespan of C. elegans under oxidative and thermal stress conditions. Transcriptomic analysis showed that the PUE/β-lg complex regulated the mRNA expression levels of genes associated with the activation of various signaling pathways, such as the longevity regulation pathway, insulin signaling pathway, and GSH metabolism. Overall, this study demonstrated the potential of the PUE/β-lg complex as an antioxidant, which can lead to its development into food products or pharmaceuticals.
Longevity Relevance Analysis
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The study claims that the puerarin-β-lactoglobulin complex enhances antioxidant activity and increases lifespan in C. elegans. This research is relevant as it explores mechanisms that may contribute to longevity and lifespan extension through antioxidant pathways.
Saha, S., Chakraborty, P., Roy, D. ...
· neuroscience
· Indian Institute of Technology Jodhpur
· biorxiv
Aging brain undergoes a structural decline over lifespan accompanied by changes in neurotransmitter levels, leading to altered functional markers. Past studies have reported human resting state brain display a remarkable preservation of coordination among neural assemblies stemmi...
Aging brain undergoes a structural decline over lifespan accompanied by changes in neurotransmitter levels, leading to altered functional markers. Past studies have reported human resting state brain display a remarkable preservation of coordination among neural assemblies stemming from an underlying neurocomputational principles along aging trajectories, however, the true nature of which remains unknown. Here, we identify the computational mechanisms with which neurotransmitters, such as altered GABA and glutamate concentrations, can preserve functional integration across lifespan aging, despite structural decline. We employ multiscale, biophysically grounded modeling, constrained by the empirically derived anatomical connectome of the human brain, where the neurotransmitter concentrations can be free parameters that are algorithmically adjusted to maintain regional homeostasis and optimal working point. The two estimated neurotransmitters can maintain critical firing rates in the brain region and mimic age-associated functional connectivity patterns, consistent with empirical observations. We identified invariant GABA and reduced glutamate as the principle computational mechanism that can explain the topological variation of functional connectivity along lifespan, validated using graph-theoretic metrics. The results are subsequently replicated on three distinct datasets. Thus, the study offers an operational framework that integrates brain network dynamics at macroscopic and molecular scales, to gain insight into age-associated neural disorders.
Longevity Relevance Analysis
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The paper claims that invariant GABA and reduced glutamate concentrations can preserve functional integration in the aging brain despite structural decline. This research is relevant as it explores the underlying mechanisms of neural dynamics in aging, potentially addressing root causes of age-related cognitive decline.
Jihwan Myung, Hélène Vitet, Sheena Yin Xin Tiong
· Aging
· Graduate Institute of Mind, Brain and Consciousness (GIMBC), Taipei Medical University, Taipei, Taiwan. [email protected].
· pubmed
Circadian freerunning periods change across the lifespan, yet most computational models do not reproduce these shifts without assuming additional mechanisms. Although the maturation and later deterioration of the suprachiasmatic nucleus (SCN) shape behavioral and humoral rhythms,...
Circadian freerunning periods change across the lifespan, yet most computational models do not reproduce these shifts without assuming additional mechanisms. Although the maturation and later deterioration of the suprachiasmatic nucleus (SCN) shape behavioral and humoral rhythms, the underlying driver of period change is more general. We show that it arises from an inherent property of a positively skewed frequency distribution, which naturally follows from a symmetric Gaussian distribution of intrinsic periods. Using a Kuramoto framework with a time-dependent coupling strength and age-related widening of period variability, we map the geometry of synchronization and macroscopic period and trace a developmental trajectory across this surface. Strong coupling in early adulthood pulls the synchronized period below the mean, matching data from C57BL/6 mice, whereas declining coupling and greater heterogeneity in late life lengthen the period and reduce amplitude. The same mechanism explains the negative correlation between amplitude and macroscopic period when period variability is high. This "circadian geometry" reveals that age-dependent variations in the macroscopic period are sufficiently explained by coupling and the width of the period distribution, and provides a parsimonious framework applicable to the SCN and other oscillator populations for understanding long-term changes in circadian dynamics during development and aging.
Longevity Relevance Analysis
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The paper claims that age-dependent variations in circadian period can be explained by coupling strength and period distribution width. This research addresses fundamental mechanisms of circadian rhythms that change with aging, which is relevant to understanding the biological processes underlying aging and potential interventions.
Junrui Wang, Haoyuan Tian, Yuanyuan Gao ...
· Research (Washington, D.C.)
· Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.
· pubmed
Activation of hepatic stellate cells (HSCs) represents a central pathological event in liver fibrogenesis, and targeted clearance of activated HSCs is considered to be a promising therapeutic strategy. However, our understanding of the underlying molecular mechanisms is limited. ...
Activation of hepatic stellate cells (HSCs) represents a central pathological event in liver fibrogenesis, and targeted clearance of activated HSCs is considered to be a promising therapeutic strategy. However, our understanding of the underlying molecular mechanisms is limited. Here, we report that Oroxylin A (OA) inhibited the activation of HSCs by inhibiting the dual roles of Sirtuin 7 (SIRT7). Single-cell transcriptome sequencing analysis and bioinformatics analysis were employed to identify critical pathways, followed by validation through molecular assays including Western blotting, immunofluorescence, and co-immunoprecipitation. In human samples, animal models, and primary cultures, the translational relevance of molecular discoveries was heightened. OA binds to the Gln299 and Asp305 residues of SIRT7, triggering a dual regulatory program in hepatic fibrosis. OA suppresses SIRT7, triggering succinylation-dependent proteasomal degradation of protein arginine methyltransferase 5 (PRMT5). This cascade attenuated symmetric dimethylation of cyclic GMP-AMP synthase (cGAS), thereby activating the cGAS-stimulator of interferon genes (STING) signaling and promoting HSC senescence. Concurrently, OA-elicited SIRT7 inhibition promotes externalized calreticulin (ecto-CRT) expression, thereby enhancing natural killer (NK) cell recognition and targeted elimination of activated HSCs. However, enzymatically dead mutant SIRT7 (H187Y) also suppressed ecto-CRT expression promoted by OA, showing that it is independent of its desuccinylase activity. Our findings reveal a dual regulatory mechanism whereby SIRT7 inhibition by OA coordinates PRMT5 degradation-mediated cellular senescence and ecto-CRT-dependent NK cell immune clearance of HSCs. This work establishes SIRT7 as a pivotal therapeutic target and provides mechanistic insights for developing antifibrotic strategies.
Longevity Relevance Analysis
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Oroxylin A inhibits SIRT7, leading to HSC senescence and enhanced NK cell clearance in liver fibrosis. The paper is relevant as it explores a potential therapeutic target (SIRT7) that could influence cellular aging processes and fibrosis, which are associated with age-related decline in liver function.
Weijia Zhang, Haoyu Ren, Wangwang Chen ...
· Cell death discovery
· The Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
· pubmed
Nicotinamide adenine dinucleotide (NAD⁺) is a critical coenzyme involved in cellular metabolism, energy balance, and various physiological processes. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in NAD⁺ synthesis, regulating the NAD⁺ regeneration p...
Nicotinamide adenine dinucleotide (NAD⁺) is a critical coenzyme involved in cellular metabolism, energy balance, and various physiological processes. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in NAD⁺ synthesis, regulating the NAD⁺ regeneration pathway. This review summarizes the multiple roles of NAMPT in both physiological and pathological states, particularly in cellular stress, aging, metabolic disorders, and cancer. We first describe the central role of NAMPT in NAD⁺ synthesis and explore how NAD⁺ levels are regulated through NAMPT to control cellular functions and metabolic adaptation. Second, we analyze the pathological roles of NAMPT in aging and related diseases, highlighting how NAD⁺ depletion leads to mitochondrial dysfunction, DNA damage, and immune system dysregulation. Notably, NAMPT exacerbates cancer immune evasion mechanisms by influencing immune cell functions and the metabolic environment of tumors. We also discuss the potential of NAMPT as a therapeutic target, particularly through NAD⁺ precursor supplementation or the use of NAMPT activators and inhibitors to modulate NAD⁺ metabolism in aging, metabolic diseases, and cancer. Future research should focus on exploring the functional differences of NAMPT in various tissues and its therapeutic potential in disease treatment.
Longevity Relevance Analysis
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Nicotinamide phosphoribosyltransferase (NAMPT) plays a crucial role in regulating NAD⁺ levels, which are essential for cellular functions and metabolic adaptation in aging and related diseases. The paper is relevant as it addresses the role of NAMPT in NAD⁺ synthesis and its implications for aging and metabolic disorders, focusing on potential therapeutic targets that could influence the aging process.
Faith Morley, Lauren Mount, Anjile An ...
· Allostasis
· Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, United States of America.
· pubmed
The rising prevalence of individuals reporting extreme stress has major public health implications as it increases vulnerability to accelerated premature biological aging, thus increasing risk of chronic disease. To examine the impact of stress on premature biological aging, we a...
The rising prevalence of individuals reporting extreme stress has major public health implications as it increases vulnerability to accelerated premature biological aging, thus increasing risk of chronic disease. To examine the impact of stress on premature biological aging, we assessed the association between exposure to increased stress, quantified by the Perceived Stress Scale, and odds of high allostatic load (AL). To illuminate previously unexplored socio-contextual factors, we controlled for self-reported individual and neighborhood social determinants of health that included discrimination, loneliness, food insecurity, neighborhood disorder, and neighborhood social cohesion. We utilized a cross-sectional design to examine the association between perceived stress and AL among 7,415 participants ages 18-65 in the All of Us Research Program, who enrolled from 2017-2022. We used logistic regression to evaluate the association between stress and high AL, controlling for sociodemographic factors and self-reported social determinants of health. Participants who were younger, receiving Medicaid, or Hispanic had increased prevalence of high stress. High stress was associated with elevated odds of high AL in age and sex-adjusted models (OR=2.18, 95%CI = 1.78, 2.66, high stress vs. low), an association which remained significant after adjusting for social determinants of health (OR=1.29, 95%CI = 1.01, 1.65). Using restricted cubic splines, high stress was significantly associated with increased odds of high AL, even after controlling for upstream individual and neighborhood-level determinants of health. While individuals living below the medium poverty-to-income ratio demonstrated little appreciable association between high stress and increased odds of high allostatic load, those living above the median poverty-to-income ratio reporting increased stress appeared to have increased odds of high allostatic load. Through addressing the upstream factors causing undue burdens of stress, which particularly affect marginalized communities and younger generations, we can begin to address premature biological aging and the comorbid conditions it accompanies.
Longevity Relevance Analysis
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High perceived stress is associated with increased odds of high allostatic load, particularly among marginalized communities. The paper addresses upstream factors contributing to stress and their impact on biological aging, which is relevant to understanding and potentially mitigating the root causes of aging.
Marena Gray, Oliver Boughton, Crispin Wiles ...
· Hip Fractures
· MSk Laboratory, Sir Michael Uren Hub, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W12 0BZ, UK. [email protected].
· pubmed
Microdefects, including microcracks and resorption trenches, may be important contributors to bone fragility. 3D microdefect morphology was imaged using synchrotron micro-CT to develop a classification system for investigating the relationship with bone mechanics and hip-fracture...
Microdefects, including microcracks and resorption trenches, may be important contributors to bone fragility. 3D microdefect morphology was imaged using synchrotron micro-CT to develop a classification system for investigating the relationship with bone mechanics and hip-fractures. Femoral heads from ageing hip-fracture patients (n = 5, 74-82 years) were compared to ageing non-fracture controls (n = 5, 72-84 years). Two trabecular cores were prepared from the chiasma; one was imaged using synchrotron micro-CT to measure microdefects and one was mechanically tested to measure tensile strength. Morphological and mechanical data were compared and correlated using Mann Whitney U test and Pearson's rank correlation. All the procedures performed were in accordance with the ethical standards of the Imperial College Tissue Bank (R13004) and the 1984 Declaration of Helsinki. Microdefects varied and were classified into four categories based on shape and measurable parameters. Hip-fracture donors exhibited significantly higher density of all microdefects (p < 0.05). Microdefect volume was strongly negatively correlated with ultimate tensile strength (p < 0.05) and stiffness (p < 0.05). Microdefects might contribute to loss of bone strength and fragility fracture via runaway resorption. Microcracks could promote focussed osteoclastic resorption and the formation of resorption pits which create stress risers leading to the re-formation of microcracks under continued load. CT-based classification methods should be used to explore the complex interaction between microdefects, metabolism, and bone fracture mechanics.
Longevity Relevance Analysis
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Microdefects in bone contribute to loss of strength and fragility fractures in aging patients. The study addresses the underlying mechanisms of bone fragility, which is a significant aspect of age-related health decline.
Francesco Neri, Shuyuan Zheng, Mark A Watson ...
· Aging
· Buck Institute for Research on Aging, Novato, CA 94945 , USA.
· pubmed
Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies ident...
Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2-arrested senescent cells feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.
Longevity Relevance Analysis
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G2-arrested senescent cells exhibit higher senescence marker expression and are more sensitive to senolytic treatment compared to G1-arrested cells. This study is relevant as it explores the heterogeneity of senescent cells, which is crucial for understanding and potentially targeting the root causes of aging and age-related diseases through senolytic therapies.
Domenico Azarnia Tehran, Paola Pizzo
· Aging
· Department of Biomedical Sciences, University of Padua, Padua, Italy. [email protected].
· pubmed
To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for c...
To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for cellular communication, mediating a broad range of physiological processes, including calcium signalling, lipid synthesis and bioenergetics. MCS are particularly abundant and indispensable in polarized and long-lived cells, such as neurons, where they support both structural and functional integrity. In this review, we explore the functional diversity, molecular composition, and dynamic regulation of key mammalian MCS: endoplasmic reticulum (ER)-plasma membrane, ER-mitochondria and contact sites involving lipid droplets. We highlight their central role in neuronal health and discuss how MCS dysfunction has increasingly been recognized as a hallmark of brain aging and various neurodegenerative diseases, most notably Alzheimer's disease, where altered MCS dynamics contribute to pathogenesis. Finally, we emphasize the therapeutic potential of targeting MCS and outline key unanswered questions to guide future research.
Longevity Relevance Analysis
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The paper claims that dysfunction of membrane contact sites (MCS) contributes to brain aging and neurodegeneration. The focus on MCS as a potential root cause of neurodegenerative diseases aligns with longevity research by exploring mechanisms that could influence aging processes.
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.
Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at...
Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at 3 time points corresponding to the peak of fibrosis, regeneration, and resolution. We find that lung injury shifts the transcriptomic profiles of three pulmonary capillary endothelial cells (PCEC) subpopulations. The associated signatures are linked to pro-angiogenic signaling with strong Lrg1 expression and do not progress similarly throughout the resolution process between young and old animals. Moreover, part of this set of resolution-associated markers is also detected in PCEC from samples of patients with idiopathic pulmonary fibrosis. Finally, we find that aging also alters the transcriptome of PCEC, which displays typical pro-fibrotic and pro-inflammatory features. We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation, thus contributing to the persistent fibrotic process typical of human pathology.
Longevity Relevance Analysis
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Aging alters the transcriptome of pulmonary capillary endothelial cells, impacting their role in lung injury resolution and fibrosis. The study addresses age-related changes in cellular mechanisms that contribute to fibrotic diseases, which is relevant to understanding the biological processes of aging and potential interventions.
Naru Sato, Susumu Goyama, Toshio Kitamura
· International journal of hematology
· Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. [email protected].
· pubmed
Clonal hematopoiesis (CH) is defined as the age-associated expansion of hematopoietic stem and progenitor cells harboring somatic mutations, most frequently in epigenetic regulators such as DNMT3A, TET2, and ASXL1. Although CH was initially recognized as a precursor to hematologi...
Clonal hematopoiesis (CH) is defined as the age-associated expansion of hematopoietic stem and progenitor cells harboring somatic mutations, most frequently in epigenetic regulators such as DNMT3A, TET2, and ASXL1. Although CH was initially recognized as a precursor to hematological malignancies, accumulating evidence has led to its broad recognition as a relevant factor in various age-related nonmalignant diseases, particularly those with inflammatory components, such as cardiovascular disease, autoimmune disorders, and solid tumors. Notably, the increased overall mortality associated with CH is primarily driven by cardiovascular complications rather than hematological malignancies. Among CH-associated genes, ASXL1 mutations are distinguished by their strong associations with adverse clinical outcomes and pro-inflammatory signatures. However, compared to TET2 and DNMT3A, the molecular and pathological implications of ASXL1-mutated CH remain underexplored. Recent studies have expanded the disease spectrum of ASXL1 mutations beyond hematological malignancies, implicating them in clonal expansion and systemic inflammation. This review aims to summarize the current epidemiological and experimental insights into ASXL1-mutated CH, focusing on its potential contributions to inflammation-associated diseases. By integrating clinical observations and emerging mechanistic data, we highlight the urgent need for deeper investigation into ASXL1-driven CH and its systemic consequences beyond hematological transformation.
Longevity Relevance Analysis
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ASXL1 mutations in clonal hematopoiesis are linked to increased mortality and systemic inflammation in age-related diseases. The paper is relevant as it explores the underlying mechanisms of clonal hematopoiesis, which may contribute to the aging process and age-related diseases, rather than merely addressing symptoms.
van den Belt, M., van de Put, M., Yüksel, E. ...
· nutrition
· Vrije Universiteit Amsterdam, The Netherlands
· medrxiv
A randomized, placebo-controlled citizen science-based dietary intervention was conducted among 147 healthy adults to evaluate the effects of 8-week high dietary fiber (HDF) and high fermented food (HFF) diets on gut microbiota, immune function, gut transit time, well-being, and ...
A randomized, placebo-controlled citizen science-based dietary intervention was conducted among 147 healthy adults to evaluate the effects of 8-week high dietary fiber (HDF) and high fermented food (HFF) diets on gut microbiota, immune function, gut transit time, well-being, and sleep quality. The HDF group significantly increased fiber intake ({Delta}10.3 g/1000 kcal/day) following high dietary fiber recipes with addition of dried chicory root, while the HFF group increased fermented food consumption (+6.3 portions/day), including a fermentation-derived liquid supplement. At the 21-week follow-up, modest improvements in fiber and fermented intake were sustained, compared to baseline. Microbial diversity significantly increased within the HFF and control groups, especially in HFF participants over 50 (p = 0.04). Compared to CG, HFF showed no difference in microbial diversity, whereas the HDF group showed a significant decrease. The HDF intervention enhanced butyrogenic potential by increasing Anaerostipes, Faecalibacterium, and Bifidobacterium spp., and significantly reduced gastrointestinal transit time (p = 0.01). The intake of high fiber improved and sustained sleep quality (p = 0.03). The HFF intervention significantly increased blood immune markers including CD5, CD6 and CD8A (T-cell activation), IL-18R1 (inflammatory signaling) and SIRT2, a longevity-associated deacetylase (Q < 0.05), and induced a modest shift in the gut microbiota of participants over 50 years toward a composition characteristic of younger participants. These findings highlight distinct biological pathways through which dietary fibers and fermented foods modulate host physiology. This is the first randomized controlled nutritional intervention using a citizen science approach that demonstrates the feasibility and scientific value of engaging participants in healthier food choices.
Longevity Relevance Analysis
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The paper claims that high-fiber and fermented-food diets can modulate gut microbiota and immune function, potentially influencing longevity-related biological pathways. The study explores dietary interventions that may address underlying mechanisms of aging through gut health and immune modulation, which are relevant to longevity research.
Lingling Wu, Xiang Zhu, Yanxia Liu ...
· Cellular Senescence
· Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
· pubmed
Aging is a major risk factor for chronic diseases and cancer. Cellular aging, particularly in adult stem cells, offers a high-throughput framework for dissecting the molecular mechanisms of aging.
Aging is a major risk factor for chronic diseases and cancer. Cellular aging, particularly in adult stem cells, offers a high-throughput framework for dissecting the molecular mechanisms of aging.
Longevity Relevance Analysis
(4)
The paper claims to identify aging and inflammatory aging signatures through CRISPRi screens. This research is relevant as it aims to dissect the molecular mechanisms of aging, which could contribute to understanding and potentially addressing the root causes of aging.
Yichu Fu, Binhan Wang, Aqu Alu ...
· Signal Transduction
· College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
· pubmed
Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immun...
Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels. Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials. In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.
Longevity Relevance Analysis
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The paper discusses the mechanisms of immunosenescence and potential interventions to mitigate its effects on age-related diseases. This research is relevant as it addresses the underlying causes of aging-related immune dysfunction, which is crucial for developing strategies to promote longevity and improve healthspan.
Yi Xiang, Qiong Meng, Zitong Huang ...
· Aging
· School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
· pubmed
Biological aging is a heterogeneous process that varies across organs and systems. The dynamic hormonal changes during the menopausal transition may have profound and organ-specific impacts on biological aging. However, the relationship between the menopausal transition and both ...
Biological aging is a heterogeneous process that varies across organs and systems. The dynamic hormonal changes during the menopausal transition may have profound and organ-specific impacts on biological aging. However, the relationship between the menopausal transition and both comprehensive and organ-specific biological aging remains poorly understood. This study aimed to investigate the associations between menopausal factors and both comprehensive and organ-specific biological aging, as well as the modifying role of reproductive history.
Longevity Relevance Analysis
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The paper investigates the associations between menopausal factors and biological aging across multiple organ systems. This research is relevant as it explores the hormonal changes during menopause and their potential impact on biological aging, which aligns with understanding the mechanisms of aging and longevity.
Aurel Popa-Wagner, Dirk M Hermann, Thorsten R Doeppner ...
· Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
· Chair of Vascular Neurology and Dementia, Department of Neurology, University Hospital Essen, Essen, Germany.
· pubmed
Older individuals are typically more susceptible to stroke, and age-related differences in brain plasticity significantly affect recovery and treatment responses following cerebral ischemia and traumatic brain injury. Extracellular vesicles (EVs) have emerged as promising diagnos...
Older individuals are typically more susceptible to stroke, and age-related differences in brain plasticity significantly affect recovery and treatment responses following cerebral ischemia and traumatic brain injury. Extracellular vesicles (EVs) have emerged as promising diagnostic and therapeutic tools due to their role in intercellular communication and ability to cross the blood-brain barrier. While EVs hold potential in promoting brain repair, their efficacy is influenced by donor age-those derived from young stem cells exhibit more regenerative profiles, whereas aged donor EVs may carry senescence-related signals that impede recovery. Emerging therapies, including senolytics, exosome-based approaches, and immune modulation, aim to enhance post-stroke repair, yet a substantial translational gap persists, especially in adapting these strategies to the aged brain. Differences in immune responses, neurovascular integrity, and repair mechanisms between young and aged individuals further complicate therapeutic development. Incorporating aged animal models in preclinical research is thus essential for ensuring the relevance and safety of interventions in elderly patients. These findings underscore the need for age-tailored strategies that reflect the unique biological landscape of aging, paving the way for more effective treatments for stroke and related neurological conditions in older adults.
Longevity Relevance Analysis
(4)
The paper claims that age-related differences in neuroplasticity significantly affect recovery from stroke, and that extracellular vesicles derived from younger donors may enhance post-stroke repair in older individuals. This research is relevant as it addresses the biological mechanisms underlying aging and their implications for therapeutic strategies aimed at improving recovery in age-related conditions.
Nazma Malik, Reuben J Shaw
· Annual review of cell and developmental biology
· 1Metabolism in Immunity, Cancer & Aging Group, MRC Laboratory of Medical Sciences, Imperial College London, London, United Kingdom; email: [email protected].
· pubmed
Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of euk...
Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.
Longevity Relevance Analysis
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The paper claims that AMPK modulates mitochondrial health and metabolic adaptations. The focus on AMPK as a central regulator of energy metabolism and mitochondrial function is relevant to understanding the mechanisms of aging and potential interventions for longevity.
Najm Ul Hassan, William Kojo Smith, Hafiza Ayesha Nawaz ...
· Longevity
· Center for Circadian Clocks, Soochow University, Suzhou, China.
· pubmed
The desire to increase life expectancy, coupled with the decline in biological functions that occurs as we age, represents one of the most significant challenges facing our society. Age-related declines in biological functions contribute to frailty and morbidity, demanding innova...
The desire to increase life expectancy, coupled with the decline in biological functions that occurs as we age, represents one of the most significant challenges facing our society. Age-related declines in biological functions contribute to frailty and morbidity, demanding innovative strategies to promote healthy aging. The circadian clock, which controls daily physiological processes, is intricately linked to aging and overall health. Circadian disruptions can lead to metabolic dysfunction, impaired immune responses, increased DNA damage, and elevated disease susceptibility. On the other hand, maintaining robust circadian rhythms through interventions such as regular sleep-wake patterns, time-restricted feeding, and physical activity may extend health span and longevity. The circadian clock affects various molecular pathways associated with aging, including the insulin/IGF, mTOR, and sirtuin signaling pathways. Enhancing circadian rhythms presents a promising avenue for mitigating age-related disorders and promoting healthy aging. This review highlights the potential of circadian clock-based interventions as a transformative strategy to improve the quality of life and extend the healthspan of aging individuals.
Longevity Relevance Analysis
(4)
Resetting our circadian clock through various interventions may extend healthspan and longevity. The paper discusses the relationship between circadian rhythms and aging, focusing on how maintaining robust circadian rhythms can mitigate age-related disorders, which aligns with the goal of addressing the root causes of aging.
Shinji Nakamichi, Leo Yamada, Christopher Roselle ...
· GeroScience
· Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
· pubmed
Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while ...
Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.
Longevity Relevance Analysis
(4)
The paper claims that Δ133p53α can enhance cancer immunotherapy and improve therapeutic approaches for diseases associated with cellular senescence. This research is relevant as it explores a potential mechanism to mitigate the effects of cellular senescence, which is a key contributor to aging and age-related diseases.