Longevity Papers

This study reveals that acute aerobic exercise enhances memory formation through a controlled DNA damage mechanism, offering crucial insights into Alzheimer\'s disease (AD) prevention. This work challenges the traditional view that DNA damage is inherently harmful, demonstrating that minor, reversible DNA single-strand breaks (SSBs) induced by exercise serve as necessary primers for memory consolidation - a mechanism that may be impaired in AD pathogenesis. AD affects 1 in 9 adults over 65, with ~95% being late-onset cases where up to 40% of risk factors are modifiable through lifestyle interventions like exercise. While exercise demonstrably lowers AD risk, underlying mechanisms remain unclear. This study provides a missing mechanistic link by showing how exercise-induced DNA damage repair systems could counteract the DNA damage accumulation and repair dysregulation that are established hallmarks of brain aging and AD. In data presented herein, young mice showed significantly higher SSB rates in active genomic regions compared to aged mice, suggesting the decline of a protective mechanism (i.e., hormesis) with aging - potentially explaining increased AD susceptibility in older adults. The present study also suggests that exercise-induced SSBs are not random cellular damage but precisely targeted events that occur at genes essential for neuroplasticity, synaptic function, and memory formation. These breaks activate PARP1 (Poly ADP ribose polymerase 1), a crucial DNA damage sensor that simultaneously initiates repair processes while facilitating transcriptional programs necessary for memory consolidation. This mechanism may represent how exercise \"primes\" the brain against the pathological DNA damage accumulation seen in AD. In support of this, in behavioral experiments, a single exercise bout converted sub-threshold learning into robust long-term memory formation. This memory enhancement correlated with upregulation of both neurotrophic genes (BDNF, Fos) and DNA repair enzymes (PARP1, PARP2), demonstrating coordinated damage-repair processes that appear compromised in AD. We identify HPF1 as a critical cofactor enabling PARP1 to perform trans-ADP-ribosylation of histones, linking DNA damage sensing to epigenetic chromatin remodeling required for memory-related gene expression. This pathway represents a novel therapeutic target for AD, as restoring efficient DNA repair mechanisms might slow or prevent memory loss.

Aging represents a major risk for human neurodegenerative disorders, such as dementia and Alzheimer's disease, and is associated with a functional decline in neurons and impaired synaptic plasticity, leading to a gradual decline in memory. Previous research has identified molecular and functional changes associated with aging through transcriptomic studies and neuronal excitability measurements, while the role of chromatin-level regulation in vulnerability to aging-related diseases is not well understood. Moreover, the causal relationship between molecular alterations and aging-associated decline in functions of different cell types remains poorly understood. Here, we systematically characterized gene regulatory networks in a cell type-specific manner in the aging mouse hippocampus, a central brain region involved in learning and memory formation, by simultaneously profiling gene expression and chromatin accessibility at a single-nucleus level. The analysis of multiome (RNA and ATAC) sequencing recapitulated the diversity of glial and neuronal cell types in the hippocampus and revealed transcriptomic and chromatin accessibility level changes in different cell types, among which oligodendrocytes and dentate gyrus (DG) neurons exhibited the most drastic changes. We found pronounced aging-dependent chromatin-level changes among neurons, especially for genes related to synaptic plasticity. Our data suggest that BACH2, a candidate transcription factor implicated in aging-mediated functional decline of DG neurons, potentially regulates genes associated with synaptic plasticity, cell death, and inflammation during aging. Taken together, our single-nucleus multiome analysis reveals potential cell type-specific regulators involved in the aging of neurons and glial cells.

Understanding how the brain changes with age remains a central question in neuroscience. Here, we combine magnetoencephalography (MEG) recordings from young and older adults with a whole-brain dynamical model to explore how brain dynamics evolve across the lifespan. Using a network of coupled Stuart-Landau oscillators constrained by empirical structural connectivity, we systematically vary three model parameters to identify the settings that best reproduce alpha-band features observed in MEG data. Our findings reveal age-related shifts in these model parameters: older individuals exhibit stronger global coupling and more positive values of the bifurcation parameter, consistent with a transition to a supercritical regime. These results align with prior work suggesting altered excitation-inhibition balance in ageing and indicate a systematic reconfiguration of whole-brain dynamics. By situating empirical observations within a dynamical systems framework, this study provides a principled approach for quantifying the brains distance to criticality and lays the groundwork for future clinical applications.

Much focus has shifted towards understanding how glial dysfunction contributes to age-related neurodegeneration due to the critical roles glial cells play in maintaining healthy brain function. Cell-cell interactions, which are largely mediated by cell-surface proteins, control many critical aspects of development and physiology; as such, dysregulation of glial cell-surface proteins in particular is hypothesized to play an important role in age-related neurodegeneration. However, it remains technically difficult to profile glial cell-surface proteins in intact brains. Here, we applied a cell-surface proteomic profiling method to glial cells from intact brains in Drosophila, which enabled us to fully profile cell-surface proteomes in-situ, preserving native cell-cell interactions that would otherwise be omitted using traditional proteomics methods. Applying this platform to young and old flies, we investigated how glial cell-surface proteomes change during aging. We identified candidate genes predicted to be involved in brain aging, including several associated with neural development and synapse wiring molecules not previously thought to be particularly active in glia. Through a functional genetic screen, we identified one surface protein, DIP-{beta}, which is down-regulated in old flies and can increase fly lifespan when overexpressed in adult glial cells. We further performed whole-head single-nucleus RNA-seq, and revealed that DIP-{beta} overexpression mainly impacts glial and fat cells. We also found that glial DIP-{beta} overexpression was associated with improved cell-cell communication, which may contribute to the observed lifespan extension. Our study is the first to apply in-situ cell-surface proteomics to glial cells in Drosophila, and to identify DIP-{beta} as a potential glial regulator of brain aging.

Advanced aging is accompanied by marked declines in motor performance in males and females including reductions in strength, speed and power of limb muscles that begin as early as midlife (∼>40 years) and accelerate from ∼65 years of age. Low muscle power and strength is exacerbated by increased fatigability with aging of limb muscles during dynamic contraction tasks and larger performance variability (between and within older adults), especially in older females. Starting in midlife, females exhibit earlier and larger age-related reductions in muscle strength and power and athletic performance than males of the same age and this is paralleled by increased prevalence of poor health, frailty, and loss of independence. This review presents evidence of key neural and muscular mechanisms affecting the motor unit, the age-related reductions in motor performance and the increased variability in healthy old and very old males and females. Muscular atrophy, particularly of fast-twitch (Type II) fibers, contractile slowing, degradation of neuromuscular junctions, and impairments in motor unit activation collectively underpin sarcopenia and impaired motor and functional performance among older adults. This review also briefly highlights approaches to understanding the protective effects of physical activity and high-resistance training on the age-related changes in muscle and neural function, even in the oldest adults. Such interventions delay functional declines and emphasize the adaptability of the aging neuromuscular system. Opportunities abound for future research to focus on understanding the specific mechanisms driving neural and muscular degeneration and optimizing exercise strategies to improve neuromuscular health of old males and females.

Circadian time keeping system (CTS) consisting of network of central and peripheral clocks regulates physiological, metabolic, and behavioural processes in alignment with the 24 hour. Desynchrony between central and peripheral clocks contributes to the pathogenesis of age-related conditions such as metabolic syndrome, cognitive decline, immune dysfunction, and neurodegenerative diseases etc. Sex-specific susceptibilities further modulate circadian resilience, with hormonal changes and redox imbalances playing key roles in the aging trajectory. Immune senescence and hormonal dampening, particularly in cortisol and melatonin rhythms, exacerbate circadian misalignment, accelerating systemic decline with aging. Interestingly, aging and clock dysfunction is a bidirectional process, i.e. aging progressively influences circadian rhythms across multiple levels and vice versa, from the molecular architecture of core clock gene feedback loops to the functionality of the central pacemaker-the suprachiasmatic nucleus (SCN)-and its coordination with peripheral oscillators. This review critically highlights the complex alterations in circadian mechanisms associated with aging, including diminished transcriptional rhythmicity, epigenetic drift, mitochondrial desynchronization, and disruptions in neurotransmitter systems. Such changes in turn leads to weakened SCN output, impaired photic entrainment, and loss of temporal coherence across organ systems. Further, this review demonstrates CTS and aging at multiple levels such as behavioural, physiological, biochemical and molecular levels are linked in push-pull mechanism i.e., the breakdown in the harmony of circadian rhythms at systemic level pushes the organism towards early aging and aging in turn is linked to CTS disorders.

Microbial genetic variation plays a crucial role in shaping host-microbe interactions; however, its impact on healthy aging remains largely unexplored. This study investigates how genetic variations in gut-residing Saccharomyces cerevisiae affect the health and lifespan of Drosophila melanogaster. This study identifies 14 yeast mutants that significantly extended the lifespan of D. melanogaster, with 13 mutants enhancing locomotor function in aged flies and two mutants improving reproductive capacity. Metabolomic and proteomic analyses reveal that these mutant yeasts rejuvenate the metabolic state of the aging gut and alter protein levels in tissues outside the gut. Most of the proteins with at least a two-fold change are upregulated. The data also highlights mitochondrial energy metabolism as a key anti-aging mechanism driven by the yeast. Notably, terpenoid metabolites such as ergosterol acetate showed strong lifespan-extending effects and may influence energy metabolism. In conclusion, these findings establish a strong link between gut metabolic status and healthy aging, underscoring the significance of the microbial-host mitochondrial axis as a key mechanism by which gut microbes promote host health and longevity. Furthermore, genetically engineered probiotics in model organisms offer a promising potential strategy for extending healthy lifespan, thus meriting further investigation in translational research models.

Aging affects multiple organs and within the brain drives distinct molecular changes across different cell types. The striatum encodes motor behaviors that decline with age, but our understanding of how cells within the striatum change remains incomplete. Using single-cell RNA sequencing from young and aged mice we identify molecularly distinct astrocyte subtypes. We show that astrocytes change significantly with age, exhibiting downregulation of genes, reduced diversity, and a shift to more homogenous inflammatory transcriptomic profiles. By exploring where striatal astrocyte subtypes are located with single-cell resolution, we map astrocytes enriched in dorsal, medial, and ventral striatum. Age increases inflammatory marker transcripts in dorsal striatal astrocytes, which display greater age-related changes than ventral striatal astrocytes. We impute molecular interactions between astrocytes and neurons and find that age particularly reduced interactions related to Nrxn2. Our data show that aging alters regionally enriched striatal astrocytes asymmetrically, with dorsal striatal astrocytes exhibiting greater age-related molecular changes.

Aging negatively impacts proteasome activity and/or content, and this impairment contributes to disrupted protein homeostasis and cellular dysfunction. However, little is known about proteasome complex dynamics during aging, particularly in the context of immunosenescence. Indeed, only limited data are available on the immunoproteasome, a specialized variant expressed in immune cells. We establish an in vitro model of monocyte-derived human macrophages that develop a senescence-like phenotype upon long-term culture. Our data demonstrate that immunoproteasome complexes undergo deep structural and functional alterations, with the downregulation of immunosubunit expression at the mRNA and protein level, uncapping of the 20S catalytic particle by the PA28αβ regulator, and loss of activity. Immunosubunits are partly replaced by their constitutive counterparts with a shift toward the building of 19S-capped 20S complexes to maintain proteostasis. Similar proteasome dynamics are found in the lymph nodes of aged C57BL/6 and BTBR mice, the latter of which have a naturally activated immune system. Overall, these findings propose long-term cultures of human monocyte-derived macrophages as a model to study macrophage senescence. They also provide a molecular rationale for immunoproteasome dysfunction with remodeling of the proteasome, indicating that the loss of the PA28αβ regulator is a critical event and a hallmark of immunosenescence.

Osteoarthritis (OA) imposes a substantial health and economic burden globally. Currently, there is a lack of disease-modifying osteoarthritis drugs (DMOADs). This study aimed to elucidate the relationship between chondrocyte senescence and OA progression, as well as to develop an effective siRNA nanodelivery platform for OA treatment. We engineered neutrophil membrane-coated, siIL33-loaded nanoparticles (NM-NP-siIL33) for OA management. The therapeutic efficacy of NM-NP-siIL33 was evaluated through both in vitro and in vivo experiments. Our findings revealed that IL-33 expression was significantly upregulated in damaged articular cartilage in both young and aged mice following anterior cruciate ligament transection (ACLT) surgery. In vitro experiments demonstrated that IL-33 promotes chondrocyte senescence by inhibiting cellular autophagy via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Additional in vivo studies showed that NM-NP-siIL33 effectively delivered siIL33 to target cells within OA tissues, thereby mitigating the degradation of articular cartilage. Our results suggest that IL-33 plays a critical role in OA progression by accelerating chondrocyte senescence. Furthermore, NM-NP-siIL33 represents a promising therapeutic strategy for managing OA.

Uncoupling proteins, as mitochondrial transporters, allow protons to enter the mitochondrial matrix without generating ATP, a process known as oxidative phosphorylation uncoupling. Mammalian UCPs have been demonstrated to regulate metabolism, modulate reactive oxygen species levels, and maintain calcium homeostasis, which is closely linked to cardiac disease. In Drosophila, four homologs of uncoupling protein have been identified, with only UCP5 being detected in the adult heart proteome by mass spectrometry. The essential role of Drosophila UCP5 in the heart remains unknown. Our results showed that cardiac-specific UCP5 overexpression increased the incidence of fibrillation in an age-dependent trend, while cardiac-specific UCP5 knockdown induced an age-dependent increase in the incidence of asystoles, likely due to tachycardia. Additionally, UCP5 RNA levels significantly decline with age, indicating a role of UCP5 in cardiac aging. Cardiac-specific UCP5 overexpression reduced the reactive oxygen species levels within the cardiomyocyte nuclei and extended the lifespan. UCP5 RNA levels increased under high-fat diet conditions, and systemic overexpression of UCP5 can lower triglyceride levels under such dietary conditions, indicating an adaptive role of UCP5 in metabolism.

Arterial pulsation is crucial for promoting neurofluid circulation. Most previous studies quantified pulsatility via blood velocity-based indices in large arteries. Here we propose an innovative method to quantify the microvascular volumetric pulsatility index (mvPI) across cortical layers and white matter (WM) using high-resolution four-dimensional (4D) vascular space occupancy (VASO) and arterial spin labeling (ASL) magnetic resonance imaging (MRI) at 7 T with simultaneous pulse recording. We assessed aging-related changes in mvPI in 11 young (28.4 ± 5.8 years) and 12 older (60.2 ± 6.8 years) participants and compared mvPI with large artery pulsatility assessed by 4D-flow MRI. mvPI peaked in the pial surface (0.18 ± 0.04). Deep WM mvPI was significantly higher in older participants (P = 0.006) than young ones. Deep WM mvPI correlated with large artery velocity PI (r = 0.56, P = 0.0099). We performed test-retest scans, non-parametric reliability test and simulations to demonstrate the reproducibility and accuracy of the method. In conclusion, our non-invasive method enables in vivo fine-grained measurement of mvPI, with implications for glymphatic function, aging and neurodegenerative diseases.

Mitochondrial calcium (Ca

The cardiovascular system functions under continuous cyclic mechanical stretch, with disruptions in mechanical and biochemical signals contributing to disease progression. In cardiovascular disorders, these disruptions activate cardiac fibroblasts (CFs) and promote cellular senescence, yet it remains unclear whether mechanical stimuli alone can initiate this phenotype. Here, primary murine CFs are exposed to uniaxial stretch, and systematically varied mechanical parameters assessed their role in senescence induction. Loss of stretch magnitude and increase in frequency, mimicking a pathologic hypertrophy and fibrosis, led to a senescence phenotype, identified through cell cycle arrest, decreased lamin B expression, and DNA damage. Mechanically-induced CF senescence depends on p53/p21, whereas senescence triggered by oxidative stress or lamin A/C mutation proceeded via p16. Notably, mechanically-induced premature senescence is accompanied by reduced levels of the nuclear envelope protein emerin. These findings demonstrate that altered mechanical signals are sufficient to trigger premature senescence and implicate compromised nuclear integrity in the underlying mechanism.

Aging is an inevitable biological process associated with progressive physiological decline and increased disease susceptibility. Cellular senescence stands as a key mechanism among the hallmarks of aging, which is characterized by irreversible cell-cycle arrest, chromatin remodeling, and a pro-inflammatory senescence-associated secretory phenotype (SASP). Importantly, SASP drives inflammaging and propagates senescence via a bystander effect, exacerbating tissue dysfunction. Recent advances in senolytic therapies and senostatics offer promising strategies to eliminate or rejuvenate senescent cells, improving physiological function in aged and disease models. Notably, panobinostat has emerged as an effective post-chemotherapy senolytic, mitigating chemoresistance. However, current senolytics face challenges, including off-target effects and limited clinical applicability. Growing evidence highlights natural products (e.g., polyphenols, flavonoids) and stem cell therapies as potential anti-aging interventions, with demonstrated efficacy in age-related disease models and ovarian rejuvenation. Despite progress, key hurdles remain in developing personalized, multi-target therapies that safely modulate aging trajectories. This review explores the mechanisms of cellular senescence, anti-aging mechanisms of phytochemicals, and phytochemicals and stem cell-therapy in ovary rejuvenation. We further discuss the challenges in developing "tailor-made" anti-aging interventions that rewire the aging trajectory, which will be critical for achieving healthy aging.

Aging-associated decline in brown adipose tissue (BAT) function and mass contributes to energy and metabolic homeostasis disruption. Alcohol dehydrogenase 5 (ADH5) is a major denitrosylase that prevents cellular nitro-thiol redox imbalance, an essential feature of aging. However, the functional significance of BAT ADH5 in the context of aging is largely unknown. Here, we aimed to investigate the role of BAT ADH5 in protecting against age-related metabolic dysfunction. We show that aging promotes aberrant BAT protein S-nitrosylation modification and downregulates ADH5 in mice. Furthermore, BAT ADH5-deletion accelerates BAT senescence and aging-associated declines in metabolic homeostasis and cognition. Mechanistically, we found that aging inactivates BAT Adh5 by suppressing heat shock factor 1 (HSF1), a well-recognized proteostasis regulator. Moreover, pharmacologically enhancing HSF1 improved BAT senescence, metabolic decline, and cognitive dysfunction in aged mice. Together, these findings suggest that the BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline. Ultimately, unraveling the role of thermogenic adipose nitrosative signaling will provide novel insights into the interplay between BAT nitric oxide activity and metabolism in the context of aging.

Small molecular food components contribute to the health benefits of diets rich in fruits, vegetables, herbs and spices. The cellular mechanisms by which noncaloric bioactives promote healthspan are not well understood, limiting their use in disease prevention. Here, we deploy a whole-organism, high-content screen in zebrafish to profile food-derived compounds for activation of autophagy, a cellular quality control mechanism that promotes healthy aging. We identify thymol and carvacrol as activators of autophagy and mitophagy through a transient dampening of the mitochondrial membrane potential. Chemical stabilization of thymol-induced mitochondrial depolarization blocks mitophagy activation, suggesting a mechanism originating from the mitochondrial membrane. Supplementation with thymol prevents excess liver fat accumulation in a mouse model of diet-induced obesity, improves pink-1-dependent heat stress resilience in Caenorhabditis elegans, and slows the decline of skeletal muscle performance while delaying epigenetic aging in SAMP8 mice. Thus, terpenoids from common herbs promote autophagy during aging and metabolic overload, making them attractive molecules for nutrition-based healthspan promotion.

Ubiquitin is a conserved modifier regulating the stability and function of numerous target proteins. In all eukaryotes, polyubiquitin precursors are generated and processed into ubiquitin monomers. The final ubiquitin unit always contains a C-terminal extension, but its physiological significance is unknown. Here, we show that C-terminally extended ubiquitin, termed CxUb, is essential for stress resistance, mitophagy, and longevity in Saccharomyces cerevisiae and Caenorhabditis elegans. CxUb forms ubiquitin chains and binds to a previously undescribed region within the ubiquitin chain-elongating E4 enzyme Ufd2, which also functions during stress and aging. Ufd2 recognizes CxUb and conjugates it to substrate proteins, triggering their degradation. By contrast, CxUb is not required for basal housekeeping functions of the ubiquitin-proteasome system. These data suggest that the CxUb encodes a functionally unique ubiquitin form, specialized for proteostasis defects, expanding the code of post-translational modification processes.

Ageing is known to affect sleep slow waves, but the underlying mechanisms are unknown. Here we aim to precisely quantify the effect of aeging on the shape and dynamics of sleep slow waves in a large cohort of human subjects, and to explore possible underlying mechanisms using a computational model. We analyzed EEG sleep recordings from 2377 healthy individuals aged 19 to 85, collected over multiple nights in their natural environments using the DREEM headband. The fine-structure analysis of slow waves was conducted to assess changes in frequency, amplitude, and variability with age. Additionally, we developed a computational model to investigate possible underlying mechanisms. The study reveals that with aeging, sleep slow waves show a significant reduction in frequency, increase in variability, and decrease in amplitude. Older individuals also experience more sleep fragmentation. REM sleep changes are less consistent, with some findings of minor decreases and others showing no significant changes. The computational model supports these observations by replicating the age-related changes in slow waves from a decrease in excitatory drive, suggesting that ageing affects excitatory interactions at large scales. In conclusion, by examining individuals free from sleep disorders and controlled lab environments, this study provides a detailed characterisation of age-related changes in sleep slow waves and proposes a potential mechanism involving alterations in cortical network connectivity.

Skeletal muscle, which accounts for nearly 40 % of total body mass, serves as the primary effector organ for locomotion, metabolism, and thermoregulation. Skeletal muscle atrophy, a common condition associated with aging, disease, and disability, significantly compromises patients' quality of life. This review focuses on the occurrence and progression of skeletal muscle atrophy. Forkhead box protein O1 (FoxO1) is a key regulatory factor that mediates pathological mechanisms through multidimensional molecular networks. It influences skeletal muscle metabolism via post-translational modifications (PTMs), dysregulated autophagy, an imbalanced inflammatory microenvironment, and the regulation of satellite cell function. Therapeutic strategies targeting FoxO1, such as resveratrol-induced SIRT1 activation and miR-486 mimics, have shown promising results in preclinical models. This review highlights the central role of FoxO1 in molecular pathways, proposes a potential framework for addressing muscle atrophy, and offers new insights into the treatment of sarcopenia and related diseases.

The epigenome is sensitive to metabolic inputs and is crucial for aging. Lysosomes act as a signaling hub to sense metabolic cues and regulate longevity. We found that lysosomal metabolic pathways signal through the epigenome to regulate transgenerational longevity in

Ageing progressively impairs skeletal muscle regeneration, contributing to reduced mobility and quality of life. While the molecular changes underlying muscle ageing have been well characterised, their impact on muscle stem cell (muSC) behaviour during regeneration remains poorly understood. Here, we leverage telomerase-deficient tert mutant zebrafish larvae as an in vivo model of accelerated ageing to perform real-time analysis of muSC dynamics following muscle injury. We demonstrate that the ageing-like inflammatory environment in tert mutant disrupts muSC migration, impairs activation and proliferation, and compromises regenerative capacity. We further show that sustained inflammation, mediated by persistent macrophage presence and elevated matrix metalloproteinase (MMP) activity, limits muSC recruitment and migration efficiency. Pharmacological inhibition of MMP9/13 activity and genetic depletion of macrophages partially restore muSC migratory behaviour and regenerative outcomes. Notably, we demonstrate that muSC migration dynamics correlate with regenerative success, providing a functional readout for therapeutic screening. Our findings reveal zebrafish tert mutants offer a tractable system for dissecting age-associated changes to cell behaviour and for identifying rejuvenation interventions.

Ribosomal RNA (rRNA) synthesis is intricately tied to cellular growth and proliferation. Basic fibroblast growth factor (FGF2), a pivotal factor for bone marrow mesenchymal stem cells (BMSCs), can stimulates rRNA transcription, though the underlying mechanism remains unknown. Here, we demonstrate that the cytoplasm-nucleus translocation of FGF2 is determined by the stable nuclear localization motif. Meanwhile, the nuclear FGF2 regulates rRNA expression and BMSCs proliferation via phase separation. Next, through FGF2 related epigenomics and 3D genomes analysis, we identified chromatin architectures during BMSCs differentiation and aging. In the process, topologically associating domains (TADs) and chromatin loops profiling revealed the attenuated genomic interaction among proximal chromosomes 13, 14, 15, 21, and 22, where phase-separated FGF2 facilitates rDNA transcription depend on specific super-enhancers (SEs). Furthermore, we validated that FGF2 orchestrates rDNA chromatin architecture in coordination with STAT5. Together, these findings underscore the pivotal role of FGF2 in rDNA chromatin architectures, which determines BMSCs cell fate.

DNA double-strand breaks (DSBs) represent one of the most serious threats to genome integrity. Endogenous DSBs chiefly arise from cell cycle activities such as DNA replication and division, while dormant, non-proliferative cells are generally considered protected from such damage. Here we report that induction of quiescence by growth restriction in human retinal pigment epithelial (RPE) cells unexpectedly leads to rapid accumulation of DSBs within hours, reaching levels that exceed those in continuously proliferating cells. These DSBs occur in a cell cycle stage-dependent manner, predominantly in cells past the restriction point when quiescence is induced. Mechanistically, this DSB accumulation results from continued cell cycle activity under growth restriction conditions, accompanied by downregulation of DSB repair genes, allowing these breaks to persist during quiescence. Cells that accumulate more DSBs during quiescence induction enter a deeper state of quiescence, requiring stronger growth stimulation for cell cycle re-entry. Notably, cell cycle re-entry depends on DSB repair mediated by DNA-PK, an intrinsically error-prone process. Our findings establish quiescence induction as a previously unrecognized source of latent genome instability, with implications for tissue maintenance and aging where transitions between quiescence and proliferation are critical.

Network neuroscience has significantly advanced our understanding of how structural and functional connectivity evolve during healthy neurocognitive aging. Yet, integrative studies linking structural and functional brain organization with cognitive performance remain relatively limited. In this study, we analyzed resting-state functional MRI and diffusion-weighted imaging data from 600 healthy adults aged 18 to 88, drawn from the CamCAN dataset. Using a graph signal processing framework, we investigated how structural connectivity constrains functional brain signals across the adult lifespan. Our results reveal that control and semantic cognitive systems exhibit distinct age-related patterns of structure-function reorganization, potentially reflecting a shift in integrative processing during midlife. Notably, our findings suggest that structurally-coupled sensorimotor integration plays a crucial role for regulating these systems. Until midlife, it accompanies structurally-decoupled activity in transmodal cortices to sustain cognitive control. In parallel, it likely supports the formation of embodied internal models that leverage more structurally-decoupled semantic processes, thus contributing to maintain lexical production skills for longer in older adulthood. Taken together, our study offer new multimodal insights into how sensory-driven processes help reconfigure the healthy aging brain to support controlled semantic cognition.

Nutrition plays a central role in healthy living, however, extensive variability in individual responses to dietary interventions complicates our understanding of its effects. Here we present a comprehensive study utilizing the Drosophila Genetic Reference Panel (DGRP), investigating how genetic variation influences responses to diet and aging. We performed quantitative genetic analyses of the impact of reduced nutrient intake on lifespan, locomotor activity, dry weight, and heat knockdown time (HKDT) measured on the same individual flies. We found a significant decrease in lifespan for flies exposed to a restricted diet compared to those on a control diet. Similarly, a notable reduction in dry weight was observed in 7 and 16-day-old flies on the restricted diet compared to the control diet. In contrast, flies on the restricted diet exhibited higher locomotor activity. Additionally, HKDT was found to be age-dependent. Further, we detected significant genotype-by-diet interaction (GDI), genotype-by-age interaction (GAI) and genotype-by-age-by-diet interaction (GADI) for all traits. Thus, environmental factors play a crucial role in shaping trait variation at different ages and diets, and/or distinct genetic variation influences these traits at different ages and diets. Our genome-wide association study also identified a quantitative trait locus for age-dependent dietary response. The observed GDI and GAI indicate that susceptibility to environmental influences changes as organisms age. These findings could have significant implications for understanding the genetic mechanisms underlying dietary responses and aging in Drosophila melanogaster, which may inform future research on dietary recommendations and interventions aimed at promoting healthy aging in humans. The identification of associations between DNA sequence variation and age-dependent dietary responses opens new avenues for research into the genetic mechanisms underlying these interactions.

With the accelerating global population aging, establishing effective brain health assessment systems has emerged as a critical challenge in public health. Neuroimaging-based brain age prediction, serving as a potential biomarker for evaluating individual brain aging, has achieved remarkable breakthroughs in recent years. However, the accuracy of current brain age prediction models remains substantially dependent on the quality and representativeness of their training datasets. Consequently, constructing larger-scale, population-representative, and high-quality datasets is essential for enhancing the reliability of brain age prediction. This systematic review synthesizes findings from 70 peer-reviewed studies (2014-2024) that utilized the UK Biobank (UKB) for brain age prediction, focusing on paradigm-shifting advancements in machine learning and deep learning algorithms. We comprehensively analyze influential factors associated with brain age and their clinical implications, while critically evaluating the unique advantages and inherent limitations of the UKB dataset in this research domain. Furthermore, this work proposes future research directions to address existing methodological gaps and enhance clinical applicability. This study systematically elucidates the advancements in brain age prediction research based on the UKB dataset, aiming to promote deeper exploration in this field and provide theoretical foundations and practical guidance for the precise diagnosis and treatment of neurodegenerative diseases, as well as the formulation of individualized intervention strategies.

Mammalian maximum lifespan (MLS) varies over a hundred-fold, yet the molecular mechanisms underlying this diversity remain unclear. We present a cross-species analysis of alternative splicing (AS) across six tissues in 26 mammals, identifying hundreds of conserved AS events significantly associated with MLS, with the brain containing twice as many tissue-specific events as peripheral tissues. MLS-AS events are enriched in pathways related to mRNA processing, stress response, neuronal functions, and epigenetic regulation, and are largely distinct from genes whose expression correlates with MLS, indicating that AS captures unique lifespan-related signals. The brain exhibits certain associations divergent from peripheral tissues and reduced overlap with body mass (BM)-associated splicing; neither is observed at the gene expression level. While MLS- and age-associated AS events show limited overlap, the shared events are enriched in intrinsically disordered protein regions, suggesting a role in protein flexibility and stress adaptability. Furthermore, MLS-associated AS events display stronger RNA-binding protein (RBP) motif coordination than age-associated ones, highlighting a more genetically programmed adaptation for lifespan determination, in contrast to the more variable splicing changes seen with chronological aging. These findings suggest alternative splicing as a distinct, transcription-independent axis of lifespan regulation, offering new insights into the molecular basis of longevity.

To identify medications with the potential to increase human lifespan, we conducted a systematic screening of electronic health records from a national health organization, comparing medications consumed over the preceding decade by individuals over 60 who outlived the average life expectancy with those consumed by matched individuals who died before reaching it. This screen identified two antiprotozoal agents, atovaquone-proguanil and mefloquine, as strongly associated with increased longevity (odds ratios for 10-year mortality: 0.43 and 0.32; FDR = 0.0002 and 0.0001, respectively). We validated these associations in the U.S.-based TriNetX federated network, confirming that these two antiprotozoals, along with nirmatrelvir-ritonavir--a medication used to prevent severe COVID-19 outcomes and possessing antiprotozoal properties--were associated with significantly reduced mortality and a lower incidence of major age-related conditions, including diabetes mellitus, cardiovascular and cerebrovascular diseases, renal insufficiency, dementia, pulmonary disease, liver disease, and malignancies. Across both populations, antiprotozoal exposure was also associated with increased risks of specific adverse outcomes, notably hearing loss, Sjogrens syndrome, and lichen planus. The consistent observation of both benefits and risks across independent populations supports the biological plausibility of these effects and argues against confounding by indication or underdiagnosis. Taken together, these findings suggest that elimination of protozoal parasites--notably Toxoplasma gondii-- may significantly reduce human age-related morbidity and mortality while increasing the risk of specific auditory, ophthalmic, and dermatologic complications. These results offer promising new avenues to extend human lifespan and promote healthy aging through targeted antimicrobial interventions.

Aging drives cognitive decline in the adult brain with unclear mechanisms. Previously, oligodendrocyte precursor cells (OPCs), the source cells of myelin-forming cells in the central nervous system, have been linked to brain aging by their compromised differentiation and regeneration capability. Whether a myelination-independent function of OPCs is involved in brain aging remains unknown. In this study, we herein report a myelination-independent role of OPCs in exaggerating cognitive decline in the aging brain via suppressing neuronal plasticity. Our results demonstrate that macroautophagic flux declines in aged OPCs. Inactivation of autophagy promotes the senescence of OPCs, which activates C-C motif chemokine ligand 3 (CCL3)/CCL5-C-C motif chemokine receptor 5 signaling. Through this, autophagy-defective OPCs impair glutamatergic transmission, neuronal excitability, and long-term potentiation, exaggerating the cognitive decline in the aging brain. Our study demonstrates a myelination-independent role of OPCs in brain aging and identifies that a declined autophagy in OPCs is a pivotal factor in driving aging-associated cognitive decline.

In response to Taiwan's rapidly aging population and the rising demand for personalized health care, accurately assessing individual physiological aging has become an essential area of study. This research utilizes health examination data to propose a machine learning-based biological age prediction model that quantifies physiological age through residual life estimation. The model leverages LightGBM, which shows an 11.40% improvement in predictive performance (R-squared) compared to the XGBoost model. In the experiments, the use of MICE imputation for missing data significantly enhanced prediction accuracy, resulting in a 23.35% improvement in predictive performance. Kaplan-Meier (K-M) estimator survival analysis revealed that the model effectively differentiates between groups with varying health levels, underscoring the validity of biological age as a health status indicator. Additionally, the model identified the top ten biomarkers most influential in aging for both men and women, with a 69.23% overlap with Taiwan's leading causes of death and previously identified top health-impact factors, further validating its practical relevance. Through multidimensional health recommendations based on SHAP and PCC interpretations, if the health recommendations provided by the model are implemented, 64.58% of individuals could potentially extend their life expectancy. This study provides new methodological support and data backing for precision health interventions and life extension.

Cell cycle arrest in dermal fibroblasts is a critical biological process essential for maintaining skin homeostasis and serves as a central mechanism driving various skin pathologies. This review systematically summarizes the endogenous and exogenous factors triggering cell cycle arrest in dermal fibroblasts and their underlying molecular mechanisms, with a particular focus on the roles of key signaling pathways such as p53, TGF-β/Smad, and Wnt/β-catenin. Additionally, the dual effects of cell cycle arrest on the skin are discussed: transient arrest facilitates DNA damage repair and tissue regeneration, whereas prolonged arrest leads to cellular senescence, chronic inflammation, collagen degradation, and fibrosis. Advances in chemical compounds modulating cell cycle arrest are also highlighted, including potential therapeutic strategies for promoting or relieving cell cycle arrest. This review provides new insights into skin regenerative medicine and anti-aging therapies while identifying critical scientific questions for future research.

Clathrin-mediated endocytosis (CME) is a critical cellular process that regulates nutrient uptake, membrane composition, and signaling. Although replicative aging affects many cellular functions, its impact on CME remains largely unknown. We show that in budding yeast, older cells have slower assembly of early and coat CME modules, resulting in longer endocytic turnover and reduced Mup1 internalization. This change in CME dynamics is mother cell-specific, and not observed in daughters. Our data also show that perturbing vacuolar pH, a key driver of aging phenotypes, in young cells mimics aging-like CME dynamics, while maintaining an acidic vacuolar pH in aging cells preserves CME dynamics typical of young cells. We demonstrate that the vacuolar pH effect on CME is regulated through TORC1 via the effector kinase Npr1. Finally, we show that rescuing CME in aging cells improves mitochondrial health. These findings reveal that age-associated changes in cellular and vacuolar pH impair CME, and suggest CME as a potential driver of early cellular aging.

The molecular correlates of Alzheimer\'s disease (AD) are increasingly being defined by omics. Yet, the findings from different data types or cohorts are often difficult to reconcile. Collecting multiple omics from the same individuals allows a comprehensive view of disease-related molecular mechanisms, while addressing conflicting findings derived from single omics. Such same-sample multi-omics can reveal, for instance, when changes observed in the transcriptome share distinct but coordinated signals in epigenetics and proteomics, relationships otherwise unclear. Here, we apply a data-driven multi-omic framework to integrate epigenomic, transcriptomic, proteomic, metabolomic, and cell-type-specific population data from up to 1,358 aged human brain samples from the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). We demonstrate the existence of sprawling cross-omics cross-system biological factors that also relate to AD phenotypes. The strongest AD-associated factor (factor 8) involved elevated immune activity at the epigenetic level, decreased expression of heat shock genes in the transcriptome, and disrupted energy metabolism and cytoskeletal dynamics in the proteome. We also showed immune-related factors (factors 2 and 3) with discordant enrichments, reflecting reactive-like glial subpopulations and protective contributions from surveillance microglia. Both were negatively associated with AD pathology, suggesting potential immune resilience mechanisms. Finally, unsupervised clustering of participants revealed eleven molecular subtypes of the aging brain, including three clusters strongly associated with AD but displaying distinct molecular signatures and phenotypic characteristics. Our findings provide a comprehensive map of molecular mechanisms underlying AD heterogeneity, highlighting the complex role of neuroinflammatory processes, and yielding potential novel biomarkers and therapeutic targets for precision medicine approaches to AD treatment.

The process of aging is associated with a decline in cell, tissue, and organ function, leading to a range of health problems. Increasing evidence indicates that dietary restriction can counteract age-dependent effects and improve health and longevity in whole organisms, but less is known about the influence of aging and the impact of nutrition on individual organs of an organism. In this study, we examined the intestine of the very short-lived aging model system, the African turquoise killifish (Nothobranchius furzeri), throughout its lifetime. We investigated the effects of age and nutrition on the preservation of gut tissue at stages corresponding to human neonatal, adolescent, adult, and old age, and integrated morphological measurements, histology, and transcriptomics. The intestinal mucosa is characterized by folds and intervening interfold regions, where intestinal stem cells localize. The stem cells occur in clusters, and the cycle time of stem cells increases with age. We also observed a reduction in intestinal length and volume with age. Age-dependent transcriptomic profiling revealed significant changes in the expression of peripheral circadian clock genes and stem cell niche markers. Notably, the majority of these genes maintained their adult gene expression levels in old age following intermittent fasting during adulthood. Therefore, our results demonstrate that the decline in structural intestinal tissue homeostasis is associated with a decline in stem cell activity that can be counteracted by intermittent fasting. Since the intestinal mucosa of killifish is similar to that of mammals, the results of this study can be translated to general gut biology.

Over the past two decades, experimental evolution has significantly advanced our understanding of evolutionary patterns and mechanisms of genomic change. One critically underexplored dimension is the role of microbiota in host adaptive evolution. In this research we investigate the microbiota from forty laboratory-selected Drosophila melanogaster populations exhibiting four distinct aging trajectories, ranging from extremely-short lifespans to -long lifespans. Using metagenomic sequencing and colony forming unit (CFU) counts in both conventional and gnotobiotic conditions, we uncover substantial microbiota differentiation among these populations. The most striking pattern is the consistent loss of Wolbachia in populations selected for rapid aging, in contrast to its near complete dominance in long-lived populations. This suggests a positive association between relative abundance of Wolbachia and lifespan, alongside a negative correlation between Wolbachia and Acetic Acid Bacteria (AAB) titres. These findings position the microbiota, and particularly Wolbachia, as a potentially integral component in host life history evolution, with implications for understanding the microbial contributions to aging and adaptation.

Microglia are essential regulators of myelin integrity and repair, yet their regenerative capacity declines with ageing and in neurodegenerative diseases such as multiple sclerosis (MS). Neonatal microglia retain a uniquely reparative program that may offer insight into restoring lost functions in the adult CNS. Here we show that transplantation of neonatal microglia ameliorates disability, reduces leukocyte infiltration, and promotes remyelination in both inflammatory (EAE) and non-inflammatory (cuprizone) models, and reverses cognitive decline in aged mice. These benefits persisted even when transplanted cells remained confined to the meninges and were reproduced by the neonatal microglia secretome, indicating a paracrine mechanism. Multi-omic profiling revealed that the neonatal secretome is enriched in trophic factors and membrane-building lipids compared to adult microglia, while transcriptomic analyses of treated aged brains showed reactivation of developmental repair pathways and suppression of inflammatory signatures. Together, these results demonstrate that neonatal microglia re-engage rejuvenation-like programs in the adult CNS and highlight the importance of multifactorial strategies, integrating trophic, metabolic, and immunomodulatory cues, over single-target approaches. Our findings establish early microglial programs as a paradigm for designing new regenerative therapies for CNS disorders.

Alzheimer's disease (AD) is a leading cause of dementia, currently affecting over 50 million people globally. Despite decades of research, therapeutic development has continued to face high failure rates due to an incomplete understanding of the underlying disease mechanisms. Current drugs like rivastigmine focus on managing cognitive symptoms since there is no known cure to halt the disease's progression. However, recent research has suggested that advanced biological age, particularly the accumulation of senescent cells, is the most significant risk factor for AD pathology, and targeting these aging mechanisms may prove more effective in altering the disease progression. Senescent cells accumulate with age, contributing to inflammatory states and neurodegenerative diseases such as AD. Senolytic drugs, such as dasatinib and quercetin (D + Q), have shown promise in animal models by clearing senescent cells, delaying aging-related decline, and improving AD-related outcomes. This literature review aims to provide a comprehensive overview of the therapeutic potential of senolytic interventions for AD by examining the mechanisms of cellular senescence based on evidence of its accumulation in the human brain, critically analyzing the preclinical and clinical trials involving senolytic compounds, and discussing the implications and limitations of this approach. The findings from recent studies indicate that senolytics may pave the way for effective AD treatments, though further clinical validation is needed.

Growing evidence points to mitochondria as not just the "powerhouse of the cell" but as a major cellular hub for signaling. Mitochondria use signaling pathways to communicate with other organelles within the cell or organs within an organism to regulate stress response, metabolic, immune, and longevity pathways. These communication pathways are carried out by mitokine signaling molecules encompassing metabolites, lipids, proteins, and even whole mitochondrial organelles themselves. In this review, we focus on the communication pathways mitochondria use to communicate between different organs in invertebrates, mammalian models, and humans. We cover the molecular events that trigger communication, the signaling mechanisms themselves, and the impact this communication has on organismal health in the context of stress and disease. Further understanding of cross-organ mitochondrial communication pathways will inform the design of therapeutics that take advantage of their protective effects to treat diseases associated with mitochondrial dysfunction.

Oligodendrocyte progenitor cells (OPCs) have the capacity to self-renew, differentiate into mature myelinating cells, and remyelinate the central nervous system in response to demyelination. Normal aging is associated with a reduction in the functional capacity of OPCs and induces distinct transcriptional signatures even in the absence of an autoimmune inflammatory demyelination insult. To determine how aging impacts the OPC response to an acute inflammatory insult comparable to a demyelinating event in multiple sclerosis (MS), we performed adoptive transfer of young myelin-reactive Th17 T cells into young and aged mice. Spinal cord OPC responses were quantified using lineage tracing and myelin sheath thickness was quantified using transmission electron microscopy. In the subacute phase 9-10 days after adoptive transfer, the density of both young and aged OPCs is enriched in spinal cord lesions compared to non-lesion white matter. After adoptive transfer, the density of aged OPCs is significantly higher than naive/non-adoptive transfer aged spinal cord. Differentiated oligodendrocytes (OLs) are relatively preserved within lesions of aged and young animals despite an overall reduction in OL density after adoptive transfer. While lineage tracing identified newly formed oligodendrocytes after adoptive transfer in both young and aged lesions, less oligodendrocyte differentiation was observed in aged animals. Despite the reduction of OPC differentiation in aged animals, there was no significant difference in the extent of remyelination observed for young and aged lesions. Aged OPCs rise to the challenge in response to a strong auto-immune attack, suggesting that compensatory strategies allow both young and aged OPCs to survive and remyelinate in the inflammatory environment. Identifying pathways that promote resilience of young and aged OPCs in the face of an inflammatory challenge will facilitate the development of remyelinating therapies for the treatment of people with MS across the full spectrum of human aging.

Ageing is the major risk factor for Alzheimer's disease (AD), the most common neurodegenerative disorder. DNA damage is a hallmark of ageing, particularly when occurring at telomeres, genomic regions vulnerable to oxidative damage and often challenging for the cell to repair. Here, we show that brains of 3xTg-AD mice, an established AD model characterized by amyloid-β (Aβ)-induced pathology, exhibit increased activation of DNA damage response (DDR) pathways at telomeres. Exposure of mouse primary hippocampal neurons to 42-residue Aβ (Aβ42) oligomers, a significant pathogenetic contributor to AD, triggers telomeric DDR by increasing the levels of reactive oxygen species caused by calcium imbalance. Antisense oligonucleotides targeting non-coding RNAs generated at damaged telomeres in vivo (in 3xTg-AD mice) and in vitro reduce neurotoxicity in iPSC-derived human cortical neurons and mouse primary neurons while inhibiting Aβ42-induced telomeric DDR, and restore transcriptional pathways altered by Aβ and found dysregulated in AD patients. These results unveil an unexpected role of telomeric DNA damage responses in Alzheimer's disease pathogenesis, and suggest a novel target for the development of RNA-based therapies.