Longevity Papers

Chromatin, the spatial organizer of genomic DNA, is hierarchically folded into higher-order structures to facilitate DNA compaction, enabling genome surveillance. Understanding the organization and function of the three-dimensional (3D) genome is critical to profile chromatin accessibility and functional interactions that govern gene regulation across multiple biological processes, including aging and one of its hallmarks, cellular senescence. Cellular senescence constitutes a defensive stress response to various intrinsic and extrinsic stimuli, preserving cellular and organismal homeostasis through a generally irreversible cell cycle arrest. In this review article we discuss epigenetic alterations occurring to DNA and chromatin that drive and fuel the onset of this complex phenomenon. As such, we describe major large-scale chromatin events, including the formation of higher-order chromatin structures and the 3D spatial alterations of the genome that occur during senescence. We also discuss global heterochromatin loss, deficiencies in nuclear lamins, the depletion of core histones and their modifications, as well as the epigenetic regulation of the senescence-associated secretory phenotype (SASP), all of which serve key roles in the epigenome of senescent cells. To clearly demonstrate the significance of epigenetic modifications, data from a computational meta-analysis are presented, aiming to further underpin key epigenetic mechanisms occurring in senescent cells. Last, we highlight promising epigenetic modulators implemented in therapeutic strategies for senescent cell detection and elimination, possibly leading to significant clinical advances against various age-related diseases as well as the delay and prevention of the aging onset.

Study of cellular senescence is critical in aging research and anti-senescence therapy drug development. Current methods for the evaluation of the widely accepted cellular senescence marker senescence-associated beta galactosidase (SA-β-gal) activity assay rely on bright-field imaging, which is non-quantitative and tedious to perform. We have developed an effective and reproducible multiplex high-content analysis system for high-throughput screen and evaluation of senescence modulators. The IC

SIRT6, a pivotal member of the NAD

The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that are pro-apoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become senolytic-resistant. Administering senolytics to obese mice selectively decreased abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16INK4a, p21CIP1, senescence-associated {beta}-galactosidase (SA{beta}gal), {gamma}H2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus -resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/ apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/ fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of pro-apoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as senosensitizers), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible.

Aging is the primary risk factor for most neurodegenerative diseases, yet the cell-type-specific progression of brain aging remains poorly understood. Here, human cell-type-specific transcriptomic aging clocks are developed using high-quality single-nucleus RNA sequencing data from post mortem human prefrontal cortex tissue of 31 donors aged 18-94 years, encompassing 73,941 high-quality nuclei. Distinct transcriptomic changes are observed across major cell types, including upregulation of inflammatory response genes in microglia from older samples. Aging clocks trained on each major cell type accurately predict chronological age, capture biologically relevant pathways, and remain robust in independent single-nucleus RNA-sequencing datasets, underscoring their broad applicability. Notably, cell-type-specific age acceleration is identified in individuals with Alzheimer's disease and schizophrenia, suggesting altered aging trajectories in these conditions. These findings demonstrate the feasibility of cell-type-specific transcriptomic clocks to measure biological aging in the human brain and highlight potential mechanisms of selective vulnerability in neurodegenerative diseases.

In response to damage triggered by various stimuli including infections, ATP is released from damaged cells and converted to adenosine in the extracellular space by the ectonucleotidases CD39 and CD73. Extracellular adenosine is an immune modulatory molecule that signals via four G-protein receptors: A1, A2A, A2B, and A3, which can have opposing downstream effects on immune responses. In this minireview, we follow up on our mSphere of Influence commentary that focused on the A2B receptor (2019) to give a broader view of the role of the extracellular adenosine signaling pathway in host defense against infections. Studies demonstrate that extracellular adenosine serves as a key signaling molecule regulating the balance between effective pathogen clearance and immunopathology during infection. Extracellular adenosine displays dose- and time-dependent roles during infection, with individual adenosine receptors playing specific roles in controlling immune responses. Age-driven changes in this pathway contribute to the increased susceptibility of older hosts to certain infections, although there are several key unanswered questions about the role of the extracellular adenosine pathway in immunosenescence. Clinical and translational findings reveal a role for extracellular adenosine production and signaling in infections in humans, and there have been recent advances, but several ongoing challenges remain in pharmacologically targeting this pathway to reshape host immune responses.

The biological feasibility of human rejuvenation remains a subject of intense debate, yet answering this question is critical for guiding research strategies. Should aging research focus on reversing aging in older individuals, or on pausing its progression at earlier ages? We address this question with evolutionary biology. Classic evolutionary theories of aging - damage accumulation, antagonistic pleiotropy, and the disposable soma - consider aging as a detrimental byproduct of evolution. From this perspective, rejuvenation should confer strong fitness advantages and therefore be expected to evolve in species experiencing substantial aging in the wild. Its rarity in nature should thus be interpreted as evidence of its mechanistic implausibility. Yet, rejuvenation does occur in a few species, and, paradoxically, it is typically induced by stress but not used under optimal conditions. Using mathematical modeling of lifespan plasticity in eusocial insects, we show that this pattern cannot be reconciled with classic theories of aging, revealing an internal contradiction between these theories and the observed avoidance of rejuvenation. By contrast, the pathogen control hypothesis - which interprets aging as an adaptive, programmed process -offers a consistent evolutionary framework for understanding and potentially achieving rejuvenation.

Biological age refers to a person's overall health in aging, as distinct from their chronological age. Diverse measures of biological age, referred to as "clocks", have been developed in recent years and enable risk assessments, and an estimation of the efficacy of longevity interventions in animals and humans. While most clocks are trained to predict chronological age, clocks have been developed to predict more complex composite biological age outcomes, at least in humans. These composite outcomes can be made up of a combination of phenotypic data, chronological age, and disease or mortality risk. Here, we develop the first such composite biological age measure for mice: the mouse phenotypic age model (Mouse PhenoAge). This outcome is based on frailty measures, complete blood counts, and mortality risk in a longitudinally assessed cohort of male and female C57BL/6 mice. We then develop clocks to predict Mouse PhenoAge, based on multi-omic models using metabolomic and DNA methylation data. Our models accurately predict Mouse PhenoAge, and residuals of the models are associated with remaining lifespan, even for mice of the same chronological age. These methods offer novel ways to accurately predict mortality in laboratory mice thus reducing the need for lengthy and costly survival studies.

The mechanisms through which mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid malignancies, and their close association with advanced age, remain poorly understood. Here we show that telomere maintenance plays an important role in this phenomenon. First, by studying 454,098 UK Biobank participants, we find that, unlike most CH subtypes, splicing-factor-mutant CH is more common in those with shorter genetically predicted telomeres, as is CH with mutations in PPM1D and the TERT gene promoter. We go on to show that telomere attrition becomes an instrument for clonal selection in advanced age, with splicing factor mutations 'rescuing' HSCs from critical telomere shortening. Our findings expose the lifelong influence of telomere maintenance on hematopoiesis and identify a potential shared mechanism through which different splicing factor mutations drive leukemogenesis. Understanding the mechanistic basis of these observations can open new therapeutic avenues against splicing-factor-mutant CH and hematological or other cancers.

With a general increase in human lifespan, the need for technological advances to develop strategies for healthy aging has assumed great importance. In the present study, our goal is to predict the progression of selected aging phenotypes in a given healthy individual as one continues aging past 65 years. Therefore, we developed a novel framework called Dynamic Views of Aging with conditional Generative Adversarial Networks (or DyViA-GAN) which is capable of predicting the plausible personalized trajectories of a selected aging phenotype conditioned on the available measurements of the phenotype at a few initial time instances, and additional covariates. Given the prevalence of osteoporosis in the aging population, we selected total hip Bone Mineral Density (BMD) of a healthy individual as the phenotype of interest, and baseline individual Body Mass Index (BMI) as the covariate. We trained DyViA-GAN on a publicly available longitudinal dataset of a large cohort of mostly white women in the United States of age 65 years or above. Thus, it generated, for each individual, continuous phenotype trajectories, along with a corresponding region of acceptable predictions, for an age range of 66 to 98 years, for eight different combinations both with and without involving the covariate. Our results clearly demonstrate the potential of generative deep learning frameworks in healthspan research.

Aging increases the risk of a myriad of chronic diseases, which are expensive and difficult to treat owing to their various risk factors. Repurposing existing medications has accelerated the development of therapies aimed at slowing aging. In this study, using IMR90 cells and aged mice, we revealed that enalapril, a drug widely prescribed for hypertension, can improve both cellular senescence and individual health. Mechanistically, phosphorylated Smad1/5/9 act as pivotal mediators of the anti-senescence properties of enalapril. It stimulates downstream genes involved in cell cycle regulation and antioxidative defenses, facilitating cell proliferation and diminishing the production of reactive oxygen species (ROS), thus increasing the antioxidative ability of enalapril. At the organismal level, enalapril has been shown to bolster the physiological performance of various organs; it notably enhances memory capacity and renal function and relieves lipid accumulation. Our work highlights the potential of enalapril to augment antioxidative defenses and combat the effects of aging, thereby indicating its promise as a treatment strategy for aging-associated diseases and its use for healthy aging.

The relationship between the brain and aging remains unclear. Our objective is to explore the causal connections between brain structure,gene expression, and traits associated with aging. Mendelian randomization(MR) analysis was conducted to explore the associations between brain structures and aging-related traits including GrimAge acceleration(GrimAA), PhenoAge acceleration (PhenoAA), HannumAge acceleration(HannumAA), HorvathAge acceleration(HorvathAA), and leukocyte telomere length(LTL). The Linkage Disequilibrium Score Regression(LDSC) method was employed to identify the shared genetic etiology between brain structures and aging. The Summary Data-based Mendelian Randomization(SMR) was utilized to investigate which brain genes have a causal influence on aging. We also examined the expression of the 8 genes derived from the SMR analysis across different cell types in post-mortem human brain specimens. The phenotypes potentially linked to genetics, as indicated by the LDSC outcomes, are as follows:148 phenotypes with GrimAA,150 phenotypes with HannumAA, 160 phenotypes with HorvathAA, 160 phenotypes with PhenoAA,and 110 phenotypes with LTL. Concerning the causal link between brain structures and aging-related traits, 7 brain structures consistently demonstrated a causative effect on GrimAA, while 29 brain structures exerted a causal influence on PhenoAA.Additionally, 7 BIDs revealed a causal relationship with HannumAA. There are 10 and 14 brain structures have a causative effect on HorvathAA and LTL, respectively. SMR revealed that 8 genes(CCDC144B, SHMT1, FAM106A, FAIM, CTD-2303H24.2, EBAG9P1, USP32P2 and OGFOD3) expression in different brain regions affected aging. These genes exhibit different expression patterns in various cells. Our results are in line with the possibility of a causal connection between aging and brain structure.

Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood-brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis, and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo. Collectively, our findings indicate that lipid accumulation drives structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.

The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were identified by velocity-based K-means clustering (silhouette > 0.5). A subset was monitored for post-treatment survival using Kaplan-Meier analysis. Olfactory preference was preserved by all drugs (d = -1.82 to -1.28, P < 0.01), with strongest effects in rapamycin-treated individuals. Rapamycin-treated males matched or exceeded juvenile locomotor activity; phenylbutyrate reduced male activity (d = 1.49, P < 0.05) and acarbose increased walking-to-running ratios (d = -0.75, P < 0.05). Rapamycin increased central exploration and freezing (d = -1.55, P < 0.0001), while acarbose and phenylbutyrate increased peripheral freezing (d = -0.76, P < 0.05). Rapamycin and phenylbutyrate extended maximum running time (d = -2.30 to -1.32, P < 0.0001), with sex-specific jumping gains in rapamycin-treated females and acarbose-treated males. Post-treatment lifespan was prolonged by rapamycin (HR = 0.42, P < 0.001) and reduced by acarbose in females (HR = 2.92 to 3.03, P < 0.05). Intermittent rapamycin preserved survival, cognition, and locomotion, while acarbose and phenylbutyrate produced selective benefits, supporting A. domesticus as a scalable model for geroprotective drug discovery.

Skin ageing is a multifactorial process influenced by both intrinsic (genetic and metabolic) and extrinsic (environmental) factors, leading to noticeable changes such as wrinkles, loss of elasticity, and pigmentation disorders. Recent advancements in regenerative medicine have highlighted the potential of exosomes, small extracellular vesicles, in mediating cellular communication and promoting rejuvenation processes in skin tissues. Exosomes are secreted by various cell types and are rich in bioactive molecules such as proteins, lipids, and nucleic acids, which are crucial for modulating physiological responses. Exosomes derived from mesenchymal stem cells (MSCs), adipose-derived stem cells (ADSCs), and other sources have shown promising results in enhancing skin cell proliferation and collagen synthesis and reducing oxidative stress, thereby mitigating both intrinsic and extrinsic skin ageing. Therefore, this review explores the mechanisms through which exosomes exert their effects, including the modulation of signalling pathways involved in cell growth, anti-inflammatory responses, and matrix remodelling. We also explore innovative delivery systems for exosome-based therapies, such as microneedling and hydrogels, which enhance the penetration and efficacy of these vesicles in skin applications. However, despite their potential, the clinical application of exosome-based therapies faces challenges such as scalability of production, standardization of purification methods, and understanding of long-term effects. This comprehensive investigation emphasised the potential of exosomes in the fields of dermatology and regenerative medicine in combating skin ageing.

Aging varies widely across species yet exhibits universal statistical regularities, such as Gompertzian mortality and scaling laws, challenging efforts to link microscopic mechanisms with macroscopic outcomes. We present a minimal phenomenological model that captures these patterns by reducing complex physiology to three variables: a dynamic factor characterizing reversible physiological responses to stress, an entropic damage variable reflecting irreversible information loss, and a regulatory noise term. This framework reveals two fundamental aging regimes. In stable species, including humans, aging is driven by linear damage accumulation that gradually erodes resilience, producing a hyperbolic trajectory toward a maximum lifespan. In unstable species, such as mice and flies, intrinsic instability drives exponential divergence of biomarkers and mortality. Model predictions agree with DNA methylation dynamics, biomarker autocorrelation, and survival curves across taxa. Crucially, this regime-based view informs intervention strategies at three levels: (i) targeting dynamic hallmarks, (ii) reducing physiological noise, and (iii) slowing or reversing entropic damage - offering a roadmap from near-term healthspan gains to potential extension of human lifespan beyond current limits.

Background: Cognitive reserve (CR) explains individual resilience to age-related cognitive decline, yet its neurobiological basis remains elusive. Current CR proxies lack direct mechanistic links, necessitating a system-level approach integrating brain structure-function interactions. Methods: We developed a novel CR metric using structural MRI and resting-state fMRI from 1,280 older adults. A youth-derived structural-functional prediction model estimated maximal attainable brain function in elders. CR was quantified as the deviation between observed and predicted function. Cross-sectional and longitudinal analyses assessed CR's spatial distribution, cognitive associations, and pathological relevance in MCI/AD cohorts. Results: CR hubs localized to prefrontal, cingulate, and precuneus regions, organized within high-order networks. Higher CR predicted slower cognitive decline (r = -0.21, p < 0.001) and correlated with reduced A{beta} deposition (r = -0.63, p < 0.001). CR demonstrated domain-specific associations with memory, attention, and processing speed. MCI exhibited broader CR reductions than AD, particularly in frontotemporal regions, likely reflecting stage-specific neuroplastic dynamics: early MCI retains partial compensatory capacity but inefficient CR utilization under mounting pathological stress, whereas advanced AD transitions to irreversible structural damage that disrupts CR's adaptive "software" mechanisms. Conclusions: This study establishes CR as a dynamic neuroprotective framework, bridging functional resilience and structural integrity. CR's spatial specificity and inverse link to amyloid pathology highlight its potential as an early biomarker for resisting pathological aging.

The bone marrow (BM) niche plays a critical role in maintaining hematopoietic stem cell function but is highly vulnerable to damage from chemotherapy and radiation. However, current therapeutic strategies for BM niche failure remain significantly limited. The previous study demonstrate that costal cartilage-derived stem cells (CDSCs) exhibit substantial self-renewal and bone-forming capacity; however, whether and how CDSCs contribute to BM microenvironment maintenance remains unknown. In this study, the co-transplantation of CDSCs with multipotent progenitors (MPPs) successfully rescued lethally irradiated mice. By contrast, transplantation of mesenchymal stem cells with MPPs or MPPs alone fails to rescue the mice, suggesting a potential role of CDSCs in hematopoietic reconstitution. RNA-seq and experimental data suggest that CDSCs are involved in rejuvenating the BM niche. Mechanistically, CDSCs not only differentiate into niche components, including bone marrow stromal cells, endothelial cells, and osteoblasts, but also secrete pro-hematopoietic cytokines, thereby rejuvenating the irradiated microenvironment. Additionally, CDSCs protect residual hematopoietic stem and progenitor cells from radiation-induced apoptosis and DNA damage while enhancing niche repair. Finally, through synergy with cyclosporine A, CDSCs markedly enhance hematopoietic recovery in mice with aplastic anemia. Collectively, these findings establish CDSCs as a versatile platform for treating BM failure via microenvironmental restoration.

Unraveling the lifespan trajectories of human brain development is critical for understanding brain health and disease. Recent research demonstrates that electroencephalography signals are composed of periodic and aperiodic components reflecting distinct physiological substrates. This dissociation raises the possibility that they follow different developmental tendencies. Here, we delineate the lifespan trajectories of aperiodic and periodic neural oscillations using a large international cohort (N=1,563, ages 5 to 95, resting state, eyes closed). We reveal two fundamental developmental patterns: a Monotonic decrease in aperiodic activity and a Growth-and-Decline pattern for periodic activity. Both components have inflections around age 20 and transition to a stable senescent phase around age 40. Spatially, anterior regions mainly exhibit aperiodic activity, while periodic activity concentrate on posterior regions and these patterns remain stable throughout life. Crucially, multimodal analysis shows these trajectories map onto distinct biological substrates. The periodic component\'s Growth and Decline trajectory aligns with GABAergic function and myelination. In contrast, the monotonically decreasing trajectory of aperiodic activity mirrors fundamental biomarkers of biological aging, such as DNA methylation and telomere length. Transforming age to a logarithmic scale simplifies these nonlinear trajectories into a linear decreasing and a piecewise concave linear model for aperiodic and periodic components. This form provides a robust and parsimonious framework for quantifying maturation and identifying neurological deviations.

It has been shown that the gut and the brain are linked through a multimodal, bidirectional pathway called the gut-brain axis. In the gut-to-brain way, the gut microbiota has been shown to be the main regulator. In clinical practice, evidence of microbiota and brain interactions comes from the association of gut microbiota alterations with neurological and psychiatric conditions. However, until now, it remains unknown how the gut microbiota influences brain activity. In this paper, we show that different microbiota profiles from healthy older people are associated with different spontaneous activity in medial posterior cortical areas. These areas are associated with memory, language, and emotion processing abilities. Therefore, the results obtained provide evidence that non-pathological gut microbiota profiles are correlated to spontaneous cortical activity associated with cognitive functions that typically deteriorate with age. This implies that early nutritional interventions that modify microbiota composition could help delay or ameliorate natural age-related cognitive decline.

Senescent cell accumulation has been implicated in aging and fibrotic disease, which are both characterized by increased tissue stiffness. However, the direct connection between tissue mechanics and senescence induction remains disputed in the literature. Thus, this work investigates the influence of hydrogel stiffness and viscoelasticity in promoting fibroblast senescence both in combination with genotoxic stress and independently. We show that while lung fibroblast YAP signaling declines with senescence induction, senescent fibroblasts maintain their mechanosensing capabilities with increased YAP nuclear localization on higher stiffness hydrogels. Most notably, we find a unique role for hydrogel viscoelasticity in senescence induction with soft (2 kPa) viscoelastic substrates promoting both the onset and amplification of senescence, even in the absence of genotoxic stress. These changes are not associated with a decline in YAP activity, but instead with a decline in nuclear DAPI intensity, suggesting a role of nuclear organization in driving this phenotype. Overall, this work highlights the influence of mechanics on the induction of senescence and supports the key role of viscoelasticity.

Epigenetic clocks in blood have shown promise as tools to quantify biological age, displaying robust associations with morbidity and all-cause mortality. Whilst the effect of cell-type heterogeneity on epigenetic clock estimates has been explored, such studies have been limited to studying heterogeneity within the adaptive immune system. Much less is known about whether heterogeneity within the innate immune system can impact epigenetic clock estimates and their associations with health outcomes. Here, we apply a high-resolution DNAm reference panel of 19 immune cell-types, including young and adult monocyte, natural killer, and neutrophil subsets, demonstrating how shifts within these innate subtypes display associations with epigenetic clock acceleration, inflammaging, and all-cause mortality. The associations of monocyte heterogeneity with inflammation are further validated using transcriptomic and metabolomic data. Additionally, a non-negligible fraction of nucleated red blood cell-like cells in circulation is found to associate with inflammaging, markers of dysfunctional erythropoiesis, and is a major risk factor for all-cause mortality. These results extend findings obtained within the adaptive immune system to innate immune and erythrocyte-like cells, demonstrating how heterogeneity within these other blood cell compartments is also associated with inflammaging, epigenetic clocks, and health outcomes.

Cardiovascular aging is a complex biological process involving progressive cellular and molecular changes that impair heart and vascular function. This review evaluates both fundamental mechanisms and therapeutic strategies, focusing on how recent advances in pharmacology, gene therapy, and regenerative medicine can be translated into clinical practice to mitigate age-related cardiovascular decline. We conducted a comprehensive analysis of peer-reviewed studies from 2000 to 2023, examining molecular pathways of cardiovascular aging and their modulation through pharmacological, genetic, and lifestyle interventions. The review prioritized clinical trials, translational research, and meta-analyses to assess therapeutic efficacy and safety. Current evidence highlights the effectiveness of senolytic drugs such as dasatinib and quercetin in reducing age-related cardiovascular dysfunction, while rapamycin and metformin show promise in improving cardiac longevity through metabolic regulation. Gene therapies, including clustered regularly interspaced short palindromic repeats (CRISPR)-based interventions, demonstrate potential in preclinical models for cardiac regeneration. Stem cell therapies and nanotechnology-based drug delivery systems are emerging as innovative approaches to enhance tissue repair. In addition, lifestyle modifications such as Mediterranean diet adherence and exercise significantly improve vascular health in aging populations. However, challenges remain in drug delivery, patient-specific responses, and long-term safety of novel therapies. The integration of targeted pharmacological treatments, advanced regenerative techniques, and personalized lifestyle interventions represents a transformative approach to managing cardiovascular aging. Future research should focus on optimizing therapeutic combinations, refining delivery methods, and validating biomarkers for clinical monitoring. A multidisciplinary strategy combining these advances will be essential to improve cardiovascular outcomes in aging populations.

Exposure to infectious disease in early life may have long-term ramifications for health and lifespan. However, reducing pathogen exposure may not be uniformly beneficial. The rise of modern sanitation and reduction of infectious diseases has been implicated in increasing levels of allergy and immune dysregulation: termed, the "hygiene hypothesis." This study leverages quasi-experimental variation from combining precampaign hookworm exposure with the Rockefeller Sanitary Commission's deworming campaign in the early 20th century to rigorously examine the impacts of childhood hookworm exposure on adult lifespan and morbidity. Findings show deworming before age five leads to 2.5 additional months of life in a large sample of adult death records. Further, decreasing hookworm exposure is related to improvements in biomarkers for inflammation and skin-tested allergies, in contrast to predictions of the "hygiene hypothesis." Placebo tests using health outcomes that should not be affected by deworming do not show similar patterns. Overall, childhood deworming leads to improvements in morbidity and lifespan decades later.

Short and long sleep durations have been inconsistently linked to aging and health outcomes, potentially due to underexplored nonlinear associations. Using phenotypic and genomic data from the UK Biobank (n=442,664), we applied multivariable linear regression, restricted cubic splines, and Mendelian randomization (MR) to analyze nonlinear relationships between self-reported sleep duration and biomarkers of accelerated aging: PhenoAge acceleration (PhenoAgeAccel), BioAge acceleration (BioAgeAccel), and leukocyte telomere length (LTL). Functional annotation analyses were performed to assess potential shared biological pathways using epigenomic profiles. Observational analyses supported U-shaped phenotypic associations between sleep duration and PhenoAgeAccel/BioAgeAccel, with optimal sleep around 7 h/d. For LTL, linear models suggested a U-shape, while spline models indicated an inverted reverse J-pattern. MR analyses corroborated the deleterious impacts of insufficient, but not excessive, sleep, by revealing a threshold nonlinear relationship between increasing genetically-predicted sleep duration up to 7 h/d and lower PhenoAgeAccel/BioAgeAccel, and a linear relationship with longer LTL. Cell-type enrichment analyses connected short sleep to BioAgeAccel/LTL through pathways related to muscle maintenance and immune function. These findings suggest that extending sleep may mitigate accelerated aging, though further research is needed to clarify the underlying biological mechanisms and whether excessive sleep also contributes causally to biological aging.

Ageing of the haematopoietic system is characterized by phenotypic and functional impairments that are driven by alterations of haematopoietic stem cells and of the bone marrow niche. Haematopoietic stem cells are responsible for the production of all the different cell types that constitute the blood, and their maintenance and differentiation must be tightly regulated during the whole life of an organism. Exciting new data emphasize that central aspects of blood ageing, ranging from inflammageing and immunosenescence to clonal haematopoiesis, are mechanistically linked to dysfunction and ageing of other tissues, supporting a central role for the haematopoietic system in this context. Here we review some of the recent findings with a focus on ageing of the haematopoietic system and provide an overview of its role in driving healthspan and lifespan of the whole organism.

Research in the field of mitochondrial biomarkers plays an important role in understanding the processes of cellular aging. Mitochondria are not only the energy centers of the cell, but also key regulators of signaling within the cell. They significantly affect the life and function of the cell. The aging process of cells is associated with various factors, including DNA damage, disruption of the cell cycle, changes in mitochondria, and problems with signal transmission. Mitochondrial dysfunction is a major contributor to cellular and organismal aging. As we age, there is an accumulation of dysfunctional mitochondria, leading to decreased efficiency of oxidative phosphorylation and increased production of reactive oxygen species. This review focuses on the main mitochondrial markers involved in the mechanisms of cell aging: DRP1, Prohibitin, Parkin, PINK1, MFF, VDAC, TOM. These signaling molecules are involved in mitochondrial fission and the mechanisms of mitochondria-dependent apoptosis, in the regulation of mitochondrial respiratory activity, ensuring the stability of the organization and copying of mitochondrial DNA, protecting cells from oxidative stress, in the process of autophagy of damaged mitochondria, in protective mechanisms during stress-induced mitochondrial dysfunction. Analysis of mitochondrial markers can provide valuable information about the state of cells and their functional significance at various stages of aging, which could promote our understanding of cellular aging mechanisms and developing corrective methods. These insights highlight mitochondrial proteins as potential therapeutic targets to combat age-related diseases.

Most of our current understanding of genome integrity derives from studies in proliferating cells, yet most somatic cells in multicellular organisms reside in non-dividing, quiescent states. Using Schizosaccharomyces pombe, we dissected the mechanisms by which quiescent cells maintain genome stability in the absence of DNA replication. Combining time-resolved mutational analyses, DNA damage assays, and genetic dissection of DNA repair pathways, we found that quiescent cells progressively accumulate distinct types of spontaneous lesions-particularly uracil residues, abasic sites, and ribonucleotide insertions-which are counteracted by a modular network of repair mechanisms. Base excision repair (BER), ribonucleotide excision repair (RER), and R-loop resolution each contribute uniquely to genome surveillance in G0. We show that uracil incorporation becomes a predominant threat under quiescent conditions, especially when nucleotide pools are imbalanced. BER-deficient mutants (e.g., nth1{Delta}, ung1{Delta}) exhibit mutation spectra dominated by C: G > T: A transitions and oxidative lesions, while synthetic combinations reveal compensatory or epistatic interactions. Using single-cell micromanipulation and viability assays, we show that specific gene deletions (e.g., hnt3{Delta}rhp52{Delta}, sen1{Delta}rad13{Delta}) severely compromise post-quiescence recovery, underscoring the importance of cooperative DNA repair even in non-replicative contexts. Our results delineate a functionally compartmentalized hierarchy of DNA repair activities during quiescence, providing a new framework to understand how non-dividing cells limit genome instability, with implications for aging, cancer dormancy, and neurodegeneration.

The fast-paced improvements in mortality in high-income countries since the early 1900s have led to a sustained increase in life expectancy. However, whether this linear trend will continue or life expectancy gains will decelerate in the near future remains unclear. To answer this question, we apply multiple established and recently developed mortality forecasting methods to estimate cohort life expectancy for individuals born between 1939 and 2000 in 23 high-income countries. Across all forecasting methods, our results robustly and consistently indicate a deceleration in cohort life expectancy. The previously observed pace of improvement, 0.46 y per cohort, declines by 37% to 52%, depending on the method used. Robustness checks suggest that these findings are unlikely to be solely due to downward bias in cohort life expectancy forecasts. Furthermore, an age-decomposition analysis indicates that this deceleration is primarily driven by a slower pace of mortality improvement at very young ages. Over half of the total deceleration is attributable to mortality trends under age 5, while more than two-thirds is explained by mortality trends under age 20. This pattern had already emerged in the observed data for the cohorts included in our analysis. Thus, even if these estimates turned out to be overly pessimistic, it is unlikely that the deceleration will reverse in the near future.

Mitochondria are crucial for cell survival and function, partly through peptides encoded by the mitochondrial genome. Although mitochondrial dysfunction is a hallmark of age-related diseases and senescence, the role of mitochondrial-genome-encoded peptides in pancreatic β-cell senescence during type 1 and type 2 diabetes pathogenesis is largely unexplored. Here we show that MOTS-c levels decrease with aging and senescence in pancreatic islet cells. Treating aged C57BL/6 mouse pancreatic islets with MOTS-c reduced pancreatic islet senescence by modulating nuclear gene expression and metabolites involved in β-cell senescence. MOTS-c treatment improved pancreatic islet senescence and glucose intolerance in S961-treated C57BL/6 and in nonobese diabetic mice. In humans, circulating MOTS-c levels are lower in type 2 diabetes patients compared with healthy controls. Our findings suggest that mitochondrial-encoded MOTS-c regulate pancreatic islet cell senescence and that MOTS-c could act as a senotherapeutic agent to prevent pancreatic islet cell senescence and diabetes progression.

Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults, yet its pathogenesis remains incompletely understood. The retinal pigment epithelium (RPE) plays a vital role in maintaining retinal homeostasis. In this study, the expression of senescence marker protein p16 is observed to be upregulated in the RPE of early DR mouse models. Transcriptomic profiling reveals that PDZ domain protein 1 (PDZK1) expression is downregulated in RPE cells after 48 hours of high-glucose stimulation. Overexpression of PDZK1 reduces senescence markers in RPE cells, promoting cell proliferation and transport functions. Mechanistically, PDZK1 alleviates RPE cell senescence by interacting with 14-3-3ε to regulate the mTOR pathway, which is closely related to reducing oxidative stress and enhancing autophagy flux. In streptozotocin-induced DR mouse models, both PDZK1 overexpression-mediated senescence inhibition and Nutlin-3a-induced clearance of senescent RPE cells successfully downregulate retinal senescence markers and improve early-stage DR lesions. In summary, this study identifies a novel PDZK1-14-3-3ε-mTOR axis governing high-glucose-induced RPE cell senescence, and provides the first direct evidence linking RPE cell senescence to DR pathogenesis. These findings reveal a promising therapeutic strategy for DR intervention.