Longevity Papers

Aging emerges from nonlinear interactions among primary, antagonistic, and integrative hallmarks that progressively erode tissue resilience. As global demographics shift and chronic disease burden intensifies, extending healthspan with mechanistic precision has become imperative, accelerating the incorporation of artificial intelligence into geroscience. AI leverages multi-omics, spatial biology, imaging, and clinical data to reveal nonlinear structures linking hallmark interactions to tissue vulnerability and organismal decline. These mechanistic insights inform target prioritization, perturbation-based pathway modeling, and rational design of multi-target geroprotectors, including compounds already advancing through clinical trials. Beyond discovery, AI supports synthetic data generation, cross-disease repurposing, and personalized geriatric care through digital phenotyping and predictive analytics. However, these advances hinge on confronting fundamental challenges in data quality, confounding variables, batch effects, and technical artifacts that risk encoding spurious correlations, necessitating hierarchical experimental validation and explainable AI to distinguish causal mechanisms from epiphenomena. Algorithmic bias, digital ageism, privacy vulnerabilities, and infrastructural inequalities further threaten to exacerbate disparities among vulnerable aging populations. This review uniquely traces AI across the complete translational continuum, from hallmark-grounded biomarker discovery to clinical deployment, while positioning validation rigor and ethical infrastructure as core scientific determinants of a transformative AI-geroscience ecosystem.

The cerebellum contains most of the brain's neurons and supports many functions, yet how it changes with age remains unclear. Here we used three brain imaging studies spanning 47,000 adults and examined how different parts of the cerebellum age and their relation to cognition. We characterized cerebellar aging using volumetry and the T1-weighted/T2-weighted ratio, and corroborated these findings with quantitative magnetic resonance imaging in an independent sample. We show a spatially heterogeneous pattern of aging in which specific association and motor-related regions show steeper relationships with age than other lobules. Greater cerebellar volume was associated with higher cognitive scores with increasing age, suggesting that cerebellar structure may provide brain reserve that helps maintain function despite aging. In patients with Alzheimer's disease, cerebellar volume was linked to cognition in individuals with lower amyloid burden, especially in those carrying two copies of the APOE-ε4 risk gene. This supports a threshold-reserve model, in which the cerebellum helps sustain cognition until pathology becomes widespread. These results show that the cerebellum has an active role in healthy cognitive aging and resilience.

Muscle regenerative capacity declines with aging and disease, which leads to muscle loss and reduced lifespan. Muscle regenerative failure is related to a disrupted network orchestrated by multiple muscle-harbored cell types; whether and how the interplay between macrophages and myofibers contributes to this process is largely unknown. Herein, we report upregulation of histone methyltransferase G9a in both aged human muscle and mouse muscle after injury. Deletion of G9a in either myeloid cells or myofibers accelerates muscle regeneration. Mechanistically, G9a down-regulates macrophage-derived interleukin 13 (IL13) and suppresses myofiber-derived myokine musclin, respectively, to inhibit myogenesis and macrophage phenotype transition during muscle regeneration. Either IL13 or musclin, per se, accelerated muscle regeneration, and their combined administration showed synergistic effects with therapeutic potentials for muscle degeneration disorders. Collectively, we highlight a crosstalk between macrophages and myofibers through IL13-Stat6 signaling and musclin, both regulated by G9a, which steers a pro-recovery microenvironment after muscle injury, with therapeutic potentials for muscle degeneration disorders.

Identifying biomarkers that identify vulnerability to age-related cognitive decline is a major priority in aging research. Adropin, a circulating peptide that regulates metabolic and vascular homeostasis, has been associated with cognitive performance in humans, but its relevance across species has remained unclear. Here we report low plasma adropin concentrations associate with poor decision-making in aged rhesus macaques subject to an increasing food choice test paradigm. Animals with higher adropin levels exhibited faster improvement in reaction time and reductions of variability in reaction time, whereas intrinsic performance on simple tasks was preserved. These associations were most apparent under conditions requiring adaptation to novelty or stress, suggesting that adropin may signal cognitive resilience rather than baseline executive capacity. The findings parallel mechanistic data from rodent models linking adropin signaling to mitochondrial function, resistance to oxidative stress, and hippocampal-dependent learning. Together, these results support measurements of circulating adropin as a conserved, translational biomarker of cognitive aging and a potential therapeutic target.

Reproductive aging in females is characterized by the irreversible depletion of ovarian follicles, yet the structure and function of the post-reproductive ovary remain poorly defined. Using paired histological and bulk transcriptomic analyses of ovaries from reproductively young (2 m), reproductively old (18 m), and post-reproductive (24 m) mice, we mapped how ovarian identity evolves beyond follicle exhaustion. As expected, follicle loss, stromal remodeling, and increased collagen deposition were observed in the reproductively old and post-reproductive cohorts. Transcriptomic analyses revealed a shift from reproductive functionality to an immune-dominant signature with age. Correspondingly, post-reproductive ovaries exhibited increased infiltration of T cells, macrophages, and multinucleated giant cells. Although old and post-reproductive ovaries diverged substantially from young ovaries, they also showed discrete transcriptomic differences, indicating that the ovary continues to undergo molecular changes after reproductive senescence. Lastly, age-dependent changes in ovarian factors that are predicted to be secreted suggest that the post-reproductive ovary could be a source of pro-inflammatory signaling mediators with the potential to modulate extra-ovarian tissues. These findings challenge the assumption that the post-reproductive ovary is inert, instead indicating that it acquires an immune identity with potential endocrine and paracrine influence on whole-body aging.

Cardiovascular health is increasingly recognized as a key determinant of cognitive aging. The American Heart Association recently introduced Life's Essential 8 (LE8), integrating both behavioral and clinical components of cardiovascular health. However, the relative contributions of behavioral versus clinical factors to cognitive outcomes remain unclear, particularly in Chinese older adults.

Innate immunity within the central nervous system (CNS) plays key roles in shaping both healthy brain aging and vulnerability to neurodegenerative disease. Microglia, the tissue-resident macrophages of the CNS, play a key role in mediating the innate immune responses to age-associated pathologies. A growing body of literature details the roles of microglia in responding to white matter degeneration, misfolded proteins, and cell death. These functions depend on cell-surface receptors that enable microglia to sample and react to changes in their environment. Recent studies highlight the importance of receptors associated with immunoreceptor tyrosine-based activation and inhibitory motifs (ITAMs/ITIMs) in pathological brain aging. In this review, we describe how ITAM/ITIM-associated receptors and their downstream signaling pathways shape microglial responses to neurodegenerative disease and aging. A deeper understanding of microglial activation and resolution may provide tools to harness these cells' capacity to maintain and extend neurological healthspan.

In postmenopausal women, ovarian function decreases rapidly and is accompanied by senescence-related changes in skeletal muscle. Administration of human embryonic stem cell-derived mesenchymal progenitor cells (hESC-MPCs) influenced the functional maintenance of perimenopausal ovaries in female mice.

Different species age in similar ways but their lifespans differ by orders of magnitude. It is not clear how these similarities and differences arise from the accumulation of damage that underlies aging. Does long lifespan arise from reduced damage production, increased removal or enhanced robustness to damage? Here we apply the saturating removal model-a stochastic model of damage accumulation and removal-and fit it to survival data from well-studied species. Several parameters have near-universal values including ratios of removal rate, noise amplitude and death threshold. The model parameter that best predicts lifespan is the damage production rate, which spans seven orders of magnitude. We identify two distinct aging regimes: ballistic aging where damage production outpaces removal, characterizing yeast, nematodes, flies and mice, and quasi-steady-state aging, where damage tracks a moving set point of balanced production and removal, characterizing humans, dogs, guinea pigs and cats. These results provide a mechanistic model-based basis of comparative aging that awaits experimental validation.

A decline in Klotho expression is a defining feature of aging and contributes to cellular dysfunctions. Here, we developed an engineered IVT Klotho mRNA incorporating ARCA capping. Ψ-modification and poly(A) tailing, delivered using a hyperbranched poly(β-amino ester) (HPAE)-based platform to enhance intracellular delivery and translation. Using CRISPR edited KL (-/-) iPSCs and derived iMSCs, we show that loss of KL induces a robust senescent phenotype characterized by activation of p53-p21-p16 pathways, mitochondrial depolarization, elevated ROS, and altered Ca

Executive function supports goal-directed behaviour and is particularly vulnerable to age-related decline. Long-term exercise habits represent a promising lifestyle factor for maintaining cognitive health, yet it remains unclear whether exercise-associated advantages are domain-general or selectively expressed as a function of task type, age, and level of analysis. Using a cross-sectional four-group design stratified by age (younger vs. older adults) and long-term exercise-habit status (exercisers vs. non-exercisers), we integrated behavioural-efficiency indices (inverse efficiency score, IES), latent-efficiency indices (drift-rate measures derived from hierarchical drift-diffusion modelling, hDDM), and neural-efficiency indices (activation-pattern similarity from task-based functional magnetic resonance imaging, fMRI) across five paradigms: the Multi-Source Interference Task (MSIT), Stroop, task switching, N-back, and relational processing. Long-term exercise habits were associated with task-specific efficiency advantages, with age-dependent patterns emerging primarily in behavioural outcomes and cross-level gradients. Older adults showed consistently lower behavioural, latent, and neural efficiency across tasks. Exercise-related behavioural advantages were most evident in older adults and were observed in tasks showing significant Age × Exercise interactions. In younger adults, exercise-associated advantages were not reliably expressed at the behavioural level, whereas cross-level gradient analyses suggested stronger expression at latent and neural levels. Mediation analyses indicated that latent efficiency statistically mediated the association between neural efficiency and behavioural efficiency across all tasks. Cross-level gradient analyses further showed that the distribution of exercise-related advantages differed by age: in younger adults, advantages increased from the behavioural to the neural level, whereas in older adults they were more robust at the behavioural and latent levels and comparatively smaller at the neural level. Together, these findings suggest that long-term exercise habits are associated with multi-level differences in cognitive processing efficiency, with systematic age-related variation in their cross-level expression.

Aging is accompanied by progressive physiological decline and an increased risk of chronic disease, motivating the search for interventions that promote healthy longevity. We found that mid-life administration of Corylin, a flavonoid derived from Psoralea corylifolia, improves metabolic function, muscle integrity, and physical performance in mice maintained on a standard diet. Corylin significantly extends median lifespan in female mice, with an 11.9% increase and a 33% higher survival rate at 125 weeks, whereas no comparable benefit is observed in males. Here, we show that integrated multi-omics analyses across multiple tissues reveal coordinated age-associated molecular changes modulated by Corylin. These analyses link Corylin treatment to suppression of mechanistic target of rapamycin signaling, which is further supported by direct interaction between Corylin and Ras-related GTP-binding protein A. In addition, Corylin restores sirtuin 3 protein levels and energy-associated metabolic programs in female mice, providing mechanistic insight into sex-dependent longevity benefits.

Cataract, the leading cause of blindness worldwide, results from age-related misfolding and aggregation of long-lived crystallin proteins in the eye lens. The cytoplasm of fiber cells in the lens core becomes increasingly oxidizing with age, allowing non-native disulfides to drive light-scattering aggregation of γ-crystallins. Despite this vulnerability to non-native disulfides, and despite lacking any native-state disulfides, γ-crystallins are unexpectedly Cys-rich. To understand this paradox, we investigated how replacing all four Cys residues in the aggregation-prone N-terminal domain of γD-crystallin affects its stability and aggregation. Cys removal precludes the disulfide-driven aggregation pathway we reported previously. Here, we characterize two full-length human γD-crystallin variants: C18S/C32S/C41S/C78S ("NCS") and C18T/C32A/C41A/C78A ("NCA/T"). Thermodynamic and kinetic stability measurements indicate the N-terminal domain was greatly destabilized in both variants relative to WT, with NCS more destabilized than NCA/T. Upon mild heating or partial denaturation, both variants formed light-scattering aggregates, which were amorphous by transmission electron microscopy. Surprisingly, the aggregation proceeded exclusively from a dimer of natively folded molecules held together by a C-terminal disulfide bridge. These dimers form readily even in the WT protein, and evidence of them has been found in the lens. Aggregation was strongly suppressed by the lens's native chemical chaperone, myo-inositol. The aggregation rate depended linearly on protein concentration, indicating that the rate limiting step was a transformation of the natively-folded to misfolded molecules within the dimer. We propose that many age-related chemical modifications could destabilize the native fold of human γD-crystallin, favor misfolding within disulfide-bridged dimers, and thereby cause aggregation.

Heart failure is a leading cause of morbidity and mortality worldwide, particularly among the growing elderly population. In degenerative aging and autoimmune diseases, the cytoplasmic leak of mitochondrial DNA, resulting from mitochondrial cristae compromise, triggers persistent low-grade cellular inflammation through activation of the cGAS (cyclic GMP [guanosine monophosphate]-AMP [adenosine monophosphate] synthase)-STING (stimulator of interferon genes) pathway and the IFN-I (type I interferon) response. However, how and whether mitochondrial architectural components and cardiomyocyte inflammation drive cardiac aging and failure are not yet well understood.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and represents a major societal burden. Aging is the strongest risk factor for AD, and partial cellular reprogramming using Yamanaka factors (YFs) has recently emerged as a strategy to counteract age-associated dysfunction. However, the mechanisms by which partial reprogramming ameliorates AD-related phenotypes remain poorly defined. Here, we investigated whether targeted and intermittent expression of YFs in hippocampal neurons restores cognitive function and neural network integrity in the P301S mouse model of tauopathy. We first show that controlled YFs expression in hippocampal neurons increases excitatory synaptic transmission and enhances neural synchrony in GCaMP6-expressing neuronal networks. We then induced intermittent, neuron-specific YFs expression for six months in adult control and P301S mice. This intervention led to a sex-dependent improvement in cognitive and emotional behaviors in P301S mice, accompanied by a reduction in Tau pathology and partial restoration of epigenetic aging markers. At the molecular level, reprogramming restored the composition and signaling of N-methyl-D-aspartate receptor (NMDAR) macro-complexes, including key subunits and AD-associated risk factors such as proline-rich tyrosine kinase 2 (PYK2/PTK2B). Importantly, impaired hippocampal neural synchrony observed in P301S mice was also rescued. Together, these findings demonstrate that targeted, partial in vivo neuronal reprogramming reverses behavioral and network-level deficits in a mouse model of AD and identify NMDAR-associated signaling as a potential mechanistic mediator of this effect.

Obesity is a major global health issue with significant metabolic heterogeneity. While it is associated with accelerated biological aging, the relationship between distinct metabolic obesity phenotypes and biological age (BA) remains unclear. In this study, we evaluated the interaction between metabolic health status and adiposity in relation to biological aging.

Lifestyle research on cognitive health has been largely unidirectional and cross-sectional, with limited attention to multidimensional and bidirectional relationships; this study examines longitudinal associations in middle- and older adults. Data from the Korean Longitudinal Study of Aging (2006-2020) included physiological and psychosocial lifestyle factors and cognition assessed by the Korean version of the Mini-Mental State Examination (K-MMSE). Analyses used Mplus 8.9 with cross-lagged panel model (CLPM) and random intercept CLPM (RI-CLPM), adjusting for sex, age, smoking, drinking, and disability. CLPM showed significant lagged effects of lifestyle on cognition across waves (β = .010 to .013,

While happily married couples may age more slowly, the effect's magnitude varies widely. This variation could stem from partners' reinforcing each other's healthy and unhealthy behaviors. Grounded in symptom-system fit theory, we examined associations of marital quality (marital satisfaction and behavior) with biological aging in 107 middle-aged and older mixed-gender couples both cross-sectionally and over two years, assessing the moderating role of couples' health behaviors. Cross-sectionally, happier couples had lower T cell p16

Aging and degeneration are biologically distinct processes in intervertebral discs, but are difficult to differentiate radiologically. Metabolomics reflects real-time biochemical activity, and age-stratified metabolomic profiling of normal and degenerated discs may identify preclinical degeneration and reveal molecular signatures distinguishing normal aging from degeneration.

Cellular senescence is an irreversible stress response, which leads to loss of cellular function and remodelling of the cellular secretory profile. In humans, pancreatic β-cells undergo cellular senescence during the progression to type 2 diabetes (T2D). However, the mechanism linking β-cell senescence to islet dysfunction remains unknown and thus, the therapeutic potential of targeting senescent cells in T2D is not established. Herein, we identified a subpopulation of senescent β-cells expressing p21, which emerged early in the progression of T2D in humans and mice. Spatial transcriptomics, and proteomics analyses confirmed senescence and loss of cellular identity in this subpopulation in humans. Functional analysis revealed lack of glucose responsiveness, high basal insulin secretion, and transcription of senescence-associated secretory phenotype (SASP) factors. SASP factors from p21+ β-cells induced secondary senescence in neighbouring cells, characterized by dysfunction and loss of identity. Janus kinase inhibitors (JAKi) counteracted the induction of secondary senescence and restored β-cell function in islets from humans with T2D and in high-fat diet-fed mice. These findings reveal the critical role of p21+ β-cells in T2D pathogenesis and the therapeutic potential of targeting this pathophysiological process.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder globally and a leading cause of disability and death among the elderly. As populations age worldwide, the epidemiological burden of AD is expected to more than double by 2050, surpassing 150 million affected individuals. While genetic susceptibility, particularly the apolipoprotein E ε4 (APOE4) allele, modulates individual risk, most AD cases are late-onset and shaped by complex interactions between genetic background and modifiable environmental exposures. Environmental pollution has emerged as a critical and potentially preventable contributor to this burden. The 2024 Lancet Commission on Dementia Prevention, Intervention, and Care has identified 14 modifiable risk factors, with air pollution explicitly included. Drawing on evidence from human epidemiological cohorts, experimental animal models, and in vitro neuronal/glial systems, the present review aims to synthesize mechanistic evidence linking environmental pollutant classes to AD-relevant neuropathology. The review examines the growing body of evidence linking major categories of environmental pollutants (ambient particulate matter, heavy metals, pesticides, PFAS, and emerging contaminants including microplastics and nanoplastics) to AD risk and pathogenesis. Special attention is given to studies showing that the characteristic neuropathological features of AD may emerge in children and young adults chronically exposed to heavily polluted urban environments, which highlights critical concerns about when and how these changes develop throughout life. Shared mechanistic pathways through which environmental pollutants promote neurodegeneration are discussed, including neuroinflammation, oxidative stress, blood-brain barrier disruption, tau kinase dysregulation, epigenetic reprogramming, and gut-brain axis dysbiosis. The review also examines the amplifying role of biological aging on neurotoxic vulnerability and proposes a comprehensive, multi-level prevention framework addressing individual exposure reduction, clinical risk identification, and population-level policy interventions.

Excessive alcohol consumption poses significant health risks and is closely associated with oxidative damage. The KEAP1-NRF2-ARE signaling pathway serves as the primary antioxidant system. However, current small molecule inhibitors are all covalently bound to KEAP1, meaning that once bound, they are not easily dissociated, while continuous inhibition of KEAP1 exhibits severe side effects. In this study, BLI, CETSA, Pull-down, Co-IP, and HDX-MS assay analysis were conducted to detect the KEAP1 binding behavior of natural product, capsaicin (CAP), both in vitro and in cells. The ethanol-induced acute gastric mucosal damage rat model was also established to evaluate the therapeutic effect of CAP. Our findings demonstrated that CAP mitigated mitochondrial damage, facilitated the nuclear translocation of NRF2, leading to the up-regulation of downstream antioxidant response elements, HMOX1, TXN, GSS, and NQO1 in GES-1 cells. Furthermore, CAP directly bind to KEAP1 and inhibit the interaction between KEAP1 and NRF2. In the KEAP1-knockout 293T cells, CAP failed to activate NRF2 expression. We identified that CAP non-covalently bound to the Kelch domain and allosterically regulated three specific regions of KEAP1: L342-L355, D394-G423, and N482-N495. To improve drug solubility and delivery efficiency, we developed IR-Dye800 modified albumin-coated CAP nanoparticles. The nanoparticles significantly reduced the gastric mucosal inflammation and activated NRF2 downstream genes in vivo. Our hypothesis was further verified our hypothesis in Nrf2-knockout mice. This study provides new insights that CAP is a safe and novel NRF2 agonist by allosterically regulating KEAP1, which may contribute to the development of lead drugs for oxidative stress-related illness, e.g., aging, cancer, neurodegenerative, and cardiovascular diseases.

Sarcopenia, the age-associated loss of skeletal muscle mass and function, currently lacks effective pharmacological interventions. Pyr-Apelin-13, a potent endogenous peptide that stimulates mitochondrial biogenesis and myofiber regeneration, is limited by rapid plasma clearance and the need for frequent injections. We report the first preclinical evaluation of a transdermal Pyr-Apelin-13 microneedle (MN) patch (HeroPatch) in aged mice. The solid-state "drug-in-resin" design achieved near-complete release efficiency (≈100% in vitro; 83-99% in vivo), enabling reproducible multi-milligram delivery with minimal residual loss. Daily MN dosing significantly improved muscle fiber cross-sectional area and grip strength relative to controls, with outcomes comparable to daily intraperitoneal injection. Histological analysis revealed a shift toward larger fiber sizes, consistent with enhanced myofiber remodeling, and mitochondrial DNA content increased concordantly. Weekly dosing produced smaller, non-significant trends, reflecting lower cumulative exposure. These findings demonstrate that HeroPatch enables efficient, reproducible, and non-invasive systemic delivery of Apelin-13, providing a scalable platform for peptide-based therapy of sarcopenia and related muscle-wasting disorders.

Ageing and neurodegeneration are characterized by the progressive breakdown of organellar communication between mitochondria, the endoplasmic reticulum (ER), and lysosomes. Recent findings underline mitophagy as a central modulator of this interconnected network. Impaired mitophagy induces ER fragmentation, lysosomal dysfunction, imbalanced mitochondrial dynamics, and deregulation of calcium homeostasis, suggesting that mitochondrial turnover is essential for the maintenance of global organellar architecture. Conversely, restoring mitophagy re-establishes structural integrity and functional coordination across subcellular compartments. Notably, Urolithin A (UA) rejuvenates inter-organelle crosstalk through a defined calcium-dependent mechanism. UA promotes ER-derived calcium release via ITR-1/ITPR/InsP3R, EMC-3/EMC3, and TMCO-1/TMCO1, and enhances calcium uptake into mitochondria through MCU-1/MCU. This calcium flux activates DRP-1/DRP1-mediated mitochondrial fission, facilitating mi-tophagy initiation. In parallel, calcium-dependent activation of the UNC-43/CaMKII-SKN-1/Nrf2 axis stimulates mitochondrial biogenesis and metabolic adaptation. Furthermore, UA increases ER-mitochondrial contact sites (MAMs) and restores lysosomal activity, thereby re-establishing functional inter-organellar communication in nematodes and mammalian cells. These findings establish mitophagy as a central node of cellular and tissue homeostasis, acting through the stabilization of the organellar communication network to promote healthspan and lifespan while highlighting the need for future studies to validate these mechanisms across human tissues and disease-relevant cellular contexts.

Biotechnological interventions in biological aging could provide substantial opportunities to reduce, mitigate, or even eliminate this process, and could create better conditions for the pursuit of meaningful life projects. In this article, we contrast two (allegedly) opposing ethical perspectives on these interventions: on the one hand, individual welfarist approaches; and on the other, those rooted in social-structural considerations. After providing an overview of the current state of the literature on the ethics of aging, we show why it is generally believed that both perspectives offer distinct assessments of biotechnological interventions in biological aging, relying on arguments that seem a priori irreconcilable. However, in the second and third section, we argue that this idea is misguided and that both perspectives are intertwined and complement each other. First, we argue that the concepts of well-being, disability, and aging encompass both individual and social dimensions. Second, we critically discuss how both perspectives are essential for assessing the desirability of these biotechnological interventions.

Sleep and circadian disturbances precede motor symptoms in Parkinson's disease (PD), acting as early neurodegeneration indicators. Disrupted rhythms, mitochondrial dysfunction, neuroinflammation, and neurotransmitter imbalance create a self-reinforcing cycle that accelerates progression. DJ-1 (PARK7), a redox-sensitive protein, provides central neuroprotection by preserving mitochondrial integrity, mitigating oxidative stress, and curbing neuroinflammation. DJ-1 loss or mutation weakens antioxidant defences, promotes α-synuclein aggregation, and worsens dopaminergic neuron loss, positioning it as a key biomarker and therapeutic target. Oxidative stress, mitochondrial impairment, chronic inflammation, and telomere attrition link neurodegeneration to systemic and skin aging via a "neuro-cutaneous aging axis." Similar mechanisms include mitochondrial dysfunction, ferroptosis, and redox imbalance energy Alzheimer's cognitive decline. Chronotherapy, NRF2 activators, phytochemicals, nanozymes, and postbiotics offer promise in restoring redox balance and halting progression. Telomere dysfunction and genomic instability further connect neural and skin aging, modulated by environment, diet, and lifestyle. Micro physiological systems, predictive analytics, and personalized medicine enhance mechanistic insights and therapy development. Targeting interconnected pathways of redox regulation, mitochondrial function, proteostasis, and telomere maintenance provides a unified approach to combat neurodegeneration and aging. DJ-1-focused therapies, paired with antioxidants and mitochondrial interventions, hold strong potential for disease modification and healthy aging.

The pathophysiology of neurodegenerative illnesses is increasingly understood to be influenced by vascular aging, with blood-brain barrier (BBB) disruption emerging as a crucial mechanistic connection. Comprising endothelial cells, pericytes, astrocytes, and microglia, the BBB is a complex neurovascular unit (NVU) that strictly regulates molecular trafficking and shields neural tissue from circulating toxins and immune cells, therefore maintaining central nervous system homeostasis. The integrity of the BBB is compromised as people age due to structural and functional changes in the cerebrovasculature, such as endothelial senescence, pericyte loss, mitochondrial dysfunction, and persistent low-grade inflammation. These alterations speed up neuronal damage and encourage the development of classical proteinopathies like tau aggregation and amyloid-β by making it easier for neurotoxic proteins, immunological mediators, and metabolic waste to enter the brain parenchyma. BBB disruption is both an early occurrence and a factor in the development of neurodegenerative diseases including Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. It exacerbates neuroinflammation, hinders clearance processes, and contributes to cognitive decline. Recent developments in single-cell omics, fluid biomarkers, and molecular imaging have made it possible to identify and characterize BBB failure in preclinical and clinical contexts, creating new opportunities for early diagnosis and treatment. Restoring BBB function and addressing vascular aging are two viable approaches to alter the course of neurodegenerative illnesses and enhance their prognoses. The processes, effects, and translational potential of vascular aging and BBB degradation in neurodegeneration are summarized in this review, which also identifies new treatment targets and research objectives for the future.

By 2050, nearly 20% of the global population will exceed 60 years old, experiencing compromised physiological and functional abilities, neurological disorders, and sarcopenia. Geroscience has evolved immensely through OMICS approaches and high-throughput technologies, generating massive datasets requiring efficient management, annotation, and storage. This highlights the need for user-friendly databases integrated with machine learning (ML) and artificial intelligence (AI). This review provides a comparative synthesis of the state-of-the-art databases on longevity genes, age-related signaling pathways, model organism phenotypes, and manually curated aging/antiaging experimental studies. We delineate the architecture, methodology, and functional features of contemporary geroscience databases, detailing the objectives, content, and dataset size, including multiomics information. Critically, these databases facilitate geriatric interventions: from biomarker discovery to drug repositioning, significantly impacting aging-associated conditions like muscle loss and Alzheimer's. In addition, we present updated insights into the increasing use of deep aging clocks and multiomics databases, coupled with ML- and AI-dependent analyses, fostering advanced dataset development. Interestingly, these tools are capable of dataset pattern recognition, predictive modeling, and the generation of research hypotheses. By bridging manually curated and AI-driven tools, this review offers a holistic view of the complementary strengths of aging databases, paving the way for the next generation of geroscience.

Kaempferol (KMP) is a dietary compound found in a wide range of foods. The therapeutic capabilities of these foods are associated with the phenolic compounds present in their structures, particularly their antioxidant activity. Remarkable medical care areas linked to KMP include pain relief, anti-aging, antiallergic, anticancer, antidiabetic, anti-inflammatory, antioxidant, antipyretic, central nervous system regulation, wound healing, and hepatoprotective characteristics. KMP has attracted considerable attention in the examination of its possible roles in dealing with a range of age-related diseases. These conditions include cardiovascular diseases (CVDs), immunoinflammatory diseases, neurodegenerative diseases (NDs), and cancer. It can delay oocyte aging, thereby enhancing the subsequent embryonic growth cascade. Delaying oocyte aging is mainly accomplished by reducing apoptosis and reactive oxygen species (ROS) levels. Furthermore, KMP has antioxidant effects on age-related diminished ovarian reserve (AR-DOR) by reducing HSP90 expression, thereby boosting NRF2 expression. KMP treatment influences multiple processes in aging oocytes, including peroxisome function, oxidative stress, cAMP signaling, TNF signaling, and gap junction pathways. Additionally, KMP improved negative pregnancy outcomes associated with fertilized aged oocytes.

Alzheimer's disease (AD), the leading cause of dementia, is intrinsically linked to the aging process. A central mechanism driving this association is inflammaging, a state of chronic, low-grade inflammation resulting from innate immune dysregulation. Emerging evidence suggests that inflammaging is not merely a background feature of aging but an active pathogenic driver of AD, accelerating amyloid-β accumulation, tau hyperphosphorylation, and synaptic failure. This review synthesizes the molecular circuitry connecting inflammaging to AD, detailing the synergistic roles of the NLRP3 inflammasome, impaired autophagy, TREM2 signaling, and the cGAS-STING pathway. Furthermore, we critically evaluate pharmacological strategies designed to disrupt these cascades, including specific NLRP3 inhibitors, senolytic agents, and autophagy enhancers. We propose that these therapies offer a vital complementary approach to amyloid-targeting treatments, potentially modifying disease progression by extinguishing the persistent inflammatory milieu of the aging brain.

The accurate assessment of chronological age through DNA methylation (DNAm) patterns has emerged as a promising forensic-age estimation tool. This study, therefore, assessed seven age-associated CpG sites to develop an epigenetic age-prediction model capable of rendering reliable outputs especially in the Pakistani population, a population group underrepresented in current epigenetic aging studies. A total of seven age-related CpG sites, KLF14 (cg14361627), CCDC102B (cg19283806), TRIM59 (cg07553761), ASPA (cg02228185), C1ORF132 (cg10501210), FHL2 (cg06639320), and ELOVL2 (cg16867657), were selected and analyzed in blood samples of 181 individuals categorized into different age groups (1 to 76 years). A methylation SNaPshot™ multiplex assay was performed, three different age prediction models like stepwise regression, multivariate linear regression (MVLR), and support vector machine (SVM), were established based on the methylation data of SNaPshot™ multiplex assay. The stepwise regression model and multivariate linear regression enabled age prediction, with mean absolute deviations (MADs) = 3.60 and 3.69, respectively, whereas the SVM model enabled age prediction, with MAD = 3.40. An independent set of 53 samples was used to test the performance of the three models, and the prediction MADs for the validation set were 3.92, 3.73 and 3.44 for the stepwise regression, multivariate linear regression and SVM models, respectively. The number of correct predictions for ± 4 years reached high values of 69.81%, 71.69% and 77.35% for the stepwise regression, MVLR and SVM models, respectively. The results revealed that all seven markers were significantly associated with age, but ELOVL2 and FHL2 are reliable candidates for age estimation models in Pakistan due to their robustness and minimal redundancy among evaluated CpG sites. However, CCDC102B (cg19283806) had the lowest association levels, respectively. Prediction accuracy was found to decrease with increasing age, suggesting that environmental and lifestyle factors may play an increasingly important role in determining biological age-especially so in Pakistan where air pollution and other lifestyle indicators may accelerate biological age. These findings further highlight the need to study DNA methylation changes in polluted settings in order to improve age prediction systems and bridge the gap between chronological and biological age. Additional optimization using population samples and various forensic materials such as bloodstains, saliva, and body fluids is required to improve the performance and applicability of the model in real-life forensic situations.