Longevity Papers

Aging is closely associated with imbalanced transcription. Regulated transcription in different organs is significantly different during aging, indicating that organ-specific transcriptomics is critical for understanding this process. Here we analyze the transcriptomics of the intestines of 3-, 15-, 30-, 40- and 50-days old female flies, which include young, middle-aged, and old flies. We find that the differential expression of protein-coding genes and lncRNAs is significant in aging, and fly age is characterized by well-separated gene expression trajectories. The highly clustered differentially expressed genes are connected to specific biological processes and signalling pathways. In particular, the Imd and Toll pathways are the top two immune signalling pathways that are highly regulated, and members with increased expression in the Imd pathway span all upstream activating events and include many ubiquitylation-associated factors and regulators of NF-κB factor Relish. Increased expression of Toll pathway members includes sensing mediators for all kinds of microorganisms and multiple proteases in the proteolytic processing cascade. Moreover, the expression of molecular markers of intestinal cells is greatly changed. Enterocyte markers are the most significantly influenced, and enteroendocrine markers AstA and NPF, as well as intestinal stem cell (ISC)/enteroblast (EB) markers Esg and Klu are expressed at low levels in young flies and much higher levels in aged flies. Furthermore, lncRNAs show similar expression trends and clustering patterns to those of protein-coding genes. Lastly, we find that ISC/EB-specific knock-down of 13 out of 19 genes that are highly differentially expressed reduces the lifespan of the fly. Together, the characterized transcriptomics and newly identified functional genes in aging will provide potential targets for preventing intestinal aging and associated disorders.

Changes in the proteome and its dysregulation have long been known to be a hallmark of aging. We derived a proteomic aging trait using data on 1459 plasma proteins from 44,435 UK Biobank individuals measured using an antibody-based assay. This metric is strongly associated with four age-related disease outcomes, even after adjusting for chronological age. Survival analysis showed that one-year older proteomic age, relative to chronological age, increases all-cause mortality hazard by 13 percent. We performed a genome-wide association analysis of proteomic age acceleration (proteomic aging trait minus chronological age) to identify its biological determinants. Proteomic age acceleration showed modest genetic correlations with four epigenetic clocks (R

Kaempferol is a polyphenol in various fruits and vegetables. It is also commercially developed and sold to consumers as a supplement. It has been extensively assessed in clinical trials for clinical utility based upon its numerous experimentally based chemopreventive properties. Kaempferol has been evaluated at the levels of molecule, cell, and individual animal, showing a broad spectrum of biological effects. Kaempferol-induced hormetic concentration responses are common, being reported in many cell types and biological models for numerous endpoints. While the hormetic effects of kaempferol are biologically diverse, there has been a strong focus on age-related endpoints affecting numerous organ systems and endpoints, indicating that kaempferol is a senolytic agent, showing similar properties as quercetin and fisetin. This paper offers the first integrated evaluation of kaempferol-induced hormetic dose responses, their quantitative characteristics, mechanistic explanations, extrapolative strengths or limitations, and related experimental design, biomedical, therapeutic, ageing, and public health, including ageing related applications.

Polygalae Radix has high pharmacological activity and has been widely used as a sedative and tranquilizer to increase cognitive function, prevent epilepsy, and treat respiratory diseases such as bronchitis. However, its role in delaying aging and decreasing oxidative stress and its main functional factors have not been thoroughly studied.

Cigarette smoke imposes serious health hazards such as cancer and cardiovascular diseases but is also associated with cellular senescence. Recently, histone loss and modifications are reported as one of the characteristics of cellular senescence. In this study, we examined the relationship between cigarette smoke-induced cellular senescence and histone H2A variant H2AX, an important player in DNA damage response. We exposed normal human skin diploid fibroblast ASF-4-1 to cigarette sidestream smoke (CSS) extract and successfully induced premature senescence. Persistent DNA damages are known to induce cellular senescence. Double strand breaks (DSBs) formation was detected in CSS-treated cells, indicating DSBs could be the cause for the CSS-induced cellular senescence. In the senescent cells, persistent phosphorylation of histone H2AX (γ-H2AX) and unexpected increase of H2AX protein expression was observed. To elucidate the role of H2AX in CSS-induced cellular senescence, we depleted H2AX in ASF-4-1 cells with siRNA. In H2AX-depleted cells, CSS-induced elevated β-galactosidase activity was more prominent. CSS concentration-dependent increase of reactive oxygen species and DSBs formation was also facilitated by H2AX depletion. These results suggest that histone H2AX may have a protective role against DNA damage-induced premature senescence.

Honey bees (Apis mellifera, L.) play an important role in ecosystems due to their pollination, which directly impacts biodiversity and agricultural production. Understanding the biological mechanisms that determine bee aging is important for conserving bee populations and the ecosystems they serve. This study explored the dynamics of polyamine level changes and transcriptomic alterations during the aging of summer and winter worker bees. The present study's results indicate that the polyamine content in summer bees decreased overall with age, while winter bees exhibited a biphasic pattern, with an initial decrease followed by an increase in older individuals. These differences likely reflect distinct physiological needs during summer (work-intensive) and winter (survival-focused) periods. Transcriptomic analyses identified age-related changes, with key driver gene analysis highlighting critical genes associated with cuticle formation, venom activity, and polyamine metabolism, indicating structural and metabolic adaptations with age. KEGG pathway analysis identified enrichments in pathways related to peroxisome function, lipid metabolism, glycan degradation, lysosomal activity, and others underscoring shifts in cellular maintenance and energy regulation. This study underscores the complexity of polyamine dynamics and molecular adaptations in honey bee aging and provides a foundation for conserving bee populations and better understanding longevity across species.

Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

Native extracellular matrix exhibits multiscale groove and ridge structures that continuously change, such as collagen fibril-based nanogrooves in bone tissue, and regulate cellular responses. However, dynamic switching between groove and ridge nanostructures at the molecular level has not been demonstrated. Herein, materials capable of dynamic groove-ridge switching at tens-of-nanometers scale are developed by flexibly conjugating RGD-magnetically activatable nanoridges (MANs) to non-magnetic nanogrooves with independently tuned widths comparable to the sizes of integrin-presenting filopodia by modulating hydrophobicity in bicontinuous microemulsion, allowing for cyclic modulation of RGD accessibility and cellular adhesion. Nanogrooves with medium width restrict RGD accessibility in the "groove" state in which the RGD-MANs are buried, which is reversed by magnetically raising them to protrude and form the "ridge" state that fully exposes the RGDs. This reversibly stimulates integrin recruitment, focal adhesion complex assembly, mechanotransduction, and differentiation of stem cells in vivo. This is the first demonstration of molecular-level groove and ridge nanostructures that exhibit unprecedented switchability between groove and ridge nanostructures. Versatile tuning of the width, height, pitch, and shape of intricate nanogroove structures with remote manipulability can enlighten the understanding of molecular-scale cell-ligand interactions for stem cell engineering-based treatment of aging, injuries, and stress-related diseases.

Cellular senescence is recognized as a fundamental hallmark contributing to ageing and various age-related diseases, with oxidative stress playing a critical initiating role in their pathological processes. However, the anti-senescence potential of the antioxidant nuclear factor erythroid-derived 2-like 1 (Nrf1, encoded by Nfe2l1) remains elusive, despite accumulating evidence demonstrating its role as an indispensable redox-determining transcription factor for maintaining cellular homeostasis and organ integrity. This study reveals that deletion of Nrf1α significantly elevates senescence characteristics in Nrf1α

Skeletal muscle plays a crucial role in maintaining motor function and metabolic homeostasis, with its loss or atrophy leading to significant health consequences. Long non-coding RNAs (lncRNAs) have emerged as key regulators in muscle biology; however, their precise roles in muscle function and pathology remain to be fully elucidated. This study demonstrates that lncRNA maternally expressed gene 3 (MEG3) is preferentially expressed in slow-twitch muscle fibers and dynamically regulated during muscle development, aging, and in the context of Duchenne muscular dystrophy (DMD). Using both loss- and gain-of-function mice models, this study shows that lncRNA-MEG3 is critical for preserving muscle mass and function. Its depletion leads to muscle atrophy, mitochondrial dysfunction, and impaired regenerative capacity, while overexpression enhances muscle mass, increases oxidative muscle fiber content, and improves endurance. Notably, lncRNA-MEG3 overexpression in MDX mice significantly alleviates muscle wasting and adipose tissue infiltration. Mechanistically, this study uncovers a novel interaction between lncRNA-MEG3 and the polycomb repressive complex 2 (PRC2), where lncRNA-MEG3 binds to SUZ12 polycomb repressive complex 2 subunit (Suz12), stabilizes PRC2, facilitates SUZ12 liquid-liquid phase separation (LLPS), and regulates the epigenetic modulation of four and a half lim domains 3 (Fhl3) and ring finger protein 128 (Rnf128). These findings not only highlight the crucial role of lncRNA-MEG3 in muscle homeostasis but also provide new insights into lncRNA-based therapeutic strategies for muscle-related diseases.

Mitochondrial dysfunction and redox dyshomeostasis are considered crucial factors causally linked to the pathogenesis of Down syndrome (DS), a human genetic anomaly currently lacking a cure, associated with neurodevelopmental deficits in children and early onset symptoms of aging in adults. Several natural plant-derived polyphenolic compounds, known for their neurostimulator, antioxidant and anti-inflammatory activities, have been proposed as dietary supplements to manage DS-linked phenotypic alterations. However, the poor bioavailability and rapid metabolism of these compounds have limited conclusive evidence regarding their clinical efficacy in individuals with DS. Polydatin (PLD), a natural polyphenolic glucoside precursor of resveratrol derived from Polygonum cuspidatum, is instead highly bioavailable and resistant to enzymatic oxidation. PLD supplementation has shown many therapeutic efficacies in several human diseases without side effects. In this study, we used fetal trisomy 21 human skin fibroblasts (DS-HSFs) to investigate, from a mechanistic point of view, whether PLD supplementation could prevent or counteract critical cellular alterations linked to both neurodevelopmental deficits and early aging in DS. Our findings demonstrate that PLD reactivates mitochondrial bioenergetics, reduces oxygen radical overproduction and prevents oxidative stress (OS)-induced cellular senescence and DNA damage in DS-HSF. Notably, we identified a novel mechanism of PLD action involving the chromosome-21-encoded microRNA-155 (miR-155) and its direct target genes casitas B-lineage lymphoma (CBL), BAG Cochaperone 5 (BAG5) and mitochondrial transcription factor A (TFAM). These proteins play pivotal roles in regulating mitochondrial bioenergetics, biogenesis and mitophagy. Given that the deregulation of miR-155/CBL axis is also implicated in acute leukemias, which frequently occur in children with DS, PLD emerges as a promising candidate for translational application. Its ability to enhance mitochondrial bioenergetics and address critical DS-associated phenotypic alterations highlights its therapeutic potential.

During the process of aging, it is common for women to take dehydroepiandrosterone sulphate (DHEAS) supplements to prevent adrenopause. However, the potential effects of this supplementation on the adrenal cortex have not yet been fully elucidated. Therefore, the present study aimed to analyze the effects of DHEAS supplementation on the adrenal cortex of female Mongolian gerbils during the aging process. The experiment was conducted by dividing the aged female gerbils (18 months of age) into two groups (n = 5). The control group received no treatment, while the experimental group received 60 mg/kg of DHEAS for 5 weeks. The adrenal glands of both groups were then subjected to morphological, hormonal and immunohistochemistry analyses. The results showed that DHEAS supplementation led to a significant increase in the accumulation of lipofuscin granules in the adrenal cells. Furthermore, decreases in ERα and ERβ and the enzymes CYP17 and 17βHSD, and an increase in the 5α-reductase enzyme in the adrenal cortex were also observed. The results suggest that DHEAS supplementation has a negative feedback effect on the adrenal cortex, affecting its morphophysiology and, consequently, the gland's functionality. In addition, DHEAS supplementation does not reverse all aspects of the effects of aging on adrenal gland homeostasis.

The main objective of this study was to analyze the effect of a resistance training program using outdoor fitness equipment (OFE) on sagittal spine disposition and pelvic tilt in middle-aged and older adults. One hundred and twenty-eight middle-aged and older adults were randomly assigned to the training (TG) or control group (CG). The TG trained for 8 weeks, with 2 weekly sessions of one hour of resistance circuit training with OFE. Before and after the intervention, the sagittal spine disposition and pelvic tilt in the relaxed standing and sitting positions were analyzed. The results showed that the TG obtained a significant reduction (p < 0.001) in all the curvatures of the sagittal spine disposition and pelvic tilt in the standing position after the intervention, in contrast to the CG, which only showed a significant reduction in pelvic tilt (p = 0.005). Regarding the sitting position, only the TG presented a significant decrease in lumbar lordosis (p < 0.001). In conclusion, resistance training with OFE may be useful in improving sagittal spine disposition in middle-aged and older adults. Given the availability of free OFE in parks, the present research provides elders with an accessible and effective training program to curb the effects of ageing on the sagittal spine disposition.

Research has demonstrated that engaging in regular exercise has the potential to enhance cognitive function, promote neuroplasticity, and mitigate the likelihood of experiencing cognitive decline. The underlying mechanisms responsible for these effects are intricate and encompass various pathways, including the interaction between neurogranin and calmodulin. The activation of calcium signaling pathways is a significant mechanism through which regular exercise facilitates the treatment of age-related diseases. The activation of neurogranin and calmodulin induced by exercise can provide protection against neurodegeneration by promoting neuronal survival, mitigating oxidative stress, and improving mitochondrial function through the regulation of calcium homeostasis and energy metabolism. In addition, there is evidence suggesting that engaging in regular exercise can lead to an upregulation of neurotrophic factors, specifically brain-derived neurotrophic factor (BDNF). These factors are crucial for the survival of neurons, the plasticity of synapses, and overall cognitive function. Researchers have discovered the involvement of neurogranin in the regulation of BDNF signaling, underscoring its significance in exercise-induced neuroprotection and cognitive enhancement. The current work offers valuable insights into how neurogranin/calmodulin cooperation, facilitated by regular exercise, promotes the treatment of aging-related diseases. The results suggest that regular exercise could enhance memory, learning, synaptic plasticity, and resilience to neurological damage; promote recovery after brain injury; and treat aging-related disorders such as Alzheimer's disease.

Cellular senescence, a hallmark of aging, reveals context-dependent phenotypes across multiple biological length scales. Despite its mechanistic importance, identifying and characterizing senescence across cell populations is challenging. Using primary dermal fibroblasts, we combined single-cell imaging, machine learning, several induced senescence conditions, and multiple protein biomarkers to define functional senescence subtypes. Single-cell morphology analysis revealed 11 distinct morphology clusters. Among these, we identified three as bona fide senescence subtypes (C7, C10, and C11), with C10 exhibiting the strongest age dependence within an aging cohort. In addition, we observed that a donor's senescence burden and subtype composition were indicative of susceptibility to doxorubicin-induced senescence. Functional analysis revealed subtype-dependent responses to senotherapies, with C7 being most responsive to the combination of dasatinib and quercetin. Our single-cell analysis framework, SenSCOUT, enables robust identification and classification of senescence subtypes, offering applications in next-generation senotherapy screens, with potential toward explaining heterogeneous senescence phenotypes based on the presence of senescence subtypes.

Janus Kinase 2 (JAK2) has been linked to various neutrophil functions, but the intracellular mechanisms underlying its modulation are unknown. Neutrophils are essential cells for host defense. Neutrophil effector functions include migration, reactive oxygen species (ROS) production, degranulation, and neutrophil extracellular trap (NET) formation. The goal of this study was to elucidate the signaling mechanism through which JAK2 modulates neutrophil function and the effect of aging on this pathway. We hypothesized that JAK2-mediated modulation changes the molecular mechanisms associated with neutrophil function in an age- and sex-dependent manner. Neutrophils from young (3 months) and aged (22+ months), male and female C57BL/6J mice were isolated, treated with a JAK2 inhibitor (AZD1480) or a pan-JAK inhibitor (Baricitinib), and stimulated with Phorbol 12-myristate 13-acetate (PMA). Functional assays were conducted to assess migration, ROS production, degranulation, NETosis, and metabolism. Mass spectrometry and Luminex assays provided proteomic and cytokine profiles. Our data show that JAK2 promotes migration via membrane composition and actin remodeling, with age-dependent shifts in chemokine secretion. JAK2 indirectly affects NETosis by modulating IL-1 signaling and ROS production. It also primes ROS production by altering NADPH oxidase components. In young neutrophils, JAK2 influences degranulation through actin remodeling, while aged neutrophils display impaired granule release. Metabolically, JAK2 enhances pentose phosphate pathway activity in young neutrophils and decreases glycogen breakdown in aged cells. These findings reveal mechanisms by which JAK2 modulates neutrophil function and suggest age-specific therapeutic targeting in inflammatory diseases.

Aging is a major risk factor for cardiovascular diseases, and the accumulation of DNA damage significantly contributes to the aging process. This study aimed to identify the underlying molecular mechanisms of vascular aging in DNA-repair-deficient progeroid Ercc1

The intestines play important roles in responding immediately and dynamically to food intake, environmental stress, and metabolic dysfunction, and they are involved in various human diseases and aging. A key part of their function is governed by intestinal stem cells (ISCs); therefore, understanding ISCs is vital. Dysregulation of ISC activity, which is influenced by various cell signaling pathways and environmental signals, can lead to inflammatory responses, tissue damage, and increased cancer susceptibility. Aging exacerbates these dynamics and affects ISC function and tissue elasticity. Additionally, proliferation and differentiation profoundly affect ISC behavior and gut health, highlighting the complex interplay between environmental factors and gut homeostasis. Drosophila models help us understand the complex regulatory networks in the gut, providing valuable insights into disease mechanisms and therapeutic strategies targeting human intestinal diseases.

This review highlights recent advancements in our understanding of muscle protein synthesis (MPS) across the lifespan, with a focus on dietary protein strategies to support muscle health. Given that skeletal muscle is crucial for whole-body metabolism, movement and independence, maintaining muscle mass throughout life is essential. However, the gradual decline in muscle mass and strength with age, known as sarcopenia, represents a significant health concern. Muscle mass is regulated by the balance of MPS and muscle protein breakdown, with dietary protein intake playing a central role in stimulating MPS and maintaining a positive protein balance. Much of our current understanding of protein intake, specifically its quantity, quality and distribution, comes from stable isotope-labelled amino acid methods. These techniques, however, are limited by time constraints and controlled settings, providing only brief snapshots of MPS dynamics. The use of deuterium oxide (D₂O) has provided new insights, enabling long-term measures of muscle protein metabolism in free-living conditions. Measurements of longer-term MPS using D₂O suggest that older adults might benefit from protein intakes of >1.2 g/kg/day to enhance MPS. Additionally, replacing protein in the diet with higher-quality sources or enriching lower protein intakes with leucine can further increase MPS. Nevertheless, discrepancies remain regarding optimal protein requirements and the long-term efficacy of supplementing with enriched suboptimal protein doses. The continued application of D₂O in dietary protein research has the potential to provide further insights into the prolonged effects of various protein strategies on muscle preservation across the lifespan.

Frailty is characterized by an increased vulnerability to disease and physical debilitation due to a decline in the body's capacity to maintain homeostasis during aging. Therefore, effective management of frailty is crucial for promoting health. Although the role of niclosamide (NIC), an autophagy promoter, has been studied for the treatment of cancer, infectious diseases, and metabolic disorders, no research has focused on its effects on aging.

Aging is the primary risk factor for many diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. The rapid advancement of single-cell sequencing technologies has opened promising avenues for investigating aging-associated cellular changes that contribute to disrupted system homeostasis and increased vulnerability to age-related diseases. Despite the abundance of data generated over the past decade, a systematic understanding of how aging affects cell type-specific populations across the entire mammalian organism remains lacking-a critical gap for elucidating the cellular foundations of aging-related system dysfunction. In this review, we address this knowledge gap by summarizing recent single-cell studies examining the impact of aging on cell type-specific population changes across mammalian organs. We also review the impact of gender and anti-aging interventions on cell population dynamics in aged mammals. This work provides a comprehensive catalog of cellular states susceptible to aging, highlighting potential therapeutic targets for aging and age-related diseases.

Upon inflammation, the bone marrow (BM) landscape undergoes significant architectural and functional modifications. Stimulation of the hematopoietic niche triggers a series of lightning events, which begin with stem/progenitor blood elements mobilization and culminates with the activation of immune responses. Ageing partially mirrors this process, albeit with a propensity towards chronic inflammation and immune dysfunction. Age-related chronic inflammation disrupts bone homeostasis and accompanies impaired tissue regeneration. Thus, focusing on the bone marrow's dynamics during inflammatory bone diseases could lay the way for the development of novel therapeutic platforms aimed at niche reprogramming. Herein, we summarize inflammatory and age-induced processes in multiple BM compartments, with particular reference to hematopoietic, stromal stem/progenitor cells, and mature immunocytes. Finally, we focus on autophagy and its potential to clinically re-modulate the pathological "flogistic" bias, possibly by restoring functional phenotypes within the bone marrow niche elements.

Vorinostat, a pan histone deacetylases (HDACs) inhibitor clinically approved for cutaneous T-cell lymphoma, exerts therapeutic effects by inducing tumor cell death and cycle arrest. Intriguingly, a previously unrecognized hormetic role of low-dose vorinostat in Caenorhabditis elegans. Subtoxic concentrations of vorinostat (1 μM) significantly extended lifespan, enhanced healthspan, and improved resistance to oxidative and heat stress, while ameliorating Aβ-induced paralysis. qPCR analysis demonstrated dose-dependent bidirectional regulation of stress-resistance genes (sod-3, hsp-16.2, skn-1, gst-4, act-1), with low doses of vorinostat upregulating these genes whereas higher doses (10 μM) exerted suppressive or neutral effects. Mechanistically, vorinostat-induced hormesis required functional SKN-1 signaling, as evidenced by its capacity to activate skn-1 and downstream targets (hsp-16.2, gst-4, act-1). Crucially, RNAi-mediated skn-1 knockdown completely abolished the pro-longevity and stress-resistant phenotypes. These findings establish vorinostat as a novel hormetin that enhances organismal resilience through SKN-1 pathway activation, providing new insights into HDAC inhibitor biology and aging intervention strategies.

Aging is a slow and irreversible biological process leading to decreased cell and tissue functions with higher risks of multiple age-related diseases, including neurodegenerative diseases. It is widely accepted that aging represents the leading risk factor for neurodegeneration. The pathogenesis of these diseases involves complex interactions of genetic mutations, environmental factors, oxidative stress, neuroinflammation, and mitochondrial dysfunction, which complicate treatment with traditional mono-targeted therapies. Network pharmacology can help identify potential gene or protein targets related to neurodegenerative diseases. Integrating advanced molecular profiling technologies and computer-aided drug design further enhances the potential of network pharmacology, enabling the identification of biomarkers and therapeutic targets, thus paving the way for precision medicine in neurodegenerative diseases. This review article delves into the application of network pharmacology in understanding and treating neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and spinal muscular atrophy. Overall, this article emphasizes the importance of addressing aging as a central factor in developing effective disease-modifying therapies, highlighting how network pharmacology can unravel the complex biological networks associated with aging and pave the way for personalized medical strategies.

Starting at middle age, adults often suffer from visceral adiposity and associated adverse metabolic disorders. Lineage tracing in mice revealed that adipose progenitor cells (APCs) in visceral fat undergo extensive adipogenesis during middle age. Thus, despite the low turnover rate of adipocytes in young adults, adipogenesis is unlocked during middle age. Transplantations quantitatively showed that APCs in middle-aged mice exhibited high adipogenic capacity cell-autonomously. Single-cell RNA sequencing identified a distinct APC population, the committed preadipocyte, age-enriched (CP-A), emerging at this age. CP-As demonstrated elevated proliferation and adipogenesis activity. Pharmacological and genetic manipulations indicated that leukemia inhibitory factor receptor signaling was indispensable for CP-A adipogenesis and visceral fat expansion. These findings uncover a fundamental mechanism of age-dependent adipose remodeling, offering critical insights into age-related metabolic diseases.

Caloric restriction (CR) promotes longevity and metabolic health by modulating gene expression and cellular processes. However, the role of alternative mRNA splicing in CR-induced metabolic adaptation remains underexplored. In this study, we analyzed RNA sequencing data from the subcutaneous white adipose tissue of CR mice. We identified 6058 differentially expressed genes, with significant upregulation of lipid metabolism pathway genes, such as Elovl6, Fasn, and Srebp1c. We also detected 400 CR-associated alternative splicing events, with the skipped exon and retained intron events predominantly affecting lipid biosynthesis and energy metabolism. Among these events, Ncoa2, a nuclear receptor coactivator involved in lipid metabolism, exhibited increased exon 13 inclusion under CR, favoring the expression of the full-length isoform. Functional assays revealed that full-length NCOA2 enhanced PPARγ-mediated transcriptional activation, while the truncated Δ-NCOA2 isoform exhibited altered coactivator activity. Δ-NCOA2 was found to lack an LXXL motif critical for nuclear receptor interactions, potentially modifying its function. Taken together, these findings indicate that CR-induced alternative splicing fine-tunes metabolic and transcriptional networks, thereby contributing to lipid homeostasis and energy adaptation. Our study highlights a novel regulatory layer by which CR modulates metabolism through coordinated transcriptional and splicing alterations, offering new insights into the molecular mechanisms underlying the beneficial effects of CR on aging and metabolic health. Further investigations are warranted to determine the tissue-specificity of the CR-induced splicing changes and their potential implications for metabolic disorders and lifespan extension.

Multi-marker approaches are well suited for untangling the intrinsic complexity of aging and related conditions. Herein, we quantified (1) baseline concentrations of a panel of geroscience biomarkers pertaining to four biological domains (i.e., metabolism, inflammation, vascular/organ dysfunction and cellular senescence, and neurodegeneration) in individuals aged ≥60 years; (2) investigated linear and non-linear changes in biomarker levels over a 6-year period according to age and sex; and (3) described the relationships among geroscience biomarkers at baseline and follow-up. We found that repeated measures of age-dependent changes of 47 blood-borne biomarkers over 6 years had differential associations depending on the biological domains. The most relevant biomolecules in the associations between age and repeated assessments were (1) adiponectin, C-peptide, renin (metabolism), (2) CXCL10, IL-1α, IL-1β, IL-6, IL-10, IL-12p70, MPO (inflammation), (3) cystatin C, MMP7, MMP12, VCAM-1 (vascular/organ dysfunction and cellular senescence), and (4) S100B and Tau protein (neurodegeneration). Among these molecules, a negative association with increasing age was found for IL-1α, IL-1β, IL-12p70, S100B, and Tau protein. Non-linear relationships were also identified with age for IGFBP-1, leptin, β2M, TNFRSF1B, fibrinogen, GDF-15, N-cadherin, and BDNF. Our results indicate that inflammatory and metabolic biomolecules are strongly associated with aging over 6 years of follow-up. Whether the biological pathways reflected by these biomarkers contribute to the aging process or are associated with negative health-related events needs to be explored through comprehensive multi-omics longitudinal analysis in larger cohorts.

Epigenetic algorithms of aging, health, and cognition, based on DNA-methylation (DNAm) patterns, are prominent tools for measuring biological age and have been linked to age-related diseases, cognitive decline, and mortality. While most of these methylation profile scores (MPSs) are developed in blood tissue, there is growing interest in using less invasive tissues like saliva. The aim of the current study is to probe the cross-tissue intraclass correlation coefficients (ICCs) of MPSs developed in blood applied to saliva DNAm from the same people. While our primary focus is on MPSs that were previously found to be robustly correlated with social determinants of health, including second- and third-generation clocks and MPSs of physiology and cognition, we also report ICC values for first-generation clocks to enable comparison across metrics. We pooled three publicly available datasets that had both saliva and blood DNAm from the same individuals (total n = 107, aged 5-74 years), corrected MPSs for cell composition within each tissue, and computed the cross-tissue ICCs.

Preferred and maximum walking speeds decline as we age and the decline has been associated with worsening health. Slowing of gait in older individuals is correlated with biomechanical and neural factors, but historically it has been difficult to measure whole-brain activity during walking. Recent advances in mobile brain imaging with high-density electroencephalography (EEG) allow for separation and localization of electrical brain activity during walking. We studied younger (N=31) and older adults (N=59) walking on a treadmill at different speeds (0.25-1.0 m/s) while we recorded electrocortical dynamics with EEG. We hypothesized that faster walking speeds would result in greater sensorimotor and posterior parietal theta band (4-7 Hz) spectral power and lower beta band (13-30 Hz) spectral power compared to slower walking speeds for older adults, consistent with previous studies on younger adults. Additionally, we used a standardized test of physical function to group older adults into high functioning [Short Physical Performance Battery, SPPB≥10] and low functioning (SPPB<10) groups for comparison. In agreement with our hypotheses, sensorimotor and posterior parietal theta power increased, and beta power decreased at faster walking speeds. We also found that left posterior parietal, mid cingulate, and cuneus exhibited differences in theta power at faster speeds between younger and older adults. The results suggest that older and younger adults activate cortical areas throughout the brain while walking at different speeds, and older adults, particularly those with lower mobility, recruit greater cognitive resources in parietal cortex compared to younger adults. These results could inform stimulation protocols targeting parietal cortex.

Extracellular β-amyloid protein (Aβ) plaques are prominent pathological feature of Alzheimer's disease (AD). Aβ oligomers and plaques induce sustained microglial activation via the adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/interferon regulatory factor 5 (IRF5) signaling pathway. This microglial activation-mediated neuroinflammation can accelerate neuronal cell senescence. Consequently, the regulation of the AMPK/mTOR/IRF5 pathway presents a potential therapeutic target for AD, as it may inhibit neuroinflammation and delay neuronal cell senescence. Mangiferin, a bioactive natural polyphenol extracted from the leaves of

Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR face a 9.7-fold higher mortality rate-a risk equivalent to that of 55.5-year-olds with optimal IR-resulting in a 15.5-year gap in survival. Optimal IR preserves youthful immune profiles at any age, enhances vaccine responses, and reduces burdens of cardiovascular disease, Alzheimer's, and serious infections. Two key salutogenic evolutionary themes emerge: first, female-predominant IR, including TCF7, likely reflects evolutionary pressures favoring reproductive success and caregiving; second, midlife (40-70 years) is a critical window where optimal IR reduces mortality by 69%. After age 70, mortality rates converge between resilient and non-resilient groups, reflecting biological limits on longevity extension. TNFα-blockers restore salutogenesis pathways, indicating IR delays aging-related processes rather than altering aging rates. By reframing aging as a salutogenic-pathogenic balance, we establish TCF7-centered IR as central to healthy longevity. Targeted midlife interventions to enhance IR offer actionable strategies to maximize healthspan before biological constraints limit benefits.

The mechanisms regulating transcriptional changes in brain aging remain poorly understood. Here, we use single-cell epigenomics to profile chromatin accessibility and gene expression across eight brain regions in the mouse brain at 2, 9, and 18 months of age. In addition to a significant decline in progenitor cell populations involved in neurogenesis and myelination, we observed widespread and concordant changes of transcription and chromatin accessibility during aging in glial and neuronal cell types. These alterations are accompanied by dysregulation of master transcription factors and a shift toward stress-responsive programs driven by AP-1, indicating a progressive loss of cell identity with aging. We also identify region- and cell-type-specific heterochromatin decay, characterized by increased accessibility at H3K9me3-marked domains, activation of transposable elements, and upregulation of long non- coding RNAs, particularly in glutamatergic neurons. Together, these results reveal age-related disruption of heterochromatin maintenance and transcriptional programs, identify vulnerable brain regions and cell types, and pinpoint key molecular pathways altered in brain aging.

Cellular senescence is a cell fate triggered by stressful stimuli and displays a hypersecretory feature, the senescence-associated secretory phenotype (SASP). Senescent cell burden increases with aging and contributes to age-related organ dysfunction and multiple chronic disorders. In this study, a large scale screening of a natural product library for senotherapeutic candidates is performed. Apigenin, a dietary flavonoid previously reported with antioxidant and anti-inflammatory activities, exhibits capacity for targeting senescent cells as a senomorphic agent. This compound blocks the interactions between ATM/p38MAPK and HSPA8, preventing the transition of an acute stress-associated phenotype (ASAP) toward the SASP. Mechanistically, apigenin targets peroxiredoxin 6 (PRDX6), an intracellular redox-active molecule, suppressing the iPLA2 activity of PRDX6 and disrupting downstream reactions underlying SASP development. Apigenin reduces the severity of cancer cell malignancy promoted by senescent stromal cells in culture, while restraining chemoresistance when combined with chemotherapy in anticancer regimens. In preclinical trials, apigenin improves the physical function of animals with a premature aging-like state, alleviating physical frailty and cognitive impairment. Together, the study demonstrates the feasibility of exploiting a natural compound with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing a baseline for future exploration of natural agents for alleviating age-related conditions.

Age-related hippocampal alterations often accompany cognitive decline, a significant risk factor for dementias. Modifiable lifestyle factors may help preserve hippocampal neural tissue and slow neurodegeneration and potentially promote cognition in old age. Here, we sought to identify the relationship between lifestyle and cognition in the context of the hippocampal microstructure across the lifespan. We used data from 494 subjects (36-100 years old) without cognitive impairment from the Human Connectome Project-Ageing study. We estimated hippocampal microstructure using myelin-sensitive (T1w/T2w ratio), inflammation-sensitive (MD) and fibre-sensitive (FA) MRI markers. We identified microstructural-lifestyle/-cognition using non-negative matrix factorization to integrate MRI measures into a multivariate spatial signature of hippocampal microstructure covariance followed by partial least squares analysis. Our results reveal that the preservation of axon density and myelin in regions corresponding to subicular regions and CA1 to CA3 regions are negatively associated with age, and is associated with improved performance in executive function tasks, however, this is also associated with a decreased performance in memory tasks. We also show that microstructure is preserved across the hippocampus when there is normal hearing levels, physical fitness and insulin levels and this is negatively associated with age in the presence of cardiovascular risk factors like high body mass index, blood pressure, triglycerides and blood glucose that are in turn associated with hippocampal neurodegeneration. Taken together, our results suggest that lifestyle factors like normal hearing, physical fitness and normal insulin levels may help preserve hippocampal microstructure which may be useful in maintaining optimum performance on executive function tasks and potentially other modes of cognition.

Biological age (BA) and frailty represent two distinct health measures that offer valuable insights into the aging process. Comparing and analyzing blood-based biomarkers from the machine learning (ML) predictors of BA and frailty helps deepen our understanding of aging. This study aimed to develop a novel framework to identify biomarkers of aging by combining BA and frailty ML predictors with eXplainable Artificial Intelligence (XAI) techniques. We utilized data from middle-aged and older Chinese adults (≥ 45 years) in the 2011/2012 wave (n = 9702) and the 2015/2016 wave (n = 9455, as test set validation) of the China Health and Retirement Longitudinal Study (CHARLS). Sixteen blood-based biomarkers were used to predict BA and frailty. Four tree-based ML algorithms were employed in the training and validation, and performance metrics were compared to select the best models. Then, SHapley Additive exPlanations (SHAP) analysis was conducted on the selected models. CatBoost performed the best in the BA predictor, and Gradient Boosting performed the best in the frailty predictor. Traditional ML feature importance identified cystatin C and glycated hemoglobin as the major contributors for their respective models. However, subsequent SHAP analysis demonstrated that only cystatin C was the primary contributor in both models. The proposed framework can easily incorporate additional biomarkers, providing a scalable and comprehensive toolset that offers a quantitative understanding of biomarkers of aging.

The poroelastic properties of tissues regulate molecular transport and mechanical signaling, yet their evolution during aging remains poorly understood. In particular, senescent fibroblasts accumulate in aged tissues, contributing to extracellular matrix (ECM) remodeling, but their impact on tissue mechanics and permeability is unclear. In this study, we developed a microfluidic-based in vitro model to assess the poroelastic properties of collagen gels embedded with senescent fibroblasts over time. Our approach integrates periodic pressure actuation with real-time pressure monitoring in a sealed air cavity, enabling the detection of fluid permeation and solid matrix deformations. We analyze our data using analytical and numerical models based on a porohyperelastic framework. This framework combines compressible Neo-Hookean elasticity with the Kozeny-Carman permeability relationship. We demonstrate that senescent fibroblasts induce a progressive softening of the ECM without altering its permeability. Immunostaining reveals that this softening correlates with structural reorganization of the collagen network, characterized by increased branching and network remodeling. Our findings provide insights into the biomechanical effects of senescent fibroblasts on ECM homeostasis. We further argue that our platform offers a unique solution to investigate ECM remodeling not only in aging but also fibrosis, cancer progression, or regenerative medicine strategies.

Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. Oral administration of ZSS hot water extract ameliorated Aβ and tau pathology and cognitive impairment in mouse models of Alzheimer's disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved α-synuclein pathology and cognitive/motor function in Parkinson's disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging.

The increasing global longevity underscores the necessity of effective interventions for older adults. Pre-frailty and frailty affect 54.1 % and 26.3 % of the elderly population, respectively, leading to adverse physical and cognitive outcomes. This study systematically reviewed the effectiveness of interventions targeting robust, pre-frail, and frail older adults in randomized controlled trials, analyzing frailty levels both collectively and individually.

The ability of biomolecular condensates to reversibly dissolve and reform is crucial for maintaining cellular stability and functions. In metabolically active cells, stress granules can rapidly assemble and disassemble in response to environmental changes. However, as metabolic rates decline with aging, stress granules persist longer, disrupting mRNA translation and stress responses. Temperature, as a physical stimulus, plays a key role in controlling condensate formation, dissolution, and material properties. In this study, we explore how the reversibility of the liquid-to-solid transition of biomolecular condensates can be modulated by temperature change. Our findings reveal that aged condensates exhibit reduced responsiveness to external temperature stimuli. By using thermal cycling experiments to simulate repeated heat stress, we found that the time taken for irreversible fiber formation could be delayed up to 4.7-fold compared to condensates without thermal cycles. We also found the dissolution rate of condensates progressively slows as they age but remain more stable with thermal cycles. Importantly, our results indicate that continuous cycles of liquid-liquid phase separation and dissolution act as a reset mechanism, preserving the biomolecular condensates from further liquid-to-solid transition. These findings provide valuable insights into how aging impacts condensate behavior and highlight potential strategies to preserve cellular function through controlled phase transitions.

Keratinocyte differentiation is highly regulated to produce the stratified structure of the epidermis and must be balanced with cell proliferation. Our prior studies revealed that hairless mice that cannot synthesize vitamin C (VC) exhibit epidermal atrophy. VC is a cofactor for the DNA demethylation (ten-eleven translocation) enzyme, but the role of VC in DNA demethylation during keratinocyte differentiation remains unclear. In this study, we evaluated the role of VC in epigenetic regulation of epidermal proliferation and differentiation in a human epidermal equivalent model. Our findings demonstrated that intracellular VC uptake increased epidermal thickness, cell proliferation, and global levels of 5-hydroxymethylcytosine DNA. Notably, these effects of VC were attenuated by an inhibitor of the ten-eleven translocation enzyme. DNA microarray and whole-genome bisulfite sequencing analyses revealed that 12 genes related to cell proliferation were significantly upregulated by VC. Furthermore, hypomethylated DNA regions associated with these genes were revealed in the presence of VC. Collectively, our findings provide insight into how VC increases epidermal thickness by promoting keratinocyte proliferation through the DNA demethylation of proliferation-related genes. VC is a promising molecule that can be used as developing treatment for epidermal thinning, including in aging.

Aging-related cognitive impairment has emerged as a major health-threatening factor among the elderly, and cyanidin-3-glucoside (C3G) is a prominent anthocyanin with biological activities, including antioxidant, anti-inflammatory, and alleviation of neurodegeneration. However, the role of C3G in alleviating natural aging-induced cognitive impairment and the underlying mechanisms thereof remain unclear. In this study, experimental methods mainly included biochemical analysis, pathological analysis, immunofluorescence staining, transmission electron microscopy analysis, western blot, as well as the determination of the gut microbiota composition and detection of metabolites. We found that C3G may exert neuroprotective effects and promote brain health by alleviating brain atrophy and neuroinflammation, enhancing brain antioxidant capacity, regulating neurotransmitter expression and hypothalamic-pituitary-adrenal axis activity, and attenuating blood-brain barrier and hippocampal synaptic damage. Furthermore, C3G also promotes gut health by decreasing inflammatory responses and intestinal tissue crypt damage, upregulating the expression of tight junction proteins, and attenuating intestinal damage. Notably, C3G regulated the microbiota composition in different intestinal segments and intestinal mucosa, as well as the metabolic homeostasis of gut microbiota metabolites, such as short-chain fatty acids (SCFAs), amino acids, and bile acids. Substantially increased levels of SCFAs could activate the extracellular signal-regulated kinase (ERK)/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway by acting on the G protein-coupled receptors. Correlation analysis indicated that increased gut microbiota, such as Faecalibaculum and Bifidobacterium, and elevated SCFAs were positively correlated with behavioral improvement and brain health. In conclusion, our findings reveal that C3G has the potential to improve natural aging-induced cognitive impairment by modulating the gut microbiota and its metabolite SCFAs, thereby activating the ERK/CREB/BDNF pathway.

Poor sleep is a known risk factor of cognitive disorders, but the role of individual sleep problems in age-related cognitive changes remains unclear. This study used two complementary statistical models to estimate nonlinear trajectories of decline in four domains of cognitive functioning in the age period between 55 and 100 years depending on the severity of problems with falling asleep, night awakenings, and early morning awakenings, and short/long sleep duration. The sample included 5132 older adults (M = 67 years, 48% male) from the Longitudinal Aging Study Amsterdam (LASA), assessed 4-10 times every 2-3 years. Sleep problems were self-reported, and cognitive functioning was measured with the 15-Word test (reflecting episodic memory as immediate and delayed recall), Coding task (information processing speed) and Mini-mental State Examination/MMSE (global cognition). Data were analysed using quadratic and piecewise changepoint mixed models. The piecewise models provided more precise and interpretable findings. Decline in information processing speed accelerated significantly earlier in participants with short sleep duration (regression coefficient (B) = -2.3[95% confidence interval (CI): -3.86; -0.81]; p < 0.01) and faster with more severe early morning awakenings (B = -0.07 [-0.1; -0.03]; p < 0.01). Decline in immediate recall accelerated earlier in those with short sleep (B = -2.8 [-4.44; -1.14]; p < 0.01) and severe problems with falling asleep (B = -1.22 [-2.06; -0.39]; p = 0.01). Decline in delayed recall was faster with long sleep (B = -0.06 [-0.08;-0.03]; p < 0.01). Decline in global cognition accelerated faster in those with short/long sleep duration (B = -0.07 [-0.13; -0.01]/-0.10 [-0.18; -0.03]; p < 0.01) and severe night awakenings (B = -0.04 [-0.07;-0.02]; p < 0.01). To conclude, this study showed that some sleep problems can differentially predict earlier acceleration of deterioration in specific cognitive functions in older adults.

Analysis of existing lifespan-extending geroprotective compounds suggested that polypharmacological compounds are the most effective geroprotectors, specifically those that bind multiple biogenic amine receptors. To test this hypothesis, we used graph neural networks to predict polypharmacological geroprotectors and evaluated them in Caenorhabditis elegans. Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to all geroprotectors recorded in the DrugAge database. Thus, our study reveals that rationally designing polypharmacological compounds enables the design of geroprotectors with exceptional efficacy.

Senescent cells emerge with aging and injury. The contribution of senescent cells to DNA methylation age (DNAmAGE) in vivo is uncertain. Furthermore, stem cell therapy can mediate "rejuvenation", but how tissue regeneration controlled by resident stem cells affects whole tissue DNAmAGE is unclear. We assessed DNAmAGE with or without senolytics (BI01) in aged male mice (24-25 months) 35 days following muscle healing (BaCl

Aging represents a significant global challenge characterized by persistent oxidative stress and dysregulated lipid metabolism. Crocin, the primary bioactive constituent of saffron (

Vascular aging is a major contributor to age-related cardiovascular diseases (CVDs) and type 2 diabetes mellitus (T2DM) induced early arterial aging and excessive senescent cells (SCs) burden in vessels. Inhibiting cellular senescence or eliminating SCs could effectively improve aging-related CVDs. Fisetin, a flavonoid extracted from cotinus coggygria scop, has shown potential in alleviating aging by clearing SCs. This study investigated the unexplored mechanisms and efficacy of fisetin in alleviating T2DM-related aortic aging. The T2DM mouse model was induced using a high-fat diet and low-dose streptozotocin injection. Chronic fisetin treatment's protective effects against aortic aging were assessed via senescence-associated beta-galactosidase (SA-β-Gal) staining, histopathology, and vasomotor function. RNA-sequencing and western blotting identified relevant signaling pathways and protein expression. Fisetin's effects on SCs and senescence-associated secretory phenotype (SASP) factors were evaluated through cell viability, apoptosis, and co-culture assays. Docking simulations suggested fisetin as a potential Phosphoinositide 3-kinase (Pi3k) inhibitor. In vivo, chronic fisetin treatment reduced aortic SCs burden, alleviating T2DM-related and natural aortic aging. In vitro, fisetin selectively induced apoptosis of senescent endothelial cells via regulating the Pi3k-Protein Kinase B (Akt)-B-cell lymphoma (Bcl)-2/Bcl-xl pathway and suppressed SASP and its detrimental effects. Furthermore, fisetin combined with metformin therapy showed superior anti-aging effects on T2DM-related aortic aging compared to metformin monotherapy. In conclusion, chronic fisetin treatment alleviates T2DM-related aortic aging via clearing the SCs burden and abrogating the SASP factors. Fisetin combined with metformin therapy might be a potential therapeutic strategy for T2DM-related CVDs.

Mesenchymal stem cells (MSCs) and blood plasma/MSC-derived extracellular vesicles (EVs) offer promising tools to promote longevity and treat age-related diseases. MSCs have low immunogenicity and tumorigenicity, and their efficacy is relatively independent of the donor age in humans (but not in rodents). Systemic administration of MSCs and stem cell/blood-derived EVs modified the omic profiles of various organs of aged rodents towards the young ones. The application of EVs appears to be even more beneficial than MSCs. Remarkably, over 70% of microRNAs, which are over-presented in ESC-derived EVs, were found to target longevity-associated genes. Along with MSCs, other types of stem cells were reported to display health- and lifespan-extending effects. Pluripotent Muse cells, a specific subpopulation of MSCs, which possess a number of unique features, could be particularly relevant for promoting healthspan. The rejuvenation potential of MSCs, EVs, and Muse cells warrants further investigation in both animal models and clinical trials, using aging clocks for biological age determination as one of the endpoints.

Hallmark findings in age-related macular degeneration (AMD) include the accumulation of extracellular lipid and vasodegeneration of the choriocapillaris. Choroidal inflammation has long been associated with AMD, but little is known about the immune landscape of the human choroid. Using 3D multiplex immunofluorescence, single-cell RNA sequencing, and flow cytometry, we unravel the cellular composition and spatial organization of the human choroid and the immune cells within it. We identify two populations of choroidal macrophages with distinct FOLR2 expression that account for the majority of myeloid cells. FOLR2+ macrophages predominate in the nondiseased eye, express lipid-handling machinery, uptake lipoprotein particles, and contain high amounts of lipid. In AMD, FOLR2+ macrophages are decreased in number and exhibit dysfunctional lipoprotein metabolism. In mice, FOLR2+ macrophages are negative for the postnatal fate-reporter Ms4a3, and their depletion causes an accelerated AMD-like phenotype. Our results show that prenatally derived resident macrophages decline in AMD and are implicated in multiple hallmark functions known to be compromised in the disease.

Human Werner syndrome (adult progeria, a well-established model of human aging) is caused by mutations in the Werner syndrome (WRN) gene. However, the expression patterns and functions of WRN in natural aging remain poorly understood. Despite the link between WRN deficiencies and progeria, our analyses of human colon tissues, mouse crypts, and Drosophila midguts revealed that WRN expression does not decrease but rather increases in intestinal stem cells (ISCs) with aging. Mechanistically, we found that the Drosophila WRN homologue (WRNexo) binds to Heat shock 70-kDa protein cognate 3 (Hsc70-3/Bip) to regulate the unfolded protein response of the endoplasmic reticulum (UPRER). Activation of the WRNexo-mediated UPRER in ISCs is required for ISC proliferation during injury repair. However, persistent DNA damage during aging leads to chronic upregulation of WRNexo in ISCs, where excessive WRNexo-induced ER stress drives age-associated gut hyperplasia in Drosophila. This study reveals how elevated WRNexo contributes to stem cell aging, providing new insights into organ aging and the pathogenesis of age-related diseases, such as colon cancer.

Age-related immune changes increase the risk of herpes zoster (HZ) caused by varicella-zoster virus (VZV) reactivation. Understanding immune responses to VZV is crucial for reducing the burden of HZ in aging populations. Due to the limited availability of data regarding the VZV immune profiles of elderly individuals, particularly in developing countries, more comprehensive immunological investigations are warranted. A total of 213 participants aged ≥ 60 years were included in this study. VZV-neutralizing antibodies (NAb) and glycoprotein-binding antibodies (BAb) were quantified. Furthermore, VZV-specific T cell subsets and their functionality were evaluated using flow cytometry. Elderly individuals demonstrated a high VZV seropositivity rate of 98.6%, exceeding that of the younger adults. Interestingly, VZV-BAb increased, whereas the proportion of NAb decreased with age, with a significantly lower proportion in the elderly aged ≥ 70 years. The elderly showed decreased naïve T cells and accumulated VZV-specific aged T cells; central memory and effector memory CD4

Throughout humanity's existence, dance and creative movement have been used to express concepts, attitudes, and emotions, as well as to develop skills. Dance offers a paradigm to investigate neuroplasticity associated with learning sensorimotor interactions, and how these interactions enhance health, psychosocial, cognitive, and motor function, including for older individuals with neurotrauma and neurodegenerative disease. This collection explores the science of learning to move and its impact on cognition, how the neuropsychological aspects of the creative movement process is manifested in the brain, and how creative movement or dance can be harnessed to enhance health, cognitive function, and quality of life.

Parkinson's disease (PD) and sarcopenia are prevalent age-related conditions that often coexist in affected individuals. Sarcopenia is particularly common among PD patients, with severe cases affecting approximately one in five individuals with the disease. Furthermore, sarcopenia is closely linked to the accelerated progression of PD, diminished quality of life, greater susceptibility to falls and fractures, and increased mortality risk. Although the precise mechanisms remain unclear, numerous studies suggest that factors such as the accumulation of α-Synuclein in skeletal muscle, loss of motor neurons, inflammation, phosphate toxicity, hormonal dysregulation, vitamin D deficiency, intestinal flora imbalances, and dysfunction of the gut-muscle-brain axis contribute to sarcopenia in PD. Understanding these mechanisms provides valuable insights into the relationship between PD and sarcopenia and establishes a foundation for future research and therapeutic strategies. This review examines the mechanisms underlying sarcopenia in PD, methods for its screening and assessment, and potential avenues for future research, including strategies for risk reduction and treatment.

Aging is a major risk factor for neurodegenerative diseases, yet underlying epigenetic mechanisms remain unclear. Here, we generated a comprehensive single-nucleus cell atlas of brain aging across multiple brain regions, comprising 132,551 single-cell methylomes and 72,666 joint chromatin conformation-methylome nuclei. Integration with companion transcriptomic and chromatin accessibility data yielded a cross-modality taxonomy of 36 major cell types. We observed that age-related methylation changes were more pronounced in non-neuronal cells. Transposable element methylation alone distinguished age groups, showing cell-type-specific genome-wide demethylation. Chromatin conformation analysis demonstrated age-related increases in TAD boundary strength with enhanced accessibility at CTCF binding sites. Spatial transcriptomics across 895,296 cells revealed regional heterogeneity during aging within identical cell types. Finally, we developed novel deep-learning models that accurately predict age-related gene expression changes using multi-modal epigenetic features, providing mechanistic insights into gene regulation. This dataset advances our understanding of brain aging and offers potential translational applications.

It has been reported that elderly individuals exhibit reduced scarring during the wound healing process compared to younger adults. However, the underlying mechanisms responsible for this phenomenon remain poorly understood. Here, we revealed that aged mice exhibited more pronounced regenerative outcomes compared to young mice, characterized by increased hair follicle numbers and collagen fiber features closer to normal skin. Single-cell sequencing identified a reparative fibroblast subpopulation (Prss35+Fib) enriched in the aged group, which promotes regeneration through communication with epithelial cells, macrophages, and T cell subpopulations via PTN and EREG signaling. Spatial transcriptomics validated this communication pattern by elucidating cell proximity and locating the regenerative niche in the upper dermis. Finally, EREG treatment significantly enhanced regenerative outcomes in young mice, while the small wound model of aged mice, lacking the reparative fibroblast and EREG signaling, failed to achieve regeneration. Collectively, our findings advance the understanding of regenerative plasticity in aging and provide new insights for designing scarless therapeutic strategies.

Mitochondrial dysfunction is a hallmark of aging and numerous age-related diseases. A wealth of studies supports the accumulation of mitochondrial DNA (mtDNA) mutations as a contributing factor to mitochondrial dysfunction in aging and disease. One of the best models to study the relationship between mtDNA mutations and mitochondrial dysfunction is the mtDNA mutator mouse, which expresses a proofreading-deficient version of mtDNA polymerase-[gamma]; (PolgA). Despite its groundbreaking contributions to mitochondrial biology and aging research, this model is limited by the whole-body accumulation of mtDNA mutations, which prevents the investigation of tissue-specific differences in mitochondrial dysfunction. To overcome this limitation, we developed a novel inducible knock-in mtDNA mutator mouse model that allows spatial and temporal control of mtDNA mutations, enabling the precise study of mitochondrial dysfunction in a tissue- and time-specific manner. Here, we report the generation and validation of this novel model through whole-body induction via Cre recombinase. Our data demonstrate that, upon induction, this model recapitulates the phenotype of the original mtDNA mutator mouse manifesting the same behavioral and biochemical alterations. This work establishes the functionality of our model and highlights its value as a powerful tool for studying the impact of mtDNA mutations with enhanced specificity and control.

Calorie restriction (CR) provides anti-aging benefits through diverse processes, such as reduced metabolism and growth and increased mitochondrial activity. Although controversy still exists regarding CR-mediated lifespan effects, many researchers are seeking interventions that mimic the effects of CR. Yeast has proven to be a useful model system for aging studies, including CR effects. We report here that yeast adapted through in vitro evolution to the severe cellular stress caused by loss of the Ulp2 SUMO-specific protease exhibit both enhanced growth rates and replicative lifespan, and they have altered gene expression profiles similar to those observed in CR. Notably, in certain evolved ulp2Δ lines, an increase in the auto-sumoylation of Ubc9 E2 SUMO-conjugating enzyme results in altered regulation of multiple targets involved in energy metabolism and translation at both transcriptional and post-translational levels. This increase is essential for the survival of aged cells and CR-mediated lifespan extension. Thus, we suggest that high Ubc9 auto-sumoylation exerts potent anti-aging effects by promoting efficient energy metabolism-driven improvements in cell replication abilities. This potential could be therapeutically explored for the development of promising CR-mimetic strategies.

Sarcopenia, closely associated with other diseases such as diabetes, metabolic syndrome, and osteoporosis, significantly impacts aging populations. It is characterized by muscle atrophy, increased intramuscular adipose tissue, impaired myogenesis, chronic low-grade inflammation, and reduced muscle function. The mechanisms behind aging muscle remain incompletely understood. This study aims to elucidate the role of Sirt2 in the aging process of skeletal muscles and enhance our understanding of the underlying mechanisms. Sirt2 expression was reduced in aging muscle of male mice by 40%, compared to young muscle. Aged male Sirt2 knockout mice exhibit increased intramuscular adipose tissue infiltration by 8.5-fold changes. Furthermore, the deletion of Sirt2 exacerbated myogenesis impairment in aged muscle by decreasing the expression of Pax7 (50%) and NogoA (80%), compared to age- and sex- matched counterparts, emphasizing the role of Sirt2 in pathology of aging muscle. Additionally, long-term Sirt2 deletion affected other Sirtuin subfamily members, with decreased expressions of Sirt1 (65%), Sirt4 (94%), and Sirt5 (71%), and increased expressions of Sirt6 (4.6-fold) and Sirt7 (2.8-fold) in old male Sirt2 knockout mice, while there was no difference of these gene expression in young male mice. This study underscores the critical need for a deeper investigation into Sirt2, promising new insights that could lead to targeted therapies for sarcopenia, ultimately improving the quality of life in the elderly.

INTRODUCTION: Dual cognitive-motor impairment in aging is a strong predictor of dementia, yet its effects on vulnerable gray matter regions microstructure remain unexplored. METHODS: This study classified 582 individuals aged 36-90 into cognitive-motor impairment, isolated cognitive or motor impairment, and control groups. Microstructural differences in 27 temporal and motor-related gray matter regions and white matter tracts were assessed using DTI and mean apparent propagator (MAP-MRI), a technique well-suited for gray matter analysis. RESULTS: We found widespread microstructural alterations in gray and white matter among individuals with dual cognitive-motor impairment. These changes were not observed in isolated cognitive or motor impairment after multiple comparisons correction. DISCUSSION: Dual cognitive-motor impairment is associated with reduced cellular density in temporal gray matter, decreased fiber coherence, and potential demyelination in white matter tracts, suggesting widespread microstructural disruption. These findings could help understand brain aging and facilitate interventions to slow neurodegeneration and delay dementia onset.

This study aims to investigate the histological changes, sperm parameters, and their impact on embryo development rates and offspring numbers in advanced-age male repro57 heterozygous mice, corresponding to approximately 40 years of age in humans.

The retromer complex was discovered in Saccharomyces cerevisiae as a multiprotein, pentameric assembly essential for recycling of integral membrane cargo proteins through the endosomal network [1,2]. We now understand how retromer is assembled, its membrane architecture, and how it selects proteins for recycling [3-6]. Conserved across eukaryotes, analyses have revealed retromer's role in organism development, and homeostasis and has linked retromer defects with age-related Alzheimer's disease and Parkinson's disease and other neurological disorders [3,5,7]. Indeed, stabilizing retromer function is now actively considered a therapeutic strategy [8]. Here, we reflect on its structural and functional evolution rather than overviewing retromer biology (see, e.g. [5,7]). Specifically, we clarify the organization of the human retromer to provide greater focus for future research, especially within the context of retromer's function in neuroprotection.