Longevity Papers

Aging is a multifaceted biological process marked by a gradual decline in physiological functions, driven by cellular senescence, oxidative stress, chronic inflammation, and stem cell exhaustion. Extracellular vesicles (EVs), naturally occurring nanoscale vesicles secreted by various cell types, have gained attention as potential therapeutic agents due to their ability to mediate intercellular communication by delivering bioactive molecules, including proteins, lipids, and RNAs. This review provides a comprehensive overview of EV biogenesis, cargo composition, and their mechanistic roles in counteracting aging processes. EVs from diverse sources-such as mesenchymal stem cells, embryonic stem cells, dermal fibroblasts, and colostrum-exhibit regenerative properties by modulating immune responses, enhancing tissue repair, and promoting extracellular matrix homeostasis. Recent preclinical and clinical studies further highlight their potential in addressing age-related diseases and skin rejuvenation. However, significant challenges remain, including standardization of EV production, large-scale manufacturing, safety profiling, and regulatory approval. By leveraging advancements in EV engineering, targeted delivery systems, and combination strategies with existing anti-aging interventions, EV-based therapies hold promise as next-generation approaches in regenerative medicine and longevity enhancement.

The hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG) is the most readily released product of elastin degradation, a process closely associated with aging. Recent studies have demonstrated the ability of this peptide to upregulate Sirtuin 2 (SIRT2) mRNA and protein expression. The correlation between HRD1 ligase (Synoviolin 1) and the degradation of SIRT2 has been previously reported in the literature. This study aimed to explore the impact of VGVAPG-induced interaction between HRD1 and SIRT2 and its effects on autophagy in differentiated SH-SY5Y cells in vitro (a simplified model of neurons). The results revealed that VGVAPG decreases HRD1 mRNA and protein expression while correlating with SIRT2 overexpression. Further analysis showed reduced SEL1L protein levels and an increase in p97/VCP protein expression. Additionally, enhanced phosphorylation of IRE1α indicated induction of ER stress in the tested cell model without affecting mTOR. Decreased proteasome activity and accumulation of ubiquitin were also noted. This phenomenon triggered VGVAPG-induced autophagy, as evidenced by increased expression of autophagy-related proteins ATG16L1, ATG5, ATG18, and FIP200. However, autophagy was suppressed probably as a result of VGVAPG-induced phosphorylation of ERK1/2. These findings demonstrate that the aging-related hexapeptide VGVAPG downregulates the function of the SEL1L-HRD1 complex, leading to SIRT2 accumulation and subsequent ER stress due to ERAD and UPS. This cascade, in turn, activates autophagy as an alternative clearance pathway aimed at restoring proteostasis; however, the process becomes dysregulated, leading to persistent ER stress. This dual effect may have significant implications in neurobiology, given the well-established correlation between autophagy impairment and aging-related neurodegenerative disorders.

During aging, the cardiac extracellular matrix (ECM) undergoes gradual remodeling that reduces the heart's ability to function. Specific ECM changes cause alterations in cellular signaling pathways, eliciting maladaptive responses. Here, we provide insight into the current knowledge of how age-specific ECM changes contribute to altered ligand-receptor interactions, dysregulated mechanotransduction, and the propagation of pro-fibrotic signaling cascades that underpin dysfunction. We also highlight regional and sex differences that new biomolecular and bioengineered technologies have recently uncovered. We call for new biomaterial strategies that mimic spatiotemporal and sex-specific ECM alterations to equip researchers with the tools to unravel complex cellular signaling events. We believe this can be achieved through interdisciplinary cooperation amongst researchers spanning matrix biology, biomaterials, spatial omics, and biomedical engineering.

Great efforts have been established to promote healthy aging and prevent illnesses connected to aging. The prevalence of elderly population increases and this will be associated with an increase in disability and illness. This study analyzed renal aging process following administration of D-galactose (120 mg/kg/d ip for 8 weeks), and the potential protective effects of vitamin D administration (1,000 and 10,000 IU/kg/d by oral gavage for 8 weeks) in animals with D-galactose induced aging. The renal function tests (serum urea and creatinine, creatinine clearance, and 24 hours urinary albumin excretion levels), oxidative stress (MDA, TCA), renal tissue expression of TNFα, HIFα, Adropin, MAPK, eNOS, and VEGF as well as histopathological and EM alterations were assessed. D-galactose administration resulted in noticeable changes in renal histopathology, deteriorated renal function tests, elevated oxidative stress and inflammation, and significantly diminished Adropin, MAPK, eNOS, HIFα and VEGF expression. Vitamin D effectively reversed these alterations and enhanced histopathological and EM ultrastructure changes triggered by D-galactose administration.

As women age, their ovarian follicle pool naturally declines. However, female germline stem cells (FGSCs) possess a unique ability to differentiate into oocytes and continuously self-renew, providing an effective means of delaying ovarian aging by replenishing the primordial follicle pool. Therefore, activating FGSCs is critical in reshaping and safeguarding ovarian function.

Aging is accompanied by widespread DNA methylation changes across the genome. While age-related methylation studies typically focus on individual CpGs, cluster analysis provides more robust data and improved interpretation. We characterized age-associated CpG-cluster methylation changes in mouse spleens, peripheral blood mononuclear cells, and livers. We identified a novel signature termed blanket methylations (BMs), fully methylated CpG clusters absent in young tissues but appearing in aged tissues. BM formation was locus- and cell-dependent, with minimal overlap among tissues. Statistical analysis, heterogeneity assessment, and random modeling demonstrated that BMs arise through nonrandom mechanisms and correlate with accelerated aging. Notably, BMs appeared in chronologically young mice with progeroid or disease-driven aging, including in 4-month-old Zmpste24-/- (lifespan ∼5 months) and 3-month-old Huntington's disease model mice (lifespan ∼4 months). The detection of BMs in purified CD4+ T cells demonstrated that their occurrence is intrinsic to aging cells rather than a result of infiltration from other tissues. Further investigation revealed age-related downregulation of zinc-finger-CxxC-domain genes, including Tet1 and Tet3, which protect CpG islands from methylation. Importantly, TET1 or TET3 depletion induced BM formation, linking their loss to age-associated methylation drift. These findings establish BMs as a robust marker of epigenomic aging, providing insight into age-related methylation changes.

Senescence in stem cells and progenitor cells can be particularly detrimental because these cells are essential for tissue renewal and overall organismal homeostasis. In mesenchymal stromal cells (MSCs), which comprise a heterogeneous mix of stem cells, progenitors, fibroblasts, and other stromal cells, senescence poses a significant challenge, as it impairs their ability to support tissue repair and maintenance. This decline in regenerative capacity can contribute to aging-related diseases, impaired wound healing, and degenerative disorders. One hallmark of senescence is resistance to apoptosis, mediated by activation of anti-apoptotic pathways. Consequently, senotherapeutics have emerged as a promising strategy to selectively eliminate senescent cells and promote healthy aging. Plant secondary metabolites, notably polyphenols and terpenes, exhibit diverse effects on living organisms and have served as medicinal agents.

This study aims to determine if neurons derived from induced pluripotent stem cells (iPSCsNs) and directly converted neurons (iNs) from the same source cells exhibit changes in mitochondrial properties related to aging. This research addresses the uncertainty around whether aged iPSCsNs retain aging-associated mitochondrial impairments upon transitioning through pluripotency while direct conversion maintains these impairments. We observe that both aged models exhibit characteristics of aging, such as decreased ATP, mitochondrial membrane potential, respiration, NAD

In recent years indoor air pollution (IAP) has emerged as a critical public health and environmental issue and to highlight the need for coordinated efforts to promote healthy aging and sustainable development, this study determined the association between frailty and IAP among male and female and among older adults (45-59 years) and elderly (≥ 60 years) population in India.

Cholesterol oxidation leads to the development of several oxysterols such as 7-ketocholesterol (7KC), which are linked to various age-related conditions. An approach to reduce their toxicity is proposed using enzymes from microbial sources to degrade them. Our earlier studies identified Pseudomonas aeruginosa PseA and Rhodococcus erythropolis MTCC 3951 as potential strains capable of using 7KC as their sole carbon source. These strains produced cholesterol oxidase as the primary enzyme in the degradation pathway. To enhance applicability, cholesterol oxidase (ChOx) enzymes from P. aeruginosa PseA (ChOxP), R. erythropolis MTCC 3951 (ChOxR), and a commercial variant from Streptomyces sp. (ChOxS) were immobilized on silane functionalized silica nanoparticles (SNP) using covalent-coupling methods. The immobilization efficiency was 68 %, 86 %, and 83 % for ChOxP, ChOxR, and ChOxS respectively. The catalytic efficiency of the immobilized enzyme was nearly twice that of the free enzyme, with increased stability across a wide range of temperatures (10-70°C) and pH levels (4.0-9.0), although the optimum pH (7.5) and temperature (30°C) remained unchanged. The nano-immobilized cholesterol oxidases were reusable up to 10 cycles. Further, enzyme immobilization on nanoparticles was confirmed by FTIR, SEM, and TEM. Biotransformation of cholesterol and 7KC using the nanobioconjugates produced pharmaceutically important molecules 4-cholesten-3-one and 4-cholesten-3,7-dione respectively.

Monitoring intrinsic capacity and implementing appropriate interventions can support healthy aging. There are, though, few tools available for predicting decline in intrinsic capacity among older adults. This study aimed to develop and validate an interpretable machine learning model designed to identify populations at elevated risk of a decline in intrinsic capacity.

Sarcopenia, a pathology that concerns the gradual reduction of muscle mass and strength, which entered the international classification of pathologies in 2016, is one of the most critical effects of aging (primary sarcopenia) and of some pathologies, such as oncological pathologies, lung diseases, malnutrition, and obesity (secondary sarcopenia). Going to evaluate the prevalence of the pathology, the scientific literature reports that are sarcopenic: 12-13 % of elderly living at home under 70 years of age, 24 % between 70 and 80, and up to 30-50 % of over 80; 35 % of elderly who access geriatric facilities, 15 % of subjects develop sarcopenia during hospitalization; 87 % of institutionalized elderly; 18 % of diabetic people; 20-70 % of cancer patients; 12-39 % of patients with chronic obstructive pulmonary disease; 84 % of women and 100 % of men with grade II and III obesity. Given this background, Ministry of Health and the main Italian scientific societies of clinical nutrition, geriatrics and physiatry are signatories of the opinion paper entitled "Inter-society Italian Manifesto for the prevention and therapy of sarcopenia", which is presented in this paper. The manifesto's goal is to raise awareness on sarcopenia among the population, institutions and healthcare workers through various actions, in the form of a message, awareness poster and the establishment of the "National Sarcopenia Day" by the Ministry of Health. In this day, centers where sarcopenia is diagnosed and treated, such as geriatrics, rehabilitation, and clinical nutrition facilities, carry out free screening on the target population. As regards actions for healthcare workers, it is necessary to promote and support the training of general practitioners (GPs) and of staff working in healthcare and social healthcare facilities (such as nurses, physiotherapists, speech therapists, and motor science operators so that they can recognize and adequately treat sarcopenia.

A coordinated response to stress is crucial for promoting the short- and long-term health of an organism. The perception of stress, frequently through the nervous system, can lead to physiological changes that are fundamental to maintaining homeostasis. Activating the response to low oxygen, or hypoxia, extends healthspan and lifespan in C. elegans. However, despite some positive impacts, negative effects of the hypoxic response in specific tissues prevent translation of their benefits in mammals. Thus, it is imperative to identify which components of this response promote longevity. Here, we interrogate the cell-nonautonomous hypoxic response signaling pathway. We find that HIF-1-mediated signaling in ADF serotonergic neurons is both necessary and sufficient for lifespan extension. Signaling through the serotonin receptor SER-7 in the GABAergic RIS interneurons is necessary in this process. Our findings also highlight the involvement of additional neural signaling molecules, including the neurotransmitters tyramine and GABA, and the neuropeptide NLP-17, in mediating longevity effects. Finally, we demonstrate that oxygen- and carbon-dioxide-sensing neurons act downstream of HIF-1 in this circuit. Together, these insights develop a circuit for how the hypoxic response cell-nonautonomously modulates aging and suggests valuable targets for modulating aging in mammals.

Hutchinson-Gilford progeria syndrome, caused by a mutation in the LMNA gene, leads to increased levels of truncated prelamin A, progerin, in the nuclear membrane. The accumulation of progerin results in defective nuclear morphology and is associated with altered expression of linker of the nucleoskeleton and cytoskeleton complex proteins, which are critical for nuclear signal transduction via molecular coupling between the extranuclear cytoskeleton and lamin-associated nuclear envelope. However, the molecular mechanisms underlying progerin accumulation-induced nuclear deformation and its effects on intranuclear chromosomal organization remain unclear. Here, the spatiotemporal evolution of nuclear wrinkles is analyzed in response to variations in substrate stiffness using a doxycycline-inducible progerin expression system. It is found that cytoskeletal tension regulates the onset of progerin-induced nuclear envelope wrinkling and that the molecular interaction between SUN1 and LMNA controls the actomyosin-dependent attenuation of nuclear tension. Genome-wide analysis of chromatin accessibility and gene expression further suggests that an imbalance in force between the intra- and extranuclear spaces induces nuclear deformation, which specifically regulates progeria-associated gene expression via modification of mechanosensitive signaling pathways. The findings highlight the crucial role of nuclear lamin-cytoskeletal connectivity in bridging nuclear mechanotransduction and the biological aging process.

Oxidative stress and mitochondrial dysfunction are proposed to play prominent roles in the biology of aging. Human studies are limited and confounded by metabolic disturbances associated with age-related diseases. In this study we have measured biomarkers of oxidative and mitochondrial stress in blood samples from up to 864 participants in the longitudinal Dunedin Multidisciplinary Health and Development Study at age 45. We then determined the correlation between these cross-sectional biomarkers and the longitudinal Pace of Aging, a composite score that represents whole-organism functional decline in each participant from 26 to 45 years old, and facial age at 45 years old. Protein carbonyls and allantoin were selected as biomarkers for oxidative stress, and GDF-15 as a marker of mitochondrial stress. Mid-life levels of these biomarkers were low but varied across the population. GDF-15 showed the strongest associations with the Pace of Aging (β = 0.26, p < 0.0001) and facial age (β = 0.12, p =0.001) in sex and smoking adjusted models. The Pace of Aging was also significantly associated with allantoin (β = 0.14, p < 0.0001) and protein carbonyls (β = 0.09, p = 0.005), and allantoin was also associated with facial age (β = 0.08, p = 0.02). These associations remained when the limited number of participants with age-related disease were removed from the analyses. Our results provide evidence of increased oxidative stress and mitochondrial stress in faster aging humans at midlife, well before the onset of age-related disease.

During skin development, ectoderm-derived cells undergo precisely coordinated proliferation, differentiation, and adhesion to yield stratified epidermis. Disruptions in these processes can result in congenital anomalies, including ectodermal dysplasia and harlequin ichthyosis. PRMT5-an enzyme responsible for methylating arginine residues in histones and other proteins-maintains progenitor status in germ and limb bud cells. Similarly, in vitro evidence suggests that PRMT5 prevents differentiation of basal keratinocytes, leading us to hypothesize that PRMT5 preserves the stem-cell phenotype of keratinocytes in vivo. To test this possibility, we generated conditional knockout mice lacking Prmt5 in early ectoderm (embryonic day 7.5), impacting the entire epidermis. Prmt5 conditional knockouts exhibited gross skin defects, compromised skin barrier function, and reduced postnatal viability. Histological analyses revealed significant defects in epidermal stratification, without alterations in apoptosis or proliferation. Single-cell RNA sequencing and Assay for Transposase-Accessible Chromatin with high-throughput sequencing analysis identified an atypical population of basal keratinocyte-like cells in Prmt5 conditional knockouts that exhibited a senescence-like program, characterized by increased Cdkn1a (p21), elevated senescence-associated secretory phenotype molecules (Igfbp2), and decreased developmental transcription factor (Trp63) expression. Our findings suggest that PRMT5 prevents basal keratinocyte senescence by repressing Cdkn1a, shedding light on the epigenetic regulation of basal keratinocyte maintenance and senescence in congenital skin disorders.

Collagen, a protein known for its long lifespan, is susceptible to accumulation of advanced glycation end products (AGEs) with age. These AGEs are considered markers that indicate the aging severity and influence the mechanics of tissues, leading to fragile bones and hardened skin. While many cross-linking AGEs have been widely studied for their ability to reduce the elasticity of biological tissues, contributing to skin hardening and fragile bones, through strong covalent bonds, non-cross-linking AGEs, or AGE adducts, are typically investigated as indicators of aging or as signaling factors in pathological conditions. However, recent experimental findings have revealed that the number of AGE adducts in aged bone is comparable to enzymatic cross-links, which are significantly more abundant than cross-linking AGEs. Based on these observations, we consider one of the most abundant AGE adducts - carboxymethyllysine (CML) - and employ molecular dynamics simulations to explore its direct impact on the mechanical and conformational properties of single tropocollagen molecules. Our models demonstrate that tropocollagen peptides, constructed based on sequences experimentally identified with sites of CML modifications in type I collagen derived from human cortical bone, exhibit heterogeneous behaviors under tensile testing. Still, most of these modified peptides display compromised structural stability, reduction in structural strength, and diminished energy dissipation ability when tension is applied. This study highlights the potential impact of non-cross-linking AGEs on collagen behavior at molecular scale and provides insights into the mechanisms underlying these modifications. Gaining a deeper understanding of the role of AGE adducts and their contribution to the aging process may pave the way for future solutions in antiaging research.

Developmental time (or time to maturity) strongly correlates with an animal's maximum lifespan, with late-maturing individuals often living longer. However, the genetic mechanisms underlying this phenomenon remain largely unknown. This may be because most previously identified longevity genes regulate growth rate rather than developmental time. To address this gap, we genetically manipulated prothoracicotropic hormone (PTTH), the primary regulator of developmental timing in

Substantial progress in aging research continues to deepen our understanding of the fundamental mechanisms of aging, yet there is a lack of interventions conclusively shown to attenuate the processes of aging in humans. By contrast, replacement interventions such as joint replacements, pacemaker devices and transplant therapies have a long history of restoring function in injury or disease contexts. Here, we consider biological and synthetic replacement-based strategies as aging interventions. We discuss innovations in tissue engineering, such as the use of scaffolds or bioprinting to generate functional tissues, methods for enhancing donor-recipient compatibility through genetic engineering and recent progress in both cell therapies and xenotransplantation strategies. We explore synthetic approaches including prostheses, external devices and brain-machine interfaces. Additionally, we evaluate the evidence from heterochronic parabiosis experiments in mice and donor-recipient age-mismatched transplants to consider whether systemic benefits could result from personalized replacement approaches. Finally, we outline key challenges and future directions required to advance replacement therapies as viable, scalable and ethical interventions for aging.

Polycomb repressive complexes (PRCs) are pivotal epigenetic regulators that preserve cell identity by restricting transcription responses to sub-threshold extracellular signals. Their roles in osteoblast function and bone formation remain unclear. Here in aging osteoblasts, we found marked activation of PRC1.1 complex, with KDM2B acting as a chromatin-binding factor and BCOR and PCGF1 enabling histone H2A monoubiquitylation (H2AK119ub1). Osteoblast-specific Kdm2b inactivation significantly enhances bone remodeling under steady-state conditions and in scenarios of bone loss. This enhancement is attributed to H2AK119ub1 downregulation and subsequent Wnt signaling derepression. Furthermore, we developed a small molecule termed iBP, that specifically inhibits the interaction between BCOR and PCGF1, thereby suppressing PRC1.1 activity. Notably, iBP administration promotes bone formation in mouse models of bone loss. Therefore, our findings identify PRC1.1 as a critical epigenetic brake on bone formation and demonstrate that therapeutic targeting of this complex enhances Wnt pathway activation, offering a promising strategy against skeletal deterioration.

The nucleolus is a membraneless organelle and an excellent stress sensor. Any changes in its architecture or composition lead to nucleolar stress, resulting in cell cycle arrest and interruption of ribosomal activity, critical factors in aging and cancer. In this study, we identified and described the pivotal role of the RNA-binding protein (RBP) HNRNPK in ribosome and nucleolar dynamics. We developed an in vitro model of endogenous HNRNPK overexpression and an in vivo mouse model of ubiquitous HNRNPK overexpression. These models showed disruptions in translation and caused alterations in the nucleolar structure, resulting in p53-dependent nucleolar stress, cell cycle arrest, senescence, and bone marrow failure phenotype, similar to what is observed in patients with ribosomopathies. Together, our findings identify HNRNPK as a master regulator of ribosome biogenesis (RiBi) and nucleolar homeostasis through p53, providing a new perspective on the orchestration of nucleolar integrity, ribosome function and cellular senescence.

This study aims to develop a multifunctional polymer nanovesicle system, AG86-β-glucan-poly(methionine-b-carboxybetaine) (AGPMC), which integrates AG86 peptide (a targeting ligand for the α6β4 integrin on basal keratinocytes) and reactive oxygen species (ROS) responsiveness to enhance the transdermal delivery of ergothioneine (EGT). The objective is to overcome the limitations of hydrophilic drug delivery and provide a targeted, ROS-triggered strategy for treating skin lipofuscin. AGPMC was synthesized via RAFT and ROP polymerization and self-assembles into stable nanovesicles (ANVs). Physicochemical characterization confirmed that the unloaded ANVs have an average size of 106.17 ± 3.26 nm and a polydispersity index (PDI) of 0.261 ± 0.027, with excellent stability and clear ROS-triggered structural responsiveness. After EGT loading, the nanovesicles exhibited a size of 140.10 ± 3.33 nm and a PDI of 0.217 ± 0.008. In vitro studies using HaCaT cells demonstrated a significant enhancement in cellular uptake, with an increase of up to 2.2-fold compared to free FSS (p < 0.0001), as well as effective ROS scavenging and minimal cytotoxicity. The endocytosis mechanism study revealed that ANVs are primarily taken up via energy-dependent active transport, with caveolae-mediated endocytosis being the main pathway. Moreover, transdermal delivery studies confirmed that EGT-loaded nanovesicles significantly improved drug penetration through the stratum corneum. This work represents the first application of the AG86-conjugated nanovesicles for keratinocyte-targeted delivery, combined with ROS responsiveness. The "Loading-Targeting-Responding " strategy holds significant potential for enhancing hydrophilic drug delivery and offers a promising approach for treating age-related skin lipofuscin accumulation.

This study aimed to investigate the role of fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m

PM2.5 pollution is expected to worsen in many places due to climate change, as a result of hotter temperatures, less precipitation, and increases in wind speed. PM2.5 exposure has adverse effects on humans that may accelerate the aging process, such as worsening cognitive functioning and cardiometabolic disease. Less is known about whether physical and mental health conditions mediate the relationship between PM2.5 exposure and aging-related cognitive and functional limitations.

To screen drug targets of ovarian aging from a genetic perspective.

The neuromuscular junction (NMJ) is the synapse that enables the requisite electrical communication between the motor nervous system and the myofibers that respond to such electrical stimulation with movement and force development. Changes in an NMJ's normal activity pattern have been demonstrated to remodel both the synapse and the myofibers that comprise the NMJ. Significant amounts of research have been devoted to the study of aging on the neuromuscular system. Far less, however, has been focused on revealing the effects of reduced activity on the NMJ and myofibers comprising juvenile neuromuscular systems. In the present investigation, the consequences of decreased activity imposed by muscle unloading (UL) via hindlimb suspension for 2 weeks (a period known to induce muscle remodeling) were examined in both young adult, that is, mature (8 mo), and juvenile (3 mo) neuromuscular systems. In total, 4 treatment groups comprised of 10 animals (Juvenile-Control, Juvenile-Unloaded, Mature-Control, and Mature-Unloaded) were studied. Immunofluorescent procedures, coupled with confocal microscopy, were used to quantify remodeling of both the pre- and postsynaptic features of NMJs, as well as assessing the myofiber profiles of the soleus muscles housing the NMJs of interest. Results of ANOVA procedures revealed that there were significant (p < 0.05) main effects for both treatment, whereby UL consistently led to expanded size of the NMJ, and Age where expanded NMJ dimensions were consistently linked with mature compared to juvenile neuromuscular systems. Moreover, only sporadically was interaction between the main effects of Age and Treatment noted. Importantly, one variable that remained impressively resistant to the effects of both Age and Treatment was the critical parameter of pre- to postsynaptic coupling suggesting stability in effective communication at the NMJ throughout the lifespan and despite changes in activity patterns. The data presented here suggest that further inquiry must be performed regarding disuse-related plasticity of the neuromuscular system in adolescent individuals as those individuals regularly suffer injuries resulting in periods of muscle UL.

Mechanical overload is a critical contributor to cartilage degeneration in osteoarthritis (OA) pathogenesis. Circular RNA (circRNA) is expected to provide a long-lasting therapy for OA. However, the involvement of the circRNA-associated competitive endogenous RNA network in chondrocyte senescence induced by mechanical overloading remains unestablished. A mechanical overloading-induced chondrocyte senescence model in human primary chondrocytes is constructed, and differences in the expression of circRNAs and miRNAs were analyzed. The biological roles of circKIAA0586/miR-335-5p in chondrocyte senescence and OA progression under mechanical overloading and its downstream targets were determined using gain- and loss-of-function experiments in various biochemical assays in human chondrocytes. The in vivo effects of circKIAA0586 overexpression were also determined in destabilization of the medial meniscus (DMM) OA mice and aged spontaneous OA mice. The mechanical overloading-induced chondrocyte senescence was aggravated by miR-335-5p or circKIAA0586 knockdown. Accumulated DNA damage response was observed following mechanical overloading, which reduced after miR-335-5p inhibition or circKIAA0586 supplementation. MiR-335-5p was regulated by circKIA0586 adsorption. HELLS was prominently down-regulated following mechanical overloading treatment. Moreover, miR-335-5p bound to lymphoid-specific helicase (HELLS) mRNA during mechanical overloading was demonstrated to mediate the nonhomologous end joining (NHEJ) pathway, thereby inducing DNA damage and senescence. In addition, the senescence delaying and cartilage protective functions of circKIAA0586 and HELLS were validated in DMM OA mice and aged spontaneous OA mice. Our findings suggest that miR-335-5p, which escapes circKIAA0586 adsorption, facilitates mechanical overloading-induced chondrocyte senescence and OA progression by impairing the NHEJ pathway through HELLS inhibition. Overall, targeting circKIAA0586/miR-335-5p/HELLS signaling provides a novel therapeutic approach for OA.

Polydeoxyribonucleotide (PDRN) is a low molecular weight linear polyribonucleotide fragment derived from salmon sperm, known for its potential in tissue regeneration and anti-inflammatory applications. However, its specific function in cellular senescence is yet to be fully understood. Silent information regulator 1 (SIRT1), an NAD + -dependent deacetylase, plays a crucial role in regulating cellular aging and tumorigenesis. Notably, SIRT1 levels decrease with age in both mice and during cellular senescence, highlighting its significance in anti-aging processes. This study assessed the effects of PDRN on cellular aging induced by ultraviolet B (UVB) or hydrogen peroxide (H2O2) and investigated the mechanisms of its protective effects against aging at the cellular level. Our data demonstrated that PDRN treatment mitigated the decline in cell viability and inhibited cell aging when exposed to UVB or H2O2. Furthermore, PDRN ameliorated UVB-induced epidermal thickening in mouse skin. Mechanically, we found that PDRN treatment led to a reduction in nuclear autophagy and the formation of cytoplasmic stress granules by preventing the accumulation of damaged LC3 in the nuclear and inhibiting the degradation of SIRT1 and p62 in the cytoplasm during cellular senescence. In conclusion, PDRN exhibits antioxidant and anti-aging properties by diminishing autophagy and enhancing SIRT1 expression. These results suggest that PDRN has potential as a therapeutic compound for reducing skin aging induced by UVB or H2O2 through the modulation of SIRT1 levels.

Multisystem biological risk, a marker of physiological dysregulation, accumulates over time in response to exposure and adaptation to chronic stress. Spousal concordance in health and health behaviors indicates potential for shared risk to accumulate within couples. This study examined spouses' shared multisystem biological risk as a modifier of individual risk and predictor of future functional limitations and mortality.

The restoration of collagen and elastin in human dermal fibroblasts plays a crucial role in anti-aging and skin rejuvenation therapies. Numerous studies have examined the effects of various antioxidants on skin health, but there is limited research comparing their combined effects on collagen and elastin synthesis in human dermal fibroblasts.

Large-scale single-cell atlas efforts have revealed many aging- or disease-associated cell types, yet these populations are often underrepresented in heterogeneous tissues, limiting detailed molecular and dynamic analyses. To address this, we developed EnrichSci - a highly scalable, microfluidics-free platform that combines Hybridization Chain Reaction RNA FISH with combinatorial indexing to profile single-nucleus transcriptomes of targeted cell types with full gene-body coverage. When applied to profile oligodendrocytes in the aging mouse brain, EnrichSci uncovered aging-associated molecular dynamics across distinct oligodendrocyte subtypes, revealing both shared and subtype-specific gene expression changes. Additionally, we identified aging-associated exon-level signatures that are missed by conventional gene-level analyses, highlighting post-transcriptional regulation as a critical dimension of cell-state dynamics in aging. By coupling transcript-guided enrichment with a scalable sequencing workflow, EnrichSci provides a versatile approach to decode dynamic regulatory landscapes in diverse cell types from complex tissues.

Social determinants of health are social factors that affect health and survival. Two of the most powerful social determinants are socioeconomic status (SES) and race/ethnicity; people with lower SES or marginalized race/ethnicity tend to experience earlier onset of aging-related diseases and have shorter lifespans. DNA methylation (DNAm) measures of biological aging, often referred to as epigenetic clocks, are increasingly used to study the social determination of health. However, there are several generations of epigenetic clocks and it remains unclear which are most sensitive to social factors affecting health. Moreover, there is uncertainty about how technical factors, such as the tissue from which DNA is derived or the technology used to measure DNA methylation may affect associations of social determinants with epigenetic clocks. We conducted a pre-registered multi-level meta-analysis of 140 studies, including N = 65,919 participants, encompassing 1,065 effect sizes for associations of SES and racial/ethnic identity with three generations of epigenetic clocks. We found that associations were weakest for the first generation of epigenetic clocks developed to predict age differences between people. Associations were stronger for the second generation of epigenetic clocks developed to predict mortality and health risks. The strongest associations were observed for a third generation of epigenetic clocks, sometimes referred to as epigenetic speedometers, developed to predict the pace of aging. In studies of children, only the speedometers showed significant associations with SES. Effects of sex and technical factors were minimal and there was no evidence of publication bias.

Normative reference charts are widely used in healthcare, especially for assessing the development of individuals by benchmarking anatomic and physiological features against population trajectories across the lifespan. Recent work has extended this concept to gray matter morphology in the brain, but no such reference framework currently exists for white matter (WM) even though WM constitutes the essential substrate for neuronal communication and large-scale network integration. Here, we present the first comprehensive WM brain charts, which describe how microstructural and macrostructural features of WM evolve across the lifespan, by leveraging over 26,199 diffusion MRI scans from 42 harmonized studies. Using generalized additive models for location, scale, and shape (GAMLSS), we estimate age- and sex-stratified trajectories for 72 individual white matter pathways, quantifying both tract-specific microstructural and morphometric features. We demonstrate that these WM brain charts enable four important applications: (1) defining normative trajectories of WM maturation and decline across distinct pathways, (2) identifying previously uncharacterized developmental milestones and spatial gradients of tract maturation, (3) detecting individualized deviations from normative patterns with clinical relevance across multiple neurological disorders, and (4) facilitating standardized, cross-study centile scoring of new datasets. By establishing a unified, interpretable reference framework for WM structure, these brain charts provide a foundational metric for research and clinical neuroscience. The accompanying open-access trajectories, centile scoring tools, and harmonization methods facilitate precise mapping of WM development, aging, and pathology across diverse populations. We release the brain charts and provide an out-of-sample alignment process as a Docker image: https://zenodo.org/records/15367426.

Sulfur mustard (SM), a potent alkylating agent, has been widely used in chemical warfare, causing severe acute and long-term health complications. While its immediate toxic effects are well documented, the late-onset complications remain poorly understood. Chronic exposure to SM has been linked to persistent oxidative stress, inflammation, and genomic instability, contributing to the progression of various diseases, including pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and cancer. This review explores the emerging role of telomere biology in the delayed pathophysiology of SM exposure. Evidence suggests that telomere shortening and dysregulation of telomeric repeat-containing RNA (TERRA) may serve as key molecular indicators of SM-induced aging and cellular dysfunction. Furthermore, inflammatory pathways, particularly NF-κB and TGF-β signaling, appear to be closely associated with telomere attrition, perpetuating chronic inflammation and fibrosis. By integrating oxidative stress, inflammation, and telomere dynamics, we propose a novel model linking telomere biology to SM-induced late complications. Understanding these mechanisms could pave the way for targeted therapeutic strategies, including antioxidant and epigenetic interventions, to mitigate long-term effects. Future research should focus on validating telomere-based biomarkers for early detection and exploring novel interventions to alleviate SM-induced chronic health conditions.

Epigenetic modifications, including histone post-translational modifications, are central drivers of age-associated structural and functional changes in the genome, influencing gene expression and cellular resilience. Our objective was to determine the effects of inhibiting histone deacetylases (HDACs) and the histone methyltransferase SETDB1 on lifespan, reproduction, and stress response in the rotifer Brachionus manjavacas, a model organism for aging studies. We exposed rotifers to three pharmaceutical compounds, including the HDAC inhibitors {beta}-hydroxybutyrate and sodium butyrate and the SETDB1 inhibitor mithramycin A. We quantified changes in the global histone modification levels by immunoblotting, and measured lifespan, reproduction, and heat stress resistance in the drug-treated rotifers relative to a control. Global histone acetylation levels increase with {beta}-hydroxybutyrate and sodium butyrate treatments. Histone 3 K9 trimethylation (H3K9me3) levels were reduced by treatment with mithramycin A. {beta}-hydroxybutyrate significantly extended lifespan without significantly modifying heat stress resistance. In contrast, mithramycin A increased lifespan and enhanced heat stress tolerance, demonstrating a dual protective effect. Sodium butyrate specifically improved heat stress resistance without affecting overall lifespan. Importantly, none of the three treatments had a significant impact on lifetime reproduction. These findings provide insights into the role of histone modifications in aging and suggest potential interventions targeting epigenetic marks to promote longevity and resilience.

Maternal iron deficiency (ID) disrupts maternal and offspring health by impairing iron status and antioxidant defenses. Rapamycin is known to promote autophagy, enhance antioxidant activity, and extend lifespan. This study investigates the intergenerational effects of post-deficiency dietary interventions using normal and rapamycin-treated diets on Drosophila melanogaster. Female flies (F0) were subjected to an iron-deficient diet for 14 days, followed by a 30-day recovery period on either a normal diet or a rapamycin-supplemented diet. Some F0 females were subsequently mated with normal males to produce F1 offspring. Physiological, biochemical, and gene expression analyses were conducted on F0 flies post-chelation and post-intervention. Post-eclosion evaluations, including a 60-day survival study, were performed on both generations. In F0 females, iron chelation significantly reduced (p < 0.0001) body weight, iron levels, and antioxidant enzyme activity, while increasing glutathione (GSH) levels. Gene expression analysis revealed significant changes (p < 0.05) in iron storage (Fer1HCH), autophagy (ATG1), and telomere-related genes (dHeT-A, dTahre, dTart). While a normal diet partially restored iron levels and survival, the rapamycin-treated diet improved antioxidant defenses but had mixed effects on survival and gene expression. In the F1 generation, male and female offspring from mothers on a normal diet exhibited reduced and increased iron levels, respectively, alongside improved median survival. Rapamycin increased body weight and iron levels in female offspring but reduced their median survival. Post-deficiency dietary interventions significantly shape antioxidant responses and survival in both iron-deficient mothers and their offspring. While normal diets support recovery of iron status, rapamycin enhances antioxidant defenses but compromises survival, particularly in female offspring.

Since the discovery that ageing is a modifiable process in animal models, significant advancements in geroscience have led to the emergence of the field of Precision Geromedicine, which aims to optimise health and healthspan by targeting ageing-related processes. Ageing-related diseases (ARDs), accounting for 80% of Singapore's disease burden in 2019, are on the rise as the nation approaches the "super-aged" status by 2030. In response, Singapore is reshaping its healthcare system to focus on healthy ageing, as seen in the launch of the Healthier SG initiative in 2023, which empowers citizens to manage their health proactively with support from over 1800 private general practices. Additionally, Singapore is investing in geroscience to build the foundations of Precision Geromedicine, aiming to integrate gerodiagnostics and gerotherapeutics into clinical practice. Leveraging its robust healthcare system, digital infrastructure, and socio-political stability, Singapore is well-positioned to become a model for addressing ARDs amidst global demographic shifts.

Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder with both genetic and environmental contributions. Epigenetic mechanisms have been found to, at least partially, mediate the effect of environmental factors in PTSD aetiology. PTSD has also been found to be associated with all-cause morbidity and premature mortality, suggesting accelerated biological aging. However, the role of PTSD-associated epigenetic changes and aging in sub-Saharan African subjects is yet to be elucidated. We address this knowledge gap by conducting an epigenome-wide association study (EWAS) of clinician-diagnosed PTSD in 120 individuals from a 5-way genetically admixed South African population (PTSD: n=61; trauma-exposed controls: n=59). Genome-wide DNA methylation (DNAm) data was generated using the Illumina MethylationEPIC BeadChip (V1). EWAS analysis was conducted using a mixed-effects regression model adjusted for sex, age, cell-type proportions, principal components (PCs), and positional effects. Epigenetic age acceleration was calculated using Horvath, Hannum, PhenoAge, and GrimAge clocks. Three less methylated CpG sites and thirteen differentially methylated regions (DMRs) were associated with PTSD. PTSD severity, but not PTSD diagnosis, was associated with accelerated Horvath DNAm age (p = 0.039). Furthermore, individuals with PTSD and comorbid metabolic syndrome (MetS) exhibited significantly accelerated DNAm age compared to those without MetS, as measured by the Hannum (p = 0.027), Horvath (p = 6.22E-4), and Levine PhenoAge (p = 0.039) clocks. These findings suggest an increased risk of premature mortality in individuals with PTSD and comorbid MetS. This study highlights novel PTSD-associated epigenetic differences within a South African population and offers new insights into the role of age-related epigenetic mechanisms in PTSD susceptibility and progression.

Lactiplantibacillus brownii was first discovered in 2023. We previously isolated L. brownii strain MH-1 from homemade pickled Chinese cabbage in Hiroshima Prefecture, Japan, and performed whole-genome sequencing. In this study, we examined the beneficial effects of L. brownii strain MH-1 on a host using C. elegans. MH-1 and heat-killed MH-1 extended the lifespan and also alleviated motility decline during aging in worms. Feeding MH-1 to nematodes indicated its presence in the intestinal tract with no change in body or brood sizes, suggesting that dietary restrictions did not occur. There were no significant differences in intestinal barrier enhancement or fat accumulation in MH-1-fed C. elegans. The stress response of C. elegans was enhanced by MH-1 for oxidative stress tolerance. MH-1 increased the expression of genes involved in defense response and lipid catabolism. These results demonstrate the beneficial effects of MH-1 on nematodes and its potential use as a probiotic.

The application of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) holds significant promise in anti-aging cosmetics, regenerative medicine, and drug delivery systems. However, their limited production efficiency remains a critical barrier to advancing related therapies and pharmaceutical applications. In this study, a library of triterpene saponins was screened, leading to the re-discovery of an oleanane-type triterpene saponin Lucyoside H (1), along with its structural analogs, Chikusetsusaponins IVa (2), IV (3), and V (4), which were found to increase the production of EV from human adipose-derived mesenchymal stem cells (ADMSCs) at a concentration ranging from 10 to 100 µM. A comparative analysis of the chemical structures and activities of all evaluated compounds, along with oleanolic acid (5), revealed that (i) disubstitution of glycosyl on C-3 and C-28 of oleanane aglycone was crucial to the promoting effect; (ii) 3-O-β-D-glucuronopyranosyl substitution achieved the highest efficiency in the promoting effect and alteration of this group attenuated the activity. These results highlight the potential for developing a natural product-based approach to increase EV production by MSCs.

Aging manifests as the progressive declines of homeostatic resilience and repair mechanisms, marked by dysregulations across systems and increasing individual heterogeneity. However, the breadth of measures of homeostatic dysregulation remains underexplored. Here, we introduce DISCO as a novel measure of homeostatic dysregulation, integrating clinical, proteomics, metabolomics, and microbiomes data. DISCO demonstrated moderate correlation with chronological age but robustly predicted mortality, frailty, and chronic disease risk, outperforming Mahalanobis distance in health outcome prediction, comparable to the best epigenetic clocks. Organ/tissue-specific DISCO analysis revealed limited organ-disease specificity, suggesting systemic rather than localized dysregulation drives health decline. Network analysis identified aging-associated proteins as central hubs strongly linked to DISCO scores; further, organ-level DISCO metrics most predictive of age and outcomes were also central within biological networks. Collectively, DISCO emerges as a validated measure of whole-body homeostatic dysregulation, providing a tool for aging risk stratification and insights into systemic aging mechanisms.

In the post-Yamanaka era, the rolling balls on Waddington's hilly landscape not only roll downward, but also go upward or sideways. This new-found mobility implies that the tantalizing somatic cell plasticity fueling regeneration, once only known to planarians and newts, might be sparking in the cells of mice and humans, if only we knew how to fully unlock it. The hope for ultimate regeneration was made even more tangible by the observations that partial reprogramming by the Yamanaka factors reverses many hallmarks of aging [76], even though the underlying mechanism remains unclear. We intend to revisit the milestones in the evolving understanding of cell fate plasticity and glean molecular insights from an unusual somatic cell state, the privileged cell state that reprograms in a manner defying the stochastic model. We synthesize our view of the molecular underpinning of cell fate plasticity, from which we speculate how to harness it for regeneration and rejuvenation. We propose that senescence, aging and malignancy represent distinct cell states with definable biochemical and biophysical parameters.

Skeletal muscle atrophy is a pathological condition characterized by the progressive loss of muscle mass and function, driven by factors such as disuse, inflammation, and aging. While the ubiquitin-proteasome system is established as the central mediator of myofibrillar protein degradation, the role of autophagy in selective protein turnover remains largely unexplored. To address this, we employed a quantitative, time-resolved analysis of protein synthesis and degradation in C2C12 myotubes undergoing TNF--induced atrophy, using dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (dynamic SILAC) coupled with LC-MS/MS. Our data challenges the classical view of atrophy as a uniform, degradation-centric process. Instead, we reveal temporally distinct patterns of selective protein turnover, including differential degradation of myofibrillar, ribosomal, and endoplasmic reticulum (ER)-resident proteins. Early atrophy is characterized by suppressed short-term protein synthesis, increased ubiquitin-ligase expression, proteasomal activation, and ribosome turnover. In contrast, late atrophy features proteasome-dependent myofibrillar protein degradation, selective synthesis of mitochondrial ribosomes and cytoplasmic ribosome degradation, indicative of metabolic adaptation. Moreover, we identify a temporal shift in autophagic selectivity: from ER homeostasis maintenance to a stress-induced ER-degradation program. Notably, inhibition of autophagy during atrophy leads to accumulation of ER-phagy receptors Tex264 and Calcoco1, implicating ER-phagy as a key contributor to atrophic remodeling, underscoring an underexplored regulatory mechanism in muscle proteostasis. By elucidating the role of autophagy in degradation of the ER, this study opens new avenues for therapeutic interventions targeting proteostasis regulation in inflammation-induced muscle-wasting disorders, ultimately contributing to a more refined understanding of muscle atrophy beyond proteasomal degradation.

Introduction: Type-2 diabetes (T2DM) has been associated with higher dementia risks, but the mechanisms are still unclear, and there is increasing evidence of the role of cytokines. Interleukin-6 (IL-6) mediating effect has never been explored. Methods: The study included a subset of 1,927 participants from the Health and Aging Brain Study: Healthy Disparities (HABS-HD) cohort with complete data. Cross-sectional and longitudinal analyses were performed. Associations were studied using multivariable linear, logistic, and mediation analysis with non-parametric bootstrapping. Results: T2DM and IL-6 were associated with worse executive function, Hippocampus atrophy, lower A-Beta 42/A-Beta 40 ratio, and higher A-Beta 40, A-Beta 42, total Tau, and NfL levels. IL-6 mediated 5% of the association of T2DM with A-Beta 40 ([1.5%-10%], p-value<2x10-16), 4% with A-Beta 42 ([0.7%-11%], p-value=0.014), 8% with TMT-B ([0.2%-35%], p-value=0.046), 11% with total Tau ([2.5%-40%], p-value=0.010), 5% with NfL ([1.6%-8%], p-value<2x10-16), and 12% hippocampus atrophy ([3%-49%], p-value=0.004). The results, except TMT-B, were replicated in the longitudinal analysis of long-lasting T2DM on non-previously diagnosed cognitive impairment. Conclusions: The study captured a pre-clinical stage of the T2DM-dementia association. The mediating effect of IL-6 is a novelty that has to be further explored and accounted for in risk stratification and preventive measures, particularly in ethnic minorities.

Background The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) started in 2010 to study the effect of healthy adult ageing on cognition and the brain in a population-derived sample. The study design and protocol for Phases 1-3 of Cam-CAN were detailed in Shafto et al. (2014); this paper outlines the design and protocol of Phases 4-5, which enable longitudinal investigation of cognitive and brain ageing over approximately 12 years. More details about the Cam-CAN project can be found here: www.cam-can.org. Methods/Design Phase 4 was an at-home assessment of cognition, demographics and lifestyle, performed approximately 6 years after Phase 1 (baseline assessment), for which all people from Phase 1 were invited. Phase 5 combined repeated online cognitive, demographics and lifestyle assessment, followed by in-lab attendance for MRI and MEG brain scanning, approximately 12 years after Phase 1, for which all people from Phase 2 (baseline brain assessment) were invited. Demographics, lifestyle and cognitive data are therefore now available for three timepoints, and MRI and MEG brain data for two timepoints. Discussion The Cam-CAN study offers deep and wide phenotyping of neurocognitive health across the adult lifespan (18-96). These rich data will allow researchers to address questions like: why do some people maintain their cognitive abilities better than others, in terms of their brain structure or function, their lifestyle and/or their genetics? Given the shifting demographics towards old age in most countries, this knowledge will be important to help people function independently for longer, reducing both individual and societal burden.

Diabetes mellitus is one of the risk factors for periodontitis. Patients with diabetes mellitus possess higher prevalence of periodontitis, more severe periodontal destruction, yet the underlying mechanisms of action are not yet clear. Annexin A2 (ANXA2) is a calcium-dependent phospholipid-binding protein widely involved in membrane repair, cytokinesis, and endocytosis. In this study, we explore whether ANXA2 is one of the associative links between diabetes and periodontitis and find out its underlying mechanisms. Cellular senescence and mitochondrial functions (ROS, mitochondrial morphology, mitochondrial autophagy) were observed. We observed that ANXA2 expression was down-regulated in Periodontal ligament cells (PDLCs) under high glucose conditions. Furthermore, overexpression of ANXA2 delayed high glucose-induced cellular senescence and mitochondrial dysfunction. β-galactosidase activity and the mRNA levels of the senescence-relative genes(p21,p16) were decreased, mitochondrial fracture and ROS release were reduced, and the expression of mitochondrial autophagy-related proteins (LC3,p62,Parkin) was enhanced. expression was enhanced. Mechanistically, we demonstrated that it can regulate the AKT/eNOS signaling pathway by knockdown and overexpression of ANXA2 which was measured using Western blotting (WB) assay to measure the expression of eNOS, p-eNOS Ser1177, Akt and p-Akt Ser473 proteins in PDLCs. After that, we used AKT and eNOS inhibitors to demonstrate the protective effect of ANXA2 on PDLCs under high glucose conditions. The above results suggest that ANXA2 has an anti-aging protective effect, attenuates high glucose-induced cellular senescence in PDLCs, and maintains mitochondrial homeostasis. Therefore, it would be valuable to further explore its role in the link between diabetes and periodontitis in future experiments.

Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and functional loss in older adults. Obstructive sleep apnea (OSA) is common in older adults, can increase cerebrovascular disease risk, and is linked to medial temporal lobe (MTL) degeneration and cognitive impairment. However, the interaction between OSA features and CSVD burden and their combined effect on MTL structure and function are not well understood. This study tested the hypothesis that CSVD burden is a candidate mechanism linking OSA to MTL degeneration and impaired memory in older adults.

Chemotherapy is a primary modality in cancer treatment, but it may induce cellular senescence, which in turn triggers the release of senescence-associated secretory phenotypes (SASPs) that promote tumor growth and metastasis. To selectively identify senescent cells and mitigate their negative impact on cancer therapy, herein, we have developed a β-galactosidase (β-Gal)-activated and self-immobilizing photosensitizer CyGF-DBCO-T. This photosensitizer can be selectively activated and fluorescently label proteins in situ within senescent cells, enabling near-infrared (NIR) fluorescence imaging-guided photodynamic therapy (PDT) for the precise ablation of these cells. First, we developed an activatable NIR fluorescent probe CyGF-N

Age is an essential factor to understand the life history and demographic parameters of wildlife. Previously, we established an age estimation method for brown bears based on blood DNA methylation level. In this study, we first applied the brown bear-specific age estimation model to other bear species, including Asian black, polar, sun, and Andean bears. Using blood DNA, we performed bisulfite pyrosequencing to determine the methylation levels at four cytosine-phosphate-guanine (CpG) sites adjacent to a single gene,

BackgroundCognitive decline poses a significant challenge in aging societies. While some studies suggest that active social participation mitigates cognitive decline, others present conflicting findings.ObjectiveThis bidirectional two-sample Mendelian randomization (MR) study aimed to elucidate the causal relationship between social participation and cognitive function.MethodsThe cognitive performance dataset (n = 257,841) was used as the discovery sample, while cognitive function (n = 22,593) and Alzheimer's disease (AD) datasets (n = 394,705) served as replication samples and proxies for severe cognitive decline. Inverse variance weighting was the primary analytical method, supplemented by weighted median, MR-Egger, MR.RAPS, MR-PRESSO, and maximum likelihood methods for sensitivity analyses.ResultsSocial participation in sports club or gym (β = 0.09, 95% CI: 0.05 to 0.14, p < 0.001), religious group (β = 0.11, 95% CI: 0.08 to 0.14, p < 0.001) and other group activity (β = 0.06, 95% CI: 0.03 to 0.09, p < 0.001) reduced the risk of cognitive decline, while pub or social club (β = -0.06, 95% CI: -0.1 to -0.02, p = 0.005) and social inactivity (β = -0.05, 95% CI: -0.09 to -0.01, p = 0.017) accelerated cognitive decline. Improved cognitive performance promoted participation in beneficial activities and reduced pub or social club participation. Additionally, AD motivated visits to pub or social club (OR = 1.01, 95% CI: 1.00 to 1.03, p = 0.011).ConclusionsSpecific types of social participation may protect against cognitive decline, offering evidence for targeted interventions to prompt cognitive health in aging populations.

As we age, our movements become slower and less precise - but the extent of this decline remains unclear. To address this, we harmonized data from 2,185 participants across four published studies using a standard center-out reaching task. We found that older age was associated with a steady decline in reaction time (-1.2 ms/year), movement time (-2.3 ms/year), and movement precision (-0.02{degrees}/year). Although the rate of decline did not differ by sex/gender, females consistently reacted more slowly (-8 ms), moved more slowly (-37 ms), and exhibited greater precision (+0.5{degrees}) across the adult lifespan. Notably, sex/gender differences attenuated after accounting for experiential factors such as video game use and the amount of sleep per day, whereas age remained a robust and consistent predictor of motor decline. Together, these findings provide a large-scale quantification of age, sex/gender, and experiential effects on motor control, offering a normative benchmark to inform future clinical interventions aimed at preserving motor function across the lifespan.

Life's Essential 8 (LE8) is known to have a negative correlation with biological aging, while the relationship between the Life's Crucial 9 (LC9) score, which includes mental health, and biological aging remains to be further investigated.

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

Recent influenza vaccine formulations have improved the magnitude of B-cell antibody responses in older adults; however, older adults remain significantly at risk for severe influenza-related illness. Although antibodies are an important metric of vaccine effectiveness, they only represent one aspect of the immune response. In this study, we combined in vitro and ex vivo assays with human samples to investigate B, CD4+ T, and myeloid cell responses to influenza vaccine antigens. We found that older adults mounted equivalent antibody titers to younger adults but had fewer influenza-specific CD4+ T cells and reduced antiviral-associated T helper cell populations. Single-cell transcriptomics revealed that older adults had attenuated interferon transcriptional signatures in T helper and myeloid cell subsets. These data suggest that with aging, transcriptional programming alterations in myeloid cells contribute to reduced antiviral T cell responses, and formulating vaccines tailored to myeloid responses is necessary to improve outcomes in older adults.

The Ten-Eleven Translocases (Tet) family of DNA hydroxymethylases have recently been implicated in bone development, with Tet1 and Tet2 mediating Bone Marrow Stromal Cell (BMSC) growth and osteogenic differentiation. The present study investigated the effects of Tet1 and Tet2 deregulation on bone development and age-related bone loss, with respect to BMSC function. Histomorphometric and micro-CT analysis of skeletal parameters found significant reductions to trabecular structure and volume as well as reduced osteoblast numbers within the bone of Prx-1:Cre driven Tet1 and Tet2 double knockout (TetDKO) mice at skeletal maturity. Moreover, these effects were exacerbated with age, particularly in male mice. In vitro studies found a significant reduction in TetDKO BMSC osteogenic potential and a shift towards adipogenesis, as well as changes to DNA repair, proliferation and senescence properties. RNA sequencing of BMSC derived from TetDKO male mice uncovered several differentially expressed genes, and an array of significantly enriched gene set pathways. Notably Pappa2, involved in regulation of IGF-1 signalling, was significantly differentially regulated, leading to reduction in IGF-1 bioavailability and signalling in BMSC and differentiated osteoblasts. Furthermore, changes in mTOR activity in TetDKO animals indicated altered metabolic activity, differentiation and proliferation capabilities of TetDKO BMSC. These findings indicate that Tet1 and 2 regulate the IGF-1 regulatory element, Pappa2, where deregulation of Tet1 and Tet2 in BMSC can disrupt this pathway leading to enhanced bone loss and premature aging. Targeting of these novel regulatory pathways may offer new therapeutic approaches for treatment of age-related bone loss.

Cellular senescence is a fundamental yet complex defense mechanism that restricts excessive proliferation, maintains cellular homeostasis under various stress conditions-such as oncogenic activation and inflammation-and serves as a dynamic stress response program involved in development, aging, and immunity. Its reversibility depends on essential maintenance components. Cellular senescence is a "double-edged sword": on one hand, it limits the malignant proliferation of damaged cells, thereby preventing tumor development. However, by retaining secretory functions, senescent cells can also induce persistent changes in the microenvironment and disrupt homeostasis, leading to tissue inflammation, fibrosis, and carcinogenesis. Senescence plays a critical role in the pathogenesis of various chronic liver diseases, including chronic viral hepatitis, liver fibrosis, and hepatocellular carcinoma. It exerts a dual influence by facilitating immune evasion and inflammation in chronic viral hepatitis, modulating hepatic stellate cell activity in fibrosis, and reshaping the tumor microenvironment to accelerate hepatocarcinogenesis. This article reviews the characteristics of cellular senescence and its role in the pathogenesis of these chronic liver diseases while exploring potential treatment and prevention strategies. The aim is to provide a comprehensive reference for future clinical and research investigations into chronic liver disease.

Honey bees (Apis mellifera) are faced with a myriad of immunological threats, often worsened by poor nutrition. The use of functional feed additives offers a promising strategy to address colony nutritional deficiencies while helping strengthen bee immune responses and mitigate stress. Microalgae have gained recognition as beneficial diet ingredients for livestock due to their abundance of essential nutrients and immunomodulatory properties. Here, we tested the effects of microalgae-containing feed on honey bee immunity, lifespan, and nutrient assimilation. Caged bees were fed a commercial artificial diet or the same diet with added pollen, spirulina (Arthrospira platensis) or Chlorella (Chlorella vulgaris). Immune-related gene expression, longevity, and body weight were measured following six days of ad libitum feeding. All diets resulted in similar body weights, indicating adequate nutrient assimilation. While bees fed the pollen-containing diet lived the longest (median lifespan = 51 days), bees fed spirulina- and Chlorella-containing diets lived significantly longer (median lifespan = 48 and 46 days, respectively) than those fed the base diet (median lifespan = 40 days). Spirulina-fed bees exhibited significantly higher expression of several antimicrobial peptide (AMP) genes relative to the base diet and had superior bacterial clearing ability after injection with live E. coli cells. We propose that this increased immunocompetence is at least partially due to elevated AMP levels. Our findings suggest that the tested microalgae can improve honey bee longevity and immune functions with negligible health costs relative to a commonly used artificial diet. Determining the effects of microalgae feed additives in field-relevant contexts and in the face of diverse pathogen challenges should be the focus of future research efforts.

Gene expression relies on transcriptional bursts driven by dynamic chromatin-modifying enzymes that depend on metabolites like NAD+. Depletion of NAD+ contributes to cancer, metabolic disorders, and aging, emphasizing the significance of tight regulation of NAD+ production in the cell. NMNAT1, a nuclear NAD+ -synthetase enzyme, supports chromatin-modifying enzymes such as PARP1 and SIRT1; however, its direct role in transcriptional regulation remains unclear. Using integrated multi-omics, we present the first high-resolution, genome-wide study of NMNAT1s regulatory functions. We demonstrate that NMNAT1 binds to the promoters and enhancers of actively transcribed genes involved in DNA replication, cell cycle progression, and chromatin regulation. RNA-seq and CUT&Tag analyses indicate reduced RNA Polymerase II occupancy at downregulated genes in NMNAT1 knockout cells, implicating NMNAT1 in transcriptional activation through Pol II engagement. These findings position NMNAT1 as a key node linking localized NAD+ production to gene-specific transcription, offering new insights into metabolic regulation of gene expression.

Osteoporotic tendon-to-bone healing remains a major challenge, as cellular senescence disrupts tissue regeneration and impairs repair outcomes. Although the role of cellular senescence in rotator cuff repair is increasingly recognized, current strategies often overlook the complex pathological context, particularly the dual impacts of senescence on both bone marrow-derived mesenchymal stem cells (BMSCs) and tendon-derived stem cells (TDSCs). This gap hampers effective tendon-to-bone healing and integration, especially under osteoporotic conditions. Herein, a composite hydrogel system, quercetin-loaded aligned ultralong hydroxyapatite nanowire/gelatin-hyaluronic acid hydrogel (Que-AHNW/GH), has been developed to address these challenges. By integrating senolytic quercetin as a biological cue with highly aligned ultralong hydroxyapatite (HAP) nanowires as a topographical cue, the system remodels the senescent microenvironment, alleviating senescence in both BMSCs and TDSCs and promoting osteogenesis and tenogenesis. Que-AHNW/GH suppresses the PI3K/AKT pathway, enhances autophagy, and reduces senescence in both cell types. In vivo, Que-AHNW/GH improves bone tunnel regeneration, tendon repair, and tendon-to-bone integration in osteoporotic rats with rotator cuff injury. This system enhances biomechanical strength and gait performance and demonstrates excellent biosafety. These findings highlight the promising potential of Que-AHNW/GH as a multifunctional biomaterial for effectively promoting senescence-related tendon-to-bone healing, offering a promising solution for treating osteoporotic tendon-to-bone injuries.

Experimental evolution studies that feature selection on life-history characters are a proven approach for studying the evolution of aging and variation in rates of senescence. Recently, the incorporation of genomic and transcriptomic approaches into this framework has led to the identification of hundreds of genes associated with different aging patterns. However, our understanding of the specific molecular mechanisms underlying these aging patterns remains limited. Here, we incorporated extensive metabolomic profiling into this framework to generate mechanistic insights into aging patterns in Drosophila melanogaster. Specifically, we characterized metabolomic change over adult lifespan in populations of D. melanogaster where selection for early reproduction has led to an accelerated aging phenotype relative to their controls. Using these data we: i) evaluated evolutionary repeatability across the metabolome; ii) assessed the value of the metabolome as a predictor of "biological age" in this system; and iii) identified specific metabolites associated with accelerated aging. Generally, our findings suggest that selection for early reproduction resulted in highly repeatable alterations to the metabolome and the metabolome itself is a reliable predictor of "biological age". Specifically, we find clusters of metabolites that are associated with the different rates of senescence observed between our accelerated aging population and their controls, adding new insights into the metabolites that may be driving the accelerated aging phenotype.

While cardiovascular aging and frailty are strongly associated in older adults, their mechanistic relationship and how physical activity, through its frequency, intensity, and duration, may influence their association remains unclear. A prospective community cohort of older adults without cardiovascular disease were studied cross-sectionally for cardiac structure and function via echocardiogram, dynamometer-derived handgrip strength, skeletal muscle measurements and physical activity questionnaires. Based on handgrip strength and cardiac aging, we derived four phenotypic groups:

Excessive inflammatory responses within the ovary are one of the main causes of subfertility in elderly women. Eliminating these responses can reverse fertility in aged individuals. Here, we demonstrate that administering 300 mg kg

Physical inactivity exacerbates muscle function and mass loss, increasing the risk of falls in older adults. Regular exercise can prevent muscle loss, cognitive decline, and comorbidities, potentially reducing fall risk. Given the multifactorial nature of fall risk, a comprehensive assessment is required.

Retrotransposable elements (RTEs) have been implicated in the pathogenesis of several age-associated diseases. Although model systems indicate that age- and sex-dependent loss of heterochromatin increases RTE expression, data from large human studies are lacking. Here we assessed the expression levels of 795 blood RTE subfamilies in 2467 participants of the population-based Rhineland Study. We found that the expression of more than 98% of RTE subfamilies increased with both chronological and biological age. Moreover, the expression of heterochromatin regulators involved in RTE silencing was negatively related to the expression of 690 RTE subfamilies. Finally, we observed sex differences in 42 RTE subfamilies, with higher expression in men. The genes mapped to sex-related RTEs were enriched in immune response-related pathways. Importantly, we validated our key findings in an independent population-based cohort. Our findings indicate that RTEs and their repressors are markers of aging and that their dysregulation is linked to inflammation, especially in men.

Maintaining genomic stability is essential for detecting DNA damage and activating appropriate responses such as repair, apoptosis, or senescence, primarily mediated by the ATM-p53 axis. ATM is the main sensor of double-strand breaks, and once activated, it will either promote the repair of damaged DNA or eliminate the damaged cells through apoptosis. ATM and p53 mutations upset this equilibrium to cause genomic instability, therapy resistance, and tumor progression in the context of cancer. Oncogene-induced senescence is bypassed by ATM inactivation, which allows cells to progress to become tumors, and p53 mutations allow for uncontrolled proliferation and sensitivity to apoptosis. In addition, persistent ATM signaling can trigger a SASP, which paradoxically further enhances an inflammatory tumor microenvironment and contributes to aging-related diseases and cancer progression. Chemical small molecule p53 activators (PRIMA-1, Nutlin-3) and ATM inhibitors (AZD0156, M4076) sensitize cancer to DNA damaging therapy in cells and nude mice without p53. It remains to be seen whether ATM loss results in ATM/p53 signaling that is always detrimental to tumor proliferation or has context-dependent effects since ATM loss can also promote p53-dependent tumor suppression through senescence and apoptosis in specific cancer types. In this review, we consolidate state-of-the-art findings on ATM and p53 coordination in the processes involved in DNA repair, apoptosis, and senescence to show how ATM and p53 dual involvement in tumor suppression and cancer progression is occurring. It also focuses on therapeutic approaches targeting these pathways to benefit from senescence and intimidating cancer treatment outcomes.

Previous studies have consistently demonstrated that exercise mitigates cognitive decline in older adults. However, the most effective types of exercise, along with optimal frequency and duration of interventions, remain inadequately defined. To address these gaps, we conducted a network meta-analysis synthesizing direct and indirect evidence from existing literature to identify the most effective exercise interventions for enhancing cognitive function in older adults.

Considering the critical role of working memory (WM) in age-related cognitive decline, WM interventions are proposed as an effective approach for promoting healthy aging. However, traditional WM interventions often yield limited results, possibly due to a lack of interest and challenge. In light of the recent prominent trend of gamification, this study developed a challenging gamified WM intervention aimed at improving WM and providing extensive cognitive benefits for older adults, along with entertainment. Seventy-six older adults were randomly assigned to either the WM intervention group or the active control group. All participants underwent twelve 1-hr training sessions spanning 6 weeks. For each participant, cognitive assessments were completed at pretest, posttest, and 6 months after the intervention while structural magnetic resonance imaging (MRI) and resting-state functional MRI scans were conducted before and after intervention. The results revealed significant improvements in WM, inhibitory control, visuospatial processing, and episodic memory among older adults following the intervention. The left frontal pole, located in the rostral prefrontal cortex (rPFC), exhibited increased cortical thickness accompanied by reduced functional homogeneity and weakened connectivity with the left inferior temporal gyrus. Further statistical learning analysis demonstrated a consistent relationship between the changes at the left frontal pole and improved WM performance, suggesting that the rPFC may support WM and play a protective role in brain aging. The findings highlight the broad benefits of the gamified WM intervention on neurocognitive plasticity in the rPFC of older adults, indicating its potential as a promising tool for mitigating neurocognitive decline during the aging process. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

Aging-associated mitochondrial oxidative stress has been implicated in ventricular tachyarrhythmias (VT), but the specific proarrhythmic mechanisms of mitochondrial pro-oxidative systems remain unclear. NADPH oxidase 4 (NOX4) expression in the heart increases with age, leading to mitochondrial oxidative stress, dysfunction, and adverse myocardial remodeling. This study investigated the susceptibility to aging-associated ventricular arrhythmia and the associated triggers and substrates using transgenic mice with mitochondria-targeted Nox4 overexpression (Nox4TG mice). Nox4TG mice showed a significantly higher incidence of pacing-induced VT, associated with shorter action potential duration (APD) due to increased transient outward potassium currents. Fractional sarcoplasmic reticulum (SR) Ca

Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.

The glymphatic system, a vital brain perivascular network for waste clearance, hinges on the functionality of the aquaporin 4 (AQP4) water channel. Alarmingly, AQP4 single nucleotide polymorphisms (SNPs) are linked to impaired glymphatic clearance, or glymphopathy, which contributes to sleep disturbances and various age-related neurodegenerative diseases. Despite the critical role of glymphopathy and sleep disturbances in cerebral small vessel disease (CSVD) - a silent precursor to age-related neurodegenerative disorders - their interplay remains underexplored. CSVD is a major cause of stroke and dementia, yet its pathogenesis is not fully understood. Emerging evidence implicates glymphopathy and sleep disorders as pivotal factors in age-related CSVD, exacerbating the condition by hindering waste removal and compromising blood-brain barrier (BBB) integrity. Advanced imaging techniques promise to enhance diagnosis and monitoring, while lifestyle modifications and personalised medicine present promising treatment avenues. This narrative review underscores the need for a multidisciplinary approach to understanding glymphopathy and sleep disorders in CSVD. By exploring their roles, emphasising the necessity for longitudinal studies, and discussing potential therapeutic interventions, this paper aims to pave the way for new research and therapeutic directions in CSVD management.

Sphingolipids (SPLs) are essential membrane lipids with significant bioactive roles involved in various cellular processes, and their alterations have been found to be linked to many diseases, including age-related diseases. However, comprehensive studies on the association of plasma sphingolipids with aging in large, diverse cohorts remain limited. The objective of this study was to investigate the relationship between plasma sphingolipid levels and aging in a cohort of 240 normoglycemic, biracial individuals (Black and White), aged 19-65 years. Using a targeted lipidomics approach, we measured 76 sphingolipid species using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in picomole/mL and determined changes in their levels with age and their correlations with aging. We found significant age-related changes in several sphingolipid species, including ceramide C18:1 and several very long-chain sphingomyelins (VLC SMs), such as C28:1 and C30:1, increases with age, showing a positive correlation. On the other hand, glycosphingolipids (monohexosylceramide, MHC; lactosylceramide, LacCer) and sphingosine (So) showed strong negative correlations with aging. A significant correlation was also observed between the ratios of saturate/monosaturated sphingolipid species with aging. In conclusion, our findings provide novel insights into the dynamic changes of circulating sphingolipids with aging. Specific sphingolipid species, such as Ceramide C18:1 and SM, accumulate with age, while others, including MHC, LacCer, and So decrease. These results suggest that the plasma SPL profile may provide valuable information about healthy aging and age-associated disease conditions.

Physical inactivity and social isolation are key obstacles to achieving healthy and active aging. This study evaluated the association between participation in a citywide economic incentive Yokohama Walking Point (YWP) program with walking time, the risk of being homebound, and social isolation. We also explored the heterogeneities in the association across gender, socioeconomic status (SES), and built environment (BE).

BackgroundWDR23 is a regulator of cellular proteostasis and oxidative stress response processes that are critically involved in the pathogenesis of Alzheimer's disease (AD). Dysregulation of these pathways can contribute to amyloid-β (Aβ) and tau pathologies, ultimately leading to cognitive impairment.ObjectiveWe explored the effects of

Nicotinamide phosphoribosyltransferase (NAMPT) is an enzyme that involves into NMN-NAD + synthesis which involves into cellular metabolism related with aging, immune function, and neurodegeneration. However, its roles in early embryo development are still unclear.