Longevity Papers

Fibroblasts play a key role in maintaining skin structure and immune balance, but factors like aging, stress, and chronic inflammation can weaken their function, leading to collagen loss, thinning skin, and increased inflammation. Traditional collagen boosters like retinoic acid (RA), vitamin C (VC), hyaluronic acid (HA), and transforming growth factor beta (TGFβ) have drawbacks, including poor absorption, instability, and irritation. Studies reveal that Silk Bioactive Peptide (27 P peptide) binds to epidermis and dermal fibroblasts, enhancing prolonged pro-collagen 1 (pro-C1) secretion in 3D and 2D models. De-novo collagen synthesis by 27 P peptide, likely regulated at the translational level, resulted in elevated collagen deposition and matrix remodeling up to 120 h. Combination of VC and 27 P peptide rescues VC-induced intracellular collagen depletion. Unlike TGFβ and RA, 27 P peptide maintains balance between fibroblast subpopulations, without inducing markers of fibrosis or inflammation. Together, 27 P peptide presents as a promising alternative to effectively promote collagen production, fibroblast homeostasis and skin health.

Macroautophagy/autophagy, a critical cellular degradation pathway essential for maintaining neuronal proteostasis, declines with age and has been increasingly implicated in the regulation of synaptic integrity and circuit resilience. Neuropeptide Y (NPY), the most abundantly expressed neuropeptide in the mammalian brain, has emerged as a key modulator of both autophagy and aging-related processes. In Drosophila, the NPY-family peptide short Neuropeptide F (sNPF) has been shown to causally influence aging-associated changes in synaptic architecture and function, particularly at the presynaptic active zone (AZ), via non-cell autonomous mechanisms. Extending this concept to mammals, we investigated whether NPY and autophagy interact within NPY-secreting neurons to regulate age-related AZ remodeling. Our results indicate that hypothalamic NPY/AgRP neurons may exert geroprotective effects through the release of NPY and potentially other signaling molecules, thereby influencing both metabolic homeostasis and brain-wide synaptic function. These data suggest a conserved role for autophagy in maintaining presynaptic organization and resilience during aging.

Cochlear aging causes substantial hearing impairment in older adults, yet primate-specific mechanisms remain poorly characterized. Our comprehensive analysis combining single-cell and histopathological profiling in aging Macaca fascicularis demonstrates progressive cochlear degeneration featuring accelerated sensory hair cell loss, senescent spiral ganglion neurons with elevated neuroinflammation, and marked stria vascularis atrophy. We discovered that downregulation of transmembrane transport proteins, particularly SLC35F1, serves as a critical biomarker of hair cell aging. Functional validation through Slc35f1 knockdown in adult mice successfully recapitulated key aspects of age-related hearing loss, including hair cell degeneration and auditory function decline. Notably, we showed that long-term metformin administration at clinically relevant doses effectively delays cochlear aging in primates. These findings provide fundamental insights into the cellular and molecular basis of primate cochlear aging while establishing a foundation for developing targeted interventions against age-related hearing loss.

Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy.

Influenza A virus (IAV) infection causes acute and long-term lung damage. Here, we used immunostaining, genetic, and pharmacological approaches to determine whether IAV-induced cellular senescence causes prolonged alterations in lungs. Mice infected with a sublethal dose of H1N1p2009 exhibited cellular senescence, as evidenced by increased pulmonary expression of p16, p21, β-galactosidase and the DNA damage marker gamma-H2A.X. Cellular senescence began 4 days post-infection (dpi) in the bronchial epithelium, then spread to the lung parenchyma by 7 and 28 dpi (long after viral clearance), and then declined by 90 dpi. At 28 dpi, the lungs showed severe remodeling with structural bronchial and alveolar lesions, abrasion of the airway epithelium, and pulmonary emphysema and fibrotic lesions that persisted up to 90 dpi. In mice and nonhuman primates, persistence of senescent cells in the bronchial wall on 28 dpi was associated with abrasion of the airway epithelium. In p16-ATTAC mice, depletion of p16-expressing cells with AP20187 reduced pulmonary emphysema and fibrosis and led to complete recovery of the airway epithelium at 28 dpi, indicating a marked acceleration of the epithelial repair process. Treatment with the senolytic drug ABT-263 also accelerated epithelial repair without affecting pulmonary fibrosis or emphysema. These positive effects occurred independently of viral clearance and lung inflammation at 7 dpi. Finally, AP20187 treatment of p16-ATTAC mice at 15 dpi led to complete recovery of the airway epithelium at 28 dpi. Thus, virus-induced senescent cells contribute to the pulmonary sequelae of influenza; targeting senescent cells may represent a new preventive therapeutic option.

Arazyme, an enzyme derived from Serratia proteamaculans, has demonstrated efficacy in enhancing skin barrier function in studies involving skin cell treatments and topical application on animal skin. The objective of this study was to assess the anti-wrinkle and anti-aging effects of Arazyme in skin keratinocytes and fibroblasts subjected to ultraviolet B (UVB) radiation and oxidative stress. Keratinocytes (HaCaT cells) and fibroblasts (CCD-986sk) were exposed to UVB (15 mJ/cm²) radiation or oxidative stress induced by 2 mM 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH), followed by treatment with Arazyme (0.1-0.5 μM) for 24 h. The effects of Arazyme were compared to those of individual treatments with papain, trypsin, or retinol, which served as reference compounds. Key parameters examined included the expression of matrix metalloproteinases (MMP-1, MMP-3, and MMP-13), collagen synthesis, and cellular senescence markers (LMNB1, p16, p21, and p53). Additionally, the impact of Arazyme on cellular signaling pathways, including ERK, JNK, and NF-κB, was assessed. Arazyme significantly suppressed UVB-induced expression of MMP-1, MMP-3, and MMP-13 in a dose-dependent manner in HaCaT cells compared to other treatments. In UVB-exposed fibroblasts, Arazyme reduced both mRNA and protein levels of MMPs, while also enhancing procollagen concentration and collagen gene expression. Furthermore, Arazyme inhibited the activation of ERK, JNK, and NF-κB signaling pathways in keratinocytes. In AAPH-stimulated HaCaT cells, Arazyme significantly attenuated the expression of senescence-related markers, including LMNB1, p16, p21, and p53, and decreased the proportion of senescence-positive cells in fibroblasts. Our in vitro findings suggest that Arazyme may help attenuate UVB- and oxidative stress-induced markers of skin aging, indicating its potential as a candidate for further investigation in anti-aging skincare research.

Protein aggregation is a normal response to age-related exposures. According to the thermodynamic hypothesis of protein folding, soluble proteins precipitate into amyloids (pathology) under supersaturated conditions through a process similar to crystallization. This soluble-to-insoluble phase transition occurs via nucleation and may be catalyzed by ectopic surfaces such as lipid nanoparticles, microbes, or chemical pollutants. The increasing prevalence of these exposures with age correlates with the rising incidence of pathology over the lifespan. However, the formation of amyloid fibrils does not inherently cause neurodegeneration. Neurodegeneration emerges when the levels of functional monomeric proteins, from which amyloids form, fall below a critical threshold. The preservation of monomeric proteins may explain neurological resilience, regardless of the extent of amyloid deposition. This biophysical framework challenges the traditional clinicopathological view that considers amyloids intrinsically toxic, despite the absence of a known mechanism of toxicity. Instead, it suggests that chronic exposures driving persistent nucleation consume monomeric proteins as they aggregate. In normal aging, replacement matches loss; in accelerated aging, it does not. A biophysical approach to neurodegenerative diseases has important therapeutic implications, refocusing treatment strategies from removing pathology to restoring monomeric protein homeostasis above the threshold needed to sustain normal brain function.

Background: The pineal gland secretes melatonin but paradoxically calcifies more than any other intracranial structure, forming hydroxyapatite "brain-sand" (corpora arenacea) that correlates with reduced melatonin output, sleep disruption and heightened neuro-degenerative risk. Whether this mineralization is a passive dystrophic event or an active, bone-like process remains unclear. Methods: Analyzed RNA-seq datasets from pineal glands of six vertebrate species-calcifiers Homo sapiens, Rattus norvegicus and Capra hircus, versus non-calcifiers Mus musculus, Gallus gallus and Danio rerio. Species-specific transcripts were mapped to human orthologues, merged, and filtered. Phylogenetically informed differential expression testing used Brownian-motion and Pagel's lamda phylogenetic generalized least-squares models, calibrated on a TimeTree divergence phylogeny. Genes significant in both models (|logtwoFC| > 1; FDR < 0.05; lamda < 0.7) were assigned to functional pathways and visualized by PCA, heat-mapping and volcano plots. Results: Calcifying species segregated cleanly from non-calcifiers on the first two principal components, reflecting a shared 103-gene "calcifier module". Top up-regulated transcripts included developmental morphogens (GLI4, IQCE, NOTCH4), epigenetic regulators (SETD1A, ZNF274, ATF7IP), inflammatory mediators (CSF2RB), and quality-control factors (GABARAPL2, RHOT2). Every leading candidate exhibited minimal phylogenetic signal (lamda to 0), indicating that differential expression tracks the calcified phenotype rather than shared ancestry. Conversely, only three genes (RMI2, RASL11B, GPR18) formed a non-calcifier module, suggesting potential protective roles that are down-regulated during mineralization. Conclusions: Pineal calcification is not a passive by-product of aging but a regulated, lineage- restricted program that redeploys Hedgehog, Notch and chromatin-remodeling pathways classically required for skeletal ossification. The ten-gene core signature identified offers a molecular foothold for mechanistic dissection and therapeutic targeting aimed at preserving pineal function and circadian health. Significance This is the first phylogenetically controlled transcriptomic survey to link pineal "brain-sand" formation to specific developmental and inflammatory gene networks, revealing convergent evolution of calcification programs across divergent mammalian lineages.

Cardiac fibrosis, a key pathological feature of cardiac remodeling, is a major contributor to mortality in older patients with heart failure. The underlying mechanisms are complex, involving alterations in intercellular communication and chronic inflammation. This study investigates the role of indole-3-propionic acid (IPA) in aging-related myocardial fibrosis and its regulatory effects on autophagy through palmitoyl-protein thioesterase 1 (PPT1). Here, plasma levels of IPA, a tryptophan-derived metabolite, are found to be reduced in older patients with heart failure, and this reduction is associated with deteriorating cardiac function. Notably, IPA supplementation significantly attenuated aging-related myocardial fibrosis. PPT1, a lysosomal enzyme involved in autophagy, is upregulated in macrophages during aging. IPA reversed aging-induced increase in PPT1 expression. Using PPT1

Cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The mechanisms of senescence in the bronchial epithelium, however, remain largely unknown. This study aimed to elucidate whether cellular senescence in COPD epithelial cells contributes to the pathogenesis of the disease and investigated the potential molecular mechanisms involved. Single cell RNA sequencing was performed on well differentiated primary bronchial epithelial cells from COPD and healthy subjects. We evaluated the abundance and distribution of senescence markers in key epithelial differentiated subtypes and senescence-associated secretory phenotype involved in airway epithelial dysfunction. The effects of interferon pathway inhibitors on cellular senescence were also investigated. There was increased expression of cellular senescence genes in the COPD cohort, which was predominantly in basal and club cells. Enhanced expression of cellular senescence markers, p16 and p21, was observed in COPD cultures, which was histologically confirmed in the lung tissue of COPD patients. There was also a notable increase in IFN-β and IFN-γ. Senescence associated secretory phenotype productions were increased in COPD and was attenuated by JAK-STAT or cGAS-STING pathway inhibitors (baricitinib or C-176). These inhibitors also effectively suppressed expression of senescence markers. COPD bronchial epithelium displays a senescence driven phenotype which is mediated by type I/II interferons. Inhibition of JAK-STAT or STING-cGAS interferon pathways may represent targets to alleviate cellular senescence and chronic inflammation in COPD.

Background: Individuals with mental and behavioural disorders face increased risk of age-related diseases and premature mortality. Accelerated biological ageing may contribute to this disparity. We investigated differences in metabolomic ageing between individuals with and without mental disorders. Methods: The UK Biobank is a community-based health study of middle-aged and older adults. Mental disorders were identified from hospital inpatient, primary care, death registry and self-reported physician diagnosis data. Plasma metabolites were profiled using the Nightingale Health platform. We examined differences in MileAge delta, the difference between metabolite-predicted and chronological age, across broad ICD-10 diagnostic groups and for 45 individual diagnoses. We further investigated sex-specific associations and tested whether polygenic scores for mental disorders were associated with MileAge delta. Results: Amongst 225,212 participants (54% female; mean age = 56.97 years), 38,524 had at least one mental disorder diagnosis preceding baseline. Substance use, psychotic, affective and neurotic disorders were associated with a metabolite-predicted age exceeding chronological age. In contrast, obsessive-compulsive and eating disorders were associated with a younger MileAge, particularly in females. Associations were generally stronger in males, with several diagnoses showing sex-specific patterns. Higher genetic liability to major depression, autism and ADHD was associated with a MileAge exceeding chronological age, whereas psychosis, tobacco use disorder, obsessive-compulsive disorder and anorexia nervosa polygenic scores were associated with a younger MileAge. Conclusions: Metabolomic ageing varies across mental disorders, with direction and strength of association differing by diagnosis and sex. These findings highlight the heterogeneity of biological ageing across mental disorders and contribute to our understanding of the biological processes linking mental disorders to excess morbidity and premature mortality.

Cellular senescence is an aging-related mechanism characterized by cell cycle arrest, macromolecular alterations, and a senescence-associated secretory phenotype (SASP). Recent preclinical trials established that senolytic drugs, which target survival mechanisms of senescent cells, can effectively intervene in age-related pathologies. In contrast, senomorphic agents inhibiting SASP expression while preserving the survival of senescent cells have received relatively less attention, with potential benefits hitherto underexplored. By revisiting a previously screened natural product library, which enabled the discovery of procyanidin C1 (PCC1), we noticed pyrroloquinoline quinone (PQQ), a redox cofactor that displayed remarkable potential in serving as a senomorphic agent. In vitro data suggested that PQQ downregulated the full spectrum expression of the SASP, a capacity observed in several stromal cell lines. Proteomics data supported that PQQ directly targets the intracellular protein HSPA8, interference with which disturbs downstream signaling and expression of the SASP. PQQ restrains cancer cell malignancy conferred by senescent stromal cells in culture while reducing drug resistance when combined with chemotherapy in anticancer regimens. In preclinical trials, PQQ alleviates pathological symptoms by preventing organ degeneration in naturally aged mice while reserving senescent cells in the tissue microenvironment. Together, our study supports the feasibility of exploiting a redox-active quinone molecule with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing proof-of-concept evidence for future exploration of natural antioxidant agents to delay aging and ameliorate age-related conditions. Prospective efforts are warranted to determine long-term outcomes and the potential of PQQ for the intervention of geriatric syndromes in clinical settings.

T stem cell-like memory cells (TSCM cells) are considered to be essential for the maintenance of immune memory. The TSCM population has been shown to have the key properties of a stem cell population: multipotency, self-renewal and clonal longevity. Here we show that no single population has all these stem cell properties, instead the properties are distributed. We show that the human TSCM population consists of two distinct cell subpopulations which can be distinguished by the level of their CD95 expression (CD95int and CD95hi). Crucially, using long-term in vivo labelling of human volunteers, we establish that these are distinct populations rather than transient states of the same population. These two subpopulations have different functional profiles ex vivo, different transcriptional patterns, and different tissue distributions. They also have significantly different TREC content indicating different division histories and we find that the frequency of CD95hi TSCM increases with age. Most importantly, CD95hi and CD95int TSCM cells also have very different dynamics in vivo with CD95hi cells showing considerably higher proliferation but significantly reduced clonal longevity compared with CD95int TSCM. While both TSCM subpopulations exhibit considerable multipotency, no single population of TSCM cells has both the properties of self-renewal and clonal longevity. Instead, the "stemness" of the TSCM population is generated by the complementary dynamic properties of the two subpopulations: CD95int TSCM which have the property of clonal longevity and CD95hi TSCM which have the properties of expansion and self-renewal. We suggest that together, these two populations function as a stem cell population.

Aging is a complex and multifaceted biological process that results in the gradual decline of physiological functions over time. It is associated with reduced performance across multiple systems, affecting metabolic, reproductive, musculoskeletal, and immune functions. While immune aging has been extensively studied in endothermic animals, and in particular mammals such as laboratory rodents, comparatively little is known about how aging manifests in ectothermic vertebrates like reptiles. This study explored the lymphoid tissue (spleen and thymus) of Boa constrictor, a boid snake indigenous to South and Central America and Mexico, but widely kept in captivity all over the world, for potential age-related changes. We observed a significant decrease in cellularity in the spleen, coupled with an increase in organ size correlated with age. In both spleen and thymus the connective tissue of capsule and trabeculae increased significantly with age, indicative of progressive fibrosis. In addition, several changes were observed with increasing frequency in older animals, epithelial hyperplasia in the thymic medulla as well stromal fibrosis and an increasing infiltration by so-called granular cells in both organs. Granular cells likely represent a leukocyte subtype; their presence indicates a progressive chronic low-grade inflammatory state in the lymphoid organs, a feature known as inflammaging in other animal classes. They may also play a role in the progressive fibrosis of the connective tissue. The results firstly describe morphological evidence of aging in B. constrictor and indicate similarities in the aging across animal classes.

Age-related cognitive loss has been linked to a possible imbalance in the brain's oxidant/antioxidant system. Additionally, neurotransmitter concentrations, the activity and levels of receptors change in different brain regions depending on aging. The aim of this study was to investigate the effect of chronic L-carnitine administration on learning and memory in naturally aging rat, focusing on its impact on glutamate cycle and receptors. Sixty male 10-month old male Wistar rats were randomly divided into two groups as control and L-carnitine groups. For a period of 7 months, L-carnitine was given at 50 mg/kg/day via oral gavage. The cognitive performance was assessed by novel object recognition and active avoidance tests. Total oxidant capacity and antioxidant capacity levels as well as glutamate and glutamine concentrations were analyzed in the hippocampi. NMDA and AMPA receptors, VGLUT-1, VGLUT-2, EAAT-1, EAAT-2, EAAT-3 levels in hippocampi were evaluated. L-carnitine administration increased learning performance. Total oxidant capacity levels decreased and total antioxidant capacity levels increased in the hippocampus of aged rats treated with L-carnitine. Furthermore, a small shift in the glutamate and glutamine concentrations between control and L-carnitine treated groups were observed. During the aging process, L-carnitine administration caused an increase in VGLUT-1, VGLUT-2, EAAT-1, EAAT-2, EAAT-3 levels in hippocampus tissues. In addition, NMDAR1 and slightly NMDAR2 mRNA levels increased, while AMPAR1 level decreased in the L-carnitine-treated group. Our data suggest that the molecular and functional changes controlling glutamate homeostasis in the hippocampus with aging may be attenuated by long-term L-carnitine usage.

Proteoglycan 4 (PRG4) is a mucin-like glycoprotein best known as a boundary lubricant of articular cartilage; however, it also has anti-inflammatory, anti-fibrotic, and immunomodulatory properties. Loss-of-function mutations in the PRG4 gene in humans result in Camptodactyly-Arthropathy-Coxa vara-Pericarditis (CACP), a rare disease in which patients often require joint replacements at young ages. However, it remains unknown how circulating PRG4 levels change with age or how PRG4 deficiency affects aging. Therefore, the first objective of this study was to measure serum PRG4 levels in young and aged wild type (WT) mice. We found that serum PRG4 concentration was lower in aged than young WT mice. Next, we assessed the impact of PRG4 deficiency on survival and determined that Prg4 gene trap (GT, PRG4 deficient) mice had lower survival probability than WT mice. Finally, we examined how PRG4 deficiency impacts blood gases, complete blood counts, and bone in middle-aged Prg4 GT mice. Various blood parameters were altered in Prg4 GT mice versus WT and exhibited sexual dimorphism. PRG4 deficiency diminished trabecular and cortical properties of bone in middle-aged mice sex-dependently, and aging and genotype exhibited an interaction effect consistent with accelerated skeletal aging in males. Overall, this study provides an initial examination into changes in serum PRG4 levels with age in WT mice as well as the effect of PRG4 deficiency in aging. These findings pave the way for future studies to expand on this work mechanistically and assess clinical relevance in CACP and in aging populations.

Dietary restriction (DR) robustly increases lifespan across taxa. However, in humans, long-term DR is difficult to maintain, leading to the search for compounds that regulate metabolism and increase lifespan without reducing caloric intake. The magnitude of lifespan extension from two such compounds, rapamycin and metformin, remains inconclusive, particularly in vertebrates. Here, we conducted a meta-analysis comparing lifespan extension conferred by rapamycin and metformin to DR-mediated lifespan extension across vertebrates. We assessed whether these effects were sex- and, when considering DR, treatment-specific. In total, we analysed 911 effect sizes from 167 papers covering eight different vertebrate species. We find that DR robustly extends lifespan across log-response means and medians and, importantly, rapamycin-but not metformin-produced a significant lifespan extension. We also observed no consistent effect of sex across all treatments and log-response measures. Furthermore, we found that the effect of DR was robust to differences in the type of DR methodology used. However, high heterogeneity and significant publication bias influenced results across all treatments. Additionally, results were sensitive to how lifespan was reported, although some consistent patterns still emerged. Overall, this study suggests that rapamycin and DR confer comparable lifespan extension across a broad range of vertebrates.

Traditional biomaterial design often prioritizes empirical knowledge over disease mechanisms and pathological dynamics, resulting in imprecise solutions in complex clinical conditions. Age-related osteoporosis (A-OP) is a disease associated with aging, characterized by a dysfunctional pathological microenvironment that hinders the osseointegration of conventional titanium implants. To develop a targeted titanium implant for A-OP, rat single-cell transcriptomics is integrated with human serum-derived transcriptome data to investigate dynamic changes in skeletal stem cells (SSCs) during aging, which guided the implant design. These findings reveal that hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) within SSCs interact via a feedback loop: HSCs undergo premature senescence, leading to depletion of HSCs and secondary senescence of MSCs. Senescent MSCs exhibit adipogenic bias, perpetuating the pathological cycle of A-OP. Using core genes identified in the transcriptome analyses, resveratrol is selected and utilized it and a GelMA-chitosan hydrogel to decorate titanium implants for localized delivery. In the A-OP microenvironment, the hydrogel enables sustained responsive release of resveratrol, which reverses MSC senescence and redirects differentiation from adipogenic to osteogenic lineages, thereby breaking the pathological cycle. This multi-omics-driven implant design enhances precision and offers a novel methodology for biomaterial development.

Ageing has profound effects on the human brain across the lifespan. Cognitive testing and brain imaging are currently used to monitor healthy and pathological brain ageing. However, peripheral markers of cognitive function, cognitive ageing and neurological disease could provide a valuable, minimally invasive approach to tracking these processes longitudinally. In this Review, we introduce the concept of DNA methylation-based biomarkers and present current evidence of their potential to address the challenge of monitoring brain ageing and stratifying the risk of neurological disease. We focus on epigenetic clocks, which can be applied across multiple tissues and organs to estimate biological ageing, as well as on blood-based epigenetic scores (EpiScores) that can directly track brain-based phenotypes, such as cognitive function, and risk factors for neurological diseases, such as lifestyle behaviours and proteomic markers of inflammation. We discuss the associations between these epigenetic biomarkers and multiple measures of cognitive health, including cognitive test data, brain MRI measures and dementia.

The nervous system is primarily composed of neurons and glia, and the communication between them has profound roles in regulating the development and function of the brain. Neuron-glia signal transduction is known to be mediated by secreted signals through ligand-receptor interactions on the cell membrane. Here we show a new mechanism for neuron-glia signal transduction, wherein neurons transmit proteins to glia through extracellular vesicles, activating glial signaling pathways. We find that in the amphid sensory organ of Caenorhabditis elegans, different sensory neurons exhibit varying aging rates. This discrepancy in aging is governed by the cross-talk between neurons and glia. We demonstrate that early aged neurons can transmit heat shock proteins to glia via extracellular vesicles. These neuronal heat shock proteins activate the glial IRE1-XBP1 pathway, leading to the transcriptional regulation of chondroitin synthases to protect glia-embedded neurons from aging-associated functional decline. Therefore, our studies unveil a new mechanism for neuron-glia communication in the nervous system and provide new insights into our understanding of brain aging.

Cellular quiescence is a state of reversible proliferative arrest that plays essential roles in development, resistance to stress, aging, and longevity of organisms. Here we report that rapid depletion of RNase MRP, a deeply conserved RNA-based enzyme required for rRNA biosynthesis, induces a long-term yet reversible proliferative arrest in human cells. Severely compromised biogenesis of rRNAs along with acute transcriptional reprogramming precede a gradual decline of the critical cellular functions. Unexpectedly, many arresting cells show increased levels of histone mRNAs, which accumulate locally in the cytoplasm, and S-phase DNA amount. The ensuing proliferative arrest is entered from multiple stages of the cell cycle and can last for several weeks with uncompromised cell viability. Strikingly, restoring expression of RNase MRP leads to a complete reversal of the arrested state with resumed cell proliferation at the speed of control cells. We suggest that targeting rRNA biogenesis may provide a general strategy for rapid induction of a reversible proliferative arrest, with implications for understanding and manipulating cellular quiescence.

Senescence is an irreversible cell cycle arrest-characterized by morphologic alterations, genomic instability, and secretome changes-that profoundly affects the tissue structure and function. Accumulating evidence indicates that senescence plays a relevant role in gastrointestinal pathologies: senescence contributes to salivary gland hypofunction, is instrumental in the development of oral submucous fibrosis, drives age-dependent hepatic steatosis, and regulates the clinical progression of steatotic liver disease. Senescence in the biliary tract develops in response to ischemic injury in biliary complications and is characteristic of biliary conditions such as biliary atresia, primary sclerosing cholangitis, and primary biliary cirrhosis. Senescence also contributes to acute pancreatitis, plays a major role in the dysfunction of pancreatic β-cells, and is a hallmark of a number of gastrointestinal conditions such as inflammatory bowel disease and colorectal cancer. These examples illustrate the widespread effect of cellular senescence in the gastrointestinal tract, not just as a consequence of the disease but also as a driver of pathology and a potential therapeutic target. In this review we describe the mechanisms, hallmarks, and consequences of cellular senescence as well as the therapeutic potential of senescence-targeting interventions. We aim to highlight the importance of understanding the molecular basis of senescence in gastroenterology while connecting the worlds of research and clinical practice.

Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfunction of mitochondria, particularly those located at synapses. Synaptic mitochondria are specialized organelles that produce the energy required for synaptic transmission but are also important for calcium homeostasis at these sites. In contrast, non-synaptic mitochondria primarily involve cellular metabolism and long-term energy supply. Both pools of mitochondria differ in their form, proteome, functionality, and cellular role. The proper functioning of synaptic mitochondria depends on processes such as mitochondrial dynamics, transport, and quality control. However, synaptic mitochondria are particularly vulnerable to age-associated damage, characterized by oxidative stress, impaired energy production, and calcium dysregulation. These changes compromise synaptic transmission, reducing synaptic activity and cognitive decline during aging. In the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's, the decline of synaptic mitochondrial function is even more pronounced. These diseases are marked by pathological protein accumulation, disrupted mitochondrial dynamics, and heightened oxidative stress, accelerating synaptic dysfunction and neuronal loss. Due to their specialized role and location, synaptic mitochondria are among the first organelles to exhibit dysfunction, underscoring their critical role in disease progression. This review delves into the main differences at structural and functional levels between synaptic and nonsynaptic mitochondria, emphasizing the vulnerability of synaptic mitochondria to the aging process and neurodegeneration. These approaches highlight the potential of targeting synaptic mitochondria to mitigate age-associated cognitive impairment and synaptic degeneration. This review emphasizes the distinct vulnerabilities of hippocampal synaptic mitochondria, highlighting their essential role in sustaining brain function throughout life and their promise as therapeutic targets for safeguarding the cognitive capacities of people of advanced age.

Age-related hearing loss (AHL) is the primary cause of deafness in aging populations and lacks proven effective therapies. Protecting the survival and function of sensory outer hair cells (OHCs) represents a promising therapeutic strategy for AHL. Certain herbs have shown beneficial effects on OHCs, but a limited understanding of their mechanisms hinders their clinical application. This study aimed to investigate the underlying mechanism of curcumin analog C1 (C1), which has demonstrated a beneficial effect in treating AHL in aged C57BL/6 mice. Our results revealed that C1 delayed AHL progression and mitigated the loss of OHCs in both aged C57BL/6 mice and aging cultured sensory epithelium explants. Furthermore, C1 exhibited an antioxidative effect in the OHCs of AHL mice. Notably, the application of C1 reversed the inhibition of transcription factor EB (TFEB) nuclear translocation, which was accompanied by the restoration of autophagic capability in OHCs of aged mice. The knockdown of TFEB abolished the activating effect of C1 on autophagy and eliminated its antioxidative effect in aging hair cells, ultimately leading to hair cell damage. Consequently, our findings not only demonstrate the therapeutic potential of C1 for AHL but also provide deeper insights into the pathogenesis of this condition.

Menopause not only signifies the end of a woman's reproductive life, but also brings about significant changes in both mental and physical health due to hormonal changes. Age of natural menopause (ANM) and reproductive lifespan is determined by the formation and subsequent depletion of follicles in females. In this study, we identified a robust association between a common functional missense variant in PARP1 and age at menopause in a sample of 201,323 women. Using an in vitro model to generate primordial germ cells - the precursors of sperm and oocytes- we report that Parp1 affects PGCs in two different ways. Our identified missense variant (V762A) significantly reduces the germ cell population by enhanced DNA binding resulting in increased apoptosis. Conversely, deletion of Parp1 results in an increased population of PGCs and proteomic analysis revealed that transcription factors that drive PGC formation show increased expression in precursor cells. This is caused by increased transcription of Rhox genes (Rhox2A, Rhox6 and Rhox9), implicating Parp1 in downregulation of genes that determine PGC fate. We propose that Parp1 regulates PGC fate and that its increased chromatin association ("trapping") causes a decreased population of PGCs, thereby providing a molecular cause of the earlier onset menopause on female carriers of the variant.

Research utilizing epigenetic clocks has accelerated in recent years, but it is largely unknown how consistently these measures perform across country and cultural contexts, and thus, how useful they are for understanding the large differences in health outcomes across countries. We assess epigenetic aging in three countries (the US, Ireland, and Northern Ireland) utilizing survey data from each country and evaluated how these measures are associated with three well-studied health behaviors (heavy alcohol use, smoking, and BMI). In general, we found remarkable consistency across these studies, suggesting epigenetic clocks are potentially highly useful for monitoring health and aging processes in different contexts. More research is needed on other health risks and in non-Western and low- and middle-income countries.

Older adults with established cardiovascular diseases (CVD) are at elevated risk of heart failure (HF). Frailty, a hallmark of multi-system aging, may contribute to HF development through inflammation. However, population-based evidence remains scarce. Leveraging data from 49,530 CVD patients in the UK Biobank, frailty was measured by five components: weight loss, exhaustion, low physical activity, slow walking speed, and low grip strength. We employed Cox regression models to assess the association between frailty and incident HF, and conducted mediation analyses to evaluate mediating roles of 15 inflammatory markers in this association. Furthermore, we constructed a polygenic risk score (PRS) for HF risk based on the Global Biobank Meta-analysis Initiative (N = 1,020,441), and evaluated the joint association and interaction between frailty and PRS in relation to incident HF. During a median follow-up of 13.3 years, 6293 participants developed HF. Compared to robust individuals, pre-frail (hazard ratio (HR) = 1.31 [95% CI: 1.23-1.40]) or frail (HR = 1.80 [1.64-1.98]) participants had a higher risk of HF, and the potential causality was suggested by Mendelian randomization. Such relationship was partially mediated by inflammatory markers, including interleukin-6, tumor necrosis factor-α, and C-reactive protein. Moreover, individuals with both frailty and high PRS had the greatest risk of HF (HR = 4.35 [3.74-5.06]), with a relative excess risk due to interaction of 1.39, accounting for 32% of total risk. Frailty interacts with PRS to enhance risk stratification of HF. Inflammation may mediate the frailty-HF association, suggesting the potential of anti-inflammatory interventions to mitigate HF risk in frail CVD patients.

Aging is an inevitable process in living organisms, characterized by significant immunological and physiological alterations that increase susceptibility to diseases. Despite decades of research on the interplay between aging and immunity, identifying precise immunogenetic aging markers from high-dimensional (HD) transcriptomics data remains challenging due to the lack of effective pattern-discovery methods for such complex data. Recognizing the crucial role of gene-gene interactions in biological processes, and that aging is reflected in tissue-specific change in these interaction patterns, we first sought a holistic way to represent the intricate relationships among genes within the cells of each tissue. This is technically achieved by converting the scRNA-seq data of a cell into a semantically meaningful image representation, termed a "genomap", through the spatial encoding of the transcriptomic interactions. We then leverage this representation to unveil changes in interaction patterns associated with aging, rather than focusing solely on variations in gene expression profiles. This approach enables the construction of a highly accurate, tissue-specific inflammatory aging clock. Our clock significantly outperforms traditional aging-prediction methods based on blood tests, miRNA, and proteomics data. We illustrate a potential application of our framework in aging interventions via an in silico study targeting the Map3k1/Map2k4/JNK pathway, which may reverse aging-associated declines in B cell function and antibody production, thus mitigating chronic diseases linked to B cells deterioration. Thus, our strategy and pipeline may have broad implications for aging and developmental biology.

Aging is the strongest risk factor for Alzheimer's disease (AD), yet the molecular mechanisms linking aging to AD remain poorly understood. DNA methylation (DNAm) is an epigenetic modification that plays a critical role in gene regulation and has been implicated in both aging and AD. In this study, we performed a meta analysis of DNAm profiles in the prefrontal cortex using two large, independent postmortem brain cohorts, the Religious Orders Study and Memory and Aging Project (ROSMAP) and Brains for Dementia Research (BDR), to identify DNAm differences associated with aging in late life. We identified 3264 CpGs significantly associated with aging, the majority of which were hypermethylated and enriched in promoter regions and CpG islands. These aging associated DNAm changes were significantly overrepresented in genes involved in immune regulation and metabolic pathways. When compared with AD associated DNAm changes, we found a significant overlap, with nearly all CpGs and differentially methylated regions (DMRs) that were associated with both aging and AD Braak stage displaying concordant directionality. This supports the hypothesis that aging and AD are interconnected at the molecular level. Further integrative analyses indicated that a number of these DNAm variants may have functional relevance in AD. By integrating blood DNAm data, we identified multiple CpGs that showed significant brain to blood correlations and were involved in both aging and AD pathogenesis. Colocalization analyses with genomewide association study (GWAS) data revealed shared genetic regulation of DNAm and dementia at several AD risk loci. Out of sample validation using the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrated that, among 334 CpGs showing concordant DNAm changes in aging and AD, baseline DNAm levels at cg10752406 in the AZU1 promoter were significantly associated with AD progression at a 5% false discovery rate, even after adjusting for age, sex, APOE {varepsilon}4 allele status, years of education, and baseline MMSE. Notably, this CpG also showed a strong brain blood DNAm correlation, further supporting its potential as a peripheral biomarker for AD. Our study provides valuable insights into the epigenetic landscape of aging and its implications for AD, suggesting that aging related epigenetic modifications may provide a viable source of biomarkers for AD.

Aging as a complex process is marked by physiological and functional deterioration, making the individual vulnerable to age-related diseases. Different organs experience unique aging processes that lead to conditions such as cardiovascular, cancer, metabolic, and musculoskeletal disorders. Understanding of these processes is essential to formulate effective interventions. To this end, plant-derived bio-actives are effective antiaging agents due to their specific mechanism of action. Phytochemicals in these plants possess antioxidant, anti-inflammatory, and senolytic activities that qualify them as good candidates for antiaging interventions. These molecules are also reported to act on important aging pathways such as immunomodulation, control of inflammation, reduction of oxidative stress, and senescence. The current review emphasizes the organ-specific mechanisms of aging and the role of certain plant constituents that have shown promising antiaging activity. By overviewing the natural interventions against aging mechanisms, this review provides a foundation for future research focused on using natural antiaging interventions involving phytochemicals.

Ovarian failure is a key event in female reproductive aging, resulting in the depletion of follicular reserve and a decline in fertility. In addition, it triggers systemic pathological changes, including osteoporosis and cardiovascular disease, due to decreased estrogen levels. Despite extensive study, mapping senescent ovarian cells is challenging due to the multicellular composition and heterogeneity of the ovary. In the past decade, single-cell resolution technologies have provided new insights into ovarian aging by enabling the molecular characterization of individual cells. Here, we comprehensively review the application of these technologies in delaying ovarian aging and promoting reproductive health. We summarize their value in uncovering cell-type-specific mechanisms and their potential uses in the research of ovarian aging, ultimately deepening our understanding of its pathogenesis and molecular basis.

Accumulating evidence indicates that biological aging can be accelerated by environmental exposures, collectively called the 'exposome'. The skin, as the largest and most exposed organ, can be viewed as a 'window' for the deep exploration of the exposome and its effects on systemic aging. The complex interplay across hallmarks of aging in the skin and systemic biological aging suggests that physiological processes associated with skin aging influence, and are influenced by, systemic hallmarks of aging. This bidirectional relationship provides potential avenues for the prevention of accelerated biological aging and the identification of therapeutic targets. We provide a review of the interactions between skin exposure, aging hallmarks in the skin and associated systemic changes, and their implications in treatment and disease. We also discuss key questions that need to be addressed to maintain skin and overall health, highlighting the need for the development of precise biomarkers and advanced skin models.

Evidence on the impacts of volatile organic compounds (VOCs), a class of ubiquitous environmental toxics, on sarcopenia, a major age-related global health issue, remains scarce. Data from 3007 adults in the National Health and Nutrition Examination Survey (2011-2018) were analyzed to assess the individual and mixture effects of 16 VOCs metabolites (VOCMs) on sarcopenia using multivariate logistic regression, weighted quantile sum (WQS), and Bayesian kernel machine regression (BKMR) models. Network pharmacology was employed to explore potential underlying mechanisms. The phenotypic age (PhenoAge), a biomarker of biological ageing, was used to evaluate its interaction with VOCMs. Several VOCMs, including 2-aminothiazoline-4-carboxylic acid (ATCA; odds ratio: 1.30, 95 % confidence interval: 1.07-1.57), N-acetyl-S-(2-carboxyethyl)-l-cysteine (CEMA; 1.40, 1.01-1.94), N-acetyl-S-(3,4-dihydroxybutyl)-l-cysteine (DHBMA; 2.35, 1.45-3.82), and 3-methylhippuric acid & 4-methylhippuric acid (3,4MHA; 1.32, 1.05-1.64), were associated with an increased risk of sarcopenia. The mixture of 16 VOCMs was linked to a higher sarcopenia risk in both BKMR and WQS (1.79, 1.30-2.49) models. The tumor necrosis factor (TNF) signaling pathway was identified as a key mechanism underlying the VOCs-sarcopenia relationship. PhenoAge was associated with an elevated sarcopenia risk (1.05, 1.01-1.09) and intensified the adverse effects of VOCMs (P

Sarcopenia, an age-related condition, has an unclear association with cardiovascular disease (CVD) risk. We aimed to analyze whether sarcopenia and its individual components are associated with new-onset CVD in middle-aged and older adults.

This study aimed to investigate the effects of social isolation stress and intranasally administered oxytocin on physiological and behavioral alterations during aging in rats. A total of 28, aged female Sprague-Dawley rats were allocated into four groups: control (C), social isolation (SI), oxytocin (O), and oxytocin+social isolation (OI). Animals in the SI and OI groups were housed in individual cages for four weeks. Intranasal oxytocin (2 μg/kg/day) was administered to the O and OI groups 14 times during the third and fourth weeks of the study. Behavioral assessments were conducted. Levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were measured. In the Morris water maze test, all groups demonstrated improved learning performance, reflected by a progressive reduction in the time taken to locate the hidden platform. The three-chamber sociability test revealed that sociability was significantly impaired in the SI group but preserved in the O, OI, and C groups. VEGF levels in the prefrontal cortex were significantly reduced in the SI group compared to all other groups. Notably, VEGF levels were higher in the OI group than in the SI group. Hippocampal neuron density was lower in the SI group but was preserved in the OI group, suggesting a neuroprotective effect of oxytocin. These findings highlight the protective roles of oxytocin and sociability against the detrimental effects of chronic social isolation, particularly in preserving hippocampal neuron density and maintaining sociability and learning. Further research is needed to elucidate the molecular and behavioral mechanisms underlying these effects.

Oat bran hydrolysates exhibit various biological activities, including antioxidant and immunomodulation activities. Enzymatic hydrolysis can improve the antioxidant capacity of oat bran protein. In this study, Alcalase was used to hydrolyze oat bran protein and the resulting hydrolysates were separated by ultrafiltration, the antioxidant activity of fraction F1 (molecular weight > 10 kDa, OBH) was the highest in the four fractions, and selected for exploring the functional characteristics: d-galactose (d-gal; 300 mg/kg/day) induced aging of CL57BL/6J mice and OBH (200, 400, 800 mg/kg/day) intervened for 8 weeks. Normal mice were compared with aging mice induced by d-gal and aged mice treated with OBH. OBH intervention significantly improved the antioxidant oxidase activities in aging mice, such as total antioxidant capacity, catalase and glutathione peroxidase activities; it decreased malondialdehyde levels, and reduced the levels of tumor necrosis factor-α, interleukin (IL)-1β and IL-6 in the brain and serum. Pathological observations showed that OBH prevented brain damage. The results of high-throughput sequencing showed that the relative abundance of

Diets enriched with live microbes offer multiple health benefits. This study aimed to investigate the relationship between dietary intake of live microbes and accelerated biological age, as well as to examine the mediating role of insulin resistance.

Cellular senescence is a stable form of cell cycle arrest that contributes to aging and age-associated diseases through the secretion of inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). While senescence is driven by transcriptional and epigenetic changes, the contribution of higher-order genome organization remains poorly defined. Here, we present the highest-resolution Hi-C maps (~3 kb) to date of proliferating, quiescent, and replicative senescent (RS) human fibroblasts, enabling a comprehensive analysis of 3D genome architecture during senescence. Our analyses reveal widespread senescence-associated remodeling of chromatin architecture, including extensive compartment and subcompartment switching toward transcriptionally active states, and a dramatic increase in unique chromatin loops. These structural features correlate with local DNA hypomethylation and are largely independent of canonical CTCF binding. The altered 3D genome landscape supports expression of SASP genes, inflammation-related pathways, and neuronal gene signatures consistent with age-associated epigenetic drift. We further demonstrate that architectural changes at multiple levels, including compartments, subcompartments, and loops, facilitate the derepression of LINE-1 retrotransposons, linking 3D chromatin structure to activation of proinflammatory transposable elements. Interestingly, quiescent cells, commonly used as senescence controls, exhibited substantial overlap in inflammatory gene expression with senescent cells, raising important considerations for experimental design. Structural analysis of cell cycle genes showed distinct chromatin configurations in senescence versus quiescence, despite similar transcriptional repression. Together, our results establish a high-resolution framework for understanding how genome architecture contributes to the senescent state.

Reproductive aging impacts women's health through fertility decline, disease susceptibility, and systemic aging. This study explores the retinal age gap-the difference between predicted retinal age and chronological age-as a novel biomarker for reproductive aging. By developing a Swin-Transformer-based dual-channel transfer learning model with data from 1294 healthy women, we examined associations between the retinal age gap and Anti-Müllerian Hormone (AMH), a key marker of ovarian reserve. Findings revealed a negative association between the retinal age gap and AMH levels, particularly among women aged 40-50. Lower AMH levels correlated with earlier reproductive aging milestones, emphasizing the predictive value of retinal aging. Genetic data from genome-wide association studies further supported these associations and enhanced AMH prediction through multimodal modeling. These findings highlight the retinal age gap as a promising, non-invasive biomarker for reproductive aging and its potential role in disease prediction and personalized health interventions in women.

Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. The composition of the soleus muscle was unaffected and myofiber caliber was reduced comparably in type I, IIa, and IIx fibers. Muscle contractile function declined in Klotho-deficient mice, as evidenced by reduced absolute twitch and torque, and decreased rates of contraction and relaxation. RNA-sequencing analysis identified increased transcriptional expression of synaptic and fetal sarcomeric genes, which prompted us to test effects on muscle innervation. Klotho-deficiency induced morphological remodeling of the neuromuscular junction, myofiber denervation, and a functional loss of motor units. Loss of motor units correlated with absolute torque. Collectively, our findings have uncovered a novel mechanism through which Klotho-deficiency leads to alterations to the muscle synapse affecting motor unit connectivity that likely influences muscle wasting and weakness.

Biological aging and sex interact to shape systemic metabolism, yet their role in chronic pain resolution remains unexplored. We hypothesized that metabolic resilience, the ability to flexibly switch fuel sources and maintain energy homeostasis, rules successful recovery from nerve injury in a sex-dependent manner during aging. In 12-month-old male and female mice, corresponding to the perimenopausal phase in females and the onset of hormonal decline in both sexes, we induced sciatic nerve chronic constriction injury and performed multi-omics profiling during Wallerian degeneration, a phase known to trigger long-term neurobiological remodeling. Aging females exhibited early activation of fatty acid oxidation, increased resting energy expenditure, upregulation of mitochondrial redox enzymes and circulating progesterone and corticosterone. Proteomic and metabolomic analysis revealed pentose phosphate pathway enrichment and gluconeogenesis, supporting redox balance and metabolic flexibility. Conversely, males displayed persistent glycolytic reliance, long-chain acylcarnitine accumulation, suppression of adiponectin and PPARgamma, indicating metabolic inflexibility. Longitudinal behavioral analysis revealed that aging females recovered earlier and more fully than aging males, reversing the pattern previously shown in our adult mouse study, where females developed persistent pain and males recovered rapidly. These patterns highlight a non-linear, sex-specific interaction between biological aging and injury response, where hormonal decline reprograms the metabolic trajectory and reshapes pain outcomes. Metabolic resilience governs sex-specific recovery following nerve injury by directing early systemic adaptations that precede and predict long-term pain trajectories. These results define mechanistically anchored, sex- and age-specific biomarkers, and propose preclinical targets for timely, personalized interventions in age-associated neuropathic pain.

Background: Early-life growth adversity is important to later-life health, but precision assess-ment in adulthood is challenging. We evaluated whether the difference between attained and genotype-predicted adult height ("height-GaP") would associate with prospectively ascertained early-life growth adversity and later-life all-cause and cardiovascular mortality. Methods: Data were first analyzed from the Avon Longitudinal Study of Parents and Children (ALSPAC) and UKBiobank. Genotype-predicted height was calculated using a multi-ancestry polygenic height score. Height-GaP was calculated as the difference between measured and gen-otype-predicted adult height. Early-life growth conditions were ascertained prospectively via standardized procedures (ALSPAC) and mortality via death register (UKBiobank). Regression models adjusted for age, sex, genotype-predicted height and genetic ancestry. Analyses were replicated in the Dunedin Multidisciplinary Health and Development Study (DMHDS) and the Multi-Ethnic Study of Atherosclerosis (MESA). Findings: Among 4,582 ALSPAC participants (median [IQR] age: 24[18-25] years at height-GaP assessment), lower gestational age at birth, greater pre- and post-natal deprivation indices, tobacco smoke exposure and less breastfeeding were associated with larger adult height-GaP deficit (p<0.01). Among 483,385 UKBiobank participants (mean+-SD age: 56+-8 years at height-GaP assessment), height-GaP deficit was associated with death from all-causes (adjusted hazard ratio comparing highest-to-lowest height-GaP deficit quartile [aHR]:1.25 95%CI:1.21-1.29), ath-erosclerotic cardiovascular disease (aHR:1.33 95%CI:1.24-1.43) and coronary heart disease (aHR:1.68 95%CI:1.52-1.86). Early- and later-life height-GaP associations replicated in DMHDS and MESA. Interpretation: This study introduces a simple index of early-life growth adversity deployable in adulthood to investigate the developmental origins of longevity and improve health equity across the life course.

Lysosomal pH is frequently elevated in age-dependent neurodegenerations like Age-related Macular Degeneration (AMD), Alzheimer\'s Disease (AD), and Parkinson\'s Disease (PD). Tools that restore lysosomal pH to an optimal acidic range could enhance enzymatic degradation and reduce waste accumulation. Acidic nanoparticles offer a promising strategy for restoring lysosomal function, but accurate tracking of organelle delivery and long-term retention is needed to optimize dosage. To improve detection and enhance delivery, nanoparticles were synthesized from Poly(D,L-lactide-co-glycolide) (PLGA) polymers covalently linked to the fluorescent Cyanine3 amine (Cy3) probe. Nanoparticle concentration and loading times were optimized to achieve >90% delivery to lysosomes in cultured induced pluripotent stem cell-derived retinal pigment epithelial (iPS-RPE) cells. Uptake was heterogeneous, varying between adjacent cells. Once loaded into lysosomes, the nanoparticles were stably retained, with no detectable changes in concentration, distribution, or size for at least 28 days. iPS-RPE cells internalized more nanoparticles than the ARPE-19 cell line or mouse optic nerve head astrocyte cultures. Functionally, PLGA nanoparticles restored an acidic pH and cathepsin D levels in compromised lysosomes. In summary, Cy3-PLGA nanoparticles enabled improved tracking and long-term delivery to lysosomes, supporting future in vivo applications to restore lysosomal pH in aging and degenerating tissues.

Non-neuronal glial cells in the brain, such as astrocytes, play essential roles in maintaining the functional integrity of neuronal cells. A growing body of evidence suggests that cellular senescence of astrocytes, characterized by loss of proliferative potential and secretion of neurotoxic cytokines, makes significant contribution to neurotoxicity in Alzheimer's disease and a wide range of other neurodegenerative diseases. This review discusses the beneficial effects of Δ133p53α, a natural p53 protein isoform that inhibits p53-mediated cellular senescence, thereby protecting astrocytes from senescence, highlights its potential as a therapeutic target, and underscores the need for continued research in this area. Both in senescent human astrocytes in culture, whether induced by replicative exhaustion, irradiation or exposure to amyloid-β, and in brain tissues with increased senescent astrocytes from patients with Alzheimer's disease, the expression levels of endogenous Δ133p53α protein were consistently and significantly reduced. The lentiviral vector-driven expression of Δ133p53α protected cultured human astrocytes from cellular senescence and neurotoxic secretory phenotype, leading to their cellular reprogramming to a neuroprotective state associated with neurotrophic growth factors. We thus propose that Δ133p53α is worth testing as a therapeutic target that can be enhanced in a wide range of neurodegenerative diseases with accumulated senescent astrocytes, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and chronic traumatic encephalopathy due to traumatic brain injury. We hypothesize that a Δ133p53α-mediated cellular reprogramming approach and a senolytic or senomorphic approach, both targeting non-neuronal cells, may be complementary with each other, and may cooperate with neuron-protecting or amyloid-β-targeting therapies currently in use.

Adult hippocampal neurogenesis-the generation of new neurons in the adult brain-declines with age, contributing to cognitive deficits in aging. While the majority of mammalian studies on neurogenesis have utilized inbred mouse strains, these models do not fully capture the genetic diversity of humans, limiting the translational relevance of their findings. The Diversity Outbred (DO) mouse model, a genetically heterogeneous population, provides a promising alternative to traditional inbred strains. In this study, we investigated how genetic diversity influences hippocampal neurogenesis by comparing neurogenesis in adult and aged Diversity Outbred (DO) mice with the commonly used C57BL/6J inbred strain. While both strains exhibited a decline in neurogenesis with age, DO mice showed significantly lower levels of neurogenesis compared to C57BL/6J mice, even in young adults. Additionally, we observed that the wild-derived CAST/EiJ strain, one of the eight founder strains in the DO model, contributed to this reduction in neurogenesis. Our findings highlight the importance of genetic diversity in neurogenesis research and suggest that the DO model may better represent human genetic diversity associated with age-related decline in neurogenesis.

This study investigates how individual multilingual engagement modulates brain oscillatory activity and cognitive control across the lifespan, using both resting-state and task-based EEG with a Flanker task. We assessed whether degree of multilingual engagement moderates age-related changes in theta and alpha power and examined how these changes impact task-specific neural dynamics and behavioral performance. Higher degree of multilingual engagement was associated with weaker negative correlations between increasing age and resting-state theta and alpha power. Our analyses of task-based data revealed that older participants with higher degree of multilingual engagement exhibited a smaller Flanker congruency effect (CE) and less reliance on alpha suppression. These patterns may show more efficient interference suppression in this group. In contrast, older adults with lower multilingual engagement demonstrated larger CE and greater alpha suppression, reflecting potentially less efficient neural recruitment. Notably, our findings indicate that effects of higher degree of multilingual engagement extend beyond resting-state dynamics. Specifically, they also impact recruitment patterns in response to cognitive control demands across the lifespan supporting the notion of maintenance of cognitive control mechanisms with increasing age. Interestingly, the hypothesized link between resting-state and task-based power was not observed, suggesting a more complex nature of the mechanisms underlying the relationship between baseline and task-specific activity. By examining resting-state and task-based activity in cognitive control (and potential links between them), this study adds to the growing body of evidence on multilingualism as a lifestyle factor that can contribute to healthier cognitive aging through neurocognitive adaptations.

Fluid transport in the neurovascular unit is essential for maintaining brain health through nutrient delivery and waste clearance. However, these systems are complex and the inter-dependencies between elements of these systems and how they may change through aging is not well understood. MRI outcomes provide insight into the underlying biological mechanisms of these systems in vivo, including water exchange rate through the neurovascular unit (BBB k

Recent studies reported that anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) alleviate choroidal neovascularization (CNV) in young but not aged animals. We recently developed a disease-targeted anti-angiogenic therapy against secretogranin III (Scg3), which selectively binds to diseased but not healthy vessels in young mice. Herein, using a unique in vivo ligand binding assay, we predicted and confirmed that Scg3 selectively binds CNV vessels in both young and aged mice. In contrast, VEGF with minimal increased binding to CNV vessels exhibited an age-dependent decline in binding to both CNV and healthy vessels with negligible binding in aged mice. Based on these binding activity patterns, we further predicted and confirmed that a humanized anti-Scg3 antibody effectively alleviated laser-induced CNV in both young and aged mice, whereas the anti-VEGF drug aflibercept was effective only in young mice. These findings suggest that enhanced binding of Scg3 to CNV vessels in both age groups provides a molecular basis for an age-independent anti-Scg3 therapy, offering potential to address anti-VEGF resistance in clinical treatment of wet age-related macular degeneration with CNV.

Rare genetic DNA repair deficiency syndromes can lead to immunodeficiency, neurological disorders, and cancer. In the general population, inter-individual variation in DNA repair capacity (DRC) influences susceptibility to cancer and several age-related diseases. Genome wide association studies and functional analyses show that defects in multiple DNA repair pathways jointly increase disease risk, but previous technologies did not permit comprehensive analyses of DNA repair in populations. To overcome these limitations, we used fluorescence multiplex host cell reactivation (FM-HCR) assays that directly quantify DRC across six major DNA repair pathways. We assessed DRC in phytohemagglutinin-stimulated primary lymphocytes from 56 healthy individuals and validated assay reproducibility in 10 individuals with up to five independent blood draws. We furthermore developed generalized analytical pipelines for systematically adjusting for batch effects and both experimental and biological confounders. Our results reveal significant inter-individual variation in DRC for each of 10 reporter assays that measure the efficiency of distinct repair processes. Our data also demonstrate that correlations between the activities of different DNA repair pathways are relatively weak. This finding suggests that each pathway may independently influence susceptibility to the health effects of DNA damage. We furthermore developed a pipeline for analyzing comet repair kinetics and related our new functional data to previously reported comet assay data for the same individuals. Our pioneering analysis underscores the sensitivity of FM-HCR assays for detecting subtle biological differences between individuals and establishes standardized methodologies for population studies. Our findings and open source analytical tools advance precision medicine by enabling comprehensive exploration of genetic, demographic, clinical, and lifestyle factors and supporting targeted interventions to enhance DNA repair and maintain genomic integrity, thereby promoting personalized healthcare and disease prevention.

HealthAge was devised by a conglomerate of research groups in Toulouse, France, with the combined goal of narrowing the lifespan-healthspan gap through novel translational bench-to-bedside research studies. HealthAge comprises the "INStitute for Prevention" "healthy aging" and "medicine Rejuvenative" (INSPIRE) human translational, outbred SWISS mice and African turquoise killifish (GRZ strain) cohorts in which aging is studied based on the concept of intrinsic capacity (IC). In this narrative review, we describe the three INSPIRE aging models (human cohort, n = 1109, age range 20 -102 years old with mean age ± standard deviation, 62.4 ± 19.0 years and 61.9% female; outbred SWISS mice, n = 1576 and African Turquoise killifish, n = 300) and explain how IC is assessed at the clinical (in humans) and biological level over time. HealthAge strives to elucidate the underlying biology of IC and to identify biomarkers of IC declines and novel gero-therapeutics using the clinical and biological data and biospecimens collected prospectively in the three species. The data sharing policy will foster scientific discovery through new multi-disciplinary collaborations. Thus, HealthAge will promote healthy aging using a unique translational platform based on IC phenotyping with the ultimate goal of preventing loss of human independence and alleviating health costs associated with an aging population.

The enzyme arginase-II has an important role in cardiac aging, and blocking it could help hearts stay young longer.

Mitochondrial dysfunction is a hallmark of aging and has been implicated in aging-related diseases. NIPSNAP1 and NIPSNAP2 are functionally redundant homologs involved in mitochondrial quality control, yet their roles in healthy aging and longevity remain unclear. Here, we generated a Nipsnap1/2 double knockout (DKO) mouse line and examined its impacts on mitochondrial physiology and natural aging. We demonstrated that the loss of Nipsnap1/2 impaired mitochondrial function and enhanced glycolysis activity, but it did not affect mitophagy despite the significant accumulation of Parkin. Compared with wild-type mice, DKO mice exhibited reduced body weight, deteriorated muscle strength, and pronounced fragility at 24 months of age. Moreover, Nipsnap1/2 depletion exacerbates aging-associated fibrosis and inflammation in the heart, liver and kidney. RNA-seq revealed a pro-aging transcriptome reprogramming toward energy exhaustion in DKO mice, eventually leading to cachexia-like adverse metabolic remodeling. Our findings demonstrate an anti-aging role of NIPSNAP1/2 via the surveillance of mitochondrial health.

Remembering familiar versus novel stimuli is fundamental to survival, but it is compromised in several neurodegenerative disorders where aging is a key factor. Although the components of the extracellular matrix (ECM) have been suggested to be implicated in memory maintenance, the mechanistic and behavioral roles of ECM during the aging process remain unclear. Here, we employed an accelerated mouse model of aging to elucidate the causal link between ECM dynamics and recognition memory during aging. Aged mice exhibited impaired social and non-social recognition memory, accompanied by increased intensity of perineuronal nets (PNNs), specialized ECM structures in the hippocampal dorsal CA2 (dCA2). A reduction in the power of theta oscillations (3-7 Hz) in the dCA2 of aged mice was also observed. Notably, selective degradation of PNNs in the dCA2 using chondroitinase ABC (ChABC) rescued recognition memory deficits and restored theta oscillations. Together, our findings identify abnormal PNN in the CA2 as a critical factor for age-related deficits in hippocampal-dependent recognition memory and network rhythmicity. These insights raise the possibility that targeting CA2 PNNs could facilitate the development of diagnostic and therapeutic strategies to address age-associated cognitive frailty.

Serum testosterone (T) concentration declines with aging in men, potentially affecting reproduction, mental and physical well-beings. A role of immune factors in Leydig cell (LC) function is well-known, but the specific factors involved, especially these playing roles in LC aging, are still unclear. This study investigated effects of interleukin 33 (IL-33) on LC function and its expression during testicular aging.

Trauma exposure may be linked to accelerated biological aging. However, studies have largely considered childhood abuse, with limited consideration of lifetime trauma exposure, particularly for women. Furthermore, few studies have considered newer epigenetic clocks, which have enhanced links with health outcomes. Among midlife women, we investigated whether lifetime trauma exposure is associated with older epigenetic age with several generations of clocks. We explored associations between childhood maltreatment and epigenetic age and racial differences in associations between trauma and epigenetic age.

Aging represents the main risk factor for the development of several diseases, including cardiovascular and metabolic conditions, neurodegenerative disorders and cancer. As the number of elderly people is increasing worldwide, different strategies to counteract age-related diseases have been investigated. Recently, the use of molecular hydrogen (H

Taurine deficiency is a driver of aging, however the mechanisms by which taurine regulates postovulatory oocyte aging (POA) remain an unanswered question. Here, we used differential gene expressions and functional enrichment analysis of transcriptomes to determine transcriptional dynamics in POA. Transcriptional conservation between mouse and pig was determined by comparative analysis of transcriptomes. Candidate key targets were identified by WGCNA analysis combined with comparative analysis of transcriptomes. Expression levels were validated using cell-based immunofluorescence assays. We observed increased fragmentation and apoptosis of oocytes during POA, which was significantly improved after adding taurine. Transcriptome analysis showed that mitochondrial function was disrupted in oocytes. Our mitochondrial immunofluorescence assay showed that mitochondrial distribution in the POA group was abnormal compared with fresh group, and ROS levels were increased. Moreover, comparative analysis highlighted the role of mitophagy, and the immunofluorescence assay highlighted the significant decrease in PINK1. On the note, we combined comparative analysis and WGCNA results to identify TBK1 as a key gene, subsequent protein fluorescence confirmed that TBK1 was downregulated during POA. As expected, the taurine increased the expression level of TBK1 in the aged group. In summary, our evidence demonstrates that taurine can improve oocyte quality during POA via TBK1-associated mitophagy.

Bone aging, displays osteoporosis and impaired bone formation, intricately linked to the metabolic alteration of mesenchymal stem cells (MSCs). However, the precise mechanisms underlying this relationship remain unclear.