Longevity Papers

Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by substantial degeneration of dopaminergic neurons in the substantia nigra and dopamine depletion in the striatum, leading to debilitating motor and non-motor impairments. Recent studies provide clues on the pathogenic role of DNA damage in age-related neurodegenerative diseases, but the molecular mechanisms of DNA damage response in PD remain poorly understood. We found that the accumulation of DNA double-strand breaks (DDSBs), and/or DNA repair deficits, are key in the pathogenesis of PD and drives cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) immune regulatory pathway, contributing to neuroinflammation and dopaminergic neurodegeneration in human postmortem PD and non-PD brains as well as in experimental models of PD. We observed enhanced expression of γ-H2A.X (Ser139) a biomarker of DDSB, and decreased levels of DNA repair proteins in the brains of human PD compared to non-PD brains. This was positively correlated with upregulation of STING immune response pathways, microglial activation, senescence and dopaminergic neurodegeneration. Similarly, we observed increased and sustained DDSB as assessed by γ-H2A.X (Ser139) immunoreactivity, and degeneration of tyrosine hydroxylase-positive neurons in primary neuron/glia cultures and mice treated with 1-methyl-4-phenylpyridine (MPP+) or 1,2,3,6-tetrahydropyridine (MPTP). Next, we employed a mouse model of α-synucleinopathy, which exhibited elevated DDSBs alongside overactivation of the DNA-sensing cGAS-STING pathway and type-I interferon signaling, in association with dopaminergic neurodegeneration. Interestingly, pharmacological and genetic ablation of STING reduces DDSB, limits inflammatory response, improves behavioral function and attenuates the loss of dopaminergic neurons in this model. Our findings suggest that the accumulation of DDSBs and/or dysregulation in DNA repair proteins activate cGAS-STING mediated immune responses in the brain, potentially exacerbating dopaminergic neurodegeneration in PD. Furthermore, regulating these processes is essential for alleviating the pathological effects of PD and may offer potential therapeutic strategies.

Cellular senescence is a multifactorial, progressive phenomenon that disrupts biological homeostasis by increasing stress markers, causing morphological changes, and inducing inflammation, ultimately leading to irreversible cell cycle arrest. Natural plant-based bioactive products are frequently preferred over synthetic chemicals for their safety and efficacy. This study aims to assess the therapeutic effectiveness of a botanical formulation, Immunogrit, in mitigating stress-associated senescence markers in the skin. d-Galactose (D-Gal) has been used to induce senescence-associated stress markers in HaCaT human keratinocytes. Additionally, a thorough chemical characterization employing ultra-performance liquid chromatography-mass spectrometry coupled with quadrupole time-of-flight (UPLC/MS-QToF) and high-performance thin layer chromatography (HPTLC) was performed to generate a comprehensive phytochemical profile of Immunogrit. In HaCaT cells, d-Gal-induction increased oxidative and nitrosative stress with a perturbed expression of cell cycle biomarkers. Enhanced SA-β-galactosidase activity and subsequent downregulation of nuclear protein, LMNB1, further established the suitability of d-Gal-induced HaCaT cells as the relevant skin model for investigating senescence-associated interventions at the molecular levels. Treatment of Immunogrit with d-Gal induction, prevented the upregulation of p16, p21, and p53 levels; and maintained the basal SA-β-galactosidase activity. This study also identified pAMPK and iNOS2 as the targets of d-Gal orchestrating oxidative and nitrosative stress. Immunogrit mitigated the d-Gal-modulated levels of pAMPK and iNOS2. Moreover, collagen degradation and upregulation of metalloprotease (MMP1 and MMP9) in d-Gal-induced HaCaT cells were ameliorated by Immunogrit treatment. Our findings highlight Immunogrit as a promising botanical therapy for alleviating the key cellular markers of senescence, in human keratinocytes.

During prostate aging collagen-IV is modified by advanced glycation end-products, inducing crosslinking of the basement membrane surrounding glandular acini. Basement membrane stiffness sensed by Endo180 disrupts its suppressor complex with CD147, triggering epithelial-to-mesenchymal transition and limiting survival in prostate cancer patients. Here we report basement membrane stiffness and Endo180 cooperate in rewiring epithelia for mitochondrial oxidative phosphorylation (OXPHOS) and growth suppressor evasion, cell proliferation promotion, cell death resistance, inflammation, invasion and metastasis without affecting genome instability, highlighting a non-oncogenic biomechanical event in age-related neoplasia. Endo180-CD147 complex coupled to OXPHOS in Gleason 6 and in Gleason ≥7 tumors Endo180 uncoupled from CD147-OXPHOS, identifying a bio-switch for invasive cancer. Endo180 correlated with patient age in normal tissue, Gleason 6 and 7, but not Gleason 8 tumors, suggesting biological age unleashes its suppression of tumorigenesis. Application of Endo180-based diagnostics in age-related glandular cancers could inform treatment decisions, improving quality of life and survival.

Follicular atresia plays a significant role in the depletion of the ovarian reserve and the decline of overall ovarian function. Understanding its molecular mechanisms is essential to preventing ovarian aging and maintaining female reproductive health. Although NAD + depletion is known to induce apoptosis in various cell types, the dynamic changes in NAD + metabolism during follicular atresia remain unclear. Moreover, its specific impact on granulosa cells has not been fully elucidated. In this study, we examined the metabolic alterations of NAD+ during follicular atresia. We also explored the molecular mechanisms underlying granulosa cell apoptosis to provide a theoretical basis for developing novel therapeutic strategies to preserve female fertility. Using a well-established porcine model of follicular atresia, we observed a downregulation of key enzymes involved in NAD + biosynthesis during follicular regression, accompanied by an increased progesterone to estradiol (P4/E2) ratio in the follicular fluid. In granulosa cells, reduced NAD + levels and decreased NAD+/NADH ratios activated caspase-3 thereby triggering apoptosis. In a vitro model of granulosa cell apoptosis, we further demonstrated that NAD + precursors can bypass the rate-limiting enzyme NAMPT but NMNAT1 remaines essential for effective NAD

Steatosis and fibrosis are two key pathological features of the aging pancreas that contribute to inflammation, metabolic dysfunction and degenerative changes of the tissue. Pancreatic stellate cells (SCs) are thought to be the main cellular source of ectopic adipocytes and fibrotic structures. SCs are fibroblast-like mesenchymal cells that reside in various microanatomies of the tissue and whose task under healthy, homeostatic conditions is to generate extracellular matrix (ECM) and maintenance signals to ensure tissue integrity and function. To examine pathological changes of the aging pancreas, we conducted single cell RNA-sequencing to analyze murine pancreatic cell heterogeneity and examined morphological changes of the aging exocrine pancreas, comparing young adult and aged wildtype mice. We specifically focused our analyses on SCs and their cellular interaction partners and mechanisms of paracrine crosstalk. Age-dependent transcriptional differences in these cell types occur on the level of ECM-related and pro-fibrotic expression signatures mediated through transforming growth factor (TGF) and platelet-derived growth factor (PDGF) signaling pathways. SCs can be divided into distinct subsets of activated (aSCs) and quiescent stellate cells (qSCs), based on distinct expression signatures and transcript levels of Pdgfra and Pdgfrb, which encode for the PDGF receptor alpha and -beta paralogs. Activated SCs, which display PDGF receptor alpha (PDGFRα) on their surface, exhibited subsets that appeared to be either pro-adipogenic or pro-fibrogenic at the transcriptomic level and aging promoted a pro-fibrogenic switch in aSCs. We conclude that pancreatic SCs are contributors to the age-related decline of the exocrine pancreas through an increased contribution of a pro-fibrotic microenvironment.

Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca2+)- and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle performance and adaptation, these same signals become chronically elevated in aged skeletal muscle and promote functional decline. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key transducer of both Ca2+ and ROS signals during exercise. Here we show that CaMKII is chronically activated in aged muscles, promoting muscle dysfunction. Muscle-specific expression of a constitutively active CaMKII construct in young mice recapitulates features of aging muscles, including impaired contractility, progressive atrophy, mitochondrial disorganization, formation of tubular aggregates, and an older transcriptional profile characterized by the activation of inflammatory and stress response pathways. Mediation analysis identified altered heme metabolism as a potential mechanism of CaMKII-induced weakness, independent of muscle atrophy. Conversely, partial inhibition of CaMKII in aged muscle improved contractile function and shifted the transcriptome toward a more youthful state without inducing hypertrophy. These findings identify chronic CaMKII activation as a driver of functional and molecular muscle aging and support the concept that CaMKII exemplifies antagonistic pleiotropy, whereby its beneficial roles in promoting muscle performance and adaptation during youth may incur deleterious consequences in aging. We propose that persistent CaMKII activation in aged skeletal muscle reflects unresolved cellular stress and promotes maladaptive remodeling. Enhancing physiological reserve capacity through exercise, in combination with temporally targeted CaMKII inhibition, may help restore adaptive CaMKII signaling dynamics and preserve muscle function in aging.

Mitochondrial heteroplasmy, the co-existence of different mitochondrial genomes within a cell, is linked to aging and disease. Patients with heteroplasmy due to mitochondrial mutations experience multiple organ complications, particularly poor bone health and bone structure defects. However, the mechanisms involved are generally unknown, due largely to the difficulty of manipulating mtDNA in vivo. To overcome this, we leveraged a heteroplasmic mouse model and discovered that mitochondrial heteroplasmy affects a fundamental developmental process. Specifically, the differentiation of osteoclasts, which resorb bone tissue and maintain bone homeostasis. Mechanistically, there was a reduced localization of specifically respiratory complex I subunits in mitochondria in heteroplasmic mice, disrupting ATP production and osteoclast differentiation. In addition, autophagic flux is exhausted, and the autophagy inducer spermidine restores mitochondrial health and rescues osteoclast activity, both in mice and in cells from patients with primary mitochondrial disease. Together, we identify the mechanisms by which mitochondrial heteroplasmy impacts osteoclastogenesis and discover spermidine as a modulator of this process, which presents a potential treatment for human heteroplasmic conditions such as mitochondrial diseases, which are largely untreatable.

Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.

Ensuring the identity and optimal aging state of cell products is critical for the efficacy and safety of cell therapies. Despite rapid iterations, there remains an urgent need for robust and easy-to-implement tests to characterize cell products. Here, we present CIAdex (Cell Identification and Aging Index), an analytical framework that utilizes single-cell Fourier-transform infrared (FTIR) spectral fingerprints and machine learning to achieve precise label-free cell identity assessment and aging quantification. CIAdex employs a Feature Extraction Processor to automatically extract FTIR spectral variables corresponding to distinct cellular biomolecular features, enabling reliable distinction of lineage-, donor-, and batch-specific cell populations using linear discriminant analysis. Through application of the XGBoost algorithm, a quantitative aging index (trPDL/trPN) was further generated for tracking cellular aging dynamics along culture expansion. Notably, trPDL/trPN quantitatively represent subtle age-related shifts among different batches and drug-induced senescence or rejuvenation effects, which are unmeasurable by existing methods. Together, our work demonstrates that CIAdex, by simultaneously label-free identity verification and aging quantification of cell populations, offers a transformative approach to interpret single-cell FTIR spectral fingerprints and provides novel metrics for quality control in cell manufacturing with significant potential for optimization and assurance of cell therapies\' safety and efficacy.

Ovarian aging profoundly impacts reproductive health and accelerates the overall aging process, yet the development of effective therapeutic strategies remains a formidable challenge. In this study, we report the rejuvenating effects of HEP14, a natural activator of protein kinase C (PKC) pathway, on aged ovarian function by inducing mitophagy and effectively clearing reactive oxygen species. To ensure controlled and sustained delivery of HEP14 in vivo, we develop HEP14-loaded PLGA microspheres. Transcriptomic analysis reveals a significant overlap between the transcriptional profiles of HEP14-treated aged ovaries and those of adult ovaries, suggesting molecular rejuvenation process closely associated to HEP14-induced mitophagy. Histopathological evaluations further substantiate these findings, showing that HEP14 enhances mitophagy, exhibits antioxidative properties and promotes follicular regeneration. Consequently, ovarian endocrine function in aged mice is substantially restored. Using transmission electron microscopy, confocal microscopy, and western blot analysis alongside pharmocological inhibitors and PKC-specific siRNA, in vitro studies further demonstrate the restorative effect of HEP14 on mitophagy, leading to improved mitochondrial function and subsequent alleviation of oxidative stress in senescent ovarian granulosa cells. This effect is mediated through the activation of the PKC-ERK1/2 pathway, which plays an pivotal role in the action mechanism in HEP14. These discoveries offer new therapeutic hope for ovarian aging.

Combating aging has become a central challenge in the life sciences, and myocardial aging, as a fundamental pathological process underlying the development and progression of various cardiovascular diseases, has become a key area in anti-aging research. In recent years, lactylation and methylation, two metabolism-dependent epigenetic modifications, have garnered increasing attention in the context of myocardial aging. Lactylation, mediated by lactate accumulation due to metabolic dysregulation, modifies lysine residues on both histone and non-histone proteins, thereby participating in the regulation of gene transcription, metabolic homeostasis, and inflammatory responses. In parallel, methylation affects gene expression, metabolic remodeling, and mitochondrial function through DNA, RNA, and histone modifications. This review systematically summarizes the regulatory mechanisms of lactylation and methylation in myocardial aging, with a particular focus on their interplay in histone and non-histone protein modification, metabolic regulation, and signaling pathway integration. Furthermore, we evaluate the potential of these reversible modifications as early epigenetic biomarkers and discuss multilayered intervention strategies targeting both lactylation and methylation. Such strategies highlight their translational potential in delaying myocardial aging and mitigating cardiovascular disease. Precisely modulating lactylation and methylation may offer novel theoretical frameworks and therapeutic targets for the prevention and treatment of myocardial aging.

Gut microbiota exert an evolutionarily conserved influence on ageing, from invertebrates to humans. How do microbes that are physically confined to the gut lumen affect the systemic physiological process of ageing? In female Drosophila, we show that microbiota increase expression of the peptide hormone Tachykinin (Tk), which corresponds to reduced lifespan. Tk is required for microbiota to shorten lifespan, with knockdown rendering flies constitutively long-lived even in the presence of an intact microbiota. This lifespan extension does not come with canonical costs to fecundity or feeding, but impacts on triacylglyceride (TAG) storage suggest adaptive functions in metabolic homeostasis. In flies with defined (gnotobiotic) microbiotas, we show that we can model Tk-dependent effects of microbiota on lifespan and TAG by monoassociation with Acetobacter pomorum. These effects require Tk in the midgut, and the cognate TK receptor TkR99D in neurons, implicating a microbiota-gut-neuron relay. This relay also appears to compromise gut barrier function in aged flies, indicating roles in healthspan as well as lifespan. However, the effect of TkR99D is independent of its reported role in insulin signalling and adipokinetic hormone signalling which, respectively, are canonical regulators of lifespan and TAG metabolism, suggesting a non-canonical role for TkR99D elsewhere in the nervous system. Altogether our results implicate a microbiota-gut-neuron axis in ageing, via a specific bacterium modulating activity of a specific and evolutionarily-conserved hormone.

The cognitive decline associated with ageing is the most critical health issue affecting elderly individuals, and there is still a lack of effective interventions available. This study was designed to identify a drug capable of ameliorating age-related cognitive decline and the underlying mechanisms. Utilizing data mining of multisource databases and drug repositioning approaches based on transcriptome similarity, the cardiovascular drug ranolazine (Ran), was identified as a potential candidate with similar effects to those of resveratrol (RSV). Network pharmacology analysis predicted that Ran's effects on cognitive decline through the PI3K/AKT/mTOR signalling pathway. These predictions were subsequently verified using a combination of molecular, cellular, and tissue experiments, animal models of ageing induced by D-galactose, and omics studies. The results revealed that Ran extended the lifespan of Caenorhabditis elegans (C. elegans), improved the head swinging ability of ageing C. elegans, and alleviated mitochondrial membrane potential (MMP) damage in ageing hippocampal neuronal cells (HT22). In ageing rats, Ran not only enhanced spatial memory, exploratory behaviors and motor ability, but also alleviated mitochondrial structural damage in hippocampus and medial prefrontal cortex (mPFC). Notably, Ran alleviated age-related cognitive decline by regulating mitochondrial autophagy in hippocampus and mPFC through the PI3K/AKT/mTOR signalling pathway, rather than through its conventional mechanism of regulating fatty acid metabolism. In summary, this study reveals Ran's previously unrecognized role in alleviating age-related cognitive decline for the first time. These findings provide new options for the treatment of age-related cognitive decline and broaden the potential clinical applications of Ran.

Engram cells storing episodic memories are allocated to separate neuronal ensembles. However, how these ensembles maintain their stability to drive precise memory expression, and whether their destabilization contributes to aging-related memory deficits, remain elusive. Here, we show that during contextual fear memory consolidation, neuronal pentraxin 1 (NPTX1) in Fos transcription-dependent ensemble (F-RAM) of the dentate gyrus (DG) promotes memory expression in the fear context. NPTX1 facilitates K

Obesity-related proinflammatory mechanisms and genetic instability accelerate aging mechanisms. The effects of metabolic bariatric surgery (MBS) on premature aging remain unclear.

As aging is the primary risk factor for many chronic diseases, geroscience aims to target aging to delay age-related decline. Here, we identify Cyrene (dihydrolevoglucosenone), a sustainable, biocompatible solvent, as a novel geroprotective compound. Cyrene extends lifespan and healthspan in C. elegans, improving locomotor function and resistance to oxidative, thermal, osmotic, genotoxic, and proteotoxic stress. It also confers protection in neurodegenerative models of Alzheimer\'s, Parkinson\'s, and Huntington\'s disease. Cyrene is effective when delivered during development or early adulthood and requires administration before day 8 to extend longevity. Its benefits are independent of bacterial metabolism and partially independent of the FOXO transcription factor DAF-16. Importantly, Cyrene also extends lifespan and enhances oxidative stress resistance in Drosophila melanogaster, demonstrating cross-species efficacy. These findings identify Cyrene as a novel geroprotective compound that promotes longevity, resilience, and neuroprotection. Conservation across species supports future work to dissect molecular mechanisms and test its potential in mammals.

Reproductive longevity is essential for female fertility and healthy aging; however, the role of stress response, especially stress granule accumulation, in ovarian aging remains elusive and interventions are lacking. Here, we identified deleterious mutations and decreased expression of NCOA7, a stress-response protein related to granulosa cell senescence in women with physiological and pathological ovarian aging. NCOA7 deletion accelerates oxidative stress-related cellular senescence, ovarian aging and fecundity decline in mice. Mechanistically, NCOA7 partitions into the stress granule containing G3BP1-V-ATPase and facilitates autophagic degradation of stress granules to relieve stress. Boosting granulophagy with rapamycin or lipid nanoparticle-based mRNA delivery of NCOA7 accelerates stress granule clearance, alleviating cellular senescence in human granulosa cells and delaying ovarian aging in mice. This study depicts a mechanism for ovarian resilience to stress and provides potential targets for therapeutic strategies to alleviate ovarian aging.

Telomere attrition stands as a fundamental hallmark of cardiovascular aging, driving cellular senescence and dysfunction across endothelial, cardiomyocyte, and vascular smooth muscle compartments. This review systematically examines: (1) molecular mechanisms linking telomere shortening to oxidative stress (NOX2/PRDX1 axis), epigenetic dysregulation (subtelomeric methylation, H3K9me3 loss), and mitochondrial dysfunction; (2) clinical evidence positioning leukocyte telomere length and telomere-associated proteins (eg, TRF2, POT1) as predictive biomarkers for coronary artery disease, heart failure, and hypertension; and (3) emerging therapeutic strategies ranging from telomerase activation (TA-65, GRN510) to senolytic cocktails (dasatinib + quercetin) and CRISPR (regularly interspersed short palindromic reportsclustered regularly interspaced short palindromic repeats)-based editing (6-29% efficiency in Chinese hamster ovary models). The review further addresses methodological challenges in telomere measurement (quantitative polymerase chain reaction (PCR) vs Flow-FISH standardization) and proposes an integrated risk assessment model combining leukocyte telomere length, oxidative markers (AGEs/sRAGE ratio), and epigenetic clocks. Translationally, we discuss tissue-specific delivery systems to mitigate oncogenic risks of telomerase therapies while emphasizing mitochondrial-targeted approaches for telomere stabilization. This synthesis bridges basic telomere science with clinical cardiology, offering a roadmap for personalized vascular rejuvenation strategies.

Genomic instability and loss of proteostasis are two of the primary Hallmarks of Aging. Although these hallmarks are well-defined in the literature, the mechanisms that drive genomic instability and loss of proteostasis as cells age are still largely unknown. Using budding yeast replicative lifespan as a model for aging in actively dividing cells, we identified nuclear proteins that were depleted in the earliest stages of aging. We found that many age-depleted proteins were involved in ribosome biogenesis, specifically in ribosome processing, or in maintenance of chromatin stability. We focused on topoisomerase I (Top1) as a novel age-depleted nuclear protein and found that its depletion in the early stages of aging was not a result of transcriptional changes or changes in protein turnover. Despite the stark depletion of Top1 in early aging, rescue of this age-dependent depletion was actually harmful to replicative lifespan. We found that Top1, when overexpressed, disrupts the stoichiometry of the RENT complex by pulling Sir2 away from the ribosomal DNA (rDNA), a phenotype which is further enhanced when the overexpressed Top1 is catalytically dead. Loss of Sir2 from the rDNA via the overexpression of catalytically dead Top1 decreases RNA Pol II silencing of a reporter gene inside or adjacent to the rDNA, consistent with the lifespan defect. Finally, we found that the catalytic activity of Top1 plays an important role in the establishment of rDNA silencing, raising the possibility that rDNA secondary structure/DNA topology is important for RNA Pol I-dependent spreading of silent chromatin across the rDNA locus.

Aging is a complex process influenced by genetic, environmental, and psychiatric factors. Recent evidence suggests that epigenetic age acceleration (EAA), a biomarker of biological aging, may be linked to psychiatric disorders, yet the causal direction remains unclear. This study employed a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationships between EAA (IEAA, HannumAA, GrimAA, PhenoAA) and ten psychiatric disorders. Genome-wide association study (GWAS) summary statistics from large European ancestry cohorts were used, and sensitivity analyses were conducted to ensure robustness. Forward MR analysis demonstrated that PhenoAge acceleration (PhenoAA) significantly increased the risk of attention-deficit hyperactivity disorder (ADHD) (OR = 1.043, P = 0.004), suggesting that cumulative biological aging may contribute to neurodevelopmental vulnerabilities. Conversely, Hannum age acceleration (HannumAA) was associated with a protective effect against obsessive-compulsive disorder (OCD) (OR = 0.904, P = 0.004). Reverse MR analysis revealed that autism spectrum disorder (ASD) was linked to a decrease in intrinsic epigenetic age acceleration (IEAA) (OR = 0.811, P = 0.027), while major depressive disorder (MDD) significantly increased both HannumAA (OR = 1.318, P = 0.005) and IEAA (OR = 1.226, P = 0.049). These findings suggest that psychiatric conditions may both influence and be influenced by biological aging processes. This study reveals a bidirectional link between psychiatric disorders and biological aging, showing that early-life mental health conditions may accelerate epigenetic aging and increase age-related disease risk. As psychiatric disorders are recognized as aging risk factors, these findings highlight the need for research on aging-targeted interventions in psychiatric populations.

Understanding the impact of different exercise types on skeletal muscle atrophy in older adults is crucial for designing effective strategies to combat age-related muscle loss. This study explores the molecular mechanisms through which resistance exercise (RES) and endurance exercise (END) mitigate skeletal muscle atrophy. By examining microRNA (miRNA) expression profiles from aging skeletal muscle datasets (GSE165632) in the Gene Expression Omnibus (GEO) database, the research aims to uncover exercise-specific miRNA signatures and their associated regulatory pathways. Using the GEO2R analysis tool, researchers identified differentially expressed miRNAs (DEmiRNAs) between RES and END groups. Predicted target genes of these miRNAs were determined through a combination of miRTarBase, micro-T, and TargetScan databases. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, were performed via the DAVID database. Transcription factors were predicted using the ChEA3 database, while protein-protein interaction (PPI) networks were constructed with the STRING database to identify hub genes for further functional enrichment studies. The analysis revealed 30 differentially expressed miRNAs in the RES group and 21 in the END group. In the RES group, key pathways such as FoxO signaling, neurotrophic signaling, insulin resistance, and AMPK were regulated by miRNAs like hsa-miR-574-5p, hsa-miR-34a-5p, and hsa-miR-21-5p. These pathways promote protein synthesis and reduce myocyte apoptosis. In the END group, hub genes were linked to FoxO, TGF-β, MAPK, and cGMP-PKG signaling pathways, regulated by miRNAs such as hsa-miR-194-5p, hsa-miR-146a-5p, and hsa-miR-6831-5p, which enhance mitochondrial function and metabolic regulation. Both exercise types shared common regulatory pathways, including MAPK, TGF-β, and PI3K-Akt, which influence genes like SMAD4 and TRAF6 that are essential for myocyte survival and fibrosis suppression. This study sheds light on the unique and overlapping miRNA-driven regulatory mechanisms behind the effects of RES and END on skeletal muscle atrophy in older adults. Resistance exercise primarily boosts protein synthesis and inhibits apoptosis via pathways like AMPK and p53, while endurance exercise enhances mitochondrial function and energy metabolism through cGMP-PKG signaling. Both exercise modalities converge on critical pathways, providing a scientific basis for developing personalized exercise programs to counteract sarcopenia.

Mitochondria are multifunctional organelles that convert the potential energy stored in nutrients and intermediary metabolites into both heat and an electro- chemical proton-motive force. However, how these outputs are synchronized in cells remains an enduring question. In this work, leveraging multiplexed nanodi- amond quantum sensors to monitor both changes in temperature and magnetic field fluctuations in single primary cells obtained from diverse tissues in adult mice, we identified thermomagnetic correlation profiles uncovering a regulatory feedback loop in which the cell draws upon available intracellular iron to main- tain the mitochondrial electrochemical gradient. These profiles reverse in cells derived from a mouse model of Leigh syndrome and raise the intriguing pos- sibility that primary mitochondrial diseases can be understood as disorders of thermomagnetic homeostasis.

PRMT1 is a key enzyme responsible for protein arginine methylation, which regulates various cellular processes. However, its physiological significance at whole-body level remains unknown due to embryonic lethality of Prmt1-null mice. Despite only one amino acid difference at position 179, molecular dynamics simulations and biochemical assays showed that human PRMT1 exhibits enhanced methyltransferase activity compared to its mouse counterpart. Capitalizing on this finding, we generated humanized PRMT1 knock-in mice (huMice) carrying the H179Y substitution. Notably, huMice displayed distinct transcriptomic signatures associated with attenuated inflammatory responses compared to wild-type mice in an age-dependent manner. In particular, huMice exhibited reduced pro-inflammatory cytokines production following lipopolysaccharide (LPS) challenge at 12 months, revealing that heightened PRMT1 activity confers a physiological advantage in alleviating age-related inflammatory stress. Our findings underscore PRMT1's key role in the modulation of anti-inflammatory programming at the organismal level and open avenues for leveraging this knowledge in developing mitigation strategies against inflammaging.

Dimethoate (DM), a widely used organophosphate pesticide, induces significant alterations in mitochondrial-related proteomes of SH-SY5Y cells without directly affecting cell viability. After, cells were exposed to 100 μM DM for 48 h, proteomic analysis revealed that 27 proteins associated with cellular metabolism and mitochondrial function were notably altered, affecting pathways such as oxidative phosphorylation, electron transport chain, and ATP synthesis. At sublethal concentrations, DM reduced mitochondrial ATP production, oxygen consumption rates (OCR), basal and maximal respiration, while preserving spare respiratory capacity (SRC) and proton leak, indicating maintained mitochondrial membrane integrity. Despite this, DM exposure caused mitochondrial membrane depolarization and increased mitochondrial superoxide production. These mitochondrial alterations were accompanied by enhanced cellular senescence, marked by p53-independent p21 activation, p38 MAPK activation, increased senescence-associated β-galactosidase (SA-β-gal) activity, and disrupted cell cycle progression. Additionally, DM treatment led to upregulation of DNA damage response (DDR) proteins and downregulation of proteins involved in DNA repair and genome stability. Although early-stage apoptosis was observed, elevated Bcl-2 expression suggested a shift toward apoptosis resistance and senescence. DM also disrupted energy-sensing pathways by increasing AMPK subunit expression, yet suppressed autophagy, as indicated by decreased p-mTOR, p-Beclin-1, and LC3-II/I ratios. Collectively, these findings highlight a complex interplay between mitochondrial dysfunction, cellular senescence, and survival mechanisms, suggesting potential long-term effects of DM exposure on cellular health and aging processes.

Senescent bone mesenchymal stromal cells (BMSCs) play an essential role in bone homeostasis imbalance in osteoporosis; however, the mechanisms through which they regulate osteoclast activation remain unclear. In the present study, highly expressed genes in BMSCs from patients with osteoporosis group were screened using transcriptomic data from the GSE35959 dataset. Subsequently, the

Translating biological time across species is a powerful tool to identify new models of human aging and disease. Currently, it is not clear whether any animal reaches an age comparable to a human in their 80s. Most species seem to age differently compared with humans. Some preliminary observations suggest that cats may share common patterns of aging with humans. Cats could serve as a promising model for human aging. Here, we find corresponding ages between cats, humans and other species to test whether cats can live to the equivalent of a human in their 80s. We analyzed 3,754 observations across species from sudden and gradual changes in anatomy, physiology, and behavior. Some of these data are from clinical records, whereas others are from brain scans using high-resolution MRI (7T and 3T). We studied pet cats, research colony cats, and wildcats living in zoos to encapsulate species variation in the speed of development and aging. We found that cat and human brains atrophy with age, and that their age-related patterns in brain aging are sufficiently similar that we could use them to generate cross-species age alignments. We also found that human postnatal development is stretched compared with cats and mice. Interestingly, some pet cats that visit clinics are much older than those in colonies. Therefore, cats, and especially pet cats, are natural model systems of human aging. Our findings call for increased integration across veterinary and human medicine to understand aging.

Sex differences and increased mortality patterns attributable to frailty has been overlooked in upper-middle-income countries. This study aims to examine the impact of physical frailty on all-cause mortality among adults according to sex, in a Western upper-middle-income country.

Sarcopenia, an age-related clinical syndrome characterized by reduced skeletal muscle mass and strength, often leads to a loss of physical function. Nucleotides (NTs) supplementation is a potential strategy for preventing age-related sarcopenia as evidence suggests that NTs declined in muscles with aging, and 5'-CMP, 5'-UMP can mitigate muscle atrophy in C2C12 myotubes. This study aimed to investigate the effects of NTs supplementation on sarcopenia and its possible mechanism.

Background: Stress response obligates increased mitochondrial activities to meet stress induced high energy requirement. This stress mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress mitochondrial response paradigm to study the process in humans. Method: We used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress induced cf mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS), as well as high resolution brain imaging based cortical thickness focusing on the mPFC. Results: We found that salivary cf mtDNA was significant elevated immediately after the stress challenge (p=2.0x10-7) and gradually declined after. Exploratory causal analysis showed that this cf mtDNA response was not primarily driven by cortisol response. Instead, individuals with higher baseline dACC lactate+ levels, thought to in part reflect mitochondrial dysfunctions, was significantly associated with the cf mtDNA response (r=0.80, p<0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r=-0.52, p=0.01). Age had a U-shape effect such that cf mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct mtDNA response variance (p=0.003). Conclusion: This stress challenge-salivary cf mtDNA assay paradigm may offer a new, noninvasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.

Intrinsic capacity (IC), as defined by the World Health Organization (WHO), represents an individual's physical and mental capacities across five domains: locomotion, cognition, vitality, psychology, and sensory. As a key determinant of functional ability (FA), IC supports meaningful activities, and its decline predicts FA deterioration. Monitoring IC over time may help detect early decline and guide interventions. However, it is not clear how (domains of) IC change during normal ageing. Therefore, this study aimed to identify IC trajectories in both women and men and their associations with functional limitation (proxy of FA) and Quality of Life during ageing.

Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain's biology-the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.

The gut microbiota both adapts to, and shapes, the metabolic state of individuals. This bidirectional relationship is mediated via circulating metabolites and gene regulatory networks and interacts with many organs, including by the gut-brain axis. Here, we have processed the cecum from 232 mice from our recent aging colony across age (6-24 months), diet (chow or high fat), and genetics (43 BXD strains) and sequenced their metagenome, metatranscriptome, and cecal transcriptome. We quantify changes in over 300 species caused by interactions between diet, age, and genetic background. Traditional bioinformatics approaches linked particular microbes to observed phenotypes, while newer machine learning models based microbial clusters accurately predicted host outcomes, including individual body weight (AUC = 0.92) and chronological age (AUC = 0.84). This was further enhanced by a compact 10-feature multi-omics model, combining our microbiome data with prior liver expression data to increase chronological age AUC to 0.95. Mechanistically, integrative network analyses identified dozens of significant links between particular bacterial taxa and gene expression, such as a strong negative correlation between host Ido1 expression and short-chain fatty acid (SCFA)-producing Lachnospiraceae, indicating dietary fat can modulate host tryptophan metabolism via microbiota shifts. Moreover, as our study uses inbred mice sampled across time, we have identified signature sets of taxonomies that provide excellent predictive value for future metabolic outcomes driven by metabolic networks connecting the microbiome to the host organism\'s tissues (here, cecum and liver from the same mice). By better understanding the gut-liver axis, we can understand the cellular etiologies of metabolic disease and identify earlier, personalized diagnostic biomarkers attuned to the genetic background and environmental state of the individual.

Microglial senescence contributes to inflammation and various neurodegenerative diseases. Recent single-cell transcriptome data have revealed age-associated microglial substates (AAMs) and their potential roles in the development of neurodegenerative diseases. However, the characteristics identified in each study are not necessarily consistent. Here, we perform an integrative analysis of seven previously reported single-cell RNA-seq and four single-nucleus RNA-seq datasets of microglia from young and aged mouse brains. We identify four common AAMs across all datasets and two dataset-specific AAMs. Each AAM exhibits distinct transcriptomic patterns, including alterations in ribosomal genes, Apoe, cytokine genes, interferon-responsive genes, and phagocytosis-related genes. Time-series and pseudotime analyses indicate that the production of AAMs is initiated by the upregulation of ribosomal genes. Predictions based on single-cell transcriptomic data of age-associated manipulations reveal an increase in specific AAMs in a stimulation-type-dependent manner. We also identify similar AAMs in human brains. Altogether, our large-scale integrative analysis highlights promising age-associated microglial populations, which may serve as novel therapeutic targets for age-related neurodegenerative diseases.

Protein glycation is a detrimental byproduct of living cells\' reliance on carbohydrate metabolism, and nearly all organisms encode kinases that facilitate the removal of early glycation products. In humans, these repair functions are performed by Fructosamine-3 kinase (FN3K) and Ketosamine-3 kinase (KT3K) enzymes which share conserved catalytic mechanisms but differ in substrate specificity. Recent structural studies defined key active site residues required for FN3K activity on a model substrate, yet the molecular basis for differential substrate recognition by FN3K and KT3K remains unresolved. Here, we integrate phylogenetic analysis, ancestral protein reconstruction (APR), and mutational biochemistry to to elucidate how substrate specificity evolved within the fructosamine-3 kinase family. We show that conserved substrate-binding residues are required for the phosphorylation of both fructosamines and ketosamines, but do not contribute to substrate specificity. Using APR, we resurrected four ancestral fructosamine kinases that recapitulate the distinct substrate preferences of FN3K and KT3K despite differing by only 12 amino acids. Through mutational studies and structural analysis, we show that substrate specificity is modulated by an evolutionarily tuned allosteric network that enables long-range intramolecular communication. These insights provide a new mechanistic framework for understanding FN3K substrate selection and open avenues for rational design of FN3K-selective therapeutics targeting protein glycation in metabolic disease and aging.

Non-pharmacological interventions (NPIs) in aging neuroscience have largely focused on intervention-specific regional effects, with limited understanding of generalizable network-level mechanisms. Here, adopting a previously unexplored gradient-based perspective of functional brain organization, we analyzed an NPI dataset involving four interventions in older adults (training/control group: n = 112/59). NPIs led to strengthened intra-network functional integration and maintained macroscale gradient architecture. Virtual lesion analyses identified the dorsal attention network (DAN) as a key contributor to gradient maintenance. Critically, enhanced post-intervention DAN connectivity was associated with maintained gradient structure and improved global cognition. These findings establish a unifying framework in which the DAN acts as a convergent hub through which diverse NPIs preserve functional brain organization and attenuate cognitive aging.

Aging is associated with metabolic decline in the brain, increasing susceptibility to neurodegenerative diseases. While exercise is a well-established strategy to counteract these changes, no study has directly compared the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on cortical and hippocampal energy metabolism-key regulators of brain plasticity in aging. To address this gap, we investigated how 4-week MICT and HIIT protocols, structured according to the lactate threshold, affect endurance performance and brain metabolic markers in older Wistar rats. Both training modalities improved endurance, with HIIT demonstrating superior gains in maximal performance. However, molecular analyses revealed that MICT induced more extensive metabolic and angiogenic adaptations in the cortex and hippocampus, including the upregulation of key regulators of energy metabolism and vascularization. RNA sequencing confirmed broader transcriptomic changes following MICT, implicating pathways associated with neurogenesis, metabolic homeostasis, and cellular plasticity. While HIIT provided a time-efficient means of improving cardiovascular endurance and mitochondrial activity through different molecular pathways when compared to MICT, its impact on brain metabolism was more limited. These findings suggest that MICT is the preferred regimen for enhancing cerebral metabolic function and neurovascular adaptation, while HIIT serves as a complementary strategy to involve other brain metabolism-associated pathways and maximize aerobic fitness. A direct comparison of these modalities, as presented here, is essential for refining exercise prescriptions to support brain health in aging.

Blood stem cells are among the body's longest-living cells despite being highly vulnerable to proteotoxic damage, which accelerates their aging. To maintain protein homeostasis (proteostasis), hematopoietic stem cells (HSCs) employ mechanisms such as reduced translation rates, high chaperone activity, autophagy, and selective protein degradation. These strategies mitigate protein misfolding, maintain quiescence, and preserve regenerative potential. Disruptions in proteostasis can lead to the elimination of impaired HSCs through differentiation or apoptosis, ensuring the integrity of the stem cell pool. Due to the systemic impact of the blood on aging and its experimental and clinical accessibility, investigating HSC proteostasis provides insights into longevity and potential therapeutic strategies. This review examines emerging mechanistic links between proteostasis and HSC fate, concluding with unresolved questions and challenges of the current research.

Diabetic kidney disease (DKD) is characterized by kidney damage and abnormal renal energy metabolism, but the molecular mechanism of DKD is still unclear. In this study, we show that p16- positive senescent cells are an important regulator in the progression of DKD. The expression of p16 and senescence are increased in the kidneys of DM mice and DKD patients. To better understand the role of p16 in DKD, we induce type 1 diabetes in INK-ATTAC mice, a mouse model that allows the selective ablation of p16-expressing cells upon administration of the drug AP20187. We found that clearance of p16-positive cells, most of them are senescent cells, (1) decreased senescence and the expression of the components of the senescence-associated secretory phenotypes (SASPs), (2) restored kidney adenosine triphosphate (ATP) content, (3) decreased the expression of the key glycolytic genes to improve the metabolic reprogramming, (4) normalized the mitochondrial metabolism through AMPK and mTOR pathway, resulting in an amelioration of the progression of DKD. In addition, p16 mediated the blocking of the cell cycle is through the CDK4-Rb pathway in DKD kidneys. This study suggests that pharmacological deletion of p16-positive senescent cells may be a novel therapeutic strategy for DKD treatment.

Background: Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of {Delta}133p53, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate {Delta}133p53 protein levels. Methods: To investigate whether celastrol and ADZ1981 upregulate endogenous {Delta}133p53 in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays ({Delta}133p53, progerin, and p21WAF1, which mediates p53-induced senescence and is inhibited by {Delta}133p53), senescence-associated {beta}-galactosidase (SA-{beta}-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21WAF1 and IL-6). Results: Treatment with celastrol (0.1 M for 24 h) or AZD1981 (10 M for 24 h) reproducibly increased {Delta}133p53 expression and decreased p21WAF1 expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-{beta}-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin. Conclusion: Celastrol and ADZ1981 upregulate endogenous {Delta}133p53 and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which {Delta}133p53-regulated senescence plays a role.

Mitochondria are complex organelles critical to the maintenance of cellular homeostasis. Central to this regulation are Prohibitins (PHBs), a novel set of proteins involved in several mitochondrial quality control pathways, including protein folding, biogenesis, and mitophagy. PHBs mediate various cellular responses including cell survival and myogenesis, suggesting that their roles are intricate and multifaceted. While evidence suggests that PHBs facilitate mitochondrial homeostasis, their exact mechanism of action remains unclear. Elucidating the precise mechanisms driving PHB-mediated adaptations will ultimately enable the development of therapeutic strategies aimed towards the treatment of age-related diseases, characterized by mitochondrial perturbations.

Identifying the set of genes that regulate baseline healthy aging - aging that is not confounded by illness - is critical to understating aging biology. Machine learning-based age-estimators (such as epigenetic clocks) offer a robust method for capturing biomarkers that strongly correlate with age. In principle, we can use these estimators to find novel targets for aging research, which can then be used for developing drugs that can extend the healthspan. However, methylation-based clocks do not provide direct mechanistic insight into aging, limiting their utility for drug discovery. Here, we describe a method for building tissue-specific bulk RNA-seq-based age-estimators that can be used to identify the ageprint. The ageprint is a set of genes that drive baseline healthy aging in a tissue-specific, developmentally-linked fashion. Using our age estimator, SkeletAge, we narrowed down the ageprint of human skeletal muscles to 128 genes, of which 26 genes have never been studied in the context of aging or aging-associated phenotypes. The ageprint of skeletal muscles can be linked to known phenotypes of skeletal muscle aging and development, which further supports our hypothesis that the ageprint genes drive (healthy) aging along the growth-development-aging axis, which is separate from (biological) aging that takes place due to illness or stochastic damage. Lastly, we show that using our method, we can find druggable targets for aging research and use the ageprint to accurately assess the effect of therapeutic interventions, which can further accelerate the discovery of longevity-enhancing drugs.

tRNA-derived small RNAs (tsRNAs), a class of non-coding RNAs (ncRNAs), have garnered increasing research interest for their potential roles in various biological processes. Among these, 5'tiRNA-Glu-TTC has been implicated in aging, but its role in skin photoaging remains elusive. This study aimed to elucidate the impact of 5'tiRNA-Glu-TTC on skin photoaging. RT-qPCR analysis revealed that 5'tiRNA-Glu-TTC expression increased in human dermal fibroblasts (HDFs), human skin tissues, and mouse skin tissues following UVB irradiation. In HDFs, transfection of a 5'tiRNA-Glu-TTC mimic induced photoaging phenotypes, while its inhibitor alleviated UVB-induced photoaging. This study found that 5'tiRNA-Glu-TTC participates in photoaging through binding to TRPV3. Overexpression of TRPV3 rescued the photoaging effects induced by the 5'tiRNA-Glu-TTC mimic. Furthermore, 5'tiRNA-Glu-TTC influences photoaging also by activating the PI3K/AKT signaling pathway, an effect that was reversed by TRPV3 overexpression. In vivo studies in nude mice showed that intradermal injection of 5'tiRNA-Glu-TTC adeno-associated virus alleviated UVB-induced skin aging phenotypes, including epidermal thickening, dermal collagen reduction, and increased transepidermal water loss (TEWL). Collectively, our findings demonstrate that 5'tiRNA-Glu-TTC mediates photoaging by targeting TRPV3 and activating the PI3K/AKT pathway.

Aging is associated with the risk of increased infection severity and altered immune responses. In this study we investigated age- and sex-specific differences in immune cell composition in a subset of the population-based CoNAN study using a cross-sectional analysis. We identified a significant age × sex interaction in memory B cells and observed age-related declines in naive lymphocytes and an increase in CD8

Fibroblast dysregulation contributes to aberrant repair and pathological fibrosis. Emerging evidence suggest that fibroblasts accumulate in lesions following central nervous system injury, but whether and how they influence oligodendrocytes and myeloid cell responses, especially in aging, is uncertain. Here we report that fibroblasts infiltrate the parenchyma of spinal cord white matter (SCWM) lesions after lysolecithin-induced demyelination. Transcriptomic analysis reveals diverse activation states of fibroblasts in lesions and communication networks between fibroblasts, microglia/macrophages and oligodendrocyte precursor cells (OPCs). The invasion of fibroblasts is facilitated by microglia/macrophages, and areas of fibroblast accumulation are devoid of OPCs. Fibroblast density is exacerbated with aging leading to greater fibrosis in lesions. Finally, we found fibroblasts in multiple sclerosis lesions with predicted communication networks between microglia/macrophages and OPCs. These results demonstrate a role of fibroblasts in demyelination-associated neuropathology, which is exacerbated by aging, and highlight the importance of regulating fibroblasts to promote effective CNS repair.

The seeds of the Amazonian fruit, guarana (Paullinia cupana), have been used as traditional medicine and, in recent years, as an ingredient in commercial energy beverages. However, mechanisms underlying the beneficial effects of guarana are not well understood. To establish a model system to study molecular mechanisms underlying the beneficial effects of guarana, we investigated how its ingestion affects physiology in the fruit fly, Drosophila melanogaster. We found that guarana enhanced oxidative stress resistance, longevity, physical activity, and fecundity of flies. To deepen our understanding of guarana function, we performed transcriptomic, metabolomic, and fecal microbiome analyses. Transcriptomic analysis identified 58 upregulated and eight downregulated genes in guarana-fed flies. Highly upregulated genes included those encoding detoxification enzymes, such as cytochromes P450 (CYPs), glutathione S-transferases (GSTs), and Juvenile hormone epoxide hydrolase 1 (Jheh1). Metabolomic analysis identified glutathione metabolism, an antioxidant system, as being promoted by guarana ingestion. These findings likely represent the molecular basis for enhanced oxidative stress resistance and longevity in guarana-fed flies. We also analyzed fecal microbiota composition and found significant changes: guarana increased the proportion of probiotic Lactobacillus species, some species known to extend longevity. At the same time, it decreased the proportion of Enterococcus faecalis, a species known to reduce longevity. These changes might have contributed to the beneficial effects of dietary guarana. Thus, we demonstrate that guarana exerts beneficial effects in flies and provide fundamental data for further investigation of its biological mechanisms in Drosophila.

To investigate how early-life tobacco exposures implicate accelerated biological aging in adulthood and the potential mechanism.

Hand-grip strength (HGS) asymmetry may represent an indicator of overall health, yet its relationship with mortality risk remains underexplored at different cut-offs and populations. We aimed to investigate the association between HGS asymmetry and all-cause mortality in Japanese adults.

Blood is best known for its critical roles such as oxygen distribution, nutrient transport, hemostasis, and immune surveillance. However, its impact on biological aging remains unknown. Accumulating evidence indicates that interventions targeting the vascular system may decelerate or even reverse the aging process, such as heterochronic parabiosis (HPB), therapeutic plasma exchange (TPE), platelet-rich plasma (PRP) injection, extracellular vesicles (EVs) transfusion, and platelet factor transfusion.

Sleep disorders-including daytime sleepiness (DS), insomnia, and sleep apnea (SA)-have been linked to aging-related phenotypes, but their causal roles remain unclear. This study aimed to examine the potential causal effects of these sleep traits on biological aging using a Mendelian randomization (MR) approach.

Lung injury leads to pulmonary microvascular endothelial cell (PMVEC) damage, disruption of cell-cell junctions, and increased permeability. Previously, we demonstrated in a mechanical ventilation-induced model of lung injury that aging exacerbated pulmonary microvascular permeability. Based on this, we hypothesized that aging was associated with increased PMVEC barrier dysfunction due to impaired cell-cell junction integrity. PMVEC were isolated from young and aged mice and cultured to confluence in vitro. Barrier function and cell-cell junction integrity were assessed through electric cell-substrate impedance sensing, XPerT permeability assay, immunofluorescence, and western blot analysis. Further studies were conducted to examine alterations in the proteome, markers of inflammation, and actin cytoskeleton organization. To model injurious conditions, PMVEC were stimulated with inflammatory cytokines; permeability and actin cytoskeletal alterations were subsequently assessed. We observed increased basal permeability in PMVEC from aged mice, which was associated with disrupted cell-surface localization of the adherens junction protein, vascular endothelial (VE)-cadherin. Protein abundance of VE-cadherin was significantly increased with age; however, levels of the adapter protein, -catenin, and the tight junction protein, claudin-5, were decreased. Measures of inflammation, including cytokine expression and cell surface abundance of adhesion molecules, did not differ with age. Alterations in actin cytoskeleton organization, characterized by augmented presence of actin stress fibers, were observed in aged PMVEC. Under inflammatory conditions, permeability and actin stress fiber formation were exacerbated with age. It is concluded that aging predisposes PMVEC to elevated injury, due to inherent deficiencies in cell-cell junctions and barrier function, potentially mediated through altered actin cytoskeleton organization.

Mosaic loss of Y chromosome (mLOY) in blood cells is an age-related somatic mutation, but its relationship with pulmonary health remains undercharacterized. Leveraging mLOY assessment in over 12,000 men, including 5,097 from the COPDGene Study and 7,235 from six additional cohorts in Trans-Omics for Precision Medicine program, we investigated its association with respiratory outcomes and epigenetic aging. Cross-sectionally, mLOY was associated with airflow obstruction with prevalence increasing with age, particularly in men with a former smoking history. Longitudinally, mLOY associated with lung function decline. Notably, mLOY was also associated with greater CT-quantified lung emphysema and faster pace epigenetic aging. Prospectively, in participants with normal lung function at baseline, mLOY was associated with lower future lung function and faster pace of epigenetic aging. These associations remained robust after adjusting for clonal hematopoiesis and telomere length. Collectively, these findings position mLOY as a potential biomarker of respiratory aging and obstructive lung disease.

Cytomegalovirus (CMV) drives immunosenescence, while its reactivation is associated with inflammation and oxidative stress. This study investigates the interplay between CMV, oxidative stress and inflammation in a cohort of 2065 age-stratified individuals randomly recruited from the general population (RASIG), as part of the MARK-AGE study, to better understand the role of CMV in immunosenescence and its potential impact on age-related diseases. CMV IgG titers were associated with oxidative stress, antioxidant, and inflammatory biomarkers. Stepwise-linear regression identified positive associations with age, BMI, apolipoprotein J (ApoJ/Clu), ceruloplasmin, α-2-macroglobulin, proteasome peptidase activity, and malondialdehyde, and negative associations with α-tocopherol, selenium, and vitamin D. Notably, the associations with ApoJ/Clu and proteasome peptidase activity represent novel findings that point to a potential involvement of proteostasis dysregulation and cellular stress responses in CMV-related immune alterations. Quartile-based analyses revealed significantly lower antioxidant levels (α-tocopherol, selenium, ascorbic acid and vitamin D) and higher oxidative stress markers (plasma 8-isoprostanes, malondialdehyde) in the highest quartile (Q4) compared to lower quartiles. Inflammatory markers (homocysteine, ceruloplasmin and α-2-macroglobulin) ApoJ/Clu and proteasome peptidase activity were elevated in Q4. This group also exhibited a higher prevalence of cardiovascular diseases, hypertension, and diabetes. This study highlights a link between CMV IgG titers, oxidative stress, inflammation, and the prevalence of cardiovascular and metabolic diseases. Our findings suggest that CMV may contribute to immunosenescence through mechanisms involving redox imbalance and dysregulation of protein degradation pathways. Further research is needed to explore the role of CMV reactivation in aging, and its impact on age-related metabolic and cardiovascular diseases.

Health behaviors affect life expectancy, but whether disease is present can greatly impact both the individual and society. How health behavior is reflected in the utilization of health care services is yet to be investigated to support the impact of prevention efforts. Based on data from 57,053 middle-aged individuals from the Danish Diet, Cancer and Health cohort, a health score including baseline smoking status, sport activity, alcohol consumption, diet, and waist circumference was constructed as a simple measure of general health behavior. During 20 years of follow-up, healthy life expectancy among men and women aged 65 years at baseline, was 0.83 [0.74 to 0.92] and 0.86 [0.77 to 0.94] years longer on average, respectively, per one point increment in the health score. Life expectancy with disease was shorter among men (-0.18 [-0.26 to -0.09]) and women (-0.37 [-0.45 to -0.29]) with higher health scores. Among individuals with the highest scores, major chronic disease diagnosis was postponed for more than 7 years. There were fewer disability years, especially with multimorbidity, (men: -1.6 years; women: -3.3 years), and there was a clear inverse association between health score and days of hospitalization looking 20 years ahead.

Mosaic loss of chromosome Y (mLOY) is the most common somatic mutation in hematopoietic cells of aging men and is linked to cancer risk and mortality. However, its relationship with treatment modalities remains unclear. In 348 prostate cancer patients at Juntendo University Hospital, local radiotherapy was associated with a higher prevalence of mLOY (OR = 2.55, 95% CI: 1.08-6.50, P = 0.04), whereas surgery and endocrine therapy were not. We then examined BioBank Japan data from over 30,000 patients with prostate, lung, colorectal, and gastric cancers. Fixed-effect meta-analysis across these sites showed a significant association between radiotherapy and mLOY (OR = 1.48, 95% CI: 1.11-1.98, P = 0.01). No significant effect heterogeneity was observed across cancer types (Q = 0.36, I² = 0%, P = 0.95). Our findings suggest that radiotherapy may exacerbate genomic instability, indicating a potential vulnerability in certain cancer patients to DNA damage induced by radiation therapy.

Senescent cells, characterized by irreversible cell cycle arrest and inflammatory factor secretion, promote various age-related pathologies. Senescent cells exhibit resistance to ferroptosis, a form of iron-dependent cell death; however, the underlying mechanisms remain unclear. Here, we discovered that lysosomal acidity was crucial for lipid peroxidation and ferroptosis induction by cystine deprivation. In senescent cells, lysosomal alkalinization causes the aberrant retention of ferrous iron in lysosomes, resulting in resistance to ferroptosis. Treatment with the V-ATPase activator EN6 restored lysosomal acidity and ferroptosis sensitivity in senescent cells. A similar ferroptosis resistance mechanism involving lysosomal alkalinization was observed in pancreatic cancer cell lines. EN6 treatment prevented pancreatic cancer development in xenograft and Kras mutant mouse models. Our findings reveal a link between lysosomal dysfunction and the regulation of ferroptosis, suggesting a therapeutic strategy for the treatment of age-related diseases.

This study investigated 17α-estradiol's effects on aged hypothalamic physiological activity via long-term administration. Single-nucleus transcriptomic sequencing (snRNA-seq) was performed on pooled hypothalami from each group: aged male Norway brown rats treated with 17α-estradiol (O.T), aged controls (O), and young controls (Y). Supervised clustering of neurons (based on neuropeptides/receptors) evaluated subtype responses to aging and 17α-estradiol. Aging-induced elevation of neuronal cellular metabolism, stress, and reduced synapse formation-related pathways were significantly attenuated by 17α-estradiol. Neuron population analysis showed that subtypes regulating food intake, reproduction, blood pressure, stress response, and electrolyte balance were sensitive to 17α-estradiol. 17α-estradiol increased serum oxytocin (Oxt) and hypothalamic-pituitary-gonadal (HPG) axis activity (elevated plasma Gnrh, total testosterone; reduced estradiol). Gnrh1 upregulation mediated its effects on energy homeostasis, neural synapse, and stress response. Notably,

Biomolecular condensates are dynamic cellular compartments that concentrate proteins and enzymes to regulate biochemical reactions in time and space. While these condensates can enhance enzyme activity, how this function changes as condensates age remains poorly understood. Here, we design synthetic catalytic condensates that selectively recruit enzymes to investigate this temporal evolution. We show that catalytic condensates exhibit time-dependent activity: they initially accelerate enzymatic reactions but gradually lose efficiency due to the transition from liquid-like to solid-like states. This aging process, characterized by protein aggregation and loss of selective barriers, impairs enzyme function both in vitro and living cells. We further demonstrate that small molecules which influence aging dynamics can modulate catalytic efficiency of condensates. Our findings show that condensate aging as a key regulator of enzymatic activity and provide crucial insights for designing functional synthetic condensates.

With the rapid increases of older population and growing demand for longevity worldwide, frailty has become a major hurdle to sustaining healthy aging. As residential areas are the primary domains of mobility for older adults, the neighborhood environment is a crucial factor for their daily living and physical activity. This study aims to investigate whether replacing sedentary behavior with physical activity and having a supportive neighborhood environment are associated with frailty status in older adults.

Advances in antiviral treatment for HIV have led to greater longevity but there is continued risk for developing cardiovascular disease and cognitive impairment, particularly among older persons with HIV (PWH). The benefits of aerobic exercise for reducing cardiovascular disease are well established and have been shown to improve cognitive function in older adults but has had limited testing in older PWH and are inconclusive. This study aimed to test the efficacy of a home-based moderate intensity aerobic exercise intervention (Let's Move) to an attention control stretching and flexibility group (Let's Flex) over a one-year period among PWH with mild cognitive impairment and a minimum of 2 cardiovascular disease risk factors. Clinically stable (

The 2021 Aging Report of the European Union projected significant increases in healthcare costs, with some member states expecting up to a 60% rise over the next 50 years, primarily due to an aging population and related diseases. Interventions targeting aging have been proposed to reduce this burden by extending healthspan. Recent evidence suggests that vegan diets may slow the aging process.

The progressive decline in birth rates due to delayed marriage has become a significant issue in developed countries, with male spermatogenetic capabilities gradually declining with age. This study evaluated the effectiveness of a silicon-based agent (Si-based) that efficiently generates hydrogen in the body to improve spermatogenic function in aged mice.

Retinal fundus images offer a non-invasive window into systemic aging. Here, we fine-tuned a foundation model (RETFound) to predict chronological age from color fundus images in 71,343 participants from the UK Biobank, achieving a mean absolute error of 2.85 years. The resulting retinal age gap (RAG), i.e., the difference between predicted and chronological age, was associated with cardiometabolic traits, inflammation, cognitive performance, mortality, dementia, cancer, and incident cardiovascular disease. Genome-wide analyses identified genes related to longevity, metabolism, neurodegeneration, and age-related eye diseases. Sex-stratified models revealed consistent performance but divergent biological signatures: males had younger-appearing retinas and stronger links to metabolic syndrome, while in females, both model attention and genetic associations pointed to a greater involvement of retinal vasculature. Our study positions retinal aging as a biologically meaningful and sex-sensitive biomarker that can support more personalized approaches to risk assessment and aging-related healthcare.

The need to monitor the aging process as a risk factor for disease and mortality beyond chronological age (CA) has led to numerous investigations into the estimation of the biological age (BA) of individuals. However, the accuracy of BA estimation tools is often judged by their ability to approximate CA, questioning their value in capturing the variance in health status and thus correctly estimating BA. Their biological relevance is often assessed in relation to health outcomes or mortality, underexploiting their potential for real-time monitoring of BA. Furthermore, their complexity may limit their clinical translation to large populations. Here, we describe the gene expression-based age monitoring Clock (GamC), a simple biomarker of aging (BOA), and characterize its biological relevance with synchronous cardiovascular (CV) health-related functional data. GamC is calculated from the expression levels of three genes consistently dysregulated with age in blood (ABLIM1, CCR7, and LEF1). GamC shows moderate but reliable association with CA in three independent cohorts, supported by transcriptome-wide changes. It demonstrates specialized biological meaning, as it specifically describes current physical activity levels, but poorly correlates with autonomic nervous system function, both age-related factors associated with CV health. Finally, it expresses BA monitoring capacity by modestly responding to an effective exercise-based intervention in centenarians. In conclusion, GamC is proposed as a simple and affordable candidate BOA for reporting the individuals' current CV health-related BA, thus promoting its broad translation and application into measures aimed at promoting healthy aging in relation to CV health, the leading cause of death worldwide.

Age-related structural and functional deterioration of the kidneys is common among elderly individuals and contributes to increased mortality and morbidity. Mitochondrial dysfunction and cellular senescence are two hallmarks of aging that drive a progressional renal decline; however, the underlying molecular mechanisms and endogenous regulators behind these processes remain incompletely understood. The metabolism of polyunsaturated fatty acids by CYP450 enzymes produces numerous bioactive lipid mediators that can be further metabolized by soluble epoxide hydrolase (sEH) and microsomal epoxide hydrolase (mEH) into diol metabolites, often with reduced biological effects. The objective of this study was to assess renal mitochondrial alterations and cellular senescence in young and aged wild-type (WT) and sEH-deficient (sEH null) female mice. We found aged sEH null mice exhibited better physiological health, as reflected by lower frailty index scores and reduced circulating levels of GDF-15 levels, creatinine, and urea nitrogen. Notably, the expression of both sEH and mEH was significantly elevated in aged WT kidneys, accompanied by increased expression of the kidney injury marker (Kim-1) and evidence of structural abnormalities. In contrast, sEH deletion attenuated the age-related upregulation of senescence markers (p53, p21, p16) and SASP components (MCP-1, IL-1β, and caspase-1), as well as the inflammatory zBP1 expression and downstream interferons. Additionally, sEH deletion preserved age-related disruption of mitochondrial dynamics, content, and respiratory function. Together, these data suggest that sEH deletion confers renoprotective effects in aging, characterized by improved systemic health, reduced renal injury and inflammation as preserves mitochondrial integrity and function.

The escalating global trend of aging populations has brought attention to the rising prevalence of late-onset amyloid disorders. Among them, amyloid transthyretin (ATTR) amyloidosis presents a growing area of unmet medical needs. While current treatment modalities have demonstrated efficacy in preventing or delaying amyloid generation, methodology to selectively modify and neutralize existing amyloid burdens remains inadequately addressed, leaving the fundamental irreversibility and hence the fatality of these conditions, a long-standing medical challenge. Here, we report the first demonstration of therapeutic efficacy in ATTR amyloidosis via dynamic control of ATTR aggregation and toxicity, enabled by small-molecule organophotocatalysis. Selective incorporation of hydrophilic oxygen atoms into the hydrophobic amyloid core reshapes the aggregation landscape, neutralizing proteotoxicity, and mitigating cellular damage. Additionally, this targeted covalent modification significantly reduces in vivo ROS levels, correlating with the observed therapeutic effects in

Sulfur mustard (SM) is a potent alkylating agent known to cause long-term health effects, including accelerated aging. This study investigated mitochondrial dysfunction as a key mechanism underlying biological aging in 142 SM-exposed veterans (25 years post-exposure) and 54 matched controls. The SM-exposed veterans were stratified into subgroups (asymptom, mild, and severe) based on clinical criteria and lung function tests. Using buffy coat-derived leukocytes, we assessed mitochondrial DNA (mtDNA) copy number and damage frequency of long/short mtDNA fragments, and mitophagy-related gene expression (PINK1, PRKN, DRP1, FIS1). Demographic variables (age, marital status, income, smoking status, education) did not differ significantly between SM-exposed and control groups, ensuring comparability. Results showed no significant differences in mtDNA copy number between groups; however, mtDNA damage frequency was significantly elevated in the severe exposure subgroup. Gene expression analysis revealed significantly increased mRNA levels of PINK1, PRKN, DRP1, and FIS1 in SM-exposed veterans compared to controls, with the highest expression observed in the severe and mild subgroups, while PINK1 expression showed no significant subgroup differences. These findings demonstrate that SM exposure induces persistent mitochondrial dysfunction through cumulative mtDNA damage, dysregulated mitophagy signaling, and aberrant fission activation. While preserved mtDNA copy numbers suggest adaptive biogenesis, the severity-dependent patterns in fission genes and mtDNA lesions establish mitochondrial impairment as a central pathway in SM-related aging.

As the global population ages, research on the biology of ageing and its role in chronic disease is expanding, alongside a growing clinical focus on the unique needs of older adults. In the past, the liver was not thought to undergo substantial age-related changes, nor was there thought to be any liver disease characteristic of older adults. Current studies challenge this perspective, revealing that ageing substantially influences liver pathophysiology at the organ level and within each of the liver cell types. These observations have implications for understanding the pathogenesis of liver diseases common in older adults, including hepatocellular carcinoma, hypoxic hepatitis and metabolic dysfunction-associated steatotic liver disease. Previously, managing older patients with liver disease mostly addressed age-related changes in drug metabolism and liver function tests. However, current clinical practice increasingly emphasizes age-specific issues such as frailty, sarcopenia, multimorbidity and polypharmacy. Given the liver's pivotal role in systemic metabolism, immunity and detoxification, ageing of the liver can contribute to systemic diseases. In the future, interventions that target ageing biology might offer new treatment options for liver diseases. Here, we review those age-related changes in the liver that have substantial biological and clinical consequences for older adults.

DNA methylation data has been used to make "epigenetic clocks" which attempt to measure chronological and biological aging. These models rely on data derived from bisulfite-based measurements, which exploit a semi-selective deamination and a genomic reference to determine methylation states. We found that non-methylation factors lead to "pseudomethylation" signals that are both confounding of epigenetic clocks and uniquely age predictive. We also failed to predict age using human genotyping arrays, but found that epigenetic clocks were overrepresented near genomic regions whose methylation state is dependent upon sequence variants. Quantifying these covariates in aging studies will be critical to building better clocks and designing appropriate studies of epigenetic aging.

Neuroinflammation has emerged as a contributing mechanism in age-related cognitive decline (ARCD), Parkinson's disease (PD), obesity, sleep disorders, and autoimmune disorders. Orexin/hypocretin, a neuropeptide expressed in the lateral hypothalamus (LH), has well-established roles in homeostatic processes, such as energy metabolism, food intake, sleep, and wakefulness. Our laboratory and others have shown that orexin expression decreases with age, and this age-related orexin decline is exacerbated in disease states. Additionally, it has recently been shown that orexin possesses anti-inflammatory and neuroprotective properties. Based on these observations, we hypothesize that orexin is modulating neuroinflammation in brain regions that are critical in the development of ARCD. To test this hypothesis, we used lentiviral gene transfer to downregulate orexin expression in male and female young rats to mimic age-related orexin deficiency and examined neuroinflammatory responses to peripheral administration of lipopolysaccharide (LPS). We found a significant reduction of basal forebrain (BF) microglial complexity and plasma BDNF in both males and females following orexin downregulation. Notably, orexin downregulation blocked the capacity of the neuroinflammatory system to respond to LPS. These results demonstrate that neuroinflammatory responses are dependent on orexin signaling, and this system becomes dysfunctional in aging in a sex-dependent manner.

Senile osteoporosis (SOP) features reduced bone density and degraded trabecular structure, primarily mediated through senescent impairment of osteoblasts that disrupts coupled bone remodeling homeostasis. This pathological process induces systemic bone resorption and localized bone destruction accompanied by architectural deterioration. Existing treatments for senile osteoporosis tend to focus on a single mechanism, making it challenging to simultaneously address bone formation deficits and oxidative stress. Herein, we developed a multifunctional nanoplatform utilizing metal-phenolic networks (MPNs), formed

We have previously shown that prevention of GSK-3β inactivation with GSK-3β (S9A), stimulates autophagy through phosphorylation of Ulk1 at Ser913. In the current study, we investigated whether cardiac aging is accelerated in Ulk1S913A knock in mice and whether cardiomyocyte senescence plays an important role in the development of aging cardiomyopathy in these mice.

Specialized ribosomes help determine which proteins are synthesized, however, the influence of age on ribosome heterogeneity and whether dysregulation of this process drives organismal aging is unknown. Here we examined the role of ribosomal RNA (rRNA) methylation in maintaining appropriate translation as organisms age. In a directed RNAi screen, we identified 18S rRNA N6'-dimethyl adenosine (m

Frailty as an age-related health state poses a challenge to healthy aging, but as a reversible state has the opportunity to be modified. However, the effectiveness of health promotion interventions currently implemented for frailty remains unclear. Therefore, we aimed to explore the association between multidimensional health promotion behaviors and frailty in Chinese middle-aged and older adults, as well as gender and age differences in this association to provide key entry points to address frailty.

Low muscle strength, a key component of sarcopenia, is significant in the development of adverse health outcomes among older adults. MicroRNAs (miRNAs) have been implicated in mechanisms of sarcopenia; however, their specific functions in sarcopenia components, particularly low muscle strength, remain unclear. We aimed to examine distinct miRNA signatures associated with muscle mass, strength, and performance and to explore independent biomarkers for identifying older adults with low muscle strength.

While advanced maternal age is associated with significant changes in oocyte gene expression, these are not global changes but limited to a fraction of the transcriptome. However, there is little consensus on the specific genes affected, and on the transcriptomic signatures of age-related declines in oocyte quality. To characterise the effects of age on the human MII oocyte transcriptome, here we take a two-part approach. We first generated single-oocyte Smart-seq2 datasets from ten younger (21-29 years) and ten older (37-43 years) donors, identifying genes differentially expressed between the two groups, then cross-referenced our results with those of 12 studies (9 human, 3 mouse) performing equivalent analyses using a variety of single-cell transcriptomic or microarray platforms. Technical differences notwithstanding, we found considerable discordance between the datasets, suggesting that age-related signatures of differential gene expression are not easily reproducible. Independent corroboration of age-associated changes in expression was limited to few genes, with the vast majority only supported by one of the 13 datasets, including our own. Nevertheless, we identified 40 genes whose expression significantly altered with age in multiple studies, highlighting common processes underlying ageing, including dysregulated proteostasis. As human Smart-seq2 oocyte libraries are challenging to procure and rare in public archives, we next implemented a meta-analytic method for their re-use, combining our 20 oocytes with 130 pre-existing libraries sourced from 12 different studies and representing a continuous age range of 18-43 years. We identified 25 genes whose expression level significantly correlated with age and corroborated 14 of these genes with RT-PCR, including the proteasomal subunits PSMA1 and PSMA2, both of which were downregulated in older oocytes. Overall, our findings are consistent with both pronounced inter-oocyte heterogeneity in transcription and with oocyte ageing being a multifactorial process to which bona fide transcriptomic changes may only play a restricted role, while proteomic changes play more pronounced roles.

Frailty is a multidimensional geriatric syndrome characterised by reduced physiological reserves. Multidomain interventions combining physical and cognitive activities show promise in delaying frailty and cognitive decline. However, existing programs often face high dropout rates due to joint discomfort and balance concerns among older adults. This study aimed to evaluate the impact of a pole-assisted multicomponent exercise program on physical and cognitive function in community-dwelling older adults.

Diet is widely considered essential in dementia, but its association with white matter lesions (WMLs) remains unclear. This cross-sectional study investigated the associations between dietary patterns, dementia, and WMLs in a large, nationwide, multicenter population of older Japanese adults. A total of 8,938 adults (aged ≥ 65; 73 ± 6.3 years old) from the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) were included. Dietary intake was assessed using a Food Frequency Questionnaire. Principal component analysis was used to derive dietary patterns. A trained Convolutional Neural Network model segmented WMLs from brain MR images. Logistic regression estimated odds ratios (ORs) for dementia by dietary pattern quartiles, while linear regression assessed associations with WML volumes. Five dietary patterns were extracted. A Japanese diet including protein and minerals was significantly associated with lower prevalence of all-cause dementia (OR = 0.56) and Alzheimer's disease (OR = 0.47), and with reduced WML volume (β = - 0.03). Similar directional trends in ORs were observed across study sites. The reverse association with WMLs remained significant among individuals without dementia, reducing the likelihood of reverse causation. A Japanese diet including protein and minerals was associated with lower dementia prevalence and smaller WML volume in older Japanese adults. Drawing on nationwide, large-scale, multicenter data, these findings advance our understanding of dietary patterns in older Japanese adults and provide valuable insights for future intervention studies targeting diet and age-related brain changes.

This pilot study aimed to evaluate the impact of a diet supplemented with potential geroprotectors on metabolic and aging-associated markers in domestic cats. A total of 53 adult domestic cats were randomly assigned into two groups: a control diet (CD) and a geroprotective diet (GD) containing five plant-based extracts (silymarin, green tea, grape seed, curcumin, and grapefruit seed). Animals were fed the respective diets for three months. Body weight and body condition score were recorded before and after the feeding period. Blood samples were analyzed for standard biochemical parameters. Peripheral blood mononuclear cells were isolated to assess the expression of markers associated with inflammation (NF-κB, IL-1β), senescence (p16), and metabolic regulation (SIRT1, Klotho, RAGE) by Western blot. Both diets supported adequate body weight and condition. The GD group demonstrated a significant reduction in serum creatinine and a marked decrease in inflammatory and senescence markers (lower RAGE, p16, phospho-NF-κB) compared to baseline. SIRT1 levels were significantly upregulated only in the GD group, suggesting a possible protective mechanism against age-related changes. These data reveal a mechanistic link between dietary geroprotector supplementation and the modulation of key molecular hallmarks of aging in felines, highlighting conserved pathways of aging across mammalian species and establishing a foundation for translational interventions targeting age-associated decline in companion animals. Further long-term and larger-scale studies are required to confirm and extend these observations.

G-protein coupled receptor 68 (Gpr68) was enriched in long-term hematopoietic stem cells, indicating a potential role of Gpr68 in the HSC function. However, there is no significant phenotype in the HSC biology of Gpr68 whole-body KO mice, which may be counteracted by compensation. To study an intrinsic function of Gpr68 in hematopoiesis, Gpr68

Aging is associated with declines in sensorimotor and cognitive functions that affect internal motor models, thought to mediate the risk of falls. Motor imagery, an experimental window into internal models, has been studied in aging, but it remains unclear whether age differentially impacts their predictive versus updating components. In this study, younger and older adults completed the Timed Up and Go task along with imagined trials before and after execution, enabling separate assessment of prediction and update accuracy. It was found that older adults exhibited similar or better accuracy during prediction and update, but the accuracy measures were linked with distinct cognitive and sensorimotor factors in the two age groups. These findings suggest that while internal model function is preserved in healthy aging, at least for every-day tasks, it is shaped by different compensatory mechanisms across the lifespan.

Biological age acceleration predicts multiple "diseases of aging." Objective and subjective social statuses have both been prospectively linked to this outcome. An established chain-of-risk framework suggests that "effects" of each may be mediated by one's subsequent structural position. A separate deaths-of-despair literature identifies a person's sense of futility as another potential link. Such chains remain underexplored. The current study used data from three waves (2008-2016) of the Health and Retirement Study (HRS) to fill these gaps. The analysis was done through a counterfactual regression-with-residuals (RWR) approach. Asimulated decline in a person's objective but not subjective status predicted their age acceleration 8 years later. Contrary to chain-of-risk conceptions, intermediate social standing did not channel effects. Neither did despair. Findings were more consistent with a direct "material shocks" explanation for status-aging linkages than an indirect or psychosocial one. Implications for aging theory and for interventions are discussed.

Proteins are the cornerstone of life. However, the proteomic blueprint of aging across human tissues remains uncharted. Here, we present a comprehensive proteomic and histological analysis of 516 samples from 13 human tissues spanning five decades. This dynamic atlas reveals widespread transcriptome-proteome decoupling and proteostasis decline, characterized by amyloid accumulation. Based on aging-associated protein changes, we developed tissue-specific proteomic age clocks and characterized organ-level aging trajectories. Temporal analysis revealed an aging inflection around age 50, with blood vessels being a tissue that ages early and is markedly susceptible to aging. We further defined a plasma proteomic signature of aging that matches its tissue origins and identified candidate senoproteins, including GAS6, driving vascular and systemic aging. Together, our findings lay the groundwork for a systems-level understanding of human aging through the lens of proteins.

Aging is associated with increased susceptibility to metabolic stress and chronic liver disease, yet the interactions between age and metabolic stressors and the potential for ameliorating interventions remain incompletely understood. Here, we examined the hepatic response of young (7-month-old) and old (25-month-old) C57BL/6 male mice to a 9-week high-fat diet (HFD) and assessed whether rapamycin, a well-established pro-longevity intervention, could mitigate age-exacerbated effects. While both age groups developed metabolic-associated steatohepatitis (MASH), older mice displayed more severe hepatic steatosis, inflammation, and transcriptional dysregulation. Transcriptomic profiling of whole livers and purified hepatocytes revealed that aging amplifies HFD-induced inflammatory and metabolic gene expression changes, including activation of immune pathways and suppression of metabolic pathways. Notably, treatment of aging mice with rapamycin reversed the majority of HFD-driven transcriptional alterations, including upregulation of pro-inflammatory regulators such as Stat1, and dysregulation of metabolic gene networks. Rapamycin also reduced hepatosteatosis, total body weight, and a tumorigenic transcriptomic signature associated with hepatocellular carcinoma risk. These findings demonstrate that aging intensifies hepatic sensitivity to metabolic stress and identify rapamycin as a promising therapeutic to counteract age-related liver dysfunction and MAFLD progression.

Macrophages are heterogeneous immune cells with diverse subtypes and tissue-specific distributions, displaying dynamic polarization states that critically govern their immunomodulatory functions and responses to environmental cues. As key regulators of innate and adaptive immunity, they originate from either embryonic progenitors or bone marrow-derived monocytes and exhibit remarkable plasticity in response to microenvironmental cues. Tissue-resident macrophages (e.g., Langerhans cells, Kupffer cells, microglia) display unique organ-specific functions, while inflammatory stimuli drive their polarization into proinflammatory (M1) or anti-inflammatory (M2) phenotypes along a functional continuum. This review systematically examines macrophage subtypes, their anatomical distribution, and the signaling pathways (e.g., NF-κB, STATs, PPARγ) underlying polarization shifts in acute and chronic inflammation. We highlight how polarization imbalances contribute to pathologies including neuroinflammation, liver fibrosis, and impaired tissue repair, particularly in aging contexts. Furthermore, we discuss emerging therapeutic strategies targeting macrophage plasticity, such as cytokine modulation, metabolic reprogramming, and subtype-specific interventions. By integrating recent advances in macrophage biology, this work provides a comprehensive framework for understanding their dual roles in immune regulation and tissue homeostasis, offering insights for treating inflammatory and age-related diseases through macrophage-centered immunomodulation.

Aging impairs the regenerative capacity of mammalian organs and is a major risk factor for organ fibrosis. The causalities for persistent fibrosis after lung injury in old individuals have been unclear. We used longitudinal single-cell RNA-seq after lung injury and dissected aging effects computationally and experimentally at baseline and during repair. In old mice, sustained fibroblast activation in the resolution phase of repair was associated with prolonged epithelial senescence and persistent epithelial-mesenchymal crosstalk. Single-cell interpretable tensor decomposition analysis identified the strongest link of aging with T/B-lymphocytes and macrophages. A Granzyme K-high CD8-T cell state was unique to aged mice, co-localized with progenitors, and its co-culture or Gzmk treatments in lung organoids reduced progenitor function by induction of stem cell senescence. In summary, our study highlights effects of immune aging on progenitor function and provides a high resolution map of a lung regeneration time course in the context of aging.

Aging impairs the regenerative capacity of the skin, leading to delayed wound healing and chronic tissue damage. Recent advances have highlighted the therapeutic potential of dedifferentiated fat (DFAT) cells and their secreted exosomes. However, the bioactivity and molecular mechanisms of exosomes derived from DFAT spheroids (DFAT-Sps-Exos) in aging wound repair remain unclear. This study aims to evaluate the regenerative effects of DFAT-Sps-Exos on senescent fibroblasts and aging skin wounds, and to elucidate the underlying molecular mechanisms involved in their activity.

MicroRNAs (miRNAs) function in post-transcriptional regulation of gene expression and influence numerous biological processes. This commentary and view provide integrated insights from Kumar et al. (2024) and Gabaldon et al. (2020), emphasizing the role of miR-243 in promoting longevity and stress adaptation in response to microbial cues. However, further research is necessary to identify precise molecular targets of miR-243, comprehend its interactions with other miRNAs, validate its conservation in higher organisms, and to explore its potential toward targeted therapeutic strategies against aging and stress-related diseases.

Cellular senescence is associated with various hepatic diseases. Stimulator of interferon genes (STING) signaling has been identified as a significant driver of cellular senescence and hepatic stellate cells (HSCs) activation. The blockade of STING signaling serves as a potential strategy to halt senescence. However, little is known about the anti-aging natural compound inhibiting STING signaling to date.

The effects of the prenatal environment on resting-state functional connectivity in the brain can be detected up into older adulthood. We previously identified differences in resting-state functional connectivity of the default mode network (DMN), salience network (SN), and central executive network (CEN) at age 68 between men and women in the Dutch famine birth cohort who had been exposed or unexposed to famine in early gestation. Here, we investigated longitudinal changes in resting-state functional connectivity of the DMN, SN and CEN between ages 68 (n = 115) and 74 (n = 80) in the same cohort. Within- and between-network functional connectivity of the DMN, SN and CEN were compared between individuals unexposed (born before or conceived after) or exposed to famine in early gestation using a latent change score modeling approach with full information maximum likelihood estimation. No group differences were observed in baseline within-network functional connectivity (intercept; Δχ

Obesity and aging are interrelated public health concerns, with growing prevalence, especially as global demographics shift toward an older population. This narrative review explores the mechanisms through which obesity accelerates the aging process, focusing on major aging pathways affected by obesity, including deregulated nutrient sensing, telomeres attrition, epigenetic alterations, mitochondrial dysfunction, stem cell exhaustion, and altered intercellular communication. Evidence suggests that these disruptions not only drive age-related diseases, such as cardiovascular disease, type 2 diabetes, and neurodegenerative conditions, but also exacerbate mobility limitations, cognitive decline, and reduced quality of life in older adults. The role of lifestyle interventions, particularly adherence to the Mediterranean diet, is emphasized for its anti-inflammatory and metabolic benefits, alongside strategies to address the social and psychological impacts of obesity on aging. By recognizing obesity as a significant modifiable risk factor for accelerated aging, this review advocates comprehensive and targeted interventions to promote healthier aging and improve quality of life in older populations globally.