Longevity Papers

Background: Currently, the link between cardiovascular diseases and sarcopenia is increasingly garnering attention from researchers. However, studies exploring the association between cardiac structure and sarcopenia are sparse. This study aims to investigate the potential genetic links between cardiac structural features and sarcopenia. Methods: During the discovery phase, we employed Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) to assess the genetic correlation and causality between traits related to cardiac structure and sarcopenia, with further validation of the results using validation set data. In the study, we established a scoring system to identify high-confidence trait pairs. For these pairs, we conducted sensitivity analyses to assess their heterogeneity and pleiotropy. Additionally, we undertook follow-up studies of these trait pairs, including using mediation analysis to evaluate the potential mediating effects of lipids, and enrichment analysis to explore possible shared biological pathways linking these characteristics. Results: The genetic correlation analyses during the discovery and validation phases identified 5 pairs (in forward analysis) and 16 pairs (in reverse analysis) of high-confidence trait pairs. As a key sarcopenia-related feature, appendicular lean mass (ALM) exhibited positive causal relationships with several cardiac structural features, including the volumes of the left and right atria. Mediation analysis suggested that certain lipids, such as phosphatidylcholine, might mediate these causal relationships. Notably, gene and pathway enrichment analyses revealed that genes associated with significant SNPs in high-confidence trait pairs were enriched in multiple key biological processes and pathways, such as tube morphogenesis, cardiac right ventricle morphogenesis, and muscle system processes in the forward analysis, as well as skeletal system development, heart development, and hemopoiesis in the reverse analysis. Cell-type enrichment analysis pointed to endothelial cells, smooth muscle cells, fibroblasts, and mesenchymal stem cells. Conclusions: This study provides evidence for genetic relationships between cardiac structures and sarcopenia-related traits. These findings may enhance our understanding of the biological mechanisms underlying age-related diseases and provide scientific basis for developing future preventive and therapeutic strategies.

Cellular dysfunction induced by senescent nucleus pulposus (NP) cells is a key factor in the pathogenesis of intervertebral disc degeneration (IDD). Stathmin 1 (STMN1) has been proposed as a telomere-associated senescence marker implicated in senescence in many age-related diseases. Nevertheless, its role in NP cell senescence remains unclear. This study revealed that STMN1 was significantly upregulated in human degenerative and naturally aged rat NP tissue specimens. In vitro models demonstrated that STMN1 expression levels were elevated in replicative and TNF-α-induced NP senescence models. Lentiviral knockdown of STMN1 inhibited NP cell senescence, while overexpression promoted NP cell senescence, along with extracellular matrix (ECM) degradation. An in-depth mechanism indicated that insulin-like growth factor-binding protein 5 (IGFBP5), a downstream pro-senescence gene of STMN1, can induce NP cellular senescence and ECM degradation following its upregulation by STMN1. Furthermore, STMN1 knockdown reduced IGFBP5 expression and mitigated IDD development in a rat model of caudal discs puncture-induced IDD. Combined with the abovementioned results, we demonstrated for the first time that the STMN1-IGFBP5 axis can induce NP cell senescence and ECM degradation, thereby accelerating IDD development. This provides a robust foundation for the development of molecular-targeted therapies for IDD.

Liver aging is characterized by chronic inflammation and metabolic dysfunction that contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Necroptosis, a form of inflammatory cell death, is activated in aging livers, and genetic (Ripk3-/- or Mlkl-/- mice) or pharmacological (RIPK1 inhibitor necrostatin-1s) inhibition of necroptosis attenuates liver inflammation and pathology. However, the cell type-specific role of necroptosis in liver aging remains unclear. Given that MLKL is expressed in hepatocytes, and its expression increases with age, we generated hepatocyte-specific MLKL-overexpressing mice (MLKLHepOE) to determine its role in liver aging. Unexpectedly, MLKL overexpression in hepatocytes did not induce necroptosis, but instead upregulated markers of cellular senescence (cell cycle arrest genes and SASP factors), increased macrophage infiltration, and elevated M1 macrophage marker expression. Electron microscopy and mitochondrial analyses revealed abnormal mitochondrial morphology, elevated oxidative stress, and disrupted mitochondrial dynamics, while lipidomics demonstrated alterations in hepatic lipid metabolites. In agreement with our observations in MLKLHepOE mice, MLKL overexpression in AML12 hepatocytes impaired mitochondrial respiration, increased proinflammatory extracellular vesicle (EV) release, and induced senescence markers, without triggering cell death. Together, these findings reveal a non-lethal, non-necroptotic role for MLKL in promoting hepatocyte senescence and metabolic dysfunction via mitochondrial impairment and EV-mediated inflammation. Our study highlights MLKL as a novel driver of liver inflammaging and a potential therapeutic target for age-related liver disease.

Understanding the biological mechanisms underlying extreme lifespan variation within species remains a fundamental challenge in aging research. Here, we investigated the role of gut microbiota and age in honey bee (Apis mellifera) queens combining 16S rRNA gene sequencing and transcriptomics. Analysis of 40 queen hindguts revealed that Commensalibacter melissae (Alpha 2.1) relative abundance was significantly higher in young queens compared to old queens. Using queens with the highest and lowest C. melissae relative abundance, RNA sequencing identified 1451 differentially expressed genes associated with C. melissae abundance, twice the number associated with age alone (719 genes). Queens with high C. melissae abundance showed distinct transcriptional profiles related to stress response, protein homeostasis, and longevity-regulating pathways, particularly genes involved in oxidative stress response and cellular maintenance. Our analysis revealed complex relationships between age, C. melissae abundance, and gene expression patterns, suggesting that multiple interacting factors contribute to queen quality. These findings contribute to our understanding of host-microbe interactions in honey bee queens and highlight the intricate relationship between gut microbiota composition and host physiology in honey bees.

Primary sarcopenia, an age-related syndrome, is a serious threat to the health and longevity of the elderly. Our prior studies indicated that thyroid hormone (TH) activity within muscle tissue undergoes significant age-associated alterations, mainly evidenced by a reduction in thyroid hormone receptor α (TRα) expression over time. TRα regulates the transcription of downstream target genes to exert its biological effects. Although TH is essential for skeletal muscle growth and development, the specific regulatory mechanism and broader role of TH binding its receptors in skeletal muscle aging remain unclear. We used ChIP-seq and RNA-seq to explore the aging changes of TRα target genes in gastrocnemius muscle of natural aging mouse model. ChIP-seq analysis revealed that TRα target genes are involved in nutrient synthesis, energy production, hormone secretion, and ECM-related pathways, suggesting a potential role of TRα in muscle growth, metabolism and component regulation. Further integration of RNA-seq showed that a greater number of down-regulated TRα target genes are associated with skeletal muscle aging. Through GSEA analysis and RT-qPCR screening, Col6a1 was identified as a key target gene. Col6a1 encodes collagen VI which is an important component of the ECM, ECM disorders and abnormal expression of Col6a1 can affect cell proliferation and differentiation. We confirmed that knockdown of Col6a1 inhibited the proliferation and differentiation of C2C12 cells. ChIP-qPCR and TRα silencing in C2C12 cells showed that TRα positively regulates Col6a1 transcription, and TRα deficiency inhibits the proliferation and differentiation of myoblasts, which is probably associated with Col6a1. These findings provide new insights into the molecular mechanisms underlying skeletal muscle aging and the regulatory roles of TH-TRα interactions.

The incidence of age-associated ailments has increased proportionately with the expansion of the aging demographic. This study aimed to evaluate the anti-aging potential of synbiotic pineapple beverage formulated with 100% pineapple juice, 1% inulin, and Lacticaseibacillus rhamnosus ATCC 53103 (10 log CFU) in Caenorhabditis elegans and D-galactose age-induced mice. The synbiotic juice-treated nematodes exhibited a 24.52% increase in their lifespan, accompanied by lower levels of reactive oxygen species and improved structural functions. In vivo studies demonstrated that synbiotic treatment positively influences age-induced mice's cerebellar function and spatial memory. Additionally, the synbiotic beverage containing 8-10 log CFU of Lacticaseibacillus rhamnosus showed a protective effect against hippocampal neuron damage. The control group displayed a higher Firmicutes/Bacteroides (F/B) ratio, whereas the significantly lower F/B ratio in the diseased groups indicated a reversal of microbial imbalance caused by D-galactose exposure. Furthermore, the consumption of synbiotic beverage mitigated telomere shortening in aged mice. The results highlight the anti-aging effects of a pineapple beverage formulated with Lacticaseibacillus rhamnosus and inulin as a synbiotic intervention. This study suggests that dietary interventions incorporating prebiotics and probiotics may serve as promising strategy for combating age-related disorders and promoting healthy aging.

Targeting senescent cells for cancer treatment is an important recent direction. In this work, we designed and synthesized a galactoside-functionalized pyridone endoperoxide. The endoperoxide in this form, releases singlet oxygen at a relatively slow rate, but when transformed by β-galactosidase activity, the pyridone endoperoxide releases singlet oxygen with a half-life of 30 minutes at 37 °C. We also studied this compound with a variety of cell lines with differential β-galactosidase expression levels. Cytotoxicity of the target compound is enhanced in high galactosidase-expressing SKOV-3 cells. In vivo tests with tumor models also showed significant suppression of tumor progression. Targeting singlet oxygen to senescent cells appears to be promising new approach for treating diseases concurrent with aging, including cancer.

The link between p53 tumor suppressive functions and organismal lifespan is multifaceted. Its DNA-repair mechanism is longevity-enhancing while its role in cellular senescence pathways induces pro-aging phenotypes. To understand how p53 may regulate organismal lifespan, cross-species genotype-phenotype (GP) studies of the p53 DNA-binding domain (DBD) have been used to assess the correlation of amino acid changes to lifespan. Amino acid changes in non-DNA-binding regions such as the transactivation (TAD), proline-rich (PRD), regulatory (REG), and tetramerization (TET) are largely unexplored. In addition, existing GP correlation tools such as SigniSite do not account for phylogenetic relationships between aligned sequences in correlating genotypic differences to phenotypes such as lifespan. To identify phylogenetically significant, longevity-correlated residues in full-length p53 alignments, we developed a Python- and R-based workflow, Relative Evolutionary Scoring (RES). While RES-predicted longevity-associated residues (RPLARs) are concentrated primarily in the DBD, the PRD, TET, and REG domains also house RPLARs. While yeast functional assay enrichment reveals that RPLARs may be dispensable for p53-mediated transactivation, PEPPI and Rosetta-based protein-protein interaction prediction suggests a role for RPLARs in p53 stability and interaction interfaces of tumor suppressive protein-protein complexes. With experimental validation of the RPLARs' roles in p53 stability, transactivity, and involvement in senescence-regulatory pathways, we can gain crucial insights into mechanisms underlying dysregulated tumor suppression and accelerated aging.

Decades ago, evidence of age-related reactivation of a single gene on the female inactive X chromosome was observed in mice. While stable silencing of the Barr body is crucial for balancing gene dosage between sexes, it remains unclear whether silencing is maintained during aging. Here we used allele-specific multi-omics approaches to capture a comprehensive catalog of genes escaping X chromosome inactivation throughout mouse development and aging. We found substantially elevated escape rates during aging across organs, occurring in multiple distinct cell types and concentrated at distal chromosome regions. Consistently, chromatin accessibility was increased across multiple megabases at chromosome ends, affecting regulatory elements of escapees. As several age-specific escapees are linked to human diseases, their elevated expression in females might contribute to sex-biased disease progression observed during aging.

Aging is typically associated with decreased musculoskeletal function, leading to reduced mobility and increased frailty. As a hallmark of aging, cellular senescence plays a crucial role in various age-related musculoskeletal diseases, including osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. The detrimental effects of senescence are primarily due to impaired regenerative capacity of stem cells and the pro-inflammatory environment created by accumulated senescent cells. The secreted senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, further amplifying senescent signals. Although the removal of senescent cells and the suppression of SASP factors have shown promise in alleviating disease progression and restoring musculoskeletal health in mouse models, clinical trials have yet to demonstrate significant efficacy. This review summarizes the mechanisms of cellular senescence in age-related musculoskeletal diseases and discusses potential therapeutic strategies targeting cellular senescence.

Objective The accumulation of DNA damage and mutations is a key contributor to aging. Recent studies have shown that disrupting the Beclin 1-BCL2 autophagy regulatory complex through gene editing can extend lifespan in mice. The precise application of gene editing technologies offers a promising strategy for aging. This study conducted a bibliometric analysis to map the knowledge landscape of gene editing and aging. Methods We retrieved publications related to genome editing and aging from the Web of Science Core Collection, covering the period from 2015 to 2024. The data were analyzed using VOSviewer and R package Bibliometrix. These tools enabled us to identify the most productive researchers, journals, institutions, countries and visualized current trends, emerging research hotspots. Results A total of 982 publications on genome editing and aging were identified. The United States (n=285) and China (n=214) form a dual-core structure leading global output. Harvard University (n=116) emerged as the most prolific institution. Scientific Reports was the top-publishing journal, with 23 articles in 2024. ZHANG Y (n=12, citations=102, H-index=6) was identified as the most productive author. KIM Es 2017 publication in Nature Communications (TC=494, TC/year=54.9, NTC=9.33) has had a significant and ongoing impact. The analysis indicates that future directions will include CRISPR optimization and AI-assisted genomic analysis. Conclusion This study presents the first comprehensive bibliometric analysis and visualization of the knowledge structure in gene editing and aging research up to 2024. It offers researchers a detailed overview of current developments, trends, and emerging frontiers in this rapidly evolving domain.

Aging affects the reparative potency of mesenchymal stem/stromal cells (MSCs) by diminishing their proliferation and differentiation capability; making them unsuitable for regenerative purposes. Earlier we showed that MSCs acquire the expression of CD45 as a consequence of aging, and this increased expression is associated with downregulated expression of osteogenic markers and upregulated expression of adipogenic and osteoclastogenic markers. However, whether CD45 is actively involved in the aging-mediated deregulated differentiation in the MSCs was not elucidated.

Increasing age is a risk factor of gastroesophageal reflux disease. This study aims to uncover the shared genetic architecture of gastroesophageal reflux disease (GERD) and age-related phenotypes. Based on publicly available GWAS statistics, this genome-wide pleiotropic association research was performed with multiple genetic approaches sequentially to explore the pleiotropic associations from single-nucleotide polymorphism (SNP) and gene levels, to reveal the underlying shared genetic etiology between GERD and age-related phenotypes. This study featured shared genetic mechanisms between GERD and age-related phenotypes, including frailty index (FI), telomere length (TL), longevity, and parental lifespan (PL). Strong genetic association were observed. A set of pleiotropic loci and genes were identified by PLACO, FUMA, Bayesian colocalization and additional MAGMA analysis. Our research provided strong evidence of genetic correlation between GERD and several age-related phenotypes, especially frailty index (FI) and telomere length (TL), brought novel insight into the shared genetic architecture between GERD and aging.

Cells experience oxidative stress and widespread cellular damage during stress-induced premature senescence (SIPS). Senescent cells show an increase in lysosomal content, which may contribute to mitigating cellular damage by promoting autophagy. This study investigates the dynamics of lysosomal quality control in human dermal fibroblasts (HDF), specifically examining lysosomal signaling pathways during oxidative stress-induced SIPS. Our results reveal distinct signaling responses between the initial stress phase and the ensuing senescent phenotype. During the stress phase, treatment with tBHP, which undermines the antioxidant response, leads to elevated reactive oxygen species (ROS) and lysosomal damage. ROS accumulation activates AMP-activated protein kinase (AMPK) and inhibits Akt, which correlates with the suppression of mammalian target of rapamycin (mTOR). Inactivation of mTOR during this phase aligns with the activation of transcription factor EB (TFEB), a key regulator of autophagy and lysosomal biogenesis. TFEB knockdown under stress increased apoptosis, highlighting the protective role of TFEB in the stress response. As cells transition to senescence, TFEB activity, required for the autophagic damage repair, becomes less critical. The decrease in ROS levels leads to the normalization of AMPK and Akt signaling, accompanied by the reactivation of mTOR. This reactivation of mTOR, which is critical for establishing the senescent state, is observed alongside the inactivation of TFEB. Consequently, as damage decreases, TFEB activity decreases. Our results suggest a dynamic interplay between TFEB and mTOR, highlighting a critical role of TFEB in ensuring cellular survival during SIPS induction but becoming dispensable once senescence is established.

The differentiation of human pluripotent stem cells (hPSCs) provides access to a wide range of cell types and tissues. However, hPSC-derived lineages typically represent a fetal stage of development, and methods to expedite the transition to an aged identity to improve modeling of late-onset disease are limited. In this study, we introduce RNAge, a transcriptome-based computational platform designed to enable the evaluation of an induced aging or a rejuvenated state. We validated this approach across independent datasets spanning different tissues and species, and show that it can be used to evaluate the effectiveness of existing age-retaining or age-modulating interventions. We also used RNAge to perform an in silico compound screen using the LINCS L1000 dataset. This approach led to the identification and experimental confirmation of several novel compounds capable of inducing aging or rejuvenation in primary fibroblasts or hPSC-derived neurons. Additionally, we observed that applying this novel induced aging strategy to an hPSC model of Alzheimer's disease (AD) accelerated neurodegeneration in a genotype-specific manner. Our study offers a robust method for quantifying age-related manipulations and unveils compounds that significantly broaden the toolkit for age-modifying strategies in hPSC-derived lineages.

Sarcopenia, characterized by a progressive loss of skeletal muscle mass and function, is associated with the accumulation of senescent muscle stem cells, which impair muscle regeneration and contributes to the decline in muscle health. Cdkn1a, which encodes p21, is a well-known marker of cellular senescence. However, it remains unclear whether p21 inhibition eliminates senescent myoblasts and restores the differentiation capacity.

Enormous resources have been devoted to address the suboptimal response of tumor patients to immunotherapy. However, a crucial yet often overlooked factor in these effects is the strong correlation between the occurrence and development of tumors and the immune dysfunction associated with aging. Our study aims to rejuvenate aging T cells within tumor-draining lymph nodes (TdLNs) by using targeted delivery of rapamycin, a macrolide capable of mitigating aging-related decline in immune function, thereby enhancing the antitumor efficacy of immunotherapy in aged mice. The targeted delivery system relies on a bioorthogonal reaction that harnesses the click chemistry between the azide (N

Darwinian selection, operating within the cellular ecosystem of multicellular organisms, drives a pervasive surveillance mechanism of cell-cell competition that shapes tissue architecture and function. While cell competition eliminates suboptimal cells to ensure tissue integrity across various tissues, neuronal competition specifically sculpts neural networks to establish precise circuits for sensory, motor and cognitive functions. However, our understanding of cell competition across diverse neural cell types in both developmental and pathological contexts remains limited. Here, we review recent advances on the phenomenon, and mechanisms and potential functions of neural cell competition (NCC), ranging from neural progenitors, neurons, astrocytes and oligodendrocytes to microglia. Physiological NCC governs cellular survival, proliferation, arborization, organization, function and territorial colonization, whereas dysregulated NCC may cause neurodevelopmental disorders, accelerate aging, exacerbate neurodegenerative diseases and drive brain tumor progression. Future work that leverages cell competition mechanisms may help to improve cognition and curb diseases.

Elucidating the regulatory mechanisms of human cardiac aging remains a great challenge. Here, using human heart tissues from 74 individuals ranging from young (≤35 years) to old (≥65 years), we provide an overview of the histological, cellular and molecular alterations underpinning the aging of human hearts. We decoded aging-related gene expression changes at single-cell resolution and identified increased inflammation as the key event, driven by upregulation of ARID5A, an RNA-binding protein. ARID5A epi-transcriptionally regulated Mitochondrial Antiviral Signaling Protein (MAVS) mRNA stability, leading to NF-κB and TBK1 activation, amplifying aging and inflammation phenotypes. The application of gene therapy using lentiviral vectors encoding shRNA targeting ARID5A into the myocardium not only mitigated the inflammatory and aging phenotypes but also bolstered cardiac function in aged mice. Altogether, our study provides a valuable resource and advances our understanding of cardiac aging mechanisms by deciphering the ARID5A-MAVS axis in post-transcriptional regulation.

Although DNA methylation age estimators (DNAmAges) are reliable tools for predicting aging, their effectiveness in predicting mortality risk has not been fully validated. This study compared the predictive utility of five different DNAmAges (HorvathAge, HannumAge, PhenoAgeAge, GrimAge and GrimAge2) for all-cause and cause-specific mortality among adults aged ≥ 50 years.

Aging-related cognitive decline is closely linked to the reduced function of neural progenitor/stem cells (NPSCs), which can be influenced by the neural microenvironment, particularly astrocytes. The aim of this study was to explore how astrocytes affect NPSCs and cognitive function during aging.

Longevity is influenced by various factors, including fatty acid composition and free radical stress, which relate to the membrane pacemaker and rate of living hypotheses. While these aspects are well-documented in some long-lived species, they remain largely unexplored in tree squirrels. This study aimed to compare oxidative stress, antioxidant activity, nitrosative stress, and lipid composition between the long-lived Persian squirrel (Sciurus anomalus) and the short-lived Wistar rat across age cohorts (younger and older). Tissue homogenates from skin, liver, skeletal muscle, spleen, lung, and kidney were analysed for lipid composition (monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), arachidonic to linoleic acid ratio, peroxidation index, and unsaturation index. Oxidative, nitrosative, and antioxidant markers were assessed, including NADPH oxidase, superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase (GST), nitric oxide synthase, superoxide, hydrogen peroxide, nitric oxide, malondialdehyde, 4-hydroxynonenal, and total antioxidant capacity (TAC). Squirrels demonstrated higher GST activity, lower free radical stress, lower PUFA, and higher MUFA compared to rats. Antioxidant activities, except for TAC were negatively correlated with longevity. Older squirrels exhibited similar oxidative, nitrosative, and antioxidant profiles to younger squirrels, whereas younger rats displayed highly susceptible fatty acids, similar to older rats. The Persian squirrel's longevity appears closely linked to fatty acid composition and free radical resistance, likely due to increased GST activity. We propose GST's multifunctional role in reducing inflammation, enhancing immune response, providing disease resistance, and antioxidant activity contributes significantly to the longevity of the Persian squirrel.

The dynamics of lifespan are shaped by DNA variants that exert effects at different ages. We have mapped genetic loci that modulate age-specific mortality using a new actuarial method. We started with 6,438 pubescent mice and ended with a survivorship of 559 mice that lived to at least 1100 days of age. Twenty-nine Vita loci dynamically modulate lifespan and have strong age-delimited effects after correction for multiple tests. Fourteen loci have relatively steady but genotype-dependent effects on mortality from pubescence to old age and are candidate aging rate modulators. Other loci act most forcefully over shorter periods of life, and the polarities of their genetic effects often invert with age and differ by sex. We detect 41 epistatic interactions among these Vita loci, all exclusive to males or females, and with strong signatures of sexual reciprocity. A distinct set of 19 Soma loci shape the negative correlation between larger body size in young adults with their subsequent life expectancies. These loci are direct evidence that antagonistic pleiotropy modulates mortality early in life. Another set of 11 Soma loci shape the positive correlation between heavier body weight at older ages and longer life expectancies. We provide exemplars of how to move from maps to mechanisms for two tractable loci. Our findings provide a solid empirical bridge between evolutionary theories on aging and their molecular causes. The 59 loci are keys to understand the impact of interventions on healthy lifespan in mice and humans.

Human life expectancy has increased dramatically over the past two centuries, marking a significant public health achievement. While some projections predict a future where median lifespans reach 100 years, others contend that further longevity will depend on breakthroughs targeting the biological processes of aging. Recent studies in mice have demonstrated that telomerase activation, achieved via gene therapy and transgenic approaches, can extend both median and maximum lifespans substantially without an accompanying increase in cancer risk. We analysed survival data from three such studies using the Gompertz mortality model and show that these interventions reduce the slope parameter, indicative of a slower aging rate, rather than merely lowering baseline mortality. This observation challenges traditional models that assume independent, additive damage accumulation, suggesting instead that aging is driven by a limited number of interdependent processes with significant cross-talk. Mathematical modelling indicates that only three to five processes with substantial cross-talk may account for the observed deceleration. Extrapolation using Swedish survivorship data further implies that a reduction in the aging rate, similar to that seen in mice, could elevate the median human lifespan from 85 to over 100 years. These findings provide a compelling framework for developing targeted anti-aging interventions and a new perspective on the modifiability of the aging process.

The role of dietary patterns in overall health and longevity among the elderly has not been comprehensively evaluated. We investigated the associations between multiple dietary indices and successful aging, longevity, and extreme longevity among older individuals, aiming to explore appropriate dietary patterns for the older Chinese population.

DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6C

The cardiac atrial extracellular matrix (ECM) is central to age-associated cardiac remodeling and subsequent decline in cardiac functioning. Despite this, the composition of the atrial ECM and how it changes with age is not yet known. This study utilized mass spectrometry to evaluate the composition of murine atria in young (12 weeks) and old (77 weeks) C57BL/6J mice. The tissue was decellularized, ECM and ECM-associated proteins were extracted with GuHCl, and proteins were deglycosylated to enable identification of glycosylated peptides. Two hundred and thirty-seven ECM and ECM-associated proteins were found to be significantly differentially expressed with age. Some proteins (MMP9, S100A9, VWA3A, CTSD, CCL8) were more than threefold increased with age, proteoglycans were modestly decreased, while the overall collagen content was markedly decreased. STRING network mapping of physical associations predicted that both PLOD3 and PDGFA interact with the collagens that decreased with age. The results suggest that the mechanism behind age-associated atrial stiffness is not due to an increase in collagen content as previously believed, but an increase in cross-linking, potentially facilitated by PLOD3. Additionally, several of the significant proteins have not previously been associated with cardiac aging and thus are potential drug targets for age-associated cardiac fibrosis and other age-associated conditions.

The decrease of tissue resiliency with aging is due, in part, to changes in the retention of stem cell/progenitor populations that act to restore and maintain tissue quality with age or injury. In mice, the Celsr1 gene has been identified as a regulator of quiescent stem cells, while in zebrafish, celsr1a mutants demonstrate an essential function in maintaining adult stem cell populations within the highly proliferative tissues of the gut and skin. Here, we investigate the role of celsr1a as a regulator of adult skeletal stem cells and mediator of skeletal homeostasis and repair. We find that celsr1a is essential for maintenance of bone mineral density and volume in adult zebrafish. Using an enhancer screen to identify tissue/cell-specific regulators of celsr1a, we identified enhancers active in specific tissues that reflect the normal expression of celsr1a. We characterized C1a-A an enhancer that is active within stem/progenitor cells of diverse tissues. Consistent with this role, C1a-A marks specific cells in mature skeletal structures of the zebrafish, residing on the endosteal surface of zebrafish vertebrae and fin long-bones. These cells are limited in number and contribute to osteocyte populations within the bony matrix. Using a novel long bone fracture assay in adult zebrafish, we find that celsr1a positive skeletal cells respond to damage and that celsr1a function is essential for fracture healing. Our investigation details an unexpected role of cels1a in skeletal repair and quality with age and highlights a new regulator of stem cell activity in the skeleton.

Aging is marked by the accumulation of senescent cells (SnCs), which contribute to tissue dysfunction and age-related diseases. Senotherapeutics, including senolytics which specifically induce lysis of SnCs and senomorphics, which suppress the senescence phenotype, represent promising therapeutic interventions for mitigating age-related pathologies and extending healthspan. Using a phenotypic-based senescent cell screening assay, we identified fucoidans, a class of sulfated polysaccharides derived from brown algae and seaweed, as novel senotherapeutics. In particular, fucoidan from Fucus vesiculosus (Fucoidan-FV) displayed potent senomorphic activity in different types of SnCs, reduced senescence in multiple tissues in aged mice, and extended healthspan in a mouse model of accelerated aging. Fucoidan-FV also enhanced the deacetylation and mono-ADP-ribosylation (mADPr) activity of SIRT6 and improved DNA repair and reduced senescence, in part, through SIRT6-dependent pathways. In addition, Fucoidan-FV downregulated genes associated with inflammation, Wnt signaling, and ECM remodeling pathways in SnCs and increased expression of genes involved with DNA repair. These findings support the translational potential of fucoidans as novel senotherapeutics that also are able to improve SIRT6-mediated DNA repair.

Heat shock factor 1 (HSF1) masters cellular proteostasis under stress by upregulating the expression of molecular chaperones that help refold or degrade the misfolded proteins. HSF1 activation involves a monomer-to-oligomer transition and binding to its recognition sequence, the heat shock elements (HSEs) on its target gene promoters. HSF1 activity declines with age as well as in neurodegenerative disorders (NDs) such as Parkinson disease, highlighting the need for strategies to restore its function. Azadiradione (AZD), a limonoid isolated from Azadirachta indica seeds, directly activates HSF1 in cellular and preclinical ND models, unlike other small-molecule activators reported elsewhere. We investigated the molecular basis of AZD-mediated HSF1 activation using purified variants of this protein including those without its oligomerization and transactivation domain. Fluorescence polarization and dynamic light scattering assays revealed that AZD promotes the oligomerization of monomeric HSF1 to enhance its HSE-binding affinity by engaging with its DNA-binding domain (DBD). The oligomerization domain known to be required for stress-induced activation, appears redundant in AZD-mediated activation. Furthermore, evidence suggests AZD-induced conformational alterations in the HSE facilitate its binding to the HSF1 monomer. Notably, AZD reduces the DNA-binding ability of pre-assembled oligomeric HSF1 by triggering its amyloid-like aggregation. This finding also highlighted a potential anticancer effect of AZD, as cancer cells heavily depend on this HSF1 population for rapid proliferation and survival. Overall, these findings offer novel insights into the functional regulation of HSF1 and suggest a framework for developing small-molecule HSF1 activators with therapeutic potential for protein conformation disorders.

Using the dual-pathway framework (Beach et al., a), we tested a Neuro-immune Network (NIN) hypothesis: i.e., that chronically elevated inflammatory processes may have delayed (i.e., incubation) effects on young adult substance use, leading to negative health outcomes. In a sample of 449 participants in the Family and Community Health Study who were followed from age 10 to age 29, we examined a non-self-report index of young adult elevated alcohol consumption (EAC). By controlling self-reported substance use at the transition to adulthood, we were able to isolate a significant delayed (incubation) effect from childhood exposure to danger to EAC (β = -.157, p = .006), which contributed to significantly worse aging outomes. Indirect effects from danger to aging outcomes via EAC were: GrimAge (IE = .010, [.002, .024]), Cardiac Risk (IE = -.004, [-.011, -.001]), DunedinPACE (IE = .002, [.000, .008]). In exploratory analyses we examined potential sex differences in effects, showing slightly stronger incubation effects for men and slightly stronger effects of EAC on aging outcomes for women. Results support the NIN hypothesis that incubation of immune pathway effects contributes to elevated alcohol consumption in young adulthood, resulting in accelerated aging and elevated cardiac risk outcomes via health behavior.

Balanced mTOR activity and iron levels are crucial for muscle integrity, with evidence suggesting mTOR regulates cellular iron homeostasis. In this study, we investigated iron metabolism in muscle-specific mTOR knockout mice (mTORmKO) and its relation to their myopathy. The mTORmKO mice exhibited distinct iron content patterns across muscle types and ages. Slow-twitch soleus muscles initially showed reduced iron levels in young mice, which increased with the dystrophy progression but remained within control ranges. In contrast, the less affected fast-twitch muscles maintained near-normal iron levels from a young age. Interestingly, both mTORmKO muscle types exhibited iron metabolism markers indicative of iron excess, including decreased transferrin receptor 1 (TFR1) and increased levels of ferritin (FTL) and ferroportin (FPN) proteins. Paradoxically, these changes were accompanied by downregulated Ftl and Fpn mRNA levels, indicating post-transcriptional regulation. This discordant regulation resulted from disruption of key iron metabolism pathways, including NRF2/NFE2L2, HIFs, and AKT/PKB signaling. Mechanistically, mTOR deficiency impaired transcriptional regulation of iron-related genes mediated by NRF2 and HIFs. Furthermore, it triggered ferritin accumulation through two NRF2 mechanisms: (1) derepression of ferritin translation via suppression of the FBXL5-IRP axis, and (2) autophagosomal sequestration driven by NCOA4-dependent ferritin targeting to autophagosomes, coupled with age-related impairments of autophagy linked to chronic AKT/PKB activation. Three-week spermidine supplementation in older mTORmKO mice was associated with normalized AKT/PKB-FOXO signaling, increased endolysosomal FTL and reduced total FTL levels in the dystrophic soleus muscle. These findings underscore mTOR's crucial role in skeletal muscle iron metabolism and suggest spermidine as a potential strategy to address impaired ferritinophagy due to autophagy blockade in dystrophic muscle.

The aging microenvironment promotes persistent inflammation and loss of intrinsic regenerative capacity. These are major obstacles to effective bone tissue repair in older adults. This study aims to explore how physical thermal stimulation can effectively delay the bone marrow mesenchymal stem cells (BMSCs) aging process. Based on this, an implantable physical signal-converter platform is designed as a therapeutic system that enables stable heat signals at the bone injury site under ultrasound stimulation (US). It is found that the therapeutic platform controllably reduces the mitochondrial outer membrane permeabilization of aging BMSCs, bidirectionally inhibiting mitochondrial reactive oxygen species and mitochondrial DNA (mtDNA) leakage. The leakage ratio of mtDNA decreases by 22.7%. This effectively mitigates the activation of the cGAS-STING pathway and its downstream NF-κB signaling induced by oxidative stress in aging BMSCs, thereby attenuating the pathological advancement of chronic inflammation. Thus, it effectively restores the metabolism and osteogenic differentiation of aging BMSCs in vitro, which is further confirmed in a rat model. In the GMPG/US group, the bone mineral density increases 2-3 times at 4 weeks in the rats femoral defect model. Therefore, this ultrasound-based signal-conversion platform provides a promising strategy for aging bone defect repair.

BackgroundThe increasing prevalence of depression and functional disability in older adults highlights the need for targeted interventions, with sleep as a potentially modifiable factor, yet the longitudinal effects and mediating role of sleep remain poorly understood. MethodsThis review and conceptual framework aimed to examine the pairwise bidirectional associations between sleep, depression, and functional disability and identify the longitudinal mediating role of sleep in the bidirectional relationship between depression and functional disability in older adults. The academic databases PsycArticles, PubMed, MEDLINE, Science Citation Index, Social Sciences Citation Index, ProQuest Dissertations and Theses Global, Cochrane, and Scopus were searched for research published in English between January 2000 and June 2024. Systematic review and cohort study designs were eligible. All included studies were assessed for quality using the Critical Appraisal Skill Programme checklist (CASP 2024). Results397,289 citations were identified, and 82 studies meeting the inclusion criteria were included. Cohort studies and reviews provide evidence that there is a dynamic reciprocal correlation between sleep, depression, and functional disability in the older population. We propose that sleep may increase the risk of depression and functional disability in the follow-up years, with sleep acting as a potential mediating factor between depression and functional disability. There was a selection bias in the study samples, as most studies focused on specific populations or regions. Moreover, some of the cohort studies included lacked sufficient follow-up time to observe long-term effects. ConclusionsThis review and conceptual framework highlight that sleep health can provide crucial insights for mitigating the adverse effects experienced by older adults due to depression and functional disability. For healthcare professionals and policymakers, it provides evidence about prioritizing sleep health as an accessible step to foster a healthy lifestyle. PROSPERO registration number CRD42024556536. What is already known on this topicWith the increasing aging population, improving the physical and mental health of older adults has become a key social issue. Substantial epidemiological studies have confirmed the existence of bidirectional relationships between depression, sleep disorders, and functional disability in older adults, with all three variables influencing each other. However, the complex interaction mechanisms among these three variables remain unclear, and further research is needed to explore whether sleep plays a longitudinal mediating role between depression and functional disability. What this study addsThis study significantly enhances our understanding by providing robust evidence of the dynamic, bidirectional relationships among sleep, depression, and functional disability in older adults. Unlike previous research that primarily examined pairwise relationships, our study delves deeper by proposing a comprehensive conceptual framework. This framework underscores the potential mediating role of sleep, suggesting that sleep disturbances are not merely consequences of depression and functional disability but also active contributors to their interaction and progression. By elucidating these underlying mechanisms and potential pathways, our study sheds light on the complex interplay among these three variables, ultimately enhancing the quality of life for older adults. How this study might affect research, practice or policyThis study paves the way for deeper investigation into the causal mechanisms connecting sleep, depression, and functional disability. It highlights the critical importance of prioritizing resources for sleep-related research and interventions, recognizing their significant potential to enhance the well-being of an aging population. This holistic approach aims to foster a more comprehensive understanding and effective strategies for promoting healthy aging.