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.

Non-linear dynamical methods such as Higuchi's fractal dimension (HFD) are often used to study the complexities of brain activity. In human electroencephalogram (EEG), while power in the gamma band (30-70 Hz) and the slope of the power spectral density (PSD) have been shown to reduce with healthy aging, there are conflicting findings regarding how HFD and other measures of complexity vary with aging. Further, the dependence of HFD on features obtained from PSD (such as gamma power and slope) has not been thoroughly probed. To address these issues, we computed time and frequency resolved HFD for EEG data collected from elderly population (N=217), aged between 50-88 years, for baseline (BL) eyes open state and during a fixation task in which visual grating stimuli that induce strong gamma oscillations were presented. During BL, HFD increased with age for frequencies up to 150 Hz, but surprisingly showed an opposite trend at higher frequencies. Interestingly, this change in HFD was opposite to the age-related change in PSD 1/f slope. Further, stimulus-related changes in HFD were anti-correlated with the changes in oscillatory power. However, age classification using HFD was slightly better than classification using spectral features (power and slope). Further, stimulus and age-related changes in HFD persisted even after normalization with surrogates, showing the effect of non-linear dynamics on HFD. Therefore, HFD could be jointly sensitive to various spectral features as well as some non-linearities not captured using spectral analysis, which could enhance our understanding of brain dynamics underlying healthy aging.

Age-related changes in sleep have been associated with cognitive decline, yet causal pathways have not been identified. Evidence suggests reduced cardiovascular health may be a consequence of poor sleep and a precursor to cognitive decline. This observational cohort study used path analyses to determine whether cardiovascular disease risk mediated or moderated effects of sleep on yearly longitudinal change in cognition, estimated with linear growth models. Total sleep time (TST), sleep efficiency (SE), and relative spectral power of slow wave activity (SWA; 1-4 Hz) and slow oscillations (SO; 0.5-1 Hz), were measured with single-channel home EEG. Cardiovascular disease risk (CVR) was estimated as 10-year Framingham Risk Score 1-year post-sleep. Outcomes were yearly change in executive function (EF), episodic memory (EM), and processing speed (PS) over 2-5 years post-sleep. 342 participants (mean age 73.5 +/- 5.6 years, 51 % female) were included. Shorter TST was linearly associated with increased CVR across all models (βs = -0.18(0.058) - -0.19(0.059), ps< 0.002). TST was indirectly associated with EF and PS decline through CVR, such that associations between short TST and cognitive decline were partially due to higher CVR. All other mediating and moderating effects were nonsignificant after multiple comparisons. Indirect associations between short sleep duration and greater decline in executive function and processing speed were found through higher CVR, suggesting a potential mechanism by which sleep leads to cognitive decline. Findings support the prioritization of adequate sleep duration to preserve both cardiovascular and cognitive health in later life.

Atherosclerosis (AS), a chronic inflammatory disease of the arterial wall, remains a dominant cause of death and disability globally. Quercetin has been evidenced to be effective against AS, but the exact mechanisms are still largely unclear.

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.

In recent years, aging and cellular senescence have triggered an increased interest in corresponding research fields. Evidence shows that the complex aging process is involved in the development of many chronic liver diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In fact, aging has a tremendous effect on the liver, leading to a gradual decline in the metabolism, detoxification and immune functions of the liver, which in turn increases the risk of liver disease. These changes can be based on the aging of liver cells (hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells). Similarly, patients with liver diseases exhibit increases in the aging phenotype and aging cells, often manifesting as faster physical functional decline, which is closely related to the promoting effect of liver disease on aging. This review summarizes the interplay between MASLD/MASH development and aging, aiming to reveal the complex relationships that exacerbate one another. Moreover, the corresponding schemes for delaying aging or treating diseases are discussed to provide a basis for the development of effective prevention and treatment strategies in the future.

The active hormonal form of vitamin D, 1,25(OH)

Although soil quality and gut probiotics have been extensively accepted as critical for human health, the combined effects of soil and fecal bacteria on public health remain underexplored. This study collected soil and human fecal samples from three towns with high, medium, and low proportion of longevous populations in a well-known longevity region in Yangtze River Delta, China. Beneficial elements were detected in all soils, including selenium (0.01-0.05 mg kg

Accumulation of DNA damage is a hallmark of cellular senescence and plays a critical role in brain aging. Although the DNA damage repair mechanisms are crucial in cellular senescence, they are not well understood in microglia. In this study, we found that profilin-1 (PFN1), an actin-binding protein, relocates from the cytoplasm to the nucleus in response to DNA double-strand breaks (DSBs) induced by doxorubicin. This nuclear PFN1 subsequently translocates back to the cytoplasm during the recovery period. In response to DSBs, we detected enhanced expression of genes associated with nonhomologous end joining (NHEJ), but not with homologous recombination (HR), along with increased nuclear F-actin accumulation. However, this repair process is compromised when PFN1 is either knocked down or its nuclear transport is blocked. Notably, in DNA damage-induced senescent microglia, increased nuclear localization of PFN1 and nuclear F-actin formation are associated with phagocytic dysfunction. Both ex vivo aged microglia and publicly available single-cell RNA sequencing data from aged mouse brains recapitulate the in vitro findings described above. Despite cytochalasin D treatment for actin depolymerization, the return of PFN1 to the cytoplasm was not facilitated due to its aggregation. We propose that PFN1 plays an important role in DNA damage repair in microglia. In addition, the dysregulation of the nucleocytoplasmic balance of PFN1 alongside DNA damage accumulation may contribute to the phagocytic impairment of microglia in the aged brain.

Purpose in life is a psychological resource associated with better health outcomes across adulthood. It is unknown whether it is related to lung function, a key marker of health and longevity. We evaluate the replicability and generalizability of the cross-sectional association between purpose in life and lung function and whether purpose in life is associated with lower risk of developing poor lung function over time.

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.

Aging is associated with progressive tissue decline and shifts in stem cell clonality. The role of niche signals in driving these processes remains poorly understood. Using the Drosophila testis, we identify a regulatory axis in which age-related decline of niche signals (BMPs) lead to upregulation of the co-repressor Hairless, which downregulates the RNA-binding protein Imp in aged germline stem cells (GSCs). Reduced Imp causes loss of Chinmo, a key factor in GSC aging and competition. Reduced Chinmo causes ectopic Perlecan secretion which accumulates in the testis lumen and causes GSC loss. Aging of the testis is reversed by increasing BMPs in the niche, or by overexpressing Imp or depleting Hairless in GSCs. Furthermore, GSC clones with reduced Imp or increased Hairless are more competitive, expelling wild-type neighbors and monopolizing the niche. Thus, BMPs regulate testicular niche aging through the Hairless/Imp/Chinmo axis and winning GSCs usurp these aging mechanisms.

Several DNA methylation (DNAm) algorithms have recently emerged as robust predictors of aging and adverse health outcomes in older adults, offering valuable insights into cardiovascular disease (CVD) risk stratification. However, their predictive performance for CVD varies significantly. This study aimed to systematically investigate the associations of 12 widely used DNAm algorithms with CVD and mortality risk.

Age-related decline underlies cognitive functions such as sensorimotor control, executive functioning, memory, and language production (LP), whereas language comprehension (LC) tends to remain intact or improve across healthy adult lifespan. Preservation of LC can have structural and functional origins identifiable from key brain regions of the language network (LAN). To investigate this hypothesis, we analyzed the relationships among resting-state brain functional connectivity (rsFC) derived from functional magnetic resonance imaging (fMRI) signals, structural connectivity (SC) derived from diffusion MRI metrices, and behaviour (LC and LP) using a cross-sectional cohort of healthy adults (N = 652; aged 18-88). Six cognitive tasks assessing LC and LP were employed, with neuroimaging measures focused on region-specific connections within the LAN. Using generalized additive mixed models (GAMMs), complex brain-behaviour interactions were identified. Behavioral analyses revealed established age-related dichotomy, LC abilities in vocabulary and proverb comprehension improved and in syntactic and semantic comprehension remained stable, whereas LP tasks, e.g., verbal fluency, picture priming, and tip of tongue exhibited significant decline across the lifespan. SC exhibited decline in both intra- and inter-hemispheric fronto-temporal and frontal lobe connections, contrasted by preserved or enhanced temporal lobe connectivity, supporting a pattern of frontal vulnerability concomitant with temporal resilience. Age-related FC patterns demonstrated overall preservation, reflecting compensatory mechanisms to sustain functional integrity despite structural degradation. GAMM analyses revealed complex relationships between brain connectivity and language performance across age. Thus, integrating knowledge of brain structure, function, and language abilities, we identified the brain network mechanisms associated with dichotomous language behavior along lifespan.

Olshansky and collaborators have recently proposed that the era of continuous extension of human lifespans has finally come to an end. By analysing thirty years of recent demographic data (1990-2020) from ten populations (the eight longest-lived nations, plus Hong Kong and the USA), they rejected the claims made by Oeppen and Vaupel at the start of the century (and more recently by Vaupel and collaborators) that human longevity was still far from approaching an upper limit. However, on closer examination the results by Olshansky and colleagues seem to complement rather than directly challenge the radical life extension hypothesis. The reason is that the latter was based not on country-level demographic patterns but instead on a best-practice life expectancy trend resulting from the succession of annual world-leading populations. Here we present an update based on data from the last two decades that confirms Oeppen and Vaupels original insights and demonstrates that both female and male lifespans continue to linearly increase at a global scale. This remarkably long trend observed since 1840 remains at odds with our expectation that human lifespans must at some point hit a biologically imposed ceiling.

JOURNAL/nrgr/04.03/01300535-202606000-00067/figure1/v/2026-02-11T151048Z/r/image-tiff Cmyc , a proto-oncogene, is expressed at extremely low levels in mature neurons and is traditionally thought to have no function in these cells. However, recent studies suggest that Cmyc may play a crucial role in maintaining the health and function of mature dopaminergic neurons. This study assessed the role of Cmyc in dopaminergic neurons and its significance in Parkinson's disease. We used a conditional knockout approach to specifically delete Cmyc in substantia nigra dopaminergic neurons of adult mice. Our findings showed that Cmyc deletion led to progressive neuron loss, Parkinson's disease-like symptoms, downregulation of Klotho, and upregulation of senescence-associated inflammatory factors, along with enhanced oxidative stress and nitrated alpha-synuclein accumulation, ultimately causing neuronal death. In vitro experiments confirmed increased senescence in C-MYC knockout cells, which was partially reversible by KLOTHO overexpression. We conclude that low-level Cmyc expression is essential for maintaining the health of mature dopaminergic neurons and preventing neurodegeneration, and suggest the c-Myc/Klotho axis as a potential therapeutic target for age-related neurodegenerative diseases, including Parkinson's disease. Our study introduces a novel mouse model for Parkinson's disease that replicates a condition associated with normal aging, offering a valuable tool for future research into disease mechanisms and therapeutic strategies.

Phase separation, a biophysical process that segregates subcellular environments into condensates, has been recognized for its role in transcriptional regulation. However, the extent of its influence on cellular senescence processes remains to be fully elucidated. We established that MRG15 depletion leads to cellular senescence in human mesenchymal stem cells (hMSCs). MRG15 can form phase-separated liquid condensates via its intrinsically disordered region (IDR). IDR deletion and replacement assays revealed that MRG15 condensation is crucial to hMSC senescence. According to the epigenomic and transcriptomic analysis, MRG15 depletion impacts pathways integral to the cell cycle and the senescence process, as evidenced by the diminished binding and the modified expression of key genes, including p53, CDKN1A, LMNB1, CCNB1, NPM1, MYC, and HMGB2. Our findings establish a link between phase separation and senescence regulation and present a promising new therapeutic target for the alleviation of age-related diseases and the potential extension of lifespan.

JOURNAL/nrgr/04.03/01300535-202606000-00068/figure1/v/2026-02-11T151048Z/r/image-tiff Alzheimer's disease is initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated Alzheimer's disease with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of Alzheimer's disease by using transcriptomic data from congenital diseases known to increase Alzheimer's disease risk, namely Down syndrome, Niemann-Pick type C disease, and mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of Alzheimer's disease pathology, many of which have never been associated with Alzheimer's disease. We then investigated common molecular alterations in brain samples from a Niemann-Pick type C disease mouse model by juxtaposing them with brain samples of both human and mouse models of Alzheimer's disease. Detailed phenotypic, molecular, chronological, and biological aging analyses revealed that the Npc1tm(I1061T)Dso mouse model can serve as a potential short-lived in vivo model for brain aging and Alzheimer's disease research. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on Alzheimer's disease research while highlighting shortcomings and lack of correlation in diverse in vitro models. Considering the lack of an Alzheimer's disease mouse model that recapitulates the physiological hallmarks of brain aging, the short-lived Npc1tm(I1061T)Dso mouse model can further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of Alzheimer's disease from a perspective of accelerated brain aging.

Neurotransmitter release occurs through exocytosis of synaptic vesicles. α-Synuclein's function and dysfunction in Parkinson's disease and other synucleinopathies is thought to be tightly linked to synaptic vesicle binding. Age is the biggest risk factor for synucleinopathy, and ~15% of synaptic vesicle proteins have been linked to central nervous system diseases. Yet, age- and disease-induced changes in synaptic vesicles remain unexplored. Via systematic analysis of synaptic vesicles at the ultrastructural, protein, and lipid levels, we reveal specific changes in synaptic vesicle populations, proteins, and lipids over age in wild-type mice and in α-synuclein knockout mice with and without expression of human α-synuclein. Strikingly, we find several previously undescribed synaptic changes in mice lacking α-synuclein, suggesting that loss of α-synuclein function contributes to synaptic dysfunction. These findings not only provide insights into synaptic vesicle biology and disease mechanisms in synucleinopathy, but also serve as a baseline for further mechanistic exploration of age- and disease-related alterations in synaptic vesicles.

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.

Alhagi camelorum (AC) is an herbal medicine known for its anti-inflammatory and antioxidant properties. However, the mechanism by which AC affects skin aging remains unclear. In this study, a polysaccharide with antioxidant activity was extracted from AC seeds (ACSP). The structure of ACSP was characterized by molecular weight determination, Fourier transform infrared spectroscopy, monosaccharide composition analysis, scanning electron microscopy, and physicochemical analysis. The molecular weight of ACSP was 736,831 Da. ACSP, devoid of a triple-helical conformation, comprised mannose, rhamnose, galacturonic acid, glucose, galactose, and arabinose at a molar ratio of 39.65:0.85:0.59:11.57:40.25:6.60. The anti-skin-aging activity and potential mechanisms of action of ACSP were investigated in vitro. We observed that ACSP delayed the onset of senescence, promoted cell migration, decreased the expression of DNA damage markers and the production of reactive oxygen species, and increased the mitochondrial membrane potential in damaged cells. ACSP also significantly reduced the expression of the inflammatory mediators interleukin (IL)-6, IL-1β, and tumor necrosis factor-α in HaCaT cells. In addition, ACSP attenuated the expression of proteins within the IL-17 signaling pathway and suppressed the phosphorylation of JAK2/STAT3/NF-κB proteins, thereby exerting a senescence-delaying effect on MGO-induced HaCaT cells. In conclusion, we elucidated the potential of ACSP in delaying skin aging and offer a novel plant-derived adjuvant to delay aging.

Organ-specific somatic stem cells play an important role in supporting tissue turnover and facilitating regeneration on injury. Hematopoietic stem cells are one of the most established organ-specific somatic cells that have been frequently used for transplantation therapy. Recently, there has been a growing interest in other organ-specific somatic cells, including vascular endothelial stem cells (VESCs). We have previously reported on the use of CD157 and CD200 as markers to isolate VESCs from adult mouse organs, particularly the liver. In this review, we aimed to summarize, based on our previous research, how CD157⁺CD200⁺ VESCs in the liver develop from the fetal stage to postnatal life, what transcriptional regulatory mechanisms govern them, and how VESCs change with aging.

Physical activity might be able to delay the aging process by reducing levels of advanced glycation end-products (AGEs). However, the influence of physical activity on levels of AGEs remains unclear. We investigated the associations between leisure time physical activity (LTPA) in late midlife and change in LTPA during a 15-year follow up on the levels of AGEs in old age.

Chondrocyte senescence, synovitis, and decreased level of lubrication play pivotal roles in the pathogenesis of age-related osteoarthritis (AROA). However, there are currently no effective therapeutic interventions capable of altering the progression of OA until it reaches advanced stages, necessitating joint replacement. In this study, lubricious and drug-loaded hydrogel microspheres were designed and fabricated by utilizing microfluidic technology for radical polymerization of chondroitin sulfate methacrylate and incorporating nicotinamide adenine dinucleotide (NAD)-loaded liposomes modified with lactoferrin that are positively charged. Mechanical, tribological, and drug release analyses demonstrated enhanced lubrication properties and an extended drug dissemination time for the NAD@NPs@HM microspheres.

To investigate the role of gut microbiota and bile acids metabolism on skeletal muscle strength in low density lipoprotein receptor (LDLR) knockdown aging mice. Forty-eight male C57BL/6J mice were employed in the experiment, twelve adult mice and twelve old mice were separately knocked down skeletal muscle LDLR (ALKd group, OLKd group). Other adult mice and old mice were injected with empty vectors as control (Acon group, Ocon group). After eight weeks of injection, each mouse was tested for skeletal muscle strength. The serum glycolipid biomarkers, the gut microbiota composition, the ileum apical sodium-dependent bile acid transporter (ASBT), farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), and gastrocnemius fibroblast growth factor receptor 4 (FGFR4) were detected. When compared to the Ocon group, increased grip strength, and the relative abundance of Akkermansia and Ileibacterium were found in the OLKd group. The FGF15 protein of the ileum and FGFR4 protein of the gastrocnemius were found to increase in the OLKd group than those of the Ocon group. The gut microbiota and bile acid metabolism both play an important role in the partially improved skeletal muscle strength of LDLR knockdown aging mice.

Bone diseases profoundly affect patients, particularly the elderly, leading to severe health complications and disabilities. Osteoblasts play a crucial role in bone formation and are ideal candidates for treating bone diseases and engineering living materials. However, the stem and progenitor cells that give rise to osteoblasts, as well as osteoblasts themselves, exhibit dysfunction with aging. Although chemical reprogramming of fibroblasts into osteoblasts has been achieved, effective cell-based therapies or living materials have not been established in clinical practice. Here, we present a method to engineer fibroblasts through small molecule reprogramming and spheronization, achieving functional osteoblastic materials across all age groups. By primarily targeting the WNT signaling pathway and modularizing small molecules based on their effects on stage-specific genes, we optimized the temporal regulation of small molecules during reprogramming, acquiring a large number of healthy induced osteoblasts (iOBs). These iOBs with traits of functional native osteoblasts are ideal for forming transplantable tissue spheroids. As innovative living materials, the iOB spheroids (iOB-Sps) have demonstrated improved survival, significant self-bone formation, reduced ROS levels in the defect microenvironment, and accelerated endogenous osteogenesis and angiogenesis in vivo, promoting effective healing of bone defects. These material-free iOB-Sps function as self-scaffolding building blocks for biofunctional constructs, offering a promising avenue for clinical autologous bone defect repair, especially for the elderly.

The China Brain Multi-omics Atlas Project (CBMAP) aims to generate a comprehensive molecular reference map of over 1,000 human brains (Phase I), spanning a broad age range and multiple regions in China, to address the underrepresentation of East Asian populations in brain research. By integrating genome, epigenome, transcriptome, proteome (including multiple post-translational modifications), and metabolome data, CBMAP is set to provide a rich and invaluable resource for investigating the molecular underpinnings of aging-related brain phenotypes and neuropsychiatric disorders. Leveraging high-throughput omics data and advanced technologies, such as spatial transcriptomics, proteomics, and single-nucleus 3D chromatin structure analysis, this atlas will serve as a crucial resource for the brain science community, illuminating disease mechanisms and enhancing the utility of data from genome-wide association studies (GWAS). CBMAP is also poised to accelerate drug discovery and precision medicine for brain disorders.

The aging process profoundly impacts the human brain, leading to notable changes in cognitive abilities. Although the brains structural and functional alterations with age are individually well documented, how differences in cognitive abilities emerge from variations in the underlying spatio-temporal patterns of regional brain activity is largely unknown. Patterns of increased synchronization between brain regions are taken as enhanced cognitive integration, while decreased synchronization is indicative of cognitive segregation. The ability to dynamically switch between different levels of integration and segregation across different cognitive systems is believed to be crucial for overall cognitive performance. Building on a recently proposed cognitively informed, synchronization-based framework, we study here age-related variations in dynamical flexibility between segregation and integration, as captured by changes in the variable patterns of partial synchronization or chimera states. Leveraging personalized brain network models based on large-scale, multisite datasets of cross-sectional healthy cohorts, we systematically show how regional brain stimulation produces distinct patterns of synchronization. We find that chimera states play a crucial role in regulating the balance between cognitive integration and segregation as the brain ages, providing new insights into the mechanisms underlying cognitive decline and preservation in aging. Whereas the emergent synchronization behavior of brain regions belonging to the same cognitive system often show the same aging trends, different cognitive systems can demonstrate distinct trends. This supports the idea that aging affects cognitive systems differently and that understanding this variability is essential for a more comprehensive view of neuro-cognitive aging. At the same time, dynamical flexibility increases in the oldest age groups across most cognitive systems. This may reflect compensatory mechanisms to counteract age-related cognitive declines and points towards a phenomenon of dedifferentiation. Yet, the multiplicity of behaviors highlights that whereas dedifferentiation emerges in certain cognitive systems, differentiation can also occur in others. This illustrates that these processes, though seemingly oppositional, can coexist and unfold in parallel across different cognitive systems.

Recent studies using single-cell RNA sequencing technology have uncovered several subpopulations of CD4

The brain plays a central role in aging and longevity in diverse model organisms. Morphological and functional alteration in the aging brain elicits age-associated neuronal dysfunctions. However, the primary mechanism deteriorating the brain functions to regulate the aging process remains incompletely understood. Here, it is shown that neuronal CCAAT/enhancer binding protein β (C/EBPβ) escalation during aging dictates the frailty and lifespan via inactivating nicotinamide phosphoribosyltransferase (NAMPT). Upregulated C/EBPβ drives neuronal senescence and neuronal loss, associated with NAMPT fragmentation by active asparagine endopeptidase (AEP), leading to nicotinamide adenine dinucleotide (NAD

To examine the association between body mass index (BMI) trajectories, early and recent BMI changes, and phenotypic age acceleration (PhenoAgeAccel), addressing inconsistent findings in previous studies on weight change and aging. Data from the National Health and Nutrition Examination Survey from 2005 to 2018 were used, selecting participants aged 50 years and older. A growth mixture model was employed to identify BMI trajectories. The association between different BMI trajectories and PhenoAgeAccel was assessed using linear and multinomial logistic regression models. The nonlinear effects of BMI changes were identified through threshold effect analysis. Among 5404 participants, the four BMI trajectories identified were as follows: stable weight (29.07%), midlife weight gain (24.31%), late-life weight gain (32.22%), and chronic obesity (14.41%). The chronic obesity group exhibited the most significant elevations in PhenoAgeAccel, indicating they were phenotypically older compared to other groups (β = 4.34, 95% confidence interval 3.67-5.02). Early BMI changes of less than 6% were associated with being phenotypically younger (β =  - 5.06, P = 0.029), whereas increases exceeding 6% were linked to being phenotypically older (β = 2.83, P < 0.001). The key threshold for recent BMI changes was 2%; changes below this level were associated with being phenotypically younger, while those exceeding this threshold were linked to being phenotypically older (P < 0.001). This cross-sectional study suggests that individuals with long-term chronic obesity tend to be phenotypically older, whereas those with stable body weight are more likely to be phenotypically younger.

Ependymal cells are multiciliated glial cells lining the ventricles of the mammalian brain. Their differentiation from progenitor cells involves cell enlargement and progresses through centriole amplification phases and ciliogenesis. These phases are accompanied by the sharp up-regulation of mTOR Complex 1 activity (mTORC1), a master regulator of macromolecule biosynthesis and cell growth, whose function in ependymal cell differentiation is unknown. We demonstrate that mTORC1 inhibition by rapamycin preserves the progenitor pool by reinforcing quiescence and preventing alternative cell cycle progression for centriole amplification. Overexpressing E2F4 and MCIDAS circumvents mTORC1-regulated processes, enabling centriole amplification despite rapamycin, and enhancing mTORC1 activity through positive feedback. Acute rapamycin treatment in multicentriolar cells during the late phases of differentiation causes centriole regrouping, indicating a direct role of mTORC1 in centriole dynamics. By phosphoproteomic and phosphomutant analysis, we reveal that the mTORC1-mediated phosphorylation of GAS2L1, a centrosomal protein that links actin and microtubule cytoskeletons, participates in centriole disengagement. This multilayered and sequential control of ependymal development by mTORC1, from the progenitor pool to centriolar function, has implications for pathophysiological conditions like aging and hydrocephalus-prone genetic diseases.

Methionine restriction diet has been extensively studied for its beneficial effects on metabolic health and aging. However, the impact of methionine deprivation on glucose metabolism per se and macrophage functions remains incompletely understood. In this study, we analyzed the functional roles of methionine deprivation on glucose flux and macrophage polarization. We used metabolic flux to investigate how methionine deprivation affected glucose metabolism. The functions of methionine deficiency on macrophage polarization and the underlying mechanisms were studied at both the cellular and animal levels. We found that short-term methionine deprivation represses the tricarboxylic acid (TCA) cycle in mitochondria, accompanied by rapid phosphorylation of the E1 subunit of pyruvate dehydrogenase (PDH) complex, PDHA1. This phosphorylation by methionine deprivation is dependent on increased levels of uncharged tRNA but is independent of GCN2. Furthermore, methionine deprivation promotes M1-like polarization of macrophages, consistent with metabolic reprogramming. Notably, the proinflammatory effect of methionine deprivation on macrophages is also mediated by PDHA1 phosphorylation and increases in uncharged tRNA, but independent of GCN2. Our study not only elucidates a direct regulatory role of methionine depletion on the TCA cycle but also reveals that such a regulation is tightly linked to the modulation of macrophage polarization.

Cardiac aging is associated with metabolic changes, including an increased reliance on glycolysis, and an increased susceptibility to cardiovascular diseases. This study explores the relationship between enhanced cardiac glycolysis and aging using the Glyco

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 association between biological aging and dementia, as well as the underlying mechanism, remains limited. The aim of this study was to investigate the relationships of biological age (BA) with incident dementia and examine the underlying neurobiological mechanisms.

Early-life smoking is linked to biological aging and chronic diseases, yet its specific relationship with cardiovascular disease (CVD) risk and the role of DNA methylation biomarkers of aging as potential mediators of that relationship remain underexplored.

In COPD patients, lung-tissue regenerative mechanisms are thought to be exhausted, to which cellular senescence may contribute. Lung-derived mesenchymal stem/stromal cells (LMSCs) constitute a potent supportive cell type able to self-renew and promote alveolar regeneration. We hypothesized that LMSCs are less sensitive to senescence induction in COPD than other supportive cells e.g. lung fibroblasts (LFs) and therefore more promising in regenerative strategies. We compared senescence markers in LMSCs and LFs from the same subjects with/without replicative- and stress-induced senescence. LMSCs and LFs were isolated from COPD and non-COPD lung tissue using cell-specific protocols, and expanded for multiple passages under the same culture conditions. Proliferation, SA-β-gal activity, expression of senescence markers (

Age reprogramming and cellular rejuvenation therapies are revolutionizing the approach to aging and age-related diseases. These ground-breaking interventions target fundamental biological processes, including genomic instability, telomere attrition, and mitochondrial dysfunction, to restore cellular function and delay the onset of degenerative conditions. Emerging strategies such as epigenetic reprogramming, gene editing, stem cell therapy, and senolytic drugs show immense promise in extending health spans and potentially reversing aspects of aging. Despite marked progress in preclinical studies and early-stage clinical trials, translating these therapies into practical healthcare solutions presents significant challenges. Key issues include ensuring safety, optimizing delivery mechanisms, overcoming regulatory barriers, and addressing high costs. Moreover, ethical and economic considerations, such as equitable access and societal impacts, must be carefully addressed to prevent widening health disparities. The present review examines the current state of cellular rejuvenation research, highlighting both scientific advancements and the complex challenges associated with these therapies. With interdisciplinary collaboration, robust ethical frameworks, and scalable technological innovations, these therapies have the potential to transform healthcare. By shifting the focus from disease management to proactive health preservation, they offer a future where aging becomes a manageable and equitable process.

Aging is a universal biological process that impacts all tissues, leading to functional decline and increased susceptibility to age-related diseases, particularly cardiometabolic disorders. While aging is characterized by hallmarks such as mitochondrial dysfunction, chronic inflammation, and dysregulated metabolism, the molecular mechanisms driving these processes remain incompletely understood, particularly in a tissue-specific context. To address this gap, we conducted a comprehensive transcriptomic analysis across 40 human tissues using data from the Genotype-Tissue Expression (GTEx) project, comparing individuals younger than 40 years with those older than 65 years. We identified over 17,000 differentially expressed genes (DEGs) across tissues, with distinct patterns of up- and down-regulation. Enrichment analyses revealed that up-regulated DEGs were associated with inflammation, immune responses, and apoptosis, while down-regulated DEGs were linked to mitochondrial function, oxidative phosphorylation, and metabolic processes. Using gene co-expression network (GCN) analyses, we identified 1,099 genes as dysregulated nodes (DNs) shared across tissues, reflecting global aging-associated transcriptional shifts. Integrating machine learning approaches, we pinpointed key aging biomarkers, including GDF15 and EDA2R, which demonstrated strong predictive power for aging and were particularly relevant in cardiometabolic tissues such as the heart, liver, skeletal muscle, and adipose tissue. These genes were also validated in plasma proteomics studies and exhibited significant correlations with clinical cardiometabolic health indicators. This study provides a multi-tissue, integrative perspective on aging, uncovering both systemic and tissue-specific molecular signatures. Our findings advance understanding of the molecular underpinnings of aging and identify novel biomarkers that may serve as therapeutic targets for promoting healthy aging and mitigating age-related diseases.

Myeloid-biased hematopoiesis is a well-known age-related alteration. Several possibilities, including myeloid-biased hematopoietic stem cell (HSC) clones, may explain this. However, the precise mechanisms remain controversial. Utilizing the Hoxb5 reporter system to prospectively isolate long-term HSCs (LT-HSCs) and short-term HSCs (ST-HSCs), we found that young and aged LT-HSCs co-transplanted into the same recipients demonstrated nearly equivalent myeloid lineage output, contrary to the theory of myeloid-biased HSC clones. Transcriptomics indicated no significant myeloid gene enrichment in aged LT-HSCs compared to their young counterparts. Instead, transplanting reconstituted young HSCs with the ratio of LT/ST-HSCs seen in aged mice can significantly skew the lineage output to myeloid cells. In addition, while the niche environment in the bone marrow minimally affects myeloid-biased hematopoiesis, aged thymi and spleens substantially hinder lymphoid hematopoiesis, resulting in further myeloid-domination. Thus, we demonstrate that myeloid-biased hematopoiesis in aged organisms originates due to alteration of the ratio between LT-HSCs and ST-HSCs rather than in heterogeneous HSC clones with various cell fates.

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.

Mitochondria are cellular hubs integral for metabolism, signaling, and survival. Mitochondrial dysfunction is centrally involved in the aging process and an expansive array of disease states. Elamipretide is a novel mitochondria-targeting peptide that is under investigation for treating several disorders related to mitochondrial dysfunction. This review summarizes recent data that expand our understanding of the mechanism of action (MOA) of elamipretide. Elamipretide is a potential first-in-class therapeutic that targets the inner mitochondrial membrane. Despite initial descriptions of elamipretide's MOA involving reactive oxygen species scavenging, the last ten years have provided a significant expansion of how this peptide influences mitochondrial bioenergetics. The cardiolipin binding properties of elamipretide have been corroborated by different investigative teams with new findings about the consequences of elamipretide-cardiolipin interactions. In particular, new studies have shown elamipretide-mediated modulation of mitochondrial membrane electrostatic potentials and assembly of cardiolipin-dependent proteins that are centrally involved in mitochondrial physiology. These effects contribute to elamipretide's ability to improve mitochondrial function, structure, and bioenergetics. In animal studies, elamipretide-mediated amelioration of organ dysfunction has been observed in models of cardiac and skeletal muscle myopathies as well as ocular pathologies. A number of clinical trials with elamipretide have been recently completed, and a summary of the results focusing on Barth syndrome, primary mitochondrial myopathy, and age-related macular degeneration, is also provided herein. Elamipretide continues to show promise as a potential therapy for mitochondrial disorders. New basic science advances have improved understanding of elamipretide's MOA, enabling a better understanding of the molecular consequences of elamipretide-cardiolipin interactions.

CXCL4 (PF4) is a chemokine stored in platelets that has pleiotropic effects across biological settings. These effects include driving of inflammation and fibrosis as well as reversal of the effects of ageing. We have recently demonstrated that CXCL4 function is driven, independently of known chemokine receptors, through binding to glycosaminoglycan (GAG) side chains on proteoglycans within the cell surface glycocalyx. In this study, we have used intravital imaging and radioactive tracer studies, in combination with an exogenous inhibitor and a GAG-binding CXCL4 mutant, to demonstrate that CXCL4 can enter the brain parenchyma of mice by binding to proteoglycans within the cell surface of the endothelial glycocalyx of the blood-brain barrier (BBB). Furthermore, we have also demonstrated that CXCL4 directly promotes neurogenesis in vitro, which is mediated by its ability to oligomerise and bind to GAGs. These findings provide a molecular mechanism for CXCL4 uptake and function within the brain. Furthermore, these data have important implications for understanding CXCL4 during health and disease that may enable development of CXCL4-related therapeutics for inflammatory diseases and ageing.

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.

Higher cardiorespiratory fitness (CRF) is associated with less deterioration in brain microstructural white matter (WM) integrity in older adults assessed with MRI diffusion tensor imaging (DTI) and brain WM hyperintensities (WMH) volume measured with fluid-attenuated-inversion-recovery (FLAIR) imaging. This study investigated associations of CRF measured with peak oxygen consumption (V̇O

Previous studies have shown that continuous daily consumption of polyphenolic-rich blueberries (BB) reduced neuroinflammation and improved age-related declines in motor and cognitive function in rodents and humans, but the optimal intake of BBs is currently unknown. To evaluate the beneficial effects of BBs on neuroinflammation and motor and cognitive function relative to the frequency of consumption, the diets of aged F344 rats (18 months;

Impaired cognitive function is a hallmark of advancing age, and the potential to reverse or delay these cognitive deficits through dietary intervention holds promise for improving quality of life for older adults. Specifically, ketogenic diets (KDs) have now been widely used for the treatment of several neurological and peripheral disorders, including diseases profoundly affecting cognitive health, of which advanced age is the single greatest risk factor. However, the precise mechanisms of the efficacy of KD-based interventions to reverse age-related cognitive and neurobiological declines are not fully elucidated. We have previously demonstrated that a KD improves cognitive function, with concurrent increases in global levels of proteins related to synaptic signaling in the aging hippocampus (HPC) and prefrontal cortex (PFC). Despite these advances, it remains unclear as to whether these changes reflect biochemical modifications specifically localized to synaptic terminals. To address this important, unanswered question, we purified synaptosomes from the HPC and PFC of aging rats fed a KD or control diet (CD) for a minimum of 4 months and quantified 10 proteins related to synaptic transmission. In contrast to previous studies of global protein expression, the signaling proteins measured did not show significant differences between diet groups in synaptosomes isolated from either region. When pre-mortem performance on an Object-Place Paired Association task was considered, we found a significant correlation between several proteins within the HPC and PFC synaptosomes of CD-fed rats, more pronounced in CD-fed aged rats, that are conspicuously absent in KD-fed rats from both age groups. Moreover, there is a significant alteration in the ratio of VGAT/VGluT1, markers of excitatory and inhibitory synaptic vesicles, in the PFC with dietary intervention that is absent in the HPC, confirming prior reports of regionally specific alterations in excitatory and inhibitory signaling post KD. These new and extended findings reveal important, naturally occurring associations between protein levels localized to synaptic terminals, while clarifying that effects KD likely increase synaptic abundance without altering the biochemical composition of isolated synapses.

Aortic dissection (AD) is a highly alarming clinical condition of the aorta, with a significant mortality rate. Vascular smooth muscle cell (VSMC) senescence dominantly promotes AD progression. This study planned to clarify the exact functions and mechanisms of protein arginine methyltransferase 1 (PRMT1), E2F7, and Sirtuin 6 (SIRT6) in the VSMC senescence of the AD model. Angiotensin II (Ang II) and β-Aminopropionitrile (BAPN) were used to treat VSMCs or C57BL/6J mice to establish the AD in vitro or in vivo model. Protein expressions were examined by western blot, IHC, and IF staining. Histological change or cell senescence was monitored using H&E or senescence-associated-β-galactosidase (SA-β-gal) staining. Enzyme-Linked Immunosorbent Assay (ELISA) assays were utilized to evaluate senescence-associated secretory phenotype markers' levels. The binding interactions between E2F7 and SIRT6 or PRMT1 and E2F7 were verified by the luciferase reporter, ChIP Co-IP, and GST-pull-down analysis. The ubiquitination levels of E2F7 were assessed using ubiquitination assays. PRMT1, E2F7, and SIRT6 protein levels were decreased in the Ang II-treated VSMCs of the AD model. Moreover, E2F7 repressed cell senescence by transcriptionally regulating SIRT6 in the AD model. PRMT1 silencing promoted cell senescence of VSMCs under Ang II. Further, PRMT1-mediated arginine methylation could maintain the protein stability of E2F7. PRMT1 restrained cell senescence of VSMCs via the E2F7/SIRT6 axis in the AD model. PRMT1 enhanced arginine methylation of E2F7, leading to the upregulation of SIRT6, thereby inhibiting the senescence of VSMCs in the AD model.

Peach gum polysaccharides (PGPs) have attracted increasing attention for their potential biological properties and application in the food and cosmetic industries. This study aimed to investigate the structural characteristics and anti-photoaging activity of PGPs. The purification of PGPs resulted in two polysaccharides (PGP-1 and PGP-2). Results showed that PGP-1 and PGP-2 had a molecular weight of 4515.31 kDa and 15.02 kDa, respectively. Their structures were elucidated via GC-MS and NMR spectrum and proved to be an arabinogalactan. In addition, PGP-1 and PGP-2 do not have mucous-membrane irritation on chicken embryo CAM. Mainly, PGP-1 (1.5 mg/mL) significantly inhibits the expressions of MMPs (MMP-1, MMP-3, and MMP-12) in the UVB-induced human immortalized epidermal cells (HaCaT), indicating that PGP-1 could reduce collagen loss caused by UVB irradiation. PGP-1 also can inhibit cell senescence and apoptosis by reducing p16, p21, and p53 protein expressions. Based on these findings, our data suggested that PGPs may be used to develop effective natural anti-photoaging ingredients to promote skin health.

Theta-gamma transcranial alternating current stimulation (TG tACS) over primary motor cortex (M1) can improve ballistic motor performance in young adults, but the effect on older adults is unknown. This study investigated the effects of TG tACS on motor performance and M1 excitability in 18 young and 18 older adults. High-definition TG tACS (6 Hz theta, 75 Hz gamma) or sham tACS was applied over right M1 for 20 min during a ballistic left-thumb abduction motor training task performed in two experimental sessions. Motor performance was quantified as changes in movement acceleration during and up to 60 min after training. Transcranial magnetic stimulation (TMS) was used to assess changes in M1 excitability with motor-evoked potentials (MEP) and short-interval intracortical inhibition (SICI) before and after training. We found that TG tACS increased motor performance compared with sham tACS in young and older adults (P < 0.001), with greater effects for young adults (P = 0.01). The improved motor performance with TG tACS lasted at least 60 min after training in both age groups. Motor training was accompanied by greater MEP amplitudes with TG tACS compared to sham tACS in young and older adults (P < 0.001), but SICI did not vary between tACS sessions (P = 0.40). These findings indicate that TG tACS over M1 improves motor performance and alters training-induced changes in M1 excitability in healthy young and older adults. TG tACS may therefore be beneficial to alleviate motor deficits in the ageing population.

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.

The quality and quantity of the ovarian reserve are meticulously regulated through various cell death pathways to guarantee the availability of high-quality oocytes for fertilization. While apoptosis is recognized for contributing to maintaining ovarian reserve, the involvement of other cell death pathways remains unclear. Employing chemical genetics and proteomics, this study reveals the crucial involvement of Cathepsin B in maintaining the ovarian reserve. Results indicate that apoptosis and autophagy play pivotal roles, and inhibiting these pathways significantly increases follicle numbers. Proteomics reveals a dynamic shift from apoptosis to autophagy during follicular development, with Cathepsin B emerging as a key player in this transition. Inhibiting Cathepsin B not only mimics the augmented oocyte reserve observed with autophagy inhibition but also upregulated IGF1R and AKT-mTOR pathways without compromising fertility in pre- and postpubertal mice. Further, IGF1R inhibition partially compromised the protective effects of Cathepsin B inhibition on oocyte reserves, suggesting their interdependence. This association is further supported by the finding that Cathepsin B can degrade IGF1R in vitro. Moreover, the increased IGF1R levels enhance the oocyte mitochondrial membrane potential via transcriptional regulation of mitochondrial biogenesis and mitophagy genes. Remarkably, this Cathepsin B-dependent ovarian reserve maintenance mechanism is conserved in higher-order vertebrates. Cumulatively, our study sheds valuable light on the intricate interplay of autophagy, Cathepsin B, and growth factors in ovarian reserve maintenance, offering potential therapeutic strategies to delay ovarian aging and preserve fertility.

Senescent cells are characterised by increased glycolysis dependence. Normalisation of glycolysis metabolism is essential for senescence amelioration. However, the mechanism of proteins involved in cellular glycolysis metabolism has not been fully elucidated. Here, we identified a candidate compound, an oxazole analogue (KB2764), that can improve senescence. To elucidate the mechanism of the KB2764, we investigated the interacting proteins. KB2764 interacted with alpha-enolase (ENO1) and pyruvate kinase M (PKM), ultimately allowing PKM to phosphorylate ENO1. KB2764 consequently increased mitochondrial ATP production and reduced reliance on glycolysis. Knockdown of the ENO1 experiment in senescent cells demonstrates that regulation of ENO1 activity is a prerequisite for recovery of mitochondrial function. Furthermore, the action of KB2764 extends its application to extend the lifespan of Caenorhabditis elegans. Taken together, our findings reveal a novel mechanism by which senescence is ameliorated through metabolic reprogramming and mitochondrial functional recovery via KB2764-mediated regulation of ENO1 protein activity.

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.

Oocyte quality is closely linked to metabolic integrity, and age-related metabolic dysregulation is a key factor contributing to oocyte aging. In this study, we utilized non-targeted metabolomics to explore the impact of taurine supplementation on the metabolic profile of postovulatory aging (POA) porcine oocytes. Our analysis revealed that taurine supplementation significantly altered the metabolic landscape, restoring key metabolic pathways associated with energy production, amino acid metabolism, and oxidative stress regulation. Notably, taurine supplementation enhanced mitochondrial function, increased ATP synthesis, and improved the redox balance by upregulating reduced glutathione (GSH) levels and reducing oxidative damage. Metabolomics data also indicated a restoration of critical metabolic intermediates, including those involved in the glutathione synthesis pathway and amino acid metabolism. These findings suggest that taurine can modulate oocyte metabolism, improve cellular energy status, and mitigate oxidative stress, thereby enhancing oocyte quality at the metabolic level.

Both longitudinal and cross-sectional studies have demonstrated that muscle mass, strength and power are lost with ageing. Although longitudinal studies have shown changes in muscle morphology and function in sedentary, healthy active and endurance-trained older people, less is known about such age-related changes in sprint athletes. It has been proposed that active older people may provide a better study of healthy ageing not confounded by factors of inactivity and other unhealthy behaviours. Given that the training regimens of masters sprinters consist of strength and sprint training that elicit gains in muscle force, power and mass, sprinters may not suffer from measurable decrements in muscle strength, functional performance or morphology over a 10-year period.

The pathogenesis of various chronic diseases is closely associated with aging. Aging of the cardiovascular system promotes the development of severe cardiovascular diseases with high mortality, including atherosclerosis, coronary heart disease, and myocardial infarction. Similarly, aging of the nervous system promotes the development of neurodegenerative diseases, such as Alzheimer's disease, which seriously impairs cognitive function. Aging of the musculoskeletal system is characterized by decreased function and mobility. The molecular basis of organ aging is cellular senescence, which involves multiple cellular and molecular mechanisms, such as impaired autophagy, metabolic imbalance, oxidative stress, and persistent inflammation. Given the ongoing demographic shift toward an aging society, strategies to delay or reduce the effects of aging have gained significance. Lifestyle modifications, such as exercise and calorie restriction, are now recognized for their anti-aging effects, their capacity to reduce modification, their potential to prolong lifespan, and their capacity to lower the risk of cardiovascular disease. This review elucidates the molecular mechanisms and application significance of various anti-aging approaches at the molecular level, based on research progress in aging. It aims to provide a reference for the prevention and treatment of age-related diseases in progressively aging societies.

Older adults with exceptional longevity - and their offspring - are protected from age-related diseases and have a prolonged health span. Prior research suggests that offspring of parents with exceptional longevity have larger temporal and sensorimotor cortices in mid to late-adulthood - but the association between brain health and parental longevity is not well understood in older adults. This study aimed to identify a gray matter volume pattern (or network) associated with parental longevity in older adults - and to determine if individual expressions of this gray matter pattern vary with cognitive performance.

Aging can prolong the wound healing and is associated with decline in stem cells, delays in cellular migration, and lower vascularization. Tissue engineering has largely evolved to incorporate advanced three-dimensional wound dressings, scaffolds, and hydrogels that may be seeded with mesenchymal stromal cells (MSCs) to foster an environment conducive to regeneration and enhance the healing process. The effectiveness of stem cell-seeded scaffolds can be improved by incorporating activating agents such as nucleic acids resulting in gene-activated scaffolds (GAS), thereby facilitating targeted wound healing in aged patients. In this study, we assess the

Immune resilience as a salutogenic force to preserve healthspan and resilience to challenges. The figure was created with BioRender (https://www.BioRender.com/).

With global aging and rising widowhood among middle-aged and older adults, promoting their health is an urgent public health concern. Using CHARLS data (2011-2018), this study applies OLS and mediation models to examine how social participation affects daily functioning and mental health among widowed individuals. Findings show that social participation reduces daily living difficulties and depressive symptoms. Mechanism analysis reveals these effects operate through healthier lifestyles and improved cognitive function. The impact is stronger for older and urban residents. Promoting social engagement may be an effective strategy to support the health and functioning of widowed older adults in China.