Longevity Papers

Immunoglobulin G (IgG) N-glycans have been identified as associated with aging; however, previous studies predominantly quantified changes based on the relative percentages of each glycan within the total glycan pool, neglecting the absolute concentration changes of individual glycans. Additionally, relative quantification can limit practical applications, as these often require absolute concentration measurements for consistent and interpretable biomarker values. In this study, we introduce a novel strategy for discovering aging-associated IgG glycans and establishing a prediction model based on their absolute concentration alteration. We employed a glycome quantification technology to identify the alteration in IgG glycan amount in natural aging and anti-aging (caloric restriction) models, discovering aging-related glycans. The glycomics analysis revealed key features: downregulation of bisected glycan GP3 (F(6)A2B) and upregulation of digalactosylated glycan GP8 (F(6)A2G2). These glycan changes showed significant fold changes from an early stage. Using external standards of these two glycans, we subsequently measured the absolute concentrations of them, allowing us to establish a predictive model, abGlycoAge, for biological aging. The abGlycoAge index suggested a younger state under caloric restriction, with an average age reduction of 3.9-14 weeks. Additionally, we performed RNA sequencing on splenic B cells of mice, suggesting Derl3, Smarcb1, Ankrd55, Tbkbp1 and Slc38a10 could contribute to the alteration of GP3 and GP8 in aging. This analysis enhances our understanding of glycan alterations, accounts for individual variability, and aids in designing effective anti-aging strategies. These findings highlight the crucial roles of the GP3 and GP8 as potential biomarkers for aging and health.

Impaired mitochondrial bioenergetics in macrophages can drive hyperinflammatory cytokine responses, but whether this may also be caused by inherited mtDNA mutations is unknown. Here, we address this question using a multi-omic approach that integrates super-resolution imaging and metabolic analyses to profile macrophages from a mouse model of mitochondrial disease arising from a heteroplasmic mutation (m.5019A>G) in the mitochondrial tRNA for alanine. These m.5019A>G macrophages exhibit defects in respiratory chain complexes and oxidative phosphorylation (OxPhos) due to decreased intra-mitochondrial translation. To adapt to this metabolic stress, mitochondrial fusion, reductive glutamine metabolism, and aerobic glycolysis are all increased. Upon inflammatory activation, type I interferon (IFN-I) release is enhanced, while the production of pro-inflammatory cytokines and oxylipins are restrained in m.5019A>G macrophages. Finally, an in vivo endotoxemia model using m.5019A>G mice reveal elevated IFN-I levels and sickness behaviour. In conclusion, our study identifies an unexpected imbalance in innate immune signalling in response to a pathogenic mtDNA mutation, with important implications for the progression of pathology in patients with mtDNA diseases.

Age-related diseases are often linked to chronic inflammation. Senescent cells secrete inflammatory cytokines, chemokines and matrix metalloproteinases, collectively referred to as the senescence-associated secretory phenotype (SASP). The current study discovered that aging leads to the accumulation of senescent tendon stem/progenitor cells (TSPCs) in tendon tissue, resulting in the development of a SASP. Conditioned medium from aged TSPCs induced cellular inflammation in young TSPCs. In addition, we found that Canopy homolog 2 (CNPY2) expression is reduced during tendon aging. CNPY2 deficiency causes TSPCs senescence and SASP. Our findings showed that the NF-κB signaling pathway is activated in CNPY2 knockdown TSPCs, pharmacological inhibition of NF-κB signaling pathway with BMS-345541 attenuated SASP of senescent TSPCs, which indicated that CNPY2 regulates TSPCs SASP might through NF-κB signaling pathway. Our findings suggested that CNPY2 plays an important role in TSPCs senescence and SASP, CNPY2 could be a promising target for age-related tendon disorders.

Maintaining homeostasis is essential for continued health, and the progressive decay of homeostatic processes is a hallmark of ageing. Daily environmental rhythms threaten homeostasis, and circadian clocks have evolved to execute physiological processes in a manner that anticipates, and thus mitigates, their effects on the organism. Clocks are active in almost all cell types; their rhythmicity and functional output are determined by a combination of tissue-intrinsic and systemic inputs. Numerous inputs for a specific tissue are produced by the activity of circadian clocks of other tissues or cell types, generating a form of crosstalk known as clock communication. In mammals, the central clock in the hypothalamus integrates signals from external light-dark cycles to align peripheral clocks elsewhere in the body. This regulation is complemented by a tissue-specific milieu of external, systemic and niche inputs that modulate and cooperate with the cellular circadian clock machinery of a tissue to tailor its functional output. These mechanisms of clock communication decay during ageing, and growing evidence suggests that this decline might drive ageing-related morbidities. Dietary, behavioural and pharmacological interventions may offer the possibility to overcome these changes and in turn improve healthspan.

Aging of the brain vasculature plays a key role in the development of neurovascular and neurodegenerative diseases, thereby contributing to cognitive impairment. Among other factors, DNA damage strongly promotes cellular aging, however, the role of genomic instability in brain endothelial cells (EC) and its potential effect on brain homeostasis is still largely unclear. We here investigated how endothelial aging impacts blood-brain barrier (BBB) function by using excision repair cross complementation group 1 (ERCC1)-deficient human brain ECs and an EC-specific Ercc1 knock out (EC-KO) mouse model. In vitro, ERCC1-deficient brain ECs displayed increased senescence-associated secretory phenotype expression, reduced BBB integrity, and higher sprouting capacities due to an underlying dysregulation of the Dll4-Notch pathway. In line, EC-KO mice showed more P21

Angiogenesis plays a pivotal role in ischemic cardiovascular disease, accompanied by epigenetic regulation during this process. Sirtuin 6 (SIRT6) has been implicated in the regulation of DNA repair, transcription and aging, with its deacetylase activity fully studied. However, the role of SIRT6 demyristoylase activity remains less clear, with even less attention given to its myristoylated substrates. In this study, we report that endothelial specific SIRT6 knockout attenuated angiogenesis in mice, while SIRT6 was observed to promote migration and tube formation in endothelial cell. Notably, we further determined that SIRT6 affects the intracellular VEGFA and global myristoylation level under hypoxia. Moreover, ALK14 (myristic acids analogue) treatment and SIRT6 knockdown results in a significant decrease in VEGFA secretion under hypoxia, implying the involvement of SIRT6 demyristoylase activity in angiogenesis. Mechanistically, CLICK IT assay verified that VEGFA is a myristoylated substrate of SIRT6. Further, overexpression of SIRT6 mutants (R65A, G60A and H133Y) results in profound differences in VEGFA secretion, indicating that SIRT6 promotes VEGFA secretion through demyristoylation but not deacetylation. Finally, overexpression of SIRT6 rescued the diminishment of endothelial migration, tube formation and sprouting caused by ALK14 treatment. Overall, our study demonstrates that SIRT6 regulates angiogenesis by demyristoylating VEGFA and increasing VEGFA secretion. Therefore, modulation of SIRT6 demyristoylase activity may represent a therapeutic strategy for ischemic cardiovascular disease.

During aging, microglia, the resident macrophages of the brain, exhibit altered phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFB1 and translational states using pharmacological approaches in vitro to reveal their modulation of the progression to an activated state. Furthermore, we utilized single-cell RNA-Seq in conjunction with in vivo adult microglia-specific Tgfb1 conditional genetic knockout mouse models, to demonstrate that microglia advancement through intermediate aging states drives transcriptional inflammatory activation and hippocampal-dependent cognitive decline.

Aging is a complex biological process influenced by various factors, including genetic and environmental influences. In this study, we present BayesAge 2.0, an upgraded version of our maximum likelihood algorithm designed for predicting transcriptomic age (tAge) from RNA-seq data. Building on the original BayesAge framework, which was developed for epigenetic age prediction, BayesAge 2.0 integrates a Poisson distribution to model count-based gene expression data and employs LOWESS smoothing to capture nonlinear gene-age relationships. BayesAge 2.0 provides significant improvements over traditional linear models, such as Elastic Net regression. Specifically, it addresses issues of age bias in predictions, with minimal age-associated bias observed in residuals. Its computational efficiency further distinguishes it from traditional models, as reference construction and cross-validation are completed more quickly compared to Elastic Net regression, which requires extensive hyperparameter tuning. Overall, BayesAge 2.0 represents a step forward in tAge prediction, offering a robust, accurate, and efficient tool for aging research and biomarker development.

Quantifying the mechanical response of the biological milieu (such as the cell's interior) and complex fluids (such as biomolecular condensates) would enable a better understanding of cellular differentiation and aging and accelerate drug discovery. Here we present time-shared optical tweezer microrheology to determine the frequency- and age-dependent viscoelastic properties of biological materials. Our approach involves splitting a single laser beam into two near-instantaneous time-shared optical traps to carry out simultaneous force and displacement measurements and quantify the mechanical properties ranging from millipascals to kilopascals across five decades of frequency. To create a practical and robust nanorheometer, we leverage both numerical and analytical models to analyse typical deviations from the ideal behaviour and offer solutions to account for these discrepancies. We demonstrate the versatility of the technique by measuring the liquid-solid phase transitions of MEC-2 stomatin and CPEB4 biomolecular condensates, and quantify the complex viscoelastic properties of intracellular compartments of zebrafish progenitor cells. In Caenorhabditis elegans, we uncover how mutations in the nuclear envelope proteins LMN-1 lamin A, EMR-1 emerin and LEM-2 LEMD2, which cause premature aging disorders in humans, soften the cytosol of intestinal cells during organismal age. We demonstrate that time-shared optical tweezer microrheology offers the rapid phenotyping of material properties inside cells and protein blends, which can be used for biomedical and drug-screening applications.

Ovarian function declines significantly as females enter middle-age, but the mechanisms underlying this decline remain unclear. Here, we utilize whole-organ imaging to observe a notable decrease in ovarian blood vessel (oBV) density and angiogenesis intensity of middle-aged mice. This leads to a diminished blood supply to the ovaries, resulting in inadequate development and maturation of ovarian follicles. Utilizing genetic-modified mouse models, we demonstrate that granulosa cell secreted VEGFA governs ovarian angiogenesis, but the physiological decline in oBV is not attributed to VEGFA insufficiency. Instead, through single-cell sequencing, we identify the aging of the ovarian vascular endothelium as the primary factor contributing to oBV decline. Consequently, the administration of salidroside, a natural compound that is functional to reverse oBV aging and promote ovarian angiogenesis, significantly enhances ovarian blood supply and improve fertility in older females. Our findings highlight that enhancing oBV function is a promising strategy to boost fertility in females.

Chronic low-grade inflammation observed in older adults, termed inflammaging, is a common feature underlying a multitude of aging-associated maladies including a decline in hematopoietic activity. However, whether suppression of inflammaging can preserve hematopoietic health span remains unclear, in part because of a lack of tools to measure inflammaging within hematopoietic stem cells (HSCs). Here, we identify thrombospondin-1 (Thbs1) as an essential regulator of inflammaging within HSCs. We describe a transcriptomics-based approach for measuring inflammaging within stem cells and demonstrate that deletion of

Aging is a complex and multifaceted process involving many epigenetic alterations. One key area of interest in aging research is the role of histone modifications, which can dynamically regulate gene expression. Here, we conducted a pan-tissue analysis of the dynamics of seven key histone modifications during human aging. Our histone-specific age prediction models showed surprisingly accurate performance, proving resilient to experimental and artificial noise. Simulation experiments for comparison with DNA methylation age predictors revealed competitive performance. Moreover, gene set enrichment analysis uncovered several critical developmental pathways for age prediction. Different from DNA methylation age predictors, genes known to be involved in aging biology are among the most important ones for the models. Last, we developed a pan-tissue pan-histone age predictor, suggesting that age-related epigenetic information is degenerated across the epigenome. This research highlights the power of histone marks as input for creating robust age predictors and opens avenues for understanding the role of epigenetic changes during aging.

ASXL1 is one of the three most frequently mutated genes in age-related clonal hematopoiesis (CH), with the others being DNMT3A and TET2. CH can progress to myeloid malignancies including chronic monomyelocytic leukemia (CMML), and is also strongly associated with inflammatory cardiovascular disease and all-cause mortality in humans. DNMT3A and TET2 regulate DNA methylation and demethylation pathways respectively, and DNMT3A and TET2 loss-of-function mutations in CH reduce DNA methylation in heterochromatin, allowing de-repression of silenced elements in heterochromatin. In contrast, the mechanisms that connect mutant ASXL1 and CH are not yet fully understood. CH/CMML-associated ASXL1 mutations encode C-terminally truncated proteins that enhance the deubiquitinase activity of the ASXL-BAP1 ''PR-DUB '' deubiquitinase complex, which removes mono-ubiquitin from H2AK119Ub. Here we show that ASXL1 mutant proteins interact with the EHMT1-EHMT2 methyltransferase complex, which generates H3K9me1 and me2, the latter a repressive modification in constitutive heterochromatin. Compared to cells from age-matched wildtype mice, we found that expanded myeloid cells from old (>18-month-old) Asxl1tm/+ mice, a heterozygous knock-in mouse model of CH, display genome-wide decreases of H3K9me2, H3K9me3 and H2AK119Ub as well as an associated increase in expression of transposable elements (TEs) and satellite repeats. Increased TE expression was also observed in monocytes from ASXL1-mutant CMML patients compared to monocytes from healthy control individuals. Our data suggest that mutant ASXL1 proteins compromise the integrity of both constitutive and facultative heterochromatin in an age-dependent manner, by reducing the levels of H3K9me2/3 and H2AK119Ub respectively. The resulting increase in TE expression can alter the expression of nearby genes and promote the expression of inflammation-associated and interferon-inducible genes (ISGs).

Chronological age is a cornerstone of medical decision-making but is limited because individuals age at different rates. We recently released an open-source deep learning model to assess biological age from chest radiograph images (CXR-Age), which predicts incident all-cause and cardiovascular mortality better than chronological age. Here, we compare CXR-Age to two established epigenetic aging clocks (First generation- Horvath Age; Second generation- DNAm PhenoAge), to test which is more strongly associated with measures of cardiopulmonary disease. Our cohort consisted of 2,097 participants from the Project Baseline Health Study (PBHS), a prospective cohort study of individuals from four US sites enriched for cardiovascular and cardiometabolic disease risk factors. We found that CXR-Age was most strongly associated with the presence of coronary calcium, cardiovascular risk factors, worsening pulmonary function, increased frailty, and abundance in plasma of two proteins implicated in neuroinflammation and aging. Associations with second generation epigenetic clocks were weaker for pulmonary function and for all outcomes in younger adults. No associations were found with first generation clocks. These results suggest that opportunistic screening using CXR-Age may help identify high risk individuals who could benefit from directed screening and prevention.

Aging is a process accompanied by functional decline in tissues and organs with great social and medical consequences. Developing effective anti-aging strategies is of great significance. In this study, we demonstrated that transplantation of young hematopoietic stem cells (HSCs) into old mice can mitigate aging phenotypes, underscoring the crucial role of HSCs in the aging process. Through comprehensive molecular and functional analyses, we identified a subset of HSCs in aged mice that exhibit "younger" molecular profiles and functions, marked by low levels of CD150 expression. Mechanistically, CD150

Cellular senescence plays a significant role in tissue aging. Senescent cells, which resist apoptosis while remaining metabolically active, generate endogenous DNA-damaging agents, primarily reactive oxygen species. Efficient DNA repair is therefore crucial in these cells, especially when they undergo senescence escape, resuming DNA replication and cellular proliferation. To investigate whether senescent cell transcriptomes reflect adequate DNA repair capacity, we conducted a comprehensive meta-analysis of 60 transcriptomic datasets comparing senescent to proliferating cells. Our analysis revealed a striking downregulation of genes encoding essential components across DNA repair pathways in senescent cells. This includes pathways active in different cell cycle phases such as nucleotide excision repair, base excision repair, nonhomologous end joining and homologous recombination repair of double-strand breaks, mismatch repair and interstrand crosslink repair. The downregulation observed suggests a significant accumulation of DNA lesions. Experimental monitoring of DNA repair readouts in cells that underwent radiation-induced senescence supported this conclusion. This phenomenon was consistent across various senescence triggers and was also observed in primary cell lines from aging individuals. These findings highlight the potential of senescent cells as 'ticking bombs' in aging-related diseases and tumors recurring following therapy-induced senescence.

Porphyra haitanensis proteins (PHP) are natural proteins with various nutritional and biological values. This study was to analyze the composition, stability, and antioxidant activity of PHP before and after simulation gastrointestinal digestion (SGD). Caenorhabditis elegans was used as the model to investigate the functional activity and potential mechanisms of action of the PHP digestion products (PHPDP). The results showed that PHP contained 16 amino acids and exhibited high thermal stability (up to 80 °C), but dimerization or fragmentation occurred in environments with pH 3 and pH 11. After digestion, PHP released 212 bioactive peptides, which significantly enhanced its antioxidant activity and improved the resistance of C. elegans to heat, oxidative, and ultraviolet stress. Furthermore, PHPDP improved oxidative stress in C. elegans and extended its lifespan by increasing antioxidant enzyme activity and reducing malondialdehyde, lipofuscin, and reactive oxygen species levels. The mechanism of action of PHPDP likely involved regulating the insulin signaling pathway through daf-2/daf-16 and modulating the expression of oxidative stress regulators skn-1 and sod-3, thereby enhancing the organism's stress resistance and extending lifespan. This study demonstrated that P. haitanensis could serve as a reliable protein source in daily life and provided a reference for its development and application as a functional food ingredient.

The mechanisms underlying the impact of probiotic supplementation on health remain largely elusive. While previous studies primarily focus on the discovery of novel bioactive bacteria and alterations in the microbiome environment to explain potential probiotic effects, our research delves into the role of living Lactiplantibacillus (formerly known as Lactobacillus) and their conditioned media, highlighting that only the former, not dead bacteria, enhance the healthspan of Caenorhabditis elegans (C. elegans). To elucidate the underlying mechanisms, we conduct transcriptomic profiling through RNA-seq analysis in C. elegans exposed to GTB1, a strain of Lactiplantibacillus plantarum or 3-phenyllactic acid (PLA), mimicking the presence of key candidate metabolites of GTB1 and evaluating healthspan. Our findings reveal that PLA treatment significantly extends the healthspan of C. elegans by promoting energy metabolism and stress resilience in a SKN-1/ATFS-1-dependent manner. Moreover, PLA-mediated longevity is associated with a novel age-related parameter, the Healthy Aging Index (HAI), introduced in this study, which comprises healthspan-related factors such as motility, oxygen consumption rate (OCR), and ATP levels. Extending the relevance of our work to humans, we observe an inverse correlation between blood PLA levels and physical performance in patients with sarcopenia, when compared to age-matched non-sarcopenic controls. Our investigation thus sheds light on the pivotal role of the metabolite PLA in probiotics-mediated enhancement of organismal healthspan, and also hints at its potential involvement in age-associated sarcopenia. These findings warrant further investigation to delineate PLA's role in mitigating age-related declines in healthspan and resilience to external stressors.

Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while cellular factors that trigger it are not identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2beta was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2alpha, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2beta phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2beta expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2beta axis maintains proteostasis in the axon, of which disruption may underly the onset and progression of age-related neurodegenerative diseases.

Offspring of older breeders frequently show reduced longevity, which has been linked to shorter offspring telomere length. It is currently unknown whether such telomere reduction persists beyond a single generation, as would be the case if germline transmission is involved. In a within-grandmother, multi-generational study using zebra finches, we show that the shorter telomeres observed in F1 offspring of older mothers are still present in the F2 generation even when the breeding age of their F1 mothers is young. The effect was substantial: 43% shorter telomeres in grandoffspring from the 'grandmother old at breeding' line compared with those from the 'grandmother young at breeding' line. Shorter telomeres at fledging in this species are associated with a reduction in lifespan. Our data demonstrate the need to look beyond a single generation to explain inter-individual variation in ageing rates and thereby variation in optimal allocation of age-specific reproductive effort.

Telomere attrition is a hallmark of biological aging, contributing to cellular replicative senescence. However, few studies have examined the determinants of telomere attrition in vivo in humans. Mitochondrial Health Index (MHI), a composite marker integrating mitochondrial energy-transformation capacity and content, may be one important mediator of telomere attrition, as it could impact telomerase activity, a direct regulator of telomere maintenance. In this observational longitudinal study, we examined in peripheral blood mononuclear cells (PBMCs), whether MHI predicted changes in telomerase activity over a 9-month period, thus impacting telomere maintenance over this same period of time. We secondarily examined the role of chronic stress, by comparing these relationships in mothers of children with an autism spectrum disorder (caregivers) vs. mothers of a neurotypical child (controls). Here we show that both chronic stress exposure and lower MHI independently predicted decreases in telomerase activity over the subsequent 9 months. Finally, changes in telomere length were directly related with changes in telomerase activity, and indirectly with MHI and chronic stress, as revealed by a path analysis. These results highlight the potential role of chronic stress and MHI as drivers of telomere attrition in human PBMCs, through an impairment of both energy-transformation capacity and telomerase production.

The mammalian heart contains cardiac stem cells throughout life, but it has not been possible to harness or stimulate these cells to repair damaged myocardium in vivo. Assuming physiological relevance of these cells, which have evolved and have been maintained throughout mammalian evolution, we hypothesize that cardiac stem cells may contribute to cardiomyogenesis in an unorthodox manner. Since the intermediate filament protein desmin and the matricellular Secreted Protein Acidic and Rich in Cysteine (SPARC) promote cardiomyogenic differentiation during embryogenesis in a cell-autonomous and paracrine manner, respectively, we focus on their genes and employ mouse embryonic and cardiac stem cell lines as in vitro models to ask whether desmin and SPARC cooperatively influence cardiomyogenesis in cardiac stem and progenitor cells. We show that desmin also promotes cardiomyogenesis in a non-cell autonomous manner by increasing the expression and secretion of SPARC in differentiating embryonic stem cells. SPARC is also secreted by cardiac stem cells where it promotes cardiomyogenesis in an autocrine and concentration-dependent manner by upregulating the expression of myocardial transcription factors and its elicitor desmin. Desmin and SPARC interact genetically, forming a positive feedback loop and secreted autocrine and paracrine SPARC negatively affects sparc mRNA expression. Paracrine SPARC rescues cardiomyogenic desmin-haploinsufficiency in cardiac stem cells in a glycosylation-dependent manner, increases desmin expression, the phosphorylation of Smad2 and induces the expression of gata4, nkx2.5 and mef2C. Demonstration that desmin-induced autocrine secretion of SPARC in cardiac stem cells promotes cardiomyogenesis raises the possibility that a physiological function of cardiac stem cells in the adult and aging heart may be the gland-like secretion of factors such as SPARC that modulate age-related and adverse environmental influences and thereby contribute to cardiac homeostasis throughout life.

How aging affects axon regeneration and synaptic repair in the brain is poorly understood. To study age-related changes in neural circuits, we developed a model of axonal injury in the aged (> 2 years) mouse somatosensory cortex. By directly tracking fluorescently labelled injured axons by multiphoton imaging, we find that while axon degeneration in the aged brain is comparable to the young adult brain, axon regeneration is impaired. We further examine changes in the most common type of cortical synapses, En Passant Boutons (EPBs), and observe a transient and significant increase in the number and size of boutons 6 hours post-lesion. Using a computational model of a recurrent neural network, we examined the functional consequences of these synaptic increases on memory, comparing results to models of the young adult brain. The results suggest that increased synaptic dynamics might enable partial recovery from injury via synaptic re-wiring in the aged brain.

Anemarrhena asphodeloides Bge. (AAB), a traditional medicinal herb, has a long history of delaying the aging process. Yet, the anti-aging effects of its polysaccharides have not been thoroughly investigated. This study marks the first exploration of the anti-aging activity of Anemarrhena asphodeloides Bge. polysaccharides (AABP). The MW of AABP-1a was determined to be 210.062 kDa, with a composition consisting predominantly of glucose and mannose in a molar ratio of approximately 4:1. The backbone of AABP-1a was mainly composed of →4)-2Ac-β-Man(1→ and →4)-β-Glc(1→ and a small amount of branched →4,6)-β-Glc(1→ and →3,4)-β-Glc(1→, the branching part was composed of →6)-β-Glc(1→ and t-α-Glc(1→. AABP-1a has antioxidant capacity and can improve cell cycle arrest mediated by senescence markers such as p53, p21, p16 and SASP, and reduce the accumulation of damaged DNA. In addition, it could reduce the activity of SA-β-Gal in zebrafish, prolong the lifespan of C. elegans and reduce the expression of lipofuscin. This study found a glucomannan and demonstrated its anti-aging activity in various aging models. These results provide a theoretical basis for further study of the anti-aging effect of AAB.