The oral cavity is a complex physiological community encompassing a wide range of microorganisms. Dysbiosis of oral microbiota can lead to various oral infectious diseases, such as periodontitis and tooth decay, and even affect systemic health, including brain aging and neurodegenerative diseases. Recent studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration, indicating potential avenues for intervention strategies. In this review, we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases, and dissect potential mechanisms by which oral microbes contribute to brain aging and neurodegeneration. We also highlight advances in therapeutic development grounded in the realm of oral microbes, with the goal of advancing brain health and promoting healthy aging.

Aging is inevitable processes which play a significant role in the development of various diseases, including cardiovascular diseases, neurodegenerative disorders, and cancers. The extension of lifespan and the improvement of age-related diseases can potentially be achieved by targeting evolutionarily conserved pathways and mechanisms through pharmacological interventions. Chrysophanol (Chr), a naturally occurring anthraquinone compound primarily derived from rhubarb of the Polygonaceae family, exhibits a wide range of pharmacological activities, including anti-cancer, anti-inflammatory, and anti-bacterial effects. However, its role in regulating aging remains unclear. In this study, we discovered that Chr extends both lifespan and healthspan in Caenorhabditis elegans by activating the DAF-2/DAF-16 insulin signaling pathway. Furthermore, we observed that Chr promoted longevity in natural aging mice, doxorubicin-induced aging mice, and transgenic mice through the conserved Insulin/IGF-1 signaling pathway. Additionally, Chr also influenced senescence-associated secretory phenotypes (SASPs) and enhanced the expression of antioxidant genes, contributing to delayed aging. These findings highlight that Chr exerts anti-aging effects from C. elegans to mammals via the evolutionarily conserved Insulin/IGF-1 signaling pathway, positioning Chr as a promising candidate for the prevention and treatment of aging and age-related diseases.

The jellyfish Turritopsis dohrnii (T. Nutricala) is a cnidarian of the Oceaniidae family that lives in the Mediterranean Sea. It is known as the immortal jellyfish since, through a process of cell development called transdifferentiation, it manages to return to a polyp state. The role of regeneration processes and their impact on aging have been studied in recent years for their potential applications in the development of more efficient pharmacology to address disorders related to aging. Reviewing the terms related to transdifferentiation in jellyfish and understanding the underlying mechanisms can help comprehend diverse processes such as aging, regeneration, and the molecular bases of diseases like cancer. This paper's purpose is to provide a description of the regenerative characteristics of the jellyfish T. dohrnii, investigate how its regenerative processes allow it to rejuvenate, and determine if these tissue restoration processes are also found in humans.

Muscle quality, including phase angle (PhA) and extracellular to intracellular water (ECW/ICW) ratio, assessed using multi-frequency bioelectrical impedance analysis (MF-BIA) to reflect the contractile components of the muscle, muscle cell mass, and membrane condition, is associated with health outcomes. However, its association with the incidence of disabilities remains unclear. The aim of this study was to examine the association between whole-body and segmental PhA, ECW/ICW ratio, and the incidence of functional disability compared to conventional muscle mass.

A total of 858 older adults aged ≥65 years without functional disability at baseline were followed up for 12 years. Functional disabilities were identified using the database of the Japanese Long-Term Care Insurance System. Segmental muscle quality was assessed using the raw parameters of MF-BIA, including segmental PhA and the ECW/ICW resistance ratio. For comparison, the appendicular lean mass index (ALMI) and legMI were obtained using MF-BIA.

Functional disability was identified in 258 (30.1%) participants. Cox regression analysis showed that poorer leg PhA and ECW/ICW resistance ratios were significantly associated with a higher incidence of functional disability in both sexes, independent of covariates. A dose-response relationship indicated a higher risk for individuals with values below the median in the spline analysis. Conventional ALMI and legMI were not significantly associated with functional disability.

PhA and ECW/ICW ratio, especially in the leg, is a better predictor of functional disability than muscle mass. Muscle quality by BIA may be a useful biomarker for screening for future disabilities.

To explore the association of Life's Essential 8 (LE8) levels with leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN).

A cross-sectional study.

225,692 participants aged 37-73 year from the UK Biobank cohort enrolled from 2006 to 2010.

The LE8 score (0-100) was divided into low (<50), moderate (50-79), and high cardiovascular health (CVH) (≥80) categories, based on health behaviors and factors defined by the American Heart Association. LTL was measured by a validated quantitative polymerase chain reaction method. mtDNA-CN was reacted by standardized SNP probe intensities. The association of CVH (as both a continuous and categorical variable) with LTL and mtDNA-CN was examined using multiple linear regression.

Of 225,692 participants, 5.3% had low CVH, 81.2% had moderate CVH, and 13.4% had high CVH. Participants with higher CVH were usually younger, female, better educated, of higher socioeconomic status, and with a lower prevalence of comorbidities. After adjusting for confounders, a higher LE8 score is associated with longer LTL (Beta = 0.075, P < 0.05) and increased mtDNA-CN (Beta = 0.094, P < 0.05). We also observed that this association was evident in the health behavior score (diet, physical activity, nicotine exposure, and sleep) and the health factors score (BMI, non-HDL cholesterol, blood glucose, and blood pressure), with a stronger positive association of health factors with LTL and mtDNA-CN (Beta = 0.019, P < 0.05; Beta = 0.037, P < 0.05).

Higher CVH is associated with longer LTL and increased mtDNA-CN.

Vascular aging is a key driver of age-related cardiovascular and metabolic diseases, with endothelial dysfunction and senescence as a central mechanism. In our recent study, we observed elevated ADAM10 protein levels in senescent endothelial cells, which worsened endothelial dysfunction and senescence. However, the regulatory mechanisms controlling ADAM10 expression are poorly understood. In this study, we show that ADAM10 undergoes post-transcriptional modification in senescent human umbilical vein endothelial cells (HUVECs), with the E3 ubiquitin ligase MARCHF8 predicted to facilitate its ubiquitination-dependent degradation. We also found that MARCHF8 expression was significantly reduced in senescent HUVECs. Knockdown of MARCHF8 in young HUVECs induced endothelial senescence and impaired key endothelial functions, including migration, proliferation, angiogenesis, and nitric oxide production. Conversely, overexpression of MARCHF8 in senescent HUVECs ameliorated senescence-associated dysfunctions. RNA sequencing analysis revealed that MARCHF8 knockdown disrupted pathways linked to cell senescence and atherosclerosis. In vivo, MARCHF8 overexpression in high-fat diet-fed apoE-/- mice reduced plasma interleukin-6 levels and attenuated atherosclerosis progression. Additionally, miR-34a-5p upregulation in senescence inhibited MARCHF8 expression, compromising its protective effects in delaying endothelial senescence. Collectively, these findings reveal a novel miR-34a-5p/MARCHF8/ADAM10 axis in vascular endothelial senescence, positioning MARCHF8 as a potential biomarker and therapeutic target for vascular aging and related diseases.

The triglyceride-glucose (TyG) index has been linked to impaired cardiovascular fitness (CVF). However, the available evidence regarding the direct relationship between the TyG index and maximal oxygen uptake (VO2max) is limited. This study aims to investigate the association between the TyG index and VO2max.

We conducted a retrospective cross-sectional study involving 3,571 participants who completed a CVF examination as part of the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Data on triglycerides, glucose, and VO2max were collected from all participants. The TyG index was calculated using the formula: Ln[triglyceride (TG)(mg/dl) × fasting plasma glucose (FPG)(mg/dl)/2]. Linear regression analysis was utilized to substantiate the research objectives.

The complex sampling design and mobile examination center sample weights were considered. In multivariable linear regression analyses, each 1 unit increase in the TyG index was associated with a decrease in VO2max [β = -1.24, 95% CI (-1.97, -0.51), p = 0.002] when expressed as a continuous variable, independent of confounders. The TyG index was converted into a categorical variable based on four quartiles. Compared with the lowest TyG quintile (Q1: 6.750-7.887), the fully adjusted β for Q4 (8.672-12.481) was -1.91 (95% CI: -3.24, -0.57, p < 0.007). A significant interaction (p = 0.007) between sex and the TyG index for VO2max was found in the population using subgroup analysis. The results of the sensitivity analysis remained stable. Mediation analysis showed the direct effect of the TyG index was -1.467 (-2.019, -0.948), with a total effect of -1.813 (-2.377, -1.286). The mediation effect of diastolic blood pressure (DBP), white blood cell count (WBC), and C-reactive protein (CRP) was -0.389 (-0.526, -0.268), -0.308 (-0.432, -0.177), and -0.252 (-0.453, -0.135), respectively. HGB was found to exert a suppressing effect on the relationship between the TyG index and VO2max, with a value of 1.469 (1.252, 1.702). The p-values for all the above effects were <0.05.

In the US young and middle-aged population, the TyG index was significantly adversely associated with VO2max levels. Females may exert an interaction on TyG. Evidence supported DBP, WBC, and CRP as intervening variables through which the TyG index exerts its influence on VO2max. HGB may overrule the potential inverse association between the TyG index and VO2max.NCHS IRB/ERB Protocol Number: Protocol #98-12.

Aging is a complex biological process characterized by functional decline, reduced quality of life, and increased vulnerability to diseases such as type 2 diabetes, cardiovascular conditions, neurodegeneration, and cancer. Advances in medical technology have introduced the concept of aging therapies, with growth hormone (GH) and its primary mediator, insulin-like growth factor 1 (IGF-1), receiving considerable attention for their potential to counteract age-related physiological and metabolic changes. GH plays a multifaceted role in the human body, primarily influencing body composition by increasing muscle mass, reducing fat tissue, promoting bone formation, and regulating the metabolism of proteins, lipids, and glucose. Additional effects have been noted on endothelial function, cognitive performance, and circadian rhythms. This review examines the molecular mechanisms of GH in aging, its potential as an anti-aging therapy, and findings from clinical trials involving these hormones for this purpose. It also addresses the associated adverse effects, limitations, and controversies. While some studies report significant benefits, these therapies' long-term safety and efficacy in promoting healthy aging remain uncertain, highlighting the need for further research.

Telomeres protect the ends of chromosomes but shorten following cell division in the absence of telomerase activity. When telomeres become critically short or damaged, a DNA damage response is activated. Telomeres then become dysfunctional and trigger cellular senescence or death. Telomere shortening occurs with ageing and may contribute to associated maladies such as infertility, neurodegeneration, cancer, lung dysfunction and haematopoiesis disorders. Telomere dysfunction (sometimes without shortening) is associated with various diseases, known as telomere biology disorders (also known as telomeropathies). Telomere biology disorders include dyskeratosis congenita, Høyeraal-Hreidarsson syndrome, Coats plus syndrome and Revesz syndrome. Although mouse models have been invaluable in advancing telomere research, full recapitulation of human telomere-related diseases in mice has been challenging, owing to key differences between the species. In this Review, we discuss telomere protection, maintenance and damage. We highlight the differences between human and mouse telomere biology that may contribute to discrepancies between human diseases and mouse models. Finally, we discuss recent efforts to generate new 'humanized' mouse models to better model human telomere biology. A better understanding of the limitations of mouse telomere models will pave the road for more human-like models and further our understanding of telomere biology disorders, which will contribute towards the development of new therapies.

The m6A modification is an RNA modification that impacts various processes of RNA molecules, including transcription, splicing, stability, and translation. Recently, researchers have discovered that the presence of m6A modification can influence the interaction between tumor cells and immune cells and also play a role in regulating the expression of immune response-related genes. Additionally, m6A modification is intricately involved in the regulation of tumor immune evasion and drug resistance. Specifically, certain tumor cells can manipulate the gene expression through m6A modification to evade immune system attacks. Therefore, it might be possible to enhance tumor immune surveillance and improve the effectiveness of immune-based therapies by manipulating m6A modification. This review systematically discusses the role of m6A modification in tumor immunity, specifically highlighting its regulation of immune cells and immune-related genes in tumor cells. Furthermore, we explore the potential of m6A modification inhibitors as anti-cancer therapies and the significance of m6A regulatory factors in predicting the efficacy of tumor immune therapy.

Aging is a systemic, complex, and heterogeneous process characterized by a progressive decline in physiological functions, rendering it a major risk factor for various chronic diseases. Chronic inflammation has emerged as both a hallmark and a driver in this complicated process. This persistent inflammatory state arises from a spectrum of stimuli, ranging from external pathogens to internal cellular remnants, to metabolic dysregulation, and to chronic stress. Here, we examine recent mechanistic advances into the driving forces behind age-related chronic inflammation, explore promising anti-inflammatory strategies to mitigate aging, and address current challenges, proposing future directions to propel this evolving field toward translational breakthrough.

Biological processes are often spatially regulated, ensuring molecular and cellular events occur in their most strategically advantageous locations. Cellular senescence, marked by cell cycle arrest and hypersecretion, is recognized as an important part of physiological processes like development and healing, but it also contributes to aging and disease. However, the spatial distribution of senescent cells and its physiological and pathological impact remain unclear. Here we compile evidence on senescent cell localization in development, healing, and aging. We emphasize the significance of their spatial patterns and speculate on the effects of disrupted spatial positioning of senescence in relation to pathologies. To summarize the specific spatial functions of senescent cells, we propose to refer to them as 'barrier' and 'conductor' functions. The 'barrier' function of senescent cells, due to their altered morphology and apoptosis resistance, separates tissues and builds a border between two environments. The conductor function, with the secretion of signaling factors, influences the surrounding area and stimulates migration, differentiation, or proliferation, among other processes. Overall, this Review explores the spatial patterning of cellular senescence in biological processes, highlighting its dual roles as 'barrier' and 'conductor' functions, and examines the implications of senescent cell distribution in development, healing, aging, and disease.

Cellular senescence is the basic unit of organismal aging, a complicated biological process involving several cell types and tissues. It is also an important mechanism by which the body responds to damage and potential carcinogenesis. However, excessive or abnormal cellular senescence can lead to tissue functional degradation and the occurrence of diseases. In recent years, the role of epigenetic modifications in cellular senescence has received extensive attention. Lactylation, a novel post-translational modification derived from lactate, has recently gained significant attention as a key factor in cellular metabolism and epigenetic regulation, gradually demonstrating its importance in the regulation of cellular senescence. This review emphasizes the bidirectional causal relationship between lactylation and cellular senescence, highlighting its potential as a therapeutic target for aging-related diseases.

Aging biomarkers quantify aging progression and provide actionable targets for therapeutic interventions to mitigate age-related decline. This review synthesizes emerging evidence on testicular aging biomarkers, focusing on cellular senescence (Leydig, Sertoli, and endothelial cells), protein homeostasis disruption, mitochondrial dysfunction, germ stem cell depletion, sperm telomere length, epigenetic alterations, oxidative stress, inflammation, and gut microbiota dysbiosis. We propose that testicular aging serves as a critical nexus linking reproductive decline with systemic aging processes, with its pathological progression being quantifiable through specific biomarkers including the Leydig, Sertoli, and endothelial cells, INSL3, ribosomal protein RPL39L, sperm telomere length, relative telomere length mitochondrial translocator protein, and sialic acid. By bridging systemic aging paradigms with testis-specific mechanisms, we emphasize the urgency to identify organ-selective biomarkers for targeted interventions, advancing strategies to preserve male fertility and address population aging challenges.

Neurological disorders present considerable challenges in diagnosis and treatment due to their complex and diverse etiology. Retrotransposons are a type of mobile genetic element that are increasingly revealed to play a role in these diseases. This review provides a detailed overview of recent developments in the study of retrotransposons in neurodevelopment, neuroaging, and neurological diseases. Retrotransposons, including long interspersed nuclear elements-1, Alu, SINE-VNTR-Alu, and endogenous retrovirus, play important regulatory roles in the development and aging of the nervous system. They have also been implicated in the pathological processes of several neurological diseases, including Alzheimer's disease, X-linked dystonia-parkinsonism, amyotrophic lateral sclerosis, autism spectrum disorder, and schizophrenia. Retrotransposons provide a new perspective for understanding the molecular mechanisms underlying neurological diseases and provide insights into diagnostic and therapeutic strategies of these diseases.

The innate immune signaling network follows a canonical format for signal transmission. The innate immune pathway is crucial for defense against pathogens, yet its mechanistic crosstalk with aging processes remains largely unexplored. Retinoic acid-inducible gene-I (RIG-I), a key mediator of antiviral immunity within this pathway, has an enigmatic role in stem cell senescence. Our study reveals that RIG-I levels increase in human genetic and physiological cellular aging models, and its accumulation drives cellular senescence. Conversely, CRISPR/Cas9-mediated RIG-I deletion or pharmacological inhibition in human mesenchymal stem cells (hMSCs) confers resistance to senescence. Mechanistically, RIG-I binds to endogenous mRNAs, with CDKN1A mRNA being a prominent target. Specifically, RIG-I stabilizes CDKN1A mRNA, resulting in elevated CDKN1A transcript levels and increased p21Cip1 protein expression, which precipitates senescence. Collectively, our findings establish RIG-I as a post-transcriptional regulator of senescence and suggest potential targets for the mitigation of aging-related diseases.

In vitro models of neuronal aging and gene manipulation in human neurons (hNeurons) are valuable tools for investigating human brain aging and diseases. Here, we present a protocol for applying human embryonic stem cell (hESC)-derived neurons to model aging and the further application of small interfering RNA (siRNA)-mediated gene silencing for functional investigations. We describe steps for neuronal differentiation and culture, siRNA transfection, and technical considerations to ensure reproducibility. Our protocol enables investigations of the molecular mechanism underlying neuronal aging and facilitates drug evaluation. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Aging naturally involves a decline in biological functions, often triggering a disequilibrium of physiological processes. A common outcome is the altered response exerted by the immune system to counteract infections, known as immunosenescence, which has been recognized as a primary cause, among others, of the so-called long-COVID syndrome. Moreover, the uncontrolled immunoreaction leads to a state of subacute, chronic inflammatory state known as inflammaging, responsible in turn for the chronicization of concomitant pathologies in a self-sustaining process. Anti-inflammatory and immunosuppressant drugs are the current choice for the therapy of inflammaging in post-COVID complications, with contrasting results. The increasing knowledge of the biochemical pathways of inflammaging led to disclose new small molecules-based therapies directed toward different biological targets involved in inflammation, immunological response, and oxidative stress. Herein, paying particular attention to recent clinical data and preclinical literature, we focus on the role of endocannabinoid system in inflammaging, and the promising therapeutic option represented by the CB2R agonists, the role of novel ligands of the formyl peptide receptor 2 and ultimately the potential of newly discovered monoamine oxidase (MAO) inhibitors with neuroprotective activity in the treatment of immunosenescence.

The recent observational studies have unveiled the correlation between the composition and dynamic alterations of the gut microbiome and aging; however, the causal relationship remains uncertain.

The objective of this study is to investigate the causal relationship between the gut microbiome and accelerated aging as well as frailty, from a genetic perspective.

We obtained data on the gut microbiome, intrinsic epigenetic age acceleration, and Frailty Index from published large-scale genome-wide association studies. A two-sample Mendelian randomization analysis was conducted primarily using inverse variance weighting model. We utilized the MR-Egger intercept analysis, IVW method, the Cochran Q test, and the leave-one-out analysis to assess the robustness of the results.

IVW analysis indicated a potential association between Peptococcus (OR: 1.231, 95% CI 1.013-1.497, P = 0.037), Dialister (OR: 1.447, 95% CI 1.078-1.941, P = 0.014) and Subdoligranulum (OR: 1.538, 95% CI 1.047-2.257, P = 0.028) with intrinsic epigenetic age acceleration; while Prevotella 7 (OR: 0.792, 95% CI 0.672-0.935, P = 0.006) was associated with a potential protective effect. Allisonella (OR: 1.033, 95% CI 1.005-1.063, P = 0.022), Howardella (OR: 1.026, 95% CI 1.002-1.050, P = 0.031) and Eubacterium coprostanoligenes (OR: 1.037, 95% CI 1.001-1.073, P = 0.042) were associated with an increased risk of frailty; conversely, Flavonifractor (OR: 0.954, 95% CI 0.920-0.990, P = 0.012) and Victivallis (OR: 0.984, 95% CI 0.968-1.000, P = 0.049) appeared to exhibit a potential protective effect against frailty.

The findings of this study provide further evidence for the genetic correlation between gut microbiota and accelerated aging as well as frailty, enhancing the understanding of the role of gut microbiota in aging-related processes. However, the underlying mechanisms and potential clinical applications require further investigation before any targeted interventions can be developed.

Aims: S-propargyl-cysteine (SPRC) is an endogenous hydrogen sulfide (H2S) donor obtained by modifying the structure of S-allyl cysteine in garlic. This study aims to investigate the effect of SPRC on mitigating cardiac aging and the involvement of jumonji domain-containing protein 3 (JMJD3), a histone demethylase, which represents the primary risk factor in major aging related diseases, in this process, elucidating the preliminary mechanism through which SPRC regulation of JMJD3 occurs. Results: In vitro, SPRC mitigated the elevated levels of reactive oxygen species, senescence-associated β-galactosidase, p53, and p21, reversing the decline in mitochondrial membrane potential, which represented a reduction in cellular senescence. In vivo, SPRC improved Dox-induced cardiac pathological structure and function. Overexpression of JMJD3 accelerated cardiomyocytes and cardiac senescence, whereas its knockdown in vitro reduced the senescence phenotype. The potential binding site of the upstream transcription factor of JMJD3, sheared X box binding protein 1 (XBP1s), was determined using online software. SPRC promoted the expression of cystathionine γ-lyase (CSE), which subsequently inhibited the IRE1α/XBP1s signaling pathway and decreased JMJD3 expression. Innovations: This study is the first to establish JMJD3 as a crucial regulator of cardiac aging. SPRC can alleviate cardiac aging by upregulating CSE and inhibiting endoplasmic reticulum stress pathways, which in turn suppress JMJD3 expression. Conclusions: JMJD3 plays an essential role in cardiac aging regulation, whereas SPRC can suppress the expression of JMJD3 by upregulating CSE, thus delaying cardiac aging, which suggests that SPRC may serve as an aging protective agent, and pharmacological targeting of JMJD3 may also be a promising therapeutic approach in age-related heart diseases. Antioxid. Redox Signal. 42, 301-320.

Neurofilament light chain (NfL) is a specific biomarker of neuroaxonal damage and related neurodegenerative diseases. Aging acceleration, which reflects the impact of modifiable factors on the aging process, is increasingly recognized for its relevance. While normal aging is known to contribute substantially to neuroaxonal damage and many neurodegenerative diseases, the effects of aging acceleration warrant further investigation. This study aimed to investigate the association and causality between aging acceleration and serum NfL levels.

We conducted a cross-sectional study involving 1695 adult participants from NHANES 2013-2014 to evaluate the association, dose-response relationship, and interaction network between aging acceleration and serum NfL levels. And we used Mendelian randomization (MR) to assess the causal effects between serum NfL levels and aging acceleration.

Significant positive associations were observed between aging acceleration and serum NfL levels. In linear regression, the regression coefficients were 0.016 (95 % CI: 0.011-0.021) for biological age acceleration and 0.020 (95 % CI: 0.012-0.028) for phenotypic age acceleration. In logistic regression, the odds ratios were 1.052 (95 % CI: 1.029-1.076) and 1.093 (95 % CI: 1.064-1.123), respectively. Restricted cubic spline regression identified significant positive dose-response relationships, and bidirectional MR analyses demonstrated forward causal effects.

Our study indicates that aging acceleration is significantly associated with serum NfL levels, with higher levels of aging acceleration linked to an increased risk of neuroaxonal damage. These findings provide robust evidence that aging acceleration affects the risk of neuroaxonal damage and highlight the importance of modifiable aging factors.

Ageing-induced skeletal muscle deterioration contributes to sarcopenia and frailty, adversely impacting the quality of life in the elderly. However, the molecular mechanisms behind primate skeletal muscle ageing remain largely unexplored. Here, we show that SIRT5 expression is reduced in aged primate skeletal muscles from both genders. SIRT5 deficiency in human myotubes hastens cellular senescence and intensifies inflammation. Mechanistically, we demonstrate that TBK1 is a natural substrate for SIRT5. SIRT5 desuccinylates TBK1 at lysine 137, which leads to TBK1 dephosphorylation and the suppression of the downstream inflammatory pathway. Using SIRT5 lentiviral vectors for skeletal muscle gene therapy in male mice enhances physical performance and alleviates age-related muscle dysfunction. This study sheds light on the molecular underpinnings of skeletal muscle ageing and presents the SIRT5-TBK1 pathway as a promising target for combating age-related skeletal muscle degeneration.

Aging is associated with alternative splicing (AS) defects that have broad implications on aging-associated disorders. However, which drug(s) can rescue age-related AS defects and extend lifespan has not been systematically explored. We performed large-scale compound screening in C. elegans using a dual-fluorescent splicing reporter system. Among the top hits, doxifluridine, a fluoropyrimidine derivative, rescues age-associated AS defects and extends lifespan. Combining bacterial DNA sequencing, proteomics, metabolomics and the three-way screen system, we further revealed that bacterial ribonucleotide metabolism plays an essential role in doxifluridine conversion and efficacy. Furthermore, doxifluridine increases production of bacterial metabolites, such as linoleic acid and agmatine, to prolong host lifespan. Together, our results identify doxifluridine as a potent lead compound for rescuing aging-associated AS defects and extending lifespan, and elucidate drug's functions through complex interplay among drug, bacteria and host.

Commensal bacteria and their derivatives hold significant promise as therapeutic interventions to delay aging. However, with the diverse nature of the soil microbiome and the long lifespan of mammalian models, the exploration of the influence of soil bacteria and bacteria-derived molecules on host aging remains limited. We conducted a lifespan screening in Caenorhabditis elegans using plant root bacterial collection. Our screening identified 8 genera of bacterial isolates capable of extending lifespan, with Mycobacterium sp. Root265 exhibits the most pronounced effect on lifespan extension. Biochemical analysis revealed two specific molecules derived from Root265, polysaccharides (PSs) and arabinogalactan peptidoglycan (AGP), responsible for lifespan extension via daf-16-dependent and -independent pathways, respectively. Notably, AGP exhibited a unique ability to enhance protein homeostasis effectively. Moreover, polar lipids originating from Root265 were found to extend lifespan while mitigating age-related BAS-1 decline in neurons. Intriguingly, even brief exposures to these bioactive compounds were sufficient to achieve the lifespan-promoting effects. We found diverse beneficial bacteria and anti-aging active compounds from soil bacteria. These findings highlight the potential of exploring bacterial derivatives as therapies targeting aging without the constraints associated with direct microbial interventions.

Environmental factors are linked to aging and age-related diseases. Emerging evidence suggests that enhancing body's resistance to xenobiotics might be an anti-aging strategy. The constitutive androstane receptor (CAR) regulates drug-metabolizing enzymes and transporters, coordinating metabolism and immune responses to adapt to stress triggered by exogenous exposure. However, the impact of activating CAR on aging remains unknown. In this study, Caenorhabditis elegans (C. elegans), drug-induced premature aging mice, and senescence accelerated P8 (SAMP8) mice are used as models to explore the effects of CAR activation on lifespan and healthspan, along with the underlying mechanisms. The results showed that hCAR agonist CITCO and mCAR agonist TCPOBOP prolonged the lifespan and healthspan in model organism. The longevity effects of CITCO and TCPOBOP were attenuated in CAR homozygous nhr-8/daf-12 mutant C. elegans as well as CAR-/- mice. In C. elegans, CITCO activated both anti-stress and detoxification genes, and increased the resistance to environmental adversities. Additionally, the lifespan-extending and xenobiotic resistant effects of CITCO might be related to the regulation of age-related pathways. Furthermore, CITCO improved age-related neurodegeneration in C. elegans models. Taken together, the results suggest that the longevity effects of CAR agonists may be related to the enhancement of xenobiotic resistance of animals.

The fruits of Lycium ruthenicum Murr. (Solanaceae) are employed in ethnomedicine and used as a functional food. Their antioxidant, anti-aging, and hypolipidemic activities have been investigated in modern research. This study indicated that the ethanolic extract of the fruits of L. ruthenicum Murr. (LRM) improved oxidative and heat stress tolerance, reduced the accumulation of lipofuscin, and retarded the aging process in Caenorhabditis elegans (Rhabditidae). Furthermore, the pharyngeal pumping rate and body length decreased under LRM treatment. Moreover, metabolomic analysis and the DPClusO algorithm revealed that LRM regulated a series of lifespan-related pathways centered on glycine, serine, and threonine metabolism. These results suggest that LRM prolongs the lifespan of Caenorhabditis elegans via dietary restriction. Moreover, feruloyl putrescine, a kind of polyamine, was found in differential metabolites, which may be the metabolite of caffeoyl-spermidine in LRM. These findings from this exploratory study offer a new insight into the roles of L. ruthenicum in anti-aging activity as a functional food.

It is well known that aging affects many systems in the body. The digestive system is one of the systems most affected by aging. In our study, we examined the effects of young plasma treatment on cell proliferation, growth factors, immune defense and histological parameters in the jejunum of aged male rats. For this purpose, aged male Sprague Dawley rats (24 months, n = 7) were treated with pooled plasma (0.5 ml/day, intravenously for 30 days) collected from young (5 weeks, n = 51) rats. Aged rats that received young plasma treatment were grouped as the experimental group, while aged rats formed the control group. At the end of the experiment, the jejunums of the groups were collected and histological parameters such as villus height, crypt depth, total mucosal thickness and surface absorption areas were measured and compared. In addition, cell proliferation index and proliferation intensity in the crypt glands of the jejunum were evaluated with proliferating cell nuclear antigen and expressions of growth factors such as insulin-like growth factor I (IGF-I) and its receptor (IGF-IR) expression and effects of immunoglobulin A (IgA), which plays a role in the defense of the digestive system against microorganisms, were examined. In the experimental group, an increase in histological parameters, IGF-R and IGF-IR expression, proliferation density, proliferation index and IgA expression density and IgA cell count were observed compared to the control group. These results suggest that young plasma treatment has a positive effect on the digestive system and may be a potential therapeutic for tissue regeneration.

As the global population continues to age, the prevalence of age-related diseases is increasing, significantly influencing social and economic development, the stability of social security systems, and progress in medical technology. Ferroptosis, a recently discovered form of programmed cell death driven by iron-dependent lipid peroxidation, has emerged as a key area of research. Studies have revealed a strong association between ferroptosis and senescence. In this article, we systematically summarize the molecular mechanisms and associated signaling pathways underlying ferroptosis, emphasizing its pivotal role in the onset and progression of age-related diseases. By providing new perspectives, we aim to advance understanding of the pathogenesis of age-related diseases and guide the development of effective intervention strategies.

Gastric cancer (GC) ranks as one of the most prevalent malignant tumors globally. The subtle manifestation of its early-stage symptoms often results in many GC patients being diagnosed at a late or advanced stage, thereby posing significant obstacles to the effectiveness of chemotherapy treatments. Therefore, identifying early biomarkers for GC is crucial. In recent years, an increasing number of studies have highlighted the pivotal role that aging plays in the progression of cancer. Among the various proteins involved, Cytoskeleton-associated protein 2 (CKAP2) emerges as a crucial player in controlling cell proliferation, regulating mitosis and cell division, and exerting a significant influence on the aging process. We employed a bioinformatics approach to assess the causal association between aging-related genes and GC and explore the potential significance of CKAP2 in GC by analyzing data sourced from various repositories, including Genotype Tissue Expression (GTEx), GWAS Catalog, The Database of Cell Senescence Genes (CellAge), The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Human Protein Atlas (HPA), and the Comparative Toxicology Genome Database (CTD). Our research summarized the causal relationship between CKAP2 expression and the development risk of GC, differential expression in GC, the relationship with the prognosis of GC, genetic correlation, functional analysis, and immune cell infiltration, and explored the interaction of CKAP2 and chemical substances. The findings revealed that an elevation in CKAP2 expression correlated with a reduced likelihood of developing GC. There was a significant difference in the expression of CKAP2 between GC and normal patients. Specifically, there was higher expression in GC compared to normal patients. In addition, CKAP2 has been proven to have diagnostic value in GC, and elevated levels of CKAP2 expression are indicative of a more favorable prognosis. Immune infiltration analysis revealed the relationship between CKAP2 and tumor immune microenvironment, while the Comparative Toxicology Genome Database (CTD) identified a small molecule compound that may target CKAP2. In summary, through comprehensive multivariate analyses, we identified and validated the potential role that CKAP2 may play in GC. Therefore, CKAP2 shows potential as an indicator for both the diagnosis and prognosis of GC, making it worthy of further clinical investigation.

One of the parameters observed in functional capacity over the years is the decrease in neuromuscular responses, a fact that is attributed to the contemporary lifestyle. Thus, there is a need to carry out interventions that induce the improvement of functional capacity. Some studies have associated electrostimulation (NMES) with Strength Training (ST) to enhance the results in improving neuromuscular function. However, little is known about the effects of this association due to the numerous protocols to be manipulated. Furthermore, adaptive responses to strength training are dependent on volume and intensity manipulation.

To investigate the influence of ST, concomitant with NMES (NMES+) on functional capacity.

This is a systematic review with meta-analysis. For the search of the articles, descriptors associated with functional capacity and NMES+ were selected in the Cochrane, PubMed, Embase and VHL meta-searcher databases. Inclusion criteria were articles that presented neuromuscular electrostimulation superimposed on voluntary contraction and ST intensity control; and that did not have a therapeutic purpose. The analysis of titles, abstracts and data extraction were performed by trios of reviewers. To assess the qualities of scientific evidence, the risk of bias was analyzed through the ROB2 tool, meta- analysis and evaluation of the quality of evidence (GRADE).

This meta-analysis selected 3 studies. The main outcomes observed in the studies were agility, balance, cardiorespiratory capacity and strength and power. A significant improvement in effect estimates for cardiorespiratory capacity alone was observed between the two studies.

Despite the significant effect of the use of NMES+, in relation to ST in isolation, the quality of the evidence was considered low, probably due to the limited number of scientific evidence found, requiring further studies to identify the real effect of this association.

Aging is a physiological/pathological process accompanied by progressive impairment of cellular function, leading to a variety of aging-related diseases. STAT3 is one of the core regulatory factors of aging. It is involved in body metabolism, development and senescence, cell apoptosis and so on. During the aging process, the changes of growth factors and cytokines will cause the activation of STAT3 to varying degrees, regulate the inflammatory pathways related to aging, regulate body inflammation, mitochondrial function, cell aging and autophagy to regulate and influence the aging process. Drugs targeting STAT3 can treat senescence related diseases. This review summarizes the role of STAT3 signaling factors in the pathogenesis of aging, including mitochondrial function, cellular senescence, autophagy, and chronic inflammation mediated by inflammatory pathways. Finally, the key regulatory role of STAT3 in senescence related diseases is emphasized. In summary, we reveal that drug development and clinical application targeting STAT3 is one of the key points in delaying aging and treating aging-related diseases in the future.

An increasing proportion of the aging population has led to a rapid increase in the number of elderly patients with ulcerative colitis (UC). However, the molecular mechanisms by which aging causes UC remain unclear. In this study, we explored the role of aging-related genes (ARGs) in UC pathogenesis and diagnosis prediction.

Gene expression data were obtained from four independent datasets (GSE75214, GSE87466, GSE94648, and GSE169568) in the GEO database, and ARGs were derived from multiple public databases. After identifying UC-related ARGs, consistent clustering was performed to screen aging-related molecular subtypes, followed by the exploration of differences in the immune microenvironment and pathways between distinct subtypes. Next, core module genes were screened using WGCNA and then the hub genes were characterized using LASSO and random forest methods. Besides, the associations between hub genes, immune cells, and key pathways were explored. Finally, the expression levels of key genes were determined in a dextran sulfate sodium (DSS)-induced UC mouse model by qRT-PCR.

UC samples were classified into two subtypes (1 and 2), which displayed significant differences in the immune landscape and JAK/STAT signaling pathways. A series of machine learning algorithms was used to screen two feature genes (ETS1 and IL7R) to establish the diagnostic model, which exhibited satisfactory diagnostic efficiency. In addition, these hub genes were closely associated with the infiltration of specific immune cells (such as neutrophils, memory B cells, and M2 macrophages) as well as with the JAK/STAT pathway. Later, experimental validation confirmed that ETS1 expression was markedly increased in a mouse model of UC.

Overall, aging, immune dysregulation, and UC process are closely associated. The identified feature genes, particularly ETS1, could serve as novel diagnostic biomarkers for UC. These findings have the potential to enhance the understanding of the age-related mechanisms of UC.

Aging is an inevitable multifactor process that causes a decline in organ function and increases the risk of age-related diseases and death. Thus, the development of highly effective and safe therapeutic strategies to delay aging and age-related diseases is urgently required. In this study, we isolated natural melanin nanozymes (NMNs) from the ink sacs of live octopuses. The NMNs exhibited excellent superoxide-dismutase-mimicking and radical scavenging activities. In SAMP8 mice, treatment with NMNs improved their cognition and memory functions while restoring their aging-impaired liver function and lipid metabolism, thereby prolonging their lifespan. Moreover, the NMNs reversed metabolic changes in their aged brains and reconstructed their gut microbiota composition by enhancing microbial community diversity. Our findings indicate that NMNs treatment could be a promising approach for delaying aging and preventing age-associated physiological decline in humans.

Cellular aging is a multifactorial and intricately regulated physiological process with profound implications. The interaction between cellular senescence and cancer is complex and multifaceted, senescence can both promote and inhibit tumor progression through various mechanisms. M6A methylation modification regulates the aging process of cells and tissues by modulating senescence-related genes. In this review, we comprehensively discuss the characteristics of cellular senescence, the signaling pathways regulating senescence, the biomarkers of senescence, and the mechanisms of anti-senescence drugs. Notably, this review also delves into the complex interactions between senescence and cancer, emphasizing the dual role of the senescent microenvironment in tumor initiation, progression, and treatment. Finally, we thoroughly explore the function and mechanism of m6A methylation modification in cellular senescence, revealing its critical role in regulating gene expression and maintaining cellular homeostasis. In conclusion, this review provides a comprehensive perspective on the molecular mechanisms and biological significance of cellular senescence and offers new insights for the development of anti-senescence strategies.

Our limited understanding of metabolic aging poses major challenges to comprehending the diverse cellular alterations that contribute to age-related decline, and to devising targeted interventions. This review provides insights into the heterogeneous nature of cellular metabolism during aging and its response to interventions, with a specific focus on cellular heterogeneity and its implications. By synthesizing recent findings using single-cell approaches, we explored the vulnerabilities of distinct cell types and key metabolic pathways. Delving into the cell type-specific alterations underlying the efficacy of systemic interventions, we also discuss the complexity of integrating single-cell data and advocate for leveraging computational tools and artificial intelligence to harness the full potential of these data, develop effective strategies against metabolic aging, and promote healthy aging.

The hallmarks of aging encompass a variety of molecular categories (genomic, telomeric, and epigenetic), organelles (proteostasis, autophagy, and mitochondria), cellular components (including stem cells), systems (such as intercellular communication and chronic inflammation), and environmental factors (dysbiosis and nutrient sensing). These hallmarks play a crucial role in the aging process. Despite their intricate interconnections, the relationships among the hallmarks of aging remain unclear. Although the boundaries between these hallmarks may be indistinct, they exhibit interdependence, with the influence of one hallmark extending to others. Building on this foundation, we investigated the interrelations among the various hallmarks of aging and provided a systematic overview of their logical relationships, proposing that cellular communication plays a crucial role in the aging process. Exosomes function as a primary mode of cellular communication and significantly impact the aging process. Therefore, we propose utilizing exosomes as valuable tools for understanding the mechanisms of aging and addressing age-related concerns. Exosomes may represent a novel approach for the treatment and diagnosis of aging-related conditions in animals. Furthermore, our research reveals that exocytosis in young nematodes slows the aging process, while exocytosis in aged nematodes has the opposite effect, accelerating aging. In conclusion, exosomes act as intercellular messengers that influence the maintenance of a healthy aging process and link the hallmarks of aging with indicators of well-being.

Precisely assessing an individual's immune age is critical for developing targeted aging interventions. Although traditional methods for evaluating biological age, such as the use of cellular senescence markers and physiological indicators, have been widely applied, these methods inherently struggle to capture the full complexity of biological aging. We propose the concept of an 'immunosenescence clock' that evaluates immune system changes on the basis of changes in immune cell abundance and omics data (including transcriptome and proteome data), providing a complementary indicator for understanding age-related physiological transformations. Rather than claiming to definitively measure biological age, this approach can be divided into a biological age prediction clock and a mortality prediction clock. The main function of the biological age prediction clock is to reflect the physiological state through the transcriptome data of peripheral blood mononuclear cells (PBMCs), whereas the mortality prediction clock emphasizes the ability to identify people at high risk of mortality and disease. We hereby present nearly all of the immunosenescence clocks developed to date, as well as their functional differences. Critically, we explicitly acknowledge that no single diagnostic test can exhaustively capture the intricate changes associated with biological aging. Furthermore, as these biological functions are based on the acceleration or delay of immunosenescence, we also summarize the factors that accelerate immunosenescence and the methods for delaying it. A deep understanding of the regulatory mechanisms of immunosenescence can help establish more accurate immune-age models, providing support for personalized longevity interventions and improving quality of life in old age.

Bone marrow mesenchymal stem cells (MSCs) serve a pivotal role in the hematopoietic niche. The present study collected bone marrow samples from individuals across various age groups to investigate the biological characteristics of MSCs. By modifying the bone marrow microenvironment through co‑culture techniques, changes in the stemness of MSCs were examined. An in vitro hematopoietic co‑culture system was established to simulate the impact of MSCs on hematopoietic stem cells. The results demonstrated that the mode of cell‑to‑cell contact among stem cells is more influential in shaping bone marrow function compared with the effects of aging on these stem cells. Transcriptomic analysis revealed that MSCs serve as essential mediators, with their growth variations being both a consequence and a cause of changes in the bone marrow microenvironment. Furthermore, the decline in hematopoietic function observed in the elderly is a manifestation of this phenomenon. Data from the present study suggest that targeting MSCs is essential for enhancing bone marrow function and improving the outcomes of bone marrow transplantation.

Aging is an intricate process involving interactions among multiple factors, which is one of the main risks for chronic diseases, including Alzheimer's disease (AD). As a member of cysteine protease, cathepsin S (CTSS) has been implicated in inflammation across various diseases. Here, we investigated the role of neuronal CTSS in aging and AD started by examining CTSS expression in hippocampus neurons of aging mice and identified a significant increase, which was negatively correlated with recognition abilities. Concurrently, we observed an elevation of CTSS concentration in the serum of elderly people. Transcriptome and fluorescence-activated cell sorting (FACS) results revealed that CTSS overexpression in neurons aggravated brain inflammatory milieu with microglia activation to M1 pro-inflammatory phenotype, activation of chemokine C-X3-C-motif ligand 1 (CX3CL1)-chemokine C-X3-C-motif receptor 1 (CX3CR1) axis and janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. As CX3CL1 is secreted by neurons and acts on the CX3CR1 in microglia, our results revealed for the first time the role of neuron CTSS in neuron-microglia "crosstalk." Besides, we observed elevated CTSS expression in multiple brain regions of AD patients, including the hippocampus. Utilizing CTSS selective inhibitor, LY3000328, rescued AD-related pathological features in APP/PS1 mice. We further noticed that neuronal CTSS overexpression increased cathepsin B (CTSB) activity, but decreased cathepsin L (CTSL) activity in microglia. Overall, we provide evidence that CTSS can be used as an aging biomarker and plays regulatory roles through modulating neuroinflammation and recognition in aging and AD process.