npj aging最新文献

The pursuit of understanding early genetic or protein markers for ovarian aging has garnered considerable attention in the realm of reproductive medicine. Sirtuins (SIRTs) are a group of proteins that are NAD⁺-dependent, and thanks to their properties, they are able to change the acetylation profile of proteins and post-translationally modify their functions, too. Previous research provided evidence that SIRTs influence fibrosis levels in several organs. With regard to ovaries, fibrosis is one of the features of aged ovaries and also creates a metastasis-friendly environment, thus can also be a seedbed for the development of primary cancerous lesions. Ovarian cancer remains a formidable challenge in oncology due to its high prevalence, insidious onset, and frequent recurrence. Noteworthy, ovarian cancer is the seventh most common cancer among women and the eighth leading cause of cancer death worldwide. Ovarian fibrosis runs concurrently with the activation of TGF-β/Smads signaling, as well as inflammasome (NLRP3), nuclear factor kB (NFkB) and forkhead box O (FOXO) attenuation. Reduced levels of certain sirtuins resulting from decreased nicotinamide adenine dinucleotide (NAD + ) may underlie the dysregulation of the aforementioned signaling pathways and therefore represent a potential therapeutic target. This review elucidates the role of SIRTs in ovarian aging-related fibrosis as a process that predisposes to tumorigenesis.

The Rab3 protein family is composed of a series of small GTP-binding proteins, including Rab3a, Rab3b, Rab3c, and Rab3d, termed Rab3s. They play crucial roles in health, including in brain function, such as through the regulation of synaptic transmission and neuronal activities. In the high-energy-demanding and high-traffic neurons, the Rab3s regulate essential cellular processes, including trafficking of synaptic vesicles and lysosomal positioning, which are pivotal for the maintenance of synaptic integrity and neuronal physiology. Emerging findings suggest that alterations in Rab3s expression are associated with age-related neurodegenerative pathologies, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, among others. Here, we provide an overview of how Rab3s dysregulation disrupts neuronal homeostasis, contributing to impaired autophagy, synaptic dysfunction, and eventually leading to neuronal death. We highlight emerging questions on how Rab3s safeguards the brain and how their dysfunction contributes to the different neurodegenerative diseases. We propose fine-tuning the Rab3s signaling directly or indirectly, such as via targeting their upstream protein AMPK, holding therapeutic potential.

African turquoise killifish (Nothobranchius furzeri) is the shortest-lived vertebrate that can be bred in captivity, making it an ideal model organism for aging studies. However, whether the animal can be used for studying cardiac aging and whether cellular senescence contribute to this ageing process remain unclear. Here, we conducted a longitudinal study on the GRZ strain, aiming to identify phenotypic and functional markers for cardiac aging. We found that cardiac ageing in GRZ fish can be measured by comparing fish at 16 weeks to 8 weeks of age, using systemic markers such as body/fin coloration, body weight, BMI, cardiac ageing markers such as EF, E/A ratio, and swimming capacity, and cellular senescence markers such as SA-β-gal staining, p15/p16, γ-H2A.X, and SASP markers. Senolytic treatment with D (Dasatinib) and Q (Quercetin) from 12 to 16 weeks mitigated senescence and decelerated cardiac ageing. Together, our findings established GRZ as a useful vertebrate model for studying cardiac ageing and related cardiac senescence.

Cellular senescence represents a permanent state of cell cycle arrest, also observed in neurodegenerative disorders. As p300 has been identified as an epigenetic driver of replicative senescence, we aimed to investigate whether in vitro p300 inhibition could rescue the stress-induced premature senescence (SIPS) phenotype. We exploited 2D and 3D (brain organoids) in vitro models of SIPS using two different stressor agents. In addition, we combined the treatment with a p300 inhibitor and validated p300 role in SIPS by analyzing different senescence markers and the transcriptome in our models. Interestingly, p300 inhibition can counteract the DNA damage and SIPS phenotype, detecting a dysregulation of gene expression and protein translation associated with the senescence program. These findings highlight both the molecular mechanisms underlying senescence and p300 as a possible pharmacological target. Thus, targeting p300 and, by extension, senescent cells could represent a promising therapeutic strategy for age-related diseases such as neurodegenerative disorders.

Aging is the primary risk factor for many cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival, we built individual-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for non-cancerous lung samples from GTEx project and LUAD samples from TCGA. In healthy lung, pathways involved in cell proliferation and immune response were increasingly targeted with age; these aging-associated alterations were accelerated by smoking and resembled oncogenic shifts observed in LUAD. Aging-associated genes showed greater aging-biased targeting patterns in individuals with LUAD compared to healthier counterparts, a pattern suggestive of age acceleration. Using drug repurposing tool CLUEreg, we found small molecule drugs that may potentially alter the accelerating aging profiles we found. We defined a network-informed aging signature that was associated with survival in LUAD.

Psilocybin, the naturally occurring psychedelic compound produced by hallucinogenic mushrooms, has received attention due to considerable clinical evidence for its therapeutic potential to treat various psychiatric and neurodegenerative indications. However, the underlying molecular mechanisms remain enigmatic, and few studies have explored its systemic impacts. We provide the first experimental evidence that psilocin (the active metabolite of psilocybin) treatment extends cellular lifespan and psilocybin treatment promotes increased longevity in aged mice, suggesting that psilocybin may be a potent geroprotective agent.

Mobility is a cornerstone of health and quality of life, particularly in older adults. Digital mobility outcomes (DMOs) from real-world walking data offer crucial insights into the functional status and early markers of mobility decline. This study provides reference values for walking activity, pace, rhythm, and gait bout-to-bout variability in community-dwelling older adults and evaluates the effects of age, sex, height, and weight on these parameters. Using data from 200 older adults (aged 65-94 years) from the InCHIANTI Study and applying the Mobilise-D computational pipeline, we analyzed real-world walking over a week. Significant differences by sex and age were found, with males showing higher walking activity in younger age groups (65-74 and 75-84 years) but not in the oldest group (85-94 years). Additionally, we observed non-linear trends in mobility metrics with age, indicating an accelerated reduction in mobility at certain age ranges. These findings underscore the importance of monitoring real-world walking data to pinpoint critical periods of mobility decline and guide targeted interventions. This work offers valuable benchmarks for clinical assessments and future research.

This study analyzed UK Biobank data from 46,463 postmenopausal women to investigate metabolic changes linked to years since menopause (YSM) and their impact on aging biomarkers. Elastic net regression identified 115 YSM-associated metabolites, forming a metabolic signature strongly correlated with YSM (r = 0.30, P < 0.001). Each standard deviation increase in this metabolic signature was associated with decreased odds of long telomere length (0.94, 0.92-0.96), increased odds of high allostatic load (1.53, 1.50-1.56) and high PhenoAge (2.30, 2.17-2.44). Mediation analysis indicated that the metabolic signature explained 43.5% of the association between YSM and allostatic load, 9.09% between YSM and telomere length, and 89.3% between YSM and PhenoAge. These findings reveal how menopause-related metabolic shifts drive biological aging, highlighting potential intervention targets for postmenopausal health.

Neuronal senescence (i.e., neurescence) is an important hallmark of aging and neurodegeneration, but it remains poorly characterized in the human brain due to the lack of reliable markers. This study aimed to identify neurescence markers based on single-nucleus transcriptome data from postmortem human prefrontal cortex. Using an eigengene approach, we integrated three gene panels: (a) SenMayo, (b) canonical senescence pathway (CSP), and (c) senescence initiating pathway (SIP), to identify neurescence signatures. We found that paired markers outperform single markers; for instance, by combining CDKN2D and ETS2 in a decision tree, a high accuracy of 99% and perfect specificity (100%) were achieved in distinguishing senescent neurons (i.e, neurescent). Differential expression analyses identified 324 genes that are overexpressed in neurescent. These genes showed significant associations with important neurodegeneration-related pathways, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. Interestingly, several of these overexpressed genes are linked to mitochondrial dysfunction and cytoskeletal dysregulation. These findings provide valuable insights into the complexities of neurescence, emphasizing the need for further exploration of histologically viable markers and validation in broader datasets.

Immunometabolism, encompassing metabolic processes within the immune system, plays a pivotal role in modulating the development, activity, and function of immune cells. Oxidative stress, resulting from an imbalance between pro-oxidants and antioxidants, is a critical factor in the pathogenesis of various diseases, including cancer and aging. This review synthesizes current knowledge on the interplay between immunometabolism and oxidative stress, highlighting their mechanisms in cancer progression and the aging process. We discuss how metabolic reprogramming in our body can influence immune cell function and promoting ageing and cancer development. Additionally, we examine the impact of aging on immune metabolism, leading to a decline in immune function and a predisposition to chronic diseases. The review also explores the potential of traditional Chinese medicine in targeting oxidative stress to delay aging and combat cancer, underscoring the need for further research to elucidate the molecular mechanisms underlying these effects. Our findings suggest that interventions targeting immunometabolism and oxidative stress could offer novel therapeutic avenues for cancer and aging-related diseases.