Biogerontology最新文献

Is there a limit to human lifespan? We examine upper-tail lifespan dynamics in 46 countries using reliable period life-table data. The characteristic life ( $\alpha$ ), the model-based upper-tail parameter ( $\omega$ ), and their interval ( $\delta =\omega -\alpha$ ) are estimated annually from the 1990s onward. Across countries, $\alpha$ increases steadily, whereas $\omega$ declines or stabilizes and $\delta$ narrows, a pattern consistent with postponed and increasingly concentrated late-life mortality rather than unlimited upper-tail expansion. Under the baseline $L=120$ projection model, both females and males approach $\omega \approx 120$ years and $\alpha \approx 103.5$ years by 2100. Sensitivity analyses show that the inferred asymptotic boundary is model-dependent, so the projected value near 120 years should be interpreted as a mathematical upper-tail estimate rather than a definitive biological maximum. These findings are consistent with, but do not establish, an increasingly bounded upper-tail survival regime within the present demographic and modeling framework.

Prolonged crises expose older adults to chronic psychological and social stress, irregular nutrition, reduced physical activity, reduced access to health care, and interruptions in treatment of chronic disease. Together, these factors can compound age-related vulnerabilities and increase the risk of metabolic deterioration, multimorbidity and functional decline. This Perspective argues that prolonged crises should be viewed not only as social or psychological events, but also as conditions that may affect stress-related and ageing-related biological pathways. Severe or prolonged stress, however, can make these responses maladaptive and contribute to physiological dysregulation. Under prolonged crisis conditions, such maladaptive stress responses may be linked to abdominal obesity, sarcopenic obesity, physical frailty, and functional decline through chronic activation of the hypothalamic-pituitary-adrenal axis, altered glucocorticoid signalling, sleep disturbance, inflammation, cellular senescence and senescence-associated secretory phenotype, immunometabolic dysregulation, adipose tissue inflammation, insulin resistance, mitochondrial dysfunction and anabolic resistance in skeletal muscle. Ukraine is a timely example of this broader problem, as prolonged war, population ageing, non-communicable diseases, displacement, mental health needs, and new screening initiatives now intersect. Thus, a biologically informed framework for healthy ageing needs to incorporate mental health assessment, metabolic screening, nutritional assessment, muscle function and rehabilitation rather than address these in isolation. Functional ability reflects the combined effects of psychological stress, metabolic ageing, muscle loss, multimorbidity, and changes in the living environment. It should be considered a key indicator for older adults during and after prolonged crises.

Actin is a highly conserved cytoskeletal protein that regulates numerous cellular processes essential for tissue homeostasis and healthy aging. Although genetic studies have established important roles for actin and actin-binding proteins in longevity, pharmacological approaches offer complementary advantages for manipulating conserved cytoskeletal pathways across model systems. Here, we systematically evaluated the effects of small-molecule modulators targeting distinct actin regulatory pathways on lifespan, locomotor function, and tissue-specific actin organization in Caenorhabditis elegans. Animals were treated with compounds targeting the Arp2/3 complex (CK666), tropomyosin-dependent actin regulation (TR100), formins (SMIFH2), cofilin regulation (SZ-3), or actin stabilization (phalloidin). Among the compounds tested, only CK666 consistently produced a dose-dependent reduction in lifespan and exacerbated age-associated muscle actin disorganization, identifying Arp2/3-mediated actin branching as a critical regulator of cytoskeletal integrity during aging. CK666 also transiently disrupted hypodermal actin organization early in adulthood. In contrast, SMIFH2, TR100, phalloidin, and SZ-3 produced little or no detectable disruption of muscle actin organization, despite previous genetic studies demonstrating roles for several of these pathways in aging. Comparison with prior RNAi studies suggests that pharmacological perturbation can reproduce some aspects of actin dysfunction but may be limited by compound stability, drug delivery, or inefficient targeting of proteins in C. elegans. Together, these findings establish a framework for evaluating pharmacological modulation of actin during aging, identify CK666-mediated Arp2/3 inhibition as the most robust pharmacological perturbation under the conditions tested, and highlight important considerations for translating genetic discoveries into pharmacological strategies to target cytoskeletal function during aging.

Cellular senescence, a hallmark of aging, entails the irreversible cessation of cell division in response to intrinsic and extrinsic stressors. Though metabolically active, senescent cells lose their replicative capacity and resist apoptotic signals, accumulating tissues with advancing age and contributing to age-related pathologies. Senescence is characterized by the acquisition of a senescence-associated secretory phenotype (SASP), releasing a myriad of bioactive molecules. SASP not only influences intracellular processes but also orchestrates the modification of neighboring cells and the surrounding microenvironment. In the context of aging, the proportion of senescent cells escalates, ranging from 1 to 15% in different species, tissues, and activity levels. This accumulation is associated with age-related diseases and morbidity. Beyond aging, senescence induction is observed in response to cancer treatments, including radiotherapy and chemotherapy, potentially contributing to cancer metastasis and recurrence. Consequently, the exploration of senolytic therapies aimed at eliminating senescent cells has gained considerable momentum. Addressing the limitations of free therapeutics, nano-drug delivery systems have been meticulously engineered to enhance solubility, stability, and targeted delivery. These nanocarriers overcome challenges related to poor bioavailability, uncontrolled biodistribution, and off-target effects, thereby improving therapeutic efficacy and safety. Precise control over nanoparticle size and uniformity enables targeted distribution, enhancing therapeutic precision. While nanomedicine is revolutionizing healthcare, its potential to mitigate cellular senescence remains largely unexplored despite extensive cancer research. This comprehensive review aims to consolidate the current understanding of cellular senescence and its pathological consequences. Furthermore, we present an in-depth analysis of studies employing nano-drug delivery systems in cellular senescence research, emphasizing their potential role and prospects in this evolving scientific landscape. This research is a significant step towards filling this gap and paving the way for future advancements in the field.

Berberine has been widely used in traditional and folk medicine for many years. The molecular mechanisms of berberine's action are pleiotropic and have been fairly well studied. Its applications are generally limited to cardiometabolic diseases and cancer therapy, and a focused critical evaluation of berberine and its derivatives in the specific context of immunosenescence remains limited. Immunosenescence represents an age-associated remodeling of the innate and adaptive immune systems, closely linked to impaired immunometabolism, chronic inflammation, and shifts in the AMPK/mTOR, NF-κB, autophagy, and inflammasome pathways; therefore, berberine is a logical candidate for the role of a multi-target regulator of these processes. In this review, we examine the molecular mechanisms of immunosenescence and their biomarkers, and critically evaluate the effects of berberine on these parameters. Here we provide a detailed examination of the rationale for using berberine as a modulator of immunosenescence and proposes a design for future studies.

Aged skeletal muscle is impaired at every phase of post-injury repair that has been examined, with myeloid recruitment delayed and skewed in composition, debris degradation lagging behind uptake, and muscle stem cell (MuSC) activation following a conserved trajectory at delayed kinetics. Deficits inside a phase may be differences of degree that a longer window absorbs, whereas the transition between phases offers no comparable slack. Each transition is triggered by a defined switch in signal, either the fall in damage input after debris degradation, the TNF/TGF-β balance that permits fibro-adipogenic progenitor (FAP) apoptosis, or the Ly6C^high→Ly6C^low monocyte conversion. Because positive feedback operates beyond each switch, a compartment arriving late meets a microenvironment already committed to a self-maintaining alternative state that its later output appears unable to reverse. Retained mitochondrial lesions in postmitotic myofibers are one proposed input holding the first switch open. MuSCs face pool contraction, skewed fate allocation, and cell-autonomous defects uncorrected by a young host. FAPs resist clearance past their support phase while a stiffening matrix keeps them fibrogenic, and aged myeloid cells reach the pro-repair switch late and with attenuated output. None of these lesions need be primary for the sequence to fail. Interventions should instead be judged on whether inflammation declines, matrix remodeling closes, myogenic output yields mature fibers, and reserve survives repeated injury. Aging may therefore be read as a loss of temporal coordination, in which sub-threshold delays accumulate between compartments that must act in sequence, until a failed transition settles the tissue into an inflammatory-fibrotic endpoint.

Annual killifishes of the genus Nothobranchius compress a vertebrate life cycle into a few months, which is what makes them useful in aging research, yet no broad biochemical description of ageing exists for N. guentheri. In a cross-sectional design, we measured 27 clinical chemistry analytes in whole-body homogenates of male and female fish sampled at 3, 6 and 9 months of age (20 analytical samples). Age trends were assessed by Spearman rank correlation, and age, sex and their interaction by two-way ANOVA. Twenty-four of the 27 analytes fell with age. Calcium declined most steeply (r = - 0.573, p = 0.008), followed by fructose (r = - 0.507, p = 0.023), albumin (r = - 0.486, p = 0.030) and magnesium (r = - 0.479, p = 0.033); potassium fell just short of significance (r = - 0.422, p = 0.064). Only adenosine deaminase, C-reactive protein and HDL cholesterol trended upward, none of them significantly. Males had higher creatinine, carbon dioxide and HDL cholesterol than females. The picture is one of generalised decline rather than the selective elevations of glucose, lipids and nitrogenous waste seen in long-lived mammals, and is most simply read as progressive loss of metabolically active tissue. We suggest, as a hypothesis for testing, that the abrupt terminal mortality familiar to killifish keepers follows the crossing of a threshold after months of subclinical decline. Sample sizes were small and p-values uncorrected, so individual associations need confirmation, but the panel offers endpoints that can be read out within one generation of this species.

Ageing is an independent, non-modifiable risk factor for myocardial infarction (MI). It is also characterized by chronic, low-grade inflammation (inflammaging) and progressive cardiovascular senescence. These ageing-associated processes alter cytokine networks and innate and adaptive immune-cell function, promote endothelial dysfunction, and compromise post-infarction repair, thereby increasing myocardial susceptibility to ischaemia and adverse cardiac remodelling in the elderly. Lifestyle modifications, including regular physical activity, reduce inflammaging by facilitating the release of anti-inflammatory cytokines and counteract cellular senescence. This review compiles current mechanistic and translational evidence connecting inflammaging to age-related myocardial infarction, focusing on cytokine-mediated immune interactions. Additionally, this review also examines age-related cytokine dysregulation in myocardial infarction, pro-inflammatory and anti-inflammatory cytokine networks, inflammasome-mediated pyroptosis, senescence-associated secretory phenotypes, and emerging cytokine and extracellular vesicle-based biomarkers. It further discusses translational advances in cytokine-targeted, senescence-directed, and precision immunology-guided therapeutic strategies for the ageing population. In conclusion, inflammaging is closely linked to age-related myocardial infarction, with the IL-6/IL-1 signalling axis supported by the most direct interventional evidence to date including outcome evidence from canakinumab (CANTOS) and phase 2 STEMI myocardial-salvage evidence from tocilizumab (ASSAIL-MI). Cytokine-based immunotherapies targeting this axis represent a promising therapeutic approach for age-related myocardial infarction, although their efficacy and safety in older populations remain to be established in dedicated clinical trials.

Reproductive aging in the ovary, endometrium, and testis is characterized by progressive decline in regenerative capacity, yet the upstream mechanisms coordinating stem cell dysfunction across these tissues remain incompletely understood. Emerging evidence suggests that alterations in extracellular matrix (ECM) mechanics, particularly age and disease associated increases in tissue stiffness, may contribute to impaired stem cell function through mechanotransductive signaling pathways. In the testis, increased matrix stiffness has been associated with activation of mechanosensitive pathways such as Piezo1, leading to calcium influx, mitochondrial stress, and downstream effects on steroidogenic and stem cell populations. In the ovary, age-related fibrosis and cortical stiffening correlate with disrupted follicular development and altered signaling through Hippo-YAP/TAZ pathways. Similarly, the endometrium exhibits stiffness-dependent functional changes, where excessive ECM remodeling is associated with impaired decidualization and reduced regenerative potential. Across these reproductive tissues, mechanotransduction pathways involving calcium signaling, reactive oxygen species generation, and YAP/TAZ activity appear to integrate biomechanical cues with cellular stress responses, potentially contributing to stem cell exhaustion. However, current evidence remains largely correlative, and direct causal links between tissue stiffness and stem cell failure in human reproductive tissues are still limited. We propose the "Hardened Ground" framework as a unifying working model suggesting that increased ECM stiffness may represent a contributory biomechanical factor influencing stem cell function across the reproductive axis. Importantly, this model does not replace established molecular and hormonal mechanisms of aging but instead integrates mechanical properties of the tissue microenvironment as an additional regulatory layer. Notably, clinical observations such as preserved follicular reserve in polycystic ovary syndrome despite increased ovarian stiffness, and dynamic changes in endometrial stiffness across the menstrual cycle, indicate that mechanotransduction outcomes are context-dependent and influenced by hormonal and inflammatory states. Future studies integrating quantitative elastography with stem cell and molecular markers in human tissues are needed to clarify the causal role of stiffness in reproductive aging. This framework generates testable predictions and highlights potential therapeutic avenues targeting extracellular matrix remodeling and mechanosensitive signaling pathways to preserve reproductive tissue function.

Breast cancer is among the leading causes of cancer mortality worldwide, with aging as a major risk factor. Caloric restriction (CR) is a well-established non-pharmaceutical intervention that extends healthspan and delays tumorigenesis, yet the systemic molecular mechanisms remain elusive. Both chronic and intermittent CR influence metabolic homeostasis, but their long-term effects on circulating miRNAs in breast cancer predisposition are unclear. Here, we examined how chronic and intermittent CR and subsequent refeeding remodel circulating miRNA networks in a tumor-free, female breast cancer-prone transgenic mouse model. Blood samples were collected and circulating miRNA expression levels were determined at weeks 10 (young), 49 (adult), and 81 (old) using GeneChip miRNA 4.1 Array. Differential expression and target enrichment analysis were performed to identify age- and diet-associated modulatory patterns. Aging significantly altered the global circulating miRNA profile and validated targets were enriched in the IL-7 signaling, GPCR signaling, and TCA cycle. Both chronic and intermittent CR reshaped these age-associated alterations, with the consistent target pathways. The effects were most pronounced at adult age rather than old age, while the refeeding phase of the intermittent CR partially preserved the CR-induced miRNA patterns. Integrative analyses identified three key miRNAs (mmu-miR-142-5p, mmu-miR-30e-5p, mmu-miR-494-3p), where CR reversed the expression patterns induced by aging, suggesting a shared molecular mechanism. Our findings demonstrate that chronic and intermittent CR modulate circulating miRNAs in an age-dependent manner in female transgenic breast cancer-prone mice.