Biogerontology最新文献

Longevity science has advanced faster than the public's capacity to interpret it. Biological age tests, longevity clinics, and consumer wearables now reach millions of people, yet no shared framework exists to tell an individual what those numbers mean or what to do about them. Cardiovascular medicine encountered a comparable problem and resolved it not with a new therapeutic but with a communication instrument: Life's Essential 8, which distilled a contested risk landscape into eight components scored from 0 to 100, and which has since been shown to track biological aging itself. This Perspective argues that geroscience has assembled much of the material for an equivalent instrument, even while the field continues to disagree about foundational questions. Expert panels have converged on which biomarkers are worth tracking as outcomes in aging intervention trials, and have concluded that no single biomarker suffices, which leaves a composite as the only viable path. What has not happened is the translation of that research-level agreement into a public-facing instrument. A candidate structure is proposed, comprising four behavioral and four biological pillars with explicit scoring thresholds, designed for administration by clinicians in primary care rather than by longevity clinics only, and constructed so that seven of the eight components require only a questionnaire, a bedside test, and routine bloods.

Lipoic acid is an essential cofactor for mitochondrial multienzyme complexes, and mutations in the lipoyltransferase LIPT2 cause severe metabolic and neurological defects in humans. In Drosophila, two independent lipT2 loss-of-function alleles cause severe physiological abnormalities in homozygotes. Here, we show that heterozygotes for these same alleles exhibit significantly extended lifespan and delayed age-dependent decline in locomotor performance. Metabolic analysis revealed no major alterations in central carbon metabolites or cellular energy status, indicating that overall metabolic homeostasis is largely preserved. In contrast, LipT2 heterozygosity was associated with reduced DCF fluorescence and selective changes in redox-related metabolites, including glutathione and urate. LipT2 heterozygotes also exhibited enhanced resistance to paraquat-induced oxidative stress without induction of canonical antioxidant genes. These findings indicate that partial reduction of LipT2 activity is associated with selective remodeling of cellular redox homeostasis while preserving metabolic homeostasis, providing a physiological state associated with longevity and enhanced stress resistance. Thus, the effects of LipT2 deficiency are strongly dependent on gene dosage, with moderate reduction being associated with longevity and maintenance of physiological function rather than overt metabolic dysfunction.

Aging is an inevitable physiological process characterized by progressive functional decline and degenerative alterations across organ systems. Metabolic disturbance, particularly the disruption of substance and energy metabolism, is increasingly recognized as a central hallmark of aging. Emerging evidence suggests that dysregulation of the urea cycle (UC) contributes to aging-related pathological processes, including cognitive impairment; however, its role in astrocyte-mediated brain aging remains unclear. In this study, we used a D-galactose-induced mouse aging model to investigate the involvement of UC activation in age-related cognitive decline. Aging mice exhibited marked cognitive impairment, accompanied by an increased proportion of reactive astrocytes in the hippocampus, a key pathological feature of brain aging. Metabolic analysis and molecular validation revealed enhanced UC activity and increased urea production in aging mice. Inhibition of UC activation reduced urea production and decreased the proportion of hippocampal reactive astrocytes. Mechanistically, the expression of key UC-related enzymes, including ornithine decarboxylase 1 (ODC1) and arginase 1 (ARG1), was significantly downregulated, accompanied by improved mitochondrial dynamics, particularly the restoration of mitochondrial fusion and fission balance. Furthermore, ODC1 knockdown confirmed its critical role in mediating UC activation in astrocytes and significantly alleviated aging-like cellular phenotypes. Notably, Ganoderma lucidum polysaccharide peptides (GLPs) effectively suppressed UC activation in aging astrocytes by downregulating ODC1 and ARG1. Collectively, this study identifies dysregulated astrocytic UC activity as a novel metabolic mechanism linking astrocyte reactivity, mitochondrial dysfunction, and age-related cognitive decline, suggesting that targeting ODC1-mediated UC activation and mitochondrial dynamics may provide a promising dual strategy for combating brain aging.

Aging is a complex biological process governed by conserved genetic and metabolic pathways. Increasing evidence has identified the gut microbiota as a critical modulator of host aging and healthspan. The Caenorhabditis elegans model provides a powerful system to elucidate the molecular determinants of this cross-kingdom dialogue. Recent advances in this model organism reveal that gut microbes may regulate aging through two distinct yet convergent mechanisms: (i) the production of small-molecule metabolites that modulate conserved host longevity pathways, and (ii) the presentation of structural components that trigger hormetic defense responses via immune recognition. This review synthesizes these findings, offering a framework for understanding microbial contributions to aging and highlighting potential directions for future research aimed at extending healthspan in higher organisms.

Cellular senescence is characterized by cell cycle arrest accompanied by mitochondrial dysfunction. Despite extensive efforts to overcome this stable state of growth arrest, effective strategies for treating cellular senescence have not been identified. In this study, we screened plant-derived secondary metabolites and confirmed that formononetin is a substance that potently induces the proliferation of senescent fibroblasts. Formononetin-induced proliferation was associated with the suppression of expression of key cell cycle inhibitors, including p53 and Rb-1. This proliferative response was accompanied by the restoration of mitochondrial function. Transcriptome analysis identified the Fos proto-oncogene (FOS) as a downstream regulator, and FOS expression significantly increased after formononetin treatment. Functional verification further confirmed that the increase in FOS expression recapitulates the anti-senescence effects of formononetin. In summary, the results of this study revealed a previously unknown mechanism by which formononetin promotes cell cycle re-entry and restores mitochondrial function through the regulation of FOS expression. These findings suggest that therapeutic strategies regulating formononetin-mediated FOS pathway could be promising treatments for aging and age-related diseases.

Ageing is a fundamental biological process marked by declining physiological function and the accumulation of stress-induced damage. It contributes to chronic disease and drives widespread alterations across organ systems, including the vasculature. Ageing of the macro- and microvasculature impairs nutrient delivery, promotes tissue degeneration, and reduces repair capacity in many tissues, including those of the musculoskeletal system. Tendons and ligaments become increasingly injury-prone with age, yet the relationship between vascular ageing and tendon and ligament in health and disease remains insufficiently understood. This review critically examines the effects of vascular ageing on tendons and ligaments, including their interfaces with muscle and bone. Emerging evidence indicates that age-related vascular decline contributes to structural and functional impairments in these tissues, accelerating musculoskeletal deterioration. We also discuss therapeutic approaches targeting vascular dysfunction, including growth factor modulation through use of platelet-rich plasma, gene-based strategies, and stem cell therapies, which show potential for mitigating age-related deficits. By synthesizing existing knowledge, this review emphasizes the need for further research into vascular ageing and its implications for tendon and ligament health. A deeper understanding of these processes could inform the development of innovative therapies aimed at preserving vascular function and improving quality of life in the ageing population.

This perspective distinguishes two standards that are often used as if they were interchangeable. Optimal health is a standard built by medicine and expressed through guideline targets and biomarkers. Adequate health is the threshold of functioning that allows a person to live in a way they themselves experience as sufficient and dignified. Building on the concept of homeodynamic space as the biological substrate of adequate independence, on the older salutogenic tradition that asked what sustains health rather than only what causes disease, and on clinical evidence that aligning care with patients' own priorities can reduce treatment burden without worsening the outcomes patients themselves value, this article argues that optimal health is doctor based while adequate health is patient based. In any population ageing under conditions of socioeconomic inequality and health system fragmentation, the distance between the two standards is wide and unevenly distributed within the same country. Adequate health for an older adult must therefore be defined relative to the resources, culture, attitude, and priorities actually available to that person, not only against a uniform biomedical ideal that a large share of any population has no realistic path to reach. The argument is developed using data and policy from Mexico, chosen for the scale of its ageing population and the sharpness of its socioeconomic gradient, but the distinction it defends applies wherever health systems and biomarkers are used to judge the value of an older life.

Aging is influenced by both genetic and environmental factors, yet comparative studies across species with different natural lifespans remain limited. We examined how reduced ambient temperature (18 °C vs 25 °C) and constant darkness, compared with a 12 h light/12 h dark cycle (DD vs LD), affect lifespan, age-related physiological traits, and gene expression in three Drosophila species with contrasting natural lifespans and climatic adaptations (tropical, short‑lived D. kikkawai, tropical, intermediate‑lived D. melanogaster, and temperate, long‑lived D. virilis). Low temperature extended lifespan in all three species, with the largest relative gains occurring in the shortest‑lived D. kikkawai males, yet the longest absolute lifespans were consistently attained by the long‑lived D. virilis. Constant darkness moderately increased lifespan at 25 °C, particularly in males, but its combination with low temperature became antagonistic in D. virilis, revealing that the interaction between photoperiod and temperature depends on both baseline longevity and sex. Longer lifespan correlated with lower metabolic rate, greater body mass, and sustained late‑life activity. Gene expression analyses in D. melanogaster revealed that low temperature induced a youthful metabolic and immune profile, whereas DD often counteracted these changes. Our findings do not support a simple inverse or direct relationship between baseline longevity and geroprotective efficacy. Instead, these results suggest that the responses to low temperature and darkness are species‑ and sex‑specific and reflect each species' evolutionary and ecological background.

As global population aging accelerates, maintaining locomotor function in later life has become a critical biomedical challenge. This study investigates the effects of three bioactive compounds-Luteolin (Lut), Glycitein (Gly), and α-Spinasterol (α-Spin)-isolated from the traditional Chinese medicinal herb Codonopsis pilosula (Dangshen), on age-related locomotor decline using the Caenorhabditis elegans (C.elegans) model. We demonstrate that Lut and Gly significantly ameliorate the deterioration of body bend and thrashing frequencies in aged nematodes. Further analysis reveals that both compounds mitigate age-associated sarcopenia by reducing abnormalities in muscle structure and mitochondrial morphology. Mechanistically, we found that the beneficial effects of Lut and Gly on locomotion are dependent on the transcription factor DAF-16/FOXO, as both compounds promote DAF-16 nuclear translocation and the effects are abolished upon daf-16 knockdown. However, these compounds diverge in their regulation of autophagy: Lut improves locomotion through an lgg-1-dependent autophagy-related process, whereas Gly exerts its effects independently of the autophagic pathway. In contrast, α-Spin, despite altering autophagosome levels, did not improve locomotor capacity. These findings elucidate the distinct pharmacological mechanisms of Codonopsis pilosula constituents, highlighting their potential as modulators of healthspan via DAF-16-dependent but mechanistically distinct pathways.

Background: Aging disrupts bone remodeling by increasing osteoclast activity, reducing osteogenic capacity, and elevating inflammation. Toll-like receptor 4 (TLR4)-mediated inflammatory signaling has been implicated in bone degeneration, yet its role in age-related skeletal decline remains incompletely understood. Isoorientin, a plant-derived flavonoid with reported anti-inflammatory properties, has not been evaluated in the context of skeletal aging.

Methods: Bone aging was first assessed in C57BL/6 J mice using micro-computed tomography (μCT), histology, TRAP staining, and immunofluorescence. The effects of isoorientin on osteogenesis were examined in senescent hBMSCs by alkaline phosphatase (ALP) activity, mineralization assays, and expression of osteogenesis-related genes. LPS-stimulated RAW264.7 cells were used to evaluate inflammatory responses and M1/M2 polarization. To assess TLR4/ mitogen-activated protein kinase (MAPK)/ nuclear factor-κB (NF-κB) regulation, RAW264.7 cells were treated with TAK-242 or TAK-242 plus isoorientin. Finally, aged mice were treated with isoorientin, TAK-242, or both to evaluate in vivo pathway modulation and bone protection.

Results: Aged mice exhibited reduced trabecular mass, elevated osteoclast activity, and increased osteoclast-associated markers. Isoorientin treatment improved trabecular structure, decreased osteoclast numbers, and lowered osteoclast-associated proteins. In senescent hBMSCs, isoorientin restored ALP activity, enhanced mineral deposition, and increased osteogenic marker expression. Isoorientin also reduced pro-inflammatory cytokines, suppressed M1 polarization, and inhibited TLR4/MAPK/NF-κB activation. The combination of isoorientin and TAK-242 exhibited the most potent suppression of inflammatory signaling and the most significant enhancement in bone microarchitecture.

Conclusion: Isoorientin alleviates age-related bone loss by suppressing TLR4-mediated inflammation, reducing osteoclast activation, and restoring impaired osteogenesis. These findings identify isoorientin as a promising therapeutic candidate for age-associated osteoporosis.