Aging and Disease最新文献

Muscle wasting disorders, including sarcopenia and skeletal muscle atrophy, are increasingly prevalent among older adults and those with metabolic comorbidities. Sarcopenia, a progressive age-associated condition, involves the decline in skeletal muscle mass, strength, and physical performance, affecting millions of people globally. These disorders significantly elevate the risks of frailty, falls, and premature mortality, contributing to a growing burden on healthcare systems. Current interventions, including resistance exercise and dietary supplementation, have shown limited effectiveness, particularly among individuals with concurrent conditions such as type 2 diabetes (T2D). Notably, glucagon-like peptide-1 receptor agonists (GLP-1RAs), initially developed for glycemic and weight control, have demonstrated promising effects in preclinical models of muscle degeneration. In this review, we analyzed 20 preclinical and clinical studies on sarcopenia and muscle wasting disorders. Animal studies yielded promising results, including increased grip strength and enhanced skeletal muscle cross-sectional area (CSA), while body weight remained stable within a defined dosage range. Mechanistically, GLP-1RAs mitigate muscle wasting by upregulating myogenic factors (MyoD, MyoG), promoting mitochondrial biogenesis, and suppressing proteolysis (MuRF1, MAFbx) and inflammation via AMPK/SIRT1/NF-κB/Myostatin signaling. In contrast, limited clinical studies showed body weight reduction accompanied by a decline in lean mass following GLP-1RA treatment. Collectively, these results highlight the low dose-dependent anabolic potential of GLP-1RAs on skeletal muscle, while clinical evidence indicates simultaneous weight and lean mass loss. These findings suggest low-dose GLP-1RAs as potential therapy for sarcopenic obesity or early sarcopenia with metabolic comorbidities, warranting comprehensive clinical trials that incorporate multimodal strategies to preserve muscle mass during treatment.

Ischemic stroke (IS) remains a leading cause of disability and mortality in aging populations. Recovery trajectories are shaped not only by the acute vascular insult but also by pre-existing comorbidities, genetic predisposition, and age-dependent molecular remodeling. Common vascular risk factors, such as diabetes mellitus, atrial fibrillation, hypertension, and dyslipidemia, sustain systemic and cerebral inflammation, promote endothelial dysfunction, disrupt blood-brain barrier integrity, and impair neuroplasticity, collectively limiting neurovascular repair and recovery potential. Recent advances in genomic, epigenomic, and transcriptomic profiling have identified dynamic molecular networks that regulate neuronal survival, angiogenesis, and synaptic plasticity after stroke. However, most discoveries remain correlative. Establishing causality will require perturbation-based approaches, including genome and epigenome editing, patient-derived stem cell and organoid models, and longitudinal multi-omics analyses across diverse ancestries and comorbidity profiles. Such integration will clarify how metabolic and inflammatory states imprint the epigenetic and transcriptional landscape of the aging brain. Emerging evidence implicates DNA methylation, histone modifications, and noncoding RNAs, including circular RNAs, as pivotal regulators of ischemic resilience and neurovascular recovery. Translational studies combining genomic insights with epigenetic pharmacology have demonstrated proof-of-concept efficacy for genotype-guided therapies, RNA-based interventions, and histone deacetylase inhibition. Collectively, these strategies support a systems-level framework that unites vascular biology, multi-omics, and neurorestoration. Within this paradigm, aging is reframed not as a static risk factor but as a modifiable molecular trait, guiding the timing and intensity of interventions to enhance neurorepair, restore vascular integrity, and preserve cognitive resilience.

Rising obesity rates pose significant concerns for aging and brain health. Insulin resistance (IR), prevalent in both obesity and Alzheimer's disease (AD), accelerates neurodegeneration. Adequate choline intake may help reduce obesity risk and IR, yet many individuals consume less than recommended-a deficiency associated with increased AD risk. Here, we examined circulating blood choline, metabolic dysfunction markers, inflammatory cytokines, and neurofilament light (NfL), a protein that is used as a prognostic marker for neuronal damage, in young-adult participants (mean age 33.6 years) with obesity (BMI > 30) versus healthy BMI (18.5-24.9) controls using a cross-sectional design. We also validated whether circulating choline levels correlate with NfL in a cohort of patients with mild cognitive impairment (MCI) with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderate to frequent neuritic plaques, Braak stage = IV) or severe AD (frequent neuritic plaques, Braak stage = VI), compared to age-matched controls. We found that obese participants showed reduced circulating choline, correlating with higher %Body Fat, liver dysfunction markers, increased IR, and elevated inflammatory cytokines. NfL levels were elevated in obese participants and negatively correlated with circulating choline levels, findings consistent with that observed in MCI and AD cases. These findings reveal correlations between obesity, low choline, IR, systemic inflammation and NfL-key AD risk markers. Monitoring such markers in early adulthood may be useful for assessing future AD risk in individuals prone to obesity.

Cellular senescence, once considered a protective mechanism against oncogenesis, is now recognized as a key driver of aging and age-related diseases, including Alzheimer's disease (AD). In the central nervous system (CNS), senescence-like states emerge in both proliferative and post-mitotic cells-astrocytes, microglia, oligodendrocyte lineage cells, endothelial cells, pericytes, and even neurons-contributing to chronic dysfunction. Canonical pathways, such as p16^INK4a-pRB and p53-p21, enforced by persistent DNA damage responses, lead to irreversible cell-cycle arrest. The senescence-associated secretory phenotype (SASP) links intracellular stress to extracellular inflammation, tissue remodeling, and bystander senescence. CNS senescence is triggered by diverse insults, including amyloid-β and tau pathology, oxidative stress, mitochondrial dysfunction, NF-κB and cGAS-STING signaling, impaired proteostasis and autophagy, telomere attrition, and genomic instability. Senescence markers in the CNS are heterogeneous, ranging from p16/p21 expression and lamin B1 loss to lipofuscin accumulation and cell type-specific SASP profiles, highlighting the need for multiplexed detection strategies. Targeting senescence has emerged as a promising therapeutic avenue in AD. Senolytics selectively eliminate senescent cells and improve cognition in preclinical models, while senomorphics aim to suppress harmful phenotypes without inducing cell loss. Early clinical trials suggest feasibility, but challenges remain, including biomarker development, blood-brain barrier penetration, long-term safety, and optimal timing of intervention. This review summarizes recent advances in understanding CNS senescence in aging and AD, explores emerging therapeutic strategies, and outlines future directions emphasizing precision medicine through multi-omic biomarkers, advanced imaging, and stage-specific interventions. Targeting CNS senescence holds potential to delay or alter the course of AD.

Late-life depression (LLD) represents a significant public health challenge within global ageing societies, substantially impacting older adults' quality of life and health status. Despite the widespread application of pharmacological and psychotherapeutic interventions, their efficacy is frequently constrained by individual variability and treatment adherence issues. In recent years, exercise behaviour intervention (MBI) has garnered increasing attention as a low-side-effect, highly accessible therapeutic approach. This study proposes an innovative exercise intervention model-the Q4-Mood framework-aimed at stratifying older adults based on their motivation (self-efficacy) and physical capacity (fitness level), providing a personalised, progressive exercise intervention pathway for each stratum. The Q4-Mood framework categorises exercise interventions into four tiers: Sedentary Behaviour Interruption (SB), Exercise Snacks (ES), Physical Activity (PA), and Regular Exercise (RE). This model not only enhances exercise adherence among older adults but also effectively alleviates depressive symptoms. Through personalised intervention strategies, it facilitates dual physical and psychological improvements. Through a systematic review of existing exercise intervention studies, this paper demonstrates the Q4-Mood framework's potential in treating geriatric depression and offers novel perspectives for future research. We contend that Q4-Mood provides a comprehensive, flexible, and actionable framework for geriatric depression interventions, paving the way for its future application in clinical practice.

Skeletal muscle (SKM) is now recognized not only for its classical functions but also as a secretory organ. It communicates with other tissues through myokines and extracellular vesicles, such as exosomes. Among these components, microRNAs (miRNAs) are particularly notable due to their stability, evolutionary conservation, and ability to potently regulate gene expression. Growing evidence suggests that these exosomal miRNAs act as important mediators of inter-organ communication in both glucose and lipid metabolism. Exosomal miRNAs derived from senescent SKMs drive systemic metabolic dysregulation by targeting critical signaling pathways in insulin sensitivity and lipid metabolism. Consequently, SKM-derived exosomal miRNAs have emerged as a promising new class of biomarkers and therapeutic targets for metabolic diseases.

Chronic systemic inflammation in the elderly is a hallmark of aging and a major contributor to age-related diseases. It both results from and promotes the accumulation of senescent immune cells. While the sex difference in the aging process has been widely studied, the impact of cellular sex on immune cell senescence remains unclear and was the focus of this present study. Senescence was induced in human male (THP-1) and female (HL-60) monocyte-like cells by treatment with D-galactose for 48 h. The expression of metabolic sensors (Sirt1 and pAMPK), mitochondrial biogenesis and respiration, reactive oxygen species formation, as well as pro-inflammatory markers was investigated alongside senescence markers. Treatment with D-galactose resulted in significant reduction of the nuclear proteins HMGB1 and lamin B1, and an upregulation of senescence-associated secretory phenotype factors including IL-6, VEGF, TGF-β, and MMP-9, in male and female cells. The expression of the metabolic sensors Sirt1 and pAMPK was reduced, whereas mitochondrial ROS production and mitochondrial gene expression were elevated in both male and female cells to a similar extent. In contrast, D-Galactose-induced senescence was accompanied by a significant elevation of pro-inflammatory markers (NF-κB, TNF-α, IL-1β, HLA-DR, and MCP-1) primarily in male monocytes, whereas primary monocytes did not display sex differences. This study suggests that male immune cells are more prone to developing a pro-inflammatory state under senescent stimuli. These findings highlight the potential significance of sex-specific anti-inflammatory therapies.

The adrenal gland integrates stress, metabolic, immune, and circadian signals to safeguard organismal homeostasis, yet its aging biology has been comparatively overlooked. Converging evidence from recent primate single-nucleus atlases, functional perturbations in human adrenal cells, human pathology, and multi-organ proteome aging resources reveals a coherent mechanistic picture: adrenal aging is region-specific, substrate-limited, and constrained by proteostasis, characterized by decline of dehydroepiandrosterone sulfate (DHEA-S) and aldosterone, while preserved cortisol output on average with diurnal flattening and higher prevalence of autonomous cortisol secretion with ageing. These endocrine trajectories implicate heightened vulnerability of the zona reticularis (ZR) and zona glomerulosa (ZG) versus the zona fasciculata (ZF). At the cellular level, ZR cells exhibit senescence, immune activation, and lipid metabolic disruption, including downregulation of androgen sulfation. Broad reduction of LDLR across cortex limits cholesterol import reduces DHEA-S, linking substrate scarcity to endocrine decline. Proteostatic lesions including aggresomes, amyloid, and lipofuscin accumulate across zones, aligning adrenal changes with systems-level proteome aging and vascular susceptibility. Key pathological correlates like ZR thinning, accumulation of aldosterone-producing cell clusters (APCCs), and higher prevalence of adrenal tumors underscore an age-biased remodeling of zonal identity and control hierarchies. Developmental and sex-dimorphic programs, including WNT/FRZB signaling and extracellular matrix remodeling, likely preconfigure later-life vulnerability. In this perspective, we synthesize these advances into a mechanistic model connecting centripetal differentiation, cholesterol trafficking, proteostasis collapse, inflammaging, and vascular aging to endocrine dysfunction and highlight biomarker strategies to index "adrenal age". We also outline near-term clinical deployment opportunities in older adults with adrenal incidentalomas or frailty using combined hormonal and plasma proteomic readouts, supported by human multi-organ proteomic evidence of proteostasis and vascular aging, aiming to restore cholesterol handling, reinforce proteostasis, and modulate senescence and niche signals.

Endothelial senescence is a critical contributor of arterial dysfunction and age-related cardiovascular diseases. This study demonstrates that long-term senolytic treatment with dasatinib plus quercetin (D+Q; 5 mg/kg + 50 mg/kg biweekly for 8 months) in mice significantly attenuates vascular endothelial senescence. D+Q lowered senescence markers (p21 protein and SA-β-gal positivity) in aged mesenteric arteries and human umbilical vein endothelial cells (HUVECs), while maintaining endothelial integrity. Transcriptomic analysis indicated activation of the relaxin signaling pathway and upregulation of nitric oxide synthase isoforms. Mechanistically, D+Q reversed age-related eNOS uncoupling by promoting dimerization, increased nitric oxide bioavailability, and reduced mitochondrial dysfunction, evidenced by restored mitochondrial ultrastructure, decreased mitochondrial mass, and lowered reactive oxygen species (ROS) production. Consequently, D+Q restored endothelium-dependent vasodilation and enhanced blood flow in aged mesenteric arteries following acetylcholine stimulation. These findings demonstrate that clearance of senescent endothelial cells via senolytic therapy mitigates arterial aging by restoring mitochondrial homeostasis and eNOS function, highlighting its therapeutic potential for age-related vascular dysfunction.