Mitochondrial function is essential for brain health. Its age-related decline impairs neuronal resilience and increases risk for the development of neurodegenerative diseases. As sex is an important biological variable in both physiological and pathological brain function, in this mini review, we highlight emerging evidence of sex differences in mitochondrial content and function in the brain and what is currently understood about how they change with age. Furthermore, as physical exercise is considered a key mitigating factor in brain injury and the development of neurodegenerative diseases, we review studies that address the effects of exercise on mitochondrial function in the brain, with particular attention to those that include data from both sexes. The current understanding of the effects of sex differences and exercise on brain mitochondrial function over the lifespan is limited, but nonetheless some interesting insights are emerging. We discuss the key knowledge gaps and offer some suggestions for further research. These include defining the extent and specificity of mitochondrial alterations with age in different species, brain regions and cell types, and their modification by exercise, which is both important for advancing aging biology and for designing intervention strategies to promote healthy aging, to mitigate age-dependent cognitive decline and treat neurodegenerative diseases.
Seyed Mohamadmehdi Moshtaghion, Maryam Shayan, Sarvesh Ramakrishnan, Andrew Ham, Ashkan Shafaei Gharehkoshan, Michael G. Morley, Nazlee Zebardast, Francisco Javier Díaz-Corrales, Enrique Rodríguez de la Rúa, Deeba Husain, Lucia Sobrin, Tobias Elze, David S. Friedman, Mohammad Eslami
Retinal neurodegeneration is a major cause of irreversible vision loss and a shared feature of age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma (GL). Increasing evidence suggests that these conditions share important pathways with retinal aging, including mitochondrial dysfunction, metabolic insufficiency, redox imbalance, chronic low-grade inflammation, and progressive neuronal vulnerability. While antioxidant and micronutrient supplementation, most notably the Age-Related Eye Disease Study (AREDS) formulations, has demonstrated benefit in selected AMD populations, emerging metabolic and nutraceutical strategies targeting aging-related pathways are of unproven benefit. In this review, following a brief overview of the current landscape of investigated supplements, we synthesize preclinical and clinical evidence for a group of metabolic supplements, including nicotinamide adenine dinucleotide (NAD +) boosters, citicoline, pyruvate, and omega-3 fatty acids, that directly modulate mitochondrial bioenergetics, cellular redox state, membrane integrity, and neuroinflammatory signaling—pathways that are recognized hallmarks of biological aging and are particularly relevant to aging-related processes implicated in retinal neurodegeneration. Using a structured literature and clinical trial search, we summarize mechanistic insights and translational findings across AMD, DR, and glaucoma, emphasizing convergence on core pathways linking retinal neurodegeneration and ocular aging. Overall, current evidence supports biological plausibility and early functional or biomarker signals for these agents, particularly in glaucoma and diabetic retinal disease, although long-term efficacy remains unproven. Framing retinal disease at the intersection of neurodegeneration and aging biology, this review highlights metabolic supplementation as a promising but evolving strategy for preserving retinal function.
Keqin Zhang, Peidong Zhang, Ling Chen, Housheng Wang, Wubin Chen, Yusheng Zhu, Dai Li, Wenbin Lu
We aimed to evaluate the incidence of preoperative frailty and postoperative delirium (POD) and the association of preoperative frailty, POD with one-year mortality in older patients undergoing hip fracture surgery. Patients with hip fracture were identified from 2018 to 2023 in our hospital. The patients were categorized into four groups: patients without preoperative frailty who did not suffer from POD, patients without preoperative frailty who did suffer from POD, patients with preoperative frailty who did not suffer from POD, and patients with preoperative frailty who did suffer from POD. The primary outcome was one-year mortality after surgery. Multivariate landmark Cox regression analysis was used to assess the associations of preoperative frailty and POD with one-year mortality, and adjusted survival curves from the multivariate Cox model were plotted. Of 2,659 patients, 1,715 were included in the final analysis. The incidence of preoperative frailty was 24.0% (411/1715), and the POD rate was 16.9% (290/1715). Compared with older patients without preoperative frailty who did not suffer from POD (5.6%, 61/1088), the incidence of one-year mortality was significantly higher in patients without preoperative frailty who did suffer from POD (17.1%, 37/216), patients with preoperative frailty who did not suffer from POD (11.6%, 39/337), and patients with preoperative frailty who did suffer from POD (28.4%, 21/74). Preoperative no-frailty and POD (HR: 2.09, 95% CI: 1.36–3.21), frailty and no-POD (HR: 2.30, 95% CI: 1.51–3.50), and frailty with POD (HR: 3.95, 95% CI: 2.35–6.63) were all independently associated with one-year mortality after surgery in older patients with hip fracture. Preoperative frailty and POD were each independently associated with increased one-year mortality. Patients with both conditions had the highest observed mortality risk after hip fracture surgery.
Immunosenescence refers to the structural and functional remodeling of the immune system that accompanies aging, and is closely linked to increased susceptibility to infection, diminished vaccine responses, and a higher burden of chronic disease. While flow cytometric profiling of peripheral blood lymphocyte subsets has become a key tool for characterizing immune aging, systematic age-related data on NK cell subsets (CD56hi/CD56dim/CD56neg three-way classification) and B cell subsets (IgD/CD27 four-way classification) in healthy Chinese adults remain scarce. Quantitative age trends for CD57 and TEMRA as markers of terminal T cell differentiation have also been incompletely described in this population. We prospectively enrolled 146 healthy adults attending the annual health examination center of Peking Union Medical College Hospital (Panel 1: n = 103, age 20–82 years; Panel 2: n = 43, age 25–92 years, enriched for older participants). Panel 1 was a 12-color single-tube assay covering T cells (including CD57), NK cell trisubsets, and IgD/CD27-based B cell subsets. Panel 2 was a 12-color dual-tube assay focused on detailed T cell differentiation, incorporating CD45RA/CD62L, CD28, CD31, CD38, and HLA-DR. Spearman rank correlation, Kruskal–Wallis, and Mann-Whitney U tests were used for statistical analysis. In Panel 1 (n = 103), ten parameters showed significant age correlations. CD4 + CD57 + (r = +0.421, p < 0.001) and CD8 + CD57 + (r = +0.338, p < 0.001) rose most strongly with age. Total NK frequency increased (r = +0.259, p = 0.008) while CD56hiCD16 − regulatory NK cells declined (r = −0.263, p = 0.007) and NK PD-1 expression rose (r = +0.256, p = 0.009). IgD + CD27 + marginal zone-like B cells declined significantly in Panel 1 (r = −0.257, p = 0.009). Panel 2 (n = 43) revealed the strongest signals in CD8 + T cells: TEMRA accumulation (r = +0.532), CD28 loss (r = −0.552), and naive depletion (r = −0.534) all reached p < 0.001. CD4 + naive cells also declined significantly (r = −0.303, p = 0.048). Multivariate analysis confirmed that most associations were independent of sex. This study provides a comprehensive characterization of age-related immunophenotypic changes across NK cell subsets, IgD/CD27-defined B cell subsets, and multidimensional T cell markers in healthy Chinese adults, offering reference data for clinical immune assessment and vaccine response prediction.
Giovanni Mario Pes, Steven N. Austad, Dan Buettner, Salvatore Pedde, Vittorio Romerio, Hiram Beltrán-Sánchez, S. Jay Olshansky
Exceptional longevity in Sardinia has historically been associated with the original Sardinian Blue Zone. We investigated whether Bolotana, a small mountain municipality outside that area, exhibits a distinct late-life survival profile. Using validated civil and parish records, we constructed sex-specific partial period life tables for 2021–2025. Late-life survival was defined as survival from age 70 onward and assessed through remaining life expectancy at age 70 (e 70) and conditional survival from age 70 to 100 [S (70→100) ]. Estimates were compared descriptively with Nuoro Province, Sardinia, and Italy, the original Sardinian Blue Zone, and published international benchmark. Statistical uncertainty was evaluated using parametric Poisson bootstrap. Sensitivity analyses included 2020–2025 and a period-matched 2015–2019 analysis. In 2021–2025, e 70 was 16.02 years in men (95% CI, 14.55–17.79) and 20.85 years in women (19.42–22.43); S (70–100) was 4.92% (1.58–12.76) and 13.83% (7.33–23.75), respectively. Female estimates (70–100) exceeded contemporary values for Nuoro Province, Sardinia, and Italy. Among international benchmarks, Bolotana women ranked second only to Hong Kong for both indicators, and S (70→100) was more than three times that of U.S. women. Inclusion of 2020 to address the potential effects of COVID-19 produced modest reductions, whereas the period-matched 2015–2019 analysis yielded a less pronounced late-life survival profile, particularly for survival to age 100. Bolotana exhibited a distinctive, predominantly female pattern of exceptional late-life survival and may be considered a candidate longevity blue zone. However, the magnitude of this advantage varied by calendar period. Longer observation and continued demographic validation, are required before Bolotana can be considered an established longevity blue zone.
