GeroScience最新文献

Exercise improves cognition, mental wellbeing, and protects against neurodegeneration. However, most prior neuroscience studies have focused on localized brain changes without quantifying their impact on brain ageing. To quantify the effect of resistance training on brain health using longitudinal assessments. Using resting-state functional magnetic resonance imaging (rs-fMRI) data from 2,433 healthy adults, we trained models to predict brain age and applied them to 309 participants from the Live Active Successful Aging (LISA) randomized trial. Participants in this trial were assigned to one of three groups: heavy-resistance training, moderate-intensity training, or a non-exercise control group. They underwent repeated rs-fMRI and physical fitness assessments at baseline, with follow-up assessments at 1 and 2 years. First, we examined changes in local connectivity between groups. Second, we assessed the impact of resistance training on brain ageing using brain clock models trained on the independent dataset of 2,433 adults. Local analyses revealed increased prefrontal functional connectivity following heavy training, while moderate- and heavy-resistance training significantly reduced brain age (-1.4 to -2.3 years, p_FDR < 0.05). These effects emerged at the whole-brain level, rather than within isolated networks such as the default mode, motor, or cerebellar systems. These findings suggest a hierarchical organization of brain aging, driven by distributed network-level changes and expressed through focal regional patterns. Resistance exercise training decelerates brain ageing, as indexed by brain clocks, reinforcing its role as a preventive strategy for brain health.

Alzheimer's disease (AD) is a national priority with far-reaching implications for patients, families, clinicians, researchers, and policymakers. Yet the term AD refers to multiple distinct meanings that are often overlooked or ambiguously applied, risking misaligned research and policy priorities that affect patient outcomes. Recent FDA approvals of passive immunotherapies and related biomarker developments show that differing interpretations of AD complicate research, regulatory decisions, payer coverage, and clinical use. In contrast to efforts aimed at revising AD nomenclature, this paper clarifies five key meanings of AD as currently used. It provides a practical framework to indicate how the term AD is applied in different ways within and across clinical, research, regulatory, and policy contexts. Each key meaning-clinical (symptom-focused), genetically determined (mutation-driven), pathological (autopsy-confirmed), plaque-defined (amyloid-beta-plaque-positive), and broad (can encompass multiple dementia types)-may apply alone or in combination depending on context. These distinctions also raise ethical considerations, particularly for biomarker-based diagnoses and their impact on patient communication and decision-making. Using this framework helps decision-makers identify the intended AD meaning and align research, policy, and care for better patient outcomes.

With increasing global life expectancy, the prognostic significance of kidney function in centenarians and supercentenarians should be clarified. The conventional estimated glomerular filtration rate (eGFR) threshold of < 60 mL/min/1.73 m² may not accurately reflect chronic kidney disease (CKD) in this population, highlighting the need for age-adapted definitions. This study investigated the association of kidney function with all-cause mortality across three age groups. Data from the Tokyo Centenarian Study, Japan Semi-supercentenarian Study, and Kawasaki Ageing and Wellbeing Project were analyzed in 1,918 participants with baseline serum creatinine measurements were included (median follow-up: 1,399 days). eGFR was calculated using creatinine and cystatin C according to the Japanese Society of Nephrology equation. Associations with mortality were assessed using Cox regression models, and standardized 3-year absolute risks were estimated. Lower cystatin C-based eGFR was consistently associated with higher mortality, whereas creatinine-based eGFR showed weaker associations. Prognostic thresholds for eGFR declined with advancing age-approximately 45, 30, and 15 mL/min/1.73 m² at ages 85-89, 100-104, and ≥ 105 years, respectively. The 3-year absolute risk difference (ARD) between the low and high eGFR groups was modest (≈10%) at ages 85-89 years, larger (≈30%) at 100-104 years, and attenuated at ≥ 105 years, where the 3-year mortality exceeded 80%. eGFR remained a prognostically relevant marker in very old individuals; however, the magnitude of ARDs varied by age-modest in the younger-old adults, larger in centenarians, and attenuated in semi- and supercentenarians-supporting the adoption of age-specific CKD thresholds.

Early-life exposures could affect the risk of type 2 diabetes (T2D) in adulthood, but the mechanisms remain unclear. We included 319,951 (54.5% women) UK Biobank participants free of T2D at baseline and within the first year of follow-up to investigate whether early-life exposures contribute to T2D through biological aging estimated using the Klemera-Doubal (KDM) and PhenoAge methods. We first examined associations of exposures with biological age and T2D, respectively, using multivariable-adjusted linear models and Cox regression models. Next, we investigated the role of biological age acceleration in exposure-T2D associations using mediation analyses. Overall, the mean (standard deviation) chronological age of participants was 56.3 (8.1) years, KDM age was 40.9 (13.1) years, and PhenoAge was 44.4 (10.0) years. 17,062 T2D cases developed during a median (interquartile range) follow-up of 14.3 (13.5-15.0) years. Maternal smoking around birth, being part of a multiple birth, earlier puberty, and being relatively plumper or thinner at age ten were associated with both a higher biological age and T2D risk, while having a higher birth weight and being breastfed were associated with a lower T2D risk. Biological age acceleration partly mediated the exposure-T2D associations, ranging from a proportion of 8.3% (95%CI: 6.0-13.1%) of the association between birthweight-T2D being mediated by PhenoAge to a proportion of 27.7% (95%CI: 15.3-48.5%) of the association between breastfeeding-T2D being mediated by KDM. In conclusion, early-life exposures were associated with biological age acceleration that partly mediated the exposure-T2D associations, highlighting the importance of addressing early-life risks and biological aging in prevention strategies.

The proteostatic decline in Alzheimer's disease is well established, and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that the XPO1 inhibitor KPT-330 (Selinexor), an FDA-approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases in C. elegans and Drosophila. Here, we find that KPT-330 increases autophagy in murine neuronal cells. In a murine model of Alzheimer's disease (5XFAD), KPT-330 improved spatial memory performance. Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that, despite overall increases in amyloid plaque burden, XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.

Biopsychosocial frailty, a new construct combining modifiable physical, psychological, and social domains, was associated with increased risk of dementia, mild cognitive impairment, and their subtypes. The aim of the present study was to estimate the role of biopsychosocial frailty on the incident risk of cardio- and cerebrovascular disease, i.e., myocardial infarction, peripheral artery disease (PAD), and definite stroke. From the eight municipalities of the population-based Italian Longitudinal Study on Aging, we examined 2410 older individuals in a longitudinal analysis with an 8-year follow-up. Biopsychosocial frailty operationalization was based on the results of a previous comprehensive geriatric assessment and the presence of physical frailty. Generalized estimating equation models assessed the independent contribution at three different follow-ups of baseline individuals with biopsychosocial frailty on occurring new events of myocardial infarction, PAD, and stroke. The prevalence of biopsychosocial frailty in older individuals with myocardial infarction was 10.9%, in older subjects with PAD was 8.9%, and in older individuals with definite stroke was 23.7%. After 8 years of follow-up, participants with biopsychosocial frailty showed an increased odds ratio (OR) of definite stroke [OR 2.67; 95% confidence interval 1.11-6.40]. No statistically significant associations between biopsychosocial frailty and myocardial infarction or PAD were observed. Over an 8-year follow-up, in a large, older cohort, a biopsychosocial frailty phenotype was associated with incident cerebrovascular disease, in particular with definite stroke. This complex phenotype of frailty has several modifiable components and could be an optimal target for potential interventions and prevention strategies.

Genetic studies have linked EPHX2 (encoding soluble epoxide hydrolase, sEH) and PTGS2 (encoding cyclooxygenase-2, COX-2) to Alzheimer's disease (AD). Elevated levels of sEH and COX-2 found in AD patients and animals suggest their involvement in neurodegeneration, glial activation, vascular dysfunction, and inflammation. This study evaluated the effects of a new dual sEH/COX-2 inhibitor, PTUPB, on cerebrovascular function and cognition in TgF344-AD rats. The rats received oral PTUPB (2 mg/kg/day) for 25 days. Body weight, plasma glucose, and HbA1c levels remained stable between PTUPB- and vehicle-treated AD rats. PTUPB significantly improved recognition memory in AD rats, as detected by the novel object recognition test. Pressure myography showed that PTUPB restored myogenic responses and increased the distensibility of the middle cerebral arteries (MCAs) in AD rats. Acute PTUPB (0.1 and 1 μM) enhanced myogenic contraction in response to elevated perfusion pressure in AD MCAs, with minimal effects in wild-type vessels. Transcriptomic analysis of cerebral vascular smooth muscle cells from AD rats revealed that PTUPB influences genes involved in contractility, extracellular matrix remodeling, inflammation, and oxidative stress. These results provide new evidence that dual inhibition of sEH and COX-2 improves cognition in AD and is associated with enhanced myogenic response via attenuation of vascular remodeling. Our findings highlight the potential of PTUPB as a therapeutic approach for cerebrovascular dysfunction in AD.

Aging is the progressive decline in function at the cellular, tissue, and organismal levels that ultimately leads to mortality. The longevity of an organism is influenced by various internal and external factors, including nutrition, exercise, metabolic dysfunction, genomic instability, and epigenetic imbalance. Histone modifications, such as acetylation, methylation, phosphorylation, and ubiquitination, play a critical role in aging. These modifications illustrate histone changes crucial for regulating chromatin architecture and gene expression. The epigenetic clock signifies the impact of aging on our cells and is essential for accurately determining biological age. It demonstrates significant associations with histone modifications, underscoring their mechanistic importance in age-related changes. Histone alterations are closely associated with age-related diseases such as cancer, neurological disorders, and cardiovascular conditions. While the mechanistic function of histone modifications in biological aging is well-established, clinical application remains constrained. Emerging clinical studies targeting histone-modifying enzymes are beginning to investigate their potential as therapeutic options for age-related disorders. This review seeks to provide a comprehensive examination of histone modifications, including acetylation, methylation, and phosphorylation, as well as the impact of histone alterations on biological age, age-related diseases, and the importance of the epigenetic clock, with the aim of enhancing understanding of the epigenetic mechanisms associated with aging and facilitating the development of therapies to promote healthy aging. In this review, we also focus on the current status of such clinical trials and discuss future directions for translating these epigenetic insights into clinical applications.

Although mechanistic studies support a beneficial effect of several dietary flavonoids on telomere length (TL), to our knowledge no studies have examined associations between habitual flavonoid intakes and TL in population-based studies. We examined the associations between habitual intake of major flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols and their polymers, and anthocyanins) and TL in a cross-sectional analysis of 4,944 disease-free females from the Nurses' Health Study (NHS). Flavonoid intakes were collected using food frequency questionnaire data, and TL was measured in peripheral blood leukocytes using quantitative real-time polymerase chain reaction. Multivariable-adjusted least squares mean leukocyte TL (z scores and corresponding standard error [SE]) for total and all flavonoid subclasses were calculated using generalized linear models. Although no individual flavonoid subclass was significantly associated with TL in the overall population, when we restricted analyses to younger and middle-aged participants (aged < 55 y), a higher anthocyanin intake associated with longer TL (least squares means ± SE: 0.06 ± 0.06 for the highest versus 0.24 ± 0.07 for the lowest quintile; P-trend = 0.042), corresponding to 6.6 (95% CI, 1.7-14.5) years of aging. In food-based analyses, participants aged < 55 y who consumed more berries had longer TL (Mean TL: 0.10 ± 0.04 for never/rarely; 0.21 ± 0.04 for ≤ 1 serving/week; 0.44 ± 0.26 for ≥ 2 servings/week; P = 0.033 for trend). Similarly, a higher anthocyanin intake was associated with longer TL among pre-menopausal females (0.46 ± 0.11 for the highest versus 0.02 ± 0.08 for the lowest quintile; P-trend = 0.001). Overall, habitual flavonoid intake was not associated with TL attrition in this cross-sectional analysis. However, in females aged < 55 y a higher anthocyanin intake was associated with longer TL, which raises the possibility that anthocyanin-rich foods may promote healthy aging and warrants further investigation with respect to age.