GeroScience最新文献

Sarcopenia, defined as the progressive loss of skeletal muscle mass and function associated with ageing, has devastating effects in terms of reducing the quality of life of older people. Muscle ageing is characterised by muscle atrophy and decreased capacity for muscle repair, including a reduction in the muscle stem cell pool that impedes recovery after injury. Histone deacetylase 11 (HDAC11) is the newest member of the HDAC family and it is highly expressed in skeletal muscle. Our group recently showed that genetic deficiency in HDAC11 increases skeletal muscle regeneration, mitochondrial function and globally improves muscle performance in young mice. Here, we explore for the first time the functional consequences of HDAC11 deficiency in old mice, in homeostasis and during muscle regeneration. Aged mice lacking HDAC11 show attenuated muscle atrophy and postsynaptic fragmentation of the neuromuscular junction, but no significant differences in the number or diameter of myelinated axons of peripheral nerves. Maintenance of the muscle stem cell reservoir and advanced skeletal muscle regeneration after injury are also observed. HDAC11 depletion enhances mitochondrial fatty acid oxidation and attenuates age-associated alterations in skeletal muscle fatty acid composition, reducing drastically the omega-6/omega-3 fatty acid ratio and improving significantly the omega-3 index, providing an explanation for improved muscle strength and fatigue resistance and decreased mortality. Taken together, our results point to HDAC11 as a new target for the treatment of sarcopenia. Importantly, selective HDAC11 inhibitors have recently been developed that could offer a new therapeutic approach to slow the ageing process.

Cerebral blood flow (CBF) deficits, cognitive decline, and brain structural changes have been reported in older adults with and without apolipoprotein E-e4 (APOE4)-related risk for dementia. However, it remains unclear whether brain structural changes mediate the effects of hypoperfusion on cognitive impairment in APOE4 carriers and non-carriers. We studied 166 (60–89 years) APOE4 carriers (ε3/ε4 or ε4/ε4) and APOE3 homozygotes (e3/e3) with and without cognitive impairment by clinical dementia rating (CDR) and neuropsychological testing. Pseudocontinuous arterial spin-labeling-MRI assessed regional CBF, and T1-anatomical and diffusion-MRI assessed structural integrity. Mediation analyses examined relationships among grey matter CBF, grey matter volume, and white matter integrity in regions underlying impairment in distinct cognitive ability domains. APOE4 carriers with global/memory impairment (CDR 0.5) exhibited decreased CBF in the posterior cingulate, decreased grey matter volume in the hippocampus, parahippocampal gyrus, and posterior cingulate, and decreased white matter integrity in the cingulum relative to APOE4 carriers with no impairment (CDR 0). Mediation analysis in APOE4 carriers indicated decreased posterior cingulate CBF effects on global/memory impairment were mediated by decreased cingulum integrity. In the combined APOE4 and APOE3 carriers sample, there were direct effects of frontal and inferior parietal CBF and superior longitudinal fasciculus integrity on attention/executive impairment. There were also direct effects of left inferior frontal CBF on language impairment. Findings suggest links between hypoperfusion and brain structural integrity underlying global/memory impairment in APOE4 carriers. Independent CBF relationships with structural integrity are also identified across genotypes and impairment domains.

We have previously reported that when autophagy is suppressed in endothelial cells (ECs), a glycolytic defect limits shear-stress -induced ATP production to an extent that purinergic 2Y1 receptor (P2Y1R)-mediated activation of EC nitric oxide (NO) synthase (eNOS) is compromised. Subsequently we demonstrated the functional relevance of this finding in arteries from mice with genetic, pharmacological, and age-associated EC autophagy impairment. Using gain and loss of function approaches in vitro, we further revealed that p-PKCδ^T505 serves as a signaling link between P2Y1R activation and NO generation. Here we sought to discern the functional relevance of this observation. First, shear-stress- induced activating phosphorylation of eNOS (p-eNOS^S1177) that is otherwise prevented by knockdown of autophagy-related gene 3 (Atg3) in ECs was restored by the PKC agonist bryostatin-1. Next, in murine models of genetic and age-associated EC autophagy compromise, depressed vasodilation displayed by femoral and cerebral arteries was reversed by bryostatin-1 in a manner that could be prevented by concurrent NO synthase inhibition. Finally, the bryostatin-1-mediated normalization of intraluminal flow-induced vasodilation observed in femoral arteries from both models of EC autophagy disruption was mitigated by inhibiting downstream targets of p-PKCδ^T505 i.e., p-PKD^S744/S748 and p-PKD^S916. These findings provide evidence that stimulating PKC/PKD has strategic potential to restore compromised endothelial function in pathologies associated with suppressed EC autophagy e.g., aging.

Graphical Abstract

Cancer remains a major global health challenge, and growing evidence suggests that physical activity is a key modifiable factor that may improve survival outcomes in cancer patients. However, a comprehensive, large-scale synthesis of the effects of post-diagnosis physical activity across multiple cancer types remains lacking. This meta-analysis aims to systematically evaluate the association between physical activity and survival in patients diagnosed with breast, lung, prostate, colorectal, and skin cancers. We conducted a comprehensive search in PubMed, Web of Science, Scopus, and Cochrane Library for studies on physical activity and cancer survival. Eligible studies (January 2000–November 2024) included adults (≥ 18 years) with breast, lung, prostate, colorectal, or skin cancer. Only prospective cohort and case–control studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for overall or cancer-specific mortality were included, with a minimum sample size of 100 and at least six months of follow-up. Meta-analysis was performed using metaanalysisonline.com, applying random-effects models and assessing heterogeneity via the I² statistic. Sensitivity analyses and publication bias (Egger’s test, funnel plots) were evaluated. The meta-analysis included 151 cohorts with almost 1.5 million cancer patients. Post-diagnosis physical activity was associated with significantly lower cancer-specific mortality across all five cancer types. The greatest benefit was observed in breast cancer, with a pooled hazard ratio (HR) of 0.69 (95% CI: 0.63–0.75), followed by prostate cancer (HR: 0.73, 95% CI: 0.62–0.87). Lung cancer patients who engaged in physical activity had a 24% lower risk of cancer-specific death (HR: 0.76, 95% CI: 0.69–0.84), while colorectal cancer patients experienced a similar benefit (HR: 0.71, 95% CI: 0.63–0.80). In skin cancer, physical activity was associated with a non-significant reduction in mortality (HR: 0.86, 95% CI: 0.71–1.05). These findings provide robust evidence supporting the survival benefits of post-diagnosis physical activity in cancer patients, particularly for breast, prostate, lung, and colorectal cancers. The results underscore the potential for incorporating structured physical activity interventions into oncological care to improve long-term patient outcomes.

Vascular contributions to cognitive impairment and dementia (VCID) represent a major public health challenge in the aging population, with age-related cerebromicrovascular dysfunction playing a critical role in its development. Understanding the mechanisms underlying cerebromicrovascular aging is crucial for devising strategies to mitigate this burden. Among the key hallmarks of aging, genomic instability and genetic heterogeneity have emerged as significant drivers of age-related diseases. Clonal hematopoiesis of indeterminate potential (CHIP) is a prominent manifestation of this instability, characterized by the non-malignant expansion of hematopoietic stem cell clones that harbor somatic mutations. CHIP is well-established as a contributor to atherosclerosis and cardiovascular disease through its promotion of chronic inflammation. Given that aging is also a major risk factor for cerebral small vessel disease (CSVD) and VCID, it is likely that the same aging processes driving large artery atherosclerosis in CHIP carriers also impair small vessels, including the cerebral microvasculature. While the role of CHIP in large vessel disease is well-documented, its specific contributions to cerebrovascular aging and microvascular dysfunction remain poorly understood. This review explores the potential role of CHIP in age-related cerebrovascular pathologies, with a particular focus on its contribution to CSVD. We discuss how CHIP-related mutations can promote inflammation and oxidative stress, potentially leading to endothelial dysfunction, dysregulation of cerebral blood flow (CBF), blood–brain barrier (BBB) disruption, microvascular inflammation, and cerebral microhemorrhages. Given the potential implications for VCID, elucidating these mechanisms is critical for developing targeted therapies aimed at reducing the burden of cognitive decline in aging populations. This review aims to highlight the current knowledge gaps and encourage further research into the intersection of CHIP, CSVD, and cognitive aging.

Sleep disorders, particularly insomnia and obstructive sleep apnea, are increasingly implicated as significant contributors to cognitive decline, dementia, and neurodegenerative diseases such as Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID). However, the extent and specificity of these associations remain uncertain. This meta-analysis evaluates the impact of common sleep disorders on the risk of developing dementia and cognitive decline. A comprehensive search of the literature was conducted to identify prospective cohort studies assessing sleep disorders and dementia risk. Studies reporting risk estimates for dementia, AD, or cognitive decline associated with obstructive sleep apnea, insomnia, and other sleep disorders (e.g., restless legs syndrome, circadian rhythm sleep disorders, excessive daytime sleepiness) were included. Meta-analyses were performed using a random-effects model to calculate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Thirty-nine cohort studies were included, with subgroup analyses showing significant associations between all-cause dementia and obstructive sleep apnea (HR 1.33, 95% CI 1.09–1.61), insomnia (HR 1.36, 95% CI 1.19–1.55), and other sleep disorders (HR 1.33, 95% CI 1.24–1.43). Obstructive sleep apnea increased the risk for AD (HR 1.45, 95% CI 1.24–1.69), though its association with vascular dementia did not reach statistical significance (HR 1.35, 95% CI 0.99–1.84). Insomnia was significantly associated with increased risk for both vascular dementia (HR 1.59, 95% CI 1.01–2.51) and AD (HR 1.49, 95% CI 1.27–1.74). This meta-analysis highlights the critical role of sleep disorders in dementia risk, emphasizing the need for early detection and management of sleep disturbances. Targeted interventions could play a pivotal role in reducing dementia risk, particularly among high-risk populations.

Aging and COVID- 19 are known to influence DNA methylation, potentially affecting the rate of aging and the risk of disease. The physiological functions of 54 volunteers—including maximal oxygen uptake (VO₂ max), grip strength, and vertical jump—were assessed just before the COVID- 19 pandemic and again 3 years later. Of these volunteers, 27 had contracted COVID- 19. Eight epigenetic clocks were used to assess the rate of aging during the 3-year period: DNAmAge showed accelerated aging, and five clocks showed slowed aging (DNAmAgeSkinBlood, DNAmAgeHannum, DNAmFitAge, PhenoAge, and DNAmTL). When we considered only females, we observed a stronger effect in the increase of DNAmAge acceleration, while we observed slowed aging in the case of SkinBloodClock, and DNAmTL. The methylation of the promoter region of the H1 FNT genes, which encodes testis-specific histone H1 family member N (H1fnt) and plays a crucial role in spermatogenesis decreased the most significantly. In contrast, the promoter of CSTL1, which encodes Cystatin-like 1, showed the most significant increase. We found that having COVID- 19 during the 3-year study period significantly increased the progress of aging assessed by DNAmGrimAge, DNAmGrimAge2, and DNAmFitAge (p = 0.024, 0.047, 0.032, respectively, after we adjusted the analysis for baseline variables). The data suggest that COVID- 19 may have a mild long-term effect on epigenetic aging.

Increasing evidence suggests that red and processed meat consumption may elevate the risk of colorectal cancer (CRC), yet the magnitude and consistency of this association remain debated. This meta-analysis aims to quantify the relationship between red and processed meat intake and the risk of CRC, colon cancer, and rectal cancer using the most comprehensive set of prospective studies to date. We conducted a comprehensive search in PubMed, Web of Science, Cochrane Library, Embase, and Google Scholar databases from 1990 to November 2024, to identify relevant prospective studies examining red, processed, and total meat consumption in relation to colorectal, colon, and rectal cancer risk. Hazard ratios (HR) and 95% confidence intervals (CI) were extracted for each study and pooled using a random-effects model to account for variability among studies. Statistical evaluation was executed using the online platform MetaAnalysisOnline.com. A total of 60 prospective studies were included. Red meat consumption was associated with a significantly increased risk of colon cancer (HR = 1.22, 95% CI 1.15–1.30), colorectal cancer (HR = 1.15, 95% CI 1.10–1.21), and rectal cancer (HR = 1.22, 95% CI 1.07–1.39). Processed meat consumption showed similar associations with increased risk for colon cancer (HR = 1.13, 95% CI 1.07–1.20), colorectal cancer (HR = 1.21, 95% CI 1.14–1.28), and rectal cancer (HR = 1.17, 95% CI 1.05–1.30). Total meat consumption also correlated with an elevated risk of colon cancer (HR = 1.22, 95% CI 1.11–1.35), colorectal cancer (HR = 1.17, 95% CI 1.12–1.22), and rectal cancer (HR = 1.28, 95% CI 1.10–1.48). This meta-analysis provides robust evidence that high consumption of red and processed meats is significantly associated with an increased risk of colorectal, colon, and rectal cancers. These findings reinforce current dietary recommendations advocating for the limitation of red and processed meat intake as part of cancer prevention strategies.

Cognitive decline has been postulated to predispose to presbyphagia but the neurophysiological basis of this interaction is unclear. To investigate the role of cognition for compensatory resource allocation within the swallowing network and behavioral swallowing performance in dual-task cognitive and motor interference in ageing, volunteers ≥ 70 years of age without preexisting diseases causing dysphagia were investigated using Flexible Endoscopic Evaluation of Swallowing (FEES) including a cognitive and motor dual-task paradigm and a Montreal Cognitive Assessment. The neural correlates of swallowing during dual-task were characterized using magnetoencephalography. Results were related to cognitive function. Sixty-three participants (77.7 ± 6.1 years) underwent FEES, of which 40 additionally underwent MEG. Both cognitive and motor dual-tasks interfered with swallowing function resulting in an increase in pharyngeal residue and premature bolus spillage. The extent of swallowing deterioration (“dual-task cost”) was associated with cognitive decline (cognitive dual-task: Spearman’s rho = − 0.39, p = 0.002; motor dual-task: Spearman’s rho = − 0.25, p = 0.046). When challenged with dual-tasking participants with regular cognition showed compensatory stronger and broader brain activation in cortical pre- and supplementary motor planning areas as well as in frontal executive regions within the cortical swallowing network (p = 0.004) compared to participants with cognitive deficits. They also performed better in the competing cognitive and motor dual-task and showed fewer incorrect responses (p = 0.028). Oropharyngeal swallowing involves cognitive cortical processing. Cognitive decline seems to limit the capacity for compensatory resource allocation within the swallowing network. This may lead to deterioration in both swallowing function and concurrent cognitive-motor performance in challenging dual-task situations.

Neuroimaging studies have shown age-related alterations in brain structure and function supporting semantic knowledge, although the significance of these is not fully understood. Herein, we report novel temporal, spectral, and spatial information on age-related changes from the largest dynamic functional mapping study of semantic processing. Participants (N = 130, age range 21–87 years, M_age = 51.05, SD = 14.73, 68 females) performed a semantic judgement task during magnetoencephalography (MEG), and significant task-related oscillatory responses were projected into anatomical space using a beamformer. Voxel-wise linear mixed-effects models were performed to assess semantic-related neural oscillations, irrespective of and influenced by age. Mediation analyses were performed to assess if local oscillations mediated the relationship between age and reaction time. Whole-brain analyses revealed stronger left-lateralized alpha/beta oscillations in frontotemporal cortices during semantic trials and stronger right-lateralized alpha/beta responses in temporoparietal regions during length trials (all ps <.001). Older adults showed stronger left temporoparietal alpha and left frontal beta during semantic processing and stronger alpha in the right temporal cortex during the length condition (all ps <.001). Alpha oscillations further mediated the relationship between age and reaction time in a hemisphere- and condition-specific manner, whereby right temporal activity mediated the age-behavior relationship in the length but not semantic condition (Z = 2.01, p =.022), while left temporoparietal activity significantly mediated this relationship in the semantic but not length condition (Z = − 2.41, p =.008). Altogether, our findings demonstrate accentuated oscillations in aging which are hemisphere- and condition-specific and support compensatory processing to aid in maintaining adequate behavioral performance, lending clear support to leading neuroscientific models of aging.