npj aging最新文献

Growing evidence suggests that exposure to fine particulate matter (PM_2.5) may reduce life expectancy; however, the causal pathways of PM_2.5 exposure affecting life expectancy remain unknown. Here, we assess the causal effects of genetically predicted PM_2.5 concentration on common chronic diseases and longevity using a Mendelian randomization (MR) statistical framework based on large-scale genome-wide association studies (GWAS) (>400,000 participants). After adjusting for other types of air pollution and smoking, we find significant causal relationships between PM_2.5 concentration and angina pectoris, hypercholesterolaemia and hypothyroidism, but no causal relationship with longevity. Mediation analysis shows that although the association between PM_2.5 concentration and longevity is not significant, PM_2.5 exposure indirectly affects longevity via diastolic blood pressure (DBP), hypertension, angina pectoris, hypercholesterolaemia and Alzheimer's disease, with a mediated proportion of 31.5, 70.9, 2.5, 100, and 24.7%, respectively. Our findings indicate that public health policies to control air pollution may help improve life expectancy.

Supplementation with S-adenosylhomocysteine (SAH) extends the lifespan of model organisms. To explore the impact of SAH on aging, we generated a Caenorhabditis elegans model by introducing the S-adenosylhomocysteine hydrolase (AHCY-1) variant Y145C, corresponding to the human AHCY Y143C pathogenic mutation. This mutation is anticipated to impair SAH hydrolysis, resulting in its increased levels. Our findings revealed that animals with this endogenous mutation exhibited delayed aging, accompanied by decreased S-adenosylmethionine (SAM) and moderately increased SAH levels. The extended lifespan of these worms depends on the AMP-activated protein kinase (AMPK), its activator Vaccinia virus-related kinase (VRK-1), and the DAF-16 transcription factor. The results underline the complex nature of SAH's influence on aging, proposing that the balance between SAM and SAH might play a pivotal role in defining the lifespan of C. elegans. Moreover, our partial AHCY-1 deficiency model offers a tool for studying the intersection of methionine metabolism and aging.

Glaucoma is a leading cause of blindness worldwide in older people. Profiling the aqueous humor, including the metabolites it contains, is useful to understand physiological and pathological conditions in the eye. In the current study, we used mass spectrometry (MS) to characterize the aqueous humor metabolomic profile and biological features of patients with glaucoma. Aqueous humor samples were collected during trabeculectomy surgery or cataract surgery and analyzed with global metabolomics. We included 40 patients with glaucoma (32 with POAG, 8 with NTG) and 37 control subjects in a discovery study. VIP analysis revealed five metabolites that were elevated and three metabolites that were reduced in the glaucoma patients. The identified metabolomic profile had an area under the receiver operating characteristic curve of 0.953. Among eight selected metabolites, the glutathione level was significantly decreased in association with visual field defects. Moreover, in a validation study to confirm the reproducibility of our findings, the glutathione level was reduced in NTG and POAG patients compared with a cataract control group. Our findings demonstrate that aqueous humor profiling can help to diagnose glaucoma and that various aqueous humor metabolites are correlated with clinical parameters in glaucoma patients. In addition, glutathione is clearly reduced in the aqueous humor of glaucoma patients with both IOP-dependent and IOP-independent disease subtypes. These findings indicate that antioxidant agents in the aqueous humor reflect glaucomatous optic nerve damage and that excessive oxidative stress may be involved in the pathogenesis of glaucoma.

We recently reported accelerated cognitive decline in Europeans aged > 70 years with low circulating adropin levels. Adropin is a small, secreted peptide that is highly expressed in the human nervous system. Expression profiling indicate relationships between adropin expression in the human brain and pathways that affect dementia risk. Moreover, increased adropin expression or treatment using synthetic adropin improves cognition in mouse models of aging. Here we report that low circulating adropin concentrations associate with poor cognition (worst quintile for a composite score derived from the MMSE and semantic fluency test) in late-middle aged community-dwelling African Americans (OR = 0.775, P < 0.05; age range 45-65 y, n = 352). The binomial logistic regression controlled for sex, age, education, cardiometabolic disease risk indicators, and obesity. Previous studies using cultured cells from the brains of human donors suggest high expression in astrocytes. In snRNA-seq data from the middle temporal gyrus (MTG) of human donors, adropin expression is higher in astrocytes relative to other cell types. Adropin expression in all cell-types declines with advance age, but is not affected by dementia status. In cultured human astrocytes, adropin expression also declines with donor age. Additional analysis indicated positive correlations between adropin and transcriptomic signatures of energy metabolism and protein synthesis that are adversely affected by donor age. Adropin expression is also suppressed by pro-inflammatory factors. Collectively, these data indicate low circulating adropin levels are a potential early risk indicator of cognitive impairment. Declining adropin expression in the brain is a plausible link between aging, neuroinflammation, and risk of cognitive decline.

Understanding the biological effects of low-dose (<100 mGy) ionizing radiation (LDR) is technically challenging. We investigated age-dependent LDR effects using adaptive response experiments in young (7-to 12-week-old) and middle-aged (40-to 62-week-old) C57BL/6 mice. Compared with 3 Gy irradiation, 0.02 Gy preirradiation followed by 3 Gy irradiation prolonged life in young mice but not middle-aged mice. Preirradiation also suppressed irradiation-induced 53BP1 repair foci in the small intestines, splenic apoptosis, and p53 activity in young mice but not middle-aged mice. Young p53^+/- C57BL/6 mice did not show these adaptive responses, indicating that insufficient p53 function in young mice mitigated the adaptive responses. Interestingly, p53 activation in middle-aged mice spontaneously became approximately 4.5-fold greater than that in young mice, possibly masking LDR stresses. Furthermore, adaptive responses in young mice, but not in middle-aged mice, suppressed some senescence-associated secretory phenotype (SASP) factors (IL-6, CCL2, CCL5, CXCL1). Thus, LDR-induced adaptive responses associated with specific SASP factors may be attenuated by a combination of reduced DNA damage sensor/transducer function and chronic p53 activation in middle-aged mice.

Apathy is a pervasive clinical syndrome in neurocognitive disorders, characterized by a quantitative reduction in goal-directed behaviors. The brain structures involved in the physiopathology of apathy have also been connected to the brain structures involved in probabilistic reward learning in the exploration-exploitation dilemma. This dilemma in question involves the challenge of selecting between a familiar option with a more predictable outcome, and another option whose outcome is uncertain and may yield potentially greater rewards compared to the known option. The aim of this study was to combine experimental procedures and computational modeling to examine whether, in older adults with mild neurocognitive disorders, apathy affects performance in the exploration-exploitation dilemma. Through using a four-armed bandit reinforcement-learning task, we showed that apathetic older adults explored more and performed worse than non-apathetic subjects. Moreover, the mental flexibility assessed by the Trail-making test-B was negatively associated with the percentage of exploration. These results suggest that apathy is characterized by an increased explorative behavior and inefficient decision-making, possibly due to weak mental flexibility to switch toward the exploitation of the more rewarding options. Apathetic participants also took longer to make a choice and failed more often to respond in the allotted time, which could reflect the difficulties in action initiation and selection. In conclusion, the present results suggest that apathy in participants with neurocognitive disorders is associated with specific disturbances in the exploration-exploitation trade-off and sheds light on the disturbances in reward processing in patients with apathy.

As life expectancy continues to increase worldwide, age-related dysfunction will largely impact our societies in the future. Aging is well established to promote the deterioration of cognitive function and is the primary risk factor for the development of prevalent neurological disorders. Even in the absence of dementia, age-related cognitive decline impacts specific types of memories and brain structures in humans and animal models. Despite this, preclinical and clinical studies that investigate age-related changes in brain physiology often use largely different methods, which hinders the translational potential of findings. This review seeks to integrate what is known about age-related changes in the brain with analogue cognitive tests used in humans and rodent studies, ranging from "pen and paper" tests to virtual-reality-based paradigms. Finally, we draw parallels between the behavior paradigms used in research compared to the enrollment into clinical trials that aim to study age-related cognitive decline.

Cognition, defined as the ability to learn, remember, sustain attention, make decisions, and solve problems, is essential in daily activities and in learning new skills. The purpose of this study was to develop cognitive workload and performance evaluation models using features that were extracted from Electroencephalogram (EEG) data through functional brain network and spectral analyses. The EEG data were recorded from 124 brain areas of 26 healthy participants conducting two cognitive tasks on a robot simulator. The functional brain network and Power Spectral Density features were extracted from EEG data using coherence and spectral analyses, respectively. Participants reported their perceived cognitive workload using the SURG-TLX questionnaire after each exercise, and the simulator generated actual performance scores. The extracted features, actual performance scores, and subjectively assessed cognitive workload values were used to develop linear models for evaluating performance and cognitive workload. Furthermore, the Pearson correlation was used to find the correlation between participants' age, performance, and cognitive workload. The findings demonstrated that combined EEG features retrieved from spectral analysis and functional brain networks can be used to evaluate cognitive workload and performance. The cognitive workload in conducting only Matchboard level 3, which is more challenging than Matchboard level 2, was correlated with age (0.54, p-value = 0.01). This finding may suggest playing more challenging computer games are more helpful in identifying changes in cognitive workload caused by aging. The findings could open the door for a new era of objective evaluation and monitoring of cognitive workload and performance.