Frailty, lifestyle, genetics and dementia risk.

OBJECTIVE: To optimise dementia prevention strategies, we must understand the complex relationships between lifestyle behaviours, frailty and genetics. METHODS: We explored relationships between frailty index, healthy lifestyle and polygenic risk scores (all assessed at study entry) and incident all-cause dementia as recorded on hospital admission records and death register data. RESULTS: The analytical sample had a mean age of 64.1 years at baseline (SD=2.9) and 53% were women. Incident dementia was detected in 1762 participants (median follow-up time=8.0 years). High frailty was associated with increased dementia risk independently of genetic risk (HR 3.68, 95% CI 3.11 to 4.35). Frailty mediated 44% of the relationship between healthy lifestyle behaviours and dementia risk (indirect effect HR 0.95, 95% CI 0.95 to 0.96). Participants at high genetic risk and with high frailty had 5.8 times greater risk of incident dementia compared with those at low genetic risk and with low frailty (HR 5.81, 95% CI 4.01 to 8.42). Higher genetic risk was most influential in those with low frailty (HR 1.31, 95% CI 1.22 to 1.40) but not influential in those with high frailty (HR 1.09, 95% CI 0.92 to 1.28). CONCLUSION: Frailty is strongly associated with dementia risk and affects the risk attributable to genetic factors. Frailty should be considered an important modifiable risk factor for dementia and a target for dementia prevention strategies, even among people at high genetic risk

Lower Frailty Is Associated with Successful Cognitive Aging Among Older Adults with HIV.

Aging with HIV poses unique and complex challenges, including avoidance of neurocognitive disorder. Our objective here is to identify the prevalence and predictors of successful cognitive aging (SCA) in a sample of older adults with HIV. One hundred three HIV-infected individuals aged 50 and older were recruited from the Modena HIV Metabolic Clinic in Italy. Participants were treated with combination antiretroviral therapy for at least 1 year and had suppressed plasma HIV viral load. SCA was defined as the absence of neurocognitive impairment (as defined by deficits in tasks of episodic learning, information processing speed, executive function, and motor skills) depression, and functional impairment (instrumental activities of daily living). In cross-sectional analyses, odds of SCA were assessed in relation to HIV-related clinical data, HIV-Associated Non-AIDS (HANA) conditions, multimorbidity (≥2HANA conditions), and frailty. A frailty index was calculated as the number of deficits present out of 37 health variables. SCA was identified in 38.8% of participants. Despite no differences in average chronologic age between groups, SCA participants had significantly fewer HANA conditions, a lower frailty index, and were less likely to have hypertension. In addition, hypertension (odds ratio [OR] = 0.40, p = .04), multimorbidity (OR = 0.35, p = .05), and frailty (OR = 0.64, p = .04) were significantly associated with odds of SCA. Frailty is associated with the likelihood of SCA in people living with HIV. This defines an opportunity to apply knowledge from geriatric population research to people aging with HIV to better appreciate the complexity of their health status

Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues.

Fatty acid synthase (FASN) predominantly generates straight-chain fatty acids using acetyl-CoA as the initiating substrate. However, monomethyl branched-chain fatty acids (mmBCFAs) are also present in mammals but are thought to be primarily diet derived. Here we demonstrate that mmBCFAs are de novo synthesized via mitochondrial BCAA catabolism, exported to the cytosol by adipose-specific expression of carnitine acetyltransferase (CrAT), and elongated by FASN. Brown fat exhibits the highest BCAA catabolic and mmBCFA synthesis fluxes, whereas these lipids are largely absent from liver and brain. mmBCFA synthesis is also sustained in the absence of microbiota. We identify hypoxia as a potent suppressor of BCAA catabolism that decreases mmBCFA synthesis in obese adipose tissue, such that mmBCFAs are significantly decreased in obese animals. These results identify adipose tissue mmBCFA synthesis as a novel link between BCAA metabolism and lipogenesis, highlighting roles for CrAT and FASN promiscuity influencing acyl-chain diversity in the lipidome