Background Previous studies indicated that obesity would accelerate frailty progression. However, obesity is heterogeneous by different metabolic status. The associations of metabolic heterogeneity of obesity with frailty progression remain unclear. Methods A total of 6730 participants from the China Health and Retirement Longitudinal Study (CHARLS) and 4713 from the English Longitudinal Study of Ageing (ELSA) were included at baseline. Metabolic heterogeneity of obesity was evaluated based on four obesity and metabolic phenotypes as metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obesity (MHOO), and metabolically unhealthy overweight/obesity (MUOO). Frailty status was assessed by the frailty index (FI) ranging from 0 to 100 and frailty was defined as FI ≥ 25. Linear mixed-effect models were used to analyse the associations of metabolic heterogeneity of obesity with frailty progression. Results In the CHARLS, MUOO and MUNW presented the accelerated FI progression with additional annual increases of 0.284 (95% CI: 0.155 to 0.413, P < 0.001) and 0.169 (95% CI: 0.035 to 0.303, P = 0.013) as compared with MHNW. MHOO presented no accelerated FI progression (β: -0.011, 95% CI: À0.196 to 0.173, P = 0.904) as compared with MHNW. In the ELSA, the accelerated FI progression was marginally significant for MUOO (β: 0.103, 95% CI: À0.005 to 0.210, P = 0.061) and MUNW (β: 0.157, 95% CI: À0.011 to 0.324, P = 0.066), but not for MHOO (β: -0.047, 95% CI: À0.157 to 0.062, P = 0.396) in comparison with MHNW. The associations of MUOO and MUNW with the accelerated FI progression were stronger after excluding the baseline frail participants in both cohorts. The metabolic status changed over time. When compared with stable MHNW, participants who changed from MHNW to MUNW presented the accelerated FI progression with additional annual increases of 0.356 (95% CI: 0.113 to 0.599, P = 0.004) and 0.255 (95% CI: 0.033 to 0.477, P = 0.024) in the CHARLS and ELSA, respectively. The accelerated FI progression was also found in MHOO participants who transitioned to MUOO (CHARLS, β: 0.358, 95% CI: 0.053 to 0.663, P = 0.022; ELSA, β: 0.210, 95% CI: 0.049 to 0.370, P = 0.011). Conclusions Metabolically unhealthy overweight/obesity and normal weight, but not metabolically healthy overweight/obesity, accelerated frailty progression as compared with metabolically healthy normal weight. Regardless of obesity status, transitions from healthy metabolic status to unhealthy metabolic status accelerated frailty progression as compared with stable metabolically healthy normal weight. Our findings highlight the important role of metabolic status in frailty progression and recommend the stratified management of obesity based on metabolic status.

Background Body weight variability (BWV) refers to intraindividual weight loss and gain over a period. The association of long-term BWV with dementia remains unclear and whether this association is beyond body weight change is undetermined. Methods In the Health and Retirement Study (HRS), a total of 5,547 dementia-free participants (56.7% women; mean [SD] age, 71.1 [3.2] years) at baseline (2008) were followed up to 8 years (mean=6.8 years) to detect incident dementia. Body weight was self-reported biennially from 1992-2008. BWV was measured as the coefficient of variation utilizing the body weight reported 9 times across 16 years before baseline. Cox proportional hazard model was used to estimate the hazard ratio (HR) and 95% confidence interval (CI). Results Among the 5,547 participants, a total of 427 incident dementia cases were identified during follow-up. Greater long-term BWV was significantly associated with a higher risk of dementia (HR comparing extreme quartiles: 2.01, 95% CI: 1.48-2.72; HR of each SD increment: 1.21, 95% CI: 1.10-1.32; P-trend&lt;0.001) independent of mean body weight and body weight change. This significant association was even observed for BWV estimated approximately 15 years preceding dementia diagnosis (HR of each SD increment: 1.13, 95% CI: 1.03-1.23) and was more pronounced for that closer to diagnosis. Conclusions Our prospective study suggested that greater BWV may be a novel risk factor for dementia.

Background Weight loss among middle and older adults has been associated with a higher risk of subsequent dementia. However, most of studies have limited follow-up time or suboptimal control for the potential influence of physical frailty (PF). Objectives Our study aimed to investigate the long-term and temporal relation of weight change to risk of dementia among U.S. middle-aged and older adults. Methods A total of 5985 participants aged 50 years and older were included from the Health and Retirement Study (HRS). History of long-term weight change was calculated using nine repeated BMI measurements from 1992-2008. We then followed their dementia status from 2008 to 2018. Multivariable cox proportional hazard models were used. Results During the study follow-up (mean = 7.54 years), a total of 682 (11.39%) dementia cases were documented. After controlling for basic demographic and lifestyle, participants with weight loss (median: -0.23 kg/m 2 per year) were at a significantly higher risk of dementia (HR = 1.60, 95% CI, 1.33, 1.92), compared with the stable-weight group (median: 0.11 kg/m 2 per year). This association was attenuated but remained strong and significant after further adjustment for PF (HR = 1.57, 95% CI, 1.30, 1.89). The significant association was observed for weight loss assessed approximately 14-18 years preceding dementia diagnosis (HR = 1.30, 95% CI, 1.07, 1.58), and was consistent for that closer to diagnosis. Conclusions Both recent and remote weight loss were associated with a higher risk of later-life dementia among middle-aged and older adults independent of the status of physical frailty.

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