Association Between the Serum Creatinine to Cystatin C Ratio, Physical Activity, and Frailty in Middle-Aged and Older Adults in China: A Nationwide Cohort Study

Abstract

Background: Frailty is a major barrier to healthy ageing, yet early identification strategies remain limited. The serum creatinine-to-cystatin C ratio (sarcopenia index, SI) has emerged as a cost-effective biomarker of muscle mass and function, while physical activity (PA) is a key protective factor. However, their combined role in predicting frailty is unclear. This study aimed to investigate the independent and joint associations of SI and PA with incident frailty in middle-aged and older adults. Methods: We analyzed 5307 participants aged ≥45 years from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2018). SI was calculated from serum creatinine and cystatin C levels, and PA was assessed using standardized questionnaires. Frailty was defined using a 32-item Frailty Index (FI ≥ 0.25). Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of SI and PA with incident frailty, adjusting for sociodemographic and health-related factors. Effect modification by PA was formally tested. Results: Over the follow-up period, 1483 participants developed frailty (27.9%). Higher SI was inversely associated with frailty in a dose–response manner: compared with the lowest quartile, HRs (95% CIs) were 0.84 (0.73–0.97) for Q2, 0.83 (0.72–0.96) for Q3, and 0.69 (0.59–0.82) for Q4 (p-trend < 0.001). Each 10-unit increase in SI corresponded to a 6% lower frailty risk (HR = 0.94, 95% CI: 0.91–0.97). PA significantly modified this relationship (interaction p < 0.05), with the strongest protective effect of SI observed among individuals with low PA, and attenuation at higher PA levels. Conclusions: SI is independently associated with a lower risk of incident frailty, particularly among less physically active individuals. These findings support the potential use of SI as a feasible biomarker for early frailty risk stratification and highlight the importance of integrating biomarker-based screening with lifestyle interventions to prevent frailty.