Frailty extends beyond a physical construct to encompass cognitive and social functioning. We aimed to assess the associations of these impairments, individually and in combination, with the risk of 45 non-communicable diseases (NCDs), and explore the role of accelerated biological aging.

A prospective cohort study was conducted using data from the UK Biobank.

A total of 427,026 participants with physical data, 171,269 with social data, and 49,820 with cognitive data were included in analysis.

Physical frailty, social deficits, and cognitive impairment were assessed using self-reported data and anthropometric measurements, while biological age was calculated based on blood chemistry and clinical data. Hazard ratios (HRs) and population attributable fractions were calculated to assess their associations with NCDs risk. The role of accelerated biological aging in these associations were investigated by mediation analysis.

Physical frailty, high social deficits, and cognitive impairment were associated with an increased risk of 27, 17, and 7 NCDs, respectively (HR > 1, P_adjusted<0.05). Pre-physical frailty and moderate-social deficits were also associated with numerous NCDs risk. Compared to participants with single impairment, those with impairment in multiple domains had a higher risk of NCDs (P < 0.05). In addition, physical frailty and high social deficits had a greater impact on NCDs in younger individuals (<60 years old) and females (P_interaction<0.05). These function impairments accelerated biological aging (P_trend<0.05), and mediation analysis revealed that accelerated biological aging explained 3.205%–50.296% of their associations with NCDs.

Impairments in physical, social, and cognitive functions were associated with an increased risk of numerous NCDs, with accelerated biological aging partially mediating these associations, highlighting the importance of systematically assessing frailty and biological aging and implementing interventions to prevent NCDs.