# The effect of long-term adherence to physical activity recommendations in midlife on plasma proteins associated with frailty in the Atherosclerosis Risk in Communities (ARIC) study

## TL;DR

Long-term physical activity in midlife improves proteins linked to frailty, particularly those related to the nervous system and inflammation.

## Contribution

This study demonstrates the long-term effects of physical activity on frailty-associated plasma proteins using a target trial design.

## Key findings

- Long-term adherence to recommended physical activity improved population levels of frailty-associated proteins.
- The greatest benefits were observed in proteins related to the nervous system and inflammation.
- Inverse probability weighting and iterative conditional expectations were used to estimate these effects.

## Abstract

Clinical trials have shown favorable effects of exercise on frailty, supporting physical activity (PA) as a treatment and prevention strategy. Proteomics studies suggest that PA alters levels of many proteins, some of which may function as molecules in the biological processes underlying frailty. However, these studies have focused on structured exercise programs or cross-sectional PA-protein associations. Therefore, the effects of long-term PA on frailty-associated proteins remain unknown. Among 14,898 middle-aged adults, we emulated a target trial that assigned individuals to either (i) achieve and maintain the recommended PA level (≥ 150 min/week of moderate-to-vigorous physical activity [MVPA]) through 6 (± 0.3) years of follow-up or (ii) follow a “natural course” strategy, where all individuals engage in various amounts of habitual MVPA. We estimated the effects of long-term adherence to recommended MVPA versus the natural course strategy on 45 previously identified frailty-associated proteins at the end of the follow-up using inverse probability of weighting (IPW) and iterative conditional expectations (ICE). We found that long-term adherence to recommended MVPA improved the population levels of many frailty-associated proteins (ranged from 0.04 to 0.11 standard deviation); the greatest benefits were seen in proteins involved in the nervous system (e.g., voltage-dependent calcium channel subunit alpha-2/delta-3 [CACNA2D3], contactin-1 [CNTN1], neural cell adhesion molecule 1 [NCAM1], and transmembrane protein 132D [TMEM132D]) and inflammation (e.g., high-temperature requirement serine protease A1 [HTRA1] and C-reactive protein [CRP]). Our findings suggest improved nervous system and reduced inflammation as the biological basis of long-term engagement in adequate PA as an intervention strategy for frailty.

The online version contains supplementary material available at 10.1007/s10654-025-01282-1.