Physical activity in adulthood: genes and mortality

Abstract

Observational studies report a strong inverse relationship between leisure-time physical activity and all-cause mortality. Despite suggestive evidence from population-based associations, scientists have not been able to show a beneficial effect of physical activity on the risk of death in controlled intervention studies among individuals who have been healthy at baseline. On the other hand, high cardiorespiratory fitness is known to be a strong predictor of reduced mortality, even more robust than physical activity level itself. Here, in both animals and/or human twins, we show that the same genetic factors influence physical activity levels, cardiorespiratory fitness, and risk of death. Previous observational follow-up studies in humans suggest that increasing fitness through physical activity levels could prolong life; however, our controlled interventional study with laboratory rats bred for low and high intrinsic fitness contrast with these findings. Also, we find no evidence for the suggested association using pairwise analysis among monozygotic twin pairs who are discordant in their physical activity levels. Based on both our animal and human findings, we propose that genetic pleiotropy might partly explain the frequently observed associations between high baseline physical activity and later reduced mortality in humans.

Figure 1. Rat study protocol and measurements.

(a) Schematic of study protocol. Rats were bred for high (HCR, blue) or low (LCR, orange) intrinsic fitness, then assigned to control (C) or running (R) subgroups. (b) Body weights from ages 12 to 30 months. Rats per group: 12 months: HCR-C = 18, HCR-R = 15, LCR-C = 20, and LCR-R = 20; 21 months: HCR-C = 19, HCR-R = 17, LCR-C = 18, and LCR-R = 13; 30 months: HCR-C = 12, HCR-R = 8, LCR-C = 7, and LCR-R = 3. (c) Food intakes from ages 12 to 30 months. Rats per group: same as in b), except at 12 months: HCR-C = 16. (d) Average daily spontaneous activity measured over 3 days between 13 and 15 months of age (activity index). Rats per group: 13 months: HCR-C = 18, HCR-R = 12, LCR-C = 20, and LCR-R = 11; 15 months: HCR-C = 19, HCR-R = 13, LCR-C = 19, and LCR-R = 10. (e) Average running distance per day. Rats per group: 12 months: HCR-R = 15 and LCR-R = 15; 21 months: HCR-R = 16 and LCR-R = 14; 30 months: HCR-R = 4 and LCR-R = 2. Error bars represent SEMs. Figure was drawn by Sira Karvinen.

Figure 2. Effects of genetic background and environment on lifespan.

Control rats (C) had longer lifespans than rats in the runner groups (R) of the same strain (HCR-C vs. HCR-R, P < 0.05 and LCR-C vs. LCR-R, P < 0.01). Mean lifespans were also significantly different between rat strains (HCR-C vs. LCR-C, P < 0.05). Values in the table show means±SDs.

Figure 3. Kaplan-Meier survival curves of mortality in the human study.

Follow-up started from the date of the 1990 questionnaire response to the end of July 2013. Groups comprised individuals with no vigorous activity (orange) vs. those with persistent vigorous activity (blue) at baseline (start of follow-up). (a) Survival of 2428 individuals with no vigorous activity and 2145 individuals with persistent vigorous activity; (b) survival of 134 discordant DZ twin pairs; (c) survival of 34 discordant MZ twin pairs.