Low resting metabolic rate is associated with greater lifespan because of a confounding effect of body fatness

Abstract

A negative association between resting metabolic rate (RMR) and lifespan is the cornerstone of the rate of living and free-radical damage theories of aging. Empirical studies supporting a negative association of RMR to lifespan may arise from the correlation between RMR and both daily energy expenditure (DEE) and thermoregulatory activity energy expenditure (TAEE). We screened 540 female mice for higher and lower DEE and measured RMR in the resulting 324 (60 %). We then selected 92 mice in which there was no link between residual from the regression of RMR against body mass (BM) and residual of DEE against BM to separate the effects of these traits. Lifespan was not significantly related to body mass, DEE and TAEE, but significantly negatively related to RMR. Fat-free mass (FFM) and fat mass (FM) were both significantly positively related to RMR. After removing the effect of FFM on RMR, the association between RMR and lifespan remained significantly negative; however, after statistically removing the effect of FM on RMR, the significant association between RMR and lifespan disappeared. We conclude that the negative association between RMR and lifespan is primarily due to the effect of FM, with FM positively related to both RMR and mortality and hence RMR negatively to lifespan. In 40 additional screened mice, greater FM was also associated with greater oxidative damage to DNA.

Fig. 1

Steps followed for mice screening and the respective sample size in each step

Fig. 2

Lifespan correlations. Relationships between individual lifespan of 92 female MF1 mice and body mass (a) daily energy expenditure (DEE) (b), thermoregulatory activity energy expenditure (TAEE) (c) and resting metabolic rate (RMR) (d). Only the relationship in d was significant (see text for statistics)

Fig. 3

Survival curves. Cumulative survival curve (Kaplan–Meier survival plot) of female MF1 mice. The cumulative survival rate was plotted against age in days. Log-rank test was performed to compare high and low body mass (a), daily energy expenditure (b), thermoregulatory activity energy expenditure (c) and resting metabolic rate (d) (see text for statistics)

Fig. 4

Effect of fat mass and fat-free mass on resting metabolic rate (RMR) and lifespan. Relationships between resting metabolic rate and FM (a) and FFM (b) were both significant. The respective residuals from these regression analyses resulted in the residual resting metabolic rate with no fat mass effect, which was not correlated with lifespan (c) and the residual resting metabolic rate with no fat-free mass effect which was significantly correlated with lifespan (d) (see text for details (n = 53))

Fig. 5

Effect of body fatness on lifespan and DNA damage. Negative and significant relationship between body fatness (g fat) and lifespan (days) (F = 5.32, P = .025, R ² = 0.1, n = 53) (a). Positive and significant relationship between DNA damage measured by 8-OHdG concentration and body fatness obtained from a regression between fat mass and body mass in grams (F = 5.6, P = 0.02, R ² = 0.13; n = 40) (b) (see text for details)