The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice

Abstract

Summary The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.

Overexpression of CYB5R3 and NQO1, two NAD+‐producing enzymes, mimics aspects of caloric restriction

“…Conversely, there was clear reduction in key regulators of the lipid oxidation process, including PGC‐1α, SIRT3, ACAA2, and HADHSC in RedTg livers. It has been previously reported that ad libitum‐fed animals on diets that are high in carbohydrates, but low in proteins, have greater adiposity and the longest lifespan (Solon‐Biet et al., 2014), although the association between the intake of protein/carbohydrates and adiposity is still a matter of debate (Fontana et al., 2016; Maida et al., 2016; Solon‐Biet et al., 2015) including prospective cohort studies of humans (Berryman, Agarwal, Lieberman, Fulgoni & Pasiakos, 2016; Pimpin, Jebb, Johnson, Wardle & Ambrosini, 2016). Nonetheless, the maintenance of body weight in older RedTg mice may be due to higher fat accumulation than in Wt controls, in agreement with our recent study that showed a positive correlation between mouse longevity and conservation of body fat (Mitchell et al., 2016).…”

Running‐wheel activity delays mitochondrial respiratory flux decline in aging mouse muscle via a post‐transcriptional mechanism

“…This convergence at old age may well be due to the strong decrease in their running activity. The finding that mitochondrial aging and the beneficial effect of exercise were so similar between LF and HFS diet may be more surprising, as high‐fat diets tend to accelerate aging (Solon‐Biet et al., 2014). The high degree of overlap among hierarchically regulated enzymes in different experimental groups (Figure 5e, 16 of 27 proteins shared by at least three groups), points to a common mechanism of flux decline at old age, which is only delayed in running‐wheel mice.…”

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

“…Mice lacking S6K1 or with decreased mTORC1 activity have extended lifespan, demonstrating that decreased mTORC1 signaling is sufficient to promote longevity, at least in females (Selman et al ., 2009; Lamming et al ., 2012). A similar inverse correlation between hepatic mTORC1 signaling and lifespan is also observed in wild‐type mice (Solon‐Biet et al ., 2014). …”