Macronutrient balance and lifespan

Abstract

Dietary restriction (DR) without malnutrition is widely regarded to be a universal mechanism for prolonging lifespan. It is generally believed that the benefits of DR arise from eating fewer calories (termed caloric restriction, CR). Here we argue that, rather than calories, the key determinant of the relationship between diet and longevity is the balance of protein to non-protein energy ingested. This ratio affects not only lifespan, but also total energy intake, metabolism, immunity and the likelihood of developing obesity and associated metabolic disorders. Among various possible mechanisms linking macronutrient balance to lifespan, the nexus between the TOR and AMPK signaling pathways is emerging as a central coordinator.

Keywords: AMPK; TOR; caloric restriction; dietary restriction; geometric framework; nutrient balance; protein.

Figure 1.. How the intake of protein and carbohydrate influence longevity and lifetime egg production in adults of three insect species.

Individuals were given ad libitum access to one of 28 (Drosophila and the Queensland fruit fly, Q-fly) or 24 (field cricket) diets varying in the ratio and total concentration of protein to carbohydrate (P:C). Plotted onto arrays of points of nutrient intake are fitted surfaces for the two performance variable, which rise in elevation from dark blue to dark red. Unbroken red lines indicate the dietary P:C that maximized the response variable, whereas the dotted lines indicate isocaloric intakes. In each case, insects lived longest when the diet contained a low P:C, and lifespan declined as P:C rose. Female reproductive output was maximal on higher P:C diets than sustained greatest longevity, but fell as P:C rose further, even at high total energy intakes. Data are replotted from Lee et al. [3] (Drosophila), Maklakov et al. [11] (field crickets), and Fanson et al. [4] (Q-fly).

Figure 2.. Schematic summarizing our hypothesis for how diet balance might affect lifespan via the TOR and AMPK signaling pathways.

We propose that both TOR and AMPK respond not only to the concentration of circulating nutrients (with TOR activity stimulated and AMPK depressed either directly or indirectly by increasing concentrations), but also to nutrient balance. We show hypothetical response surfaces for TOR and AMPK in relation to circulating concentrations and ratios of amino acids (aa) and glucose (glu), with responses rising from dark blue to deep red. The red boxes indicate what we have termed the vicious cycle to obesity, in which chronic exposure to a low percent protein diet can drive overconsumption, metabolic disorders and shortened lifespan unless excess ingested energy is dissipated (see [20], and further supporting evidence from rodents in [52,53]). Otherwise, low percent protein diets are life extending via the normal actions of AMPK, whereas high percent protein diets shorten lifespan and encourage aging via the TOR pathway.