Molecular mechanisms of dietary restriction promoting health and longevity

Abstract

Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic and molecular changes responsible for the prevention of multiple ageing-associated diseases in humans. We further discuss how different forms of fasting, protein restriction and specific reductions in the levels of essential amino acids such as methionine and the branched-chain amino acids selectively impact the activity of AKT, FOXO, mTOR, nicotinamide adenine dinucleotide (NAD⁺), AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21), which are key components of some of the most important nutrient-sensing geroprotective signalling pathways that promote healthy longevity.

Figure 1 |. The Hallmarks of dietary restriction.

This schematic enumerates the proven biological adaptations induced by dietary restriction (DR) that have a protective effect against ageing-related pathologies and diseases across rodents, non-human primates, and humans. These protective effects include the prevention of obesity and diabetes, cardiovascular disease, cancer, kidney disease, autoimmune and inflammatory conditions and cancer, leading to increased healthspan and lifespan. It is not yet clear what combination of transcriptional, epigenetic, proteomic, metabolomic, and microbiota changes drive such benefits of DR on healthspan and lifespan. Relevant references can be found in Supplementary information 1.

Figure 2 |. Multiple molecular pathways engaged by dietary restriction.

Dietary restriction (DR) results in reduced consumption of most macronutrients, including carbohydrates and specific amino acids, the building blocks of proteins. Reduced levels of glucose and its catabolite dihydroxyacetone phosphate (DHAP) are sensed by AMP-activated protein kinase (AMPK) and mTOR complex 1 (mTORC1), resulting in increased AMPK activity and decreased mTORC1 signaling, mediated through activation of TSC as well as modulation of the Rag-GATOR pathway that controls lysosomal localization of mTORC1. Downstream of mTORC1, ribosomal biogenesis and protein synthesis are downregulated and autophagy is increased. Decreased levels of methionine, branched-chain amino acids (BCAAs), or of protein similarly reduce mTORC1 signaling via the Rag-GATOR pathway. Decreased levels of protein and amino acids are also sensed by the integrated stress response pathway via GCN2, eukaryotic translation initiation factor eIF2α and cAMP-dependent transcription factor ATF4, leading to the induction of the pro-longevity hormone fibroblast growth factor 21 (FGF21). Reduced levels of carbohydrates and calories lead to decreased insulin/insulin-like growth factor 1 (IGF-1) signaling, which leads to decreased activity of the PI3K/mTOR complex 2 (mTORC2)/AKT signaling cascade that normally inhibits forkhead box protein O (FOXO)-dependent gene transcription, as well as decreased mTORC1 activity. Decreased levels of methionine lead to decreased levels of the metabolite S-adenosyl methionine (SAM), altering DNA and histone methylation. Collectively, DR induces repair and recycling pathways, including autophagy, mitophagy, DNA repair, and oxidant defense, and enhances stem cell function. As a result, cell senescence is downregulated and proteostasis is improved. Together these positive effects on cell and tissue function (shown in blue) contribute to extension of lifespan and healthspan. Proteins or protein complexes with kinase activity are depicted in red. SIRT1, sirtuin 1.

Figure 3 |. Species-specific effects of fasting on ketone bodies production and survival.

Remarkable differences in biological adaptations to fasting exist between mice and humans that should be considered when determining how studies from rodent models can inform human trials. Because of their high-energy metabolism, most strains of mice starve to death after a 48–60 hour fast. In contrast, even lean men and women can undergo a 57–73 days of water-only fasting before death occurs, and some severely obese individuals can fast for more than a year. Similarly, serum ketone levels increase after approximately 4–7 hours of fasting and peak after 24 hours in rodents, whereas in humans ketone bodies usually start to increase after 18–24 hours of fasting and do not peak until 2 weeks.