Nutrients and Pathways that Regulate Health Span and Life Span

Abstract

Both life span and health span are influenced by genetic, environmental and lifestyle factors. With the genetic influence on human life span estimated to be about 20-25%, epigenetic changes play an important role in modulating individual health status and aging. Thus, a main part of life expectance and healthy aging is determined by dietary habits and nutritional factors. Excessive or restricted food consumption have direct effects on health status. Moreover, some dietary interventions including a reduced intake of dietary calories without malnutrition, or a restriction of specific dietary component may promote health benefits and decrease the incidence of aging-related comorbidities, thus representing intriguing potential approaches to improve healthy aging. However, the relationship between nutrition, health and aging is still not fully understood as well as the mechanisms by which nutrients and nutritional status may affect health span and longevity in model organisms. The broad effect of different nutritional conditions on health span and longevity occurs through multiple mechanisms that involve evolutionary conserved nutrient-sensing pathways in tissues and organs. These pathways interacting each other include the evolutionary conserved key regulators mammalian target of rapamycin, AMP-activated protein kinase, insulin/insulin-like growth factor 1 pathway and sirtuins. In this review we provide a summary of the main molecular mechanisms by which different nutritional conditions, i.e., specific nutrient abundance or restriction, may affect health span and life span.

Keywords: aging; health span; life span; nutrient-sensing pathways; nutrients.

Figure 1

Interplay between nutrient-sensing pathways potentially affecting health span. A complex crosstalk exists between nutrient and energy-sensing pathways in mammals. Caloric restriction (CR), that is a 25–30% reduction of caloric intake without malnutrition, as well as other dietary restriction (DR) interventions such as protein restriction (PR) or low protein/carbohydrate diets represent conditions that downregulate the insulin-like growth factor 1 (IGF1) mediated pathway. A reduced signaling of this pathway leads to a decrease of AKT, which causes the inhibition of mammalian target of rapamycin (mTOR) and activation of forkhead box O transcription factor (FOXO) which, in turn, suppresses mTOR. Reciprocal modulation of mTOR and FOXO induced by CR correlates with reduced global protein synthesis and decreased cell growth and proliferation. In PR conditions, low levels of essential dietary amino acids, particularly of methionine, stimulates the expression of fibroblast growth factor 21 (FGF21), a main inhibitor of IGF1 signaling. Through these mechanisms, DR orchestrates a program of genes involved in protein homeostasis and stress resistance that positively affects health span. Under conditions of CR, increased cellular AMP/ATP and NAD⁺/NADH ratios cause activation of AMP-activated protein kinase (AMPK) and sirtuins (SIRTs), respectively. AMPK, a critical cellular energy sensor, inhibits mTOR and contributes to stimulate SIRTs, including SIRT1 and SIRT3. In turn SIRTs, through a positive loop, further favor activation of AMPK itself. Both AMPK and SIRTs activate FOXO and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) through phosphorylation and deacetylation, respectively. PGC1α coactivates FOXO thus favoring the expression of key antioxidant enzymes as well as pathways involved in autophagy and mitophagy. Moreover, PGC1α induces the transcription of many important genes involved in mitochondrial biogenesis, complete fatty acid oxidation and stress resistance pathways. Therefore AMPK, SIRTs, FOXO and PGC1α can engage in a positive feedback loop, thus connecting these sensors into a unified response which may improve health span. This simplified model does not account for macronutrient-specific responses or tissue-specific nutrient detection and it does not distinguish between different tissues when summarizing downstream signaling effects.

Figure 2

Specific nutrients and dietary manipulations affecting insulin/insulin-like growth factor signaling (IIS) pathway. IIS pathway activates the kinase mammalian target of rapamycin (mTOR) and promotes growth and aging. High-glycemic index foods as well as high intake of some amino acids (AAs) like leucine are the dietary components most involved in increasing insulin levels after feeding. Other AAs like methionine and tryptophan act on growth hormone-insulin-like growth factor 1 (GH-IGF1) pathway. Moreover, the downstream effector mTOR is directly stimulated by specific AAs including leucine and arginine, simple carbohydrates like glucose and fructose, and saturated fatty acids like palmitate. Other nutritional conditions suppress IIS pathway. In particular, this pathway is downregulated by caloric restriction (CR), protein restriction (PR) and by diets having a low ratio between proteins and carbohydrates (CHO), as well as by the stress-responsive hormone fibroblast growth factor 21 (FGF21). Other nutrients such as ω3-polyunsaturated fatty acids (ω3-PUFAs) cause mTOR repression by acting as negative modulators of fosfoinositide 3-chinasi (PI3K)/AKT pathway. Inhibition of mTOR may be also induced by CR, PR and low protein/CHO diets through mechanisms involving AMP-activated protein kinase (AMPK) and sirtuin (SIRT) activation.