Nutrition, longevity and disease: From molecular mechanisms to interventions

Abstract

Diet as a whole, encompassing food composition, calorie intake, and the length and frequency of fasting periods, affects the time span in which health and functional capacity are maintained. Here, we analyze aging and nutrition studies in simple organisms, rodents, monkeys, and humans to link longevity to conserved growth and metabolic pathways and outline their role in aging and age-related disease. We focus on feasible nutritional strategies shown to delay aging and/or prevent diseases through epidemiological, model organism, clinical, and centenarian studies and underline the need to avoid malnourishment and frailty. These findings are integrated to define a longevity diet based on a multi-pillar approach adjusted for age and health status to optimize lifespan and healthspan in humans.

Figure 1.

Conserved pathways associated with longer lifespan identified in yeast, worms, flies, and mice. Altered metabolism involves signature changes related to energy saving, activation of lipid fuel use, and dampened growth and synthetic pathways. At the cellular level the delayed aging phenotype is associated with increased metabolite recycling, autophagy, reduced translation, protein turnover, and enhanced maintenance and repair linked to antioxidant and other stress response pathways. Interactions among organelles are influenced by energy status and associations shift to accommodate the metabolic state linked to lower nutrient availability and low growth signaling conditions. The overall outcome is a reprogrammed metabolism, enhanced repair and recycling mechanisms, and reduced growth and macromolecular synthesis.

Figure 2.. Dietary modulation of longevity.

Longevity can be promoted in different ways; however, diet composition and levels must be optimized to avoid malnourishment and frailty and should be personalized based on characteristics including the genome, size and adiposity, biological age range, sex and health status (Top). The Longevity Diet includes limiting calorie intake (left: calorie restriction (CR), adopting 11–12 hour time restricted eating (TRE) as well as a few yearly cycles of 5 day fasting/FMDs) or selective age range-sepcific reduction in specific dietary components (right: protein restriction (PR), methionine restriction (MR)), through a high legume, high whole grain pesco-vegan diet or mostly plant-based everyday diet including nut consumption which provides 45–60% of calories from non-refined complex carbohydrates, 10–15% from mostly plant-based proteins, and 25–35% from mostly plant-based fats. Together, these nutritional patterns promote low insulin and insulin resistance, low adiposity, moderate levels/activity of GH/IGF-1, and reduced mTOR signaling and potentially increased autophagy in different cell types. Prolonged and periodic FMDs and possibly other fasting methods may activate autophagy during the late portion of the fasting period and increase the levels of stem cells and regeneration in various tissues, especially during the re-feeding period. Downstream of these changes are improved metabolic function, reduced inflammation with delayed immunosenescence, reduced oxidative damage and improved proteostasis. The regulation of this pro-longevity network can delay aging, and reduce the risk factors and/or incidence of age-related diseases including diabetes, cancer, cardiovascular and neurodegenerative diseases. The effects of the Longevity Diet on diseases appears to be both dependent and independent of its effect on aging and biological age.