Metabolic reprogramming, caloric restriction and aging

Abstract

Caloric restriction (CR) without malnutrition slows the aging process and extends lifespan in diverse species by unknown mechanisms. The inverse linear relationship between calorie intake and lifespan suggests that regulators of energy metabolism are important in the actions of CR. Studies in several species reveal tissue-specific changes in energy metabolism with CR and suggest that metabolic reprogramming plays a critical role in its mechanism of aging retardation. We herein describe common signatures of CR and suggest how they can slow aging. We discuss recent advances in understanding the function of key metabolic regulators that probably coordinate the response to altered nutrient availability with CR and how the pathways they regulate can retard the aging process.

Figure 1. Systemic signaling regulates the shift in mitochondrial fuel utilization in response to CR

We propose a model where an AMPK and PGC-1α dependent signaling pathway permits a coordinate shift in fuel utilization in response to systemic input. Mitochondrial fatty acid oxidation is promoted through enhanced expression of genes encoding enzymes involved in β-oxidation and molecules involved in fatty acid transport.

Figure 2. Nutrient sensitive metabolic regulators are strong candidates as effector molecules in the mechanisms of CR

A complex network of interactions among these molecules has been described, although much remains to be learned about their regulation specifically in the context of CR. A unifying theme is the regulation of energy metabolism: alterations in energy metabolism are a hallmark of CR and likely are critical events in CR’s mechanisms of aging retardation.

Figure 3. The improvement in healthspan and lifespan by CR is a coordinated active response

Key effector molecules implement a reprogramming of energy metabolism in response to reduced energy availability. This altered metabolic state is maintained and perpetuated though systemic signaling.