Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD⁺ homeostasis and contributes to longevity

Abstract

Nutrient sensing pathways and their regulation grant cells control over their metabolism and growth in response to changing nutrients. Factors that regulate nutrient sensing can also modulate longevity. Reduced activity of nutrient sensing pathways such as glucose-sensing PKA, nitrogen-sensing TOR and S6 kinase homolog Sch9 have been linked to increased life span in the yeast, Saccharomyces cerevisiae, and higher eukaryotes. Recently, reduced activity of amino acid sensing SPS pathway was also shown to increase yeast life span. Life span extension by reduced SPS activity requires enhanced NAD⁺ (nicotinamide adenine dinucleotide, oxidized form) and nicotinamide riboside (NR, a NAD⁺ precursor) homeostasis. Maintaining adequate NAD⁺ pools has been shown to play key roles in life span extension, but factors regulating NAD⁺ metabolism and homeostasis are not completely understood. Recently, NAD⁺ metabolism was also linked to the phosphate (Pi)-sensing PHO pathway in yeast. Canonical PHO activation requires Pi-starvation. Interestingly, NAD⁺ depletion without Pi-starvation was sufficient to induce PHO activation, increasing NR production and mobilization. Moreover, SPS signaling appears to function in parallel with PHO signaling components to regulate NR/NAD⁺ homeostasis. These studies suggest that NAD⁺ metabolism is likely controlled by and/or coordinated with multiple nutrient sensing pathways. Indeed, cross-regulation of PHO, PKA, TOR and Sch9 pathways was reported to potentially affect NAD⁺ metabolism; though detailed mechanisms remain unclear. This review discusses yeast longevity-related nutrient sensing pathways and possible mechanisms of life span extension, regulation of NAD⁺ homeostasis, and cross-talk among nutrient sensing pathways and NAD⁺ homeostasis.

Key words： nutrient sensing; NAD⁺ homeostasis; yeast longevity

Acknowledgements

We are grateful to the researchers whose work provided the basis for this review. We thank Dr. Christol James and Trevor Croft for critical review of this manuscript and suggestions. The Lin laboratory is supported by the National Institute of Health. NIGMS (GM102297)

Felicia TSANG, Su-Ju LIN declare that they have no conflict of interest.This article does not contain any studies with human or animal subjects performed by any of the authors.

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