Overview
Currently, available evidence strongly supports the idea that anabolic signaling (the signal that promotes growth and proliferation) accelerates aging, and decreased nutrient signaling extends longevity (Fontana et al., 2010). Further, a pharmacological manipulation that mimics a state of limited nutrient availability, such as rapamycin, can extend longevity in mice (Harrison et al., 2009). In this article, the principal nutrient-sensing pathways are introduced and connected to the NAD+ metabolism.
Growth Hormone and Insulin
Growth hormone is a well-known hormone that promotes the growth and proliferation of cells. Its secondary mediator, insulin-like growth factor 1 (IGF-1), is produced in response to growth hormone by many cell types, most notably in the liver. The intracellular signaling pathway of IGF-1 is the same as that elicited by insulin, which informs cells of the presence of glucose. For this reason, IGF-1 and insulin signaling is known as the “insulin and IGF-1 signaling” (IIS) pathway.
Insulin and IGF-1 Signaling Pathway is the Most Conserved Aging-controlling Pathway
Remarkably, the IIS pathway is the most conserved aging-controlling pathway in evolution. Among its multiple targets are the FOXO family of transcription factors and the mTOR complexes, which are also involved in aging and conserved through evolution. Genetic mutations that reduce the functions of growth hormone, IGF-1 receptor, insulin receptor, or downstream intracellular effectors such as AKT, mTOR, and FOXO have been linked to longevity, both in humans and in model organisms.
Consistent with the relevance of deregulated nutrient sensing as a hallmark of aging, dietary restriction (DR, by decreasing the calorie intake by up to 25%) increases lifespan or healthspan in all investigated eukaryote species, including nonhuman primates (Colman et al., 2009; Fontana et al., 2010; Mattison et al., 2012).
Other Nutrient-Sensing Systems: mTOR, AMPK, and Sirtuins
In addition to the IIS pathway that participates in glucose sensing, three additional related and interconnected nutrient-sensing systems are the focus of intense investigation: mTOR, for the sensing of high amino acid concentrations; AMPK, which senses low-energy states by detecting high AMP levels; and sirtuins, which sense low-energy states by detecting high NAD+ levels (Houtkooper et al., 2010).
mTOR: The Most Effective Anti-aging Drug Target
The mTOR kinase is part of two multiprotein complexes that regulate essentially all aspects of anabolic metabolism (Laplante and Sabatini, 2012). Genetic downregulation of mTOR complex 1 (mTORC1) activity in yeast, worms, and flies extends longevity and attenuates further longevity benefits from DR, suggesting that mTOR inhibition is the underlying mechanism of DR (Johnson et al., 2013). In mice, treatment with rapamycin also extends longevity in what is considered to be the most robust chemical intervention to increase lifespan in mammals (Harrison et al., 2009). Genetically modified mice with low levels of mTORC1 activity also have increased lifespan (Lamming et al., 2012). Therefore, the downregulation of mTORC1 appears as the critical mediator of mammalian longevity in relation to mTOR.
Moreover, mTOR activity increases during aging in mouse hypothalamic neurons, contributing to age-related obesity, which is reversed by direct infusion of rapamycin to the hypothalamus (Yang et al., 2012). These observations indicate that intense anabolic activity signaled through the IIS or the mTORC1 pathways are major accelerators of aging. Although inhibition of TOR activity clearly has beneficial effects during aging, it also has undesirable side effects, such as impaired wound healing, insulin resistance, cataracts, and testicular degeneration in mice (Wilkinson et al., 2012). It will thus be important to understand the mechanisms involved in order to determine the extent to which beneficial and damaging effects of TOR inhibition can be separated from each other.
AMPK: Potential Mediator for the Anti-aging Effect of Metformin
The other two nutrient sensors, AMPK, and sirtuins, act in the opposite direction to IIS and mTOR, meaning that they signal nutrient scarcity and catabolism instead of nutrient abundance and anabolism. Accordingly, their upregulation favors healthy aging. AMPK activation has multiple effects on metabolism and, remarkably, shuts off mTORC1 (Alers et al., 2012). There is evidence indicating that AMPK activation may mediate lifespan extension following metformin administration to worms and mice (Anisimov et al., 2011; Mair et al., 2011; Onken and Driscoll, 2010).
Sirtuins: NAD+ Dependent Longevity Protein
The role of sirtuins in lifespan regulation has been discussed in the previous series. Also, SIRT1 can deacetylate and activate the PPARg coactivator 1a (PGC-1a) (Rodgers et al., 2005). PGC-1a orchestrates a complex metabolic response that includes mitochondriogenesis, enhanced antioxidant defenses, and improved fatty acid oxidation (Fernandez-Marcos and Auwerx, 2011). Moreover, SIRT1 and AMPK can engage in a positive feedback loop, connecting both sensors of low-energy states into a unified response (Price et al., 2012).
NAD+ Level is Sensitive to Nutrient Status
NAD+ levels are closely related to the nutrient-sensing system. Rodents fasted for 48 hours show increased levels of the NAD+ biosynthetic enzyme Nampt and a concomitant increase in mitochondrial NAD+. Increased Nampt protects against cell death and requires an intact mitochondrial NAD+ salvage pathway and the mitochondrial NAD+-dependent deacetylases SIRT3 and SIRT4 (Yang et al., 2007). Therefore, fasting/dietary restriction can provide an alternative way to increase the NAD+ level. Similarly, supplementing NAD+ precursors that increase the cellular NAD level can also partially mimic the longevity effect of dietary restriction by activating sirtuins.