Dietary restriction involves NAD⁺‐dependent mechanisms and a shift toward oxidative metabolism

Abstract

Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD+-dependent deacylases known as sirtuins, and increases in NAD+ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol. DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD+ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption. We conclude that stress response and NAD+-dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD+ salvage. Under DR conditions, NAD+-dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.

Characterization of skn-1/wdr-23 phenotypes in Caenorhabditis elegans; pleiotrophy, aging, glutathione, and interactions with other longevity pathways

“…7C). This residual effect could be due to SKN-1b and SKN-1-independent mechanisms (Bishop and Guarente, 2007;Moroz et al, 2014). 3.7.…”

“…(A-F) P values of <0.0167 were taken to indicate statistical significance. longevity (Iwasa et al, 2010;Jung and Kwak, 2010;Moroz et al, 2014). Over the last three decades, hundreds of genes and diverse pathways have been identified that influence lifespan, but understanding how these genes and pathways influence specific aging processes is far more limited.…”

“…CNCs have been also been implicated in ensuring longevity when conserved nutritional pathways are manipulated. For example, SKN-1 is required for longevity extension in dietary restricted (DR) worms (Bishop and Guarente, 2007;Moroz et al, 2014) and in worms with reduced activity of insulin/IGF-1 like signaling (IIS) (Ewald et al, 2014;Tullet et al, 2008) and target of rapamycin signaling (TOR) (Robida-Stubbs et al, 2012). Nrf2 is required for protection against age-related diseases in DR mice (Pearson et al, 2008).…”

“…Although delayed aging can be associated with long lifespan, they are sometimes uncoupled or poorly correlated (Bansal et al, 2015;Iwasa et al, 2010;Moroz et al, 2014). This distinction is important, because promoting healthy aging, and not maximum lifespan, is the ultimate goal of aging research (Jung and Kwak, 2010;Moroz et al, 2014).…”

“…Although delayed aging can be associated with long lifespan, they are sometimes uncoupled or poorly correlated (Bansal et al, 2015;Iwasa et al, 2010;Moroz et al, 2014). This distinction is important, because promoting healthy aging, and not maximum lifespan, is the ultimate goal of aging research (Jung and Kwak, 2010;Moroz et al, 2014). CNCs (particularly SKN-1) are now clearly implicated in lifespan and evidence exists for a role in promoting the age-related proteostasis processes (Alavez et al, 2011), but their ability to delay degenerative tissue changes with age is poorly defined.…”