Pyruvate imbalance mediates metabolic reprogramming and mimics lifespan extension by dietary restriction in Caenorhabditis elegans

Abstract

SummaryDietary restriction (DR) is the most universal intervention known to extend animal lifespan. DR also prevents tumor development in mammals, and this effect requires the tumor suppressor PTEN. However, the metabolic and cellular processes that underly the beneficial effects of DR are poorly understood. We identified slcf-1 in an RNAi screen for genes that extend Caenorhabditis elegans lifespan in a PTEN ⁄ daf-18-dependent manner. We showed that slcf-1 mutation, which increases average lifespan by 40%, mimics DR in worms fed ad libitum. An NMR-based metabolomic characterization of slcf-1 mutants revealed lower lipid levels compared to wild-type animals, as expected for dietary-restricted animals, but also higher pyruvate content. Epistasis experiments and metabolic measurements support a model in which the long lifespan of slcf-1 mutants relies on increased mitochondrial pyruvate metabolism coupled to an adaptive response to oxidative stress. This response requires DAF-18 ⁄ PTEN and the previously identified DR effectors PHA-4 ⁄ FOXA, HSF-1 ⁄ HSF1, SIR-2.1 ⁄ SIRT-1, and AMPK ⁄ AAK-2. Overall, our data show that pyruvate homeostasis plays a central role in lifespan control in C. elegans and that the beneficial effects of DR results from a hormetic mechanism involving the mitochondria. Analysis of the SLCF-1 protein sequence predicts that slcf-1 encodes a plasma membrane transporter belonging to the conserved monocarboxylate transporter family. These findings suggest that inhibition of this transporter homolog in mammals might also promote a DR response.

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

“…More recent findings support the direct involvement of a hormesis mechanism in handling neuronal degeneration through preconditioning mediated by a dynamic balance between ER stress and autophagy (21). In C. elegans, the notion of hormesis has been previously related to the effect of oxidative stress on longevity and dauer diapause (31)(32)(33), and mildly elevated temperature on heat-induced necrosis (34). Chromatin has been proposed to be involved in hormesis-like responses to stress in yeast, where transient treatment with sublethal doses of reactive oxygen species (ROS) was shown to modulate the activity of a histone demethylase (35).…”

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

“…Caenorhabditis elegans lifespan assays were carried out at 20°C as described (Mouchiroud et al., 2011). Briefly, each condition included 100 worms and the scoring was performed every 2 days until all worms were dead.…”

Mitochondrial metabolites extend lifespan

“…Solari and colleagues previously reported that pyruvate supplementation could extend the lifespan of wild‐type worms (Mouchiroud et al ., 2011). This work was undertaken in the context of characterization of a mutant monocarboxylate transport protein, SLCF‐1, which at the time was a novel longevity factor in C. elegans .…”

“…These findings are consistent with our current work where we now show that pyruvate triggers life extension in wild‐type worms in a HIF‐1‐dependent manner. We speculate that NAC abrogated the life‐prolonging effects of the slcf‐1(tm2258) mutation in the studies of Solari and colleagues (Mouchiroud et al ., 2011) because it functioned either alongside or in conjunction with ascorbate—another antioxidant, which is required to keep the active site of EGL‐9 and other α‐ketoglutarate‐dependent hydroxylases in the Fe(II) state (Myllyharju, 2008). Finally, Solari and colleagues (Mouchiroud et al ., 2011) also showed the life extension following slcf‐1 RNAi did not further extend the lifespan of isp‐1(qm150) Mit mutants.…”

“…We speculate that NAC abrogated the life‐prolonging effects of the slcf‐1(tm2258) mutation in the studies of Solari and colleagues (Mouchiroud et al ., 2011) because it functioned either alongside or in conjunction with ascorbate—another antioxidant, which is required to keep the active site of EGL‐9 and other α‐ketoglutarate‐dependent hydroxylases in the Fe(II) state (Myllyharju, 2008). Finally, Solari and colleagues (Mouchiroud et al ., 2011) also showed the life extension following slcf‐1 RNAi did not further extend the lifespan of isp‐1(qm150) Mit mutants. Again, this observation is consistent with our current findings where we show that treatment of isp‐1(qm150) worms with 2,4‐PDA, which mimics pyruvate in both its stabilization of HIF‐1 and its ability to extend the life of wild‐type worms, did not further extend the lifespan of these mutants.…”