Abstract
Age-dependent changes in metabolism can manifest as cellular lipid accumulation, but how this accumulation is regulated or impacts longevity is poorly understood. We find that Saccharomyces cerevisiae accumulate lipid droplets (LDs) during aging. We also find that over-expressing BNA2, the first Biosynthesis of NAD+ (kynurenine) pathway gene, reduces LD accumulation during aging and extends lifespan. Mechanistically, this LD accumulation during aging is not linked to NAD+ levels, but is anti-correlated with metabolites of the shikimate and aromatic amino acid biosynthesis (SA) pathways (upstream of BNA2), which produce tryptophan (the Bna2p substrate). We provide evidence that over-expressed BNA2 skews glycolytic flux from LDs towards the SA-BNA pathways, effectively reducing LDs. Importantly, we find that accumulation of LDs does not shorten lifespan, but does protect aged cells against stress. Our findings reveal how lipid accumulation impacts longevity, and how aging cell metabolism can be rewired to modulate lipid accumulation independently from longevity.
Highlights
Age-dependent changes in metabolism can manifest as cellular lipid accumulation, but how this accumulation is regulated or impacts longevity is poorly understood
Metabolism slows, which can manifest as a gradual accumulation of neutral lipid, an important energy source stored in lipid droplets (LDs)
We describe a new link between the biosynthesis of NAD+ pathway and lipid droplets during aging
Summary
Age-dependent changes in metabolism can manifest as cellular lipid accumulation, but how this accumulation is regulated or impacts longevity is poorly understood. We find that overexpressing BNA2, the first Biosynthesis of NAD+ (kynurenine) pathway gene, reduces LD accumulation during aging and extends lifespan. Intense research has focused on interventions to increase cellular NAD+, such as with NAD+ precursors (e.g., niacin, nicotinamide mononucleotide, and nicotinamide riboside), and to mitigate age-associated changes in metabolism, including reducing fat. Our genetic and metabolomic approaches reveal that increasing the BNA pathway (by overexpressing BNA2, the first gene of the pathway) reduces LD accumulation during aging This reduction is achieved by pulling metabolic flux, likely from glycolysis, through the shikimate and aromatic amino acid biosynthesis (SA) pathways, which are upstream of the BNA pathway and which synthesize and supply tryptophan, the major substrate of the BNA pathway. These findings reveal how lipid-droplet accumulation impacts longevity, and provide a new strategy for lessening lipid accumulation during aging independently from longevity
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