Independent regulation of age associated fat accumulation and longevity

Anthony O. Beas (), Patricia B. Gordon, Clara L. Prentiss, Carissa Perez Olsen, Matthew A. Kukurugya, Bryson D. Bennett, Susan M. Parkhurst and Daniel E. Gottschling
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Anthony O. Beas: Fred Hutchinson Cancer Research Center
Patricia B. Gordon: Fred Hutchinson Cancer Research Center
Clara L. Prentiss: Fred Hutchinson Cancer Research Center
Carissa Perez Olsen: Fred Hutchinson Cancer Research Center
Matthew A. Kukurugya: Calico Life Sciences LLC
Bryson D. Bennett: Calico Life Sciences LLC
Susan M. Parkhurst: Fred Hutchinson Cancer Research Center
Daniel E. Gottschling: Calico Life Sciences LLC

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16358-7

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