Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Nat Commun. 2020 Jun 3;11(1):2790. doi: 10.1038/s41467-020-16358-7.
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.
年龄相关的代谢变化可能表现为细胞脂质积累，但这种积累是如何调节的，或者对寿命有何影响，人们知之甚少。我们发现，酿酒酵母在衰老过程中会积累脂滴（LDs）。我们还发现，过量表达 NAD（犬尿氨酸）生物合成途径的第一个基因 Bna2 可以减少衰老过程中 LD 的积累，并延长寿命。从机制上讲，这种衰老过程中的 LD 积累与 NAD 水平无关，而是与芳香族氨基酸生物合成（SA）途径（Bna2p 上游）的代谢物呈负相关，这些代谢物产生色氨酸（Bna2p 的底物）。我们提供的证据表明，过量表达的 Bna2 将糖酵解通量从 LD 转移到 SA-Bna 途径，有效地减少了 LD。重要的是，我们发现 LD 的积累并不会缩短寿命，但确实可以保护衰老细胞免受应激。我们的研究结果揭示了脂质积累如何影响寿命，以及衰老细胞的代谢如何被重新布线，从而独立于寿命来调节脂质积累。
