In most organisms, age-dependent changes in metabolism are inevitable. As we age, we our cells start to accumulate neutral lipids in the form of lipid droplets, which is a manifestation of metabolic decline. Fat accumulation during aging is widely considered to be detrimental to lifespan, based on countless studies that are mostly based on high fat diets. However, little is known about how fat accumulation is regulated during aging under normal conditions. And what impact does fat accumulation have on longevity?
A recent study led by Dr. Anthony Beas, a postdoc in the Gottschling and Parkhurst labs (Basic Sciences Division) sought to answer these questions using budding yeast, as the model is highly amenable to genetic manipulation. The study published in Nature Communications sought to uncover the genetic mechanisms underlying lipid accumulation during aging.
The study found that fat accumulates in aging budding yeast, especially around middle age, which is fascinatingly similar to when metabolism slows and increases the risk of fat accumulation in aging humans. Interestingly, the authors found that when fat accumulated during aging under normal conditions, it did not impact longevity, a striking finding that runs contrary to popular belief. By genetically manipulating different genes involved in lipid droplet metabolism, the researchers found that lipid droplet accumulation is separable from longevity. For example, over-expression of the gene BNA2, known to code an enzyme catalyzing the first step of NAD+ synthesis, suppressed lipid droplet accumulation during aging.
Another important finding of the paper is that while lipid accumulation does not shorten lifespan, it affords protection to aged cells against cold stress. Indeed, aged yeast cells that failed to accumulate lipid droplets were less able to survive cold exposure and restoration of lipid accumulation rescued the cold sensitivity in aged cells.
In summary, the study challenges the widely held belief that fat accumulation during aging is detrimental. It also provides novel genetic strategies to independently modulate fat accumulation during aging and longevity. Finally, the authors suggested that future studies of homologous genes in mammalian cells may provide insights into how lipid metabolism may regulate growth and proliferation in both normal and cancer cells.
UW/Fred Hutch Cancer Consortium member Susan Parkhurst contributed to this work.
This study was made possible by funding from the National Institutes of Health
Beas AO, Gordon PB, Prentiss CL, Olsen CP, Kukurugya MA, Bennett BD, Parkhurst SM, and Gottschling DE. 2020. Independent regulation of age associated fat accumulation and longevity. Nature Communications. doi: 10.1038/s41467-020-16358-7