Collaborations between Johns Hopkins and National Taiwan University researchers have successfully manipulated the life span of common, single-celled yeast organisms by figuring out how to remove and restore protein functions related to yeast aging.
“This control of longevity is independent of the type described previously in yeast which had to do with calorie restriction,” Boeke says. “We believe that for the first time, we have a biochemical route to youth and aging that has nothing to do with diet.” The chemical variation, known as acetylation because it adds an acetyl group to an existing molecule, is a kind of “decoration” that goes on and off a protein — in this case, the protein Sip2 — much like an ornament can be put on and taken off a Christmas tree, Boeke says. Acetylation can profoundly change protein function in order to help an organism or system adapt quickly to its environment. Until now, acetylation had not been directly implicated in the aging pathway, so this is an all-new role and potential target for prevention or treatment strategies, the researchers say.
The team showed that acetylation of the protein Sip2 affected longevity defined in terms of how many times a yeast cell can divide, or “replicative life span.” The normal replicative lifespan in natural yeast is 25. In the yeast genetically modified by researchers to restore the chemical modification, life span extended to 38, an increase of about 50 percent.
The researchers were able to manipulate the yeast life span by mutating certain chemical residues to mimic the acetylated and deacetylated forms of the protein Sip2. They worked with live yeast in a dish, measuring and comparing the life spans of natural and genetically altered types by removing buds from the yeast every 90 minutes. The average lifespan in normal yeast is about 25 generations, which meant the researchers removed 25 newly budded cells from the mother yeast cell. As yeast cells age, each new generation takes longer to develop, so each round of the experiment lasted two to four weeks.
“We performed anti-aging therapy on yeast,” says the study’s first author, Jin-Ying Lu, M.D., Ph.D., of National Taiwan University. “When we give back this protein acetylation, we rescued the life span shortening in old cells. Our next task is to prove that this phenomenon also happens in mammalian cells.”
* The yeast AMPK β subunit Sip2 is acetylated by NuA4 and deacetylated by Rpd3
* Sip2 acetylation decreases with age, and increasing Sip2 acetylation extends life span
* Acetylated Sip2 binds and inhibits Snf1, reducing Sch9 phosphorylation
* The anti-aging effect of Sip2 acetylation is independent of nutrition and TORC activity
Acetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory β subunit of the Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), and ultimately leading to slower growth but extended replicative life span. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a protein acetylation-phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging, and extends replicative life span in yeast.