Living High on the HOG
Authors: Beckman Mary 
Published: August 2003

Sprinkle salt on a snail and it will bubble, dehydrate, and die. But the same type of stress causes yeast to live especially long. Researchers have found that viscous, water-sucking growth solutions prolong yeasts' lives. The fungus evades death by harnessing part of the biochemical pathway used in calorie restriction, another life-extension method. The results support the idea that stresses help organisms live longer by inducing the activity of protective pathways.

Reducing calorie intake by about a third stretches the lives of several species, including yeast, worms, and rodents. In the yeast
Saccharomyces cerevisiae
, the life-span benefits conferred by calorie restriction require respiratory metabolism and Sir2p, a protein that alters gene activity (see
"High-Octane Endurance"
). Sir2p runs on the metabolite NAD, and the calorie-restriction pathway employs the enzyme that makes NAD, Npt1p. Because reduced amounts of glucose extend yeast life-span, Kaeberlein and colleagues wanted to know what high concentrations of glucose did.

The team counted how many daughters yeast moms produced while soaking in a solution containing 20% glucose. Yeast in normal, 2%, glucose concentrations reproduced about 22 times, whereas cells in 20% sugar churned out 35 new generations. Extra sugar provides more than food, however: The solution sucks water from cells due to its high osmolarity, much like Epsom salt baths wrinkle skin. To test whether the sugar's fuel content or its osmolarity extends yeast life, the researchers measured the life-spans of yeast growing in concentrations of three inedible sugars that contribute the same degree of osmotic tug as glucose does. Cells immersed in these sugars produced six or seven more generations than normal, indicating that the solution's osmotic quality, not its energy stores, extends life.

Yeast respond to these conditions by turning on genes in the so-called high-osmolarity glycerol (HOG) stress-response pathway. Some of the HOG proteins help combat high osmolarity by turning glucose into glycerol to balance the osmotic pressure outside, and the researchers determined that osmolarity-sparked life extension requires the glycerol-production portion of the HOG pathway. Coincidentally, glycerol fabrication generates NAD, Sir2p's gasoline, and the researchers found that the HOG pathway requires Sir2p as well as NAD-making Npt1p for extended vigor, like calorie restriction does. Additional experiments showed that this new youth-promoting method does not require respiration, unlike the low-cal long-life method, indicating that the osmotic stress longevity pathway only partially overlaps with the dietary one.

"They did a beautiful job tying in phenomenological observations with the overall [Sir2] theme of their lab," says molecular geneticist John Aris of the University of Florida, Gainesville. The results lead to easily tested predictions, he adds: "Other pathways that divert carbon out of [glucose consumption] that also yield NAD should also extend life." Worm researcher Gordon Lithgow of the Buck Institute for Age Research in Novato, California, says that the "osmolarity pathway overlaps with other stress responses" that are known to extend life-span, such as those induced by heat, radiation, and metals. Snails' and yeasts' response to osmotic stress confirms the adage: What doesn't kill you makes you stronger.

--Mary Beckman

M. Kaeberlein, A. A. Andalis, G. R. Fink, L. Guarente, High osmolarity extends life span in
Saccharomyces cerevisiae
by a mechanism related to calorie restriction.
Mol. Cell. Biol.
22
, 8056-8066 (2002).
[Abstract]
[Full Text]