A Sir2 homologue can deacetylate a metabolic enzyme.

Starai/AAAS

The discovery of a novel substrate for CobB, a bacterial Sir2 protein, has provided a link between a cell's energy status and carbon usage. The finding, described by Vincent Starai, Jorge Escalante-Semerena (University of Wisconsin, Madison, WI), and colleagues, may also help explain how Sir2 slows aging in yeast, worms, and, perhaps, mammals.

The team started out with a mutant, cobB, that could not grow on low levels of acetate. They found that the acetyl coenzyme A (CoA) synthetase (Acs) that initially derivatizes acetate to form acetyl CoA was inactive because of acetylation of a specific lysine residue of Acs. CobB, the bacterial Sir2, removed this acetylation and thus activated Acs.

The link to energy status and redox comes about through NAD+. A bacterial cell that is low in energy will use up most of its NADH to generate ATP. The resulting high levels of NAD+ provide the necessary cosubstrate for Sir2 proteins like CobB. Active CobB activates Acs, which generates more acetyl CoA, thus shunting more carbon into the energy- and NADH-generating TCA cycle.

Active Sir2 is now known both to generate more acetyl CoA and to extend lifespan. How are these two phenomena linked? More acetyl CoA for the TCA cycle means more respiration, which has been associated with yeast lifespan extension when caloric intake is restricted. And perhaps Sir2 activation allows for better scavenging of acetate—a molecule that is generated by lipid breakdown and can be easily lost to excretion. How an increase in carbon utilization efficiency leads to reduced aging is anyone's guess.

A standard aging argument is that aging involves a hunkering down—when animals are short of food they alter their metabolism so that both aging and reproduction are postponed until better times. The new findings are consistent with this metabolism-centric view. “People have taken for granted that we know everything about metabolism,” says Escalante-Semerena, but aging research may be proving them wrong. ▪

Reference:

Starai, V.J., et al.
2002
.
Science.
298
:
2390
–2392.