Sci. Aging Knowl. Environ., 7 January 2004
Vol. 2004, Issue 1, p. nf5
[DOI: 10.1126/sageke.2004.1.nf5]


UnSIRtainty Principle

Conflicting results underscore questions about how calorie restriction activates yeast longevity enzyme

R. John Davenport

Stemming sugar intake sparks a yeast longevity protein, and two new studies offer differing views of the mechanism. The data clash on whether cutting calories reduces amounts of a particular enzyme blocker. Resolving this issue could help clarify how metabolic changes induced by this diet lengthen life in yeast--and whether related changes might do the same in mammals.

Whittling calories extends life in numerous species (see Masoro Review). In the yeast version of calorie restriction (CR), researchers deprive cells of glucose. The fungi respond by activating a longevity protein called Sir2p, which snips acetyl groups off particular proteins. The Sir2p boost allows cells to produce extra offspring--a measure of yeast life span. To function, Sir2p must grab a molecule called NAD+, and molecular geneticist Leonard Guarente of the Massachusetts Institute of Technology wondered whether CR boosts NAD+ concentrations.

To address the question, Guarente and colleagues grew yeast in broth containing 2% or 0.5% glucose, removed all of the cells' NAD+, and measured it. The two groups carried the same quantity of NAD+. In another study, Harvard University geneticist David Sinclair and colleagues used nuclear magnetic resonance (NMR) to demonstrate that CR fails to elevate NAD+ concentrations in intact yeast cells.

Cells make NAD+ from a molecule called NADH during respiration, the oxygen-consuming process that turns food into fuel. Guarente's team found that dieting yeast boast less NADH than normal and hypothesized that it prevents NAD+ from binding to Sir2p. To test whether NADH hinders Sir2p, the researchers mixed Sir2p with acetylated proteins and various concentrations of NAD+ and NADH. As NADH quantities rose, Sir2p's acetyl-paring ability suffered. The team proposes that CR prods Sir2p by draining NADH from cells. Consistent with that idea, Guarente's group previously showed that yeast CR cranks up respiration, which consumes NADH (see "High-Octane Endurance").

Sinclair disagrees. His group depleted NADH from yeast cells and found that Sir2p activity didn't diminish, suggesting that CR doesn't rouse Sir2p by exhausting NADH. Furthermore, his NMR studies--which measure only the molecules not stuck to proteins--showed that NADH quantities remained far lower than those measured by Guarente's team--whose method tallies both bound and unbound molecules. Based on previous studies, Sinclair proposes that reduced quantities of nicotinamide, a molecule related to NAD+ that quells Sir2p activity, underlie CR's effects (see "Hungering for Simplicity"). No one knows whether nicotinamide quantities drop during CR, but blocking production of an enzyme that breaks down nicotinamide thwarts the life extension usually conferred by the low-glucose diet. Guarente says that although nicotinamide might be crucial for other life-extending treatments--such as exposure to unusual salt concentrations--deleting the nicotinamide destroyer could artificially crank up nicotinamide concentrations and mask the true CR regulator, NADH.

Because free molecules are the ones most likely to influence Sir2p, Sinclair's results are "very persuasive," says physiologist Roger McCarter of the University of Texas Health Science Center (UTHSC) in San Antonio. Still, whether CR works through a change in NADH is unresolved. Furthermore, although yeast crank up respiration under CR, rodents seem to maintain normal metabolic strategies, says gerontologist Edward Masoro of UTHSC. However, CR might induce changes in particular tissues, he adds. Stay tuned to see if scientists rise to the next challenges of clarifying the yeast results and testing whether those secrets of life extension apply to mammals.

January 7, 2004
  1. R. M. Anderson et al., Yeast life-span extension by calorie restriction is independent of NAD fluctuation. Science 302, 2124-2126 (2003). [Abstract/Free Full Text]
  2. S.-J. Lin, E. Ford, M. Haigis, G. Liszt, L. Guarente, Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev. 18, 12-16 (2004). [Abstract] [Full Text] [Links are expected to work 14 January 2004.]
Citation: R. J. Davenport, UnSIRtainty Principle. Sci. Aging Knowl. Environ. 2004 (1), nf5 (2004).

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