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Molecular physiology

Tuned for longer life


Sometime early in the sixteenth century, 40-year-old Luigi Cornaro decided to cut his food intake dramatically for health reasons — he then lived on to the age of 102, writing treatises on the merits of his abstemious lifestyle. Five centuries later it is not clear whether severely limiting food consumption can, in general, extend human life, although calorie restriction does indeed extend the lifespan of commonly studied organisms such as yeast, nematode worms and mice. The latest turn of events is described by David A. Sinclair and colleagues elsewhere in this issue (R. M. Anderson et al. Nature 423, 181–185; 2003). In studies of the yeast Saccharomyces cerevisiae, the researchers have pinpointed an enzyme, Pnc1, that seems to be a key link between environmental stress, metabolic energy and lifespan.

Sinclair and colleagues explore the control of an intriguing protein named Sir2 (silent information regulator 2), which has been shown to extend the lifespan of various laboratory organisms. Sir2 is a histone deacetylase, found in cell nuclei, where it is thought to turn genes on and off by influencing the packing of chromosomal DNA. Sir2 action requires the ubiquitous energy cofactor NAD+, generating nicotinamide in the reaction, and nicotinamide also turns out to be a potent inhibitor of Sir2. But how exactly does metabolic energy affect Sir2 activity and lifespan?

The involvement of nicotinamide led Sinclair and co-workers to Pnc1, an enzyme that breaks nicotinamide down to nicotinic acid. They find that increasing the levels of Pnc1 in yeast leads to a dramatic lengthening of lifespan, as nicotinamide depletion results in Sir2 activation (yeast lifespan is usually measured by the number of buds, or daughters, produced by a given cell, individual bud scars showing up as darker circles on the blue-stained yeast cells shown here). Various types of stress are known to extend yeast life, including glucose restriction, high temperatures and elevated salt concentrations, and Pnc1 levels are raised in all of these circumstances. This suggests that Pnc1 is a key regulator of Sir2, and is responsible for tuning a yeast's lifespan and reproductive capacity to the quality of its environment.

Whether these ideas apply to multicellular organisms will have to be tested in worms and mice. On the one hand, one might imagine that mechanisms designed to protect single yeast cells from the vicissitudes of their environment would not be needed in more complex organisms, which possess homeostatic systems designed to protect and nourish individual cells. On the other, lifespan is likely to be controlled by evolutionarily ancient mechanisms. So understanding Sir2 regulation in multicellular organisms, and identifying the genes that are controlled by Sir2 and its relatives, should prove generally rewarding.

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