It has been known for sometime that reduced intake of calories increases the lifespan of many species, including mammals, but just exactly how this works is unclear. One theory suggests that reduced metabolic rates minimize exposure to damaging reactive oxygen species (ROS), which are by-products of respiration. However, work from Leonard Guarente’s lab at MIT, published in the July 18 Nature, suggests that increased respiration is what extends lifespan-at least in yeast.
First author Lin, and colleagues from MIT and Johns Hopkins University, examined the effect of switching yeast metabolism from anaerobic fermentation to oxidative respiration. They achieved this by a variety of means including using a strain that lacks hexokinase, an enzyme required to initiate glycolysis, and by overexpression of the transcription factor Hap4, which is known to induce yeast to respire. In all cases the yeast lived longer, i.e. more generations, while consuming more oxygen, just as they do when grown on 0.5 percent glucose as opposed to 2 percent. What’s more, the authors found these longer-lasting yeast had normal levels of most antioxidant genes and, if anything, slightly decreased resistance to oxidative stress, suggesting that ROS play no role in determining lifespan.
So what does this mean for humans? Well, in contrast to yeast cells which are constantly dividing, most human cells are postmitotic, stationary phase cells, so the same rules may not apply. However, the increased lifespan of the respiring yeast seems to be tightly associated with expression of the protein Sir2, which is responsible for gene silencing and is regulated by the cofactor NAD +. Levels of NAD + are sensitive to the respiratory state of the cell and increase with respiration, thus tying Sir2 in with caloric restriction. Why is this important? Well it just so happens that Sir2 homologs are also found in humans.—Tom Fagan