Is Sir2 a link between metabolic rate and aging?

One of the most consistent observations in aging is the link between metabolic rate and the pace of aging (Weindruch et al. 1986). Thus, if the metabolic rate of an organism is slowed down, for example, by lowering caloric intake or by lowering ambient temperature for cold-blooded animals, life span is significantly extended (Finch 1990). Interestingly, this link breaks down in comparisons between organisms. For example, rodents and bats have comparable metabolic rates, yet bats live up to 10-fold longer. Thus, each species appears to have a predetermined rate of aging that is further regulated by the rate of metabolism integrated over the life time.
Calorie restriction appears to be efficacious in a wide range of organisms, including rodents (Weindruch et al. 1986), worms (Lakowski and Hekimi 1998), yeast (Muller et al. 1980), and probably primates (Roth 1999). There are no data yet pertaining to humans. In addition to promoting longevity, a nutritious yet calorie-restricted diet gives rise to robust health and a high level of motor activity in experimental animals. The billion dollar question is: What is the mechanism by which calorie restriction increases life span? One school of thought relates to the possible link between oxidative damage by reactive oxygen species (ROS) and aging (Harman 1981). By this reckoning, lowering calories simply lowers the production of ROS in mitochondria and thus slows aging. A different view is that calorie restriction provokes a radical shift in the metabolic strategy in cells, which somehow favors longevity. Gene-array analysis in calorie-restricted mice shows altered expression of ∼2% of genes, many involved in some aspect of cellular metabolism (Lee et al. 1997), suggesting that a simple shift in cellular metabolism may favor longevity.
In this regard, the fact that the histone deacetylase activity of Sir2 is driven by NAD and thus linked to cellular metabolism is quite provocative. Might Sir2 proteins offer an explanation of how calorie restriction regulates longevity? If calorie restriction were to increase the levels of available NAD, then Sir2 activity would likely be enhanced, resulting in greater silencing and potentially a longer life span. It is likely that Sir2 is in competition with other NAD-using enzymes in cells for the dinucleotide. When cells have high levels of calories, the carbon flow through glycolysis would be high (Fig. 3A). The glycolytic enzyme glyceraldehyde-3-P-dehydrogenase (GAPDH) uses NAD, and the resulting NADH is recycled by the delivery of electrons to oxygen via the electron transport chain or, if oxygen is scarce, to acetyl-CoA to generate fermentation products. Thus, a substantial portion of the NAD pool may be recruited by this high flow of carbon through gylcolysis. In contrast, when calories are restricted, the flow of carbon through glycolysis is low (Fig. 3B). Under these conditions more carbon is fully oxidized to CO2 via the enzymes of the TCA cycle in mitochondria, which also use NAD with the resulting NADH recycled via the electron transport chain. However, because the carbon flow is much lower when calories are restricted, less NAD may be siphoned from the common pool, leaving more for other NAD-binding proteins, including Sir2. In conclusion, I suggest that Sir2 proteins may link metabolic rate to the pace of aging by sensing NAD levels and generating the mandated level of chromatin silencing.