Much excitement has been generated by the recent observations that sirtuin proteins might play a significant role in the genetic control of aging. In S. cerevisiae
, lifespan is shortened by a null mutation in SIR2
and is extended by the presence of an extra copy of SIR2
]. Loss of Sir2p leads to a derepression of silencing at the rDNA locus, which increases recombination between rDNA repeats and results in the accumulation of extrachromosomal rDNA circles. High numbers of these circles in older mother cells promote senescence by an undefined mechanism, possibly through the titration of necessary factors away from other promoters [73
]. Likewise, the C. elegans
Sir2p homolog, Sir-2.1, mediates dauer-larva formation and regulates lifespan [15
]. The dauer larva represents a specialized survival form of the worm; the molecular mechanisms by which Sir-2.1 controls dauer formation remain to be elucidated, however.
It has been speculated that the metabolic rate of the cell may be important in the regulation of the function of various sirtuins, given their dependency on NAD for enzymatic activity. This idea is further supported by evidence that NAD metabolism directly participates in controlling the aging process [12
]. Translating these ideas to mouse and human sirtuins could give novel insights into the regulation of mammalian lifespan. In mammals, Sirt1 could be a key part of the decision of a cell whether to live or die in response to DNA damage. As the cell ages and NAD levels become lower, the resulting reduced activity of Sirt1 could drive the decision to cell senescence or apoptosis rather than cellular survival. Likewise, lowered activity of Sirt2 via reduced levels of NAD could alter the rate of cell division through cell-cycle regulation. The localization pattern of Sirt3 in the mitochondrial matrix and its dependence on NAD suggest a possible function in the regulation of cellular metabolism as a sensor for intramitochondrial NAD levels. Further work is required to determine the endogenous target of this deacetylase in the mitochondrial compartment, however. Genetic deletion of the genes encoding different sirtuins in mice will facilitate studies of their roles in mammalian aging.
In addition to a connection between metabolism and sirtuin activity via NAD, the formation of O
-acetyl-ADP-ribose as an enzymatic byproduct represents another promising area of investigation. Microinjection of O
-acetyl-ADP-ribose delays or blocks oocyte maturation and cell division in blastomeres [45
]. A similar effect is observed after microinjection of low levels of active yeast Hst2 or human Sirt2 enzyme, but not with a catalytically impaired mutant, indicating that the enzymatic activity is essential for the observed effects.
Human Sirt4, Sirt5, Sirt6, and Sirt7 show low or undetectable enzymatic activity on histone H4 peptide [47
]. This could reflect differing substrate specificities or different requirements for cofactors, a field of investigation that is likely to yield interesting insights in the future. Finally, an increased understanding of the relationship between the structure and function of sirtuin proteins will be important in designing specific inhibitors and exploring their potential therapeutic value in a variety of pathological conditions.