I find the study interesting because our work suggests that SIR2 will be a universal regulator of aging (definitely in yeast and worms) and we recently found that it functions as a negative regulator of p53 in mammalian cells. My hunch is that this is only one of several relevant SIR2 activities that may impact aging. This paper shows that up-regulation of p53 in a whole mouse can elicit symptoms that are aging-like. One hopes there is a window in which SIR2 can be up-regulated (pharmacologically?) to slow aging without increasing cancer. One cautionary note—it is always difficult to say that a mutant phenotype is premature aging rather than pathology. It is much more convincing to make the organism live longer by genetic intervention.

View all comments by Leonard Guarente

Homeostatic Control: Relevance to Alzheimer Disease
Larsen and Clarke highlight that endogenous homeostatic control over energetics and endogenous antioxidant defenses make cells and organisms better adapted to survival than exogenous intervention. These authors show that Caenorhabditis elegans deprived of exogenous Coenzyme Q (CoQ) have an extended life span over those replete with endogenous CoQ provided by biosynthesis plus external food-derived CoQ. Genetic manifestations of food sources and worms shows that the life span extension is specific to exogenous CoQ restriction, even though exogenous CoQ is required to complete the life cycle/development of worms unable to synthesize it. The authors and attached commentary (Tatar and Rand, 2002) interpret the effect through signaling or oxidative stress, but an additional consideration is the...  Read more

Homeostatic Control: Relevance to Alzheimer Disease
Larsen and Clarke highlight that endogenous homeostatic control over energetics and endogenous antioxidant defenses make cells and organisms better adapted to survival than exogenous intervention. These authors show that Caenorhabditis elegans deprived of exogenous Coenzyme Q (CoQ) have an extended life span over those replete with endogenous CoQ provided by biosynthesis plus external food-derived CoQ. Genetic manifestations of food sources and worms shows that the life span extension is specific to exogenous CoQ restriction, even though exogenous CoQ is required to complete the life cycle/development of worms unable to synthesize it. The authors and attached commentary (Tatar and Rand, 2002) interpret the effect through signaling or oxidative stress, but an additional consideration is the tight metabolic control that operates on factors proscribed by metabolic need over those that are only limited by ingestion. Massive quantities of a metabolic cofactor or antioxidant will disrupt this delicate balance; this is why vitamins generally are not promising therapeutics, and it underscores the importance of a varied diet. Therefore, indiscriminate administration of metabolic cofactors and antioxidant therapy may, in fact, be detrimental without an in-depth understanding of basic homeostatic mechanisms.

The role of endogenous responses and compensations is apparent in Alzheimer's disease, where strict regulatory controls exist for the response to oxidative stress by redox-balance (Russell et al. 1999), amyloid (Nunomura et al., 2001; Takeda et al. 2000) and neurofilament (Wataya et al. High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. J Biol Chem, in press.) It is critical to consider these basic processes when developing novel therapeutic modalities in Alzheimer's and other degenerative diseases since, despite evidence of redox stress in these disorders, this data may in fact explain the modest efficacy of antioxidant treatments.

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