Paper
- Alzforum Recommends
Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, Lu X, Soron G, Cooper B, Brayton C, Hee Park S, Thompson T, Karsenty G, Bradley A, Donehower LA. p53 mutant mice that display early ageing-associated phenotypes. Nature. 2002 Jan 3;415(6867):45-53. PubMed.
Recommends
Please login to recommend the paper.
Comments
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 GuarenteHomeostatic 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.
References:
Larsen PL, Clarke CF. Extension of life-span in Caenorhabditis elegans by a diet lacking coenzyme Q. Science. 2002 Jan 4;295(5552):120-3. PubMed.
Tatar M, Rand DM. Aging. Dietary advice on Q. Science. 2002 Jan 4;295(5552):54-5. PubMed.
Russell RL, Siedlak SL, Raina AK, Bautista JM, Smith MA, Perry G. Increased neuronal glucose-6-phosphate dehydrogenase and sulfhydryl levels indicate reductive compensation to oxidative stress in Alzheimer disease. Arch Biochem Biophys. 1999 Oct 15;370(2):236-9. PubMed.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. PubMed.
Takeda A, Smith MA, Avilá J, Nunomura A, Siedlak SL, Zhu X, Perry G, Sayre LM. In Alzheimer's disease, heme oxygenase is coincident with Alz50, an epitope of tau induced by 4-hydroxy-2-nonenal modification. J Neurochem. 2000 Sep;75(3):1234-41. PubMed.
Wataya T, Nunomura A, Smith MA, Siedlak SL, Harris PL, Shimohama S, Szweda LI, Kaminski MA, Avila J, Price DL, Cleveland DW, Sayre LM, Perry G. High molecular weight neurofilament proteins are physiological substrates of adduction by the lipid peroxidation product hydroxynonenal. J Biol Chem. 2002 Feb 15;277(7):4644-8. PubMed.
View all comments by Jim JosephMake a Comment
To make a comment you must login or register.