p66ShcA and ageing: modulation by longevity-promoting agent aurintricarboxylic acid.
Many mutations that extend the lifespan of the lower organisms such as C. elegans and Drosophila, are associated with signaling or apoptotic pathways. Recently, such a possibility was shown in mammals: p66ShcA-deficient mice were more resistant to oxidative stress and lived longer than the wild-type animals [Migliaccio, E., Giorgio, M., Mele, S., Pelicci, G., Reboldi, P., Randolfi, P.P., Lanfrancone, L., Pelicci, P.G., 1999. The p66Shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313]. There is evidence to implicate p66ShcA in age-related degenerative pathology, including atherosclerosis, sarcopenia, and Alzheimer's disease. We hypothesized that a low level expression of p66ShcA could be associated with longevity. Also, we suggested that the level of p66ShcA could be modulated by a putative longevity-promoting agent aurintricarboxylic acid [aurintricarboxylic acid (ATA); Fraifeld, V., Wolfson, M., Sagi, O., Seidman, R., Asraf, H., Utko, N., Muradian, K., 2002. Effects of anti-apoptotic agent aurintricarboxylic acid on longevity and longevity-associated processes. Biogerontology 3, 48]. We have found that: (i) the level of p66ShcA decreases with advanced age. Thirty-six-month-old mice have the lowest, whereas newborns have the highest p66ShcA levels; (ii) ATA significantly decreases the p66ShcA level in mouse lungs. In addition, the lifespan-prolongation effect of ATA in a Drosophila model was further validated. The results support the suggested role for the p66ShcA as one of the lifespan determinants in mammals; p66ShcA therefore represents a potential target for pharmacological longevity-promoting intervention.
Sagi
Orli
O
Department of Microbiology and Immunology, Faculty of Health Sciences, Center for Multidisciplinary Research in Aging, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel.
Wolfson
Marina
M
Utko
Natalie
N
Muradian
Khachik
K
Fraifeld
Vadim
V
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000375:Aging; D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D015153:Blotting, Western; D002245:Carbon Dioxide / Q000378:metabolism; D004331:Drosophila melanogaster; D008136:Longevity / Q000187:drug effects*; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation; D009584:Nitrogen / Q000378:metabolism; D018384:Oxidative Stress; D020033:Protein Isoforms; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D020033:Protein Isoforms; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D002245:Carbon Dioxide; D001312:Aurintricarboxylic Acid; D009584:Nitrogen