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: p66(ShcA)-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 p66(ShcA) adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313]. There is evidence to implicate p66(ShcA) in age-related degenerative pathology, including atherosclerosis, sarcopenia, and Alzheimer's disease. We hypothesized that a low level expression of p66(ShcA) could be associated with longevity. Also, we suggested that the level of p66(ShcA) 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 p66(ShcA) decreases with advanced age. Thirty-six-month-old mice have the lowest, whereas newborns have the highest p66(ShcA) levels; (ii) ATA significantly decreases the p66(shcA) 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 p66(ShcA) as one of the lifespan determinants in mammals; p66(ShcA) therefore represents a potential target for pharmacological longevity-promoting intervention. (C) 2004 Elsevier Ireland Ltd. All rights reserved.