1. Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy
2. Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, Molecular Biology and Cell Biology Programs, Sloan-Kettering Institute, New York, New York 1021, USA
3. Istituto di Patologia Medica, Perugia University, 06100 Perugia, Italy
4. Istituto di Medicina Interna e Scienze Oncologiche, Perugia University, 06100 Perugia, Italy
5. These authors contributed equally to this work

Correspondence to: Pier Giuseppe Pelicci^1,3 Correspondence and requests for materials should be addressed to P.G.P. (e-mail: Email: pgpelicci@ieo.it).

Gene mutations in invertebrates have been identified that extend life span and enhance resistance to environmental stresses such as ultraviolet light or reactive oxygen species¹. In mammals, the mechanisms that regulate stress response are poorly understood and no genes are known to increase individual life span. Here we report that targeted mutation of the mouse p66^shc gene induces stress resistance and prolongs life span. p66^shc is a splice variant of p52^shc/p46^shc (ref. 2), a cytoplasmic signal transducer involved in the transmission of mitogenic signals from activated receptors to Ras³. We show that: (1) p66^shc is serine phosphorylated upon treatment with hydrogen peroxide (H₂O₂) or irradiation with ultraviolet light; (2) ablation of p66^shc enhances cellular resistance to apoptosis induced by H₂O₂ or ultraviolet light; (3) a serine-phosphorylation defective mutant of p66^shc cannot restore the normal stress response in p66^shc-/- cells; (4) the p53 and p21 stress response is impaired in p66^shc-/- cells; (5) p66^shc-/- mice have increased resistance to paraquat and a 30% increase in life span. We propose that p66^shc is part of a signal transduction pathway that regulates stress apoptotic responses and life span in mammals.