Pier Giuseppe Pelicci
Dr. Pier Giuseppe Pelicci is Scientific Co-Director of the European Institute of Oncology, Chairman of the Department of Experimental Oncology (DEO) at the European Institute of Oncology, Milan (Italy), Scientific Director of the SEMM Foundation (European School of Molecular Medicine, Milan, Italy). IEO is a comprehensive cancer center focused on advanced treatments, diagnostics, clinical trials, cancer prevention, training, higher education and advanced research. SEMM is private foundation whose mission is to foster innovative education in molecular medicine, medical nanotechnology and bio-ethics. At IEO, Pelicci is responsible for the strategic planning of the IEO institute research programs, including basic, translational (Molecular Medicine Program) and clinical research. At SEMM, Pelicci is responsible for the development of three PhD programs (Molecular Medicine, Medical Nanotechnology, Life sciences: foundationsðics)
Dr. Pelicci is member of the American Association for Cancer Research, the European Molecular Biology Organization, the European Haematology Association, the European Society for Engineering and Medicine, the European Cytokine Society, The New York Academy of Sciences, the American Society for Microbiology, the Italian Association of Biophysics and Molecular Biology, the Italian Society of Cancerology. He is past president (1998-2000) of the Italian Society of Experimental Hematology.
Dr. Pelicci was honored with several prestigious international fellowships and awards, such as the "C. Cioffrese" Prize for Cancer Research (Fondazione Carlo Erba, Italy), the “Foundation Chiara d'Onofrio” (Italy), the “Guido Venosta” Prize of the Italian Foundation for Cancer Research, the Award for “Excellence in Medicine” of the American-Italian Foundation for Cancer Research (New York, US), the H. S. Raffaele Prize (Italy). He is presently Full Professor of Pathology at the University of Milan and cofounder of the Biotech holding Genextra. Genextra controls four Biotech companies (Congenia, DAC, Tethis and Intercept).
Dr. Pelicci is co-founder and co-director of the IFOM-IEO Campus, a research infrastructure that host IFOM, the IEO laboratory research activities, SEMM, Genextra and Cogentech.
Molecular genetics of Longevity
Genetic manipulations can extend the lifespan as much as tenfold. Hundreds of mutant genes have been identified that increase longevity in model organisms, including nematodes, yeast, fruitflies and mice. Most of them function in evolutionarily conserved pathways (insulin signalling pathway, TOR pathway, mitochondrial electron transport chain) that regulate nutrition sensing, energy metabolism, growth or reproduction. In mammals, many pro-longevity mutations are associated with delayed aging and resistance to aging-related diseases. Evidence is accumulating that the identified pro-ageing pathways can be manipulated by pharmacological interventions, to extend lifespan or to reduce incidence/severity of aging-associated diseases. A better understanding of the physiological function of these targets, however, is essential to understand whether retarding aging in mammals is a realistic vision.
To address these issues, we have used p66Shc−/− mice as model. P66 is a vertebrate protein whose deletion in mice (p66Shc−/−) induces resistance to obesity, atherosclerosis, ischemic injury and diabetes. P66Shc regulates the intracellular redox balance and related processes, including apoptosis and cellular growth. It increases intracellular levels of reactive oxygen species (ROS) by enhancing ROS production by mitochondria and plasma membrane oxidases, and inhibiting expression of ROS-scavenging enzymes. Notably, oxidative stress is reduced in p66Shc−/− mice and they showed extended lifespan.
The multiple benefits of p66Shc deletion raise the question of how this gene has been selected during evolution and what is its physiological function. Testing subtle impairments of biological fitness under laboratory conditions, however, is a difficult task, particularly when the relevance of the gene for survival under natural conditions is unknown. To address these questions, we have analyzed the effects of p66Shc deletion on early-life fitness by exposing mice to natural selection under outdoor conditions in a harsh environment (food competition and exposure to winter temperatures). Under these conditions, deletion of p66Shc was strongly counterselected. Laboratory studies revealed that p66Shc−/− mice have defects in fat accumulation, thermoregulation, and reproduction.
These findings indicate a function of the p66Shc protein in adapting the organism to changes in the energetic niche, e.g., food access and environmental temperature, and suggest that, mechanistically, p66Shc exerts this function by regulating the fat tissue. These metabolic effects of p66Shc increase fitness when food is scarce and energetic resources are to be stored, suggesting that the degree of fat accumulation in mammals is evolutionarily set early in life for optimal reproduction and survival in the wild. When food is constantly available and individuals are protected from low temperatures, as it occurs in mammals in captivity and humans with westernized lifestyles, fat accumulation becomes instead detrimental, by predisposing to diseases such as diabetes, cardiovascular disease, and cancer, eventually leading to accelerated aging. The negative effect of the fat tissue on aging-associated diseases is not programmed, it manifests late in-life and in protected environments. In conclusion, p66Shc functions may adapt populations to the changeability of resources, thus increasing the distribution of species, and become disadvantageous if food availability becomes excessive, as it has happened with western diets and habits.
These findings imply that the health impact of targeting aging genes might depend on the specific energetic niche and caution should be exercised against premature conclusions regarding gene functions that have only been observed in protected laboratory conditions.
