The p66Shc gene paves the way for healthspan: Evolutionary and mechanistic perspectives

•Increased life expectancy is accompanied by greater incidence of neurodegenerative disorders.•The p66Shc gene is a crucial regulator of reactive oxygen species and aging.•p66Shc has been conserved through evolution because of its role in energy metabolism.•p66Shc appears as a good candidate molecule to address the mechanisms underlying healthy aging.

Life expectancy in the last century has greatly increased although, in most industrialized countries, this has been paralleled by an increased incidence of neurodegenerative disorders, in addition to cardiovascular and metabolic pathologies. The p66Shc gene has emerged as a novel gerontogene affecting health throughout life and during aging. In the last decade, studies on p66Shc knock-out mice have indicated that this gene is a crucial regulator of reactive oxygen species (ROS) levels and is involved in age-related dysfunctions. p66Shc−/− mice show indeed a healthy phenotype characterized by greater brain and behavioral plasticity – associated to increased central levels of the neurotrophin Bran-Derived Neurotrophic Factor (BDNF) – in addition to reduced oxidative stress, fat accumulation and incidence of metabolic and cardiovascular pathologies. Studies performed in a semi-naturalistic setting, involving exposure to low temperatures and food shortage indicate that p66Shc has been conserved through evolution because of its role as “thrifty gene” in energy metabolism. This feature, which allows survival in harsh natural conditions, can be deleterious when food is constantly available, as in westernized lifestyles, leading to fat accumulation and predisposing to metabolic, cardiovascular diseases and accelerating brain aging. Being at the crossroad of signaling pathways involved in both central and peripheral stress responses and in the regulation of energy homeostasis, p66Shc is a good candidate molecule to address the mechanisms underlying healthy aging and to be targeted for the development of novel pharmacological tools for the prevention or cure of age-related pathologies.