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Caloric restriction (CR) is currently the only therapeutic intervention known to attenuate aging in mammals, but the mechanisms underlying this phenomenon are still poorly understood. To study this issue, the transgenic model of alpha MUPA mice, which previously were reported to spontaneously eat less and live longer compared with their wild-type (WT) control mice, were used. Currently, two transgenic lines that eat less are available, thus implicating the transgenic enzyme, that is, the urokinase-type plasminogen activator (uPA), in causing the reduced appetite. Recently, several changes in the alpha MUPA liver were noted, at the mitochondrial and cellular level, which consistently pointed to an enhanced capacity to induce apoptosis. In addition, alpha MUPA mice showed a reduced level of serum IGF-1 and a reduced incidence of spontaneously occurring or carcinogen-induced tumors in several tissues. Overall, the alpha MUPA model suggests that long-lasting, moderately increased apoptotic capacity, possibly linked in part to modulation of serum IGF-1 and mitochondrial functions, could play a role in the attenuation of aging in calorically restricted mice.