Many studies have indicated that the inhibition of autophagy by genetic manipulation provokes age-related pathological changes and reduces the lifespan of many organisms, e.g. C. elegans, Drosophila and mice [71,73,74]. Wu et al. [75] demonstrated that the deletion of the Atg7 gene induced mitochondrial disturbances, e.g. increased production of ROS and alterations in the metabolic profile, in mouse skeletal muscle. Cuervo and Dice [76] observed that also chaperone-mediated autophagy (CMA), not only macroautophagy, was impaired in rat liver during aging. They revealed that the decline was caused by an age-related decrease in the expression of LAMP-2A, the receptor protein of CMA. Interestingly, in subsequent studies [77], they demonstrated that the prevention of the age-related loss of LAMP-2A protein in transgenic mice could maintain efficient CMA and that this was associated with a reduction in the level of damaged proteins and improved liver function during aging. Many studies have also demonstrated that increasing the autophagic capacity by pharmacological or genetical manipulations can prevent the pathology linked to the aging process and even extend lifespan [78-80]. For instance, pharmacological induction of autophagy, e.g. by inhibiting mTOR by rapamycin can increase the lifespan of mice [79] (see below).
