Serum Insulin-like Growth Factor I (IGF-I) levels decline with age. We have recently reported that in aging rats the exogenous administration of IGF-I restores IGF-I circulating levels and age related-changes improving glucose and lipid metabolisms, increasing testosterone levels and serum total antioxidant capability and reducing oxidative damage in brain and liver associated with a normalization of antioxidant enzyme activities.

Understanding that mitochondria are one of the most important cellular targets of IGF-I, the aim of this study was to characterize mitochondrial dysfunction and study the effect of IGF-I therapy on mitochondria leading to cellular protection in the following experimental groups: young controls; untreated old rats and aging rats treated with IGF-I.

Compared with young controls, untreated aging rats showed an increase of oxidative damage in isolated mitochondria with a mitochondrial dysfunction characterized by: depletion of membrane potential with increased proton leak rates and intramitochondrial free radical production and a significant reduction of ATPase and Complex IV activities. In addition, mitochondrial respiration from untreated aging rats was atractyloside-insensitive, suggesting that the adenine nucleotide translocator (ANT) was uncoupled. ANT has been shown to be one of the most sensitive locations for pore opening. Accordingly untreated aging rats showed a significant overexpression of the active fragment of Caspase 3 and 9. IGF-I therapy corrected these parameters of mitochondrial dysfunction and reduced caspase activation.

In conclusion, these results show that the cytoprotective effect of IGF-I is closely related to a mitochondrial protection leading to reduce free radicals production, oxidative damage and apoptosis and to increased ATP production.