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Abstract
BackgroundSerum IGF-I and IGF-II levels decline with age. IGF-I replacement therapy reduces the impact of age in rats. We have recently reported that IGF-II is able to act, in part, as an analogous of IGF-I in aging rats reducing oxidative damage in brain and liver associated with a normalization of antioxidant enzyme activities. Since mitochondria seem to be the most important cellular target of IGF-I, the aim of this work was to investigate whether the cytoprotective actions of IGF-II therapy are mediated by mitochondrial protection.MethodsThree groups of rats were included in the experimental protocol young controls (17 weeks old); untreated old rats (103 weeks old); and aging rats (103 weeks old) treated with IGF-II (2 μg/100 g body weight and day) for 30 days.ResultsCompared with young controls, untreated old rats showed an increase of oxidative damage in isolated mitochondria with a dysfunction characterized by: reduction of mitochondrial membrane potential (MMP) and ATP synthesis and increase of intramitochondrial free radicals production and proton leak rates. In addition, in untreated old rats mitochondrial respiration was not blocked by atractyloside. In accordance, old rats showed an overexpression of the active fragment of caspases 3 and 9 in liver homogenates. IGF-II therapy corrected all of these parameters of mitochondrial dysfunction and reduced activation of caspases.ConclusionsThe cytoprotective effects of IGF-II are related to mitochondrial protection leading to increased ATP production reducing free radical generation, oxidative damage and apoptosis.
Highlights
Serum IGF-I and IGF-II levels decline with age
Potential (MMP) The membrane potential (MMP), which is considered a good marker of mitochondrial function, was monitored by FL quenching of Rh-123 in mitochondria from the livers of rats under different conditions: the resting state 4; the active state 3; and with oligomycin, which deactivates ATPase showing the conditions of maximum intramitochondrial negativity
According to previous data [5], a reduction of MMP was observed in untreated aging rats compared with young controls, which IGF-II therapy was able to restore to similar values to those found in young controls, as IGF-I replacement therapy had reached [4,5]
Summary
Serum IGF-I and IGF-II levels decline with age. IGF-I replacement therapy reduces the impact of age in rats. We have recently reported that IGF-II is able to act, in part, as an analogous of IGF-I in aging rats reducing oxidative damage in brain and liver associated with a normalization of antioxidant enzyme activities. Understanding that aging is an unrecognized condition of “IGF-I deficiency”, we have recently reported that IGF-I replacement therapy restores many agerelated changes increasing testosterone levels and serum total antioxidant capability and reducing oxidative damage in brain and liver [4]. This cytoprotective (neuroprotective and hepatoprotective) activity of IGF-I in. The MMPT is an endpoint to initiate cell death because the pore opening lead to the release of the mitochondrial cytochrome c activating the apoptotic pathway of caspases
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