Long-Term IGF-I Exposure Decreases Autophagy and Cell Viability

PLoS One. 2010; 5(9): e12592.
Published online 2010 September 7. doi: 10.1371/journal.pone.0012592.

Alessandro Bitto,1 Chad Lerner,1 Claudio Torres,1 Michaela Roell,2 Marco Malaguti,2 Viviana Perez,3 Antonello Lorenzini,1,2 Silvana Hrelia,3 Yuji Ikeno,4 Michelle Elizabeth Matzko,5 Roger McCarter,4 and Christian Sell1*
1Department of Pathology, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
2Department of Biochemistry, “G. Moruzzi” University of Bologna, Bologna, Italy
3Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
4Barshop Institute for Longevity and Aging Studies and Department of Pathology, University of Texas Health Science Center at San Antonio, Research Service, Audie Murphy VA Hospital (STVHCS), San Antonio, Texas, United States of America
5Department of Biobehavioral Health, Penn State University, State College, Pennsylvania, United States of America
Matt Kaeberlein, Editor
University of Washington, United States of America


Abstrac

A reduction in IGF-I signaling has been found to increase lifespan in multiple organisms despite the fact that IGF-I is a trophic factor for many cell types and has been found to have protective effects against multiple forms of damage in acute settings. The increase in longevity seen in response to reduced IGF-I signaling suggests that there may be differences between the acute and chronic impact of IGF-I signaling. We have examined the possibility that long-term stimulation with IGF-I may have a negative impact at the cellular level using quiescent human fibroblasts. We find that fibroblast cells exposed to IGF-I for 14 days have reduced long-term viability as judged by colony forming assays, which is accompanied by an accumulation of senescent cells. In addition we observe an accumulation of cells with depolarized mitochondria and a reduction in autophagy in the long-term IGF-I treated cultures. An examination of mice with reduced IGF-I levels reveals evidence of enhanced autophagy and fibroblast cells derived from these mice have a larger mitochondrial mass relative to controls indicating that changes in mitochondrial turnover occurs in animals with reduced IGF-I. The results indicate that chronic IGF-I stimulation leads to mitochondrial dysfunction and reduced cell viability.

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