Holzenberger et al (2003) recently reported that mice heterozygous for the IGF-I receptor gene in all tissues (Igflr+/- mice) have extended life span in association with resistance to paraquat toxicity. This finding would be seminal since it shows that the increased life span and resistance to oxidative stress observed in invertebrate models with reduced insulin/IGF-l signaling extends to mammals. This result also provides elegant support for the hypothesis that the mechanism of extended life span of calorie-restricted (CR) animals and GH-deficient dwarf mice is, at least in part, reduced IGF-I action. However, there are major conceptual and technical concerns about the report of Holzenberger et al. First, the literature provides abundant evidence that IGF-I signaling protects against oxidative stress. Secondly, there is no evidence yet available that oxidative damage is reduced over the life span of Igf1r+/- mice, nor are there any evidence of reduced age-related pathology and other markers of biological aging. Third, the life span of the control wild- type mice in the study of Holzenberger et al was short, suggesting the possibility that enhanced life span of the lgf1r+/- mice was due to resistance to a stress of their particular housing environment rather than reduced biological aging. Related to the problem of poor overall survival was the observation that male lgf1r+/~ mice had a 16% extension of life span that was not statistically significant and that male mice were not resistant to paraquat. In the facilities at UTHSCSA, a 16% increase in life span using the proper number of mice would be statistically significant. In view of these deficiencies in the report of Holzenberger et al, it is essential to use the combined resources and expertise available at UTHSCSA in the areas of IGF-I signaling, oxidative stress and damage, and biological aging to test the hypothesis that Igflr+/- mice have extended life span in association with reduced oxidative damage and reduced biological, aging. The following Specific Aims will be pursued to test this hypothesis by determining over the lifespan of the lgf1r+/- mice and wild-type control mice whether: 1) the lgf1r+/- phenotypes of reduced numbers of IGF-I receptors and reduced activation of IGF-I signaling pathways are maintained and the effects of these changes on the GH/IGF-I axis and insulin and glucose tolerance; 2) lgf1r+/- mice are more resistant to paraquat-induced oxidative stress and have reduced oxidative damage to macromolecules and increased anti-oxidant enzymes over the lifespan; and 3) Igflr+/- mice exhibit reduced age-related pathology and markers of biological aging and have extended life span. Outcomes of this research will provide the first definitive data whether a reduction in IGF-I receptor signaling decreases oxidative stress and damage and leads to a broad reduction in biological aging with extended life span in mammals. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG026012-01A1
Application #
7033369
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
2006-03-15
Project End
2011-02-28
Budget Start
2006-03-15
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$269,370
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Biochemistry
Type
Other Domestic Higher Education
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Thakur, Sachin; Garg, Neha; Zhang, Ning et al. (2017) IGF-1 receptor haploinsufficiency leads to age-dependent development of metabolic syndrome. Biochem Biophys Res Commun 486:937-944
Thakur, Sachin; Garg, Neha; Adamo, Martin L (2013) Deficiency of insulin-like growth factor-1 receptor confers resistance to oxidative stress in C2C12 myoblasts. PLoS One 8:e63838
Hitt, Brian; Riordan, Sean M; Kukreja, Lokesh et al. (2012) ?-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects. J Biol Chem 287:38408-25
Elis, Sebastien; Wu, YingJie; Courtland, Hayden-William et al. (2011) Increased serum IGF-1 levels protect the musculoskeletal system but are associated with elevated oxidative stress markers and increased mortality independent of tissue igf1 gene expression. Aging Cell 10:547-50
Garg, Neha; Thakur, Sachin; McMahan, C Alex et al. (2011) High fat diet induced insulin resistance and glucose intolerance are gender-specific in IGF-1R heterozygous mice. Biochem Biophys Res Commun 413:476-80
Hammers, David W; Matheny Jr, Ronald W; Sell, Christian et al. (2011) Impairment of IGF-I expression and anabolic signaling following ischemia/reperfusion in skeletal muscle of old mice. Exp Gerontol 46:265-72
Bokov, Alex F; Garg, Neha; Ikeno, Yuji et al. (2011) Does reduced IGF-1R signaling in Igf1r+/- mice alter aging? PLoS One 6:e26891
Matheny Jr, Ronald W; Nindl, Bradley C; Adamo, Martin L (2010) Minireview: Mechano-growth factor: a putative product of IGF-I gene expression involved in tissue repair and regeneration. Endocrinology 151:865-75
Matheny Jr, R W; Adamo, M L (2010) PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts. Cell Death Differ 17:677-88
Matheny Jr, Ronald W; Adamo, Martin L (2009) Current perspectives on Akt Akt-ivation and Akt-ions. Exp Biol Med (Maywood) 234:1264-70

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