Among the most important issues in biogerontology today is an understanding of the mechanisms that underlie lifespan extension associated with reduced activity in the insulin/IGF-I signaling pathway. Whereas single mutations in the IGF-I receptor and signaling pathways impart lifespan extension in Caenorhabditis elegans and Drosophila melanogaster, the most robust examples of lifespan extension in mammals are associated with reductions in both IGF-I and growth hormone. Mouse models exhibiting deficiency in pituitary development or growth hormone production and/or signaling show decreased IGF-I levels and a dramatic increase in lifespan. Against a backdrop of growth hormone deficiency, however, it is impossible to attribute the effect on lifespan in these animals solely to reductions in IGF-I, excluding a potentially distinct role for growth hormone in mammalian lifespan modulation. Mouse lines which exhibit reduced IGF-I signaling show much smaller increases in lifespan suggesting that IGF-I suppression alone may not be sufficient to produce the robust lifespan extension seen in animals which lack both growth hormone and IGF-I. However, current models do not provide the tools necessary to define the roles that IGF-I and growth hormone play in modulating longevity in mammals. We propose to create novel mouse models, exhibiting growth hormone independent production of IGF-I. We will perform a characterization of these mice in terms of IGF-I production, development, metabolism, bone growth and lifespan. If we find a major influence of GH on longevity independent of IGF-I, the results of these studies would pave the way for a paradigm shift in our thinking regarding the influence of IGF-I and longevity.

Public Health Relevance

The work proposed in this application will create new mouse line that do not produce growth hormone but will produce one of the primary targets of growth hormone, known as the Insulin-like growth factor type 1. These mice will be used to evaluate the relative contribution of these hormones to late life changes and lifespan. The studies will provide insight into potential therapeutic uses for these hormones in the elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Guo, Max
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Drexel University
Schools of Medicine
United States
Zip Code
Croco, Eleonora; Marchionni, Silvia; Storci, Gianluca et al. (2017) Convergent adaptation of cellular machineries in the evolution of large body masses and long life spans. Biogerontology 18:485-497
Nacarelli, Timothy; Azar, Ashley; Sell, Christian (2015) Aberrant mTOR activation in senescence and aging: A mitochondrial stress response? Exp Gerontol 68:66-70
Sell, Christian (2015) Minireview: The Complexities of IGF/Insulin Signaling in Aging: Why Flies and Worms Are Not Humans. Mol Endocrinol 29:1107-13
Crowe, Elizabeth P; Nacarelli, Timothy; Bitto, Alessandro et al. (2014) Detecting senescence: methods and approaches. Methods Mol Biol 1170:425-45
Bitto, Alessandro; Crowe, Elizabeth P; Lerner, Chad et al. (2014) The senescence arrest program and the cell cycle. Methods Mol Biol 1170:145-54
Bitto, Alessandro; Lerner, Chad A; Nacarelli, Timothy et al. (2014) P62/SQSTM1 at the interface of aging, autophagy, and disease. Age (Dordr) 36:9626
Nacarelli, Timothy; Azar, Ashley; Sell, Christian (2014) Inhibition of mTOR Prevents ROS Production Initiated by Ethidium Bromide-Induced Mitochondrial DNA Depletion. Front Endocrinol (Lausanne) 5:122
Sell, Christian (2013) Comment on: C57BL/6 neuromuscular healthspan scoring system. J Gerontol A Biol Sci Med Sci 68:1325
Pirrone, Vanessa; Libon, David J; Sell, Christian et al. (2013) Impact of age on markers of HIV-1 disease. Future Virol 8:81-101
Klionsky, Daniel J (see original citation for additional authors) (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445-544