This project defines how mechanisms of aging, biological changes with age, and life spans are affected by specific deficiencies in the insulin and IGF-1 pathways in mice. The broad objectives are to understand effects of the insulin/IGF-1 pathways on mammalian aging, and to retard deleterious changes with age in human beings. The following hypotheses are tested:
Aim 1 : That, in mice, elimination of insulin signaling in specific tissues reproduces the benefits of (a) the combined insulin/IGF-1 signal impairment of the Ghrhrlit (lit/lit) mutation or of (b) diet restriction (DR);also, that the effects of the (lit/lit) mutation reproduce effects of DR. Changes with age in mice targeted to lack the insulin receptor (IR) in white fat (FIRKO), in neural tissue (NIRKO), and in both (FIRKO &NIRKO) are contrasted with aging in the lit/lit mutant, and in the DR-treated mouse. Here and in Aims 2 &3, the C57BL/6J X C3H/HeJ F1 hybrid (B6C3HF1) background provides a robust standardized foundation for direct comparisons.
Aim 2 : That the beneficial effects of reduced insulin and IGF-1 signaling are additive. The effects of the combined mutants ([FIRKO &lit/lit , [NIRKO &lit/lit], and [FIRKO &NIRKO &lit/lit) are compared with the mutants in Aim 1 and with DR, to determine whether the benefits of the impaired insulin pathway in specific tissues are redundant, additive, or synergistic to the diminished insulin and IGF-1 of lit/lit mutants.
Aim 3 : That reduction in insulin signaling, not adiposity, mediates beneficial effects on aging in FIRKO mice. The hyperphagic Lepob (ob/ob) mutation is combined with the FIRKO mutation, producing obese FIRKO mice, to test if aging rates are retarded despite increased levels of body fat. Health relevance: In each aim, aging mechanisms and rates are tested in biological systems with clinical relevance: resistance to leukemias or oxidation;rates of aging in collagen, T cells, body composition, metabolism, glucose, insulin, IGF-1, leptin, hematocrit and bone composition;life spans and pathological lesions. These experiments define function of the insulin and IGF-1 pathways as regulators of underlying mechanisms causing increases, with age, in vulnerability to disease and death. Understanding how reductions in function of the insulin and IGF-1 pathways delay aspects of mammalian aging may suggest treatments to improve health as human beings age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026074-05
Application #
8048959
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
2007-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2011
Total Cost
$332,643
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Flurkey, Kevin; Astle, Clinton M; Harrison, David E (2010) Life extension by diet restriction and N-acetyl-L-cysteine in genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 65:1275-84
Flurkey, Kevin; Harrison, David E (2010) Reproductive ageing: Of worms and women. Nature 468:386-7
Alderman, J McKee; Flurkey, Kevin; Brooks, Natasha L et al. (2009) Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp Gerontol 44:26-33
Ertl, Robin P; Chen, Jichun; Astle, Clinton M et al. (2008) Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated. Blood 111:1709-16