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.
| 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 |
