Maximum life spans are significantly increased in mice by Leg 1a, a genetic variant in Mus m molossinus (MOLD) on chromosome 8 near microsatellite marker D8Mit171. The same chromosome region reduces blood insulin without affecting glucose levels or normal growth. Defining this gene that retards mammalian aging may suggest clinical treatments to improve health in old age.
Aim 1 tests if Leg1a has effects on aging like those already defined for caloric restriction (CR) by comparing four groups of 84 mice: Leg1a carriers and non-carriers, each with a fed ad lib group and a CR group. At 4 and 24 months of age, biological aging will be assessed with a battery of non-harmful measures including blood insulin and glucose, T cell subset distributions, wound healing and collagen denaturation. In addition, growth will be followed from weaning, and life spans and pathology will be determined. Splenic T cell telomere lengths will be tested in separate groups.
Aim 2 maps Leg1a to a 1 cM region, and tests if Leg1 is the locus that regulates insulin. Progeny will be produced from 10 males; each with a different chromosomal recombination carrying a unique subset of MOLD alleles in the 10 cM region now defined. For statistical power, each male will produce 84 progeny carrying the recombination and 84 non-carrier controls with no MOLD alleles in the 10 cM region. Insulin and glucose levels will be tested at 4 months in these mice, and life spans of the longest-lived 18 and 40 percent will be compared to map Leg1a to a 1 cM region. If the long-lived recombinant groups all have low insulin, it will strongly support the hypothesis that Leg1a regulates insulin.
Aim 3 uses the progeny of Aim 2 to map the locus regulating insulin to within 1 cM. Subsequently, progeny from 10 males with recombinations within this 1 cM region will be used to refine the map location to 0.1 cM (roughly 10 genes), comparing 79 carriers of each recombination with 79 non-carrier progeny. Candidate genes will be tested to see whether MOLD alleles differ from those of NZW, LP and BALB. The gene will ultimately be identified by homologous recombination.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018003-05
Application #
6845096
Study Section
Metabolism Study Section (MET)
Program Officer
Mccormick, Anna M
Project Start
2001-01-01
Project End
2006-12-31
Budget Start
2005-01-15
Budget End
2006-12-31
Support Year
5
Fiscal Year
2005
Total Cost
$366,750
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Brooks, Natasha L; Trent, Chad M; Raetzsch, Carl F et al. (2007) Low utilization of circulating glucose after food withdrawal in Snell dwarf mice. J Biol Chem 282:35069-77
Yuan, Rong; Flurkey, Kevin; Van Aelst-Bouma, Renee et al. (2006) Altered growth characteristics of skin fibroblasts from wild-derived mice, and genetic loci regulating fibroblast clone size. Aging Cell 5:203-12
Yuan, Rong; Astle, C M; Chen, Jichun et al. (2005) Genetic regulation of hematopoietic stem cell exhaustion during development and growth. Exp Hematol 33:243-50
Klebanov, Simon; Astle, Clinton M; DeSimone, Olga et al. (2005) Adipose tissue transplantation protects ob/ob mice from obesity, normalizes insulin sensitivity and restores fertility. J Endocrinol 186:203-11
Chen, Jichun; Flurkey, Kevin; Harrison, David E (2002) A reduced peripheral blood CD4(+) lymphocyte proportion is a consistent ageing phenotype. Mech Ageing Dev 123:145-53
Klebanov, S; Harrison, D E (2002) Optimizing detection of QTLs retarding aging: choice of statistical model and animal requirements. Mech Ageing Dev 123:131-44
Klebanov, S; Astle, C M; Roderick, T H et al. (2001) Maximum life spans in mice are extended by wild strain alleles. Exp Biol Med (Maywood) 226:854-9
Klebanov, S; Flurkey, K; Roderick, T H et al. (2000) Heritability of life span in mice and its implication for direct and indirect selection for longevity. Genetica 110:209-18