Disturbances of metabolism, often linked to mitochondrial function, have a major impact on disease risk and healthspan among human populations. Type 2 diabetes mellitus, non-alcoholic fatty liver disease, hypertension, hyperlipidemia, and cardiovascular diseases are all linked to major changes in metabolic and mitochondrial function. A complex set of genetic and environmental factors-including diet-underlie individual differences in the risk and severity of metabolic syndrome. This project is focused on the complex gene-by- environmental interactions (GXE) that contribute to mitochondrial and metabolic syndrome, and that reduce healthy lifespan. We use a new integrative systems genetics approach to study effects of a high fat Western diet. This work relies on a large family of isogenic and genetically diverse murine lines-including F1 hybrids- that serve as a translational and mechanistic bridge between reductionist and integrative approaches. Identical cohorts will be studied as a function of age on markedly different diets.
In Aim 1, we study lifespan using BXD strains and non-inbred but isogenic F1 cohorts of females under high and low fat diets. We map and quantify novel GXE-type modifier loci, candidate genes, and molecular networks that modulate healthspan and longevity.
In Aim 2 we generate deep molecular, mitochondrial, and metabolic biomarker data as a function of age and diet. We expect that gene variants and diet will be causally linked to mitochondrial function and to metabolism in key organs and tissues.
In Aim 3 we model complex and integrative molecular and cellular networks that define differences in vitality and healthspan. We use sophisticated bioinformatic and statistical frameworks (eQTL analysis, ANOVA, and structural equation modeling). Finally, in Aim 4 we validate and translate networks involved in metabolism, mitochondria, and healthspan. We test candidate genes using gain- and loss-of-function strategies in C. elegans. We evaluate translational relevance of candidate genes and biomarkers by testing for associations in a remarkably well studied cohort of 161,000 postmenopausal women (Women's Health Initiative data sets). The WHI is an ideal translation companion to test effects of diet. This project will (1) identify high impact variants and molecular/metabolic networks involved in metabolic diseases and healthspan, and (2) provide an experimental and predictive systems biology framework that links genotype and environmental factors to disease risk in human populations.

Public Health Relevance

Disturbances of metabolism, often linked to mitochondrial function, have a major impact on disease risk and healthspan among human populations. This project will (1) identify high impact gene variants and molecular/metabolic networks involved in metabolic and mitochondrial diseases and healthspan, and (2) provide an experimental and predictive systems genetic framework that links differences in genotype and diet to disease risk and longevity in human populations.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG043930-02
Application #
8716630
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$505,811
Indirect Cost
$108,383
Name
University of Tennessee Health Science Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Williams, Evan G; Mouchiroud, Laurent; Frochaux, Michael et al. (2014) An evolutionarily conserved role for the aryl hydrocarbon receptor in the regulation of movement. PLoS Genet 10:e1004673
Mouchiroud, Laurent; Eichner, Lillian J; Shaw, Reuben J et al. (2014) Transcriptional coregulators: fine-tuning metabolism. Cell Metab 20:26-40
Khan, Nahid A; Auranen, Mari; Paetau, Ilse et al. (2014) Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med 6:721-31
LaBarge, Samuel; McDonald, Marisa; Smith-Powell, Leslie et al. (2014) Estrogen-related receptor-* (ERR*) deficiency in skeletal muscle impairs regeneration in response to injury. FASEB J 28:1082-97
Jovaisaite, Virginija; Mouchiroud, Laurent; Auwerx, Johan (2014) The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease. J Exp Biol 217:137-43
Cerutti, Raffaele; Pirinen, Eija; Lamperti, Costanza et al. (2014) NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab 19:1042-9
Lo Sasso, Giuseppe; Menzies, Keir Joe; Mottis, Adrienne et al. (2014) SIRT2 deficiency modulates macrophage polarization and susceptibility to experimental colitis. PLoS One 9:e103573
Wu, Yibo; Williams, Evan G; Dubuis, Sébastien et al. (2014) Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population. Cell 158:1415-30
Pirinen, Eija; Cantó, Carles; Jo, Young Suk et al. (2014) Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab 19:1034-41
Lo Sasso, Giuseppe; Ryu, Dongryeol; Mouchiroud, Laurent et al. (2014) Loss of Sirt1 function improves intestinal anti-bacterial defense and protects from colitis-induced colorectal cancer. PLoS One 9:e102495

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