Interaction of Genotype and Level of Dietary Restriction on Lifespan and Aging

  • Richardson, Arlan G, (PI)

Project: Research projectResearch Project

Description

Over the past three decades, dietary restriction (DR) has become the gold standard against which
manipulations that retard aging are compared. Because DR has been shown to increase the lifespan of a wide
variety of organisms ranging from invertebrates to rodents, DR is viewed as a universal aging intervention.
However, a recent study suggests that the genotype of an animal is a major determinant in the ability of the
animal to respond to DR, e.g., two-thirds of the 41 recombinant inbred (RI) lines of mice studied either did not
respond or showed reduced lifespan when fed 40% DR (40% less diet than that consumed by mice fed ad
libitum). The overall goal of this grant is to explore the interaction between genotype and the level of DR using
nine genetically diverse RI lines of mice. We hypothesize that DR will increase lifespan and delay aging in
all genotypes; however, the effect of DR will be both genotype- and dose-dependent, i.e., one level of
DR is not optimal for all genotypes. The comprehensive design of this study, allows us for the first time to
obtain an accurate view of how genetic diversity impacts the effect of DR on lifespan and aging. Specific Aim 1: To determine whether DR affects lifespan in a genotype- and dose-dependent manner. The
lifespans of nine RI lines of female mice that show maximum diversity in response to 40% DR will be fed ad
libitum or 10, 20, or 40% less diet than the amount consumed by each RI line fed ad libitum. Based on our
hypothesis, we predict that all nine RI lines will show an increase in lifespan; however, the level of restriction
necessary to obtain an increase in lifespan will vary with genotype. Specific Aim 2: To determine whether DR affects end-of-life pathology in a genotype- and dose-dependent
manner. Because a reduction in most age-related pathologies is a hallmark feature of DR, we will conduct a
comprehensive pathological analysis of all the female mice that die in Aim 1. We predict that the increase in
lifespan by DR will be accompanied by a reduction/delay in most age-related pathological lesions, which would
support the premise that DR increases lifespan by retarding aging. We also predict that the effect of DR on
end-of-life pathological lesions will be genotype- and DR dose-dependent. Specific Aim 3: To identify potential pathways involved in the anti-aging mechanism of DR. We will
measure the levels of transcripts in RNA isolated from liver and epididymal fat of mice fed AL and the three DR
diets for 12 months using Illumina Mouse microarrays. Employing unbiased analyses of our microarray data,
we will identify pathways that are altered significantly by DR. Because we will have transcriptome data on 27
cohorts of mice fed DR (nine strains of mice fed 10, 20, and 40% DR), we are in a unique position to identify
gene profiles that have the greatest predictive power to identify the cohorts of mice that show a significant
increase in lifespan when placed on a DR diet, and from these data, we can identify potential mechanisms key
in the life-extending action DR.
StatusActive
Effective start/end date8/1/144/30/19

Funding

  • National Institutes of Health: $468,723.00
  • National Institutes of Health: $483,220.00
  • National Institutes of Health: $444,000.00

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Genotype
Diet
Pathology
Organized Financing
Invertebrates
Microarray Analysis
Transcriptome
Rodentia
Fats
RNA
Liver

Keywords

  • Medicine(all)