How diet interacts with longevity genes

Abstract

In laboratory mice, suppression of growth hormone (GH) signaling by spontaneous mutations or targeted disruption of GH-or IGF1-related genes can lead to an impressive increase of longevity. Hypopituitary Ames dwarf (Prop1 df ) and GH receptor knockout (GHRKO) mice live 35-70% longer than their normal littermates. Many phenotypic characteristics of these longlived mutants resemble findings in genetically normal animals subjected to calorie restriction (CR). Microarray and RT-PCR studies of gene expression suggest that effects of the "longevity assurance genes" (Prop1 df or Ghr-/-) and CR are overlapping but not identical. Subjecting Ames dwarf mice to 30% CR starting at 2 months of age leads to a further significant extension of their average and maximal lifespans. In contrast, identical CR regimen has either no or very little effect (depending on gender) on longevity of GHRKO mice. We suspect that this difference in response is related to the fact that CR improves insulin sensitivity in Ames dwarfs but does not further increase the extreme insulin sensitivity of GHRKO mice. To search for effects of CR associated with extension of longevity, we are studying expression of insulin and IGF1-related genes in the liver, skeletal muscle and heart of normal and GHRKO mice. Results obtained to date suggest that reduced Akt phosphorylation and PPAR β/δ expression in the liver, reduced JNK1 phosphorylation and increased PGC1α expression in the muscle, and increased expression of IGF1 and insulin receptor in the heart are either related to mechanisms of CR action on longevity or represent potential biomarkers of delayed aging.

Expression of oxidative phosphorylation components in mitochondria of long-living Ames dwarf mice

“…Our lab (this study) as well as others, have reported that Ames mice exhibit greater levels of PGC-1α mRNA in tissues as compared to control animals Bartke et al 2008). The high levels of liver PGC-1α mRNA did not result in greater mitochondrial numbers as estimated by the mitochondrial-nuclear DNA ratios.…”

Genome-Environment Interactions That Modulate Aging: Powerful Targets for Drug Discovery

“…SIRT1 activators have been evaluated this way by Sirtris (Smith et al, 2009). Because some mouse models respond differently to CR, studies have focused on identifying differential responses that can be associated with the mechanisms of CR and/or used as biomarkers (Bartke et al, 2008). More recent work has also focused on identifying genes that influence the life-extending effects of CR by classic genetics using differences in lifespan in different mouse recombinant inbred strains (Liao et al, 2010).…”

The contribution of visceral fat to improved insulin signaling in Ames dwarf mice

“…Ames dwarf mice not only exhibit an increase in longevity, living 40–60% longer relative to N mice, but also an enhanced healthspan, maintaining their youthful appearance with age. These mutants show no signs of diabetes; they are extremely insulin sensitive with low levels of glucose and insulin in circulation (Brown-Borg et al ., 1996; Bartke et al ., 2001, 2008). Ames dwarf mice have improved cognitive function and show no age-related decline in memory (Kinney et al ., 2001) and are less prone to cancer (Ikeno et al ., 2003).…”

“…The fact that df/df mice are inclined to get obese as they age but yet maintain high adiponectin levels in circulation (Bartke et al ., 2008) and live longer and healthier lives compared with N mice leads us to hypothesize that VF in these mutants, developed in the absence of GH signaling, contributes to the enhanced insulin sensitivity of df/df mice, presumably by secreting low levels of pro-inflammatory IL-6 and increased levels of anti-inflammatory adiponectin.…”