H.M. Brown-Borg, S.G. Rakoczy

Various types of stress including environmental stressors and endogenous and exogenous compounds have been shown to affect longevity. Resistance to stress has been identified as a factor common to many long-living organisms. Ames dwarf mice exhibit growth hormone deficiency, enhanced antioxidative defense capacity, increased insulin sensitivity and a remarkable life span extension compared to normal, wild type mice. Elevated tissue glutathione levels contribute to the enhanced antioxidative defense and detoxification activities observed in dwarf mice. Upstream of the glutathione metabolic pathway is methionine, an essential amino acid pathway that serves as the main source of cysteine residues for glutathione biosynthesis. This pathway has strong links to aging and life span and is significantly influenced by dietary methionine. We observed significant alterations in multiple components of the methionine pathway in Ames mice with evidence suggesting that this pathway is modulated by GH. We conducted preliminary studies evaluating methionine-supplementation in Ames and wild type mice and found that this dietary manipulation significantly alters overall methionine metabolism. Another integral component of the methionine pathway is S-adenosylmethionine, a critical substrate that supplies methyl groups utilized to methylate DNA. DNA methylation contributes to epigenetic variation thus altering gene activity/function. DNA methyltransferase activity is markedly upregulated in Ames mice. Accordingly, we detected significant methylation differences between dwarf and wild type mice. Of the 97 genes that were differentially methylated in a methylation array (>3000 genes), 79 were methylated in the Ames dwarf compared to wild type mice. In addition, we found that these differences in methylation corresponded to changes in gene expression between wild type and dwarf mice. Thus, epigenetic modification may be one of the mechanisms by which GH influences a wide-variety of processes linked to aging. Determination of thiol metabolic pathway components in long-living organisms represents a key to understanding how this single amino acid appears to control aging and aging-related processes such as stress resistance.

Keywords (Optional): 
stress resistance
dwarf mice