The role of manganese homeostasis in life span extension by dietary restriction

By: George Sutphin

Dietary restriction shortens life span in mutants lacking genes related to manganese homeostasis. Reduced glucose concentration dramatically reduces replicative life span of yeast lacking either the Golgi calcium/manganese ATPase, Pmr1, or the mitochondrial manganese superoxide dismutase, Sod2.

Dietary restriction extends life span and improves numerous age-associated health parameters in a variety of evolutionarily divergent species ranging from the budding yeast to the rhesus monkey. The majority of dietary restriction studies have been carried out in a control laboratory environment on populations of genetically homogenous individuals. In genetically heterozygous populations such as humans, it remains unknown whether dietary restriction will have a generally positive effect on survival and health, or whether different genotypes within the population will display a differential response.

In the budding yeast, we have identified single gene deletion mutants that show a wide range of responses to dietary restriction ranging from severely shortened to greatly extended life span, and we are in the process of characterizing strains on both ends of the spectrum. Two of the genes with the greatest negative response to dietary restriction are PMR1 and SOD2. PMR1 encodes a Golgi apparatus calcium/manganese ATPase. Pmr1 is responsible for transporting calcium and manganese from the cytosol into the Golgi lumen. Several lines of evidence indicate that manganese transport is the relevant function for the altered response to dietary restriction. SOD2 encodes the mitochondrial superoxide dismutase and requires manganese. Together, these suggest that proper control of intracellular manganese is important for an appropriate response to dietary restriction. Current efforts are focused on identifying the specific manganese-associated processes involved in the poor response to dietary restriction in these mutants in order to develop a more general understanding of the role of manganese homeostasis in yeast nutrient response.