Extended longevity and survivorship during amino-acid starvation in a Drosophila Sir2 mutant heterozygote

Abstract

The regulation of energy homeostasis is pivotal to survive periods of inadequate nutrition. A combination of intricate pathways and proteins are responsible for maximizing longevity during such conditions. The sirtuin deacetylase Sir2 is well conserved from single-celled yeast to mammals, and it controls a number of downstream targets that are active during periods of extreme stress. Overexpression of Sir2 has been established to enhance survival of a number of model organisms undergoing calorie restriction, during which insulin receptor signalling (IRS) is reduced, a condition that itself can enhance survivorship during starvation. Increased Sir2 expression and reduced IRS result in an increase in the activity of the transcription factor foxo, an advantageous activation during stress but lethal when overly active. We have found that a lowered gene dosage of Sir2, in mutant heterozygotes, can extend normal longevity and greatly augment survivorship during amino-acid starvation in Drosophila. Additionally, these mutants, in either heterozygous or homozygous form, do not appear to have any disadvantageous effects upon development or cell growth of the organism unlike IRS mutants. These results may advance the understanding of the biological response to starvation and allow for the development of a model organism to mimic the ability of individuals to tolerate nutrient deprivation.