G×G×E for Lifespan in Drosophila: Mitochondrial, Nuclear, and Dietary Interactions that Modify Longevity

Abstract

Dietary restriction (DR) is the most consistent means of extending longevity in a wide range of organisms. A growing body of literature indicates that mitochondria play an important role in longevity extension by DR, but the impact of mitochondrial genotypes on the DR process have received little attention. Mitochondrial function requires proper integration of gene products from their own genomes (mtDNA) and the nuclear genome as well as the metabolic state of the cell, which is heavily influenced by diet. These three-way mitochondrial-nuclear-dietary interactions influence cellular and organismal functions that affect fitness, aging, and disease in nature. To examine these interactions in the context of longevity, we generated 18 “mito-nuclear” genotypes by placing mtDNA from strains of Drosophila melanogaster and D. simulans onto controlled nuclear backgrounds of D. melanogaster (Oregon-R, w 1118, SIR2 overexpression and control) and quantified the lifespan of each mitonuclear genotype on five different sugar:yeast diets spanning a range of caloric and dietary restriction (CR and DR). Using mixed effect models to quantify main and interaction effects, we uncovered strong mitochondrial-diet, mitochondrial-nuclear, and nuclear-diet interaction effects, in addition to three-way interactions. Survival analyses demonstrate that interaction effects can be more important than individual genetic or dietary effects on longevity. Overexpression of SIR2 reduces lifespan variation among different mitochondrial genotypes and further dampens the response of lifespan to CR but not to DR, suggesting that response to these two diets involve different underlying mechanisms. Overall the results reveal that mitochondrial-nuclear genetic interactions play important roles in modulating Drosophila lifespan and these epistatic interactions are further modified by diet. More generally, these findings illustrate that gene-by-gene and gene-by-environment interactions are not simply modifiers of key factors affecting longevity, but these interactions themselves are the very factors that underlie important variation in this trait.

Reproductive activity triggers accelerated male mortality and decreases lifespan: genetic and gene expression determinants in Drosophila

“…Indeed, our observations are in agreement with suggestions that germline removal promotes longevity in part by modulating insulin signaling and lipid metabolism (Hansen et al, 2013), and with expectations that naturally occurring variation in mitochondrial function and metabolism specifically affects male aging (Zeh and Zeh, 2005;Camus et al, 2012). Moreover, mitochondrialnuclear genetic interactions tied to aging are likely to include nuclear-encoded genes associated with reproduction-induced mortality (Tanaka et al, 1998;De Benedictis et al, 1999;Rand et al, 2006;Clancy, 2008;Zhu et al, 2014). A recent study found that interactions between genes spanning the mitochondrial and nuclear genomes were associated with components of male reproductive aging via direct effects on ejaculate weight and indirect effects on the size of eggs produced by females (Immonen et al, 2016).…”

Genetic Interactions Between Shox2 and Hox Genes During the Regional Growth and Development of the Mouse Limb

“…Mice harboring Shox2 mutations (Cobb et al 2006), a complete deficiency of the HoxD cluster (Spitz et al 2001), and a Cre-dependent deletion of the entire HoxA cluster (Kmita et al 2005) were crossed, and the limbs of resultant progeny were analyzed for evidence of epistasis as newborns ( Figure 2). Intriguingly, while the removal of an individual Shox2 allele did not lead to limb shortening when the Hox genes were intact, this same mutation gave significantly truncated humeri when the HoxD cluster was disrupted (30% shorter than expected if HoxD genes did not affect the outcome of Shox2 mutation) [ Figure 2, A and A9: nonparallel lines in interaction plots are characteristic of interaction (e.g., Zhu et al 2014)]. Additionally, Prrx1-Cre; Shox2 fl/2 (or Shox2 c/2 ) animals, which have both copies of Shox2 removed from the limb mesenchyme, have disproportionately shorter ulnae when the HoxA genes are concomitantly disrupted (25% shorter than expected if…”

Mitochondrial reactive oxygen species: Do they extend or shorten animal lifespan?

“…Lifespan studies in flies and worms are affected by diet and genetic background [162], so it is possible that ROS extends lifespan in certain conditions but not in others. Similarly, differences could be related to the nature of expression i.e.…”