| dc.description.abstract | The near ubiquity of ageing across the tree-of-life with one sex typically living longer than the other has long fascinated evolutionary biologists. Here, I seek to address fundamental questions about the genetic and environmental contributions to lifespan within an ultimate (evolutionary) framework that can facilitate further proximate (mechanistic) analysis. I conducted three empirical studies in Drosophila followed up by a Mendelian Randomization study in humans to determine genetic and environmental contributions to lifespan.
Sex differences in lifespan remain an intriguing puzzle in evolutionary biology. While explanations range from sex differences in selection to sex differences in the expression of recessive lifespan-altering mutations (via X-linkage), little consensus has been reached. One unresolved issue is the extent to which genetic influences on lifespan dimorphism are modulated by the environment. Here I took an experimental approach, manipulating multiple axes of social environment across inbred long- and short-lived genotypes and their reciprocal F1s in the fly Drosophila serrata. I show subtle but significant genotype dependent effects for social environment, but ultimately find the genetic contributions from the unguarded X hypothesis insufficient to fully explain sexual dimorphism in D. serrata lifespan.
With genetic components only explaining a portion of the response to lifespan, in my second chapter I assessed the evolutionary potential of lifespan in D. serrata in response to five different diets that varied systematically in their sugar (carbohydrate) to yeast (protein) content (S:Y). I also examined the developmental plasticity of lifespan to these novel diets, by raising a set of control lines in each diet. While there was a shared directionality in the response of lifespan to evolutionary diets in both sexes, the plastic responses of lifespan to developmental diets on the ancestral diet were quite sex-specific and bore little resemblance to the evolved lifespan responses.
Having found that diet elicited significant sex-specific evolutionary and plastic responses on the regulation of adult lifespan, in my third chapter I aimed to determine whether the evolved and plastic responses were conserved across variations in contemporary diets for both sexes. I employed a fully factorial design with twenty-five combinations of the five evolutionary and developmental diets used previously. I found the interaction between evolutionary and developmental diets for lifespan to provide evidence for a sex- and condition-dependent nature of diet-induced changes to lifespan.
There was support for positive carry-over effects of Dietary Restriction (DR) on low S:Y evolutionary diets, but this evolved response was not maintained under low S:Y developmental environments. Lifespan was maximised when evolutionary diets and developmental diets were matched to their ancestral diet, but typically reduced in other evolutionary-developmental diet combinations. In contrast to females, males demonstrated very little plasticity across almost all developmental diets, regardless of evolutionary diet background. These findings may bear relevance to the consequences of rapid changes in contemporary diets, and how these consequences might differ depending on the evolutionary history of the populations under consideration.
During evolutionary discordance, I found the energy derived from varying proportions of dietary macronutrients to have different outcomes on longevity. However, there is still a large gap between translating findings from model organisms to humans and consequently, the effects of macronutrient intake on lifespan in humans is still debated. In my final chapter, I used a two-sample Mendelian randomization (MR) design to determine whether the relative proportion of different dietary macronutrients has causal effects on longevity in humans. Genetic instruments were extracted from an existing GWAS of dietary macronutrient data in individuals of European ancestry, and associations of these variants with parental longevity were obtained using MR. Genetically predicted fat however was positively associated, and sugar consumption negatively associated with longevity. There was little evidence to support a significant association between carbohydrate or protein intake on longevity. However, given that for macronutrient status there are only a few genetic instruments currently available, this cannot be interpreted as an absence of causality.
Lifespan is clearly evolvable — likely a consequence of gene-environment interactions involving contrasting genetic contributions and variations in the strength of natural selection to shape mortality risk under different environmental conditions. While I have tackled several questions throughout my thesis, contributions of genetic background and environmental factors over evolutionary time is an ongoing area of research with much work needing to be done. A sex- and condition-dependant role for plasticity in shaping lifespan is also implicated in environmental associations on longevity phenotypes. Interpreting and connecting environmental conditions such as nutrition experienced by laboratory-based populations to populations outside the lab remains a challenge. Further research considering age and sex-specific effects of macronutrient intake quantity and quality is necessary to define the implications for health and lifespan. Whilst my thesis began to elucidate the evolutionary genetic architecture of heritable variation in lifespan, integrated evolutionary, epidemiological, and functional genomic-level investigations into genotype by environment contributions to ageing is only beginning. | en_GB |
