Dissecting out the mechanisms to longevity through eating less

We are currently in the midst of a revolution in ageing research, with several dietary, genetic and pharmacological interventions now known to modulate ageing in model organisms. Whilst it has been known for almost 100 years that dietary restriction (DR) extends lifespan across wide evolutionary distances, the mechanisms through which it acts are still unknown. Using three different recombinant inbred ILSXISS mouse strains, which vary in response to DR; from lifespan extension to lifespan shortening, my PhD has sought to identify the mechanisms involved in DR-induced lifespan extension. Ultimately by exploiting the genetic heterogeneity of these mouse strains may help identify the mechanisms through which DR acts to slow ageing. During my PhD I (1) examined how these animals respond metabolically to DR, (2) determined the impact of DR on mitochondrial function, as mitochondrial dysfunction is a well characterised hallmark of ageing, and DR is known to attenuate age-related mitochondrial dysfunction, and (3) investigated proteostasis in these mice using isotopic labelling. A number of metabolic changes were found to be important to lifespan extension with DR, namely maintenance of gonadal white adipose tissue (WAT) stores and increases in brown adipose tissue (BAT). Conversely, large losses of WAT was associated with lifespan truncation following 40% long-term DR. Surprisingly, enhanced glucose homeostasis was not found to be a prerequisite to lifespan extension with DR. Hepatic mitochondrial dysfunction associated with reduced lifespan of TejJ114 mice under 40% DR, but similar dysfunction was not apparent in skeletal muscle mitochondria, highlighting tissue-specific differences in the mitochondrial response in ILSXISS mice to DR. Increased proteostasis as measured by the newprotein/newDNA ratio, was increased following short-term DR, highlighting increased synthesis of cytoplasmic proteins in the skeletal muscle as important to DR-induced lifespan extension, however results were both tissue and protein specific. The evidence produced in this thesis strongly suggests that numerous aspects of metabolism and mitochondrial function are associated with lifespan shortening, and that the inability for metabolic adaptability may be detrimental to lifespan. This thesis helps to elucidate the impact of genotype on key hallmarks of DR and highlights the importance of utilising both genders and genetically heterogeneous murine strains in order to understand the shared features of slowed ageing