Using massive-scale mRNA sequencing to unravel the mechanisms of ageing and its modulation by diet

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Elucidating the causal mechanisms of ageing is one of the most pertinent scientific questions of our time. Brain ageing in particular is a major health concern of ageing adults. It is a cause of cognitive decline and a major risk factor for neurodegenerative diseases like Alzheimer's and Parkinson's disease. A major tool available to researchers studying the mechanisms of ageing is caloric restriction (CR) which consists of restricting the normal (Ad lib) food intake of organisms. In different model organisms, including mammals, CR results in a robust extension of lifespan and preservation of health. In rodents, CR has been shown to delay brain ageing. Changes in gene expression levels are associated with many biological processes, cellular responses and disease states. Although several gene expression studies of ageing and CR have been conducted using microarrays, elucidating the transcriptional features of ageing remains a critical challenge. Microarrays have important limitations, for example in terms of low sensitivity to low abundance transcripts. In order to unravel transcriptional networks of ageing and of dietary interventions that modulate ageing, it is necessary to obtain a global view of gene expression changes under ageing and CR. This project will take advantage of next-generation sequencing technology to characterize the ageing gene expression changes with exceptional resolution and provide new mechanistic insights about ageing and its modulation by diet. Genes differentially expressed with age in the rat brain and those whose differential expression with age is attenuated in longer-lived animals will be identified. This will allow molecular biomarkers of brain ageing to be determined with outstanding precision. Alpha-lipoic acid (LA) was recently shown to induce a memory effect in rats switched from CR to Ad lib feeding: animals switching from CR to Ad lib feeding maintained the extended longevity characteristic of CR while conversely animals switching from Ad lib to CR did not exhibit extended longevity. Because LA preserves the longevity benefits of CR animals switched to Ad lib, transcripts identified in these different dietary conditions will be triangulated to identify those transcripts specifically associated with the longevity effects of CR with the memory effects of LA. This will provide insights into the genetic and molecular mechanisms of CR and LA. In conclusion, by employing samples from animals with varying longevity, these studies will provide important mechanistic insights about ageing and its modulation by diet.