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

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.

Brain ageing is a cause of cognitive decline and a major risk factor for neurodegenerative diseases. 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 and results in a robust extension of lifespan and healthspan. Changes in gene expression 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. This project will take advantage of next-generation sequencing technology to characterize the ageing transcriptome with exceptional resolution and provide new mechanistic insights about ageing and its underlying mechanisms. Transcripts differentially expressed with age in the rat brain and those whose differential expression with age is attenuated in long-lived animals will be identified. This will allow molecular biomarkers of brain ageing to be determined with outstanding precision. Alpha-lipoic acid (LA) was shown to induce a memory effect in rats switched from CR to Ad lib feeding: animals switching from CR to Ad lib maintained the extended longevity characteristic of CR while conversely animals switching from Ad lib to CR did not exhibit life-extension. 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, functions and processes specifically associated with the longevity effects of CR and with memory effects of 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.

Ageing is major biomedical challenge of the 21st century and research on the basic mechanisms of ageing has an unparalleled potential to improve quality of life and health (BMJ, 326, 1297-1299 (2003); BMJ, 337, a399 (2008)). The importance of biogerontology to the UK is recognized in the fact that ageing research is a strategic priority of the BBSRC. This project will provide new mechanistic clues about ageing and its modulation by diet. It will identify genes and processes involved in ageing and its manipulation by diet and thus contribute to improve quality of life, as detailed below. Because ageing is the biggest risk factor for several clinical conditions, no other biomedical field has so much potential to improve human health as research on the basic mechanisms of ageing and thus this project may have a profound social and economic impact. Who will benefit from this research? The insights gained by this project may benefit pharmaceutical companies by helping them focus on combinatorial sets of biomarkers of ageing to predict age-related pathology and by providing new foci of how diet can modulate ageing and health. Furthermore, this project will be of value in providing information to policy-makers involved in healthcare. How will they benefit from this research? In the long-term, it may be possible to translate the outcomes from this basic research project into medical research and help ameliorate age-related diseases and preserve health. As such, this project focuses on an area with a profound long-term impact on health. Given the social and economic consequences of the greying of the population (e.g., for healthcare and social security), this project may have a major long-term economic and social impact. Neurodegenerative diseases, like Alzheimer's and Parkinson's disease, are among the major health concerns of aging adults and are recognized as important targets of biomedical research. By focusing on brain ageing, this project has a huge potential to enhance quality of life and health. Furthermore, because this project will focus on dietary manipulations of ageing, it will be of value in providing information to policy-makers involved in healthcare regarding the influence of diet on ageing and health. What will be done to ensure that they benefit from this research? Dr de Magalhaes will be primarily responsible for managing and undertaking impact activities with the assistance of his research group and of the Corporate Communications Team (see below). Since 1997 that Dr de Magalhaes maintains a website dedicated to the biology of ageing (http://www.senescence.info). This website attracts roughly 7,000 unique users per month and serves to inform potential beneficiaries and the general public about ageing research and its impact. Dr de Magalhaes also maintains a group website (http://pcwww.liv.ac.uk/~aging/) to highlight results and publications. The University of Liverpool's Corporate Communications Team works closely with departments to promote their research. It works to ensure publicity enhances the reputation of the University of Liverpool as well as that of any partner institutions and funding councils involved. The team supports the Department's Outreach activity by enhancing web presence for the research, assisting with distilling complex scientific ideas into language which can be understood by the public, advertising events such as seminars, workshops and other dissemination events, engagement with the media, and enhancing the Department's presence in publications produced by the University.