THE ROLE OF SIRT1 IN AGEING AND FRAILTY

Abstract

Ageing and old age are major determinants of disease and disability, therefore an important challenge is to increase our understanding of ageing biology and strategies that delay ageing. Studies on ageing in animal models have revealed that a class of proteins known as Sirtuins influences ageing and the response of ageing to nutritional interventions such as caloric restriction. However, the role of sirtuins in human ageing and longevity remains unclear. Hence the intention of this thesis was to investigate the role of sirtuins, particularly SIRT1, in human ageing, longevity and age-related outcomes. This research studied participants in the Concord Health and Ageing in Men Project (CHAMP). CHAMP is a prospective observational cohort study addressing a wide range of aged-related health issues in older Australian men. To understand and explore the role of SIRT1 in older men, two blood-based assays were utilized. The first was the serum-induced SIRT1 expression bioassay which reflects circulating factors that influence SIRT1 expression and has been shown to be elevated in animals and humans undergoing caloric restriction. This phenotypic approach was used to determine: The relationship of serum-induced SIRT1 expression with age, frailty and longevity in the CHAMP participants. The relationship of serum-induced SIRT1 expression with nutritional and body composition biomarkers. The second approach was a genotypic assay to ascertain SIRT1 gene polymorphisms to determine: The associations of SIRT1 gene polymorphisms with age, frailty, survival and age-related diseases. Whether there are any correlations between the SIRT1 gene polymorphisms and markers of nutrition and body composition, and the serum-induced SIRT1 expression assay. Serum-induced SIRT1 expression was not associated with age or survival. Serum-induced SIRT1 expression was not significantly different between frail, prefrail and robust men, however subjects with lowest quintile of serum-induced SIRT1 expression were more likely to be robust and less likely to be frail. Serum-induced SIRT1 expression was associated with some markers of body composition: height, weight, whole body fat, body mass, whole body percent fat and whole body percent lean. Serum-induced SIRT1 expression was significantly associated with some nutritional and haematological markers in ageing: calcium, phosphate, albumin, potassium, urea, ALT, haemoglobin, platelets, cholesterol and LDL. Serum-induced SIRT1 expression levels tended to be greater in all age-related disease states, although this was only statistically significant for osteoporosis. The results suggest that serum-induced SIRT1 expression reflects nutritional status, with diseases, frailty, and caloric restriction all associated with reduced nutritional intake and hence, greater levels of circulating factors that induce SIRT1 expression. The findings of the studies of the SIRT1 gene polymorphisms were somewhat similar to those seen in the serum-induced SIRT1 expression assay. SIRT1 polymorphisms rs2273773, rs3740051 and rs3758391 showed no association with age, frailty and survival. However, these SNPs were associated with weight, height, BMI and body fat, body lean and albumin, suggesting an association between SIRT1 polymorphisms and nutritional and body composition factors. There were some associations between SIRT1 SNPs and age-related diseases: SIRT1 SNPs rs3740051 and rs3758391 were associated with arthritis; rs3758391 was also associated with heart attacks and deafness; and rs2273773 was associated with the MMSE. All three SNPs were associated with a history of smoking. The statistical significance of these associations are limited by multiple comparisons. There was no association between any of the SIRT1 SNPs and the serum-induced SIRT1 assay. In this thesis, a comprehensive study of sirtuins and their links to human ageing, age-related disease and nutrition is presented. The study links basic biology of ageing with broader medical and epidemiological aspects of ageing. These results may contribute to the development of strategies based on SIRT1 pathways that impact on ageing; improving the health of older men and the extension of healthy lifespan in humans.