The impact of the interaction between SIRT1 and lifestyle factors on Alzheimer’s disease risk and related phenotypes

Author Identifier

mehrane mehramiz

Date of Award


Document Type

Thesis - ECU Access Only


Edith Cowan University

Degree Name

Doctor of Philosophy


School of Medical and Health Sciences

First Supervisor

Simon Laws

Second Supervisor

Stephanie Rainey-Smith

Third Supervisor

Tenielle Porter

Fourth Supervisor

Eleanor O'Brien


Background: Alzheimer’s Disease (AD) onset is 10-15 years before symptoms appear; therefore, the early detection of AD is critical. Literature shows the impact of genetics and environment on AD pathology; however, recently, attention has focused on potential interactions between genetic make-up and the environment. Silent information regulator-1 (protein, Sirt1; gene, SIRT1) contributes to a wide range of biological pathways, and its function depends on NAD+/NADH ratio which is influenced by lifestyle factors such as physical activity and sleeping habits; therefore, it appears that this gene might be a promising target for the study of gene and lifestyle interaction.

Aims: The aim of this thesis was to assess the impact of the SIRT1 gene, both independently and in interaction with modifiable lifestyle factors, on AD-related markers of brain health. We first studied the independent relationship between SIRT1 single nucleotide polymorphisms (SNPs) and DNA methylation and the aforementioned AD-related markers of brain health (Chapter 2). We then introduced sleep (Chapter 3) and physical activity (Chapter 4), to evaluate their interaction with SIRT1 SNPs and the subsequent modification of relationships with markers of brain health. In the final study (Chapter 5), SIRT1 gene expression levels were assessed and included in analyses examine whether it mediated any association between the exercise intervention and AD-related markers of brain health.

Methods: Data for Chapters 2 to 4 of the thesis were extracted from the Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL). Genetic and epigenetic data that covered the genetic region of the SIRT1 gene was extracted from the AIBL genetic datasets. Positron Emission Tomography (PET) coupled with amyloid-binding radioligands was used to determine neocortical A burden and cognitive composites, derived from a neuropsychological test battery, were calculated to assess cognitive performance. Participants also underwent magnetic resonance imaging (MRI) to calculate brain structure volumes. Genome-wide methylation data were available for a single time-point.

Sleep characteristics (Chapter 3) were determined via the Pittsburgh Sleep Quality Index (PSQI). Selfreported physical activity data described were determined via the International Physical Activity Questionnaire (IPAQ) (Chapter 4). Metabolic Equivalent of Tasks (METs) were used to produce a METminutes/week score as an indicator of physical activity volume.

Data for Chapter 5 were drawn from the Intense Physical Activity and Cognition (IPAC) Study; an exercise intervention study. Gene expression data were measured at baseline and at six months (immediately post-intervention) using RNA extracted from blood, and Taqman real-time PCR assays. Peak aerobic capacity (VO2peak) assessed via a cycling-based graded exercise test was used as a measure of cardiorespiratory fitness, whilst cognitive performance was assed via a comprehensive battery of neuropsychological tests.

Results Results showed that SIRT1 SNPs are differentially associated with AD phenotypes and that they moderate the association between brain A and AD-related markers of brain health (Chapter 2), between sleep and AD-related markers of brain health (Chapter 3), and between physical activity and AD-related markers of brain health (Chapter 4). We also found a significant difference between SIRT1 methylation across SNPs (Chapter 2). In Chapter 5, using data from an exercise intervention study (IPAC cohort), we also showed a moderation effect of SIRT1 SNPs on the relationship between change in SIRT1 gene expression and change in AD-related markers of brain health.

Conclusions This thesis highlights the impact of genetic variation in SIRT1 on AD-related markers of brain health, as well as providing evidence to support individualised response, based on SIRT1 genotype, to lifestyle factors in relation to AD-related markers of brain health. Together the findings of this thesis provides further evidence to support the investigation of gene dependent effects of lifestyle changes with the view towards the potential development of individualised lifestyle interventions and advice.



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