The aging brain and nutrition

Old age is the greatest risk factor for most neurodegenerative diseases. During recent decades, there have been major advances in understanding the biology of aging, and the development of nutritional interventions that delay aging including calorie restriction (CR) and intermittent fasting (IF), and chemicals that influence pathways linking nutrition and aging processes. CR influences brain aging in many animal models and recent findings suggest that dietary interventions can influence brain health and dementia in older humans. The role of individual macronutrients in brain aging also has been studied, with conflicting results about the effects of dietary protein, branch-chained amino acids, and carbohydrates. Chapter 1 is a general introduction which reviews these concepts and highlights the need for future research in macronutrient composition intake and cognitive health. Additionally, evaluation of behaviour and cognition in rodent models underpins mechanistic and interventional studies of brain aging and neurodegenerative diseases, especially dementia. Commonly used tests include the Morris water maze, Barnes maze, Novel object recognition, fear conditioning, radial arm water maze and Y maze. These tests each reflect some aspects of human memory including episodic memory, recognition memory, semantic memory, spatial memory and emotional memory. Although most interventional studies in rodent models of dementia have focused on pharmacological agents, there are an increasing number of studies that have evaluated nutritional interventions including caloric restriction, intermittent fasting and manipulation of macronutrients. Chapter 2 outlines the most commonly used behavioural tests used in the context of nutritional studies and their main mechanistic underpinnings. Calorie restriction (CR) is one of the most robust interventions to improve brain health, increase memory, and delay the onset of neurodegenerative disease in mice. It was recently reported that low-protein, high carbohydrate (LPHC) diets provided ad libitum (i.e. without CR) extended life and improved cardiometabolic health in mice, but it is not known whether LPHC diets would also be beneficial for brain health. Therefore, one of the primary purposes of the data and research in Chapter 3 is to explore the roles of low-protein, high-carbohydrate diets on brain aging and neurobiology in male and female mice and compare those diets to traditional 20% CR. Here, male and female mice subjected to 20% CR or provided with ad libitum access from weaning to one of three LPHC diets (%P:%C 5:75, 10:70, 15:65), or to a standard rearing diet (19:61). As expected, LPHC (notably 5% protein) and CR diets were both associated with improvements in glucose and insulin metabolism. Overall patterns of total gene expression in hippocampus differed between LPHC and CR diets, although there were similarities with respect to specific genes known to be associated with longevity, CR, cytokines and dendrite morphogenesis. There were also similarities between LPHC and CR in protein expression and activation of SIRT1, MTOR and PGC1α, however the effects varied by sex. CR and LPHC (5% protein) diets were associated with increased dendritic spine densities in dentate gyrus neurons, and although the results were modest and primarily seen in middle age, both diets led to improvements in performance in the Barnes Maze and Novel Object Recognition tests. The diets differed in their effects on hippocampus biology and varied by sex. However, several of the main findings provide the first evidence that ad-libitum LPHC diets confer similar benefits to traditional 20% CR by improving key neurobiological and histological markers of hippocampus health, while simultaneously improving memory on two cognitive-behavioural tasks. Furthermore, there is a link between increased branch-chain amino acid (BCAA) consumption and adverse health outcomes. However, the relationship between BCAA consumption and brain health is not yet known. Therefore, the data in Chapter 4 continues with the topic of nutrition, brain health and underlying cognitive processes, but focuses on BCAA consumption and mouse brain health. There is evidence to suggest that circulating branch-chain amino acids (BCAA) are partly responsible for adverse cardiometabolic effects in mice, partly by increasing hepatic mechanistic target of rapamycin (MTOR) activation. While it is generally accepted that increased dietary BCAA consumption results in adverse metabolic health outcomes in mice, there is a lack of knowledge of whether the result would be similar for brain health. To this end, this study investigated the effects of 4 isocaloric ad-libitum diets ranging in BCAA content (20%, 50%, 100%, or 200%) on markers of hippocampus health and cognitive function in mice. Biochemical analyses including nutrient sensing pathway protein expression, markers of hippocampus function and inflammation, total hippocampus RNA analysis, and cognitive behavioural memory tasks were performed. The results of the current study reveal that dietary BCAA consumption influences hippocampus biology and memory in mice. Elevated dietary BCAA intake may be harmful to hippocampus health; consequently, reducing BCAA consumption may mitigate some of those harmful effects. Chapter 5 explores the role of Sirtuin 1 (SIRT1) in the formation of fear conditioning memory in the hippocampus. SIRT1 is a NAD+-dependent enzyme that has important roles in many biological processes involved in aging, including cell growth and repair, inflammation, and energy regulation. SIRT1 is also implicated in brain health and may be important in the preservation of memory processes that deteriorate during aging. Here, the role was investigated of brain-associated SIRT1 expression in the acquisition of fear memory and anxiety related behaviour in mice at 45 and 65 weeks of age. Mice with brain-specific knock-out or overexpression of Sirt1 were assessed on a fear conditioning paradigm and elevated plus maze test to determine the role of SIRT1 in fear memory acquisition and anxiety related behaviour. While there were no differences among groups in anxiety related behaviour, mice lacking brain SIRT1 could not learn the fear conditioning paradigm during training, context, or cue phases. The results of the study indicate that SIRT1 expression in the brain is critical for the formation of fear memory in male mice but not anxiety related behaviour. Chapter 6 is a conclusion and general discussion. Given the growing recognition of the role of aging biology in dementia, these analyses and studies may provide a new approach for dietary interventions that optimize aging brain health and prevent dementia in older people. Dietary interventions have been shown to influence various behavioural tests and underlying neurobiology in rodents indicating that nutrition can influence brain aging and possibly prevent or reduce neurodegeneration in humans. Given the growing recognition of the role of aging biology in dementia, these analyses and studies may provide a new approach for dietary interventions that optimize aging brain health and prevent dementia in older people. Dietary interventions have been shown to influence various behavioural tests and underlying neurobiology in rodents indicating that nutrition can influence brain aging and possibly prevent or reduce neurodegeneration in humans