Intermittent fasting as a therapeutic strategy for alzheimer’s disease: behavioral and molecular evidence

Abstract

Intermittent fasting (IF) has emerged as a promising non-pharmacological intervention to improve brain health and mitigate neurodegenerative disease progression. Alzheimer’s disease (AD) is characterized by impaired metabolic functions that disrupt neuronal function and contribute to cognitive decline in aging populations. This dissertation examines IF as a therapeutic strategy for AD, focusing on behavioral parameters and molecular evidence. Chapter 1 provides a thorough review of the current literature from human and animal studies examining the impact of IF on brain health, brain aging, and neurodegenerative pathology with a particular focus on AD. Chapter 2 is an experiment into the effects of IF in young male and female rats, in which male IF feeding patterns resulted in lower body mass and lower mTOR expression in the cortex. The female IF feeding pattern, however, did not result in shifts in body mass or mTOR expression. This led to the next experiment (Chapter 3), which further explored the sex-specific adaptations observed in Chapter 2. Chapter 3 sought to determine IF-induced body composition shifts and metabolic adaptations. The animals maintained the same IF feeding patterns and mTOR cortical expression as in Chapter 2 and now we confirmed that IF did not induce differences in body composition in either males or females. Building on these findings, Chapter 4 sought to determine how IF-induced neuroprotective mechanisms influence the aged brain. Brain inflammation (via TNF alpha) was lower in aged IF females but not in males. Protein synthesis (via mTOR) remained unchanged following IF intervention. These results indicate that in aging brains, the benefits of acute IF may be driven by its anti-inflammatory effect rather than by modulation of the mTOR pathway. Chapter 5 evaluates the effects of IF in the transgenic AD model (TgF344-AD rats), focusing on cognitive functions and brain inflammation. IF attenuates neuroinflammation in AD brains. These findings highlight the potential of IF as a non-pharmacological intervention to attenuate AD-related behavioral deficits and neuroinflammation. Collectively, these findings may provide insight into translating IF into clinical strategies aimed at preserving cognitive functions, reducing the prevalence of AD and improving the quality of life.