# Regulation of autophagy‐mediated pathways by diet, physical activity, and sleep in Alzheimer's disease

## TL;DR

This paper reviews how diet, exercise, and sleep affect autophagy in Alzheimer's disease, highlighting lifestyle's role in brain health.

## Contribution

The paper systematically reviews lifestyle-autophagy links in Alzheimer's and identifies gaps in biomarkers and translational models.

## Key findings

- Diet, physical activity, and sleep modulate autophagy, a key process disrupted in Alzheimer's disease.
- Mouse models and traditional autophagy markers have limitations in translating findings to human Alzheimer's biology.
- Brain-specific biomarkers and improved study designs are needed to evaluate lifestyle interventions' impact on autophagy.

## Abstract

Alzheimer's disease (AD) is a progressive, age‐related, neurodegenerative disorder marked by cognitive decline, memory loss, and accumulation of amyloid beta (Aβ) plaques and tau tangles. A key feature of AD is impaired protein homeostasis, often driven by autophagy dysfunction. Autophagy, a cellular degradation and recycling process, plays a vital role in maintaining neuronal health and is increasingly recognized as a therapeutic target in AD. Lifestyle factors such as diet, physical activity, and sleep can positively influence autophagy and support cognitive function. Intermittent fasting (IF) and calorie restriction (CR) activate autophagy and promote longevity; physical activity enhances cerebral blood flow and neurotrophic signaling; and adequate sleep supports autophagic processes, while sleep deprivation disrupts them. However, excessive autophagy may be detrimental. Understanding how lifestyle modulates autophagy is essential for developing non‐pharmacological strategies to delay or prevent AD. This review explores the mechanistic links between autophagy and lifestyle interventions to support brain health in aging.

Lifestyle factors modulate autophagy in AD: Diet, physical activity, and sleep significantly influence autophagy, a key cellular process disrupted in AD. However, the exact mechanisms remain unclear, and effects can vary depending on intervention type, duration, and model organism.Autophagy is a dynamic and context‐dependent process: Autophagy fluctuates naturally with time of day, nutritional status, and physical activity. Both overactivation and impairment can be detrimental, underscoring the need for a balanced autophagic response to maintain cellular health.Current models and markers have limitations: Mouse models may not fully translate to human AD biology, and commonly used autophagy markers like LC3 and p62 can be misleading without complementary techniques. Emerging human‐relevant models such as brain organoids and induced pluripotent stem cell‐derived neurons may improve translational accuracy.Measuring brain autophagy remains a major challenge: There are no reliable biomarkers for monitoring autophagy in the human brain, complicating efforts to evaluate lifestyle interventions. Future research must focus on identifying dynamic, brain‐specific biomarkers, and safe thresholds for autophagy activation.Lifestyle interventions show promise but require rigorous study design: Despite being safe and accessible, lifestyle interventions face challenges in trial design, adherence, and interpretation due to their complex, multidomain nature. Well‐powered, long‐term studies are needed to evaluate their true impact on autophagy and AD prevention.

Lifestyle factors modulate autophagy in AD: Diet, physical activity, and sleep significantly influence autophagy, a key cellular process disrupted in AD. However, the exact mechanisms remain unclear, and effects can vary depending on intervention type, duration, and model organism.

Autophagy is a dynamic and context‐dependent process: Autophagy fluctuates naturally with time of day, nutritional status, and physical activity. Both overactivation and impairment can be detrimental, underscoring the need for a balanced autophagic response to maintain cellular health.

Current models and markers have limitations: Mouse models may not fully translate to human AD biology, and commonly used autophagy markers like LC3 and p62 can be misleading without complementary techniques. Emerging human‐relevant models such as brain organoids and induced pluripotent stem cell‐derived neurons may improve translational accuracy.

Measuring brain autophagy remains a major challenge: There are no reliable biomarkers for monitoring autophagy in the human brain, complicating efforts to evaluate lifestyle interventions. Future research must focus on identifying dynamic, brain‐specific biomarkers, and safe thresholds for autophagy activation.

Lifestyle interventions show promise but require rigorous study design: Despite being safe and accessible, lifestyle interventions face challenges in trial design, adherence, and interpretation due to their complex, multidomain nature. Well‐powered, long‐term studies are needed to evaluate their true impact on autophagy and AD prevention.