Autophagy, a critical cellular degradation process, is pivotal in maintaining neuronal homeostasis and combating age-related brain decline. Understanding autophagy’s contribution to brain longevity is essential as global aging populations increase. This chapter explores the mechanisms of autophagy and its decline in aging, linking impaired autophagic flux to the accumulation of toxic proteins such as amyloid-beta and alpha-synuclein, which drive neurodegenerative diseases like Alzheimer’s and Parkinson’s. Recent advances in therapeutic strategies, including pharmacological agents (e.g., rapamycin, metformin), natural compounds (e.g., resveratrol, trehalose), and lifestyle interventions (caloric restriction, exercise) are reviewed for their potential to enhance autophagy and mitigate neurodegeneration. Challenges in clinical translation and future directions for targeted autophagy modulation are discussed, emphasizing the need for balanced approaches to preserve neuronal health and cognitive function in aging populations.