Aging and related diseases significantly affect the health and happiness index around the world. Cellular senescence is the basis of physiological aging and is closely related to various senile diseases. AMP-activated protein kinase (AMPK) is associated with both the regulation of cellular energy metabolism and the regulation of cellular senescence. Another set of proteins, sirtuins, has also been demonstrated to play an important role in cell senescence. However, it is not clear how AMPK and sirtuins coordinate to regulate cellular senescence. Herein, we summarized the role of AMPK and sirtuins in regulating metabolism, repairing DNA damage, and even prolonging human life. We have provided a detailed explanation of the clinical trials relating to the AMPK and sirtuins involved in aging. Systematically analyzing individual senescence genes and developing functional reference notes will aid in understanding the potential mechanisms underlying aging and identify therapeutic targets for both anti-aging interventions and age-related illnesses.