Unveiling the AcSirt2-FOXO-Mitophagy Axis: Insights Into Mitochondrial Quality Control and Delayed Aging in Apis cerana

Abstract

Cellular senescence is closely associated with mitochondrial dysfunction. Sirtuin 2 (Sirt2), a member of the Sirtuin deacetylases family, plays a pivotal role in regulating energy metabolism and aging in mammals. However, its function in social insect aging remains unclear. Here, using the Eastern honey bee (Apis cerana) as a model, we demonstrate that the age-related downregulation of A. cerana Sirt2 (AcSirt2) in brain tissue is coupled with progressive mitochondrial damage, reactive oxygen species (ROS) accumulation, and a biphasic change in autophagy activity. Conversely, overexpression of AcSirt2 alleviates cellular senescence by promoting mitochondrial fusion/fission balance (via Mfn1, Mfn2, and Drp1), activating the PINK1/Parkin-mediated mitophagy pathway, improving mitochondrial integrity, reducing oxidative stress, and enhancing ATP production. In vivo, AcSirt2 knockdown shortens honey bee lifespan and impairs locomotor ability, whereas its activation reverses these aging phenotypes. Furthermore, we show that AcSirt2 interacts with the transcription factor FOXO and mediates its deacetylation. This study reveals for the first time that the AcSirt2-FOXO-mitophagy axis delays aging by maintaining mitochondrial homeostasis in a social insect, providing novel insights into the development of anti-aging strategies and the promotion of healthy beekeeping.