Mediating a host cell signaling pathway linked to the overwinter mortality offers a promising therapeutic approach for improving bee health

Overwintering mortality is the greatest threat to the supply of healthy bee colonies available for pollination of spring-blooming crops, but efforts to mitigate colony losses are hindered because underlying mechanisms remain poorly understood. In the present study, we identified that sirtuin signaling pathway is the most significantly affected pathway in collapsing overwintering colonies that carried a high prevalence of pathogens and is a convergent signaling hub that links mitochondrial dysfunction and metabolism alterations. We showed that the expression of SIRT1, a major sirtuin regulating energy and immune metabolism, was significantly downregulated in diseased overwintering bees and bees exposed to cold challenge alone. We demonstrated that activation of SIRT1 expression by SRT1720, a SIRT1 activator, could result in increased robustness and lifespan extension of cold-stressed bees. The novel information gained from this study provides a promising avenue for the development of therapeutic strategies for mitigating colony losses, both overwinter and annually. Overall design: The study is divided into four distinct phases. Phase I involved continuous pathogen screening of overwintering bees for four years. Phase II was where RNA-Seq transcriptional profiling of overwintering honey bee host responses to pathogenic infection was conducted. qRT-PCR was performed in Phase III to confirm the results of the differential expression analysis of transcriptome data of selected genes. Lastly, laboratory bioassays were conducted in Phase IV to measure the effects of cold challenges on bee survivorship and stress responses and to assess the effect of SRT1720, an activator of sirtuin 1 (Sirt1) which is a crucial modulator of energy and immune metabolism, on lifespan extension of cold-challenged honey bees.