PhD Student The University of Hong Kong Hong Kong, Hong Kong
Abstract: Aging is a multifaceted process modulated by an intricate network of molecular pathways. Sirtuin 6 (Sirt6), a member of the sirtuin protein family, is essential for maintaining genome stability, metabolic homeostasis, and regulating aging. Sirt6-deficient mice displayed significant reduction in lifespan, surviving no longer than 4 weeks of age. In this study, we address the knowledge gap surrounding the interplay between Sirt6 and HnRNP A1, a multifunctional RNA-binding protein implicated in cellular stress responses and aging. Our novel approach explores the hypothesis that haploinsufficiency of HnRNP A1 can rescue the severe aging phenotypes associated with Sirt6 deficiency. Our findings reveal that haploinsufficiency of HnRNP A1 significantly extends the lifespan of Sirt6 knockout (KO) mice, enabling them to survive beyond 200 days compared to the typical lifespan of less than 4 weeks observed in Sirt6 KO mice. Furthermore, HnRNP A1 haploinsufficiency rescues intestinal structure and restores the expression of intestinal stem cell markers LGR5 and DCAMKL1, which are otherwise downregulated in Sirt6 KO mice. These results suggest that HnRNP A1 heterozygosity serves as a compensatory mechanism, ameliorating the adverse phenotypic effects associated with Sirt6 deficiency. In addition, the loss of intestinal stem cells markers Lgr5 and Dcamk1 were highlighting a critical role for HnRNP A1 in mitigating Sirt6-related intestinal deterioration. These results suggest that HnRNP A1 heterozygosity serves as a compensatory mechanism, ameliorating the adverse phenotypic effects associated with Sirt6 deficiency. Our work advances the field by elucidating a potential molecular interaction between Sirt6 and HnRNP A1, providing insights into the compensatory pathways that modulate aging phenotypes. These findings could inform the development of novel therapeutic strategies targeting the Sirt6-HnRNP A1 axis to address age-related diseases and promote healthy aging.
