SUMO wrestles with mitophagy to extend lifespan.

SUMOylation, a conserved protein post-translational modification that performs multiple functions including regulation of nuclear transport and transcription, is implicated in numerous biological processes including aging. RNAi knockdown of the sole SUMO gene, smo-1, in C elegans shortened lifespan, while overexpression in the intestine modestly increased lifespan. Smo-1 is required for mitochondrial fission in a tissue-specific manner. Fission, in turn, is needed for mitophagy to maintain mitochondrial homeostasis during aging. SUMOlyation affects DAF16, which can be directly SUMOylated, and SKN-1, the homolog of mammalian Nrf2. These regulators play key roles in maintaining mitochondrial homeostasis. However, given the modest effect of overexpressing smo-1 on lifespan enhancement and potential interference with other genes that can promote increased lifespan, caution is advised in the translation of this work based on C elegans. Although inhibitors of SUMOlyation have been developed for cancer and activators have been identified, broad-acting biochemical pathway modifiers such as SUMO are often suboptimal drug targets and may not be as promising for anti-aging applications as they may appear.