Autophagy is the process of cellular recycling, in which macromolecules and organelles are targeted for lysosomal degradation and the resulting metabolites are distributed back to the cell. Genetic analysis of aging in the nematode and other model organisms has identified many interventions that can influence lifespan, and autophagy has emerged as a common mechanism contributing to longevity. However, the role that specific sugars, recycled from the autolysosome by the Spin/Spns1 family of sugar transporters, play in mediating longevity has received very little attention. There are four Spinster/Spin orthologs in C. elegans. We have found that spin-1 is required for lifespan extension mediated by down-regulation of the target-of-rapamycin (TOR) pathway in worms, while spin-2 is required for lifespan extension in insulin receptor (daf-2) mutants. These data lead to our hypothesis that SPIN proteins mediate recycling of different cellular metabolites via autophagy and the requirement for these metabolites differs with the mechanism of lifespan extension. This hypothesis is supported by cross species rescue experiments. Homozygous spns1 mutation in zebrafish (zspns1) leads to developmental senescence associated with autolysosomal defects, while zspns1 haploinsufficiency leads to shortened lifespan in adulthood. We have determined that the zspns-1-mutant phenotype can be rescued by wild-type zspns1, Drosophila spin (dspin), human spns1 (hspns1) as well as worm spin-1 and spin-4, indicating that these proteins are functionally conserved and therefore have the capacity to transport the same substrate(s). Furthermore, we have determined that the sugar acid, glucuronic acid (GlucA), can be transported by hSpns1 in vitro, suggesting that this molecule is a potential substrate for worm SPIN-1 and SPIN-4, as well as zebrafish and human Spns1. Interestingly, neither worm spin-2 or spin-3 rescue the mutant fish phenotype indicating that these proteins likely have a different substrate preference. In this proposal we will further characterize the role of C. elegans spin genes in different models of lifespan extension. In parallel, we will identify the exact nature of their substrates and investigate the physiological relevance of candidate substrates, in order to provide a metabolic basis for the effects of SPIN proteins on different paradigms of lifespan extension. In addition to autophagic recycling of amino acids and lipids, we propose that recycling of specific sugars is also important in specifying the lifespan effects of a particular longevity intervention. The identification of these sugars will not only provide an opportunity to address whether they are causal in driving longevity, but will further define the importance of sugar recycling in the late stages of autophagy. This in turn is likely to have implications for lysosomal storage diseases, as well as cancer and age-related disease.
Autophagy, the process of cellular recycling, has emerged as a common feature of many longevity models in the nematode C. elegans. While amino acid and lipid recycling has been implicated in aging, the role of carbohydrate recycling is less well-defined. We hypothesize that recycling of specific sugars, derived from degradation of glycolipids during autophagy, by members of the Spin / Spinster family of transport proteins drives longevity in different models of lifespan extension.
| Gurkar, Aditi U; Robinson, Andria R; Cui, Yuxiang et al. (2018) Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging. Redox Biol 18:191-199 |
