Grant: Project Grant

Aging is associated with multimorbidity, the presence of 3 or more concurrent diseases, and this is an enormous burden for our modern societies. Multimorbidity increases exponentially with age, and therefore in our aging societies there is a urgent need to identify pathways and drugs that could promote healthy aging, without necessarily prolonging lifespan. Currently, there is no single medication that prevents age-associated diseases and it is highly desirable to develop such single treatment to tackle the root causes for these comorbidities, rather than treating diseases individually. Our current knowledge suggests that the age-associated diseases are due to multiple alterations, in particular in the metabolism of glucose in organs and the damage of various tissues by highly reactive "glycating compounds". These glycating compounds are produced in aging cells from glucose in excess. Therefore, diversion of some of the glucose entering the aging cells, away from pathways that can produce toxic compounds, should be beneficial. We recently discovered an enzyme called glycerol 3-phosphate phosphatase (G3PP) and found that it is able to divert part of the excess glucose in the cells to a less dangerous substance, glycerol, away from the formation of toxic glucose-derived compounds. We named this newly identified process of glucose to glycerol conversion by G3PP, "Glycerol shunt". Employing a model of worm, we recently found that enhanced activity of G3PP promotes healthy aging of the animal and protects from glucotoxicity. Mutations in G3PP were found in centenarians. We now propose that the glycerol shunt orchestrated by G3PP can be harnessed for healthy aging and the prevention of damage by glycation. We plan to test this by enhancing the activity of G3PP in the worm and mouse models and also in human liver slices. Results from these studies should identify novel approaches to prevent and treat age-related metabolic diseases, as well as promote healthy aging.