Grant: Doctoral: Vanier Canada Graduate Scholarships

Hutchinson Gilford-Progeria Syndrome (HGPS) is a rare premature aging disease affecting 1 in 4 million live births. Children with HGPS exhibit parallel but highly accelerated features of aging, including; hair loss, loss of fat deposits under the skin, arthritis and brittle bones. These children usually succumb to heart attack or stroke at ~14 years of age. HGPS is caused by a mutation in the laminA/C gene, generating the toxic protein Progerin. Progerin accumulates within the cell, disrupting the function and organization of the patient's genetic material (the genome), causing cells to become "old" (senescent) at a faster rate. No effective therapeutic strategies exist for the treatment of HGPS; however, the immunosuppressant rapamycin has been reported to stimulate Progerin degradation. Although promising, potential severe side effects of rapamycin have generated concern over its use as a treatment for HGPS. The aim of this project is to explore alternative treatment strategies that promote Progerin degradation and restoration of normal genome function and organization. Depletion of the essential amino acids leucine and arginine, glucose restriction as well as treatment with the anti-diabetic drug metformin function similarly to rapamycin but with fewer side effects. As metformin is already used to treat type 2 diabetes and is safe in humans, it is a logical choice as a potential HGPS treatment. The aim of this proposed research is to determine if depleted levels of amino acids/glucose or metformin can: 1) stimulate Progerin degradation, 2) decrease rates of cellular senescence and 3) re-establish normal function and organization of the genome within HGPS cells. These findings will not only provide alternative treatment strategies for patients with HGPS, but also -as increased levels of Progerin have been detected in aged cells from healthy humans-provide novel understanding of the underlying biological processes of aging.