The role of advanced glycation end products in modulating healthspan using C. elegans

Buck Institute For Research On Aging, Novato CA

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Abstract

Summary Aging and hyperglycemia results in an accumulation of a series of reactive ?-dicarbonyl compounds (?-DCs, e.g. glyoxal/GO, methylglyoxal/MGO, 3-deoxyglucosone/3DG) and ?-DC-derived metabolites, called advanced glycation end products (AGEs). AGEs form due to the reaction of ?-DCs with proteins, lipids, and DNA causing cellular stress linked with specific age-related processes, diabetic complications and neurodegeneration. Therefore, preventing ?-DC and AGE buildup is of quintessential importance for slowing aging and limiting the progression of various age-related diseases. A major bottleneck in understanding the biochemistry behind the progression of these complications, and hence rapid drug development, is the lack of genetically tractable models that can recapitulate the effects of ?-DC and AGE accumulation in a short time frame. To that end, we have established a Caenorhabditis elegans model based on an impaired glyoxalase gene to study ?-DC and AGE-related pathologies. These animals exhibit several phenotypes reminiscent of diabetic complications, such as accumulation of MGO and AGEs, and hyperesthesia (or hyper sensitivity to touch), within two weeks of adulthood. Most interestingly they demonstrate increased age-related neuronal damage and shortened lifespan. Using this model we have identified a critical role for TRPA-1, a transient receptor potential (TRP) channel in sensing MGO and activating Nrf2 (Nuclear factor erythroid-2 like 2, or NFE2L2) to counteract the effects of AGEs. A preliminary drug screen using this model has resulted in 2 promising compounds that can ameliorate AGE-related pathologies in C. elegans through TRPA-1/SKN-1 activation. We propose to use C. elegans as an invertebrate model to study the effects of AGE accumulation within two weeks which can take years to develop in humans, to allow rapid discovery of genetic and pharmacological targets relevant to aging and age-related diseases where AGEs play an important role. In this proposal we will: 1) Characterize the role of TRPA-1/ SKN-1 both genetically and pharmacologically in detoxifying MGO; 2) Characterize the glyoxalases downstream of SKN-1 that mediate detoxification of ?-DCs like MGO and 3) examine the conservation of the TRPA-1/SKN-1 pathway in detoxifying MGO in mammals using human neuronal cells. Together these aims will help to decipher the ?-DC detoxification network and identify therapeutic targets and novel compounds that can mitigate diabetic complications and extend healthspan of diabetics.