Graduation Year

2020

Document Type

Master's Thesis

Degree

Master of Science

Program

Biological Science

Partner Organization

Buck Institute for Research on Aging

Program Director

Meredith Protas, PhD

First Reader

Pankaj Kapahi, PhD

Second Reader

Ian Barr, PhD

Abstract

Reactive a-dicarbonyls (a-DC’s), such as methylglyoxal (MGO), are unavoidable metabolites generated during glycolysis that accumulate with age and have been linked with chronic age-related metabolic diseases such as Diabetes Mellitus. Diabetes Mellitus is generally characterized by peripheral neuropathy and sustained hyperglycemia. Chronic hyperglycemia leads to an increase in glycolysis and a downstream increase in reactive a-DC’s. The human body has a natural method of detoxifying these a-DC’s. Glycolytic cells have enzymes which can detoxify a-DC’s, but if overwhelmed, a-DC’s can accumulate and react non-enzymatically with proteins, lipids and DNA to yield a group of molecules called advanced glycation end-products (AGEs). A Caeonorhabditis elegans model, used to study the effects of a-DC accumulation, has paved the way for a study which has aimed to mitigate a-DC stress in a vertebrate model. Here we propose that the accumulation of AGEs in vivo enhances the likelihood of physiological phenotypes associated with age-related metabolic diseases such as diabetes. We propose that we are able to reduce metabolic disorder phenotypes, partly through activation of the conserved TRPA-1 ion channel, and the metabolic NAD+ salvage pathway, and rescue their pathological effects in a type II diabetic mouse model through drug interventions. Reconstituting the idea that AGEs are sufficient to cause adverse behavioral and physiological metabolic complications is necessary in establishing a novel target for drug treatment. Instituting a successful mouse model of drug-induced a-dicarbonyl detoxification could lead to human clinical trials for alternative diabetic treatments, and a reduction in secondary diabetic complications.

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