CELLULAR ENERGETICS IN THE CANINE MODEL OF AGING & SIRT6 AS A THERAPEUTIC TARGET FOR PARKINSON'S DISEASE

Abstract

PART 1: Dogs display exceptional lifespan variation across their many breeds, presenting an opportunity to discover longevity-determining traits. We performed a genome-wide association study on 4,169 canines representing 110 breeds and identified novel candidate longevity-genes controlling coat phenotypes, like hair length, and mitochondrial properties, suggesting that thermoregulation and bioenergetics contribute to lifespan variation. Using primary dermal fibroblasts, we investigated mitochondrial properties of short-lived (large) and long-lived (small) breeds. We found that cells from long-lived breeds have more uncoupled mitochondria and more efficient electron transport chains. Moreover, our data suggest that long-lived breeds have higher rates of catabolism and  oxidation, likely to meet elevated electron demand of their uncoupled mitochondria. Conversely, cells of short-lived (large) breeds accumulate amino acids and fatty acid derivatives, likely for biosynthesis and growth. The uncoupled metabolic profile of long-lived breeds likely stems from their smaller size, reduced volume to surface area ratio, and therefore a greater need for thermogenesis. Molecularly, the uncoupled energetics of long-lived breeds increases respiration, mitigates production of reactive oxygen species, and prevents stiffening of the actin-cytoskeleton, promoting cellular stress tolerance and survival. We propose that these cellular characteristics delay tissue dysfunction, disease, and death in long-lived dog breeds, contributing to canine aging diversity. PART 2: Parkinson’s disease is characterized by progressive death of dopaminergic neurons, leading to motor and cognitive dysfunction. Epidemiological studies consistently show that the use of tobacco reduces the risk of Parkinson’s. We report that nicotine reduces the abundance of SIRT6 in neurons and brain tissue by proteasome-mediated degradation. We find that reduction of SIRT6 is partly responsible for neuroprotection afforded by nicotine. Additionally, SIRT6 abundance is greater in Parkinson’s patient brains, and decreased in the brains of tobacco users. We also identify SNPs that promote SIRT6 expression and simultaneously associate with an increased risk of Parkinson’s. Furthermore, brain-specific SIRT6 knockout mice are protected from MPTP-induced Parkinson’s, while SIRT6 overexpressing mice develop more severe pathology. Our data suggest that SIRT6 plays a pathogenic and pro-inflammatory role in Parkinson’s and that nicotine can provide neuroprotection by accelerating its degradation. Inhibition of SIRT6 may be a promising strategy to ameliorate Parkinson’s and neurodegeneration.