4.4 Article

Cellular energetics and mitochondrial uncoupling in canine aging

Journal

GEROSCIENCE
Volume 41, Issue 2, Pages 229-242

Publisher

SPRINGER
DOI: 10.1007/s11357-019-00062-6

Keywords

Aging; Dogs; Mitochondria; Uncoupling; GWAS; Primary cells

Funding

  1. American Federation for Aging Research (AFAR) [2015-030]
  2. Cornell University Center for Vertebrate Genomics
  3. Glenn/AFAR Scholarship for Research in the Biology of Aging
  4. National Institute of Health [U19-AG023122]
  5. National Science Foundation [CMMI 1435655]

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The first domesticated companion animal, the dog, is currently represented by over 190 unique breeds. Across these numerous breeds, dogs have exceptional variation in lifespan (inversely correlated with body size), presenting an opportunity to discover longevity-determining traits. We performed a genome-wide association study on 4169 canines representing 110 breeds and identified novel candidate regulators of longevity. Interestingly, known functions within the identified genes included control of coat phenotypes such as hair length, as well as mitochondrial properties, suggesting that thermoregulation and mitochondrial bioenergetics play a role in lifespan variation. Using primary dermal fibroblasts, we investigated mitochondrial properties of short-lived (large) and long-lived (small) dog breeds. We found that cells from long-lived breeds have more uncoupled mitochondria, less electron escape, greater respiration, and capacity for respiration. Moreover, our data suggest that long-lived breeds have higher rates of catabolism and -oxidation, likely to meet elevated respiration and electron demand of their uncoupled mitochondria. Conversely, cells of short-lived (large) breeds may accumulate amino acids and fatty acid derivatives, which are likely used for biosynthesis and growth. We hypothesize that 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. The uncoupled energetics of long-lived breeds lowers reactive oxygen species levels, promotes cellular stress tolerance, and may even prevent stiffening of the actin cytoskeleton. We propose that these cellular characteristics delay tissue dysfunction, disease, and death in long-lived dog breeds, contributing to canine aging diversity.

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