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Cellular energetics and mitochondrial uncoupling in canine aging

  • Justin W. NicholatosEmail author
  • Timothy M. Robinette
  • Saurabh V.P. Tata
  • Jennifer D. Yordy
  • Adam B. Francisco
  • Michael Platov
  • Tiffany K. Yeh
  • Olga R. Ilkayeva
  • Frank K. Huynh
  • Maxim Dokukin
  • Dmytro Volkov
  • Michael A. Weinstein
  • Adam R. Boyko
  • Richard A. Miller
  • Igor Sokolov
  • Matthew D. Hirschey
  • Sergiy LibertEmail author
Original Article

Abstract

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 β-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.

Keywords

Aging Dogs Mitochondria Uncoupling GWAS Primary cells 

Notes

Acknowledgements

J.W.N and J.D.Y thank Siri who is a good dog (12 out of 10). We also thank the NVIDIA Corporation for their donation of the Titan Xp GPU used in this work. Lastly, we thank the Cornell Veterinary Bank for primary canine fibroblast donations, as well as William Kohler and Melissa Han of the Miller lab for fibroblast preparations.

Author contributions

Conceptualization, J.W.N. and S.L. Formal analysis, J.W.N. Investigation, J.W.N., M.P., T.M.R., S.V.T., A.B.F., J.D.Y., T.K.Y., D.V., M.W., F.K.H., and O.R.I. Writing—original draft—J.W.N. Writing—review and editing—J.W.N., T.M.R., J.D.Y., T.K.Y., I.S., M.D.H., and S.L. Supervision, S.L. Funding acquisition, J.W.N. and S.L.

Funding information

S.L. and J.W.N. were in part supported by a grant from the American Federation for Aging Research (AFAR, grant no. 2015-030). S.L. received seed grant funding from the Cornell University Center for Vertebrate Genomics. J.W.N. was supported by a Glenn/AFAR Scholarship for Research in the Biology of Aging. R.A.M was supported by the National Institute of Health grant U19-AG023122. I.S. group was supported by the National Science Foundation grant CMMI 1435655.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11357_2019_62_MOESM1_ESM.docx (1.3 mb)
Supplemental File 1 Supplemental Figs. 1–4 & Methods. Fig. S1 Acylcarnitine profiles have strong predictive power for canine breed. Fig. S2 PCA plot for all metabolites. Fig. S3 Fibroblasts from long-lived dog breeds may have a more flexible cytoskeleton than those from short-lived. Fig. S4 IGF-1 expression in primary fibroblasts is not different across breeds. (DOCX 1285 kb)
11357_2019_62_MOESM2_ESM.xlsx (4.4 mb)
Supplemental File 2 Mass spectrometry raw data (XLSX 4537 kb)

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Copyright information

© American Aging Association 2019

Authors and Affiliations

  • Justin W. Nicholatos
    • 1
    Email author
  • Timothy M. Robinette
    • 1
  • Saurabh V.P. Tata
    • 1
  • Jennifer D. Yordy
    • 1
  • Adam B. Francisco
    • 1
  • Michael Platov
    • 1
  • Tiffany K. Yeh
    • 1
  • Olga R. Ilkayeva
    • 2
  • Frank K. Huynh
    • 2
  • Maxim Dokukin
    • 3
  • Dmytro Volkov
    • 3
  • Michael A. Weinstein
    • 4
  • Adam R. Boyko
    • 1
  • Richard A. Miller
    • 5
  • Igor Sokolov
    • 3
    • 4
  • Matthew D. Hirschey
    • 2
  • Sergiy Libert
    • 1
    Email author
  1. 1.Department of Biomedical SciencesCornell UniversityIthacaUSA
  2. 2.Duke Molecular Physiology Institute and Sarah W. Stedman Nutrition and Metabolism CenterDuke University Medical CenterDurhamUSA
  3. 3.Department of Mechanical EngineeringTufts UniversityMedfordUSA
  4. 4.Department of Biomedical EngineeringTufts UniversityMedfordUSA
  5. 5.Department of PathologyUniversity of MichiganAnn ArborUSA

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