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Late-life voluntary wheel running reverses age-related aortic stiffness in mice: a translational model for studying mechanisms of exercise-mediated arterial de-stiffening

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Abstract

Aortic stiffening, assessed as pulse-wave velocity (PWV), increases with age and is an important antecedent to, and independent predictor of, cardiovascular diseases (CVD) and other clinical disorders of aging. Aerobic exercise promotes lower levels of aortic stiffness in older adults, but the underlying mechanisms are incompletely understood, largely due to inherent challenges of mechanistic studies of large elastic arteries in humans. Voluntary wheel running (VWR) is distinct among experimental animal exercise paradigms in that it allows investigation of the physiologic effects of aerobic training without potential confounding influences of aversive molecular signaling related to forced exercise. In this study, we investigated whether VWR in mice may be a suitable model for mechanistic studies (i.e., “reverse translation”) of the beneficial effects of exercise on arterial stiffness in humans. We found that 10 weeks of VWR in old mice (~ 28 months) reversed age-related elevations in aortic PWV assessed in vivo (Old VWR: 369 ± 19 vs. old sedentary: 439 ± 20 cm/s, P < 0.05). The de-stiffening effects of VWR were accompanied by normalization of age-related increases in ex vivo mechanical stiffness of aortic segments and aortic accumulation of collagen-I and advanced glycation end products, as well as lower levels of aortic superoxide and nitrotyrosine. Our results suggest that late-life VWR in mice recapitulates the aortic de-stiffening effects of exercise in humans and indicates important mechanistic roles for decreased oxidative stress and extracellular matrix remodeling. Therefore, VWR is a suitable model for further study of the mechanisms underlying beneficial effects of exercise on arterial stiffness.

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Data availability

The data generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgments

The authors would like to thank David Hutton and John Van Hecke for study assistance.

Funding

This work was supported by grants from the National Institutes of Health: AG000279, HL107120, and AG013038.

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Authors and Affiliations

  1. Department of Integrative Physiology, University of Colorado Boulder, 354 UCB, Boulder, CO, 80309, USA

    Rachel A. Gioscia-Ryan, Zachary S. Clayton, Jason S. Eng, Lawrence C. Johnson, Matthew J. Rossman, Melanie C. Zigler, Trent D. Evans & Douglas R. Seals

  2. Human Performance Laboratory, Ball State University, Muncie, IN, USA

    Bradley S. Fleenor

Authors
  1. Rachel A. Gioscia-Ryan
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  2. Zachary S. Clayton
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  3. Bradley S. Fleenor
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  4. Jason S. Eng
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  5. Lawrence C. Johnson
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  6. Matthew J. Rossman
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  7. Melanie C. Zigler
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  8. Trent D. Evans
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  9. Douglas R. Seals
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Contributions

Conception and design (RGR, BSF, MCZ, DRS); data collection (RGR, ZSC, JSE, LCJ, TDE); data analysis and interpretation (RGR, ZSC, BSF, JSE, LCJ, MJR, MCZ, DRS); manuscript writing (RGR, ZSC, DRS); figure development (RGR, ZSC, DRS); critical revision and final approval of manuscript (RGR, ZSC, BSF, JSE, LCJ, MJR, MCZ, TDE, DRS).

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Correspondence to Douglas R. Seals.

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Gioscia-Ryan, R.A., Clayton, Z.S., Fleenor, B.S. et al. Late-life voluntary wheel running reverses age-related aortic stiffness in mice: a translational model for studying mechanisms of exercise-mediated arterial de-stiffening. GeroScience 43, 423–432 (2021). https://doi.org/10.1007/s11357-020-00212-1

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