Collagenase-resistant collagen promotes mouse aging and vascular cell senescence

Authors

  • Faran Vafaie,

    1. Robarts Research Institute, Western University, London, ON, Canada
    2. Departments of Medicine and Biochemistry, Western University, London, ON, Canada
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    • These authors contributed equally to the manuscript.

  • Hao Yin,

    1. Robarts Research Institute, Western University, London, ON, Canada
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    • These authors contributed equally to the manuscript.

  • Caroline O'Neil,

    1. Robarts Research Institute, Western University, London, ON, Canada
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  • Zengxuan Nong,

    1. Robarts Research Institute, Western University, London, ON, Canada
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  • Alanna Watson,

    1. Robarts Research Institute, Western University, London, ON, Canada
    2. Departments of Medicine and Biochemistry, Western University, London, ON, Canada
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  • John-Michael Arpino,

    1. Robarts Research Institute, Western University, London, ON, Canada
    2. Department of Medical Biophysics, Western University, London, ON, Canada
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  • Michael W. A. Chu,

    1. Department of Surgery, Western University, London, ON, Canada
    2. London Health Sciences Centre, London, ON, Canada
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  • David Wayne Holdsworth,

    1. Robarts Research Institute, Western University, London, ON, Canada
    2. Department of Medical Biophysics, Western University, London, ON, Canada
    3. Department of Surgery, Western University, London, ON, Canada
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  • Robert Gros,

    1. Robarts Research Institute, Western University, London, ON, Canada
    2. Department of Physiology and Pharmacology, Western University, London, ON, Canada
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  • J. Geoffrey Pickering

    Corresponding author
    1. Robarts Research Institute, Western University, London, ON, Canada
    2. Departments of Medicine and Biochemistry, Western University, London, ON, Canada
    3. Department of Medical Biophysics, Western University, London, ON, Canada
    4. London Health Sciences Centre, London, ON, Canada
    • Correspondence

      J. Geoffrey Pickering, MD, PhD, London Health Sciences Centre, 339 Windermere Road, London, ON, Canada N6A 5A5. Tel.: 519 663 3973; fax: 519 434 3278; e-mail: gpickering@robarts.ca

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Summary

Collagen fibrils become resistant to cleavage over time. We hypothesized that resistance to type I collagen proteolysis not only marks biological aging but also drives it. To test this, we followed mice with a targeted mutation (Col1a1r/r) that yields collagenase-resistant type I collagen. Compared with wild-type littermates, Col1a1r/r mice had a shortened lifespan and developed features of premature aging including kyphosis, weight loss, decreased bone mineral density, and hypertension. We also found that vascular smooth muscle cells (SMCs) in the aortic wall of Col1a1r/r mice were susceptible to stress-induced senescence, displaying senescence-associated ß-galactosidase (SA-ßGal) activity and upregulated p16INK4A in response to angiotensin II infusion. To elucidate the basis of this pro-aging effect, vascular SMCs from twelve patients undergoing coronary artery bypass surgery were cultured on collagen derived from Col1a1r/r or wild-type mice. This revealed that mutant collagen directly reduced replicative lifespan and increased stress-induced SA-ßGal activity, p16INK4A expression, and p21CIP1 expression. The pro-senescence effect of mutant collagen was blocked by vitronectin, a ligand for αvß3 integrin that is presented by denatured but not native collagen. Moreover, inhibition of αvß3 with echistatin or with αvß3-blocking antibody increased senescence of SMCs on wild-type collagen. These findings reveal a novel aging cascade whereby resistance to collagen cleavage accelerates cellular aging. This interplay between extracellular and cellular compartments could hasten mammalian aging and the progression of aging-related diseases.

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