These authors contributed equally to the manuscript.
Collagenase-resistant collagen promotes mouse aging and vascular cell senescence
Article first published online: 19 SEP 2013
© 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 13, Issue 1, pages 121–130, February 2014
How to Cite
Vafaie, F., Yin, H., O'Neil, C., Nong, Z., Watson, A., Arpino, J.-M., Chu, M. W. A., Wayne Holdsworth, D., Gros, R. and Pickering, J. G. (2014), Collagenase-resistant collagen promotes mouse aging and vascular cell senescence. Aging Cell, 13: 121–130. doi: 10.1111/acel.12155
- Issue published online: 16 JAN 2014
- Article first published online: 19 SEP 2013
- Accepted manuscript online: 19 AUG 2013 10:23PM EST
- Manuscript Accepted: 13 AUG 2013
- Canadian Institutes of Health Research. Grant Numbers: FRN-11715, FRN-126148
- Heart and Stroke Foundation of Canada. Grant Number: T7081
- vascular smooth muscle
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.