title: Collagenase-resistant collagen promotes mouse aging and vascular cell senescence.
abstract: 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 (Col1a1(r/r) ) that yields collagenase-resistant type I collagen. Compared with wild-type littermates, Col1a1(r/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 Col1a1(r/r) mice were susceptible to stress-induced senescence, displaying senescence-associated ß-galactosidase (SA-ßGal) activity and upregulated p16(INK4A) 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 Col1a1(r/r) or wild-type mice. This revealed that mutant collagen directly reduced replicative lifespan and increased stress-induced SA-ßGal activity, p16(INK4A) expression, and p21(CIP1) 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.
authors: Robarts Research Institute, Western University, London, ON, Canada; Departments of Medicine and Biochemistry, Western University, London, ON, Canada.
authors: Faran
authors: F
authors: Vafaie
authors: Hao
authors: H
authors: Yin
authors: Caroline
authors: C
authors: O'Neil
authors: Zengxuan
authors: Z
authors: Nong
authors: Alanna
authors: A
authors: Watson
authors: John-Michael
authors: JM
authors: Arpino
authors: Michael W A
authors: MW
authors: Chu
authors: David
authors: D
authors: Wayne Holdsworth
authors: Robert
authors: R
authors: Gros
authors: J Geoffrey
authors: JG
authors: Pickering
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology*; D016922:Cellular Senescence; D024042:Collagen Type I / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D017364:Collagenases / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D059748:Proteolysis / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D039302:Integrin alphaVbeta3; D000804:Angiotensin II; D017364:Collagenases
keywords: collagen; integrin; senescence; vascular smooth muscle
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