title: Caveolin-1 null (-/-) mice show dramatic reductions in life span.
abstract: Caveolae are 50-100 nm flask-shaped invaginations of the plasma membrane found in most cell types. Caveolin-1 is the principal protein component of caveolae membranes in nonmuscle cells. The recent development of Cav-1-deficient mice has allowed investigators to study the in vivo functional role of caveolae in the context of a whole animal model, as these mice lack morphologically detectable caveolae membrane domains. Surprisingly, Cav-1 null mice are both viable and fertile. However, it remains unknown whether loss of caveolin-1 significantly affects the overall life span of these animals. To quantitatively determine whether loss of Cav-1 gene expression confers any survival disadvantages with increasing age, we generated a large cohort of mice (n = 180), consisting of Cav-1 wild-type (+/+) (n = 53), Cav-1 heterozygous (+/-) (n = 70), and Cav-1 knockout (-/-) (n = 57) animals, and monitored their long-term survival over a 2 year period. Here, we show that Cav-1 null (-/-) mice exhibit an approximately 50% reduction in life span, with major declines in viability occurring between 27 and 65 weeks of age. However, Cav-1 heterozygous (+/-) mice did not show any changes in long-term survival, indicating that loss of both Cav-1 alleles is required to mediate a reduction in life span. Mechanistically, these dramatic reductions in life span appear to be secondary to a combination of pulmonary fibrosis, pulmonary hypertension, and cardiac hypertrophy in Cav-1 null mice. Taken together, our results provide the first demonstration that loss of Cav-1 gene expression and caveolae organelles dramatically affects the long-term survival of an organism. In addition, aged Cav-1 null mice may provide a new animal model to study the pathogenesis and treatment of progressive hypertrophic cardiomyopathy and sudden cardiac death syndrome.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Alex W
authors.initials: AW
authors.lastname: Cohen
authors.forename: Philippe G
authors.initials: PG
authors.lastname: Frank
authors.forename: Babak
authors.initials: B
authors.lastname: Razani
authors.forename: Hyangkyu
authors.initials: H
authors.lastname: Lee
authors.forename: Terence M
authors.initials: TM
authors.lastname: Williams
authors.forename: Madhulika
authors.initials: M
authors.lastname: Chandra
authors.forename: Jamshid
authors.initials: J
authors.lastname: Shirani
authors.forename: Andrea P
authors.initials: AP
authors.lastname: De Souza
authors.forename: Baiyu
authors.initials: B
authors.lastname: Tang
authors.forename: Linda A
authors.initials: LA
authors.lastname: Jelicks
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Factor
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiss
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Tanowitz
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000473:pathology; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology; D008136:Longevity / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology; D016019:Survival Analysis
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins