Caveolin-1 null (-/-) mice show dramatic reductions in life span.
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.
Park
David S
DS
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cohen
Alex W
AW
Frank
Philippe G
PG
Razani
Babak
B
Lee
Hyangkyu
H
Williams
Terence M
TM
Chandra
Madhulika
M
Shirani
Jamshid
J
De Souza
Andrea P
AP
Tang
Baiyu
B
Jelicks
Linda A
LA
Factor
Stephen M
SM
Weiss
Louis M
LM
Tanowitz
Herbert B
HB
Lisanti
Michael P
MP
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
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins