X-Message-Number: 26046 Date: Sun, 17 Apr 2005 22:42:55 -0700 (PDT) From: Doug Skrecky <> Subject: Caveolin-1 as a prime modulator of aging? [Caveolin-1 might be a "side issue", since caveolin-1 knockdown mice do not live longer. If one regards aging as a game of dominoes, it is easy to mix up causes with effects. As these aging dominoes fall down, it is diffcult to tell which domino is causing the others to fall down. My money is on caveolin-1 being far downstream from the really important dominoes, which cause the others to fall down.] Mech Ageing Dev. 2005 Jan;126(1):105-10. Caveolin-1 as a prime modulator of aging: a new modality for phenotypic restoration? Aging can be characterized by structural changes and functional deterioration during the lifetime, for which hundreds of explanations have been put forward. Recently, we have proposed the gate theory of aging, in which gatekeeper molecules at the membrane level would play the prime role in determining the senescent phenotype. Caveolin-1 would be a prime candidate for such a role as a major determinant of the aging process. Caveolin-1 can associate with a variety of molecules, involved in signal transduction, endocytosis and transcytosis, cytoskeletal arrangement, etc. The level of caveolin-1 is strictly regulated to maintain cellular integrity, leading to cellular transformation if depleted, and to the senescent phenotype if overexpressed. In case of senescent cells, the functional and physiological responses to the mitogenic stimuli can be restored and the morphological shape can be resumed by simple adjustment of caveolin-1 status. Therefore, it is suggested that prime modulator molecules, represented by caveolin-1, play a key role in determining the senescent phenotype, either as a physiological response or altered morphology. Mech Ageing Dev. 2005 May;126(5):551-9. Epub 2005 Jan 18. Increased caveolin-1, a cause for the declined adipogenic potential of senescent human mesenchymal stem cells. Mesenchymal stem cell (MSC) has drawn much attention in the aspect of tissue renewal and wound healing because of its multipotency. We initially observed that bone marrow-derived human MSCs (hMSCs) divided poorly and took flat and enlarged morphology after expanded in culture over a certain number of cell passage, which resembled characteristic features of senescent cells, well-studied in human diploid fibroblasts (HDFs). More interestingly, adipogenic differentiation potential of hMSCs sharply declined as they approached the end of their proliferative life span. In this study, altered hMSCs were verified to be senescent by their senescence-associated beta-galactosidase (SA-beta-gal) activity and the increased expression of cell cycle regulating proteins (p16(INK4a), p21(Waf1) and p53). Similar as in HDFs, basal phosphorylation level of ERK was also significantly increased in senescent hMSCs, implying altered signal paths commonly shared by the senescent cells. Insulin, a major component of adipogenesis inducing medium, did not phosphorylate ERK 1/2 more in senescent hMSCs after its addition whereas it did in young cells. In senescent hMSCs, we also found a significant increase of caveolin-1 expression, previously reported as a cause for the attenuated response to growth factors in senescent HDFs. When we overexpressed caveolin-1 in young hMSC, not only insulin signaling but also adipogenic differentiation was significantly suppressed with down-regulated PPARgamma2. These data indicate that loss of adipogenic differentiation potential in senescent hMSC is mediated by the over-expression of caveolin-1. J Biol Chem. 2004 Oct 1;279(40):42270-8. Epub 2004 Jul 19. Morphological adjustment of senescent cells by modulating caveolin-1 status. Morphological change is one of the cardinal features of the senescent phenotype; for example, senescent human diploid cells have a flat large shape. However, the mechanisms underlying such senescence-related morphological alterations have not been well studied. To investigate this situation, we characterized the senescence-dependent changes of cellular structural determinants in terms of their levels and activities. These determinants included integrins, focal adhesion complexes, and small Rho GTPases, and special emphasis was placed on their relationships with caveolin-1 status. We observed that the expression integrin beta(1) and focal adhesion kinase (FAK) were increased and that the phosphorylations of FAK and paxillin, hallmarks of focal adhesion formation, were also increased in senescent human diploid fibroblast cells. Moreover, the Rho GTPases Rac1 and Cdc42 were found to be highly activated in senescent cells. In addition, focal adhesion complexes and Rho GTPases were up-regulated in the caveolin-rich membrane domain in the senescent cells. Activated Rac1 and Cdc42 directly interacted with caveolin-1 in senescent cells. Interestingly, caveolin-1 knock-out senescent cells, achieved by using small interfering RNA and antisense oligonucleotide, showed disrupted focal adhesion formation and actin stress fibers via the inactivation of FAK, which resulted in morphological adjustment to the young cell-like small spindle shape. Based on the results obtained, we propose that caveolin-1 plays an important role in senescence-associated morphological changes by regulating focal adhesion kinase activity and actin stress fiber formation in the senescent cells. Neurobiol Aging. 2004 Jul;25(6):753-9. Increased caveolin-1 expression in Alzheimer's disease brain. Increasing evidence suggests that cholesterol plays a central role in the pathophysiology of Alzheimer's disease (AD). Caveolin is a cholesterol-binding membrane protein involved in cellular cholesterol transport. We investigated the changes in the protein amount of hippocampal caveolin of autopsy-confirmed AD and aged-matched control subjects. Our results demonstrate that caveolin protein levels in the hippocampus and caveolin mRNA in the frontal cortex are up-regulated in AD by approximately two-fold, compared to control brains. These results suggest a relationship between caveolin-1 expression levels and a dysregulation of cholesterol homeostasis at the plasma membrane of brain cells. In support of this hypothesis, a significant increase in caveolin protein levels has also been observed in hippocampal tissue from ApoE-deficient (knockout) and aged wild-type mice; two situations associated with modifications of transbilayer distribution of cholesterol in brain synaptic plasma membranes. These results indicate that caveolin over-expression is linked to alterations of cholesterol distribution in the plasma membrane of brain cells and are consistent with the notion of a deterioration of cholesterol homeostasis in AD. Biochemistry. 2003 Dec 30;42(51):15124-31. 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. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=26046