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

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.

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