X-Message-Number: 26653
Date: Sun, 17 Jul 2005 12:42:37 -0700 (PDT)
From: Doug Skrecky <>
Subject: rodents can not be used to model human aging

[The results with P66(shc) differ sharply between humans and
rodents. This suggests a that great deal of caution must be
exercised when attempting to characterise human aging based
on experiments with rodents.]

Mech Ageing Dev. 2005 Aug;126(8):839-44. Epub 2005 Apr 8.
p66(shc) is highly expressed in fibroblasts from centenarians.
  p66(shc-/-) mice exhibit prolonged lifespan and increased
resistance to oxidative and hypoxic stress. To investigate p66(shc)
involvement in human longevity, p66(shc) mRNA and protein were
evaluated in fibroblasts from young people, elderly and centenarians,
exposed to oxidative or hypoxic stress. Unexpectedly, centenarians
showed the highest basal levels of p66(shc). Oxidative stress
induced p66(shc) in all samples. At variance, hypoxic stress caused
p66(shc) reduction only in cells from centenarians. These changes
occurred in absence of any modification of p66(shc) promoter
methylation pattern. Intriguingly, in cells from centenarians,
p66(shc) induction was affected by p53 codon 72 polymorphism. Thus,
cells from centenarians present a peculiar regulation of p66(shc),
suggesting that its role in mammalian longevity is more complex than
previously thought.

Trends Mol Med. 2003 May;9(5):206-10.
p66(Shc): at the crossroad of oxidative stress and the genetics of
aging.
  The biology of aging has been mysterious for centuries. Removal
of the p66(Shc) gene, which encodes an adaptor protein for cell
signaling, extends lifespan by approximately 30% in mice and confers
resistance to oxidative stress. The absence of p66(Shc) correlates
with reduced levels of apoptosis. Oxidants induce phosphorylation of
serine36 on p66(Shc), contributing to inactivation of members of the
Forkhead transcription factor family, some of which appear to regulate
the expression of antioxidant genes. The expression of p66(Shc) is
regulated by the methylation status of its promoter. This leads us to
hypothesize that increased methylation of the p66(Shc) promoter might
contribute to the absence of its expression and therefore extended
longevity in particular individuals.

Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2112-6. Epub 2003 Feb 5.
Deletion of the p66Shc longevity gene reduces systemic and tissue
oxidative stress, vascular cell apoptosis, and early atherogenesis
in mice fed a high-fat diet.
  Several experimental and clinical studies have shown that oxidized
low-density lipoprotein and oxidation-sensitive mechanisms are
central in the pathogenesis of vascular dysfunction and
atherogenesis. Here, we have used p66(Shc-/-) and WT mice to
investigate the effects of high-fat diet on both systemic and tissue
oxidative stress and the development of early vascular lesions. To
date, the p66(Shc-/-) mouse is the unique genetic model of increased
resistance to oxidative stress and prolonged life span in mammals.
Computer-assisted image analysis revealed that chronic 21% high-fat
treatment increased the aortic cumulative early lesion area by
approximately 21% in WT mice and only by 3% in p66(Shc-/-) mice.
Early lesions from p66(Shc-/-) mice had less content of
macrophage-derived foam cells and apoptotic vascular cells, in
comparison to the WT. Furthermore, in p66(Shc-/-) mice, but not WT
mice, we found a significant reduction of systemic and tissue
oxidative stress (assessed by isoprostanes, plasma low-density
lipoprotein oxidizability, and the formation of arterial
oxidation-specific epitopes). These results support the concept that
p66(Shc-/-) may play a pivotal role in controlling systemic oxidative
stress and vascular diseases. Therefore, p66(Shc) might represent a
molecular target for therapies against vascular diseases.

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