X-Message-Number: 27863
Date: Sat, 22 Apr 2006 14:08:38 -0700 (PDT)
From: Doug Skrecky <>
Subject: mammalian aging is different

[HDACs extends lifespan in drosophila flies. However HDACs exert a
harmful effect on human cells, probably because the biochemical basis of
aging is completely different between these two species.]

BMC Cell Biol. 2005 Oct 26;6:37.
HDACs and the senescent phenotype of WI-38 cells.
  BACKGROUND: Normal cells possess a limited proliferative life span
after which they enter a state of irreversible growth arrest. This
process, known as replicative senescence, is accompanied by changes in
gene expression that give rise to a variety of senescence-associated
phenotypes. It has been suggested that these gene expression changes
result in part from alterations in the histone acetylation
machinery. Here we examine the influence of HDAC inhibitors on the
expression of senescent markers in pre- and post-senescent WI-38
cells. RESULTS: Pre- and post-senescent WI-38 cells were treated
with the HDAC inhibitors butyrate or trichostatin A (TSA). Following HDAC
inhibitor treatment, pre-senescent cells increased p21WAF1 and
beta-galactosidase expression, assumed a flattened senescence-associated
morphology, and maintained a lower level of proteasome activity. These
alterations also occurred during normal replicative senescence of WI-38
cells, but were not accentuated further by HDAC inhibitors. We also found
that HDAC1 levels decline during normal replicative
senescence. CONCLUSION: Our findings indicate that HDACs impact numerous
phenotypic changes associated with cellular senescence. Reduced HDAC1
expression levels in senescent cells may be an important event in
mediating the transition to a senescent phenotype.

[The effect of sirtuins on yeast longevity and mouse cell longevity are
completely different.]

Cell Metab. 2005 Jul;2(1):67-76. Erratum in:
Cell Metab. 2006 Jan;3(1):75.
Mammalian SIRT1 limits replicative life span in response to chronic
genotoxic stress.
  The Saccharomyces cerevisiae chromatin silencing factor Sir2 suppresses
genomic instability and extends replicative life span. In contrast, we
find that mouse embryonic fibroblasts (MEFs) deficient for SIRT1, a
mammalian Sir2 homolog, have dramatically increased resistance to
replicative senescence. Extended replicative life span of SIRT1-deficient
MEFs correlates with enhanced proliferative capacity under conditions of
chronic, sublethal oxidative stress. In this context, SIRT1-deficient
cells fail to normally upregulate either the p19(ARF) senescence
regulator or its downstream target p53. However, upon acute DNA damage or
oncogene expression, SIRT1-deficient cells show normal p19(ARF) induction
and cell cycle arrest. Together, our findings demonstrate an unexpected
SIRT1 function in promoting replicative senescence in response to chronic
cellular stress and implicate p19(ARF) as a downstream effector in this
pathway.

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