X-Message-Number: 27786
Date: Sun, 2 Apr 2006 10:17:23 -0700 (PDT)
From: Doug Skrecky <>
Subject: basis of aging may differ between drosophila and mammals

[There has been an unspoken assumption that the biochemical basis of
aging is similar in all animal species. This may be a false

Med Hypotheses. 2006;66(2):332-6. Epub 2005 Oct 5.
Histone-deacetylase inhibitors may accelerate the aging process in
stem cell-dependent mammals: stem cells, Ku70, and Drosophila at
the crossroads.
  The exact contribution of the sirtuin family of NAD+-dependent
histone deacetylases to longevity in metazoans is, at present, not
completely understood but nonetheless regarded as significant.
Despite the rapidly accreting evidence solidifying the role of
NAD+-dependent histone deacetylase activity in longevity-promoting
experimental interventions, the utility of histone-deacetylase
inhibitors in the management of a diverse group of oncologic
conditions draws question to the notion of universally beneficial
effects of experimental interventions designed to promote
deacetylase activity. The recent determination that overexpression
of any one of the seven human sirtuin deacetylases fails to extend
replicative lifespan in differentiated human cells calls attention
to the possibility of unforeseen complexity in the determinants of
human lifespan. Furthermore, inhibitors of histone deacetylases
have been shown to actually increase lifespan in Drosophila.
Delineation of the disparate effects of histone-deacetylase activity
in stem cells, progenitor cells, and fully differentiated cells may
confirm initial findings suggesting that histone-deacetylase
inhibitors push malignant cells towards terminal differentiation,
while simultaneously exerting a proliferative and differentiating
effect on normal stem cells. This effect may ultimately exert an
accelerating influence on the aging of the stem cell population and
consequently produce detrimental alterations in stem and progenitor
cell populations that compromise organismal-level longevity in
mammals, in contrast to findings in Drosophila. This opens the
possibility of a new side effect to a widely used chemotherapeutic,
as well as the possibility of the generation of novel experimental
systems that could leverage the putatively pro-aging influence of
histone-deacetylase inhibitors to explore aging.

Acta Biochim Biophys Sin (Shanghai) 2004 Sep;36(9):618-22.
Trichostatin A extends the lifespan of Drosophila melanogaster by
elevating hsp22 expression.
  The level of acetylation of histones in nucleosomes is related to
the longevity of yeast and animals. However, the mechanisms by which
acetylation and deacetylation affect longevity remain unclear. In
present study, we investigated the influence of histone acetylation
modification on the expression of hsp22 gene and the lifespan in
Drosophila melanogaster using histone deacetylase (HDAC) inhibitor
Trichostatin A (TSA). The results showed that TSA could extend the
lifespan of Drosophila melanogaster. Furthermore, TSA significantly
promoted the hsp22 gene transcription, and affected the chromatin
morphology at the locus of hsp22 gene along the polytene chromosome.
Present data implicate that TSA may affect the lifespan of Drosophila
through changing the level of histone acetylation and influencing
the expression of hsp22 gene that is related to aging.

Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):838-43. Epub 2002 Jan 15.
Life extension in Drosophila by feeding a drug.
  We report that feeding Drosophila throughout adulthood with
4-phenylbutyrate (PBA) can significantly increase lifespan, without
diminution of locomotor vigor, resistance to stress, or reproductive
ability. Treatment for a limited period, either early or late in
adult life, is also effective. Flies fed PBA show a global increase
in histone acetylation as well as a dramatically altered pattern of
gene expression, including induction or repression of numerous genes.
The delay in aging may result from the altered physiological state

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