X-Message-Number: 26094
Date: Tue, 26 Apr 2005 21:09:03 -0700 (PDT)
From: Doug Skrecky <>
Subject: ceroid, lipofuscin, beta-amyloid, plaque

[Call it the Garbage or even Gunk theory of aging. What toxins your body
can not get rid of will eventually kill it, seems at least superficially
to be reasonable. Plaque has been strongly implicated in cardiovascular
related mortality. Beta-amyloid gets the nod for Alzheimer's dementia.
Ditto for ceroid and macular degeneration. A component of lipofuscin
called ceramide has recently been identified as the keystone of that
signature event in human aging: menopause. The impact of accumulating gunk
on human maximum lifespan remains unknown. However it is doubtful if
large increases in lifespan would be possible, without addressing this

Neurobiol Dis. 2005 Jun-Jul;19(1-2):194-9
Cathepsin D-deficient Drosophila recapitulate the key features of
neuronal ceroid lipofuscinoses.
  Neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal storage
disorders characterized pathologically by neuronal accumulation of
autofluorescent storage material and neurodegeneration. An ovine NCL form
is caused by a recessive point mutation in the cathepsin D gene, which
encodes a lysosomal aspartyl protease. This mutation results in typical
NCL pathology with neurodegeneration and characteristic neuronal storage
material. We have generated a Drosophila NCL model by inactivating the
conserved Drosophila cathepsin D homolog. We report here that cathepsin D
mutant flies exhibit the key features of NCLs. They show progressive
neuronal accumulation of autofluorescent storage inclusions, which are
also positive for periodic acid Schiff and luxol fast blue stains.
Ultrastructurally, the storage material is composed of membrane-bound
granular electron-dense material, similar to the granular osmiophilic
deposits found in the human infantile and ovine congenital NCL forms. In
addition, cathepsin D mutant flies show modest age-dependent
neurodegeneration. Our results suggest that the metabolic pathway leading
to NCL pathology is highly conserved during evolution, and that
cathepsin D mutant flies can be used to study the pathogenesis of NCLs.

Ann N Y Acad Sci. 2002 Apr;959:57-65
Pigments in aging: an overview.
  Although during the normal aging process there are numerous pigmentary
changes, the best recognized are those of melanin and lipofuscin. Melanin
may increase (e.g., age spots, senile lentigo, or melanosis coli) or
decrease (e.g., graying of hair or ocular melanin) with age, while
lipofuscin (also called age pigment) always increases with age. In fact,
the time-dependent accumulation of lipofuscin in lysosomes of postmitotic
cells and some stable cells is the most consistent and phylogenetically
constant morphologic change of aging. This pigment displays a typical
autofluorescence (Ex: approximately 440; Em: approximately 600 nm),
sudanophilia, argyrophilia, PAS positiveness, and acid fastness. Advances
on its biogenesis, composition, evolution, and lysosomal degradation have
been hampered by the persistent confusion between lipofuscin and the
large family of ceroid pigments found in a variety of pathological
conditions, as evidenced by the frequent use of the hybrid term
lipofuscin/ceroid by investigators mainly working with in vitro systems
of disputable relevance to in vivo lipofuscinogenesis. While lipofuscin
and ceroid pigments may share some of their physicochemical
properties at one moment or another in their evolutions, these pigments
have different tissue distribution, rates of accumulation, origin of
their precursors, and lectin binding affinities. Although it is widely
believed that lipofuscin is a marker of oxidative stress, and that it can
be, therefore, modified by antioxidants and prooxidants, these assumptions
are mainly based on in vitro experiments and are not generally supported
by in vivo studies. Another common misconception is the belief that
lipofuscin can be extracted from tissues by lipid solvents and measured
spectrofluorometrically. These and other disturbing problems are reviewed
and discussed in this presentation.

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