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 issue.] 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. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=26094