During normal ageing, the gradual loss of telomeric DNA in dividing somatic cells can contribute to replicative senescence, apoptosis, or neoplastic transformation. In the genetic disorder ...dyskeratosis congenita, telomere shortening is accelerated, and patients have premature onset of many age-related diseases and early death. We aimed to assess an association between telomere length and mortality in 143 normal unrelated individuals over the age of 60 years. Those with shorter telomeres in blood DNA had poorer survival, attributable in part to a 3·18-fold higher mortality rate from heart disease (95% CI 1·36–7·45, p=0·0079), and an 8·54-fold higher mortality rate from infectious disease (1·52–47·9, p=0·015). These results lend support to the hypothesis that telomere shortening in human beings contributes to mortality in many age-related diseases.
X-linked adrenoleukodystrophy (X-ALD) is a rare and often fatal progressive disease characterized by neurodegeneration and accumulation of very long-chain fatty acids (VLCFA). The gene responsible ...for X-ALD encodes a peroxisomal half ATP-binding-cassette transporter that carries VLCFAs and their acyl-CoA esters into peroxisomes where they are degraded by β-oxidation. Wide phenotypic variability is observed within kindreds segregating the same mutation; thus, environmental and/or genetic factors must act as disease modifiers. Previous studies had shown that the activity of Acyl-CoA synthetase, ACS, functioning upstream of the transporter in targeting VLCFAs for degradation is reduced in fibroblasts of X-ALD patients. Mutation of the bubblegum (bgm) Drosophila ACS results in an autosomal recessive neurodegenerative phenotype. bgm homozygotes exhibit impaired vision and a "bubbly" optic lobe, phenotypes attributed to a loss of nervous tissue. Accumulation of VLCFAs in bgm mutant animals raised the possibility of a link to X-ALD pathogenesis. However, bgm mutant flies recapitulate only some aspects of ALD, and the model is far from perfect. Current computational methods identify five additional ACS genes in Drosophila. One of these genes, double bubble ( dbb), a close homolog of bgm and thus of particular interest, was independently identified in our laboratory as a ventrally restricted transcript in an automated screen for transcriptionally regulated targets of signaling pathways. In the present study, we concentrate on these two homologous duplicated genes with the aim to analyze their functional relationship. We have demonstrated that dbb and bgm exhibit overlapping expression profiles and are co-regulated by the Dorsal pathway that is essential for specification of ventral cell fates during dorsoventral patterning in Drosophila embryos. We generated dbb and bgm dbb double mutant animals by homologous recombination. Amorphic mutations in bgm, dbb, or bgm dbb are homozygous viable, but exhibit optic love and retinal degeneration. We have shown that mutations in Drosophila ACSs lead to neuronal necrosis and VLCFA accumulation. Our analysis shows that the consequences of the double knockout in the fly are profound, providing the best evidence of an animal model for X-ALD to date. Our data indicate that ALD is a disease of lipid-rich cells, and that accumulation of fatty acids can lead to cell death in affected areas of the brain.
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