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Description:
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Recent advances in molecular gerontology have provided important clues about the fundamental biology of the aging process including the role of oxidative stress and the genetic basis of longevity . Progressive accumulation of oxidative damage to macromolecules is thought to underlie the aging -associated decline in physiologic function characteristic of the senescent phenotype . Mitochondria are a major intracellular source of reactive oxygen species (ROS ) ; however , other organelles are also endogenous sources of oxyradicals and oxidants that can damage macromolecules . This investigation examines the relationship between aging and oxidative damage to ER resident proteins , which exist in a strongly oxidizing environment necessary for disulfide bond formation . In these studies , young and aged mouse liver homogenates were separated into enriched sub -cellular fractions , and the ER /mitochondrial fraction was resolved by 2 -dimensional gel electrophoresis and then assayed for oxidative damage as indicated by protein carbonylation . MALDI /TOF analysis and N -terminal sequencing of these proteins identified BiP /Grp78 , protein disulfide isomerase (PDI ) , and calreticulin as exhibiting a specific age -associated increase in carbonyl content . This increase in oxidative damage to critical ER proteins in aged liver strongly indicates an impairment in protein folding , disulfide cross -linking , and glycosylation which may significantly contribute to the functional decline observed in aging liver .
Providing evidence for the genetic basis of aging , several murine models demonstrate that longevity can be increased by mutations affecting endocrine signaling , particularly via the GH /IGF -1 axis . In this investigation of long -lived GH /IGF -1 -deficient mice , characteristic patterns of hepatic gene expression in Pit1dw /dwJ dwarf mice were revealed . Comparative microarray analysis of young and aged male livers was utilized to identify specific genes differentially expressed in Pit1dw /dwJ mice . Further examination of both male and female livers by real -time RT -PCR demonstrated striking transcriptional differences in Pit1dw /dwJ mice comprised of genes regulating cholesterol biosynthesis , fatty acid utilization , and lipoprotein metabolism . Affecting global energy homeostasis , this programmatic shift in hepatic expression may contribute to longevity by influencing bioenergetic and oxidative reactions occurring within mitochondria , ER , and peroxisomes . Intriguingly , these long -term patterns in metabolic gene expression in Pit1dw /dwJ livers mirror many transcriptional changes induced by caloric restriction and fasting , further implicating energy metabolism in longevity . |