Histologic disc alterations can reliably be graded based on the proposed classification system providing a morphologic framework for more sophisticated molecular biologic analyses of factors leading to age-related disc changes. Diminished blood supply to the intervertebral disc in the first half of the second life decade appears to initiate tissue breakdown.

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We immunohistochemically investigated the pattern of RAGE expression and NFkappaB translocation into the nucleus in 43 complete cross-sections of human lumbar intervertebral discs (neonatal-85 years) and compared this with the carboxymethyl-lysine (CML) modification of proteins as a marker for oxidative stress. No significant expression of RAGE, no obvious activation of NF-kappaB, and no deposition of CML-modified proteins were seen in fetal, juvenile, and young adolescent discs (until age of 13 years). In adults, 25-50% of nucleus pulposus cells were labeled for RAGE and activated NF-kappaB, which correlated well with the occurrence and extent of CML staining in the pericellular matrix. In the annulus fibrosus significantly lower values were seen than in the nucleus pulposus. In consequence, we provide evidence for activation of the NF-kappaB system in intervertebral discs in vivo, which correlates with accumulated oxidative stress and increases in age and disc degeneration. Oxidative stress (as monitored by CML modifications) may lead to RAGE activation and NF-kappaB translocation.

Abstract. The actual increase in the rate of malignant tumors has been ascribed to a higher life expectancy and the influence of various environmental factors. Herein, we present data on the frequency of malignant tumors in paleopathologically well-defined historic populations. Thereby, we looked for malignant growth affecting the skeleton in three study populations of 905 individuals that have been excavated from the necropoles of Thebes-West and Abydos, Upper Egypt covering the time period between 3200 and 500 BC and 2547 individuals that have been buried in a Southern German ossuary dating from between AD 1400 and 1800. The tissue preservation of both the Egyptian and Southern German material was excellent. All available specimens were subjected to a very careful macroscopic examination; isolated findings were also radiologically investigated. In parallel, anthropological data, such as gender and age at death, were recorded. We identified 5 cases of malignant tumors affecting the skeleton in the Egyptian material and 13 cases affecting the skeletal material from Southern Germany. In most instances, multiple osteolytic lesions with slight osteoblastic reaction are strongly suggestive for metastatic carcinoma. Few cases with poorly reactive osteolyses were most compatible with plasmacytoma. Relative tumor frequencies on an age-and sex-adjusted population basis (using a mathematic model of skeletal involvement of malignant tumors in a well-defined English study population from AD 1901 to 1905) indicated that the tumor rates were not statistically different between ancient Egyptian, the historical Southern German and the recent English reference population. These observations indicate that malignant tumors were present in spatially and temporarily different populations over the last 4000 years with an ageand gender-adjusted frequency not different from Western industrial populations of c. 100 years ago. Therefore, we conclude that the current rise in tumor frequencies in present populations is much more related to the higher life expectancy than primary environmental or genetic factors.

cal studies of the respiratory chain complexes in these and Defects of the respiratory chain are a typical feature of mitochondrial diseases and occur also during normal aging other tissues [11][12][13][14][15][16][17] have revealed that aging is an inhomogeneous process at the cellular level leading to randomly diswhere they have been described in postmitotic tissues. The present study addresses the question of defect expression in tributed defects of cytochrome-c-oxidase (complex IV of the respiratory chain) and to intercellular and interorgan differthe normal and cirrhotic liver. Randomly distributed defects of complex III (ubiquinone-cytochrome-c-oxidoreductase) and ences of the defect manifestation.Recently a decline of respiratory rates with age was also of complex IV (cytochrome-c-oxidase) of the respiratory chain have been detected with age-related increasing frequency both reported for the human liver 18 both for unstimulated (state 4) and adenosine diphosphate-stimulated respiration (state in normal and cirrhotic livers. No defects were present for complex II (succinate-dehydrogenase) and complex V (adeno-3). In the last few years molecular genetic studies have revealed that mutations of mitochondrial DNA (mtDNA) such sine triphosphate-synthase) and in liver cell carcinomas. Sixty-one of 107 normal livers (57%) showed defects of the as deletions, duplications, point mutations in transfer RNAs (tRNAs), and structural genes are involved in the pathogenerespiratory chain. The defects occurred in advanced age (over 50 years) in 87%. In contrast 50 of 64 cirrhotic livers (78%) sis of mitochondrial diseases. [19][20][21][22] Similar mutations also accumulate with age although at a lesser degree both in huhad defects and approximately 60% occurred after age 50. The defects were caused by a loss of enzyme protein involving mans 23-38 and in animals. [39][40][41][42][43][44][45][46][47] The present study reports on a random defect pattern of the respiratory chain in normal and both nuclearly and mitochondrially coded subunits. Ninetyfour percent of the defects (n Å 275) involved complex IV cirrhotic livers during aging underlining that aging occurs primarily at the individual cellular level and that similar selectively. In 4% selective defects of complex III were found and combined defects of both complexes occurred in only pathogenetic mechanisms are involved in postmitotic fixed muscular tissue and in liver. Although the random defect 2%. In situ hybridization and polymerase chain reaction (PCR) studies for the detection of the common deletion (4.977 bp) pattern favors a stochastic process, molecular genetic analyses failed to reveal a pathogenetic role of various mutations and of various point mutations of mitochondrial DNA (mtDNA) revealed no consistent molecular genetic abnormali-of mtDNA. Loss of respiratory chain function is a typical feature of normal livers and to the 8th decade in patients with cirrhosis. The mitochondrial diseases. 1-3 To a lesser degree respiratory chain tissue probes were stored fr...