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Rel 3.1 - 28th February 1998

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The B-cell biology of aging.

Klinman NR, Kline GH

Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA. nklinman@scripps.edu

Immunol Rev 1997 Dec;160:103-114

Although both the number and responsiveness of peripheral B cells in aged mice remain relatively intact, there are dramatic changes in B-cell generation. Alterations in B-cell development include both a skewing of V-gene utilization, especially in cells responsive to phosphorylcholine, and a decrease in the generation of various developmental B-cell subsets. The altered representation of these subsets appears to be the consequence of two developmental blocks. The first developmental block occurs during the maturation of pro-B cells and is evidenced by a decrease in the number of pre-B cells. The second developmental block occurs at the earliest stage of sIg(+)-cell maturation (sIgMvery lo). Because of this block in B-cell maturation, in spite of a decrease in incoming pre-B cells, the number of sIgMvery lo cells appears to increase in aged mice. Additionally, the time of residence of cells within this maturational stage increases dramatically, while the proportion of cells in more mature (sIgMhi) stages of bone marrow development are decreased. In addition to the decreased number of maturing bone marrow B cells, the population of splenic B cells that represent recent bone marrow emigres (HSAvery hi) is markedly decreased. In the face of this decrease in newly emerging cells from the bone marrow, the population of mature splenic B cells is maintained by their increased longevity.

Psoralen photoactivation promotes morphological and functional changes in fibroblasts in vitro reminiscent of cellular senescence.

Herrmann G, Brenneisen P, Wlaschek M, Wenk J, Faisst K, Quel G, Hommel C, Goerz G, Ruzicka T, Krieg T, Sies H, Scharffetter-Kochanek K

J Cell Sci 1998;111(6):759-767

Premature aging of the skin is a prominent side effect of psoralen photoactivation, a treatment used widely for various skin disorders. The molecular mechanisms underlying premature aging upon psoralen photoactivation are as yet unknown. Here we show that treatment of fibroblasts with 8-methoxypsoralen (8-MOP) and subsequent ultraviolet A (UVA) irradiation resulted in a permanent switch of mitotic to stably postmitotic fibroblasts which acquired a high level of de novo expression of SA-ß-galactosidase, a marker for fibroblast senescence in vitro and in vivo. A single exposure of fibroblasts to 8-MOP/UVA resulted in a 5.8-fold up-regulation of two matrix-degrading enzymes, interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3), over a period of >120 days, while TIMP-1, the major inhibitor of MMP-1 and MMP-3, was only slightly induced. This imbalance between matrix-degrading metalloproteases and their inhibitor may lead to connective tissue damage, a hallmark of premature aging. Superoxide anion and hydrogen peroxide, but not singlet oxygen, were identified as important intermediates in the downstream signaling pathway leading to these complex fibroblast responses upon psoralen photoactivation. Collectively, the end phenotype induced upon psoralen photoactivation shares several criteria of senescent cells. In the absence of detailed molecular data on what constitutes normal aging, it is difficult to decide whether the changes reported here reflect mechanisms underlying normal cellular aging/senescence or rather produce a mimic of cellular aging/senescence by quite different pathways.

Biochemical parameters for the diagnosis of mitochondrial respiratory chain deficiency in humans, and their lack of age-related changes.

Chretien D, Gallego J, Barrientos A, Casademont J, Cardellach F, Munnich A, Rotig A, Rustin P

Unite de Recherches sur les Handicaps Genetiques de l'Enfant, INSERM U393, Hopital des Enfants-Malades, 149, rue de Sevres, 75743 Paris Cedex 15, France.

Biochem J 1998 Jan 15;329( Pt 2):249-254

It is now widely acknowledged that a large number of human diseases originate from respiratory-chain dysfunctions. Because the molecular bases of these diseases are still poorly known, a biochemical approach has to be used in the screening procedures for the diagnoses of these conditions. Assessment of respiratory-chain function in human samples faces several problems: (i) the small size of available samples, (ii) the determination of discriminating parameters, and (iii) the interfering factors, such as age and physical activity. The present study focuses on isolated mitochondria prepared from a minute amount (100-200 mg) of skeletal-muscle biopsies from 201 patients between 0 and 65 years. Whereas 42 patients presented an isolated complex (C)I, CII, CIII or CIV deficiency, no respiratory-chain dysfunction or indirect evidence for a mitochondrial disorder could be attested in 159 of these patients. In this reference group, there was little correlation between enzyme activities and age, whatever the age class considered, 0-3 or 0-65 years of age. However, a confident handling of data points was largely hampered by the marked scattering of enzyme activities measured in the reference population. Activity ratios between the various respiratory-chain complexes presenting a much reduced scattering may be considered as diagnostic tools. As to the effect of age, no correlation with any of the enzyme-activity ratios could be shown. Use of age-matched controls for the diagnosis of respiratory-chain disorders may therefore be avoided, enzyme-activity ratios being highly discriminating and age-independent parameters.

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