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4.7 - 15th January 1999


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The Immune-Endocrine Loop during Aging: Role of Growth Hormone and Insulin-Like Growth Factor-I.

Burgess W, Liu Q, Zhou J, Tang Q, Ozawa A, VanHoy R, Arkins S, Dantzer R, Kelley KW

Laboratory of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana, Ill., USA.

Neuroimmunomodulation 1999 Jan;6(1-2):56-68

Why a primary lymphoid organ such as the thymus involutes during aging remains a fundamental question in immunology. Aging is associated with a decrease in plasma growth hormone (somatotropin) and IGF-I, and this somatopause of aging suggests a connection between the neuroendocrine and immune systems. Several investigators have demonstrated that treatment with either growth hormone or IGF-I restores architecture of the involuted thymus gland by reversing the loss of immature cortical thymocytes and preventing the decline in thymulin synthesis that occurs in old or GH-deficient animals and humans. The proliferation, differentiation and functions of other components of the immune system, including T and B cells, macrophages and neutrophils, also demonstrate age-associated decrements that can be restored by IGF-I. Knowledge of the mechanism by which cytokines and hormones influence hematopoietic cells is critical to improving the health of aged individuals. Our laboratory has recently demonstrated that IGF-I prevents apoptosis in promyeloid cells, which subsequently permits these cells to differentiate into neutrophils. We also demonstrated that IL-4 acts much like IGF-I to promote survival of promyeloid cells and to activate the enzyme phosphatidylinositol 3'-kinase (PI 3-kinase). However, the receptors for IGF-I and IL-4 are completely different, with the intracellular beta chains of the IGF receptor possessing intrinsic tyrosine kinase activity and the alpha and gammac subunit of the heterodimeric IL-4 receptor utilizing the Janus kinase family of nonreceptor protein kinases to tyrosine phosphorylate downstream targets. Both receptors share many of the components of the PI 3-kinase signal transduction pathway, converging at the level of insulin receptor substrate-1 or insulin receptor subtrate-2 (formally known as 4PS, or IL-4 Phosphorylated Substrate). Our investigations with IGF-I and IL-4 suggest that PI 3-kinase inhibits apoptosis by maintaining high levels of the anti-apoptotic protein Bcl-2. The sharing of common activation molecules, despite vastly different protein structures of their receptors, forms a molecular explanation for the possibility of cross talk between IL-4 and IGF-I in regulating many of the events associated with hematopoietic differentiation, proliferation and survival.

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Protein metabolism in rats during long-term dietary restriction: influence of aging.

Felgines C, Savanovitch C, Farges MC, Cynober L, Vasson MP

Laboratory of Biochemistry, Molecular Biology and Nutrition, Pharmacy School, Clermont-Ferrand, France.

JPEN J Parenter Enteral Nutr 1999 Jan-Feb;23(1):32-7

BACKGROUND: Protein depletion is frequent in the elderly, but the underlying mechanisms are not yet fully understood. In particular, it is unknown whether there is a defect of adaptation to a restriction of food intake in the elderly. This study was performed to compare the effects of 6-week dietary restriction (DR) on protein metabolism in both adult and aged rats. METHODS: Adult (3-month-old) and aged (22-month-old) rats were acclimatized for 2 weeks and then fed a standard diet for 6 weeks, either ad libitum (control adult [C(Adult)] and aged [C(Aged)] rats) or with only 50% of the average intake of the second week of acclimatization (restricted adult [R(Adult)] and aged [R(Aged)] rats). Protein metabolism, in terms of tissue protein content, nitrogen balance, and 3-methylhistidine (3-MH) urinary excretion, was evaluated. RESULTS: C(Adult) rats gained 30.4% of initial weight, whereas the body weight (BW) of C(Aged) rats was maintained. DR induced a rapid decrease in BW during the first 2 weeks in R(Adult) rats, but afterward BW remained stable. In R(Aged) rats, BW loss was linear during the 6 weeks and significantly higher than for R(Adult) rats (p<.01). In both restricted groups, muscle protein content was moderately affected by DR, whereas DR induced a marked decrease in visceral protein content. Nitrogen balance was decreased by DR but stayed positive in R(Adult) rats, whereas it became null in R(Aged) rats. CONCLUSIONS: In terms of protein metabolism, aged rats adapted less efficiently than adult rats to a long-term dietary restriction.

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T-kininogen is a biomarker of senescence in rats.

Walter R, Murasko DM, Sierra F

Center for Gerontological Research, Allegheny University of the Health Sciences, Philadelphia, PA 19129, USA.

Mech Ageing Dev 1998 Dec 1;106(1-2):129-44

We have previously reported on the identification of T-kininogen (T-KG) as a gene whose expression is increased during senescence in male Sprague-Dawley (S-D) rats. Serum T-KG levels increase 2.5-4 months before the time of death for any given animal, irrespective of the actual age of the animal at the time of this event. Furthermore, dietary restriction (DR) delays, but does not prevent, the increase in serum T-KG levels. In the present study, we have assessed whether or not the age-related increase in T-KG is a common feature of senescence in other strains of rat. We have analyzed hepatic T-KG mRNA levels in male Fischer 344 rats (F344), as well as in male and female (Fischer 344 x Brown Norway)F1 rats (F1). In both of these strains, we observed a dramatic increase in hepatic T-KG mRNA levels when male rats approach senescence. The mRNA levels behave similarly in F1 and S-D rats, in that the increase occurs late in life, and it is either repressed or delayed by DR. In contrast, the increase in T-KG mRNA levels in F344 rats occurs earlier in life, and is not significantly affected by DR. Young female F1 rats fed ad libitum (AL) show a statistically significant (P = 0.0009) 2.6-fold higher level of T-KG mRNA, as compared to their male counterparts. Thus, while we still observe an age-related increase in this parameter in both AL and DR female F1 rats, the difference is statistically significant (P = 0.0001) only in DR animals. We conclude that the increase in T-KG gene expression is a common feature of senescence and that, at least in males of these commonly used rat strains, T-KG can be used as a reliable biomarker of aging. Since the increase in T-KG gene expression does not appear to correlate with inflammatory processes, and since different strains of animals succumb to different pathologies, these results further suggest that the increase in T-KG expression might be related to the process of aging per se, rather than to any given age-related pathology.

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