The overall objective of this study is determine whether or not changes in immunes parameters, alone or in conjunction with changes in a ubiquitous cysteine protease inhibitor T-kininogen (T-KG) or in endogenous retrovirus expression, can be used as indicators of the """"""""physiologic age"""""""" of an individual. Cross-sectional studies accomplished during the first four years of this grant have demonstrated that genetic background has a significant impact on the level of each immunological markers assessed. However, in spite of this genetic diversity, four immunological parameters have been identified as possible candidates for biomarkers of aging based on that fact that they demonstrate similar age associated alterations in both Fischer 344 (F344) and Brown Norway (BN) rats and that their alterations are postponed by caloric restriction (CR). These parameters are ConA induced proliferation, and interferon (IFN) production and calcium ionophore (Cal) induced proliferation and IFN Production. Data indicate that expression of the ubiquitous cysteine T-KG is increased several months prior to .death in at least one strain of rat and that endogenous retrovirus expression is increased with age in three strains of mice. The proposed study will: 1. Longitudinally assess ConA induced proliferation and TFN production, Cal induced proliferation and IFN production, T-kininogen levels in plasma of three strains of rats and two strains of mice fed ad libitum (AL). Assessment will begin at 6 months of age, continue until death of the animals, and include equal numbers of males and females. 2. Determine the effect of long term CR on these five parameters by concurrent longitudinal assessment of similar numbers of CR rats and mice. 3. Perform cross-sectional studies on age, strain, gender and diet matched animals recently acquired from NCTR to confirm the data obtained during the initial granting period and to ascertain that environmental conditions are not influencing the longitudinal assessment. 4. Examine whether an association exists between any of these parameters and histopathology determined by autopsy. Results of these studies will definitively establish whether or not any of these parameters are candidates for further exploration as biomarkers in humans.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Biological and Clinical Aging Review Committee (BCA)
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Mcp Hahnemann University
Schools of Medicine
United States
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Acuna-Castillo, Claudio; Leiva-Salcedo, Elias; Gomez, Christian R et al. (2006) T-kininogen: a biomarker of aging in Fisher 344 rats with possible implications for the immune response. J Gerontol A Biol Sci Med Sci 61:641-9
Walter, R; Murasko, D M; Sierra, F (1998) T-kininogen is a biomarker of senescence in rats. Mech Ageing Dev 106:129-44
Goonewardene, I M; Murasko, D M (1995) Age-associated changes in mitogen-induced lymphoproliferation and lymphokine production in the long-lived brown-Norway rat: effect of caloric restriction. Mech Ageing Dev 83:103-16
Goonewardene, I M; Murasko, D M (1993) Age associated changes in mitogen induced proliferation and cytokine production by lymphocytes of the long-lived brown Norway rat. Mech Ageing Dev 71:199-212
Murasko, D M; Nelson, B J; Matour, D et al. (1991) Heterogeneity of changes in lymphoproliferative ability with increasing age. Exp Gerontol 26:269-79