The objective of this proposal is to validate a panel of proposed biomarkers of mammalian aging in animals supplied by the NIA/NCTR biomarker research colony.
The specific aims are to apply and evaluate six potential biomarkers as indexes of age- dependent changes in cell physiology in the Fischer 344 rat at 2, 6, 12, 18, 24 and 30 months of age. Ad libitum fed animals will be studied through age 24 months and dietary restricted rats will be studied through age 30 months. The biomarkers are: 1) plasma membrane Ca2+-ATPase ('calcium pump') activity in rat erythrocytes and its in vitro responsiveness to physiological concentrations of thyroid hormone; 2) cytoplasmic content (radioimmunoassay) of calmodulin, a calcium-binding regulatory protein in erythrocytes and dermal fibroblasts; 3) glycosylated hemoglobin content of erythrocytes (mini-ion exchange column); 4) plasma membrane glucose transport (glucose flux) activity in fat pad adipocytes and mononuclear cells; 5) responsiveness, in terms of glycosaminoglycan synthesis, or dermal fibroblasts in vitro to thyroid hormone, glucocorticoid and to various growth factors (epidermal growth factor, platelet-derived growth factor, insulin); 6) microalbuminuria (microgradient gel electrophoresis). Except for glucose flux studies, initial measurements of biomarkers will be followed at 1-to-3 month intervals by repeated assessment in order to estimate reproducibility and determine longitudinal changes in individual animals. Results from ad libitum fed animals will be compared with those from dietary restricted rats whose lifespans are extended. Susceptibility of the Fischer 344 rat to chronic nephropathy requires that glomerular filtration rat (GFR) be monitored and that putative aged-related changes in biomarkers be distinguished from the possible contribution to these measurements of decreased GFR. The collaborating investigators have published their own methods for each of these biomarkers with the exception of glycohemoglobin, and the applicant institution has established laminar flow caging in dedicated nonbarrier rooms in its animal colony for maintaining rodents previously raised in Specific Pathogen Free (SPF) barrier facilities. The advantages of the biomarkers proposed are their nonlethality, minimal invasiveness, relative simplicity and prospect for longitudinal application. Support currently exists for relevance to human aging of the proposed biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG007736-01
Application #
3118998
Study Section
Aging Review Committee (AGE)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Type
Schools of Medicine
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Bernardis, L L; Benedict, M R; Deziel, M R et al. (1996) Increased plasma IGF-1 levels but lack of changes in adipocyte glucose transport in weanling rats with dorsomedial hypothalamic nucleus lesions 1 year after lesion production. Physiol Behav 59:689-97
Rosenberg, D W; Drummond, G S; Smith, T J (1995) Depletion of cytochrome P-450 by thyroid hormone and cobalt-protoporphyrin IX in rat liver: evidence that susceptibility varies among forms of the heme protein. Pharmacology 51:254-62
Holt, P R; Higgins, P J; Atillasoy, E et al. (1995) Abnormal cell proliferation and p52/p35-CSK expression in the colons of aging rats. Exp Gerontol 30:495-503
Lawrence, W D; Deziel, M R; Davis, P J et al. (1993) Thyroid hormone stimulates release of calmodulin-enhancing activity from human erythrocyte membranes in vitro. Clin Sci (Lond) 84:217-23
Van Liew, J B; Davis, P J; Davis, F B et al. (1993) Effects of aging, diet, and sex on plasma glucose, fructosamine, and lipid concentrations in barrier-raised Fischer 344 rats. J Gerontol 48:B184-90
Hori, N; Hirotsu, I; Davis, P J et al. (1992) Long-term potentiation is lost in aged rats but preserved by calorie restriction. Neuroreport 3:1085-8
Van Liew, J B; Davis, F B; Davis, P J et al. (1992) Calorie restriction decreases microalbuminuria associated with aging in barrier-raised Fischer 344 rats. Am J Physiol 263:F554-61
Tzung, S P; Gaines, K C; Henderson, M et al. (1991) Isolation and characterization of a novel liver-derived immunoinhibitory factor. Hepatology 14:888-94
Davis, F B; Deziel, M R; Van Liew, J B et al. (1991) Effects of caloric restriction and aging on erythrocyte membrane Ca(2+)-ATPase activity in specific pathogen-free Fischer 344 rats. Metabolism 40:819-24
Smith, T J; Drummond, G S (1991) Retinoic acid can enhance the stimulation by thyroid hormone of heme oxygenase activity in the liver of thyroidectomized rats. Biochim Biophys Acta 1075:119-22

Showing the most recent 10 out of 12 publications