Aging is associated with changes in the release of neurotransmitter substances from central and peripheral nerve terminals and in the secretion of hormones from glandular tissues. These alterations may underlie the functional deficits which are often noted during the aging process and suggest an age- associated alteration in the exocytotic process. Recent studies in a number of laboratories including our own, have described the involvement of protein kinase C-mediated phosphorylation in the modulation of stimulated release of biologic substances. In preliminary studies performed in Fisher-344 rats, we have found marked age-related deterioration in the ability of protein kinase C to modulate release of brain serotonin. In the present application, we propose to explore the responsiveness to protein kinase C activation of serotonin release in brain and blood platelets as (1) a biological marker of aging, and (2) a tool for assessing physiological aging during interventions which aim to improve longevity such as dietary restriction. Specifically, we propose to (1) precisely define the age dependency of the PKC effect in two strains of rats and their Fl hybrids, which have been fed ad libitum or were food restricted, (2) test the generalizability of the effect in other neurotransmitter systems, and (3) elucidate the molecular mechanisms which underlie the loss in protein kinase C mediated response. Understanding of the fundamental role of PKC in exocytosis and how it is altered during aging will be valuable as a biologic marker of aging and a tool for assessing potential interventions of the aging process. This biologic marker, when examined in blood platelets is easily accessible for use and testing in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG007700-04
Application #
3118920
Study Section
Aging Review Committee (AGE)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Wang, H Y; Bashore, T R; Tran, Z V et al. (2000) Age-related decreases in lymphocyte protein kinase C activity and translocation are reduced by aerobic fitness. J Gerontol A Biol Sci Med Sci 55:B545-51
Zhen, X; Uryu, K; Cai, G et al. (1999) Age-associated impairment in brain MAPK signal pathways and the effect of caloric restriction in Fischer 344 rats. J Gerontol A Biol Sci Med Sci 54:B539-48
Bhamre, S; Wang, H Y; Friedman, E (1998) Serotonin-mediated palmitoylation and depalmitoylation of G alpha proteins in rat brain cortical membranes. J Pharmacol Exp Ther 286:1482-9
Gurdal, H; Friedman, E; Johnson, M D et al. (1998) Decrease in apparent alpha1-adrenoceptor-G protein coupling during maturation in rat aorta. J Gerontol A Biol Sci Med Sci 53:B268-73
Gurdal, H; Seasholtz, T M; Wang, H Y et al. (1997) Role of G alpha q or G alpha o proteins in alpha 1-adrenoceptor subtype-mediated responses in Fischer 344 rat aorta. Mol Pharmacol 52:1064-70
Cai, G; Wang, H Y; Gao, E et al. (1997) Reduced adenosine A1 receptor and G alpha protein coupling in rat ventricular myocardium during aging. Circ Res 81:1065-71
Tilakaratne, N; Friedman, E (1996) Genomic responses to 5-HT1A or 5-HT2A/2C receptor activation is differentially regulated in four regions of rat brain. Eur J Pharmacol 307:211-7
Gurdal, H; Tilakaratne, N; Brown, R D et al. (1995) The expression of alpha 1 adrenoceptor subtypes changes with age in the rat aorta. J Pharmacol Exp Ther 275:1656-62
Undie, A S; Wang, H Y; Friedman, E (1995) Decreased phospholipase C-beta immunoreactivity, phosphoinositide metabolism, and protein kinase C activation in senescent F-344 rat brain. Neurobiol Aging 16:19-28
Gurdal, H; Friedman, E; Johnson, M D (1995) Effects of dietary restriction on the change in aortic alpha 1-adrenoceptor mediated responses during aging in Fischer 344 rats. J Gerontol A Biol Sci Med Sci 50:B67-71

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