We hypothesize that oxidative stress contributes to the aging process. The oxidative stress stems from reactive intermediates of oxygen's reductive metabolism during aerobic metabolism and from cell exposure to oxygen in excess of the small amount required for respiration. We have shown that oxygen modulates the growth and lifespan of human fibroblasts under physiologic tensions. We want to determine whether, and for what reason, old cells are more vulnerable than young to oxidative stress. Differences in cellular response to a progressive oxidative stress will be sought between: a) cells early and late in their cultural lifespan; b) cells obtained from the skin of young and old individuals; c) tissue homogenates from the skin of young and old individuals. Human fibroblasts will be grown at partial pressures of oxygen ranging from 3-720mm Hg. To measure response to oxidative stress we will note changes in rate of growth, number of cells at confluence, cultural lifespan, Cr51 release and spontaneous tissue autoxidizability. to determine the biochemical response to oxidative stress we will isolate newly synthesized proteins and mRNA induced in response to alteration in oxygen tension. We will determine if oxidative stress impairs the ability of old cells to induce antioxidant protective enzymes or maintain cellular reducing potential. We will determine if addition of liposomes containing either antioxidant protective enzymes or their inhibitors can modify the cytotoxicity of oxygen and the cultural lifespan. Monitoring oxygen consumption, we will measure metabolic rate in young and old cells; determine the influence of metabolic rate on cultural lifespan; and ascertain whethere cultural atmosphere affects metabolic rate. We will determine if incubated samples of human skin differ with age in their endogenous antioxidant protective capability, as measured by the rate of formation of thiobarbituric acid reaction products. Direct comparison of cells aged in vivo and in vitro with their younger counterparts with respect to their ability to counter the cytotoxic effects should directly test the hypothesis that oxidative stress contributes to aging. Knowledge gained from these studies will enhance our understanding of the biology of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG004993-02
Application #
3115540
Study Section
Cellular Biology and Physiology Subcommittee 1 (CBY)
Project Start
1985-09-30
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1987-08-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Balin, Arthur K; Reimer, Richard J; Reenstra, Wende R et al. (2010) Effects of oxygen, growth state, and senescence on the antioxidant responses of WI-38 fibroblasts. Age (Dordr) 32:435-49
Allen, R G; Balin, Arthur K (2003) Effects of oxygen on the antioxidant responses of normal and transformed cells. Exp Cell Res 289:307-16
Balin, Arthur K; Pratt, Loretta (2002) Dilute povidone-iodine solutions inhibit human skin fibroblast growth. Dermatol Surg 28:210-4
Balin, Arthur K; Pratt, Loretta; Allen, R G (2002) Effects of ambient oxygen concentration on the growth and antioxidant defenses of of human cell cultures established from fetal and postnatal skin. Free Radic Biol Med 32:257-67
Balin, Arthur K; Fisher, Allan J; Anzelone, Michael et al. (2002) Effects of establishing cell cultures and cell culture conditions on the proliferative life span of human fibroblasts isolated from different tissues and donors of different ages. Exp Cell Res 274:275-87
Balin, Arthur K; Pratt, Loretta (2002) Oxygen modulates the growth of skin fibroblasts. In Vitro Cell Dev Biol Anim 38:305-10
Caldwell-Brown, D; Stern, R S; Lin, A N et al. (1992) Lack of efficacy of phenytoin in recessive dystrophic epidermolysis bullosa. Epidermolysis Bullosa Study Group. N Engl J Med 327:163-7
Horikoshi, T; Balin, A K; Carter, D M (1991) Effects of oxygen tension on the growth and pigmentation of normal human melanocytes. J Invest Dermatol 96:841-4
Balin, A K; Pratt, L A (1989) Physiological consequences of human skin aging. Cutis 43:431-6
Allen, R G; Balin, A K (1989) Oxidative influence on development and differentiation: an overview of a free radical theory of development. Free Radic Biol Med 6:631-61

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