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Fibroblast cell lines from young adult mice of long-lived mutant strains are resistant to multiple forms of stress

¹Cellular and Molecular Biology Graduate Program, University of Michigan School of Medicine, Ann Arbor, Michigan; ²Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky; ³Departments of Internal Medicine and Physiology, Geriatrics Research, Southern Illinois University, School of Medicine, Springfield, Illinois; ⁴Edison Biotechnology Institute and Department of Biomedical Sciences, Ohio University, Athens, Ohio; ⁵Department of Pathology, University of Michigan School of Medicine; and ⁶University of Michigan Geriatrics Center and Institute of Gerontology and the Ann Arbor Department of Veterans Affairs Medical Center, Ann Arbor Michigan

Submitted 7 December 2004 ; accepted in final form 2 February 2005

Previous studies have shown that dermal fibroblast cell lines derived from young adult mice of the long-lived Snell dwarf mutant stock are resistant, in vitro, to the cytotoxic effects of H₂O₂, cadmium, UV light, paraquat, and heat. We show here that similar resistance profiles are seen in fibroblast cells derived from a related mutant, the Ames dwarf mouse, and that cells from growth hormone receptor-null mice are resistant to H₂O₂, paraquat, and UV but not to cadmium. Resistance to UV light, cadmium, and H₂O₂ are similar in cells derived from 1-wk-old Snell dwarf or normal mice, and thus the resistance of cell lines derived from young adult donors reflects developmental processes, presumably hormone dependent, that take place in the first few months of life. The resistance of cells from Snell dwarf mice to these stresses does not reflect merely antioxidant defenses: dwarf-derived cells are also resistant to the DNA-alkylating agent methyl methanesulfonate. Furthermore, inhibitor studies show that fibroblast resistance to UV light is unaffected by the antioxidants ascorbic acid and N-acetyl-L-cysteine. These data suggest that postnatal exposure to altered levels of pituitary hormones leads to development of cellular resistance to oxidative and nonoxidative stressors, which are stable through many rounds of in vitro cell division and could contribute to the remarkable disease resistance of long-lived mutant mice.

oxidation; life span; Snell dwarf; aging; insulin-like growth factor I

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