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

Abstract

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 H2O2are 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.

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…In agreement with the findings in lower eukaryotes, the activities of anti-oxidant enzymes superoxide dismutases and catalase are decreased in murine hepatocytes exposed to GH or IGF-I and in transgenic mice overexpressing GH (Brown-Borg and Rakoczy, 2000;Brown-Borg et al, 2002). In addition, cultured cells derived from long-lived mice with deficiencies in the GH/IGF-I axis are resistant to oxidative stress (H 2 O 2 , paraquat), UV, genotoxins (methylmethanesulfonate; MMS), heat and cadmium (Salmon et al, 2005;Murakami, 2006), even though they are cultured in standard medium, suggesting that some of the protective effects observed in long-lived organisms may be also due to epigenetic changes acquired during chronic exposure to reduced growth factors.…”

Hormonal regulation of longevity in mammals

“…Work by Murakami and coworkers (2003) exemplifies this idea well in showing that fibroblasts from the skin of longliving Snell dwarf mice are resistant to multiple forms of cellular stress including heat, paraquat, H2O2, UV light, and the toxic metal cadmium. This data is supported by similar work in the Ames mouse (Salmon et al, 2005).…”

Single-gene mutations and healthy ageing in mammals

“…Proliferative and anti-apoptotic actions of IGF-1 are believed to enhance the progression (and perhaps also initiation) of neoplastic disease, and tumours are the most common cause of death in laboratory mice. -Increased resistance of dermal fibroblasts to a variety of oxidative, cytotoxic and metabolic stresses in vitro [16,17], which in Snell dwarfs is combined with somewhat greater capacity for DNA base excision repair [18]. In Ames dwarfs, this is associated with increased activity of antioxidant enzymes [19] and increased in vivo resistance to paraquat, an agent producing oxidative stress, primarily in the lungs [20].…”