X-Message-Number: 25743 Date: Tue, 1 Mar 2005 20:44:51 -0800 (PST) From: Doug Skrecky <> Subject: why dwarf mice live longer is under investigation J Gerontol A Biol Sci Med Sci. 2004 Dec;59(12):1244-50 Hormone-treated snell dwarf mice regain fertility but remain long lived and disease resistant. Snell dwarf mice have multiple hormonal deficits, but the way in which these deficits postpone aging are still uncertain. In this study, Snell dwarf mice received 11 weeks of growth hormone and thyroxine injections that increased their weight by approximately 45%, although they remained much smaller than controls. The hormone treatment also restored fertility to male dwarf mice. Despite these effects on growth and maturation, the hormone treatments did not diminish life span or lower the resistance of dwarf mice to cataracts and kidney disease. Administration of thyroxine in food throughout adult life did diminish longevity of Snell dwarf mice, although these mice remain longer lived than control animals. These results show that a 45% increase in body size does not impair longevity or disease resistance for dwarf mice of either sex, and that the exceptional longevity of Snell dwarf mice does not, at least for males, depend on prepubertal immaturity. Am J Physiol Endocrinol Metab. 2005 Feb 8; [Epub ahead of print] Fibroblast Cell Lines From Young Adult Mice of Long-Lived Mutant Strains Are Resistant to Multiple Forms of Stress. 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 hydrogen peroxide, cadmium, ultraviolet 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 hydrogen peroxide, paraquat, and UV but not to cadmium. Resistance to UV, cadmium, and hydrogen peroxide are similar in cells derived from one-week 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 anti-oxidant defenses: dwarf-derived cells are also resistant to the DNA-alklyating agent methyl methanesulfonate. Furthermore, inhibitor studies show that fibroblast resistance to UV light is unaffected by anti-oxidants 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. Endocrinology. 2005 Mar;146(3):1138-44. Epub 2004 Nov 24. Increased neurogenesis in dentate gyrus of long-lived ames dwarf mice. Neurogenesis occurs throughout adult life in the dentate gyrus of mammalian hippocampus and has been suggested to play an important role in cognitive function. Multiple trophic factors including IGF-I have been demonstrated to regulate hippocampal neurogenesis. Ames dwarf mice live considerably longer than normal animals and maintain physiological function at youthful levels, including cognitive function, despite a deficiency of circulating GH and IGF-I. Here we show an increase in numbers of newly generated cells [bromodeoxyuridine (BrdU) positive] and newborn neurons (neuronal nuclear antigen and BrdU positive) in the dentate gyrus of adult dwarf mice compared with normal mice using BrdU labeling. Despite the profound suppression of hippocampal GH expression, hippocampal IGF-I protein levels are up-regulated and the corresponding mRNAs are as high in Ames dwarf as in normal mice. Our results suggest that local/hippocampal IGF-I expression may have induced the increase in hippocampal neurogenesis, and increased neurogenesis might contribute to the maintenance of youthful levels of cognitive function during aging in these long-lived animals. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=25743