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.

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