Aging is a nonadaptive process resulting from cumulative damage in cells, and
the genes that control oxidative or other damage may have an
effect on the timescale of the aging process. Insulin also has a role in the
modulation of longevity, mediated via one of the insulin-like growth factor 1
receptor (IGF1-R) signal transduction pathways. The Caenorhabditis elegans
IGF1-R homolog is known as DAF-2, and daf-2 signaling negatively
regulates
daf-16, a forkhead transcription factor controlling
expression of genes involved in metabolism and redox control. This gene has
multiple targets that could be involved in modulating the several functions of
the insulin-signaling pathway. In the May 16
Science, Ao-Lin Hsu and
colleagues at the
University of California, San Francisco, demonstrate that a molecule
important in modulating heat shock response also has a role in the control of
aging and that DAF-16 and the heat shock factor 1 (HSF-1) transcription factor
may work together to promote longevity (Science, 300:1142-1145, 2003).
Hsu et al. demonstrated by gene knockout, overexpression, and RNA inhibition
studies that, although HSF-1 functions in the DAF-2 (IGF-1) system and although
DAF-16 functions in the heat shock system, both proteins function independently
of each other. Using DNA microarrays, the authors found that the levels of
expression of various heat-induced genes, including four small heat shock (shsp)
genes, were markedly affected when either daf-2 or hsf-1 were
mutated or inhibited. The authors also demonstrated that each of these shsp
genes was necessary for increased longevity.
"The small heat-shock proteins also delay the onset of
polyglutamine-expansion protein aggregation, suggesting that these proteins
couple the normal aging process to this type of age-related disease. Because at
least some of these sHSPs are likely to be functionally redundant, together they
may make a substantial contribution to longevity," conclude the authors.
Links for this article
B.M. Burgering, G.J. Kops, "Cell cycle and death control: long live
Forkheads," Trends in Biochemical Sciences, 27:352-360, July 2002.
[PubMed Abstract]
S. Lee et al., "DAF-16 target genes that control C. elegans
life-span and metabolism," Science, 300:644-647, April 25, 2003.
[PubMed Abstract]
A-L. Hsu et al., "Regulation of aging and age-related disease by DAF-16
and heat shock factor," Science, 300:1142-1145, May 16, 2003.
http://www.sciencemag.org/
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