Remaining Issues And Conclusion

Numerous questions remain concerning silencing mechanisms, some of which can be posed with specific reference to senescence. For example, do stress and developmental pathways overlap in a manner that links them to the silencing apparatus? If this is the case, activation of stress pathways might have broader consequences than heretofore considered. Heterochromatin-based structures appear to be very temperature sensitive in Drosophila. Is the same true for heterochromatin-mediated silencing in vertebrates? What, if anything, might this have to do with the temperature dependence of the life span in poikilothermic species, or even the slight hypothermia associated with dietary restriction? Ecdysone, a steroid hormone that regulates differentiation in Drosophila, influences HP1-dependent het-erochromatin during embryogenesis and the late stages of the third larval instar (67). How might hormonal and other environmental factors affect the formation of inherited chromatinic structures during mammalian development? Could this impact on subsequent risk patterns for cancer (e.g., adenocarcinoma in daughters of women treated with diethylstilbestrol during pregnancy [68]) or other age-related diseases? Variegation is a characteristic aspect of heritable silencing—and indeed, in at least one experimental model, the Avy/a mouse, variable epigenetic regulation of a retroviruslike element inserted near the agouti gene influences longevity (69). Could variegated silencing in human siblings, or even in identical twins, contribute to variation in life span? If so, this might lead to an overestimate of the importance of environmental factors in aging.

In sum, there are numerous facets to the study of senescence, including metabolic control and signaling pathways, oxidative stress and mitochondrial regulation, and DNA repair and chromosomal instability. Of these facets, the general notion of chromosomal instability is in some ways the most intriguing. Here, a case has been made that such instability can be extended to include higher order chromatin structures. Much work remains to be done to develop a more complete picture as to which types of heritable chromatinic domains are subject to age-related damage in, for example, various organisms, and tissues. Although no sim ple picture may emerge, one potential reward is linked to a special aspect of these structures; namely, their natural linkage to developmental programs that depend on epigenetic memory. This may provide a means to tie such programs to the plasticity of aging, as well as to understand how developmental inputs can be "imprinted" in a manner that influences patterns of age-related disease.

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