Normal human lifespan is marked by a complex series of developmental events, relative stability during adulthood, and ultimately a gradual decline in viability. Biological clocks presumably underlie the developmental events that occur through childhood and adolescence, but the nature of those clocks has remained obscure. Progess in this area would be of considerable importance, not only for our understanding of child development, but also because instability in putative clock-like mechanisms may occur as part of the aging process. Such instability could well compromise tissue function and contribute to many of the common degenerative diseases of later life.

We propose to investigate whether developmental clocks and related aspects of the aging process are attributable in part to age-related epigenome remodeling. Experiments done to date with cultured human fibroblasts derived from tissue banks provide tentative support for this hypothesis. To exclude tissue culture-related artifacts and to continue the work, it is essential to have access to fresh tissue material in the form of surgically obtained skin specimens that would otherwise be discarded.

Elective breast reduction mammoplasty is a frequently performed surgery at Suburban Hospital, Bethesda, Maryland. Small skin specimens will be obtained from this procedure, as well as from normal skin derived from mastectomies. Patients who are to undergo these procedures will be asked to sign a consent form allowing the specimens, normally discarded, to be used instead for research on the mechanism of aging. They will be informed that clinical information will accompany the specimens, including age and known disease conditions.

Twenty patients in each of two age ranges, 21-30 yr and 65-90 yr, will be enrolled in the study. The primary outcome will be confirmation of age-related epigenome change in the chromosome 4q35.2 region, previously documented using tissue bank-derived cultured skin fibroblasts. Mapping and sampling chromatin from this region revealed higher histone H4 acetylation in young (24-30 yr) than old (80-85 yr) individuals. Confirmation of this change in primary fibroblasts will be followed by more detailed mapping of chromatin structure and extension beyond the currently defined limits. Secondary outcomes will include examination of two areas of epigenome remodeling that appear to occur between birth and adulthood, as well as searches for additional regions of age-related chromatin change.