Epigenetics in the Aging Process
|ClinicalTrials.gov Identifier: NCT00242255|
Recruitment Status : Completed
First Posted : October 19, 2005
Last Update Posted : July 16, 2018
This study will examine the role of epigenetics (heritable changes in gene function that occur without a change in DNA sequence) in the aging process. DNA is the primary genetic material, responsible for transmitting information from one cell to the next or from one generation to the next. A second layer of heredity is described by the term "epigenetics."
Epigenetic information is reset from one generation to the next. It works in two ways: 1) by modification of the DNA, like balloons stuck at irregular intervals onto the sides of the DNA helix that encodes genes, and 2) through specialized protein shells that wrap around some regions of DNA. As in DNA, these shells can copy themselves and can transmit instructions. Because they are used to turn genes on and off, errors in their settings cause critical misinformation to be transmitted.
Aging involves many changes, such as muscle weakening, graying hair, skin wrinkling, and so forth. There are several current theories of aging, including damage to genes by oxidation, shortening of tiny structures at the ends of chromosomes called telomeres, and the ability to stretch lifespan with caloric restrictions. This study will investigate the possible role of epigenetics in aging by examining and comparing the shell-like epigenetic settings in skin cells in young adults and older individuals. Preliminary results from earlier studies show differences in these settings in younger and older people.
Women between the ages of 21 and 30 years and 65 and 90 years who are undergoing breast reduction or mastectomy at Suburban Hospital in Bethesda, Maryland, may participate in this study. Tissue removed during surgery for pathological examination will also be used by researchers in this study to validate the preliminary findings noted above and to continue studies into the new area of epigenetics and aging.
|Condition or disease|
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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. Progress 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 support for this hypothesis. To continue the work, it is essential to have access to normal human cells of two types: monocytes and skin fibroblasts.
Several sources for these cells are proposed. For normal human skin fibroblasts from newborns, foreskin fibroblasts will be obtained from the Department of Obstetrics and Gynecology, George Washington University. Approval for this is covered by an exemption for fully anonymized tissue (GWU IRB Protocol #100527). For normal skin fibroblasts from adults, surgical specimens will be obtained from Suburban Hospital, Bethesda, Maryland. Approval for this is covered by this currently active document (Protocol 06-CH-0010). Skin specimens will be obtained from elective breast reduction mammoplasty, as well as from normal skin derived from mastectomies.
For newborn monocytes, cord blood will be obtained from the Perinatology Research Branch, NICHD. Approval for this is already in place (Protocol OH98-CH-N001). For adult monocytes, packets of apheresis-enriched white blood cells will be obtained from the Department of Transfusion Medicine, NIH. Approval for this is likewise already in place (see attached printout from the DTM On-Line Request System, http://www2.cc.nih.gov/bprs/default.asp). For adult monocytes from monozygotic and dizygotic twins, peripheral blood specimens will be obtained from the Mid-Atlantic Twin Registry (MATR), which is affiliated with Virginia Commonwealth University, Richmond, Virginia. Receipt of cells from twins will not begin until approval of the currently pending amendment request.
For fibroblasts, 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.
For monocytes, fifty twin pairs, age range 14 to 90+ yr, will be enrolled by MATR. The primary outcome will be documentation of gene expression and epigenome disparities in monozygotic twins at two genetic loci: TLR3 and TGM2.
Secondary outcomes will include examination of areas of epigenome remodeling in both monocytes and fibroblasts. Changes will be sought that occur between birth and adulthood, as well additional examples of age-related chromatin change in adults.
In addition to the human cells described above, an invaluable resource for continuing analysis will be controlled access data from the International Human Epigenome Consortium (IHEC). Multiple such datasets, which provide sequence read files and coded (but no personally identifiable) information on donors, are available upon approval by the appropriate IHEC Data Access Committee (DAC). For some datasets, DAC acceptance is contingent on documentation that this protocol has received appropriate Ethics review and IRB approval.
|Study Type :||Observational|
|Actual Enrollment :||90 participants|
|Official Title:||Remodeling of Chromatin-Based Epigenetic Structures in Development and Aging|
|Study Start Date :||October 14, 2005|
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00242255
|United States, District of Columbia|
|GW University Medical Center|
|Washington, District of Columbia, United States, 20037|
|United States, Maryland|
|Bethesda, Maryland, United States, 20814|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|United States, Virginia|
|Virginia Commonwealth University|
|Richmond, Virginia, United States, 23284|
|Principal Investigator:||Bruce H Howard, M.D.||Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|