Epigenetics in the Aging Process
| Status: | Completed |
|---|---|
| Conditions: | Healthy Studies |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 14 - 90 |
| Updated: | 4/6/2019 |
| Start Date: | October 14, 2005 |
Remodeling of Chromatin-Based Epigenetic Structures in Development and Aging
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.
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.
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.
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.
- INCLUSION CRITERIA:
Age 21-30 or 65-90, female or male
Normal liver function, renal function adjusted for age
Written informed consent
EXCLUSION CRITERIA:
Down's or other premature aging syndromes
Mastectomies: skin involvement in the malignant process or damage due to prior radiation
therapy
Active skin infection
Skin damage due to photoaging will be noted but will not be a basis for exclusion
We found this trial at
4
sites
Suburban Hospital Suburban Hospital is a community-based, not-for-profit hospital serving Montgomery County and the surrounding...
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9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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Virginia Commonwealth University Since our founding as a medical school in 1838, Virginia Commonwealth University...
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