Epigenetics in the Aging Process
Condition: Aging
Study type: Observational

Summary: 
      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.

      ...
    

Detailed description: 
      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 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.
    

Observational model: Case-Only
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Neonatal cord blood samples collected in association with normal deliveries at a NICHD
        obstetrics service in Wayne State University (PI Dr. Roberto Romero). Adult samples
        collected from volunteers at the NIH Blood Bank.
      
Keywords: Histone; Chromatin; Epigenome; Senescence; Acetylation; Aging; Tissue Sample