CELLULAR AGING: TELOMERES
Aging is a complex process that occurs on multiple levels. The end result of aging is that life span is limited in multicellular organisms. The cells that make up multicellular organisms also have limited life spans. The limitation on cellular life span is comprised of two parts: (1) cells become unable to continue dividing but remain metabolically active, and (2) at some future time cell death occurs. Many cells in the human body are continually undergoing cellular division. Cellular division is a normal condition of certain tissues; examples include hair growth, the sloughing off of skin every several days, and the complete turnover and replacement of the cells of the immune systems every few months. In some instances, cellular division occurs in order to heal damaged tissues. Thus, having a limited number of cellular divisions available could contribute to aging by slowing down processes such as wound healing, as well as affecting general tissue maintenance.
In the 1960s, Leonard Hayflick first noted that human cells undergo a limited number of divisions when placed in culture. Furthermore, he noted that the number of divisions cells undergo is related to the number of prior divisions undergone by the cells. This observation suggested the existence of an intracellular clock that marked the division history of each cell. In addition, it suggested that once a predetermined number of divisions has occurred, a signal (or signals) is generated that prevents the cell from undergoing further divisions. The timing mechanisms underlying and regulating this process remained elusive until the end of the twentieth century. The first of these clocks to be identified and characterized, the telomere, is active in several human cell types.
Telomeres are chromosome caps
Telomeres are specialized structures present at the end of liner chromosomes; they serve the essential function of protecting and stabilizing chromosome ends. The telomere was first defined in the 1930s following observations that naturally occurring chromosome ends behave differently than chromosome breaks induced by damaging agents such as ionizing radiation. Both structures are ends of double-stranded DNA molecules. However, chromosome ends are stable, allowing accurate transmission of chromosomes from generation to generation without loss of genetic material, whereas induced breaks are very unstable, reacting with other chromosomes in the cell to create rearrangements and chromosome fusions. In addition, broken ends of DNA trigger cellular protective responses. These responses act either to allow the DNA damage to be repaired, or to remove the cell from the population by cellular suicide, called apoptosis. Even though telomeres are the physical end of a DNA molecule, they do not trigger these protective responses. These observations indicated that there is something special about naturally occurring chromosome ends.
Telomere structure
Telomeres are made up of short tandem repeats of a simple DNA sequence and associated proteins. In humans, and all other vertebrates, the telomeric DNA sequence is 5'(TTAGGG)3', oriented towards the end of one DNA strand, with the complimentary sequence 5'(CCCTAA)3' oriented towards the interior of the chromosome. The duplexed telomeric repeats are arranged in tandem and are present in more than a thousand copies at the end of each human chromosome. At the very end of the chromosome there is a single-stranded protrusion of the G-rich strand that extends for twenty or more repeats.
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