Stem Cell Aging

Asymmetric Division of Stem Cells

Aging, in its broadest sense, is driven by entropic decomposition of materials. In living organisms, this is manifest by aging processes that eventually cause tissue dysfunction and death. To begin to discuss aging, one must recognize that most human tissues are simply arrayed, continuously renewed lineages of distributed adult stem cells. Many tissues undergo programmed, continuous cellular turnover based on the proliferative properties of these stem cells. Most cells are born by cell division, undergo differentiation, mature with or without pool-expanding, permanently arrest further division, function for a finite time, and then die. In contrast, adult stem cells retain their proliferative capacity for a lifetime via asymmetric self-renewal. Because adult stem cells produce many cells of the body, investigators think that the decrease in the body’s functionality with aging originates in these self-renewing stem cells.

Because of limitations in the isolation and study of stem cells, much of the groundwork underlying stem cell-related theories of aging have been advanced as a priori hypotheses (proposed explanations based on theory rather than experiment). Several studies have provided support for these hypotheses, but there is still much work to be done. As a disclaimer, parts of the following theory regarding stem cell function have been advanced via general biologic principles, as experimental research has been difficult to conduct. Nevertheless, the stem cell mutation aging hypothesis holds that in much the same way that accumulation of carcinogenic mutations are thought to initiate malignant transformation, other types of accumulating mutations in stem cells may compromise their function and viability, resulting in aging of tissues. Since the information encoding cell construction and function are eroded by these mutations, the stem cells, as well as the cells composing the tissues they produce, will predictably show functional deterioration.

[Page 1051]To appreciate the mechanisms by which stem cells are hypothesized to maintain their genome without accumulating mutations, one must compare these mechanisms to those of differentiated cells. During mitosis, the chromosomes are unwound, and the DNA is replicated, doubling the genome. The chromosomes line up along the center of the cell and are segregated randomly to the two daughter cells in symmetric division. This process of random segregation, more commonly known as independent assortment, is held as a law of Mendelian Inheritance. In the 1960s, K. G. Lark used radioactive labels to study mitoses in plant root tips and found that some cells (presumably stem cells) diluted their labels too rapidly to be consistent with random chromosome segregation. From this observation, he concluded that the cells were undergoing a form of asymmetric division, in which chromosomes composed of the oldest DNA always cosegregated together.

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