Cellular Aging: Cell Death

"Running out of cells" because of apoptosis does not cause aging. Nevertheless, apoptosis is considered to be an important gerontological issue for many reasons. Diseases that increase with aging include cardiovascular diseases, deterioration of the immune system, neurodegenerative diseases such as senile dementia/Alzheimer's type, and cancer. Apoptosis plays a major role in all of these diseases, as it is ably described by Huber Warner (Warner, Hodes, and Pocinki, 1997; Warner, 1999).

Many cancers, such as B-cell lymphoma, are diseases of cell death rather than cell proliferation; that is, the excess of cells arises from the failure of cells to die on schedule rather than from excess production. B-cell lymphoma arises from the inappropriate activation of Bcl-2 (the name of the gene derives from the disease), which protects the cells from death. For many other cancers, conversion to the most dangerous phase involves the loss of a surveillance mechanism, a protein called p53, that can detect abnormal DNA. This change (loss or alteration of p53) occurs in as many as 50 percent of some tumors. P53 can either block mitosis of a cell with abnormal DNA, or, if mitosis has already begun, force the cell into apoptosis. In the absence of p53, the abnormal cell survives. Therefore, mutation or loss of p53 is considered to be an ominous development in the progress of a cancer. For those cancer cells that do not appear to derive directly from abnormalities of apoptosis, there is some hope of eventually targeting signals to cancer cells to force them into apoptosis. (Cancer cells do not typically lose the ability to undergo apoptosis, but they become insensitive to the signals.)

Conversely, many of the problems of the immune system in the elderly stem from a failure to maintain high numbers of specific types of lymphocytes. Throughout life the number of immunocompetent cells is adjusted by a balance of proliferation and specifically induced apoptosis. For instance, loss of cells in AIDS is caused by suicide of cells that are not heavily infected with HIV, but are located near cells that are infected. Biomedical research aims to prevent these losses.

Autoimmune diseases, which also increase with aging, probably result from dysregulation of the controlled and normal down-regulation of the immune system. Indeed, the two best animal models of autoimmune diseases are mice in which Fas and Fas Ligand are mutated and ineffective. In many neurodegenerative diseases, most dramatically Alzheimer's disease, the cells that die have been under chronic stress before they succumb. Dead neurons cannot be replaced, but if the suicide of these stressed cells can be prevented, the disease can be alleviated or prevented. Even in an acute situation, such as an infarct (more frequent among the elderly), only those cells immediately affected by the infarct die by necrosis. Many cells on the periphery are injured, and only later undergo apoptosis. The delayed and apoptotic death of these cells indicates that there is a window in which these cells might be protected, thus lessening damage.