What Does Cell Death Have To Do with Aging? (1997)

When Lockshin and Zakeri discussed the relevance of apoptosis to aging 7 years ago, the common view was that apoptosis would have primarily a negative impact on aging by destroying essential and often irreplaceable cells. That view has now changed to one that acknowledges that there are two general ways in which apoptosis can play a role in aging: (1) elimination of damaged and presumably dysfunctional cells (e.g., fibroblasts, hepatocytes), which can then be replaced by cell proliferation, thereby maintaining homeostasis, and (2) elimination of essential post-mitotic cells (e.g., neurons, cardiac myocytes), which cannot be replaced, thereby leading to pathology. Evidence exists in two systems (fibroblasts and thymocytes/lymphocytes) that there are age-related decreases in the potential for apoptosis, although the molecular bases for the decreases in these two systems appear to differ. Upon becoming senescent, fibroblasts lose the ability to down-regulate expression of the bcl-2 gene in response to an apoptotic signal; thus, apoptosis is blocked even though an initiating signal has been received. In contrast, thymocytes/lymphocytes lack the ability to initiate the signal because of down-regulation of the cell surface receptor Fas. There is limited information available for other tissue types, and nothing is known about why and how age-related changes occur. An interesting observation is that the frequency of up-regulation of the bcl-2 gene as a result of chromosome translocation in otherwise normal B cells increases with age; the functional consequences of this phenomenon during aging are not known. The role of apoptosis in regulating cell number is also a promising area of research. The studies on liver damage and neoplastic lesions suggest an extremely important role for apoptosis in controlling cancer. This may be particularly important in the prostate where hypertrophy and/or cancer are a virtual certainty with ever-increasing age. It is not known whether the ability to undergo apoptosis declines in the prostate with increasing age, but it appears possible that it may, thus explaining the loss of control over cell number in this tissue. A particularly important area of research is whether apoptosis plays a role in the changing balance between bone formation and resorption observed during osteoporosis. Monica Driscoll has already pointed out that, "regulation and execution of cell death is an absolutely critical process that interfaces with nearly every aspect of life. Future investigation of the links of cell death to cellular aging and the aging of organisms should be an exciting enterprise." The results currently available do suggest that apoptosis is a process that may be important in aging, at least in some tissues, and the mechanism of its regulation, in particular, needs to be understood. Several tumor suppressor gene and oncogene products are involved in signal transduction associated with apoptosis, but it remains to be shown which of these, if any, are actually involved in "on-off" switches for apoptosis. Where great progress has been made is in understanding the events occurring after binding of either Fas ligand or tumor necrosis factor to their respective receptors. However, one area about which little is known is the identity of the signals that initiate this process in response to intracellular damage. Through continuing research on cell death mechanisms, funded by the NIA, we hope to provide answers to such fundamental questions as: 1. Are there age-related changes in apoptosis, and what role, if any, do these have in the aging process? 2. If age-related changes in apoptosis do occur, what molecular mechanisms are altered to produce these changes? 3. Can approaches be developed to improve the detection and elimination of damaged cells in vivo in tissues where cell replacement is possible? 4. Can death of damaged cells be attenuated or delayed in nonrenewable tissues, and, if so, is it advantageous to the org