An expanding number of human health problems and diseases have been linked to abnormalities in the occurrence of cell death, and thus therapeutic strategies designed to modulate apoptosis in specific cell types or tissues hold significant clinical promise. 1–3 However, in those instances where the desired outcome is a suppression of cell death, it remains unclear if the cells prevented from executing apoptosis would actually retain full functional competence and thus continue to serve their biological role (s) in vivo. Indeed, in in vitro models where apoptosis was inhibited by one means or another, the cells eventually succumbed to a nonapoptotic type of death resembling primary necrosis. 4 Still, the ability to regulate apoptosis in vivo as a means to produce some type of beneficial clinical outcome remains one of the most important goals of research in this field. For example, considerable attention has been focused on the utility of caspase inhibitors to treat a host of neurodegenerative conditions. 5 Numerous studies have now documented the occurrence of caspase activation in neurons under conditions of either acute (eg head injury, stroke) or progressive (eg Alzheimer’s disease, Huntington’s disease) brain damage. In addition, peptide-based inhibitors of caspases prevent neuronal loss in animal models of head injury or stroke, whereas transgenic mice bearing a dominantnegative inhibitor of caspase-1 show a reduced level of tissue injury following brain trauma. 6, 7 Interestingly, caspase-1 inhibition has also been reported to delay neurodegeneration in a transgenic mouse model of Huntington’s disease. 8 Other examples where a repression of apoptosis has been suggested as a potential therapeutic strategy include promoting lymphocyte survival during septic shock, 9, 10 myocardial cell survival in various types of heart disease, 11–13 and germ cell survival for fertility preservation. 14–16 As pointed out earlier, however, one of the key criteria that must be met in the development and validation of any therapeutic antiapoptosis strategy is the long-term preservation of cellular viability and function, rather than a simple maintenance of cell numbers or tissue mass. Indeed, a cell prevented from executing apoptosis in response to an external stress is being forced to by-pass an inherent response to some type of insult or macromolecular damage that normally would have eliminated that cell from the body. In other words, by suppressing apoptosis to achieve hopefully a beneficial therapeutic outcome, will we be left with nothing more than a population of ‘undead’cells–devoid of capacity to fulfill their normal biological function or, worse yet, capable of propagating even greater harm to the body sometime later in life?

This point can be made by closely evaluating the neurodegeneration studies discussed above. There is no question that caspase inhibitors are capable of delaying, if not reducing, neuronal loss in vivo. However, in these same studies, the functional competency of the nerve cells ‘rescued’from apoptosis was never directly tested. In addition, it remains unclear if the neurons initially prevented from undergoing apoptosis in response to traumatic injury continue to survive long term. Obviously, if the ultimate goal of these apoptosis-based therapies is to prevent neurodegenerative disorders and diseases, then these end points must be evaluated since simply maintaining neuronal cell numbers without neuronal cell function will in all likelihood lead to clinical failure. Indeed, this caveat of apoptosis-based therapies in neurodegenerative models has been recognized, as exemplified by recent work showing that transgenic overexpression of p35–a …