Regulation of apoptosis resistance and ontogeny of age-dependent diseases.

Diseases of the elderly, including neurodegenerative and cardiovascular disorders and cancer, may develop through the accumulation of "hits" composed of genetic and epigenetic risk factors. The "iceberg" buildup of these hits over time may exceed the tolerance threshold of a particular tissue, thus precipitating disease. Resistance to apoptosis, a self-eliminating cellular program, is one risk factor; it is attributed to persistent survival factors, or the absence of killer factors, which form a "Yin-Yang" mechanism directing cells to either live or die. Most apoptosis-associated genes can be categorized into four groups, providing signals, signal processors, activators, or substrates for the apoptotic pathway. Senescent human fibroblasts resist apoptosis, perhaps through the lack of key G1-phase gene expressions, also necessary for apoptosis initiation; they also lack key proteolytic activity, and maintain high levels of survival factor bcl2, reflecting a triple blockage to apoptosis. Accumulations of these apoptosis-resistant fibroblasts in aging individuals may impair proper tissue function, not only as noncontributing members, but also as the seed for the buildup of further hits. With time, these cells with multiple hits and apoptosis resistance may induce susceptibility to developing age-dependent diseases.