Multiple longevity phenotypes and the transition from health to senescence.

Three different longevity phenotypes exist in Drosophila and other model systems, but only two are known in humans. The "missing" phenotype is the delayed onset of senescence phenotype, which can be induced by various interventions, including pharmaceuticals. The lability of the onset of senescence indicates that the mechanisms involved are plastic and can be altered. Only interventions that involve the upregulation of stress resistance genes, probably via the JNK pathway and/or dFOXO3a transcription factor, seem capable of generating a delayed onset of senescence phenotype. The data suggest that the cellular mechanisms responsible for maintaining the cell in a healthy state are under constant attack by ROS and/or abnormal protein accumulation. A stochastic growth factor/signal transduction failure may be the proximal event responsible for the decreased efficiency of the cell's defenses, resulting in the onset of senescence, degradation of the gene interaction network, and continuing loss of function.