Aging is accompanied by a general decline of physiological function and significant increases in the incidence of cancer and other degenerative diseases. It has been hypothesized that alterations in apoptosis may contribute to these age-associated changes. Changes in the extent of apoptosis as a function of age have been observed in a number of tissues or cell types. However, the implication of these changes in apoptosis during aging and how the aging process itself may modify the regulatory machinery of apoptosis remains an enigma. Further confounding such studies is the fact that the contribution of different tissues to aging is not equal. Currently, the most popular explanation for how aging occurs at the biochemical/molecular level is the oxidative stress theory of aging. Oxidative damage to cellular components (and mitochondria in particular) by reactive oxygen species (ROS) is proposed to alter the structure and function of a variety of macromolecules, e.g., DNA, lipid, and proteins. These alterations in turn can lead to reduced physiological function and eventually aging and increased pathology. Oxidative stress is also a potent inducer of mitochondrial apoptosis suggesting that oxidative stress over the lifespan of an organism may elicit its effects on aging via regulation of mitochondria-dependent apoptosis. We have recently defined the age-dependent changes in apoptosis that occur in a number of organs during normal aging (Zhang et al., 2002, Reprint 1). Amongst our findings is that normal aging is accompanied by up regulation of the activity of the intrinsic pathway of apoptosis. More recently, we have generated exciting preliminary data that implicates a specific caspase, caspase-2 as a potential mediator of mitochondrial oxidative stress in an age-dependent fashion. Our data has led us to hypothesize that caspase-2 modulates mitochondrial oxidative stress-induced apoptosis in hepatocytes and neurons and such apoptosis affects aging in a tissue specific fashion. To test this hypothesis we will undertake the following specific aims: 1) Determine the age-dependent sensitivity of hepatocvtes, cortical neurons, mesencephalic cells and fibroblasts obtained from caspase-2-/-, caspase-2 liver specific (caspase-2L-/-), caspase-2 brain specific (caspase-2B -/-) and WT mice to various oxidant stressors in vitro. 2) Measure the survival and cross sectional pathology of the caspase-2-/-, caspase-2L-/- and caspase-2B-/- mice compared to WT mice. 3) Determine if caspase-2-/-, caspase-2L-/- and caspase-2B -/- mice are more or less resistant to oxidative stress. These studies are both significant and innovative, as they address the mechanisms of a fundamental biological process, apoptosis, involved in a number of normal and pathological activities of organisms and will provide important information about the relationship between oxidative stress, apoptosis and aging in a tissue specific fashion. ? ? ?
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