Pollack-1 - Journal of Gerontology BIOLOGICAL SCIENCES 2001 Vol 56A No 11 B475B482 Copyright 2001 by The Gerontological Society of America

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Journal of Gerontology: BIOLOGICAL SCIENCES Copyright 2001 by The Gerontological Society of America 2001, Vol. 56A, No. 11, B475–B482 B475 Apoptosis and Aging: Role of the Mitochondria Michael Pollack and Christiaan Leeuwenburgh Biochemistry of Aging Laboratory, College of Health and Human Performance, University of Florida, Gainesville. Apoptosis research is a rapidly developing area, but the role of apoptosis is still unclear and con- troversial. For example, several studies document a significant loss of cardiac and skeletal myo- cytes during normal aging, possibly by apoptotic mechanisms. This loss in cells may be directly mediated by mitochondrial dysfunction caused by chronic exposure to oxidants and increased activation of mitochondrial permeability transition pores. This review will discuss apoptosis in the context of normal aging of T cells, cardiac myocytes, skeletal muscle, and brain cortex. Par- ticular attention is paid to the role of the mitochondria, because they have been implicated as a major control center regulating apoptosis. Mitochondrial oxidative stress and a decline in mito- chondrial energy production in vitro often leads to activation of apoptotic pathways, but whether this occurs in vivo is unclear. N 1951, Gluckmann first described the apoptotic process. In 1972, Wyllie, Kerr, and Currie coined the term apop- tosis to describe a form of cell death with morphological characteristics that are distinct from necrosis (1). Necrosis is a passive form of cell death that results from acute cellular injury, which causes cells to swell and lyse. In contrast, apoptosis is an active process in which cells die by design and apoptotic bodies are removed without inflammation (Figure 1). These findings were largely ignored in the early 1980s, but since 1987 the number of papers in this field has been growing rapidly. Researchers became interested in apoptosis after it was demonstrated in the nematode Cae- norhabditis elegans , followed by the identification of ho- mologous death genes in other organisms (2). For example, CED-9, CED-4, and CED-3 are homologous to the mamma- lian gene products for Bcl-2, Apaf-1, and caspase-9, respec- tively (1,3,4). Apoptosis can be divided into three nondistinct phases: an induction phase, an effector phase, and a degradation phase. The induction phase depends on death-inducing sig- nals to stimulate proapoptotic signal transduction cascades. Some of these death-inducing signals include reactive oxy- gen and nitrogen intermediates, TNF- a , ceramide, overacti- vation of Ca 2 1 pathways, and Bcl-2 family proteins such as Bax and Bad (5–8). In phase two, the effector phase, the cell becomes committed to die by the action of a key regulator, that is, death domain activation on the cell surface, nuclear activators (such as p53), endoplasmic reticulum pathways, or activation of mitochondrial-induced pathways (release of cytochrome c or apoptosis-inducing factors; Figure 2). The degradation phase involves both cytoplasmic and nuclear events. In the cytoplasm, a complex cascade of protein- cleaving enzymes called caspases
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This note was uploaded on 05/19/2011 for the course BCH 3218 taught by Professor Johnsteward during the Fall '08 term at University of Florida.

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Pollack-1 - Journal of Gerontology BIOLOGICAL SCIENCES 2001 Vol 56A No 11 B475B482 Copyright 2001 by The Gerontological Society of America

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