Aging and Regulation of Apoptosis

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Introduction

Cell death in biological systems can be separated into two distinct forms: necrotic death and programmed death or apoptosis 10., 38.. Necrosis results from massive cell injury and often is accompanied by inflammation. Apoptosis is a more subtle process, and until recently it was generally assumed to be a biological process whose major function is to destroy unwanted cells during development (72). This perception began to change in the 1980s, particularly as roles emerged for apoptosis in the negative selection of thymocytes and lymphocytes (53), in the attenuation of autoimmunity (55), and as a balancing factor in maintaining proliferative homeostasis 71., 74., 83.. When cells become extensively damaged, apoptosis may also become either a preferred or an essential alternative to repair. This may be particularly important during the use of irradiation and drugs to damage and ultimately destroy cancer cells.

Increasing evidence suggests that most mammalian cells may exist in a state of unstable equilibrium, poised to either proliferate or die, depending on the balance of factors impacting on them. Thus, most, if not all, of the cell death machinery may be present at all times, but whether it actually gets used depends on a variety of both extracellular and intracellular signals. The four most active areas of research on cell death concern the following questions: What are the components of the cell death machinery? What are the signals that trigger cell death? How are these signals transduced to the machinery? How is the overall process regulated?

The beneficial physiological roles of apoptosis are counterbalanced by deleterious cell death occurring in a variety of pathological conditions, including the neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis; ischemia; and acquired immunodeficiency syndrome (AIDS). Bonfoco et al. (5) have concluded that in neurons “mild excitotoxic or free radical insults result most often in apoptotic neuronal death, whereas necrosis predominates after intense, fulminate insults.” Thus, it is particularly important to learn how apoptosis is regulated so that strategies can be devised to slow down or delay it in cells which cannot be replaced by cell proliferation.

Franceschi et al. (21) have proposed that apoptosis is an important cellular defense mechanism in maintaining genetic stability and that centenarians have “aged successfully” because their cells are more prone to apoptosis. Evidence now suggests the possibility that changes in apoptosis may be an important factor in aging, and the purpose of this chapter is to review the evidence that is beginning to accumulate. For the purposes of this chapter, I will assume that apoptosis and programmed cell death refer to the same ultimate biological process, which is the rapid but controlled destruction of a cell following the activation of cell death proteins by any one of a variety of signals; for brevity I will refer to it only as apoptosis (10). In most cases, the exact signals which trigger this process have not been identified, but it will be assumed that the actual killing process (i.e., the machinery employed) is fairly universal, regardless of the initiation signal transduction pathway employed.

Section snippets

Genes Involved in Apoptosis

The meteoric rise in research on apoptosis and the mechanisms of cell death stems directly from the pioneering work of Robert Horvitz and colleagues with the nematode Caenorhabditis elegans 15., 68.. This has been a useful model system because the developmental history of every cell in this organism has been determined; of the 1090 somatic cells formed, 131 are destined to die during development (15). Assuming that the death of these cells must be genetically programmed, Horvitz has identified

Cell Senescence and Apoptosis

Although senescent cells, by definition, can no longer proliferate, they are by no means dead or dying cells (42). In fact, they are remarkably resistant to stimuli which normally induce apoptosis, such as growth factor deprivation (75), suggesting that senescence may be in some way linked to the potential to undergo apoptosis.

This linkage has been investigated by Eugenia Wang and colleagues 28., 75., 76., 77.. They suggest that when quiescent human fibroblasts attempt to reenter the cell

Immunological Aging and Apoptosis

It is well known that many parameters of immune function decline with increasing age (32), but how important this is in aging remains unclear. This decline could be due either to a decrease in the total number of lymphocytes produced or to an alteration in the kinds of lymphocytes produced (or both); current evidence best supports the latter alternative. For example, Miller (50) states: “The population of T cells in aging mice can be viewed as a changing mosaic of cells with different

Caloric Restriction and Apoptosis

Caloric restriction (CR) is an intervention which retards aging and extends the maximum life span of not only rodents but also a wide variety of other animals (81). CR has also been shown to delay the onset of age-related disease, including cancer. Although CR prevents a large number of age-related changes, it is not known whether any of these factors play a causal role in life-span extension or retardation of disease.

Two papers suggest that a common mechanism may be at least partly responsible

Neurodegenerative Disease and Apoptosis

Death of neurons can be induced either by removal of survival factors such as nerve growth factor, ciliary neurotrophic factor, and brain-derived neurotrophic factor (61), or as a result of damage to the cell. One of the factors in the death of neurons leading to age-related neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is thought to be low-level but chronic oxidative damage occurring in specific regions of the

Summary

When Lockshin and Zakeri (44) discussed the relevance of apoptosis to aging, the common view was that apoptosis had primarily a negative impact on aging by destroying essential and often irreplaceable cells. That view has now changed to one that acknowledges that there are two general ways in which apoptosis can play a role in aging: (1) elimination of damaged and presumably dysfunctional cells (e.g., fibroblasts, hepatocytes) which can then be replaced by cell proliferation, thereby

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