[Frontiers in Bioscience 3, d25-43, January 1, 1998]

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Ana Maria Cuervo and J. Fred Dice

Department of Physiology Tufts University School of Medicine, Boston, USA

Received 12/5/97 Accepted 12/9/97


Aging is associated with a progressive reduction in almost all physiological functions. Senescent organisms show an impaired responsiveness to environmental stimuli and to physiological stress (1). A deterioration of the immune system in aging has also been described, and this immune system impairment is believed to contribute to increased mortality from infections, autoimmune diseases, and cancer in the elderly (reviewed in ref. 2).

At the cellular level, aging results in the inability of cells to proliferate. Senescent cells resemble cells that are arrested at the G1-S boundary of the cell cycle (3). A blockage in the expression of the c-fos gene, which leads to changes in the AP-1(active gene regulatory protein), along with changes in CREBP (cyclic AMP response element binding protein) and CTF (CAAAT transcription factor) transcription factor complexes, are believed to contribute to the loss of cellular proliferation in senescent cells (4, 5). Age-related changes in the activity of several cell cycle regulatory components such as Rb (retinoblastoma protein), Cdk2 (cyclin-dependent kinase 2), p21 (inhibitor of cyclin-dependent kinases), and p53 (tumor suppresser protein) seem also to participate in the mechanism of proliferation arrest in aging (reviewed in ref. 6). Genetic studies have shown that the senescent phenotype is dominant, and at least four separate genes are involved in the suppression of cellular proliferation (7). Senescent cells remain metabolically active for long periods of time, but there are progressive changes in cell structure and function. For example, cells accumulate somatic mutations in their DNA and lipofuscin-containing dense bodies in their cytoplasm (8).

Protein degradation together with protein synthesis take place continuously in all cells (9). Small modifications in the balance between these processes allow cells to rapidly adapt to changes in the extracellular environment (10). In addition to this continuous turnover of proteins inside cells, abnormally synthesized proteins or proteins incorrectly modified are also eliminated from the cells by the proteolytic systems (11). Intracellular proteases also participate in many other fundamental cell processes including cell differentiation, cell cycle progression, antigen presentation, and intracellular traffic of proteins (reviewed in ref. 12).

Because of these many cellular functions in which the proteolytic systems participate, the consequences of a reduction in intracellular protein degradation are widespread. Along with a severe difficulty in adapting to environmental changes, cells with impaired protein degradation are less able to eliminate abnormal or damaged proteins. Accumulation of those altered proteins may cause a variety of further problems within cells. In addition, defects in the processes of intercellular communication (i.e. antigen presentation, hormone and peptide secretion) will make those cells more vulnerable to the attack of exogenous agents and unable to develop a coordinated systemic response. These changes may contribute to common phenotypes of senescent cells, including the inability to progress through the cell cycle (reviewed in ref. 13).

Several hypotheses have been proposed about the mechanisms responsible for aging. A detailed description of each of these theories is beyond the scope of this review (for review see ref. 13). However, in general, these theories can be separated into catastrophic (aging is the result of damage accumulation throughout the cells' lifespan) and genetic (aging is due to a genetic clock that causes age-related phenotypes in cells). Lately, a multifaceted origin for senescence is becoming generally accepted (14-16). Thus, along with a genetic program, the effect of extracellular agents during the cellular lifespan modulates the severity of the age-related alterations. It is in that modulation that proteolytic systems play an important role. In many different tissues including liver, cardiac and skeletal muscle, and brain, a decline in protein degradation with age has been described (17-22).

Several proteolytic systems participate in intracellular protein degradation (reviewed in ref. 23). They mainly differ in their intracellular localization and in the regulation of their activities. We will consider the ubiquitin-proteasome proteolytic pathway located in the cytosol and nucleus, the calpains located in cytosol and associated with the cytoskeleton, and several different pathways of lysosomal proteolysis. Although all of these degradation pathways are present in all cells, the activity of each of these systems varies from tissue to tissue and also depends on environmental conditions. Specific groups of substrate proteins have been assigned to each of these proteolytic pathways, but it is becoming apparent that some proteins can be substrates for multiple proteolytic systems. Thus, single proteins have been described to follow one or another proteolytic pathway depending on the cellular conditions (i.e. c-fos and c-jun (24); IkB (25); membrane receptors (26), and components of one proteolytic system influence the activities of other proteolytic systems (27-30). In the present work, we have first addressed what is known about the effect of age on the main intracellular proteolytic systems, followed by several examples of how those systems are differently affected by age depending on the tissue analyzed.