[Frontiers in Bioscience 3, d25-43, January 1, 1998]
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HOW DO INTRACELLULAR PROTEOLYTIC SYSTEMS CHANGE WITH AGE?

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

6. CONCLUSIONS AND PERSPECTIVES

Many of the changes that happen in senescent cells can be explained based on reduced rates of intracellular protein degradation. The decrease in total protein breakdown with age has been extensively reported, and the specific intracellular proteolytic systems responsible for this decrease are now becoming clear. Dietary restriction extends the lifespan of rats, and this treatment also delays the age-related decline in liver protein degradation (195), consistent with reduced protein degradation being an important parameter in aging.

We have presented a general review of age-related changes in different proteolytic systems. However, possible modifications in the proteolytic susceptibility of substrate proteins with age should also be considered, because both a decrease in the activity of proteolytic pathways and also a decrease in the proteolytic susceptibility of substrate proteins could result in accumulation of proteins in senescent cells. For example, certain oxidized proteins and cross-linked proteins are poor substrates for proteases and are slowly degraded by cells (188). This stabilization may contribute to the observed accumulation and damaging actions of oxidized proteins during aging (188). However, these reductions in proteolytic susceptibility with age do not seem to apply to the majority of protein modifications (for review see ref. 90). In fact, there is an increase in susceptibility to degradation by exogenous proteases of cytosolic proteins from liver of old rats (186), and from senescent fibroblasts (187), and it has been proposed that different age-specific protein modifications must contribute to the increased susceptibility to proteolytic attack (186).

There are still many aspects of intracellular protein degradation that need to be addressed in order to identify the primary defects with age. The discovery of proteolytic activities in some cellular compartments until recently unknown (i.e. endosomes and mitochondria) has already expanded the roles of the protein breakdown inside cells. Identification of other new proteases might also explain the decrease in non-acidic protease activity in some models of senescence.

As described above, one of the principal pathways contributing to the age-related degradation failure is the hsc73-mediated lysosomal pathway. Several mechanistic aspects of this specific lysosomal pathway are unclear; the exact mechanism underlying cytosolic hsc73 stimulation of substrate binding to the lysosomal membrane receptor; the role of other cytosolic regulators of the hsc73 function; the existence of other lysosomal membrane and matrix protein(s) that participate in the transit of substrates into the lysosomal matrix. New substrates for this pathway need to be identified, and the contribution of this proteolytic system to the overall intracellular degradation in different organs and under different conditions must be further established.

The identification of proteolytic defects with age will also allow the development of different corrective methods to eliminate the cytosolic accumulation of abnormal proteins. One approach is to reduce protein damage (209). However, the use of protective enzymes is limited because cells are exposed to a large number of potential injurious agents. A more general solution for this problem will be to facilitate the elimination of the accumulated proteins.

We have previously demonstrated that the overexpression of the receptor protein for the hsc73-mediated lysosomal pathway in normal cultured cells results in an increase in the activity of this pathway (146). Regulated gene expression systems, such as the Tet-Off and Tet-On system regulated by tetracycline, are now available. Those systems allow a high-level expression of cloned genes in response to varying concentrations of tetracycline (210). The regulated expression of lgp96 in fibroblasts may allow us to increase the activity of the hsc73-mediated lysosomal pathway at different times of senescence. Thus, we could determined the reversibility of the age-related decrease in the activity of the selective lysosomal pathway, along with the effect of its activation in the elimination of the protein deposits in the cell. That procedure may result in a recovery of other normal cellular functions.