[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

3. MODEL SYSTEMS FOR THE STUDY OF AGING

There are many different model systems used for the study of aging. For some studies, it is possible to work with whole animals of different ages, and genetically defined strains of mice and rats are commonly utilized (31, 32; reviewed in ref. 33). A mouse model of accelerated senescence has also been established (34), and senescence biomarkers on those animals have been very well characterized (35-37; for review see ref. 38). Recently, transgenic mice have also proved to be useful in the analysis of spontaneous mutations accumulating during aging (39). In addition, the insertional mutation of a gene in one of those transgenic mice has allowed the identification of a new gene, klotho, that is involved in the suppression of several aging phenotypes (40).

In order to simplify the study of aging in organisms, animal species with shorter lifespans than mammals have also been used. Thus, the nematode Caenorhabditis elegans, with a lifespan of 20 days and 1% of the mammalian genome, has allowed an extensive analysis of the genetics of senescence (reviewed in ref. 41). Some insects, such as Drosophila melanogaster, with a relatively short lifespan (1-3 months) but with more genetically heterogeneous populations, have been utilized for the analysis of genetic influences on lifespan (41).

Some unicellular organisms, such as the yeast Saccharomyces cerevisiae, have considerably simplified studies in aging. The highly developed molecular biology of yeast and the ability to select for mutants in this microorganism have allowed the identification of several genes that show altered expression with age. Still, the senescence of budding yeast is a process that differs in several respects from the senescence in multicellular organisms (41).

The study of some cellular processes is difficult to perform in whole aged animals, since compensatory mechanisms are frequently activated. Several in vitro models of aging have also been established (reviewed in ref. 42). Specific cell types such as human diploid fibroblasts, endothelial cells, keratinocytes and lymphocytes have been shown to have finite replicative lifespans in culture. DNA synthesis and cell division cease, but metabolic activity and cellular viability may be maintained for an extended period of time (43). The loss of proliferation in these in vitro systems is interpreted as an expression of aging at the cellular level. The more relevant facts of those senescent cultures and their correlations with aging in complete organisms are summarized in table 1. Whether or not aged organisms contain cells that have reached the end of their proliferative potential has been a controversial topic. However, the analysis of variant beta-galactosidase activities has recently been successfully applied to identify senescent cells in aging skin in vivo (49).

Table 1. Senescent fibroblasts as a model of aging

CHARACTERISTICS OF SENESCENT CELLS IN CULTURE

REFERENCE

  • The proliferative potential of cells depends on the number of cell doublings undergone and is independent of the chronological age of the cells

44

  • There is an inverse relationship between the age of a donor and the proliferative potential of their fibroblasts in vitro

45

  • There is a correlation between the proliferative potential of cells from different species and the average life span of that species

46

  • Cells from patients with premature aging disorders show reduced proliferative potential

47

  • Senescent fibroblasts in culture display enlarged, flattened morphology and fail to replicate their DNA in response to normal growth stimuli

48