Replicative capacity of cells from disease states

The gradual appearance of senescent cells may contribute to the development of age-related disease. However, the presence of disease by other mechanisms may result in accelerated senescence. Disease may cause tissue damage which leads to cellular turnover for the purpose of replacing lost cells. This exhausts the replicative capacity of the cells and accelerates the appearance of senescent cells. For example Goldstein and co-workers (1978) looked at the replicative lifespan of fibroblasts from normal, prediabetic, diabetic donors. Diabetes mellitus is a common genetically determined disorder associated with reduced life expectancy. This study confirmed earlier findings that there is an inverse correlation between donor age and replicative lifespan, but emphasised the importance of physiological state of the donors. Normal cell strains showed significantly better growth capacity than diabetic and prediabetic cells. The results indicated that with an increasing predisposition to diabetes, there is a progressive decrease in replicative capacity.

Another group investigating atherosclerosis took vascular smooth muscle cells (VSMC) from human atherosclerotic plaques and grew them in culture (Bennett et al, 1998). Results showed that VSMCs taken from plaques have lower rates of proliferation and underwent senescence earlier than cells derived from normal vessels.

A more recent study looked at the replicative capacity of osteoblasts in Rheumatoid arthritis (RA) compared with Osteoarthritis (OA) (Yudoh et al, 2000). The results indicated that the replicative capacity of osteoblasts decreased gradually with donor age and this decrease was higher in RA patients than with OA patients at any donor age. They also reported an increase in senescent osteoblastic cells with age in both groups in which the rate of expression of senescent cells was higher in RA patients than with age-matched OA patients.

Tesco et al (1993) looked at the replicative capacity of fibroblasts in patients with familial Alzheimer’s disease (FAD) to examine whether features compatible with a systemic premature aging were present. Data showed that there was no significant difference in replicative capacity of fibroblasts between FAD patients and controls. This is not a surprising result, since the fibroblasts studied are unrelated to the development of FAD and if features of premature ageing were present they would have most likely manifested themselves as other diseases other than just Alzheimer’s. For example, Werner’s syndrome is a premature ageing disorder which displays a multitude of age-related afflictions including diabetes and heart disease (Kipling and Faragher, 1997). When fibroblasts were taken from patients with Werner’s syndrome and grown in culture, the number of population doublings achieved was smaller compared with normal cells of a similar chronological age (Martin et al, 1970)

These studies suggest that disease is an important factor contributing to the exhaustion of the replicative capacity of cells. However, it is possible that some diseases arise as a result of the gradual increase in senescent cells with time. It is also possible that unknown factors result in accelerated senescence, which subsequently manifests itself as a biological impairment or disease.

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Factors, other than disease, which may contribute to cellular injury and cell loss, may be environmental such as UV radiation, chemical damage from smoking and foods, and normal biological damage from general wear and tear.

Replicative capacity of tissues from normal human populations

The maximum replicative potential for mitotic cells varies between different cell types. Some cell types, such as endothelial cells, may have a maximum replicative capacity around 30 cPD (cumulative population doublings) while other cell types such as embryonic fibroblasts may have a maximum replicative capacity of 100 cPD. For example, one early study looked at the replicative capacities of several different tissue types (skeletal muscle, bone marrow spicules and mesial of the midupper arm) taken from donors of the same age (Martin et al, 1970). It was found that the replicative capacity of these tissues, despite being taken from the same individual, displayed variation in their replicative capacity. Cultures derived from skin fibroblasts achieved the greatest number of population doublings, bone marrow spicules the least and skeletal muscle giving intermediate results. There are a number of explanations for these observations. The first is that all cells do have the same replicative capacity, but the replicative history (rate of cell turnover) of each tissue at the time of extraction is so different that such variation is observed. Some tissues may have undergone a higher rate of cellular turnover than others, thereby exhausting its replicative capacity earlier. The second is that the replicative history of each tissue is similar, but it is the length of the telomeres between tissues that differs. Some tissues may senesce sooner than others because they started out with shorter telomeres. It is unlikely that these explanations alone are correct. A combination of the two is the most likely cause for such variation in replicative capacity. Tissues differ in both their replicative history and replicative capacities.

The results also show that the replicative capacity of the same tissues between individuals of the same age also differs. This difference may again be due to the same differences which effect proliferative variability between different tissues of the same individual. For example, one individual may have a shorter replicative capacity in a particular tissue than another of the same age due to increases in cell turnover, maybe in response to disease or injury, or maybe differences in initial telomere lengths. Cultured human embryonic fibroblasts were found to senesce at 50±10 cPD (Hayflick and Moorehead, 1961). This meant that some cultures were senescent only after 40 cPD while others at 60 cPD. These differences in replicative lifespan may be a consequence of the stochastic mechanism which triggers a cell to senesce. Therefore, the difference in replicative capacities of the same tissues between individuals of the same age may also be due to the stochastic events which govern a cell becoming senescent. Thus, the replicative capacity of a tissue measures biological age and not chronological age. Unfortunately there have been few studies looking at the replicative capacity of different tissues from the same individuals. This would have given a better insight into the relationship between chronological and biological age.