Aging and Apoptosis: Cellular Senescence

CELLULAR SENESCENCE

When normal adult cells from a mouse or a human are grown in laboratory dishes, the cells divide for a certain number of generations and then stop dividing. Even the addition of growth inducers has no effect. However, the cells do not die as long as they are fed and maintained properly. This is called cellular or replicative senescence . When cells are isolated from a mammal, they have an internal clock that controls when senescence will occur. Human fibroblasts from a fetus will divide 60 to 80 times in culture, whereas fibroblasts from an older person only divide 10 to 20 times. Replicative senescence depends on the number of cell divisions, not the calendar. The allowed number of divisions is programmed into the cell, rather than being controlled by circulating hormones or surrounding tissues. Additionally, cells from animals with short life spans divide fewer times than cells from animals with long life spans; therefore, replicative senescence correlates with the life span of the organism itself.

There are three main characteristics associated with replicative senescence. First, the senescent cells arrest their cell cycle in G 1 and never enter S phase. The cells are metabolically active, that is, they produce proteins, generate energy, and function in their normal capacity, yet the cells do not replicate their DNA or divide. Second, many become terminally differentiated . In other words, once cell divisions are over, the cell specializes in a particular function. For example, immature melanocytes divide until the alarm bell rings on the senescence clock; the melanocytes then stop dividing and produce melanin to protect skin tissue from sun damage. Both terminally differentiated and senescent cells no longer divide, but the terminally differentiated cells have also changed their physiology. Cells can senesce without changing their physiological role. Finally, senescent cells become resistant to apoptosis or programmed cell death (see later discussion).

Interestingly, cellular senescence varies among species. Often mouse tissue is used in laboratory settings because it is easy to obtain. Because mice are mammalian, many parallels are made to humans. However, when mouse cells are cultured in vitro , a small percentage of the cells will never senesce. Eventually, the nonsenescent cells will outnumber the senescent ones, and a dish of immortal cells is obtained. Such an escape from senescence is never seen in cultured human cells.

If all our cells entered a senescent state, then we would never be able to heal a wound or recover from damage due to bacterial or viral attack. Therefore, some of our cells never enter a senescent state. Obviously during embryogenesis and development very few cells are senescent. Developing bodies are filled with stem cells , immature or precursor cells from which differentiated cells originate. As we age, the number of stem cells decreases, but some remain to replenish various tissues, especially the skin, intestinal lining, immune system, and blood cells. Beside stem cells, germline cells do not enter senescence and always maintain the ability to divide when necessary. Tumor cells are another example of nonsenescent cells. Unlike stem cells and the germline, tumor cells have mutated in a way that overrides the entry into senescence.