Other Free Encyclopedias » Medicine Encyclopedia » Aging Healthy - Part 1

Cellular Aging

age physiological chromosome genetic cells dna senescent senescence

When they are placed in a culture environment, human cells exhibit a finite proliferative capacity and are usually able to divide only forty to sixty times before reaching a senescent (nondividing) phase. The limited proliferative capacity of human cells in a culture environment is thought to result from multiple environmental and genetic mechanisms, and has been widely used as a model of human aging. The hallmark of senescence is the inability of cells to replicate their DNA following stimulation with the appropriate growth factors. Senescent cells are not dead, and in fact can be maintained for long periods with appropriate culture techniques; however, they no longer divide. The irreversible growth-arrested condition of senescent cultures is distinct from the G0 (resting) phase that young cells enter when deprived of growth factors. In spite of their apparent inability to complete DNA replication following stimulation, the DNA synthetic machinery of old cultures remains intact, as is demonstrated by the fact that senescent cells can be forced to replicate their DNA by infection with simian virus 40.

Many factors are believed to contribute to the process of senescence. The appearance of growth inhibitors in late passage cells has been frequently reported. For example, poly A+ RNA, derived from senescent fibroblasts, inhibits entry into DNA synthesis when microinjected into proliferation-competent cells. It has also been observed that the expression of replication-dependent histones is repressed in senescent cells while a variant histone is uniquely expressed. The factors controlling senescence are dominant over those that control proliferation. Fusion of late passage cells with early passage normal cells and with immortal cells has been used to demonstrate that the nonproliferative phenotype of senescent cells is dominant over normal proliferative cells and immortalized cells (for review, see Cristofalo and Pignolo). Changes in cellular signaling pathways have been observed in senescent cells that may significantly alter the way in which cells respond to growth factors and other stimuli (Cristofalo et al.).

The shortening of chromosomal telomeres appears to be a major factor that limits proliferative life span. Telomeres protect chromosomes from degradation, rearrangements, end-to-end fusions, and chromosome loss. During replication, DNA polymerases require an RNA primer for initiation, but they are unable to replace the primer with DNA when they have completed synthesis. As a result, telomeres become slightly shorter each time DNA is replicated. Immortalized cells avoid this problem by expressing an enzyme that compensates for telomere loss by adding repetitive DNA units to the telomeres after mitosis. The importance of telomeres to senescence has been demonstrated by showing that senescence is delayed and possibly eliminated by overexpression of telomerase in normal cells (Bodnar et al., 1998). In summary, expression of growth inhibitory genes, changes in cellular signaling, and telomere loss are all factors that govern cellular senescence. However, the relationship of senescence, and the factors that cause it, to the aging of organisms remains a subject of much controversy.

VINCENT J. CRISTOFALO R. G. ALLEN

BIBLIOGRAPHY

BODNAR, A. G.; OUELLETTE, M.; FROLKIS, M.; HOLT, S. E.; CHIU, C.-P.; MORIN, G. B.; HARLEY, C. B.; SHAY, J. W.; LICHTSTEINER, S.; and WRIGHT, W. E. "Extension of Life-span by Introduction of Telomerase into Normal Human Cells." Science 279 (1998): 349–352.

CRISTOFALO, V. J., and PIGNOLO, R. J. "Replicative Senescence of Human Fibroblast-like Cells in Culture." Physiological Reviews 73 (1993): 617–638.

CRISTOFALO, V. J.; VOLKER, C.; FRANCIS, M. K.; and TRESINI, M. "Age-Dependent Modifications of Gene Expression in Human Fibroblasts." Critical Reviews in Eukaryotic Gene Expression 8 (1998): 43–80.

Cellular Aging: Basic Phenomena - Changes In Cell Morphology And Contact, Senescence And Cell-cycle Progression, Growth Signals And Senescence [next] [back] Case Management - Definition, History, Integrating Health Care, Case Management In Medicare, Consumer-directed Care

User Comments

The following comments are not guaranteed to be that of a trained medical professional. Please consult your physician for advice.

Your email address will be altered so spam harvesting bots can't read it easily.
Hide my email completely instead?

Cancel or