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Evolutionary Considerations in Aging and Cancer
Posted on: September 26, 2006

Is cell division a risky process that accumulates mutations? How to prevent pre-malignant cells from dividing after accumulating only a few mutations, and block their progression? What are the natural tumor prevention strategies? How do senescent cells impact aging and tumorigenesis?

Knowledge of the pathogenesis of cancer includes not only dominant changes that accelerate growth (oncogenes), but, just as importantly, recessive changes involving growth inhibition (tumor suppressors, or gatekeeper genes), elements that control the stability of DNA and chromosomes (caretakers or longevity assurance genes), and programmed cell death pathways (apoptosis genes).

One could speculate that cell division is potentially a risky process, and organisms with renewable tissues have evolved mechanisms to limit the maximal number of permitted divisions in order to prevent the occurrence of genomic instability and premature onset of cancer yet permit appropriate cellular DNA repair and maintenance. Cancer cells must accumulate many mutations before acquiring malignant characteristics. Each mutation probably requires at least 20–30 cell divisions: the cell in which an initial mutation occurs must expand to perhaps 1 million cells before there is a reasonable probability of a second mutation occurring. Furthermore, as most mutations are recessive, an additional clonal expansion is required to eliminate the remaining wild-type allele (usually through loss of heterozygosity). Limiting the number of available cell divisions to less than 100 would thus prevent pre-malignant cells from dividing after accumulating only a few mutations, and thus block their progression.

Obviously the most efficient tumor prevention strategy would be to have few or no available divisions, but this is clearly incompatible with the growth, maintenance and repair needs of the body of long-lived species. How then does one "set" the maximal number of permitted divisions? Having many more divisions than one needs for an average lifespan would increase the risk of cancer without any benefit. The number of permitted divisions has thus probably been reduced to the point of providing "optimal" cell turnover for one’s expected lifespan in the wild (e.g. Stone Age conditions for humans). As modern improvements in sanitation, vaccines, antibiotics and other modern medical interventions have extended the average lifespan beyond that, we may now expect that proliferation limits may adversely affect the function of some tissues, especially in situations of chronic diseases involving increased cell turnover.

Senescent cells, while not dividing, remain metabolically active and produce many secreted factors, some of which stimulate and others inhibit the growth of tumors. This cellular arrest of proliferation is accompanied by changes in cell function (such as changes in secretory pathways, expression of proteases, extracellular matrix components and inflammatory cytokines). In some contexts, a threshold of senescent stromal cells could potentially provide a permissive environment for adjacent pre-malignant epithelial cells to survive, migrate and divide. These alterations in gene expression in senescent cells may change tissue homeostasis and impact on both aging and tumorigenesis in the elderly.

There are good theoretical reasons for believing a regulated and restricted proliferative capacity contributes to declining tissue homeostasis with increasing age. Although the presence of telomere shortening provides strong circumstantial evidence that replicative senescence occurs in vivo, thus far there is only very limited direct evidence for actual physiologic effects of replicative senescence.

Source: Jerry W.Shay and Woodring E.Wright; Senescence and immortalization: role of telomeres and telomerase; Carcinogenesis vol.26 no.5 pp.867--874, 2005
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