Cancer And Aging
The largest single risk factor for developing cancer is age. The incidence of cancer increases exponentially with age, although death from cancer (cancer mortality) may decline at very old age. The inevitable age-dependent rise in cancer incidence is a feature of multicellular organisms that contain a substantial fraction of mitotic cells. Model organisms such as Drosophila melanogaster (flies) and Caenorhabditis elegans (worms) are composed primarily of postmitotic cells, and hence do not develop cancer. Mammals, on the other hand, contain tissues that have a large population of mitotic cells, many of which tend to develop cancers with increasing age. There are a number of known and suspected causes of age-dependent susceptibility to cancer.
Mutations increase with age. There is little doubt that mutations are a critical cause of cancer. Virtually all tumors harbor mutations. In fact, most tumors harbor dozens of mutations, many of which are detectable as large genomic amplifications or losses. The copious genomic changes that are characteristic of most tumor cells reflect an end stage in tumorigenesis—the point at which cells have presumably acquired genomic instability. Hence, mutations are rampant and have enabled the tumor cell to overcome the substantial intrinsic (e.g., cellular senescence) and extrinsic (e.g., cellular microenvironment) tumor-suppressive mechanisms. Prior to this stage, however, cells accumulate mutations, at least some of which are potentially oncogenic, in an age-dependent manner. Thus, mitotic (but, interestingly, not postmitotic) tissues have been shown to accumulate a variety of mutations with increasing age, as detected by a neutral mutation-reporter gene integrated into the genome of transgenic mice. Likewise, p53 mutations have been shown to accumulate in apparently normal tissue, particularly in skin exposed to ultraviolet radiation. Finally, apparently normal human tissue has been shown to accumulate mutations, particularly loss of heterozygosity, which predisposes cells to loss of tumor suppressor genes. Thus, potentially oncogenic mutations accumulate with increasing age.
Aging tissue and cellular microenvironments. Given that the tissue microenvironment can exert a powerful suppressive effect on oncogenically mutated genomes, mutation accumulation alone cannot explain the exponential rise in cancer incidence with age. Although this phenomena has been explained by the accumulation of four to eight critical mutations, tumors typically harbor dozens of mutations. Moreover, as noted above, cells with oncogenic mutations are present in normal tissue. Finally, the difference between a nonaggressive and relatively benign tumor and an aggressive metastatic tumor cannot be easily explained by the number of mutations alone.
One possible explanation for the age-dependent rise in cancer is that mutation accumulation synergizes with the cellular microenvironment provided by aged tissue. Many tissues show an age-dependent decline in tissue function and structure, the latter often obvious by simple histological inspection. The cause(s) of the changes in tissue structure are incompletely understood. One cause may be the accumulation of senescent cells, which, as discussed earlier, secrete enzymes and cytokines that disrupt normal tissue architecture. However, other factors—such as crosslinking of extracellular matrix molecules by nonenzymatic glycation, or changes in circulating hormone levels—may also contribute to age-dependent changes in tissue structure and the cellular microenvironment.
Results from cell culture and animal experiments support the idea that aged tissues are a more fertile environment than young tissues for the growth of cancer cells. There is also evidence that senescent cells can create a more favorable environment than presenescent cells for the growth of tumor cells. Thus, the functional and structural changes that occur in aging tissues are likely an epigenetic cause for the development of cancer.
Despite the increased incidence of cancer with age, cancer mortality tends to decline at very advanced ages. Some cancers tend to be more indolent (slower growing and less aggressive) when they develop in very old individuals, compared to middle-aged individuals. The reasons for this are not well understood. As discussed earlier, angiogenesis may be less efficient in very old individuals. In addition, the hormonal milieu in very old individuals may be less conducive than that of middle-aged individuals to tumor progression. Whatever the case, cancer poses a major limitation to the health and longevity of mammals, and it appears to result from an accumulation of mutations, as well as from age-dependent changes in tissue structure and function.
Tumor suppressor and longevity assurance genes. During the evolution of complex multi-cellular organisms, there was a need to evolve genes that would protect organisms from developing cancer, that is, tumor suppressor genes. As such, at least some tumor suppressor genes act as longevity assurance genes (LAGs)—genes that function to assure the health and fitness of organisms during their reproductive life span. Among mammals, cancer incidence begins to rise at about the midpoint of the maximum life span, or after reproductive fitness declines. Thus, tumor suppressors are effective LAGs, postponing cancer in young organisms during the peak of reproduction and declining in efficacy, or even acting with antagonistic pleiotropy, only after reproductive fitness has declined.
Tumor suppressor genes encode a variety of proteins, and many of them function during development as well as in adults (e.g., those that control fundamental features of the cell cycle, differentiation, or apoptosis). Such genes cannot be considered LAGs per se because their functions are also critical for normal development. However, other tumor suppressor genes, such as TP53, are classic LAGs because they are dispensable for normal development but critical for preventing cancer in young organisms.
At least among mammals, the rate of aging, the rate of cancer development, and maximum life span are very tightly linked. Thus, most mice live a maximum of roughly three years and develop cancer largely after a year and a half or so, whereas the human maximum life span is roughly 120 years—cancers develop largely after fifty years or so. Despite this remarkable species difference in the rates of cancer development and aging, the major tumor suppressor pathways—those controlled by p53 and pRB—are well conserved between mice and humans. That is, the mouse and human proteins that participate in the p53 and pRB pathways are very similar in their sequence and function. There are, however, many gaps in our knowledge about the molecular mechanisms that link cancer and aging.
See also BREAST; CANCER, DIAGNOSIS AND MANAGEMENT; CELLULAR AGING; CELLULAR AGING: CELL DEATH; CELLULAR AGING: TELOMERES; GENETICS, TUMOR SUPPRESSION.
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