Cancer and Aging – What Determine Cancer Age Risk ?
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. Organisms such as flies and worms are composed primarily of post-mitotic cells, and hence do not develop cancer. Humans, 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 in Cancer 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 tumor genesis—the point at which cells have presumably acquired genomic instability. Hence, mutations are ram pant 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 on-cogenic, in an age-dependent manner. Thus, mitotic (but, interestingly, not post-mitotic) tissues have been shown to accumulate a variety of mutations in cancer 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 ex- posed to ultraviolet radiation. Finally, apparently normal human tissue has been shown to accumulate mutations, particularly loss of heterozygosis, which predisposes cells to loss of tumor suppressor genes. Thus, potentially oncogenic mutations accumulation with increasing age.
Aging Tissue and Cancer Age Risk
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 non aggressive and relatively benign tumor and an aggressive metastatic tumor can not be easily explained by the number of mutations alone.
One possible explanation for the cancer age risk 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, secrete enzymes and cytokines that disrupt normal tissue architecture. However, other factors— such as cross linking of extra cellular matrix molecules by non enzymatic 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 pre-senescent 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.
Cancer Mortality Among Aging People
Despite the increased incidence of cancer and aging, cancer mortality tends to decline at very advanced ages. Some cancers tend to be more indolent (slower growing and less aggressive) when cancer develop in elderly or 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 human, and it appears to result from a mutations accumulation, as well as from age-dependent changes in tissue structure and function.