The evolution of lifespan and age-dependent cancer risk

Abstract

The Armitage-Doll multi-stage model of carcinogenesis tremendously refocused cancer science by postulating that carcinogenesis is driven by a sequence of genetic changes in cells. Age-dependent cancer incidence thus has been explained in terms of the time necessary for oncogenic mutations to occur. While the multi-step nature of cancer evolution is well-supported by evidence, the mutation-centric theory is unable to explain a number of phenomena, such as the disproportion between cancer frequency and animal body size or the scaling of cancer incidence to animal lifespan. In this paper, we present a theoretical review of the current paradigm and discuss some fundamental evolutionary theory postulates that explain why cancer incidence is a function of lifespan and physiological, not chronological, aging.

Figure 1. Age-dependent physiological events

Roughly half of all mutations and epigenetic changes occur before full body maturation [7]. The accumulation of genetic and epigenetic changes significantly slows down later, followed by a slowdown in stem cell division rates when stem cells transition from body maturation to body maintenance (example based on HSC) [9]. Both elevated aging rates and cancer incidence are significantly delayed and do not follow the mutation accumulation curve. However, cancer incidence increase mirrors the curve of physiological decline (aging).

Figure 2. The evolution of lifespan and cancer incidence

(A) The lifespan of animals in the wild (dark green curve) is usually defined by external hazards, such as predators, food availability, and infectious diseases (dark green arrows). Their maximum lifespan, limited by their rates of physiological aging (blue line), can only be observed in captivity or in modern humans. Germline selection acts to maintain high body fitness (solid blue arrows) for the duration of likely survival and reproduction in the wild. Physiological aging in humans and captive animals accelerates after the time of their likely survival in the wild promoted by progressively relaxing germline selection for body fitness. (B) If external hazards are reduced, animals survive into more advanced ages in the wild and trigger germline selection to extend (hollow blue arrows) their maximum lifespan, pushing the curve of physiological aging rightwards on the age axis and leading to the evolution of a longer potential lifespan. (C) Cancer is rare in wild animals, as well as in humans and captive animals during the period of their likely survival in the wild (natural lifespan), with carcinogenesis being suppressed by higher tissue and stem cell fitness relative to ages past natural lifespan. A dramatic increase in cancer incidence coincides with higher rates of physiological decline.

Figure 3. The effect of fitness landscapes on selection processes

(A) A cellular phenotype (red dot) is driven by the evolution at the germline level to adapt to the tissue microenvironmental fitness landscape (represented here by the simplest Shelford curve of tolerance model [49]), moving the phenotype towards the fitness peak. The strength of selection triggered by a mutation is proportional to the fitness difference the mutation creates. Germline selection reduces the number of mutations capable of increasing fitness (green area), limits the strength of positive selection that such a mutation can confer (compare the fitness differential between wild type versus A-mutant and wild type versus the negatively selected B-mutant), and increases the number of negatively selected mutations (orange area). (B) In an altered environment, the intensity of many environmental factors is changed (represented here with a rightward-shifted Shelford curve). In an altered environment to which a cell is not adapted through germline evolution, the same cellular phenotype results in lower cellular fitness. Also, the number of mutations capable of elevating fitness is greater and the strength of positive selection they can trigger is increased (compare fitness differential between wild type versus A-mutant and wild type versus B-mutant with those in panel A). The directionality of selection triggered by a specific mutation can also change, such as represented here by mutation B which is negatively selected in the normal microenvironment, but strongly positively selected in the altered one.

Figure 4. Rates of aging and cancer incidence in DNA polymerase mutant mice

Mutations L604K and L604G in the heterozygous state both increase mutations rates more than 5 times in mice. Mutation L604G does not have any effect on lifespan and cancer incidence. Mutation L604K, however, causes a shortening of the lifespan and a symmetrical acceleration of the cancer incidence curve relative to +/+ (wild type) and +/L604G [34].