The Tumor Suppressing Theory of Aging

August 08, 2014

This is a review of the following paper.

The basic idea is that any organism has a fundamental tension between suppressing cancer and growing/replicating to maintain stasis. So the longer organisms live/the larger they are, the more the chance of a cancerous mutation which will end up killing the organism. However, if you look at body size vs cancer rate across, you find that it's actually mostly uncorrelated: https://en.wikipedia.org/wiki/Peto's_paradox. However, within the same species, you do see a strong link between body volume and age.

So the idea is that various species put more or less effort into suppressing tumors based on how likely they are to get cancer in the first place (which happens when regular reproduction of cells in the body goes wrong). These tumor suppression mechanisms are what lead to aging (in various ways). For instance, cells will be made senescent, i.e., retired, if they show lots of indicators for becoming cancerous like heavy DNA damage. As the proportion of such cells grows, various things in the body stop working as well which looks like aging. 

A second point is that this explains why calorie restriction (CR) works against an obese control - under low calorie regimes the body slows the metabolism/cell regeneration rate by a lot which sharply decreases the rate of cancer and hence the rate at which tumor suppression has to be done. The author suggests that for healthy weight organisms, CR should have no effect on age. The other explanation for CR which seems plausible to me is the free radical theory, where aging is caused by DNA damage due to the presence of free radicals released in the process of burning food. These two theories aren't necessarily contradictory...

The paper goes into many more pieces of evidence that support this theory (and discredits other popular theories of aging) but the reason I like this idea is that it seems quite fundamental. If we think of any organism as an "agent" of evolution, produced in order to try and maximize some fitness function (like spreading genes), then there is a fundamental tension already visible here. Evolution gives the organism some basic drives but mostly, it has to leave the organism fairly flexible to navigate the world. In the course of this navigation, the organism might often have divergent goals from evolution at which point this contradiction manifests itself as "suffering". The relation between individual cells growing cancerous at the cost of the organism seems very parallel to this story between evolution and the organism and I wonder if this is just a fundamental tension in all "life"...

Let me end by quoting the conclusion, which is quite concise and legible: 

> First, mutations driving excess cell division are proposed as the main, proximal cause of aging and the relevant type of somatic mutation, not (like the prevailing view) those causing loss or impairment of function. Mutations arise mostly during proliferation, so second, the pace of stem cell division is concluded to determine the rate of aging, together with the mutation rate per mitosis. This makes the tumor suppression theory of aging compatible with findings linking longevity to growth, nutrition and obesity through their effects on the rate of cell division. And third, dedicated tumor suppression mechanisms like cell senescence are postulated to cause most of the phenotypes of functional decline that characterize aging. Cancer and aging would be seen as the side effects of too much and too little capacity for self-renewal, the latter having evolved to suppress the further. Because it rests significantly on evolutionary arguments, the tumor suppression theory of aging, like the antagonistic pleiotropy and disposable soma theories of aging, explains primarily why we age: because the positive effect of tumor suppression through senescence and cell elimination was large enough to improve reproductive success. Since the etiology of cancer is well understood (Michor et al., 2004; Vogelstein et al., 2013), it is concluded that somatic mutations are, albeit indirectly, responsible for aging as well.