Michael Fossel Michael is President of Telocyte

June 13, 2018

Aging and Disease: 2.6 Cell Senescence, Changes In Molecular Turnover, DNA Repair

Why are we more likely to get cancer as we age?

Not only does the incidence of cancer go up with age, but it goes up exponentially. Why? Moreover, the exponential rise is seen in most species, regardless of their lifespan. It’s not the years, it’s the aging process, regardless of time. Why? The key to these questions lies with the rise of DNA damage as we age. But just as with other kinds of cell damage – free radicals in the mitochondria, for example – the issue is not the rate of damage, but the rate of maintenance. In the case of DNA, however, the key feature to maintenance isn’t the rate molecular turnover, but the rate of DNA repair. DNA is the only molecule that is repaired rather than simply replaced. We replace (i.e., recycle) all other molecules in our cells (and even outside of our cells), but we never replace DNA. Instead, we repair it with great effort and in exquisite detail. DNA carries priceless information in its structure, so rather that just recycling the molecule (breaking it down and building a new molecule), our cells go to enormous lengths (and enormous metabolic cost) to find and repair every single error. Without delving into detail, let’s look at an overview of DNA damage, DNA repair, and the clinical implications for aging cells – and aging people.

DNA damage is continual, as is repair. DNA damage occurs continually due to radiation, oxidation, toxins, viruses, and even spontaneous thermal disruption (even at normal body temperatures) with an incidence estimated at up to 106 hits per cell per day. If unrepaired, the result will not only be a dysfunctional individual cell, but a cell that divides without control, thereby harming (and even killing) the entire organism. Ultimately, uncontrolled cell division is expressed clinically as cancer. Left unrepaired, DNA damage becomes fatal. Clearly DNA repair is critical, and must be both constant and all-but-flawless for any organism to survive.

 

DNA repair is, like most biological concepts, remarkably (almost indescribably) complex. No matter how we discuss it, there will be exceptions, qualifications, and additional intricacies which remain unaddressed in our discussion. We will therefore and of necessity, present a simplified summary of DNA repair, one which presents only a high-level, conceptual view of the cell’s response to a single type of DNA damage (single-base errors), while ignoring other types of DNA damage (e.g., double-strand breaks). With this caveat in mind, we will characterize DNA repair as being handled by four basic families of DNA repair enzymes which have these functions:

  1. Identification: find the damaged DNA base and flag it for removal
  2. Excision: remove the damaged DNA base from the strand
  3. Replacement: insert the correct DNA base into place in the strand
  4. Ligation: link the new DNA base to neighboring bases in the strand

In the aging cell, and correlated with telomere shortening, the expression of all four of these types of DNA repair enzymes are down-regulated. This down regulation is typical of cell senescence and is modulated by the telomere. As the telomere shortens, all four repair processes are down-regulated. DNA repair continues, but at a slower pace. Young cells repair DNA almost instantly, older cells repair DNA but at a more lackadaisical pace. The result is that, at any given moment, older cells are more likely to have unrepaired DNA.

The result is that slower DNA repair – and the rising percentage of (as yet) unrepaired DNA damage – means a higher likelihood that such damage will affect the cell’s ability to control cell division. For example, if the damage occurs to the DNA repair genes themselves or to the genes that are central to the cell cycle braking system (which would otherwise prevent cells with DNA damage from dividing), then the cell may replicate and carry the DNA damage into the daughter cells. The result is a cascade of increasing cell damage and a decreasing ability to control cell division. In short, the stage is set for malignancy, clinical cancer, and death.

We begin to see why cancer rises with age. As cells lose telomere length, DNA repair slows, and the risk of cancer rises. Worse yet, however, each of the steps involved in DNA repair are multiplicative, that is, each step will have an impact on all subsequent steps. So if detection slows and the number of DNA errors doubles, then if excision slows, the number of DNA errors goes up another factor of two, i.e., the DNA errors go up four-fold. When you add in replacement and ligation, the effects multiply one another again, with the result that if we down-regulate all of the steps in DNA repair, the increase goes up exponentially.

Most people assume that cancer rates climb with age because of a longer lifetime means a greater cumulative exposure to carcinogens. In fact, the rate of cancer isn’t correlated with years so much as it is with percent of lifespan. For example, mice have an exponential increase in cancer, just as humans do, despite the fact that the average lifespan of a mouse is about 40 time shorter than the average lifespan of a human. It’s not the years, it’s the rate of DNA repair that determines how fast that exponential curve rises. Ultimately, the deciding factor is not cumulative exposure, but the rate of repair. Mice slow DNA repair over a short lifespan and their rate of cancer goes up exponentially in only two years; humans slow DNA repair over a long lifespan and their rate of cancer goes up exponentially over a much longer lifespan. It’s not a matter of having good DNA repair genes, nor is it a matter of chronology. The deciding factor is neither time nor genes, but gene expression and gene expression is controlled by telomere shortening.

If we take the curves for cancer in mice and humans and overlap them to show not years but lifespans, then the curves become identical. It’s not the years, it’s the rate of repair. If we want to prevent or treat cancer, we shouldn’t be focusing as much on exposure to carcinogens, but on cell senescence. Putting it bluntly, if only slightly simplistically, the reason we get more cancer as we age isn’t a matter of what we were exposed to, but the rate at which we repair the damage that is constantly in play over our lifetimes.

We get cancer because of cell senescence.

 

Next Time: 2.7 Cell Senescence, Changes In Molecular Turnover, Mitochondria

3 Comments

  1. Awesome insight that cancer incidence isn’t related to years, but fraction of lifespan. I think you are probably right that this is mediated by telomere shortening, but it would be good to show how this occurs differently in mouse and man, given the senescence pathways of these species appears to be different – with mice mainly experiencing cellular senescence without their telomeres getting critically short, unlike humans who mainly suffered from replicative senescence.

    Comment by Mark — June 17, 2018 @ 5:02 am

  2. The human and mouse senescence pathways are the same. The confusion derives from confusing absolute telomere length (which is irrelevant) with relative telomere loss (which is determinative). Cell senescence (defined by the chromosomal-wide shifts in gene expression) are determined by changes in telomere length and not by telomere length per se. In short, whether you have 150kb pairs or 15 kb pairs is irrelevant to predicting senescence. You can, however, easily predict senescence if you know the recent history of how many kb pairs have been lost. It’s much like trying to predict cancer incidence in a species by age: the relevant variable (given an otherwise comparable incidence of cancer over the lifespan) is not age, but the percentage of lifespan to date. Whether you are looking at the percentage of senescent cells in a given tissue, the SASP in a given tissue, or the incidence of DNA damage, the correct inter-species comparison is not years, but percent of lifespan.

    Comment by webmaster — June 25, 2018 @ 12:14 pm

  3. Thank you for taking the time to respond.

    Comment by Mark — June 28, 2018 @ 9:43 am

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