Who wants to live forever?
So, I actually had something planned for today. I was going to talk about that Italian paper I mentioned in one of my posts last week. But that got bumped down the list because I read Cracked. Yeah…that’s a shameful admission. (probably not the only one I am making this week if I stick to my tentative schedule). Anyway, they posted up an article about entitled 5 Ways Science Could Make Us Immortal. So I pop it open expecting some delightfully fanciful conjecture involving Robocop and maybe Ras al Ghul’s Lazarus pits. And honestly? #4-1 on their list are exactly that: Some wishful thinking mixed with a seed of scientific basis with a few minor flaws, some humour, and the realistic realisation that most of these are long shots (although notably there is a lab at my university working on a crude implementation of #3). But #5…I hate #5. And I don’t blame Cracked for that. I hear this repeated constantly even by very bright people. The reason for that is that it is another one of those things that seems to make sense on a cursory glance, but then completely falls to pieces when thought through (and as I have mentioned before, a lot of people are a lot more willing to do the first than to do the second).
This is the myth that telomere degradation is the primary cause of aging and that reactivating telomerase will help us immortals.
To understand why this is an appealing and to understand why it is a mistake, we need to do some background. A telomere is a repetitive sequence of DNA found at the ends of your chromosomes. Bacteria have this nice system going where there DNA is circularised and replicated bi-directionally and nice enzymes choreograph the splitting and splicing point in an elegant X fashion and in the end you have two circular genomes. We eukaryotes have a bit more of a sloppy approach. See, our DNA is arranged in linear chromosomes, and the enzymes that replicate our DNA are not flawless. They cannot run all the way to the end of the chromosome, and so with each replication we knock off more and more of the repetitive, non-coding sequences in the telomeres. They essentially work like a buffer. I am sure by now you have spotted what the original telomere researchers did. If each replication loses a little more telomere, then there must be a finite limit to the number of replications any particular cell strain can have. There is also an enzyme called telomerase (or TERT, Telomerase Reverse Transcriptase, if you want to be pedantic). It replenishes telomeres and one of the characteristics of immortal cell lines is the presence of activated telomerase.
What all this means is: telomeres are the cause of cellular aging. Cellular aging, known as senesence, describes the process by which cells stop dividing after a certain number of replications. This number is known as the M1 or Hayflick limit. If cells are forced to continue to replicate beyond the Hayflick limit (which, for instance, certain viruses can force them to do) then their telomeres degrade fully, this is known as the M2 limit. At the M2 limit genetic damage results as continual wear begins to lop off the ends of genes. It’s messy and generally leads to cell death. However, if telomerase is active, then the cells never reach either limit and become immortal.
It is really quite tempting to assume that as it is in the micro it would be in the macro. And many people these days read about telomeres and cellular aging, and try to claim that the aging process of the entire organism stems from the same phenomenon. Indeed, some scientists have even proposed research into mechanisms to reactivate human telomerase as a way to stave off aging. There is both a serious flaw in the principle and a serious flaw in the plan itself.
The flaw in the principle is this: there is no actual causative link that has been shown between telomere length and life span. As a for instance, the average mouse has telomeres three times yours in length and higher levels of active telomerase, yet a lifespan of about three years. Further, experiments with mice have shown conflicting results: inhibiting the enzyme itself has little effect, inhibiting the gene that produces it entirely causes decrepitude (It should also be noted that wholesale inhibition of telomerase does not in fact provide a proper model of the human situation. Even we keep telomerase active in multiple systems, most notably our immune system and reproductive system). Studies in humans have shown only a correlation between age and shortened telomeres, which confirms the theory that telomeres shorten over time and repeated replications but does not provide a causative link between age and telomere length.
However, there is one thing that reactivated telomerase is causatively associated with, and it leads us to the flaw in the plan to reactivate it. Survival is good. Life will go to amazing lengths to survive and reproduce, and immortality sounds like a pretty sweet gig for a genetic line. So if we have this delightful little enzyme floating around, why don’t we have it active in higher levels? Why hasn’t evolution done for us what some scientists are proposing to do? It is a highly conserved enzyme and must have been around for ages. Well, truth be told, people with highly active telomerase are selected against. This is because they get cancer significantly faster than the rest of us.
The cancer biologist’s rule of thumb is that it takes about three mutations to get a benign neoplasm and about five mutations to get a malignant one. One of these mutations is always the reactivation of telomerase or the activation of so called ALT (Alternate mechanism for Lengthening Telomeres). See, cellular aging thing isn’t just a sad accident consigning us to mortality, rather it is a defence against tumours. Cancer cells replicate a lot. And mutations are relatively rare occurrences (~10^-8 per nucleotide per generation). So the average cell that starts replicating out of control will hit the M2 limit signalling a process of controlled cell death to start. Unless it mutates and upregulates telomerase (or activates ALT). To have constitutively active telomerase would increase the chance of any cell becoming cancerous by multiple orders of magnitude. Advocates say that perhaps we could activate telomerase temporarily to replenish things and then turn it of again, but haven’t really provided mechanisms for that (nor even established that the underlying principle is correct).
Besides, myopic focus on telomerase takes attention away from the other clear causes of aging: like accrued replication errors in DNA, and the ever present threat of oxidative stress from by-products in cellular metabolism (Protip: this second one is what is actually going to kill you, not even evolution can beat physics and build a perfect engine). If we can eek a few more years out of reactivating telomerase while simultaneusly dodging increased cancer risk, I am all for it. But it won’t be immortality. Aging is a global process and there are just too many things that don’t work quite efficiently enough to keep us going forever.
This article written with many much thanks and respect to Nobel laureates Elizabeth Blackburn, Carol Greider, and Jack Szostak who managed to solve the problem of how the hell linear chromosomes work anyway and who have opened up a fascinating field of telomere research.