The immortality paradox

"Untold stories" © EEG

This is an old post, which I originally wrote in response to a friend's question. I'm reposting today because it's one of the topics you will discover in the plot of my detective thriller CHIMERAS, which will be released on Amazon next week. Here's the question my friend Tim raised:

Is it true that our cells die and are replaced every 7 days? Now it is my understanding that as we age the memory of the cells is that of the previous cell’s age. Can we turn off that memory and allow the cell to be a youthful one that replaces our older one or to replace them in such a way as not to age or at least not as rapidly?

Every cell in our body undergoes a certain number of replications before it dies. In children, cells replicate ten, maybe twenty times. By the time we reach our senior years, cells replicate once or twice and then die.

The "memory" Tim's talking about is the telomere, a non-coding part of the DNA that sits at the end of our chromosomes. Every time cells duplicate, the telomeres shorten: they lose about 100 base pairs with every cell division, until they reach a point that "signals" it's time for the cell to die. This mechanism prevents cells from replicating too many times, as each replication carries a certain risk of damaging the DNA. Telomeres shorten as we age, hence our cells undergo less replication cycles. What keeps us young is the ability of cells to regenerate.

Now, here's the interesting bit. There's an enzyme, called telomerase, which allows for the replacement of the telomeres. Not all our cells have this enzyme. It's expressed where it's most needed: in embryonic cells, because those cells need to divide many times in order to form a new person; in the immune system; in tissues that undergo periodic renewal.

So, if shorter telomeres means less cell divisions, and less cell divisions implies faster aging, could we possibly tweak this enzyme to keep the telomeres from shortening and effectively slow down aging?

Researchers from the Dana-Farber Cancer Institute [1] engineered telomerase-deficient mice by knocking out the TERT gene, which codes the telomerase enzyme. These mice, inbred through several generations, showed considerable damage to several organs, tissue atrophy, and half the life span of normal mice. The researchers then devised a clever way to reactivate the enzyme by activating TERT transcription only in the presence of a molecule called 4-OHT. In the presence of 4-OHT, in vitro cell cultures showed that the telomerese ends lengthened and cell proliferation resumed. Furthermore, after a 4-week treatment with the 4-OHT molecule, the degenerative damage induced by the lack of telomerase in the the knock-out mice was considerably reversed and their life span lengthened:

"Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signalling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines."

Do the telomeres hold the secret of eternal youth, then? All we would need to do is use the telomerase enzyme to prevent the telomeres from shortening ...

Unfortunately, there's a catch in all this. It's called cancer.

A cancer cell is a cell that replicates abnormally. In 1951 George Otto Gey took a few cancer cells from his patient Henrietta Lacks and propagated them in vitro. That cell line, called HeLa cells, is still alive today (I'm sure you've all heard or read Rebecca Skloot's wonderful book The Immortal Life of Henrietta Lacks). Henrietta's cells, placed on a feeding substrate, continue to replicate. If you did the same experiment with healthy cells, the cell line would eventually die because of aging. But the HeLa cells don't. They don't age. Why? You've guessed it. The telomere ends never shorten and there's no signal for the cell to die.

Bottom line: a cell that never dies is a cancerous cell. That's the immortality paradox.

It reminds me of Jorge Luis Borges's story, The Immortal. I was in high school when I read it the first time, and I clearly remember that until then it had never occurred to me that immortality could be such a sad state of mind as in Borges's story. All fantasy stories I had read portrayed immortality as a god-like quality. I think Borges was onto something.

[1] Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadiñanos J, Horner JW, Maratos-Flier E, & Depinho RA (2011). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature, 469 (7328), 102-6 PMID: 21113150

[2] Hartwig FP, Bertoldi D, Larangeira M, & Wagner MS (2014). Up-regulating telomerase and tumor suppressors: focusing on anti-aging interventions at the population level. Aging and disease, 5 (1), 17-26 PMID: 24490113