The immortality paradox

My friend Tim Bowen posed a really interesting question. Tim is a retired Los Angeles Police Officer, a writer, and a fantastic story teller. If you don't believe me, check out his book (Kindle edition available from Amazon), a collection of stories from when he was an LAPD street cop. A forewarning, though: don't read it in public places unless you don't mind people staring at you. Before you know it, you'll burst out laughing and everybody will be wondering what you've been adding to your breakfast cereal.

So, here's Tim's question:

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 is 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.

Of course, the concept is intriguing. What if we could use this amazing enzyme to rejuvenate our cells? That's what researchers from the Dana-Farber Cancer Institute did [1]: they 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 of reactivating 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."

Quite remarkable. So, is this the holy grail of anti-aging techniques?
Well, 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.

And on this sad note, I'm going back to Tim's book to cheer myself up.

Photo: pink clouds after the storm. Canon 40D, focal length 17mm, exposure time 1/20.

[1] Jaskelioff, M., Muller, F., Paik, J., Thomas, E., Jiang, S., Adams, A., Sahin, E., Kost-Alimova, M., Protopopov, A., Cadiñanos, J., Horner, J., Maratos-Flier, E., & DePinho, R. (2010). Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice Nature, 469 (7328), 102-106 DOI: 10.1038/nature09603