Forever Young? Telomerase promises the possibility

[stephendare]

http://ouroboros.wordpress.com/2008/11/16/telomerase-expression-slows-aging/


Telomerase overexpression slows aging

Somatic cells may divide only a limited number of times before undergoing replicative exhaustion. Originally mysterious, the Hayflick limit (named after the scientist who first characterized it) is now understood at a mechanistic level: Each time a cell divides, the telomeres (repetitive DNA sequences found at the ends of each chromosome) become shorter; critically short telomeres trigger a permanent growth arrest known as cellular senescence. (Telomere shortening is in itself a consequence of the physical limitations of template-directed DNA replication; using the inevitable shortening of chromosome ends as a kind of physiological “clock” is a wonderful example of nature making a virtue out of necessity.)

Not all cells are mortal, of course: Germ line cells and the pluripotent somatic cells known as stem cells express telomerase, the enzyme the lengthens telomeres, and thereby sidestep the Hayflick limit. Stem-ness and germ-ness of a given cell aside, introducing the gene for TERT (the catalytic subunit of telomerase) appears to be sufficient to confer clonal immortality. Within a tissue, telomerase-expressing cells provide a theoretically infinite reserve of replacements for other cells that die due to tissue injury, wear and tear, or even the clonal death resulting from hitting the Hayflick limit.

Expressing telomerase in a wide variety of somatic cells would therefore seem a tempting strategy for lifespan extension. Specifically, telomerase expression could prevent any age-related decline in tissue function can be attributed to decreased regenerative potential.

We know why this is a non-starter, of course. Telomerase is tightly repressed in most somatic cells, and for a very good reason: What do you call a cell with an unlimited division potential that’s not a stem cell or germ cell? Usually “cancer.” Even for a tumor cell that has overcome the senescence checkpoints, the physical rules of DNA replication still apply, and telomeres will shorten every division until the cell is eating into its own coding DNA. Therefore, it’s essential for an ambitious young cancer cell to find a way to lengthen its own telomeres; indeed, this problem is significant enough that it’s considered one of the major steps in tumor progression. In any case, an organism with widespread telomerase expression in its somatic cells would very likely find itself dealing with multiple neoplasias â€" hardly the right animal in which to ask questions about division potential and lifespan.

But what if cancer couldn’t form for other reasons? In such a case, we could test the hypothesis that increased regenerative capacity confers increased lifespan. That’s precisely what a multi-lab collaboration from Spain has done; they find that mice that express TERT in most of their cells live significantly longer than the wildtype. From Tomás-Loba et al.:

    Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant Mice

    Telomerase confers limitless proliferative potential tomost human cells through its ability to elongate telomeres, the natural ends of chromosomes, which otherwise would undergo progressive attrition and eventually compromise cell viability. However, the role of telomerase in organismal aging has remained unaddressed, in part because of the cancer-promoting activity of telomerase. To circumvent this problem, we have constitutively expressed telomerase reverse transcriptase (TERT), one of the components of telomerase, in mice engineered to be cancer resistant by means of enhanced expression of the tumor suppressors p53, p16, and p19ARF. In this context, TERT overexpression improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span. These results demonstrate that constitutive expression of Tert provides antiaging activity in the context of a mammalian organism.

In mice expressing higher levels of three different tumor suppressors, cancer is essentially unable to form (one way to think about it is that tumors are delayed longer than the lifespan of the animal). In these animals, TERT indeed confers increased regenerative capacity and a significant increase in median lifespan.

Two questions, of many that one might raise:

First, why is the effect only on median lifespan? Inspection of the figures in the paper reveals that the cancer-resistant/TERT-expressing mice have a 50% survival time that is 20-30% longer than the wildtype â€" but by the time all of the oldest wildtype animals have died, so have all of the painstakingly engineered mutants. The clear implication is that exhaustion of regenerative potential is more relevant to early-life mortality than late-life mortality â€" counterintuitive, because one would expect regenerative failure to get progressively worse as a function of time, and to make an increasingly important contribution to mortality later in life.

Second: Mouse cells have really long telomeres, and telomerase expression is widespread in mouse tissues (though not usually at high enough levels to prevent some telomere shortening at every cell division). It takes mouse TERT knockouts around four generations of homozygosity to even begin to see a phenotype. Granted, mouse generations are far shorter than mouse lifespans, so this is not the same as saying that it takes four lifetimes for TERT to make a difference, or for replicatively senescent cells to begin to appear within a given mouse. But still, it makes me wonder what’s going on. Could telomerase be doing something else â€" i.e., something other than lengthening telomeres â€" that is particularly important in determining median lifespan?

[Jason]

Man, its only a matter of time before stuff like this hit the mainstream and we're all living MUCH MUCH longer.  I still believe that there will always be an eventual end to life, but the idea of staying younger for longer seems very feasible, especially after reading that.


Great article Stephen.

[BridgeTroll]

Artificially extending lifespans sounds great... especially to me!  This advancement would bring other social, scientific and moral problems.

Population growth, retirement age and benefits, medical costs, jobs and employment, the list goes on...

[Ocklawaha]

We've been there, Done that:

Timothy Leary's dead.
No, no, no, no, He's outside looking in.
Timothy Leary's dead.
No, no, no, no, He's outside looking in.
He'll fly his astral plane,
Takes you trips around the bay,
Brings you back the same day,
Timothy Leary. Timothy Leary.

Timothy Leary's dead.
No, no, no, no, He's outside looking in.
Timothy Leary's dead.
No, no, no, no, He's outside looking in.
He'll fly his astral plane,
Takes you trips around the bay,
Brings you back the same day,
Timothy Leary. Timothy Leary.

Along the coast you'll hear them boast
About a light they say that shines so clear.
So raise your glass, we'll drink a toast
To the little man who sells you thrills along the pier.

He'll take you up, he'll bring you down,
He'll plant your feet back firmly on the ground.
He flies so high, he swoops so low,
He knows exactly which way he's gonna go.
Timothy Leary. Timothy Leary.

He'll take you up, he'll bring you down,
He'll plant your feet back on the ground.
He'll fly so high, he'll swoop so low.
Timothy Leary.

He'll fly his astral plane.
He'll take you trips around the bay.
He'll bring you back the same day.
Timothy Leary. Timothy Leary.
Timothy Leary. Timothy Leary.
Timothy Leary.

OCKLAWAHA

[Jason]

Where does the line form for the "telo" shots?! 

[St. Auggie]

This is truly what Ponce was looking for.  I laughed because I saw the title of the thread and thought "dont we aleardy know this?", until I saw the date of the actual posting. Always on top of things Stephen! This is not something knew and the only real question is which happens first: perfecting this or just regrowing new bodies to download our thoughts into. Its a brave new world!!!

[Captain Zissou]

How coincidental.  I just watched a lecture by Aubrey De Gray yesterday.  He says that some people who are alive today will live to 1,000.  He's a bit wacky, but this article is much more believable.

[KenFSU]

Man, its only a matter of time before stuff like this hit the mainstream and we're all living MUCH MUCH longer.

This is the part that I'm not necessarily sure about. If and when such treatment becomes available to the public, it surely isn't going to be cheap. I really fear a society where the same 5% that control the majority of America's wealth are able to extend their lives much, much longer than that of the working class American.

[Captain Zissou]

http://www.ted.com/talks/aubrey_de_grey_says_we_can_avoid_aging.html

The comments below the video are pretty interesting.  People discussing what it would look like to live 1,000 years, and what that would do to the economy.  Also, what would motivate and sustain us mentally if longevity wasn't an issue.   

[Jason]

Could the human brain even store a few hundred years worth of information and still function properly?

[Jason]

God only knows what you could tell about Lady GaGa and Teletubbies....



Seriously, how could our minds adequately sustain that much information for that long?  I've read that mental exhaustion (essentially overload) could be a potential contributer to dimensia as old age sets in.  Would the Telo actually improve brain function as well?