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 — 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 — 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 — 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 — i.e., something other than lengthening telomeres — that is particularly important in determining median lifespan?