A paper that became available today in Cell from the Spanish National Cancer Centre (CNIO) reports on the anti-aging effects of telomerase in cancer resistant mice.

Traditionally, the anti-aging effects of telomerase have been poorly explored because of its unfortunate cancer-promoting activity. Consequently, the researchers genetically engineered cancer-resistant mice by up-regulating their expression of tumor suppressor proteins p53, p16, and p19ARF.

TElomerase Reverse Transcriptase (TERT, or just ‘telomerase’) was additionally overexpressed to observe the anti-aging effects of increasing its concentrations in the cell. It was found that TERT overexpression improved the fitness of epithelial barriers (particularly the skin and the intestine) and produced a systemic delay in aging, as well as an actual extension of the median life span.

Also, the genetically enhanced mice showed a better preservation of both the thickness of the epidermis and of the subcutaneous fat layer compared to the controls. What this means is, if they were humans, one of the main factors that is the cause of the appearance of old age, i.e. subcutaneous fat loss, would be somewhat reduced.

Interestingly, with regard to their lifespans: The mice that had their tumor suppression capabilities enhanced, but lacked TERT enhancement, saw no increase in lifespan. Those mice with both modifications saw a 26% increase in median lifespan. Of these mice, those that did not die of cancer (i.e., those that could be considered to have died of ‘old age’) experienced a 38% increase in median lifespan.

Translated into human terms, this would make living to an age of 110 years commonplace.

All in all, this is a very exciting study that suggests that if we can somehow eliminate the threat of cancer, steps towards markedly slowing the rate of aging are definitely in the pipeline. This is just one of the many fronts on which aging is being gradually defeated by the force of human ingenuity. I’m looking forward to the future developments of this research!

Some brief fundamentals:

What are telomeres?
Inside the nuclei of our cells, DNA doesn’t just sit there in a loose, tangled string. It is highly organized, with several orders of organization that become apparent as it is viewed at an increasing scale. At the smallest level, DNA is wrapped around a disc-shaped protein called a histone octamer. There are many of these histone complexes running along the DNA strand, giving it a ‘beads on a string’ appearance. These ‘beads’ are refered to as ‘nucleosomes’.

Nucleosomes then arrange themselves into fibrils, then the fibrils are super-coiled into chromatin fiber. The chromatin fiber forms loops or ‘domains’ ranging from 30,000-100,000 base pairs in length, which are eventually aggregated to form the highest order structure, the chromosome. It can be thought of as coils upon coils upon coils upon coils, and this is how such a long strand of DNA (around 3 metres in humans) can fit inside the nucleus of a cell.

At the end of each chromosome is where we find the telomere. Telomeres consist of short, repeating, TG-rich DNA sequences. Human telomeres have a variable number of repeats of the sequence 5′-TTAGGG-3′, which can extend for several kilobases.

What causes telomere shortening?
Functional telomeres are essential for continuous cellular proliferation; however, maintaining telomeres of adequate length is problematic for the cellular machinery. For a variety of complicated hypothetical reasons to do with the mechanics of DNA replication, each time the cell divides, the two resulting chromosomes have slightly shorter telomeres than the original.

The average rate of loss is estimated to be around 50-75 base pairs per telomere per cell division.

To compensate for this loss, we have the enzyme telomerase. Telomerase is a multisubunit RNA-containing complex related to viral RNA-dependent DNA polymerases (reverse transcriptases). It is the enzyme responsible for telomere synthesis and thus for maintaining the length of the telomere.

In adult cells, telomerase is inactive or only present at very low levels. It has been suggested that the purpose of this progressive erosion of the telomeres, coupled with the progressive inactivation of telomerase, is to place an upper limit on the number of times a cell can divide, so that cells whose proliferative schedule is corrupt – i.e., tumors – will be automatically limited to a set number of replications, limiting the potential for damage. Of course, cunning as they are, tumors often turn the production of telomerase back on, thereby immortalizing themselves.

Telomere shortening prevents cancer, but promotes aging
Because our cells have an upper limit placed on their proliferative capacity, at some point in time they lose their ability to replicate. As we grow older, the regenerative capacity of our cells deteriorates, and this is considered to be one of the main reasons that we age.

So, we’re faced with a dilemma: If we activate telomerase, we facilitate the unrestricted cellular division that is cancer; if we inactivate it, our life force is doomed to eventually grind to a sad, grey halt.

Fortunately for the mice in the above study, they were genetically engineered to have super tumor-resistant cells.

What are p53, p16, and p19ARF, and how do they prevent tumors?

p53 is a transcription factor that has the following important properties:

• It can activate DNA repair proteins when DNA has sustained damage.
• It can also hold the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.)
• It can initiate apoptosis, programmed cell death, if the DNA damage proves to be irreparable.

p16 is a gene that can produce a protein that can interact with and sequester MDM2, a protein responsible for the degradation of p53. So in essence, p16 stops p53 from being destroyed, maintaining adequate levels in the cell.

p19ARF is a mouse protein that also regulates MDM2’s ability to inhibit p53. The absence of the gene that encodes this protein (INK4a) leads to inappropriate cell survival and a higher incidence of cancer.

Reference: Telomerase Reverse Transcriptase Delays
Aging in Cancer-Resistant Mice. Cell 135, 609–622, November 14, 2008

Photo credit: lesliemiperry, Flickr