Telomere Dynamics in Mice are Not the Same as in Human Tissues

There is a lot of interest in telomeres and telomerase these days, and in particular the prospect of slowing some aspects of aging by increasing the gene expression of telomerase. Life span has been extended in mice through telomerase gene therapies, for example, and BioViva claims a human implementation. I suspect they are only the most vocal initiative, and I doubt that the patient there is the only individual to have undergone telomerase gene therapy, given how widely available gene therapy technologies have become in the past few years. I am cautious on this front, however, and one of the cautions I usually bring up is that telomere dynamics in mice are different from those in humans, and different in ways that are probably important in this matter. I'd want to see studies of telomerase therapies in mammals with more human-like telomere dynamics before taking the leap myself. But what do I mean by different? The open access paper I'll point out today is a review of telomeres and telomerase in our two species; if you want an overview the details, then take a look.

Telomeres are repeating DNA sequences tacked onto the ends of chromosomes. Every time a cell divides, a little of that telomere length is lost, and when it becomes short enough a suite of mechanisms ensure that the cell self-destructs or irreversibly halts replication. This is the basis for the well known Hayflick limit: that ordinary somatic cells that make up the bulk of our tissues only divide so many times and then stop. Stem cells, however, use telomerase to lengthen their telomeres as necessary, and thus can continually deliver a supply of new cells with long telomeres to support tissues by replacing cells that have reached the limit. This arrangement only really makes sense in the context of cancer: the setup in which only a tiny number of cells have privileged replication rights exists because it keeps the cancer rate low enough to allow for complex, structured species such as ourselves and our ancestors.

As I'm sure you're aware, average telomere length as presently measured in white blood cells tends to fall with aging, but this is a complicated number. It depends on a mix of (a) the rate of cell division, which in the immune system relates to health in a number of ways, and (b) the activity of stem cells as they deliver new daughter cells with long telomeres into the tissue they support. Stem cell activity declines with age, and this is probably enough to expect declines in average telomere length. Thus telomere length looks a lot like a marker of aging, not a cause. Even so, in immune cells there are so many environmental influences on cell division and replacement rates that it is a bad marker of aging - only useful over populations, in statistical studies, and not all that helpful for individuals.

Increasing the activity of telomerase will result in longer telomeres. The primary role of telomerase is to add new repeating sections of telomeric DNA at the ends of chromosomes. Longer telomeres produce cells that will divide more often, but it also means that more worn cells will survive rather than be destroyed, and more damaged cells will undertake more activity. If telomerase activity is increased in all or a majority of cells, the result might look somewhat like the effects of much greater stem cell activity, but with the addition that the extra cells are older and more damaged. In stem cell populations, more telomerase may also spur greater stem cell activity in and of itself. The consensus view is that all of this will likely increase cancer risk, but in mice telomerase gene therapy both slows aging and reduces cancer risk. This may be because immune function is improved, and thus more cancerous threats are defeated than are produced, but there is no assurance that the balance of changes will work out the same way in humans.

Human Specific Regulation of the Telomerase Reverse Transcriptase Gene

In humans, telomeres serve as an aging clock because most somatic cells lack telomerase (i.e., hTERT) expression and their telomeres progressively shorten upon successive cell division. Indeed, studies have shown that telomere shortening is a critical factor of human aging and its stabilization is essential for the development of most human cancers. Human TERT (hTERT) expression increases significantly during tumorigenesis, correlating with the increased proliferative potential of cancer cells. Telomere length regulation and mechanisms of proliferative senescence are not evolutionarily conserved, even among mammals. In a comparative analysis of telomere length and telomerase expression in cells of over 60 mammalian species, researchers concluded that the ancestral mammalian had human-like short telomeres and repressed telomerase expression. Cells in these animals undergo replicative aging, providing a barrier for tumor progression. On the other hand, many other mammals, especially some of the smaller and shorter-lived animals, such as rodents, telomeres become much longer, and telomerase is found in most somatic tissues. These studies provided a conceptual framework for understanding different telomere homeostasis in mammals and identified the need to use appropriate models for studying the role of telomere in human cancer and aging.

Laboratory mice are the most commonly used animal models for human development, aging, and diseases. While telomere length serves as a critical counting mechanism for cellular senescence in human cells, mice do not exhibit telomere-mediated replicative aging. Compared to humans, telomere homeostasis in mice is distinctive in two ways: Laboratory mice express ubiquitous telomerase activities in somatic tissues and possess long heterogeneous telomeres. There exist significant differences in telomerase expression between humans and mice. Unlike the hTERT, which is not expressed or expressed at extremely low levels in the most of human somatic tissues and cells, the mouse TERT (mTERT) expression is found in most adult tissues and organs. This difference likely results in, or at least contributes to, much longer telomeres (50-100 kb) in laboratorial mice, in comparison to human telomere (5-15 kb). As a result, telomere length is not apparently a limit to cellular lifespan in mouse cells.

Mouse models of human diseases have become a central part of biomedical research. Laboratory mice provide the most experimentally accessible mammalian models that share genes, organs, and systemic physiology with humans. However, many mouse models do not comprehensively mimic human disease progression, posing challenges in their exploitation to study human diseases. This may have contributed to the high failure rates of human clinical trials, particularly in oncology, predicating the need for improved preclinical data from mouse models. A principal difference between mice and humans relates to a longtime observation that murine fibroblasts grow in culture undergo spontaneous immortalization at a high frequency, owing to their long telomeres and constitutive telomerase expression. In conclusion, hTERT expression strictly limits telomerase activation in most of somatic cells, whereas mTERT expression is detectable in most of mouse tissue cells. The interspecies differences between human and mice suggest an improved mouse line, in which both telomerase regulation and telomere length controls are humanized, would considerably benefit the studies of human aging and cancer using mouse models.

Comments

You forgot it's interaction with the wnt pathway which acts in a growth hormone like manner. Telomerase also plays a vital role with mitochondrial function via p53 and the pcg1a pathway. Blasco will get it to work safely in humans if anyone can.

No comment on the claims of others testing it in humans I'm sure the full story will be revealed in time.

Posted by: Steve h at July 8th, 2016 4:54 AM

Telomere shortening is an indication of oxidative damage. There are telomere-lengthening products on the market, but actually a good antioxidant will do that. Telomere lengthening is not a longevity marker per se.

Posted by: Bill Sardi at July 10th, 2016 11:59 AM

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