Featured Article July 05, 2020

Telomere length in mice

Telomere length in animals is not significantly affected by inbreeding and domestication. It varies across strains and sub-strains of mice, as does lifespan, and there is no direct correlation between telomere length and longevity within a population.

The telomere conundrum

The use of mice as a model for human biology—as a stand-in for ourselves—began more than a century ago. Since that time, and for more than 90 years at The Jackson Laboratory (JAX), countless discoveries in mice have taught us about mammalian genetics, cancer, immunology, reproductive biology, neuroscience and much more.

Nonetheless, there have been questions about how well discoveries made in mice actually translate to human clinical care. Recently, conflicting data about the biology of telomeres, the specialized structures at the ends of chromosomes, has led to an assumption that puts into question the usefulness of mice for preclinical discovery and therapy development. The problem is, the assumption is wrong.

Why are telomeres important?

Telomeres are needed for cell division, and because they shorten with each cell division, over time cells become unable to divide. This has obvious implications for aging as well as for cancer, because cancer cells overcome the limitations of their telomeres and just keep dividing. If mouse telomeres have significantly different properties from human telomeres, that would certainly affect findings from aging and cancer research in mice.

What do people assume about mouse telomeres?

Carol Greider, who won the Nobel Prize for discovering and characterizing telomeres, observed more than 20 years ago that telomeres in some inbred mouse strains are significantly longer than they are in some wild species. The data indicated that telomere length isn’t a major factor in determining how long the mice live. But some researchers inferred that inbred laboratory strains, because of their controlled breeding regimens and other factors, had developed longer telomeres over time. If true, that inference had the potential to skew cancer and aging research data and the quality of the drugs and therapies ultimately produced based on mouse experiments.

How do you know the assumptions are wrong?

Further inquiry at JAX, in its efforts to fully characterize the mice it uses in its own research and distributes to the global biomedical community, has revealed that telomere length varies between mouse species and subspecies. Length is not determined by whether a mouse is inbred or wild-derived, and it is not affected by how long an inbred strain has been domesticated. Indeed, various wild-derived mice have telomeres that are shorter or longer on average than those of C57BL/6J, one of the original inbred mouse strains. And, as Greider hypothesized 20 years ago, telomere length does not predict lifespan.

What about cancer?

It is true that mouse cancers are different from human cancers, although in ways not involving telomere length. That is why cancer researchers are now developing and using better models for human cancer in experimental systems. An example is the ability to leverage patient-derived tumor tissue, in a system called PDX, for research in mice. Those mice can also be engineered to model a human immune response, a key component of cancer growth and therapy response, for more accurate preclinical testing.

How well do mice really model human disease?

Mice and humans share myriad biological similarities, and working with mice allows researchers to perform experiments that are simply not possible in humans, and in a much shorter time frame. Nonetheless, there are also important differences between mice and humans. As a result, JAX researchers are thoroughly exploring those differences so they may be understood and accommodated in biomedical research. Fortunately, modern research methods and tools have greatly increased our capacity to do just that, allowing a more complete understanding of the advantages and limitations of mouse-based biomedical research. The more we know about the biological details of different mouse strains—down to the molecular level—the better we can model the variation seen in human subjects. And, as our capabilities continue to expand, we can increasingly enhance our models and improve our ability to translate preclinical findings to the patients we need to treat.