Hibernation and health

The University of Alaska Fairbanks (UAF) is a hotbed of arctic research. One particular branch of study concerns adorably rotund rodents called arctic ground squirrels (Urocitellus parryii). Like almost all ground squirrels, arctic ground squirrels hibernate to survive periods of resource scarcity. This unique adaptation is characterized by an extended period of inactivity, low body temperature and decreased metabolism.

Historically, researchers at UAF have focused on determining general hibernation parameters (e.g. when arctic ground squirrels drop into and come out of hibernation, extremes in internal body temperature and spring reproductive activity). Today, researchers are discovering how hormonal shifts in the brain and gonads during hibernation may signal the annual onset of reproductive maturation (males go through puberty each spring!).

Knowledge gained from hibernation studies may also support human health by broadening our understanding of, for example, cardiac arrest recovery and how to keep astronauts healthy during extended space travel.

Bringing together hibernation and telomeres

Alongside the investigation into arctic ground squirrels’ yearly hormonal cycles lies my own thesis work: using arctic ground squirrels as a new model to investigate how telomere length changes in a tissue-specific manner. “Telomere” is a bit of a buzzword. When I mention my work to non-scientists, many have heard of the term, know that it’s somehow tied to health and aging, and have a general idea that short telomeres aren’t ideal.

Allow me to provide a little more background onto what telomeres are, how they shorten and lengthen, and how telomere length could be used as a biomarker for health. After the telomere introduction, I’ll describe why looking at telomeres in a hibernator is a logical next step in understanding how telomeres change in vivo (within a living organism).

DNA and its special end-cap

To fully appreciate telomeres, it’s helpful to have a reminder of basic DNA structure.

DNA is the molecule that codes for the proteins responsible for nearly every cellular reaction in living organisms, including your body. DNA is made of two chains of nucleotide bases, with each base composed of one of four nucleic acids (T = thymine, A = adenine, G = guanine, and C = cytosine) and a sugar-phosphate backbone. Each nucleotide base pairs with its complement (T with A and G with C) to form a stable double helix (see below). These helices are organized into chromosomes, of which humans have 23 pairs.

Telomeres, the end caps of a chromosome, are related to aging and genetic protection of the chromosomes.

Telomeres, the end caps of a chromosome, are related to aging and genetic protection of the chromosomes.

Telomeres are the terminal sequences that cap both ends of each of our chromosomes. In humans, as in all vertebrates, the telomere sequence is TTAGGG and is repeated 300-8,000 times. Telomeres serve to maintain chromosome integrity through two mechanisms: they “hide” the end of the chromosome from DNA repair proteins (which, left unchecked, would join chromosome ends together!) and act as a buffer to prevent the breakdown of coding DNA (which translates into proteins). It is well known that telomeres erode over time due to an inability to completely replicate telomere ends during cell division. Thus, as an organism ages, its telomeres decrease in length.

Another mechanism of telomere shortening

Oxidative stress can also shorten telomeres via single-strand breaks. You may have heard of oxidative stress before, perhaps in connection with inflammation or disease. Oxidative stress is a state of unchecked oxidative damage, induced in part by mitochondrial activity and/or low antioxidant supply. As the energy suppliers of our cells, mitochondria produce reactive oxygen species (ROS) as a natural byproduct. These highly unstable molecules can bind to nucleic acids (particularly guanine, which telomeres are rich in) and impact their structure.

Although it has been shown that telomeres shorten in vitro (in a cell culture – think Petri dish) due to oxidative stress, it is unclear how oxidative stress affects telomeres in vivo. Most of what we do know about telomere dynamics in living systems comes from human and common laboratory animal (mouse and rat) studies. There is a need to quantify how telomere length changes over time in non-traditional animal models, and that’s where my research plays a part.

What happens during hibernation?

Hibernators like arctic ground squirrels are perfectly suited for studies of telomere dynamics in vivo as they can help us tease apart how telomeres change in a tissue-specific manner. When nestled in their burrows, hibernators undergo dramatic fluctuations in body temperature, from the lowest extreme of -2.9°C (26.8°F) in arctic ground squirrels to a normal temperature of 34°C (93°F). The rise from cold (torpid) to warm (aroused) body temperatures occurs a dozen or so times throughout hibernation, and each arousal cycle lasts about 40 hours.

Patterns of body temperature (solid line) and ambient temperature (dashed line) in a free-living arctic ground squirrel near Toolik Lake, Alaska. Reproduced with permission from the Journal of Experimental Biology. Williams et al. 2011.

Fueling these arousal cycles is brown adipose tissue (BAT), an organ that is commonly mentioned in obesity research (for example, see Leitner et al. 2017). BAT is rich in mitochondria, the cellular organelles that produce adenosine triphosphate (ATP). ATP is considered the body’s energy currency molecule. It is broken down to allow for muscle contraction, transport of ions and molecules through cell membranes, and making molecules to support growth and reproduction.

How does brown fat warm a hibernator?

In tissues other than brown adipose tissue, the primary function of mitochondria is to produce ATP via the electron transport chain with heat as a by-product. In contrast, BAT mitochondria contain a protein called UCP1 (uncoupling protein 1), which can cease the production of ATP and increase the amount of heat byproduct (see Brondani et al. 2012).

Brown fat cell rich in mitochondria and having lipid droplets scattered throughout. Credit: Manu5, via Wikimedia.
Brown fat cell rich in mitochondria and having lipid droplets scattered throughout. Credit: Manu5, via Wikimedia.

Brown fat accumulates in pockets surrounding the heart and brain stem in arctic ground squirrels. Replenished each fall, these fat stores are used up throughout hibernation to warm the animal during arousal episodes, a process known as non-shivering thermogenesis. As effective as BAT is at warming the animal, it comes at a price: a dramatic release of ROS accompanies UCP1 activity in BAT. As mentioned above, ROS interfere with nucleic acids and are known to shorten telomeres in vitro.

After all that: a cute squirrel photo. Also, what can telomeres tell us?

An arctic ground squirrel freshly emerged in spring 2013, North Slope, Alaska. Photo copyright Øivind Tøien, Insitute of Arctic Biology.

Often, scientific discovery is driven by the potential benefit that humans will gain. Can telomere research in hibernators support human health and longevity?

In a simpler world than ours, telomeres would work like this: a person lives for so long, participates in x amount of unhealthy activities and y amount of healthy ones, goes in to have blood drawn, the telomeres are measured, and the doctor tells the person how healthy they are and how long they can expect to live. In reality, it is far more complex.

Current research suggests that telomere length is a useful correlative marker for health but should be used in conjunction with other markers to generate a more complete health diagnosis. I like this idea, that telomere length is but one part of an incredibly complicated system — the human body — that is highly specific to the individual. And to better understand telomere’s role in affecting or measuring our health, I think that hibernator-focused telomere studies support a more nuanced, accurate understanding of how these special sequences work and their usefulness as health biomarkers.