Dynamic telomeres and the aging process

My name is Sara Wilbur. I’m a third-year masters student in biology at the University of Alaska Fairbanks.

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Me and my dog Junie biking the White Mountains trail. Photo credit: Jason Clark.

I’ve written for NiB before, about work-life balance in academia, and yesterday I was introduced as the newest contributor to NiB. I’m very excited to write for this wonderful project! You can expect future articles to focus on telomeres, arctic ground squirrels/hibernation, and scientific life in Alaska.

Aging, DNA structure, and the dynamic telomere

The mind simplifies difficult concepts to support graspability. One example of this tendency is found in our attempts to define the aging process. Aging is complex, nuanced, and expressed differently across individuals. It would be quite useful if there was a quantifiable “thing” in the body that indicated how long an organism had left to live. In the mid-1970s, a discovery came that presented itself as a solution to the problem of measuring age: protective, terminal chromosome sequences known as telomeres.

2930423615_5320362dea_o.jpgAging is complex and nuanced. Photo credit: Flickr.

As is widely understood, DNA provides the molecular “blueprint” for all organisms, influencing what they look like and how they behave. The particular nucleic acid sequences (the Ts, As, Gs, and Cs) of an individual’s DNA codes for specific proteins, which are involved in virtually every cellular process. However, of all the DNA you have, only 1% of DNA contains coding sections. Initially considered “junk DNA,” the remaining 99% of noncoding DNA fulfills many important functions, including transcriptional regulation (turning genes “up” to make more of a particular protein or “down” to lessen protein production) and DNA protection, a duty fulfilled by the dynamic telomere.

Telomeric duties

Telomeres have two main purposes. One is to maintain chromosome integrity. If you’re a molecule of DNA, a double-strand break is cause for alarm. Fortunately, DNA repair enzymes are recruited to double-strand breaks, allowing DNA to replicate properly and be transcribed faithfully. However, if you think about it, a chromosome end could be seen as a double-strand break. What prevents chromosome ends from being unnecessarily repaired? It turns out that telomeres aren’t simply naked DNA sequences, but are instead intimately associated with several proteins in a complex known as shelterin. Shelterin proteins help the telomere fold back and associate with itself. This forms a “t-loop” to essentially hide and protect the chromosome end.

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Telomeric structure and associated proteins. Figure credit: Blackburn et al. 2015.

Perhaps more famously, telomeres also act as a buffer to prevent coding DNA erosion during cell replication. An important consequence of the evolution of linear chromosomes (found in all eukaryotes, from yeast to elephants) is that a few nucleotides are lost with each round of cell division. The DNA replication machinery cannot fully replace the outermost nucleotides, so the DNA strand gets shorter over time. As it is the telomere sequence that caps chromosomes, it is these sequences—rather than the DNA in between—that take the hit.

How are telomeres implicated in the aging process?

Telomere shortening over time is thought contribute to the aging process. Before I describe why this might be, let’s explore a more fundamental idea: what is aging, anyway? Basically, it’s a loss of physiological—or bodily—function. A proposed root case of declining functionality in the body is cellular senescence, or when a cell ceases dividing; a buildup of these cells within a tissue is associated with aging. Telomere shortening is one cause of cellular senescence: when telomeres reach a critically short length, cells cease to divide. This is a mechanism to prevent cells from becoming cancerous. However, there is a tradeoff: a buildup of senescent cells that can no longer induce tumor growth could be driving the aging process.

Telomere length does change with time, but shortening is also influenced by lifestyle and genetics. Some species have “mega-telomeres” (including mice, which are a common model for in vivo telomere length research), which have a different biology than more run-of-the-mill telomeres (as we humans possess). To further complicate matters, some species possess the enzyme telomerase in their body cells. This enzyme replaces lost nucleotides, essentially preserving telomere length over time. However, telomerase isn’t the answer to short telomere’s prayers: 80 to 90% of all cancers are associated with over-active telomerase activity.

The future of telomere research

The initial excitement surrounding telomeres’ discovery forty years ago and the potential for its use as a simple biomarker of aging and disease are still with us today. However, like any biological process, telomere dynamics are much more complicated than we first thought. For instance, while there is overwhelming evidence from the past few decades that telomeres do decline with age across species, it is still unclear if telomere length can accurately predict calendar age. The future of telomere research will continue to evolve away from cell culture work into living systems, and from common laboratory animals to a wider species diversity, including ectotherms (“cold-blooded” animals), plants, and hibernators. Stay tuned for more on telomere dynamics in these “non-traditional” organisms!

What’s happening in hibernator telomeres? Juvenile arctic ground squirrel hiding in some willows. Photo credit: the author.