Science AMA Series: I am David Zappulla, from Johns Hopkins University. I research telomeres, the caps that protect the ends of chromosomes in eukaryotic organisms from baker’s yeast to humans. Ask Me Anything about the role of telomeres in aging and cancer AMA!

Abstract

Hi Reddit, I am David Zappulla, an NIH-funded researcher in the Department of Molecular Biology & Genetics at Johns Hopkins University’s School of Medicine. I am here so you can Ask Me Anything about telomeres, which protect the ends of chromosomes in eukaryotic organisms from baker’s yeast to humans, and the enzyme telomerase, which is dedicated to the critical job of replenishing eroded telomeres.

In order for a cell to divide into two, it must first make a copy of its genome. The genome of each cell is composed of linear chromosomes, from yeast to humans. Linearity poses a serious problem, since DNA polymerases cannot completely replicate ends. This end-replication problem must be addressed somehow, or else chromosomes whittle down with each cell-division cycle, ultimately causing cellular senescence and death.

The Nobel-prize-winning (https://www.nobelprize.org/nobel_prizes/medicine/laureates/2009/) enzyme telomerase solves the end-replication problem by replenishing telomeres during the process of human reproduction, resulting in offspring with full lifespan potential. However, by adulthood, telomerase is no longer present in the cells of most tissues in the body, leading to progressive telomere shortening with age. In contrast, most cancer cells aberrantly regain telomerase expression, permitting dangerously unchecked cell-proliferation potential. Thus, at least conceptually, telomerase has represented a tantalizing potential drug target for treating cancer and/or promoting healthy longevity.

My lab is working to understand how telomerase maintains telomeres at the molecular level. My colleagues and I have just published a paper in Cell (http://www.cell.com/cell/abstract/S0092-8674(17)31450-2)http://www.cell.com/cell/fulltext/S0092-8674(17)31450-2) that includes discovery of the long-sought, three-dimensional structures for both of the complexes of proteins and RNA that physically recruit the telomerase enzyme to chromosome ends in yeast. These new structural insights — spurred my lab’s 2015 eLIFE article (https://elifesciences.org/articles/07750) — move us closer to understanding the molecular mechanism by which telomeric DNA is maintained by the telomerase RNA-protein complex in yeast. My lab’s ongoing study of the molecular mechanisms of telomerase function in the advantageously manipulable yeast organism helps to pave the way for better understanding telomere biology in humans, and hopefully also identifying interventions to improve our health.

I am excited to read and respond to your questions at 1 pm. Today, January 22!

How do organisms that have achieved a functionally infinite lifespan through telomere regeneration protect themselves against deleterious side effects such as increased disposition towards cancer? If this is still a subject of ongoing research, are there any leads?

Thank you for your time

asnell91

That is a great and fascinating question that I would love to answer (and so would many other basic researchers). This is certainly still an active research area. To my knowledge, many of the known “negligibly-aging organisms” are not life forms that get cancer, but please let me know if you have a specific organism in mind and we can talk more!


Hey man, thanks for doing this. What effect do foreign substances like medications/alcohol/drugs have on tolomeres?

MarkMajorRadio

This is just now starting to be investigated more thoroughly. What is becoming clear is that various aspects of stress — in a wide variety of forms — seems to have negative impacts on telomere length. However, my sense is that careful studies on medications are in their infancy and there are so many, and the experiments are so challenging, that it will take a long time to determine which drugs are substantially impacting telomere length.

In baker’s yeast — the organism that I research — these experiments are quite a bit easier than they are in humans, and it is becoming clear that alcohol lengthens telomeres, whereas caffeine shortens them. At this point, dozens of common molecules have been tested in yeast, but their relevance to human beings is still unknown. You can read more about similar research by my colleague Martin Kupiac here: https://www.sciencedaily.com/releases/2013/12/131205142127.htm


Hi and thanks for joining us today!

Is telomere biology relatively the same across in the Animal Kingdom?

What are the phenotypic consequences if there are differences?

PHealthy

Very interesting question. The short answer is yes, and also no. ;) All eukaryotes have some form of telomeres at the ends of their chromosomes, but not necessarily the same system to maintain them. Some animals, such as fruit flies, have telomeres, but they do not have telomerase to make them. All organisms with linear chromosomes must have a dedicated means to replicate their chromosome ends since they are all subject to what is called “the end-replication problem.” In the case of the telomerase-deficient fruit flies, they have a DNA recombination system that protects the ends of their chromosomes from being whittled away by “copy and pasting” telomeric DNA bits from other chromosomes to where the ends where they are needed.

In general, including organisms outside of the animal kingdom, there are some astonishing differences in telomere length between organisms. We basic researchers are learning a lot from looking at evolutionary conserved features of telomerase and telomeres, as well as the aspects that seem — at least at first blush — not to be conserved. Oftentimes, first looks can be deceiving and things that may not be shared between organisms can turn out to actually be similar! We can even learn interesting and important things about aspects that are specific to certain organisms.

Although they are not animals, ciliates are one extremely interesting organism when it comes to telomeres. Telomerase was originally identified in this life form by Carol Greider and Elizabeth Blackburn, leading to them receiving a Nobel Prize in 2009 (https://www.hopkinsmedicine.org/news/media/releases/telomere_expert_carol_greider_shares_2009_nobel_prize_in_physiology_or_medicine). These organisms develop two nuclei in their lifetime. One holds all of the genetic information needed for cellular division while another is used for “day to day” genetic needs. This “macronucleus” has a highly amplified version of the genome, where it has been copied into many gene-sized fragments. Telomerase attaches telomeres to the ends of each fragment, resulting in thousands of “mini chromosomes,” in contrast to the 92 telomeres in a human cell.


Is there any evidence to suggest that a potential therapy manipulating telomeres / telomerase could have a regenerative effect on neurodegenerative disorders? Or at least preventative?

Thank you for your time

asnell91

I am not an expert on this topic. However, I can speculate that neurons are believed to be post-mitotic, meaning no longer dividing. Since the end-replication problem is linked to cell duplication cycles, neurons probably don’t face much of an issue with maintaining their telomeres.


Are there any reliable ways we've learned within our personal control to improve the lifespan of our telemores? Or is it really all just a gamble of genetics and environment? Thanks for doing this, super interesting stuff.

HFXmer

Therein lies the million-dollar question. I can’t speak to what is on the market at this time, but your question gets to whether there are supplements, drugs or lifestyle changes that can be undertaken to extend our lives. Obviously, this is a question of great importance and interest to us all. The evidence thus far points towards exercise and a nutritious, limited-calorie diet as being good bets for extending ‘healthspan’ and perhaps also lifespan. The most famous research that has been done regarding this question is probably the encouraging studies involving caloric restriction, but there is also still some debate as to what is quantitatively a calorically-restricted diet for any given organism along their lifespan. Overall, the answer to this critical question is still being investigated. Furthermore, we don’t know yet if it’s the shortest telomere or the average length of all your telomeres that affects aging the most.


Any suggestion we can stop aging in humans any time soon?

in4real

We have not stopped the aging process in any model organism so far, so we are still quite a ways from halting aging in humans. We have had some success increasing lifespan in certain model organisms and seemingly improving their fitness. We hope that this will soon lead to evidence-based approaches to do the same in humans. Ironically, we are all aging as the research is done on our own harder-to-study species! My sense is that we need to avidly invest in basic research so that we can come up with compelling modes of improving human health and lifespan. Before we reach these evidence-based approaches, we need to be cautious of aging “cures” on the market before we are able to test their efficacy. Meanwhile, eat your veggies and go out for a run or walk!


Could you talk about potential tradeoffs/cost-benefit that might occur trying to manipulate such ubiquitous system pharmacologically? I could see benefits of being able to access a switch like this in a cancer to a specific organ system, but what systematic effects might you expect? Are there areas/organ systems where telomerase activity is adaptive that may be impacted?

oak_F

I think you’re thinking about this correctly. Telomeres are at the center of a yin-yang relationship between aging and cancer. In a simplistic point of view, more telomerase should lead to greater potential lifespan. However, increased levels of telomerase could also tip the scale towards cancer. For this reason, it is believed that the natural shortening of telomeres with lifespan is a form of tumor suppression. There were some interesting studies done in mice that relate directly to your question and this balancing relationship. Maria Blasco (http://www.sciencedirect.com/science/article/pii/S0092867408011914?via%3Dihub) showed that increasing telomerase expression in mice led to more tumors, but if her group also increased the levels of tumor-suppressing genes, this afforded an increase in lifespan without as much cancer development.

As for your last question, one reason why telomerase is an attractive potential target for drugs is that it is essentially absent in adult tissues of the body, except for the germ line (i.e., cells that turn into sperm and eggs). So, drugs that would attack a telomerase-expressing tumor should be relatively specific to the cancerous cells. However, this drug might indeed affect the patient’s reproductive system. There are some telomerase-targeting drugs that are being investigated, such as imetelstat, but I must refer you directly to those researchers (Drs. Jerry Shay and Woody Wright at UT Southwestern) for more on this topic.


Can a telomere be completely destroyed?

Pandasarecute89

I assume that you mean completely destroying a telomere without the cell dying. The short answer is no. However, there was an interesting study done by Drs. Peter Baumann and Tom Cech in fission yeast (http://science.sciencemag.org/content/292/5519/1171), which has only 3 chromosomes. In the absence of telomerase, their telomeres shortened, as in any other organism, but ultimately the chromosomes rearranged into a circular form, protecting their ends from further erosion. I don’t think this is likely to be possible in humans, which have 46 chromosomes — the hypothesis is that the more chromosomes they have, the less likely it is that the ends of each individual chromosome could find one another.


Is there any research into the telomeres of mitochondrial DNA, and specifically is telomere shortening also found there?

mr-nixon

There are some organisms that have linear mitochondrial genomes, but most are circular, including in humans and yeast. To my knowledge, the mitochondrial genomes that are linear have a telomerase-independent mechanism to maintain their DNA ends. However, I’m not an expert in this field of telomere biology, though it is fascinating.


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