The Triple Helix @ UChicago

Fall 2015

"Hydra and the Immortality Gene" by Irena Feng

 

Greek mythology told of a fearsome nine-headed monster named the Hydra. The fact that the Hydra had nine heads meant it was virtually immortal, for when one head was chopped off, two more would grow in its place. Today, over 2000 years later, the Hydra of legend no longer terrorizes society, but still lives on in a genus of small, freshwater animals called the Hydra. These centimeter-long organisms span only about 20 different cell types,[1] but underneath their apparent simplicity lies a secret ability that they share with their namesake: Hydra, despite their humble appearance, are immortal.

The Process of Growing Old

The large majority of a living organism’s genetic information is stored as DNA, which needs to be protected from damage. Each time a cell undergoes DNA replication in preparation for cell division, an unfortunate limitation on the proteins involved causes DNA at the ends of chromosomes to be lost. Over time, the persistent loss of genetic information could lead to serious problems for the cell and for the organism in general, like deformation or cancer.[2] Luckily, the cell has found ways to postpone this eventual crisis by capping chromosomes with repeated sequences of nucleotides called telomeres. These telomeres can be shortened freely, acting as expendable protection for the chromosome because they don’t code for any genes and can afford to be lost. 

Telomeres play a crucial role in the cell by protecting the chromosome from damage as well as indicating when DNA has reached the critical point in damage when it can no longer be repaired properly. Similar to how the plastic tips at the ends of shoelaces prevent them from fraying, telomeres keep chromosomes separate from each other, preventing ends from fusing together and other issues like DNA disintegration. These issues contribute strongly to chromosomal instability, which is one of the leading causes of the development of tumors and cancer.[3] Since telomeres shorten with each cell division, the length of a chromosome’s telomeres can indicate how many times a cell has divided.[4] Once a cell divides too many times, the telomeres can’t protect chromosomes anymore and so DNA damage accumulates, eventually causing the cell to commit cellular suicide (apoptosis).[5] Apoptosis is necessary so that the damaged cell does not continue to accumulate mutations, which could lead to the development of a variety of illnesses, including cancer. This gradual loss of dividing cells forms the basis of a process called replicative cellular senescence, which is the aging of the organism through effects on stem cell populations and the immune system.[4,6]  

Hydra are an exception to this rule, never aging despite frequent cell division. Cells in the Hydra’s three tissue layers are created and discarded in a flash, allowing for a constant displacement of cells away from the body column.[1] As cells continuously move outwards, they are quickly replaced. With so much cell division, one would expect Hydra to reach replicative cellular senescence rapidly. However, oddly enough, it has been proven that Hydra does not undergo senescence.[7] They can still succumb to the typical death, such as being ingested by other organisms, but theoretically, Hydra can exist forever in ideal conditions.

Telomeres,Telomerase, and the FoxO Gene

As mentioned above, telomeres shorten every time a cell divides, a situation that eventually leads to apoptosis for cells and senescence for the organism. To promote longevity, cells employ another mode of protection in the form of the enzyme telomerase. Telomerase is composed of RNA and a catalytic subunit[8,9] which work together to elongate telomeres during DNA replication to offset the normal shortening of telomeres. Despite being hailed as a miracle enzyme, telomerase is mysteriously absent in most differentiated cells, appearing only in cancerous and/or immortalized cells (mutated cells that just keep dividing). Unlike most organisms, Hydra cells utilize functioning telomerase to counteract telomere shortening. As a result, these cells have sufficiently long telomeres and do not age. 

Longevity and senescence strongly correlate with the FoxO gene in particular.[6,10] It is with FoxO that we can make a connection between a “longevity gene” and telomerase. FoxO transcription factors play many roles throughout the cell, from regulating apoptosis to counteracting stresses such as overheating or starvation.[11] They also control parts of the cell cycle, telling the cell when to do at checkpoints depending on internal and external signals. One protein in the FoxO family, FOXO3a, is a longevity factor – its overexpression leads to a marked increase in an organism’s lifespan.[12] FOXO3a prevents senescence by enhancing the expression of the gene coding for telomerase’s catalytic subunit,[13] thereby enhancing its activity within the cell. Therefore, FOXO3a plays a critical role in the regulation of telomerase activity. 

FOXO3a is strongly expressed in all cell layers of Hydra,[1] and is thus one of the primary factors contributing to Hydra’s ability to self-renew. The relationship between FOXO3a expression, telomerase, and longevity in Hydra suggests the possibility of a future where immortality transitions from a whimsical motif in Greek mythology to an attainable reality.

What About Us?

In addition to the constant presence of telomerase, Hydra’s asexual method of reproduction[1] also factors into its immortality. This method requires the presence of stem cells that constantly renew themselves in further cycles of cell division. Also, the more frequently cells divide, the easier it is to avoid a build-up of cellular and genetic damage since the cells are so quickly discarded. For humans, however, this rapid replacement of cells may not be as practical. Highly specialized cells such as neurons in the brain and cardiomyocytes in the heart depend strongly on their connections with other cells so that organs can function as cohesive units. Replacing cells would reset these connections and reduce the functionality of our complex organs. Despite this disparity between Hydra and humans, the similarities between genes are important to our understanding of how aging works. Although immortality still remains out of reach with our current levels of knowledge, future studies in senescence and immortality may help to uncover the key to longevity for the human race.

References

[1] Klimovich, Alexander, Anna Marei Bohm, and Thomas C.G. Bosch. “Hydra and the Evolution of Stem Cells.” In Stem Cell Biology and Regenerative Medicine, edited by Charles Durand and Pierre Charbord, 113-35. Denmark: River Publishers, 2015. E-book. https://books.google.com/books?id=yRjjBQAAQBAJ&printsec=frontcover
[2] Clancy, Suzanne. 2008. “DNA Damage & Repair: Mechanisms for Maintaining DNA Integrity.” Nature Education 1(1): 103. Accessed November 21, 2015. http://www.nature. com/scitable/topicpage/dna-damage-repair-mechanisms-for-maintaining-dna-344
[3] Wai, Lin Kah. 2004. “Telomeres, Telomerase, and Tumorigenesis -- A Review.” The Medscape from WebMD Journal of Medicine. http://www.medscape.com/viewarticle/482667
[4] Kuilman, Thomas, Chrysiis Michaloglou, Wolter J. Mooi, and Daniel S. Peeper. 2010. “The essence of senescence.” Genes & Dev 24(22): 2463-79. doi: 10.1101/gad.1971610. 
[5] Shay, Jerry W., and Woodring E. Wright. 2000. “Hayflick, his limit, and cellular ageing.” Nature Reviews Molecular Cell Biology 1(1): 72-76. doi: 10.1038/35036093. 
[6] Boehm, Anna-Marei, Philip Rosenstiel, and Thomas C.G. Bosch. 2013. “Stem cells and aging from a quasi-immortal point of view.” Bioessays 35(11): 994-1003. doi: 10.1002/bies.201300075. 
[7] Khokhlov, A.N. 2014. “On the immortal hydra. Again.” Moscow University Biological Sciences Bulletin 69(4): 153-7. doi: 10.3103/S0096392514040063. 
[8] Cong, Yu-Sheng, Woodring E. Wright, and Jerry W. Shay. 2002. “Human Telomerase and Its Regulation.” Microbiol. Mol. Biol. Rev. 66(3): 407-25. doi: 10.1128/MMBR.66.3.407-425.2002. 
[9] Zhang, Yong, LingLing Toh, Peishan Lau, and Xueying Wang. 2012. “Human Telomerase Reverse Transcriptase (hTERT) Is a Novel Target of the Wnt/-Catenin Pathway in Human Cancer.” J Biol Chem 287(39): 32494-511. doi: 10.1074/jbc.M112.368282. 
[10] Kenyon, Cynthia J. 2010. “The genetics of ageing.” Nature 464(7288): 504-12. doi: 10.1038/nature08980. 
[11] Dumas, Kathleen Johanna. 2013. “Characterization of Novel Regulators of FoxO Transcription Factors.” PhD diss., University of Michigan. 
[12] Carter, Matthew E., and Anne Brunet. 2007. “FOXO transcription factors.” Current Biology 17(4): R113-4. doi: 10.1016/j.cub.2007.01.008. 
[13] Boehm, Anna-Marei, Konstantin Khalturin, Friederike Anton-Erxleben, Georg Hemmrich, Ulrich C. Klostermeier, Javier A. Lopez-Quintero, Hans-Heinrich Oberg, Malte Puchert, Philip Rosenstiel, Jorg Wittlieb, and Thomas C.G. Bosch. 2012. “FoxO is a critical regulator of stem cell maintenance in immortal Hydra.” PNAS 109(48): 19697-702. doi: 10.1073/pnas.1209714109. 
[14] Yamashita, Shuntaro, Kaori Ogawa, Takahiro Ikei, Tsukasa Fujiki, and Yoshinori Katakura. 2014. “FOXO3a Potentiates hTERT Gene Expression by Activating c-MYC and Extends the Replicative Life-Span of Human Fibroblast.” PLoS ONE, 9(7): e101864. doi: 10.1371/journal.pone.0101864.

 
UChicago Triple Helix