Lack of Senescence in Hydra by Byron Lee

Why should Hydra become a model organism for aging research?

The quest for eternal life has endured over centuries and thousands of years. Some people believe we are on the brink of finding the cure for aging. Currently, we can regenerate the liver, kidney, heart, and cartilage. This process does not use embryological stem cells. Instead, adult stem cells can be used to form new organs on the structure of a donated organ. This reduces the possibility of rejection and any other possible complications. In addition to using a donated organ’s structure, there are printers that will be able to recreate the cardiac skeleton. There are not many animals that can regenerate or lack aging. There is an exception that is fast becoming a model for aging research: Hydra. Hydras seem to be biologically immortal and have virtually unlimited regenerative potential in the right environments.

Hydras are small (~1-3 mm), solitary, cnidarian polyps that can be found in unpolluted freshwater pools and streams. On the underside of vegetation, these simple multicellular animals grow and reproduce as stalks. They basically consist of a stalk containing a gastric cavity with tentacles around the opening.  An acellular mesoglea resides within two germ layers, which are the ectoderm and endoderm. They may lack multiple tissue organs, but do have a diffuse nervous system. The primary reproduction method is asexual, but some conditions can lead to sexual reproduction. (Austad 2009)

Hydra vulgaris lacks senescence since it lacks an increasing mortality rate due to aging, which the time period of experiment was 4 years. Induction of sexual reproduction results in increasing mortality with age and survival around 4 months on average. Multiple physiological functions also show deterioration. Aging and the absence of aging can be found in the same species, which makes a great model organism for aging research. (Austad 2009)

Hydra magnipapillata’s has been sequenced and can act as a better model organism. Transgenic animals have been produced by injecting a plasmid with the green fluorescent protein into oocytes. Bacteria producing dsRNA have been fed to Hydra and resulted in gene silencing. Overall, Hydra are on the cusp of being excellent model organism for aging research. (Austad 2009)

Genome

Hydra is an important model for studies of axial patterning, stem cell biology and regeneration. The genome of Hydra magnipapillata has been sequenced and compared to the genomes of other animals. It’s genome has been shaped by quick expansions of transposable elements, horizontal gene transfers, trans-splicing, and simplification of the gene structure and gene content. The simplification of the gene structure and gene content paralleled the simplification of its life cycle. When comparing this genome to other genomes of other animals, comparisons can be made in regards to the evolution of epithelia, contractile tissues, developmentally regulated transcription factors, the Spemann-Mangold organizer, pluripotency genes and the neuromuscular junction. (Chapman, Kirkness et al. 2010)

Proof for Lack of Senescence

Senescence is a deteriorative process that increases the probability of death of an organism with increasing age. This has been found in all animals so far. Cnidaria are one of the earliest diverging groups from the metazoans. Hydra is a member of this group and researchers think that they may be immortal. They are capable of refreshing the tissue of their bodies. Within a study by Daniel E. Martinez, he was able to test for the presence or absence of aging. This included following three cohorts of Hydra for a period of four years, which suggests that there is no evidence of aging. He found that mortality rates remained extremely low and that there were no apparent signs of decline in reproductive rates. (Martinez 1998)

Hydra has a very simple body plan. It consists of a foot or basal disk at one end and a head on a tube at the other end. The head has two parts: the apical hypostome, or mouth region, surrounded by the tentacle zone, which around six tentacles emerge. Two epithelial layers compose the body wall that is separated by the mesoglea, which is an acellular basement membrane. Within the body, there are only about 20 cell types that are split into three cell lineages: two epithelial and one interstitial. Each of these lineages consists of a population of stem cells with indefinite self-renewal capacity and several differentiation products. Epithelial cells found in the tentacles, the tip of the hypostome, and the foot are nondividing products of epithelial cells of the body column. Nuerons, nematocytes, secretory cells, and gametes are products of differentiating interstitial cells. (Martinez 1998)

The tissue dynamics within Hydra are pretty amazing. The epithelial cells of the body column are always in the mitotic cycle. The body conserves epithelial cells within buds and the rest are sloughed off at the tip of the tentacles, hypostome, and basal disc. This results in displaced epithelial cells falling apically onto the head, basally onto developing buds, or onto the foot. (Martinez 1998)

Individual cells do not exist for very long in the Hydra and nondividing differentiated cells from all three lineages are lost within 20 days by the displacement from the body column. The cell cycle of the dividing cells for the interstitial lineage is around 18-30 hours. Stem cells from the epithelial lineages cycle every three to four days. This means that cells are constantly renewing by cell division or they are lost in a short period of time. Hydra are considered immortal since they have a large capacity for constant renewal. (Martinez 1998)

In Martinez’s paper, he tested the presence or absence of senescence in Hydra by analyzing the mortality patterns of four groups of individuals of Hydra vulgaris. The control consisted of around 45 animals extracted from a freshwater lake and the beginning ages were unknown. Three cohorts derived from this control group were separated using asexual reproduction. Animals were raised and maintained for up to four years. After each feeding, they were moved to a new plate and the offspring were discarded at that time. At one point, the Hydra were moved and the conditions changed.

Martinez thinks that an important parameter to his research is the probability of survival for the metazoan to start at age x and reach x+1, which is the age-specific survival or the inverse age-specific mortality. Martinez thinks that if senescence is present, the researcher should see an increase in age-specific mortality. This is a deviation from the classical method of plotting the logarithm of a cohort survival probabilities vs. age and then inspect the shape of the curve. The curve should be diagonal for constant mortality rates and no senescence. (Martinez 1998)

An example of this type of curve can be found in a paper written by Helen Forrest. Dr. Forrest reproduces a figure showing the classic survivorship curve, but goes on to suggest that others were wrong in saying that Hydra are potentially immortal. This means that Hydra are more likely to meet there end at any stage within their lifespan. Dr. Forrest provided good evidence at the time that the curve was strong evidence for the potential immortality, but could not be proved with researchers spending too little time on investigating the lifespan of animals. They just stick up their arms and use statistics to say that the creature is immortal, but cannot wait forever to prove their assumption. (Forrest 1963)

Figure 1. A diagonal survivorship curve (Forrest 1963)

Martinez’s results can be found in Figure 2. This figure includes the age-specific mortality rates for the three cohorts and the control group of unknown age. Drosophila melanogaster and others are shown for comparison. These other species were chosen because they are known to undergo senescence and their longevities can be plotted in the same graph. Within this graph, Hydra mortality rates remained close to zero for four years. The other species show an increase in mortality rate with increasing age, which s typical of species that do undergo aging. He goes on to explain that the independence of mortality from age is due to the lack of aging in Hydra. The second hypothesis is that Hydra may live much longer than four years and this mortality pattern only relate to “young” Hydra. He goes on to predict the potential longevity of Hydra. (Martinez 1998)

Figure 2. Age-specific mortality rates. (Martinez 1998)

In Figure 3, Martinez shows mean age-specific budding rates. There is a separation in the figure due to the fact that they moved the Hydra from one location to another. He states the budding rates are lower due to the different conditions, which include a lower temperature and feeding frequency result lower growth. (Martinez 1998)

Figure 3. Mean age-specific budding rates and standard errors. (Martinez 1998)

Figure 3. Mean age-specific budding rates and standard errors. (Martinez 1998)

In Martinez’s discussion, he tries and confirms the lack of senescence in Hydra. Reproductive rates may have fluctuated wildly after the move, but each cohort shows almost identical fluctuations independent of their age (Figure 3). He uses some math to say that budding rates decline due environmental factors since it occurs in all there cohorts and the control group. (Martinez 1998)

The low and constant mortality rates for Hydra provide strong evidence for the lack of senescence. After four years, Martinez thinks that it is enough due to theoretical and comparative considerations. Having a deleterious gene early in life is much worse than later in life. This means that animals that start reproducing early in life will have a smaller life span compared to animals that reproduce later in life. Hydra start reproducing 5 to 10 days and this predicts that they should only live 1.2 to 2.6 months based on Martinez’s math, but they lived up to 4 years and counting. Other animals with the same start time of reproduction live between 1 and 8 months. Martinez thinks that 4 years is enough time to exhibit senescence and they do not.  The lack of senescence may only be found in animals with simpler, dynamic bodies that can be renewed from stem cells. Over this time, Martinez calculated that epithelial cells divided on average 300 times and the whole body may have been replaced at least 60 times. Martinez states that evolution may have resulted in a decreased capacity of renewal with increased complexity. (Martinez 1998)

Overall, it seems that Martinez has proved that Hydra lack senescence and are potentially immortal. We cannot test this since that would take forever to investigate. Instead, he was able to follow the same cohort without contamination and prove that they live for long periods of time. The mortality rates for Hydra were much lower than expected and remained constant for long periods of time compared to other animals with similar reproductive start times. The disturbance during the move may have resulted in different reproductive rates, but it did not affect the mortality rate. Instead, we may have found an immortal being that we can use as a model organism in the fight against aging and the ability to regenerate.

In addition to Hydra vulgaris, Hydra magnipapillata exhibits unlimited growth, which is important since it has been sequenced and used for comparisons. (Watanabe, Hoang et al. 2009) Immortality does not exist in all Hydra. The challenge will be to unravel the molecular mechanism causing aging and senescence in other related species.

Signaling and Nuclear Factors Related to Stem Cells

Virtually nothing is known about the molecular mechanisms of stem cell systems in basal metazoan groups, which includes cnidarians. There may be a common evolutionary origin since the same signaling pathways act in a diversity of vertebrates and invertebrates stem cells. Hydra are ideal since are ideal since they diverged early on the evolutionary tree and lack aging due to their stem cell activity and renewal. This is exciting since it will help identify common principles of regulatory mechanisms at the level of signaling molecules and epigenetic machinery within animals and plants. Figure 4 summarizes the cnidarian orthologs of nuclear factors involved in stem cell maintenance and differentiation know from bilaterians.

Figure 4. Cnidarian orthologs of signaling and transcription factors know to be stem cell-specific in bilaterians. (Watanabe 2009)

Transcription factors that have been shown to induce pluripotency when expressed in differentiated somatic cells of mammals: Nanog, Oct4, and Sox2. These are found actively expressed in pluripotent stem cells of the inner cell mass of the mouse embryo. Myc and Klf4 are importan stem cell maintenance genes. In the Hydra genome, two Sox2 and three Myc orthologs are present (Figure 4).  (Watanabe, Hoang et al. 2009)

Argonaute proteins are small non-coding RNAs, which are important for gene regulation. These are Piwi proteins in metazoans and can be deducsed that they are important regulators of geneome integrity and stem cell function, which the function involves heterochromatin formation. (Watanabe, Hoang et al. 2009)

The list goes on to include Wnt signaling, Notch signaling, Bone morphogenetic proteins (BMPs), and Peptides. Each are very valuable in regulating stem cells and regeneration within mice and other other eukaroytes. It is very difficult to study stem cell gene regulation in upper animals since gene interactions are very complex. Hydra are not nearly as complicated and provide researchers a simple model with unlimited growth potential. They are easy to cultivate and provide an excellent system for study stem cells and regeneration. Now, we will be able to deduce how all of these systems interact and start applying it to more complicated systems.

Conclusion

It seems that we have found a link between animals and plants. Hydra have the ability to regenerate and potentially live forever, which is common in plants, but not in animals. Now, we have found a model organism that can provide molecular pathways using orthologs found in higher animals, including mice and humans. This will result in understanding the pathways behind regeneration using stem cells and why humans are not able to live forever using the same regeneration techniques that Hydra use. Please keep looking for exciting research involving this simple animal and, hopefully, we will be able to incorporate what we learn in medicine and our own lives.

Works Cited

Austad, S. N. (2009). “Is There a Role for New Invertebrate Models for Aging Research?” Journals of Gerontology Series a-Biological Sciences and Medical Sciences 64(2): 192-194.

Chapman, J. A., E. F. Kirkness, et al. (2010). “The dynamic genome of Hydra.” Nature 464(7288): 592-596.

The freshwater cnidarian Hydra was first described in 1702(1) and has been the object of study for 300 years. Experimental studies of Hydra between 1736 and 1744 culminated in the discovery of asexual reproduction of an animal by budding, the first description of regeneration in an animal, and successful transplantation of tissue between animals(2). Today, Hydra is an important model for studies of axial patterning(3), stem cell biology(4) and regeneration(5). Here we report the genome of Hydra magnipapillata and compare it to the genomes of the anthozoan Nematostella vectensis(6) and other animals. The Hydra genome has been shaped by bursts of transposable element expansion, horizontal gene transfer, trans-splicing, and simplification of gene structure and gene content that parallel simplification of the Hydra life cycle. We also report the sequence of the genome of a novel bacterium stably associated with H. magnipapillata. Comparisons of the Hydra genome to the genomes of other animals shed light on the evolution of epithelia, contractile tissues, developmentally regulated transcription factors, the Spemann-Mangold organizer, pluripotency genes and the neuromuscular junction.

Forrest, H. (1963). “IMMORTALITY AND PEARLS SURVIVORSHIP CURVE FOR HYDRA.” Ecology 44(3): 609-&.

Martinez, D. E. (1998). “Mortality patterns suggest lack of senescence in hydra.” Experimental Gerontology 33(3): 217-225.

Senescence, a deteriorative process that increases the probability of death of an organism with increasing chronological age, has been found in all metazoans where careful studies have been carried out. There has been much controversy, however, about the potential immortality of hydra, a solitary freshwater member of the phylum Cnidaria, one of the earliest diverging metazoan groups. Researchers have suggested that hydra is capable of escaping aging by constantly renewing the tissues of its body. But no data have been published to support this assertion. To test for the presence or absence of aging in hydra, mortality and reproductive rates for three hydra cohorts have been analyzed for a period of four years. The results provide no evidence for aging in hydra: mortality rates have remained extremely low and there are no apparent signs of decline in reproductive rates. Hydra may have indeed escaped senescence and may be potentially immortal. (C) 1998 Elsevier Science Inc.

Watanabe, H., V. T. Hoang, et al. (2009). “Immortality and the base of multicellular life: Lessons from cnidarian stem cells.” Seminars in Cell & Developmental Biology 20(9): 1114-1125.

Cnidarians are phylogenetically basal members of the animal kingdom (> 600 million years old). Together with plants they share some remarkable features that cannot be found in higher animals. Cnidarians and plants exhibit an almost unlimited regeneration capacity and immortality. Immortality can be ascribed to the asexual mode of reproduction that requires cells with an unlimited self-renewal capacity. We propose that the basic properties of animal stem cells are tightly linked to this archaic mode of reproduction. The cnidarian stem cells can give rise to a number of differentiated cell types including neuronal and germ cells. The genomes of Hydra and Nematostella, representatives of two major cnidarian classes indicate a surprising complexity of both genomes, which is in the range of vertebrates. Recent work indicates that highly conserved signalling pathways control Hydra stem cell differentiation. Furthermore, the availability of genomic resources and novel technologies provide approaches to analyse these cells in vivo. Studies of stem cells in cnidarians will therefore open important insights into the basic mechanisms of stem cell biology. Their critical phylogenetic position at the base of the metazoan branch in the tree of life makes them an important link in unravelling the common mechanisms of stem cell biology between animals and plants. (C) 2009 Elsevier Ltd. All rights reserved.

1 Response to Lack of Senescence in Hydra by Byron Lee

  1. Jung Choi says:

    Krulwich and Radiolab did a nice animated video on Hydra and lack of senescence:
    http://www.radiolab.org/story/everything-dies-right-does-everything-have-die-heres-surprise_kw/

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