The short story is this: you can place two species of hydra animals in the same environment at a temperature of 10 degrees Celsius. One will age (Hydra oligactis) and the other one won’t (Hydra vulgaris).
Now here are the details.
Hydras are primitive multicelullar animals. When well-fed, they reproduce asexually by budding. But when nutrients are scarce, they undergo sexual reproduction. Many other things can influence their sexual differentiation, one of them being lowering the surrounding temperature. And this is exactly what Belgian researcher Paul Brien did in 1953 (!). Yes, you read that right – 1953. He dropped the culture temperature from 18 to 10 degrees Celsius. And while both Hydra oligactis and Hydra vulgaris species underwent sexual differentiation, the first one aged while the latter didn’t. The one that aged stopped asexual budding too. The other one didn’t.
So here we have a case of related organisms developing two metabolic pathways: a senescent one and a non-senescent one.
The first question that crossed my mind after stumbling upon the original paper is that a lab error could have occurred. But his initial experiments have been replicated in the meantime in two different labs.
Martinez reproduced part of the initial experiments in 1998 when he showed that Hydra vulgaris doesn’t age. He kept those polyps in culture for 4 years and didn’t notice any sign of aging. For a tiny animal that is able to reproduce a couple of days after starting life, that is a huge lifespan. He didn’t notice any decrease in mortality or fertility with age.
The second part of the initial experiments was reproduced by Yoshida et al in 2006 when they showed that Hydra oligactis does age after being induced to reproduce sexually. While reading the paper, I was in awe in how much the way this kind of hydra ages resembles human aging.
The little fellow starts aging when the main cells responsible for its self-renewal – the interstitial cells – start to differentiate into germ stem cells rather than somatic stem cells mimicking the trade-off between germ and soma that takes place in mammals like us after puberty. And as its body has fewer and fewer somatic cells, the hydra can’t catch prey like it used to. Its tentacles atrophy. It can’t swallow the prey anymore. It can’t reproduce – sexually or asexually. And its body becomes smaller.
30 days after starting life these hydras start changing their morphology. By 60 days they enter middle age and their probability to die increases exponentially. By 4 months all aging hydras are dead.
What I find fascinating is that all these traits are visible when you place Hydra oligactis at lower temperatures like 10 degrees Celsius. Do that the same with Hydra vulgaris and it won’t blink an eye. While temperature is one external factor for switching aging on, tissue response is the counterbalance. The two types of hydras respond differently to decreased temperature. And not all Hydra oligactis strains are built the same either. Basically, there are 3 types of strains: cold-sensitive,cold-resistant and cold-insensitive ones.The more sensitive to cold such a hydra strain is, the more likely it is to undergo sexual differentiation after cold exposure and confront aging afterwards.
And while most species escaping senescence – as depicted in The aging gap between species – evolved in environments with low external mortality through the sheer lack of predators, negligible senescence in hydra evolved in a highly risky environment where death looms on the horizon.
I tried to understand what makes the two species of hydra age differently – here are the bits of data I found with references at the end of this blog post:
-the aging hydra has almost no heat shock protein response to stress, while the non-aging hydra does
-the aging hydra decreases its FoxO expression with age, while the non-aging hydra maintains it constant
Since hydras can be found wherever you live as you read these lines, this is a case that aging can be hacked. Too bad this hasn’t been achieved in half a century since the publication of Brien’s experiments. Maybe you can do something about it.
Image credit:
By Corvana – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=6349873
References:
Anca Ioviţă is the author of Eat Less Live Longer: Your Practical Guide to Calorie Restriction with Optimal Nutrition ,The Aging Gap Between Species and What Is Your Legacy? 101Ways on Getting Started to Create and Build One available on Amazon and several other places. If you enjoyed this article, don’t forget to sign up to receive updates on longevity news and novel book projects!
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That’s interesting.
I was wondering why biologists don’t immediately compare both species’ genomes and start genetic enhancement experiments.
But this site illustrates that it took an international effort with 74 authors to get the first genome in 2010
https://www.gesundheitsindustrie-bw.de/en/article/news/the-hydra-genome
and in 2015, they only managed to re-sequence for the same hydra vulgaris species: https://research.nhgri.nih.gov/hydra/
Progress is kinda slow 🙁 . But luckily, we are still young 🙂
(oh, I meant you can remove the above comment, to which I’m replying right now, as the comment below this one largely subsumes/includes the above)
Indeed a useful pair of species for research. That hydra vulgaris indeed holds some precious secrets.
I was wondering why don’t biologists (at least gerontologists) immediately sequence both species and start doing genetic modification experiments…
But I read it took 74 or so authors to sequence hydra vulgaris in 2010, and today we only have a 2015 re-sequencing of same species https://research.nhgri.nih.gov/hydra/
Even the cost is not quite affordable for many labs in the world: although it’s currently advertised at a price of most of a couple hundred dollars https://en.wikipedia.org/wiki/$1,000_genome
a 2019 study suggests that there are many additional costs, raising it to > 1000 https://www.nature.com/articles/s41436-019-0618-7
I guess in 5-10 years cost will be trully affordable for most labs in the world, and in another 5-10 perhaps as cheap that even citizen scientists could routinely do it in their experiments…
Should get more interesting in the future
This is a long comment, which I hope will give interesting ideas to you, and maybe even make a new post about possibility that aging is not inevitable.
I became interested in the question of whether hydra (vulgaris I mean in this comment) indeed doesn’t age, or it’s just a potential statistical error from that 1998 article of Martinez.
So I searched all about hydra aging, and found 2 articles from (most recent I could find, as of April 2020) that finally convinced me that indeed doesn’t show any sign of aging for at least 7-8 years:
1. “Diversity of ageing across the tree of life”,2014, https://www.ncbi.nlm.nih.gov/pubmed/24317695 ,which uses new datasets for hydra (and has a nice summary figure for many species’s mortality rate curves),
2. “Constant mortality and fertility over age in Hydra”,2015, https://www.pnas.org/content/112/51/15701 , this is the definite blow: “… using data from careful, large-scale studies over 8 y with 2,256 individuals.”
Is it possible that hydra vulgaris doesn’t age at all, no matter how many years we wait to measure? (My final conclusion will be at the end)
I found 2 papers discussing models of aging with conflicting answers:
A. “Stability analysis of a model gene network links aging, stress resistance, and negligible senescence “, 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551969/ .
In their model, they find 2 possible configurations for a genome: stable and unstable, a trait that can be considered “hardwired”. In the stable, due to sufficiently effective (thus not necessarily perfect) repair systems, “gene damage remains constrained along with mortality of the organism.” and the unstable mode , found that under most common circumstances: “Over a time it undergoes an exponential accumulation of gene-regulation deviations leading to death”
B. “Intercellular competition and the inevitability of multicellular aging”, 2017, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724245/.
The authors include in their model intercellular competition and interaction between cooperative, selfish, and senescent traits, and find that aging is necessary/inevitable, no matter what genome you have “Multicellular organisms would age even if selection were perfect.”
Given that there’s no evidence that hydra ages at all, paper A wins. I looked at the assumptions in B, and they don’t all hold for hydra: they assume that selfish cells would always win over cooperative cells, and that accumulation of defects within a body is inevitable, thus their model concludes constant and sufficiently effective rate of repair is impossible.
The crucial characteristic for hydra, IMO, is the very high cell replacement rate in the whole body. Cell division rate is about 1 in 3-4 days: which is, importantly, about same as for cancerous cells (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829925/). In 1 week (or at most a couple, according to other authors), hydra replaces all (with no exception!) cells in its body.
It’s cells in the central body part are stem cells and continuously divide and migrate towards the head and foot, and displace the differentiated, non-dividing cells over there.
This means that DEFECTS IN HYDRA DON’T ACCUMULATE beyond a week or so: it is largely impossible to have a progressive accumulation of cells harboring these defects.
My understanding is that defect accumulation over long periods of time, either in form of garbage within cells leading to senescent cells, or mutations leading to cancerous cells, is the essence of aging.
In hydra, the body plan (2 sheets of cells surrounded by water and separated by internal liquid again) facillitates this:
— differentiated cells in the non-dividing regions are soon and regularly replaced (washed away in water) by new coming cells.
— shall a mutation appear to make for accumulation of senescent-inducing garbage in a cell, wither in central part or in extremities, that cell will soon be displaced by healthy cells, preventing accumulation of senescent cells. Also the body plan prevents the influence of a senescent cells onto many others.
— shall a mutation appear to make a cancerous cell: since rate of division of rest of cells is similarly high, the proportion of cancerous cells won’t increase. In fact, they will be displaced too, even if you get a cancer cell located right in the center of the body: over long time, natural perturbations will cause drift of them towards extremities, and then replaced in totallity.
As to the possibility hydra may still age very slowly over the course of many tens (or hundreds?) years: I think this would only happen if an individual would slowly accumulate such mutations to cause the rate of whole-body turn over to drop gradually over those years (so that it will get increasingly susceptible to appearance of cancer cells, which would divide that much faster and may overwhelm the body). I think this is extremely unlikely for any particular individual:
1. Such division-slowing mutations would have to appear within a majority of cells of the body, and during the same whole body cell replacement period (~ 1 week) (otherwise, the mutated cells, dividing slower, will be displaced away by the rest of cells ).
2. We have evidence of immortalized cell lines (https://www.sciencedirect.com/topics/neuroscience/immortalised-cell-line, some, of cancerous cells, for more than 70 years: HeLa cells), and also rough similarity and endurance of fastest cell division rates across the life forms on earth, which suggests that dividing at a nearly constant rate similar to that of cancer cells is such a fundamental characteristic of cell function, that it’s probably a certain local, and pronounced, energetic minimum of the dynamical system consisting of the cells and surrounding constant feeding environment. It’s simpler for cells to keep dividing at that optimal rate, than at a slower rate.
Which means mutations that would make the cells to divide slower are UNSTABLE, and will be soon reversed either by cell’s repair mechanisms, OR simply by other mutations that will undo the work of the former.
Your feedback will be appreciated!
Hello,
Thank you so much for your thoughtful comment and for your patience until this reply!
I didn’t finish reading paper A yet, but I did paper B and I found it very interesting in how the authors explained the non-aging aspect of the germ line in multicellular organisms: by the alternation of life stages between unicellular selection (in germ cells themselves) and then multicellular selection at the level of the individual. I started getting interested in aging after wondering why are all babies born young when parents always age and I appreciate explanations in gerontology on this aspect. While I don’t agree with their main hypothesis (that intercellular competition always leads to aging, sooner or later) which I’ll detail below, that explanation made me connect many dots between the many species displaying negligible senescence this way:
1. many such species reproduce sexually and asexually, including hydras, many sea invertebrates like sponges, corals. Such species alternating between sexual and asexual reproduction probably makes their soma cells just as indispensable as germ cells.
There are both sexually and asexually species that age, some very fast, but this combination is something I’ve noticed in animals with very long lifespans.
2. many such species are remarkably resistant to cancer. (Here is a blog post I wrote on this: https://longevityletter.com/10-animal-species-that-made-cancer-a-thing-of-the-past/) The only caveat is that as much as I searched, I haven’t found any paper whatsoever on whether hydras develop cancer.
Getting back to the hypothesis from paper B that intercellular competition leads to the removal of senescent cells but will always favor cancer cells, so aging is inevitable sooner or later in multicellular organisms, I disagree with it for the following reasons:
1. Negligible senescence already exists in multicellular organisms. I like to give as examples organisms that do not show signs of aging and also live very long lifespans, so I won’t quote the naked mole rat; instead I’ll quote the many species of corals and sponges that can live for thousands of years when they grow very slowly (in very cold water and stable environments) – I don’t know the name of particular species out of my head right now, but I can check out the references in a future comment if you’re interested. I find the naked mole rat interesting because it is a mammal and because it is very resistant to cancer (especially for a rodent), but I’m already older than its maximum lifespan (30 years) and I’m more inspired by organisms that survive for thousands of years. Given how fragile life is, even as a human being not afraid of technology, I find it amazing that there are organisms surviving for millennia, especially since many of them do not even have a brain to help them survive.
2. Many approaches that slow down aging favor the removal of senescent cells without also increasing the risk of cancer. Calorie restriction favors competition between mitochondria and cells, yet the risk of cancer increases with weight added. Granted, if you are underweight like me, you are more likely to die if you get cancer. Given that the metabolic syndrome is a risk for developing cancer, I wonder whether there is a causality relationship between the number of senescent cells in an organism and its cancer rate.
Off-topic: I appreciated that paper B mentioned the near lack of metastases in multicellular plants as cancer cells don’t get to spread thanks to a rigid extracellular matrix that prevents the movement of cells like it happens in animals.
Thank you also for the new papers on hydras!
Fun fact: since an adult hydra can be formed, from a bud, in less than 1 week (as I understood indirectly from many articles), comparing it with human biological maturity at say 15 years, hydra living for 8 years (as was found in one study) would be equivalent to over 6000 human years, and still be perfectly healthy.
Hi Anca,
thank you for accepting to research this!
>>The only caveat is that as much as I searched, I haven’t found any paper whatsoever on whether hydras develop cancer.
(hate to write this, but… science demands truth 🙂 ) perhaps you did your search prior to 2014: here is a paper, about rare cancer developing when hydra is induced to reproduce sexually, via problems with differentiation of interstitial stem cells into gametes (Hydra oligactis and Pelmatohydra robusta);
https://www.nature.com/articles/ncomms5222 (it also shows a nice phylogenetic tree in fig 1)
I note that it’s not H. Vulgaris and that H.oligactis is the one you mention yourself in this article that it ages when reproducing sexually…
I found out about this soon after writing my conclusions on why I think H.Vulgaris doesn’t age: however, when I wrote that big comment , I had in mind only _asexual_ reproduction. I suspect induction of sexual reproduction (via some kind of environmental stress) changes many things, in particular the constant and high turnover rate of cells in the body. For this reason, I think my ideas still hold for the case of asexually reproducing H. Vulgaris.
What do you think?
You wrote nothing of my hypothesis that the high turn over rate of all cells in body is at least an important (if not main) mechanism that hydra uses. I won’t get offended if you say you don’t think so.
>> I’m more inspired by organisms that survive for thousands of years.
me too, but only by “real” organisms. See the comments I left on your sponges’ article https://longevityletter.com/why-sponges-are-potentially-immortal ; sponges (unlike at least cnidarians) don’t even have tissues or organs.
While for the coral: that is not an individual… it’s a colony of individuals (I have a deja-vu that we talked about this before). Essentially, a population of polyps very much hydra-like, that happen to have some filaments connecting each other for exchange of some nutrients. And times of stress, those polyps can bail out and move on to live by themselves and later create another colony elsewhere. So, why would you be surprised that a colony can live for many thousands of years. Its individuals may die and get born, colony survives.
By the way, with the very low mortality rate of H.Vulgaris, if you start with 100 individuals, and just removing away any new budded polyps, then after 1400 years there will still be 5 or more original individuals left (see paper 1. in my comment above). If you keep the new polyps… there’s your immortal “coral” 🙂
>> a rigid extracellular matrix that prevents the movement of cells like it happens in animals.
– maybe that’s an approach too; genetically engineer the adult body to make all cells secrete some durable but elastic form of exoskeleton. Prevent every kind of cell from over-proliferating 🙂
Hmmm, that paper on tumors in hydras seems familiar and I probably dismissed it because I expected tumors in a hydra that ages (H. oligactis), especially one that sexually reproduces itself.
Yes, I think your ideas still hold for the asexually reproducing Hydra vulgaris, although not sure whether they still hold for other types of asexually reproducing hydras. The high turn over rate of cells may normally induce errors but somehow, this type of hydra maintains its totipotency of some of its cells, so in this case, this high turn over rate may dilute accumulated damage. This is why I was curious whether Hydra vulgaris develops cancer.
Unlike you, I don’t classify organisms into real ones and fake ones. We are colonies of cells too, only that some of our cells are more differentiated than others while others are more essential to keeping the germ line alive. Sponges living so long without having proper tissues just shows me how important it is to maintain a supply of totipotent cells since young in order to regenerate tissues later on. Sponges do that naturally. Humans could do that in the lab.
Hi, thanks for the feedback.
So you suspect that the higher probability of errors caused by high-rate turn over could destroy totipotency. Well, you know much more about this aspect than I do. I guess hydra has good gene repair mechanisms as well, if not, one possible consequence could be that after many years, particular individuals of h. vulgaris could begin to produce a smaller number of buds and viable offspring or less ability for sexual reproduction.
WRT we are colonies of cells – yes, I understand; though in case of corals, they are not colonies of cells, but of individual polyps – which are essentially hydra-like organisms. More akin to aspen trees colonies, connected by the root system.
I just learned one thing that helps explain, for my ideas in my long comment above, why the high replication rate of the stem cells don’t lead to accumulation of DNA errors (and perhaps eventual loss of totipotency) in hydra vulgaris:
Josh Mitteldorf, on https://joshmitteldorf.scienceblog.com/2014/04/07/no-the-body-doesnt-just-wear-out-as-we-get-older/ , writes:
“When stem cells divide to form new, differentiated cells, the old, original strand of DNA stays with the stem cell and the newly-copied strand goes consistently with the differentiated cell. It seems that Nature has been thinking about DNA copying errors, and has taken care of the problem.”
Based on that, the stem cells in the central part of hydra’s body maintain their DNA integrity, while the more differentiated cells in the periphery, even if they get a mutation, they are soon replaced by others. QED.
The above quote is true if the stem cells divide asymmetrically, not so with symmetrical stem cell division.
OOPs! you know better. Where could I learn more about this?
I tried to read more about this, and it’s about “immortal strand hypothesis” which does not have full confirmation in-vivo.
But, hydra does have asymmetrical (as well as symmetrical) stem cell divisions, so that mechanism still helps where present. (In fact, in my original explanation in the long comment above, I didn’t even rely on this asymmetric division to explain how it can avoid aging)
Meanwhile, there is an article “Unraveling the non-senescence phenomenon in Hydra” https://www.sciencedirect.com/science/article/pii/S0022519315003227#bib30
that uses many other mechanisms (besides fast replication) to explain non-senescence in hydra.
But they also pose, as the main distinguishing mechanism present in hydra, and not in other organisms, the continual replacement: “The core of the model is based on two processes that we believe are responsible for the long-term maintenance of a Hydra: the continuous and constant production of new cells of all three stem cell populations, and the continuous removal of cells by differentiation, programmed cell death, or budding. ” .
In more detail: “.. we hypothesize that Hydra is able to achieve “non-senescence” because of four specific characteristics of its body plan: (i) a large number of stem cells; (ii) the continuous division of stem cells; (iii) a high proportion of dividing cells relative to non-dividing cells within each polyp; and (iv) the constant removal of cells by differentiation, programmed cell death, or budding (see above). ”
And “..Finding sufficient conditions for non-aging in Hydra-like animals is helpful for understanding why most animals, including humans, cannot easily avoid aging.”
…and this is a commenting-article easier read https://www.cell.com/current-biology/pdf/S0960-9822(16)00065-8.pdf
This is relevant too: 2020, Deficient autophagy in epithelial stem cells drives aging in the freshwater cnidarian Hydra, https://dev.biologists.org/content/147/2/dev177840
I’m glad that in the meantime you found out more about it, especially as it applies to the hydra.
I still wonder whether the non-aging hydras – even when sexually replicating – have some particular genes that allow such continuous replacement. Basically they’re doing at an individual level what we do at the level of the species: continually replacing old with young.
I find this part key from the paper by Maciej J.Dańko et al:
“Our results suggest that non-senescence is possible only in simple Hydra-like organisms which have a high proportion and number of stem cells, continuous cell divisions, an effective cell selection mechanism, and stem cells with the ability to undertake some roles of differentiated cells.”
Thank you for the other links too, they are highly appreciated!