As I noted in a recent post on naked mole rats, there are at least two good reasons to study the comparative biology of aging, which is to say how and why aging differs between species. Why are some species long lived, some short lived, and some very few exhibit negligible senescence, a near absence of age-related changes across their life spans? Why do whales live longer than humans, humans longer than other primates, primates longer than horses, and naked mole rats nine times as long as standard issue rats? Firstly, isolating small but important differences between similar species with different life spans may help to conclude debates over which of the possible causes of aging are more important. (Though to my eyes less time spent debating and more time spent trying to repair all known forms of cellular damage associated with aging is the better, faster way to figure out what is and isn't important). Secondly, some researchers see the potential to generate therapies or enhancements for humans from the biological differences present in other species. There are several lines of research here funded to varying degrees, including identification of the basis for exceptional regeneration in salamanders, or the roots of longevity and cancer resistance in naked mole rats, to pick two examples from the crowd.
It is hard to say whether or not the quest for ways to alter human biochemistry to produce effects seen in other species is going to lead to meaningful results in the near term. On the one hand, it is clear that there is a lot of shared biology between even comparatively distant species such as humans and lizards. On the other hand there is no reason to expect that even a fully understood mechanism would be easy or even possible to bring to humans as enhancement or therapy: the devil is in the details, and the answer will probably vary widely mechanism by mechanism. So it is too early to say what will come of all of this. That said, I think the odds of beneficial outcomes in the near term shrink the further away from our species you go. When investigating the biology of tiny possibly ageless organisms such as the highly regenerative hydra, I suspect that the end result will be knowledge and little more. Hydra are just too different, and their regenerative prowess is based on constant aggressive reconstruction that is simply impractical in a higher organism that must keep the fine structure of its central nervous system basically intact. Nonetheless some researchers are optimistic that hydra studies will teach us some things that we can use to produce regenerative treatments in humans:
"Since the mid-20th century, scientists have been interested in the longevity of this animal," Galliot explains. "When it's maintained in satisfactory conditions, hydrae reproduce asexually. They bud. We could observe them for years, and we wouldn't see any decline. They stay in shape." One day, Belgian researcher Paul Brien decided to plunge one of his group of hydrae into 10° C. "In that species, cold is a natural stimulus that tells them 'Oh, life is going to become harder,' because they don't survive very low temperatures." The result was incredible. Although they lived until then without partners, hydrae suddenly started looking for other hydrae to mate. They developed oocytes or testicles. "The animal started a sexual cycle. It reproduced. Then parents died and only their offspring survived in a small gangue that allowed them to survive the winter at the bottom of the water."
In 2000, a Japanese team renewed the experiment and confirmed the result. Then Brigitte Galliot came along, but something wasn't quite right. "The first year, the poor student who was checking on the hydrae was going nowhere. We were working with the same species, the very common Hydra oligactis, but the animals remained super happy. We maintained them for over a year at 10°. They were fine, they were still budding. So we thought ... drat!" The solution to this mystery was simple and ideal for the scientists. "There are, in the same species, different strains. One can resist, the other can't, and it ages. So by comparing the molecular and cellular processes of these two strains, we can understand what induces aging and what enables hydrae to resist it."
In practical terms, there could be two ways to take advantage of these findings to stop our own aging. "One of the approaches consists in telling ourselves that with evolution, these species developed all sorts of small molecules, some peptides and lipids that could be used as a source for new pharmacological agents," she says. The other approach, on which Galliot and her team are currently focusing, centers on autophagy, "a process through which cells digest their own content." A temporary survival strategy when faced with a lack of food but also a self-cleaning method to evacuate toxic waste, autophagy is controlled by very similar molecular tracks in animals that could not be more different, hydrae and mice.
Therefore, if this cellular process survived through millennia of evolution, it might still be triggered. The stakes are immense. "It's about understanding how to promote an efficient autophagy, which would enable our cells to digest the increasing number of aggregates we produce as we age, and which are at the root of Alzheimer's disease, as well as other neurological pathologies," Galliot explains. To achieve this, the comparison between "immortal" hydrae and those that age is illuminating. "The two strains seem to have different efficiencies in the way they get rid of these toxic aggregates." Galliot, however, remains cautious. "I'm not saying that we'll have a ready-to-use molecule in five years. What we're doing is very basic, but the implications can be very relevant. We do have, at the moment, a molecular candidate that is most interesting."
If you are going to try to slow down aging, which isn't the best approach to the problem at all, then it has long seemed to me that artificially upregulating the cellular housekeeping mechanisms of autophagy is a more promising approach than trying to more blindly mimic other aspects of the calorie restriction response that enhances health and longevity. Upregulated autophagy is present in many slow-aging animal models, and there are very good reasons to believe it is a cause rather than an effect of this outcome. Despite a fair number of researchers including this sort of work in their portfolio not much has come of it in the past decade, however. I don't see much going on today to convince me that we are closer to a generation of practical, effective autophagy-inducing treatments than we were at the turn of the century. Want more autophagy? Either practicing calorie restriction or regular moderate exercise will get you further in terms of upregulated autophagy than what was has emerged from the labs to date - and neither of those options will do much for your longevity in the grand scheme of things. Thus it isn't surprising to see that these hydra researchers are still at a fairly early stage in their studies:
H. oligactis is a model that has numerous features that complement the drawbacks of existing invertebrate model systems used for aging research, namely hundreds of human orthologs that were lost in nematode and fruit fly ancestors. To identify the putative aging genes present in Hydra but missing in C. elegans and D. melanogaster, we analysed the hydra-human orthologs associated with aging. Among 259 human aging genes retrieved from The Human Ageing Genomic Resources, we found that 207 (80%) were conserved in Hydra. Interestingly, some of these genes are missing or poorly conserved in D. melanogaster and C. elegans, such as the p53 regulator MDM2 or the TGFβ inhibitor noggin. The aging-induced regulation of these genes is currently under investigation.
As an alternative approach to aging studies, several studies aimed at dissecting the mechanisms that underlie the lack of senescence in Hydra focused on FoxO, an evolutionarily conserved transcription factor. In bilaterian organisms, FoxO regulates the response to stress, the proliferation of stem cells, and modulates lifespan. In nematodes and fruit flies, the knockdown of FoxO significantly shortens lifespan. In Hydra, FoxO is expressed in stem cells, and appears to respond to stress. Reduction in FoxO levels in the H. vulgaris AEP strain negatively affected the proliferation of stem cells, the speed of the budding process, the growth of Hydra population, and the production of immune peptides. However, no mortality was observed in FoxO deficient polyps, suggesting that other factors contribute to negligible senescence in H. vulgaris.