Puzzling out elephant longevity

As readers of this blog know, I love weird animal science. Hummingbirds who don’t get diabetes; turtles who survive the winter underwater; obese, blind long-lived cavefish; ants who voluntarily live a long time; all of them fascinate me.

There’s a risk, though, of these weird animal science stories turning into “just so” stories. We have a certain set of what seem to be effects, like hummingbirds who can eat copious amounts of sugar without getting diabetes, and what seem to be causes, like certain suggestive mutations in glycolytic proteins. Then we put them together and say, “These mutations cause this phenotype, ‘just so’”.

On this blog, I try to be careful about the science that I highlight to select the strongest cause and effect relationships, or at least make sure that the scientists involve note the uncertainties. So, for example, in that hummingbird paper, the scientists involved did do work to make sure that the mutations would cause at least some of the “non-diabetic” phenotype in hummingbird cells, and to note the limitations of their work.

But we’re still left with some issues. Are these mutations sufficient for hummingbirds to avoid diabetes? No, and nobody’s claiming they are. Diabetes is a disease of complex systems, and there are enough ways to get to it that one mutation isn’t going to do much. Are these mutations necessary for hummingbirds to avoid diabetes? Well, that’s a harder question. The authors of the paper have recently written a follow-up examining other nectivores to see convergent mutations, which gets to the idea of which mutations seem to come up over and over again, which suggest that they’re necessary. But, still, we can’t say for sure.

I don’t mean to pick on this hummingbird paper. I think it’s an excellent paper, which is why I highlighted it in the first place. This is a problem inherent to biology, and how we try to find legible answers to complex systems. As long as we insist on trying to understand the mechanisms of biology, we will face the specter of just so stories.

I bring all this up because there’s a “just so” story that’s been bothering me for a while, and I’ve been struggling to write about it. It has to do with why elephants are so long-lived. I’ll tell you the university press release version first, and then we can dive into how we might fix it, or at least think about it better.

The university press release version of elephant longevity is that elephants are long-lived because they don’t get cancer. Elephants not getting cancer is a prime example of “Peto’s Paradox”, which notes that large animals, who should have the highest rates of cancer because of their increased number of cells, paradoxically tend to have the lowest rate. They don’t get cancer because, unlike other animals, they have 20 copies of the TP53 gene, which encourages apoptosis in cancerous cells. This is unlike humans, who only have 1 copy of the TP53 gene. If both alleles get disabled, as they frequently are in cancer, the cells won’t self-destruct when they need to.

I searched for images of “Peto’s Paradox” on Google Images, and this was by far the worst one. Naturally, I picked it as my header image.

This is an ok story at first glance, but gets weirder the more that you think about it. If you were an engineer designing a cancer-resistant large animal, you wouldn’t necessarily go for replicating the same gene over and over again. That doesn’t exactly limit the point of failure. Also, if this is such an effective anti-cancer strategy, it’s weird that no other animal has evolved it, including other long-lived animals like bowhead whales or humans. It would seem relatively straightforward, given that failure of TP53 is a big problem across all mammals.

And then, last, there’s the biggest problem, which is that longevity isn’t just about avoiding cancer. Think about old people. Sure, cancer is a big problem for them, but so is dementia, sarcopenia (muscle wasting), osteoporosis, organ failure, and everything else that comes with being old. Are we saying that elephant longevity in general is about this 20 copies of TP53 story, or are we just searching where we have a light?

Let’s take a step back before we dive deeper into this. This is, frankly, where I got stuck before, so I think it’s good to survey the landscape first. I’m going to start by just discussing what we know about elephants and longevity.

Elephants are models of healthy aging. Despite being very large and very long-lived, they:

1. Don’t seem to get dementia or Alzheimer’s, unlike whales, humans, or even parrots. If anything, the oldest elephant females may be more cognitively sharp than other elephants.

2. Don’t get cancer

3. Are generally infection-resistant in old age

4. Remain fertile/virile through their old age (no menopause or andropause)

5. Generally maintain healthy bones and muscles through their old age, with no universal osteoporosis or sarcopenia

6. Can go 48 hours without sleep or obvious sleep debt, regardless of their age

The main reason why elephants don’t live forever is that they’re still affected by the wear and tear of aging. So, old elephants do still get cataracts, osteoarthritis (especially in their feet), and tooth decay, and die when they have too few teeth and functioning joints to continue being migratory herbivores.

So, whatever explanations we provide for why elephants are so long-lived, we have to account for the fact that elephants seem to have solved a surprising amount of the problems of aging, even compared to other long-lived animals. If I were to simplify it, I’d say something like they don’t seem to have any of the problems of aging where systems get dysregulated, and only have the problems of things getting slowly worn down and not replaced. Already, it seems unlikely that “20 copies of TP53” will cut it.

Let’s also discuss what we know about how other animals have solved the problems of aging and cancer. Now, there are a number of different places we could take this, but I think looking at the example of bats is the most interesting. Compared to their size and nearest relatives, bats are very long-lived and cancer resistant. They also:

1. Seem to lack cognitive decline (although this is not as well studied as elephants’)

2. Have low rates of cancer while aging

3. Remain generally infection-resistant in old age

4. Remain fertile/virile through old age (no menopause/andropause)

5. Seem to maintain healthy muscles and bones through their old age

The only thing they lack is resistance to sleep debt, although this isn’t particularly well studied.

Counter-intuitively, they do not do this by making their cells ready to apoptose at any moment. Instead, they do the opposite, as I’ve discussed before. Bats have a very high tolerance for DNA damage, which is occurring constantly because their body temperature is elevated during flight. Instead of encouraging their cells to apoptose, they invest heavily in DNA repair.

As part of this, bats have a reduced sensitivity to random bits of DNA or RNA floating around, including those that would indicate invasion by a pathogen or tumor cell. Their innate immune system, by contrast, is ramped up, preventing infections or tumors from ramping up out of control.

TP53-related apoptosis in bat cells is reserved for absolutely necessary cases. But, when it is necessary, bat cells do not hesitate, and indeed show much higher rates of p53 apoptosis when exposed to gamma radiation than human or mouse cells. This is helped by their increased copy number of TP53 genes (like elephants have), which, suggestively, increase in number in longer-lived bat species

But bats pair their increased TP53 gene activity and gene number with also increased p53 inhibition machinery. Bat cells invest in both being able to apoptose when necessary and stop apoptosis when necessary.

So, now, we’re starting to get some intriguing ideas about TP53 copies actually contributing to longevity: possibly sufficiently, maybe even necessarily. But, the story is complicated: humans and mice have 1 copy, shorter lived bats have 1 copy, longer lived bats have 3-7 copies, elephants have 20 copies. Bats also pair their TP53 genes with complex regulatory apparatuses, which don’t just inhibit p53 activation when it’s unnecessary, but also makes it more potent per gene when it’s necessary.

Let’s make it more complicated by going back to one of our original questions. How can 20 (or 7) identical copies of a gene actually help? Is that really adding redundancy, given that a deactivation of one would probably deactivate the rest as well?

Well, identical copies of a gene don’t actually help add redundancy. In fact, they probably don’t help at all. That’s why it’s fortunate that elephants don’t have 20 identical copies of TP53, and bats don’t have 7 identical copies either.

Instead, elephants have 1 normal copy of TP53, ~17 retrogene ¹ copies of mutated TP53 that prevent the original copy of TP53 from being deactivated, and 1 retrogene copy of mutated TP53 that’s so mutated that it has a completely independent apoptotic mechanism. They also have a reanimated pseudogene ² that works with TP53 to help with apoptosis. There’s a similar story with bats, but the exact functionality of their 2-6 mutated copies is less well studied.

So, going back to our original story, there does seem to be an advantage to creating multiple copies of TP53, as long as they aren’t all identical.

It’s hard to say if multiple different copies of TP53 are sufficient for longevity, though. Elephants evolved one unique immune system model to cope with their challenges, which is that they’re gigantic and rely on their matriarchs to navigate to historical watering holes. This made their cells hyperalert for any foreign DNA. Bats evolved a different unique immune system model to cope with their challenges, which is that they run such a high body temperature from flying that they’re constantly causing DNA damage to themselves. This made their cells very tolerant of DNA strands up to a point, and hyperalert thereafter.

Both did converge on multiple copies of TP53 for that hyperalertness, and both ended up being models of healthy longevity, even healthier than humans in many ways. It’s tempting to say that any animal that also had multiple different copies of TP53, regardless of what other immune features it had, would also be able to age as gracefully as elephants and bats.

Unfortunately, elephants’ multiple TP53 copies are closely integrated into the elephant immune system and DNA regulatory system. Managing to get the same working in, say, mice, would require a ton of work to integrate these copies into the mouse immune system and DNA regulatory system. This is, as far as I know, currently beyond the capabilities of genetic engineering.

1. Retrogenes are a clever way of (accidentally?) creating new, mutated copies of pieces of DNA. When normal DNA is transcribed into mRNA, there’s a chance that the mRNA can be reverse transcribed back into DNA. When it’s reverse transcribed, it naturally lacks introns (regulatory/promoter regions), so it will probably remain inert, unless it accidentally acquires new introns or borrows from another existing gene’s.

2. Pseudogene: it used to work as a gene, but got mutated so it doesn’t. Reanimated: it got mutated again, so it works again. Basically, they brought a gene back from the “dead”.