Comment by dkirmani on ChristianKl's Shortform · 2021-06-10T22:56:26.685Z · LW · GW

This is why it would make sense if there was some (perhaps small) positive effect of transposons on an individual's fitness.

(Also, aren't there any less costly ways to increase mutation rate? Maybe error-prone DNA polymerases, or just allocating less resources to DNA repair.)

Comment by dkirmani on Hypothesis: lab mice have more active transposons then wild mice · 2021-06-08T21:08:06.046Z · LW · GW

Sure, but wouldn't a hunter that stayed physically 25 until the age of 45 have a higher inclusive genetic fitness, all else being equal?

Comment by dkirmani on Hypothesis: lab mice have more active transposons then wild mice · 2021-06-07T16:19:42.200Z · LW · GW

If the difference would be just about transposon-supressors in the soma in mole rats, we wouldn't see them to have less transposon-derived repeats in their genome.

That's a good point, my previous idea about NMR somatic transposon suppression is probably incorrect.

According to the article naked mole rats have "efficient DNA damage repair". Efficient DNA repair in germline tells means that transposons will doublicate less in the germline cells and it's therefore easier for evolution to reduce the transposon count.

Following the article's citation for the 'efficient DNA damage repair' claim, we get this study, that analyzes NMR, human and mouse liver tissue (not germline), and finds that, compared to mice, humans and NMRs have higher expression of genes central to DNA repair pathways. The paper then reminds the reader that both humans and NMRs live longer than mice, so maybe DNA repair makes organisms live longer.

This is consistent with johnswentworth's model of:

Transposon activity -> (DNA damage <-> mitochondrial ROS feedback loop) -> age-associated cellular dysfunction

where DNA repair pathways slow the progress of the DNA damage / mitochondrial ROS feedback loop, making aging progress at a slower rate.

So it looks like:

  • NMRs have DNA repair pathways in the soma that are abnormally active for a rodent their size
  • NMRs have fewer transposon-derived repeats in their genome, indicating vigilant transposon suppression in the germline
  • These mechanisms counter aging, but come with some hidden cost to fitness, and that's why humans don't have even higher DNA repair activity, or more vigilant germline transposon suppression

But what are these hidden costs? Surely there is variation among humans w.r.t rates of somatic DNA repair, and effectiveness of germline transposon suppression. Why aren't people with beneficial versions of these traits aging less, living longer, and having more children?

Edit: I think I might have (partially) answered my own question:

Comment by dkirmani on Hypothesis: lab mice have more active transposons then wild mice · 2021-06-07T01:14:18.146Z · LW · GW

Okay, so I think I realize what's going on.

(Epistemic status: A lot of the evidence here is remembered from papers I read a month ago. The third-last and second-last paragraphs are mostly just conjecture. Tread with caution.)

Transposons are present in basically every genome. Animals can choose to invest in transposon suppression mechanisms (the PIWI/piRNA pathway), but doing so comes with a metabolic cost that increases proportionally to the amount of tissue in which these mechanisms are active.

Humans have (to a first approximation) transposon suppression active in the germline cells of the gonads, and nowhere else. If a human gets a mutation that expresses transposon-supressors in the soma, he/she would have (in the ancestral environment) suffered a small metabolic cost, but would enjoy reduced aging. However, the additional fitness conferred by the reduced aging rate would not offset the metabolic costs enough to be worth it. The mutation disappears.

Naked mole rats live in groups with a size of, on average, 75 individuals. There is one queen, three fertile males, and everyone else is an infertile worker. To the worker, the chance of being the next queen / a mating male is vanishingly small. Therefore, the worker can best optimize their fitness by serving the needs of the collective. Some workers tunnel for food (they eat tubers), others raise the pups, and the 'soldiers' defend the tunnels from predators.

For humans (in the ancestral environment), the critical period in determining the majority of one's reproductive success is between the ages of 15 and 35. That's why it makes sense to sacrifice one's welfare in middle/late age in order to better compete for mates during the physical prime of one's life. So, no somatic transposon suppression for us.

Naked mole rat workers take food from the collective, and provide labor to the collective. Old naked mole rats are less efficient at turning food into labor than young naked mole rats. So why not go the route of bees and ants, and give the workers short, but productive, lifespans? For insects, reproduction is relatively cheap: just lay a small egg. For mammals, like the Queen Naked Mole Rat, there is a more restrictive bottleneck to how many pups may be produced in a year. Additionally, gestating a mammalian pup comes at a higher relative marginal metabolic cost than producing an insectoid egg. Therefore, in order to best utilize resources to serve the collective, workers should both be long-lived and also not get frail.

Investing in transposon-suppression mechanisms is worth it to the naked mole rat's genes, but not to the genes of the human.

Comment by dkirmani on Hypothesis: lab mice have more active transposons then wild mice · 2021-06-06T20:39:10.916Z · LW · GW

I remember Brad Weinstein talking about how some biologist (maybe it was his professor?) predicted that if there's a species with negligible senescence it would have a bunch of characteristics that are true for naked mole rats. He didn't know about naked mole rats at the time and it turned out to be one of the successful theoretic predictions based on modern evolutionary theory.

I remember this too (vaguely)! I think it was from this episode of The Portal podcast with Bret and Eric Weinstein.

If I look at hydras, the way there sexual reproduction works differently then for a lot of other animals. The male and female don't meet but the male releases their gamete into the water and thus it doesn't stop reproducing.

Fish do this too, and I don't recall anything about fish not aging, so I don't think this is useful.

Hydras also have asexual reproduction where new Hydras seem to be created out of somatic cells and not via the sexual production. If hydras would allow for transposon activity in their somatic cells then children they prodcue with asexual reproduction would also have a higher transposon count which would be very inconvenient.

I think this is the key factor. In humans (and most animals), transposons are suppressed only in the germline cells, but if a hydra can reproduce via budding with its somatic cells, then all of its 'somatic' cells are in fact potential germline cells, and it is important that they have transposon suppression mechanisms.

However, naked mole rats don't reproduce by budding, so the mystery of NMR negligible senescence is still unresolved. I'm going to give that podcast another listen, and keep an ear open for that section you mentioned.

(Edit: 43:30 - 1:06:00 is the relevant section of the podcast)

Comment by dkirmani on Hypothesis: lab mice have more active transposons then wild mice · 2021-06-06T18:47:13.839Z · LW · GW

Given that naked mole rats also happen to be less transposons it starts getting less of a mystery to me. To register another hypothesis, I would expect hydras also to have less transposons.

I agree! It makes sense that NMRs have fewer transposons and also age less. As for hydras, they do have less transposon activity in the soma, as the PIWI/piRNA pathway is active in their somatic tissue. (From The Mechanism of Ageing: Primary Role of Transposable Elements in Genome Disintegration, which is a (very informative) paper that states and supports the transposon hypothesis)

What I was wondering was why NMRs / hydras have less transposon activity than us, and what selective pressures caused this to come about.

Comment by dkirmani on Hypothesis: lab mice have more active transposons then wild mice · 2021-06-06T18:03:43.768Z · LW · GW

as an organism ages active transposons within it's stem cells duplicate and that mechanism might lead to increased average transposons count in stem cells

My model is that transposons duplicate in all somatic (non-reproductive) cells, not just stem cells.

If that hypothesis is true, there's evolutionary pressure to keep the count of active transposons low. That evolutionary pressure is greater in organism that reproduce at a later age then for organisms that reproduce at an earlier age.

The evolutionary basis of aging (and negligible senescence, like in hydras and naked mole rats) is still a total mystery to me. The arguments for why aging is adaptive all rely on group-selection, which I am wary of. The argument is basically that you grow old and die to benefit the tribe, just as your cells commit suicide when it is useful for you. I'm relatively unconvinced by this argument, as I believe that intra-tribal competition is a much more powerful selective force than inter-tribal competion, giving rise to (machiavellian) intelligence as well as extremely metabolically costly dominance competitions. Getting old doesn't make sense if you're the only one doing it.

Those who oppose the adaptive aging hypothesis generally fail to take into account the fact that naked mole rats exist, leaving us without an explanation as to why we have senescence and they don't.

As Bret Weinstein describes, breeding protocols for lab mice have lab mice reproducing at an earlier age then mice that live in the wild because it's economical to make the mice reproduce at a young age. Weinstein made the hypothesis that this leads to laboratory mice having elongated telomeres.

My model here is:

Longer teleomeres -> Higher Hayflick limit (number of times cell can divide before dying) -> Higher cancer risk, as tumor cells can divide more (decreases chance of being alive in late-life), as well as higher capacity for tissue damage repair, as existing cells can divide more to replace missing ones (greater chance of being alive in early-life)

This is consistent with longer telomeres being a reallocation from late-life health to early-life heath, and that tradeoff starts making sense when you reproduce at an earlier age. With respect to transposons, though, I don't understand what the trade-off is. With longer telomeres, you get an increased tissue regen rate at the expense of increased cancer risk. With transposons, you get senescence, but for what?

Comment by dkirmani on Core Pathways of Aging · 2021-03-28T18:52:41.057Z · LW · GW

 The first steps are (probably) to come up with an estimate of both material and labor costs for all 3 of the above options. The labor costs might be mostly nullified if you can find altruistic biologists, or biologists that are status-seeking and have sufficient confidence that the transposon hypothesis is true. Or if a motivated person who isn't a biologist takes a crack at it.

UMichigan offers a transgenic mouse service for $5,800. From the item description: 

The Transgenic Core guarantees that at least 300 fertilized mouse eggs will be microinjected with CRISPR/Cas9 reagents. Microinjected eggs will be transferred to pseudoopregnant female mice. Tail tip biopsies will be provided to the Investigator's laboratory for genotyping. Mouse pups will be transferred to the investigator at weaning.

This is the service for C57BL/6 (C57 black 6) mice, the mice most commonly used as disease models, and the best-selling mice from mouse-breeding laboratories. For another $1,100, UMich will also "build CRISPR/Cas9 reagents to target a specific location in the mouse or rat genome". So, for $7,000, one can get a founder population of transgenic mice, targeting any genome location the customer desires. Another transgenic mouse service from UMich, also for $5,800, guarantees at least 3 transgenic founder mice will be produced. 'Founder' implies that the actual experimental subjects will be the children of the transgenic mice you get, so you'd need to head down to PetStop and buy a few dozen hamster cages, some rodent chow, and a mouse-breeding manual.

Jackson Labs, the primary provider of experimental mice, sells C57BL/6 mice for $90 per mouse at 25 weeks old, and at $430 per mouse at 90 weeks old, with cost per mouse growing roughly linearly in between. At 25 weeks old, that's $2,700 for 30 mice (enough for a pilot study's control group). 

There's also the cost of shipping and handling live mice, which will vary depending on where the experiment is conducted. There are probably a bunch of auxiliary costs I haven't considered yet as well. My main point is, as far as the Crispr route goes at least, I don't anticipate material costs over $50,000, meaning an unofficial pilot study is probably quite doable by a small group of motivated individuals / one crazy person in a shed / crowdfunding.

Comment by dkirmani on Core Pathways of Aging · 2021-03-28T16:56:19.741Z · LW · GW

Wow, I had no idea that methylation was that impermanent, thank you for the belief update. I guess that leaves upregulation (via acetylation?) of transposon-suppressing RNA, extending lifespan by varying expression of other genes that alter chromatin structure to be more transposon-hostile, or as this comment says, using Crispr/CAS9 to incapacitate transposons. I wonder if anyone has done/will soon do an experiment like this in mammals.

Comment by dkirmani on Core Pathways of Aging · 2021-03-28T13:42:04.605Z · LW · GW

Thanks! I changed "transposons" to "active transposons" to be more accurate. Much of my knowledge in this domain comes from a genetics course I took in the 10th grade, so it's not super comprehensive.

piRNAs/siRNAs repress transposon activity, but they don't remove existing transposons outright. So this would effectively put aging on pause, and clear up symptoms of aging, but not reverse aging. Once the administration stopped, things would bounce right back to normal.

My understanding was that methylated DNA stayed methylated (silenced), and methyltransferases made sure that copies of the methylated DNA sequences were also themselves methylated. If all transposons in a cell were methylated by piRNAs and siRNAs, wouldn't all descendants of the cell also have methylated transposons, making those transposons effectively removed? (Of course, that assumes that methyltransferases and  transposon-suppressing RNAs have 100% success rates, which I'm sure they don't. This would explain why babies have a few active transposons, but not nearly as many as their parents.)

This paper asserts that piRNAs both methylate transposons, and also cleave the RNA transcripts of transposons in a cell's cytoplasm, and that doing so guards the germline against transposons. Cleaving the transcripts of transposons would repress transposon replication in the short term, but, as I understand it, methylation of transposons would silence them in the long term, including in daughter cells. Therefore, even if there's a one-time transposon-methylating event (as opposed to a permanent epigenetic upregulation in transposon-suppression mechanisms, which seems to be a promising idea as well), the number of active transposons in the genome should still be reduced, pushing the growth trajectory of transposons backward.

Comment by dkirmani on Core Pathways of Aging · 2021-03-28T03:21:49.772Z · LW · GW

(I made an account to post this)

We do have mechanisms to repress transposon activity, most notably epigenetic mechanisms. Most DNA is usually tightly coiled up around little cylindrical proteins (called histones), where it can’t be easily transcribed. “Epigenetics” typically refers to modifications of the DNA and/or histones which make the coils tighter or looser, making the DNA difficult or easy to access. Most transposons are epigenetically tagged so that they’re kept tightly coiled most of the time.

These mechanisms are small interfering RNAs (siRNAs) and Piwi-interacting RNAs (piRNAs), that increase methylation of the histones associated with transposons, making them 'tighter', or harder to access. According to the Wikipedia page for transposon silencing, these siRNAs and piRNAs are most active in the gonads. This makes sense, as it would avoid germline transmission of active transposons, allowing offspring to be born with a lower active transposon count than their parents.

After reading that, I wondered why on earth we don't have these transposon-suppressing RNAs coursing through our bloodstream in the same concentration as we do in our gonads. According to this paper, suppressing transposons also has the effect of suppressing neighboring genes, leading to a possible reduction in the organism's fitness. The same paper claims that having transposons could have beneficial effects on genome evolution, as transposons create regions of suppressed recombination around them, although I don't fully understand the reasoning behind this being good for organism fitness. Also, if suppressing transposons does have negative effects on the genome, that doesn't at all explain why it happens more in the gonads. Perhaps aging just wasn't selected against enough in the ancestral environment.

If nothing else, these siRNAs and piRNAs seem to be effective at making babies have fewer active transposons than their parents. If someone has injected old mice with a bunch of copies of these RNAs (probably wrapped in viruses first) and observed the results, then I can't find their paper published anywhere. On the off chance that the transposon model is correct, and that the cure for transposon proliferation really is as simple as an RNA injection, this is one experiment we can't afford not to do.