Core Pathways of Aging

(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.

Wouldn't the role of transposons be easy enough to investigate by incapacitating functional transposons with Crispr/CAS9? Has something like that been done in mice? 

A private message (from someone who may name themselves if they wish) asked about the claim that "the effects of senolytics rapidly wear off once the drug stops being administered".

This is a lower-confidence claim than most in this piece; I do not have a study on hand directly proving it. The vast majority of papers on senolytics either use regular administration (frequency ~1 per 2 weeks or faster) or do a short regimen and then measure results within ~2 weeks; the ubiquity of those practices is itself a significant piece of evidence here. If a single dose does nothing long-term, then I mostly expect to see very few papers published using a single dose on long-term outcomes (because people don't publish negative results), and that is indeed what I see.

Of course, lots of people still claim that long-lived senescent cells are a thing, but it's always either uncited or cites someone else who also has no actual data directly supporting the claim. I have yet to see any compelling data backing it up, and this is a case where I expect absence of evidence to be evidence of absence. It feels very similar to the claims about amyloid beta as a cause of Alzheimers, or collagen:elastin ratio as a cause of vascular stiffening: lots of people claim it, but following the citation chains shows no compelling evidence.

What I'd really like to see is an experiment which gives one (or a few) doses of a senolytic to reasonably-old mice (maybe ~20 mo), measures outcomes ~ 1 week later, then waits at least a couple months before evaluating outcomes again. If persistent senescent cells are both real and relevant, then we'd expect to see relatively little regression in outcomes over time. If persistent senescent cells are not real or not relevant, then we'd expect to see the mice mostly regress to the pre-treatment state after a couple months. (Though they would probably be slightly better off than control mice, since they'd have effectively taken a couple weeks with the core aging feedback loop on pause.)

Both this document and John himself have been useful resources to me as I launch into my own career studying aging in graduate school. One thing I think would have been really helpful here are more thorough citations and sourcing. It's hard to follow John's points ("In sarcopenia, one cross-section of the long muscle cell will fail first - a “ragged red” section - and then failure gradually spreads along the length.") and trace them back to any specific source, and it's also hard to know which of the synthetic insights are original to John and which are insights from the wider literature that John is echoing here.

While eschewing citations makes the post a little easier to scan, and probably made it a lot easier to write, I think that it runs the risk of divorcing the post from the wider literature and making it harder for the reader to relate this blog post to the academic publications it is clearly drawing upon. It would have also been helpful if John had more often referenced specific terms - when he says "Modern DNA sequencing involves breaking the DNA into little pieces, sequencing those, then computationally reconstructing which pieces overlap with each other," it's true, but also, DNA sequencing methods are diverse and continue to evolve on a technological level at a rapid pace. It's hard to know exactly which set of sequencing techniques he had in mind, or how much care he took in making sure that there's no tractable way to go about this.

Overall, I'm just not sure to what extent I ought to let this post inform my understanding of aging, as opposed to inspiring and motivating my research elsewhere. But I still appreciate John for writing it - it has been a great launch point.

I found a nice table of theories of aging from this paper.

Naked mole rats don't age. Other mammals do. Therefore, whatever causes ageing must be hard but not impossible for evolution to stop. Here is one plausible hypothesis. 

The environment of naked mole rats provides unusually strong evolutionary pressure against ageing. So transposon-killing RNAs are unusually prevalent. Every time a mutation breaks a transposon, that provides an advantage, the fewer transposons you start with, the slower you age. This selection is balanced by the fact that transposons occasionally manage to replicate, even in the gonads.  In naked mole rats, that selection was unusually strong, and/or the transposons unusually unable to replicate. So evolution managed to drive the number of functioning transposons down to 0. 

If naked mole rats have no functioning transposons, and animals that age do contain transposons, that would be strong evidence for transposon based ageing. 

Of course, even if ageing is transposon based, evolution could have taken another route in mole rats. Maybe they have some really effective transposon suppressor of some kind.

I don't know how hard this would be to test. Can you just download the mole rat DNA and put it into a pre-made transposon finder?

If aminoguanidine temporarily reverses arterial stiffening, and if arterial stiffening reduces paravascular cerebral fluid flow, which in turn inhibits clearance of Alzheimer's-causing proteins, then aminoguanidine could potentially work as an Alzheimer's drug if it can be transported to the right area. The severity of Alzheimer's might even justify taking aminoguanidine despite the side-effects.

Indeed, there is some recent research into applying aminoguanidine to Alzheimer's. It appears that aminoguanidine does penetrate the blood-brain barrier via diffusion. And there are several studies, mainly from the last 5 years, exploring aminoguanidine as a neuroprotectant against dementia/Alzheimer's in murine models.

And encouragingly, moderate-dose aminoguanidine in conjunction with pyridoxine was found to maintain the neuroprotective effect while eliminating appreciable toxicity. There are several papers on pyridoxal-aminoguanidine adducts, and on pyrodoxal phosphate.

I've only read a few abstracts, so I can't vouch for the quality of the evidence so far, but it's nice to see that the gears-level reasoning in your model can successfully predict existing lines of research.

As a thought experiment mostly for testing my own understanding, suppose we could do a bulk culling of transposons in all of an elderly human's stem cells (or all cells). If I understand correctly, this post's main hypothesis (DNA damage <-> ROS feedback loop) would imply the following should happen:

• Senescent cell fraction quickly (within days or months) starts reverting to its healthy level.
• Atherosclerosis heals on its own because ROS production reduces to its healthy level meaning the plaque equilibrium returns to the young level.
• Similarly, vascular stiffening reverses for the same reason AG works temporarily.
• Alzheimer's remains unclear without further understanding but we can guess this might help.
• Sarcopenia same story as atherosclerosis and stiffening.
• Lens and elastin fibers continue to build up, so we'll all be blind and wrinkly but otherwise healthy...

The one thing I'm less clear on is where immune system aging fits into this. I feel pretty confident that a treatment like this wouldn't cause the thymus to spontaneously grow for example but am more uncertain about some of the other aged immune system phenotypes. It seems plausible that reducing the load on the immune system would allow it to regain some of its ability to deal with infectious diseases for example.

Does this fit with your understanding?

It's been 2 years. Has there been much followup work on this?

I'm only asking because I have a biological human body and it keeps aging and I don't want to get old....

https://www.sens.org/therapy-to-destroy-cells-with-reactivated-jumping-genes/

This is interesting work, and I like seeing how your other writing (on gears-level models, constraints, etc) seems to lie behind your approach to this research.

That said, there’s a fair bit of evidence that most symptoms of aging - including the major age-related diseases - share a common root cause, or at least a common core pathway. Some kinds of evidence of this:

• Most symptoms/diseases of aging are correlated - someone who has one early is likely to have others. Conceptually, if you do a factor analysis on aging symptoms, there’s one big factor for a bunch of diseases, even after controlling for the number of years one has lived. (“Aging clock” is a relevant piece of jargon here.)
• At the cellular level, a lot of diseases of aging “look similar”, and involve similar pieces. There’s a decrease in cell count, increase in damaged proteins/DNA/fats, and inflammation. We see roughly this pattern in Alzheimers, atherosclerosis, muscle loss, and many others.
• Certain simple interventions reliably produce many diseases of aging - for instance, progerias are single mutations which produce a whole “early aging” phenotype
• Conversely, certain simple interventions reliably delay many diseases of aging - e.g. calorie restricted diets.

One interpretation of the idea of a "common core pathway" is an argument that there's some single aging factor (SAF), which triggers various forms of damage, which in turn cause the major diseases of aging. Hence, fighting those intermediate forms of damage would be ultimately futile, while fixing the SAF would be a panacea, at least if followed by other treatments that fix lingering damage.

An alternative idea is that there are multiple aging factors (MAFs), each of which triggers a particular form of damage. The damage it triggers goes on to cause a range of other forms of damage, which cause still others, resulting in a damage chain reaction that causes the major diseases of aging. Under this model, there are many MAFs that can trigger this chain reaction, and it's just the first one that's responsible for kicking off the aging process.

The difference is that preventing or curing one MAF wouldn't halt or prevent aging. Preventing one MAF still leaves you open to others. And since it's not the MAF, but a self-reinforcing chain reaction of damage, that drives aging, curing the MAF wouldn't reverse or halt the damage.

As an analogy, in the SAF model, aging is like a flood. It causes a range of problems: washing away buildings and roads, drowning deaths, erosion. Try to repair the buildings while the flood's going on, and you'll make little progress. But if you can stop the flooding, then you can repair all the damage it caused and be "good as new."

By contrast, in the MAFs model, aging is like a collapsing building. It could be caused by many underlying problems: termites, an earthquake, a bomb, demolition, fire, rot, a flood. But once the process is underway, the building enters a feedback loop. The flood introduces mold, which leads to rot, which opens holes in the house to allow the entry of vermin, which cause support beams to sag, and increases the risk of a short-circuit that could cause a fire. At a certain point, the original cause (the flood) can vanish entirely, but the accumulated damage is just perpetuating itself, and you can only save the house by eliminating all the damage sources.

The MAFs model can also explain many forms of evidence you cite. Since any given MAF can kick off the damage chain reaction, you'd expect the diseases caused by that damage to be correlated, though perhaps with some "leading" and the others "following" in any given case. The types of damage would be common, so you'd see common damage symptoms. You'd expect to see that certain interventions would cause the whole phenotype (an early MAF causes an early damage chain reaction).

The harder one to explain is the interventions that delay diseases of aging. Why should one intervention avoid many MAFs, unless all those MAFs had an underlying SAF that caused them all? So the crux of the MAF vs. SAF models seems to be whether calorie restricted diets (or other similar interventions) really work.

Can you give some broad explanation about what are plants doing differently? As I understand most plants (except annuals which have a specific live-fast-die-young strategy) are biologically immortal and hey tend to die from external stressors, like pathogens or getting struck by lightning. They do have a whole lot of transposons, and plastids in addition to mitochondria...

Curated, for delving into an important topic with gears-level models.

For a while, people hypothesized that senescent cells accumulate with age without turning over, acting as a root cause. As mentioned earlier, the actual evidence suggests that senescent cells turn over on a timescale of days to weeks, which would mean this theory is wrong - senescent cell accumulation is not a root cause.

However, there is a saving throw: maybe a small subset of senescent cells are longer-lived, and the experiments measuring senescent cell turnover time just weren’t capturing the long-lived subset in particular. Results from senolytics (drugs which kill senescent cells) suggest this is also wrong: the effects of senolytics rapidly wear off once the drug stops being administered, whereas reversing a root cause should set an organism back to a youthful state longer-term.

Edit: I'm not sure that the claim that senolytics rapidly wear off is accurate. ^[1]

Senolytics do not have to be continuously present to exert their effect. Brief disruption of pro-survival pathways is adequate to kill senescent cells. Thus, senolytics can be effective when administered intermittently.22 For example, dasatinib and quercetin have an elimination half-life of a few hours, yet a single short course alleviates effects of leg radiation for at least 7 months.

An alternative possibility is that senolytics kill senescent cells in a tissue-selective manner. We see this here.

Briefly, the team uses a mouse breed in which senescent cells can be killed with a drug called AP. In the skeletal muscle, eye, kidney, lung, heart, and spleen, AP works better in some tissues, worse in others. AP doesn't work at all in the colon or liver.

Decreasing the overall senescent cell burden seems to increase lifespan. But if the colon and liver are reservoires for senescent cells, allowing the cells to rapidly take over once AP administration stops, that would explain why senescent cells bounce back rapidly. Take Afghanistan as an analogy: America was able to suppress the Taliban for decades, as long as it maintained a constant military presence. But there were regions they couldn't touch, which became safe harbor for the Taliban. As soon as America withdrew its military, the Taliban were able to take over the country immediately.

If senescent cells stimulate their own production and dampen their own removal in a way that's concentration dependent, and if most senolytics are tissue-specific and therefore leave highly concentrated reservoires of senescent cells behind, this leaves intact the possibility that stem cells are a root cause of aging.

Fortunately, combination senolytics that cover the full range of tissues may be more tractable than chemotherapy for cancer. With cancer, we primarily target cells undergoing mitosis.^[2] That impacts human cells as well, just somewhat less. And cancer's constant growth means that it's got lots of opportunities to evolve evasion to chemotherapies. But with senolytics, we may be able to target biomarkers that don't especially impact healthy cells. And since senescent cells don't proliferate, they don't have the same opportunities to evolve mechanisms to evade senolytics (1).

Another advantage of senolytics is that cell division– dependent drug resistance is unlikely to occur, because senescent cells do not divide and therefore cannot acquire advantageous mutations, unlike the situation in treating cancers or infectious agents.

1. ^{^}

   Kirkland, J. L., Tchkonia, T., Zhu, Y., Niedernhofer, L. J., & Robbins, P. D. (2017). The clinical potential of senolytic drugs. Journal of the American Geriatrics Society, 65(10), 2297-2301.
   Chicago

   
    

2. ^{^}

   Although new strategies are emerging, such as pH-based drug delivery and immune modulation, since cancer creates an acidic and anti-inflammatory microenvironment.

↑ comment by johnswentworth · 2022-12-16T17:53:17.716Z · LW(p) · GW(p)

I'd be careful about taking the claims in these sorts of papers at face value.

One problem is just the usual statistical abuse. For instance, this:

Briefly, the team uses a mouse breed in which senescent cells can be killed with a drug called AP. In the skeletal muscle, eye, kidney, lung, heart, and spleen, AP works better in some tissues, worse in others. AP doesn't work at all in the colon or liver.

I haven't looked carefully at that paper, but on the face of it, it sounds like a "garden of forking paths" situation. I wouldn't be surprised if the colon/liver were just noise due to testing lots of different things.

Aside from that, the other problem which comes up all the time is:

• Team does some experiment
• Their abstract summarizes the result in a way which isn't really backed by the data
• Review articles or other future citers then repeat the claim from the abstract

This one happens a lot with cellular senescence, largely because people use the word "accumulate" to indicate that senescent cell counts are going up, and it's easy to misintepret that as a claim that the cells are sticking around. Or, sometimes people just don't have"senescent cell counts are going up without the individual cells sticking around" in their hypothesis space at all, so they do an experiment which finds that counts go up, and then interpret that as evidence that senescent cells stick around.  Or, even worse:

• Somebody outright speculates
• Review articles and other future citers repeat the speculative claim, but fail to mention that it's pure speculation
• Later review articles cite the earlier review articles, and vaguely claim that there's some kind of empirical evidence

That's what happened in the case of the collagen:elastin ratio hypothesis for vascular stiffening (mentioned in the OP).

Point is, if you see a claim in a review article (like the one you cited), and it's not extremely obvious where that claim came from, you should be extremely skeptical. You do actually need to follow the citations, not only to the abstract but all the way to the methods and data.

Replies from: AllAmericanBreakfast

↑ comment by DirectedEvolution (AllAmericanBreakfast) · 2022-12-16T19:28:52.220Z · LW(p) · GW(p)

OK, let's take a look. Note that the claim about senescent cells being protected from AP in the colon and liver is not from a review article - the citation is to an orginal research article on Nature. They don't talk about correcting for multiple comparisons, although it's possible that this was left unstated or is dealt with automatically via Prism, the software they used for analysis. I'll contact the authors and ask.

This is the relevant figure (extended data figure 3). Red bars are no AP treatment, pink bars are with AP treatment (which ought to kill senescent cells). Eyeballing it, we see fairly consistent equal or higher expression levels across the range of senescence markers in the no AP group, and then this pattern vanishes in the liver and colon with the exception of p21 in the liver, which seems like it's "trending toward significance" (my words, not theirs). Based on my visual spot-checking, I would have said that the liver and colon really do seem to respond differently to AP than other organs. And that's a perfectly normal, expected outcome for any drug.

Error bars indicate s.e.m. *P < 0.05; **P < 0.01; ***P < 0.001 (unpaired two-tailed t-tests). Asterisks above individual bars in a denote significant changes to 2-month-old mice; asterisks above brackets denote significant differences between 18-month-old vehicle and AP-treated mice.

In the statistical analysis section, we have:

Prism software was used for statistical analysis and generation of survival, cataract and tumour latency curves... Investigators were blinded to allocation during experiments and outcome assessment, except for rare instances where blinding was not possible.

Replies from: johnswentworth

↑ comment by johnswentworth · 2022-12-16T19:38:58.306Z · LW(p) · GW(p)

Cool, I buy the basic result.

Replies from: AllAmericanBreakfast

↑ comment by DirectedEvolution (AllAmericanBreakfast) · 2022-12-16T19:52:35.275Z · LW(p) · GW(p)

I agree with you that we are probably seeing AP being selectively broken down by the liver and colon. It therefore fails to reach the normal senescent cells in these tissues, and does not trigger their destruction. This causes a higher level of senescent cells to remain in these tissues after AP administration stops. If those liver and colon senescent cells can go on to trigger senescence in neighboring cells, that may explain why a temporary administration of senolytics fails to provide lasting protection against aging, despite the accumulation of senescent cells being a root cause of aging. 

Under this hypothesis, senescent cells are a root cause of aging, as they trigger conversion of other cells to senescence - as suggested in the ODE model paper you linked - but this root cause can only be controlled in a lasting way by ensuring that senolytics eliminates senescent cells in a non-tissue selective manner. We can't leave any pockets of them hanging out in the liver and colon, for example, or they'll start spreading senescence to other nearby organs again as soon as you stop senolytics. Or alternatively, they might simply leave the mouse with an aged liver and colon, which might be enough to kill the mouse consistently, so that there's no real lifespan benefit.

Edit: Sorry if I'm responding to a rebuttal you changed your mind about :)

Replies from: johnswentworth

↑ comment by johnswentworth · 2022-12-16T21:20:54.964Z · LW(p) · GW(p)

Edit: Sorry if I'm responding to a rebuttal you changed your mind about :)

Yeah, sorry, I went back and looked at the context of the earlier comments and was like "oh, right, I see what the claim is" and then updated my comment.

The first and most important thing to know about Alzheimer’s (aka dementia, aka old folks losing their memory) is that it is not caused by accumulation of amyloid beta.

Well geez, I guess you called it. Congratulations on earning all of these Bayes points.

How does animal cloning fit in the picture? Transposon count should be preserved as part of the DNA in the cloned animal and that seems to imply that we'd see accelerated aging, especially if the source cell has been taken from an aged animal. That doesn't seem to happen, though, cloned animals and their offspring appear to have normal lives and lifespans as long as they get past the early development process (https://doi.org/10.1159/000452444).

Here’s the core positive feedback loop again:

• A cell’s DNA is damaged, inducing a damage response.
• As part of this damage response, mitochondria are shifted into a lower-efficiency state, producing less energy and more ROS.
• The ROS then further damage DNA.

Since this is a positive feedback loop, it has two stable states: one state with low damage and ROS (the “normal” cell state), and one with high damage and ROS (the “senescent” cell state).

So here's something I find confusing: apparently, nuclear bomb survivors (who almost certainly have incurred more DNA damage than average) do not seem to have an increased risk of dementia or worse cognition compared to controls (in fact, in the study I linked, the risk of dementia was non-significantly lower for those with .005-1Gy of radiation exposure compared to those with <0.005, even though the average age in each group was almost identical).

There's also the finding that only 30% of the excess mortality in nuclear bomb survivors is not from cancer. This is almost certainly confounded by the fact that cancer usually kills people earlier than other old-age diseases, but perhaps not much, since the decrease in lifespan among survivors seems to be only a few months (2 months on average for those exposed to <1 Gy, which IIRC was probably around 80% or so of them). So it tentatively seems that (as one would perhaps expect) DNA damage from ionizing radiation disproportionately increases cancer risk, rather than uniformly increasing the risk of every age-related disease.   

(On the other hand, this study of nuclear weapons workers does find a pretty large increase in dementia risk, even though those workers seemed to have gotten a similar-ish average dose of ionizing radiation as the nuclear bomb survivors did (although we don’t have data for all of them). So I don't know what is going on here, but I thought this was perhaps interesting enough to share.)

Could another root cause of aging be buildup of autoimmune problems? It seems like that would be a form of irreversible damage, though admittedly I know of no way for it to connect to ROS. (Maybe it would become Aging 2.0, a relevant constraint for health and longevity once aging is solved?)

This was a fascinating post, but I found a surprising statement in the introduction:

 "who are shy about telling us when their peers’ work is completely wrong."

This runs deeply against my experience. I would say writing a paper gleefully proving your peers wrong is second only to  writing a paper with an important new discovery in terms of academic satisfaction. In the middle of one controversy a colleague claimed (or maybe quoted) "Every paper published is a shot fired in a war". 

This is obviously running counter to your experience and I wonder how you came to that conclusion? Are we talking about well-cited papers that are "completely wrong" - or just that newer papers have effectively replaced them in the corpus.

Very interesting post! you have radically changed my way of thinking about aging. Until now, I have always thought of aging as a very complex problem with most part of the body beginning to independently fail in different ways. The idea that all the symptoms of aging might ultimately be caused by a few 'root causes' is really very interesting.

If I follow the logic correctly, the root cause of aging is that stem cells can irreversibly and invisibly accumulate active transposones, which are then passed on to derived cells, which then become senescent much faster. Also, for some reason this process is supressed in gonads. So, I see these alternatives:

1. Transposone activation is essentially blocked in gonades, or
2. There is a barrier which prevents embryos with above-normal number of active transposones from developing, or
3. Children born from parents of old age will age faster, or
4. Active transposone accumulation is not a root cause of aging.

Would a good experimental test of the transposon hypothesis be gene editing a simple model organism to remove transposons? Is CRISPR/Cas9 precise enough to do something like that?

DNA damage is typically repaired on a timescale of hours or faster, depending on the type. If DNA damage levels increase with age, that is due to an increase in rate of damage or decrease in rate of repair, not permanent accumulation.

Edit: I now see from your post on homeostasis that you're using "DNA damage" for forms of damage that do not cause a change of sequence, and "DNA mutations" for damage that does cause a permanent change of sequence. A lot of this is not really a critique then of your statement here - just a misreading of your specific terminology.

DNA damage repair mechanisms do not have a 100% chance of resolving the damage, and when this fails, permanent damage does accumulate in that cell and its lineage. A rare but highly cytotoxic example are double-strand breaks. While most DNA damage allows the cell to use information stored in the complementary nucleotide to repair the break accurately, double-strand breaks sever the chromosome and lose the ability to exploit the complementary nucleotide to guide repair. Normal processes of transcription and DNA replication during mitosis have been estimated to cause about 50 double-stranded breaks per cell per cell cycle (1).

It is true that mechanisms such as apoptosis and senescence can eliminate cells that have accumulated high levels of DNA damage. But setting those mechanisms aside, permanent accumulation of DNA damage does result from spontaneous double-strand breaks. And even taking those mechanisms into account, we will see selection for forms of DNA damage that evade the self-control mechanisms of apoptosis and senescence, and we may also see accumulated DNA damage leading to progressive degredation of the ability of immune cells to actively trigger apoptosis in damaged cells.

Edit: Note also that the proposed mechanism by which transposons cause aging is that they are a second form of accumulated, irreparable, and therefore permanent DNA damage within a particular cell lineage. While we can appeal to higher-order mechanisms to eliminate this accumulated damage, such as cell turnover, DNA damage most certainly does permanently accumulate within particular cell lineages.

I have not yet looked into the literature on senolytics, but if it typically wears off quickly, that may be because at a given age, all cells are likely to have accumulated DNA damage, among other dysregulations. Senolytics kills some of them, but other near-senescent cells on the verge of senescence that are not killed by senolytics quickly generate replacement senescent cells. If this were the case, it would be necessary to complement senolytics with transplant of young and healthy stem cells.

If this paper is right in positing that senescent cell accumulation is explained by saturation of the native senolytic capacity of the body and a linear increase of senescent cell production rate over time, then this tackles both aspects of the problem. If we only ablate senescent cells, we clear up the body's removal capacity, but do not deal with the linear increase in production rates. The latter may be dealt with by the addition of young cells, which would then be responsible for responding to growth signals and would lead to proliferation of a population of cells that does not become senescent. We might expect even a small number of these cells to do the trick, since they would be more proliferative as they are not rapidly becoming senescent and non-proliferative, while their nearly-senescent competitors are constantly blocked by growth arrest.

Overall, I see a guiding metaphore here as a game of telephone. The body does not have a mechanism for very long-term storage and refreshment of the fundamental message, which is probably due mainly to a lack of evolutionary pressure and antagonistic pleiotropy to emphasize reproductive success at the age of puberty. The age of puberty in turn was targeted in the ancestral environment to give a factor of safety of several decades before the average pubescent human would be killed by extrinsic factors. We have evolved a set of native repair mechanisms that equalize the risk of intrinsict causes of death with the risk of extrinsic causes of death, as there is no point in investing resources to prolong the lives of humans much beyond the age at which they'd typically be killed by factors in the environment.

However, we have many extrinsic biomedical mechanisms by which an individual's biological data can be stored, retrieved, amplified, and reorganized. Figuring out the minimal intervention that restores the original telephone message that cells are conveying to each other, that tells them what sort of cell to be, what sort of tissue architecture to form, and so on, could potentially prolong life indefinitely. This is probably more or less what "immortal" organisms are doing: they have found a set of mechanisms that preserves a particular biological telephone message for a very long period of time.

Edit 2: Senescent cells don't proliferate, but they do create an inflammatory environment that seems to trigger additional cellular senescence. And mitochondria can be transferred between cells. If mitochondria attain a proliferative advantage, this gives them an opportunity to be a fundamental driver of aging - a sort of "mitochondrial cancer."

(1) Mehta, A., & Haber, J. E. (2014). Sources of DNA double-strand breaks and models of recombinational DNA repair. Cold Spring Harbor perspectives in biology, 6(9), a016428.

(2) Torralba, D., Baixauli, F., & Sánchez-Madrid, F. (2016). Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Frontiers in cell and developmental biology, 4, 107.

The transposon thesis is really interesting.  If the problem is about those transposons, then aging might be more tractible then we currently assume.

With siRNA there's an established way of silencing RNA that gets expressed in a cell. When it comes to retrotransposons you would create siRNA for every specific retrotransposon. For DNA transpopons you can create siRNA against Transposase. 

From a research standpoint you would synthesie a chain of DNA that codes for siRNA for all the retrotransposons and transposase and CISPER it into mice. Then you wait and see whether the mice have extended lifespan. That's relatively easy if you do it on the embryo level. 

If it works with the mice it will be harder to do gene therapy on all the types of stem cells we have to nuke their siRNA but it's a clear engineering challenge.

Modern DNA sequencing involves breaking the DNA into little pieces, sequencing those, then computationally reconstructing which pieces overlap with each other. That’s a lot more difficult when the pieces you’re interested in have millions of near-copies filling most of the genome. Also, the copy-events we’re interested in will vary from cell to cell.

While it's true that most DNA sequencing is based on the approach of Sanger where you get a lot of short reads (~100 basepairs windows) and use the computer to puzzle them together, Long-Read Sequencing technology is emerging. 

One interesting observation about transposons is that they were likely more plentiful millions of years ago given that our DNA is full with mutated transposons. If transposons are a major factor in aging across species then there's evolutionary pressure as organisms have longer lifespan to reduce the transposon count. It would be very interesting to see whether active transposon count correlates with lifespan across different organisms. 

Eric Weinstein argues that given that we chose to bread lab mice in a way that makes them get children at a younger age then wild mice there's there are evolutionary forces that radically changed their telomere length.

If that mechanism holds we should expect that's there's also less evolutionary pressure to keep active transposon count in lab mice that we breed the standard way low and lab mice should have more active transposons then wild mice. 

In which types of cells the most of transpasone damage happens? In stem cells? Other types of cells are recycled quickly. The same question arises about ROS. 

Also, how your theory explains difference in life expectancy between different species?

What might the best ways of transposon quantity/activity approximation methods for this effect that are average human affordable & accessible?

Wondering if correlation data collection can be taken to a different scale + the concept can be popularized as a self-care metric.

There's one additional crucial phenomenon that I think needs to be better highlighted here, which is natural selection for cancer as an organism ages.

Cancer isn't best understood as a manifestation of genetic damage that the body is unable to remove or repair. That's what causes individual cancer cells to emerge and survive. But that alone does not guarantee that the damaging agent (the cancer cell) will replicate itself. Damage and failure of disposal alone only leads to local blockage.

Cancer goes beyond this to propagate itself throughout the organism. It evolves, developing drug resistance, the ability to colonize new "soils," and better evade the immune system with time. This is a feature that, as far as I know, is unique to cancer. And it depends on the mechanism of natural selection.

By contrast, lipofuscin, transposon-caused DNA damage, and protein plaques seem mainly to accumulate, causing local dysfunction. It's deadly, but it's ultimately a passive force. 

Hence, I think that "selection for cancer" deserves to be mentioned as a "further up the chain" core pathway of aging. This is an active, antagonistic force actively working to defeat our efforts to cure it.

Main upshot of all this: since aging involves changes on a timescale of decades, there must be some component which is out-of-equilibrium on a timescale of decades or longer (i.e. does not turn over significantly across a full human lifespan). These are the components which we’ll call “root causes”. Everything else which changes with age, changes only in response to the root causes.

A quibble: Just because some component turns over frequently, doesn't mean that higher-level structures made from that component aren't degraded in the process. For example, if I accidentally cut off the tip of my finger, the relevant cells will all grow back, but the finger will not; the larger-scale pattern remains degraded for life.

In the case of my fingertip, obviously we would consider that an injury, not an aspect of aging. But it seems hard to be sure that there aren't any aspects of aging that work this way?

↑ comment by johnswentworth · 2021-04-01T17:57:45.605Z · LW(p) · GW(p)

The key idea here is the difference between "local" vs "nonlocal" changes in a multistable system - moving around within one basin vs jumping to another one. The prototypical picture:

For your finger example, one basin would be with-finger, one basin without-finger. For small changes (including normal cell turnover) the system returns to its with-finger equilibrium state, without any permanent changes. In order to knock it into the other state, some large external "shock" has to push it - e.g. cutting off a finger. Once in the other state, it's there permanently (as long as there aren't more large shocks); the new state is stable.

In the absence of large external shocks, the system hangs around in a stable basin. In terms of information in the high-level structures, this means that any information is either (a) degraded quickly, on roughly the same timescale as component turnover, or (b) maintained indefinitely. Picture an actual ball being gently shaken around in a bowl: information about the ball's exact position at any given time will be lost quickly; its position a minute or two later won't tell us much about its position now. However, the fact that it's in the bowl will be maintained indefinitely (more technically, maintained for an exponentially long time, assuming the average shaking energy is substantially lower than needed for the ball to jump out). Any information which isn't lost quickly, will likely stick around for a very long time.

If I understand correctly, increasing the activity of transposons should speed up aging assuming the theory is true. Are you aware of any studies which attempt this?

I am a bit confused why some of these theories would be so hard to test? It seems like some core pathways that seem like they wouldn't be reversible even in naive stem cells under any circumstances (like transposons copying themselves successfully), could possibly be tested by checking if clones derived from older cells age faster or something along those lines? The same goes for children from older parents? (Not sure to which extent that test would be made harder by all the mechanisms keeping the germ line immortal)

Mammals of any age have “fatty streaks” along the walls of the vasculature, which are exactly what they sound like. (These are the slightly lighter patches in the pictures above - more obvious in the older aortas, but faintly visible in the young pair as well.) In older mammals, the fatty streaks tend to be larger, until in old age they necrotize (aka die) in the middle and turn into thick “atherosclerotic plaques” (the dark patches in the lower right picture above). These can block blood circulation, and sometimes a chunk of the plaque can break off and block circulation in smaller vessels; either of these can cause e.g. heart attack or stroke. 

At any age, a lower-fat diet is associated with smaller fatty streaks and lower chance of atherosclerosis, though the streaks universally grow with age holding diet constant.

Aren't those way less bad in rats/mice (which tend not to suffer from arteriosclerosis at the ages they manage to survive to simply b/c they die of cancer before they can develop them?)

Does this blood finding change anything here?

I don't understand this:

For any X with turnover much faster than aging (i.e. decades), if we see the level of X increase/decrease on the timescale of a human lifetime, then that is not due to permanent “accumulation of X” or “depletion of X”; it is due to increase/decrease in the rate of creation/removal of X.

Is it not just how accumulation and depletion exactly occur in biological systems? Not even specifically at the cellular level?

How do the ROS and/or damaged molecules move between compartments, e.g. nucleus/cytoplasm/extracellular? I have seen very little on this, and consider it a major blindspot. I’m not sure if it’s a blindspot for the field or if I just haven’t found the right cluster of papers.

Man, I wrote up a whole summary of the mitochondria free radical theory of aging for you after reading this paragraph, then read the rest of your post and realized you already know about it. I'm surprised though that you still have questions about this, because the mechanism of export is described in Aubrey de Grey's book. At least it's described in his book "Ending Aging". I haven't read the other one, so I'm not sure if it contains less information.

A very quick description is that cells overtaken by clonal mutant mitochondria export electons from their cell membranes to keep themselves alive via the Krebs cycle (since the electron transport chain in mitochondria, which normally receives these excess electrons, is shut down).

The receptor molecule for these excess electrons is oxygen. These oxygen molecul\es with extra electrons are very powerful free radicals, and end up reacting with whatever molecule they bump into first. Unfortunately some decent fraction of these reactions are with low-density lipoproteins, which are then transported by the bloodstream to a much larger area of the body, and eventually deposited on blood vessel walls, contributing to atherosclerosis.

I'm glossing over a lot of details here, so if you want to read more about it, check out Chapter 5 of Ending Aging.

This book did come out in 2008, and I imagine quite a few new things have been learned in that time, so I'm not sure if this theory is still accepted. I'd be interested to know if there's been any follow-up research.

I don’t know whether there’s any evidence that these molecules actually accumulate long-term. (Just because they’re not broken down doesn’t mean they’re not simply excreted.) I haven’t seen direct evidence, but I haven’t searched very carefully either, and I haven’t seen direct evidence against.

If I understand correctly, accumulation of A2E in the lysosomes of microglia in the retina is one of the main causes of macular degeneration. There is also a big section of Ending Aging dedicated to the topic of lipofuscin in general (non-digestible material that accumulates in the lysosomes of long-lived cells)

Final Thoughts

This is an amazing write-up. I am very surprised that De Grey's book didn't mention transposons. Is that new?

Regardless, it doesn't seem like a stretch at all that they could play a key role in aging.

One thing I noticed was missing from your post: any mention of the role of information loss in the epigenome as part of aging. That seems to be Dr. Sinclair's main theory for the root cause of aging. Sounds like that could actually be closely intertwined with transposon activity since transposons are repressed by methylation or histone structure most of the time.

And of course, since I am always thinking of genetic engineering, this whole post made me think that removing transposons from the human genome via genetic editing, should we find a way to do it safely without affecting desired function, would be a great victory against aging. Evolution has not and will not act in our best interest, and there is no better example of this than the existence of transposons. They are basically parasites within our genomes.

What do you think about the ability to predict age to surprising accuracy using ~350 DNA methylation sites? Sadly I can't work out  if the author has considered looking at the sites to see much of what the methylation is changing the transcription of, other than the PGCT genes which based on a cursory search seem to be linked by being targets of a specific process rather than doing a specific thing. Again this makes it unclear whether this is upstream or downstream of ageing.

Mitochondrial mutation accumulation seems to be a big thing, mitochondrial dysfunction is implicated in Alzheimer's, and might be linked to a bunch of signalling around epoxyeicosatrienoic acids [LW · GW]. This is confused by the fact that EETs might induce mitogenesis but are also also anti-inflammatory and regulate the vascular system (?!) because biochemistry just like this sometimes.

Oddly enough, mitophagy also seems to be a potential target of anti-ageing drugs. Possibly the (selective) turnover of mitochondria can be used to remove the most dysfunctional ones? Perhaps the two processes might be coupled in such a way that speeding up one speeds up the other. Also some people have suggested combining these before but then as far as I can tell just didn't bother to check if it actually worked (!?!?)

Whether mitochondrial mutations are upstream or downstream of other things is unclear. I think Nick Lane has suggested a mechanism by which mitochondrial mutations could actually accumulate faster than by chance (definitely in "The Vital Question" but possibly elsewhere) but I don't know if it has been tested.

(Posting as a top-level comment since I have a few points to say but the stuff about DNA methylation is sort of in response to comments below)

Thanks for writing this up! We need more people thinking about how to defeat aging. 

Curious if you've read Nintil's posts? https://nintil.com/categories/aging/

In principle, we could test it by looking for an age-related increase in transposon count in non-senescent cells, but that turns out to be actually-pretty-difficult in practice. (Modern DNA sequencing involves breaking the DNA into little pieces, sequencing those, then computationally reconstructing which pieces overlap with each other. That’s a lot more difficult when the pieces you’re interested in have millions of near-copies filling most of the genome. Also, the copy-events we’re interested in will vary from cell to cell.)

I wonder if something like single cell ATAC-seq could help here? There's still the problem of aligning near-copies but it seems like there's already some work trying to deal with this problem. (I haven't read either of these papers in detail but the second specifically mentions transposons as a use-case.)

Could prions be another potential root cause? Either contributing to the DNA damage <-> mitochondrial ROS feedback loop, or as a cause of some separate conditionally independent aging factor?

This post focuses on the cellular scale and below, but what about the larger scales?

Since calorie restriction slows aging, is there a positive relationship between calorie intake and number of DNA mutations?