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In reply to:

WILT, for example, might kill people or animals for years and years whilst the bugs are ironed out because they won't get the cell replacement therapy right.

'Ironing out' is an understatement... how the heck do you get fingernail stem cells into the right spots and replenish every hair follicle? Bone marrow is easy, those cells move through the blood and colonize their proper niches when they flow through the bone. But solid tissue, with immobilized cells and extracellular matrix?

MitoSENS will unearth the complexities of mitochondrial DNA and why it's hard to move it into the nucleus.

Oh hell yes. The animal mitochondrion is a crazy jerry-rigged mess with a genome more overoptimized than many viruses, bizarre specialized ribososomes specifically optimized for making the handful of proteins that the mitochondrial genome codes for while at the same time being obviously slapped together from spare parts, RNA-editing that sometimes is unclear what is important and what is noise, and some of the genes may need to be in the mitochondrion for the purpose of real-time regulation. And the same core set of genes coding for large, hydrophobic, membrane-bound proteins have failed to move into the nuclear genome in all branches of life because that stuff is damn hard to get through two membranes without having it congeal into pellets of inert goo. I've seen interesting work of late involving trying to get RNA-channels embedded in mitochondrial membranes to allow cytosolic RNAs with the proper signal sequences to get into the mitochondrion to be translated there, with some success, but I have little reason to think that such a system would improve upon normal mitochondrial function because poking a complicated system will often just make it worse. This is not to say that mitochondria are perfect, you can imagine in five seconds about twenty ways to make them better than they are - none of which are things you can do by simply going in and making a few simple mods to an existing eukaryotic system.

On another note it is pretty well impossible to get in and modify large fractions of cells in a living organism as opposed to a monolayer of cells in a controlled environment in a laboratory. This being said, I think one of the most fruitful avenues for actual anti-aging research would be looking for ways to chemically boost protein chaperone/recycling activity and improve the regulatory interactions between mitochondria and the cytosol.

"because poking a complicated system will often just make it worse."

yeah that was my view. I have only an amateur interest in biology though.

See comment in full context

Tentative Thoughts on the Cost Effectiveness of the SENS Foundation

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Jan 4, 2015

It should be emphasized that back-of-the-envelope calculations, such as the one given in this post, ought to be adjusted to account for the fact that interventions can look much more cost-effective than they are, especially when the interventions were only shallowly investigated.

Previously, Givewell has looked into the cost-effectiveness of life sciences funding, as well as publishing a simple estimate of the impact of the average dollar spent on cancer research, which suggested that, in the past, each $2790 spent on cancer-relevant biomedical research in the US added one year of life lived (YLL) to the life of a US resident. Givewell has also interviewed Aubrey de Grey of the SENS foundation. Owencb has previously estimated the cost-effectiveness of funding SENS/ anti-aging research as being around $50 per QALY. Aubrey de Grey has previously been averse to giving explicit cost-effectiveness estimates regarding how many QALYs would be gained per unit of funding supplied to SENS, though he has been clear that SENS's funding needs are "$100 million per year for each of the next ten years".

This part of the post will consist of me using lots of best guesses to produce something vaguely resembling a cost-effectiveness estimate for SENS. You should not take this cost-effectiveness estimate literally.

If SENS needs one billion dollars to ensure that rejuvenation technologies that give individuals 30 extra years of healthy life are available to the public in 30 years, we might (completely arbitrarily) assume that someone else will come along and fund SENS in ten years if we don't contribute to funding SENS today. This means that if we fund SENS today instead waiting for it to be hypothetically funded in ten years from now, about ten times the number of people who die each year would live 30 years of healthy life that they wouldn't have lived otherwise. Given that there are about 57 million deaths per year worldwide, this translates to about 17 billion YLLs lost by waiting ten years to fund SENS; since SENS ostensibly requires only 1 billion of philanthropic funding, this implies that $0.059 of funding for SENS produces a YLL.

Of course, regenerative medicine won't be free to the people receiving it, and I have no idea how to account for this, given that I don't have a good idea of how much regenerative therapies will initially cost. The above estimate hasn't been adjusted to account for the fact that there is a time-delay between when funding is provided, and when the benefits of regenerative therapies are available to the public. Perhaps Aubrey isn't well-calibrated, and the "$100 million per year for ten years" figure is entirely wrong. It may be the case that starting work on SENS's research agenda earlier rather than later would allow certain people who would have otherwise died to live until aging escape velocity is reached, which would have lots of utility. There are plenty of other issues with this cost-effectiveness estimate which I am sure that readers could point out.

The point I wanted to make, though, was that maybe, possibly, SENS is competitive with GiveWell's top charities-- I'm legitimately not sure whether I would fund SENS or GiveWell if I were making a charitable donation today. Does anyone have any further thoughts on this topic?

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$0.059 versus $2790 is a massive difference. I think what this mostly reflects is that SENS is claiming to make a massive difference in health outcomes, whereas contemporary biomedical research is much more modest in its ambition.

The real question is what chance SENS has of succeeding. I'm unfortunately not enough of a domain expert to have a good idea about this, but over the years I have become increasingly skeptical; it seems to me that SENS is a great idea that will fail for a bunch of interesting reasons.

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The real question is what chance SENS has of succeeding. I'm unfortunately not enough of a domain expert to have a good idea about this...

Right, I'm in a similar position here, and I was hoping that someone with some relevant knowledge could make a case for SENS either being a better or a worse funding opportunity than GiveWell. I'm closer to being a risk-neutral expected value maximizer when it comes to charitable donations than most people around here are-- I can think of lots of examples of EA's who are risk-averse regarding their allocation of money they have set aside for charity, at least.

...SENS is a great idea that will fail for a bunch of interesting reasons.

Do you have any predictions for what these might be, or were you generally expressing a belief that, say, large and complex projects like SENS have high failure rates in general?

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On the subject of SENS vs givewell, I think givewell have already kind of abandoned the goal of rational philanthropy in the way that they dismissed x-risk and continue to pour money into developing world aid. SENS could at least change the world eventually and affect billions/trillions of lives, whereas givewell's third world aid is always going to be a tiny drop in a gargantuan ocean.

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SENS could at least change the world eventually and affect billions/trillions of lives, whereas givewell's third world aid is always going to be a tiny drop in a gargantuan ocean.

This seems backwards to me. GiveWell's third-world aid probably has big indirect effects, since it's acting to lift these societies from a bad equilibrium of enduring poverty and underdevelopment. SENS is an interesting research program within gerontology, but that's the kind of thing that's going to be pursued anyway if there's any chance of it being useful. We see this quite directly with RepleniSENS, i.e. stem-cell research, which is a thriving field already - there's no reason why this could not apply to other parts of the SENS project. Sustained economic growth in the third world would be a big boon to all sorts of science anyway, due to increased scale if nothing else.

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since it's acting to lift these societies from a bad equilibrium

If I agreed with this then I'd be more positive about givewell. I think it's wishful thinking, though. In reality, societies in Africa are not in a bad equilibrium primarily because of malaria or malnutrition, they're in a bad equilibrium because of the backwards values that African people hold, such as loyalty to the tribe/extended family rather than the state, lack of support for western values like accountable government, basic rationality, equality under the law, fair enforcement of contracts, etc. We don't hear much about this because it doesn't fit with the political narrative of the kind of people who spend their time trying to help the third world.

Malnutrition is the visible surface symptom of "these are uncivilised, backwards people caught in a series of petty tribal wars".

EDIT: Just let me disclaim that this is not supposed to be an excuse to not help the developing world. I think we should help them, but not by giving out food or bed nets or medicine. They need better political and value systems, which we could (and should) give them via charter cities.

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Countries with bad institutions (including the bad cultural values you list) generally end up in the middle-income range; there are many examples in Latin America. And there's still hope for these to grow further once civil-society institutions get strong enough. Obviously you can find examples where abject poverty is entirely the fault of bad institutions (North Korea), but that's not the case for the countries that are targeted by top GiveWell charities.

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So I looked up the poorest countries in the world. Depending on how you measure it, Malawi, the DR of congo and the Central African Republic are at the bottom.

Wikipedia on the Democratic Republic of Congo:

DR Congo is extremely rich in natural resources but political instability, a lack of infrastructure and a culture of corruption have limited development, extraction and exploitation efforts

The Central African Republic

The Central African Republic Bush War began in 2004 and, despite a peace treaty in 2007 and another in 2011, fighting broke out between government, Muslim, and Christian factions in December 2012, leading to ethnic and religious cleansing

Malawi:

Corruption within the government is seen as a major issue, despite the Malawi Anti-Corruption Bureau's (ACB) attempts to reduce it. The ACB appears to be successful at finding and prosecuting low level corruption, but higher level officials appear to be able to act with impunity

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I wouldn't say pouring money into the developing world is a tiny drop.

Bill Gates 2014 Annual Letter gives evidence that it's a very good investment.

http://annualletter.gatesfoundation.org/

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I have specific ideas about why it will fail: the various interventions to combat the 7 damage types will all meet with complications and unexpected difficulties.

WILT, for example, might kill people or animals for years and years whilst the bugs are ironed out because they won't get the cell replacement therapy right.

MitoSENS will unearth the complexities of mitochondrial DNA and why it's hard to move it into the nucleus.

etc, etc.

But as we do this work, we will learn a lot about the body and there will be some amazing spinoffs. For example LysoSENS and AmyloSENS will probably help with age related diseases. Eventually it might even come together to extend lifespan for another 50 years until the next unforseen problem crops up. But I expect that to take at least till 2090, and a lot will have changed by then. By 2090, cryo, AI and uploading will probably look a lot better than being the next human lab-rat for SENS.

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WILT, for example, might kill people or animals for years and years whilst the bugs are ironed out because they won't get the cell replacement therapy right.

'Ironing out' is an understatement... how the heck do you get fingernail stem cells into the right spots and replenish every hair follicle? Bone marrow is easy, those cells move through the blood and colonize their proper niches when they flow through the bone. But solid tissue, with immobilized cells and extracellular matrix?

MitoSENS will unearth the complexities of mitochondrial DNA and why it's hard to move it into the nucleus.

Oh hell yes. The animal mitochondrion is a crazy jerry-rigged mess with a genome more overoptimized than many viruses, bizarre specialized ribososomes specifically optimized for making the handful of proteins that the mitochondrial genome codes for while at the same time being obviously slapped together from spare parts, RNA-editing that sometimes is unclear what is important and what is noise, and some of the genes may need to be in the mitochondrion for the purpose of real-time regulation. And the same core set of genes coding for large, hydrophobic, membrane-bound proteins have failed to move into the nuclear genome in all branches of life because that stuff is damn hard to get through two membranes without having it congeal into pellets of inert goo. I've seen interesting work of late involving trying to get RNA-channels embedded in mitochondrial membranes to allow cytosolic RNAs with the proper signal sequences to get into the mitochondrion to be translated there, with some success, but I have little reason to think that such a system would improve upon normal mitochondrial function because poking a complicated system will often just make it worse. This is not to say that mitochondria are perfect, you can imagine in five seconds about twenty ways to make them better than they are - none of which are things you can do by simply going in and making a few simple mods to an existing eukaryotic system.

On another note it is pretty well impossible to get in and modify large fractions of cells in a living organism as opposed to a monolayer of cells in a controlled environment in a laboratory. This being said, I think one of the most fruitful avenues for actual anti-aging research would be looking for ways to chemically boost protein chaperone/recycling activity and improve the regulatory interactions between mitochondria and the cytosol.

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"because poking a complicated system will often just make it worse."

yeah that was my view. I have only an amateur interest in biology though.

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"about ten times the number of people who die each year would live 30 years of healthy life that they wouldn't have lived otherwise."

This is wrong - those people get to live for thousands of years of SENS works. Or possibly even more.

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Mark_Friedenbach

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Well, now you're getting into the next stage: preventing accidental and intentional death. Estimates I read a long time ago and would love to see an updated cite if anyone has one said that once "natural" / ageing causes are removed, the average person would still only be expecting to live a few hundred years until something else (probably an automobile) kills them.

Of course once ageing is dealt with we will have bought ourselves some time to deal with protecting our biological bodies from accidental and intentional harm.

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It can't be a few hundred because that would imply that the non-natural-causes death rate is about 20-30% of the natural-causes death rate, which isn't true. At least in the developed world.

I think it's more like a few thousand.

And driverless cars are on the way, which would reduce the death rate drastically.

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It can't be a few hundred because that would imply that the non-natural-causes death rate is about 20-30% of the natural-causes death rate, which isn't true.

If you have a 0.1% per year chance of dying "non-naturally", the probability of you surviving for 100 years is 0.999^100 = 90% which looks to be order-of-magnitude correct for contemporary Western countries. This implies that your chances to live for 500 years are 0.999^500 = 60%, for a thousand years -- 37%.

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if P(life length=x) = p(1-p)^(x-1) with p=0.001, then E(life length) = 1/p = 1000. It's a geometric random variable.

Which is NOT A FEW HUNDRED YEARS

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The key thing that's missing to be able to productively discuss whether to give to SENS is a justification for thinking that they have a decent chance of curing ageing if given $1 billion over 10 years. I've asked Fluttershy about this and they said that they hadn't found a justification of this, even after looking around for a while.

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Seems like your model completely neglects to include uncertainty in it... it assumes that in 10 years breakthroughs will definitely be made... a better cost effectiveness model might be cost effectiveness of how much funding would increase the likeliness of a breakthrough, and would almost certainly lead to immediately lower estimates (without even trying to account for the typical reasons that interventions are less effective than they initially appear)

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This is an enormous problem with this model.

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