Fight Aging!

The members of the effective altruism community are interested in rationally identifying the most cost-effective ways to make the world a better place, involving both the usual metrics by which we might judge "better," but also an analysis of whether or not those usual metrics are in fact helpful. Tear it all down and build it up again from first principles. Particularly at the large scale, a great deal of the status quo in philanthropy is wasted effort, virtue signaling, or even actively counterproductive. There are many ostensibly charitable organizations that, at best, do no good, and at worst exacerbate the problems they engage with. There are many ways to choose poorly as an individual donor. Philanthropy as an institution and as a personal choice can definitely be improved. The effective altruists are on to something there.

Quite some time ago I decided that the best and most effective form of philanthropy takes the form of supporting efforts that have a good chance of producing progress towards the medical control of aging. The rationale here is simple, possibly unfashionably so. Firstly, aging causes by far the greatest amount of human suffering and death. Secondly, aging is a tractable problem, in that the members of the research community collectively know enough to make progress rather than spinning their wheels, given suitable strategic choices in research and development. Lastly, suffering and death are bad things that should be brought to an end as soon as it is feasible to do so. That last opinion is both ubiquitous, judging by people's actions in their day to day lives, and yet somehow unpopular in our culture, a situation that has long confused me.

If one sets forth to blindly support any and all projects that claim to be doing something about aging, then a good three quarters of what is spent will be wasted. Yet the harms of aging are so great in comparison to other harms that the effort will still create more good in the world by far than for any other rational single choice in philanthropy. Given a little self-education, it is perfectly possible to avoid most of the obvious waste - the fraudulent side of the "anti-aging" marketplace, for example. The more challenging divide lies in the legitimate scientific community, between those focused on ways to modestly slow aging, such as via work on existing drugs like metformin and rapamycin, and those focused on ways to reverse aging, such as via senolytics to destroy senescent cells and the other lines of rejuvenation research advocated by the SENS Research Foundation. Few laypeople new to the field find it easy to determine what is more or less likely to be effective, and why.

I have long looked at this divide and taken the obvious position (obvious to me, anyway) that if funding and time is directed to this field, then it should be directed towards the goal of rejuvenation, not merely slowing aging. Rejuvenation is very much better than a slowing of aging. Rejuvenation via repair of fundamental molecular damage might even be easier to achieve than a method of reliably and safely slowing aging. It requires far less new knowledge about the operation of cellular metabolism, and obtaining that knowledge is slow, uncertain, and expensive. Where we can compare the pace of progress at a given level of funding, calorie restriction mimetic research from the 1990s to today, the best example of attempts to slow aging, looks like a very poor choice in comparison to the past seven years of senolytic development, the best example of attempts to reverse the causes of aging.

Returning to the topic of effective altruism, the article quoted below is an example of the sort of exercise that community specializes in: obtaining a handle on the usefulness of any given project by building a model and putting some numbers into it. The process is the important thing, thinking about it methodically, not any specific answer. In this case the analysis focuses on the TAME trial for metformin in older adults. This is a great example of work that I think has little technical merit. The evidence for metformin to reliably slow aging is terrible, the results from individual studies all over the map. Even if we take the best results as indicative of its performance, which given the full scope of the data seems unlikely, then the outcome is still significantly worse than the expected, reliable outcomes of more exercise and fewer calories. If someone can run the numbers on efforts to push forward metformin as a treatment for aging and find it to be a highly effective use of time and funding, then this says much more about the urgency of treating aging - and the waste in so much of the rest of philanthropy - than it does about the viability of metformin. Take that urgency and direct it to a better project, such as senolytics, or anything else under the SENS rejuvenation research umbrella.

Expected cost per life saved of the TAME trial

In this post I will try to calculate the expected cost per life saved of the Targeting Aging With Metformin (TAME) trial, in an attempt to improve Turchin's estimate. I found some of Turchin's assumptions were unnecessary or unjustified. He didn't provide an expected value calculation and he didn't apply the necessary discounts. His figure is true only if some of his many assumptions are, and this led to a result that I thought to be many orders of magnitudes off: $0.24 per life saved. In reality, if you look at the calculation section, you can see that, accounting for the icebreaking effect of the TAME trial on the FDA, I came to a result that isn't distant to Turchin's. This happened because Turchin didn't account for the icebreaking effect, compensating the omission of the discounts. Otherwise, if the icebreaking effect is disregarded, the results are different, yet still show high cost-effectiveness.

The TAME (Targeting Aging With Metformin) trial is motivated by two reasons: 1) According to AFAR, the TAME trial could have an icebreaking effect on the FDA. It will pave the way for the Food and Drug Administration (FDA) to consider aging a modifiable condition and an official indication for which treatments can be developed and approved, and 2) Testing metformin on a healthy population could prove its beneficial effects, and the approval of metformin by the FDA would cause physicians to start suggesting it to their patients.

The core of Turchin's idea is right: Let's say Longevity Escape Velocity (LEV) will happen at date x. If we extend the lives of people who would have died before date x, making them reach date x, we are then "saving their lives". This could be done by raising the life expectancy of a portion of the world using simple interventions such as metformin, or alternatively by accelerating research to make LEV occur sooner. The given in this rationale is that Longevity Escape Velocity will happen at some point, and I think this is very safe to assume.

Many studies suggest that metformin could postpone age-related pathologies. Data from the largest study translates to around 1 year of more life for diabetics than the non diabetic control. More important is the number of years LEV will be advanced by, considering the icebreaking effect of TAME. The model here shows that most of the cost-effectiveness of TAME comes from its icebreaking effect. Will advancing the date of the icebreaking effect by x years result in an advance of LEV of x years? Probably not, since the FDA not recognising aging as an indication doesn't stop aging research, and it's not clear if the icebreaking effect is a bottleneck for achieving LEV. Such an effect could, though, increase the budget of aging research and make research in this field more focused on translation and on the hallmarks of aging instead of single diseases.

If the icebreaking effect enables the funding of one or more projects which are bottlenecks to LEV, then LEV's date is advanced. The main probability at play here is if the NIH would indeed increase its budget on aging or spend it better. If this doesn't happen I don't anticipate other actors would step in who wouldn't otherwise. The expert opinion on this is that such a thing will happen - it is the objective of TAME as stated by the organizers.