The Unknown Interactions of Drugs that Slightly Slow Aging

In this post, someone much more enthusiastic than I about the use of traditional drug development to slightly slow the progression of aging makes the point that next to nothing is known about how the present collection of candidates interact. This is of interest from a pure science perspective, but not - to my eyes - from a getting things done perspective. The expected outcome for this sort of drug development, largely meaning reuse of existing drugs, as measured in terms of how much additional healthy life we would expect to obtain, and how much that progress would cost, is just not worth it in comparison to focusing on the establishment of SENS-like rejuvenation therapies based on damage repair. That doesn't stop the science of drug interactions from being interesting, but it does mean we should be looking elsewhere for meaningful progress towards healthy life extension.

I take about a dozen different pills for longevity. There is some evidence behind each of them, but what we really don't know is how they interact. It would be nice to think that their benefits simply add, so that if one pill produces a 10% average increase in life span, then 10 pills increase life span 100%. Fat chance. Some of them are ineffectual, of course. But for the ones that offer a benefit, most of the benefits are probably redundant. (When different treatments work via the same pathway, we can't expect that two together work any better than either one of them separately). A few may mutually interfere. But there also may be a few magic combinations that synergize positively. If they work via pathways that are substantially independent, we might hope that the life extension from the two together might be equal or even greater than the sum of the benefits separately. Most of the life extension drugs that we have target a single pathway: they work through the insulin metabolism. The remainder work to suppress inflammation, or re-energize mitochondria, or lengthen telomeres, or reduce TOR signaling.

Almost no work has been done with combinations of longevity treatments. In 2013, Steve Spindler's lab published a study based on eight different commercial formulas of vitamins and supplements. Their data were beautiful - and the survival curves for each of the eight fell exactly along the survival curve of the control group. I have heard that the NIA's Interventions Testing Program (ITP) has tested rapamycin in combination with metformin, with successful results (to be published next year). In a rational world, some of the billions of dollars that go into "me too" drug development and chemotherapy trials by Big Pharma would be diverted to test all of the above compounds, alone and in combination. But in the branch of the multiverse where you and I live, this will not happen in 2016. Hence "quick and dirty" (meaning cheap) alternatives look attractive.

This is a research proposal, the germ of an academic publication that I have been working on in recent months: the plan is to screen for combinations of drugs that offer dramatic life extension in mice, using the minimum number of mice to test the maximum number of combinations. Standard practice is to use 30-80 mice for each test in order to get a clean survival curve. The innovation I am offering is to use just a few mice for each combination of treatments so that more combinations can be tested, albeit less precisely. How many mice do we really need to be reasonably sure of not missing an outstanding combination of treatments? I have been modeling the situation with computer-generated data, testing different statistical methods to see which works best, and how many mice are needed in order to be reasonably certain of not missing a great combination. My definition of a great combination is that it extends life span in excess of 50%. The test I propose will not be capable of distinguishing "which is better" among the rank-and-file of many treatments and combinations. However, there will be enough statistical power to identify the really hot performers, which are of most interest to us.

I believe that using about 1400 mice in an experiment lasting about 3 years, we should be able to evaluate all combinations of 15 separate life extension treatments, and narrow the field to 6 candidate triples that show offer life extension in excess of 50%, and thus show promise for further testing. The program I have outlined could be undertaken for less than the cost of testing the 15 separate treatments using traditional methodology, and I think what we would learn from the combinations protocol could be a great deal more useful. The total cost might be $1 to $3 million, depending mostly on where the work is done. The biggest risk is that the high-benefit "magical" synergistic combinations that this program is designed to look for simply don't exist. If they do exist and can be found, the public health impact is likely to be enormous.

I would wager on these synergies not existing, but of course you don't know for sure if you don't look - again pure science versus getting things done. Everything is a trade-off. However, even if such synergies do exist, note that growth hormone receptor knockout (GHRKO) mice, the current record holders for mouse longevity, live more than 60% longer than their unaltered peers. Yet the small human population with the hereditary condition of Laron-type dwarfism, caused by a dysfunctional growth hormone receptor, doesn't appear to enjoy any meaningful extension of healthy life span, though it is possible they are modestly more resistant to diabetes and cancer.



You'd have to be naive to assume that whatever works in mice works in human beings but you have to be careful with this argument because it cut both ways. De Grey has put his focus on robust mouse rejuvenation. The argument being that once you can rejuvenate a mouse using SENS, then you can rejuvenate a human being. The first counterargument that de Grey is going to get, if indeed robust mouse rejuvenation is observed, is "well, sure, it works with mice, but human beings are different".

If you dismiss the mouse as a model, then I am afraid that it puts a serious dent in all of anti-aging research, including your favourite approach. I would recommend caution when invoking this argument.

Posted by: Daniel Lemire at December 29th, 2015 9:44 AM

@Daniel: Actually, it's not so much focused on mice. For example, glucosepane is not so important for mice, and the good AGE-breakers we know that work well in mice have no effect against glucosepane, that amounts to more than 90% of human AGEs. Transthyretin and Alzheimer's aren't much important for mice either. So I consider it a mixed human-murine research strategy.

Posted by: Antonio at December 29th, 2015 5:01 PM

@Daniel: Also, I think Reason's argument is not "what works in mice usually doesn't work in humans" but "messing with metabolism produces big lifespan gains in short-lived species but not in long-lived species".

Posted by: Antonio at December 29th, 2015 5:05 PM

@Daniel Lemire: If there were a first generation SENS therapy that needed to be applied life-long to create 50% life extension in mice, I'd not expect that to do much in humans either. Mice have greater plasticity of life span in response to interventions, and that's across the board.

The continuous life-long treatment model, however, is a different picture from a one-time treatment that produces 50% life extension in mice, or a treatment that produces 100% life extension when applied intermittently starting at half the normal life span, or an approach that doubles remaining life span in an old animal after a single treatment. All very different dynamics of cause and effect, and I'd have greater expectations for translation to human therapies for any of those results, when they come to pass.

Posted by: Reason at December 29th, 2015 5:06 PM

The MMTP is currently working with Josh and other researchers to come up with a workable model suitable for confirming quickly synergies. I am thinking more of combined interventions such as senolytics combined with Alk-5 or Senolytics combined with stem cell replacement. I am personally less interested in supplements though if a model can be perfected we may be able to rapidly test for synergies.

The ideal of course would be us or someone else to test Senolytics and AGE breakers (if we had one).

Mice do have a reasonable translation to humans for the most though so SENS is right to seek RMR. If there were more interventions for MMTP to test that supported SENS we would do it.

Posted by: Steve H at December 30th, 2015 6:28 AM

We are certainly looking at combining Senolytics and Alk-5 inhibiting as this would potentially show some of the benefits of cleaving AGE and how clearing senescent cells would work with restored stem cell signalling environment in terms of lifespan.

Posted by: Steve H at December 30th, 2015 6:30 AM

Nice to hear that, Steve. It looks more promising now.

Posted by: Antonio at December 30th, 2015 7:46 AM

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