Takeaways from the Undoing Aging 2019 Conference

SamBlake

@Roey Tzezana and I attended the Undoing Aging conference in Berlin from March 28-30, where we attended various conference sessions — including the opening keynote from Dr. Nir Barzilai and a debate between Aubrey de Grey and Dr. Vadim Gladyshev on the validity of the “damage repair” approach — and conducted nearly 50 interviews with longevity experts.

Based on the many conversations we had, the XPRIZE team reached the following conclusions:

● We still lack a deep understanding of what drives aging; the “mechanisms” are just a start.
● More funding is needed for basic science, e.g., to better understand aging.
● There is a significant need to improve our ability to measure biological aging.
● The clinical trial process is a bottleneck. Translating science from animal models to humans is fraught with failure; the Valley of Death, or the period between drug discovery research and market entry, was frequently mentioned.
● There is widespread doubt whether we can perceive molecular interaction with enough precision in order to help us expedite development of aging treatments, e.g., through AI.
● The importance and prevalence of personalized medicine is trending up; the same is true, to a lesser extent, of biohacking, for which concern of risks persists.
● There is strong evidence that diet and exercise extend lifespan, and widespread belief that personalized programs would increase the impact of such treatments, including supplements; precise prescription across a wide range of heterogeneity, however, is at best in its infancy.
● Some of the most commonly mentioned aging treatments were those related to stem cells, the extracellular matrix, senotherapy, and epigenetic reprogramming.
● Proper messaging around fighting aging is essential, though there seems to be no consensus.
● There is optimism that one success (e.g., the TAME trial) could cascade more funding and interest.
● Concern remains about the side effects of emerging treatments like rapamycin, resveratrol and senotherapy.

Please, share your own views on any of these or related topics here!

NickOttens

@mkaeberlein, you may have more insight for us on the mechanisms of aging.

mkaeberlein

Well, I can certainly share my opinion on these topics!

• While it's true we still lack a deep understanding of aging, I think that will be the case for a long, long time. That's the nature of biological research - the more you learn, the more you realize how little you really know. Having said that, we've learned a lot in the past 30 years and now have targets for intervention that seem likely to work in humans. The progress has been dramatic and we shouldn't undersell it.
• Yes, lack of funding is the biggest factor delaying breakthroughs in this field. This is mostly because a majority of funding for biomedical research goes toward curing specific diseases. It's an inefficient approach to improving human health, but there are many factors that are working to maintain the status quo here.
• I agree we need better tools for measuring biological aging, but I've yet to hear anyone come up with a good plan for how you actually validate such tools in people. "Biomarkers" of aging rate are not particularly useful if you can't prove that they work. That's why I think functional measures of aging are more useful from a translational perspective, at least for now.
• Clinical trials are a bottleneck and will continue to be so. There are some good strategies that are being taken here. For humans, I like resTORbio's model of working toward approval for a functional indication that declines during aging and has a large health impact (immune function in this case). Of course, my personal favorite is the approach we are taking in pet dogs where it's possible to perform true clinical trials for healthy longevity in a reasonable cost and time frame.
• I think AI has great potential to accelerate preclinical progress in the field in several ways. Identification of candidate interventions and biomarkers are just a couple. The bigger challenge still remains how do you test and validate these things in people.
• Personalized medicine will obviously be important for optimizing translation of geroscience interventions to people, and this is where having good biomarkers could be particularly useful. Personally, I think that biohacking is fine if people want to do that, but I'm skeptical we are going to learn anything useful as a field from self-experimentation. It's also potentially damaging to the reputation of the field when high profile biohackers get a lot of media attention for doing crazy things.
• Of course, diet and exercise are important to maximizing healthy longevity. The value of supplements is obviously far less clear, and to my knowledge there is nothing that convincingly works. Certainly not to the same extent as not overeating and exercising regularly. I am optimistic that in the relatively near future, we will see the first interventions that significantly impact human health by targeting biological aging. I'm doubtful these will be supplements, however, since there is little incentive (and large disincentive) for people selling them to actually test those.
• I think the most important and effective messaging should be simple and to the point. (1) Aging is just biology. Dogs age faster than people. Mice age faster than dogs. The only difference is genes and environment. That's biology. (2) We understand enough about the biology of aging that we can slow it down and speed it up - at least in laboratory animals. We don't know for sure if the same tricks will work in people, but we think some of them will. (3) Targeting aging directly is the most effective and efficient way to keep people healthy longer. 20th century medicine is about waiting until people are sick and trying to cure their disease, often unsuccessfully. 21st century medicine is about targeting the biology of aging directly to keep people from getting sick in the first place, or to at least push those diseases of aging back as far as we can.
• I think the least effective - and actually quite damaging messaging - is talk of immortality and extreme lifespan extension. First of all, there is no data to support the idea that this is probably or even possible, and this kind of talk displays a profound lack of understanding of the complexity of biology. Second, it comes off to the average person as either delusional or snake oil and gives the field a bad reputation. Third, it damages the credibility of legitimate geroscientists among the broader scientific and medical community and makes it harder to convince serious policy makers that we need (or deserve) more funding for aging research.
• A successful FDA approval for a drug that plausibly targets the biology of aging, even if the indication itself is not aging, has the potential to be a powerful catalyst for translational geroscience. Personally, I think mTOR inhibitors are more likely to be successful in this regard, but I also appreciate the sound reasons for moving forward with metformin in the TAME study.
• My own opinion is that we need to change the discussion around side effects. Everything has side effects. Anyone who exercises regularly knows that there are side effects associated with exercise - sore muscles, broken bones, sometimes even death. One problem is that we think about side effects from drugs differently than we do for things like diet and exercise. Another problem is that we consider the declines in function with aging to be "normal", so the tolerance for side effects in a "normal" person are much less than they are in a "sick" person who might get better. We need to reframe this to consider that a "healthy" 70 year old is really extremely sick compared to a healthy 30 year old. In my opinion, we should tolerate some level of risk if the reward is making that 70 year old functionally more like the 30 year old. People in the field talk too much about the risk of side effects rather than emphasizing the potential reward of successfully delaying (or even reversing) functional declines of aging.
• My personal pet peeve: people who think the side effects from rapamycin are inconsistent with its use as a therapy to promote healthy longevity are not paying attention. There is enough data out there that rapamycin and other mTOR inhibitors in monotherapy, at doses likely to be used for this purpose, do not have significant or serious side effects. I'm not sure about side effects from resveratrol, but I'm also not sure that resveratrol does anything. I would be cautious about senolytics for now - not because I think they have bad side effects, but because I don't know of any data in people one way or the other, including whether any of them actually do anything positive in people. Give it a couple of years for the field to mature before you start taking your favorite senolytic.

SamBlake

@mkaeberlein, thank you for such a thoughtful response! I have a couple of follow-up questions.

Yes, lack of funding is the biggest factor delaying breakthroughs in this field. This is mostly because a majority of funding for biomedical research goes toward curing specific diseases. It's an inefficient approach to improving human health, but there are many factors that are working to maintain the status quo here.

• I'd love to hear you elaborate on some of these other factors.

I agree we need better tools for measuring biological aging, but I've yet to hear anyone come up with a good plan for how you actually validate such tools in people. "Biomarkers" of aging rate are not particularly useful if you can't prove that they work. That's why I think functional measures of aging are more useful from a translational perspective, at least for now.

• Help me understand your point a bit better, please; how would you describe the difference between a biomarker and a functional measure?

JessicaYoon

@mkaeberlein so great to see you here on this community discussion--thank you for joining! I also have the same question that @SamBlake mentioned: what would be some examples of a functional measure of aging?