The first day of the ARDD2022 conference started with several different workshops and I would like to share my initial impressions of these. It was without a doubt an amazing day with many great panelists!
However, even though I enjoyed it a lot, I would nevertheless like to write something critical or provocative. It is simply more interesting to talk about our disagreements than to give a boring conference recap and recite the geroscience hypothesis once again (which by the way should be renamed to the geroscience paradigm, according to one panelist, which I would endorse).
In the morning the conference started with a very informative workshop on web3 and the excellent work of vitaDAO to get more decentralized science funding for everyone. Unfortunately, due to a meeting, I could not attend the first half of the workshop so I do not have much to say on this.
What I do like about vitaDAO in general (and impetus for that matter) is the reduced level of bureaucracy allowing for faster funding. The panelists also pointed out how NFTs would make fractional ownership easier, which I think is great. It is often hard for an individual to invest in companies doing aging research. Nevertheless, people are still skeptical. One of my colleagues said they will take vitaDAO more seriously as a source of funding if they are still around in a couple of years. Hence stability and continuity should be an important "proof of principle" to achieve for this new project to convince the skeptics. Finally, one interesting question from the audience was "how do you defend a patent on the blockchain"? While defending IP, according to the panelists, would still work the same as normally, I am a bit worried about coordination. If the IP is owned by many small actors, will they be able to coordinate in order to do so?
Then in the end the panelists discussed some juicy almost philosophical questions:
- what is the importance of cosmetic applications?
- we do not like the term anti-aging due to the snake oil connotation and we should be cautious not to oversell the science (talking about living forever). Although one panelist correctly pointed out that biological immortality is more or less a real phenomenon.
Still struggling a bit with gender diversity in some aspects.
Later during the day, Felipe Sierra from the Hevolution Foundation walked us through his criticisms of the "hallmarks of aging". More or less in agreement, I think that the hallmarks are just a rough guide. He thinks that loss of resilience is the most important outcome of aging**, which reminded me of an idea I was mulling over. Treatments that improve resilience may increase lifespan without slowing aging. While these treatments may be good in terms of being low hanging fruits, they could lead the field astray because they fail to target aging per se. It is unlikely that we can increase resilience considerably in the face of damage accumulation and aging. Some longevity benefits are possible but the treatments may not be additive. I am worried that rapamycin is one such treatment because even short courses of rapamycin are beneficial, which is inconsistent with slowed aging or damage accumulation theories. Maybe it is consistent with rejuvenation (optimistically) or indeed "it only affects resilience" or maybe it is programmed aging, or a combination of multiple effects.
Ultimately he thinks we are not very good at linking the hallmarks with physiologic and pathophysiologic outcomes. Also he is very interested in defining halmarks of health rather than focusing on disease -- and he does not believe that aging is a disease, which is one of my favourite controversies.
We have come very far in this debate and it seems the overton window has shifted quite a bit. Evelyne Bischof, another panelist, for example, disagreed because she thinks aging is a disease. Even Nir Barzilai entertained the notion that aging might be a disease. I doubt we could have had such conversations 10 years ago! Finally we can start saying what we think...
Another problem with Felipe's focus on resilience is that a loss of resilience may not be a universal marker on the tissue or cell level. For cancer cells, clonally selected populations and senescenct cells it is actually increased resilience (or resistance?) to environmental (apoptotic) stressors that is the problem! Finally, he was not quite convinced by telomeres as a hallmark of aging - and I used to agree with this until recently, but after taking another look at the literature I am somewhat more positive.
Joan Mannick talked about the phase II and III trials of the mTOR inhibitor RTB101 to restore the antiviral interferon-1 response which is lost during aging. Apparently it worked in phase II to decrease (PCR?) diagnosed infections in the elderly but failed in phase III on a very soft endpoint of self-diagnosed(?) respiratory tract infections. The data they showed on incidence of severe infections seemed quite promising. Hopefully they can go back into phase III and prove that this was not a lucky post-hoc analysis.
Nir Barzilai was bullish on SGLT2 inhibitors and I am starting to believe him.
The things I disagree with for the most part
James Kirkland today played the role of a "reasonable conservative" and said all the things I disagree with. While none of them were outrageous, many of them were wrong, in my opinion. For example, he asked whether longevity should be still considered the "gold standard" in aging research because he doubts that lifespan correlates with healthspan. Igf-1 reduction was one of the negative examples he chose. Well, first of all, he is wrong because in mouse models longevity and healthspan almost always go hand in hand. Rich Miller, a major figure in the NIA ITP, agrees and anyone who takes even a casual look at the literature should do the same. Just think of rapamycin, caloric restriction or dwarfism, all these interventions extend lifespan and have well-documented health benefits in mice (even if the data is imperfect).
I think many people who claim that healthspan does not follow lifespan simply do not know how to read a mouse lifespan study (sorry). Most of the so-called examples are from mouse models that show only modest lifespan extension that has never been replicated under rigorous conditions (e.g. weak Igf-1 reduction models or other weird models instead of GH dwarfs). This is a topic that I wrote about extensively if you are interested in more counterarguments. I am also not convinced by his example of the Bolivian Laron dwarfs. The human data is way too preliminary to make such a sweeping conclusion.
Kirkland also questions whether people actually want to live to 120. This is because he is asking the wrong people (the very sick elderly) the wrong questions (how long do you want to live?). To the contrary, when you ask the right question roughly 30% of want to live forever (1). That is extremely radical.
If I recall correctly it was also him who suggested running smaller trials on severe conditions to first prove that a drug is safe enough for large studies. I think this is problematic, because there are often no severe hereditary conditions sufficiently similar to aging and because it slows down research a lot. Longevity drugs should be immediately trialed in small studies in healthy volunteers. We need to think big. Aging is a difficult target and it will require a heroic effort to target -- and, at any rate, there are millions of healthy volunteers that would absolutely love to be part of such trials.
He also thinks that it is dangerous to talk about combinations when we don't have evidence for single compounds. This is again a problematic approach because (human) aging is so multifactorial that it may never be possible to target it with just a single drug. What then? Secondly, polypharmacy is pretty standard in the real world. Might as well test it in clinical trials from the get-go. Third, combination therapies have statistical advantages and lead to more efficient use of resources. Fourth, combination therapies can potentially reduce and not enhance the side-effects of treatments. I think we need to shy away from such absolutes.
In a similarly misguided "primum non nocere" spirit Joan Mannick argues we should not use drugs off-label. However, Matt Kaeberlein would likely disagree (UW Rapamycin Study) as would I. There is a place for RCTs and a place for observational trials of patients who use drugs off-label. Both study designs can teach us something, however, off-label use will give us data much faster. In either case people will experiment with their own health and we might as well learn from it.
In one of the panels, Eric Verdin once again showed that he is a reasonable conservative and not a visionary. He was arguing that nutrition, diet, lifestyle and exercise should have a bigger role in aging research, I strongly disagree for multiple reasons. Exercise only leads to very modest health benefits in animal models - arguing that rapamycin and other drugs will produce better bang for the buck. In addition these treatments, by and large, have nothing to do with aging research. A healthy lifestyle is a question of public health policy. We do not need biogerontology for that and the incentives to promote healthy living have to be implemented on a national level by politicians. Finally, as Matt Kaeberlein points out - who in contrast to Verdin is more of a visionary - exercise is not harmless. It is just that the harms of exercise are not well documented and downplayed: risk of injury, pain and discomfort (DOMS etc), waste of time (not everyone actually enjoys exercise and this is okay!). Telling people to "just eat healthy" is simply not realistic and our conference demonstrates the irony of this suggestion. A room full of longevity and health researchers, yet the breakfast catering consisted of croissants and chocolate pastries.
All in all, I would argue that lifestyle is very important but should only play a tiny role in our discourse. Similarly, the fight against ultraprocssed foods is also very important but has little to do with aging per se.
1. Asked “If doctors developed a pill that enabled you to live forever at your current age, would you take it?” a surprising number of people turned out to be hardcore life extensionists: "There were no differences by age...Among young adults, 40.0% indicated they would not take the pill, 34.2% indicated they would take the pill, and 25.8% indicated they were unsure."
Barnett, Michael D., and Jessica H. Helphrey. "Who wants to live forever? Age cohort differences in attitudes toward life extension." Journal of Aging Studies 57 (2021): 100931.
**presumably in a less trivial and tautologic way than you imagine - since aging is defined as a loss of resilience to begin with, this statement at first sounds a bit trivial