Live blogging ARDD2022 - aging is not the enemy?

Aging is not the enemy
As Matt Kaeberlein put it, we need to be more precise in our language.  At the very least say that biological age is the enemy and not "aging", implying old people. I would add: be precise and honest. Another example, one he alluded to, we should not conflate strong and marginal lifespan-extending interventions (e.g. rapamycin with exercise). We need to be clear on these distinctions, just as we need to be clear that the work of current aging-related biotechs, as amazing as it is, still remains a far cry from real interventional biogerontology.

How do biotech people think?
I came away with a better understanding of the way small and big biotech companies like Altos or Cambrian operate on a conceptual level. Despite my disagreements I have a lot of respect for the current batch of biotechs. Basically, there are two approaches towards getting real anti-aging therapies. One is to operate within the current regulatory framework and maybe reform it from the inside, while the other one is to upend and change the frameworks, e.g. the work of Matt Kaeberlein on dogs or Nir Barzilai's TAME study.

The way our VC panelists explained it makes actually a lot of sense. The idea is to assign the value of longevity to be zero so it can be sold to the more conservative VC investors. For them, things have to work and make money even if they do not extend lifespan. Aging is perceived as being very risky and a quick clinical proof of concept is necessary for pharma to become interested.

However, this leads to some very interesting disagreements and misunderstandings between the old guard of biogerontologists and the researchers at these new biotechs. I like to put it this way: many of the Altos people, to use one example, are researchers doing aging-related work and not aging researchers (obviously there are plenty of exceptions). Thus they have completely different views than "we" do and have never seen or read many of the seminal papers that we know by heart. When I say "we" I count myself as part of the old guard, or aligned with their views, because I grew up on a diet of mouse studies from the 80s and worshipped survival curves.

However, there is nothing wrong with these young upstarts having different opinions. I totally agree that the field needs fresh blood and just because I disagree with them doesn't mean they're wrong or that we are enemies. Edit: Also I am sure not all biogerontologists of the 90s worshipped mouse survival as much as I do today, but I do get the impression that Walford, Weindruch, Spindler, Rich Miller, even Aubrey de Grey all believed (or do still believe) that lifespan extension in the mouse is the gold standard for preclinical. So maybe it is not quite appropriate to talk about a homogenous "we" the oldschool-influenced biogerontologists, although I do think there is some kind of divide.

This difference in the way we think about aging explains my many disagreements with Morgan Levine and the discussion of exercise is a very typical example. As a (mouse) gerontologist I am hard-pressed to call an intervention anti-aging if it fails to meaningfully slow aging in a model as simple as the mouse.

Somewhat against the single disease focus of biotech
Now having explained how biotech people may think, on to the actual topic. The problem with their way of doing things. The focus on targeting single diseases. The rationale for the TAME trial is that a composite endpoint of age-related diseases is more powerful (more events in a trial) because all of these endpoints should be affected by slowed aging. If this is true, which we generally do believe as a field, then targeting single diseases is inefficient per definition.

Imagine drug X slows five age-related diseases by 10% or reduces their incidence by 10%, each of those diseases led to 50 events. Because they all change together you get a reduction of 25 events out of a total of 250. If you ran the study just targeting a single disease with the same compound it would need to be 5x larger. To be fair, it is not like biotech companies get a choice, because the TAME style design is not acceptable to the FDA (yet).

Nevertheless, we should be honest about the shortcomings of the single disease approach and given those issues, as a field, we need to focus a little bit more on reforming the drug approval process instead of celebrating biotech just because they are doing something, which is better than nothing. Again, I am a friend of pharma, but we need more. I fully disagree that their approach alone will be enough.

I know there are other complexities, as treatments may not slow all age-related diseases across the board. It is very possible that you can find a condition that responds more to a class of drug and ride to FDA approval on the back of such a condition. Like diabetes for metformin.

How then do we cure aging?
That was the question I was asked at the bar. I, of course, do not know the answer to this, just like everyone else, but I do have an idea on a conceptual level. First of all, let us be bold. We can say that we want to increase human lifespan and healthspan, but do add that our longterm goal is to eliminate aging as well. Investors and the general public are neither dumb nor overly conservative, contrary to popular opinion in the field.

I found it very interesting that Anu Wartiovaara in today's talk used the words "I want to cure mitochondrial disease". It seems that all researchers are allowed to dream big except aging researchers. This has to stop. We can and should dream of a world without cancer, aging and war. Now we can take the first steps towards this goal.

We need to create a virtuous cycle of exponential growth in investment until most of the medical R&D across the globe is spent on aging research. For this to happen, we need biopharma to be successful, but even more so we need people like Matt Kaeberlein to pressure regulators and politicians by showing that drugs can extend the lifespan of companion animals, we need people like Nir Barzilai who will show that treatments can slow age-related conditions in reasonably sized trials. We need a first success or something that will be perceived as a success by the public.

Healthspan is not the gold standard
Back to the topic of being precise and my constant disagreements with Morgan Levine and other researchers like her (1). In fact, I am getting a de ja vu of having had this debate on twitter a million times already. So to be precise, healthspan is not the gold standard, because it is simply a surrogate for lifespan extension. We study healthspan because studying healthspan and lifespan together is too expensive. Only marginally beneficial treatments* can show differential effects on healthspan and lifespan. This will never happen with robust treatments. Since aging causes the diseases of aging and these cause the suffering of aging, the postponement of aging per definition improves healthspan. If you ask me, this is trivial if not a tautology.

Today it was Gordon Lithgow from the Buck institute who was arguing against the recent healthspan hype; or at least that is the way I am going to interpret it. We need to make animals live longer to be on the right track and I totally agree. In animal models we have to aim for the best possible outcomes because most treatments are likely to be less effective in humans. If you start already low in animals, you will end up with nothing of value once you get into the clinic. A million things improve the healthspan of mice, but only few treatments reliably extend their lifespan.

*the reduced healthspan of women which seems to happen despite increased lifespan is one such example. You might think it is a counter-example to my claim but far from it. For an interventional biogerontologist the difference in lifespans between men and women is marginal at best. I am NOT saying this is a useless phenomenon. I am just saying to be clear on the difference between real anti-aging and marginal treatments. As long as we have nothing better than exercise and the study of sex-differences, it is totally justifiable and necessary to investigate these.

Aging is really hard but...
If you compare the number of successful GWAS hits for cardiovascular disease and aging it appears that aging yields fewer hits. This is consistent with the idea that aging is really, really difficult, if you ask me. There are also issues with the endpoints in those GWAS studies because things like (parental) lifespan are still often driven by effects on healthspan and not aging per se, as Joris Deelen pointed out. He is also more keen to study aging per se rather than healthspan, if I may add. It is therefore not a surprise that no one wants to target aging per se and we fool ourselves into thinking that exercise is an anti-aging treatment. The true revolution is yet to come, but it will be big when it does and the world will never be the same. Hopefully, within our lifetimes my favorite curse will become reality: may you live in interesting times.

Notes and corrections

1. That happens when you use names for illustrative purposes. As it turns out Morgan Levine is a trained biogerontologist. Perhaps another way of putting it is: The "new guard" whether they are trained as gerontologists or not, is not as focused on chasing lifespan extension in mice as interventional biogerontologists of the old days. As people have observed at the conference, the field used to be all caloric restriction and most of that work was in mice and the 20-30% lifespan extension by CR in highly inbred mouse models was our holy grail. Now there are people emphasizing healthspan as the way forward instead, or focusing on specific age-related diseases in the clinic and doing real cell biology, reprogramming, clocks and all that cool stuff. Many of these things are necessary for biogerontology to progress and some of the things are not biogerontology itself.
I did not want to single out a single person. My point was more that pharma companies simply hire good researchers to do good work rather than just biogerontologists. In addition, many out-of-field researchers are pivoting towards aging research, so there is an influx of new people giving rise to an old guard and a new one. Unfortunately, some of these non-biogerontologists or "new guard" gerontologists are almost hostile to concepts like lifespan extension and the longterm goal of significant lifespan extension (I had quite a lot of disagreements with the way Vittorio Sebastiano was talking about healthspan at the vitaDAO symposium I was covering).

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