We Should Actually Try to Treat Aging for a Change

I am generally in favor of the sentiment offered in this commentary on recent clinical trial failures for the first attempts to guide anti-aging technologies through the FDA gauntlet, which is that researchers and developers should be aiming to treat aging, not specific age-related diseases. There is likely to be a greater incidence of failure on the way to the clinic, and for entirely avoidable reasons, if everyone is attempting to force a more or less square peg into a more or less round hole.

Longevity trials: time to change the approach?

Following the recent clinical trial failures by Unity Biotechnology and resTORbio, Buck Institute professor Brian Kennedy feels that a change in approach is potentially needed. "I get the idea that you target aging pathways, but then you try to treat disease because you need to get FDA approval and reimbursement from insurance companies - but if that strategy doesn't work, we've got to stop doing it. I think we should actually try to treat aging for a change."

While Kennedy agrees that effort needs to continue to convince the FDA to recognise aging as a treatable disease, Kennedy also believes that there are alternative approaches that can be employed. "You don't need the FDA to approve your trial, you need an institutional review board to approve your trial. From an academic standpoint, as long as you can convince people that the trial is safe, you can use biomarkers and study the effects of these drugs. So I think if we start generating that kind of data, then it'll be a lot easier to get the FDA on board, and hopefully the rest of the world on board. We need to nail down the foundation here and stop giving people excuses why this won't work. I'm still optimistic about drugs, but if you develop a drug for A and try to treat B, and then you wonder why it doesn't work - I'm starting to feel like the strategy may not work that well."

Of course, if companies are going to run trials on aging, then a clearer consensus is needed on the definition of aging, and Kennedy is encouraged by developments in the various clocks that measure biological age. "There's a bunch of clocks and we don't really know how they relate to each other yet, and how specific clocks relate to specific kinds of age-related disease. There are a lot of questions to answer, but I think that the most advanced clocks are starting to look like good biomarkers. Some may be better than others but I'm very optimistic about these biomarkers."

At present the FDA doesn't recognize aging as a condition that can be treated, so the first generation of companies working on therapies that target mechanisms of aging will all attempt to apply their approach to specific age-related conditions. If successful, the vast majority of usage will then be off-label, as physician networks apply the therapy at their judgement, based upon the extensive literature suggesting that it will be effective for many age-related conditions. It is in the arena of widespread off-label use that the real battle to lighten the regulatory burden will take place. While off-label use is entirely legal, the FDA will likely attempt to shut down providers and manufacturers, in order to force further trials when a therapy becomes widely used in this way.

It would be much easier if we could all just obtain clinical approval by directly assessing the impact of a potential rejuvenation therapy on aging. Or better, obtain clinical approval by demonstrating safety only, rather than safety and efficacy as presently required by the FDA, and letting later studies, reviews, and the marketplace sort out what actually works. It would also be much easier if the FDA was not the bureaucratic monstrosity that it presently is, operating under perverse incentives that cause regulators to have more than doubled the cost of compliance in the past twenty years, at the same time as reducing the number of new therapies that arrive on the marketplace. I don't see any of this changing any time soon, however. Which is why we will continue to see companies in the longevity industry applying their therapies to specific age-related conditions in order to obtain regulatory approval.

As a sidebar, the trial failures in question were those of UNITY Biotechnology, for senolytics versus knee osteoarthritis, and resTORbio, for an mTORC1 inhibitor versus influenza risk in the elderly. In the former case, the present consensus among observers is that UNITY took a risk on localized senolytic treatment being good enough, and has demonstrated that it isn't. Senescent cells are present throughout the body, and the inflammatory signals that they generate circulate widely. For an inflammatory joint disease, the background inflammation may well be more relevant in many individuals than the local inflammatory process of joint tissue. In the case of resTORbio, the whisper mill suggests that they were tripped up by a change to the trial endpoint forced on them by the FDA between phase 2 (successful) and phase 3 (failure). Equally, one might suspect that the effect sizes for mTOR inhibition on the immune system are just not that large or that reliable in a general population of humans - this may well be the case for all approaches derived from calorie restriction and stress response upregulation research. We shall see.


I think that declaring aging itself as disease would be too big of a leap for the moment. On the other hand, there are multiple pathways and syndromes that are age related. If a pathway is attacked closer to the root cause the effects will be very real. We don't understand well the senescent cells' pathway very well but we can use senolytics to remove them, for example. With enough pathways addressed up to the root causes we will have effective stop or even age reversal. The moment we have one accepted treatment with large enough effect and many others in the pipeline the public perception will be altered and either aging will be recognized as a disease or there will be some equivalent definition at FDA and WHO.

As for why UBI failed. Probably, the arthritis, especially in the knees is not a good target for Senolytics, if their chemical was a good Senolytic to start with. A cheaper proof of concept study can be done to see if arthritis can be improved by local injections of slow release dasatinib, quercetin and fisetin. Apparently, a single dose is not enough. Probably an effective treatment works require both multiple senolytic injections followed be stem cells to provide signaling promoting regeneration.

And calorie restriction mimetics that we expected to improve flu outcomes... Again, a simple study can be done with people doing different forms of calorie restriction or none for control. Without such a proof of concept why try to partially emulate something that you don't even know will work...

Posted by: Cuberat at September 8th, 2020 8:48 PM

I think the FDA know we can cure aging in the future, but they don't recognize it as a disease not because of faisability, but because they consider aging should not be treated at all, it's more like a philosophical problem than a technical one.

Posted by: Jonathan Weaver at September 9th, 2020 4:18 AM

Since all humans age it can't be a disease. As much as I want to stop/reverse aging for selfish reasons, it would wipe out pension funds and be a disaster for humanity because of long-lived politicians.

Imagine your most despised politician living indefinitely....

Posted by: Lee at September 9th, 2020 7:31 AM

@Lee Why healthy 100 years old people would get pensions ? If you are 100 and have the body of a young adult, you will never get a pension. I don't get why people don't understand this.

Posted by: Jonathan Weaver at September 9th, 2020 8:15 AM

@Lee Your argument is: Let's let everyone die of old age because some people who don't deserve to live (longer) would also benefit from it. Regarding your other arguments:
1. Since many humans get flu, it's not a disease. Since all cars rust, we shouldn't clasify rust as a problem. Since all humans get cardiovascular diseases they should not be seen as such. etc
2. Pension funds are already a pyramid scheme in most countries. They will collapse because there's too many old and frail people, unable to work, and being supported by taxes paid by a shrinking (percentage-wise) number of young people. Reversing aging would be absolutely the best thing for any pension fund. They could immediately reduce/stop payments and require "fit for work" people to go back to the grind.
3. There are a lot of other more important reasons to reverse aging, being selfish is at the bottom of the list. Losing amazing individuals with 50-90 years worth of wisdom and knowledge to aging is terrible. I would also like to point out that you seem to contradict yourself: on the other hand reversing aging is selfish and on the other you casually condemn millions to decrepitude and death. So are you selfish for wanting to not die and altruistic for letting people die of old age?

Posted by: PCB at September 9th, 2020 8:26 AM

re: politicians living forever.
Hitler committed suicide (or would have faced military court and eventual execution)
Stalin was allegedly poisoned.
Ghadafi was bombed and executed
Saddam was executed
US has 2 terms limit , so it is already addressed in more elegant way.
A lot of politicians were forced to step down and "spend more time with their families"

On the other hand, North Korea has changed the leadership without changing anything.

it is a straw man.

Posted by: cuberat at September 9th, 2020 9:53 AM

@Reason - there is the argument that without the trust generated by rigourous trials, people will just spend less on medicine, or waste more of their own money on bunk treatments.

There is also the point that rivals could claim a new treatment is better without having to prove it.

Maybe a system of stage 1 safety trials (with a less arduous burden of proof before those trials are approved) combined with a stage 2 efficiency trial before sales are allowed, and an after sales efficiency study before marketing is allowed?

"Mr Trump has already successfully harried the fda to authorise drugs, such as hydroxychloroquine, with no scientific evidence for their efficacy. He has accused the regulator (unfairly) of being part of a "deep state" effort to try to slow down vaccine development until after the election. It looked like part of a strategy to get the regulator to hurry up.

Big pharma is clearly worried. Drug firms stand to lose a great deal if their products are seen as being waved through prematurely. The industry relies on the fda to make business possible. In the same way that people fly because they trust the aviation regulator, they take medicines because these are believed to be safe and effective. Take away the trust and the medicines' makers would suffer.

So would investment in research. Pharmaceutical firms have little incentive to develop better drugs if they can simply claim a new product is superior without having to prove it. When Mr Trump came into office, some in his entourage lobbied him to install as head of the fda someone with a more relaxed approach to efficacy standards. Doctors and patients immediately raised the alarm. But so did drugmakers, who pushed for a more serious candidate to assume the position."


"Numerous factors affect the cost of a clinical trial. The major ones are:

Increased costs of clinical supplies and equipment
Extended timelines of clinical trials
Increased regulations, particularly at the clinical and CMC levels
Monitoring complexities
Patient recruitment intricacies
Workforce competence
Data collection and synergy complexities"


Posted by: jimofoz at September 11th, 2020 4:04 AM

Aging is not a disease -it is a disorder.

Posted by: Nicholas D. at September 11th, 2020 3:01 PM
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