Aubrey de Grey on Choosing the Right Research and Development Projects in the Treatment of Aging

There are many different potential approaches to the treatment of aging as a medical condition. It is a sad truth, however, that funding the wrong type of project will almost certainly fail to move the needle on human aging. Further, it is almost certainly the case that most present effort in research and development is going towards the wrong type of project. A majority of the projects that could lead towards treatments for aging are focused on upregulation of the cellular stress response mechanisms triggered by exercise, calorie restriction, hypoxia, heat, and the like. We have a good idea as to the likely outcome of such approaches in humans: look at the results of structured exercise programs and calorie restriction, meaning a modest slowing of health that does little to change the present shape of a human life, and its decline into disability and mortality.

A different approach is needed if the goal is rejuvenation rather than a gentle slowing of the aging process. That approach should be to repair the various well-described accumulations of cell and tissue data that lie at (or close to) the root of aging, thereby allowing restored function. Clearance of senescent cells from aged tissues is an important example of this type of approach. Senescent cells secrete signals that provoke chronic inflammation and tissue dysfunction: their presence actively maintains a more aged, damaged state of organs. Targeted removal of even only a third of such errant cells produces quite startling demonstrations of rejuvenation in mice, reversals of age-related conditions that are greater and more rapid than can be obtained by even the best of stress response upregulation approaches (such as mTOR inhibition). And yet there is a great deal more of work analogous to mTOR inhibition taking place than work analogous to selective destruction of senescent cells.

Aubrey de Grey on Rejuvenation Policy at EARD2021

If we look at the maintenance approach, the damage repair approach, that, of course, I founded more than 20 years ago now, that has become very much the focus or one of the major focuses of the anti-aging research field. We can see that potentially, there is a bit of an issue, because there are lots of different types of damage that we have to go after.

Of course, the whole reason why geriatric medicine was originally seen to be a non-starter that would never really have all that much effect on the healthspan of the human race was because of that precise problem that there are so many things you have to fix. The maintenance approach kind of sidesteps that; it makes the divide-and-conquer problem more manageable in ways that I've talked about many times and I won't reiterate now.

But still, it's a divide-and-conquer problem. And that means that we have to make quite sure that the most difficult parts of that divide and conquer approach are not left behind and neglected. Of course, SENS Research Foundation was set up more than a decade ago, with exactly that in mind; we set it up as an independent charity, an independent nonprofit funded almost entirely by philanthropy.

We did that precisely in order to avoid the constraints that forced both industry and mainstream academia into short-termism into focusing on low-hanging fruit and neglecting the harder but equally important problems that otherwise they might work on. Of course, the past decade of work that we and others have done, has had great successes, and certainly some of those successes constitute progress in the most difficult areas of damage repair.

For example, in the area of mitochondrial mutations, in the area of extracellular matrix stiffening, these are areas which were completely stalled when we started, and they're not stalled anymore. But they're still nowhere near as far along as getting into clinical trials, for example. So we've got to make absolutely sure that that does not persist, that these things are continuing to be pushed forward.

That's where emerging challenge number one is: it is extraordinarily hard to get most people to not focus on the low-hanging fruit. In industry, of course, we know that people who want to make money, they want to make it soon, and therefore they are going to put pressure on to cause that to happen. Some of you who have long memories may recall a company called Elixir Pharmaceuticals, which were founded by two absolute demigods of gerontology, Cynthia Kenyon and Leonard Guarente. The reason why those of you with short memories will probably not remember Elixir is because it ended up being a complete waste of time. That was why: they took the wrong money, they got pressured into doing stuff that wasn't useful, and nobody remembers them at all.

It's, of course, exactly the same in academia, that short-termism arises from the need to publish or perish. And same result. The worst of it is that it's quite easy in biology in general, and certainly in our field, to identify areas where you can make quick progress and make a big splash and get a terribly interesting paper on the front page of Science Magazine. Unfortunately, it doesn't go anywhere, because there is no actual way to take it forward to something that would have clinical relevance in the long run.

And the final problem, a final aspect of this problem, is that most of the real visionaries who have money are actually capitalists: they are people who made their money in the private sector, and they believe in that kind of way of doing things. Many of them simply do not believe in philanthropy, or in charity in general.

Now, some of those people have been visionary enough to recognize that they have to bite that bullet. Of course, the person who gets the greatest credit for that in our world is Peter Thieltps://">Peter Thiel, who started funding Methuselah Foundation back in 2006. But the fact is now that these people have the opportunity to invest rather than to donate, they are very, very tempted to do exactly that. So we absolutely need to be vigilant in making sure that the most difficult components of the damage repair portfolio are not neglected.


OT (as usual sorry)

Emerging evidence is revealing that alterations in gut microbiota are associated with colorectal cancer (CRC). However, very little is currently known about whether and how gut microbiota alterations are causally associated with CRC development. Here we show that 12 faecal bacterial taxa are enriched in CRC patients in two independent cohort studies. Among them, 2 Porphyromonas species are capable of inducing cellular senescence, an oncogenic stress response, through the secretion of the bacterial metabolite, butyrate. Notably, the invasion of these bacteria is observed in the CRC tissues, coinciding with the elevation of butyrate levels and signs of senescence-associated inflammatory phenotypes. Moreover, although the administration of these bacteria into ApcΔ14/+ mice accelerate the onset of colorectal tumours, this is not the case when bacterial butyrate-synthesis genes are disrupted. These results suggest a causal relationship between Porphyromonas species overgrowth and colorectal tumourigenesis which may be due to butyrate-induced senescence.

Interesting as I assumed butyrate was beneficial. Perhaps the study (or my interpretation) is missing something?

Posted by: Robert Read at September 29th, 2021 1:01 AM

If he creates a new foundation I'll donate to it.

Posted by: Antonio at September 29th, 2021 1:05 AM

I'd support AdG as well.

Posted by: Robert at September 29th, 2021 2:24 AM

@Antonio, Robert: My thoughts exactly.

Posted by: Morpheus at September 29th, 2021 11:37 AM

I don't know....

I'm of the thought that Aubrey is unfortunately done..

It doesn't seem any of his big donors are standing up for him publicaly at all

And it's nice that everyone wants to help him start anew, but based on the history, this is by no means a path to the big $$$ needed at this point of the longevity industry's inflection

Posted by: Greg Kellman at September 29th, 2021 4:18 PM

@Greg Kellman:

Whatever the degree of success of the new foundation, I'll not donate to SRF anymore, and I'm not the only one. So better having it than not.

Posted by: Antonio at September 30th, 2021 2:52 AM

@Greg Kellman

I agree

Where is a big announcement of support from Richard Heart (who got that $27 million for SRF??) or Vitalik Buterin? or Peter Thiel?

He's been abandoned....

Posted by: Tim Willis at September 30th, 2021 3:40 AM

I wish the SRF vs AdG thing went differently. But, not being able to rewind time, I have decided that defeating aging is more important than picking sides in this drama. As long as SRF continues doing important work to reverse aging, I will continue to support them. If AdG begins anew, and starts important new initiatives to end aging, I will support him too. Defeating aging is the big picture here. SRF vs AdG is the distraction.

Posted by: Neil at September 30th, 2021 9:47 AM

@Greg Kellman,

The big donors may easily show up anonymously to avoid any public criticism from Aubrey's detractors.

Posted by: Morpheus at September 30th, 2021 11:17 AM

For me, there are two important things here, surviving aging and what kind of society I want to live in. It's not simply a SRF vs AdG personal problem.

Posted by: Antonio at September 30th, 2021 4:10 PM

If you don't survive aging, you won't live in ANY society. Forever. So surviving aging is by far more important.

Posted by: Nicolai at October 1st, 2021 3:42 PM

Well, I think I can survive for the few months that AdG will spend creating a new foundation. Also, there are other options, like investing in antiaging companies or funds. And there is cryonics too.

Posted by: Antonio at October 2nd, 2021 1:06 AM

Targeting these "more deserving" projects is fine but what are they doing? How long has research been done on senolytics & still no meaningful number of clinical trials started. For another example take Underdog - they've been working on 7-ketocholesterol for how many years, have been well funded by Kizoo Technology yet in their latest (successful) funding result they state "The company expects to begin clinical trials in 2023". Will they actually achieve anything of available use to the public this decade. I'm not holding my breath. At least the "low hanging fruit" as Reason calls them, are offering available options now which is more easy to relate to.

I need to understand what is required (the steps needed to be taken) in the research field to get a product even to clinical trials. Does anyone have any links I can refer too?

Posted by: TB at October 3rd, 2021 5:44 PM

@TB: "For another example take Underdog - they've been working on 7-ketocholesterol for how many years"
Two years.
"At least the "low hanging fruit" as Reason calls them, are offering available options now which is more easy to relate to."
Huh? Like what? AFAIK, no antiaging, non-SENS drug has passed a clinical trial yet.

Posted by: Antonio at October 4th, 2021 11:57 AM

@Antonio Quote at the launch of Underdog "Underdog was built from an SRF flagship program that has driven two years of applied development designed to explore and repair the underlying causes of cardiovascular disease." So circa 6 years from research commencement before clinical trials even start. I'm curious to know if this Is a normal timespan? I have no idea as I am not a scientist but it is hard, for me anyway, to get excited & invest in a process that will take (say) 10 years to prove successful or not. In the meantime why ignore the "low hanging fruit" as at least it is available (totally proven or not) now.

Posted by: TB at October 4th, 2021 11:25 PM

Underdog homepage says initial seed funding was completed in November 2019. So that is two years.
Development of a new drug (not a repurposed drug) takes around 15 years (usually first at an startup and later at big pharma). Once outside academia and managed by a company, there should not be so much difference in development times between SENS-like and non-SENS-like therapies, the main difference being that there are more companies in the latter camp.

Posted by: Antonio at October 5th, 2021 9:16 AM
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