Aubrey de Grey & Charles Brenner Emails, Twitter Threads & Transcripts - On Longevity Escape Velocity

Episode 01

May 12, 2022

Hello! 👋 This is the Let’s Talk Longevity newsletter where you can find the bonus content for the podcast.

This post includes:

A foreword by David Gobel, co-founder of the Methuselah Foundation
Email communication between Dr. Aubrey de Grey & Dr. Charles Brenner
Twitter threads with more discussion on LEV
A link to the transcript of the episode

Thank you to Florina Linco, Dane Gobel, and David Gobel of the Methuselah Foundation for their support and encouragement of this idea.

Foreword

David Gobel, co-founder of the Methuselah Foundation, could not attend the debate but here is a foreword on his behalf.

“I love a good debate, but I dislike how taking one side of a debate makes both parties sound doctrinaire and even closed minded. On the other hand, debates can bring into sharp focus what might be key issues to further explore. When I coined Longevity Escape Velocity while working with Aubrey and Peter Diamandis on the historical influence of prizes and their great power to accomplish “impossible things”, there was no legitimate scientific effort to directly address extending healthy lifespan nor to reverse aging. Thanks to Methuselah, Aubrey, and SENS, today there are billions of dollars and hundreds if not thousands of scientists and entrepreneurs monomaniacally focused on breaking through aging’s “impossible things”. For our part at Methuselah we’re humble in that we don’t yet know all the scientific hows to get to LEV or the Methuselarity - all we know is that it’s a goal of such worthiness that almost everything else pales into insignificance. Time is the greatest pressure - the deadline. It’s well past time to collectively attack it and force it into irreversible retreat.”

David Gobel, Methuselah Foundation

Email Communication

On Fri, Apr 29, 2022 at 2:45 PM Aubrey de Grey wrote:

Hey all,

In thinking about how to make the Q&A as valuable as possible for the audience, I had an idea: maybe we should preface it with a very brief summary of what the debate itself achieved and failed to achieve. My attempt at that is as follows (and yeah, I know it's not brief yet!):

The topics covered in any debate can be divided into three categories according to the outcome:

1) The combatants established that they already agreed

2) The combatants initially disagreed but partly or wholly converged

3) The combatants initially disagreed and did not converge

[I elide here the more esoteric options, e.g. the combatants initially agreed and then diverged]

and a debate can be considered a success if there are some things in (2), and also if the things in (1), of which there are always many more than the audience was expecting, have been not only established but also articulated in a manner that the audience can understand.

In our case, category 1 includes several heartening things on which others often disagree: (a) the definition of aging (we are both happy with defining it as accumulating self-inflicted damage), (b) the irrelevance, at least when discussing the prospect of big improvements, of distinguishing between healthy/total/individual/mean/maximum longevity (since they all basically go in lock step), and (c) the non-existence of a good chronological age to get sick and die (we both think that health is preferable to sickness however long ago you were born). (I realise we established most of these before the debate rather than during it, but hey, that's how we did the articulating part quite well on the day.) Oh, and that LEV can certainly never be achieved solely by interventions that slow down the creation of aging damage (such as CR or its mimetics), only (if at all) by damage repair.

I feel that there is a big item in category (2). Initially, Charles seemed to be very focused on the idea that there is a natural limit to longevity that is dictated by our genes, and I retorted that that is only true in the absence of medicine. We went back and forth on this a lot, but towards the end Charles acknowledged that in principle, if aging damage could be medically repaired sufficiently comprehensively, the consequence would indeed be a big increase in longevity. I think this is a big deal, because a great many terrible papers have been published in top (aka glitz-focused) journals, by people who really ought to know better, insinuating that there is indeed a limit that is even in principle beyond the reach of medicine.

Category (3), therefore, consists (I believe) of two main items. The first is what our future debates should ideally be focused entirely on, namely just how hard is it to make damage repair sufficiently comprehensive? I feel that the chance of getting there this century is maybe 90%, while Charles thinks it is infinitesimal. This item breaks down into several distinct sub-items and will definitely take more than one subsequent debate, but that's good, because ideally we can pick off (i.e. move into category 2) one sub-item at a time. The second item is assays: Charles stuck firmly to his guns that the only valid way to determine whether a multi-component intervention will greatly extend longevity is to determine whether each of the components slightly extends longevity, and I stuck to my guns that no, that's not how technology works at all. I think that should be the first topic that we discuss in round 2, because I feel optimistic that we can dispose of it fairly efficiently now that we have had time to understand each other's initial positions.

I don't know whether it makes sense to explicitly spend a few minutes at the start of the Q&A outlining the above, but regardless, I thought it valuable to circulate it among ourselves, not least to see whether there are any aspects that Charles disputes. Maybe put it in the folder?

Cheers A

On Monday, May 02, 2022 at 2:00 PM Charles Brenner wrote:

As I ponder the debate I can see the whole thing coalescing into the three categories you mentioned. At first blush, I like what you've presented. I'll ponder some more over the weekend and see what Laura has to say as well. Charles, please chime in. Enjoy the weekend.

MY COMMENTS BELOW ARE IN ALL-CAPS

I DON’T KNOW WHAT YOU MEAN BY SELF-INFLICTED DAMAGE. ALSO, I SAID THAT I CONSIDER A LOSS OF REPAIR CAPACITY AS A FUNDAMENTAL FEATURE AND CAUSE OF AGING. YOU APPARENTLY DISAGREE.

B and C) YOUR WORDS NOT MINE. I SAID I WOULD BE PLEASED WITH A LONG AND PRODUCTIVE LIFE. I ALSO SAID THAT I’D LIKE PEOPLE TO BE HEALTHIER LONGER.

NO AND YOU ARE PRESENTING A LOGICAL FALLACY THAT DOESN’T WORK WITH ME. YOU ACKNOWLEDGED THE LIMITS OF ALL KNOWN MEDICINE. YOU ARE POSITING A TYPE OF MEDICINE THAT DOESN’T EXIST AND THEN EXPECTING TO PEOPLE TO ACCEPT YOUR COUNTERFACTUAL ARGUMENT. IN OTHER WORDS YOU CONCEDE THAT THE EASTER BUNNY DOES NOT EXIST. THEN YOU WANT TO HAVE A SERIOUS CONVERSATION ABOUT THE POWERS OF THE EASTER BUNNY. THEN YOU INSULT PEOPLE WHO REJECT YOUR ARGUMENTS BY SAYING THAT THEY OUGHT TO KNOW BETTER.

YES, I AM HAPPY TO HAVE THIS CONVERSATION ON THE RECORD. NO, I DON’T AGREE TO AUBREY’S CHARACTERIZATION OF MY VIEWS OR THOSE OF HIS CRITICS. NOTE ALSO THAT HE CONTINUES TO SAY THAT NO ONE HAS FOUND ANY OTHER CAUSES OF AGING EVEN AFTER HIS CAUSES OF AGING HAVE BEEN DISPUTED SINCE HE PROPOSED THEM AND HE STILL DOESN’T THINK HE NEEDS TO EXPERIMENTALLY TEST THEM.

NOTE THAT WHEN WE ARE ON THE RECORD, MY COMMENTS SHOULD NOT BE ALL CAPS. THAT’S JUST SO THAT YOU CAN FIND MY COMMENTS…..CHARLES BRENNER

On Monday, May 02, 2022 at 3:16 PM Aubrey de Grey wrote:

Many thanks Charles, this is terrific. I reply as follows:

Quote from Charles:

I DON’T KNOW WHAT YOU MEAN BY SELF-INFLICTED DAMAGE

Reply from Aubrey: I thought that was the term I used in the debate; anyway, I mean damage that occurs as a side-effect of essential metabolic processes like breathing, rather than through avoidable external sources like bullets or mercury poisoning.

Quote from Charles:

YES BUT YOU DON’T APPEAR TO ACCEPT THAT THERE IS A GENETICALLY ENCODED AND EPIGENETICALLY EXPRESSED SET OF PROGRAMS THAT ALLOWS DAMAGE TO INCREASE AND DEPRESSES REPAIR AND REGENERATIVE CAPACITY.

I SAID THAT I CONSIDER A LOSS OF REPAIR CAPACITY AS A FUNDAMENTAL FEATURE AND CAUSE OF AGING

Reply from Aubrey: Ah, thank you. I absolutely agree that it is a feature of aging - both a cause and a consequence, in that it arises because of the accumulation of damage and because it also accelerates the subsequent creation of more damage. I chose my definition because it is couched in terms of structure rather than function, and is thus useful for the discussion of how changes in structure might lead to changes in function. I thought you said that you were happy with that as a definition of aging, even though we indeed disagreed later on about whether loss of repair is "fundamental". More below on that.

Quote from Charles:

IT IS A CAUSE AND ONE YOU HAVE PROPOSED NO WAY AROUND. THAT’S PROBABLY WHY YOU ARE OPPOSED TO IT BEIGN NAMED AN 8TH CAUSE OF AGING.

B and C) YOUR WORDS NOT MINE

Reply from Aubrey: Absolutely. However, I don't see any incompatibility between my words and yours in this regard, and I infer that you don't either.

Quote from Charles:

IF I AGREED, I WOULD HAVE TOLD YOU SO.

YOU ACKNOWLEDGED THE LIMITS OF ALL KNOWN MEDICINE. YOU ARE POSITING A TYPE OF MEDICINE THAT DOESN’T EXIST

Reply from Aubrey: Wait... I'm sure you said towards the end that, in principle, IF such medicine CAME to exist, it would indeed greatly extend lifespan. Am I misremembering? Of course I am positing medicine that doesn't exist. All medicine that does exist once didn't exist, and a lot of it would have seemed Easter-Bunny-esque, even to experts, until not long before it did exist. So when I say people should know better, I'm saying that it is unscientific to say that medicine that sounds Easter-Bunny-esque but would not break the laws of physics and chemistry will definitely never exist. Nothing more. Is that so controversial?

Quote from Charles:

BECAUSE THE LOSS OF REPAIR CAPACITY IS A FEATURE ENCODED IN OUR GENES, YOUR COUNTERFACTUAL QUESTION REMAINS COUNTERFACTUAL AND YOUR CHARACTERIZATION OF THOSE WHO DISAGREE WITH YOU IS NOT SOUND.

THEY ARE NOT COMPREHENSIVE (YOU DON’T INCLUDE LOSS OF REPAIR CAPACITY)

Reply from Aubrey: Thank you - I should definitely have included this in my "category 3". This should certainly be the topic of a future debate and/or the Q&A, because I indeed maintain that loss of repair capacity is not fundamental in a medical sense. My criterion for being fundmental is, does it happen at a steady (or only mildly accelerating) pace throughout adult life, or does it accelerate greatly with chronological age? If the latter, the thing is not fundamental, because the fadct that it did not appreciably change before age (say) 40 shows that body has homeostatic mechanisms that stabilise it just so long as they are not impeded by changes against which we do not have such homeostatic mechanisms even in youth. So my question to you is, for illustration, what is the trajectory of NAD loss in aging? What proportion of the difference (in an average person) in NAD levels between 20 and 80 has already occurred by age 50? (Before you answer: there are some exceptions the other way, i.e. things that I claim are non-fundamental for other reasons even though they do change appreciably during early adulthood, but let's get to that only if you claim that NAD loss is fairly linear.)

Quote from Charles:

THIS DOES NOT DEPEND ON LOSS OF NAD. YOUR LIST IS NOT COMPREHENSIVE AND YOU DON’T HAVE A RESPONSE TO WHY LOSS OF REPAIR/REGENERATIVE CAPACITY IS NOT AS PRIMARY A CAUSE OF AGING AS ANY YOU PROPOSED IN 2000.

AND NOT ACTIONABLE (YOU HAVE NO FITNESS TEST FOR WHETHER YOU ACHIEVE ANY ONE OF YOUR 7 PROGRAMS). YOU DON’T NEED TO EVEN SHOW ME THAT YOU CAN EXTEND LIFESPAN WITH ANY OF YOUR PROGRAMS: YOU JUST NEED SOME FUNCTIONAL OR FITNESS TEST TO DEMONSTRATE ITS UTILITY

Reply from Aubrey: This is great. I remember you bringing us back to lifespan quite often, so if you are up for other tests, that means we are closer than I thought. I won't, however, accept that the test needs to be functional: structural will suffice for me, because the fact that structure defines function tells us that if we fix ALL structural changes, function will return, even if we don't know which structural changes mattered.

Quote from Charles:

NO, AUBREY, YOU ARE MAKING THE CASE FOR SENS MUCH WORSE. YOU ARE NOW PROPOSING THAT SOMEONE SHOULD SUPPORT THE SENS PROGRAM BASED ON YOUR DEMONSTRATION THAT YOU CAN REVERSE ONE TYPE OF DAMAGE WITHOUT AGREEING THAT YOU NEED A TEST THAT THE REVERSION OF ANY PARTICULAR TYPE OF DAMAGE IS BENEFICIAL. YOUR PROGRAM DEPENDS ON A GURU-LIKE TRUST THAT YOU HAVE A COMPREHENSIVE LIST OF DAMAGES, WHICH YOU DON’T HAVE; THAT YOU HAVE A WAY TO REPAIR THOSE DAMAGES IN ALL CELLS, WHICH YOU DON’T HAVE; AND THAT PEOPLE SHOULD AGREE TO GENETIC INTERVENTIONS FOR MULTIPLE TYPES OF DAMAGES WITHOUT THE UPSIDE OF A LONGEVITY OR FITNESS ADVANTAGE UNTIL THEY HAVE CORRECTED MULTIPLE TYPES OF DAMAGE. THE CASE FOR LEV IS NOT ONLY ABSURDLY IMPROBABLE, IT IS CULTY, NON-FALSIFIABLE, ILLOGICAL & GRIFTY.--CB

WHEN WE ARE ON THE RECORD, MY COMMENTS SHOULD NOT BE ALL CAPS

Reply from Aubrey: Whew :-)

Cheers A

On Monday, May 02, 2022 at 18:40 Aubrey de Grey wrote:

Quote from Charles:

THERE IS A GENETICALLY ENCODED AND EPIGENETICALLY EXPRESSED SET OF PROGRAMS THAT ALLOWS DAMAGE TO INCREASE AND DEPRESSES REPAIR AND REGENERATIVE CAPACITY

Reply from Aubrey: Certainly I accept that. The worst I would do by way of nitpicking is to say that the thing that allows this is what is LACKING in those programs, rather than what is present. I would certainly have disagreed if you'd said "causes" rather than "allows", but you didn't. The purpose of the so-far-noexistent medicine that SENS proposes is to augment those programs, removing the damage that they (by virtue of their gaps) allow to accumulate.

Quote from Charles:

IT IS A CAUSE AND ONE YOU HAVE PROPOSED NO WAY AROUND

Reply from Aubrey: I have indeed proposed such: I have proposed that if we were to remove the seven SENS categories of damage, fairly comprehensively, then the loss of repair capacity would be repaired automatically by the very programs you mention above - programs which do NOT allow repair to be depressed until middle age or later. I have no DIRECT evidence for this, but reciprocally I claim that you have no evidence to the contrary. The balance of probabilities must therefore be assessed indirectly, and since you are the one expressing certainty for your position, the onus is on you to offer such indirect arguments - which you have not yet done.

Quote from Charles:

IF I AGREED, I WOULD HAVE TOLD YOU SO.

Reply from Aubrey: OK. Normally in my experience debates work the other way, i.e. the combatants are assumed to agree unless stated otherwise. However, do you really think there is a chronological age at which it is GOOD for people to get sick? If so, I'm going to ask you to justify that...

Quote from Charles:

THE LOSS OF REPAIR CAPACITY IS A FEATURE ENCODED IN OUR GENES

Reply from Aubrey: That form of words is dangerously close to the monogenic rhetoric that we established we both reject. Let's be totally rigorous here: loss of repair capacity happens because we LACK the genes to STOP it from happening. Such genes COULD exist - they would work by stopping the accumulation of the types of damage that increasingly hinder repair - but they don't.

Quote from Charles:

THIS DOES NOT DEPEND ON LOSS OF NAD

Reply from Aubrey: Apologies, I didn't mean to imply that loss of repair depends on loss of NAD (though I'd personally be surprised if there isn't any contribution). I was using NAD as an illustration of my general principle that negligible change between say 20 and 40 implies not fundamental, regardless of contribution beyond 60.

Quote from Charles;

YOU ARE MAKING THE CASE FOR SENS MUCH WORSE

Reply from Aubrey: If you say so - but you will find that I have been saying exactly this since SENS was born. Maybe that's why my funders tend to be mostly technologists - they don't find it a turn-off at all.

Cheers A