# Venki Ramakrishnan: The New Science of Aging

An episode of [Ground Truths](https://invisiblenetwork.ai/podcast/1728526108), 28 May 2024, 50 min.

Audio: https://api.substack.com/feed/podcast/145038781/06fa755aa1d38668c1d0a2ebe3d5f6e1.mp3

Professor Venki Ramakrishnan, a Nobel laureate for his work on unraveling the structure of function of the ribosome, has written a new book WHY WE DIE which is outstanding. Among many posts and recognitions for his extraordinary work in molecular biology, Venki has been President of the Royal Society, knighted in 2012, and was made a Member of the Order of Merit in 2022. He is a group leader at the MRC Laboratory of Molecular Biology research institute in Cambridge, UK. A brief video snippet of our conversation below. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are available on Apple and Spotify. Transcript with links to audio and external links Eric Topol (00:06): Hello, this is Eric Topol with Ground Truths, and I have a really special guest today, Professor Venki Ramakrishnan from Cambridge who heads up the MRC Laboratory of Molecular Biology, and I think as you know a Nobel laureate for his seminal work on ribosomes. So thank you, welcome. Venki Ramakrishnan (00:29): Thank you. I just want to say that I'm not the head of the lab. I'm simply a staff member here. Eric Topol (00:38): Right. No, I don't want to give you more authority than you have, so that was certainly not implied. But today we're here to talk about this amazing book, Why We Die, which is a very provocative title and it mainly gets into the biology of aging, which Venki is especially well suited to be giving us a guided tour and his interpretations and views. And I read this book with fascination, Venki. I have three pages of typed notes from your book. The Compression of Morbidity Eric Topol (01:13): And we could talk obviously for hours, but this is fascinating delving into this hot area, as you know, very hot area of aging. So I thought I'd start off more towards the end of the book where you kind of get philosophical into the ethics. And there this famous concept by James Fries of compression of morbidity that's been circulating for well over two decades. That's really the big question about all this aging effort. So maybe you could give us, do you think there is evidence for compression of morbidity so that you can just extend healthy aging and then you just fall off the cliff? Venki Ramakrishnan (02:00): I think that's the goal of most of the sort of what I call the saner end of the aging research community is to improve our health span. That is the number of years we have healthy lives, not so much to extend lifespan, which is how long we live. And the idea is that you take those years that we now spend in poor health or decrepitude and compress them down to just very short time, so you're healthy almost your entire life, and then suddenly go into a rapid decline and die. Now Fries who actually coined that term compression or morbidity compares this to the One-Hoss Shay after poem by Oliver Wendell Holmes from the 19th century, which is about this horse carriage that was designed so perfectly that all its parts wore out equally. And so, a farmer was riding along in this carriage one minute, and the next minute he found himself on the ground surrounded by a heap of dust, which was the entire carriage that had disintegrated. Venki Ramakrishnan (03:09): So the question I would ask is, if you are healthy and everything about you is healthy, why would you suddenly go into decline? And it's a fair question. And every advance we've made that has kept us healthier in one respect or another. For example, tackling diabetes or tackling heart disease has also extended our lifespan. So people are not living a bigger fraction of their lives healthily now, even though we're living longer. So the result is we're spending the same or even more number of years with one or more health problems in our old age. And you can see that in the explosion of nursing homes and care homes in almost all western countries. And as you know, they were big factors in Covid deaths. So I'm not sure it can be accomplished. I think…

## Transcript

[0:06] SPEAKER_01: Hello,
[0:06] SPEAKER_01: this is Eric Topol with Ground Truce,
[0:09] SPEAKER_01: and I have a really special guest today,
[0:11] SPEAKER_01: Professor Venki Ramakrishnan from Cambridge,
[0:17] SPEAKER_01: who heads up the MRC Laboratory of Molecular Biology,
[0:21] SPEAKER_01: and I think,
[0:22] SPEAKER_01: as you know,
[0:23] SPEAKER_01: is a Nobel laureate for his seminal work on ribosomes.
[0:27] SPEAKER_01: So, Venki, welcome.
[0:29] SPEAKER_00: Thank you.
[0:32] SPEAKER_00: I just want to say that I'm not the head of the lab.
[0:35] SPEAKER_00: I'm simply a staff member here.
[0:38] SPEAKER_00: Right.
[0:38] SPEAKER_01: No, I don't want to give you more authority than you have.
[0:42] SPEAKER_01: So that was certainly not implied.
[0:45] SPEAKER_01: But today we're here to talk about this amazing book, Why We Die, which is a very provocative title.
[0:51] SPEAKER_01: And it mainly gets into the biology of aging, which I think is especially well suited to be giving us a,
[1:00] SPEAKER_01: guided tour and his interpretations and views.
[1:04] SPEAKER_01: And I read this book with fascination, Venky.
[1:09] SPEAKER_01: I have three pages of type notes from your book.
[1:14] SPEAKER_01: And we could talk obviously for hours,
[1:17] SPEAKER_01: but this is a fascinating delving into this hot area,
[1:22] SPEAKER_01: as you know,
[1:23] SPEAKER_01: very hot area of aging.
[1:25] SPEAKER_01: So I thought I'd start off
[1:27] SPEAKER_01: more towards the end of the book, where you kind of get philosophical into the kind of ethics.
[1:33] SPEAKER_01: And there,
[1:35] SPEAKER_01: this famous concept by James Freese of compression of morbidity that's been
[1:42] SPEAKER_01: circulating for well over two decades.
[1:45] SPEAKER_01: That's really the big question about all this aging effort.
[1:49] SPEAKER_01: So maybe you could give us, do you think there is evidence for compression of morbidity so that
[1:55] SPEAKER_01: you can just extend healthy aging and then you just fall off the cliff?
[2:00] SPEAKER_00: I think that's the goal of the most of the sort of what I call the saner end of the
[2:05] SPEAKER_00: aging research community is to improve our health span.
[2:10] SPEAKER_00: That is the number of years we have healthy lives,
[2:14] SPEAKER_00: not so much to extend lifespan,
[2:17] SPEAKER_00: which is how long we live.
[2:19] SPEAKER_00: And the idea is that you take those years that we now spend in poor health or
[2:25] SPEAKER_00: decrepitude and compress them down to just very short time.
[2:30] SPEAKER_00: So you're healthy almost your entire life and then suddenly go into a rapid decline and die.
[2:37] SPEAKER_00: Now,
[2:38] SPEAKER_00: Fries,
[2:39] SPEAKER_00: who actually coined that term,
[2:41] SPEAKER_00: compression of morbidity,
[2:43] SPEAKER_00: compares this to the one-horse shay after a poem by Oliver Wendell Holmes from the
[2:48] SPEAKER_00: 19th century,
[2:50] SPEAKER_00: which is about this horse carriage that was designed so perfectly that all its
[2:54] SPEAKER_00: parts wore out equally.
[2:57] SPEAKER_00: And so a farmer was riding along in this carriage one minute,
[3:01] SPEAKER_00: and the next minute he found himself on the ground surrounded by a heap of dust,
[3:06] SPEAKER_00: which was the entire carriage that had disintegrated.
[3:09] SPEAKER_00: So the question I would ask is,
[3:12] SPEAKER_00: if you're healthy and everything about you is healthy,
[3:15] SPEAKER_00: why would you suddenly go into decline?
[3:17] SPEAKER_00: And it's a fair question.
[3:19] SPEAKER_00: And every advance we've made that has kept us healthier in one respect or another,
[3:25] SPEAKER_00: for example,
[3:26] SPEAKER_00: tackling diabetes or tackling heart disease,
[3:29] SPEAKER_00: has also extended our lifespan.
[3:33] SPEAKER_00: So people are not living a bigger fraction of their lives healthily now,
[3:40] SPEAKER_00: even though we're living longer.
[3:42] SPEAKER_00: So the result is we're spending the same or even more number of years with one or
[3:47] SPEAKER_00: more health problems in our old age.
[3:51] SPEAKER_00: And you can see that in the explosion of nursing homes and care homes in almost all Western countries.
[3:59] SPEAKER_00: And as you know, they were big,
[4:02] SPEAKER_00: factors in COVID deaths.
[4:04] SPEAKER_00: So I'm not sure it can be accomplished.
[4:08] SPEAKER_00: I think that if we push forward with health, we're also going to extend our lifespan.
[4:17] SPEAKER_00: Now,
[4:17] SPEAKER_00: the argument against that comes from studies of these so-called supercentenarians
[4:24] SPEAKER_00: and semi-supercentenarians.
[4:26] SPEAKER_00: These are people who live to be over 105 or 110.
[4:31] SPEAKER_00: And Tom Pearls,
[4:32] SPEAKER_00: who runs the New England study of centenarians,
[4:36] SPEAKER_00: has published findings which show that these supercentenarians live extraordinarily
[4:42] SPEAKER_00: healthy lives for most of their life and undergo rapid decline and then die.
[4:48] SPEAKER_00: So that's almost exactly what we would want.
[4:50] SPEAKER_00: So they have somehow accomplished compression of morbidity.
[4:55] SPEAKER_00: Now, I would say there are two problems with that.
[4:57] SPEAKER_00: One is I don't know about the data sample size.
[5:00] SPEAKER_00: The number of people who live over 110 is very, very small.
[5:06] SPEAKER_00: The other is they may be
[5:10] SPEAKER_00: benefiting from their own unique genetics.
[5:13] SPEAKER_00: So they may have a particular combination of genetics against a broad genetic
[5:18] SPEAKER_00: background that's unique to each person.
[5:21] SPEAKER_00: So I'm not sure it's a generally translatable thing,
[5:25] SPEAKER_00: and it also may have to do with their particular life history and lifestyle.
[5:31] SPEAKER_00: So I don't know how much...
[5:33] SPEAKER_00: of what we learn from the centenarians is going to be applicable to the population as a whole.
[5:40] SPEAKER_00: And otherwise, I don't even know how this would be accomplished.
[5:45] SPEAKER_00: Although some people feel there's a natural limit to our biology,
[5:51] SPEAKER_00: restricts our lifespan to about 115 or 120 years.
[5:55] SPEAKER_00: Nobody has lived more than 122.
[5:57] SPEAKER_00: And so as we improve our health, we may come up against that natural limit.
[6:04] SPEAKER_00: And so you might get a compression of morbidity.
[6:09] SPEAKER_00: I'm skeptical.
[6:10] SPEAKER_00: I think it's an unsolved problem.
[6:13] SPEAKER_01: Right.
[6:13] SPEAKER_01: And I think I'm with you about this, but
[6:17] SPEAKER_01: You know, there's a lot of conflation of the two concepts.
[6:20] SPEAKER_01: One is to suppress age-related diseases,
[6:26] SPEAKER_01: and the other is to actually somehow modulate,
[6:29] SPEAKER_01: control the biologic aging process.
[6:32] SPEAKER_01: And we kind of lump it all together.
[6:35] SPEAKER_01: And,
[6:36] SPEAKER_01: you know,
[6:37] SPEAKER_01: as you're getting at,
[6:38] SPEAKER_01: which is one of the things I loved about your book,
[6:40] SPEAKER_01: is you really give a balanced view.
[6:42] SPEAKER_01: You present the contrarians and the,
[6:45] SPEAKER_01: you know,
[6:46] SPEAKER_01: the different perspectives,
[6:48] SPEAKER_01: you know,
[6:48] SPEAKER_01: the perspective about people having age differences.
[6:51] SPEAKER_01: limits potentially much greater than 120,
[6:53] SPEAKER_01: even though,
[6:54] SPEAKER_01: as you say,
[6:54] SPEAKER_01: we haven't seen anyone live past 122 since 1997.
[6:56] SPEAKER_01: So that's quite a long time.
[7:02] SPEAKER_01: So,
[7:02] SPEAKER_01: you know,
[7:02] SPEAKER_01: this,
[7:03] SPEAKER_01: I think,
[7:03] SPEAKER_01: conflation of,
[7:04] SPEAKER_01: you know,
[7:05] SPEAKER_01: what we do today,
[7:08] SPEAKER_01: you know,
[7:08] SPEAKER_01: as far as things that will reduce heart disease or diabetes,
[7:13] SPEAKER_01: That's age-related diseases.
[7:15] SPEAKER_01: That's very different than controlling the biologic aging process.
[7:19] SPEAKER_01: Now,
[7:20] SPEAKER_01: getting into that,
[7:22] SPEAKER_01: one of the things that's particularly alluring right now,
[7:26] SPEAKER_01: my friend here in San Diego,
[7:29] SPEAKER_01: Juan Carlos Belmonte,
[7:31] SPEAKER_01: who went over from Salk,
[7:34] SPEAKER_01: which surprised me, to the Altos Labs.
[7:36] SPEAKER_01: As you pointed out in the book, there's been several- Oh, I'm not surprised.
[7:39] SPEAKER_00: I mean, you have a huge salary and all the resources you want to carry out the same kind of research.
[7:47] SPEAKER_00: I wouldn't blame any of these guys.
[7:50] SPEAKER_01: No, I understand.
[7:51] SPEAKER_01: I understand.
[7:52] SPEAKER_01: It's kind of like the live golf tournament versus the PGA.
[7:55] SPEAKER_01: It's pretty wild.
[7:58] SPEAKER_01: At any rate, he's a good friend of mine, and I visited with him recently.
[8:03] SPEAKER_01: And as you mentioned, he has over 100 people working on this partial epigenetic reprogramming.
[8:10] SPEAKER_01: And just so reviewing this for the uninitiated is giving the four Yamanaka
[8:17] SPEAKER_01: transcription factors here to the whole animal,
[8:20] SPEAKER_01: the mouse,
[8:21] SPEAKER_01: and rejuvenating old mice,
[8:23] SPEAKER_01: essentially,
[8:24] SPEAKER_01: at least those with progeria.
[8:26] SPEAKER_01: And then others have, as you point out in the book, done this with just old mice.
[8:30] SPEAKER_01: So one of the things that strikes me about this,
[8:35] SPEAKER_01: and in talking with him recently,
[8:37] SPEAKER_01: is it's going to be pretty hard to give these Yanamaka factors to a person,
[8:41] SPEAKER_01: you know,
[8:41] SPEAKER_01: an intravenous infusion.
[8:43] SPEAKER_01: So what are your thoughts about this, you know, rejuvenation of a whole person?
[8:51] SPEAKER_00: What do you think?
[8:51] SPEAKER_00: You know, if I hadn't seen some of these papers, I would have been even more skeptical, okay?
[8:58] SPEAKER_00: But the data from
[9:01] SPEAKER_00: Well, Belmonte's work was done initially on progeric mice.
[9:05] SPEAKER_00: These are mice that age prematurely.
[9:08] SPEAKER_00: And then people thought, well, they may not represent natural aging.
[9:12] SPEAKER_00: And what you're doing is simply helping with some abnormal form of aging.
[9:20] SPEAKER_00: But he and other groups have now done it with normal mice and observed similar effects.
[9:29] SPEAKER_00: Now, I would say,
[9:32] SPEAKER_00: Reprogramming is one way,
[9:35] SPEAKER_00: it's a very exciting and powerful way to almost try to reverse aging because you're
[9:42] SPEAKER_00: trying to take cells back developmentally.
[9:46] SPEAKER_00: You're taking possibly fully differentiated cells back to stem cells and then having
[9:54] SPEAKER_00: helping regenerate tissue uh which uh you know one of the problems as we age is we
[10:00] SPEAKER_00: start losing uh stem cells so we have stem cell depletion so we can no longer
[10:05] SPEAKER_00: replace our tissues as we do when we're younger and i think you know anyone who
[10:10] SPEAKER_00: knows who's had a scrape
[10:13] SPEAKER_00: or, you know, been hurt in a fall or something, knows this.
[10:17] SPEAKER_00: Because if I fall and scrape my elbow and get a big bruise and my grandson falls,
[10:25] SPEAKER_00: we repair our tissues at very,
[10:27] SPEAKER_00: very different rates.
[10:28] SPEAKER_00: You know,
[10:28] SPEAKER_00: it takes me days or weeks to recover,
[10:33] SPEAKER_00: and my grandson's fine,
[10:35] SPEAKER_00: and two or three days you can hardly see he had a scrape at all.
[10:38] SPEAKER_00: So...
[10:41] SPEAKER_00: I think that's the thing that these guys want to do.
[10:47] SPEAKER_00: And the problem is Yamanaka factors are cancer, two of them are oncogenic factors.
[10:55] SPEAKER_00: If you give Yamanaka factors to cells,
[10:58] SPEAKER_00: you can take them all the way back to what are called pluripotent cells,
[11:02] SPEAKER_00: which are the cells that are capable of forming any tissue in the body.
[11:06] SPEAKER_00: So for example,
[11:08] SPEAKER_00: a fertilized egg or an early embryo, cells from the early embryo are pluripotent.
[11:15] SPEAKER_00: They could form anything in the body.
[11:17] SPEAKER_00: Now,
[11:19] SPEAKER_00: if you do that to cells with Yamanaka factors,
[11:23] SPEAKER_00: they often form teratomas,
[11:25] SPEAKER_00: which are these unusual forms of cancer tumors.
[11:31] SPEAKER_00: And so I think there's a real risk.
[11:34] SPEAKER_00: And so what these guys say is, well, we will give these factors transiently.
[11:40] SPEAKER_00: So we'll only take the cells back a little ways and not all the way back to pluripotency.
[11:46] SPEAKER_00: And that way, if you start with skin cells, you'll get the progenitor stem cells for skin cells.
[11:54] SPEAKER_00: And the problem with that is when you do it with a population,
[11:59] SPEAKER_00: you're getting a distribution.
[12:01] SPEAKER_00: Some of them will go back just a little, some of them may go back much more.
[12:05] SPEAKER_00: And I don't know how to control all this.
[12:10] SPEAKER_00: So I think it's very exciting research.
[12:13] SPEAKER_00: And of course, if I were one of these guys, I would certainly want to carry on doing that research.
[12:20] SPEAKER_00: But I don't think it's anywhere near ready for prime time in terms of
[12:25] SPEAKER_00: giving it to human beings as a sort of anti-aging therapeutic.
[12:31] SPEAKER_01: Yeah,
[12:31] SPEAKER_01: well,
[12:35] SPEAKER_01: I couldn't agree more on that because this is a company that's raised billions of
[12:40] SPEAKER_01: dollars to go into clinical trials.
[12:43] SPEAKER_01: And the question that comes up here, which is a theme in the book and a theme
[12:48] SPEAKER_01: with the aging process to try to artificially, if you will, affect it, is this risk of cancer.
[12:57] SPEAKER_01: And as we know, the hallmarks of aging overlap considerably with the hallmarks of cancer.
[13:04] SPEAKER_01: And this is just one example,
[13:06] SPEAKER_01: as you mentioned,
[13:07] SPEAKER_01: where these transcription factors could,
[13:10] SPEAKER_01: you know,
[13:10] SPEAKER_01: result in generating cancer.
[13:12] SPEAKER_01: But as you also point out in the book at many places,
[13:16] SPEAKER_01: methylation changes, DNA repair.
[13:21] SPEAKER_01: And telomeres.
[13:22] SPEAKER_01: Telomeres.
[13:24] SPEAKER_00: All of those are related to cancer as well.
[13:27] SPEAKER_00: And,
[13:27] SPEAKER_00: you know,
[13:27] SPEAKER_00: this was first pointed out to me by Titi Adelange,
[13:30] SPEAKER_00: who's a world expert on telomeres at Rockefeller.
[13:34] SPEAKER_00: And, you know, she was pointing out to me the intimate connection between cancer and aging.
[13:40] SPEAKER_00: And many mechanisms that have evolved to prevent cancer early in life tend to cause
[13:48] SPEAKER_00: aging later in life,
[13:50] SPEAKER_00: including a lot of DNA damage response,
[13:54] SPEAKER_00: which sends cells into senescence and therefore causes aging.
[13:58] SPEAKER_00: Buildup of senescent cells is a problem later in life with aging.
[14:04] SPEAKER_00: But it has a role, which is to prevent cancer early in life.
[14:09] SPEAKER_00: And so I think it's going to be the same problem with stem cell therapy.
[14:14] SPEAKER_00: I think very targeted stem cell therapy
[14:18] SPEAKER_00: which is involved in replacing certain tissues,
[14:22] SPEAKER_00: the kind of regenerative medicine that stem cells have been trying to address for a
[14:26] SPEAKER_00: very long time.
[14:27] SPEAKER_00: And only now we're beginning to see some of the successes of that.
[14:31] SPEAKER_00: So it's been very slow, even when the goal and target is very specific and well-defined.
[14:39] SPEAKER_00: And there, you're using that stem cell to treat
[14:45] SPEAKER_00: a pretty bad disease or some really serious problem.
[14:51] SPEAKER_00: I think with aging,
[14:52] SPEAKER_00: the idea that somebody might take this so they can live an extra 10 years,
[14:56] SPEAKER_00: it's a much higher bar in terms of safety and long-term safety and efficacy.
[15:02] SPEAKER_00: So I don't think that this is going to happen anytime soon, but it's not to say it'll never happen.
[15:10] SPEAKER_00: There is some serious biology underlying it.
[15:12] SPEAKER_01: Right.
[15:13] SPEAKER_01: Well, you just touched on this, but of course the other
[15:17] SPEAKER_01: There's several big areas that are being explored,
[15:20] SPEAKER_01: and one of them is trying to deal with these senescent cells and trying to get rid
[15:26] SPEAKER_01: of them from the body because they can secrete evil humors,
[15:30] SPEAKER_01: if you will.
[15:31] SPEAKER_01: And the problem with that, it seems that these senescent cells are kind of protective.
[15:35] SPEAKER_01: They stop dividing cells.
[15:37] SPEAKER_01: they're not going to become cancerous, although perhaps they could contribute to that in some way.
[15:42] SPEAKER_01: So like you say,
[15:44] SPEAKER_01: with telomeres and so many things that are trying to be manipulated here,
[15:48] SPEAKER_01: there's this downside risk.
[15:51] SPEAKER_01: And it seems like this is where we're going to have to confront this.
[15:54] SPEAKER_01: Like we have seen,
[15:56] SPEAKER_01: Venky,
[15:56] SPEAKER_01: with the CAR-T,
[15:58] SPEAKER_01: the T-cell engineering,
[15:59] SPEAKER_01: there's this small risk of engendering cancer while you're trying to deal with the
[16:05] SPEAKER_01: immune system.
[16:07] SPEAKER_00: Yeah, I think with senescent cells, early in life, senescent cells have an important role in biology.
[16:15] SPEAKER_00: They're essentially signaling to the immune system that there's a site that's
[16:20] SPEAKER_00: subject to viral infection or wounds or things like that.
[16:25] SPEAKER_00: So it's a signal to send other kinds of cells there to come and repair the damage.
[16:33] SPEAKER_00: Now,
[16:35] SPEAKER_00: Of course, that evolved to help us early in life.
[16:37] SPEAKER_00: And also many senescent cells were a response to DNA damage.
[16:42] SPEAKER_00: And that's again,
[16:43] SPEAKER_00: a way for the body that if your DNA is damaged,
[16:46] SPEAKER_00: you don't want that cell to be able to divide indefinitely because it could become cancerous.
[16:52] SPEAKER_00: And so you send it into senescence and get it out of harm's way.
[16:56] SPEAKER_00: So early in life, we were able to get rid of these senescent cells.
[16:59] SPEAKER_00: We were able to come to the site
[17:01] SPEAKER_00: and then clean up the damage and eventually destroy the senescent cells themselves.
[17:08] SPEAKER_00: But as we get older, the response mechanisms also deteriorate with age.
[17:15] SPEAKER_00: Our immune system deteriorates with age.
[17:17] SPEAKER_00: All the natural signaling mechanisms deteriorate with age.
[17:22] SPEAKER_00: And so we get this buildup of senescent cells.
[17:25] SPEAKER_00: And there, people have asked, well, these senescent cells don't just sit there.
[17:28] SPEAKER_00: They secrete inflammatory compounds, which originally was a feature, not a bug.
[17:34] SPEAKER_00: And
[17:35] SPEAKER_00: and uh but then it becomes a problem later in life and so people have found that if
[17:40] SPEAKER_00: you target senescent cells in older animals those animals improve they their
[17:46] SPEAKER_00: symptoms of aging improve dramatically uh or significantly anyway and uh so this
[17:53] SPEAKER_00: has led to this whole field called senolytics which is being able to specifically
[17:58] SPEAKER_00: target uh senescent cells
[18:01] SPEAKER_00: Now there,
[18:02] SPEAKER_00: the problem is how would you design compounds that are highly specific for
[18:08] SPEAKER_00: senescent cells and don't damage your other cells and don't have other long-term
[18:13] SPEAKER_00: side effects?
[18:15] SPEAKER_00: So again,
[18:15] SPEAKER_00: I think it's a promising area,
[18:17] SPEAKER_00: but a lot of work needs to be done to establish long-term safety and efficacy.
[18:23] SPEAKER_00: Right.
[18:24] SPEAKER_01: You know, in fact, just today in nature, there's a feature on killing the zombie cells.
[18:30] SPEAKER_01: So and it discusses just what you're pointing out,
[18:33] SPEAKER_01: which is it's not so easy to tag these specifically and target them,
[18:37] SPEAKER_01: even though,
[18:38] SPEAKER_01: as you know,
[18:38] SPEAKER_01: there's some early trials and things like diabetic macular edema.
[18:43] SPEAKER_01: And, you know, we'll see how that plays out.
[18:45] SPEAKER_01: Now, one of the things that comes up is the young blood story.
[18:53] SPEAKER_01: So,
[18:54] SPEAKER_01: in the young blood,
[18:55] SPEAKER_01: whether it's this parabiosis or however you want to get at it,
[18:59] SPEAKER_01: and I guess it even applies to the young microbiome of a gut,
[19:03] SPEAKER_01: but there's this consistent report that there's something special going on there.
[19:09] SPEAKER_01: And of course,
[19:10] SPEAKER_01: the reciprocal relationship of giving the old blood to the young mice,
[19:14] SPEAKER_01: whatever,
[19:15] SPEAKER_01: but no one can find the factor,
[19:17] SPEAKER_01: whether it's platelet factor four,
[19:19] SPEAKER_01: GDF11,
[19:20] SPEAKER_01: or
[19:21] SPEAKER_01: What are your thoughts about this young blood story?
[19:25] SPEAKER_00: I think there's no question that the experiments work because they were reproduced.
[19:32] SPEAKER_00: And they were reproduced over quite a long period.
[19:36] SPEAKER_00: Which is that when you connect an old mouse or rat with a young equivalent...
[19:43] SPEAKER_00: Then the old mouse or old rat benefits from the young blood from the younger animal.
[19:50] SPEAKER_00: And conversely, the younger animal suffers from the blood from the older animal.
[19:54] SPEAKER_00: And then people were wondering whether this is simply that the young animal has
[19:59] SPEAKER_00: better detoxification and things like that,
[20:02] SPEAKER_00: or whether it's actually the blood.
[20:04] SPEAKER_00: And they gave it just as transfusion without connecting the animals and showed that
[20:09] SPEAKER_00: it really was the blood.
[20:11] SPEAKER_00: And so this,
[20:13] SPEAKER_00: of course,
[20:14] SPEAKER_00: then leads to the question,
[20:15] SPEAKER_00: well,
[20:15] SPEAKER_00: what is it about young blood that's beneficial?
[20:18] SPEAKER_00: And what is it about old blood that is bad?
[20:24] SPEAKER_00: But the problem is blood has hundreds of factors.
[20:28] SPEAKER_00: And so they have to look at which factors are significantly different.
[20:33] SPEAKER_00: And they might be in such small quantities
[20:36] SPEAKER_00: that you might not be able to detect those differences very easily.
[20:40] SPEAKER_00: And then once you've detected differences, then you have to establish their mechanism of action.
[20:47] SPEAKER_00: And first of all, you have to establish that the factor really is beneficial.
[20:52] SPEAKER_00: Then you have to figure out how it works and what its potential side effects could be.
[20:57] SPEAKER_00: And so,
[20:59] SPEAKER_00: again,
[20:59] SPEAKER_00: this is a promising area where there's a lot of research,
[21:04] SPEAKER_00: but it has not prevented people from jumping the gun.
[21:07] SPEAKER_00: So in the United States, and I should say a lot of them in your state.
[21:12] SPEAKER_00: Yes, yes.
[21:15] SPEAKER_00: California somehow seems to attract all these immortality types.
[21:20] SPEAKER_00: Well,
[21:20] SPEAKER_00: anyway,
[21:21] SPEAKER_00: a lot of companies set up to take blood from young donors,
[21:26] SPEAKER_00: extract the plasma,
[21:28] SPEAKER_00: and then give it to rich,
[21:31] SPEAKER_00: old recipients for a fee,
[21:35] SPEAKER_00: for a healthy fee.
[21:36] SPEAKER_00: And I think the FDA actually shut down one of them.
[21:40] SPEAKER_00: on the grounds that, you know, they were not approved, you know, following approved procedure.
[21:46] SPEAKER_00: And then they tried to start up under a different name.
[21:50] SPEAKER_00: And then eventually, I don't know what happened.
[21:54] SPEAKER_00: But at one point, the CEO said something I thought was very amusing.
[21:58] SPEAKER_00: He said, well, the problem with clinical trials is that they take too long.
[22:05] SPEAKER_00: So I'm afraid that's...
[22:09] SPEAKER_00: that's characteristic of some portion of this sort of anti-aging therapeutics community.
[22:17] SPEAKER_00: There's a very mainstream rigorous side to it,
[22:22] SPEAKER_00: but there's also at the other end of the spectrum,
[22:25] SPEAKER_00: you know,
[22:26] SPEAKER_00: kind of the wild west where people just sell whatever they can.
[22:30] SPEAKER_00: And I think this exploits people's fear of getting old and
[22:36] SPEAKER_00: and and and, you know, being disabled or things like that and then and then dying.
[22:41] SPEAKER_00: And I think the fear seems to be stronger in California,
[22:44] SPEAKER_00: where people like their lives and don't want to age.
[22:49] SPEAKER_01: You may be right about that.
[22:50] SPEAKER_01: I like your term in the book, immortality merchants.
[22:54] SPEAKER_01: And of course,
[22:54] SPEAKER_01: we'll get into a bit,
[22:55] SPEAKER_01: I hope,
[22:56] SPEAKER_01: the chapter on the crackpots and profits that you called it was great.
[23:01] SPEAKER_01: But that quote,
[23:03] SPEAKER_01: by the way,
[23:03] SPEAKER_01: which was precious from,
[23:05] SPEAKER_01: I think it was Ambrosia,
[23:07] SPEAKER_01: the name of the company and the CEO.
[23:09] SPEAKER_01: But there's another quote in the book I want to ask you about.
[23:13] SPEAKER_01: Most scientists working on aging agree that dietary restriction
[23:19] SPEAKER_01: can extend both healthy life and overall life in mice and also lead to reductions
[23:24] SPEAKER_01: in cancer,
[23:25] SPEAKER_01: diabetes,
[23:26] SPEAKER_01: and overall mortality in humans.
[23:30] SPEAKER_01: Is that true?
[23:31] SPEAKER_01: Most scientists think that you can really change these age-related diseases.
[23:39] SPEAKER_00: if you had to pick one area in which there's broad agreement, it is caloric restriction.
[23:45] SPEAKER_00: But I wouldn't say the consensus is complete.
[23:48] SPEAKER_00: And the reason I say that is,
[23:51] SPEAKER_00: that most of the comparisons are between animals that can eat as much as they want,
[23:57] SPEAKER_00: called an ad libitum diet,
[24:00] SPEAKER_00: and mice that are calorically restricted,
[24:03] SPEAKER_00: or same with other animals,
[24:05] SPEAKER_00: even yeast.
[24:07] SPEAKER_00: You either compare it with an extremely rich medium or in a calorically restricted medium.
[24:13] SPEAKER_00: And this is not a great comparison.
[24:17] SPEAKER_00: And people,
[24:19] SPEAKER_00: there's one discrepancy,
[24:21] SPEAKER_00: and that was in monkeys,
[24:22] SPEAKER_00: where an NIH study didn't find huge differences,
[24:27] SPEAKER_00: whereas a Wisconsin study found rather dramatic differences between the control
[24:35] SPEAKER_00: group and the calorically restricted group.
[24:38] SPEAKER_00: And so what was the difference?
[24:40] SPEAKER_00: Well, the difference was
[24:41] SPEAKER_00: that the NIH study,
[24:44] SPEAKER_00: the control group didn't have a calorically restricted diet,
[24:47] SPEAKER_00: but still had a pretty reasonable diet.
[24:50] SPEAKER_00: It wasn't given an unhealthy, rich diet of all you can eat.
[24:57] SPEAKER_00: And then they tried to somehow reconcile their findings in a later study,
[25:03] SPEAKER_00: but it leads to the question of whether
[25:06] SPEAKER_00: What you can conclude is that a rich,
[25:09] SPEAKER_00: all-you-can-eat diet,
[25:10] SPEAKER_00: in other words,
[25:11] SPEAKER_00: gorging on an all-you-can-eat buffet,
[25:14] SPEAKER_00: is definitely bad for you.
[25:16] SPEAKER_00: So you could draw that conclusion rather than saying it's actually the caloric restrictions.
[25:23] SPEAKER_00: So I think people need to do a little more careful study.
[25:26] SPEAKER_00: There was also a study on mice,
[25:28] SPEAKER_00: which took different strains of mice and showed that in some strains,
[25:33] SPEAKER_00: caloric restriction actually shortened lifespan,
[25:35] SPEAKER_00: didn't increase lifespan.
[25:39] SPEAKER_00: much of the aging community says, ah, that's just one study.
[25:41] SPEAKER_00: But nobody has actually shown whether there was anything wrong with that study or
[25:45] SPEAKER_00: even tried to reproduce it.
[25:48] SPEAKER_00: So I think that study still stands.
[25:51] SPEAKER_00: So I think it's not completely clear.
[25:55] SPEAKER_00: But the fact is...
[25:57] SPEAKER_00: that there's some calorie dependence that's widely been observed across species.
[26:05] SPEAKER_00: So between the control group and the experimental group,
[26:07] SPEAKER_00: however you may define it as,
[26:11] SPEAKER_00: there's been some effect of calories intake.
[26:16] SPEAKER_00: And the other interesting thing is that
[26:21] SPEAKER_00: one of the pathways affected by caloric restriction is the so-called TOR pathway.
[26:26] SPEAKER_00: And one of the inhibitors of the TOR pathway is rapamycin.
[26:30] SPEAKER_00: And rapamycin in studies has also shown some of these beneficial effects against
[26:38] SPEAKER_00: the symptoms of aging and in lifespan.
[26:41] SPEAKER_00: Although rapamycin has the same issue as with many other remedies, it's an immunosuppressive drug.
[26:48] SPEAKER_00: And, you know, that means it makes you more prone to infection and wound healing and many other things.
[26:56] SPEAKER_00: I believe one of them was, there's a question of whether it affects your libido.
[27:02] SPEAKER_00: But nevertheless, that has not prevented rapamycin clinics from opening up, need I say, in California.
[27:11] SPEAKER_00: So, you know, I do think that
[27:17] SPEAKER_00: There's often serious science and which leads to sort of promising avenues.
[27:25] SPEAKER_00: But then there are,
[27:25] SPEAKER_00: of course,
[27:26] SPEAKER_00: people who jump the gun and and want to go ahead anyway,
[27:29] SPEAKER_00: because they figure by the time trials are done,
[27:32] SPEAKER_00: they'll be dead.
[27:33] SPEAKER_00: And they'd rather, you know, right now.
[27:36] SPEAKER_01: Right.
[27:36] SPEAKER_01: And you make a good,
[27:38] SPEAKER_01: I mean,
[27:38] SPEAKER_01: the rapamycin and mTOR pathway,
[27:41] SPEAKER_01: you really develop that quite a bit in the book.
[27:43] SPEAKER_01: It's really quite complex.
[27:45] SPEAKER_01: I mean,
[27:46] SPEAKER_01: this is a,
[27:47] SPEAKER_01: this is a pleiotropic intervention,
[27:49] SPEAKER_01: whether it's rapalogs or rapamycin,
[27:51] SPEAKER_01: it's not so simple at all,
[27:53] SPEAKER_01: right?
[27:53] SPEAKER_00: It's not at all simple because the TOR pathway has so many consequences.
[27:57] SPEAKER_00: It affects so many different processes in the cell, including my own field of protein synthesis.
[28:04] SPEAKER_00: It's one of the things it does is shut down global protein synthesis,
[28:10] SPEAKER_00: and that's one of the effects of inhibiting TOR.
[28:14] SPEAKER_00: And it turns up autophagy, which is this recycling of defective
[28:19] SPEAKER_00: uh proteins and entirely defective entire organelles so i think tor the tor pathway
[28:27] SPEAKER_00: is like a hub in a very large network and so when you start playing with that
[28:35] SPEAKER_00: you're going to have multiple consequences
[28:37] SPEAKER_00: Yeah, no.
[28:38] SPEAKER_01: And another thing that you develop so well is about this garbage disposal,
[28:43] SPEAKER_01: waste disposal system,
[28:45] SPEAKER_01: which is remarkably elaborate in the cell,
[28:48] SPEAKER_01: whether it's the proteasome for the proteins and the autophagosomes for the
[28:55] SPEAKER_01: autophagy with the lysosomes and the
[28:59] SPEAKER_01: mitochondria, mitophagy.
[29:01] SPEAKER_01: Do you want to comment about that?
[29:02] SPEAKER_01: Because this is something I think a lot of people don't appreciate that waste
[29:06] SPEAKER_01: management in the cell is just,
[29:08] SPEAKER_01: it's a big deal.
[29:09] SPEAKER_00: Yeah,
[29:10] SPEAKER_00: so we always think of,
[29:12] SPEAKER_00: you know,
[29:12] SPEAKER_00: producing things in the cell as being important,
[29:15] SPEAKER_00: you know,
[29:15] SPEAKER_00: making proteins and so on.
[29:17] SPEAKER_00: But the fact is,
[29:19] SPEAKER_00: destroying proteins is equally important because sometimes you need proteins for a
[29:26] SPEAKER_00: short time,
[29:26] SPEAKER_00: then they've done their job and you need to get rid of them,
[29:30] SPEAKER_00: or proteins become dysfunctional.
[29:35] SPEAKER_00: They stop working, or even worse, they start clumping together and causing diseases.
[29:40] SPEAKER_00: For example, you could think of Alzheimer's as a disease which involves protein tangles.
[29:45] SPEAKER_00: Of course,
[29:46] SPEAKER_00: the relationship between the tangles and the disease is still being worked out,
[29:51] SPEAKER_00: but it's a characteristic of Alzheimer's that you have these protein tangles.
[29:56] SPEAKER_00: And the cell has evolved very elaborate mechanisms to constantly turn over proteins
[30:04] SPEAKER_00: you know, defective proteins.
[30:05] SPEAKER_00: Well,
[30:06] SPEAKER_00: for example,
[30:07] SPEAKER_00: it senses when proteins are unfolded and essentially the chain has unraveled and is
[30:13] SPEAKER_00: now sticking to all sorts of things and causing problems.
[30:17] SPEAKER_00: So I think in all of these cases, cells evolved very elaborate mechanisms
[30:23] SPEAKER_00: to recycle defective products,
[30:27] SPEAKER_00: to have a proper turnover of proteins,
[30:30] SPEAKER_00: and in fact,
[30:31] SPEAKER_00: recycling of entire organelles like mitochondria when they become defective,
[30:36] SPEAKER_00: the whole mitochondrion can be recycled.
[30:39] SPEAKER_00: So these systems also break down with aging.
[30:46] SPEAKER_00: And so as we age,
[30:48] SPEAKER_00: we have more of a tendency to accumulate unfolded proteins or to accumulate
[30:53] SPEAKER_00: defective mitochondria.
[30:55] SPEAKER_00: And it's one of the more serious problems with aging.
[30:59] SPEAKER_01: Yeah, there's quite a few of them, unfortunately, quite a few problems.
[31:03] SPEAKER_01: Each of them are being addressed.
[31:04] SPEAKER_01: So there's many different shots on goal here.
[31:07] SPEAKER_01: And as you also aptly point out, they're interconnected.
[31:10] SPEAKER_01: So many of these things are not just standalone strategies.
[31:15] SPEAKER_01: You know, I do want to get your sense about another popular thing, especially here in California.
[31:21] SPEAKER_01: are the clocks, epigenetic clocks in particular.
[31:24] SPEAKER_01: And these people are paying a few hundred dollars and getting their biologic age, which what is that?
[31:32] SPEAKER_01: And they're also thinking that I can change my future by getting clocks.
[31:38] SPEAKER_01: Some of these companies offer every few months to get a new clock.
[31:43] SPEAKER_01: This is actually remarkable.
[31:45] SPEAKER_01: And I wonder what your thoughts are about it.
[31:48] SPEAKER_00: Well, again, this is an example of some serious biology and then people jumping the gun to use it.
[31:58] SPEAKER_00: So the serious biology comes from the fact that we age at different rates, individuals.
[32:04] SPEAKER_00: So anyone who's been to a high school reunion knows this.
[32:09] SPEAKER_00: You'll have classmates who are unrecognizable because they've aged so much,
[32:14] SPEAKER_00: and others who've hardly changed since you knew them in high school.
[32:18] SPEAKER_00: So, of course, at my age, that's getting rarer and rarer.
[32:22] SPEAKER_00: But anyway, but you know what I mean.
[32:24] SPEAKER_00: So the thing is that,
[32:28] SPEAKER_00: is there a way that we can ask on an individual level,
[32:32] SPEAKER_00: how much has that individual aged?
[32:37] SPEAKER_00: And there are markers that people have identified.
[32:41] SPEAKER_00: Some of them are markers on our DNA, which you mentioned in California.
[32:45] SPEAKER_00: Horvath is a very famous scientist who has a clock named after him,
[32:51] SPEAKER_00: actually,
[32:53] SPEAKER_00: which has to do with methylation of our DNA.
[32:56] SPEAKER_00: And the patterns of methylation affect the pattern of gene expression.
[33:01] SPEAKER_00: And that pattern changes as we age.
[33:04] SPEAKER_00: And
[33:06] SPEAKER_00: They've shown that those patterns are a better predictor of many of the factors of aging,
[33:12] SPEAKER_00: for example,
[33:13] SPEAKER_00: mortality or symptoms of aging.
[33:16] SPEAKER_00: They're a better predictor of that than chronological age.
[33:20] SPEAKER_00: And then,
[33:21] SPEAKER_00: of course,
[33:22] SPEAKER_00: there are blood markers,
[33:23] SPEAKER_00: for example,
[33:23] SPEAKER_00: levels of various blood enzymes or blood factors,
[33:27] SPEAKER_00: and there are dozens of these factors.
[33:29] SPEAKER_00: So there are many different tests
[33:32] SPEAKER_00: of many different kinds of markers which look at aging.
[33:37] SPEAKER_00: Now, the problem is these all work on a population level.
[33:42] SPEAKER_00: And they also work on an individual level for time comparison.
[33:46] SPEAKER_00: That is to say,
[33:47] SPEAKER_00: if you want to ask,
[33:48] SPEAKER_00: is some intervention working,
[33:51] SPEAKER_00: you could ask,
[33:52] SPEAKER_00: how fast are these markers changing in this person without the intervention and how
[33:57] SPEAKER_00: fast are they changing with the intervention?
[34:00] SPEAKER_00: So for these kind of carefully controlled experiments, they work.
[34:05] SPEAKER_00: But another case is, for example, glycosylation of proteins, especially proteins of your immune system.
[34:15] SPEAKER_00: It turns out that adding sugar groups to your immune system changes with age and
[34:21] SPEAKER_00: causes the immune system to misfire.
[34:26] SPEAKER_00: And that's a symptom of aging.
[34:27] SPEAKER_00: It's called inflammation.
[34:31] SPEAKER_00: People have used different markers.
[34:34] SPEAKER_00: Now, the problem is these markers are not always consistent with each other because you may
[34:42] SPEAKER_00: be perfectly fine in many respects,
[34:44] SPEAKER_00: but by some particular marker,
[34:47] SPEAKER_00: you may be considered old just because of that,
[34:50] SPEAKER_00: just because they're comparing you to a population average,
[34:55] SPEAKER_00: okay?
[34:56] SPEAKER_00: But it's, how would you say, one person said, look, we all lose height as we age.
[35:03] SPEAKER_00: uh but just but that doesn't mean if you take a short person you can consider them
[35:07] SPEAKER_00: old you know so it's it's a difference between an individual versus uh you know a
[35:14] SPEAKER_00: population and it's a difference between what happens to an individual by following
[35:18] SPEAKER_00: that individual over time versus just taking an individual and comparing it to some
[35:23] SPEAKER_00: population average so that's one problem
[35:28] SPEAKER_00: The other problem is that our aging is not homogeneous.
[35:32] SPEAKER_00: So there's a recent paper from,
[35:35] SPEAKER_00: I believe,
[35:36] SPEAKER_00: Tony Wiskoray's group,
[35:38] SPEAKER_00: which talks about the age of different organs in the same person.
[35:43] SPEAKER_00: And it turns out that,
[35:44] SPEAKER_00: you know,
[35:44] SPEAKER_00: our organs,
[35:45] SPEAKER_00: and this is not just one paper,
[35:47] SPEAKER_00: there are other papers as well,
[35:49] SPEAKER_00: our organs don't necessarily age at the same rate.
[35:53] SPEAKER_00: So
[35:54] SPEAKER_00: giving a person a single number, saying this is your biological age, it's not clear what that means.
[36:03] SPEAKER_00: And I would say, all right, even if you do it, what are you going to do about it?
[36:08] SPEAKER_00: What can you do about it knowing the so-called number of a biological age?
[36:13] SPEAKER_00: So I'm not a big fan.
[36:15] SPEAKER_00: I'm a big fan of using these markers as a tool in research to understand what
[36:22] SPEAKER_00: interventions work,
[36:24] SPEAKER_00: because otherwise it would take too long.
[36:26] SPEAKER_00: You know, you'd have to wait 20 years to see some large-scale symptoms.
[36:30] SPEAKER_00: And certainly, if you want to look at mortality, you'd have to wait possibly even longer.
[36:36] SPEAKER_00: But if you were to be able to follow track these...
[36:40] SPEAKER_00: interventions and see that these markers slowed down with intervention,
[36:45] SPEAKER_00: then you could say,
[36:46] SPEAKER_00: well,
[36:46] SPEAKER_00: your intervention's having an effect on something related to aging.
[36:52] SPEAKER_00: So I would say these are very useful research tools, but they're not, you know,
[36:58] SPEAKER_00: meant to be used at $500 a pop in your age.
[37:04] SPEAKER_00: But of course, that hasn't stopped lots of companies from doing it.
[37:07] SPEAKER_01: No, it's just amazing, actually.
[37:08] SPEAKER_01: And by the way,
[37:09] SPEAKER_01: we interviewed Tony Whiskery about the Oregon Clock paper because I thought it
[37:14] SPEAKER_01: really was quite a great contribution,
[37:16] SPEAKER_01: again,
[37:17] SPEAKER_01: on a research level.
[37:18] SPEAKER_00: I mean, he's a very serious scientist.
[37:21] SPEAKER_00: And he actually spoke here at the LMB as well.
[37:24] SPEAKER_00: He gave a very nice talk here.
[37:25] SPEAKER_01: No, he's the real deal.
[37:27] SPEAKER_01: And I think that's going to help us to,
[37:29] SPEAKER_01: you know,
[37:30] SPEAKER_01: it's to have that organ specific type of tracking is another edge here to
[37:35] SPEAKER_01: understand the effects.
[37:37] SPEAKER_01: Well, before we wrap up, I want to ask you a question that you asked in the book.
[37:44] SPEAKER_01: Is aging a disease?
[37:49] SPEAKER_00: That's, again, a controversial subject.
[37:52] SPEAKER_00: So the WHO,
[37:54] SPEAKER_00: and I believe the FDA,
[37:57] SPEAKER_00: decided that aging was not a disease on the grounds that it's inevitable and ubiquitous.
[38:03] SPEAKER_00: It happens to everybody and it's inevitable.
[38:06] SPEAKER_00: So how could something that happens to everybody and inevitable be considered a disease?
[38:11] SPEAKER_00: A disease is an abnormal situation.
[38:13] SPEAKER_00: This is a normal situation.
[38:14] SPEAKER_00: right so but the anti-aging researchers and especially the anti-aging therapeutics
[38:22] SPEAKER_00: people don't like that because if it's not a disease how could they run a clinical
[38:29] SPEAKER_00: trial so they want aging to be considered a disease and their argument is that if
[38:35] SPEAKER_00: you look at almost every condition of old age every disease of old age like cancer
[38:42] SPEAKER_00: diabetes
[38:44] SPEAKER_00: heart disease, dementia, the biggest risk factor in all of these diseases is age.
[38:50] SPEAKER_00: That's the strongest risk factor.
[38:53] SPEAKER_00: And so they say,
[38:54] SPEAKER_00: well,
[38:54] SPEAKER_00: actually,
[38:55] SPEAKER_00: you could think of these diseases as secondary diseases,
[38:59] SPEAKER_00: the primary disease being age,
[39:02] SPEAKER_00: and then that results in these other diseases.
[39:05] SPEAKER_00: And I am a little skeptical of that idea.
[39:08] SPEAKER_00: I tend to agree with the WHO and the FDA, but I can see both sides of the argument.
[39:16] SPEAKER_00: And as you know, I've laid them both out.
[39:21] SPEAKER_00: My view is that it should be possible to do trials that help with aging.
[39:30] SPEAKER_00: regardless of whether you consider aging a disease or not,
[39:33] SPEAKER_00: but that will require the community to agree on what set of markers to use to
[39:40] SPEAKER_00: characterize success,
[39:42] SPEAKER_00: okay?
[39:42] SPEAKER_00: And that's,
[39:43] SPEAKER_00: you know,
[39:43] SPEAKER_00: people,
[39:44] SPEAKER_00: you know,
[39:44] SPEAKER_00: for example,
[39:45] SPEAKER_00: Tony Viscoray has this,
[39:47] SPEAKER_00: you know,
[39:47] SPEAKER_00: his proteome,
[39:49] SPEAKER_00: blood proteome markers,
[39:51] SPEAKER_00: Horvath has his DNA methylation clock.
[39:54] SPEAKER_00: You know, there are a whole bunch of these, and then there are people with glycation or glycosylation of,
[39:59] SPEAKER_00: various proteins as markers.
[40:01] SPEAKER_00: These people need to all come together.
[40:04] SPEAKER_00: Maybe we need to organize a nice conference for them in some place like Southern
[40:09] SPEAKER_00: California or Hawaii or somewhere.
[40:12] SPEAKER_00: Put them together in a locked room for a week so that they can thrash out a common
[40:19] SPEAKER_00: set of markers and at least agree on what experiments they need to do to even come
[40:25] SPEAKER_00: to that
[40:26] SPEAKER_00: agreement.
[40:28] SPEAKER_00: And then, you know, use that to evaluate anti-aging therapies.
[40:33] SPEAKER_00: I think that would be a way forward.
[40:35] SPEAKER_01: Yeah,
[40:36] SPEAKER_01: you're bringing up a really valuable point because they're,
[40:39] SPEAKER_01: at the moment,
[40:40] SPEAKER_01: they're kind of competing with one another,
[40:41] SPEAKER_01: whether it's the glycosylated proteins or the transcriptomics or the epigenetics.
[40:48] SPEAKER_01: And, you know, we don't know whether these are additive or
[40:50] SPEAKER_00: what they're really measuring, you know, maybe some of them may be highly correlated and that's okay.
[40:57] SPEAKER_00: Yeah.
[40:57] SPEAKER_00: But I think, I think, you know, they need to know that.
[41:00] SPEAKER_00: And they also need to come,
[41:02] SPEAKER_00: come up with some criterion of what is,
[41:04] SPEAKER_00: how do we define age in an individual?
[41:06] SPEAKER_00: It's not one number.
[41:07] SPEAKER_00: Okay.
[41:09] SPEAKER_00: Just like, you know, we have many things that characterize our health.
[41:13] SPEAKER_00: Cholesterol is one, blood pressure is another, you know, various other, you know,
[41:20] SPEAKER_00: lipids, they're all liver enzymes.
[41:23] SPEAKER_00: All these things are factors in defining our so-called biological health.
[41:30] SPEAKER_00: So I don't think there's some single number that's going to say, this is your age.
[41:34] SPEAKER_00: Just like there isn't one single thing that says you're healthy or not healthy.
[41:38] SPEAKER_01: Right.
[41:38] SPEAKER_01: That's well put.
[41:41] SPEAKER_01: The last topic on aging is on about DNA repair, which is an area that you know very well.
[41:49] SPEAKER_01: And one of the quotes in your book, I think, is important for people to understand.
[41:54] SPEAKER_01: take in.
[41:55] SPEAKER_01: Nevertheless, they will make an error once every million or so letters.
[42:00] SPEAKER_01: In a genome with a few billion letters,
[42:02] SPEAKER_01: that means several thousand mistakes occur each time a cell divides.
[42:06] SPEAKER_01: So the DNA repair enzyme,
[42:08] SPEAKER_01: as you point out,
[42:09] SPEAKER_01: the sentinels of our genome,
[42:12] SPEAKER_01: the better we repair,
[42:14] SPEAKER_01: the better we age.
[42:16] SPEAKER_01: Can we fix the DNA repair problem?
[42:20] SPEAKER_00: I think...
[42:22] SPEAKER_00: Maybe.
[42:24] SPEAKER_00: Again, I'm not sure what the consequences would be and how much it would take.
[42:32] SPEAKER_00: There's one curious fact, and that is that
[42:36] SPEAKER_00: There was a paradox called Pitot's paradox after the scientists who discovered it,
[42:41] SPEAKER_00: which is why don't big animals get cancer much more frequently than,
[42:47] SPEAKER_00: say,
[42:47] SPEAKER_00: a mouse?
[42:47] SPEAKER_00: In fact, a mouse gets cancer far more readily than an elephant does.
[42:55] SPEAKER_00: In reality,
[42:56] SPEAKER_00: the elephant should actually get cancer more because it has many orders of
[43:00] SPEAKER_00: magnitude more cells.
[43:02] SPEAKER_00: And all it takes is for one cell to become cancerous, for the animal to get cancer and die, right?
[43:09] SPEAKER_00: So the chances that one cell would become cancer would be larger if there are many, many more cells.
[43:17] SPEAKER_00: And it turns out that elephants have many copies of DNA repair proteins or DNA
[43:23] SPEAKER_00: damage response proteins,
[43:26] SPEAKER_00: not so much DNA repair,
[43:27] SPEAKER_00: but the response to DNA damage.
[43:30] SPEAKER_00: And, you know, in particular, a protein called P53.
[43:36] SPEAKER_00: And so this leads to the question that if you had very good DNA repair or very good
[43:41] SPEAKER_00: DNA damage response,
[43:43] SPEAKER_00: would you then,
[43:43] SPEAKER_00: you know,
[43:47] SPEAKER_00: live longer or solve this problem.
[43:50] SPEAKER_00: I'm not entirely sure because it may have other consequences.
[43:55] SPEAKER_00: For example, you don't want to send cells into senescence too easily.
[44:02] SPEAKER_00: So I think these things are all carefully balanced evolutionarily depending on
[44:08] SPEAKER_00: what's optimized to optimize fitness for each species.
[44:13] SPEAKER_00: For a mouse,
[44:14] SPEAKER_00: the equation is different than for a large animal because a mouse can get eaten by
[44:18] SPEAKER_00: predators and so on.
[44:19] SPEAKER_00: So there it doesn't pay for evolution to spend too much,
[44:24] SPEAKER_00: you know,
[44:24] SPEAKER_00: select for too much spending of resources in maintenance and repair.
[44:31] SPEAKER_00: For larger animals, the equation's different.
[44:34] SPEAKER_00: So I just don't know enough about...
[44:38] SPEAKER_00: about what the consequences would be?
[44:40] SPEAKER_01: No,
[44:40] SPEAKER_01: it's really interesting to speculate because as you point out in the book,
[44:44] SPEAKER_01: the elephant has 20 copies of P53 and we have two as humans.
[44:49] SPEAKER_01: And, you know, the question is that protection from cancer is very intriguing.
[44:54] SPEAKER_01: Especially with the concerns that we've been talking about.
[44:56] SPEAKER_00: Yeah.
[44:57] SPEAKER_00: And it was also true.
[44:59] SPEAKER_00: I believe they did some analysis of genomics of these whales that live very long.
[45:04] SPEAKER_00: And they found all sorts of,
[45:05] SPEAKER_00: you know,
[45:06] SPEAKER_00: genes that are probably involved in DNA repair or DNA damage response.
[45:13] SPEAKER_00: Yeah.
[45:14] SPEAKER_01: Well, you know, this is a masterful book.
[45:17] SPEAKER_01: Congratulations, Venky.
[45:18] SPEAKER_01: I thoroughly enjoyed it.
[45:20] SPEAKER_01: It's very stimulating.
[45:21] SPEAKER_01: I know a lot of the people that will listen or read the transcript will be grabbed by it.
[45:28] SPEAKER_00: I think what I've tried to do is give the general reader a real understanding of
[45:32] SPEAKER_00: the biology of aging so that even a complete non-scientist
[45:37] SPEAKER_00: can get an understanding of the processes,
[45:39] SPEAKER_00: which in turn empowers them to take action,
[45:43] SPEAKER_00: to do the sort of things that will actually really help.
[45:47] SPEAKER_00: And also, it'll guard them against excessive hype.
[45:51] SPEAKER_00: you know, of which there's a lot in this business.
[45:54] SPEAKER_00: And so I think that was the goal, to try and present a balanced view of the field.
[46:00] SPEAKER_00: You know, I'm merely trying to be a realist.
[46:03] SPEAKER_00: I'm not being a pessimist about it,
[46:06] SPEAKER_00: but I also think this excessively optimistic hype is actually bad for the field and
[46:12] SPEAKER_00: bad for science and bad for the public as well,
[46:15] SPEAKER_00: so.
[46:16] SPEAKER_01: Well, and you actually were very kind.
[46:17] SPEAKER_01: You know,
[46:18] SPEAKER_01: in the chapter you have on crackpots and profits,
[46:21] SPEAKER_01: you could have been even tougher on some of these guys.
[46:24] SPEAKER_01: You were very, you know, relatively diplomatic and gentle, I thought.
[46:27] SPEAKER_01: I don't know.
[46:28] SPEAKER_01: Well, you know, two lawyers looked at it, so...
[46:33] SPEAKER_01: I believe it.
[46:35] SPEAKER_01: And now one thing apart from what we've been talking about because of your
[46:40] SPEAKER_01: extraordinary contribution on the structural delineation of the ribosome back in
[46:47] SPEAKER_01: the early 2000s and the 2009 Nobel Prize.
[46:51] SPEAKER_01: Now, the world of AI now with...
[46:56] SPEAKER_01: you know, AlphaFoam 3 and all these other large language models.
[47:02] SPEAKER_01: Would that have changed your efforts?
[47:05] SPEAKER_01: Would it have accelerated things, or is it not really?
[47:09] SPEAKER_01: Well,
[47:10] SPEAKER_00: it would have helped,
[47:11] SPEAKER_00: but you would still need the experimental data to solve something like the ribosome,
[47:15] SPEAKER_00: a large complex like the ribosome.
[47:18] SPEAKER_00: And the other thing that would really change
[47:24] SPEAKER_00: well,
[47:24] SPEAKER_00: has changed our world,
[47:26] SPEAKER_00: is the advent of cryo-electron microscopy,
[47:30] SPEAKER_00: of which Scripps is one of the leading places for it.
[47:36] SPEAKER_00: And that has really changed it so that now nobody would bother to crystallize a
[47:43] SPEAKER_00: ribosome and try to get an X-ray structure out of it.
[47:46] SPEAKER_00: You would just throw it into an EM grid,
[47:50] SPEAKER_00: collect your data and be off to the races.
[47:52] SPEAKER_00: So new ribosome structures are being solved, you know, all the time.
[47:56] SPEAKER_00: And a fraction, a tiny fraction of the time it took to solve the first one.
[48:01] SPEAKER_00: So.
[48:02] SPEAKER_01: Wow.
[48:02] SPEAKER_01: It's fascinating.
[48:04] SPEAKER_01: This has been a real joy for me, Venky, to discuss your book and your work.
[48:08] SPEAKER_01: And thanks so much for what you're doing to enlighten us and keep the balance, you know, and
[48:14] SPEAKER_01: It may not be as popular as the immortality merchants, but it's really important stuff.
[48:19] SPEAKER_00: Yeah,
[48:20] SPEAKER_00: no,
[48:20] SPEAKER_00: I just,
[48:20] SPEAKER_00: I hope,
[48:21] SPEAKER_00: actually,
[48:21] SPEAKER_00: you know,
[48:22] SPEAKER_00: I found that many of the public want to read about,
[48:27] SPEAKER_00: you know,
[48:28] SPEAKER_00: the biology of aging.
[48:29] SPEAKER_00: They're curious.
[48:30] SPEAKER_00: You know,
[48:31] SPEAKER_00: humans have been curious ever since we knew about mortality,
[48:34] SPEAKER_00: about why some species live so short lives and other species live such a long time
[48:39] SPEAKER_00: and why we actually have to age and die.
[48:42] SPEAKER_00: So there's natural curiosity.
[48:44] SPEAKER_00: And then it also empowers the public to,
[48:48] SPEAKER_00: once they understand the basis of aging,
[48:50] SPEAKER_00: to take action,
[48:52] SPEAKER_00: to live healthy lives and do that.
[48:55] SPEAKER_00: So it's an empowering book rather than a recipe book.
[48:59] SPEAKER_00: Yeah, no, I think that would be true.
[49:01] SPEAKER_00: I think a lot of the public actually does appreciate that.
[49:04] SPEAKER_00: And of course, scientists, you know, will like the sort of more balanced and
[49:12] SPEAKER_01: tone.
[49:13] SPEAKER_01: Well, you do it so well.
[49:15] SPEAKER_01: All throughout, you have metaphors to help people really understand the concepts.
[49:21] SPEAKER_01: I really applaud you for doing this.
[49:22] SPEAKER_01: In fact, a couple of people who we both know, Max and John Brockman, apparently, were
[49:29] SPEAKER_01: influential for you to get to do it.
[49:31] SPEAKER_01: So I think it's great that you took it on and all the power to you.
[49:36] SPEAKER_01: So thank you.
[49:37] SPEAKER_01: And I hope that we'll get a chance to visit further as we go forward.

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