====================================================== Strategies for Engineered Negligible Senescence (SENS) ======================================================
Dear Mr. Wieser, thank you very much for the nice introductory words. Ladies and Gentlemen, you can already tell it by the title: This evening´s subject is about two antipodes, the question of health within our chronological age, the second is aging per se - Is aging a normal process? Is aging a disease?
As a geriatrician, I would like to divide the talk into two parts. The first one is the question of this concept, whether aging is a disease, and here I will come back to Aubrey de Grey´s theories. I´m also going to show you these theories, for those who don´t know him personally or haven´t heard from him yet. Then, however, in the second part, I´m going to integrate it into a higher concept - why I´m somewhat sceptical about his theories, also from an everyday life´s point of view, from someone who accompanies the elderly through health and diseases.
As I said, I would like to start with the question: What does aging mean from a biogerontologist´s point of view? And Aubrey de Grey is a biogerontologist and you see him here. Mr. Aubrey de Grey was born 1963 in London. He is an Englishman. This picture is from an interview back in 2008. And now, I would say, he´s primarily active as a biogerontologist in Cambridge in England, but he also has a relatively strong connection to the United States, as you will see in what follows.
I´m presenting here his résumé a bit more broadly, because I believe it´s important for the understanding of his professional socialization, if you like. His was born, as I said, in 1963, he studied in Cambridge at the Trinity College in England. In fact, he was initially a bioinformatician, then he worked as bioinformatician in laboratories in Cambridge, at first in the field of genetics in mathematical modelling. He also received his PhD for that in Cambridge in 1990. Nowadays he´s called a theoretical biogerontologist; I think, these two terms, "theoretical" and "biogerontologist" will be later of certain importance, when we go into his theories more closely.
He is married to Adelaide Carpenter, she´s a molecular biologist, and I have it listed here simply because it´s always important for every research scientist that he´s socially integrated very well, be it with a man or a woman or differently - but this has affected him very clearly. Because at first he was, as I said, a bioinformatician and his wife, this molecular biologist, who he got acquainted with, she introduced him to this field of genetics, to the relatively fundamental questions of the human condition or the biology, and actually determined his further life.
Additionally I´ve listed here two, three more things, he has, above all -- he became particularly known through a book where is is co-editor, in 2007, entitled "Ending Aging" - thus "Aging ends somewhere along the way", but he means, not by death - this I can already tell you - but aging per se is an obsolescent model, if you like. He´s editor-in-chief of a journal, it´s listed, thus it´s a good journal: "Rejuvenation Research". And he also has a foundation that I will show you, and there a price is awarded, that´s the methuselah mouse project. Via this project, prices are awarded time after time.
There are of course - maybe let it be introduced already here - nowadays models in the research field, not only in Drosophila melanogaster (fruit flies) or in C. elegans, the little roundworm, but also in higher species, so-called knockout strains, where you can study aging, and there is for example the knockout mouse where you can really say, how can we better research aging processes. Well, he´s known for the so-called SENS. And SENS means Strategies for Engineered Negligible Senescence. And what does this theory mean?
It´s basically a theory that negates aging as a process and portrays negated aging as a predetermined biological factor. About human aging it must be said: To him, human aging is unfavourable biochemical processes, that can be - get ready for it - stopped or reversed by targeted interference. So, maybe at this point, I´m going to say the word "anti-aging" once again. Anti-aging, as we can read today in the media, is not actually the question of stopping per se anymore, but in fact a sort of reversal, be it by hormonal things or things you can do using a knife or Botox or whatever. Conceptually, SENS is based on seven working points which are propagated by him.
There are basically seven dogmas which support this concept of the Strategies of Engineered Negligible Senescence, and I have listed them here. I will read them aloud for you, and after that, I´m going to give you some little examples for each one of them, at least for the most important ones, the first four. I will summarize the last three in one slide. The first one is nuclear mutations of the DNA/epimutations. Epimutations - maybe here very briefly - We had been thinking for a long time, when the possibility arised, this humane genome with the Human Genome Project, that we would basically know the entire genome of the human, and then would not only be able to understand, but also be able to interfere in a positive way.
Unfortunately, this has not exactly come true, although we now know it - If we come back to aging, there are far more than 100 so-called "aging genes", it´s actually not the case that there is one gene mediating our aging, be it a normal process or a disease, but it is a very complex interaction und therefore I believe, this idea coming with the entire wind of the Human Genome Project, namely that we can treat the scourges of mankind with pinpointed therapy strategies very soon, somewhat took a backseat.
Epimutations mean that it´s not only the genetic setting each single human has, but, if you like, which genes are switched on when and in which constellation. As an extreme example I would like to tell you, nowadays we already know that for a foetus in the uterus, depending on the the metabolic situation of the mother, chances are higher after birth to develop adult-onset diabetes in older age. And that depends on the combination of the genetic setting which we get from our parents on the one hand, but also on the influences of the environment leading to what shapes us then.
By the way, since we´re already talking about genes: To which degree do genes determine our lifespan? We assume, to around 25%. That means, 75% is not genetically determined and is theoretically modulatable, and among those is of course a part of what we try to achieve as medics. When we are now talking about these mutations in de Grey´s SENS, then we could basically say: Very much is focussed on these 25% of course, and we negate a bit, that there are still other 75 percents. Mitochondrial mutations, then intracellular junk, this we may summarize together with point 4, that we also accumulate bio junk during life which can be situated in the cell itself but it can also be outside around the cell.
[10:00] Protein-crosslinking: to this I say something. The replacement of lost tissues, so how is our possibility on lost to replace. There will also be the question: Is loss always bad? This is also important, we must loss certain tings and then the superfluous cells.
As already said I want now especially for those of you few that are not professionally engaged in the biomedical area, I am taking out some points and hope to present something understandable to you.
First of all regarding the mutations of the nuclear DNA and epimutations, there the de Grey says through environmental toxids like viruses and radiation and errors during the cell division it comes to alteration within the nucleus. Within the nucleus is the genetic material that is partitioned at each cell division. As you known that in every cell of us the complete genome contained is. So that a cell knows that it has to become a skin cell or it has to become a heart-muscle cell depends on turning on of these genes: what will be activated and what will actually be kept low.
Mutation in contrast have no significant influence on the lifespan, because they are quantitative to rare (there I see have two typos, this is totally bad). Here comes the bioinformatician, because he says actually this mutations are within a cell division quantitative relative less and because of this they will not play an eminent role overall. This seems to be reductionism, I have to say, because it can be that even a very tiny alteration of a switch changes in such a way that, what at actually comes as last point, also can be a cause for cancer, but it can also be for other things. Cancer is not only scourge of the affected one, but is also something that one can see relatively good. However, it can also be that we accumulate smaller alterations which per se as single alterations are not becoming apparent but in the accumulation of many different also can have influence.
The mitochondrial mutations, to this it is to say that the mitochondria which are organelles that are within a cell, so they constitute are part of them and within these organelles is the so called respiratory chain of the cells. And this mitochondria, that is highly interesting also of course for the questions regarding the cell division or what comes from one partner or the other, have the feature that they have their own DNA. So they do not have the DNA which is in all the cells, they have their own.
These mitochondria are as said there that they with oxygen and food components actually are own energy storage. One could that say tat they are the power station in every cell, this are mitochondria and they produce this ATP, this Adenosintriphosphate, which then will be disintegrated into ATP-diphosphate and this can than again be reverted. Good, important is that this mitochondrial DNA in contrast to the other DNA has relatively less DNA-repair mechanisms. So if it comes there to damages, so you can say, that over time, this cell may have to less energy and this leads that of course the cell "darpt" or even dies.
Here comes an important concept in the third point, namely one of the big concepts: can aging be modulated? What can we do to extend the lifespan, is the caloric restriction. This we know since the thirties, at firs in the field of flies, then there is also data of rodents and there are also data of primates. So if you reduce you caloric intake you can increase your lifespan. This is I have t admit around 30% of your caloric intake you have to reduce, which is with a middle Franconian diet not necessarily easy to accomplish. And than I have to say there are also relatively controversial data in humans. One of the main question on humans is of course than also when one has to start and to this I will show in than in the second part more to this medical practical part, because this is not so easy.
The intracellular junk: the body posses about a further organelle which is called the lysosome and they have a own facility for the degradation of of not anymore required waste material. I have called this here: Recycling. So one could say that there is a green branch in us which tries to bring back waste materials to the organisms in a meaningful way. This we have to know, as it is a phylogenetic evolutionary meaningful because it was not a long tie that we lived in an environment where we had sufficient food available. So an optimization in the sens of the selection in Darwin's concept: how can we as species reproduce optimaly with less resources?
For incomplete recycling it results into the accumulation of e.g. lipofuscin. Lipofuscin is a compound which de Grey often mentions in his research and he means with it to explain causallu diseases, like Arteriosclerosis as aftereffect of for instance heart infarct, stroke, neurodegenerative disease, this would be for instance the Alzheimer's dementia or Parkinson's disease or also macular degeneration which I have here listed which s oe of the most common forms of blindness of aging humans. As therapy he sees here especially gene-technological transfers so tat one can manipulate specific genes or introduce gene parts into the human genome, which could restore this dismounting processes, respectively, the possibility to improve the constricted or restricted degradation processes, as this could then be achieved with this.
The extracellular junk: so number four of the seven different items in SENS is the Accumulation of potential detrimentally substances. Here he mentions the amyloid placks of the Alzheimer's disease. I will tell you briefly what this is. Die amyloid placks: amyloid is a protein which is folded differently that is a atypical amyloid, the beta 42 amyloid of the Alzheimer's disease and in patients with Alzheimer's disease there one finds this in the brain and one assumes that they play a central role in the genesis of the Alzheimer's disease. Here he sees again a therapeutic approach, namely the vaccination. At this example you can see that the theory, which I do not want to assess negatively or positively, is not just invented from Mr de Grey. Everything what I told you is also in the used in the whole biogerontological research. For example the vaccination is in the moment in the tour. There is now a second wave. There was a first, which was unfortunately not so successful as it come to "Meridian skin" inflammation. So this is based on that one wants to prevent the build up of that atypical junk, in this case amyloid. Eventually here if I can come in to the critic: We know today about the so called nun studies. The nun study is an american work. These were nun which have said you can follow our life and see who of us gets dementia and when we die you are allowed to conduct an autopsy. This is a relatively good cohort, if you you like to call it this, because nuns have a relatively coherent vita which is also good comparable. Now I can tell you that by nuns which had a Alzheimer's disease, severe dementia one had found those that had no Amyloid and there were also those that were full of Amyloid but did not had Dementia. Also here it will not be like that there is a simple single cause.
The last three I have summarized for you, just to show you. Protein-crosslinking: There is a substance which could lead to the reduction of glycosylation of proteins. There are such glycosilation and glycation products which one today determines. One thinks that one can for example determine them in the skin and with this deduct how the aging process of someone is.
Replacement of lost tissues, that is of course the idea of the stem cell therapy. I told you before that we have the complete genetic material in every of our cells. [20:00]
[40:55] And now I want to show you that de Grey’s theory about caloric restriction can’t be quite right. As far as caloric restriction is concerned, I want to show you this: It’s also about the question of health span vs. life span – how long are we living chronologically per se, and for how much of that are we going to be in reasonably good shape?
For those of you who don’t know what the BMI is – that’s the weight in kilograms, if you jump on the scales tonight, and then divide it by your height in meters squared [...]. 41:35 And then you can calculate. If you’re 21-25 then you’re normal weight, 25-30 overweight and >30 you’re obese. So if you did the de Grey’an theory of calorie restriction, then you would have a BMI of about 19 or 20, so that’s slight underweight, and then you wouldn’t have to age anymore. That’s not correct, at least if you get to advanced ages -- here you see a study from two nursing homes done by Rebecca Kaiser. That’s her doctoral thesis. So she took 200 people and she looked for one year. And after one year those with the lowest BMI, so that’s those that would have done calorie restriction in the widest sense (or would have burned more calories), 25% were deceased, whereas the ones with BMI >35, which is what I like to call a decent Middle-Frankian statue, have all survived. So as you can see here, it’s never that easy. 40:55 And now I want to show you that de Grey’s theory about caloric restriction can’t be quite right. As far as caloric restriction is concerned, I want to show you this: It’s also about the question of health span vs. life span – how long are we living chronologically per se, and for how much of that are we going to be in reasonably good shape?
For those of you who don’t know what the BMI is – that’s the weight in kilograms, if you jump on the scales tonight, and then divide it by your height in meters squared [...]. 41:35 And then you can calculate. If you’re 21-25 then you’re normal weight, 25-30 overweight and >30 you’re obese. So if you did the de Grey’an theory of calorie restriction, then you would have a BMI of about 19 or 20, so that’s slight underweight, and then you wouldn’t have to age anymore. That’s not correct, at least if you get to advanced ages -- here you see a study from two nursing homes done by Rebecca Kaiser. That’s her doctoral thesis. So she took 200 people and she looked for one year. And after one year those with the lowest BMI, so that’s those that would have done calorie restriction in the widest sense (or would have burned more calories), 25% were deceased, whereas the ones with BMI >35, which is what I like to call a decent Middle-Frankian statue, have all survived. So as you can see here, it’s never that easy.
And then we had the question earlier, when would you have to start CR?
[43:00] And finally the question was health span vs. life span. We can study this with functional testing. But here you see mortality again. And now we’re going one slide back – we said BMI 21-25 for young people, is where you should be at. Now we can ask, is this really the case for old people that the BMI for 21-25, that would be from here to here, do they live the longest? No, they don’t live longest. Older people live longest when they have a BMI of 27, when they have some reserves, if you will. So here too, it seems that the “unidirectional” thesis of CR isn’t right.
And now we want to ask about health span. So that’s not just about survival, but how are we doing functionally? There you see that [the optimum] does get shifted down a bit, to about 24. Anyway, we’re still in the range that you would see as the upper end of normal in a young adult, and we’re certainly far above where you would be if you did the CR diet for a few decades.
This leads me to the question where would I now place Dr. de Grey and his theory? At least in that particular health-system that we live under, in a society that’s aging, that we’re in, and for which we should be grateful (I think) – it’s really nice after all that we have a long average life span these days, which allow us to get older and older.
I have summarized that here under the term “disease burden”. That’s a term de Grey uses too, and he wants to get rid of it. In fact he wants to start really early using something like “reparative medicine” on it. Unfortunately today disease is largely perceived as a burden. Even the people in medical ethics would agree with that -- … uh, many of whom are of course in the audience today. And one of the questions for you guys is about allocation of resources, about justice in the end – should we prevent aging simply because, because aging per se poses a financial burden.
Today’s medicine is totally focused on treating deficiencies once they exist. That’s what we do in internal medicine, and that’s where de Grey would be too. There’s stuff like accumulation of waste products, inside cells, outside cells. These are deficiencies, and we’re trying to remedy them. That has implications for the individual, but also for society.
And then there’s the other philosophy, that’s geriatrics, if only we could accept! [his emphasis – but what? He’s not finishing the sentence]. And what we do accept is diametrically opposed to Dr. de Grey, we accept that aging exists and that it carries functional deficiencies, and that our task is less to reverse aging, but rather accept it, and then how can we optimally intervene to improve the health span, and it’s subjective what the health span should be. And here too that has implications on society as well.
And here I have listed a few examples for you. We have an EF, ejection fraction here. If you’ve ever had an ultrasound of your heart, then how much are you pushing out? You have a heart attack, it’s reduced, and then we give you a beta-blocker and then it’s coming back up. Peak Flow – pff – how quickly can I push breath? Clearance – how is my kidney function? MMSE is a test for your memory function. It’s all just about see if if we’re having functional deficiencies.
I think in a resource-oriented medical system, one of the concepts of Dr. de Grey would need to be implemented. That means, when you find something [a deficiency], then that would have to be taken into account to improve how you’re allocating resources. [No he really isn’t making sense].
And in this case it’s the ADL, like I showed you earlier, the Activities of Daily Life, can somebody take a bath, can they get up, can they eat? And here’s the instrumental activities of daily life, can they pick up the phone, can the go shopping? And Qol, quality of life, and this one is really really important for somebody’s subjective concept of health span, far more important than genetics. And then there’s care giver burden, how does it work in an aging society, when you have aging couples living together, and one can look out and care for the other (or has to care – whatever)?
So now I want to summarize. For de Grey, aging is a disease. For the geriatrician, it’s a normal process. They often say “normal aging”, or “successful aging”. De Grey’s concept of SENS is essentially an extreme variant of the concept of anti-aging. He says yes, there is such a thing as aging, but we’re reversing it. That is optically, superficially, but also systemically. Anyway, he says, aging per se is pathological. For the medical doctor, aging means diversity. And with that, it creates special challenges for medicine. Geriatricians work in multidisciplinary teams. We need the social worker, need the physical therapist standing next to the nurse and the doctor, because we don’t think it’s unidirectional, it’s more than just a biochemical process. Diversity in medicine often goes along with co-morbidities and multiple complications. And that’s one of the places where de Grey is lacking – How do I deal with multiple parallel changes happening? For example there could be one of his seven theories happening in one organ system, but a different one in an other organ system. How does he mix things together, a SENS-cocktail? So far I haven’t seen such a suggestion from him. And then there’s stuff beyond physiology – aging has a physio-psycho-sociological, if you will, a social basis.
The seven strands propagated by de Grey through the SENS concept are not primarily made up by him, but rather they unite diverse aspects of research pre-existing biogerontological research. That is in my view not negative. But it’s also not like he’d come up with the gerontological equivalent of general relativity. That’s not the case. I think what he is good at bringing disparate strands together.
My criticism of SENS is largely that aging is getting viewed as too unidirectional and reductionistic, and that hopes are raised for eternal life that are not backed by current science. Aging, and now that’s a personal view, is that according to the peridicity of all life, not just humans, is not really plannable, and is evolutionarily meaningful. I thinkit would not be good if aging was entirely plannable. We probably would not have as many different colorful flowers [51:10].