Strategies for Engineered Negligible Senescence

Created on May 20, 2013, 1:11 p.m. by Hevok & updated by Hevok on May 26, 2013, 7:06 p.m. nicolai on May 26, 2013, 7:06 p.m. NilsAHizukuri on May 26, 2013, 7:06 p.m. Dennis on May 26, 2013, 7:06 p.m.

Strategies for Engineered Negligible Senescence (SENS)

Aubrey de Grey

  • Aubrey David Nicolas Jasper de Grey, 20. April 1963
  • studied in Cambridge, U.K.
  • Bioinformatician, theoretical Biogerontology
    • PhD 2000 in Cambridge
  • Married with Adelaide Carpenter (Geneticist)
  • Book "Ending Aging" (2007, Co-Editor)
  • Editor in chief "Rejuvenation Research"
  • Founder Methuselah-Mouse Project

Strategies for Engineered Negligible Senescence

  • Negation of aging as prescribed unit
  • human aging = adverse biochemical processes, which can be stopped or reversed through targeted interventions
  • SENS as concept is based on seven from him propagated attack points

SENS

  • Mutation of Nuclear-DNA/Epimutations
    • Environmental toxins, viruses, radiation, and errors during cell division result into lateration of the nucleus
    • Mutations have however no considerably influence on the lifespan, because their amount is quantitative to rare (here shows the bioinformatician)
    • however, the can be causes of cancer
  • Mitochondrial Mutations
    • in mitochondria energy (ATP) is produced out of food and oxygen
    • mitochondria have own DNA, which have less own repair mechanism
    • caloric restriction extends lifespan of mitochondria via reduction of oxidative stress
  • Intracellular Junk
    • body possess, with lysosomes, own facility for the degradation of not any more required materials ("recycling")
    • incomplete "recycling" leads to the accumulation of lipufuscin, which de Grey attributes to be (concurrently) causative for diseases like Arteriosclerosis, neurodegeneration and maculardegeneration
    • as theorapy he sses the gene-technological transfer of certain enzymes, which degrade lipofuscin
  • Extracellular Junk
    • during aging there is an accumulation of potential dangerous by-products
    • he mentions as example the Amyloid-Plaques of the Alzeihmer's Dementia
    • vaccination against beta-Amyloid as therapy here
  • Protein-crosslinking
    • Alagebrium for the reduction of glycation of proteins
  • Replacement of lost tissue
    • Stem cell therapy (e.g. reactivation of thymus cells)
  • Superfluous cells
    • immune system, fat tissue

SENS Research Foundation (SRF)

  • SRF leads the way in developing, promoting, and ensuring widespread access to treatments that repair the damage underlying the diseases of aging
  • the challenge is not small. We are proposing nothing less than a transformation of medicine; away from the increasingly burdensome and unprofitable chase to treat pathologicies, and towards a functional and, for society as a whole, more cost-effective approach to maintaining and extending individual health
  • [http://www.sens.org]
  • Aubrey de Grey has some kind of "Fan-club", which support him via his charity
  • His theories and work however are criticized by the "scientific community"
  • Two comments to this:
    • MIT Technology Review
      • Citations
        • ... "so wrong that it is unworthy of learned deabte"
        • "the proponents of SENS have not made a compelling case for SENS"
        • is defeating aging only a dream?" Technology Review. August 23, 2012
    • EMBO reports
      • An article about SENS published in the viewpoint section of EMBO Reports by 28 scientists concluded that none of Grey's therapies "has ever been shown to extend the lifespan of any organism, let alone humans".
      • EMBO Reports 6 (11): 1006-1008. doi:10.1038/sj.embor.7400555
      • The 24-member Research Advisory Board of his own SENS Foundation have singed an endorsement of the plausibility of the SENS approach.
  • it remains unclear to which extend the observed alterations are really primary causes of the aging process, representing secondary results or even developed independently from pathological process - and aging is understood by de Grey as a disease
  • as bioinformatician de Grey negates that chronological and biological aging are equivalent

  • (Denis Diderot - 1713-1784)

    "Who wants to think endless, has to come back to a flexible thinking, rather than a causality reduced thinking"


Average Life Expectancy for Women


Jeanne er les savants


"Normal Aging" - 30 versus 80 Years

Function Reduction (%)
cardiac output 30
vital capacity 50
renal perfusion 50
Maximal O2-Absorption 70

Shock NW et al. Baltimore Longitutinal Study, NIH, no 84ff


Reduction in Functional Reserve: Survival of Cardiac Insufficiency

  • Croft JB et al. Arch Intern med 1999;159:505-510

Geriatric Medicine

[UEMS, accpeted in Malta, May 3, 2008]

Geriatric Medicine is a specialty of medicine concerned with physical, mental, functional and social conditions occurring in the acute care, chronic disease rehabilitation, prevention, social and end of life situations in older patients.

This group of patients are considered to have a high degree of frailty and active multiple pathology, requiring a holistic approach. Diseases may present differently in old age, are often very difficult to diagnose, the response to treatment is often delayed and there is frequently a need for social support.

Geriatric medicine therefore exceeds organ orientated medicine offering additional therapy in a multidisciplinary team setting, the main aim of which is to optimize the functional status of the older person and improve the quality of life an autonomy.

Geriatric medicine is not specifically age defined but will deal with the typical morbidity found in older patients. Most patients will be over 65 years of age but the problems best dealt with by the specialty of geriatric medicine become much more common in the 80+ age group.


Geriatrics

  • Frailty is a clinical syndrome characterized through at least three of the following criteria:
    • Weight loss (>5 kg in 12/12)
    • perceived exhaustion
    • weakness (hand grip)
    • slow moving
    • low physical activity

=> Sarcopenie!

Fried LP et al. J Gerontol A Biol Scie Med Sci 2001;56:M146-M156


The Two main Reasons of the Geriatric Medicine

Patient

  • Nosology
    • Diagnosis
      • Causal Therapy
      • Spezialists
      • Technology
  • Problem
    • Disability
      • Functional analysis
      • demand for treatment
      • Assessment
    • Functional results count

Adapted from HB Stähelin


Dimensions of Aging and Frailty

  • Physical Dimension
  • Psychological Dimension
  • Social Dimension

Prevention     Genetic factors, atheroscleroisis, chronic inflammation
    |                  low level of excercise, malnutrition
    |                      |                    |
    |                      v                    v
    |               Clinical disease  <- Primary fraility
    |                      |                    |
    V                      v                    V
Pallation             Secondary frailty -> Disability

Strandberg and Pitkälä. Lancet 2007;369:1328-1329


"Sarconenic Obesity"

computer tomography thigh

Zamboni M et a.. Nutr Met Cardiovasc Dis 2008;18:388-395


Clinical Relevance of Frailty

Fried et al. J Gerontol Med Sci 2001;56A:M145-M156


Frailty at Home Living

(general practitioner)

  • >56 J N=100
  • N=14 Frail
  • N=52 Prefrail
  • N=34 Not frail

Drey M et al. Z Geront Ger 2011;44:48-54


Prevalence of Frailty-Criteria of infirm elderly home-living People

  • Gait speed
  • Exhaustion
  • Hand grip strength
  • Activity
  • Weight loss

Drey M et al. Z Geront Ger 2011;44:48-54


BMI

BMI = body mass index (kg/m2)

standard value for adults (not aged humans)

  • BMI 21-25 normal
  • BMI 25-30 overweight
  • BMI > 30 obesity

BMI und Mortality in Nursing Home ("Reverse Epidemiology")

Kaiser R et al. JAMDA 2010;11:428-435


BMI and Mortality

Al Snith S et al. Arch Int Med 2007;167:774-780


"Disease Burden"

  • Deficiency-orientated (Organ medicine)
  • Resource-Oriented (Geriatrics)
    • Individual Society
    • ADL
    • IADL
    • Qol (SF-36)
    • Care-giver burden

THM-1

  • Aging is for de Grey a disease, for the geriatrician it is a normal process
  • De Grey and his concept of "Strategies for Engineered Negligible Senescence" (SENS) is quasi a extreme variant of "Anti-Aging"
  • Aging for the physician means diversity and with this it is a special challenge for the medicine (Geriatric)
  • Diversity is medical often along with multimorbidity and Polymedication
  • aging has a physio-psycho-sociological basic

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. H 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 to be 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 that we nowadays 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 focused 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 ones to replace. There will also be the question: Is loss always bad? This is also important, we must lose certain things and then the superfluous cells.

As already said, I now want, especially for those of you few that are not professionally engaged in the biomedical area, to point out some points and hope to present something understandable to you.

First of all regarding the mutations of the nuclear DNA and epimutations, there de Grey says that through environmental toxins like viruses,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 know, the complete genome is contained in every cell of us. So, 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 too rare (there I see have two typos, this is totally bad). Here the bioinformatician joins the game, because he actually says that these mutations within a cell division are relatively rare and that´s why they will not play an eminent role overall. This seems to be reductionism, I have to say, because it is possible that even a very tiny alteration of a switch changes in such a way that, what 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 well. However, it can also be that we accumulate smaller alterations which per se as single alterations are not becoming apparant but in the accumulation of many different alterations, influences are possible.

The mitochondrial mutations: The mitochondria are organelles within a cell, so they constitute a part of them. Within these organelles, you find the so called respiratory chain of the cells. And these 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 that 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 plaques of the Alzheimer's disease. I will tell you briefly what this is. The amyloid plaques: 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]


Replacement of lost tissue. This, of course, would be the idea of stem cell therapy. I told you before that we have the complete genetic material in every cell and of course it would be theoretically possible that one takes such a stem cell in which there is the complete genetic material and somehow told the cell in a nice way that, starting tomorrow, your destination is to become a hair cell (this, for example, has not worked so well for me as you can see) and then it would do only this. This is this stem cell therapy. Of course, bioethically a big question. Where do these cells come from? There are quite different ones. There are embryonic stem cells. but there are also those stem cells that we have ourselves and for those we would tell them “you are no longer a skin cell, you go back to your primordial state and, starting tomorrow, you will create red blood cells. This is the idea of stem cell therapy. [20:47]

Here I listed reactivation of thymus cells [2nd bullet point on the slide]. The thymus is located here [demonstrating]. The thymus is essential for the immune system. In a child it is huge and then it becomes very small. But the thymus would theoretically have the potential to reactivate cells that lie here. Finally, superfluous cells [3rd bullet point on the slide], that is his theory, I kind of like this somehow , because this is a really innovative approach. He says in principle our immune system has to constantly differentiate between foreign and self. The “foreign” it has to fend off, otherwise we would soon be dead, we’d have infections. The “self” has to be accepted. You belong to me, hence I do not fight you. You know this, it’s a big problem: all allergies or autoimmune diseases are caused by the body suddenly no longer realizing seeing this belongs to me. So he says there can be an imbalance so that the cells at old age may no longer know should we be more on the fending-off side or more protective. [21:52]

The fat tissue is also interesting. The fat tissue is anything but a simple energy storage, for some maybe too much [joke], but it is also one of the most active organs regarding hormonal control. Well, this may have been, for some, quite medicinal... or biological ... but now I come back to the credo of mister de Grey. And then you will see, mister de Grey does not lack self-confidence. He has a SENS research foundation and there it says on this webpage, it is listed below, “SRF leads the way in developing, promoting, and ensuring widespread access to treatments that repair the damage underlying the diseases of aging.” That would still be ok. We do this as well. We also try to repair diseases or to alleviate the condition. “The challenge is not small. We are proposing nothing less than a transformation of medicine;” So he says we are transforming medicine now “Away from the increasingly burdensome and unprofitable chase to treat pathologies, and towards a functional and, for society as a whole, more cost-effective approach to maintaining and extending individual health”

So, this is quite an august goal, I’d say. And of course now the question is “Can he action it?”, now or at least as a vision for the future. He has kind of a Fandom that also supports him via a foundation, as I said this is the SENS research foundation. However, his theories and work are regarded quite skeptical by the scientific community and this, I would like to demonstrate you with 2 commentaries (...) because you may think maybe Sieber is so critical that is for one [23:52] the MIT Technology Review (the... ehemm... the [searching for the correct term] Massachussets Institute for Technology) at the East Coast in Boston, and there it says “so wrong it is unworthy of learned debate”. That, one has to say, is a relatively harsh critique. I think one can always debate in science, you don’t have to accept everything. [PB: this, I think, is a huge misunderstanding: this sentence was part of the challenge that MIT Tech Review proposed and it was followed by a question mark. Here it is portrayed as statement!!]

“the proponents of SENS have not made a compelling case for SENS”. So they question the theories behind the 7 points, that they haven’t answered any of them. This is in this article “Is defeating aging only a dream” last year. The EMBO too, is for molecular science one of the most important journals, very high ranking, and there it says “an article about SENS published in the viewpoint section of EMBO reports by 28 scientists” and now I also read the conclusion “has ever been shown to extend the lifespan of any organism, let alone humans” So they also question what he is referring to in his 7 theses, also his 24 member research advisory board, they say this is all quite sound and in principle proven but as you can see, this is questioned critically. [25:20]

For me, how I see it, in contrast to (just before) the scientific community, for me it remains unclear how much the observed changes are really primary cause for aging processes (so these points, e.g. the mitochondrial DNA mutations etc.), are secondary events or may even develop independently from disease – and de Grey understands aging as a disease. (I think this is a very important point: aging, for de Grey, is a disease and... hence, preventable, approachable by prevention. This, in my opinion, is not solved: what comes first, what comes, what is a reaction to it and I also think that as a bioinformatician de Grey negates that the chronological and biological age cannot be put on a same level. A 70-year old man is chronologically 70 years old but you have a whole spectrum of people. Some are quite well, others are not. And here I think that as a concept to follow research ideas or research lines, the 7 points he makes may make sense but then to conclude that you could say practically that this line that you have as a probability question as a bioinformatician that this directly translates to questions of health span or aging per se, I think, is a bit bold to say the least. [Even as a native speaker, this part is not clear to me. He just seems to say to his audience: Aubrey has a point but I do not completely agree...][27:00]

Therefore, I would like to briefly cite Diderot “He who wishes to think eternity (and that’s a little bit what it is about with him) , must resort to flexible thinking that is not reduced to causality” and one misses a bit this flexibility in the credo of de Grey, if I may say so. But one has also to agree with him in certain aspects. This is a very important figure here [showing the slide with the life expectancy of women, Science 2002] from Oeppen and Vaupel, very important gerontologists, it shows the average life expectancy of women from 1840 till about now, and you see that this is an absolutely straight line. So, what one could say, if there really were aging in the sense of health reduction that then would finally lead to reduction in life expectancy, then one would expect here [pointing to the upper end of the graph] a so-called rectangularization of the line and, this we do not see at the moment. And, of course, we do not know how exactly this will develop. This, one has to say. So, maybe we have already started and intervened to make sure this stays a straight line. [28:18]

As I have explained to you, I would like (now that I have this concept aging is disease, aging is approachable by prevention, can be circumvented if one applies these 7 points in a construct or in a combination. Of course, I have a bit a different view. And I’d like to start with this picture [showing Jeanne Calment] of Jeanne Calment. Jeanne Calment is the woman that livest the longest, a bit less than 123 years. Here she is 118 years old. She is being visited by 3 gerontologists that collect old people so not butterflies but old people. Bernard Jeune for example, is a friend of mine from Ostende, is only collecting so-called ultra-centenaires, so people around 110 because there are too many 100 year-olds now. And they, of course, examine what makes one live so long. They also take blood for telomeres. Telomeres are also something that shows up in the concept of de Grey and one can say that, if you see at Jeanne Calment here. She has had a content life. Her hearing was very bad. So, she DID age. She was almost blind. By the way, she stopped smoking at 100. Not to reduce the intra- or extracellular debris but because she had severe rheuma and she couldn’t light her own cigarette and it was embarrassing to her that she needs someone. A late preventive approach with Jeanne Calment (joke).


Why I have trouble with the concepts of de Grey is also, because for me, aging means diversity. And here we have listed: urea and creatinine, these are 2 compounds that you can measure in the bloodstream, many of you might have seen it at a medical checkup, this is used to test the kidney function.

You see here on the graphic, on the Y-axis (ordinate) and if you take here 90 years, then move to the side, here you see the normal values, and you see, many people this age have very normal values. So you could say, that is de Grey (note by the translator: not sure what he means by that. he is a bit confused, sometimes), aging isn't there, it doesn't have to be. But you can see, the graphic looks like a bouquet of flowers, and that means you have many more outliers. So the idea, that, when we age, we constitute a homogeneous mass, like a C. elegans worm who lives 21 days and then he dies, and then you do a genetic manipulation, and then he lives 23 days, then he gained 10% life expectancy, but luckily, us humans, are not structured in such a simple manner, I believe. You see also here, older data from the Baltimore longitudinal study, when you look at 30 and 80 year old people, there is indeed something like "normal aging", the cardiac output - how much we can pump out of the heart per minute - this is reduced by approx. 30%. The vital capacity - how much we can breathe out by force - furthermore the kidney blood circulation, and so on, there are various factors, that are reduced during aging. They are modifiable through sportive activities and healthy nutrition, but they are there. And a 90 year old Olympic champion from 50 years ago, even if he keeps running his whole life, he won't be as swift as when he was young. So there is something, that is changing. That is in relation to the decline of the "functional reserve". This is a construct, no only of biochemical processes, but of the interaction of various organs, various cell-types, and this is depicted on the following graphic: [32:27] Here we see the survival of humans with cardiac insufficiency, and they all have the same amount of insufficiency, but you see that those with 67 to 74 years die less often, over the years, than the 85+ year olds. And because these people have the same cardiac insufficiency, it has to be something else. Be it biochemical, like Dr. de Grey is saying, or on a level of the entire organism, we can not merely focus on only 1 aspect, because we are not consisting of merely 1 organ.

[33:08] Here you see the definition of the geriatric medicine. In red, you see the physical things, but there are psychological, functional, and social things, and that brings me to my next point. I think it is too reductionistic, if you recognize aging factors only through physical and biological factors. And older people are - as you know - more frail, and often have the need for social support, in order to have a good healthspan. A long healthspan is not only biologically determined, it is part of a bigger picture, in which a human revolves. So the geriatric medicine exceeds the mere organic medicine. But it might be the case, that Dr. de Grey has not many people in his circles, who come from the realm of geriatric medicine, who can fully understand this, but rather people who think it might be something small, or rather a mono-causal source of an illness. Many people think of mono-causal sources of illness for example with high blood pressure, or with cardiac arrest, and so on, but that is not the truth. That leads us to think, when we look at the health span of an old person, that he is suffering from an Alzheimer's type of dementia, according to the hypothesis of Dr. de Grey. Dr. de Grey says, that in order to fight it, we need a technology. We need to be able to measure the Amyloid protein, then we send the patient to an expert and have a causal therapy. But we know, from the Alzheimer's type dementia, that there is no causal therapy, because it isn't caused mono-causally. That is, once again, probably why the SENS approach is interesting as a construct, to define research lines, but it's practical implementation, into pin-pointed therapies, in order to maximize health span is, in my opinion, not reasonable.

And further more, with older people, it is independent of whether or not there is a mono-causal or poly-causal relation, in whether or not a person is in danger of being handicapped in his functionality. For this case we use special instruments to test the entire health state of an older person.

So when we look at aging and frailty, there is a physical dimension [36:00], that is where Dr. de Grey says: If we intervene, we can not avoid aging, but we can have a longer healthspan. But there is also the psychological dimension, just think of the isolation or depression of an older person, that very essentially plays into the healthspan - into the perceived healthspan. And there is a social dimension. There is no use in doing e.g. stem cell therapy, while we have poverty of the old people, at the same time. Then we wouldn't help this person's healthspan wholistically.

When we get back to the topic of frailty prevention, that Dr. de Grey is talking about - a very important topic - there are the genetical factors, but they are only a part. [37:08] There is also the inflammation, which he depicts with the theory of thymus within the immune system, but probably much more important, in the next level, is the question of movement and nutrition. And if then, there is a clinical disease, there is the danger of the older person coming into a vicious cycle. And if you take the question of healthspan, then the definition of "frailty" is a good one: You can measure it, here are 5 questions that you have to ask [37:44], 5 questions: weight loss, perceived fatigue, weakness (touch of hand), slow walking style, low physical activity) and those questions are really related to functionality, and not with a SINGLE biochemical, rather uni-directional approach. The "strength" factor is related to sarcopenia [38:08], but there are indeed relations to what Dr. de Grey says. Here you see a normal tigh of a young person, the grey area depicts the muscle tissue, and on the right side you see an older persons tigh, he has first of all much less muscle tissue, because most of the outer tissue is fat. And the white areas within the muscles on this graphic also depict fat tissue.

So yes, we have changes in aging people, and if we have an obese person, there are various changes happening, and it will be hard to lengthen healthspan with isolated therapeutic approaches.

That the frailty - the aging - is a normal process, and that it is important, you see here (videotime 39:09) if you answer 2 of the questions positively, you will die earlier statistically. So this is indeed of clinical relevance.

And to show, that this is real life, and not only research, [39:14], but everyday life, we have here a dissertation that has been made in the Franconian area (germany). A medical practitioner took over 150 people 65+ years, and you see here, a third is not frail, half is prefrail, and 14 are frail.

So now you could say, yes, if all dreams come true, these issues will be settled in 20 years time, according to de Grey, of whom you can find many video sequences on the internet. And then we wouldn't have any of the frailty anymore, which the above study depicts.

And then we would not have a medical practitioner in Germany who makes his dissertation about frailty, because we wouldn't have frail people. And now you see why this is important, [40:25], when you look at the type of problems these people have, we look only at the frail ones (black beams on the graphic), you see over 80% of people have problems with walking swiftly. So, aging means also problems in functionality, and not in isolated, organ-specific problems, but more in the complexity of processes.


[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].


Tanslation of the talk given by Prof. Cornel Sieber, Institute of the Biomedicine of Aging, FAU Erlangen [http://www.youtube.com/watch?v=zj3YxBUUxlg].

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Tags: translation, aging, presention, Aging
Categories: reST

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