Aging - Mechanisms, Interventions and Possibilities

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There's a lot of hype around slowing down, or even reversing aging. Here's my view.


INTRODUCTION

I've long been intrigued with the idea of slowing aging and living longer. While some get emotional about it - that you're denying nature's plan and order - I've no such issues. But I have listened to the views of advocates for life extension and those of mainstream science. And rather than mainstream science being a killjoy, it does have a detailed picture of ageing, one that's worth understanding.


Morality and Motivation

I have no issues with the morality of increasing longevity. People's choices are, broadly speaking, their own. I'm concerned about how much such interventions might cost - that only the wealthy could afford it. While I don't think it is impossible to manage a growing population, or try to get it to steady state - I worry that we're contemplating these sort of initiatives while we're unable to deal with urban planning, growth, congestion, housing affordability and so on. If we were already on top of these issues, we could better adapt to such a different world. But, apart from these concerns, I've no broader practical or moral concerns about life extension.


How I got here

My understanding of aging was informed by discussions with Dr. Robin Holliday, who passed away several years ago. "The Holliday Structure" was named after him, and I acknowledge the intellectual debt I owe him. I developed my ideas around abiogenesis through discussions with him, with Robin observing "so you're challenging the central dogma of molecular biology?".

In his own way he was irrascible and irritated when I did not "get" something he was talking about. He was also secure in his position as someone with qualifications and long experience in the field of aging - he wrote a book on the subject published by Springer-Verlag - a great book, but with a rather expensive price tag.

Dr. Holliday was also puzzled that I would even bother to engage with the ideas of Aubrey de Grey, considering him an amateur who didn't really "get" the details. While giving a nod to scientific authority, I do have some Libertarian ideas as well. You want to acknowledge the scientific tradition and the mainstream; I see it as the default position. But that does not mean you should ignore other viewpoints. And if you want to say the alternative views are wrong, you should state your reasons. While I was willing to engage with those alternate ideas, and willing to find them wrong, Dr. Holliday had a feeling similar to Richard Dawkin's refusal to engage with creationists. Maybe he had a point. But, fundamentally, I think it reasonable to work through the ideas to your own satisfaction. His satisfaction was not my satisfaction.

But Dr. Holliday did not dismiss all self taught people. He acknowledged the contribution P.G. Price who developed the Price equation, but started out in fields outside biology. Ah. The Price equation. That's a luvly, luvly equation ( something I consider in the talk I gave on Evolutionary Psychology, broadcast on Radio National's Big Ideas program. )

Now, it was to a large degree an accident of the people and circles I was in that heard about de Grey's ideas - in fact I attended a talk he gave to the Sydney Futurists - and they did seem intriguing on the face of it. I can appreciate the the criticisms of de Grey's ideas, though I do try to be finessed in my endorsement of those criticisms.

While I think I need to acknowledge this debt, I'm aware that rather than me acknowledging him, this could be seen as parisitising off his much greater scientific stature. My ideas are nevertheless my own, and should stand or fall on their own. Nevertheless, it may be easier to understand how I came to where I am. I hope this acknowledgement walks the moral tightrope. Robin, I remember you and the discussions I had with you fondly. Thankyou for spending that time with me. I appreciate it.


Other ideas

I've trawled the internet, but there's also people in Sydney who are interested in science and biology in particular. There's Ian Woolf; I've heard many of his ideas, and there's also people in the Sydney Futurians and also the Sydney Biohack group. These other people have also given me things to think about. In particular, I've stumbled across Professor David Sinclair while trying to find out if anyone really had improved the longevity of at least - experimental animals.

So, this is where I draw from. However, looking at the horizon, it does seem I'm in the shadow of battles fought by others which may have been far wider ranging than I can cover in this article. But, I can only talk about what I've experienced and felt inclined to pursue. Perhaps, though the thing I struggle will have been done to death in other discussions in other realms. Perhaps there's a lot of detail, and other research initiatives I'm completely missing. What I can say is that in terms of people I talk to in Sydney, my ideas are in response to what I hear.


CONTENTS

  • 1. INTRODUCTION
  • 5. CONTENTS
    • 6. EVOLUTION AND AGING
    • 11. THE DETAILS OF AGING, AND HOW WE CAN CHANGE IT
    • 20. The technology of intervention

    • EVOLUTION AND AGING


      Evolutionary origins

      But first, let's understand why there's aging. Our ancestors improved reproductive success by specialising into germ and soma. Our germ cells - sperm and ova - carry information onto the next generation, while our soma cells - the rest of us - carry around the germ cells. By making our somatic cells mortal, with those germ cells that reproduce immortal - you have better reproductive success, because you only need maximal accuracy in the germ cells; you can be a bit more lax with the somatic cells ( At least, that's my understanding).

      How do evolution and genes influence our longevity and how aging catches up with us? We need to reach reproductive age and well, reproduce. We live long enough to produce our first progeny, or even a few, with this being set to maximise reproductive success. But, why do we live beyond reproductive age? Because in order to have say, a 95% chance we'll reach reproductive age, you need some redundancy. This means, say, you'll have perhaps an 85% chance of getting 20% beyond reproductive age.

      That's just plain evolution without cultural transmission. However, if grandparents are reserviors of information that assist the reproductive success of their grandchildren ( or even their children), this could be an effect which evolves for survival beyond reproductive age, as compared to it being merely a side effect of reaching reproductive age.


      The Set-Point

      So, we have the evolutionary set-point for aging. But what extends the lifetime? Maintenance, set by genes. There are some definitional issues. Our metabolism has innevitable side effects which contribute to aging, and structures degrade over time. In theory, you could develop metabolic processes which use more energy with fewer side effects, but evolution mostly spends energy correcting these problems after they have appeared. Over time, even if possible and practical, the energy needed for maintenance increases. Energy expenditure is a trade off between operation, maintenance and reproduction.

      Longer lived species have better maintenance. I understand flies do not generate new cells after hatching, but humans cells divide many times during life. While this means a greater lifespan, it also opens up the possibility of cancer.

      Some posit an "aging gene" where a "self-destruct" mechanism is turned "on" at some time stage of the life cycle, and if only we could turn that gene off, we would live longer. David Sinclair seems to have this belief - broadly speaking, I think it's wrong headed. Nevertheless, he does have a credible approach for reversing some of the of errors that accumlate through aging. There's a subtle evolutionary context here - but even assuming he is onto something, what he refers to would be better described as "expoliting an evolutionary oversight" rather than reversing evolution's attempt to deliberately "shut things down".

      Our life trajectory is better described as an "epigenetic unfolding" without any such genes ever intentionally being turned "on". If we lived longer and our bodies were able to do that with marginal cost, we'd do it. However, in terms of the evolutionary trade off, there's a cost to "pushing" it further. Our bodies have a certain capacity to "cope" with the environment, and depending on what the environment is we in fact encounter, our biological capacities will degrade. Some aging depends on the environment, but some is unavoidable.

      For example, a horse's teeth can withstand a certain amount of abrasion. However, at a late stage in the horse's life, its teeth have worn down and it cannot eat, so it starves. This time is based both on both its genetic profile and the quality of food it eats during its lifetime.

      Perhaps some aging is the result of genes which are evolutionary baggage. There are identifiable genetic diseases. We could imagine processes which are not essential and have a timeframe much longer than the reproductive age to act, and have not yet been filtered out, even though there might be a weak grandparent effect working against them. But the point is that evolution "intentionally" putting in a self destruct gene which kicks in at a particular time makes no sense ( And of course philosophers will slap me on the wrist for claiming that evolution has an "intention" about anything. But hopefully you get what I mean.)

      Aging is a difficult thing to measure - it happens in many different ways over the body. I'll say more later, but - broadly speaking - it is a loss of molecular fidelity, or accuracy in the copies made throughout the body. This loss in molecular fidelity makes the body susceptible to age-related diseases. We go "off blueprint".


      Modulation of the set point

      Dr. Holliday did agree you could "modulate" lifespan, but there was always a big difference between "modulation" and "interventionist lifespan extension", which many longevity advocates are on about. We could, through "modulation" improve our lifespan by perhaps 15%. This is however operating within the constraints of our inherited biological machinery, involving "twiddling the settings", rather than changing anything dramatic. I think it is reasonable to distinguish "Modulation" and "Lifespan extension", and we should be careful not to confuse them.

      However, to be sure, if we're living good lives which are 15% longer, that's nothing to sneeze at, and would certainly be worthwhile - though we are probably talking about a treatment that needs to be applied from birth, or something that has to be bred for. However, people rarely properly distinguish this goal from the much grander aspirational hopes which form part of the overall picture.


      Universality of Ageing

      Hayflick notes the unversality of ageing - that it occurs in every multicellular organism that reaches a fixed size at reproductive maturity. Animals like Hydra, Lobsters, Sea Tortises and also the so-called "immortal jellyfish", Turritopsis dohrnii, are supposed to not age, or age very slowly. These deserve closer analysis.

      Hydra do not have a fixed size of reproductive maturity, and will bud asexually, only undergoing sexual reproduction - specialising to germ and soma cells - at certain times. They do not always have the "germ and soma" specialisation, and are a lot more simple than vertebrates. So, they are a special case, not covered by the fixed-size-at-reproductive- maturity germ-and-soma specialisation picture.

      Lobsters are rather more complex, but the story changes under close examination. First, lobsters do not have a fixed final size, they just keep growing, albeit slowly. But, while it is not clear they will die of "old age", they do age, they do change, and they can die of age-related issues. They might die during moulting, which takes more and more energy as the lobster grows. They might stop moulting, in which case they are then susceptible to death from bacterial infection as the shell wears out. So, they do "age", just not in the way we mammals are used to. This is something Zen Faulkes wrote about in the neurodojo blog.

      The so-called "immortal jellyfish", Turritopsis dohrnii, has the ability to revert to the pre-differentiated stage in case of stress, and - it is assumed - reset some of what goes on with aging. However, the situation is similar to the lobster. These jellyfish do not have a "final maturity size", because they can reverse the maturity. But another clue is that these jellyfish are known to die of disease, and it seems reasonable that they become more susceptible to disease the more they age. While the "reverse differentiation" can reverse some of the loss of fidelity associated with aging, I suspect it doesn't reverse all of it, so errors accumulate, eventually making the jellyfish susceptible to age-related diseases or more vulnerable to predators.

      On observing the immortal jellyfish and lobster, I can hear people saying "why can't we change ourselves to not have a final maturity size?". Well, if you want to develop that line of thought, be my guest. We're very different to lobsters and jellyfish, they use copper based blood if they have blood at all, not to mention us having a bone structure that is not well suited to continuous growth. So, I consider that to be an option so far out there as to be irrelevant, but by all means pursue it if you want to.

      Turtles are known to live a very long time, but they're not necessarily immortal. They are interesting in that their environment and evolution so far means it makes sense to keep on reproducing, and it also seems that they reach maturity very late in life. So, in this sense they're part of the aging continuum - just way up at one end of it. Either they have a "setting" on maintenance where a lot more energy is put into maintenance as compared to reproduction - hence the late maturity - or perhaps even they have more efficient ( or slow?) metabolic approaches which mean less need for maintenance or more energy available for maintenance. Turtles do not have a regular heartbeat. It may well be their heart has an effective finite number of beats in it - it is just that clever use of it extends this number over a very long time period.


      THE DETAILS OF AGING, AND HOW WE CAN CHANGE IT


      Causes and Mechanisms of Ageing - "Maintenance" and "Cumulative Damage" models

      On the one hand ageing is an evolutionary trade off. Equally, we can ask what causes the associated molecular degeneration - why are the molecules different to what they would be if they were effective ?

      Hayflick, ( and I expect others), seem to think ageing, age-related diseases and longevity are different notions. Ageing is the loss of molecular fidelity and can result in non-pathological changes, age-related diseases arise because of increased vulnerability of body systems to mishap, and longevity is the result of evolutionary "spare capacity" - the major genetic determinant of longevity.

      Holliday calls ageing "multi-causal" - there are a myriad of mechanisms that would need to be nailed down. He does not so much disagree with Hayflick's ideas of "fidelity" but seems to emphasise the diversity hidden behind that sweeping statement. You would never be able to make progress under one umbrella - each element would have to be dealt with, and "solved" separately. A sweeping universalisation can lose this impact - and this is a criticism he would apply to de Grey.

      They emphasise "maintenance". Things go wrong, and animals with greater longevity are not those that have better "natural" fidelity, but rather those who "correct for" and "maintain" the losses which are innevitable and naturally occuring . Evolution seems to have found it "easier" to fix the consequences of problems rather than remove them at the source, though maybe it's a bit arbitrary to distinguish "source" from "consequence".

      Perhaps there are hard thermodynamic/chemical limits in preventing them at their source. For example - if Reactive Oxygen Species (ROS) cause damage, you could fix the damage they cause, or you could reduce their concentration. Both approaches would have a metabolic cost. It could become prohibitively "energetically expensive" as you reduce the concentration of ROS by each order of magnitude. Perhaps ROS are an innevitable consequence of some necessary biological reactions, or they are needed for other reactions, and it is hard to contain them. ROS are used "actively" in the immune system to "kill" things as I understand, so perhaps they're a necessary evil - you get leaks from the fuel tank you cannot do without.

      Perhaps some biological reactions run with 99% efficiency; with 1% unavioidable by products. Pollutants, so to speak. It well be that it is thermodynamically impossible to get any chemical reaction to run better than what evolution has come up with.

      While you'd expect that the more "resources" are spent on fixing problems, the longer you'd live, there may only be so much correction you can do. You may have ample energy but be unable to reduce the ROS concentration beyond a certain point. If we have ample resources, rather than living longer because we allocate more to "maintenance", we become obese and have a shorter lifespan. This could be because evolution saw saving against future resource shortage as a better bet than seeking a longer lifespan, but it could be that there's no "knob you can turn" - the biological reactions just aren't there to take advantage of the available energy. In any case, this "correct-after-the-problem" seems a very effective way of understanding aging.


      Thing "wear out"

      There's the innevitability and reversability of age related effects. Things "wear out". But what exactly does that mean? Could the effects could be corrected for or reduced? Are the changes "intimately connected" to the organ in question, or can they be identified and isolated - so that if you remove the "effect" the original organ would be rejuvenated ?

      Consider muscle. If cells die or become ineffective, then the ineffective cells would have to be removed and replaced without interfering with the structure, unless the entire muscle is replaced by surgery, which is a different emphasis. Alternatively, there could be "residues" which "stop" otherwise "effective" muscle cells from working - and all you have to do is remove them.

      If the problem is isolated to an organ ( with the exception of the brain ), you can replace it. Also, if it related to active cells "floating" inside an organ, these could be replaced - for example in the liver.

      Arthritis involves surfaces "wearing down". Perhaps that's innevitable, but equally there is a great deal of variation in arthritis, suggesting the underlying wear time may be a lot longer than the age at which arthritis is often seen - so maybe there's ways of putting it off.


      Playing the odds, Longevity and the quality of life, the nature of science and investment as a personal choice

      One goal is not so much increased longevity as an improved life in older age. A great advance would be making the last years of people's lives healthier, even if you do not improve their lifespan.

      Some diseases lower the quality of life rather than lifespan. Interventions for alzheimers, arthritis and diabetes would be much appreciated - quite separately to any other advances. In fact, there is talk of "immunising" the body against alzheimer's degeneration. If this were effective, would it be described as "slowing down aging" or "slowing down age-related brain degeneration" ? Still, while we might increase longevity by curing an age related disease, this might tell us nothing about the process of aging itself.

      de Grey talks about "early intervention". Is this early intervention reducing the progress of an age-related disease, reducing susceptibility to age related diseases, or "slowing down" aging ? If you were to slow down one factor which is indicative of aging, are you slowing down aging, or doing something else?

      Good health does not mean you stop aging, at below the minimum level - though bad lifestyle can cause ongoing damage to the body. Is this "aging more rapidly", or is it best described as something else ? Good health can minimise the impact of aging, but it does not stop it. There's a semantic issue around "health" - what is health ? What is ageing ? If we are "living well beyond our years", have we "maintained our health in spite of aging", have we "reduced the impacts of aging", have we "cured or mitigated against age related diseases that develop", or have we "slowed aging" ? Maybe we have aged more slowly, this being more a matter of luck than anything else.

      Even if there are clear cut answers, it is very easy to become confused. It seems to me a lot of the language used in discussions of aging is quite confused.

      According to the SMH, in 2014, the Longevity Science Panel in Britain said the lack of consensus regarding which mechanisms of ageing were dominant in humans presented challenges. "Many potential anti-ageing interventions have been explored but their effectiveness on humans is unclear and their side effects are potentially unacceptable". This is in fact a reasonable statement in its way, but also rather frustrating - saying that because things are "ambigous" that means there's little potential. But, considered more carefully, it is saying that some things might be possible, but nothing has been demonstrated, or is even reasonably promising at this stage. I think this sort of assessment reflects the overall terminological confusion. At one level, biologists will seek to understand detailed chemical and biological mechanisms - and I wouldn't ever want to challenge their understandings. At the same time, however, the overall language we are using to engage with these issues is causing a lot of trouble, and I think that's plain to see whether you're a biologist or not.

      Another issue is that well, scientists decide what is scientific; this tells us what science is. They have a certain threshold at which they'll recognise something as valid, and that's their perogative. But, rather than just recognising success, there seems to be at times a certain dismissiveness of potential, which is a lot more negative than saying something like "get back to us when you have something to show". Listening to Professor Sinclair, I can only feel sympathetic to those suffering under this sort of unfair criticism.

      Now, it is the perogative of others to pursue possibilities based on their own assessment of possibility. Fair enough. People can spend their money on self-indulgent parties just as they can on their own preferred longevity research. It's their choice. But, at the same time, is for the scientists to recognise science when they see it, and only then. A lot of tension in this whole area happens when people try to justify their interest/investment in a particular area as "science", when it is in fact their choice, which is different. And I think there's a lot of marketing, trying to give a mere choice "scientific" credibility. And that's on top of the terminological confusion. So, the field is a mess, and I can understand that scientists would shake their heads.


      Death and dying of "old age"

      Once upon a time, we died of "old age", when our heart finally stopped beating and there was no other noticeable problem. In this case, the issue is keeping the heart going. We could say you died of cardiovascular disease.

      You can still talk to people who rememember the time before and after open-heart surgery. Someone developed a heart condition before this was available, and they died. Someone else developed a similar heart condition after it was available, and they lived. They are very dramatic stories. However, if you look at mortality graphs over that period, there's no obvious kink corresponding to the introduction of open-heart surgery. I do not deny its significance to so many people's lives. However, it must have been overwhelmed by other changes in overall lifespan of those people who did not develop heart diseases treatable by open heart surgery. It may well be that you need to reduce the impact of a lot of age related diseases over a short period before you see the effect on the mortality graphs.

      But, if your heart stops and you die while suffering from some other noticeable illness, for example cancer, we'd say you died of cancer. However, when we talk about "other noticeable diseases", there are plenty of them, and they also include so called "metabolic diseases". Unchecked, these diseases "wear you down", so you eventually die of a heart attack. Some say a hip fracture destroys your will to live, so that a heart attack later could in fact be said to be caused by the earlier hip fracture.

      If you reduce the susceptibility of people to age-related diseases, are you reducing susceptibility, or are you slowing down aging? It's a bit of a muddle.

      This provides an important qualifier to longevity improvement. If we want to say you've "extended life", maybe what you're trying to say is that you've held off other noticeable age-related diseases and have finally died of a heart attack. However, this definition seems messy and unsatisfying. I think that's because there are no neat and tidy categories, much as people seem to think they're seeking a clear target.


      Statistical improvements and an increased lifespan

      Rather than improving quality of life, you could reduce the prevalence of age-related diseases which reduce lifespan. So, statistically, as you "cure" or "prevent" more and more age-related diseases, you will improve the lifespan. You're statistically "chiseling away" at things which would otherwise stop you from dying of the the "old age" death above, but again - it does not feel very satisfying as a goal.

      It is a statistical thing - there are a lot of things to go wrong you'd have to cover. Further, it is not, by itself a magic wand. It gives you a few extra years to die of something else for which there might currently be no intervention or cure. There might be hundreds of other diseases to take the places of the ones you've eliminated. Maybe diseases we don't see at present - because the human body has never before been in a situation to develop them. Maybe after you reach a critical point you'll be on a plateau and then get significant improvements in longevity. So, an interesting question would be : if you eliminated cancers and cardiovascular disease, how much longer would you be expected to live ?

      There are known lifestyle interventions ( eating well, exercise, not smoking, etc. etc. ) that statistically increase lifespan. Nevertheless, these do not get the attention that medical interventions to possibly "slow aging" do. Strange to say, a lot of longevity advocates do things like smoke and vape - there's something very wrong with this picture! On the other hand, Prof. David Sinclair also embraces these "conventional" longevity-enhancing approaches.

      But is something is an "age related disease" or we are "just getting old"? "Age related diseases" are defined as "mishaps" - a "point event", where things go wrong and you can see the impacts. A blood clot is an obvious example, as is the occurence of cancer. You were fine beforehand, and suddenly, there's a "point" transition - a "mishap" - which then develops, and may or may not kill you, or may perhaps be treated and removed or the consequences rectified. High cholesterol is however a sliding thing which gradually rises, and does not really "feel" like a "mishap" in the same sense.

      How we define aging is important. It seems to me the semantic issues are deep seated, and cannot be conquered merely through strong assertion.


      Trauma

      But you don't only die of disease - you die of trauma, of accidents. When you're involved in a car accident that is clearly the other person's fault - well, that's outside of medicine and you. However, if you fall off a ladder or are involved in an accident which is partly caused by your declining ability to drive a car - well, that's maybe "age-related" but not in the manner in which we normally think of diseases.

      de Grey notes that 2/3 of people die from age - presumably that's as compared to trama like road crashes. He sees that as a concern. However, if more people were to die of old age it could mean our roads and living environment are safer. The longer people live, the more likely they are to die of trauma. People have to die of something. I find it a strange emphasis.


      Interventions to improve longevity

      Till recently, there have been no demonstrated methods for slowing aging in humans, let alone mice - apart from calorie intake restriction. Recently, though, there have been some drugs which have been applied to mice and improved their lifespan.

      Researchers have managed to change some biochemical markers which are indicative of slowing down aging. However, because our metabolism is so finely balanced, I focus on increased lifespan. Because in changing one thing, which improves lifespan, you might have a more-than -compensating effect elsewhere which reduces lifespan, and you in fact have an overall net reduction in lifespan.

      One example is messing around with telomeres. You might well be able to increase the life of cells by doing this. However, you also make the whole body more susceptible to cancer, because telomeres are one of the fail-safe mechanisms by which the body avoids cancer. So, you might end up with a net overall decline in lifespan ( though those lucky enough to escape cancer might end up less susceptible to other diseases). Overall, though people might be now more likely to die sooner, and die of cancer. You're shuffling deckchairs on the titanic.

      And it may be that some chemical which seems to promote health is turned off for a reason, because its continued presence has other overwhelming negative effects. A woman I know who migrated to Australia from Denmark says one of her children, after visiting Denmark, reflected that "You know, mum had reasons for leaving Denmark." ( but having said that, I've been to central Copenhagen and it is indeed a wonderful, amazing place.) The point is there may be reasons the body does what it does, and we just don't know what they are yet.

      However, you can equivocate that your of objective is improved health in later life, rather than increased lifespan. Well, maybe some of these proxies will be good indicators of better health. Maybe. But be clear, and don't mix in talk about life extension. You might even shorten it, much as you increase the overall quality of life.

      Another curve ball is that a hormone can rejuvenate the heart of mice. However, that still leaves the whole circulatory system - which loses elasticity as the polymers become crosslinked. I understand there are also cholesterolic resides to cleared out too. Yes, improving the heart might help a little, but may not make that much difference compared to everything else going on. Then you have the fact that this approach might have side effects which act to kill you in other ways. It may be that if this hormone remained in the bloodstream then you'd have increased mortality through other causes as a side effect - with the increase being more than the "saving" through keeping the heart muscle pristine. Further our hearts could be very different to those of mice. That wouldn't devalue the phenomena as being an interesting side point to aging, but it might make it difficult to apply it therapeutically in humans.

      So, much as you do get sensationalist stories from time to time, often they are just that: sensationalist stories.


      David Sinclair - reversing the increase in errors

      I've so far considered how aging is a "loss of fidelity". Professor David Sinclair's approach is not as radical as de Grey's. In its way, it does fit into the conventional understanding of aging. He talks about reversing some of the loss in fidelity - our body can "recover" from accumulated errors.

      We can compare information on our body to two losses of information in a disk drive. In the first one, the magnetic fields decline, and the ones turn to zeros. The information is lost permanently. But, in a second from of reading loss, dust builds up on the disk and we are less able read information. But the information is not permanently lost. Blow away the dust from the disk, and you can read the information again! This captures some of what Prof. Sinclair is on about.

      One source of loss in fidelity are epimutations. This is where the cell loses its idea of "what sort of cell it is". A skin cell might start to think it is more like a liver cell, for example. The details of epimutations are covered from another perspective in my article on cancer, also on this website. Now, one sort of epimutation is where molecules get "stuck" on the gene-blockers, meaning the genes which aren't supposed to present themselves do. And, one thing you can do is "blow away" these "stuck" molecules and restore the cell's original situation.

      Now, there's a real possible "gotcha": that there could be side effects; your drug might blow away apparently "stuck molecules" that are in fact supposed to be there - actually adding to the number of errors. It might also have other unintended chemical effects elsewhere in the body. As with leaving Denmark, there could be a reason why our bodies don't "go to town" with this approach. Interferon was expected to be a magic drug at first. But then people found there were side-effects ...

      However, barring "gotchas", I'm open to the possibility of it working. But there's still obstacles that could reduce the impact of a therapy based on this approach, even if it might still be worthwhile. One is that while you're reducing epimutations, you're not having any effect on regular mutations, or indeed other sources of aging. The problem is that we don't know the "proportion" of aging caused by epimutations, and of that proportion, what proportion of these could be reversed by this therapy.

      A related issue is that things wear out, and reversing epimutations may not help, or the help might be limited. For example, teeth. It is difficult to imagine the wearing down of teeth slowing down. More complex would be muscles and heart muscles. I could imagine muscles remaining more robust because they are freer of epimuations, but still wearing down, albeit at a slower rate. But, worse case, we could imagine that the main cause of "aging" in certain tissues, muscles etc. is not related to epimuations, and so the therapy would have a limited effect.

      Such a therapy focuses on one aspect of aging. But we don't understand where such a therapy would "fit into" the whole aging picture, even if it worked. And if aging is as "multi-causal" as many gerontologists claim, the impact of this therapy will be reduced. Still, it might indeed be useful. The studies in mice seem promising, and I would not want to fall foul of the Nirvana Fallacy, as I write about elsewhere. The perfect should not become the enemy of the good. The point to be made is that this approach may end up worthwhile, but fall well short of current expectations and hopes.

      There a wierdness about it, too. You'd think that if it were easy, evolution would have done something about it. Perhaps, I guess, we're talking about metabolic approaches that are more apparent to us than evolution as it searches out the solution space. Evolution is normally pretty thorough, but I guess it could miss some things, too. Its survival beyond reproductive age, but it might help survival to reproductive age. If these "epigenetic mutations" really only come in after reproductive age, you could see the "evolutionary incentive" as smaller. Further, the "grandparent effect" might not be large enough to push this sort of metabolic tweaking. Certainly, I will thump the table and say that there's no intentionally developed gene which "shuts down" our body because we've been around for long enough ( to the extent you can talk about "intentionality" with regard to evolution. Philosophers can slap me on the wrist. ). But, if this approach does work the way Prof. Sinclair claims it does, I'll accept the world is that way. But there will be an issue of reconciling it with evolution and how aging fits into the evolutionary picture.


      The technology of intervention


      Add enough zeros ....

      Add enough zeroes to the timeframe and anything becomes possible. We could just teleport people and clean up the noise along the way. That would work. My feeling is that many people "jump between" technological levels without identifying just how far away or feasible the things they posit are - confusing a grand technological possibility with a more mundane future, but trying to harness the grand technological possibility for its emotional appeal. But let's try to piece together that progression as we add those zeroes.


      Chemical intervention

      We can try to change our metabolism so it does not produce waste products, or remove those waste products, so that our body - and its important functions - continue to be effective as we age.

      Using current-ish pharamaceuticals, we might be able to make improvements - but we could hit two barriers. One is that it might be impossible to make chemicals which dissolve only the stuff we want to dissolve. It might also be impossible to change our body's chemistry to reduce the generated contaminants.

      Consider cardiovascular disease. Blood vessels lose elasticity as the polymers become crosslinked, not to mention cholesterolic resides. Now, maybe in principle you could make chemicals which "dissolve" the cholesterolic residues, but the difficulty is making them specific so they don't significantly damage other tissues along the way. However, to selectively depolymerise the vessels - without making them completely crumbly so they just dissapear into the bloodstream - seems hard to me.

      However, it's important to recognise that this approach has no particular technological barrier. If it is possible ( a big if ), we'll get there with, well, relatively linear technological developments within the realms of biology, chemistry and pharmacology.


      Nanobot "chemical style" intervention

      Rather than using a "chemical" approach, as outlined above, nanobots, using a "physical" approach, can be a lot more selective. They can scoop away cholesteric residues. Using a combined physical/chemical approach, they could inject particular amounts of depolymerising fluid into the blood vessels, while if these fluids were in circulation in the blood stream, they could just corrode the blood vessels from the surface downwards. Such nanobots could also destroy cancer cells, with a specificity that drugs could not match. At the same time - just like our immune system - you'd not want them to go wrong.

      All these things are "technically" possible. However, unlike relatively creative pharmacological approaches, we're a long way from functional complex nano-machines that have complex parts let along are motile and can perform complex operations. It's a definite "techonological step" to such devices.


      Organ replacement and supplementation

      A simple form of organ enhancement is to inject cells which sit inside an existing organ and do something that it used to be able to do - for example, the cells that produce insulin inside the liver, or bone marrow generating blood cells or providing the immune system.

      The next stage is to replace an organ with some plumbing - like the heart, liver or kidneys. To the extent that heart failure causes a decline in mortality - well, you'll get around that. An important source of age-related illness are are "metabolic" illnesses. I don't know the source of them, but perhaps replacing the liver and a few other glands would fix them. After that, you have big organs - like the lungs, stomach intestines and so on. Intestinal failure is another age-related problem.

      Then you have complex nerve endings. At the easy end you have hands, arms legs and so on. At the far end you have things like spinal cord connections, ears and eyes. And you have the ultimate replacement - of the whole human body apart from the brain.

      There's a fundamental difference here - between "active cells" that float inside an organ, and making complex connections. It's like constructing a building. During fabrication, you can lay down cables and then seal them away. But afterwards, you're doing things like poking cables through holes in the walls to replace them. Similarly, while we are forming in the womb, it is a lot easier to connect up our nervous system. To make these sort connections after we've been "wired up" - is much harder.


      More exotic possibilities

      However, adding more zeros to our timeframe - we can image atomic manipulation, higher level nanobots, and 3-D printing of whole human bodies. At this level, you'd be able to get around inherent chemical barriers.


      Near and long term possibilities

      Solving our problems by adding more and more zeros to the timeframe involved is different to saying we need to approach current research differently. Some of these technologies are just "so far out there" as to be science fictional. Now, I'm not trying to be derogatory, just put them on a continuum. There's so many stepping stones to reach these goals that to put them in the frame of current research seems just a bit ... well, wierd. Some people say we are "close" to get immortality or significant life extension. But to me, we are not close to these "science fiction" options. The question remains "what are we close to?". And are the current barriers to progress likely to lift any time soon?

      Researchers are working on age-related diseases such as cancer - and mainstream research embraces that. Mainstream research also works at understanding aging - there's the maintenance approach I've mentioned; it emphasises its evolutionary context. It works at measuring and defining aging - perhaps research into aging will assist in limiting age-related diseases. There's a push to understand Alzheimer's - quite apart from mortality, improvements to quality of life are also important. All this is endorsed by mainstream science.

      Two obvious sources of mortality to hold back are cancer and cardiovascular disease. Some cancers can be substantially cured; but there's a great variety. Curing one cancer does little other cancers. So, it may be quite some time till there's a significant effect.

      It does seem that a hormone can rejuvenate mice hearts. However, there's still the whole circulatory system - which loses elasticity as polymers become crosslinked. Could any enzymes or other substances could be created to reverse these conditions?

      Assuming we get past these problems - I'd expect we'd have immune system decline, general metabolic dysfunctions, diminishing lung capacity and diminishing muscle tone to deal with. These conditions amongst others would be waiting to take the place of cancer and cardiovascular disease - and if not act on mortality, at least the quality of life.


      The "Engineering Approach" - Turning a corner?

      Mainstream gerontology says things are hard, and will remain hard for the forseeable future. So, "talking big" is just that - talking big in the face of a reality that will push back. It seems to me this sort of approach has a "centre-of-gravity" in the US. Not that they have a monopoly, but the US encapsulates the idea that - whatever the problem - we'll fix it by throwing enough money at it. And maybe that does work sometimes. But no matter your money, you won't push back against thermodynamics. There are some limits ...

      Anti-aging advocates seem to say that in the moderate term we'll make significant advances in our understanding and will make dramatic progress towards holding back aging. We'll develop a superior "overall" understanding of biology and be "more able" to manipulate the body in ways we are currently unable to do. We'll "turn a corner". Aubrey de Grey, for example, promotes an "engineering" approach to reversing aging.

      A first point is that getting a new scientific handle on things that are practical is hard. Many things which sound reasonable on further investigation turn out to be plain wrong, or while maybe vaguely sound theoretically cannot be turned into a therapeutic method. If things sounding reasonable, that's no guarantee of success - reality is known to have - in the past - applied a very harsh filter. So, just because de Grey's ideas ( or anyone's ) may sound reasonable - some criticise him as using buzzwords - that's different to having confidence in their worth.

      In a technical sense, anything and everything is possible - but experience tells us a a small subset of ideas that sound promising actually work. That's the "real world" experience of far more mundane excursions into biology - and you'd wonder why this would not be replicated in anti-aging research.

      Perhaps "buzzword" is an overstatement. In terms of current understanding, the statements may well be valid possibilities - its just that they are not likely to be realised.

      Will biology will "turn a corner" so that things now "hard" will become "easy"? Or will the hard things stay hard ? It is all a matter for judgement. Fundamentally, things could be a lot harder than is made out, with no possibility that discoveries and the ability to make use of them will not "accelerate" any time soon.

      de Grey's notion of the "senescence escape velocity" may be a null concept in any reasonable short term, because you need to nail down a great many things at once - and until then, you won't really get off the launchpad.

      So, I'm more sympathetic to mainstream gerontology than to deGrey's views. But having said that, if de Grey can show experimental progress that uniquely derives from his perspective, rather than pointing to things that sound reasonable, I will give him credit. If that is currently the case, my apologies for being unaware of it.


      A "breakthrough" ... Past experience


      Several things make me circumspect about the idea of "turning a corner".

      Moore's law has meant that computational power has increased dramatically over the last few decades. But there has not be a proportionate increase in the user experience. We do not have a base on the moon, orbital industry, personal helicopters available like cars, and nor are we working 1 hour weeks, sitting in the back yard running our radio-control lawnmowers, as was predicted decades ago.

      Further, if you look at mainstream media - there's an unending stream of medical breakthroughs. But changes to our everyday lives that we can track back to a media article seem few and few between. So, just as we can solve a problem by adding zeros to the timeframe, we can imagine solving problems will suddenly become easier as we turn a corner. But, how soon will this be? I side with mainstream science in thinking later, not sooner.

      Of course, people have in the past said that something is "impossible", with people like Kelvin saying " No balloon and no aeroplane will ever be practically successful." Yes, sometimes science has made sweeping statements and got it wrong - but it also gets it right most of the time, too. This critical viewpoint is not just that of one researcher, but is the consensus amongst gerontological researchers.

      They claim that de Grey has arrogance - an exagerated sense of one's abilities - and that is something to be considered. The argument is more detailed than the "wave of the hand" which dismissed aeroplanes. Equally, if you can only appreciate this by becoming qualified and active in the field, the assertion has problems because it lacks transparency. You have to not just make an assertion - but rather explain it in terms comprehensible to those with an interest - even if it's an interest without qualifications.


      De Grey - Seven Deadly things vs. the mainstream

      But now, let's look in a bit more detail at de Grey's approach. There's other perspectives out there, but I'm more aware of de Grey's approach, more through cooincidence than anything else.

      In contrast to the "Maintenance" model, de Grey's emphasises "accumulating damage" resulting from "metabolism". "Damage" is the intermediate between metabolism and "pathology", which it eventually causes. This is fair enough as far as it goes; the question is how useful the approach is, and whether we can actually reduce "damage", given that we've identified it.

      Add a few zeros to the timeframe, and you could have nano-machines pulling these things out, half-mechanically, as it were. However, de Grey seems to focus on "enzyme" based chemical intervention. Part of de Grey's argument is about the "proximity" of possibilities. The more creative you get with your technological possibilities, the less "proximate" ( near term ) is that possibility.


      Comparing Holliday/The Mainstream's aging processes

      While there are many different ageing mechanisms, Dr. Holliday identifies a subset : 1. Accumulated mutations, including epigenetic mutations. 2. ROS. 3. Mitochondrial DNA. 4. Abnormal protein chemical changes, including "Advanced Glycation End Products". 5 Declining immune system. He links these with "maintenance mechanisms".

      Dr. Holliday never really wanted to engage with de Grey's approach to aging, I should point out. I saw both approaches and wanted to compare them, which I'll do now - in my own way.

      de Grey does not seem to spend much time considering the evolutionary context of aging, he tries to identify "what it is" and posits "seven deadly things" :

      • Mutations - in Chromosomes causing cancer due to nuclear mutations/epimutations

        Certain mutations can lead to cancer, and, according to de Grey, non-cancerous mutations and epimutations do not contribute to aging within a normal lifespan, so cancer is the only endpoint of these types of damage that must be addressed. Prof. David Sinclair, in contrast, sees epimutations as crucial to at least some part of aging, and something to be reversed - and it is something Dr. Holliday thought important, too.

      • Mutations - in Mitochondria

        Mitochondria are cells organelles involved in energy production. They contain their DNA, and mutations to can affect a cell's ability to function properly, potentionally contributing to aging. Holliday identified this as well.

      • Junk - inside of cells, aka intracellular aggregates

        Our cells are constantly breaking down proteins and other molecules that are no longer useful or which can be harmful. Those molecules which can't be digested accumulate as junk inside. Atherosclerosis, macular degeneration and all kinds of neurodegenerative diseases (such as Alzheimer's disease) are associated with this problem.

      • Junk - outside of cells, aka extracellular aggregates

        Harmful junk protein can also accumulate outside of our cells. The amyloid senile plaque seen in the brains of Alzheimer's patients is one example.

      • Cells - too few, aka cellular loss

        Some of the cells in our bodies cannot be replaced, or can only be replaced very slowly - more slowly than they die. This decrease in cell number causes the heart to become weaker with age, and it also causes Parkinson's disease and impairs the immune system.

      • Extracellular protein crosslinks

        Cells are held together by special linking proteins. When too many cross-links form between cells in a tissue, the tissue can lose its elasticity and cause problems including arteriosclerosis and presbyopia.

      • Cells - too many, aka Cell senescence:

        Here cells cannot divide, but do not die to make room. They may also go awry like secrete proteins that could be harmful. Cell senescence has been proposed as cause or consequence of type 2 diabetes. Immune senescence is also caused by this.

      How useful is this identification? It is a different way of slicing the problem to Holliday's approach. It might be a good start. But even though something can can be easily stated, it can hide a whole world of complexity. Does this automatically and naturally yield a feasible solution?

      For example, mutations and cancer. It's not clear how this approach helps us cure more cancers. There seems to be a claim that this area is somehow "different" to regular biological research. Further, while there's a lot unproven, good-sounding ideas, we can supposedly move forward with certainty on those ideas.

      Identifying one cause does not mean we have meaningfully identified a path to a solution. Rather than representing a scientific advance, we might be saying "and then we sprinkle magic fairy dust". We can hope to find enzymes which can break down damaging accumulating side products - but just how valid is such a hope? On the one hand, you can wonder if there's a detailed understanding of enzymatic reactions, their chemistry and thermodynamics, so we at least have a solid foundation to build on. On the other, giving de Grey the benifit of the doubt, his main public communications might of necessity have to be short on detail. The question remains whether there is a detailed appraisal backing up those assertions.

      In fact, I see some blindness on both sides. Few regular researchers are willing to consider de Grey's ideas. But, at the same time, de Grey ( from what I've seen) seems to emphasise his preferred causes of aging, without looking at what mainstream gerontology says about the evolutionary context, its ideas about the mechanisms and measures of aging, or ideas like maintenance. I've tried to make the comparison, but I'm not sure if anyone else has tried to. I mean, most every research project begins with a "literature review" ....


      Further Reading

      Ummm ... I hesitate to say "references". Look, either you find my writing persuasive or you don't. It sure ain't peer-reviewed. Yup. Definitely. Yawn. ( Hi, Dr. Rachie ! Grrrr .... ).

      But, if you do want to get a better idea of how I got where I am now, here's some material you might want to look at.

      I've listened to a lot of material on diffusion radio, and had discussions with Ian Woolf - that's all a bit of a blur. But check out www.diffusionradio.com
      Robin Holliday, Aging: The Paradox of Life - Why We Age - Springer, 2007

      A Sydney Morning Herald general coverage article, in particular on David Sinclair : http://www.smh.com.au/good-weekend/never-say-die-david-sinclairs-antiageing-quest-20150916-gjocnm.html

      David Sinclair's TedX talk: https://www.youtube.com/watch?v=vCCdmGKtxPA

      Anti-Aging Medicine: The Hype and the Reality. A special publication of the Journal of Gerontology: Biological Sciences. Gerontological Society of America, 2004

      A web article on the mortality of lobsters: http://neurodojo.blogspot.com.au/2013/05/all-lobsters-are-mortal.html

      "The Extreme Arrogance of Anti-Aging Medicine", Robin Holliday: http://www.ncbi.nlm.nih.gov/pubmed/18726707

      Science fact and the SENS agenda, EMBO Reports : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1371037/