What is the Goal of Treating Aging as a Medical Condition?
Thanks to a great deal of hard work and advocacy, there is now a much greater enthusiasm and public discussion in the research community regarding treatment of the causes of aging than was the case at the turn of the century. This is as opposed to continuing the past strategy of attempts to patch over the late stages of age-related diseases without addressing their root causes. Nonetheless, many researchers are still reluctant to openly advocate for significant extension of human life spans, and bury that goal in favor of talking about compression of morbidity, shortening the period of disability at the end of life.
What is the point of the exercise, however, if not to aim high, at pushing out the duration of both health and overall life span by decades and more in the only practical way possible, which is by repairing the damage that causes aging? We are machines, and like all machines, our working, fully functional life span is determined by the degree of ongoing repair. Only when repair fails will we decline. To my eyes, failure to acknowledge radical life extension as a primary goal only serves to strengthen support for poor approaches to the treatment of aging, strategies such as calorie restriction mimetic drug development that cannot possibly produce meaningful gains in healthy human life spans - because they not not forms of repair, only ways to modestly slow damage accumulation.
Life extensionism is a global movement with long-term traditions. The idea, that aging is similar to a disease and should be treated as such, was first suggested in the early 1900s. Since then, the study of aging biology has revealed the underlying processes of aging, such as DNA damage, toxic proteins aggregation and cross-links, cellular senescence, nutrient sensing deregulation and others, and proven the plausibility to address these processes to modify the dynamics of aging.
Even though aging itself is not described as a disease in the International Classification of Diseases (ICD), there is no doubt that aging is the major cause of many severe diseases, and the global population could benefit from bringing aging under medical control. Many existing drugs have been found to be geroprotective (protecting the body against the the aging process). However, what would happen if scientists applied geroprotective technologies to humans, remains a subject of numerous misconceptions.
This is the human life course as it was before the development of modern medicine: somewhere around their 50s people started to develop different age-related diseases, then died from them some 15-20 years later. As a result of the past century of development, however, now people reach their 50s, age-related diseases start to manifest, but modern medicine allows us to slow down their progression, so people live longer - but this is the period of illness that is extended, because this medicine fails to address the causes of aging. This is exactly why Brian Kennedy from the Buck Institute calls our healthcare system a "sickcare" system: we are keeping people alive for longer, but we are keeping them sick, generating a burden for our system of healthcare and social support: we have many people living longer in disability.
We can do better by developing interventions to address the aging processes. These interventions are meant to be applied in middle age, before the manifestation of age-related diseases, in order to extend the healthy period of life, or healthspan, while the period of illness is postponed and will remain relatively short. This could allow people in their 50s to look like they are 30, and in their 70s also look younger, be stronger, and feel as good as in their 50s. So what we mean by life extension is actually the extension of the healthy and productive period of life, free of disease and disability. In this "extended" society the majority of people could enjoy their lives for much longer and actively contribute to the development of the economy regardless of their chronological age.
Link: http://www.leafscience.org/what-is-the-goal-of-life-extension/
There is no better time capsule to illustrate the deathist habit then the peanut gallery from Morton Downey Jr, 1989 episode on cryonics. I signed up right after I saw it when I was 19, I'm guessing the youngest member Alcor had to see up themself and I believe the first in Pennsylvania, sad it didn;t catchon. https://youtu.be/53Od9F88JU4
A penny saved IS a penny earned...
Damage never done IS damage repaired, or, likely much better...
Improved metabolism is the necessary foundation of any healthy life extension. It is very little use at all laboring to fill in the ditch if the excessive rate of erosion that caused it in the first progression of events is still a fundamental reality...
Moreover, any ethos other than a pre-eminent regard for first-line functional constructive metabolism, number one, and first-line natural metabolic repair processes number two, will have a misaligned, misdirected and/or insufficient regard for emergency interventions to artificially make up for defects in these two first-line functions...
The root of aging is unambiguously a process, not a result... No process--no result... Attend to the process, and the result necessarily follows...
Repair interventions against aging can never be more than second-line compromises... These may be valuable, but never more than in a subordinate proportion...
I agree neo morse.
@Morse
You're making a big assumption - that the process is modifiable. As far as we know it isn't.
There isn't a single cause of damage that we've identified that isn't absolutely critical for us to live. Whether it's ROS, amyloid beta, or senescent cells, they all play a role in the normal function of your body and your development from embryo to adult.
We might discover something modifiable in aging (the process) along the way - but since so far everything seems to be completely necessary for human life, we operate on the assumption such a process does not exist.
So far the only realistic option seems to be repairing aging (the outcome) from outside.
Hallmarks are the processes of aging and they are the root of damage/error/dysfunction and the reason why metabolism goes wrong. Repairing the hallmarks should restore metabolism as the various studies strongly suggest.
You can boost autophagy and other repair processes but that will not stop the underlying hallmark continuing to damage the system.
Anonymoose:
The assumption(s) on your side are both greater leaps, and prior in the order of things to any assumption you may think I'm making...
I don't say science must be capable of determining whether and how to modify metabolism; I simply say that there is, necessarily, nothing else to modify...
Also: Unless the very first ROS, or the very first senescent cell during the lifetime of a person is already functionally integral at the earliest moment of its arising to a concretely then-present aging-unto-death process measurably underway, based merely on the circumstantial presence of that ROS or senescent cell and nothing else, then that is not the problem per se...
If metabolism in total wasn't fatally faulty at the very first moment in an individual, then it had to become modified in order to begin mishandling/accumulating damage at and beyond point zero...
Damage doesn't accumulate itself... Thus if the damage is metabolic, the damage is neither the original nor prime cause of the ongoing process of worsening degradation, declining metabolism, compounding damage...
Nemo: That's totally nonsense. ROS are a inevitable consequence of breathing. Stop breathing and you are dead. Senescent cells are necessary for body development, wound healing and cancer prevention. Congenitally eliminate them and you aren't even born.
@Morse
"Unless the very first ROS, or the very first senescent cell during the lifetime of a person is already functionally integral at the earliest moment of its arising "
Based on what we know currently - they absolutely are. Your cells wouldn't function at all without ROS. You wouldn't develop into a viable organism if it wasn't for cellular senescence. Damage is integral to our functioning.
You can't easily modify that. Realistically you probably can't modify it - you simply need to build an organism from the ground up to function on a different paradigm than ours and I'm not sure how that is going to end up as a human or even close to us.
This is why mainstream researchers, the ones working on metabolism especially, are skeptical about extending the lifespan of humans beyond 120 - if you want to change the process there is only so much you can fine-tune, everything beyond that requires a completely new process, thousands of new genes, completely new pathways, new interactions, new problems will arise and so on.
So theoretically it is possible. But in reality it's about as possible as reaching a new galaxy. It's like trying to build a faster than light space craft before building the first airplane kind of thing - it's so far beyond us even thinking about it is a waste of time.
It is an interesting argument - the classic chicken and egg situation, which comes first and drives the loss of homeostasis? Damage accumulating throughout life, even when young, then leading to downregulation of the body's repair processes (SENS argument) - or does the downregulation come first, driven by telomere erosion through cell replication, or other epigenetic changes (this opinion seems prevalent outside of SENS)?
My personal opinion is that both occur, I do not know which is primary, but I would rather advocate intervening where we can most easily do so, and examine the results empirically.
"Damage accumulating throughout life, even when young, then leading to downregulation of the body's repair processes (SENS argument)"
Is there a downregulation of repair processes later in life? I thought there rather would be inflammation und thus upregulation of immunorelated mechanisms. Why would damage lead to downregulation of repair processes rather than upregulation as a compensation mechanism anyway?
And why would telmoere erosion cause downregulation of repair processes?
Hi K.
DNA repair, autophagy (and mitophagy specifically), clearance of senescent and cancerous cells, all get worse with age. I'm sure there are other examples. This might be driven by damage exceeding the damage repair response (even when those systems are in a good state).
The other side of the coin is that could be caused by changes is gene expression. Shorter telomeres are one such mechanism (there may be others) because they way they and DNA in general coil around histones brings telomeres into close contact with genes, therefore as they get shorter they interact with less genes.
I suspect even with restores youthful levels of cell repair there will be some imperishables that build up, so SENS will be vital, but we'll have to wait and see to find out.
Hi Mark,
Thanks for that.
"DNA repair, autophagy (and mitophagy specifically), clearance of senescent and cancerous cells, all get worse with age. I'm sure there are other examples. This might be driven by damage exceeding the damage repair response (even when those systems are in a good state)."
Ok, but that means that there is not necessarily a downregulation of the repair mechanisms but they rather get overwehlmed by the accumulating damage.
"The other side of the coin is that could be caused by changes is gene expression. Shorter telomeres are one such mechanism (there may be others) because they way they and DNA in general coil around histones brings telomeres into close contact with genes, therefore as they get shorter they interact with less genes."
But I think we have to be careful with the distinction you made because of the following reasons: First, telmoere shortening can be viewed as a form of damage as well which would then trigger the changes in gene expression. Telomere length depends on stem cells and the telomeres shorten with age due to stem cells declining function, probably caused by damage and their (of the stem cells) shortening of the telomeres. The shortening of telomeres, accumulation of senescent cells, lipofuscin aggregation etc. all seem inherent to human cells right from the start, so if senescent cell accumulation is a form of damage, then telomere erosion must be as well.
Hi K.,
'Ok, but that means that there is not necessarily a downregulation of the repair mechanisms but they rather get overwehlmed by the accumulating damage.'
We do know cell repair gets worse with age, but we don't know why - it could be damage comes first, it could be the other way around. There is not enough evidence to confirm for certain one way or another at this time.
'First, telmoere shortening can be viewed as a form of damage as well which would then trigger the changes in gene expression. Telomere length depends on stem cells and the telomeres shorten with age due to stem cells declining function, probably caused by damage and their (of the stem cells) shortening of the telomeres. The shortening of telomeres, accumulation of senescent cells, lipofuscin aggregation etc. all seem inherent to human cells right from the start, so if senescent cell accumulation is a form of damage, then telomere erosion must be as well.'
Yes, Stem Cells no doubt accumulate damage, and we know senescence stops stem cells that are too damaged from replicating out into somatic tissues. But we also know that telomere erosion occurs through cell division (including Stem cells), even in the absence of other damage - the end replication problem (can't copy the entire length, so a little at the end gets lost). This to me suggests that the bulk of the shortening is caused by replication not damage and therefore it is damage repair that is downregulated prior to most damage accumulating. (Again, I acknowledge some damage will need to be addressed by SENS even in the case I am right).
We could go around in circles forever. We need more data.
Ok thanks. Let's see what future data will tell us about the hierarchy of the mechanisms.
Concerning the end replication problem, I'm curious how this would be solved in extremely long-lived organisms. Is there another way of DNA replication or an altered stem cell cycle? Don't know if this has been researched.
I think all we know about negligibly senescent species such as Turtles is that their telomeres do not shorten much during aging. Which is what we would expect from being negligibly senescent!
So the argument of cause or effect is still open.
Anonymoose:
Are you always that handy at selective (and egregious) misquoting, or only on this particular occasion?
Here's what you left out when you selectively misquoted 1/2 a sentence:
"...to a concretely then-present aging-unto-death process measurably underway, based merely on the circumstantial presence of that ROS or senescent cell and nothing else, then that is not the problem per se."
If a 0-1 year-old human isn't measurably along an incremental/discrete damage-unto-death aging continuum--based, somehow, solely upon the presence but not the production of damage--then damage per se isn't the original cause or prime mover of aging...
The faulty metabolism that produces the 'damage' and doesn't repair it is the obvious cause... If this unrepaired 'damage' (not ROS or senescent cells, etc., per se... but enduring, categorically off-program, unmanaged damage) isn't measurably already accumulating at moment 0+ in the life of the individual, then (as we would entirely expect) damage isn't the original cause of itself...
If you want to artificially intervene externally to partially repair some of the damage from what you assume is an uncontrollably faulty process (metabolism)--fine--just don't laud that limited and partial damage remediation as 'rejuvenation', or as the highest and best possible healthspan and lifespan extension that should be pursued...
@Morse
"The faulty metabolism that produces the 'damage' and doesn't repair it is the obvious cause... If this unrepaired 'damage' (not ROS or senescent cells, etc., per se... but enduring, categorically off-program, unmanaged damage) isn't measurably already accumulating at moment 0+ in the life of the individual, then (as we would entirely expect) damage isn't the original cause of itself... "
Does damage exist at point zero? YES. They oocyte is just another cell. Furthermore de novo mutations happen readily during gametogenesis. Even if it was possible to stop exogenous damage - the one caused by senescence and ROS and so on, DNA replication is imperfect and by nothing else besides mitosis you would still accumulate damage.
Loss of homogeneity and eventually - when a coding or regulatory region is hit - functionality is inevitable.
Mark said: "DNA repair, autophagy (and mitophagy specifically), clearance of senescent and cancerous cells, all get worse with age."
No, it's not known whether clearance of senescent cells gets worse with age. Indeed, SRF and the Buck have just started a research project to study that. See Michael's comment here:
https://www.fightaging.org/archives/2017/04/sens-research-foundation-expands-collaboration-with-the-buck-institute-to-work-on-senescent-cells-and-immune-aging/
@Mark
Also, DNA damage seems not to increase particularly quickly in old age, which contradicts your DNA-repair-getting-worse explanation:
http://www.sens.org/research/introduction-to-sens-research/cancerous-cells
"In addition, studies performed across the lifespan in the tissues of mice appear to confirm that mutations do not accumulate substantially during the aging process per se in most tissues. In fact, the great bulk of mutations that will ever occur in the body occur during embryonic and childhood development, because a growing body requires rapid cell division, and cell division requires error-prone DNA replication."
@Nemo
"If a 0-1 year-old human isn't measurably along an incremental/discrete damage-unto-death aging continuum--based"
Of course it is! One example is thymic involution.
https://en.wikipedia.org/wiki/Thymic_involution#Age-related_Involution
"Though some sources continue to cite puberty as the time of onset, studies have shown thymic involution to start much earlier.[1] The crucial distinction came from the observation that the thymus consists of two main components: the true thymic epithelial space (TES) and the perivascular space (PVS).[5] Thymopoiesis, or T-cell maturation, only occurs in the former. In humans, the TES starts decreasing from the first year of life at a rate of 3% until middle age (35-45 years of age), whereupon it decreases at a rate of 1% until death.[5] Hypothetically, the thymus should stop functioning at around 105 years of age;[9] but, studies with bone-transplant patients have shown that the thymi of the majority of patients over forty were unable to build a naïve T cell compartment.[10]"
@ Antonio
the basic point I was making is that cells are worse at removing or repairing damage with age - I don't think that is in dispute (I did not say what the cause of this was) . You point out some doubts regarding specific examples I picked out of the air - senescent cell clearance and DNA repair both getting worse with age. The first I agree needs to be investigated more closely, though I suspect we will find that they don't accumulate at a constant rate - whether this is due to faster accumulation, slower removal or a combination of the two is hard to say at this point.
I would say that DNA repair getting worse with age has been adequately demonstrated by Sinclair et al. (nuclear and mito), and referenced previously in this blog. You probably need to remove the development stage from your analysis as of course with greater division there will be more errors. A better comparison would be to compare young mature adults with old adults.
Again I must repeat we need more data to see what is causative and what is only correlated.
Also, IMO your example of Thymus involution as damage is not a good example - clearly this is an organ which is dare I say it, programmed to decay quickly, although we could quickly get into semantics here.
@Mark
"the basic point I was making is that cells are worse at removing or repairing damage with age - I don't think that is in dispute"
Huh?? You still think that it's not in dispute after I showed you that it's false for DNA, according to experimental data, and unknown for senescent cells, since research institutions say they don't know the answer at all and will spent money researching it?
"The first I agree needs to be investigated more closely, though I suspect we will find that they don't accumulate at a constant rate"
Since you suspect something it's true, then it's not in dispute that it's true??
"I would say that DNA repair getting worse with age has been adequately demonstrated by Sinclair et al. (nuclear and mito)"
Where?
"Also, IMO your example of Thymus involution as damage is not a good example - clearly this is an organ which is dare I say it, programmed to decay quickly, although we could quickly get into semantics here."
It's not semantics. Can you show the genes that make the thymus decay? Are there mutants whose thymus doesn't decay?
So Antonio, you are saying that cells don't get worse at repair as they age?!?
For DNA repair: not to a degree that matters to aging.
For senescent cells clearance: nobody knows.
For the rest: I don't know.
For protein crosslinks, there's no way for metabolism to prevent or get rid of them. In this case, damage comes first.
"For DNA repair: not to a degree that matters to aging."
A very bold statement considering there is no consensus in the research community regarding DNA damage and its contribution to aging. Hallmarks places it as a primary damage so the matter is far from settled.
"For protein crosslinks, there's no way for metabolism to prevent or get rid of them."
Well the body does break them down the problem is the halflife of crosslinks is incredibly long in the case of glucosepane, so your statement isnt completely accurate.
Here's a slightly more accurate statement that really doesn't change anything: there's no way for metabolism to prevent or get rid of protein crosslinks fast enough to make any significant difference in disease progression.