A View of the Important Divide in Longevity Science from the Other Side of the Fence

Here I'll point out a view of the great divide in aging research from the other side. I have long argued that the most important divide in the field of aging research is between (a) the minority position of those who see aging as an evolved program, so that, for example, epigenetic changes occur that cause altered cellular behavior that in turn leads to an accumulation of damage, dysfunction, and death, and (b) the majority position of those who see aging as a matter of accumulated damage occurring as a side-effect of the normal operation of metabolism, and that damage results in epigenetic changes, dysfunction, and death. There is a horse and a cart, and some argument over which is which.

Researchers in fact know a great deal about the differences between old tissue and young tissue. They have a very good catalog of those differences. They also have a pretty good catalog of the dysfunctions in specific organs and tissues that accompany age-related disease. The middle ground between those two things, the enormously complex biochemical interactions spanning decades of time that produce aging, is much more of a blank spot on the map. Only tiny slices have been mapped, and it is this gap that allows the freedom to theorize over whether change produces damage or damage produces change.

Why is this important? Because whether you stand on one side or the other of this theoretical divide determines which approach to treating aging you should favor. Treatments for aging must aim at root causes to be effective. If change, such as epigenetic change leading to altered levels of proteins in cells, is the root cause of the damage of aging, then treatments should consist of restoring the right protein levels and epigenetic markers rather than addressing damage. But if damage is the root cause of aging then treatments should be repairing that damage. The potential rejuvenation therapies that are on the wrong side of the line will likely be ineffective in comparison to those on the right side of the line.

Obviously, given my support for the SENS approach to treating aging, I'm in the damage camp. I think that the evidence, such as the presence in old tissues of harmful cross-links that our biochemistry cannot break down, strongly supports the view that aging is caused by damage accumulation, and the observed epigenetic and protein level changes are reactions to that damage. Here, however, is a view from the other side, the programmed aging camp:

Aging is an accumulation of damage. If we want to return the body to a more youthful state, we're going to have to repair that damage. Or ... the body never forgets how to be young. Given the appropriate signaling environment, the body will restore itself to a youthful state. The future of medicine is the future of anti-aging medicine. I don't think anyone seriously disputes this. Infectious diseases are a minuscule problem compared to a century ago, and with hygiene, good public health practices, and responsible restraint in applying antibiotics, we may hope to avoid a return to the days when tuberculosis and syphilis were pandemic. We are fast learning to treat congenital disorders, and safe gene therapies are already being tested.

This leaves diseases of old age as the next frontier. To slow the progress of aging, there is no doubt that signaling approaches work in animals, and will work (probably with less efficacy) in humans. Caloric restriction (CR), exercise and other forms of hormesis are the best approaches we know at present. Pills (e.g. metformin) may offer some of the benefits of CR without the hunger, and an "exercise pill" has been proposed. The next step is to actually reverse aging, to restore the body to a more youthful state. Among those of us who advocate research in the technology of age reversal, there are two prevailing paradigms. I am with the school that says the same signaling approach can be extended to trick the body into thinking it is younger than it is, and the body will renew its cells and replace damaged biomolecules on cue. The other school says that once the toothpaste is out of the tube, it's not going back in. We will have to engineer prosthetics, use bioengineering and regenerative medicine to replace body parts that have worn out.

In the beginning, anti-aging medicine was thought to be fanciful, if not impossible. How could human engineering improve on processes that Nature has been perfecting for a billion years? Then a science of regenerative medicine began very slowly chipping away at that conventional wisdom, and a glimmer of hope pointed to promise of fixing the body directly with engineering, at least in the long run. But a funny thing happened along the way. There are indications in many areas that the body knows perfectly well how to rejuvenate itself, and we need only learn to speak the body's (biochemical) language in order to say, "Have at it!" A few people like me are pointing out that this contradicts everything we thought we knew about evolutionary biology, and that the "selfish gene" is in need of an overhaul. But bench scientists are choosing to sidestep this theoretical debate and simply to do the practical thing. They are pursuing a signaling approach because it works.

I would argue that the signaling approach is largely characterized by failure to obtain meaningful outcomes, and at great cost. Just look at the end result of sirtuin research; enough money expended to fully implement SENS rejuvenation programs in mice, and nothing to show for it but greater knowledge of a small slice of our biochemistry. Where there are successes in more recent years, these seem to result from activation of stem cells in old tissues - and restoring stem cell populations is on the SENS agenda - without any accompanying repair of other root cause damage. This will produce benefits, and fortunately it seems that putting damaged cells in damaged tissues back to work has far less of an effect on cancer risk than was feared, but this doesn't do anything to clear out issues such as amyloids, lipofuscin, and persistent cross-links.

Link: http://joshmitteldorf.scienceblog.com/2015/11/19/anti-aging-medicine-two-paths-diverge/

Comments

Hey all !

''Or ... the body never forgets how to be young. Given the appropriate signaling environment, the body will restore itself to a youthful state.''

This.

This, this is it.

I'm in the programmed aging camp now (but fully respect the pro-damage camp), I used to be in the damage one - but I was gravely
damaged ; D and awaken once, I realized that it's all basically a big programm in motion and the damages are effects of that programm running itself (not the other way around, the programm happens first and allows these damages (imperfections) to happen, nothing is perfect).
It's under different codes. Genes of the DNA strand dictate this damage accrual because when they are activated they create inflammation so let's put this in order :

1-New Life ->
2-Gene Activation (Anti-Inflammatory/Redox homeostasis/High Telomeres/No Damage) ->
3-Aging (Start of the Programm/natural imperfection to program (anti-oxidant are limited/telomeres loss base pair nucleotides/DNA loss of nucleotides per replication, imperfect replication 'Replication End Problem', loss of nucleotides = aging and activation of next steps) ->
4-Gene Activation (Death program when programm sufficiently advanced/Inflammatory genes activation accelerating things (TNF, p53 and myriad of other gene contributors to that inflammation damage) ->
5-Damage accrual (lipofuscin, telomere loss, ceroid, cross-links AGEs, genome dysfunction all over, etc) ->
6-Death.

That is the program I feel.

In a sense it really doesn't matter which camp you are
as many here have suggested, scientists pro-damage or pro-program must band together and
stop the hating, this is petty and only if we work on all these variables, correlative
causative, magical or not, it's a team effort and we stop arguing and do the doing. Curing with scientific breakthroughs, enough talking about it, let's walk the talk,
and if we have too much difficulty stopping damages (aka 'slightly slow aging'), let's focus on (re/retro)programming the program back to original 'young program code' phenotype state
through the genes and their DNA codes. Induced pluripotent stem cells are biorejuvenated and show all the same markers that young people have - no damage, no problems, silenced death genes, high telomeres full of DNA (the lost DNA is back! so the nucleotides are back in town inside, this commands the system to retroERASE all damages that are accumulated, the code does that somehow, whatever damages accumulated the genome can 'dissolve them' (through the proteasome and autophagy, yes even lipofuscin or glucosepane mostly through exocytosis/endocytosis and lyososomal degradation).

The fact that some super aged and suped damaged cells from elders can be totally Reversed or Programmed/Transformed (that is rejuvenation) in them through reprogrammation is a testament it's all one big coded auto-program that can be retroprogrammed and erased as if it never happened in the first place. So to sum, don't lose your DNA nucleotides : D.

1. http://www.ncbi.nlm.nih.gov/pubmed/24268696
2. http://www.ebioscience.com/knowledge-center/cell-type/induced-pluripotent-stem-cells.htm

Posted by: CANanonymity at November 23rd, 2015 9:52 AM

Oh boy, here we go again with this pointless slapfight. Blind men and the elephant, every time.

Each aspect of aging must be analyzed independently of every other. Nobody in his right mind believes that glucosepane is programmed. And whether the craptastic signaling environment that Irina Conboy's been researching is caused by a program or not is immaterial at best.

Isn't it obvious by this point that damage and programmed changes feed on each other? Damage accumulation leads to cellular mistakes leads to damage accumulation leads to...

Some therapies are going to be one way, and other therapies are going to be another. Focusing on this divide like it means anything is counterproductive as all hell.

Posted by: Slicer at November 23rd, 2015 11:03 AM

@Slicer

Chicken and egg dilemma (is the chicken or the egg of the chicken that came first ? !...me thinks it's the chicken, because evolution tells us that the chicken is a descendant of dinosaurs and is a 'mini-remnant' of dinosaur like say a crocodile or alligator ancient lizards (an evolution from dinos to birds), thus like dino eggs, there was a very long evolution to get to the bird (like chicken, a type of bird) : multicellular organism -> dino -> egg -> dino -> egg -> dino -> egg -> bird-dino -> egg -> bird-dino -> egg -> bird -> egg -> bird (chicken). The egg is only the sexual reproduction offspring, there had to be an animal behind that, we can backtrack to dinos to show it is indeed the animal not the egg the real thing that came first (dinos made eggs too, but they were dinos before being eggs, they were an evolution too).

You are very right we should still not waste energy on that and it is obvious damage/programm feed of each other, and damages sure are no good for us.

I feel damages help feed the course of the programm, but the programm started this whole thing.
And if the program is altered, so will the damages be, vice versa for damages to the program.
But at the basic, the damages arrived 2nd in the tree of things happening.

Damages don't make the Creation of the program (what I mean by that, DNA arrived first before it could be damaged, once its structure matter was 'created' it could the be damaged by laws of replication imperfection and imperfection causing stress to that structural DNA).
DNA read like a program that says : '1. you are born and small, 2. you grow to big adult to full sexual maturity, 3. you make children and continue specie, 4. your purpose is done, you die'

Without the program, there wouldn't be any damages or ...life for that matter - in the first place. There would be 'nothing' but thin air...
I know my logic sounds really flawed :D lol but you have to have Life (DNA) before Death (damage accrual)...well that's how I perceive it (again just my 2 cents : )

Posted by: CANanonymity at November 23rd, 2015 11:56 AM

If we look it from a evolutionary angle, it makes sense that damage would come second : cancer cells are a result of nucleotide base pair recombination errors and inflammation all over the system from damage accrual vicious circle. Evolution has chosen that they were would be a trade-off, either we live longer lives, but are not immortal in complex animals (such as us), or we are small uncomplex animals who get immortality and very little DNA division 'errors', little mutation (we have so much DNA mutations going on inside, it's bound to go haywire). So it chose this : We give you a 'long-enough life' but we remove Telomerase from your somatic cells, you are not immortal, if we give you immortality the level of cancer will rise dramatically; because of your complexity and mutational load; cancer will be totally all over you. Thus, it is a Safe Guard Mechanism against uncontrolled cancer in humans, the immune system destroys these tumor cells, but the cost is mortality for us. How is that mortality feasible, well damage accrual is the product. And also, this cancer=protection mechanism IS a damage mechanism. Don't aks yourself why telomeres DROP in tumors etc or other damaged tissues. The body is fighting this by DAMAGING it, the immune system attack (macrophage ROS production reactive oxygen production) the cancer cells and use 'FIRE with FIRE'. So...damages are 2nd thing in the programm, they are *control* code on our life and our safety against cancer. We get a mortal life for that (by damage accrual life-control mechanism.)

Posted by: CANanonymity at November 23rd, 2015 12:26 PM

Quote of Dr. Uri Frank on jellyfish immortallity :

" So why don't humans keep their pluripotent cells as adults [humans, just like in the immortal Irish jellyfish/sea anemone Hydractinia] ? It's a good question. Keeping them in a complex body like ours is
probably too dangerous, as they can easily form cancer.

It's not [so much] a problem in simple animals - [these jellyfish's pluripotent cells] they would probably cut a cancer off.

The price to become complex is to lose the ability to be immortal. "

Posted by: CANanonymity at November 23rd, 2015 12:37 PM

CANanonymity, what do you think someone who subscribes to programmed aging would do about crosslinks?

Regarding the programmed theory of aging in general, one huge problem is that if it's wrong, then we'd be knee-deep-in-you-know-what; damage will continue to accumulate until it kills us. Fortunately, this doesn't affect the damage theory of aging, because it's an absolute fact that damage is what directly causes disease and death. And if you remove the damage thoroughly enough, you'll eliminate disease by definition, regardless if aging is programmed or not.

Posted by: Florin Clapa at November 23rd, 2015 10:07 PM

@Florin Clapa

Hi Florin !

Thanks for your comment and question, to answer your question :
pro-program he/she would advocate reprogramming like iPSC reprogramming stuff all over this field. Why ? Because induced pluripotent stem cells definitely show all the markers and the 'youth' rejuvenation phenotype we seek (the same way that repairing damages do) but this even more powerful, it's a Reversal of aging and back to a young biological age phenotype (the damages are gone/erased from the code - damages such as crosslinks AGEs, so your crosslinks we crossed out of the collagen ECM and other areas where they accumulate...how is that possible, that is hard to say, reprogramming does magic, it may involve stem cell total repair and REconstruction of entire body back to young age; as you can see that iPSC reprogrammation needs stem cell factors Nanog, Oct, Sox, etc, these powerful stem cell factors dictate things to the telomeres and DNA, and litterally reprogrammed the whole thing. And in this reprogrammation, crosslinks and other damages are removed entirely; to be a young phenotype these damages must be removed. You what it makes think of the scar analogy...foetus don't get scars they get full skin healing; they have Very high stem cell factors such as NANOG and Oct, they are Necessary to heal the skin completely back to original; whereas adults...we have scarrification (scar formation in place of skin wound) why not full healing like in the foetus ? because our stem cells are nowhere near has rejuvenating and strong as those in a foetus; our stem cell factors are much less efficient; so we end up with scars when hurt on our skin....). Stem cell factors are dangerous they contribute to cancer formation in humans, cancers are 'stem-cell like' in quality and maintain a biorejuvenated state to proliferate infinitely; they high jack stem cell factors such as Nanog. That is hurdle in programming somatic cells and stem cells that we will have to counter. Still foetus don't necessarily get cancer, so it's not like playing with stem cell factors is always cancer causing; cancer is at the basic mostly inflammation, oxidative stress and dysfunction caused. Foetus are youth-like, have little inflammation or stress, so little cancer formation.

You are right, true or not, this programmed aging theory is a theory (for me it gels (had my epiphany, hope it was not one big joke illusion lol), but not for everyone) and if we totally 'out in the field', then I guess I will feel a little bad (lol), it would mean all along I was right at the start when I was damaged-focused and it's all damaged-caused. But when we are capable of reprogramming this whole think and making the damage be all repaired as if they never happened (as in iPSC PROVE, I don't know what more proof we need, it really is a solid proof that genes reprogramming of the program/code does something very Particular and Unique that none of these other 'repair damage/slow damage' treatment do), you have to ask yourself the funny basic questions : ' Why do we get these damages in the first place ? Is there a reason ? Is it because we Must Die and Deserve it ? Is it because we breathe oxygen and it oxidizes us and kills us slowly; and really there is a big Scheme behind all of this Master Plan (evolution yet again ?) Is it because Evolution chose that, as a human specie, we live long lives and make a couple of childrens, and then die, but to get to that point we would need to die and be safe from getting all those bad muations like cancer that would destroy the specie and its genetics when transfered/inherited by its children ???

One of my favorite quote lines in the movie The Cube from the character 'cube builder' character :
''The Cube...It's ...A Headless Blunder Beneath A Master Plan''.

We can try to figure out that CUBE (3), or just accept that there is NO reason for it for Existing and that all the Laws, Concepts, Calculus, Mathematics and other Theory in our life will never explain anything - because they are Flawed and Life is Imperfect (Perfection is not of this world, only God is Perfect (supposedly), even then...what is Perfection ?? exactly..it's what WE want to believe IT to be, as we assign some definition to it that WE Like...we make these laws etc but they don't add up because they are flawed by nature and life as we THINK we understand it is flawed. There may be - no - magical explanation after all. It's like me asking you, can you explain what is death ? What happens after we die ? Is there God ? Can you explain to me ?...
yeah we have no answers to the unexplainable (because as said no words, no laws, no numbers or magic algorithm explain that, we are flawed and infinitely small in this universe, we know nothing! The first step to being humble is saying, I know very little to nothing and only real thing I know, is that I know nothing).

Posted by: CANanonymity at November 24th, 2015 9:40 AM

CANanonymity, crosslinks accumulate between proteins in the ECM, so I don't see how reprogramming stem cells is going to help. I've heard that one way to deal with crosslinks is to upregulate protein turnover but that leads to leaky blood vessels. Also, crosslinks are created by simple chemistry that can't be reprogrammed away. In other words, it seems physically impossible to prevent crosslinks from forming. This is one example where the programmed theory of aging fails. The nice thing about the damage theory of aging is that it can't fail: if we repair the damage, we eliminate the diseases and death cause by aging regardless of why the damage happens.

Regarding rejuvenating stem cells via iPSC reprogramming, I'm skeptical that reprogramming is actually rejuvenating the cells rather than reversing an adaptation to aging damage, for instance.

Posted by: Florin Clapa at November 24th, 2015 12:51 PM

@Florin Clapa

Hi Florin, maybe you are totally right and ECM crosslinks are really irreversible like you say because of a basic chemical cross-linking reaction in ECM collagen.
But, there is a but, AGEs Advanced Glycation/Glycosylation End Products are the ones that create this crosslinking reaction and irreversible crosslinks (like in the collagen). Perhaps, what I'm getting at, is that reprogrammation has a capability to enhance proteasomal disposition of AGEs and the current crosslinks; as you suggest might be disposed some other way (upregulation of protein turnover or collagen turnover ?)

''Meanwhile endosomes with AGEs fuse with lysosomes, following by processing of AGEs by lysosomal proteases. Grimm et al. demonstrated that lysosomal proteases, such as cathepsins D, L and B play a crucial role in AGE disposal. After processing, small soluble AGE modified peptides are probably released by unknown mechanisms from the cells and transported to the renal system by processes which are not known yet. Impaired function of the kidney would result in accumulation of AGEs. In addition Sano et al. demonstrated that insulin can also lead to AGE elimination over enhanced uptake via macrophage scavenger receptors.''

1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949097/
2. http://www.ncbi.nlm.nih.gov/pubmed/22245096
3. http://www.ncbi.nlm.nih.gov/pubmed/20560835
4. http://www.ncbi.nlm.nih.gov/pubmed/9535837
5. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051457/
6. http://jcs.biologists.org/content/early/2011/12/08/jcs.087858
7. http://www.springer.com/gp/book/9783642168604

''Regarding rejuvenating stem cells via iPSC reprogramming, I'm skeptical that reprogramming is actually rejuvenating the cells rather than reversing an adaptation to aging damage, for instance.''

I can't say about that, but I think telomere elongation back to original size is definitely rejuvenation because it creates a new (original youth) phenotype
and somehow must affect the ECM and its existing crosslinks (perhaps what we accumulated is the best we can backtrack/rejuvenate to (no farther), still if we freeze our age at our 'current biological age' who cares it's better than continuing aging ? Freezing aging is far better than slowing it or repairing it in a catch up mop up game that we lose at), how that is a mystery ?

''Phenotypic transition
from naive to memory T lymphocytes induced by antigen stimulation was characterized by extensive clonal expansion caused by cell division, which induced oligoclonal diversity
and
a rapid loss of telomere length of these lymphocytes.5–8,24 Eventually they enter a state of replicative senescence if they undergo a finite number of cell divisions''

''Ursolic acid ameliorates aging-metabolic phenotype through promoting of skeletal muscle rejuvenation''

''Moreover, there is evidence that the increased expression of specific genes is able to reverse/rejuvenate the aged-phenotype of stem cells''

8. http://www.ncbi.nlm.nih.gov/pubmed/24268696
9. http://www.ncbi.nlm.nih.gov/pubmed/25976755
10. http://www.sens.org/outreach/conferences/have-we-reached-point-vivo-rejuvenation

Posted by: CANanonymity at November 24th, 2015 8:34 PM

CANanonymity, AFAIK, the AGEs which crosslink the ECM are produced in the extracellular space, and so, they can't be eliminated by cellular processes.

And I don't see how extending telomeres could eliminate ECM crosslinks either.

As for claims of rejuvenation, they're a dime-a-dozen nowadays, as I've mentioned elsewhere. On closer examination, it seems that nearly all of these kinds of rejuvenation claims turn out to be either inconclusive, potentially dangerous (might cause cancer, for instance), or don't provide real rejuvenation. So, I'll wait for people like Aubrey de Grey and Michael Rae to analyse them before I take them seriously. For me, all of them are guilty until proven innocent.

Posted by: Florin Clapa at November 25th, 2015 4:16 PM

@Florin

Hi Florin, I understand. I guess this is a big problem. You are very right, these crosslinks are like a frigging crossword you can't solve. Up, down, left, right, you're Crossed every way.

I was reading this from Glucosepane crosslinking product:

'' α-Dicarbonyl trap,

One method attempted to inhibit glucosepane formation is to use an α-dicarbonyl trap molecule, aminoguanidine (AG). AG reacts with the α-dicarbonyl intermediate with a higher affinity than arginine, thus *blocking the cross-link*. While this method has been seen to have some success, it did not greatly interfere with the normal aging of rats.''

And Aminoguanidine AG is a AGEs blocker too, but just like Carnosine (another AGEs blocker) they are not miracle cures; they slow aging quite well and improve health. Still as shown, aminoguanidine barely does nothing on the rat's lifespan. Me thinks, AGEs accumulation is too massive later on and crosslinks end up winning (again with the damage repair 'catch up mop up' losing game), even if AG slows this a bit. Pentosidine and Glucosepane are both crosslinking AGE ones, and Pentosidine is correlated to MLSP, so I don't understand why AG can't do more if it does break crosslinks (there maybe too much AGEs, or quantity and types of crosslinks that are just not broken down by AG).

I understand your skepticism on reprogrammation claims, I too share partly your feeling, I also slightly share some of Ham's sinking feeling.

Posted by: CANanonymity at November 26th, 2015 12:10 AM

''excessive ECM deposition, tissue stiffening and ultimately scarring''

AGEs caused crosslinks stiffen the ECM and here I read that scarring IS tissue stiffening and excess ECM deposition.

Yet,

foetus can heal their skin wounds back to original state as if nothing happened (no scars left after injury wound is healed). Foetus activate a plethora of stem cell factors such as Nanog, Oct, Sox and Zincfinger domains (command stem cells rejuvenation and telomere elongation, when zincfinger is activated telomeres are dramatically and sporadically elongated in an instant).

This would mean that the ECM can be remodelled by stem cells or degradation/turnover or some combination; when telomeres get back up they signal the stem cells (stem cells' own telomeres are back up too, so stem cells must do something or communicate with the ECM and fibroblasts). Crosslinks dissapear during that process (? how) and as you can see in foetus skin is fully healed (skin ECM crosslinks gone ! (supposedly)). The skin is rejuvenated in foetus after the injury; this means full reconstruction of ECM scaffolds and disposal of crosslinks somehow.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967791
2. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046088

Posted by: CANanonymity at November 26th, 2015 12:25 AM

CANanonymity, what's happening during human development seems to be similar to increased protein turnover which has been tried and has been found to produce unacceptable side effects as I've mentioned before.

Posted by: Florin Clapa at November 27th, 2015 12:25 PM

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