76 replies to this topic

[Bogomoletz II]

To me the premise seemed reasoable — so much so, in fact, that I ended up taking the conclusions for granted (and you never want to take anything for granted). After all, organisms are just cells and bundles of cells doing their thing. However, I ran into a critique of SENS critisizing, in particular, this very approach. Here's an excerpt:

“The bankruptcy and falsity of any hypothesis directly connecting some cellular processes with the aging of the organism as a whole, are confirmed by the very existence of animals with negligible senescence. When making this or that aging hypothesis or interpreting this or that aging phenomenon, biogerontologists [. . .] as a rule miss the existence of those multicellular taxa the organisms of which are in fact free of aging and possess potential immortality hampered neither by the generation of reactive forms of oxygen nor telomere shortening, apoptosis or any other processes by which organismal senescence is normally explained. Moreover, these taxa have a long evolutionary history and the orgasnisms of their evolutionary progenitors in most cases also possess potential immortality. The disregard of all these fundamental facts is likely explainable by this very simple circumstance: researchers just cannot explain them.

“In reality, nowadays nobody could argue against the proposition that the set of cellular mechanisms characteristic of Metazoa has specific differences. This feature has become stable enough in the course of evolution, so that Metazoa are now a single phylogenetic tree. But if species of both aging and non-aging animals with a similar set of cellular and molecular mechanisms are equally existant, then it is quite likely that aging should be explained not by cellular mechanisms but by something completely different; for instance, by certain design elements of animals subject to aging. That’s not just a speculative conclusion, but a quite evident one, as suspicious cellular processes of animals with negligible senescence do not negate their eternal youth. (It should be mentioned that those molecular processes which cause the very 7 key SENS damages according to Aubrey de Grey do not exclude eternal youth either.) This is why most hypotheses directly connecting certain cellular processes with the aging of the organism as whole have fulfilled their initial role and turned into both a dangerous myth preventing the progress of biogerontology and into a branch of metabiology infesting all fundamentals of biogerontology and of ‘Strategies for Engineered Negligible Senescence’ in particular. As a result, the whole of modern gerontology consists, as any metascience does, primarily of completely unproved hypothesis, dogmata, pseudo-postulates, beliefs and SENS projects of Aubrey de Grey. The outcome: in recent deades there has been no serious technological breakthrough in the field of radical life extension.”

From ‘The SENS Project and the Tragedy of Biogerontology,’ by Olexiy Boyko, the developer of the astrocytic hypothesis of mammalian aging. Written for the SENS challenge initiated by ‘Technology Review.’ (Translated from Russian by an unknown translator.)

Edited by Bogomoletz II, 05 March 2014 - 04:24 AM.

[addx]

I would go so far as to say that the cause of aging is infact an increasing inability of the the nervous system response to orchestrate and regulate repair of tonic and acute damage to tissues.

Exacerbations of nervous system disorderdness causes degenerative and autoimmune diseases which are the leading cause of death in elderly, but as said, I feel a slow "lack" or "drag" of the nervous system is infact responsible for general aging as well. The nervous systems absorbs experience and it just gets all filled up like a harddrive, starts to overwrite, merge, fuse, overassociate or underassociate or corrupt data.

Autoimmune diseases are "manias" of the uncoscious nervous system that regulates the immune response. Cancer is like a depression of the uncoscious nervous system that regulates cell proliferation.

The unconscious nervious system also accumulates experience and it might have accumulated some glitch under some weird extreme circumstances that causes it to react manicaly to some body tissue or chemical(your thyroid for example). Various kinds repeated activity of organs(for example breasts are "activated" by sexual hormons each ovulation cycle) might cause an decrease in nervous system inhibition of the activity in the end resulting in unchecked activation and cancer.

The only thing in the human body that is theoretically hard to imagine to be regenerateable is the stored memory of the nervous systems. All else can be replenished with new exogenous resources, cells can be patched and replaced. Only the stored memory ends up more and more wrong and corrupt and off as time goes on and it can not "fix itself".

Here's one example where they made a connection http://www.scienceda...30711142357.htm.

Edited by addx, 06 March 2014 - 04:16 PM.

[nowayout]

So is Boyko saying that organisms with negligible senescence actually do experience the same amount of accumulation of senescent cells with aging as organisms that do senesce? That seems wrong almost by definition.

[xEva]

So is Boyko saying that organisms with negligible senescence actually do experience the same amount of accumulation of senescent cells with aging as organisms that do senesce? That seems wrong almost by definition.

No, he is saying that, on the cellular level, the organisms with negligible senescence experience the same pressures that typically account for aging -- mitochondria ROS production, telomeres shortening, apoptosis, etc -- and yet this does not lead to the emergence of senescent phenotype. He stresses that cellular mechanisms in both aging and ageless species of Metazoa are virtually indistinguishable.

Last night I did some reading of his articles, and even though I am not too keen on his 'Astrocytic hypothesis', I find his arguments against of the prevalent hypothesis (that aging is accumulation of damage at cellular level) quite compelling.

IMO one of the strongest arguments against the prevailing hypothesis are parabiosis experiments, where surgically joined animals, young and old, share circulatory system (or when tissues of an old individual are implanted into a young) with the result that old cells rejuvenate. This clearly implicates something that goes on on the whole organism level. And yes, it is possible that aging starts in the brain, the largest endocrine organ that orchestrates the workings of all other systems.

[Marios Kyriazis]

This accords with our view that aging is not just a matter of components (such as cells) but it is something more profound, involving not just the entire organism but also the environment of that organism (such as society and culture). We will soon be publishing a 10-part special issue on this, here:

http://benthamscienc...20140109-01.pdf

[addx]

And yes, it is possible that aging starts in the brain, the largest endocrine organ that orchestrates the workings of all other systems.

Yea, although I feel calling it an endocrine organ is a drastic understatement of its function. Also, I would say there are more than one "brains" and they are interconnected. The enteric nervous system is capable of working severed from the rest. The whole digestive system looks like a big wormlike creature inside us caught in a symbiotic enslavement relationship with the rest of the organs and even has its own autonomous brain.

The nervous system is the only system whose "state" can not, even in theory, be rejuvenated by new materials because by definition it records learned states and facts about interaction with the world(senses, foods, even bacteria and viruses) which must be preserved over time and not erased by some rejuvenation process which should by definition restore the "default state"(young and eager).

The brain doesnt just provide conscious and subconscious processing. The unconscious processing handles all organs but even things like infiltration from bacteria and viruses. The brain operates internal threats(bacteria, damage, proliferate) using a fear/desire response(modulated primarily by opioids), the same mechanisms and neurotransmitters that it uses for conscious threat and fear response. It has to remember everything, it can not reset as this is not evolutionary smart for survival, and the amount of such memories starts to become overwhelming. Evolution does not favour survival of one generation. If what I'm saying is right then evolution has to balance between the individual learning fast enough and living long enough to take advantage of the learned skills.

This abstract function of emotionaly sacrificing/dissociating from the unwanted "now" in order to reach the wanted future (projected, to which we attach emotionaly instead of to "now") is infact the correct explanation of the primary abstract function modulated by the opioids. The opioids effect is essentially a drive to learn how to control an object which facilitates its integration. The opioids provide the motivation to sacrifice the current wellbeing(relaxedness, contentess) in order to learn of a control method. Learning a 100% efficient control method results in mentally integrating a pleasuring object as ones own, just like when you learn to move your hands as an infant, repeatedly being urged to move them to achieve control as when they're integrated they can provide move pleasuring well being.

I would very much presume that aging is infact mostly correlated with opioid activity. But that's just me, I think the opioids are a holy grail.

Edited by addx, 06 March 2014 - 07:38 PM.

[adamh]

An interesting theory for sure. I particularly like the part about old tissues becoming young when implanted on young hosts. Does this happen also when the circulatory systems are joined? I hadn't heard that part. That brings to mind some science fiction stories I've read in which young people are drained of their "life force" or some such and this allows older people to live on forever.

If mean if it really works then it stands to reason its being done, perhaps covertly. They would have to match blood type at a minimum, perhaps thats all that would have to be matched since only blood is interchanged? And would the young donor become more aged or would he/she retain their youth? I wonder how long this would take if even possible? It makes ya think, don't it?

[nowayout]

IMO one of the strongest arguments against the prevailing hypothesis are parabiosis experiments, where surgically joined animals, young and old, share circulatory system (or when tissues of an old individual are implanted into a young) with the result that old cells rejuvenate.

I thought this actually didn't really work. See for example the recently published work on rejuvenating skeletal muscle in old mice via manipulation of MAP kinase pathways in old stem cells.

http://med.stanford....ruary/blau.html

They mention that

the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles. - See more at: http://med.stanford....h.OAMRgXb4.dpuf

[Stem cell from old mice] are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles.
the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles. - See more at: http://med.stanford....h.OAMRgXb4.dpuf
However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles.” - See more at: http://med.stanford....h.OAMRgXb4.dpuf
However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles.” - See more at: http://med.stanford....h.OAMRgXb4.dpuf

However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles. - See more at: http://med.stanford....h.OAMRgXb4.dpuf
However, when we isolated stem cells from older mice, we found that they exhibit profound changes with age. In fact, two-thirds of the cells are dysfunctional when compared to those from younger mice, and the defect persists even when transplanted into young muscles. - See more at: http://med.stanford....h.OAMRgXb4.dpuf

Yet they were able to reverse senescence in the older stem cells by manipulating certain biochemical pathways at the individual cellular level, transplant them back into old mice, and got rejuvenation of muscle tissue. This whole experiment is IMO a strong argument against Boyko's hypothesis, and casts a strong question mark over the parabiosis experiments you mention (which I admit I am not too familiar with).

Sorry, the editor is going completely bananas on me, causing the problems in the quote of the previous post, and preventing me from fixing it. Tech support?

[xEva]

Re parabiosis experiments, there are a couple of threads here about this, if you care to search. They have links to studies themselves and discussion.


Re Boyko, last night I skimmed a few of his articles, but this morning, looking for a quote I bumped into this 'popular version' (in Russian), supposedly written by him, and it contains gross errors in description of mitochondrial biology [*]. If this article is written by him, as it is claimed upfront, then.. Who is this Boyko?

The central issue of his hypothesis, that mammalian brain stops development soon after birth, is not supported by evidence either. It continues to grow, in humans apparently at least until the age of 6, and it has been established back in the 1990s that neurogenesis takes place in adult brain too (even though some of it is still being contested -?).

However, this does not invalidate the argument that organisms with negligible senescence experience the same stresses on the cellular level.


------------

[*] In the offending paragraph (section 4), he uses liposomes instead of lysosomes, 3 times in a row, which precludes it from being a typo. And in the second instance he states that "liposomes are responsible for mitochondrial biogenesis". Even if he meant lysosomes instead of liposomes, this is still nonsense.

Edited by xEva, 07 March 2014 - 06:14 AM.

[addx]

Yet they were able to reverse senescence in the older stem cells by manipulating certain biochemical pathways at the individual cellular level, transplant them back into old mice, and got rejuvenation of muscle tissue. This whole experiment is IMO a strong argument against Boyko's hypothesis, and casts a strong question mark over the parabiosis experiments you mention (which I admit I am not too familiar with).

They manipulated the p38 map kinase if I read that correctly, probably inverting it somehow.

This pathway is normally activated by stress and degrades the cell.

Dynorphin on kappa opioid receptors activates p38 map kinase in response to stress.

The young body did not reverse the accumulated stress in the old cells. The old cell suffered through a life of p38 map kinase activating, degrading the cell, the young nervous system does not reverse this, why would it?

It is becoming evident that kappa opioid receptors(antagonism of them) are crucial for rescuing a whole line of mental issues such as depression, anhedonia, addiction, anxiety and all related.

Kappa opioid receptors provide a counterbalance opposition to mu opioid receptor activity(the ones that heroin binds to). They upregulate to counter and thus facilitate tolerance(aversion) and withdrawal to all rewarding activities. All of those effects are infact consequences of the fear response faciliated by kappa opioids.

Kappa opioids regulate "attitude" towards "bad objects"(that bring pain) - or in other word the fear response. They do this for the conscious but also for the unconscious, regulating the immune response (bacteria are also bad objects) using the fear response mechanisms. Within that scope they are able to "sever"/"destroy" bad objects from being integrated with the body which includes bacteria and such. Within the mental scope they give rise to selfdestructive and isolating tendencies when involved in maladaptive thinking processes..

"The aging process is associated with various morphological and biochemical changes in the nervous system that may affect the processing of noxious inputs. This study showed greater hyperalgesia and up-regulation of spinal dynorphin (DYN) expression in aging than in young adult rats during CFA-induced peripheral inflammation. These data indicate that nociception is regulated differently in aging individuals, a fact that should be considered when selecting treatment strategies for aging populations with persistent pain. © 2003 Elsevier B.V. All rights reserved."

http://hub.hku.hk/handle/10722/188561

I think more could be found that proves it.

Edited by addx, 07 March 2014 - 10:48 AM.

[nowayout]

The young body did not reverse the accumulated stress in the old cells. The old cell suffered through a life of p38 map kinase activating, degrading the cell, the young nervous system does not reverse this, why would it?

Exactly.

[xEva]

The young body did not reverse the accumulated stress in the old cells. The old cell suffered through a life of p38 map kinase activating, degrading the cell, the young nervous system does not reverse this, why would it?

Exactly.

I'm not qualified to judge why old muscle cells' "defect persists even when transplanted into young muscles" in Helen Blau's study. This could be due to many factors and various details in the technique used, or specific tissues examined. This finding goes in contrast to the previous research:

"The results of these studies unequivocally pointed to the aged environment contributing substantially to the impaired regenerative potential of older individuals (Conboy et al., 2005). When exposed to youthful influences, aged stem cells adopted a more youthful potential, and when exposed to the influences of an aged systemic milieu, young stem cells lost regenerative potential (Conboy et al., 2005; Brack et al., 2007; Villeda et al., 2011). These studies also definitively confirmed, using genetic lineage tracing, that the tissue regeneration phenotype was due to the resident stem cells, not due to those that could potentially migrate to the tissue from the partner parabiont."

Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity, Aging Cell, April 2013

As for "Why would it?" question, addx made 2 mistakes with it. First, he presumes that "young nervous system" should be responsible for age-associated reversal of defects in transplanted tissues. Second, the way he posed it suggests that if we do not know why some things should be possible then they really should not be possible. This unfortunately widespread attitude in science is antithetical to science.

So why, when exposed to youthful influences, aged stem cells adopt a more youthful potential? This is the 'million dollar question' the answer to which we surely would want to know


But we sidetracked. The question is, why animals with negligible senescence do not age. Their cells are subject to the same stresses as the cells of the aging species. Is it due to their superior ability to repair? Or something else? What exactly accounts for the difference?

Edited by xEva, 07 March 2014 - 06:01 PM.

[nowayout]

The question is, why animals with negligible senescence do not age. Their cells are subject to the same stresses as the cells of the aging species. Is it due to their superior ability to repair?

Probably. And what I am missing is why assume whole-body mechanisms for repairing (besides maybe some immune-system cleanup of haywire cells)? Seems more likely that the superior repair mechanisms would be at the cellular level.

[xEva]

And what I am missing is why assume whole-body mechanisms for repairing (besides maybe some immune-system cleanup of haywire cells)? Seems more likely that the superior repair mechanisms would be at the cellular level.

It's cause in these heterochronic parabiosis experiments old cells improved their 'cellular level' repair mechanisms when exposed to 'young blood'.

Here is a popular press article about the last year study. Interesting that the protein they identified, GDF-11, "involved in mesodermal formation and neurogenesis during embryonic development." (wiki) So, both addx and Boyko maybe onto something.

[Bogomoletz II]

I would go so far as to say that the cause of aging is infact an increasing inability of the the nervous system response to orchestrate and regulate repair of tonic and acute damage to tissues.

That would exclude plants and, indeed, all remaining kingdoms. The CNS controls a lot, including some involuntary processes, but not everything. On the macro level it's the main point of control, but its control is not as fundamental and centralized as that of protein-coding genes. For example, the main difference between the sexes is hormonal rather than genetic, but the way gonadal steroids work is by influence over gene expression, and besides, it's genes that program the development and maintanance of the glands that secrete these steroids to begin with.

Exacerbations of nervous system disorderdness causes degenerative and autoimmune diseases which are the leading cause of death in elderly, but as said, I feel a slow "lack" or "drag" of the nervous system is infact responsible for general aging as well. The nervous systems absorbs experience and it just gets all filled up like a harddrive, starts to overwrite, merge, fuse, overassociate or underassociate or corrupt data.

The mnemonic capacity of the unaged brain is really too great to be talking about overload or scarcity (maybe it wouldn't be if our lifespans were hundreds and thousands of years long). The brain prioratizes recollections, so that the ones that are recollected less frequently become forgotten, and that's why, for example, your command over a language deteriorates if you don't practice. Different regions of the brain are responsible for regulation of involuntary processes and consolidation of memories.
================================

Edit. Do you specifically mean the neuroendocrine theory of aging?

Edited by Bogomoletz II, 08 March 2014 - 04:43 AM.

[addx]

The young body did not reverse the accumulated stress in the old cells. The old cell suffered through a life of p38 map kinase activating, degrading the cell, the young nervous system does not reverse this, why would it?

Exactly.

I'm not qualified to judge why old muscle cells' "defect persists even when transplanted into young muscles" in Helen Blau's study. This could be due to many factors and various details in the technique used, or specific tissues examined. This finding goes in contrast to the previous research:

"The results of these studies unequivocally pointed to the aged environment contributing substantially to the impaired regenerative potential of older individuals (Conboy et al., 2005). When exposed to youthful influences, aged stem cells adopted a more youthful potential, and when exposed to the influences of an aged systemic milieu, young stem cells lost regenerative potential (Conboy et al., 2005; Brack et al., 2007; Villeda et al., 2011). These studies also definitively confirmed, using genetic lineage tracing, that the tissue regeneration phenotype was due to the resident stem cells, not due to those that could potentially migrate to the tissue from the partner parabiont."

Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity, Aging Cell, April 2013

As for "Why would it?" question, addx made 2 mistakes with it. First, he presumes that "young nervous system" should be responsible for age-associated reversal of defects in transplanted tissues. Second, the way he posed it suggests that if we do not know why some things should be possible then they really should not be possible. This unfortunately widespread attitude in science is antithetical to science.

It was a question expressing high logical improbability, nothing else. I presume that the young nervous system can not know of a stressed cell it did not stress so there's no logic of it activating a reversing mechanism on it. The regular activities of the young nevous system might at some point trigger a reversing mechanism for some other reason. The old nervous system might be less inclined to do so, since it is busy doing the opposite, stressing the cell. But the introduction of the cell has high logical improbability of resulting in spontaneous p38 map kinase activity inhibition or in triggering the nervous system to cause it.

Also, I do not suggest it is not possible. They did it in vitro via a drug that inhibits p38 map kinase, which mediates stress, rejuvenated the cells and made them divide happily into fresh new young looking operating stem cells. This means it is possible that the body has a mechanism that CAN do it. But why would it in response to basicaly nothing, no triggering event? Or do you think the nervous system detects the old cell introduced into the body? If it does it means it would reverse ageing of all old cells in a young body. I find this quite unreasonable for reasons that are too long to explain but in short, my general idea of how the mechanisms of the body and nervous system form.

Nevertheless, regardless of that, the experiment proved that cell degradation that happens in aged rats is caused and rescued by manipulating a pathway that is normally operated by the nervous system.

This to me translates that the nervous system causes primary ageing of rats with other factors probably contributing.

It also quite precisely pointed to a logical pathway - the p38 mapk stress pathway enabling my theory to extend this. Still, any fallacy in my theory does not deny the stress pathway of ageing being proven by the above mentioned study.

With a little knowledge of how the nervous system works we can see that generally learned stress is hard to unlearn which means life experience causes a constant increase in stress levels(primarily unconscious) which explains why old aged rats cells endure so much stress signalling rendering them disabled.

But we sidetracked. The question is, why animals with negligible senescence do not age. Their cells are subject to the same stresses as the cells of the aging species. Is it due to their superior ability to repair? Or something else? What exactly accounts for the difference?

Because judging by that research senescence is caused by stress signalling. For me, most interesting are more "normal"(more evolved) animals that reach and adult state and live long. Could we perhaps, just for kicks, review how stressed their life is using some idea of an interspecies scale? This would include diet(long lived whales eat krill AFAIR which for me seems like quite an unstressfull, healthy and also regular meal). They also have no natural enemies. Feel free to chime in if you like

For the less evolved animals like hydras and ever growing aquatic life there seems to be another key factor which I don't really think we can make use of, but what the heck. The ever growing or regenerating factor creates new cells that function even if the old endured much stress. Some of them might have different stress signalling, there's all kinds of weird adaptations among these and I think we can not use either of them to help humans, but that's just my opinion. They are interesting to research still, but I don't think they'll give us what we're really after.

[Bogomoletz II]

This accords with our view that aging is not just a matter of components (such as cells) but it is something more profound, involving not just the entire organism but also the environment of that organism (such as society and culture). We will soon be publishing a 10-part special issue on this, here:

http://benthamscienc...20140109-01.pdf

Do you mean the way culture influences people to make choices about their lifestyle? That's still about biology, at its root. Or do you mean psychological and social aging? Mental senility is caused by biological changes, at least for the most part, and the social aspects of old age are quite another story for another time. Looking forward to the issue.

Edited by Bogomoletz II, 08 March 2014 - 05:08 AM.

[Bogomoletz II]

An interesting theory for sure. I particularly like the part about old tissues becoming young when implanted on young hosts. Does this happen also when the circulatory systems are joined? I hadn't heard that part. That brings to mind some science fiction stories I've read in which young people are drained of their "life force" or some such and this allows older people to live on forever.

It's the central element of folklore about Countess Elizabeth Bathory, who supposedly bathed in the blood of virgins to rejuvinative her skin. Someone on these forums made a good joke about this whole tissue transplantation thing: "Suddenly the Third World adoptions of the ever-young Madonna take a sinister twist."

And would the young donor become more aged or would he/she retain their youth?

Reportedly, in studies where the circulatory systems of young and old mice were joined, the change was mutual: the aged mice improved while the unaged mice worsened.

[Bogomoletz II]

Re Boyko, last night I skimmed a few of his articles, but this morning, looking for a quote I bumped into this 'popular version' (in Russian), supposedly written by him, and it contains gross errors in description of mitochondrial biology [*]. If this article is written by him, as it is claimed upfront, then.. Who is this Boyko?

I'm not familiar with him, but apparently he is a Candidate of Sciences from the The Odessa I. I. Mechnikov National University. The aforementioned critique of SENS, written by him (through the bulk of which he ranted against Aristotelianism), made me raise an eyebrow more than once, too, but maybe we should stick to the rule that "The message is more important than the messanger" and focus on inferring the implication of the fact that animals with negligible senescence experience the same cellular pressures.

On an emotional level, I hope Boyko is wrong about the alleged futility of repairing cellular demage with the aim of organismal rejuvination, since that would oblige us to restart and rethink so many things, particularly as it relates to SENS, which currently due to neglect of the field is one of the few serious projects offering at least some potential solution to the problem of biological aging.

Edited by Bogomoletz II, 08 March 2014 - 06:24 AM.

[Marios Kyriazis]

This accords with our view that aging is not just a matter of components (such as cells) but it is something more profound, involving not just the entire organism but also the environment of that organism (such as society and culture). We will soon be publishing a 10-part special issue on this, here:

http://benthamscienc...20140109-01.pdf

Do you mean the way culture influences people to make choices about their lifestyle? That's still about biology, at its root. Or do you mean psychological and social aging? Mental senility is caused by biological changes, at least for the most part, and the social aspects of old age are quite another story for another time. Looking forward to the issue.

I mean that the environment we are in influences our biology. This is the basic tenet of epigenetics. Also we need to consider the human body as part of life in the general, wider sense, subjected to all the laws of physics and cybernetics (see here for some details: http://arxiv.org/abs/1402.6910).

SENS-related concepts fail to consider this and that is why I believe that will not be successful in eliminating aging.

[addx]

I wonder if rubbing the scalp in some kind of penetrating p38 map kinase inhibitors would enable restart of hair growth?

*keeps fingers crossed*


I do believe they rescued(!!) alopecia-like balding in some stressed/anxious genotype of rats that bald prematurely by using I think CRF antagonists or something very near CRF in the stress cascade, not sure.

Edited by addx, 08 March 2014 - 12:01 PM.

[addx]

Heres another example of them finding the same connection

"Ataxia-telangiectasia and rad3 (ATR)-related Seckel syndrome is associated with growth retardation and premature aging features. ATR-Seckel fibroblasts have a reduced replicative capacity in vitro and an aged morphology that is associated with activation of stress-associated p38 mitogen-activated protein kinase and phosphorylated HSP27. These phenotypes are prevented using p38 inhibitors, with replicative capacity restored to the normal range. However, this stressed phenotype is retained in telomerase-immortalized ATR-Seckel fibroblasts, indicating that it is independent of telomere erosion. As with normal fibroblasts, senescence in ATR-Seckel is bypassed by p53 abrogation. Young ATR-Seckel fibroblasts show elevated levels of p21^WAF1, p16^INK4A, phosphorylated actin-binding protein cofilin, and phosphorylated caveolin-1, with small molecule drug inhibition of p38 reducing p16^INK4Aand caveolin-1 phosphorylation. In conclusion, ATR-Seckel fibroblasts undergo accelerated aging via stress-induced premature senescence and p38 activation that may underlie certain clinical features of Seckel syndrome, and our data suggest a novel target for pharmacological intervention in this human syndrome."

http://biomedgeronto.../68/9/1001.full

There are many more studies proving p38 map kinase stress activation causes "a kind of ageing" that degrades the cells function. There is no doubt about this.

What can be doubted is if it is the primary mechanism of ageing.

My point that I throw on the table in hopes of sparking some out of the box thinking is the idea that the nervous system evolved so that it never forgets an adaptation required by the environment. It doesn't forget fears or adaptations that were made to cope with them and this is quite reasonable if you ask me. The adaptations to fears mainly involve increase of stress signalling and in long term increase of numbing of awareness stress so the person doesn't suffer from the experience of chronic increased stress signalling resulting from the adaptation, but merely suffers the consequences - ageing..

In other words, once the nervous system concludes that it needs to stress a population of cells chronically, it is improbable that it will ever forget the adaptation. Now, if this is on a spectrum, the "accumulated intensity" of the fear-stress adaptation determines speed of premature ageing. I doubt a process that reverses this is biologically sound to evolve so I believe the intensity of the adaptation can only grow with time and new stressful experience.

My idea is that, given a huge amount of all kinds of factors causing varying acute or chronic situations that result in stress signalling - some tissues to start to age more than others in some people and one could fathom this creating an entire palette of different downstream cascades of ageing caused by decreased function of certain tissues unraveling and causing more stress eventually in tissues that struggle to compensate etc.


Wiki on MAPK has a nice line that nicely ties all causes of ageing to JNK and p38 signalling.

"Both JNK and p38 signaling pathways are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in adaptation to stress, apoptosis or cell differentiation."


ERK mapk signalling on the other hand is about cell proliferation.

But these pathways are also regulated from outside the cell. Kappa opioid receptors, mediators of the fear/stress response and adaptation, cause aversion when activated by activating p38 mapk pathway on serotonergic neuron cells which causes a decrease in serotonergic signalling (which probably results in a dopamine disinhibition somewhere in the brain that produces aversion type urges).

Edited by addx, 08 March 2014 - 12:23 PM.

[xEva]

On an emotional level, I hope Boyko is wrong about the alleged futility of repairing cellular demage with the aim of organismal rejuvination, since that would oblige us to restart and rethink so many things, particularly as it relates to SENS, which currently due to neglect of the field is one of the few serious projects offering at least some potential solution to the problem of biological aging.

But we are obliged "to restart and rethink so many things" regardless -- due to the simple fact that our knowledge of even basic anatomy and physiology is still incomplete. I am talking about the primo-vascular system, which is the third circulatory system that is formed first, before anything else. It plays fundamental role in development, growth and, presumably, aging -- certainly in repair (and cancer). Most people here or at SENS know nothing about it, the assumptions being that what we don't know can't possibly be important. But, if I may venture a prediction, 50 years from now, when more about it will be known (the West 'discovered' it in 2008), they will say about our time and our efforts something like this: 'No advancement in understanding of aging could be made at the time, because they did not account for this system'.

I bet you too hear about it for the first time right?

With such huge gaps in our knowledge, all we can hope for is to stumble on some solutions by chance.

[addx]

I believe the flaw of most research base is lack of agreement and research into fundamental abstract "biologic life concepts" that can be used as a guide to predict concrete research direction.

I have been able to conceptualize neuron network functions in that way - colored by their modulating neurotransmitter, but most other bodily functions can be abstractized like that as well.

Here's an example:

Dopaminergic networks are ALWAYS about relational processing - distance between real state and projected state. In that sense they provide executive guidance to projected states of ALL "integrated/controlled objects" including muscles(alzheimers vividly explains it, muscle movement works by projecting a position and the dopaminergic networks provide autimatic guidance to that position. Dopaminergic networks provide/facilitate guidance/control methods of EVERYTHING, even people, providing for social paranoia, love infatuation etc.

This is not just wishful thinking abstraction. Dopaminergic networks always provide this function because the electrochemical properties of dopaminergic signalling, the electric functions it provides, the frequency of signalling is suitable for such computations. Evolutions reuses it over and over again for the same abstract function each time it evolves something new. Dopaminergic signalling infact provides brain waves.

Serotonergic networks are ALWAYS about "level of integration" processing. They keep a "state" record and tonically regulate "strenth" of associated dopaminergic relational control methods which is a much useful/better way of saying "serotonin inhibits dopamine". Serotonin regulates level of integration with "bad objects" just as it does with "good objects". Integration is provided by dopaminergic methods of control. Level of integration is provided by their success in execution confirming methods of control to work. There are also methods of control that control us. These are methods of control of "bad objects" or in other words, dopaminergic networks provide "control to avoid" the "bad" and thus facilitate a basis for anxiety as well. There's serotonergic receptors that excite rather than inhibit - these handle control methods of bad.

Opioid networks are ALWAYS about modulating immediate sacrifice for a better future level of "well being". Well being "measure" is, as said provided by serotonin as an increase in methods of control/intergration of good objects, an increase in methods of avoidance control of bad object and an increase of methods of control(pleasing) of bad objects that are integrated and also denied to be bad because of failure to avoid(repressed knowledge about the tamer of the horse being infact its abuser, stockholm syndrome etc). Opioidergic signalling provides ability to sacrifice the now for the future by numbing/easing the painful, negative, opposing body stimuli of the now in order to execute and confirm a control method that when confirmed will provide a new level of well being. There is positive - mu opioid - providing the ability to sacrifice the now(emotional now) and generate a rise in motivation to put in effort to learn to control a pleasurable/positive object. Kappa opioid provide the ability to sacrifice the now to generate increasing motivation to learn to control a negative object, or if helplessness has been learned from too much failure, kappa opioids provide means of repressing the knowledge of being integrated with a bad object but still potentiating the required dopaminergic urges to please it(stockholm syndrom, horse taming, whatever learned helplessness denial).

This actually works at the social psyche level, bodily functions level, all levels. Food is processed as objects. The body recognizes good or bad and processes using the same mechanisms as it does social objects. Social objects have an extra piggy back of vasopressin and oxytocin signalling also potentiating dopaminergic relational control urging, but the underlying system is the same. Pathogens are also processed as objects, regulated as threats, fears etc. All these subnetworks have evolved some of their own specialities perhaps and I guess there has to be some wierd exceptions to these abstract concepts, but I have not yet been dissapointed with how these basic concepts predict studies.

I have more, but just to give an example. It can easily be seed - the main abstract biologic functions of life - evolving through time. Control methods integration with the real world providing well being levels. The most basic life forms follow the same paradigm and the paradigm can be tracked through evolution easily.

Evolving such concepts can actually predict systems that we overlooked. It takes a multidimensional approach to get at these basic concepts but I think it can be worth it. You can see how concepts of aging "oozes" from the function of opioids providing sacrifice(aging) mechanisms. It is sacrifice for "life", even for offsrpings, maternal care and sacrifice for the offspring is also a function of opioids(and piggybacking oxytocin. the mammalian urge to take care of offsprings evolved though oxytocin providing a piggyback "wellbeing input" on top of opioidergic signalling if the attached offspring survives). It takes a wider understanding to create these concepts.

Aging is evolutionary and conceptually sacrifice for future life(primary abstract function of opioids). If an animal did not age there would be less genetic changes, less generations and evolution/adaptation of such species would be slower - they would not surive faster aging competition. I can't really understand why this whole line of research fails to see this. It's almost as if people think aging is a glitch, an imperfection in mother nature, cells that can't last long, whatever, as if it could not create us better. While infact it did it on purpose.

An animal that has been beaten by other animals, stressed too much SHOULD die. Gathering too much stress causes premature death. It as an evolutionary function which the individual experiences as punshiment for failure but from the one order up perspective of life this punishment is actually pro-life. The ones that cant cope, die to provide more chance for the ones that can cope to procreate and spread their superior genetic material and control methods. Life is bigger than an individual or a single generation.

A species that is in danger and being overrun by other conditiones experiences more stress, lives shorter, procreates more(stress increases procreation) in order to speed up evolution and make up for the lack of adaptation.

Anyway, lack of perspective and understanding of *life* is driving scientists into dead ends and random experimenting.

Edited by addx, 09 March 2014 - 02:54 PM.

[nowayout]

It as an evolutionary function which the individual experiences as punshiment for failure but from the one order up perspective of life this punishment is actually pro-life. The ones that cant cope, die to provide more chance for the ones that can cope to procreate and spread their superior genetic material and control methods.

This is a misunderstanding of how evolution works. There is no "pro-life" purpose to it of the kind you ascribe to it; that kind of teleological reasoning (note, teleo-, not theo-) has no place in science. Also read Dawkins's writings on the fallacy of group-level selection.

[addx]

It as an evolutionary function which the individual experiences as punshiment for failure but from the one order up perspective of life this punishment is actually pro-life. The ones that cant cope, die to provide more chance for the ones that can cope to procreate and spread their superior genetic material and control methods.

This is a misunderstanding of how evolution works. There is no "pro-life" purpose to it of the kind you ascribe to it; that kind of teleological reasoning (note, teleo-, not theo-) has no place in science. Also read Dawkins's writings on the fallacy of group-level selection.

I beg to differ. I think they're wrong and I explained the "sacrifice" for life being inbuilt into organisms through evolution of nervous system mechanisms present from the birth of species right down to cell degradation caused by stress and modulated by opioidergic functioning.

What do you think depression->suicide is? Simply random insanity? Or extreme group altruism: the person actually accepted the worthlessness conviction from the "group" and killed itself? These fallacy finding scientists should get their blindness glasses of their eyes, seriously. "Fallacy-shmallacy", a bunch of claims, logical mistakes and blindness.

And further more, "science" in this category has to be quite arrogant to declare what can and what can not help it find solutions. When just taking a short look at ageing theories one can see the childish narcissistic attempts to find and correct DNA "errors" that cause ageing. Narcissistic human-centric view that we can repair natures "mistakes" rather than learn about natures "truths" is simply a function of projection of our deluded omnipotency. As long as they consider them errors they'll never find the true mechanisms.

Edited by addx, 09 March 2014 - 05:47 PM.

[addx]

Look at their arguments, and they dare talk about fallacy.

http://old.richardda...group-selection

"

• There are formidable theoretical problems with many concepts of group selection. These include the fact that individuals reproduce faster than groups, so that an adaptation that is good for groups (say, pure altruism, in which individuals sacrifice their reproduction through behaviors that bring no benefits to the genes producing such behaviors), won’t spread because the rate of propagation of groups is undermined by the evolutionary disadvantage of altruistic behaviors within groups (non-altruists, or “cheaters,” will replace the altruists since they get the benefits without the costs). In other words, altruistic groups may do better than non-altruistic ones, but that won’t produce species-wide altruism because non-altruists do better than altruistswithin groups—unless, of course, altruists aren’t “pure” altruists and their genes reap some benefit from the behavior, in which case it’s kin selection

Now I have to say this is one of most blind sighted piece of argumentation I ever read. Group selection is in balance with individual selection within group and this balance even provides circumstances for individuals sprouting off, emigrating, forming different groups that eventually evolve into different species.

The fact the he projects all observations of natural selection onto group selection and then disputes that group selection can explain all of them and thus group selection itself is invalid is almost intentionally misleading and blinding. This level of blind attacking of theories quite nicely depicts why "there is no place for such teleology" in such science. It seems there is not much room for logic either.

A group of highly altruistic animals that procreates little will be powerful due to altruism and this will extend its life and provide extended time for procreation. This group will live harmoniously, increase its social, emotional well being. Whales for example.

This is in balance with the long term "endangerment" of the group(lack of resources for whatever reason) which will cause a drop in altruism, increase in selfishness and isolation attempts, an increase in procreation and an increase in ageing to provide faster generation changes to increase DNA adaptation to over come the endangerment.

When the group is endagerent "every man for himself" syndrome arises which results in increased procreation. Whoever evolves better genes first will give birth to a new and improved group.

Theres no fallacy there. Im appalled when I stumble onto what science has to say about some topics. Seriously.

Edited by addx, 09 March 2014 - 06:38 PM.

[Bogomoletz II]

But we are obliged "to restart and rethink so many things" regardless -- due to the simple fact that our knowledge of even basic anatomy and physiology is still incomplete.

Good point indeed. It's just the way science is. One of the most beneficial values is willingness to adapt your understanding to new data if emerging evidence contradicts your old assumptions.

I am talking about the primo-vascular system, which is the third circulatory system that is formed first, before anything else. It plays fundamental role in development, growth and, presumably, aging -- certainly in repair (and cancer). Most people here or at SENS know nothing about it, the assumptions being that what we don't know can't possibly be important.

As significant as this discovery is, I doubt that it bears any consequences for the SENS project specifically. Unlike the criticism at hand, it doesn't threaten the paramount premise of the SENS project; that this gradual deterioration of function and increase in mortality is effectively treatable by repair of cumulative cellular and molecular damage.

(the West 'discovered' it in 2008)

It's unfortunate that even in the age of the Internet transregional exchange of information is still far from perfect. It's one thing if it's about the popularity of a movie or music band, but it's much more serious when it comes to science and technology. This is an epoch when it has been agreed upon that science should be an international endeavor, remembering that both the object of science (nature itself in the case of the natural sciences) and the importance of scientific knowledge are objective and universal, whatever part of the world you inhabit.

I bet you too hear about it for the first time right?

Yes. I, at least, can point out in my defense that I'm a layperson; otherwise, I would be alarmed by my delay to update my knowledge, especially when it comes to such far-reaching findings.

But, if I may venture a prediction, 50 years from now, when more about it will be known, they will say about our time and our efforts something like this: 'No advancement in understanding of aging could be made at the time, because they did not account for this system'.
[. . .]
With such huge gaps in our knowledge, all we can hope for is to stumble on some solutions by chance.

To aging? This was Boyko's third argument, questioning de Grey's claim that a full understanding of aging is unnecessary to come up with a solution to it. You seem to concur with Boyko when you say, "the assumptions being that what we don't know can't possibly be important" But, look, it's not unusual for an ailment to be "fixed" despite all the gaps in its understanding, let alone gaps in understanding or knowledge of the entire body and all its functions. For instance, we know how acne forms, but not why it does, yet many treatments for acne are available. In the opposite situation, the disease itself is understood well enough, but the praxis lags behind. Cystic fibrosis is understood well enough for us to know how it happens, what the underlying cause is (i.e., mutations in the CFTR gene) and that getting functional CFTR protein expressed would cure it, but -- no one known how it can be done, and for the time being the disease remains incurable.

[Bogomoletz II]

I mean that the environment we are in influences our biology. This is the basic tenet of epigenetics. Also we need to consider the human body as part of life in the general, wider sense, subjected to all the laws of physics and cybernetics (see here for some details: http://arxiv.org/abs/1402.6910).

SENS-related concepts fail to consider this and that is why I believe that will not be successful in eliminating aging.

Oh! I should have figured out what you meant. Yes, now that you bring it up, I know that ultraviolet radiation can accelerate skin aging. Famine can decrease the life expectancy of certain descendents.

This reminds me of an important point that hasn't been made in this thread: different parts of the body age at different rates, so regardless of whether cellular senescence underlies organismal senescence, organisms don't senesce as wholes -- that is, uniformly -- to begin with.

I'm also reminded that the Wikipedia article for senescence doesn't just say cellular senescence underlies organismal senescence, but goes even further and defines senescence by cellular damage. I'll change the definition to a more neutral one.

Edited by Bogomoletz II, 09 March 2014 - 08:15 PM.

[Bogomoletz II]

I believe the flaw of most research base is lack of agreement and research into fundamental abstract "biologic life concepts" that can be used as a guide to predict concrete research direction.
[...]
Anyway, lack of perspective and understanding of *life* is driving scientists into dead ends and random experimenting.

Can you, please, provide an example of that? Understanding of the evolutionary causes of a given biological structure or process does not always help us in gaining understanding of the proximate causes thereof. The theory of evolution is very, very important for biology, but it should be obvious that it's not all there is to biology.

Opioid networks are ALWAYS about modulating immediate sacrifice for a better future level of "well being".
[. . .]
You can see how concepts of aging "oozes" from the function of opioids providing sacrifice(aging) mechanisms.

Even if by "aging" you meant psychological defense mechanisms against the knowledge of mortality (I know you don't), there is no pain to numb in the case of aging unless the animal knows it's doomed and cares.

It is sacrifice for "life", even for offsrpings, maternal care and sacrifice for the offspring is also a function of opioids(and piggybacking oxytocin. the mammalian urge to take care of offsprings evolved though oxytocin providing a piggyback "wellbeing input" on top of opioidergic signalling if the attached offspring survives).
[. . .]
Aging is evolutionary and conceptually sacrifice for future life(primary abstract function of opioids)

What you are saying is all so thought-provoking, but with all due respect, it's my impression that you have fallen victim to the unnecessary teleological manner of speaking characteristic of modern biology. When biologists say that the heart beats to pump blood, they don't mean that it makes a conscious decision to do so; when evolutionary psychologists say that sexual arousal evolved as a means of reproductive success, they don't mean that an infertile person can have no sex drive (think people who choose never to have children). You mustn't confuse the body with the soul. The organism is just the body, an unconsious physical structure; the organism is not the person, the mind. The mind, the soul, the psyche -- whatever you choose to call it, is a separate entity altogether.

It's almost as if people think aging is a glitch, an imperfection in mother nature, cells that can't last long, whatever, as if it could not create us better. While infact it did it on purpose.

No one did it on purpose. Nature cannot do anything on purpose. Why? It follows syllogistically from (1) the primary premise that only conscious entities can do something on purpose and (2) the secondary premise that nature is not a conscious entity.

A species that is in danger and being overrun by other conditiones experiences more stress, lives shorter, procreates more(stress increases procreation) in order to speed up evolution and make up for the lack of adaptation.

Species or individual organisms? If you mean the latter, then at least in the case of sexual reproduction it can only be true for male animals (minus seahorses). For those females who cannot reproduce without gestation, it's pointless because if death is imminent, it's counterproductive for reproductive purposes to waste time and other resources on a lengthy pregnancy -- and, in altricial taxa, rearing -- instead of struggling for personal survival. This also is a known observation in evolutionary psychology.

Edited by Bogomoletz II, 09 March 2014 - 08:06 PM.