Involvement of the Extracellular Matrix in Age-Related Memory Loss in Mice
All of the myriad conditions of degenerative aging stem from comparatively simple roots: a small number of different types of cellular and molecular damage that accumulate over the decades. From there secondary forms of dysfunction spin off into spirals of cause and effect, becoming ever more complex and challenging to interpret at each new turn. It is just the same as rust in a complex metal framework: a simple root cause, but thousands of ways in which the rust can progress to cause the structure to finally collapse.
Treating the consequences of aging has been difficult for the medical research community because they have traditionally started their investigations at the final and most complicated end point, which is to say full-blown age-related disease. From there researchers try to work backwards towards progressively earlier causes. The first points at which they find ways to intervene are the closest proximate causes, which tend to be complex dysregulations of metabolism or cell state. Treatments involve the use of drugs to produce alterations in protein levels or epigenetic changes which in turn change the operation of cells or metabolism - but since everything in cellular biology influences everything else this is hard to get right, and it is also hard to produce benefits without significant side-effects. Also, since this is a matter of targeting proximate causes rather than root causes, the root cause of the problem continues chewing away underneath it all, making any solution temporary and fragile at best.
This is the present state of medicine. In the future, we would like to see a growth in targeting of root causes in aging and age-related disease, as exemplified by the SENS research program that I'm sure you're all at least passingly familiar with by now. A change of this nature in research and development will produce a sweeping improvement in the quality and capabilities of clinical medicine. This is very much a work in progress, however, and still in the earliest stages. The overwhelming majority of medical research continues to focus on end states and proximate causes rather than root causes, and is consequently the hard path to limited benefits.
Occasionally there are moments of luck in the present process, however, where it turns out that a pocket of comparative simplicity in the progression of degeneration from root cause to end state extends a fair way along the chain of consequences. This recently published research suggests that this might be the case for age-related memory loss in mammals. This is an aspect of cognitive decline that I would not have guessed had any simple points of intervention. The nature of the changes involved is also surprising, as it lies outside cells, not inside:
Rigid connections: Molecular basis of age-related memory loss explained
Brain cells undergo chemical and structural changes, when information is written into our memory or recalled afterwards. Particularly, the number and the strength of connections between nerve cells, the so-called synapses, changes. To investigate why learning becomes more difficult even during healthy ageing, the scientists looked at the molecular composition of brain connections in healthy mice of 20 to 100 weeks of age. This corresponds to a period from puberty until retirement in humans. "Amazingly, there was only one group of four proteins of the so-called extracellular matrix which increased strongly with age. The rest stayed more or less the same."The extracellular matrix is a mesh right at the connections between brain cells. A healthy amount of these proteins ensures a balance between stability and flexibility of synapses and is vital for learning and memory. "An increase of these proteins with age makes the connections between brain cells more rigid which lowers their ability to adapt to new situations. Learning gets difficult, memory slows down."
Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wildtype mice have hippocampus-dependent proteome changes at 20, 40, 50, 60, 70, 80, 90 and 100 weeks of age.Extracellular matrix proteins were the only group of proteins that showed a robust and progressive upregulation over time. This was confirmed by immunoblotting and histochemical analysis, indicating that the increased levels of hippocampal extracellular matrix may limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission.
Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance at old age.
Note that the paper is open access, and the full PDF version is available.
You write as if the Damage-based theories of aging were proven beyond doubt. That's incorrect:
Did you ever wonder why A. de Grey states that you need to repair 4-5 types of damage before you see any results?
That would be because increasing types of damage in experiments involving laboratory animals consistently proved to have little effect on aging:
http://www.senescence.info/causes_of_aging.html
Of course, that's not the only glaring error to be found in A. de Grey's musings: off of the top of my head, he also states that the few cells with damaged mitochondia influence huge numbers of neighboring cells (by magic, apparently), that rats (and other short-lived animals) have higher levels of damage when they reach maturity (feel free to point to any evidence backing this up), etc.
Indeed, the theory of aging that best fits the available evidence is a Programmed theory of aging - the Developmental theory of aging:
http://www.senescence.info/programmed_aging.html
Note, this is NOT the programmed theory of aging you keep discussing on this site (which involves aging as a genetic program there due to group selection and other non-sense).
I'm sure, as mean spirited as Edit_XYZ's post is, he is pointing out something worth talking about. In a couple days, (around 4-6 days?) I will be doing some major helping for SENS to help spread it's research to more public attention.
But with a subject like this, I am still uneasy with my choice to help. I constantly check everywhere to see if anyone has proven anything false, and I have not found such.
Basically what I wish to say/ask is that I would like a better explanation of what Edit_XYZ means. I'm going to be reaching out to over 100,000 people to bring awareness, I don't want to look like a fool by overstepping anything.
"Of course, that's not the only glaring error to be found in A. de Grey's musings: off of the top of my head, he also states that the few cells with damaged mitochondria influence huge numbers of neighboring cells (by magic, apparently)"
@Edit_XYZ - the idea that few cells could not possibly influence large numbers of neighboring cells was a criticism leveled at senescent cells... until the negative effects of a few senescent cells were proven.
Of course just because this is true for senescent cells doesn't mean that it is true for cells with damaged mitochondria. I think the best way to settle this argument is to remove this mitochondrial damage in an animal model and see what happens, rather than argue against this research being allowed to be carried out.
@Edit_XYZ: The body is full of small populations of cells that influence large numbers of other cells in distant parts of the body. They do it by emitting proteins, or changing the levels of proteins they emit. How do you think metabolism is regulated by tiny clusters of cells in the brain? Magic?
In the case of cells with damaged mitochondria, one of the ways in which they can influence many other cells and tissues throughout the body is by emitting reactive molecules that then damage lipids. Those lipids are carried throughout the body in the blood, and contribute to atherosclerosis.
Programmed aging is not the mainstream consensus in the scientific community. That's about all there is to that, though the various forms of programmed aging theory are pushed by a fairly vocal minority contingent. That aging is accumulated damage is in fact the dominant position: SENS is just one way of approaching aging within this context. All of the debate is over which forms of damage are more important and how exactly some forms of damage connect to observed late stage pathology.
@personthing
At present, the damaged-based theories of aging are quite respectable within the field. You will most definitely NOT look like a fool by supporting them.
But I do recommend that you do not treat them as already proven truths (as this site does).
Indeed, you should read the information to be found at the links I posted in my previous post for a more grounded perspective.
@Jim
As you have acknowledged, senescent cells and cells with damaged mitochondria are two quite different situations.
@Reason
Those "tiny clusters of cells in the brain" evolved to regulate metabolism; that's their function - and the other cells in the body evolved to listen to their signals.
In the case of cells with damaged mitochondria, this does not apply; indeed, your non-defined 'reactive molecules' that somehow manage to very specifically influence LARGE numbers of other cells are a hand-waving (and not a small one).
About your remark vis-a-vis 'consensus' - science is not decided by vote, but by evidence. And the damage-based theories of aging are based on quite a few hand-wavings.
"All of the debate is over which forms of damage are more important"?
Really? The links I provided my previous post prove the contrary (feel free to read the peer reviewed papers linked there); btw, I'm still waiting for that evidence that rats (and other short-lived animals) have higher levels of damage when they reach maturity.
@Edit_XYZ writes:
Did you ever wonder why A. de Grey states that you need to repair 4-5 types of damage before you see any results?
That would be because increasing types of damage in experiments involving laboratory animals consistently proved to have little effect on aging:
http://www.senescence.info/causes_of_aging.html
Of course, that's not the only glaring error to be found in A. de Grey's musings
Er... hang on. That's not an "error," glaring or otherwise: it's Dr. de Grey's statements being consistent with the experimental evidence. Dr. de Grey states that fixing up only one or two forms of aging damage will not lead to substantial life extension -- and, indeed, experimentally increasing just one type, or decreasing just one type, worsens or slows some specific pathologies associated with that damage (as noted in the examples on the page you link),a but unsurprisingly fails to dramatically affect lifespan.
Observing that many forms of cellular and molecular damage accumulate in aging tissues over time, and postulating that aging is the result of this accumulated damage, it follows necessarily that cleaning up only one or two of them is not going to dramatically affect lifespan, on rather obvious "weakest link in the chain" grounds. This is a standard part of the standard evolutionary theories of aging (see, for instance, the Holliday and Kirkwood references given on the page you link, and papers by Olshansky), and has been argued that I know of since at least Walford and Weindruch in the early 1980s. It's also why Miller, Olshansky, and everyone in biogerontology insists that going after individual diseases one by one is not going to substantially increase lifespan: you cure heart disease (caused by accumulations of oxysterols in arterial macrophage lysosomes) , and everyone gets cancer shortly thereafter; you eradicate cancer (caused by nuclear DNA mutations and epimutations), and everyone gets Alzheimer's (caused by Abeta and tau aggregates) in short order; etc.
@Edit_XYZ writes:
off of the top of my head, he also states that the few cells with damaged mitochondia influence huge numbers of neighboring cells (by magic, apparently)
Others have already pointed to senescent cells as one example where this happens; the parabiosis experiments are similar proofs of the concept. But this "by magic," in the specific case of the few cells that are homoplasmic for mitochondia with large mtDNA deletions, is just a pure straw man: Dr. de Grey's proposed mechanism was laid out in detail in this paper, and more briefly in this paper; in his PhD thesis; in our book; and was later supported by evidence from CR animals that were consistent with his predictions on the mechanism, and other data.
@Edit_XYZ writes:
that rats (and other short-lived animals) have higher levels of damage when they reach maturity (feel free to point to any evidence backing this up), etc.
I'm not sure what you're arguing here. Are you saying that animals do not have higher levels of damage when they reach maturity than when they're born? Are you defining "maturity" as weaning? The latter is disingenuous; the former is just wrong.
@Edit_XYZ writes:
Indeed, the theory of aging that best fits the available evidence is a Programmed theory of aging - the Developmental theory of aging:
http://www.senescence.info/programmed_aging.html
Note, this is NOT the programmed theory of aging you keep discussing on this site (which involves aging as a genetic program there due to group selection and other non-sense).
The so-called "programmed theory of aging here" is entirely in line with standard evolutionary theory of aging, which is a damage-based theory. It starts from the necessary facts of the Second Law of Thermodynamics that aging will happen by default as a result of entropy, so that survival necessarily requires some level of investment in "anti-aging" maintenance and repair machinery and entropy-resistant biomolecules, and then demonstrates why variations in the robustness of those systems can be explained on the basis of the forces of natural selection via antagonistic pleiotropy, nonselection against late-acting mutations, the "dispensable soma," etc. This is exactly the damage-based evolutionary theory promulgated by Medarwar, Williams, Holliday, Kirkwood, Austad, and nearly everyone in biogerontology generally and specialists in the evolutionary theory of aging specifically.
Oh well that's how I intend to go about it, It's very obvious, that if different environments such as the International Space Station can amplify the effects and signs of aging, then there are other factors that can do the reverse. In fact, that realization is how i found SENS, and all of this in the first place due to my own curiosity.
See, in my perspective, both you (Edit_XYZ), and Reason, are both wrong, and right.
Both sides are pointing to a similar issue, and both sides are not 100% confirmed. The same question towards Reason with changing proteins in the brain and their relation to cells throughout the body, it could also be asked to you that how do you know if it's truly these brains cells that regulate all metabolism activity throughout the body.
If I where someone who could not build a opinion, I would side with Reason due to Jim, as he provided the most reasonable answer without delving into theories. But I think everyone here has different view points on the same subject that then branches out based off what they understand, and what is being researched.
XYZ, in his sassy manner, wants answers towards cells asides the brain being a cause of damage to the body i would assume? While Reason does not exactly state anything is a fact, but lists all forms of research and theories being conducted. How can Reason be wrong if hes not stating anything? As theories change, stated current research is proven wrong or right. Thus by relation, that is wrong or right.
Once again though, nothing is proven false, nothing is proven as a wild goose chase. I support SENS research and rather not die to crippling age, I will be helping them regardless of how new frontier this all is. (even if it's been in decades of research)
@personthing: On that topic, you might find this worth reading:
https://www.fightaging.org/archives/2009/12/the-maesgarreau-tendency.php
Pretty much the title of that can summarize my approach. I am fortunate in a couple ways, that helped decide what i planned to do. A.) I have the internet archiving everything for me, and B.) I have over 15 years of debates and notes to read over and look up due to said internet.
When you have decades of research clumped up together in a maybe little hard to follow, but still tangible timeline, it makes it a lot easier to decide how strongly something has been holding.
Squabbles about theories of aging are just arguments between clerics. All the targets described by SENS are legitimate targets of medicine and that's all we need to know.
@Michael
""Did you ever wonder why A. de Grey states that you need to repair 4-5 types of damage before you see any results?
That would be because increasing types of damage in experiments involving laboratory animals consistently proved to have little effect on aging:
http://www.senescence.info/causes_of_aging.html
Of course, that's not the only glaring error to be found in A. de Grey's musings"
Er... hang on. That's not an "error," glaring or otherwise: it's Dr. de Grey's statements being consistent with the experimental evidence."
My first post here started with:
'You write as if the Damage-based theories of aging were proven beyond doubt.'
This is the glaring error I mentioned (as is widely known, A. de Grey repeatedly said the same thing).
""Note, this is NOT the programmed theory of aging you keep discussing on this site (which involves aging as a genetic program there due to group selection and other non-sense)."
The so-called "programmed theory of aging here" is entirely in line with standard evolutionary theory of aging, which is a damage-based theory. It starts from the necessary facts of the Second Law of Thermodynamics that aging will happen by default as a result of entropy, so that survival necessarily requires some level of investment in "anti-aging" maintenance and repair machinery and entropy-resistant biomolecules, and then demonstrates why variations in the robustness of those systems can be explained on the basis of the forces of natural selection via antagonistic pleiotropy, nonselection against late-acting mutations, the "dispensable soma," etc. This is exactly the damage-based evolutionary theory promulgated by Medarwar, Williams, Holliday, Kirkwood, Austad, and nearly everyone in biogerontology generally and specialists in the evolutionary theory of aging specifically."
The programmed theory of aging sometimes discussed on this site argues that there's a genetic program that evolved, as a result of group selection, specifically to kill its hosts.
That's non-sense - indeed, the advocates of this theory have a poor understanding of darwinian selection, evolutionary pressure, etc.
BTW, the second law of thermodynamics says that you can't use the available energy with 100% efficiency; some of this energy will be transformed into heat, increasing the entropy (AKA the amount of unusable heat) of the system.
It most definitely does NOT forbid an organism from maintaining its organisation indefinitely; nor does it say that the degradation of an organism has anything to do with entropy (it merely says that an organism cannot use its energy with 100% efficiency, generating heat).
As such, your use of the second law of thermodynamics in this context is non-sense.
And now, that we're done with the fluff:
"Dr. de Grey states that fixing up only one or two forms of aging damage will not lead to substantial life extension -- and, indeed, experimentally increasing just one type, or decreasing just one type, worsens or slows some specific pathologies associated with that damage (as noted in the examples on the page you link),a but unsurprisingly fails to dramatically affect lifespan.
Observing that many forms of cellular and molecular damage accumulate in aging tissues over time, and postulating that aging is the result of this accumulated damage, it follows necessarily that cleaning up only one or two of them is not going to dramatically affect lifespan, on rather obvious "weakest link in the chain" grounds. This is a standard part of the standard evolutionary theories of aging (see, for instance, the Holliday and Kirkwood references given on the page you link, and papers by Olshansky), and has been argued that I know of since at least Walford and Weindruch in the early 1980s. It's also why Miller, Olshansky, and everyone in biogerontology insists that going after individual diseases one by one is not going to substantially increase lifespan: you cure heart disease (caused by accumulations of oxysterols in arterial macrophage lysosomes) , and everyone gets cancer shortly thereafter; you eradicate cancer (caused by nuclear DNA mutations and epimutations), and everyone gets Alzheimer's (caused by Abeta and tau aggregates) in short order; etc."
First, your comparing aging with the diseases of aging is invalid:
If a disease of aging is cured, a few other are ready to thrive on the weakened organism.
But, if you restore the organism to a youthful state, a few decades will pass until he/she will be aged; until then, nothing is waiting in the wings.
Second, you claim that by eliminating 7 forms of damage, the organism will be restored to a youthful state.
But, a few forms of this damage were shown to have minimal effect on aging (for example, relating to protein defects, reactive oxygen species, etc - see my posted links for the papers); these forms of damage combined will still have minimal effect on aging (unless you can prove a very large multiplicative effect - which you have NOT done).
So - either, from these forms of damage, some are far more important than others in causing aging, or the causative factor of aging is not among them.
"But this "by magic," in the specific case of the few cells that are homoplasmic for mitochondia with large mtDNA deletions, is just a pure straw man: Dr. de Grey's proposed mechanism was laid out in detail in this paper, and more briefly in this paper; in his PhD thesis; in our book; and was later supported by evidence from CR animals that were consistent with his predictions on the mechanism, and other data."
I see A. de Grey did mention a concrete mechanism; I retreat my 'by magic' comment.
However, that his mechanism is able to influence a large number of cells to the required (very large) degree is more than a little doubtful.
Furthermore, the evidence for mitochondrial mutations as significant in aging is lacking:
Ameur et al., 2011 found no increase in mtDNA mutations with age in mice; Norddahl et al., 2011 found that accumulating mutations to mitochondrial DNA are also unlikely to drive stem cell aging.
There are studies that found effects of mtDNA mutations on aging (you find them even at my already posted links) but these effects are so small, the matter is open to interpretation.
""that rats (and other short-lived animals) have higher levels of damage when they reach maturity (feel free to point to any evidence backing this up)"
I'm not sure what you're arguing here. Are you saying that animals do not have higher levels of damage when they reach maturity than when they're born? Are you defining "maturity" as weaning? The latter is disingenuous; the former is just wrong."
You may be aware that, in mammals, the time they need to reach sexual maturity is proportional to how fast they age. For example, mice reach sexual maturity in 0,1 year and age at ~1 year; humans reach sexual maturity at 13,5 years and age at ~40 years; etc.
The only way A. de Grey found to reconcile this fact with his damage-based theory of aging is to posit (in his book) that, when they reach sexual maturity, mice (for example) have FAR more damage in their system than humans.
If true, this should be easy enough to prove; present the proof.
Is there something specific about the research or the classifications of damage that you disagree with or should not be pursued by medical science? I would like to hear your critique of research projects rather than your theoretical musings.
@Michael
"I would like to hear your critique of research projects rather than your theoretical musings."
Very well. First, I will present my reasoning:
As I said, I find the developmental theory of aging has a VERY good chance of being accurate (http://www.senescence.info/programmed_aging.html#The_Developmental_Theory_of_Aging).
It essentially says that the developmental program (that ensures the coordinated growth of the organism until he/she reaches sexual maturity) does not stop after sexual maturity is reached, but continues to act upon the organism with damaging effects - the systemic degradation known as aging.
Why doesn't the developmental program stop?
Because, until very recently, the life expectancy of humans (and their immediate evolutionary ancestors) was about ~35 years; death came from predation, disease, famine, etc.
Given how the overwhelming majority of humans did not have children after ~35 years of age, there was no evolutionary pressure to optimise anything in the human body after this age. Not the developmental program (fine tuned to ensure reaching sexual maturity, afterwards stupidly running with the same settings, now deleterious), nor anything else (after ~35 years, the changes in the human body are due to the roll of the dice).
The developmental theory of aging explains nicely why in species of mammals (and not only), the time they need to reach sexual maturity is proportional to how fast they age*.
It also explains nicely the findings regarding the GH/IGF-1 axis - that maintaining a higher level of the hormons after sexual maturity tends to accelerate aging, while a lower level tends to delay aging (of course, this axis is just a part of the developmental program).
It explains why long-lived and negligibly senescent species (birds, tortoises, etc) evolved so quickly the ability to age slower or not age at all - they lived in safer environments, didn't die of external causes and, as such, they quickly evolved to change the settings of their developmental program, as opposed to 'quickly' evolving complex (and, in the case of negligibly senescent species, all but perfect) mechanisms for damage reduction.
Etc.
Now, based on what I said above, I find research should concentrate on determining the components of this developmental program and how to change its settings in order to slow/prevent aging.
Why?
Because this research goal could be attained FAR MORE QUICKLY than SENS' goal:
Yes, the damage is categorised in only 7 categories of aging, but each category is very large.
As to the developmental program, as far back as the 19th century, chicken hearts grown separately in the lab lived as long as 20 years, longer than the toughest chicken - suggesting that a large part of this program exists at the organism level (not cellular, tissue or even organ level).
Failing that, the research should concentrate on removing the types of damage that may be important in creating the frailties of aging, being the main effects of the developmental program (for example, senescent cells is a prime suspect), not on removing the damage already proved to be of minor or no importance (such as mtDNA mutations).
*BTW, I still expect you to present the evidence that supports A. de Grey's affirmation that, when they reach sexual maturity, mice (and other short-lived mammals) have FAR more damage in their system than humans.
As said, if this is true, it should be easy enough to prove; present the proof.
If the evidence supports the contrary - that, when they reach sexual maturity, mice, humans and the other mammals have comparable levels of damage in their systems - well, that pretty much disproves the damage-based theory of aging, supporting the developmental theory of aging.
Hi XYZ, just to be clear you are having most of your discussion with Michael Rae who works for the SENS Research foundation. You can delineate your discussion by the fact his name is hyper-linked to his website. From this point I will use the name of Michael-2.
My point is if mtDNA mutations is the only category you think should not be researched then you are none the less more than 90% in favor of what the SENS Research Foundation does and/or promotes. Your posts would suggest otherwise by the absence of your endorsement. Ideas on the theory of aging are fine but you should at least include the aspects of SENS you are in favor of (senescent cells being one you have named.)
Edit_XYZ: your style of formatting your replies is extremely hard to follow, and I would be grateful if you would try to structure them more clearly. But meanwhile, I will try to answer a few of your points:
1) The question whether a small number of mitochondrially mutant cells can be significantly toxic to the whole body is indeed unclear, and the reason why I started to examine that question so early on (back in 1997) was precisely because it was being somewhat swept under the carpet by others. The "reductive hotspot" mechanism that I postulated is elaborate, but all its components are either plausible or already established, and it certainly could deliver the required amount of "amplification" of the originating problem. Only one other such theory is out there, namely Aiken's proposal that mutant mtDNA drives sarcopenia. However, I have never disputed the fact that the role of mutant mtDNA in aging remains open - it may indeed be harmless in a currently normal lifetime. Our policy is simply that if something MIGHT contribute to the ill-health of old age, and it seems to be very difficult to determine definitively whether it does, we would be unwise to wait and see - we should prepare for the worst and figure out a way to fix it.
2) The "non-individual fitness benefit" variant of programmed aging is not so daft as you suggest. I think it is incorrect, but for quite subtle reasons. I am actually in the middle of writing a detailed paper on this topic, so I won't elaborate now - watch this space - except to note that one strong argument against it is precisely that, contrary to what you say about birds etc, the evolution of long life as a result of reduction in causes of extrinsic mortality seems to be much SLOWER than any programmed aging theory would predict.
3) The "developmental inertia" variant of programmed aging is also not daft, but there has been suspiciously little progress in fleshing it out. Contrary to what you suggest, the period during which low levels of GH/IGF1 result in longer lives is the period PRIOR to sexual maturity. If the theory is correct, then there must be certain genes, in certain tissues, that are expressed throughout life in a manner similar to how they are expressed prior to sexual maturity, and whose expression causes us to age faster than if they were not expressed at all. No such genes have been identified, so the alternative possibility (that there really are no such genes) must be considered more plausible. Nonetheless, I fully support continuing efforts to find such genes, because you are quite right that if they do exist then switching them off should be a lot easier than SENS. Saying that, though, we must never forget that such a scenario would still only slow aging down, whereas SENS offers bona fide rejuvenation.
4) I'm confused by your reference to chicken hearts. It is certainly true that the aging of one part of the body can affect the rest of the body, most notably via the circulation - witness the recent celebrated results using heterochronic parabiosis - and of course the reductive hotspot theory is potentially another case. But that doesn't say anything one way or the other about the plausibility of the developmental inertia theory.
5) I'm even more confused by your assertion that I have said that short-lived species have more damage at sexual maturity than long-lived species. What are you quoting? I have certainly said that short-lived species accumulate damage faster than long-lived species (as well as being less able to tolerate a given quantity of damage than long-lived ones), but since they also reach sexual maturity at a younger (chronological) age than long-lived ones, this says nothing about the relative amounts of damage at the point of sexual maturity. I also have no idea why you think such an assumption is necessary for an "aging as damage" theory.
@Aubrey de Grey
Damage theory of aging:
1. "Our policy is simply that if something MIGHT contribute to the ill-health of old age, and it seems to be very difficult to determine definitively whether it does, we would be unwise to wait and see - we should prepare for the worst and figure out a way to fix it."
The current research all but established that mtDMA mutations have only a minor contribution, if any, to aging within a current human lifespan (see the studies I named above, for example). Apparently, the human body has defense&repair mechanisms against mtDNA mutations (and reactive oxygen species, protein damage, etc) good enough to keep their influence minimal within a human lifespan.
My understanding of SENS is that it seeks to harvest the lowest hanging fruit with regards to aging AKA treatments that could significantly prolong life. As such, from the 7 categories of damage (and their subcategories) it established as part of its damage theory of aging paradigm, it should concentrate on eliminating the types of damage that could have an important contribution to aging, not on those that are all but proven to have, at most, a minimal contribution to aging.
After robust rejuvenation is demonstrated and funds will be plentiful, there will be time to research secondary contributions to aging such as mtDNA mutations.
Programmed theory of aging:
2."The "non-individual fitness benefit" variant of programmed aging is not so daft as you suggest."
Group selection is pretty much proven to be non-sense. See, for example: http://edge.org/conversation/the-false-allure-of-group-selection ; the discussion is pretty thorough.
As such, the group selection based, programmed theory of aging is pretty much proven to be non-sense.
"I am actually in the middle of writing a detailed paper on this topic, so I won't elaborate now - watch this space - except to note that one strong argument against it is precisely that, contrary to what you say about birds etc, the evolution of long life as a result of reduction in causes of extrinsic mortality seems to be much SLOWER than any programmed aging theory would predict."
I await the paper - by what criteria have you established the required speed of evolution under the programmed theory of aging; have you compared the speed of evolution under a programmed aging theory and the speed of evolution under a damage aging theory; have you analysed Steven Austad's opossums?
Developmental inertia theory of aging
4. My 'chicken hearts' comment was a reference to Alexis Carrel's experiment which showed how tissue obtained from small fragments of embryonic chick heart tissue, when maintained in, essentially, petri dishes, separate from the command&control signals of the organism, neither grows nor ages.
5."I'm even more confused by your assertion that I have said that short-lived species have more damage at sexual maturity than long-lived species. What are you quoting?"
Aubrey de Grey, Michael Rae: "Ending aging", pg. 39:
"The organism has a choice between doing a quick and dirty job of its growth, leading to early fertility but sloppy construction, or a more perfectionist job that delays sexual maturity but creates a more smooth-running machine in the end. And a more sloppily constructed animal will on average live less long—partly because it may be less able to defend itself against predators, famine, and such like, but also because the molecular and cellular damage that it laid down during its headlong rush to maturity has effectively given it a head start in the aging process."
"I also have no idea why you think such an assumption is necessary for an "aging as damage" theory."
This is because of the strong correlation between age at sexual maturity and maximum lifespan in mammals; also, because of the correlation between the growth rate and maximum lifespan. The correct theory of aging must explain these relations.
Within the damage theory of aging, your above quoted assumption established a link between speed of development and aging. Without it, the remaining explanations involve ecological constraints - always positing ad-hoc, unconvincing assumptions in an attempt to square the circle.
Within the developmental inertia theory of aging the link between speed of development and aging is clear, the correlations explained.
3."Contrary to what you suggest, the period during which low levels of GH/IGF1 result in longer lives is the period PRIOR to sexual maturity."
It is established that smaller mice, rats, horses, and dogs appear to live longer (according to a study, smaller humans also tend to live longer)*.
And yes, partly, the lower GH/IGF1 level prior to sexual maturity resulted in their smaller stature; but, after sexual maturity is reached, the GH/IGF1 level continues to be lower than in normal-sized specimens - and this is, in part, responsible for the increased longevity of smaller animals. It has been found that even little people with lower levels of IGF-1 after sexual maturity live longer - Krzisnik et al., 1999.
Separate from that, increasing the levels of GH in mature test subjects have been found to have negative effects.
All this is in complete accord with the consequences of the developmental inertia theory of aging - after sexual maturity is reached, dialing down the developmental program extends lifespan.
*Given how smaller animals tend to die sooner in the wild, due to ecological constraints, how do you explain this correlation from the POV of the damage theory of aging (without involving ad-hoc, unconvincing assumptions)?
"If the theory is correct, then there must be certain genes, in certain tissues, that are expressed throughout life in a manner similar to how they are expressed prior to sexual maturity, and whose expression causes us to age faster than if they were not expressed at all. No such genes have been identified, so the alternative possibility (that there really are no such genes) must be considered more plausible."
The fact that smaller animals tend to live longer in captivity pretty much proves the existence of genes that control the developmental program and that affect aging.
"Nonetheless, I fully support continuing efforts to find such genes, because you are quite right that if they do exist then switching them off should be a lot easier than SENS. Saying that, though, we must never forget that such a scenario would still only slow aging down, whereas SENS offers bona fide rejuvenation."
Finding the genes responsible for the developmental program is the developmental inertia theory of aging equivalent of ~'the long road to nowhere'.
A faster road would involve comparing the command&control signals (the endocrine system, but not only) from smaller mice, rats, horses, dogs, humans and from normal-sized specimens - in order to discover what 'settings', after sexual maturity, lead to the longer life of the smaller beings.
Or comparing the command&control signals from negligibly senescent species with those from their aging, close cousins - for the same purpose.
Also, this approach has the potential to stop aging in humans for a few centuries - when mtDNA and other forms of damage become important.
Of course, at first, it will slow down aging - but not only: the human body has shown the ability to regenerate many of its systems, if it receives the proper command&control signals (for example, see the recent results about thymus regeneration or about heterochronic parabiosis) as opposed to damaging signals (and the metabolic cascade these create.
"The current research all but established that mtDMA mutations have only a minor contribution, if any, to aging within a current human lifespan"
You’re welcome to your opinion on that, but it’s not my interpretation, and it is my foundation :-) Also, don’t forget that from an evolutionary perspective, if you were correct we would need some way to explain why the genes that maintain mtDNA haven’t mutated a bit, to become slightly less good at that, thus restoring mutation/selection balance. In contrast to nuclear DNA damage, I don’t think there is a “protagonistic pleiotropy” explanation for mtDNA.
"Group selection is pretty much proven to be non-sense … As such, the group selection based, programmed theory of aging is pretty much proven to be non-sense."
Yes, group selection as typically defined has serious inconsistencies with evolutionary theory. However, kin selection does not - and there is a very important elaboration of kin selection, called multi-level selection, which is what serious advocates of the non-individual benefit position (such as Mitteldorf) base their arguments on.
"by what criteria have you established the required speed of evolution under the programmed theory of aging; have you compared the speed of evolution under a programmed aging theory and the speed of evolution under a damage aging theory; have you analysed Steven Austad's opossums?"
Austad’s opossums are a good data point; probably a better one is Rose’s Drosophila, since we have more precise information on the rate of change in longevity per generation and also the selection (i.e. the change in what was optimal) was even stronger. The upshot is that that rate has never been shown able to exceed 1%. While different versions of the mechanism underlying different programmed theories may lead to somewhat different predictions, I believe we can certainly say that 1% is far too low, just because the program needs to actually do something - it needs to change the epigenetic state of the offspring in such a way as to make them age more slowly than their parents did. Whereas, non-programmed theories say that the only option is a change to the genetic state, which can only occur by mutation and selection so is much slower.
"My 'chicken hearts' comment was a reference to Alexis Carrel's experiment which showed how tissue obtained from small fragments of embryonic chick heart tissue, when maintained in, essentially, petri dishes, separate from the command&control signals of the organism, neither grows nor ages."
I’m still confused; as I said before, that doesn't say anything one way or the other about the plausibility of the developmental inertia theory. If you disagree, please be clearer.
"The organism has a choice between doing a quick and dirty job of its growth, leading to early fertility but sloppy construction, or a more perfectionist job that delays sexual maturity but creates a more smooth-running machine in the end. And a more sloppily constructed animal will on average live less long—partly because it may be less able to defend itself against predators, famine, and such like, but also because the molecular and cellular damage that it laid down during its headlong rush to maturity has effectively given it a head start in the aging process."
Thanks. The context (see the paragraph following the one you quote) was the comparison between fast-growing and slowly-growing individuals of the SAME species. With regard to that comparison I do indeed make the claim you describe, but it doesn’t extend to the interspecies case, mostly because long-lived species have better damage repair systems than short-lived ones whereas ad-lib and CR individuals of the same species have the same such systems.
" "I also have no idea why you think such an assumption is necessary for an "aging as damage" theory." This is because of the strong correlation between age at sexual maturity and maximum lifespan in mammals; also, because of the correlation between the growth rate and maximum lifespan. The correct theory of aging must explain these relations. Within the damage theory of aging, your above quoted assumption established a link between speed of development and aging. Without it, the remaining explanations involve ecological constraints - always positing ad-hoc, unconvincing assumptions in an attempt to square the circle."
Go on then: exactly WHAT (allegedly ad-hoc) assumptions you think the damage theory needs to make if it doesn’t assert that mice have more damage at sexual maturity than humans? Until you tell me that, we can’t discuss either whether they are indeed ad-hoc or whether the damage theory indeed needs them, so this discussion remains moot.
"after sexual maturity is reached, the GH/IGF1 level continues to be lower than in normal-sized specimens - and this is, in part, responsible for the increased longevity of smaller animals."
Can you show me a study (in any species) that demonstrated that the effect was not entirely due to a pre-maturity difference? In other words, a study that lowered GH/IGF1 only in adulthood and still got a longevity effect? Note that I won’t accept adult-onset CR as an example, because that causes all the (evolutionarily selected!) metabolic changes that early-onset CR causes, not only the lowering of GH/IGF1.
"It has been found that even little people with lower levels of IGF-1 after sexual maturity live longer - Krzisnik et al., 1999."
As above, these individuals had an inherited mutation, so they had lower levels before maturity too. Please be less sloppy in your logic.
"Separate from that, increasing the levels of GH in mature test subjects have been found to have negative effects."
GH is not IGF1, and of course the “negative effects” you describe would be rather hotly disputed by many people. As above, is there any particular study you’re referring to that shows a shortening of lifespan from GH supplementation? (Not that such a study would mean much, of course, since shortening lifespan is easy.)
"All this is in complete accord with the consequences of the developmental inertia theory of aging - after sexual maturity is reached, dialing down the developmental program extends lifespan. Given how smaller animals tend to die sooner in the wild, due to ecological constraints, how do you explain this correlation from the POV of the damage theory of aging (without involving ad-hoc, unconvincing assumptions)?"
I am still entirely in the dark as regards any inconsistency that you may be referring to. Please actually spell out, carefully, how the damage theory leads (in your view) to any prediction of any correlation or lack of correlation between any pair of things you like, and then we can talk about whether it really does make that prediction, whether the correlation or lack of it is as you claim in the first place, or whether you have a point. So far you have just been hand-wavy and sloppy.
"The fact that smaller animals tend to live longer in captivity pretty much proves the existence of genes that control the developmental program and that affect aging."
Yes it does. What it doesn’t do, though, is challenge the hypothesis that the chain of events that brings about that correlation involves damage as a necessary intermediate. It also doesn’t challenge the hypothesis that the only activity of those genes that mediates the correlation (whether via damage or otherwise) is their pre-maturity activity.
"Finding the genes responsible for the developmental program is the developmental inertia theory of aging equivalent of ~'the long road to nowhere'. A faster road would involve comparing the command&control signals (the endocrine system, but not only) from smaller mice, rats, horses, dogs, humans and from normal-sized specimens - in order to discover what 'settings', after sexual maturity, lead to the longer life of the smaller beings. Or comparing the command&control signals from negligibly senescent species with those from their aging, close cousins - for the same purpose."
My sense is that if such signals were discovered, it would be a very short road to the subsequent discovery of the genes responsible, so I am happy not to make that distinction. However, just as no genes satisfying the criteria predicted by the developmental theory have been discovered, similarly it seems that no such signals have been. Of course I await your challenge to that assertion, but I believe it would need to come in the form of identifying specific studies in response to my other questions above.
"Also, this approach has the potential to stop aging in humans for a few centuries - when mtDNA and other forms of damage become important. Of course, at first, it will slow down aging - but not only: the human body has shown the ability to regenerate many of its systems, if it receives the proper command&control signals (for example, see the recent results about thymus regeneration or about heterochronic parabiosis) as opposed to damaging signals (and the metabolic cascade these create."
That’s true, but there are also plenty of aspects of aging that are not regenerated in any such experiments performed to date, and it is those aspects that are the focus of SENS, because they are the “primary damage” - the damage that accumulates even in young adults, and indeed without whose accumulation the regenerative capacity of young adults would not decline in the first place.