1028 replies to this topic

[johnhemming]

It is a paradox (and we should always be interested in paradoxes) that we lose energy as we age, but restricting energy input seems to delay this process. 

 

An alternative view is that having higher quality mitochondria means slowing up the aging process. 

[ambivalent]

It is a paradox (and we should always be interested in paradoxes) that we lose energy as we age, but restricting energy input seems to delay this process. Blagosklonny has come closest to explaining this with hyperfunction theory - growing faster means you die faster (2). But putting mTOR at the head of this river seems a mistake to me, it is more likely to be energy. Physics trumps biology.

 

I have never seen this as paradoxical, since it makes perfect sense from an evolutionary perspective, it is I would suggest necessary.

 

I remember watching a talk by Cynthia Kenyon many years ago where she stated, when referring to the epigentic changes of fasting and or CR, that 'well, we seem to have this latent capacity to live longer, but no one really knows why'. I thought it as quite obvious, which is a good reason to doubt it. 

 

If we restrict food - energy - throughout life then we can extend it, so when resources are abundant we die quicker, when they're scarce we live longer. There are, it seems to me, two evolutionary drivers in play for the species, in fact as there are life drivers for us all. There are long term evolutionary goals to maintain the species and short term ones. 

 

If food is bountiful, then we may procreate-a-plenty. With IGF1 stimulated we die early and so within a given time period there are more iterations or generations of the species churned out and thus an expedited evolutionary process - more opportunities for natural selection to improve the species and so make the cut in the distant future. 

 

However, when food is lacking then the imminent survival of the species is under threat, females have reduced fertility, puberty delayed, and so fertility extends later into life. 

 

And surviving for longer beyond fertility makes perfect sense too, since with numbers likely down, the group benefits by inducing a larger community through the longer lived.       

 

Better a reduced gene pool than no gene pool and so the drive for species (or at least group) advancement takes a backfoot, since evolution is obviously predicated on species survival which through low energy intake appears under threat. So the low calorie consumption signals a need for life extension, which is duly, biologically, met.

 

If it were not the case, then the group under starvation would be more vulnerable, brittle, there would be no levers to pull during tough times - if fertility and the window for child rearing remained fixed under lean times, then there is a greater likeihood that the energy expended, for want of a better expression, by the group in attempting to procreate is lost. And so in shutting everything down - delaying aging - during starvation times is extremely advantageous.

 

The life extending benefits of reduced energy through CR would be better the earlier and longer it occurrs. And so it isn't so much, that, I would say, it is paradoxical, since endogenously induced energy reduction is a symptom of age but exogenous induced energy reduction isn't - it is a forced state, we aren't recreating a marker of old age when we are starved. The causes are different - early protracted energy reduction seems to stall the fall, and that youthful extended haitus will hopefully correspond to a higher energy state level 50 years hence than had we feasted during those lean years.       

Edited by ambivalent, 05 October 2022 - 02:09 PM.

[johnhemming]

If we look at other species there are long lived turtles that continue to grow.   My own hypothesis of aging is that it arises from a failure of cells to produce the right proteins primarily as a consequence of a shortage of Acetyl-CoA in the nucleus.  This causes lots of things to not happen properly and some of the cells become senescent and emit SASP which through IL-10 causes cells to fail to differentiate properly.

 

That can be fixed without stopping growth or at least without stopping renewal.

 

 

 

 

[QuestforLife]

I have never seen this as paradoxical, since it makes perfect sense from an evolutionary perspective, it is I would suggest necessary.

I remember watching a talk by Cynthia Kenyon many years ago where she stated, when referring to the epigentic changes of fasting and or CR, that 'well, we seem to have this latent capacity to live longer, but no one really knows why'. I thought it as quite obvious, which is a good reason to doubt it.

If we restrict food - energy - throughout life then we can extend it, so when resources are abundant we die quicker, when they're scarce we live longer. There are, it seems to me, two evolutionary drivers in play for the species, in fact as there are life drivers for us all. There are long term evolutionary goals to maintain the species and short term ones.

If food is bountiful, then we may procreate-a-plenty. With IGF1 stimulated we die early and so within a given time period there are more iterations or generations of the species churned out and thus an expedited evolutionary process - more opportunities for natural selection to improve the species and so make the cut in the distant future.

However, when food is lacking then the imminent survival of the species is under threat, females have reduced fertility, puberty delayed, and so fertility extends later into life.

And surviving for longer beyond fertility makes perfect sense too, since with numbers likely down, the group benefits by inducing a larger community through the longer lived.

Better a reduced gene pool than no gene pool and so the drive for species (or at least group) advancement takes a backfoot, since evolution is obviously predicated on species survival which through low energy intake appears under threat. So the low calorie consumption signals a need for life extension, which is duly, biologically, met.

If it were not the case, then the group under starvation would be more vulnerable, brittle, there would be no levers to pull during tough times - if fertility and the window for child rearing remained fixed under lean times, then there is a greater likeihood that the energy expended, for want of a better expression, by the group in attempting to procreate is lost. And so in shutting everything down - delaying aging - during starvation times is extremely advantageous.

The life extending benefits of reduced energy through CR would be better the earlier and longer it occurrs. And so it isn't so much, that, I would say, it is paradoxical, since endogenously induced energy reduction is a symptom of age but exogenous induced energy reduction isn't - it is a forced state, we aren't recreating a marker of old age when we are starved. The causes are different - early protracted energy reduction seems to stall the fall, and that youthful extended haitus will hopefully correspond to a higher energy state level 50 years hence than had we feasted during those lean years.

I've heard those arguments before - they're not based on any evidence, they're a nice story that seems to accord with what evolution might do. But we have tonnes of energy input - more calories that imaginable to our ancestors, and yet we somehow have to choose between maintenance and fertility?

Blagosklonny's argument that aging is growth is better and simpler. Less energy, less growth, less aging.

[QuestforLife]

If we look at other species there are long lived turtles that continue to grow. My own hypothesis of aging is that it arises from a failure of cells to produce the right proteins primarily as a consequence of a shortage of Acetyl-CoA in the nucleus. This causes lots of things to not happen properly and some of the cells become senescent and emit SASP which through IL-10 causes cells to fail to differentiate properly.

That can be fixed without stopping growth or at least without stopping renewal.

What made you think acetyl-coA was the culprit? Note, pyruvate dehydrogenase is downregulated by having too much ATP.

[johnhemming]

What made you think acetyl-coA was the culprit? Note, pyruvate dehydrogenase is downregulated by having too much ATP.

 

I did a page on this here:

https://johnhemming....hortage-of.html

 

The key paper was this one:

https://www.nature.c...587-021-00105-8

[QuestforLife]

I did a page on this here:

https://johnhemming....hortage-of.html

 

The key paper was this one:

https://www.nature.c...587-021-00105-8

 

Interesting, I'll give them a read.

 

The only note of caution I'd sound at this time, is that aging is tricky and loves to laugh at our theories. You have rightly identified acetyl-coA export from the mitochondria as a age-related change, and then moved to link that to reduced acetylation of the genome and from here to the harm of aging. But for all you know the age related decline in the mitochondrial carrier is protective against aging (which would be worse otherwise). 

 

I say this because I remember reading all about the age related decline in mitochondrial SHMT2 gene (that makes glycine from serine as well as driving round the folate cycle) and an elegant study that showed that de-differentiation of old human cells returned SHMT2 activity to normal; they then also supplemented old human cells with glycine and this also had benefits (restoring mitochondrial ETC because the cells could now make new loops of mito DNA). Note this works because glycine can also be cleaved to drive round the folate cycle (1) And it also reminds me of your acetyl-coA idea because glycine is important for other things that are age-related like collagen synthesis. Anyway, from this you'd say that SHMT2 was a major cause of mitochondrial decline in the elderly. But I later read a worm study where they found glycine levels rose with age and that this was protective. It turns out that dysfunction in SHMT2 (or whatever the equivalent gene is in worms, I forget) led to a rise in glycine (as the pathway is two-way and glycine can be converted to serine and this change prevented that). Then feeding the worms extra glycine made them live even longer (2). So it turned out that things were more complicated than originally anticipated. I should also add that the authors of the second paper didn't actually understand their results either, but I won't go into that here. 

 

So glycine did turn out to be highly important to mitochondria and aging, and this is reflected in recent GlyNAC trials (3). But it was a mistake to think that SHTM2 dysfunction was the cause of the problem, it was actually a compensation made by super-clever cells to deal with insufficient glycine. 

 

Now I'm not saying that falling acetyl-coA export from the mitochondria is the same, but it could be - it looks like a compensation to me. And it is not hard to see why that might be, given krebs cycle is what drives acetyl-coA abundance and this does fail with age, for reasons that are related to mitochondrial function. So we might be better off looking at why cells decided to stop exporting citrate from mitochondria. 

 

(1) Hashizume O, Ohnishi S, Mito T, Shimizu A, Ishikawa K, Nakada K, Soda M, Mano H, Togayachi S, Miyoshi H, Okita K, Hayashi J. Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci Rep. 2015 May 22;5:10434. doi: 10.1038/srep10434. Erratum in: Sci Rep. 2015;5:14591. Iashikawa, Kaori [corrected to Ishikawa, Kaori]. PMID: 26000717; PMCID: PMC5377050.

 

(2) Liu YJ, Janssens GE, McIntyre RL, Molenaars M, Kamble R, Gao AW, Jongejan A, Weeghel MV, MacInnes AW, Houtkooper RH. Glycine promotes longevity in Caenorhabditis elegans in a methionine cycle-dependent fashion. PLoS Genet. 2019 Mar 7;15(3):e1007633. doi: 10.1371/journal.pgen.1007633. PMID: 30845140; PMCID: PMC6424468.

 

(3) Kumar P, Liu C, Suliburk J, Hsu JW, Muthupillai R, Jahoor F, Minard CG, Taffet GE, Sekhar RV. Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial. J Gerontol A Biol Sci Med Sci. 2022 Aug 17:glac135. doi: 10.1093/gerona/glac135. Epub ahead of print. PMID: 35975308.

[johnhemming]

So we might be better off looking at why cells decided to stop exporting citrate from mitochondria. 

 

Thats a result of an increase in IL-10 which arises as a result of increased senescence.

[QuestforLife]

Thats a result of an increase in IL-10 which arises as a result of increased senescence.

 

There are diverse causes of cellular senescence, but the final kingpin in the matter is of course telomeres...

[johnhemming]

There are diverse causes of cellular senescence, but the final kingpin in the matter is of course telomeres...

 

I think Telomeres are a consequence of exogenous factors (that is exogenous to the cell).  There are a number of examples of this, but i think this is particularly relevant:

 

http://repositorium....ndle/1822/54794

[ambivalent]

I've heard those arguments before - they're not based on any evidence, they're a nice story that seems to accord with what evolution might do. But we have tonnes of energy input - more calories that imaginable to our ancestors, and yet we somehow have to choose between maintenance and fertility?

Blagosklonny's argument that aging is growth is better and simpler. Less energy, less growth, less aging.

 

 

Well, we since can't rerun evolution all evidence is circumstantial.  So we take the what we see, reason the cause and consider consquences of it not being the case.

 

There is of course evidence of the impact of CR on fertility, shutting down cycling and extending the fertility window, as Mark Mattson discusses:

 

 

And again what is the alternative? That the window is fixed, and if the female is unlucky enough to need to procreate during that window she just has to give it a go - far better to shut down cycling, extend fertility and wait for better times. 

 

That the are levers to pull during times of difficulties is obviously an evolutionary advantage and necessity, which is what we see in fasting - changes in female fertlity, improved health and life extension. Better to have adaptive responses to challenging circumstances, than not - that is evolution. We clearly have them - if our biology used them to maximise our own survival, then the group would suffer.  

 

The main point I was communicating was that I don't see the contradiction in the paradox - that we lose energy as we age, but restricting energy delays that process:

 

Throughout our lives we have access to external energy, a biologcial mechanism to convert it to "internal energy". We are a biologcial system when we are old obviously distinct from when we are young - what the old body can do with 2000 calories is very different to the young one, we are not the same efficient machine. What is true mostly throughout life, albeit it differently and perhaps not so when young, is that we can improve the state or stall the decay of that biological system when fasting or CR. If it didn't have this effect, then we would arrive at the same state when old, regardless of our prior CR or fasting. And of course we can hack this process, and generate the same effects through fasting without fasting - so the energy is irrelevant, we can consume the same energy or restrict it and have no impact on aging if we are mimicing the effects already. It's not about the energy, but the signalling the lack or surplus of energy triggers - if we can fake it then it doesn't matter what energy we consume - to a point.  

 

I have done some extensive fasting and have felt very old old, as young children overtake me, walking down the street - a problem solved through refeeding, but not so for the infirmed. 

 

Anyhow, its semantics really, and not that important.

 

More interstingly, I'd to understand more about telomere lengthening and shortening, as there seems to be opposing positions between yourself and Turnbuckle.

[QuestforLife]

 

That the are levers to pull during times of difficulties is obviously an evolutionary advantage and necessity, which is what we see in fasting - changes in female fertlity, improved health and life extension. Better to have adaptive responses to challenging circumstances, than not - that is evolution. We clearly have them - if our biology used them to maximise our own survival, then the group would suffer.  

 

 

 

Declines in fertility (to take your example) can be explained by hyperfunction. Reduced feeding reduces hyperfunction, therefore fertility improves. There is no requirement for 'levers'.  This was explained by Blagosklonny in 2006.

 

 More interstingly, I'd to understand more about telomere lengthening and shortening, as there seems to be opposing positions between yourself and Turnbuckle.

 

I flatter myself as being a scientist. Therefore I must accept what I observe. Much that I have learnt in 10 years of aging research says that telomeres are of great importance, hence this thread and all the many arguments contained within. But if the evidence of my observations, be that from interventions following Turnbuckle's protocol, or from ideas about acety-coA from Mr Hemming, prove a better fit for observations, then so be it. 

[ambivalent]

Declines in fertility (to take your example) can be explained by hyperfunction. Reduced feeding reduces hyperfunction, therefore fertility improves. There is no requirement for 'levers'.  This was explained by Blagosklonny in 2006.

 

 

Declines in fertility occur directly due to a lack of energy, that is understood. And a reduced supply of external energy leads to poor procreation outcomes. Getting pregnant during times of famine is obviously a bad bet. There is a biological response attempting to avoid this scenario and that is quite clearly to shut down reproduction and extend out the window. It's a lever and its being pulled. And if it isn't there, species survivability is under increased threat. There isn't much to debate here. Reduced feeding doesn't improve present moment fertility it is harms, well, except, I would guess where fertility is damaged through other causes that fasting might address. 

 

This is a bit like Feynman responding to why the woman slipped on the ice - we can see causes at a biological level, and provide explanations within that space and they are all true but relatively - zoom out enough then we start to see the sense at different levels and eventually to evolution. 

 

If fertiliy doesn't shut down during famine, then there will be an increase in poor outcomes, if decline in fertility doesn't stall during those times and with it extend into later life, the opportunity to procreate at that fertile state will be lost for good - which is bad for the species, so we've evolved to preserve it.   

  

Consequently the female with fertility that shuts down during tough times is likely to fair better than one whose doesn't but if she stops cycling without preserveing, then this is a more conflcted outcome - maybe the other female is better off through running the gauntlet at peak fertility, rather than wait for a more prosperous environemnt accompanying a decline in fertility.

[QuestforLife]

Declines in fertility occur directly due to a lack of energy, that is understood. And a reduced supply of external energy leads to poor procreation outcomes. Getting pregnant during times of famine is obviously a bad bet. There is a biological response attempting to avoid this scenario and that is quite clearly to shut down reproduction and extend out the window. It's a lever and its being pulled. And if it isn't there, species survivability is under increased threat. There isn't much to debate here. Reduced feeding doesn't improve present moment fertility it is harms, well, except, I would guess where fertility is damaged through other causes that fasting might address. 

 

This is a bit like Feynman responding to why the woman slipped on the ice - we can see causes at a biological level, and provide explanations within that space and they are all true but relatively - zoom out enough then we start to see the sense at different levels and eventually to evolution. 

 

If fertiliy doesn't shut down during famine, then there will be an increase in poor outcomes, if decline in fertility doesn't stall during those times and with it extend into later life, the opportunity to procreate at that fertile state will be lost for good - which is bad for the species, so we've evolved to preserve it.   

  

Consequently the female with fertility that shuts down during tough times is likely to fair better than one whose doesn't but if she stops cycling without preserveing, then this is a more conflcted outcome - maybe the other female is better off through running the gauntlet at peak fertility, rather than wait for a more prosperous environemnt accompanying a decline in fertility.

 

There is no point arguing for the existence of a lever to 'avoid this scenario and that is quite clearly to shut down reproduction and extend out the window' when this is obviously not required given less food will automatically reduce all physical performance including fertility!

[ambivalent]

If it were simply about energy then fasting mimetics wouldn't work in the presence of energy. In many ways the body becomes more active when fasting, autophagy for example is energy consuming - why not do this recycling when we are energised? It is a response to the environment. We becomne more focussed, our body repairs - our body chooses to repair when we are low on resources, it does so because the environment is challenging and we may face an existential threat

 

Epigenes are nature's levers, we can inherit different traits going back generations because of those different expressions at conception.

 

I am guessing that through fasting mimitecs we can alter fertility in fact, metformin, I believe does this - if we have two groups one with a fasting mimetic and the other without on identical energy and the former improves fertility, then it isn't about the energy, its about the signalling of a lack of energy and that is a step removed, just like autophagy. And the very fact that there is a derivative rather than a direct causal response to the lack of energy - i.e. we need energy, we have no energy therefore we shut down - but that there is in fact a choice as to how to respond to the lack of energy, is one that can be toyed with through evolution and it appears is so. 

 

I would bet for example, that fertility could be switched on and or up epigenetcially while calorie-restricted.  

[QuestforLife]

If it were simply about energy then fasting mimetics wouldn't work in the presence of energy. In many ways the body becomes more active when fasting, autophagy for example is energy consuming - why not do this recycling when we are energised? It is a response to the environment. We becomne more focussed, our body repairs - our body chooses to repair when we are low on resources, it does so because the environment is challenging and we may face an existential threat

 

Epigenes are nature's levers, we can inherit different traits going back generations because of those different expressions at conception.

 

I am guessing that through fasting mimitecs we can alter fertility in fact, metformin, I believe does this - if we have two groups one with a fasting mimetic and the other without on identical energy and the former improves fertility, then it isn't about the energy, its about the signalling of a lack of energy and that is a step removed, just like autophagy. And the very fact that there is a derivative rather than a direct causal response to the lack of energy - i.e. we need energy, we have no energy therefore we shut down - but that there is in fact a choice as to how to respond to the lack of energy, is one that can be toyed with through evolution and it appears is so. 

 

I would bet for example, that fertility could be switched on and or up epigenetcially while calorie-restricted.  

 

Again, no. Metformin has benefits on later life fertility because it is reducing available energy. The body isn't choosing to repair when resources are low. It is breaking down itself because it needs the energy to survive. And this is construed as beneficial because 'damaged' macromolecules are turned over at a higher rate. But the actual benefit is coming from the reduced energy. 

 

Now you can argue it is not the energy but the signalling that is resultant from this energy. That is where the likes of mTOR inhibition come in. Rapamycin has many of the benefits of calorie restriction but doesn't require a reduction in energy. But the body is fooled by it and reacts as if there were a lack of energy - hence mobilisation of lipids, greater autophagy, etc. So we may be able to fool the system to some extent whilst still eating like pigs. But the point is that the benefits are mainly coming from turning down the growth signals, not from the adaptions the body is making*. That fooled a lot of people for a long time.

 

High mTOR is beneficial in youth (and more food just makes you grow faster, for the most part), but high mTOR becomes harmful in adulthood. There is some evidence this is linked to telomere length and I've discussed that here.

 

* I discussed this a few posts up with SHMT2 (glycine export to serine) is blocked with age as a way to restrict energy whilst keeping glycine available to make new mitochondria. In this case it turned out this was an adaptation to aging, not the cause. Similarly citrate export being blocked with age looks like a reaction to me, not the cause of harm.

 

The real problem here is that if all of aging is metabolic, how are we going to live forever? A human has a human metabolic rate and can't turn into a whale. 

[QuestforLife]

I think Telomeres are a consequence of exogenous factors (that is exogenous to the cell).  There are a number of examples of this, but i think this is particularly relevant:

 

http://repositorium....ndle/1822/54794

 

So they created a mouse with over-active IL-10 and it looked like accelerated aging. 

 

Where is the reasoning to link this as an exogenous cause of cellular aging?

 

Forgive me but this is a monster read (127 pages)!

[ambivalent]

 we may be able to fool the system to some extent whilst still eating like pigs.

 

So we're talking switches and so no 1-1 direct cause and effects. And the point is this - if we under the same energy state can alter fertility levels, so in other words there can be many energy states corresponding to many fertility states, and many fertility states corresponding to many energy states, then there is simply no sense in reasoning that fertility is switched off because a specific energy state can no longer be maintained because the body has 'run out of juice to support it' - as if there is some direct gas line connected to it: there isn't. 

 

Once that is established as the case, then nature can mutate away - it can shut down fertility earlier than it needs to or later than it should if trying to optimise preserving itself. And so a mutation that improves species survivability will emerge.

 

Once those mutations are in play, then natural selection will take its course. And the mutation which responds in tough conditions, and shuts down early will fair better that those maintaining it or indeed the instance of those females whose fertility increases under calorie restriction - you can bet it will have happened. 

 

And of coruse the early shutdown responders to famine will make hay while the sun shines and pass on those genes.

 

Once there is separation between energy and fertiliy, there is a switch that can be gamed, a lever pulled.

 

In a sense autophagy was a poor example because it isn't separating from the species survivial form the individual, but autophagy is ever present and ramped up. Under a certain lens, we are looking at a system with drastically reduced energy, increasing in activity - zoom out and it makes sense. Energy is taken from one place to another. And that really was the point, there may be better examples. 

 

And as for fasting, well much of the benefits do occur during refeeding and it is reparative, but for example in the case of white blood cells, the returned level is above pre-fasting baseline and this process can carry on raising white blood cell levels through each fasting cycle (Longo). Why does the immiune system need to be better than it was before? It is not merely replacing what was lost, the capacity to eat the inferior white cells, replace them and add more to improve the immune system was always there in bountiful times, but not taken. It is a response to an anticipated tough environment, clearly, as so much of the reparative work is.    

 

As for metformin, well it does improve fertility in younger women, though it s a bad example, because it involves PCOS and may seem to counter it, because it improves fertility while taking it - one assumes it is high blood sugar levels are deleterious to fertility, and that would be the over-riding factor.

 

But in summary, if there is no way of fooling fertility under some CR mimic, then your position would be right, but if not the case then obviously evolution will have found a hack benefitting species survival because it can play with fertility at different energy levels and given that the body doesn't optimise for personal survival - we'll live longer, be healthier, if certain genes are switched permanently on but they're not - why would we assume that nature is purely acting on individual survival when allocating resources under starvation.  

 

edit: in fact here we have an example in c-elegan worms of metformin reducing fertility:

 

"Metformin is a drug commonly used to treat type-2 diabetes in humans; it extends lifespan in non-diabetic mice, as well as reducing all-cause mortality in non-diabetic humans (Scarpello, 2003; Anisimov et al., 2011). Onken and Driscoll (2010) observed that metformin treatment at 10 or 50 μM in the medium increased median lifespan by 40%. Metformin treatment reduced the number of eggs laid early in the reproductive period, while also extending the total reproductive period by 1 day" 

 

So in c-elegans, fertility can be fooled through the intervention of a fasting mimetic - there is no fasting or loss of energy causing the redution in fertility - it is responding to the signalling of low energy, not the explicit lack of energy.

 

 

Edited by ambivalent, 07 October 2022 - 12:28 PM.

[QuestforLife]

 

So in c-elegans, fertility can be fooled through the intervention of a fasting mimetic - there is no fasting or loss of energy causing the redution in fertility - it is responding to the signalling of low energy, not the explicit lack of energy.

 

In worms, as with other species, you can mess with the energy signalling and in many cases get extended life. 

 

You might argue it is not exactly energy availability but rather the related signalling. But they are strongly coupled.

 

For example mTOR signals growth and it does that in response to nutrient availability (essentially energy). This will drive all manner of things from time to sexual maturity, bone growth rate, nail growth rate, stem cell proliferation rate, telomere shortening rate (possibly), respiration rate, etc., etc. 

 

Now of course that will be calibrated to the required evolutionary development rate of that species, mouse vs. dog. vs human. Hence if we take the example of growth rate it will be mice>dog>human. Also age related decline will be mouse>dog>human.  

 

I've not seen an intervention where a mouse could suddenly live as long as a dog. Even as long as rat is pushing it. This shows us that so far we are only messing with intra-species rates of aging. What we all want to see are interventions in the inter-species rates of aging. That would be interesting. And in all likelihood it wouldn't be achieved by messing with energy metabolism. 

[ambivalent]

We have evidence in c-elegans of de-coupling through a CR-mimetic and fertility is switched down in youth and extended into later life - there is reduced fertility with raised energy and raised fertility with reduced energy, through energy signalling, rather than through explicit energy states. Yes, you're right it isn't humans, but they c-elegans aren't being researched because we're just trying to understand c-elegans. 

 

But it demonstrates that in c-elegans at least, that even though fertility is inevitably predicated on some requisite level of energy supply, fertility can be altered independently of the available energy and that it is the signalling of that energy state which determines the expression of fertility. 

 

That is decoupling. And that of course, permits additional variables to set fertility, not just energy-state - so context matters and that is much smarter for species survival.   

 

note: to "needs references" - its in the previous post. Unless, you believe a logical statement derived from a reference, must also require a reference - we'll end up at modus ponens. Flawed logic, which it maybe well be, should be countered with logic, not a reference-request. 

Edited by ambivalent, 07 October 2022 - 01:57 PM.

[QuestforLife]

We have evidence in c-elegans of de-coupling through a CR-mimetic and fertility is switched down in youth and extended into later life - there is reduced fertility with raised energy and raised fertility with reduced energy, through energy signalling, rather than through explicit energy states. Yes, you're right it isn't humans, but they c-elegans aren't being researched because we're just trying to understand c-elegans. 

 

But it demonstrates that in c-elegans at least, that even though fertility is inevitably predicated on some requisite level of energy supply, fertility can be altered independently of the available energy and that it is the signalling of that energy state which determines the expression of fertility. 

 

That is decoupling. And that of course, permits additional variables to set fertility, not just energy-state - so context matters and that is much smarter for species survival.   

 

note: to "needs references" - its in the previous post. Unless, you believe a logical statement derived from a reference, must also require a reference - we'll end up at modus ponens. Flawed logic, which it maybe well be, should be countered with logic, not a reference-request. 

 

In no way is that decoupling, you are merely making the body (in this case the worm body) think it has less energy. 

 

There are no levers that turn up autophagy (or whatever) to make sure the worm has a chance to reproduce later on, when things are better.  

 

You are just making the worm eek out the measure of its time rather than rush through, by rationing energy.

 

This will extend out life - fertility will last longer, the worm will be active longer, but the worm is still just a worm. It won't live a year long because all its signalling it set to the growth pattern of a worm. So far we've only been able to adjust its energy sensing within the limits of that creature's metabolism. 

[ambivalent]

We may be on semantic of decoupling - sure we're not decoupling energy from fertility, but rather the state of energy from a one to one relationship. 

 

I made the point that metformin would like impact on fertility becauae it mimics fasting and signals CR to which you replied:

 

"Again, no. Metformin has benefits on later life fertility because it is reducing available energy."

 

What we are seeing in c-elegans is that metformin is triggering reduced fertility, when energy is at its highest. This demonstrates that for a range of given energy states R, we can achieve a fertility state F. And likewise, for a range of fertility states S, can be achieved from an energy state E.

 

This doesn't obviously decouple energy from fertility, naturally, but counters the idea a specific level of fertility exists because of some specific energy state - i.e. there is one-to-one mapping. Clearly, there isn't as this study demonstrates, as we should hope from evolution. 

 

And the very fact that there is such flexibility, that biology clearly permits given fertility-states to exist at multiple energy states, in c-elegans at least, is an evolved adaption - so it doesn't shut down because of the energy level, but because of the energy signal - it could keep going for longer, or it could shut down earlier. So why shut down at alpha energy state and not beta or gamma, if all energy states can support fertility? Because that is what suits evolution, not because it is some biological imperitive. And what suits evolution will be some trade off between the individual and the group. And if those beholden to an alpha fertility threshold setting result in less opportunity to procreate during famine, but are compensated by increased opportunity in prosperous times unlike its counter setting, gamma, say, then alpha will expect to win out and be selected for, presumably.

 

And what we end up with is a closing down of fertility not because of reduced energy, but because of reduced energy-signalling.   

 

We may need to draw a line under this, since this is your thread and its not about telomeres. I have at least saitisfied myself through this discourse - unless of course fertility isn't so pliable in humans with energy signalling via say fasting mimetics. What happens with c-elegans is at least consistent with that contention - that nature pulls levers during tough times. 

 

Edited by ambivalent, 07 October 2022 - 03:02 PM.

[QuestforLife]

We may be on semantic of decoupling - sure we're not decoupling energy from fertility, but rather the state of energy from a one to one relationship.

I agree with most of what you are saying. Evolution can make selection based on the set point of this signalling.

I don't see this as a lever an animal can pull, but you could argue evolution treats it as lever.

The area I'd like to steer the conversation to is why this energy signalling has such, mild intra-species effects. So what - a longer lived mouse is still just a longer lived mouse. It doesn't even match a rat in years.

So this signalling may be flexible but still remains bounded within the parameters of what is permitted for that species, i.e. the niche it is adapted to live in.

How can we break free of this? What levers (see what I did there!) can we pull to completely break through the bounds of what evolution has permitted our species.

Could it be telomeres? Maybe...

[ambivalent]

I agree it's not a conscious choice around animal or nature, but it is often the language we used because the "unintelligent solutions" tend to be weeded out by natural selection, especially under examining conditions. 

 

So some questions on telomeres. 

 

After doing some reading I felt uncertain as to the role in telomere shortening in senescence and apoptosis. Both correlate with telomere shortnening but why state and not the other when telomeres reduce - do enzyme levels have an influence?  Can we shorten senescent telomoeres into apoptosis? Additionally, I noted one bit of research showed that average telomere length wasn't an important as a marker for senescence, that the shortest telomere length was the driver into senescence. 

 

Extending telomeres - TB seems to believe they are nothing more than sell by dates and shouldn't be extended; however, and doubtless you don't agree, I seem to recall reading the other week in some literature than extending them reversed some disease states presumably in rodents. I can look for it, though I am sure you know this work. I would also be interested in what therapeutic role this might have in neurological disorders such as Huntingtons Disease which are characterised in part by shortened telomeres. 

 

I suppose the key difference between perhaps yours and Turnbuckle's might be where the telomeres of healthy cells are shortened through some stress factor, rather than division.   

 

 

[QuestforLife]

So some questions on telomeres.

After doing some reading I felt uncertain as to the role in telomere shortening in senescence and apoptosis. Both correlate with telomere shortnening but why state and not the other when telomeres reduce - do enzyme levels have an influence? Can we shorten senescent telomoeres into apoptosis? Additionally, I noted one bit of research showed that average telomere length wasn't an important as a marker for senescence, that the shortest telomere length was the driver into senescence.

Extending telomeres - TB seems to believe they are nothing more than sell by dates and shouldn't be extended; however, and doubtless you don't agree, I seem to recall reading the other week in some literature than extending them reversed some disease states presumably in rodents. I can look for it, though I am sure you know this work. I would also be interested in what therapeutic role this might have in neurological disorders such as Huntingtons Disease which are characterised in part by shortened telomeres.

I suppose the key difference between perhaps yours and Turnbuckle's might be where the telomeres of healthy cells are shortened through some stress factor, rather than division.

TB's protocol is triggering cellular division of progenitor cells. If you combine this with telomerase activation those cells will be able to divide more times and this seems to drive advance of the epigenetic clock - I first encountered this when combining epitalon with my statin-sartan protocol, which also causes expansion of progenitor cells (albeit to a lesser extent than TB's protocol). This was in 2019.

I did some research and identified alpha ketoglutarate as a way to prevent this effect. I started experimenting with this in early 2020. I was successful and since then I've been able to use telomerase activators without increasing epigenetic (methylation) age. I've gone into detail on this thread for why this is.

Whether or not TB can continue getting the benefits from his protocol indefinitely or whether this will deplete the telomeres of his stem cells is an open question.

Similarly, whether I can meaningfully increase the TL of my stem cells or whether my TA will just benefit downstream cells is another good question.

I'd say the role of telomeres in senescence is very clear. Levels of telomerase are critical in setting telomere length, with TERC levels also important. Telomeres below a certain length trigger senescence. It is reckoned the persistence of short telomeres causes inflammaging. But average telomere length is clearly linked to how many short telomeres you have. Because the telomere itself affects how easy it is for telomerase to do its job, short telomeres are preferentially lengthened. It's an averaging effect.

Edited by QuestforLife, 08 October 2022 - 08:44 PM.

[Learner056]

I found your skin aging post to be very informative, about ROCK inhibitor usage and also the cell competition theory. 

 

Question1: 1a: Would you be able to update if your views have evolved on this, and 1b: if you feel comfortable sharing, what you currently use (orally vs topical)? While I am roughly 2x your age, so your protocol may not apply to me, but can still help me understand. 

 

FYI: I had a very brief experience of using Apocynin (Col17a1 stimulator).  It seemed potent, that I had to stop its use.  My skin erupted with a Tinea fungal infection which I at the time attributed to its possible NOX inhibition (NADPH Oxidase).  I view my immune system to be overly reliant on Neutrophils, so I interpreted that Neutrophils were keeping fungus in check, but Apocynin de-weaponized my Neutrophils and so Tinea erupted. Though in fairness that episode could as well be connected to my mRNA vaccine at the time, so your post made me think.

 

Question2: 2a: I use Myricetin (DHM) and Stearic (mango butter), orally and "topically".  You earlier mentioned that Myricetin shifts metabolism to fat burning, which in hindsight is not what one would want topically.

 

2b: But when I consult research, it points to DHM being potent GLP-1 agonist, that it sucks in glucose/energy into cell i.e. transports glucose through GLUT2 (and possibly GLUT4).  And not just that, it stimulates Glycogen Synthase.  So that in hindsight, is OPPOSITE to my concern of losing epidermal tissue fat (as well to what you explained earlier)?  How would you explain this contradiction? 

FYI: obviously I am not saying you are wrong.  Indeed I am wrong.  I am merely trying to understand the contradiction.  As well views evolving is not negative, it is positive. 

 

 

Looking at 'Stem cell competition orchestrates skin homeostasis and ageing', I think their conclusions require further elaboration. Here is their abstract:

 

 

What is actually happening, as I stated in my last post on the subject, is that stress on the skin is selecting a population of more stress resistant stem cells (as defined by their expression of COL17A1). This leads to less asymmetric division and skin replacement and therefore thinner skin, which presumably then leads to higher stress on the remaining cells and the process continues. Eventually you are left with a population of super stress resistant basal stem cells, analogous to the super-quiescent VSELs that exist in other tissues. They authors say ‘eventual loss of COL17A1 limits their competition, thereby causing ageing’, but actually this is only the final part of skin aging. Overly stress resistant cells is as much a part of the problem as loss of the cells that are more easily stimulated.

They leave the best for last, showing that low doses of a ROCK inhibitor (or high doses of an anti-oxidant, Apocynin) both increase wound healing in mice, and prevent the thinning of skin in a model of aged skin.
My research has shown that statins are effective ROCK inhibitors even at very low doses, and have even been used in increase wound healing (https://www.ncbi.nlm...pubmed/28740761).

 

Edited by Learner056, 09 October 2022 - 09:58 PM.

[QuestforLife]

I found your skin aging post to be very informative, about ROCK inhibitor usage and also the cell competition theory. 

 

Question1: 1a: Would you be able to update if your views have evolved on this, and 1b: if you feel comfortable sharing, what you currently use (orally vs topical)? While I am roughly 2x your age, so your protocol may not apply to me, but can still help me understand. 

 

FYI: I had a very brief experience of using Apocynin (Col17a1 stimulator).  It seemed potent, that I had to stop its use.  My skin erupted with a Tinea fungal infection which I at the time attributed to its possible NOX inhibition (NADPH Oxidase).  I view my immune system to be overly reliant on Neutrophils, so I interpreted that Neutrophils were keeping fungus in check, but Apocynin de-weaponized my Neutrophils and so Tinea erupted. Though in fairness that episode could as well be connected to my mRNA vaccine at the time, so your post made me think.

 

 

 

I subscribe primarily to the cell size theory of aging, which I discussed here. Telomeres are one part of this but there are other factors. But the cell size is what seems to be important. I have an idea for why this is, but I need to get together my thoughts and write a proper post on it.

 

Cell competition might well be important. The fact we all end up with just a few HSC stem cell lines, and they don't work properly - is this because they've outcompeted the good ones, and that is what has caused aging, or is aging another factor altogether and we are just blaming the survivors? If you came across a village where everyone was the descendent of the few who survived a terrible plague sometime previously, because of genetic resistance, you wouldn't blame the survivors. So cell competition might be important, but it might be a red herring.

 

I made a statin (rock inhibitor) skin cream, it healed cuts quicker, but didn't seem to lead to any rejuvenation. 

 

Question2: 2a: I use Myricetin (DHM) and Stearic (mango butter), orally and "topically".  You earlier mentioned that Myricetin shifts metabolism to fat burning, which in hindsight is not what one would want topically.

2b: But when I consult research, it points to DHM being potent GLP-1 agonist, that it sucks in glucose/energy into cell i.e. transports glucose through GLUT2 (and possibly GLUT4).  And not just that, it stimulates Glycogen Synthase.  So that in hindsight, is OPPOSITE to my concern of losing epidermal tissue fat (as well to what you explained earlier)?  How would you explain this contradiction?

FYI: obviously I am not saying you are wrong.  Indeed I am wrong.  I am merely trying to understand the contradiction.  As well views evolving is not negative, it is positive.

 

Interesting about the glucose transporters, do you have a source?

 

DHM has been shown fairly convincingly to turn up SIRT3 and increased fatty acid burning,  for example see here.  

[ambivalent]

On TB's stem cell protocol, there shouldn't be a problem if fusion is keeping stem cells repleted. I assume, though, extending telomere length does impact on the mitochondrial fusion protocol because telomere length is presumably a recycling signaller during mitophagy. The argument being that extending telomeres prolongs the life of defective mitochondria.  

 

Out of interest, the paper on the shortest rather than the average telomere length appears critical.

 

https://pubmed.ncbi.....gov/11595186/ 

 

One question is why some cells turn senescent and others don't if telomere length is a signaller, and why others move to apoptosis and we know that senescence --> aopotosis is tough. 

[Learner056]

That is helpful.  Yes there are infinite resources, patents, 'tricks of the trade', research papers.  No offense to our pharma friends (as I believe we are all pharma now), but in fairness most synthetics (Semiglutide, GLP-1 agonist whatever its called) how do they make them, from puff air?  No, these are tricks of the trade, that you (young but seasoned) biohackers should be telling me (old hag albeit a budding biohacker)

https://journals.plo...al.pone.0231543

https://onlinelibrar....1002/fsn3.2513

https://www.ncbi.nlm...les/PMC8743163/

https://www.mdpi.com...abetic subjects

on and on and on ...

 

 

 

Interesting about the glucose transporters, do you have a source?

 

DHM has been shown fairly convincingly to turn up SIRT3 and increased fatty acid burning,  for example see here.  

 

Edited by Learner056, 10 October 2022 - 03:43 PM.

[QuestforLife]

On TB's stem cell protocol, there shouldn't be a problem if fusion is keeping stem cells repleted.

How so? You know telomeres shorten with division? So you'll have more in number, but all with reduced telomere length.

I assume, though, extending telomere length does impact on the mitochondrial fusion protocol because telomere length is presumably a recycling signaller during mitophagy. The argument being that extending telomeres prolongs the life of defective mitochondria.

Telomerase upregulates mitophagy. I've written numerous posts on this. So that's not the problem. I can think what the problem is, but like I said to Learner, I need to write a long, referenced post to explain it.

One question is why some cells turn senescent and others don't if telomere length is a signaller, and why others move to apoptosis and we know that senescence --> aopotosis is tough.

Senescent cells secrete growth signals. This cause other cells to divide and replace them. But if too many cells are close to senescence, this just causes senescence to spread.

Edited by QuestforLife, 10 October 2022 - 05:28 PM.