85 replies to this topic

[niner]

 

 

More turnover = more variety generated per time unit = more DNA combinations thrown under whatever natural selection pressure exists at the time = faster evolution/adaptation per time unit

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 

 

If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms. 

This is why non-ageing animals are increasingly rare as evolution went on through time. 

 

This is internally consistent, but doesn't it make the assumption that the beginning state was animals that don't age, or don't age much?  It's hard to make animals that live a long time-- They need all sorts of elaborate repair mechanisms.  It seems far more likely that early organisms aged rapidly, and only evolved longer lives if it improved reproductive fitness.  In an environment of predation and infection, animals didn't need any extra help dying, so I don't see a driving force for evolution of aging.

 

Single cell life forms are pretty much immortal. Ageing developed in tandem with multicellularity and sexual reproduction in animals. 

 

First multicellular lifeforms simply kept their "offspring" cells attached to them and this created primitive bodies. Eventually the attached offspring cells differentiated to form different tissues via parent cells leaking "enslaving"(differentiating) chemicals in a timed/triggered manner etc. This process of "growing (fruiting) bodies" eventually evolved into very complex proliferation sequences and within it - ageing developed - as a part of the sequence - the life cycle.

 

Similarly to the way multicellular body plan (how many legs/hand/segments etc) is determined by a set of HOX genes in basicly all animals https://en.wikipedia.org/wiki/Hox_gene, so is the lifecycle of the multicellular body determined by a set of FOX genes https://en.wikipedia...ki/FOX_proteins in all of them. 

 

First multicellular animals didn't age rapidly, quite the contrary. The most primitive animal species we still have present today are often immortal or long lived - the most prominent are hydras or corals. As the evolutionary tree of life branched out - it became harder and harder for "immortal" animals to survive the competition from ageing animals within rich niches that can sustain a lot of turnover. It also became increasingly hard to for complex bodies to make large scale repairs from physical damage. It's one thing to grow a tentacle, but an entirely different thing to grow an arm with skeleton, knuckles, joints and muscles properly attached and innervated. It also became increasingly hard to sustain ever growing bodies (like the crustaceans among which there are some that also seem to grow and live indefinitely) as the vast differences in size require differences in behavior, different food etc.

 

And you are right, pressure from predators is similar to ageing pressure, but still, ageing enhances pressure from predators and makes for even better selection - against predators! If you have enough bodies to throw at it, why would this mechanism not evolve? Think long term... 
If you have a system that produces steady evolution (species with sexual reproduction are exactly that) then you expect to have "better"/"more evolved" offspring than their parents (on average). If your offspring is expected to be more evolved why not kill off the parents in this ingenious way that provides more selection (and releases more resources/food for the young offspring - animals sometimes do need help dying, if they want to make room for their more evolved offspring)? 
As body repairs are slowly stopped to a halt, the parent still has some fighting chance, depending on how good his final/mature state was. If it was good he'll survive a bit longer than some other member of the same species and make a few extra offspring in his lifetime thanks to his other important "niche abilities" which his species actively evolves, rather than general endless repair ability which evolved millions of years ago and was since "shunned" by most species. These few extra offspring will provide more spread of his proven and able genes that warrant a good final/mature state..... if the final/mature state developed from his genes was not good he'll die off faster as he begins to age and will not make the extra few offspring.

 

Species with most turnover produce most evolution: insects, fish, krill, season plants etc. The sheer number of species that evolved along those lineages is overwhelming and so is the even bigger number of already extinct species! Species with least turnover are usually "evolutionary" oldest in a sense - they are the same now as they were millions of years ago - living fossils.

 

 

BTW, welcome back, addx!  You've been away for a while.   This thread is keeping you busy; it's a lot to keep up with.  Unicellular organisms that divide symmetrically don't age, at least in the right environment.  The very earliest multicellular organisms might not have aged if they could divide continuously and reproduce by budding.  Sophisticated multicellular organisms are another story, however.  I think that aging of the soma may be a required consequence of the elaborate structure of such creatures.  I understand the argument that death is a necessary part of evolution, and that quicker generations provide more adaptability, but we are left with the question of whether aging arose as a consequence of multicellularity and sexual reproduction, or if the earliest multicellular/sexual organisms were ageless, with aging arising later due to the evolutionary advantages it conferred.   I'm not sufficiently versed in this area to argue it competently, but I can tell you what I think is the most likely--  That is that aging is a consequence of multicellularity and sexual reproduction.  I suspect that early lifespans tended to be very short, primarily due to predation and infection, so the evolutionary advantages of aging never had a chance to exert any evolutionary pressure.   I think it's more likely that long lifespans evolved, rather than the other way around.

[addx]

More turnover = more variety generated per time unit = more DNA combinations thrown under whatever natural selection pressure exists at the time = faster evolution/adaptation per time unit

Ageing enhances natural selection pressure and provides more turnover for it to work with - so makes evolution faster. 
 
If a food supply can sustain 100 animals of some species - if the animals age faster - there will be more turnover - and so more evolution. If the animals never age there will be almost no evolution. If you split them 50 vs 50, the 50 that ages will eventually evolve to outcompete the 50 eternal life forms. 

This is why non-ageing animals are increasingly rare as evolution went on through time.

 
This is internally consistent, but doesn't it make the assumption that the beginning state was animals that don't age, or don't age much?  It's hard to make animals that live a long time-- They need all sorts of elaborate repair mechanisms.  It seems far more likely that early organisms aged rapidly, and only evolved longer lives if it improved reproductive fitness.  In an environment of predation and infection, animals didn't need any extra help dying, so I don't see a driving force for evolution of aging.

 
Single cell life forms are pretty much immortal. Ageing developed in tandem with multicellularity and sexual reproduction in animals. 
 
First multicellular lifeforms simply kept their "offspring" cells attached to them and this created primitive bodies. Eventually the attached offspring cells differentiated to form different tissues via parent cells leaking "enslaving"(differentiating) chemicals in a timed/triggered manner etc. This process of "growing (fruiting) bodies" eventually evolved into very complex proliferation sequences and within it - ageing developed - as a part of the sequence - the life cycle.
 
Similarly to the way multicellular body plan (how many legs/hand/segments etc) is determined by a set of HOX genes in basicly all animals https://en.wikipedia.org/wiki/Hox_gene, so is the lifecycle of the multicellular body determined by a set of FOX genes https://en.wikipedia...ki/FOX_proteins in all of them. 
 
First multicellular animals didn't age rapidly, quite the contrary. The most primitive animal species we still have present today are often immortal or long lived - the most prominent are hydras or corals. As the evolutionary tree of life branched out - it became harder and harder for "immortal" animals to survive the competition from ageing animals within rich niches that can sustain a lot of turnover. It also became increasingly hard to for complex bodies to make large scale repairs from physical damage. It's one thing to grow a tentacle, but an entirely different thing to grow an arm with skeleton, knuckles, joints and muscles properly attached and innervated. It also became increasingly hard to sustain ever growing bodies (like the crustaceans among which there are some that also seem to grow and live indefinitely) as the vast differences in size require differences in behavior, different food etc.
 
And you are right, pressure from predators is similar to ageing pressure, but still, ageing enhances pressure from predators and makes for even better selection - against predators! If you have enough bodies to throw at it, why would this mechanism not evolve? Think long term... 
If you have a system that produces steady evolution (species with sexual reproduction are exactly that) then you expect to have "better"/"more evolved" offspring than their parents (on average). If your offspring is expected to be more evolved why not kill off the parents in this ingenious way that provides more selection (and releases more resources/food for the young offspring - animals sometimes do need help dying, if they want to make room for their more evolved offspring)? 
As body repairs are slowly stopped to a halt, the parent still has some fighting chance, depending on how good his final/mature state was. If it was good he'll survive a bit longer than some other member of the same species and make a few extra offspring in his lifetime thanks to his other important "niche abilities" which his species actively evolves, rather than general endless repair ability which evolved millions of years ago and was since "shunned" by most species. These few extra offspring will provide more spread of his proven and able genes that warrant a good final/mature state..... if the final/mature state developed from his genes was not good he'll die off faster as he begins to age and will not make the extra few offspring.
 
Species with most turnover produce most evolution: insects, fish, krill, season plants etc. The sheer number of species that evolved along those lineages is overwhelming and so is the even bigger number of already extinct species! Species with least turnover are usually "evolutionary" oldest in a sense - they are the same now as they were millions of years ago - living fossils.

 
 
BTW, welcome back, addx!  You've been away for a while.   This thread is keeping you busy; it's a lot to keep up with.  Unicellular organisms that divide symmetrically don't age, at least in the right environment.  The very earliest multicellular organisms might not have aged if they could divide continuously and reproduce by budding.  Sophisticated multicellular organisms are another story, however.  I think that aging of the soma may be a required consequence of the elaborate structure of such creatures.  I understand the argument that death is a necessary part of evolution, and that quicker generations provide more adaptability, but we are left with the question of whether aging arose as a consequence of multicellularity and sexual reproduction, or if the earliest multicellular/sexual organisms were ageless, with aging arising later due to the evolutionary advantages it conferred.   I'm not sufficiently versed in this area to argue it competently, but I can tell you what I think is the most likely--  That is that aging is a consequence of multicellularity and sexual reproduction.  I suspect that early lifespans tended to be very short, primarily due to predation and infection, so the evolutionary advantages of aging never had a chance to exert any evolutionary pressure.   I think it's more likely that long lifespans evolved, rather than the other way around.

Well I think I established a well founded truth.

An evolutionary conserved pathway within most animal life from worms to humans - regulates lifespan and reproductive lifespan according to perceived nutrient availability. This means that a phenotype of shorter lifespan is deliberately induced when there is enough nutrients to throw around - meaning that available resources regulate turnover!

[corb]

 

On the contrary, the negative relation between caloric intake and lifespan is compatible with Wear and Tear Hypotheses and Stochastic Hypothesis because a reduced metabolism caused by caloric restriction should slacken aging.

 

A quote from programmed-aging.org.

Whether you slow metabolism through lower caloric intake or through pharmacological means that isn't proof of any theory because it's applicable in both cases. Metabolism is the main cause of damage in our body after all.

[addx]

On the contrary, the negative relation between caloric intake and lifespan is compatible with Wear and Tear Hypotheses and Stochastic Hypothesis because a reduced metabolism caused by caloric restriction should slacken aging.

 
A quote from programmed-aging.org.
Whether you slow metabolism through lower caloric intake or through pharmacological means that isn't proof of any theory because it's applicable in both cases. Metabolism is the main cause of damage in our body after all.

Yes, but in the example I posted above, calorie restriction was only imposed during early development. The test specimens were fed a normal diet for the remainder of the lifespan. This means that early on calorie restriction induced a phenotype with increased longevity.

You could argue that early on calorie restriction induced a phenotype with permanently altered metabolism which handled the regular diet for the remainder of the lifespan in a different way causing less damage to accumulate but this again only means regular metabolism evolved to provide more turnover at the expense of longevity.

As I see it, at first there was much ability in life for longevity as ancient hydras or jellyfish prove, but longevity/immortality was lost or became regulated by perceived nutrient availability in later evolved life due to selection pressure for turnover.

Selection pressure for higher turnover is a real thing. Surplus nutrients would be invested into evolution (or into the future of the species) via increased turnover.

[addx]

You could argue that early on calorie restriction induced a phenotype with permanently altered metabolism which handled the regular diet for the remainder of the lifespan in a different way causing less damage to accumulate but this again only means regular metabolism evolved to provide more turnover at the expense of longevity.

Now that I think about it, it may also mean that regular metabolism evolved to sustain high levels of activity(body stress) at the expense of longevity.

If you can be twice as strong via "faster/stronger metabolism" but are penalized for that with a 30% or 50% lifespan reduction it's still quite a beneficial strategy for the species.
In the long term species perspective, offspring will always be there to replace you, so the population remains the same regardless of sacrificed lifespan (in balance with available resource), it's just that the same population is twice as strong and turnover is also twice as fast.

It seems that evolution had every reason to evolve mortality either way.

[Never_Ending]

Another issue that comes up is ... if we take the aging as adaptive (and reproduction as the end goal ) to an extreme  we get boom and bust animals.  Animals like wild salmon that go into a reproduction boom and die after.... or animals that have super fast turnovers like drosophilia. I don't believe salmon or fruit flies are superior to humans...  Turnover and cycling is ONE strategy , naturally long lifespans in a species is another strategy. There are many strategies that result in survival of a species, these can seem almost like 180 from each other... 

[Avatar of Horus]

... 
muscle
 
Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging
Liu et al. 2013
http://www.ncbi.nlm....pubmed/23810552
...

 

...
Epigenetic regulation of satellite cell activation during muscle regeneration
Dilworth and Blais, 2011
http://www.ncbi.nlm....pubmed/21542881
...

A research result connected to the above has been published:
Back to the Start: Re-activation of Embryonic Genes Leads to Muscle Aging
Nov 30, 2016
Leibniz-Institute on Aging – Fritz Lipmann Institute (FLI)
http://www.leibniz-f..._pi1[news]=3310

its topic in BioscienceNews:
Embryonic Gene Hoxa9 Reactivates with Age to Limit Muscle Stem Cells
http://www.longecity...cle-stem-cells/
 

The study:
Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals
Schwörer et al. 2016
http://www.nature.co...ature20603.html

Its significance is that that its results show that manipulating these pathways "... improved myofibre regeneration in injured muscle of aged mice almost to the levels in young adult mice (Fig. 2c, Extended Data Fig. 5f), ..."

[Never_Ending]

 

You could argue that early on calorie restriction induced a phenotype with permanently altered metabolism which handled the regular diet for the remainder of the lifespan in a different way causing less damage to accumulate but this again only means regular metabolism evolved to provide more turnover at the expense of longevity.

Now that I think about it, it may also mean that regular metabolism evolved to sustain high levels of activity(body stress) at the expense of longevity.

If you can be twice as strong via "faster/stronger metabolism" but are penalized for that with a 30% or 50% lifespan reduction it's still quite a beneficial strategy for the species.
In the long term species perspective, offspring will always be there to replace you, so the population remains the same regardless of sacrificed lifespan (in balance with available resource), it's just that the same population is twice as strong and turnover is also twice as fast.

It seems that evolution had every reason to evolve mortality either way.

 

 

I've  thought about the turnover argument , it seems deeply flawed.

 

But to address this quote of yours above,

The extra food triggers so called "faster stronger" metabolic phenotype  at the EXPENSE of lifespan. It means that the benefit of lifespan was eclipsed by the benefit of immediate fitness.   Its like you tweak a cheap car to drive like a sports car, the cheap car performance-wise gets boosted but it's going to break down fast.

 

Now ask yourself,

Do you tweak it for the purpose of breaking down faster?

 

Does evolution advance(perhaps with side-affects on mortality) for the sake of dying faster?

 

The answer to both is no. 

Edited by Never_Ending, 13 December 2016 - 12:54 AM.

[Avatar of Horus]

An interesting recent discovery about cross-seeding in aging-related protein aggregation:
 

Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation
Groh et al. 2017 May
https://www.ncbi.nlm...pubmed/28567012

Abstract
Aging is the most important risk factor for neurodegenerative diseases associated with pathological protein aggregation such as Alzheimer's disease. Although aging is an important player, it remains unknown which molecular changes are relevant for disease initiation. Recently, it has become apparent that widespread protein aggregation is a common feature of aging. Indeed, several studies demonstrate that 100s of proteins become highly insoluble with age, in the absence of obvious disease processes. Yet it remains unclear how these misfolded proteins aggregating with age affect neurodegenerative diseases. Importantly, several of these aggregation-prone proteins are found as minor components in disease-associated hallmark aggregates such as amyloid-β plaques or neurofibrillary tangles. This co-localization raises the possibility that age-dependent protein aggregation directly contributes to pathological aggregation. Here, we show for the first time that highly insoluble proteins from aged Caenorhabditis elegans or aged mouse brains, but not from young individuals, can initiate amyloid-β aggregation in vitro. We tested the seeding potential at four different ages across the adult lifespan of C. elegans. Significantly, protein aggregates formed during the early stages of aging did not act as seeds for amyloid-β aggregation. Instead, we found that changes in protein aggregation occurring during middle-age initiated amyloid-β aggregation. Mass spectrometry analysis revealed several late-aggregating proteins that were previously identified as minor components of amyloid-β plaques and neurofibrillary tangles such as 14-3-3, Ubiquitin-like modifier-activating enzyme 1 and Lamin A/C, highlighting these as strong candidates for cross-seeding. Overall, we demonstrate that widespread protein misfolding and aggregation with age could be critical for the initiation of pathogenesis, and thus should be targeted by therapeutic strategies to alleviate neurodegenerative diseases.

[Avatar of Horus]

Two studies from the same group:
 
Age-related changes in lamin A/C expression in the osteoarticular system: laminopathies as a potential new aging mechanism
Duque & Rivas 2006.
https://www.ncbi.nlm...pubmed/16445967
 

Role of the nuclear envelope in the pathogenesis of age-related bone loss and osteoporosis
Vidal et al. 2012
https://www.ncbi.nlm...pubmed/23951459
 
Abstract
The nuclear envelope is the most important border in the eukaryotic cell. The role of the nuclear envelope in cell differentiation and function is determined by a constant interaction between the elements of the nuclear envelope and the transcriptional regulators involved in signal transcription pathways. Among those components of the nuclear envelope, there is a growing evidence that changes in the expression of A-type lamins, which are essential components of the nuclear lamina, are associated with age-related changes in bone affecting the capacity of differentiation of mesenchymal stem cells into osteoblasts, favoring adipogenesis and affecting the function and survival of the osteocytes. Overall, as A-type lamins are considered as the 'guardians of the soma', these proteins are also essential for the integrity and quality of the bone and pivotal for the longevity of the musculoskeletal system.

Some quotes:

...
A-type lamins have been recently linked to a number of human
progeroid syndromes and adult-onset degenerative diseases; 6 – 8
therefore, in this review we will focus on the role of A-type lamins
in bone cells particularly in the age-related changes that
predispose to osteoporosis and fractures. By reviewing this
evidence, we will propose that modulating the expression of
A-type lamins in the musculoskeletal system could become a
new therapeutic intervention to prevent age-related bone loss
and osteoporosis.
...
In conclusion, the understanding of the intrinsic mechanisms
of normal aging in bone is essential to develop novel therapeutic
targets for osteoporosis. In this case, lamin A / C fulfills the
criteria as a strong longevity gene that regulates bone mass
and bone turnover. Increasing lamin A / C processing in MSC of
aging bone is an attractive approach to increase bone formation
and prevent osteoporosis. In addition, the benefits of increasing
lamin A / C levels are not limited to bone, as decreasing levels of
lamin A / C in other systems such as muscle and cartilage could
have a role in other age-related degenerative diseases.

[OP2040]

I've come to really disagree with the SENS/damage view of aging, and have a strong preference for the Hallmarks of Aging.  The damage view is the ancient and intuitive view, and like most ancient and intuitive things, it's probably wrong despite it's popularity.  The crux of the matter is that for 20-30 years the body can fix itself just fine thank you.  The breakdown certainly causes damage at later stages.  But the earlier, primary forms of aging are "loss of function" for maintenance systems.  Proteostasis, epigenetics, telomeres and DNA repair.  All of these things can be perceived as loss of the ability to maintain and fix types of damage that are already occuring throughout life.  Embryology, and negligibly senescent animals also prove this.  The germline is cleared of damage very easily by upregulating a few maintenance systems (including lysosomes). 

 

Some might say this makes no difference as the goal is still to clear damage.  Well the difference in perspective does have important practical consequences.  There are thousands of types of damage, and I've seen the damage crowd get bogged down in each and every one of them.. 

 

The next step for anti-aging research should be based on this framework.  Upregulate DNA repair (NAD+ should do it), telomeres (we can do that), proteostasis (lots of ways to ramp up autophagy, chaperoning and the proteasome) and finally reverse epigenetic aging (with OSKM).  All of these are now based on standard technology for mice, and I think if we do ALL of them at once, we will see dramatic gains in lifespan.   If we focus on the other end (on the damage), we will be plugging away for years playing whack-a-mole with AGE's, amyloids, mitochondrial genes, etc. etc. etc. ad nauseum.  I can understand if some people disagree with this assessment.  But fixing those four things in a mouse just to see what happens seems like a no brainer that we should all agree on. 

 

I do see one exception to this, where these four hallmarks may not be enough.  The immune system seems to have its own unique aging process that starts very young and sort of works through inertia until it fades away.   But we can do that too with thymic rejuvenation.

[Avatar of Horus]

It seems that the changes in the nuclear lamina and chromatin participate also in the aging of the liver:
 

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver
Whitton et al. 2018
 
Abstract
Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) using lamin B1 ChIP-Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24-deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de-repression of PPAR- and LXR-dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de-repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.
 
KEYWORDS: Foxa2; forkhead factors; heterochromatin; lipid metabolism; liver; nuclear lamina

[Avatar of Horus]

Results and hypothesis of a research project:
http://www.bancoadn....r-disease..html
 

Título: Role of A-type lamins in aging and cardiovascular disease.
IP: Dr. Vicente Andrés García
Resumen del proyecto: This project is framed in the context of the broad interest of our laboratory to investigate the molecular ana cellular mechanisms responsible of cardiovascular disease and premature and physiological aging. Cardiovascular disease (CVD) is the number one killer in developed countries and by 2020 is expected to be the main cause of morbi-mortality worldwide. This is due in part to progressive societal aging, which is one of the most salient demographic phenomena of our times and has a high medical and socioeconomic impact. A-type lamins (lamin A and C encoded by LMNA gene) are key regulators of nuclear structure and cell functions, as DNA transcription and replication, DNA damage repaired response, or mechano-sensing and signal transduction. In addition, LMNA mutations provoke several human diseases termed laminopathies, such as Hutchinson-Gilford progeria syndrome (HGPS), a rare disease caused by accumulation of the mutant lamin A protein called progerin. HGPS is a premature aging disease characterized among other signs by excessive atherosclerosis and death of patients in adolescence mainly from myocardial infarction or stroke. Progerin has also been detected at low level in aged non-HGPS individuals, suggesting a potential role for progerin in normal aging. Our group has made seminal contributions over the last decade to understanding the role of A-type lamins in different physio-pathological processes. We have recently started studies on the role of A-type lamins expression in immune cells in atherosclerosis development and aging. Using transgenic mouse models, we have demonstrated increased atherosclerosis development when lamin A/C is missing in hematopoietic precursors. However, the aggravation of atherosclerosis in the absence of lamin A/C is not due to changes in the number of circulating leukocytes or in the adherence of monocytes and neutrophils to the inflamed vessel wall, but is associated with increased leukocyte extravasation and reduced migration velocity after extravasation. In a complementary pilot study with peripheral blood mononuclear cells (PBMCs) from wild-type mice ranging from 3 to 102 weeks of age, we found lower levels of lamin A/C in neutrophils and Ly6CLow patrolling monocytes isolated from old versus young mice; by analysing PBMCs from age-matched men and women ranging 20 to 40 years of age, we also found higher level of lamin A/C protein in B-lymphocytes and classical and non-classical monocytes of women versus men (age range when women show normal hormonal activity). Based on these preliminary results, we propose the following working hypothesis: 1) lamin A/C expression in PBMCs protects from atherosclerosis development; 2) the down-regulation of lamin A/C in murine leukocytes from old mice might represent a novel mechanism contributing to age-dependent atherosclerosis development; 3) hormonal factors in young women may help to maintain higher levels of lamin A/C in some subpopulations of PBMCs compared with age-matched men, and thus contribute to cardiovascular protection in premenopausal women. In the present project we propose to investigate the levels of expression of lamin A/C in different populations of PBMCs from age-matched men and women ranging from young to old age. This investigation should improve our knowledge on the role of A-type lamins in monocyte effector differentiation/function and atherosclerosis (AIM 1), identify new mechanisms underlying age- and gender-dependent regulation of A-type lamins expression (AIM 2), and assess the contribution of progerin to physiological aging and to age-dependent atherosclerosis development (AIM 3).
Entidad financiadora: Ministerio de Ciencia e Innovación, Programa Estatal de I+D+i

[Turnbuckle]

 and finally reverse epigenetic aging (with OSKM).  All of these are now based on standard technology for mice, and I think if we do ALL of them at once, we will see dramatic gains in lifespan.   

 

 

Can you point to any normal (non genetically modified) mice that lived longer with OSKM?

[HighDesertWizard]

Can you point to any normal (non genetically modified) mice that lived longer with OSKM?

 
Great question Turnbuckle... I've also been thinking about this question lately. I'm not especially familiar with studies of mice. Will a couple of human studies do?
 
Well, ok, I can't actually point to a human study in which a positive impact on lifespan was determined definitively to be a result of the OSKM mechanism.
 
But I can point to a handful of study-content-sets that I take together as profound support for the following conjecture...

• OSKM-Factor-Related activity is the mechanism of action explanation for increased survival probability in wild-type humans in multiple studies

I believe that...

• the conjecture above is virtually impossible to falsify given the study-volume and study-content-density of already published study knowledge and given our existing limited knowledge
• the independent intervention variable I have in mind (HSPs) impacting OSKM activity has an essentially indisputable positive impact on survival probability in wild-type humans.
• it's silly not to proceed as individuals, and as a community, to try to impact that independent variable to test it because of that fact

Here is a list of the two categories of studies.

• Heat Shock Intervention -->> in multiple studies shown to "regulate" -->> OSKM
• Heat Shock Intervention -->> in multiple studies shown to increase -->> survival probability, and profoundly so in wild-type humans

A lot of ground is covered in the opening post of a Longecity thread I recently established, The title is a conjecture, A "Heat Shock" and iPSC Related Epigenetic Turn Initiates an Aging Process in Humans that can be Modulated".
 
I do not believe the conjecture of that thread will ever be falsified. And I'm going to try to, both, attack it and defend it.
 
That thread's opening post contained the following list of studies.

.

HSPs, the OSKM “Yamanaka Factors”, and iPSCs

• 2010, Differentiation and upregulation of heat shock protein 70 induced by a subset of histone deacetylase inhibitors in mouse and human embryonic stem cells
• 2012, Regulation of embryonic stem cell pluripotency by heat shock protein 90
• 2013, Heat shock instructs hESCs to exit from the self-renewal program through negative regulation of OCT4 by SAPK/JNK and HSF1 pathway
• 2015, A Chemical Biology Study of Human Pluripotent Stem Cells Unveils HSPA8 as a Key Regulator of Pluripotency
• 2016, Altered Expression of High Molecular Weight Heat Shock Proteins after OCT4B1 Suppression in Human Tumor Cell Lines
• 2018, Heat shock induces the depletion of Oct4 in mouse blastocysts and stem cells
• 2018, HSP60 is required for stemness and proper differentiation of mouse embryonic stem cells
• 2018, The Relationship between the Expression of Small Heat-Shock Proteins and Suppression of OCT4B1

 
There are more studies not listed above that are equally relevant. Perhaps those I left out are more relevant to the question.
 
I also strongly suggest that Vincent Giuliano's recent blog post of September 2, 2018, is a must-read on this topic. I quoted his summary on this topic in the opening post referenced above.
 
 
There are multiple studies showing that Heat Shock Protein Expression is implicated in increased survival probability in humans. But let's first take note of 2 of many interventions that increase Heat Shock Protein.
 
2016, Exercise, heat shock proteins and insulin resistance
 
2017, The Effect of Hyperthermic Whole Body Heat Stimulus (Sauna) on Heat Shock Protein 70 and Skeletal Muscle Hypertrophy in Young Males during Weight Training
 
 
Let's sample just two studies, 1 for exercise and 1 for sauna vis-a-vis survival probability.
 
2015, Fitness predicts long-term survival after a cardiovascular event: a prospective cohort study
 

 
2015, Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events
 
j
 
 
Again, I admit that this is not definitive proof for the conjecture I stated at the beginning of this post. But I believe all knowledge is conjectural, so this is nothing new from my point of view.
 
And practically speaking, it's of no consquence...
 
Increasiong Heat Shock Protein has such profoundly positive effects on survival probability that it's a no-brainer that we should try to increase it by one of the means known to increase it in healthy ways.
 
And, then, in due time, we'll find out if the conjecture can be falsified, or not.

Edited by HighDesertWizard, 08 November 2018 - 03:07 AM.

[Avatar of Horus]

Some info on thymus aging:

Age-associated loss of lamin-B1 in thymic epithelial cells disrupts the thymic microenvironment for thymopoiesis and leads to thymic involution
Sibiao Yue, 2017
http://www.jimmunol....pplement/202.13
Abstract
Lamins are abundant type V intermediate filaments important for the structure and function of the nucleus. By studying the Drosophila immune organ, the fat body, recent work in our lab has uncovered a mechanism by which lamin-B loss in the fat body upon aging induces age-associated systemic inflammation and gut hyperplasia, suggesting that lamin-B loss triggers a phenomenon known as immunosenescence. A role of B-type lamins in mammalian immune aging, however, remains unexplored. Here, we report an age-related reduction of lamin-B1 inthymic epithelial cells (TECs) in the thymus, the primary immune organ for T-cell generation. We further demonstrate that genetic ablation of lmnb1 in TECs causes remarkably similar phenotypes as these observed in aged thymus. Furthermore, RNA-seq analyses reveal that depletion of lmnb1 accelerates age-related transcriptional changes in TECs, suggesting that loss of lamin-B1 in TECs upon aging may lead to global transcriptome alterations and trigger a degenerative cascade in the thymus. This work provides new insights into the cause and consequence of immunosenescence during mammalian immune aging.

[HighDesertWizard]

Some info on thymus aging:

Age-associated loss of lamin-B1 in thymic epithelial cells disrupts the thymic microenvironment for thymopoiesis and leads to thymic involution
Sibiao Yue, 2017
http://www.jimmunol....pplement/202.13
Abstract
Lamins are abundant type V intermediate filaments important for the structure and function of the nucleus. By studying the Drosophila immune organ, the fat body, recent work in our lab has uncovered a mechanism by which lamin-B loss in the fat body upon aging induces age-associated systemic inflammation and gut hyperplasia, suggesting that lamin-B loss triggers a phenomenon known as immunosenescence. A role of B-type lamins in mammalian immune aging, however, remains unexplored. Here, we report an age-related reduction of lamin-B1 inthymic epithelial cells (TECs) in the thymus, the primary immune organ for T-cell generation. We further demonstrate that genetic ablation of lmnb1 in TECs causes remarkably similar phenotypes as these observed in aged thymus. Furthermore, RNA-seq analyses reveal that depletion of lmnb1 accelerates age-related transcriptional changes in TECs, suggesting that loss of lamin-B1 in TECs upon aging may lead to global transcriptome alterations and trigger a degenerative cascade in the thymus. This work provides new insights into the cause and consequence of immunosenescence during mammalian immune aging.

.
Lamin B is a prompt heat shock protein
https://www.ncbi.nlm...pubmed/9886487/
.

Edited by HighDesertWizard, 09 November 2018 - 02:07 PM.

[Lazarus Long]

I have been inactive here for some time but I'm very pleased with how this thread has progressed. New research is emerging fast and both genetic markers and epigenetic switches are being identified.

https://medicalxpres...ing-clocks.html

Quote:"Importantly, the clocks respond to interventions, which could allow scientists to study how biological age responds to environmental exposures and lifestyle choices. Being able to ascertain an accurate biological age can give a person an indication of how much better or worse he or she is doing relative to the general population and could potentially help monitor whether someone is at heightened risk of death or a certain disease."

[Avatar of Horus]

I have been inactive here for some time but I'm very pleased with how this thread has progressed. New research is emerging fast and both genetic markers and epigenetic switches are being identified.

https://medicalxpres...ing-clocks.html

Quote:"Importantly, the clocks respond to interventions, which could allow scientists to study how biological age responds to environmental exposures and lifestyle choices. Being able to ascertain an accurate biological age can give a person an indication of how much better or worse he or she is doing relative to the general population and could potentially help monitor whether someone is at heightened risk of death or a certain disease."

Welcome back.
Yes, this is a good thread, especially as (from the sources below):
"Studies of the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS) can potentially reveal cellular defects associated with physiological aging.",
"Studies of progerin may identify treatments for HGPS and reveal novel cellular and molecular characteristics of normal aging."
"studying what goes wrong in ... premature aging disorder Hutchinson-Gilford progeria can provide useful insights into normal health ... and aging",
"Premature aging disorders provide an opportunity to study the mechanisms that drive aging."

For example:

Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging
Chang et al., 2019 Feb
https://www.ncbi.nlm...pubmed/30808750

Abstract
Studies of the accelerated aging disorder Hutchinson-Gilford progeria syndrome (HGPS) can potentially reveal cellular defects associated with physiological aging. HGPS results from expression and abnormal nuclear envelope association of a farnesylated, truncated variant of prelamin A called “progerin.” We surveyed the diffusional mobilities of nuclear membrane proteins to identify proximal effects of progerin expression. The mobilities of three proteins - SUN2, nesprin-2G, and emerin - were reduced in fibroblasts from children with HGPS compared with those in normal fibroblasts. These proteins function together in nuclear movement and centrosome orientation in fibroblasts polarizing for migration. Both processes were impaired in fibroblasts from children with HGPS and in NIH 3T3 fibroblasts expressing progerin, but were restored by inhibiting protein farnesylation. Progerin affected both the coupling of the nucleus to actin cables and the oriented flow of the cables necessary for nuclear movement and centrosome orientation. Progerin overexpression increased levels of SUN1, which couples the nucleus to microtubules through nesprin-2G and dynein, and microtubule association with the nucleus. Reducing microtubule-nuclear connections through SUN1 depletion or dynein inhibition rescued the polarity defects. Nuclear movement and centrosome orientation were also defective in fibroblasts from normal individuals over 60 y, and both defects were rescued by reducing the increased level of SUN1 in these cells or inhibiting dynein. Our results identify imbalanced nuclear engagement of the cytoskeleton (microtubules: high; actin filaments: low) as the basis for intrinsic cell polarity defects in HGPS and physiological aging and suggest that rebalancing the connections can ameliorate the defects.

Significance
The rare, premature aging syndrome Hutchinson-Gilford progeria syndrome (HGPS) arises from expression of a pathological prelamin A variant, termed “progerin.” Studies of progerin may identify treatments for HGPS and reveal novel cellular and molecular characteristics of normal aging. Here, we show that progerin selectively affects mobilities of three nuclear membrane proteins - SUN2, nesprin-2G, and emerin - that position the nucleus and establish cell polarity essential for migration. We find that both processes are defective in fibroblasts from children with HGPS and aged (>60 y) individuals. The mechanism underlying these defects is excessive interaction of the nucleus with microtubules. Our work identifies nuclear-based defects in cell polarization as intrinsic factors in premature and physiological aging and suggests a means for correcting them.

On the clocks and epigentic switches

I wonder whether those are merely "clocks" or there may be a connection between them and the causes themselves, considering the role of epigenetics, for instance the Polycomb group proteins, in the maintenance of the cells' identity, as it was presented in the studies cited previously, in order to avoid the expression of outside genes, also shown by other cited studies. These may be mechanisms for the cells to track the time elapsed from the starting ESC states, and later to know what type of cells they are and supposed to do in the given periods, i.e. for controlling it. If these become disrupted that can cause tissue disorganization and, thereby, dysfunction, e.g. in the case of mentioned HOX genes in the aged muscle.


Regarding the ribosomal connection, also to the "turnover" thing discussed before in the topic:

Protein turnover could be clue to living longer
Overactive protein synthesis found in premature aging disease may also play role in normal aging
August 30, 2017
https://www.salk.edu...-living-longer/

It may seem paradoxical, but studying what goes wrong in rare diseases can provide useful insights into normal health. Researchers probing the premature aging disorder Hutchinson-Gilford progeria have uncovered an errant protein process in the disease that could help healthy people as well as progeria sufferers live longer.



Scientists at the Salk Institute found that protein synthesis is overactive in people with progeria. The work, described in Nature Communications on August 30, 2017, adds to a growing body of evidence that reducing protein synthesis can extend lifespan - and thus may offer a useful therapeutic target to counter both premature and normal aging.

“The production of proteins is an extremely energy-intensive process for cells,” says Martin Hetzer, vice president and chief science officer of the Salk Institute and senior author of the paper. “When a cell devotes valuable resources to producing protein, other important functions may be neglected. Our work suggests that one driver of both abnormal and normal aging could be accelerated protein turnover.”

Hutchinson-Gilford progeria is a very rare genetic disease causing people to age 8 to 10 times faster than the rest of us and leading to an early death. The rare mutation occurs in one of the structural proteins in the cell nucleus, lamin A, but it has been unclear how a single defective protein in the nucleus causes the myriad rapid-aging features seen in the disease.

Initially, Salk Staff Scientist Abigail Buchwalter, first author of the paper, was interested in whether the mutation was making the lamin A protein less stable and shorter lived. After measuring protein turnover in cultured cells from skin biopsies of both progeria sufferers and healthy people, she found that it wasn’t just lamin A that was affected in the disease.

“We analyzed all the proteins of the nucleus and instead of seeing rapid turnover in just mutant lamin A and maybe a few proteins associated with it, we saw a really broad shift in overall protein stability in the progeria cells,” says Buchwalter. “This indicated a change in protein metabolism that we hadn’t expected.”

Along with the rapid turnover of proteins, the team found that the nucleolus, which makes protein-assembling structures called ribosomes, was enlarged in the prematurely aging cells compared to healthy cells.

Even more intriguing, the team found that nucleolus size increased with age in the healthy cells, suggesting that the size of the nucleolus could not only be a useful biomarker of aging, but potentially a target of therapies to counter both premature and normal aging.

The work supports other research that appears in the same issue showing that decreasing protein synthesis extends lifespan in roundworms and mice. The Hetzer lab plans to continue studying how nucleolus size may serve as a reliable biomarker for aging.

“We always assume that aging is a linear process, but we don’t know that for sure,” says Hetzer, who also holds the Jesse and Caryl Philips Foundation Chair. “A biomarker such as this that tracks aging would be very useful, and could open up new ways of studying and understanding aging in humans.”

The work was funded by the National Institutes of Health, the Nomis Foundation, and the Glenn Center for Aging Research.

The study:

Nucleolar expansion and elevated protein translation in premature aging
Buchwalter and Hetzer, Nat Commun. 2017 Aug 30
https://www.ncbi.nlm...pubmed/28855503

Abstract
Premature aging disorders provide an opportunity to study the mechanisms that drive aging. In Hutchinson-Gilford progeria syndrome (HGPS), a mutant form of the nuclear scaffold protein lamin A distorts nuclei and sequesters nuclear proteins. We sought to investigate protein homeostasis in this disease. Here, we report a widespread increase in protein turnover in HGPS-derived cells compared to normal cells. We determine that global protein synthesis is elevated as a consequence of activated nucleoli and enhanced ribosome biogenesis in HGPS-derived fibroblasts. Depleting normal lamin A or inducing mutant lamin A expression are each sufficient to drive nucleolar expansion. We further show that nucleolar size correlates with donor age in primary fibroblasts derived from healthy individuals and that ribosomal RNA production increases with age, indicating that nucleolar size and activity can serve as aging biomarkers. While limiting ribosome biogenesis extends lifespan in several systems, we show that increased ribosome biogenesis and activity are a hallmark of premature aging. HGPS is a premature aging disease caused by mutations in the nuclear protein lamin A. Here, the authors show that cells from patients with HGPS have expanded nucleoli and increased protein synthesis, and report that nucleoli also expand as aging progresses in cells derived from healthy individuals.

[Lazarus Long]

This article on the stabilization of telomere shrinkage more accurately belongs in the thread area on telomeres but since it is also relevant to a cellular model of aging I decided to post it here.

https://m.medicalxpr...ed-disease.html


Stabilizing ends of chromosomes could treat age-related disease
March 28, 2019 , Baylor College of Medicine

Steffen Dietzel/Wikipedia

A study led by researchers at Baylor College of Medicine has uncovered a new strategy that can potentially treat age-related disease and decline. The study, published in the journal Cell Metabolism, demonstrates that shortening of telomeres—the ends of the chromosomes—impairs a class of enzymes called sirtuins, which play an important role in maintaining cell fitness by affecting many metabolic processes and repairing damaged chromosomes. The researchers showed that restoring the activity of sirtuins with a small compound stabilized telomeres and reduced DNA damage, which in turn improved liver disease in a mouse model. These studies suggest that maintaining telomere length might help sustain the regenerative capacity of cells and tissues and improve disease outcome....


Previous studies have shown that both telomeres and sirtuins contribute to aging and tissue fibrosis and seemed to interact with each other. In this study, Sahin and his colleagues investigated the molecular mechanisms that connected telomeres and sirtuins. For this, they developed a mouse model of liver disease in which the animals were genetically engineered to develop shorter, dysfunctional telomeres and age prematurely. When exposed to certain compounds, these animals quickly develop liver fibrosis—scarring of the liver that over time can lead to cirrhosis.

"In these mice, we discovered that shorter telomeres triggered a reduction in the production of sirtuins in liver and other tissues as well," Sahin said. "Telomere shortening signaled the cell to reduce the production of sirtuins. This observation indicates that telomeres regulate sirtuins."

Interestingly, the researchers also found that in turn, sirtuins can affect telomeres. When Sahin and his colleagues increased the activity of sirtuins by feeding mice a small molecule—nicotinamide mono mononucleotide, or NMN, an NAD+ precursor—telomeres were stabilized.

"Furthermore, feeding NAD+ precursor to the mice not only maintained telomere length but also improved liver condition in these mice," Sahin said.

More research is needed before these findings can be translated into treatments for human conditions.

"It's important to keep in mind that telomere length can also affect cancer growth. Having shorter telomeres would set cancer cells on a path to self-destruction, but keeping their telomeres long would likely allow them to continue proliferating," Sahin said. "We plan to continue our investigation on the molecular mechanisms involved in the telomere-sirtuin interactions in order to better understand the benefits as well as the potential risks of telomere length manipulation in health and disease.".....

[kurdishfella]

I think water has tremendous anti aging benefits. The life expectancy of Japan,korea and New york are over 80 and they are surrounded by water. I think just by living near big areas of water you somehow reap benefits but more so if you ingested it. Look at this guy he has to ingest 20 liters of water daily, look how healthy he looks 

 

And the other south east asian countries like china have a lot of forest which the oxygen is more purer (anti-aging) but is counteracted by the release of pollution they have. And I think cold water is more beneficial than warm since it triggers your body to work but im unsure. Maybe cool water (inbetween) is ideal. So perhaps the way water works in the body we can learn  something on living longer.

Edited by kurdishfella, 09 November 2020 - 10:58 AM.

[Avatar of Horus]

I think I could finish another round of this unified theory of aging,
and this may be even the key to immortality, or even more.
If true then it has come to full circle, and BTW transhumanism itself.

It is rather large amount of information so I intent to divide it into a couple of posts,
and also it is in draft state, and I list also some keywords to elaborate on them later.

The main theme of this thread is aging, so it is biology and chemistry and pharmacology,
but I've found relevant informations in my other research areas and
there seems to be some convergence in these:

theology, search for God, or deities, heavenly beings, i.e. religions, myths, and the like;
so these also will be included.

The motto of this writing is two quotes:
"We drank the Soma; we have become immortal; we have gone to the light; we have found the gods.
What can hostility do to us now, and what the malice of a mortal, o immortal one?"
Rigveda (8.48.3)
and
"I will disclose to you, Gilgamesh, a secret matter,
and I will tell you a mystery of the gods."
Utnapishtim to Gilgamesh, Epic - Tablet XI

The starting point is these two previous studies:

Lamin Dysfunction Mediates Neurodegeneration in Tauopathies
Frost B, Bardai FH, Feany MB
Curr Biol. 2016 Jan 11
http://www.ncbi.nlm....pubmed/26725200
...

and:

...
Imbalanced nucleocytoskeletal connections create common polarity defects in progeria and physiological aging
Chang et al., 2019 Feb
https://www.ncbi.nlm...pubmed/30808750

Abstract
... SUN1, which couples the nucleus to microtubules through nesprin-2G and dynein, and microtubule association with the nucleus. Reducing microtubule-nuclear connections through SUN1 depletion or dynein inhibition rescued the polarity defects. Nuclear movement and centrosome orientation were also defective in fibroblasts from normal individuals over 60 y, and both defects were rescued by reducing the increased level of SUN1 in these cells or inhibiting dynein. Our results identify imbalanced nuclear engagement of the cytoskeleton (microtubules: high; actin filaments: low) as the basis for intrinsic cell polarity defects in HGPS and physiological aging and suggest that rebalancing the connections can ameliorate the defects. ...

so the lamins, chromatin, Tau protein, microtubules, cytoskeleton
and the new ones:
"Tau promotes neurodegeneration through global chromatin relaxation - 2014 - 24464041
https://pubmed.ncbi....h.gov/24464041/
Abstract
The microtubule-associated protein tau is involved in a number of neurodegenerative disorders, including Alzheimer's disease. Previous studies have linked oxidative stress and subsequent DNA damage to neuronal death in Alzheimer's disease and related tauopathies. Given that DNA damage can substantially alter chromatin structure, we examined epigenetic changes in tau-induced neurodegeneration. We found widespread loss of heterochromatin in tau transgenic Drosophila and mice and in human Alzheimer's disease. Notably, genetic rescue of tau-induced heterochromatin loss substantially reduced neurodegeneration in Drosophila. We identified oxidative stress and subsequent DNA damage as a mechanistic link between transgenic tau expression and heterochromatin relaxation, and found that heterochromatin loss permitted aberrant gene expression in tauopathies. Furthermore, large-scale analyses from the brains of individuals with Alzheimer's disease revealed a widespread transcriptional increase in genes that were heterochromatically silenced in controls. Our results establish heterochromatin loss as a toxic effector of tau-induced neurodegeneration and identify chromatin structure as a potential therapeutic target in Alzheimer's disease."
---
Reversible paired helical filament-like phosphorylation of Tau is an adaptive process associated with neuronal plasticity in hibernating animals - 2003 Aug 6
https://pubmed.ncbi....h.gov/12904458/
---
Cytoskeletal arrest: an anoxia tolerance mechanism - 2021 Aug 23
https://pubmed.ncbi....h.gov/34436502/
---
The inhibition of neurons in the central nervous pathways for thermoregulatory cold defense induces a suspended animation state in the rat - 2013 Feb 13
https://pubmed.ncbi....h.gov/23407956/
Abstract
The possibility of inducing a suspended animation state similar to natural torpor would be greatly beneficial in medical science, since it would avoid the adverse consequence of the powerful autonomic activation evoked by external cooling. Previous attempts to systemically inhibit metabolism were successful in mice, but practically ineffective in nonhibernators. Here we show that the selective pharmacological inhibition of key neurons in the central pathways for thermoregulatory cold defense is sufficient to induce a suspended animation state, resembling natural torpor, in a nonhibernator. In rats kept at an ambient temperature of 15°C and under continuous darkness, the prolonged inhibition (6 h) of the rostral ventromedial medulla, a key area of the central nervous pathways for thermoregulatory cold defense, by means of repeated microinjections (100 nl) of the GABA(A) agonist muscimol (1 mm), induced the following:
(1) a massive cutaneous vasodilation;
(2) drastic drops in deep brain temperature (reaching a nadir of 22 C),
heart rate (from 440 to 207 bpm), and electroencephalography (EEG) power;
(3) a modest decrease in mean arterial pressure; and
(4) a progressive shift of the EEG power spectrum toward slow frequencies.

After the hypothermic bout, all animals showed a massive increase in NREM sleep Delta power, similarly to that occurring in natural torpor. No behavioral abnormalities were observed in the days following the treatment. Our results strengthen the potential role of the CNS in the induction of hibernation/torpor, since CNS-driven changes in organ physiology have been shown to be sufficient to induce and maintain a suspended animation state.

rostral ventromedial medulla
RVMM, a key area in the central nervous pathways for thermoregulatory cold defense, a region including the
raphe pallidus (RPa) and the raphe magnus,
where the putative sympathetic premotor neurons to the brown adipose tissue (BAT),
the cutaneous blood vessel,
and the heart are located (Cano et al., 2003).

By choosing a nonhibernator we aimed to explore a possible translational extension of the results in view of the hypothesis that the capacity for suspended animation may represent a common trait for mammals (Harris et al., 2004).
To assess whether the effects induced by muscimol resembled those observed in natural hibernators during and/or after a torpor bout, we monitored some autonomic parameters and related indices, wake-sleep behavior, and electroencephalographic (EEG) activity.
...
example of the suspended animation state induced by repeated injection of muscimol in the RVMM. In an animal exposed to constant darkness at a Ta of 15°C

---
muscimol, and that is Amanita muscaria:

Antipsychotic inductors of brain hypothermia and torpor-like states: perspectives of application - 2017 Jan
https://pubmed.ncbi....h.gov/27933367/
... thermoregulation. In these conditions called torpor-like states, the mammalian ability to recover from stroke, heart attack, and traumatic injuries greatly increases.
Torpor state in hibernation ... is highly adjustable and reversible process in which the metabolism is lowered and state of consciousness is different from sleep or coma (Carey et al. 2003). It presents a paradox, but the electrophysiological evidence reveals that the natural torpor could be regarded mostly as a sleep deprivation because in some animals the deep post-torpor sleep may immediately follow torpor.
... Muscimol, a psychoactive agent, isolated from the mushroom Amanita muscaria, and a selective agonist of GABAA receptors, exerts powerful sedative, hypnotic, and hallucinogenic effects. It has been shown that administration of muscimol to the rostral area of the nucleus raphe pallidus causes a deep hypothermia, which, according to the parameters of the EEG, recalls torpor-like states (Cerri et al. 2013). It should be noted that this area of the brain is responsible for the regulation of thermogenesis of brown adipose tissue.
---

hibernation, body temperature, thermoregulation, fever, hypothermia
metabolic rate, hypoxia, anoxia, hypometabolism

which leads to one of the main candidates of the ritual drink Soma, aka Haoma and Amrita, the Sanskrit word for English Immortality:

Soma - Divine Mushroom of Immortality - R. Gordon Wasson



some of the involved brain regions in humans:
Medulla oblongata


and the diencephalon,interbrain - hypothalamus


"Neurons that regulate mouse torpor - 2020 Jul - PMID 32528180
... the ... entry into mouse torpor, a fasting-induced state with a greatly decreased metabolic rate and a body temperature as low as 20 degrees C, is regulated by neurons in the medial and lateral preoptic area of the hypothalamus."
and
"A discrete neuronal circuit induces a hibernation-like state in rodents - 2020 Jul - 32528181
... a hypothalamic neuronal circuit in rodents induces a long-lasting hypothermic and hypometabolic state similar to hibernation"
and
2 comment articles on these 2:
Flipping the switch on the body's thermoregulatory system - 2020 Jul - 32601488
Chill out - 2020 Aug - 32612215


sleep deprivation
Utnapishtim, Ziudsura, Noah - rest

sleep induction
oleamide, oleic acid, olive oil
anandamide, arachidonic acid

wakefullness, sleep-wake cycle

How sleep clears brain
https://www.nih.gov/...ep-clears-brain

How sleep resets the brain
https://directorsblo...sets-the-brain/

Sleep loss encourages spread of toxic Alzheimer's protein
https://directorsblo...eimers-protein/
 

---

bears, (vampire) bats, other hibernating animals, fasting, caves,
deep sleep, slumber, dreams, dreaming,
Jesus, Lazarus, Eleazar, Tau cross,
holy anointing oil, Messiah, Christ, Kalki, Saoshyant, Maitreya, Mahdi, Magi,
Elohim, YHWH, Asherah,
Brahma, Vishnu, Lakshmi-Narayana,
Anunaki, Damu, Baba,
ziggurats, tumulus,
Osiris, Ankh, pyramids, Houses of Eternity, Mansions of millions of years, Egyptian Book of the Dead,
near drowning, near death,
mummification, embalming,
resurrection, resuscitation,
vampires, blood, hibernaculum,
incense, shamanism, Logos, Thelema,
tryptophan, tryptamine, DMT,
coronavirus, COVID, turtles, gold fish,
Paradise, Eden, tree of life, water of life, bread of life, elixir of life,
Adam, Eve, tardema, trance, prophets.

Summary:
The hypothesis I am proposing is that
humans are genetically programmed for eternal life,

and the lack of this "deep rest" is a main cause of aging,

and an intervention based on the the things outlined above can lead to regeneration, rejuvenation, and life extension, and with applying periodically who knows for how long, maybe even ...

and the Otherworld, Heaven, Fairyland, Spiritworld, described by the shamans and others, may be this "state of consciousness is different from sleep or coma" which is a trance state that leads to another real realm or quantum dimension, inhabited by intelligent beings, and it can be accessed by the human brain.
If true then humans truly are "like gods".
And these are the main teachings of all the major religions.

to be continued ...

Edited by Mind, 03 September 2023 - 03:31 PM.

[Avatar of Horus]

...
It is rather large amount of information so I intent to divide it into a couple of posts,
and also it is in draft state, and I list also some keywords to elaborate on them later.
...
Cytoskeletal arrest: an anoxia tolerance mechanism - 2021 Aug 23
https://pubmed.ncbi....h.gov/34436502/
...
Amanita muscaria
...
(vampire) bats,
...
coronavirus, COVID, turtles, gold fish,
...
to be continued ...

In a bizarre way a significant portion of the thing I described can be deduced also from the coronavirus.
And also these are proofs in connection with human physiology.

A sister group of tha Amanita muscaria mushroom is the

Amanita pantherina:

but it's almost the same thing.
Also these mushrooms were usually taken dried, but the point here is the burst suppression EEG pattern and the GABAergic signaling.

 

"Burst suppression electroencephalogram with mushroom poisoning, Amanita pantherina - 2015
https://pubmed.ncbi....h.gov/23423290/
Abstract
We report on a patient with Amanita pantherina poisoning who showed a burst suppression pattern on electroencephalography during a comatose state. The patient recovered without sequelae a week after ingestion. Burst suppression pattern is defined as alternating bursts and periods of electrical silence, and it is associated with comatose states of various causes. The major toxins contained in A. pantherina are ibotenic acid, an excitatory amino acid at the glutamate receptors, and muscimol, an agonist of the gamma-aminobutyric acid receptors. Alteration of the synaptic transmission in the central nervous system by these toxins may lead to a burst suppression pattern."

"Cytoskeletal arrest: an anoxia tolerance mechanism - 2021 Aug 23
https://pubmed.ncbi....h.gov/34436502/
Abstract
Polymerization of actin filaments and microtubules constitutes a ubiquitous demand for cellular adenosine-5'-triphosphate (ATP) and guanosine-5'-triphosphate (GTP). In anoxia-tolerant animals, ATP consumption is minimized during overwintering conditions, but little is known about the role of cell structure in anoxia tolerance. Studies of overwintering mammals have revealed that microtubule stability in neurites is reduced at low temperature, resulting in withdrawal of neurites and reduced abundance of excitatory synapses. Literature for turtles is consistent with a similar downregulation of peripheral cytoskeletal activity in brain and liver during anoxic overwintering. Downregulation of actin dynamics, as well as modification to microtubule organization, may play vital roles in facilitating anoxia tolerance. Mitochondrial calcium release occurs during anoxia in turtle neurons, and subsequent activation of calcium-binding proteins likely regulates cytoskeletal stability. Production of reactive oxygen species (ROS) formation can lead to catastrophic cytoskeletal damage during overwintering and ROS production can be regulated by the dynamics of mitochondrial interconnectivity. Therefore, suppression of ROS formation is likely an important aspect of cytoskeletal arrest. Furthermore, gasotransmitters can regulate ROS levels, as well as cytoskeletal contractility and rearrangement. In this review we will explore the energetic costs of cytoskeletal activity, the cellular mechanisms regulating it, and the potential for cytoskeletal arrest being an important mechanism permitting long-term anoxia survival in anoxia-tolerant species, such as the western painted turtle and goldfish."
---
"Protective down-regulated states in the human brain: A possible lesson from COVID-19 - 2022 Nov
https://pubmed.ncbi....h.gov/36343241/
Abstract
The COVID-19 pandemic has created a large population of patients who are slow to recover consciousness following mechanical ventilation and sedation in the intensive care unit. Few clinical scenarios are comparable. Possible exceptions are the rare patients in post-cardiac arrest coma with minimal to no structural brain injuries who recovered cognitive and motor functions after prolonged delays. A common electroencephalogram (EEG) signature seen in these patients is burst suppression [8]. Biophysical modeling has shown that burst suppression is likely a signature of a neurometabolic state that preserves basic cellular function "during states of lowered energy availability." These states likely act as a brain protective mechanism [9]. Similar EEG patterns are observed in the anoxia resistant painted turtle [24]. We present a conceptual analysis to interpret the brain state of COVID-19 patients suffering prolonged recovery of consciousness. We begin with the Ching model and integrate findings from other clinical scenarios and studies of the anoxia-tolerant physiology of the painted turtle. We postulate that prolonged recovery of consciousness in COVID-19 patients could reflect the effects of modest hypoxic injury to neurons and the unmasking of latent neuroprotective mechanisms in the human brain. This putative protective down-regulated state appears similar to that observed in the painted turtle and suggests new approaches to enhancing coma recovery [12].

Keywords: COVID-19; burst suppression; coma recovery; enhanced GABAergic state; neurometabolic state."
---
"A neurophysiological-metabolic model for burst suppression - 2012 Feb
https://pubmed.ncbi....h.gov/22323592/
Abstract
Burst suppression is an electroencepholagram (EEG) pattern in which high-voltage activity alternates with isoelectric quiescence. It is characteristic of an inactivated brain and is commonly observed at deep levels of general anesthesia, hypothermia, and in pathological conditions such as coma and early infantile encephalopathy. We propose a unifying mechanism for burst suppression that accounts for all of these conditions. By constructing a biophysical computational model, we show how the prevailing features of burst suppression may arise through the interaction between neuronal dynamics and brain metabolism. In each condition, the model suggests that a decrease in cerebral metabolic rate, coupled with the stabilizing properties of ATP-gated potassium channels, leads to the characteristic epochs of suppression. Consequently, the model makes a number of specific predictions of experimental and clinical relevance."
---

And the bats:

"Vampire bats go with the flow - 2013 Mar
https://pubmed.ncbi....h.gov/23423290/
...
Bats - regardless of their feeding habits - are valuable in other areas of research as well. The genomes of two bat species, the fruit-eating Pteropus alecto and the insectivorous Myotis davidii, were recently sequenced and analyzed 7. The results provide insight into immunity and flight. The bats carry lethal viruses, such as Ebola and SARS, but don't often succumb to disease; understanding the adaptations that contribute to their resistance may lead to better treatments for human diseases.

Additionally, bats have extraordinarily long lives compared with other mammals. Typically, lifespan correlates with size in mammals: smaller mammals have shorter lifespans and larger ones live longer. Several explanations have been proposed for bats' long lives: lowered energy expenditure thanks to hibernation and daily torpor; lack of predation pressure; and low reproductive rates. One study of Mexican free-tailed bats () and cave myotis bats () suggests that preservation of protein structure is essential to bats' long lifespans 8."

to be continued ...

[QuestforLife]

So you want to induce this 'burst suppression' state in the brain, in order to induce regeneration? Any candidate substances? What about the long history of meditation, QiGong, etc.; how does that fit in?

Also, as this state is electrical in nature, what about external stimulation of the brain with EM? Also, could brainwaves be influenced to induce this state, for example by auditory stimulation (biurnal beats)?

Edited by QuestforLife, 25 August 2023 - 11:49 AM.

[Avatar of Horus]

So you want to induce this 'burst suppression' state in the brain, in order to induce regeneration? Any candidate substances? What about the long history of meditation, QiGong, etc.; how does that fit in?
Also, as this state is electrical in nature, what about external stimulation of the brain with EM? Also, could brainwaves be influenced to induce this state, for example by auditory stimulation (biurnal beats)?

 

I was just about to post the next part, which is about these questions.

Yes, this hypothesis is that the lack of this "deep rest" state is a main cause of aging and some disease.

The candidate substances are the putative Soma drink, an ancient shamanistic preparation based on those 2 mentioned mushrooms, mainly namely muscimol;
 
and/or the mentioned oleamide and the like in sleep induction, which I want to cover later. I have 3-4 more posts to complete all.
 
But I don't have an exact, ready protocol yet. The signaling is called GABAergic, which is also a class of pharma drugs.

Meditations and the other things you mentioned are similar to this, I intended to write also about them some info in a later post.
 

...

suspended animation

...
hibernation, ... hypothermia
metabolic rate, hypoxia, anoxia, hypometabolism
...
bears, other hibernating animals, fasting, caves,
...
deep sleep, slumber,
...
turtles
...
Adam, Eve, tardema, trance, prophets.

Summary:
The hypothesis I am proposing is ...

the lack of this "deep rest" is a main cause of aging,

and an intervention based on the the things outlined above can lead to regeneration, rejuvenation, and life extension, and with applying periodically who knows for how long,...
...
to be continued ...

 

This post is about the protective and anti-aging capabilities of these torpor-like, reduced metabolic, "deep rest" states.

In my previous post I presented data regarding the recent discovery of the existence of a similar state (albeit latent) in humans, of this hypoxic "protective down-regulated metabolic state", an "enhanced GABAergic state".

parallels occur in religious texts, like:
Bible, Genesis 2:21-22 (KJV):
"And the LORD God caused a deep sleep to fall upon Adam, and he slept:
and he took one of his ribs, and closed up the flesh instead thereof;
And the rib, which the LORD God had taken from man, made he a woman, and brought her unto the man."

the word used is:
tardema

meanings in English:
deep sleep, slumber, trance,
and in modern language also: hibernation

in later chapters it's connected also to prophets with divine visions.
---

 

And about its similarity to that of the anoxia-tolerant turtles.

Some more infos on turtles and aging:
(based on their Wiki entry)
"Lifespan
Turtles can live long lives.
The oldest living land animal is said to be a giant tortoise, alive at an age of 190.
... a tortoise was collected by Charles Darwin in 1835 ... lived for at least 176 years.
Another tortoise was with an estimated age of between 150 and 255 years.

They age slowly."

"Decades of field data reveal that turtles senesce in the wild - 2016 Jun
https://pubmed.ncbi....h.gov/27140634/
...
slow or even negligible senescence
...
Keywords: aging; lifespan; painted turtle; reproduction; senescence."

---

anti-aging
slowing and reversing aspects

an article about bear hibernation research in arctic biology:

"Take a nap - hibernating animals live longer! - March 2011
https://www.nbcnews....id/wbna42342579

... winter hibernation sounds like a pretty cushy lifestyle. ... that drives some animals into a wintry slumber ...
in an artificial den ..."
---
and some other studies:

Hibernation slows epigenetic ageing in yellow-bellied marmots - 2022 Apr
https://pubmed.ncbi....h.gov/35256811/
Abstract
Species that hibernate generally live longer than would be expected based solely on their body size. Hibernation is characterized by long periods of metabolic suppression (torpor) interspersed by short periods of increased metabolism (arousal). The torpor-arousal cycles occur multiple times during hibernation, and it has been suggested that processes controlling the transition between torpor and arousal states cause ageing suppression. Metabolic rate is also a known correlate of longevity; we thus proposed the 'hibernation-ageing hypothesis' whereby ageing is suspended during hibernation. We tested this hypothesis in a well-studied population of yellow-bellied marmots (Marmota flaviventer), which spend 7-8 months per year hibernating. We used two approaches to estimate epigenetic age: the epigenetic clock and the epigenetic pacemaker. Variation in epigenetic age of 149 samples collected throughout the life of 73 females was modelled using generalized additive mixed models (GAMM), where season (cyclic cubic spline) and chronological age (cubic spline) were fixed effects. As expected, the GAMM using epigenetic ages calculated from the epigenetic pacemaker was better able to detect nonlinear patterns in epigenetic ageing over time. We observed a logarithmic curve of epigenetic age with time, where the epigenetic age increased at a higher rate until females reached sexual maturity (two years old). With respect to circannual patterns, the epigenetic age increased during the active season and essentially stalled during the hibernation period. Taken together, our results are consistent with the hibernation-ageing hypothesis and may explain the enhanced longevity in hibernators.
---
Daily torpor is associated with telomere length change over winter in Djungarian hamsters - 2012 Apr
https://pubmed.ncbi....h.gov/21920955/
Abstract
Ageing can progress at different rates according to an individual's physiological state. Natural hypothermia, including torpor and hibernation, is a common adaptation of small mammals to survive intermittent or seasonal declines in environmental conditions. In addition to allowing energy savings, hypothermia and torpor have been associated with retarded ageing and increased longevity. We tested the hypothesis that torpor use slows ageing by measuring changes in the relative telomere length (RTL) of Djungarian hamsters, Phodopus sungorus, a highly seasonal rodent using spontaneous daily torpor, over 180 days of exposure to a short-day photoperiod and warm (approx. 20°C) or cold (approx. 9 C) air temperatures. Multi-model inference showed that change in RTL within individuals was best explained by positive effects of frequency of torpor use, particularly at low body temperatures, as well as the change in body mass and initial RTL. Telomere dynamics have been linked to future survival and proposed as an index of rates of biological ageing. Our results therefore support the hypothesis that daily torpor is associated with physiological changes that increase somatic maintenance and slow the processes of ageing.
---
Late-born intermittently fasted juvenile garden dormice use torpor to grow and fatten prior to hibernation: consequences for ageing processes - 2014 Dec
https://pubmed.ncbi....h.gov/25377448/
Abstract
Torpor is thought to slow age-related processes and to sustain growth and fattening of young individuals. Energy allocation into these processes ...
garden dormice (Eliomys quercinus) fed ad libitum ('AL') or intermittently fasted ('IF') use short torpor bouts to enhance growth and fat accumulation to survive winter. IF juveniles displayed more frequent and longer torpor bouts, compared with AL individuals before hibernation. Torpor frequency correlated negatively with energy expenditure and water turnover.
... relative telomere length (RTL), an indicator of ageing ... Percentage change in RTL was negatively associated with mean and total euthermic durations among all individuals during hibernation. We conclude that torpor use promotes fattening in late-born juvenile dormice prior to hibernation. Furthermore, we provided the first evidence for a functional link between time spent in euthermy and ageing processes over winter.
---
among the features of aging are muscle and bone loss

Polar bears (Ursus maritimus), the most evolutionary advanced hibernators, avoid significant bone loss during hibernation - 2008 Feb
https://pubmed.ncbi....h.gov/18249018/

---
Reversible paired helical filament-like phosphorylation of Tau is an adaptive process associated with neuronal plasticity in hibernating animals - 2003 Aug 6
https://pubmed.ncbi....h.gov/12904458/

Synthetic torpor triggers a regulated mechanism in the rat brain, favoring the reversibility of Tau protein hyperphosphorylation - 2023 Mar
https://pubmed.ncbi....h.gov/36969585/

Torpor enhances synaptic strength and restores memory performance in a mouse model of Alzheimer's disease - 2021 Jul
https://pubmed.ncbi....h.gov/34326412/

---

protective:

Antipsychotic inductors of brain hypothermia and torpor-like states: perspectives of application - 2017 Jan
https://pubmed.ncbi....h.gov/27933367/

"... In these conditions ... the mammalian ability to recover from stroke, heart attack, and traumatic injuries greatly increases. ..."

Intermittent hypothermia is neuroprotective in an in vitro model of ischemic stroke - 2014
https://pubmed.ncbi....h.gov/25170301/

Hypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia - 2022 Nov
https://pubmed.ncbi....h.gov/36371436/

Perspectives on benefit of early and prereperfusion hypothermia by pharmacological approach in stroke - 2022 Apr-Jun
https://pubmed.ncbi....h.gov/35909706/


enhanced wound healing:
Hibernating bears' wounds heal without scars - 19 March 2012 - BBC Nature

Wound healing during hibernation by black bears (Ursus americanus) in the wild: elicitation of reduced scar formation - 2012 Mar
https://pubmed.ncbi....h.gov/22405448/


stress reduction:
Microinjection of muscimol into raphe pallidus suppresses tachycardia associated with air stress in conscious rats - 2003 Jan
https://pubmed.ncbi....h.gov/12509492/

to be continued.

[Castiel]

As I see it, at first there was much ability in life for longevity as ancient hydras or jellyfish prove, but longevity/immortality was lost or became regulated by perceived nutrient availability in later evolved life due to selection pressure for turnover.

Selection pressure for higher turnover is a real thing. Surplus nutrients would be invested into evolution (or into the future of the species) via increased turnover.

 

Immortality was not lost, it was just limited to select cells.  Neurons suffer due to support cells like glia aging.  But neurons are believed to be multicentury immortal, they live as long as their host allows.  Mice neurons live twice as long as mice if transplanted into longer lived rats.  And would likely live for a century+ in humans, and multiple centuries in bowhead whales.

Edited by Castiel, 21 November 2024 - 07:31 AM.