• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo

Creating a unified theory of aging


  • Please log in to reply
79 replies to this topic

#61 niner

  • Guest
  • 16,276 posts
  • 2,000
  • Location:Philadelphia

Posted 19 February 2016 - 02:16 AM

 

 

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.


  • like x 1

#62 addx

  • Guest
  • 711 posts
  • 182
  • Location:croatia
  • NO

Posted 19 February 2016 - 08:04 AM

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!

Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#63 corb

  • Guest
  • 507 posts
  • 213
  • Location:Bulgaria

Posted 19 February 2016 - 08:56 AM

 

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.



sponsored ad

  • Advert
Advertisements help to support the work of this non-profit organisation. [] To go ad-free join as a Member.

#64 addx

  • Guest
  • 711 posts
  • 182
  • Location:croatia
  • NO

Posted 19 February 2016 - 12:17 PM

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.

#65 addx

  • Guest
  • 711 posts
  • 182
  • Location:croatia
  • NO

Posted 19 February 2016 - 03:56 PM

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.
  • like x 1

#66 Never_Ending

  • Guest
  • 166 posts
  • 4
  • Location:United States

Posted 19 February 2016 - 09:15 PM

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... 


  • Good Point x 1

Click HERE to rent this BIOSCIENCE adspot to support LongeCity (this will replace the google ad above).

#67 Avatar of Horus

  • Guest
  • 229 posts
  • 287
  • Location:Hungary

Posted 06 December 2016 - 02:22 PM

... 
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), ..."



#68 Never_Ending

  • Guest
  • 166 posts
  • 4
  • Location:United States

Posted 13 December 2016 - 12:45 AM

 

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.


#69 Avatar of Horus

  • Guest
  • 229 posts
  • 287
  • Location:Hungary

Posted 03 April 2018 - 02:31 AM

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.



#70 Avatar of Horus

  • Guest
  • 229 posts
  • 287
  • Location:Hungary

Posted 04 May 2018 - 05:59 AM

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.



#71 OP2040

  • Guest
  • 426 posts
  • 79
  • Location:United States
  • NO

Posted 04 May 2018 - 08:57 PM

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.


  • Good Point x 2
  • Cheerful x 1

#72 Avatar of Horus

  • Guest
  • 229 posts
  • 287
  • Location:Hungary

Posted 02 August 2018 - 06:17 PM

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


  • Agree x 1

#73 Avatar of Horus

  • Guest
  • 229 posts
  • 287
  • Location:Hungary

Posted 06 November 2018 - 07:25 PM

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



#74 Turnbuckle

  • Location:USA
  • NO

Posted 07 November 2018 - 11:39 AM

 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?


  • Good Point x 1

#75 HighDesertWizard

  • Member
  • 812 posts
  • 770
  • Location:Bend, Oregon, USA

Posted 08 November 2018 - 03:00 AM

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

 
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
 
Scgs6Tll.png
 
2015, Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events
 
xtaOIKNl.pngj
 
 
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.


#76 Avatar of Horus

  • Guest
  • 229 posts
  • 287
  • Location:Hungary

Posted 09 November 2018 - 07:44 AM

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.


  • like x 1

#77 HighDesertWizard

  • Member
  • 812 posts
  • 770
  • Location:Bend, Oregon, USA

Posted 09 November 2018 - 02:04 PM

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.

  • like x 2
  • Informative x 1

#78 Lazarus Long

  • Topic Starter
  • Life Member, Guardian
  • 8,086 posts
  • 236
  • Location:Northern, Western Hemisphere of Earth, Usually of late, New York

Posted 17 February 2019 - 01:28 PM

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."
  • Informative x 1
  • Cheerful x 1

#79 Avatar of Horus

  • Guest
  • 229 posts
  • 287
  • Location:Hungary

Posted 27 March 2019 - 09:34 PM

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.



sponsored ad

  • Advert
Advertisements help to support the work of this non-profit organisation. [] To go ad-free join as a Member.

#80 Lazarus Long

  • Topic Starter
  • Life Member, Guardian
  • 8,086 posts
  • 236
  • Location:Northern, Western Hemisphere of Earth, Usually of late, New York

Posted 29 March 2019 - 09:23 AM

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.".....
  • Informative x 1




0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users