34 replies to this topic

[Cameron]

I will add, that with regards to genomic integrity considering the massive genetic redundancy that exists in glia, it is not inconceivable that an even more advanced error correction making use of the myriad copies exists within neural tissue, such that neuronal genomic integrity can be maintained for over two centuries of high metabolic activity. Though that would be hypothetical.

[Avatar of Horus]

A theory:

Human body rids itself of damage when it really matters
http://www.scienceda...10920075516.htm
Date: September 21, 2011
Source: University of Gothenburg
Summary: Although the body is constantly replacing cells and cell constituents, damage and imperfections accumulate over time. Cleanup efforts are saved for when it really matters. Researchers in Sweden are able to show how the body rids itself of damage when it is time to reproduce and create new life.

"I have a daughter. She is made of my cells yet has much less cellular damage than my cells. Why didn't she inherit my cells including the damaged proteins? That's the process I'm interested in," says Malin Hernebring from the Department of Cell- and Molecular Biology at the University of Gothenburg.

A few days after conception, the cells in the embryo all look the same -- they are unspecified stem cells that can develop into any bodily cell type. As the process of cell specification (differentiation) begins, they go from being able to keep dividing infinitely to being able to do so only a limited number of times. This is when they start cleansing themselves.

"Quite unexpectedly we found that the level of protein damage was relatively high in the embryo's unspecified cells, but then it decreased dramatically. A few days after the onset of cell differentiation, the protein damage level had gone down by 80-90 percent. We think this is a result of the damaged material being broken down."

In the past, researchers have believed that the body keeps cells involved in reproduction isolated and protected from damage. Now it has been shown that these types of cells go through a rejuvenation process that rids them of the inherited damage.

Some types of protein damage in the body increase with age. Although all the necessary information is stored in the DNA, something keeps the body from using it to keep repairing the body.

"These types of protein damages are what make us appear old, like wrinkles around the eyes. While wrinkles are relatively harmless, serious problems may arise elsewhere in the body. I'm thinking of age-related diseases like Parkinson's, Alzheimer's, type 2 diabetes and cancer."

Hernebring can show that the damaged proteins in the cells are probably broken down by molecular machines called proteasomes. The proteasome activity increases considerably during the initial steps of embryonic stem cell differentiation in mice. Deciphering this rejuvenation process helps us better understand what aging really is, which in turn may help us slow it down and also prevent the occurrence and ill effects of age-related diseases.

[Vardarac]

 

A theory:

Human body rids itself of damage when it really matters
http://www.scienceda...10920075516.htm
Date: September 21, 2011
Source: University of Gothenburg
Summary: Although the body is constantly replacing cells and cell constituents, damage and imperfections accumulate over time. Cleanup efforts are saved for when it really matters. Researchers in Sweden are able to show how the body rids itself of damage when it is time to reproduce and create new life.

"I have a daughter. She is made of my cells yet has much less cellular damage than my cells. Why didn't she inherit my cells including the damaged proteins? That's the process I'm interested in," says Malin Hernebring from the Department of Cell- and Molecular Biology at the University of Gothenburg.

A few days after conception, the cells in the embryo all look the same -- they are unspecified stem cells that can develop into any bodily cell type. As the process of cell specification (differentiation) begins, they go from being able to keep dividing infinitely to being able to do so only a limited number of times. This is when they start cleansing themselves.

"Quite unexpectedly we found that the level of protein damage was relatively high in the embryo's unspecified cells, but then it decreased dramatically. A few days after the onset of cell differentiation, the protein damage level had gone down by 80-90 percent. We think this is a result of the damaged material being broken down."

In the past, researchers have believed that the body keeps cells involved in reproduction isolated and protected from damage. Now it has been shown that these types of cells go through a rejuvenation process that rids them of the inherited damage.

Some types of protein damage in the body increase with age. Although all the necessary information is stored in the DNA, something keeps the body from using it to keep repairing the body.

"These types of protein damages are what make us appear old, like wrinkles around the eyes. While wrinkles are relatively harmless, serious problems may arise elsewhere in the body. I'm thinking of age-related diseases like Parkinson's, Alzheimer's, type 2 diabetes and cancer."

Hernebring can show that the damaged proteins in the cells are probably broken down by molecular machines called proteasomes. The proteasome activity increases considerably during the initial steps of embryonic stem cell differentiation in mice. Deciphering this rejuvenation process helps us better understand what aging really is, which in turn may help us slow it down and also prevent the occurrence and ill effects of age-related diseases.

 

 

Many have said that a cause of aging as a manifestation of damage is not so much the damage itself as it is the diminished ability of the body to respond to it, and that this diminished ability is not so much caused by "damage" as it is a direct inhibition or lack of signal to engage the damage repair mechanisms.

 

This might be compared to a crew of maintenance workers in a factory. The factory falls apart over time, and the maintenance workers keep it in good working condition.

 

Now, what's responsible for the factory's inevitable deterioration may vary here:

- Perhaps the workers age as well, diminishing their own ability to repair the factory. (Our stem cells and protein turnover mechanisms decay naturally.)

 

- Perhaps something is directly preventing the workers from repairing the factory; the factory's owner has experienced deteriorating signalling health and gives bad orders, like to stop working on maintaining the factory. (Our brain and/or endocrine system changes in a way that shuts down stem cell division and protein turnover.)

 

- Perhaps the workers are not being paid enough to maintain the factory. (Our brain and/or endocrine system changes in a way that does not do enough to activate stem cell division and protein turnover.)

 

The difference between case 1 and cases 2 and 3 is of paramount importance. If it's true that our native repair mechanisms remain perfectly (or at least adequately viable) over time, then fixing signalling is the first step that needs to be made in remediating the biological differences between an old and a young human.

 

If cases 2 or 3 are the cause, and that first step is not taken, then the absence of a good repair mechanism will result in a quick and unmitigated deterioration of any youthful restorations we attempt to make.

Edited by Vardarac, 04 May 2014 - 07:43 PM.

[Avatar of Horus]

Many have said that a cause of aging as a manifestation of damage is not so much the damage itself as it is the diminished ability of the body to respond to it, and that this diminished ability is not so much caused by "damage" as it is a direct inhibition or lack of signal to engage the damage repair mechanisms.
 
This might be compared to a crew of maintenance workers in a factory. The factory falls apart over time, and the maintenance workers keep it in good working condition.
 
Now, what's responsible for the factory's inevitable deterioration may vary here:
- Perhaps the workers age as well, diminishing their own ability to repair the factory. (Our stem cells and protein turnover mechanisms decay naturally.)
 
- Perhaps something is directly preventing the workers from repairing the factory; the factory's owner has experienced deteriorating signalling health and gives bad orders, like to stop working on maintaining the factory. (Our brain and/or endocrine system changes in a way that shuts down stem cell division and protein turnover.)
 
- Perhaps the workers are not being paid enough to maintain the factory. (Our brain and/or endocrine system changes in a way that does not do enough to activate stem cell division and protein turnover.)
 
The difference between case 1 and cases 2 and 3 is of paramount importance. If it's true that our native repair mechanisms remain perfectly (or at least adequately viable) over time, then fixing signalling is the first step that needs to be made in remediating the biological differences between an old and a young human.
 
If cases 2 or 3 are the cause, and that first step is not taken, then the absence of a good repair mechanism will result in a quick and unmitigated deterioration of any youthful restorations we attempt to make.

Yes, you phrased it well IMO.
Some vague, speculative thoughts:
These cases of yours are similar to the distinction between the damage and programmed theories of aging.
And while all of these theories still need scientific confirmation, some things are sure.
Namely that in the case of reproduction, none of the damage theories are working, since here, all of the stochastic damages are nonexistent or dissappear, up to, let say, 99.99 %, but that is the evolution, i.e. it is 'encoded' in the system.
This is what I named for myself as the: immortal molecular/atomic composition of the given species. And this is a set of atoms/molecules and a course of chemical reactions that can operate and continue for millions or billions of years or even indefinitely in an intended, purposeful manner.

Regarding the germ cells, based to my current knowledge I entertain three possibilities, or 3 possible hypotheses:
- one is similar to the one mentioned in the above quoted text: "In the past, researchers have believed that the body keeps cells involved in reproduction isolated and protected from damage."
- the second is that the germ line cells have elevated defense capacity against the damages and/or improved repair abilities; and the normal cells lack these mechanisms and/or they decrease during aging.
- and the third is that their atomic/protein content is different from the other cells, in that aspect that they for example don't contain / express damage-prone proteins, which are irreparable in the current cellular repair mechanisms, but are needed for the given differentiated cells' tasks.
(Or a combination of the above is also possible.)
The first and the second would suggest that the aging, on the cellular level, is a controlled process.

And there is also the extracellular damage, but in this context this has not much role, since the new organism is rebuilding it in the development process of its new body. In this case a 'microdamage inflicting / re-generation inducing' approach/therapy may be developed/applied.

In the tissue homeostasis, there is a process called the asymetric cell division, which would be relevant to the above third case. I.e. stem cells are living longer because their have only such proteins that are less prone to damage and/or they are capable of offloading the damaged parts to their progeny.

On the concrete bioscience background relating to the above:
one study of the author cited in the quote:

Elimination of damaged proteins during differentiation of embryonic stem cells
Hernebring et al., Proc Natl Acad Sci U S A. 2006 May 16;103(20):7700-5.
http://www.ncbi.nlm....pubmed/16672370
full: http://www.pnas.org/...03/20/7700.long

... This elimination of damaged proteins coincides with a considerably elevated activity of the 20S proteasome. Moreover, damaged proteins were primarily observed in the inner cell mass of blastocysts, whereas the cells that had embarked on differentiation into the trophectoderm displayed drastically reduced levels of protein damage. Thus, the elimination of protein damage occurs also during normal embryonic development in vivo. This clear-out of damaged proteins may be a part of a previously unknown rejuvenation process at the protein level that occurs at a distinct stage during early embryonic development.

and another:

Removal of damaged proteins during ES cell fate specification requires the proteasome activator PA28
Hernebring et al., Sci Rep. 2013;3:1381.
http://www.nature.co.../srep01381.html

These studies highlight a possible role of the proteasome in aging.

In connection with this following studies may also worth noting:

Aging and dietary restriction alter proteasome biogenesis and composition in the brain and liver
Dasuri et al. 2009
http://www.ncbi.nlm....pubmed/19896962
PMC2942759

some quotes:

"the brain and liver exhibit age-dependent decreases in 26S and 20S proteasome activity"
"the brain and liver undergo selective changes in proteasome biology, including increases in proteasome biogenesis in response to aging and DR, with the liver exhibit more robust plasticity as compared to the brain. Lastly, studies demonstrated that aging and DR alter the interaction of Hsp90 with the 20S proteasome complex in the brain and liver."

and

Altered Composition of Liver Proteasome Assemblies Contributes to Enhanced Proteasome Activity in the Exceptionally Long-Lived Naked Mole-Rat
Rodriguez et al. 2012
http://www.plosone.o...al.pone.0035890

... In this study, we examined proteasome activity in naked mole-rats and mice in whole liver lysates as well as three subcellular fractions to probe the mechanisms behind the apparently enhanced effectiveness of UPS. We found that when compared with mouse samples, naked mole-rats had significantly higher chymotrypsin-like (ChT-L) activity and a two-fold increase in trypsin-like (T-L) in both whole lysates as well as cytosolic fractions. Native gel electrophoresis of the whole tissue lysates showed that the 20S proteasome was more active in the longer-lived species and that 26S proteasome was both more active and more populous. ... both 19S subunits and immunoproteasome catalytic subunits are present in greater amounts in the naked mole-rat suggesting that the observed higher specific activity may be due to the greater proportion of immunoproteasomes in livers of healthy young adults.

a Longecity search on 'proteasome' (in the top-right search box) may give further useful infos and related topics.

Perhaps some mouse/rat experiments with genetically elevated levels of this would give some clues of its role in the aging process.

Edited by Avatar of Horus, 05 June 2014 - 04:58 PM.

[Avatar of Horus]

Many have said that a cause of aging as a manifestation of damage is not so much the damage itself as it is the diminished ability of the body to respond to it, and that this diminished ability is not so much caused by "damage" as it is a direct inhibition or lack of signal to engage the damage repair mechanisms.
...

 

an article:

Proteostasis and longevity: when does aging really begin?
Labbadia J, Morimoto RI.
F1000Prime Rep. 2014 Feb 3;6:7. doi: 10.12703/P6-7. eCollection 2014.
http://www.ncbi.nlm....pubmed/24592319

 

Abstract
Aging is a complex process regulated by multiple cellular pathways, including the proteostasis network. The proteostasis network consists of molecular chaperones, stress-response transcription factors, and protein degradation machines that sense and respond to proteotoxic stress and protein misfolding to ensure cell viability. A loss of proteostasis is associated with aging and age-related disorders in diverse model systems, moreover, genetic or pharmacological enhancement of the proteostasis network has been shown to extend lifespan and suppress age-related disease. However, our understanding of the relationship between aging, proteostasis, and the proteostasis network remains unclear. Here, we propose, from studies in Caenorhabditis elegans, that proteostasis collapse is not gradual but rather a sudden and early life event that triggers proteome mismanagement, thereby affecting a multitude of downstream processes. Furthermore, we propose that this phenomenon is not stochastic but is instead a programmed re-modeling of the proteostasis network that may be conserved in other species. As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans.

 

and some related studies:
Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging
http://www.ncbi.nlm....pubmed/19706382

Remodeling of Proteostasis Upon Transition to Adulthood is Linked to Reproduction Onset
http://www.ncbi.nlm....pubmed/24822030

Germline stem cell arrest inhibits the collapse of somatic proteostasis early in Caenorhabditis elegans adulthood
http://www.ncbi.nlm....pubmed/23734734