11 replies to this topic

[maestro949]

Quite a bit of research, particularly in the cancer space is hinting that many pathologies related to aging tie back to gene expression regulation, particularly what is known as chromatin damage.

Aging by epigenetics - a consequence of chromatin damage?

If targets can be found that fix this chromatin damage for cancer, where significant investments are currently being made, it's likely that they may also have the side benefit of slowing the accumulation of aging damage as well. A lot of questions still remain as the data is still emerging but this is research that has a lot of potential upside for longevity.

Could the silver-bullet drugs of the future be a concoction of cancer targets being used off-label to slow aging and rejuvenate the elderly too?

[caston]

Maestro: i'd also like to suggest the market could include a therapy or drug to repair the chromatin damage (e.g. Chromatin Restitution) in ex-smokers, people with extensive sun damage and skin cancer risk as well as a potential treatment for male infertility.


I don't know if this helps but I decided to google chromatin and D3 and found the following:

VITAMIN D3-STIMULATED TEMPLATE ACTIVITY OF CHROMATIN FROM RAT INTESTINE*

http://www.pnas.org/.../2/528.abstract

Edited by caston, 29 August 2008 - 01:40 PM.

[maestro949]

Maestro: i'd also like to suggest the market could include a therapy or drug to repair the chromatin damage (e.g. Chromatin Restitution) in ex-smokers, people with extensive sun damage and skin cancer risk as well as a potential treatment for male infertility.

I would think that any of these that have damaged chromatin would be candidates for therapeutics that target them.

For giggles I searched ClinicalTrials.gov for the term epigenetics and found one related to aging...

Epigenetics in the Aging Process

It's not a trial for targeting Chromatin with a fix but rather examining the role of epigenetics in the aging process.

[Mind]

While we are on the subject of epigenetics and aging, check out this thread about epigenetics as well.

[caston]

While we are on the subject of epigenetics and aging, check out this thread about epigenetics as well.

Oh that one.. I ended up suggesting cellular fusion as a possible way to fix epi-genetic disregulation. e.g. two aged / damaged cells fuse together with the idea being that the resulting cell will have a normal metabolism.

[maestro949]

...I ended up suggesting cellular fusion as a possible way to fix epi-genetic disregulation. e.g. two aged / damaged cells fuse together with the idea being that the resulting cell will have a normal metabolism.

Why would you fuse two aged cells and why do you think this would reverse epigenetic damage that result from aging? It might be a more interesting experiment to see changes in DNA methylation that result from fusing of an aged cell with a young cell. An even more targeted experiment might be to inject a young organelles such as mitos and lysosomes into aged cells. Cancer researchers use a technique called Restriction Landmark Genomic Sequencing (RLGS) to look for hypermethylated genes. The same technique could be used for finding aging genes that could suppress the aging phenotype.

Edited by maestro949, 31 August 2008 - 03:54 PM.

[Athanasios]

After reading the paper, I have a hard time seeing what pathologies, besides cancer, are casually related. I guess we probably just haven't lived long enough to see it?

See:

de Grey ADNJ. Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging. Mech Ageing Dev 2007; 128(7-8):456-459.

Available here:
http://www.mfoundati...ns/nucmutPP.pdf

[caston]

...I ended up suggesting cellular fusion as a possible way to fix epi-genetic disregulation. e.g. two aged / damaged cells fuse together with the idea being that the resulting cell will have a normal metabolism.

Why would you fuse two aged cells and why do you think this would reverse epigenetic damage that result from aging?

For the same reason one might buy 2 wrecked motor vehicles of the same make and year. Each vehicle on it's own does not have enough working parts to run but there is a good chance that you could take working parts from one vehicle (e.g if one has a good engine) and transplant them into the other.

So for this to work it would assume that each of the cells does have some age related damage but this damage effects different parts of the cellular machinery to the cell it is fusing with.

The ying and the yang applies to cells too. There is always some good in with the bad and some bad in with the good. This applies even to cancer cells.

It might be a more interesting experiment to see changes in DNA methylation that result from fusing of an aged cell with a young cell. An even more targeted experiment might be to inject a young organelles such as mitos and lysosomes into aged cells. Cancer researchers use a technique called Restriction Landmark Genomic Sequencing (RLGS) to look for hypermethylated genes. The same technique could be used for finding aging genes that could suppress the aging phenotype.

I like the way you think, you are a smart man and those suggestions are gold

We can do calculations to save us time in the lab but the calculations will never be able to replace real lab experimentation. Not to mention it can be a lot of fun.

Edited by caston, 01 September 2008 - 01:46 AM.

[maestro949]

After reading the paper, I have a hard time seeing what pathologies, besides cancer, are casually related. I guess we probably just haven't lived long enough to see it?

Cancer is indeed the hallmark disease most cited as this is where all of the resources are currently focused thus it makes perfect sense that we have more data here however the paper is definitely suggesting that much more of the aging phenotype may have chromatin damage at its root such as tissue regeneration, decline in damage repair pathways, cardiac issues, immune system decline, etc.

See:

de Grey ADNJ. Protagonistic pleiotropy: why cancer may be the only pathogenic effect of accumulating nuclear mutations and epimutations in aging. Mech Ageing Dev 2007; 128(7-8):456-459.

Available here:
http://www.mfoundati...ns/nucmutPP.pdf

Its perfectly plausible that gene expression abnormalities that result from regulatory disruption could in theory, mimic any and all genetic disorders. The fact that most aged individuals shows signs of numerous Mendelian developmental disorders at various stages is fairly compelling indicator that the upstream genetic regulatory machinery may be breaking down with age thus explaining the stochastic nature of the aging phenotype.

Another way to look at this is to flip the conventional thinking around by looking at a chromosomal defects such as the progerias and instead of saying "Hey, these look like premature aging" but rather ask whether aging is similar to these disorders. In doing so you can see how many of the so-called aging diseases may actually be mimicking developmental disorders that are rooted in chromosomal dysfunction, manifesting themselves in a more subtle manner and weakening the organism at all levels; from biomolecular pathways to subcellular functions, organs and entire systems.

While epigenetic damage may not be the sole target for damage intervention it's one worth considering for further investigation IMO as the upside has quite a bit of potential for fixing damage before it becomes too costly, or perhaps even pointless, e.g. advanced stages of Alzheimer's.

Edited by maestro949, 01 September 2008 - 02:15 PM.

[maestro949]

Here's a good example of the overlap between cancer and aging research targeting the same damage.

Epigenetic regulation of telomeres in human cancer

Edited by maestro949, 02 September 2008 - 05:16 PM.

[caston]

In doing so you can see how many of the so-called aging diseases may actually be mimicking developmental disorders that are rooted in chromosomal dysfunction, manifesting themselves in a more subtle manner and weakening the organism at all levels; from biomolecular pathways to subcellular functions, organs and entire systems.

So what are the differences between an early onset genetic disorder e.g. a Lysomal Storage Disorder and a late onset genetic disorder?

We would assume the early onset disorder was there since birth and was a genetic defect in the zygote but the late onset genetic disorder could be a result
of damage.

If you took a sample of tissue effected by the late onset disorder would you find that every cell within that tissue has the same problem or that some of those cells do and some don't? In my guess it would based on the progression of the disease. e.g. early on 10% of the cells with have the genetic dysfunction and 90% would have normal metabolism. The 10% percentage grows and the 90% shrinks until we have organ failure.

Edited by caston, 04 September 2008 - 06:59 AM.

[maestro949]

So what are the differences between an early onset genetic disorder e.g. a Lysomal Storage Disorder and a late onset genetic disorder?

We would assume the early onset disorder was there since birth and was a genetic defect in the zygote but the late onset genetic disorder could be a result
of damage.

Indeed. An early onset genetic disorder would likely be inherited or through a spontaneous mutation during embryonic development whereas similar late-onset symptoms might be a result of a stochastically tripped epigenetic events relating to environmental exposures, through chemically induced damage, a loss in functionality simply due to the loss in genomic plasticity with time (i.e. some gene products are simply switched off through regulatory mechanisms and don't have equivelent mechanisms for being turned back on) or more likely, a combination of all of these. This epigenetic damage would be in the same neighborhood of the gene products affected by the inherited polymorphism(s).

If you took a sample of tissue effected by the late onset disorder would you find that every cell within that tissue has the same problem or that some of those cells do and some don't?

It probably varies considerably. Cell division is one way for chromatin damage to spread and the obvious example is cancer. Environmental, errant signaling, viruses, hyperimmune responses, circulating toxins, prions etc. could also cause like lateral damage to non dividing cells.

In my guess it would based on the progression of the disease. e.g. early on 10% of the cells with have the genetic dysfunction and 90% would have normal metabolism. The 10% percentage grows and the 90% shrinks until we have organ failure.

I suspect that all cells are accumulating chromatin damage and some accumulate enough of the same type to mimic genetic ailments. For those with a genetic predisposition to experiencing this damage at a lower threshold will do so in a more significant manner and at a younger age. Redundancy, damage repair, immune, apoptosis, stem cell renewal and damage clearance mechanisms keep damage at bay but when these pathways also wear out you see the disease phenotypes emerge.

If this turns out to be the case then a viable anti-aging strategy would be to target phenotypes at the epigenetic level. Efficacy and stage of intervention would improve as researchers discover more precise candidate gene products and biomarkers to screen for them.

I've got this book on my radar but I've already got a stack to digest, not to mention that I'm going broke buying all these books ...

Chromatin and Disease