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Human aging

Genetics as it applies to evolution, molecular biology, and medical aspects.

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Human aging

Postby pomkon » Wed Jan 07, 2009 1:39 am

I am some very deep questions about aging genes which concerning my eassy. The human aging genes, the theory of death/aging which there was a discussion in here before, about596-12.html . Finally ethics.

1. Mitosis shortens the telomere appendix on DNA, how, why did telomere evolve and how the process works? and how come the Hayflick limit (only able to divide about 70 times) only apllies on fully differenated cells, what is the point, but not on stem cells which the DNA can always maintains its integrity. Also stem cells exist in every tissue, and stem cell do not age, they divide in all parts of the body into differntiated cells, some suggests this is selected because if differentiated cells turn into cancer cells, then the Halflick limit would stop the spread of cancer, but tis is 1 big reason that we age, why can the stem cells keeping on making new replicate cell and keep us immortal? In contrast, some says cancer was intended for the cause of death, it seems silly because for a such devastating destruction?

Somewhat interesting to me, cells die because they age, I heard the brain and one other part of the body cant repair itslef, and we know the nerve connections in our brain are always reconnecting (some die and make some new ones) that means our brain is aging really fast?

2. What other genes do u think its significant in the senescence process? very important! Klotho, Methuselah are the ones I think more of, what do u think of them?

there may be some mistakes due to my partial knowledge, correct me :D
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Postby biohazard » Wed Jan 07, 2009 7:48 am

Like stem cells indicate, the human body has all the tools it needs to keep its cells dividing indefinitely, thus avoiding telomere-dependent aging. However, for a reason or another, the nature has switched off this machinery from differentiated cells. The most common explanation I have heard is an evolutionary one: we are programmed to stay alive long enough to have offspring and see to it that they reach adult age, after which we become obsolete - we need to make way for the "newer models". If every individual stayed alive indefinitely, we'd soon become competitors even to our own descentants, which is not how evolution works.

The Hayflick limit probably protects us from cancer in some cases, but it could be more a side effect than the limit's actual purpose - which is to ensure that we die in due time (at least I think that's what Dawkins said in "The Selfish Gene"). In a way, I think, you can say that cancer is the way we are meant to die: if you do not die to an infectious disease, trauma or some acute faliure of an organ, it is cancer that eventually finishes you off. Though in the end cancer is just the outcome of accumulating mutations in the genome (sometimes aided by chemicals or viral infections), but even if there was no cancer, you'd eventually die because your organs simply couldn't regenerate efficiently enough despite some stem cells still existing.

Even though the brain has very limited regeneratory capacity, I don't think you can say the brain ages particularly fast. To the contrary, unless there is some neurodegenerative disease involved (Alzheimer's, CJD, other forms of dementia etc), the human body very rarely, if ever, dies because the brain is "too old". Rather, some other system in the body always fails before the actual brain tissue becomes too old to maintain life.

What all genes take part in the process of ging? I do not know, nobody probably knows the whole picture. Klotho, Methuselah are probably just pieces of the puzzle, maybe somewhat more important than others, but I dare to say that even if we'd manage to "prevent" aging by tweaking some of these genes, then if nothing else would take us, an overwhelming accumulation of mutations into our cells and ensuing onset of multiple cancers would top us soon enough. Thus I'm not sure if we'd live much over 100 years even if aging was "disabled" :)
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Postby pomkon » Wed Jan 07, 2009 5:24 pm

The resources limiting thoery is well reputable, but how was it selected and evolve? And I just got of this one, you are saying marcomolecule damage also exhibit on stem cells? there are not really immortal? The damaged enzymes and lipids doesnt matter, because new copies would be made from the DNA. but what if the DNA also mutates and somehow loss an gene coding for a vital molecules, that it would die?
Is death by senesence really differnet to death by accumulated mutations?
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Re: Human aging

Postby jonmoulton » Wed Jan 07, 2009 5:29 pm

You might be interested in looking into the lamin A gene which, when mutated, can cause the premature aging disease called progeria.

Here are some places to start.

Scaffidi P, Misteli T. Lamin A-dependent nuclear defects in human aging. Science. 2006 May 19;312(5776):1059-63. Epub 2006 Apr 27.
http://www.ncbi.nlm.nih.gov/pubmed/16645051

Scaffidi P, Misteli T. Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med. 2005 Apr;11(4):440-5. Epub 2005 Mar 6.
http://www.ncbi.nlm.nih.gov/pubmed/15750600
http://www.pubmedcentral.nih.gov/articl ... d=15750600
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Postby biohazard » Thu Jan 08, 2009 7:48 am

Pomkon, yes, death by senescence and death by accumulated mutations differ from one another: the (non-stem) cells will stop dividing and eventually die even if there were no mutations accumulated in their genome. Of course there is a huge variation in the life span of different cell types. E.g. neurons, muscle cells and some immune cells live decades, whereas many others days or months. But the outcome is nonetheless same: they are not immortal, and sooner or later lose their ability to divide further. Muscle cells and neurons actually pretty much lose the ability to divide very early in the human life, but these cells are very long living.

Death by mutations is a different story: it can happen at any stage of the cells' life, especially if we are talking about dividing cells. Unless the proofreading mechanisms and error repair can fix the genome, and the mutation is "fatal" for the cell, it dies either because of failed mitosis, lack of some crucial gene product, or by apoptosis induced by CD8+ lymphocytes that detect "non-self" proteins produced by a mutated gene. As far as I know, stem cells are not any more immune to mutations or cancer than other cells. Non-dividing cells such as neurons rarely develop into cancer, because cancer requires dividing cells. Stem cells, epithelium, progenitor blood cells and such are much more likely cause of cancer. Developing a cancer is a sum of many factors, however. A single mutation very rarely, if ever(?), leads to cancer. Thus several pro-cancer mutations are required and the accumulation of these usually takes decades, which is why most cancers occur in older people.

Death by senescence = cells eventually lose their ability to divide due to diminished telomeres. Otherwise these cells can be just as good as new.

Death by mutations = one or several mutations in the genome, if they happen in essential genes, cause the cell to fail mitosis or lose some important protein and die. These cells may have much of their natural dividing capacity left (=telomeres). The immune system also destroys mutated cells in certain cases.
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Postby pomkon » Thu Jan 08, 2009 10:00 pm

Ok, stem cells do accumulated mutations, and they would be passed on to offspring when one reproduces, then how come youngful generations are produced time to time with no premature aging???

The answer should be no I think, simply the fact. or may be the inherited mutated individuals would be selected against, but that is hard to observe... I cant get my head round this one.

Anyway if stem cells do age, and the most important factor to counter senescence is thorugh mainting the integrity of the genome, then even if the adult stem cells is able to replace ALL the old cells with new cells (even for muscle and nerve cells in the future) which we are not capable of because of the increase loss of functions and structures in our body tissues over time. Then we cant never be immortal unless a 100% DNA repairing system is discovered/made.

Please if you can state your sources so I can reference. It is annoying because I read stuff on the web myself and I cant refer it and people (scientists) want the official source. Its so much harder to read journals and time-consuming although more 'accurate' but its very painful.
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Postby biohazard » Fri Jan 09, 2009 6:50 am

Pomkon, you got me wrong now.

Stem cells do not "age" - getting a mutation in your genome is not aging in a way I mean it. Instead, telomere shortening and ensuing cessation of cell divisions and thus the loss of body's regenerative capabilities is what I meant as aging (i.e. cellular senescence). Only eggs and sperm (their genomes) are transfered to future generations, so that is why stem cell mutations do not accumulate further. Naturally, germ line cells can also undergo mutations, which provides new tools for evolution. We are full of previously happened (i.e. "accumulated") mutations already! :)

What comes to references... uhh, I can try to find some for you, but currently I'm bit too busy for that. I'll look into that later. Meanwhile, perhaps take a look at the links jonmoulton posted (unless you already have done so), there are some interesting details about mechanisms involved in the aging process.
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Postby mcar » Fri Jan 09, 2009 9:59 am

It is also good to read about the free-radicals that were found to be associated with increased rate of human aging. For an instance, hydrogen peroxide that is commonly present inside our cells has a high oxidative property and they are also responsible for the formation of hydroxyl radicals. Enzyme like glutathione peroxidase must act on these radicals to prevent the harmful effect to the cells. Nowadays, glutatathione-containing soaps are were widely sold to markets believing on its promising effect of making the skin look younger and healthier.
---Just one act of random kindness at a time and you can change the world---
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Re:

Postby pomkon » Fri Jan 09, 2009 3:19 pm

biohazard wrote:Pomkon, you got me wrong now.

Only eggs and sperm (their genomes) are transfered to future generations, so that is why stem cell mutations do not accumulate further. Naturally, germ line cells can also undergo mutations, which provides new tools for evolution. We are full of previously happened (i.e. "accumulated") mutations already! :)



I am not so sure on this process, accumulated DNA mutations also happens in germline cells and when they replicate, sure the genome has DNA mutation carried to gametes as well. The gametes would still have the mutations (although its new to itself) from the parents and when they reproduce, more and more accumulations ???
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Postby pomkon » Fri Jan 09, 2009 6:10 pm

Also, you know Hydra which it hs been oberseved that they live for very long period without intrinsic aging because the stem cells permeate its body. It sounds like their stem cells do not accumulated mutations...
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Postby biohazard » Sat Jan 10, 2009 10:21 am

Many lower organisms do not age the way we do. The reason why their genome (or our gametes) do not acquire an overwhelming amount of detrimental mutations is simple: those offspring who have too much or too disadvantageous mutations die. Humans have mischarriages, lower organisms simply do not survive the competition with their "siblings" who do not have these kind of mutations. Instead, some of them may have beneficial mutations, and soon they and their offspring gain increase in numbers.

So, germline cells do mutate, but only embryos with viable genomes survive. Also, because we have two alleles for each gene, many bad mutations remain in the background, and only if the person happens to get a similar, defective gene also from the other parent they may suffer from it. Like I said before, our genomes are full of (accumulated) mutations already. But the bad mutations are continuously eliminated from the gene pool.
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Postby pomkon » Sat Jan 10, 2009 9:40 pm

Yes, I think I understand more aspects of aging now. I have also read on wiki that DNA damage and DNA mutations are 2 distinctive ideas. They say DNA mutations do not really accelerate aging but DNA damage does.

Anyway I am still struggling with the anti-aging genes..
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