Can DNA repair enzymes reverse oxidative damage and combat aging?

[bioquest]

Are there synthetic DNA repair enzymes that are being used/made or anything that could solve the oxidative dna damage issue? I mean I know they've made synthetic DNA

 

[Mike H]

Are you talking about known DNA repair proteins that were the focus of site-directed mutagenesis studies to modify their behavior or proteins designed from scratch? If the former, I have not a clue. I imagine that literature would be quite an effort to map and analyze. If the latter, there are only a few published results of proteins being designed from scratch to do actual chemistry (not just ligand or cofactor binding) and none of them, as I recall, had anything to do with DNA repair.

You should probably look up "protein engineering" and "protein design"/"de novo protein design" for a better idea about the latter, if that's what you were asking about in your question. It's a very interesting but very challenging field.

 

[bioquest]

are there 2000 year old trees or anything, or is it just the bark or something from those that are alive after thousands of years? I thought there was a type of tree that lived to 2000

 

[bioquest]

I mean, is it just the bark on trees like this http://www.Earth'sky.org/teachers/article/giant-sequoia that live a really long time, or is it the tree itself, like could the dna damage ability etc of these trees be transferred to animals and could the animal then live a really long time, or it is just the bark or something on the trees that live a really long time?

it says here
The oldest big trees are about 3000 years old.

http://www.icogitate.com/~tree/species/sequoiadendron.giganteum.htm

 

[bioquest]

Flooding cells with antioxidents/things that kill free radicals wouldn't stop all oxidative dna damage because the mitochondria/free radical production and the mitochondrial dna are so close together right?

Also sorry if this is an ocd question but you wouldn't be able to change a human into a different organism than a human using genetic manipulation or something right?

 

[Mike H]

Some antioxidants (such as certain vitamins) are known to be lipid soluble and therefore prone to accumulation and subsequently become toxic since they can't be excreted as quickly as water soluble compounds. So why would anyone want to flood an organism with them? Derivatives of vitamin A are known to serve as hormones which end up involved in regulating gene transcription. Things are never as simple as they seem, which seems to be a point that is overlooked.

Also, this interest in somehow quenching all oxidative chemistry in the cell is getting a little odd. We oxidize carbohydrates and fats in our cells for energy. We oxidize foreign substances to ultimately aid in us excreting them. We oxidize various unreactive compounds in our cells to subsequently functionalize them with new chemical moieties. There are entire journals dedicated to free radicals in chemistry and biology, both their important roles and their damaging effects. The NIH link to free books I shared earlier is a resource you should be focused on fully exploiting - there's solid material in genetics, molecular & cell biology, and biochemistry that should be worked through before trying to tackle the immense research literature out there in DNA repair, free radicals in biology, and the like.

I really don't have anything else knowledgeable to say about any of these topics at this point.

 

[bioquest]

So, when you say you'd have to overexpress every repair mechanism, would that solve the problem of higher problems with mismatched bases since one of those would also fix those? Could you go into more detail about what you meant when you said every repair mechanism? Also what stuff is there to repair dna other than enzymes?

the little I've read since undergrad molecular biology, one would probably have to find a way to upregulate (overexpress) EVERY repair mechanism in order to ensure that adequate fidelity is ensured.

 

[Mike H]

Regarding your questions, it's impossible to say with any degree of certainty. (I'm starting to sound like a broken record here...) We're still learning about what various mechanisms trigger DNA repair, there are still plenty of questions about how genes get turned on and off, and it's impossible to speculate about your proposed experiments since - as has been noted before - data trumps theory every time, so it's very possible there are other pathways which link together processes that we might not expect. Also, my point stands about having to overexpress being a potentially inefficient idea stands, as I described in my earlier post.

As for what I meant by every repair mechanism, I meant exactly that - every mechanism listed and described to varying degrees of detail in the Wikipedia article, the Roswell Park lectures, and in the books on the online bookshelf at NIH. Not to mention all of the citations/references listed in those sources! As for what proteins (including enzymes) are involved in DNA repair, all of that information is contained in those sources that have been very kindly linked to in this thread.

You should be thankful that we've provided you with such a pool of references to dig into this topic more deeply. Unless someone who actually specializes in DNA repair/free radical biochemistry shows up, you have pretty much reached a generalist's knowledge limit in this field. If you want more information/insight, you either have to contact someone who does this stuff for a living or become something of an expert yourself. Sorry.

 

[bioquest]

I am really thankful you were helping me
Sorry if I sounded stupid

 

[Mike H]

It's not a matter of sounding stupid at all, it's a matter of recognizing that the questions you're asking are good ones that can't be answered simply by possessing a relatively general knowledge base in biochemistry, molecular biology, and the like. Your questions that layer synthetic biology, gene therapy, and other current areas that are very much still in a research stage on top of one another make it very difficult to answer speculations that involve them all to one degree or another. That's why I've been suggesting to you to take advantage of the resources and links that we've provided. The specialized books on DNA repair and other fields that are cited in these links build upon that baseline of knowledge, as does the research literature. And you may still come to the point where the only way to really obtain any sort of answer to some of these questions is to do the experiments. I don't know what your career intentions are, but if you really are interested in these questions that you've put forth, either you or someone else will have to run those experiments, most likely in multiple model organisms at that.

It's part and parcel of becoming familiar with a field of inquiry - I spent the first six months of working in a lab in grad school mostly reading papers and getting some simple basic experiments worked out for subsequent studies. There's no way to circumvent it.

 

[bioquest]

Delivering lots of the dna repair enzymes would not be enough to overexpress them right?- You'd probably have to genetically modify a mouse or something to overexpress the enzymes?

 

[Mike H]

Saying you want to deliver DNA repair proteins sounds as if you want to pump an organism full of DNA repair proteins.

Saying you want to overexpress DNA repair proteins sounds as if you want to coax the cell into making more DNA repair proteins.

They're not the same thing. If you want to inject an animal full of proteins, that does not necessitate doing any sort of genetic manipulation. If you want to overexpress the proteins, you either need to genetically engineer it or find an alternate way to induce overexpression. This ties back to my point about being able to figure out what triggers DNA repair mechanisms, and how it all ties together.

I can't believe I did this (I'm just too pleasant for my own good at times), but there is a very recent review on regulation of DNA repair during the cell cycle that came out this year. The citation is:

Dana Branzei and Marco Foiani. (April 2008) "Regulation of DNA repair throughout the cell cycle." Nature Reviews Molecular Cell Biology. 9(4): 297 - 308.

This is mostly full of citations from work done after 2001 (which is after the last time I studied any of this material in even the slightest bit of detail). I found it on the first page of a Google search for "DNA repair regulation." It contains over 150 citations, which I am sure will serve as a superb starting point for some more modern information on DNA repair in cells, and will probably make some of the earlier responses obsolete or even incorrect in this thread.

Have fun!

 

[bioquest]

Is adding tons of the protein to the cell with endosomes or something, a temporary way to induce overexpression of the protein?

Saying you want to deliver DNA repair proteins sounds as if you want to pump an organism full of DNA repair proteins.
Saying you want to overexpress DNA repair proteins sounds as if you want to coax the cell into making more DNA repair proteins.
They're not the same thing. If you want to inject an animal full of proteins, that does not necessitate doing any sort of genetic manipulation. If you want to overexpress the proteins, you either need to genetically engineer it or find an alternate way to induce overexpression.

It just seems like having a cell make it's own proteins and having a cell have tons of proteins delivered to it seems really similar

 

[Mike H]

It is a matter of semantics, but one which is important to grasp. I'm oversimplifying here, but I think it captures the basic differences.

Delivery indicates that you are adding something externally to the cell, to increase the concentration of some (macro)molecule within the cell.

Overexpression indicates that you are coaxing the cell to synthesize more of a particular (macro)molecule either by genetic means or other methods, to increase the concentration of some (macro)molecule within the cell.

In the first case, you need to make sure that what you deliver is stable to be administered in a suitable way (oral, inhalation, intravenously, direct injection) and can then be routed to the desired area without being degraded or inducing an immune response. Even when it reaches the target area, it has to be able to enter the cell without too much difficulty. You may want to make sure that you avoid any feedback mechanisms which shut down natural production of the (macro)molecule upon an increased concentration of the desired (macro)molecule if that's important to you - this is the issue, for example, with steroid use, where externally taken steroids shut down the body's natural production of them, and why getting off steroids can be problematic for some people since they're not producing enough (or any) naturally.

In the second case, you need to make sure you can induce overexpression of the desired (macro)molecule in its functional form without causing negative effects upon the cell. This may require extensive genetic manipulations or delicate chemical induction methods. It may require both. Or it could require that you expose the organism to particular conditions that "shock" the organism into some desired response.

Again, I reiterate my suggestion to peruse standard undergraduate-level textbooks available at the NIH Online Bookshelf to further your broad-spectrum background in biochemistry, molecular/cell biology, and genetics. Any such discussion you want to get into regarding this topic or related ones will depend on such knowledge.

 

[Ygggdrasil]

Overexpression specifically means to inducing a cell to produce more of a specific protein. So, no, although injecting tons of a specific protein into a cell will increase the amount of protein in the cell, it will not induce overexpression of the protein. To induce overexpression, you would have to perform some genetic manipulation or inject the DNA for the specific protein.

Overexpression (having the cell make its own proteins) v. delivering proteins are slightly different. Overexpression is harder to accomplish, but can also lead to more permanent elevation of the amounts of protein. Delivering proteins raises the amount of protein only temporarily because proteins are constantly being degraded by the cell.

 

[bioquest]

Do we only know how to overexpress some repair mechanisms (as opposed to them all?) through genetic manipulation? I mean I read once that they overexpressed dna repair enzymes in mice, but I don't know if they did that with each repair mechanism. I'll try to read as much as I can about it, it seems like overexpressing each one of them might be a bit complex?

 

[Ygggdrasil]

Causing cells to overexpress all of the DNA repair enzymes would be a very tough task. Overexpressing one gene is hard enough to accomplish, and performing it on a large set of proteins would be a very difficult and time consuming task.

That said, there may be some tricks and shortcuts. Some proteins are known to sense DNA damage and cause the expression of a variety of proteins that help the cell to respond to DNA damage (e.g. DNA repair enzymes, proteins that halt the cell cycle, and even proteins that induce programmed cell suicide if the damage is too severe). One such protein is the very famous tumor suppressor protein p53, sometimes referred to as the "guardian of the genome." The wikipedia article on p53 isn't that great (http://en.wikipedia.org/wiki/P53), but you can probably find some decent resources on p53 in a molecular biology text.

 

[bioquest]

It would probably be possible to deliver the proteins etc to the cells though rather than make the cells produce more of them?
Maybe it's possible to deliver every type of DNA repair protein/mechanism to the cells so that they have a large amount of them (rather than make the cells produce more themselves) and see what happens. But if the proteins that fix mismatched bases are identical to the ones that fix oxidative damage wouldn't you just get an increase in mismatched bases? So basically I was wondering if the enzymes were the same/was wondering about those things thanks for the previous information though, I'll try to do all the reading

 

[Mike H]

Ygggdrasil's earlier point about the constant turnover of proteins by the cell stands - even if a large amount of desired proteins could be delivered to a cell, they would eventually be degraded. It would be a one-time-only increase, unless you're thinking to supplement these proteins regularly to the organism. The other aspect is that there is the entire timing thing that is discussed in the article that I cited regarding the regulation of DNA repair at different points in the cell cycle, which adds another level of complexity.

Mismatch repair uses mostly different proteins, although as I recall certain ones like single-strand binding proteins are used in both cases, and there may some fine point about different DNA polymerases being used, although I can't remember whether that's organism-dependent, someone will probably want to check me on that. It would be good to read up on that, especially as many of these mechanisms were first worked out in bacteria and then in eukaryotes.

Is there a citation to back up this claim that overexpression of proteins involved in mismatch repair results in more mismatched base pairs, or is this all going off a vague mention somewhere that no one can really remember? Because I can very easily imagine someone did something with a specially bred model organism that may have been the product of years of breeding that was used to answer a particular set of similar but not directly overlapping questions, and thus makes generalizing the observations about something it wasn't really intended to figure out to all organisms a bit of a stretch, at least in my book. Hope that made sense...

 

[bioquest]

yah I was thinking about supplementing the proteins regularly to the organism
Do you think it would be impossible right now to genetically manipulate a mouse/mammal to overexpress the protiens?

I just read somewhere that overexpressing enzymes caused higher problems with mismatched bases but that's not very specific about which enzymes or anything and then my friend said they were the same and I thought the dna repair enzymes worked together, but I guess the proteins could still be different?

 

[bioquest]

I know for sure though that I read somewhere that overexpressing enzymes caused more problems with mismatched bases in mice but it didnt' say which enzymes and I don't remember where I read it- I know for sure that I read this though and I think it was a legitimate source I read it in. but it could have been any enzymes they overexpressed right- I just thought they worked together to repair dna damage when they did it

I would want to supplement them to a mouse regularly but I'd prefer to geneticallly modify it to overexpress them would that be possible does anyone know how to do that? What I mean is, is anyone a high level geneticist or knows one- or do you think genetically modifying a mouse or something to overexpress them all would be impossible?

I really appreciate you guys talking to me about this and I am really glad I got to talk with other people who were at least somewhat interested in the same thing

 

[Mike H]

My interest in DNA repair is pretty much non-existent, I think being asked to regurgitate mechanistic details of the various pathways did me in as an undergraduate. But that's perhaps another story for another day...

While I've never worked with mice, most of what I've seen reports of in the literature are work with various transgenic mice, either with selected genes knocked out or overexpressed. It's typically not the whole pantheon of proteins that are involved in a process, especially in what I've seen of proteins being overexpressed in mice - it's a protein or two involved in metabolism that's overexpressed in muscle tissue, as an example, not every single protein involved in the various energy-producing pathways in muscle. Proposing to do it in all tissue types sets the bar even higher. It would make for a neat opening scene in a sci-fi novel at the moment, but reengineering entire chunks of a mammal's genome, I'd say, is a bit beyond our current capabilities. That's what you're really getting at - it's not just about DNA repair, but about manipulating everything from the cell cycle (remember that citation I listed about the regulation of DNA repair in the cell cycle) to other proteins that are involved in a number of processes that work with DNA (helicases, polymerases, single-stranded DNA binding proteins, ligases and so on), and all without killing the organism.

Here's another question - what would you do to support the cell's demand for energy to overexpress of all of these DNA repair proteins? More carbohydrates, fats, and lipids would have to be oxidized for energy (outside of suggesting that we reengineer the eukaryotic cell to obtain energy from alternate processes that have yet to be devised, heh), generating even more potentially toxic metabolic byproducts. This is perhaps related to the caloric restriction idea I've mentioned earlier here and elsewhere, where it seems restricting calories (but not necessarily nutrients) may be of benefit in extending longevity.

Another thing to keep in mind is potential roles of other macromolecules in DNA repair. It's been suggested that various chemical modifications to the histones may be an influence in not only gene expression and regulation but also DNA repair. It's been suggested that there's a "histone code" which suggests that the various types of modifications to the histones acts as a certain sort of code itself, but it's still a very active area of research from what I know.

One factor to consider is that if aging is caused by an accumulation of genetic errors over the years, you'd have to keep these functions upregulated for quite some time to garner any real benefit. Basically such that you're spending a lot of effort and energy that might be disproportionate to what it may be worth, and - not surprisingly - you'd have to test to make sure that years of upregulation (overexpression) in and of itself was not dangerous due to unexpected consequences.

I am, to be honest, a bit skeptical about the overly optimistic prospects some present for life extension. I do think that the potential maximum human lifespan has not been reached, and I do think that distinct improvements in the quality of life as one gets older is definitely possible. (80 is the new 40 - that's what I hope they're saying when I'm 75. Heh.) I do think that if we're really serious about pursuing such ends, we need to do so responsibly (we need to make sure that the global society is no longer shackled to fossil fuels but rather has switched over to solar power so there's plenty of energy for our expanding population) and equitably (EVERYONE needs to be able to benefit from such life-extension/quality-of-life-improvement technologies and methods, not just an elite few).

The ultimate point to all of this is that there's a lot of things to read and understand, not just about DNA repair in particular, if you really want to understand what's going on, and especially if you intend to pursue research in this area. Of course, depending on what comes from the research into the evolution of aging, the path might get even steeper if it turns out there might be good evolutionary reasons for aging...

 

[bioquest]

well my friend who said the enzymes were the same...she says the enzymes that repair mismatched bases and oxidative damage are different but then she said that they cause the same thing to happen/have the same purpose and so there would be an increased problem with mismatched bases

I mean I know that aging's a pretty complex thing to try to understand...and a lot of people have told me they think 120 or 150 is the limit to lengthening the human lifespan but I mean they didn't say they were 100% or anything..and I know if we could extend life we'd have to deal with the consequences such as overpopulation and the problems caused by that

 

[Mike H]

The standard textbook presentation would go something like this.

- Mismatch repair corrects errors in DNA replication in newly replicated DNA, not damaged DNA that has long since been produced. A particular mechanism involving what I'm going to call Mut proteins (at least in E. coli, there's something analogous in eukaryotes by my understanding) identify mismatches using the fact that the parent strand is methylated while the daughter strand is unmethylated. It cuts out the section where the mismatch occurs and then a DNA polymerase and ligase fill in the gap. Its purpose is to catch the rare but occasional error in the replication process.

- Excision repair corrects damage to the DNA well after it's been produced. It does not rely upon the same recognition method as in mismatch repair since the DNA has long since been methylated in this situation. Yes, it can cut out a stretch of nucleotides as happens in mismatch repair, and yes, polymerase and/or ligase is needed to fill in the gap. Its purpose is to repair damage so damage/mutation is avoided.

Yes, there may be some overlap in the proteins used in the cleanup stage (there are a couple of different DNA polymerases, I can never keep them straight in my mind), but the substantive work of identifying and snipping out the offending nucleotide(s) are being done by very different sets of proteins. They may have a similar general strategy for fixing their individual problem, but they identify different problems in different ways. I don't remember all of the details of the biochemistry involved, that's something you would be better served by going to a textbook as they usually have the chemical structures all sketched out very neatly.

Sure, in the abstract, both are being used to preserve the fidelity of genetic information as it is passed along from generation to generation. If that was what was meant, that's fine. But, in the specifics, I'm not entirely sure how an increase in the concentration of proteins involved in excision repair would cause DNA replication to somehow become more error-prone. That's what gets me. I'm sure someone can come up with some sort of explanation for why an increased concentration of proteins involved in mismatch repair might backfire, but it sounds kind of wonky at first pass.

I would also ask your friend for citations. It's impossible to compose any sort of response to what amounts to second-hand information without them.

 

[bioquest]

Would you eventually be screwed due to mismatched dna if you solved all other types of dna damage/potential causes of aging?
So mismatch repair would never repair old errors...even if you overexpressed all proteins/repair mechanisms and you'd possibly eventually be screwed due to old mismatch errors if they were serious/numerous? (ie due to overexpressing another protein or something) yes next time I get any info from my friend I'll ask for citations or something

 

[Mike H]

What's the criterion for "screwed" exactly? If one could somehow manage to minimize the effect of oxidative DNA damage as much as you seem to want to do, and that the only errors are likely going to be the ones that slip past the relatively faithful replication process and mismatch repair, you've essentially cleaned the slate clear of oxidative damage. I'm not sure that point has been made entirely clear - the chance that a particular nucleotide could be copied incorrectly during a round of replication is extremely tiny, something like one in a billion. Mismatch repair enhances the fidelity of the replicated DNA by a factor of 100, as I recall. You should probably try and work out the numbers for yourself regarding the fidelity of DNA replication, the quality of mismatch repair and the various other repair pathways, and see what would happen if you only had the occasional slip-up in replication and mismatch repair. The numbers I've given are off the top of my head. And I'm not sure how you'd suppress spontaneous genetic mutations either, most of which tend to be neutral ones. I'm not sure *why* you'd want to suppress these, as they - by definition - don't have any known effect on an organism.

Mismatch repair, at least in its standard default role, corrects for mistakes that escape proofreading during replication. It leaves correcting damage/errors post-replication to the other pathways which have been mentioned earlier in this thread a number of times. Some of the proteins involved in mismatch repair are somehow involved in other processes that involve DNA, but that's an active area of research which is not something I'm familiar with - I will leave you to investigate that on your own.

There's another potential issue that this made me remember - oxidative stress, as I may have mentioned before (I can't remember), can trigger apoptotic pathways to kill off the cell before it becomes cancerous/infected/otherwise bad for the organism as a whole. Being able to respond to one's environment may be essential and initiate mechanisms to aid the organism in its survival.

While I know this isn't a homework problem or assignment, I do hope you start showing more initiative in following up on the suggestions for reading. What I mentioned about mismatch repair in this reply and my previous one about its role is very clearly laid out in textbooks, for instance. I don't know where you are in your education, but I can assure you that if you do want to pursue research in these fields, you will have a lot of reading to do on your own.

 

[bioquest]

Yah, I know that not having cells with oxidized cells/that would get killed would cause problems with cancer, I thought making something have white blood cells that are resistant to cancer like with par4 gene therapy might help with that

I was just wondering if problems with mismatched bases could be fatal it just seemed like it could be a problem if the mechanism only fixed new wrong mismatched bases and not old ones but what you said made things a lot clearer, sort of

 

[Mike H]

I understand that the question here was how to reduce oxidative stress (as manifested in damage to DNA) that may arise from normal metabolism, but if that starts interfering with various mechanisms intended to allow an organism to adapt to and survive stressful situations...it's like keeping a small clutch of trees safe while you ignore the fact the rest of the forest is burning. One needs to keep an eye on the big picture. And I'm not sure counting on gene therapy just yet (which is still, overwhelmingly, in research) is a sure-fire way out. Maybe in 20 years gene therapy might be reliable and robust enough, though, although I imagine reengineering a mammalian genome will still be a work in progress.

It may be helpful to think about what a mutation actually is, and that what genes code for (most of the time) are proteins. Whether leucine gets coded for by one codon or another doesn't matter, as it will not affect the protein with regard to its structure or folding or function. If leucine was mutated into another hydrophobic amino acid, and it was just serving a structural role (not involved in the protein's function - catalysis, protein-protein interaction, etc.), it would be neutral. Mutation is what causes variation, which is what natural selection acts upon in evolution. Mutation is not some sort of horrific phenomenon that always causes death, despair, and woe. The Wikipedia article on http://en.wikipedia.org/wiki/DNA_damage_theory_of_aging" even points out that while related, mutation and DNA damage can't be simply considered the same.

I'm going to have to bow out of this discussion at this point, as I've long since reached my limit of understanding without becoming an expert on DNA repair myself. I can't imagine that I can say anything that a couple of texts and plenty of review articles can't do a hundred times better, with a wider perspective, and in more detail. If, however, you have questions about the material presented in the texts we've linked you to, I imagine that many more of us can help you since it's far less speculative in nature and on firmer scientific ground.

Disclaimer: This post was written while infectious and on decongestants, to say nothing of the fact that genetics was years ago for me. Corrections welcomed...

 

[bioquest]

Is it dna damage (oxidative, deletions, etc) + mutations/dna mutations that cause aging/problems? In that context what would the mutations mean? I understand you're saying some of them would have neutral effects?

 

[Mike H]

RTFM. Or, in this case, RTFReferences.

The first person to suggest that DNA damage, as distinct from mutation, is the primary cause of aging was Alexander (1967). By the early 1980s there was significant experimental support for this idea in the literature (Gensler & Bernstein, 1981. By the early 1990s experimental support for this idea was substantial, and furthermore it had become increasingly evident that oxidative DNA damage, in particular, is a major cause of aging (Bernstein & Bernstein, 1991; Ames & Gold, 1991; Holmes et al., 1992; Rao & Loeb, 1992; Ames et al., 1993).

-- From http://en.wikipedia.org/wiki/DNA_damage_theory_of_aging" Bold text highlighted by me to make the hypothesis regarding what causes aging (at least in this presentation of the theory) clear. It is DNA damage, NOT mutation, that seems to be the culprit in aging (at least as it is presented on Wikipedia).

Below, selected quotes from http://en.wikipedia.org/wiki/Mutation" :

Mutations create variation within the gene pool...The majority of these mutations will have no effect

Neutral mutations are defined as mutations whose effects do not influence the fitness of an individual. These can accumulate over time due to genetic drift. It is believed that the overwhelming majority of mutations have no significant effect on an organism's fitness. Also, DNA repair mechanisms are able to mend most changes before they become permanent mutations

A neutral mutation is a mutation that occurs in an amino acid codon (presumably within an mRNA molecule) which results in the use of a different, but chemically similar, amino acid. This is similar to a silent mutation, where a codon mutation may encode the same amino acid (see Wobble Hypothesis); for example, a change from AUU to AUC will still encode leucine, so no discernible change occurs (a silent mutation).

Silent mutations are DNA mutations that do not result in a change to the amino acid sequence of a protein. They may occur in a non-coding region (outside of a gene or within an intron), or they may occur within an exon in a manner that does not alter the final amino acid sequence. The phrase silent mutation is often used interchangeably with the phrase synonymous mutation; however, synonymous mutations are a subcategory of the former, occurring only within exons.

As noted above, it is DNA damage, not mutations per se, that is responsible for aging. Your focus on mutations being some sort of major problem or crisis makes no sense. Most of them are neutral in effect - they are neither beneficial nor deleterious.

You really need to read the references that are linked here or where we point you in the general direction. They're all quite clear, lucid and can answer your questions, at least in my opinion. I'm kind of disappointed - here we've pointed you to a resource that, if you had to buy all those books yourself, would run you a bill in the thousands of U.S. dollars (the NIH Online Bookshelf), those Wikipedia articles must have taken some time to prepare by people (especially the better-referenced and written ones), and still it seems you can't find any of this information on your own.