senesence - why do we age?

[murraybiscuit]

http://en.wikipedia.org/wiki/Senescence

although "old age" isn't really a cause of death, i still wonder why organisms age and die.
obviously natural selection favours those mutuations which lead to the longest life, but why is death necessarily hardcoded into all cellular life?
given the infinity of the universe, why does life on earth only have a window of a few hundred years, rather than centuries or aeons?
is death a necessary part of the metabolic process: that in order for us to live, we must grow, and because we grow, we must therefore die?

what i'm getting at here is whether we could ever achieve longer lives not only by controlling environmental risks, but also through genetic modification.

this was probably covered in bio 101 in high school, help me out if the answers are obvious.

 

[Techne]

http://en.wikipedia.org/wiki/Senescence

although "old age" isn't really a cause of death, i still wonder why organisms age and die.
obviously natural selection favours those mutuations which lead to the longest life,

I don't think this is necessarily true (forgetting for a moment about the fact that natural selection does not "favour" anything). Short-lived organisms are quite successful. There isn't anything to suggest that mutations (or genetic programs if you want) for "longer lives" are more more prevalent or more successful so natural selection as an explanatory paradigm to explain ageing and senescence seems a bit sterile.

but why is death necessarily hardcoded into all cellular life?
given the infinity of the universe, why does life on earth only have a window of a few hundred years, rather than centuries or aeons?
is death a necessary part of the metabolic process: that in order for us to live, we must grow, and because we grow, we must therefore die?

All good question, who knows really?

Cell death is a necessary part of growth and development though. There are several ways in which cells may die, for example apoptosis (programmed cell death), autophagy (where the cell literally eats itself to death) or necrosis etc. This is a very active area of research at the moment and scientists are trying to understand how these ways of cell death are controlled via cell signalling (redox regulation, protein regulation, genetic regulation etc.) and how the environment plays a role.

what i'm getting at here is whether we could ever achieve longer lives not only by controlling environmental risks, but also through genetic modification.

Possibly yes since ageing seems to be preprogrammed. So the idea is that if you can modify genetic and/or epigenetic programs controlling the ageing process, you should in theory be able to alter it in such a way to prolong lives.

 

[porchrat]

obviously natural selection favours those mutuations which lead to the longest life

Not necessarily.

but why is death necessarily hardcoded into all cellular life?

Ever heard of a telomere? They're probably the closest thing I can think of (in eukaryotes anyway) to a "hard-coding" of death.

Telomeres are sections of DNA that sit on the end of a chromosome and protect it from damage on the ends. Kind of like the aglet of a shoelace. Eukaryotic DNA replication always happens in the 5' --> 3' direction (DNA strands each have a 3' end and a 5' end named so because the arrangement of the DNA molecules leads to a different numbered carbon sticking out). However replication itself starts in the middle of a DNA strand. So replication shoots off in the 5' --> 3' direction leaving a long strand behind that doesn't get replicated in that initial replication procedure. That extra unreplicated area is then replicated in a different way in smaller pieces which are later bonded together. The problem is the small piece on the very end never replicates properly due to the way these proteins interact.

It isn't so much that it is hard-coded but more that the proteins involved in DNA replication are not perfect and as a result pretty much always skip that last end of the telomere on the one end. Eventually the telomere disintegrates and is no longer able to protect the chromosome. After that point chromosomal degradation quickly reaches the point at which it is impossible for the molecular machinery that facilitates DNA replication to replicate the DNA.

 

[Techne]

Ever heard of a telomere? They're probably the closest thing I can think of (in eukaryotes anyway) to a "hard-coding" of death.

Telomeres are sections of DNA that sit on the end of a chromosome and protect it from damage on the ends. Kind of like the aglet of a shoelace. Eukaryotic DNA replication always happens in the 5' --> 3' direction (DNA strands each have a 3' end and a 5' end named so because the arrangement of the DNA molecules leads to a different numbered carbon sticking out). However replication itself starts in the middle of a DNA strand. So replication shoots off in the 5' --> 3' direction leaving a long strand behind that doesn't get replicated in that initial replication procedure. That extra unreplicated area is then replicated in a different way in smaller pieces. The problem is the end piece never replicates properly due to the way these proteins interact.

It isn't so much that it is hard-coded but more that the proteins involved in DNA replication are not perfect and as a result pretty much always skip that last end of the telomere on the 5' end. Eventually the telomere disintegrates and is no longer able to protect the chromosome. After that point chromosomal degradation quickly reaches the point at which it is impossible for the molecular machinery that facilitates DNA replication to replicate the DNA.

yes, porchie touches on another interesting aspect of ageing, telomeres. Human cells tend to have a limited lifespan, meaning they can go through a limited amount of cell replications before dying and telomere length does play a role. Interestingly, in cancer cells that are immortalized (the ones being used in cancer research labs like HeLa cells), telomerase gene expression is up-regulated and plays a role in maintaining telomere integrity. So there is a lot of research involved in trying to understand teleomere homoeostasis as well.

 

[porchrat]

yes, porchie touches on another interesting aspect of ageing, telomeres. Human cells tend to have a limited lifespan, meaning they can go through a limited amount of cell replications before dying and telomere length does play a role. Interestingly, in cancer cells that are immortalized (the ones being used in cancer research labs like HeLa cells), telomerase gene expression is up-regulated and plays a role in maintaining telomere integrity. So there is a lot of research involved in trying to understand teleomere homoeostasis as well.

It is a truly interesting topic.

I also recently saw an article on anti-oxidants and how quite a few studies have demonstrated that their anti-aging and anti-disease-state (yes I know made up word alert ) properties may not be as clear-cut as we might think. Marketing people love to tell you that their product contains some or other anti-oxidant. Sort of like when they sell you fat-free margarine . It would be strangely funny to find out that anti-oxidants have a negative effect on your health and longevity.

EDIT: Also just to clarify it isn't just human cells that suffer from this telomere problem but pretty much every eukaryote. Most prokaryotes don't share this problem... though a few of them do.

 

[Techne]

Yeah, the anti-oxidant business is a scam. The problem is that at large concentrations these compounds do in fact act as reactive oxygen or nitrogen or even superoxide scavengers (anti oxidants) but these concentrations are typically in orders of magnitude to high to get in vivo in humans. But at the low levels that they are found in the body, they actually contribute to producing these radicals and are thus not anti-oxidant, but pro-oxidant. And in cells, there needs to be a redox balance and a pro-oxidant state contributes to cell proliferation. So these anti-oxidants can actually make cancers more dangerous by activating pro-growth signals as a result of causing a pro-oxidant status in these cells.

A "scientific consensus" slowly being turned on its head I guess.

 

[Ockie]

Yeah, the anti-oxidant business is a scam. The problem is that at large concentrations these compounds do in fact act as reactive oxygen or nitrogen or even superoxide scavengers (anti oxidants) but these concentrations are typically in orders of magnitude to high to get in vivo in humans. But at the low levels that they are found in the body, they actually contribute to producing these radicals and are thus not anti-oxidant, but pro-oxidant. And in cells, there needs to be a redox balance and a pro-oxidant state contributes to cell proliferation. So these anti-oxidants can actually make cancers more dangerous by activating pro-growth signals as a result of causing a pro-oxidant status in these cells.

A "scientific consensus" slowly being turned on its head I guess.

Except for Melatonin. It is appratently a very strong anti-oxidant and does not react in the same way as other anti-oxidants do to produce free radicals as a by product....or something like that I read about it briefly on Wikipedia when I started taking it to help me sleep.

There is also a product called reservatrol that basically has the same effect as calory restriction, which is said to slow down the aging process dramatically. This however has not been proven I think.

 

[Techne]

Except for Melatonin. It is appratently a very strong anti-oxidant and does not react in the same way as other anti-oxidants do to produce free radicals as a by product....or something like that I read about it briefly on Wikipedia when I started taking it to help me sleep.

There is also a product called reservatrol that basically has the same effect as calory restriction, which is said to slow down the aging process dramatically. This however has not been proven I think.

Resveratrol is active (as an antioxidant) at the micromolar range, way too high to get into the blood. As for melatonin, it also acts though various receptors so its action is not dependant on it being an antioxidant.

 

[Jonny Two Shoes]

@ porchrat I have absolutely no idea about that stuff but I think I more or less understand what you said. Thanks

These telomeres though, is that just simply a "design flaw" (not to imply conscious design) in how cell replication works? And what is the correlation with different forms of life from trees to elephants to day-flies that makes their life-span different? Metabolism and/or cell structure or something?

Bare in mind once again I know absolutely nothing here, would probably do me well to google and wiki

 

[porchrat]

@ porchrat I have absolutely no idea about that stuff but I think I more or less understand what you said. Thanks

Thank you for taking an interest . I try to write things as simply as I can because I know when I'm not familiar with a topic I learn more about it when people put it into words that I can understand. I appreciate it when people do it for me, so I try to do it for everyone else. I hope it didn't get too complex. You can mostly ignore the 5' and 3' stuff as that was just additional information and really only needs to be considered if you're interested in knowing how scientists number carbon in chemical structures.

These telomeres though, is that just simply a "design flaw" (not to imply conscious design) in how cell replication works?

Well I suppose you could call it a design flaw. The molecular machinery that facilitates DNA replication is far from perfect. To me it isn't the telomere that is "flawed" it is the machinery that replicates DNA. Telomeres do their job wonderfully.

The replication proteins are only really able to work in one direction kind of like the tread on a tyre can only throw water when it is moving in one direction and not the other. The replication of the parts that are missed is a cludge that works sort of OK but definitely has room for improvement. I mean any system that is leaving off the last few hundred nucleotides (that's those TACG things... just in case ) is not as efficient as it could be.

You'll find most things in the molecular world are like this though.

And what is the correlation with different forms of life from trees to elephants to day-flies that makes their life-span different? Metabolism and/or cell structure or something?

Bare in mind once again I know absolutely nothing here, would probably do me well to google and wiki

A combination of metabolism and cell structure yes.

Regardless of the lifeform once a telomere is fully degraded cell replication will quickly cease. Research also seems to suggest that the longer an organism can maintain it's telomeres the longer it lives. The rate of degradation of the telomeres ranges from organism to organism and depends on many things. Some of which are:

1. The time between replication of cells: Cells that replicate every few hours or every few days will reduce the telomere rapidly because the telomere loses length with each replication.
2. The length of the telomere: Not all cells have telomeres of the same length.
3. The amount of the telomere lost in each replication: Not all organisms lose the same amount of telomere DNA with each replication cycle.
4. Environmental factors: When a cell's DNA is irreparably damaged by some or other environmental factor (e.g. sunlight, chemical exposures, internal regulatory processes run a mock) then the cell commits suicide through a method called apoptosis. This helps to stop badly damaged DNA from being replicated because after all who knows what would result in.
5. Enzyme activity: As Techne mentioned there is an enzyme called telomerase. Telomerase facilitates the elongation of telomeres by recreating the repetitive DNA sequence that telomeres are made up of (in vertebrates telomeres are made up of constantly repeating units of "TTAGGG" over and over again) and sticking it on the end of the chromosome. It has been demonstrated that increasing telomerase formation in mice through gene manipulation increases their lifespans by rather large percentages. (If anyone is interested just let me know and I'll see if I can find the article again). Through telomerase the organism can maintain it's telomeres for longer thus allowing cells to go on reproducing normally for longer.

1, 4, and 5 are pretty much metabolic in nature and 2 and 3 have to do with cell structure.

 

[porchrat]

A "scientific consensus" slowly being turned on its head I guess.

Yup I agree with you.

I'm sure I still see "fat-free" margarine in the stores these days. Curse marketing.

 

[Techne]

Talk of "design-flaw" and "improvement" to me always seem to imply some imaginary subjective standard (never mind a designer) with which to compare these so-called design flaws. It is not really scientific. Instead, I think it is better just to try and fully understand all the mechanisms and refrain from judging the design of a system based on incomplete knowledge. For example, the so-called "design-flaw" in the replication machinery is absolutely necessary for a fully functional immune system and absolutely vital for adaptation.

 

[porchrat]

Talk of "design-flaw" and "improvement" to me always seem to imply some imaginary subjective standard (never mind a designer) with which to compare these so-called design flaws. It is not really scientific. Instead, I think it is better just to try and fully understand all the mechanisms and refrain from judging the design of a system based on incomplete knowledge. For example, the so-called "design-flaw" in the replication machinery is absolutely necessary for a fully functional immune system and absolutely vital for adaptation.

The flaw that causes telomeres to shorten is not the same as the flaws you have mentioned.

 

[Techne]

I wouldn't call it a "design-flaw" though, there are too many factors that needs to be accounted for and some imaginary subjective standard with which to compare these so-called design flaws.

 

[murraybiscuit]

Yup I agree with you.

somebody take a photo

I'm sure I still see "fat-free" margarine in the stores these days. Curse marketing.

probably "trans-fat" free. i can't see how they could in any way call margarine "fat free".
the bigger sin for me is labelling high-carb items as "fat free".
you know... like a bucket of fat-free sugar

I wouldn't call it a "design-flaw" though, there are too many factors that needs to be accounted for and some imaginary subjective standard with which to compare these so-called design flaws.

perhaps "inefficient" is a better term?

 

[murraybiscuit]

anyways, nice posts in this thread, i didn't know about telomeres, and that part about antioxidants is interesting.

 

[porchrat]

I wouldn't call it a "design-flaw" though, there are too many factors that needs to be accounted for and some imaginary subjective standard with which to compare these so-called design flaws.

I also agree with that. I was just saying that I suppose you could call it a design flaw. Not that it actually was one. I don't like the imagery it conjures anymore than you do.

somebody take a photo

LOL it happened again! Take another photo!

probably "trans-fat" free. i can't see how they could in any way call margarine "fat free".
the bigger sin for me is labelling high-carb items as "fat free".
you know... like a bucket of fat-free sugar

Supermarkets used to sell margarine marketed as "fat-free". All it was was fats formulated so that they are not absorbed by our digestive tract. So when you consume it you don't get an fat from it. The problem is it isn't fat-free... it is a lump of fat. There was a court case about it in the States if I recall correctly.

perhaps "inefficient" is a better term?

Even that is perhaps not correct. This anomaly/phenomena call it what you will happens because those little chunks that are created when replicating the left-over unreplicated part are actually RNA. The proteins required to translate the RNA into DNA only function when they have a chunk of DNA to grab hold of after the RNA piece. At the end of the chromosome there is no more DNA to grab hold of so that piece of RNA is never translated into DNA and incorporated into the new DNA strand.

While it doesn't appear to have any real regulatory function and doesn't really occur outside of this one scenario that we can see it may still be vital to our existence. We just don't know. It might be perfectly efficient and changing it could be disastrous

 

[Jonny Two Shoes]

I wouldn't call it a "design-flaw" though, there are too many factors that needs to be accounted for and some imaginary subjective standard with which to compare these so-called design flaws.

Sorry for my lack of a better term I guess. Perhaps I should say rather a "hindrance as a result of" sort of thing rather than a "flaw", hmmm that also seems wrong :/ . Lets just call it a thing that happens I will have to get back to you on those other terms you mentioned, should be worth a read thanks.

 

[Sherbang]

Don't have much to add here but it's interesting topic, thanks! Aging is still a mystery really, but this is a page: http://en.wikipedia.org/wiki/Evolution_of_ageing

Modern genetics science has disclosed a possible problem with the mutation accumulation concept in that it is now known that genes are typically expressed in specific tissues at specific times (see regulation of gene expression). Expression is controlled by some genetic "program" that activates different genes at different times in the normal growth, development, and day-to-day life of the organism. Defects in genes cause problems (genetic diseases) when they are not properly expressed when required. A problem late in life suggests that the genetic program called for expression of a gene only in late life and the mutational defect prevented proper expression. This implies existence of a program that called for different gene expression at that point in life. Why, given Medawar's concept, would there exist genes only needed in late life or a program that called for different expression only in late life? The maintenance mechanism theory (discussed below) avoids this problem.

Also
http://en.wikipedia.org/wiki/List_of_life_extension-related_topics