Why aren't we 200,000 years old when we're born?

The causes of aging (gerontology) has been a very active research area lately with a great deal of theoretical and experimental progress in elucidating several contributing causes at the molecular level, although the work is still in an early stage and no remedies are near ready for clinical application. While all these causes probably make some contribution to the aging process, the one that most researchers seam to favor as the major contributor is chemical disruption of the mitochondrial genome due to the corrosive effect of reactive oxygen species ROS.Don't freak out just yet. I'll try to explain some of this before I get to my question. The mitochondria are small organelles that we have in each of our cells and their primary function is to process sugar to produce energy for all of the other cellular processes. These organelles have their own genome consisting of several copies of a circular DNA molecule that codes for 13 proteins and 24 RNA molecules. The process of producing high energy ATP molecules from sugar that the mitochondria carry out involves several very reactive chemical intermediaries that slowly degrade the mitochondria 'innards' including its genome. The mitochondria are constantly reproducing and dying out, and when the cell they are in duplicates to make new cells, it doubles the number of its mitochondria to supply both cells. The DNA errors mentioned above are propagated to the new mitochondria and cells. There is strong experimental evidence that this continuous propagated degradation over the years is the major cause of aging. We get old because our mitochondria get old.On to my question. We get our mitochondria from our mothers. All the mitochondria in all the cells of our entire body are descendants of the mitochondria that were in the egg cell in our mothers ovaries before it was even fertilized. Our fathers sperm did not contribute any mitochondria. Each of our mothers produced the 200,000 to 300,000 eggs that she has in her ovaries during that last stages of her gestation, i. e., during the last couple of months that she was in her mother's (grandma's) womb. Female mammals are born with all their eggs already produced and waiting in the ovaries until the female reaches sexual maturity. (This has some fascinating implications for divine conceptions, but thats outside the scope of this thread.) Those eggs in her ovaries are of course derived from the fertilized egg that produced her in her mother's womb, so that all of our mitochondria also come from our maternal grandmother, and so on back to some first female homo sapien.Now I really am getting to my question. Since we are typically born when our mothers are about 20 years old, and that egg with its original load of mitochondria has been sitting patiently in mama's ovary for that twenty years, why aren't these mitochondria 20 years old with 20 years of ROS induced degradation? In fact, these mitochondria were reproduced from some of grandmas already 20 year old mitochondria, which were produced from some of great grand-mama's....etc, etc. I. e., this long chain of females - about 10,000 in homo sapiens 200,000 year history, has been reproducing mitochondria for all that time and just passing them from body to body. Before conception, the eggs really aren't doing too much and probably are not very chemically active, but they are alive and must be undergoing some level of metabolism, so their mitochondria must be active and producing some level of ROSs. So, why aren't we 200,000 years old when we are born? (or at least a lot more aged and decrepit that a new born baby?)Is there some sort of mitochondria genome resetting mechanism, and if so, can this be exploited to ameliorate aging? Or is there something I just don't understand about the reproductive process? (My wife votes for the second option.)Regards, AnInGe--------------------------------I've heard that the downside of immortality is that the second trillion years can drag on a bit.

Thread moved here from the Proposed New Topics forum.

Warning - I'm not a biologist, so I might have this wrong.It is my understanding that when cells replicate (mitosis), there is some shortening of the telomeres. According to some theories, this is related to aging. The telomeres are sections of DNA at the ends of chromosomes.As far as I know, mitochondrial DNA does not have telomeres, so there is no mitochondrial aging that is analogous to cell aging.In sexual reproduction, the DNA replication is done with meiosis rather than mitosis, and the meiosis repairs the telomeres and thereby rejuvenates them.

well . . .
let's look at bacteria.In order to increase in population, they split into two. (not that this is the purpose--the cell's just too big).It takes twenty minutes before the split. Is each daughter cell then 20 minutes old? No.Mitochondria are essentially bacteria. So methinks that their age is reset when they split inside the cell.Don't know though.

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Very interesting question. Off course, the short answer is that I don't know.(Ask wounded King, he might know). But I want to venture an answer anyways. As kuresu pointed out, mitocondria are simmilar to bacteria, so we should be asking how do bacteria survive the acumulation of genetic mistakes over time. May be the few lucky ones that did not get their genome in a sorrow state outcompete the other ones. May be during the fast cell duplication that happens between the egg stage and the baby stage calls for a faster reproduction rate of mitocondria. fat enough that only the best fit mitocondria are able to keep up, that way rejuvenating the mitocondria population. That's off couse just an idea. I'll be coming back to that thread to see what else comes up.Edited by fallacycop, : typo

Well, not quite. Its true that the mitochondria are very similar to bacteria, hence the endosymbiosis theory of how they were first acquired by complex cells. In particular, their DNA is circular as in most bacteria and does not have telomeres at the ends (no ends). The telemeters in the cells of eukaryotes (cells with their chromosomes in a nuclear membrane and critters made up of such cells, like us) do shorten with each division, which limits the number of divisions they can undergo to about 40. Except for stem cells, which regenerate their telemeres making them 'immortal', which is one of the reasons they are of such interest. However, that is not at all the type of damage that is caused by ROS and is of interest in the aging process. This type of damage is most generally point mutations of protein and RNA encoding DNA caused by the chemical insults of those highly reactive ions. (I love this terminology - 'insults' - commonly used in the professional literature. It conjures up all kinds of amusing images.) Its worth noting at this point of our discussion that this is what the 'Anti-Oxidant' business is all about and why we down vitamin E tablets and Dr. Putzyanker's rejuvenation pills: to neutralize those oxidizing radicals (or rascals if you prefer) in our mitochondria.I also am not a biologist, so I am in part looking for someone with the right credentials and knowledge to validate or correct what I have been describing.As an aside, the telomere replacement thing is also of great interest in cancer research, since the enzyme process that maintains telomere length in stem cells but is inactivated in other cells seams to become reactivated in many types of cancer cells, allowing them to replicate without limit; to become 'immortalized'.

Bacteria average about four million base pair in their chromosomes (our mitochondria have only about 16,500 base pairs in their chromosome and rely on the cell nuclear chromosome to provide most of the proteins they need). As I have explained in a post in another thread (sorry, I'm just too damn lazy to look up and provide a link but will do so if you are interested and can't find it.), the mutational error rate is very roughly one in 400 million base pairs as a result of cell division. Thus the bacteria will suffer about one mutation every 100 divisions.So, yes, the daughter cells of such a division will usually have chromosomes identical to the initiating cell and can not be said to age. But if you start with one bacterial cell in a petri dish, after a couple of days it will have grown into billions of bacteria that differ by many base pairs. Genomes are actually highly tolerant to having a large number of such point defects, and these differences do not even constitute different strains: the bacteria will still be metabolically identical. So, chromosomally, the bacterial colony does age, but metabolically it doesn't. This is referred to as genetic drift, but I like the term genomic diffusion as presenting a more accurate image. What I just said isn't exactly true. Occasionally, some of those mutations will lead to new strains, which is what evolution is all about. This diffuse cloud of genomes is what allows the bacterial population to adjust to a changing environment. There is a good chance that some, perhaps tiny, component of that diverse cloud will have the right stuff to survive in the new environment.So now back to our mitochondria. The human cellular environment has not changed in 200,000 years. In an individual human, this diffusion of the mitochondrial genomic cloud is (believed to be) ultimately detrimental and a major contributer to aging. However, The mitochondria that have been passed down through 10,000 generations of mothers appears to not have diffused, since babies are not born senile. So, your last statement: "So methinks that their age is reset when they split inside the cell." is really just restating my question. What is the mechanism for this resetting and can it be exploited to curtail aging?

In addition to the 9 months from egg to baby we also have the 20 years that the egg just hangs around the ovary waiting for its cue to go on stage. Perhaps this is a time of some sort of dormancy and mitochondrial action is too limited to cause the kind of damage I described. I don't know. But even if this is part of the explaination, the 9 month gestation period is certainly not dormant and their have been 10,000 such gestations periods in sequence from the first human mother to you and me. Thats about 7,500 years worth of active mitochondrial life with the reactive oxide species (ROS) degradation I described in my OP. Why hasn't this 7,500 years of mitochondrial duplication not led to senility in new borns when 75 years of such mitochondrial life in a single individual does?

Interesting. As far as I know, children of older women have statistically more problems and disfunctions as childrens of younger ones. Is it due of "aging" of eggs in ovaries, or decreased ability of older women nurture childs in placenta? In first case it somehow can corroborate theory, that mitochondrias in eggs aged during dormancy too but somehow reset themsleves (even I would prefer "something" reset them) during duplication in gestation activity.

Well to some extent this is the case, after all that is why the rate of mutation in mtDNA is higher and gives better resolution for molecular phylogenetics. On the other hand the assumption that because a mitochondrion has, in theory at least, been sitting in an arrested oocyte fo 20 years it has therefore accumulated 20 years of mtDNA mutations at the same rate as in an equivalently old somatic cell is as you yourself suggest a somewhat naive one.A further consideration is that as a stochastic phenomena the distribution of mtDNA mutations will vary between different oocytes and between mitochondria within an oocyte. Consequently there is considerable potential for selection occurring at various stages of oocyte and emryonic development which may remove metabolically compromised mitochondria from the mitochondrial genetic pool (Barritt et al., 1999). The Barritt study also found no increase in rearrangement freuqency in either oocytes or embryos with age.TTFN,WKEdited by Wounded King, : No reason given.

Wounded King: Thank you greatly! This reference is spot on for addressing my question. Perhaps in the future when I have such a question, instead of googling I will first try woundedkinging (wookiing?). I will have to study Barritt et al's paper and some of their references is some detail to get my brain wrapped around what they are saying and to exactly what degree it answers my question, but two key points stand out immediately:1) Here they are referring to the age of the human mother, up to 50 years, and infer that between the time of the eggs creation in the mother and the time the egg is fertilized to become an embryo, no mitochondrial degeneration occurs. During this time the egg is in an arrested state, so that this is probably not surprising, but I am curious to know if there is any chemical activity occurring during this arrested state or is the egg totally dormant like a plant spore.2) This is the most pertinent finding and suggests that there is a strong selection process for embryos with 'good' DNA. This selection process could occur when the oocyte is released from the ovarian wall, when fertilization occurs, or in allowing or not allowing embryo development to occur, or all of the above. Since Barritt used eggs that had been extracted for IVF and were fertilized and raised to embryos in test tubes, they could not check for further selection by uterine wall cells that strongly interact with developing fetuses.It is known that in mammals roughly two thirds of fertilized eggs that implant in the uterine wall are spontaneously aborted, usually in the very early stages of pregnancy. For example, in the US there are in very approximate numbers about 14 million conceptions a year but only 4 million of these go to completion with a live birth. Of the 10 million failed pregnancies, 1.5 million are artificially induced (the woman gets a clinical abortion) and 8.5 million abort naturally. This might be an interesting issue to bring up in one of the abortion threads since it implies that nature is a rather avid abortionist. But here it implies that chemical mechanisms exist to identify variant embryos and to dispose of them.To summarize point 2 using my genomic diffusion cloud picture, the center of that cloud corresponds to cells whose DNA is pristine or only insignificant altered, and only eggs from that center are selected for progression to mature adults. This would seem to dash my hopes for a mechanism that could be used to forestall aging in mature animals (like me), since I don't see how the duplication of somatic cells could be adjusted to just save a tiny fraction of the duplicates while discarding the vast majority. It would still be interesting to understand the precise biochemical mechanism by which the 'good' cells are recognized and selected.Again, my thanks for helping me with this question that has perplexed me for quite some time. I am curious as to how you came to the Barritt reference. Did you google, and if so what key words did you use, or were you already familiar with work in this field.Regards, AnInGe

For scientific literature on a subject I always start off trying pubmed. I can't remember quite what search terms I used but it was something like 'oocyte mitochondrial mutation'. I can't find that actual paper in the list that search turns up, but there are several other papers by the same authors which have links to that paper in the 'related links' menu.TTFN,WK

Yes, it is a very good question.I'm currently starting on a MSc thesis on this subject, only not with humans (they age too slow). Instead, I'm working with fungi, in particular with Podospora anserina. It's quite remarkable that there is a fungus to experiment with, as fungi don't normally age. Give them enough resources and they could live for hundreds or even thousands of years. However this one, P. anserina, lives on herbivore dung and doesn't have a long lifespan in nature before it releases its (sexual) spores. However if you grow it in laboratory conditions, they stop growing and wither after a week or a month, even if it has enough resources.So naturally, it is quite an interesting subject for doing research on aging on it. If you grow a mycelium out of an ascospore (a sexual spore) and let it grow for a few days, collect a bit of mycelium and put it on a new plate, it will grow with a normal lifespan. If you wait for more than a few days, say a week, then the new mycelium will only grow for a short period, about the same period as the original mycelium. So apparently at some time somewhere an irreversible process
of aging starts and it carries over to new cells.However, when it crosses with another strain (or itself), then the new spores will grow with a normal lifespan, as if the clock had reset itself somehow. How this happens, I have no idea, and probably nobody else has. Problem is we're not exactly sure what causes aging, so we need to figure out that first before we can look for a process that reverses it (although I'm very curious at what it is).As what causes aging in P. anserina, we have some ideas but still not a complete picture. Mitochondria (almost) certainly play a large role, and ROS is also a factor, but we have a lot of correlations but not much causative relations. There's a whole project with various European universities working on it, but I hope I can shed a small ray of light on it.I've only started my thesis this week, with a lot of reading, so I can't give you much information right now, but if you have any further questions I'd be happy to answer them as much as I can.

The egg cell that became me was as old as my mum until it (presumeably) died. The same goes for its mitochondria. When it divided, its m did likewise, producing 2 new cells containing new mitochondrial bacteria. New replaces old. Then new becomes old. If your scenario were true, babies with older mums would be older babies - but the chaotic processes that apply statistically to large bodies of cells can only start working after the zygote has started dividing.(ps i'm yet another non-biologist)

i dunno. i haven't looked at (yeast) mitochondrion since like. freshman year of college.but. i'd be interested to hear what implications you think it has for divine conception. i'll have to wait, i know. *sigh*