Please note that I do know that aspects of this idea have been under discussion for years, in various places. But at least some of what is written here was independently thought up by myself.
At the end of each strand of DNA is an "end cap" called a "telomere". The main feature of a telomere is that it contains a number of repetitions of a particular sequence of base-pairs. The process of cell-division involves, as you know, copying all the data from existing DNA strands to new DNA strands. However, the actual mechanism for doing that copying is imperfect, and can't QUITE copy all the duplicate stuff in the telomeres. This is OK, because that is what the telomers are FOR! They exist to be partially sacrificed during cell-division, so that all the critical genetic code BETWEEN the end-cap telomeres is completely copied.
Well, in single-celled creatures, after cell division occurs, a certain enzyme, known as "telomerase", is produced that causes certain cellular machinery to get into action, to add some new duplicate base-pairs to the ends of the telomeres, replacing the portion lost during cell-division. Thus the final result is a cell that is as identical as possible to the parent cell, before division occurred. It is practically impossible to declare that one particular cell, that resulted from the division, IS the parent cell, while the other cell is simply "offspring". BOTH are offspring, and yet both are equal to the parent cell. Single-celled creatures are considered to be immortal, as a consequence.
Now, it happens that in multicellular animals, telomerase generally is NOT produced after cell-division. Each animal starts out with an initial length of telomeres at the ends of its strands of DNA, and after some number of cell-divisions, that length shrinks to the point of worthlessness. A cell usually stops dividing, grows old, and dies. Eventually the whole multicellular animal dies too, of course -- including humans.
There are two main exceptions. First, in the reproductive organs, cells are "singled out" to produce telomerase, to rebuild their telomeres, and to then divide into 4 half-cells, which become the sperm and egg cells necessary for the next generation. (I may have the details slightly mixed up, but the general notion is correct.) At least one genetic disease ("progeria", I think its called) is associated with the failure of the parent reproductive cells to rebuild the telomeres. Human children suffering from that disease usually die by age 12, of old age -- and LOOK old, too.
The second exception is called "cancer". Cancerous cells grow and divide, alarmingly continuously, practically forever -- and they can do that because cancerous cells do indeed produce the telomerase needed to rebuild telomeres after cell-division.
Because of the association of telomerase with cancer, there is/was considerable concern whether or not cancer can be caused by introducing telomerase into an ordinary multicellular organism. The experiments that I've read about, however, so far indicate that various test-animals have successfully rebuilt telomeres, restarted cell division, and become more youthful, WITHOUT developing cancer. I'm sure lots of other experiments are going on, about which I've heard nothing, so I won't claim that the final verdict on the matter is in.
With most of the background information now presented, only a little remains. Telomerase is one of those delicate enzymes that cannot be put into a pill and swallowed -- the digestive system will destroy it before it enters the bloodstream. However, telomerase is a natural cellular product, and cells are, individually, purely stimulus/response mechanisms....
Simply BECAUSE the production of telomerase by a cell can be turned on and off, there MUST exist a trigger-signal (maybe two, but an OFF signal is only needed if the ON signal is not time-limited). I will refer to that trigger as "Telomerase Production Hormone", because hormones are a general category of substances that a multicellular animal normally uses to tell specific parts of its body to begin producing various proteins (such as enzymes) for various purposes.
Immediately there is a bit of a conundrum involved here, because in Nature telomerase is an INTERNAL enzyme. INSIDE a cell is where ALL the production-triggers are located, with respect to the normal workings of telomerase. Inside the cell something triggers something that triggers something ... that triggers production of telomerase, which in turn triggers the rebuilding of the telomeres.
Nevertheless, telomerase itself, when located OUTSIDE a cell, can enter the cell and immediately begin triggering the rebuilding of telomeres. This implies that among all those OTHER triggers, we should be able to find something (which we can CALL, even if it isn't really, "Telomerase Production Hormone") that can also enter the cell, and set the process in motion. Depending on just how many triggers there are in the chain, we may even be able to find something we can put in a pill.-- Vernon, Aug 17 2001 Telomerase and Cancer http://www.findarti...74/p1/article.jhtmlRelevant to preceding, dated 1999 [Vernon, Aug 17 2001, last modified Oct 06 2004] General telomerase stuff https://web.archive...omere/telomere.htmlRelevant to annotations, page last updated 1998 [Vernon, Aug 17 2001, last modified May 11 2015] Site devoted to Aging research http://www.arclab.org/Last reference to telomerase dated 1999 [Vernon, Aug 17 2001, last modified Oct 06 2004] Following genetic expression to the end of the trail http://www.ncbi.nlm...71398&dopt=AbstractOn the way to regenerative medicine [reensure, Aug 17 2001] Alternative Recipe for Illmortality Now http://www.illumatron.com/Resources for immortality via human cloning. [Qualien, Aug 17 2001, last modified Oct 06 2004] metformin http://www.lef.org/...tml?GO.X=9\&GO.Y=10Diabetes drug that increases mouse life span by 20% [pluterday, Oct 04 2004] A current researcher! http://mcb.berkeley...y/BMB/collinsk.htmlWell, well, various people are still studying it, and publishing. [Vernon, Oct 04 2004] US Patent 6,686,159 http://patft.uspto....86159&RS=PN/6686159Thanks, [acgt]! [Vernon, Oct 04 2004, last modified Oct 18 2006] metformin http://www.lef.org/...tml?GO.X=9/&GO.Y=10Diabetes drug that increases mouse life span by 20% [pluterday]A current researcher! http://mcb.berkeley...y/BMB/collinsk.htmlWell, well, various people are still studying it, and publishing. [Vernon, Oct 06 2004] Some recent research http://www.wpi.edu/...stricted/hirsch.pdfSomebody seems to be looking for an easy way to extend telomeres. [Vernon, Dec 10 2008] Relevent http://www.methusel...n.org/why_end_aging [Voice, Dec 14 2008] Ready to be baked? http://nextbigfutur...of-human-cells.htmlNote this progress, in spite of lack of tiny details about how to cause a cell to produce telomerase for internal use. [Vernon, Apr 07 2010] More Progress! http://www.nature.c.../news.2010.635.htmlMice get rejuvinated! [Vernon, Nov 29 2010] SENS http://sens.org/sen...rch-themes/oncosensControversial new strategy actually advocates getting rid of telomerase altogether and replenishing aging tissues. [DrWorm, Nov 30 2010] Testicular cancer incidence citation http://info.cancerr...s/testis/incidence/"Testicular cancer ... is the most common cancer in men aged 15-44 years." [Loris, Dec 01 2010] Worm power http://www.nottingh...ms-defy-ageing.aspxIf you go back along the evolutionary tree far enough, you will find that a variety of flatworm is an ancestor. The flatworms described in this link are using telomerase to keep their telomeres an appropriate length for long long lifespans. [Vernon, Feb 28 2012] The latest news as of May 2012 http://www.scienced...05/120514204050.htmNow, what is a mad scientist supposed to say to his detractors? DON'T take that! (because I will, and thus I'll outlive you!) Mwoo hoo hoo heh heh heh ha ha hah! [Vernon, May 16 2012] uh, yeah!
Your TPH is probably custard.-- quarterbaker, Aug 17 2001 waugsqueke, I agree. I HAVE noticed that the popular literature these days is almost suspiciously empty of any and all references to telomerase, so sometimes I wonder if the key hasn't already been found, and good old "they" don't want you to know. On the other hand, I haven't looked on the Web lately for any recent results....
Anyway, one of the things I was trying to point out here IS related to that "Better Dentition" post. With respect to telomerase, we need to learn more about existing genetic machinery. With respect to growing new teeth, we need to learn more about existing genetic machinery. This is NOT WIBNI stuff, especially since once we know the design of the NATURAL substance/key/trigger/hormone, we can use existing technology to tinker.
If, for example, all the triggers in the telomerase sequence involve delicate compounds, that can't be put into a pill, THEN we would begin studying exactly how those compounds are physically structured. In biochemistry, just about everything involves physical shapes interacting, even while chemicals also interact. HOW MUCH of the SHAPE of telomerase is really needed to trigger rebuilding of telomeres? HOW MUCH of the shape of any prior trigger is really needed? We can CRAFT molecules to desired shapes these days...and we can make those crafted molecules tough enough to survive digestion, too.-- Vernon, Aug 17 2001 There is an unusual degree of conservation between species for the telomere; its simple nucleotide order is identical in most species. The task of charging a cell with an expressive gene for the purpose of activating c-fos pathways or some other developmental tract seems easy. Most yeast artificial chromosomes owe their stability to the telomere acquired during cloning. Anti-aging researchers are speculating that the biological clock <grail> keeps time by telomere length reduction, and this may be true. Is a cell's loss of telomerase production the beginning of its demise? What of the concept of the cell as a system with multiple and potentially alternative pathways for development or expression--I've linked to one that is becoming better known, the GLI (a segment polarity gene) pathway to complete normal accurately expressed development.
The addition of telomerase to a cell will likely require a correctly expressed cell surface receptor, similar to steroid or ILGF receptors. You might otherwise need to design RNA that expresses its own receptor, substrate and antisense-- reensure, Aug 17 2001 This technology would be inferior to simply cloning (via nuclear transfer) yourself as a means to immortality.
As a result of years of jogging on hard surfaces, I have painful heel spurs. There is no reliable way to cure them. I can't jog anymore. Most people acquire these kinds of conditions as they age, and many are untreatable and incurable. I am fifty-three. What kinds of conditions could I expect my body to be beset by at the age of a hundred and fifty three? I already have a lot of crowns and fillings on and in my teeth, what shape will they be in in fifty years? Things will beset the 150-year-old which we've never even heard of now because no one keeps their body that long. Things like heel spurs, tooth problems, and so on are not necessarily related to aging but just to damage over time. I want a fresh, new body. My DNA can build me one.
In reality, I have probably already lost more than 90% of the memories I had acquired in my lifetime. What will be left of my memories of being 20 when I am 220 years old? Probably none.
I don't like the dreams I have recurringly of my childhood and youth. They are almost uniformly unpleasant. I have the same sorts of dreams of my youth which I had twenty years ago. If my aging were stopped, as a method of immortality, would I still be having those dreams a thousand years from now?
I don't want those dreams. I want new dreams.
At what point would a person stop aging? At eighteen? Twenty-five? Forty? How would you know you had chosen the best stopping time if you never experienced the later years? If you stop at age twenty-five, will you retain you biological urge to have children, forever raising successive waves of babies for eternity? And will your children do the same?
A life which never attains maturity is not a life but rather a life cut short.
A human life is a progression, characterized by development. To stop growing toward maturity is retardation, arrested development at best (it is the last thing I wanted to happen when I actually was young in years), and probably, in reality, would just be a form of death. To expect that your mind will grow toward maturity without your brain changing is foolisness.
Attaining immortality by simply stopping aging is a naive solution, it only sounds good until you really think about it.-- Qualien, Aug 18 2001 [Qualien]: // A life which never attains maturity is not a life but rather a life cut short. // clap…clap.
I have seen two disturbing cases recently that I feel deserve the full effort of the sciences in this regard. One, a victim of a mysterious infection caused by eating freshly killed bear meat that produced an irreversible quadriplegia. The other a horrible case of rheumatoid arthritis resulting from exposure to an unknown agent in the South American rain forest. Are scientists compelled to study cell processes and plan for treating these types of affilictions? I say yes. Longevity, as interesting as it is on its face, does not hold the fascination for me that it seems to for others. Maybe that will change; because, the older I get ...!-- reensure, Aug 26 2001 Qualien, I've been attempting to find the best way to disagree with you, since you wrote your annotation. I doubt that I've succeeded in finding it, so I'll say various things that I think need to be said, and hope you'll understand.
The WORST thing I wanted to say is this: When I first read what you wrote, I couldn't help thinking, "This guy is a stooge trying to cover up the telomerase breakthroughs in a 'snow job' of gobbledegook." I still wonder, but don't actively accuse you of it.
For evidence, however, there is that first line about cloning. You are somehow missing the distinction between doing something to make your DNA immortal, and doing something to make YOU immortal. A clone will not be you; it will be its own person. And we already know from Nature that all you have to do to encourage immortality of your DNA is to have a lot of offspring. Cloning is unnecessary! But to make YOU immortal, your body has to persist, not just your DNA.
So the main point of this reply is that you seem to have missed the essence of GROWTH that telomerase represents. You have spurs on your heels? With telomerase allowing cells to divide youthfully, you can have those spurs surgically removed, and you will heal just fine. Growth of new cells will ensure it! The same is true of cartilige cells, retinal cells, eyeball-lens cells, etcetera. Deterioration always sets in when cells stop dividing, and telomerase appears to be the answer to that. As for neural cells, they too are known to be able to divide, but usually don't after a certain point in Life. So deterioration of them and their capabilities is the consequence, and the solution once again is to restore their abitity to divide. Lost memories will probably remain lost, but new ones that last a longer time can probably be formed.
One aspect to Growth is that it can take place in a couple different ways. You could literally grow physically larger, for example. An advantage to that is you would gain a larger head, with room for lots more brand-new brain cells. A disadvantage is that you could only grow to 10 feet tall or so, before associated physical phenomena, like the Law of Gravity, or the Square-Cube Law, makes life precarious. But growth can be controlled; and many decades might pass before such growth becomes dangerous. By then such problems might be solved (move to Mars, maybe?), but if you don't make the effort to live to find out, you'll never have a chance to enjoy such solutions.
An alternate kind of Growth is "dynamic stability". Life in general is a dynamically stable series of a vast collection of chemical reactions. All sorts of deterioration are the results of breakdowns in the dynamic stability of Life; Growth can restore it. One does not have to give up maturity to avoid biophysical dilapidation.-- Vernon, Oct 14 2001 Does anybody know, what sort of DNA does telomerase lay down? How does it make sure it doesn't write a gene that codes for something poisonous? Does it all look the same, a predefined 'nothing pattern'?-- sadie, Apr 25 2002 sadie, telomerase doesn't create ordinary gene-coded DNA. Think about an average cassette tape, and the "leader" on each end of the tape. Ordinary DNA is like the data-holding main length of tape, while telomeres constitute the equivalent of "tape leader" -- and telomerase merely rebuilds lengths of "leader" that is lost during the imperfect cell-reproduction process.-- Vernon, Apr 25 2002 I APOLOGIZE
Someone left a message to which I wanted to reply, and somehow I wasn't paying close enough attention to the text under the link, when I clicked on Delete instead of Annotate.
Anyway, the gist of the message was something about being careful of side-effects of telomerase -- multicellular organisms stopped making it during growth, for some sort of evolutionarily sound reason, right?
Well, that certainly seems reasonable. Obviously cautious experimentation is in order. Nevertheless, it remains a fact that various cells in the body do tend to die, and replacing them is more-probably a good thing than not.
Telomerase merely ensures that accurate replacements can be produced. That "tape leader" analogy I mentioned in a prior annotation is a key notion: If some length of "leader" is lost after every cell-division, then after enough divisions, eventually actual DNA will be lost, as well. The resulting cells will by no means be as capable as before. And THAT is what telomerase can prevent.
Sure, it is normally thought that the cells that have run out of "leader" simply don't divide any more, and that may be the only thing preventing major systemic breakdown due to incomplete DNA duplication during cell-division. But as already mentioned, telomerase allows cells to rebuild their used-up telomeres (or "leader"), so that they can rejuvinate themselves via fission, rather than simply age to death.
So, as long as we avoid the "too much of a good thing is usually a bad thing" problem, I say that telomerase-production research should proceed.
Then there is the OTHER huge huge issue to tackle, should we successfuly increase lifespan by some enormous factor: What about the population explosion? That topic probably deserves its own thread here on the HalfBakery (and indeed there are a few out there already).-- Vernon, Apr 26 2002 I think the population explosion problem will be a non-issue, provided the use of any telomerase-based treatment is properly limited.
One could imagine that decreasing infant mortality rates would lead to higher populations. In fact, the opposite is true - if people (mothers) expect their children to survive they are more willing to use contraceptives.
The great benefit of telomerase isn't its extended lifespan. It's the extended youth - the slowing down of the damage that we happily call 'ageing'. If people expect to be young and fertile for longer, they'll be more willing to wait a few more years before having children.
Unless they're catholic, of course.-- sadie, Apr 26 2002 sadie, a longer reproductive period is more likely going to be true of men than of women. Women are born with a fixed number of eggs to ripen, and when they are all ripened and gone, the ovaries are empty. A woman could still be fully youthful in all respects, at age 200, but she isn't going to have any eggs left by then (probably not even by age 100, if she youthfully has regular menstrual cycles the whole time). SOME extension of a woman's fertility is likely, because I think that menopause normally tends to happen before all the ova have ripened. So a limited extension seems likely. Meanwhile guys manufacture sperm constantly, so if the guys are youthful, no matter what their age, so is their sperm.-- Vernon, Apr 26 2002 Actually, it doesn't matter if the fertile period really is longer - just that people *think* it is. If it has no effect whatsoever, that's even better, as more people will reach the end of their shelf life before they get round to reproducing. *evil grin*-- sadie, Apr 26 2002 Perhaps, sadie, perhaps. On the other hand, when women talk about their "biological clock ticking away", they are usually referring to the end of the reproductive years. A change in the definition of the last such year will not necessarily cause women to feel more carefree about the fact that their reproductive clocks are still ticking.-- Vernon, Apr 27 2002 One problem with this is that a key aspect of aging does not seem to be involved with telomerase. Many oldsters have sound bodies but become progressively demented. Brain neurons do not divide, and not because they lack telomerase.
Cancer and viral hijacking are the two big bugbears of multicellularity. There are many failsafe mechanisms to prevent a rogue cell from running amuck. Possibly we could do without telomerase and rely on the others. I'd like to see how the mice do first.-- bungston, Mar 07 2003 The recent hoopla (and lots of email spam) about Human Growth Hormone makes me wonder whether IT is one of the triggers for telomerase production... among the other things that that hormone may do.-- Vernon, May 08 2003 While waiting for the magic telomerase, I’ve started taking metformin (aka "Glucophage", used in the treatment of type II diabetes for 40 years now – see link) This has been shown, in rats, to produce similar longevity results to calorie restriction. I’ll let you know in 40 years if it works.-- pluterday, May 08 2003 I think that most people would probably be very satisfied with just having their lifespans doubled or tripled to about 200-300 years.Being immortal would get very tiring and boring after a while if you have had a chance to do everything you wanted to in life several times over and we might want to "move on" to something even more spectacular than our lives on Earth.On the other hand,it would be great to be young for a much longer period of time than we have now,especially if someone doesn't get to enjoy being young the first time around,if they had a difficult life during their youth and missed out on love or having a chance to go to university and do stuff that you need to be young to experience fully.In one of the other posts,someone raised to point of having children forever and creating overpopulation.I think that if we get to be advanced enough to stop aging,than we may be advanced enough to colonize other worlds.There are many thousands or maybe even millions of Earth like planets out there just waiting for us to explore and inhabit.Hopefully some potent anti aging breakthroughs are just around the corner,but with the lack of funding and ignorance of the topic with the public,it seems to be tediously slow!-- Lew27, Jun 14 2003 These techniques are in active development. For example see US Patent 6,686,159.-- acgt, Aug 21 2004 Your last couple of paragraphs look a bit odd to me. First, are you sure that telomerase can be taken up by cells and do its business? I'm not saying you're wrong, just that it would be very odd. Most cells won't take up proteins unless there's a specific signal on the uptaken protein (and unless the uptaking cell is the correct type); and even then, uptaken telomerase would need to be transported into the nucleus. As far as I'm aware, telomerase is not a protein you'd expect to do this.
Second, expression of telomerase is regulated by a bunch of factors. There will be various transcription factors (themselves proteins), and a whole bunch of chromatin remodelling (essentially opening up that part of the genome for business) required to activate expression. There may also be translational controls (ie, post-gene- expression). For that reason, I think the use of the term "hormone" is misleading.
It may well be possible to activate telomerase by means of a drug, but it's not going to be easy.
Having said all that, the prevention of ageing is much much easier than the prevention of cancer, because we're not trying to improve on something that evolution has already tried to do.-- MaxwellBuchanan, Dec 10 2008 Tyrell: We've already tried it. Ethyl methane sulfonate as an alkylating agent - a potent mutagen. It created a virus so lethal the subject was dead before he left the table.-- normzone, Dec 10 2008 what?-- MaxwellBuchanan, Dec 10 2008 Possibly a quotation from the film 'Blade Runner', [MB].-- pertinax, Dec 10 2008 [MaxwellBuchanan], it's been years since I wrote the main text here, and I don't recall the sources I used as a basis for it, but I'm pretty sure I had read that it had been noticed that telomerase external to a cell could enter it, all the way to the nucleus, and start extending telomeres.
The goal here is not about making telomerase outside a cell, but making something that would enter a cell and cause that cell to produce its own telomerase.
It occurred to me earlier today that perhaps one place to study, to find such a molecule, is in the testicles. Their job is to make sperm, and inside those sperm the telomeres on the DNA needs to be lengthened, lest offspring suffer from progeria. Since it is known that even fairly old men can have normal children, it must be true that telomerase has to be getting produced in the testicles, as part of the sperm-manufacturing process. So, perhaps there is a gene that is turned ON there, making telomerase, which is turned OFF in most ordinary cells, and which could be turned ON in a whole adult body after appropriate research identifies it and its activator-protein --the Telomerase Production Hormone.-- Vernon, Dec 11 2008 //perhaps there is a gene that is turned ON there, making telomerase, which is turned OFF in most ordinary cells, and which could be turned ON in a whole adult body after appropriate research identifies it and its activator-protein --the Telomerase Production Hormone.//
Well, yes, there is a gene that is turned on there - the telomerase gene. However, I don't think it's going to be straightforward to find something that you can use as a "telomerase production hormone". As you note, it will be an activator protein (a transcription factor), which is unlikely to be useable as a 'drug' (unlikely to be taken up by cells, and unlikely to get to the nucleus).
The relevant transcription factors (probably several) and the other proteins which regulate telomerase transcription are likely to be intracellular only. They will also probably be tied intimately into the whole differentiation programme for the cell. Telomerase is a potential oncogene, so it's likely that it's regulated quite robustly, and won't be easily turn-on-and-offable.
In short, it's not generally easy to use external factors to activate genes which are normally off, unless either (a) they are designed to be turned on and off in response to an external signal or (b) you turn entire programmes of differentiation on or off.-- MaxwellBuchanan, Dec 11 2008 [MaxwellBuchanan], I have yet to see any evidence that telomerase is associated with CAUSING cancer. It is of course necessarily associated with cancer in that cancer can't do its thing without telomerase, but just because a cell's DNA has had its telomeres extended, that is no reason to think the cell must divide immediately. The evidence I've seen is that telomerase is more of a clean-up-after-division substance, than a prepare-for-imminent-division substance. More evidence in favor of that interpretation involves the rate of testicular cancer; if telomerase was so dangerous that way, most men would die that way. Instead their testicals are making and therefore are exposed to the stuff for decades, and typically men die of other things than that particular variety of cancer.
Next, in the main text I thought I was clear in that while it might be nice to find a substance that can enter cells and directly cause them to make telomerase, finding something else that could cause a chain of events leading to the production of telomerase could be just as good. In that way, at least, restrictions can be bypassed on just what is allowed to enter a cell and directly affect it. I might prefer not to mimic the technique used by a virus, but, hey, if the payload inside a viral shell was Telomerase Production Hormone, instead of viral DNA, maybe that's not such a bad technique, after all.-- Vernon, Dec 11 2008 Well, yes. The only snag is going to be activating telomerase transcription without the re-differentiation that would normally be necessary. In other words, you're trying to turn on one switch which is normally turned on only as part of a much more extensive reprogramming of the cell.
Re cancer - it's generally believed that most cancers go through a gradual process of accumulating favourable mutations, going through successive stages of dysplasia and dysregulation. Probably a lot of potential cancers get snuffed out because they run out telomeres before they acquire telomerase activity, so you run the risk of activating or rescuing those.
But, telomerase activation is certainly one line of anti- ageing research. Personally, I'd work on mitochondria first, though.-- MaxwellBuchanan, Dec 11 2008 // I have yet to see any evidence that telomerase is associated with CAUSING cancer.//
You mean apart from the fact that cancer cells express telomerase?
Division of cells in a multicellular organism is tightly regulated. Cancer formation isn't a single event. It's a series of events by which a cell loses the checks and balances which limit its division. If you go off activating telomerase in every cell in the body, you've just removed one of those checks.
Incidentally, even though there may well be more checks in sperm production, the rate of testicular cancer is apparently 1 in 250. With an average total volume of 36cm^3, they represent about 36/70000 ~= 1/2000 of the average male body (70 kilo man of density about 1g/cm^3). So the risk of cancer is quite high relative to their proportion of the body.-- Loris, Dec 11 2008 [MaxwellBuchanan], mitochondria have DNA and telomeres, too....
[Loris], you ignored what I wrote: "[Telomerase] is of course necessarily associated with cancer in that cancer can't do its thing without telomerase, but just because a cell's DNA has had its telomeres extended, that is no reason to think the cell must divide immediately." In other words, the fact that a cancer cell can make telomerase is not automatically the reason why it is a cancer cell.
Next, you are ignoring the fact that in any newborn the telomeres are reasonably longer than in adults, while it is adults that get cancer more often than newborns (and what about cancer rates during fetal development, with furious-cell-division going on, and even-longer-telomeres present?). Why, therefore, should an extension of telomeres from adult-shortness to somewhat-longer be associated with CAUSING cancer?
Finally, what about the rate of testicular cancer before the Industrial Revolution started polluting everything? Probably not much data available, but again the point is that for telomerase to be accused of causing cancer is, so far as the evidence shows, just scaremongering.-- Vernon, Dec 11 2008 Vernon, the mitochondrial genome is circular and has no telomeres. It has its own problems, though.-- MaxwellBuchanan, Dec 11 2008 [MaxwellBuchanan], OK, thanks, I didn't know that the DNA in mitochoncria was circular. I knew that it was once its own separate organism, and many bacteria have circular DNA, but the two didn't connect in my mind. My bad.-- Vernon, Dec 12 2008 // who wants to be immortal? // I would like to be immortal until such time as I may choose otherwise.-- MaxwellBuchanan, Dec 12 2008 Vernon, I read what you wrote. You seem to have missed my point - there is (usually) no one cause of cancer. Cancers are the product of several steps, each of which moves the cell along the path to out-of-control replication.
Because of this multi-step pathway, many cancers take a long time to develop. An old person may well have several small pre-cancerous growths in their body. Suppose that these may be limited by reaching the end of their division ability. Add telomerase, and they will become cancerous.
That's not to say that children (and babies) don't get cancers. They're from different cell types to what adult cancers are mainly derived from - leukemia, for example, is from white blood cells. Unsurprisingly, this type of cell is differentiated with the potential for rapid growth and division.-- Loris, Dec 12 2008 "Add telomerase, and they will become cancerous." [Loris], that is not sufficiently logical. Telomerase would extend their telomeres and give them the ability to do some dividing, but they won't truly be cancerous until they can manufacture their own telomerase. There is no data suggesting that telomerase in a cell begets more telomerase.-- Vernon, Dec 13 2008 Hmm. Transient and reversible activation of telomerase would certainly be safer than irreversible activation.
However, the danger remains. Cancer cells (as Loris and I have pointed out) evolve. They have to pass through a whole series of challenges and evolutionary bottlenecks, just like any evolving population. In most cases, the population becomes extinct before it evolves the adaptations it needs to get through the next selective round (for example, to escape the immune system or telomere exhaustion). In a very few cases, a lucky cell acquires the necessary mutations to get through each bottleneck, and the result is cancer.
If you add telomerase, then you will rescue a population of precancerous cells which otherwise would have become extinct. They will then be able to go through many more divisions before their telomeres are once again exhausted. During these additional divisions, they have many more chances to acquire the mutation that allows them to produce telomerase, and hence to become "independently cancerous", so to speak.
So, adding telomerase will effectively rejuvenate many pre-cancerous lesions, giving them a greater opportunity to progress to cancer. It's a risk, and possibly a large risk. The truth is that we don't know how many pre-cancers are obliterated through lack of telomeres, and how many of these would survive and become cancerous if they were rescued by telomerase.-- MaxwellBuchanan, Dec 13 2008 In some ways it doesn't matter whether the treatment leads to temporary or permanent telomerase expression. Telomerase reverse transcriptase is bound to be regulated by the overall length of the telomere somehow. If it were not, telomeres would either lengthen or shorten with each organism generation.
If reeastablishing telomeres resets them back to the germ-cell level then a precancerous cell would have the theoretical ability to generate at least as many cells as are in an adult human. (My calculations indicate that this is around 43 divisions.) In practice many times more - because the cell lineages are not symmetrical, and also many, many cells die during a lifetime. A cancer doesn't need that much material to kill the patient (In societies with the medical ability to remove lumps, metastasis is often involved).
I suppose you could, after some genetic tinkering, settle on a 'useful' number of further divisions. But that would need genetic material to be inserted into the cell, so doesn't fit with your 'hormone' strategy. (I'm siding with MaxB regarding telomerase not blindly leaking through cell membranes. For all I know it may be transferred into sperm precursor cells from the nurse cells, but that's by-the-by.) And of course, the process would then need to be repeated when those divisions ran out.
You should notice that I'm not saying that it's a bad idea to think about repairing telomeres. Just that cancer may be a risk of the treatment. There probably isn't any need to treat the whole organism, just those organs which need constant cell division.-- Loris, Dec 13 2008 [MaxwellBuchanan and Loris], thank you. Now I ask you to re-read the subtitle of this Idea, which has always had "a key" in it. It is possible that the only other key needed is a generic cancer-prevention method.-- Vernon, Dec 13 2008 //It is possible that the only other key needed is a generic cancer-prevention method.//
You post that and I'll m-f-d it for magic.-- Loris, Dec 13 2008 [Loris], heh, it depends. I understand they once found a compound that does wonders at killing all sorts of mouse tumors, but is useless in humans. The IMPLICATION is that a similarly-effective compound for human tumors should be able to exist....
That's not cancer-prevention, of course, but I think I could accept, should it manifest, winning the battle all the time. :)-- Vernon, Dec 14 2008 It’s perfectly okay to cure cancer, or Alzheimer’s disease, or heart diseases. When the time comes to look at the aggregate solutions and realize that they add up to the end of aging, people become frightened.
Here is this evil thing that has always been inevitable. And because of its erstwhile inevitability we've all build up excuse after excuse as to why it’s okay. And suddenly it doesn't have to happen. It takes a good deal of courage to lay aside those excuses.
If you think it’s a good idea for people to die, start with yourself! When you're 90 and healthy will you say goodbye and take a pill "because its nature's way"? When you're 110 and healthy will you shoot yourself to stop overpopulation? Then you're 120 and playing tennis will you lay down your racket, declare that it’s the next generation's turn, and jump in front of a car?
When the phrases "he had his whole life ahead of him" and "lived a good, long life" become meaningless it is no more natural to die at 90 than at 30. It is not better for cancer to kill an old man than a young boy.
Death is NEVER a good thing unless you are homicidal or suicidal-- Voice, Dec 15 2008 Lew27, you're serious? You can't find enough to do? I, for one, want to learn 10 languages, get doctorial degrees in 50 specialties, travel the world a thousand times, tell stories to children, make music for millions, create new dances, sculpture, and entire new art forms. I want to see the bottom of the ocean and the far side of the moon. I want to taste every varient of every flavor of every food known to man. And that doesn't scratch the surface. Do you think that before I'm through there won't be a world of new things to experience? For me life is far, far too short.-- Voice, Dec 15 2008 I recently read a book about one gerontologist who actually wants to get rid of telomerase altogether in order to eliminate cancer and fight that aspect of aging. His strategy is called SENS (strategies for engineered negligible senescence) and while I don't completely agree with it, it's certainly interesting. (linky link link)-- DrWorm, Nov 30 2010 // His strategy is called SENS (strategies for engineered negligible senescence) //
Anyone who comes up with a meaningless acronym like that is not really doing much.-- MaxwellBuchanan, Nov 30 2010 Don't know if this thread is still followed, but here is an update:
Geron Corp is continuing to develop a telomerase enhancer as an AIDS treatment. A pill based on their compound (a nutraceutical derived from astragalus) IS commercially available as the Patton Protocol, and companies are working on making a synthetic version of it, so as to sidestep the patents involved.
Limited human testing has been done with some positive results, and the compound seems to lengthen telomeres in vitro, but it is still not at all clear to me if an effective longevity product now exists or is on the horizon. I think, perhaps, that there are issues in delivery.-- MSantos, Dec 01 2010 It's an interesting field.
Seriously, ageing is not an especially difficult thing to cure. The search for eternal youth went out of fashion before molecular biology came of age, and it's only in the last 5-10 years that it's started to become respectable. Even now, though, there's a huge ambivalence over funding it.
If the same effort were put into ageing as has been put into cancer, we'd have it sorted in 20 years tops.-- MaxwellBuchanan, Dec 01 2010 Yes, [MB], but what if we were to joke about it?-- daseva, Dec 01 2010 Lengthening telomeres is not, on its own, a complete cure for aging. There's still the matter of cancer which , while not directly caused, can be made worse by lengthening the 'meres.-- DrWorm, Dec 01 2010 [DrWorm], so far as I've been able to discover, there is NO connection between the lengthening of telomeres and the causing of cancer. While it is certain that a cancer needs to lengthen telomeres in order to keep doing its thing, that is a consequence of the cell already being cancerous, not a cause.
After all, if, just because a telomere is long, a cell has an increased chance of becoming cancerous, then almost every baby ever born should be born with lots of tumors (the exceptions would be the few suffering from "progeria").
Also, if telomerase itself promoted cancer, then most males with testicles would have cancer, since the testicles are where sperm are created from cells and telomerase is used, during the manufacture of sperm, to ensure the telomeres of the DNA in the sperm are refreshed, for the next generation of offspring.-- Vernon, Dec 01 2010 I think we did those points in earlier annos. I think we did those points in earlier annos.-- MaxwellBuchanan, Dec 01 2010 //so far as I've been able to discover, there is NO connection between the lengthening of telomeres and the causing of cancer. While it is certain that a cancer needs to lengthen telomeres in order to keep doing its thing, that is a consequence of the cell already being cancerous, not a cause.//
You need to get your head round the idea of cancer development being a multi-step process.
//After all, if, just because a telomere is long, a cell has an increased chance of becoming cancerous, then almost every baby ever born should be born with lots of tumors (the exceptions would be the few suffering from "progeria").//
No. Because there are several steps required for a cell to become cancerous. At conception the created cell has long telomeres on its chromosomes, but also a whole set of genes which protect the organism against cancer forming. If a cell's genetic material is damaged, it may decide to kill itself rather than risk becoming cancerous. There is also a large amount of regulation on progression through the cell cycle (that is, cell division). However, these checks and balances can be overcome one by one until eventually, a cell line which can grow continuously evolves.
//Also, if telomerase itself promoted cancer, then most males with testicles would have cancer, since the testicles are where sperm are created from cells and telomerase is used, during the manufacture of sperm, to ensure the telomeres of the DNA in the sperm are refreshed, for the next generation of offspring.//
A man's lifetime risk of testicular cancer is apparently 0.4%, which is quite a lot given the relative size of the organ.
Consider - there are people walking around with some defect in one of their protective genes (oncogenes). These mutations increase their risk of developing cancer - typically they are prone to cancer forming in some particular tissue, depending on which gene is inactivated. They don't necessarily get cancer; they're at increased risk. The explanation is that the number of steps for cancer to evolve is reduced. Obviously human genetics is very complicated and not all that well understood - there are many genetic factors involved, and at the moment scientists are really only finding the most significant ones.-- Loris, Dec 01 2010 All of what [Loris] just said.
On the other hand, there is a company offering a treatment which activates telomerase for a finite period, allegedly restoring telomere length in one go. Thereafter, the telomeres presumably start shortening again.
This one-off treatment might not be a huge cancer risk. It will lengthen the "window" within which a precancerous cell population has to activate its telomerase before it fizzles out, but it wouldn't be as carcinogenic as constitutive telomerase activation.
[EDIT - I just checked their website, and they tell me that telomeres are made of protein. This makes me wonder if they have the faintest fuck of a clue.]-- MaxwellBuchanan, Dec 01 2010 [Loris], I'll guess that the rate of testicular cancer is more related to the fact that lots of cell-division already goes on in the testicles (to make halves of DNA, one half for each sperm), rather than because telomerase is part of the operation. Cancer is cell-division-gone-wild, not telomeres-growing-wild.
[MaxwellBuchanan], perhaps that site is a scam/snake-oil.-- Vernon, Dec 01 2010 //I'll guess that the rate of testicular cancer is more related to the fact that lots of cell-division already goes on in the testicles (to make halves of DNA, one half for each sperm), rather than because telomerase is part of the operation. Cancer is cell-division-gone-wild, not telomeres-growing-wild.//
I'm wincing at your description of DNA replication, but rapid cell division is probably at least part of it - all the rapidly growing tissues have well known cancers associated with them. But my understanding is that cancers fall into types by the originating tissue, and that this is clearly due to the differentiation of that tissue. It may be that telomerase being switched on in some cells contributes to that (I've not looked into the research). If that's the case, there may even be enhanced regulatory mechanisms aimed at preventing cancer in the testes.
Regardless, I don't think you're doing your argument any favours by pointing to a shortage of testicular cancer, when it's the most common cancer in men aged 15-44 years. (link)-- Loris, Dec 01 2010 [Loris], what I'm actually pointing out is "scare tactics". Remember that if there exists ANY way to rejuvenate people, then somebody is going to want to restrict it, because the overpopulation problem we have now will become trivial if the global annual old-age death rate suddenly becomes a trickle. That means scaring people away from trying whatever breakthrough might have been discovered --and cancer is one of the scariest things, so....
Telomerase does not cause a cell to divide. All it does is, by lengthening the telomeres, set up a condition in which if some other appropriate part of a cell is taking notice, then that part of the cell might decide to trigger a cell-division. Remember that cells usually CAN divide even after normal full growth is achieved (for example, when repairing an accidental cut), which means they have telomeres long enough to allow such divisions to occur. But they normally don't divide JUST because their telomeres are still long enough in a recently-full-grown body, since they simply don't need to. There is always some other trigger that is required for cell division to occur, in an adult body.
If cancer happens, it will be because of something associated with that other trigger. In other words, if the telomeres of a new-adult cell are still long enough to allow a cell to divide, and if they get lengthened by telomerase, exactly WHY would that make a difference, with respect to cancer?
So, while telomerase is indeed present in the testicles, doing its part in preparing usable DNA for the next generation, the real cancer-causing culprit is something else, very very probably linked to all the cell-divisions that also take place in the testicles.-- Vernon, Dec 02 2010 //If cancer happens, it will be because of something associated with that other trigger. In other words, if the telomeres of a new-adult cell are still long enough to allow a cell to divide, and if they get lengthened by telomerase, exactly WHY would that make a difference, with respect to cancer?//
Vernon, the point's been made by Loris and others. No, telomeres don't cause cell division. However, they do *allow* cell division and, if they are constitutively restored, will allow unlimited cell division.
In other words, long telomeres are not the engine that drives carcinogenesis, but short telomeres are a brake on carcinogenesis. The only cancers that get far enough to be a problem are the ones that overcome this brake by activating their telomerases.-- MaxwellBuchanan, Dec 02 2010 I fully understand the distinction, but that distinction is not being pointed out by most of those here who have put "telomerase" and "cancer" in the same text. The wordings they have chosen imply that you have to worry about GETTING cancer if you use telomerase, and that's wrong. Think about that statistic [Loris] presented, about 0.4% of men getting testicular cancer just because they have testicles manufacturing sperm --but another statistic is that about 15% of long-term smokers get lung cancer, and knowledge of this does not seem to have reduced the smoking rate all that much (not compared to the effect of increases in cigarette taxes!). Between the two statistics, I'll take telomerase, thank you!-- Vernon, Dec 02 2010 I wouldn't rely too heavily on the numbers.
You've probably got at least a few tens (probably a few hundreds) of pre-pre-cancerous cell clusters in your body at the moment. Of these, most will fizzle out. A few more will strike it lucky and get the mutations they need to become dysplastic. Of these, sooner or later one will progress further.
I don't think anyone really knows how many cancers are stopped before they even start because they lack telomerase.
Anyway, I'm basically keen on the idea of trying telomerase as an anti-ageing solution. But I would ensure that you can turn it back off once it's done its job and restored shortened telomeres.-- MaxwellBuchanan, Dec 02 2010 Would increasing telomerase expression have any effect on the tissue of the central nervous system? I was under the impression that once you enter adulthood, you don't regenerate any neurons, or that neural regenerative capability is drastically lower compared to that during childhood.
If the telomerase gene was "turned on" in these tissues, would that still prevent senility which often accompanies old age?-- Cuit_au_Four, Dec 04 2010 [Cuit_au_Four], telomerase is not a trigger for cell-division. All it does is prepare one of the things that is necessary for a cell to be able to divide. So, something else must still be present to actually initiate cell-division.
That said, I do think I have encountered some evidence in recent years that at least some neurons CAN divide after adulthood. Personally, I suspect the low rate of neural cell-division after adulthood is reached has nothing to do with telomeres, and is related to a completely different factor: memory. See, a memory is stored in a manner related to the CONNECTIONS between various neurons. Suppose one of them divides? The pattern of connections will be altered, and the memory could be corrupted!
So, more research needs to be done before we can expect telomerase to benefit brain cells.-- Vernon, Dec 04 2010 The largest non genetic lifespan increaser i have heard of this month could use corraborating studies
pubmed has a record where ip mouse placenta makes mice live 1.7 times longer http://tinyurl.com/3esjygd
I suggest veterinarians start using this on dairy cows where notably longer lifespan would have a highly valued benefit whilst also verifying the technology. If I had kids I would gladly give them their own placentas IP to give them multicentury lifespan.-- beanangel, Jun 16 2011 //If I had kids I would gladly give them their own placentas IP//-- MaxwellBuchanan, May 16 2012 it would be easier to give mouse placentas IP as they are smaller, plus there are more of them.-- bungston, May 16 2012 // Well, in single-celled creatures, after cell division occurs, a certain enzyme, known as "telomerase", is produced that causes certain cellular machinery to get into action, to add some new duplicate base-pairs to the ends of the telomeres, replacing the portion lost during cell-division // This is, with a few exceptions, incorrect. Most (possibly all) “immortal” single-celled organisms have circular chromosomes, so have no telomeres, and thus need and have no mechanism for producing telomerase. Not an important detail unless you’re thinking of using a bacterial “factory” to manufacture telomerase.
In the late 1980s, there was a lot of excitement about possibly extending human lifespans via “telomere therapy”, and lots of fruitful research about “gene therapy” to activate the genes that produce telomerase, including some that extended mouse lifespans by about 25%. Since then, though, it’s become clear that there are many more cell and whole-body senility factors than just the Hayflick limit, so telomere therapy is no longer thought to be a possible “silver bullet” immortality therapy.-- CraigD, May 11 2015 At the cell membrane there is active and passive transport of molecules. Membrane transport molecules linked to telomerase could cause possibly orders of magnitude more telomerase getting to cells from the circulatory system. Also, if you think of 20 different amino acid or protein specific membrane transport channels then you could attach telomerase with an enzymatically degradeable linker to each of those 20 different molecules and cause 20 times more cytoplasm concentration and 20 times higher concentrations from a plural molecule telomerase drug.
Once at the cytoplasm, enzymes at the cytoplasm would divide the combination molecule into active telomerase and the other protein or peptide.
GI tract bacteria, probiotics, could be genetically engineered to produce telomerase linked to 20 transport molecules, and skipping stomach digestion could keep the telomerase absorbable.
As a probiotic you could just take the engineered bacteria pill until a cheek swab said you had the telomere length of a 4 year old.
Also, there are nuclear membrane transport peptides, it is possible that attaching telomerase to those would transport more of the telomerase to the nucleus to benefit the human being.-- beanangel, Jul 16 2019 //At the cell membrane there is active and passive transport of molecules. Membrane transport molecules linked to telomerase could cause possibly orders of magnitude more telomerase getting to cells from the circulatory system. Also, if you think of 20 different amino acid or protein specific membrane transport channels then you could attach telomerase with an enzymatically degradeable linker to each of those 20 different molecules and cause 20 times more cytoplasm concentration and 20 times higher concentrations from a plural molecule telomerase drug.//
Um, right. Beanangel, when you have these ideas about how things could be done, you could consider sanity checking them first. I'm glossing over a number of assumptions you've made which I believe to be incorrect, and also whether this plan is wise, and am only considering whether your proposal could have a chance of working.
In this case for example, you're trying to get telomerase - a ribonucleoprotein - into a cell. What you are actually proposing isn't exactly clear to me, but I think it's to ligate telomerase enzyme to either:
a) a membrane transport channel, or b) an amino acid.
If you meant the former, then we're generally talking about a large, multi-protein complex. These are typically manufactured inside a cell to be assembled in the membrane. Obviously then, the primary issue with this as a delivery vector would be how to get this much larger device into the cell. You've therefore taken the problem of how to get one molecule into the cell, and replaced it with the problem of how to get many molecules - including the first - into the cell. Plus some other problems.
In the latter case - which I think is more likely what you really meant, you propose to attach the telomerase to an amino-acid. My concern with this is not that this would be impossible to do, but that I think it quite unlikely that the composite molecule would continue to behave in the manner in which such a model requires. Wikipedia has this to say on telomerase (trimmed and paraphrased for clarity):
Human telomerase consists of two molecules each of human telomerase reverse transcriptase (TERT), telomerase RNA (TR or TERC), and dyskerin (DKC1). TERT protein is 1132 amino acids long. TERT polypeptide carries TERC, a non-coding RNA, which is 451 nucleotides long.
So, what you're proposing is that your supposed amino-acid-specific channel on the cell surface would permit passage of your hybrid molecule, even though it's WELL OVER A THOUSAND TIMES the size of its normal substrate. I think it's legitimate to say that if that worked, it would be a surprising result.-- Loris, Jul 16 2019 [beany]'s scheme may be whacko, but there are certainly ways to deliver both foreign proteins and large nucleic acids into cells, in vivo. As it happens, my company needs to deliver either DNA or DNA+protein or DNA+RNA into cells in live animals, and we're looking at several viable options.-- MaxwellBuchanan, Jul 16 2019 //[beany]'s scheme may be whacko, but there are certainly ways to deliver both foreign proteins and large nucleic acids into cells, in vivo. As it happens, my company needs to deliver either DNA or DNA+protein or DNA+RNA into cells in live animals, and we're looking at several viable options.//
But of course. Their scheme was, however, just too far gone for me to pass without comment.
Nevertheless, if you find that adding[1] a single residue of any of the 20 standard amino-acids, or reasonable analogues, to 'any' arbitrary protein of your choice[2] enables efficient uptake to a eukaryotic cell[3] via a dedicated specific amino-acid channel please come back and post here and I'll happily eat my words.
[1] attaching in any configuration; not just chain-extend [2] excludes proteins evolved to enter the cell via pores, e.g. colicins. Protein is presumed to have a function other than entering (and/or breaking) the cell. [3] excludes cells with genetically modified cell-membrane proteins involved in the translocation.-- Loris, Jul 16 2019 //Their scheme// My gods - you think [beany] may be more than one person? That's alarming.-- MaxwellBuchanan, Jul 16 2019 My theory (which I may have posited here before...) is that [beanangel] IS the internet, gained sentience and learning/growing by posting and reading. There has certainly been a lot of progress (with comprehensibility, etc) since early posts. (No disrespect, [beanangel]...)-- neutrinos_shadow, Jul 16 2019 I think that's a clumsy construction necessitated by English lacking a widely accepted gender-neutral third-person singular, and me not knowing whether beanangel is a he, she, it or other.-- Loris, Jul 17 2019 // English lacking a widely accepted gender-neutral third-person singular, and me not knowing whether beanangel is a he, she, it or other. //
'They'/'them' is pretty widely accepted, and has been for centuries. It's just that people don't realize it's already widely accepted, and use that ignorance as an argument against its usage. Anyway, I'm pretty sure [beany]'s a he, and furthermore I vaguely remember seeing a picture of him.
Anyway, part of his suggestion was attaching telomerase to another protein, not just another amino acid. Presumably this other protein could be much larger, and therefore maybe whatever transports it into the cell might not notice the telomerase attached to an inconspicuous location on it.
Another part of his suggestion was to use his "enzymatically degradable linker" idea, which he's posted about somewhat recently, and which (IIRC) means attaching the telomerase to the other protein using some kind of 'glue' molecule that can be broken (and presumably any residue removed from the payload and maybe also from the carrier) by an enzyme that is expected to be present already at the target location (in this case, inside the cell).-- notexactly, Jul 22 2019 random, halfbakery