My (perhaps incorrect) understanding was that a cell's vitality doesn't just drop off when telomeres run out, but that vitality declines in some measure as telomere's shorten, perhaps due to some program activating. Does anyone know of there is evidence for this?
StephenB
Yes, this is indeed the case, telomeres don't actually run out before a cell goes into senescence, it has to do with them getting short enough, which acts as a signal or switch to the cell to go into senescence, and which may even be different between people irrespective of telomere length. Take a look at
this paper. We see that even our stem cells lose telomere length as we age, and it begins mostly after middle age, which is when age related deterioration that's not pathology linked usually really begins to become evident. Again, this is why our stem cells are not immortal, only cancers, which have to have telomerase fully active to become a malignant cancer (a telling fact of telomere importance) rather than a benign tumor (which can still be deadly, however, if they occur in the wrong places like that brain) are immortal age wise.
Here's
another nice paper showing how DNA damage and telomere length contribute to senescence, and that this is based on the length of telomeres not species. Another interesting thing to note, is many cancers have very short telomeres, and that they are maintained as such. This has to do with one aspects of cancer transformation, which is ignoring signals for apoptosis and senescence. Telomeres never run out when a cell senescence via programming, and a cancer that can continue to grow beyond the usual critical point for several generations, then will turn on telomerase, otherwise the telomeres do run out and chromosomes literally start to unravel and the cell dies. See
here for an interesting paper looking at breast cancer risk related to telomere length. Shorter telomeres actually increase the risk of cancer, so longer telomeres might actually be a cancer preventative. But in any case, telomerase itself is not a tumor inducing agent, that is, it isn't an oncogene, but it is a necessary final step to take to go into cancer mode (unlimited replication). Finally,
this paper looks at long lived species verses short lived species, and shows telomeres are longer in long lived ones verses short lived ones (Leach's storm-petrels are a great one to look at, extreme long life for their size, but eventually other factors still get them, so telomeres are still only one factor of aging).
Just for a better, and easier to read, summary on the history of telomeres in science than I can give, take a look at
this, and
this on telomere length and cloning of animals, and finally
this from UCSF on their link between stress and reduced telomere length.
In all, the conclusions we see are: telomere length defines the absolute life span maximum for an organism, indefinite telomeres mean indefinite life and senescence in our cells happens only once telomeres get short enough (or if enough DNA damage accrues that isn't repaired, very important point), not when they run out (which directly causes cell death); due to studies on people who live a long time, their telomere length compared to most people, scientists do have an idea that the maximum length a human could live based on their telomeres and extremely rare individuals is about ~110-120 years (a 70 year old's cells still have roughtly 20-30 population doublings left, when a new born has about 90), however there's only one reported case of a human ever reaching 122, we all usually die long before we get to our actual maximal life span limit; thus, to increase the maximal life span limit in any organism, telomere length must be repaired, but other cellular factors that lead to death long before the limit must also be repaired (also need non cellular factors to prevent life span decrease like antibiotics to ward off infection, not getting hit by a bus, etc).
This ties right back into the discussion that's been throughout this thread. Sirt1 and mitochondrial dysfunction are two factors that lead to cell and organismal death long before maximal life span is reached let alone surpassed (you'd have to live ~152 years to be significantly past the
maximal life span for a human), and will kill an organism eventually even if telomeres are maintained indefinitely (Leach's storm-petrels). Mitochondrial dysfunction is a major source leading to DNA damage due to the greatly increased ROS production and metabolic dysregulation that occurs. This increased DNA damage then titrates away Sirt1 (which is a required early responder to DNA damage for repair) from its function as a gene transcription watch dog, and soon cell lines start expressing proteins they shouldn't be for their differentiated type and you get aging, and eventually death (see
here). Sirt1 dysfunction is also a conserved pathway of aging from yeast to humans. That's worth typing again, it's a
conserved pathway of aging in eukaryots, and addressing it is a fundamental issue. So, to lengthen maximal life span, we need to address all three principle mechanisms of aging. That's where resveratrol comes in, proven to upregulate Sirt1 function and activate PGC-1alpha as a consequence (hence why it mimics CR which does the same).
So, resveratrol can only help us with the sirti issue. What if we combined RSV with other supplements that affect mitochondria and telomeres, do you think that combination would result in life extension? Are there any studies that combine RSV with R-Lipoic Acid? Studies on rats have shown that RLA can improve mitochondrial function, increase it's metabolic rate and decrease oxidative damage. Isn't there also a new supplement that interacts with telomeres out in the market? There should be a study that combines all those three (if there isn't already) and see if it extends life in rats instead of using one by itself?
That's the theory, and why no one compound or method of living has ever worked on its own. Unfortunately I cannot find any life span studies done with resveratrol and alpha-Lipoic acid, or other factors that combat mitochondrial/telomere dysfunction. I think the product you are thinking about for telomeres is astrogaloside IV in the product astral fruit. We should find out this February if it may work or not when Anthony takes another telomere length test. There totally needs to be a study with all of these factors to see if the theory holds out.
In the meantime, we can enjoy resveratrol, even if it alone likely doesn't increase maximal life span, for its ability as a CR mimic (mice taking resveratrol on a high fat diet have many of the same healthy parameters as mice on an EOD or standard diet), to fight diabetes, to increase bone density and strength (in all diets of mice), keeping the heart and arteries just as healthy throughout life as in early life, and to fight many other effects of aging irregardless of diet (all
here, ignore the title, they saw significant life span increases in high fat and EOD fed mice in the actual data of the paper, and
here). All these factors which could reduce life span in the real world. And of course, resveratrol's ability to resist and ward off neurodegeneration is another huge reason to take it, as we've seen in numerous in vivo studies in many mice models of Alzheimer's [
1,
2,
3,
4], ALS [
4,
5], Parkinson's [
6,
7], multiple sclerosis [
8,
9], and to protect neurons in general [
10,
11,
12]. Not to mention its cancer preventative and killing abilities, on which there are so many scientific papers I'm not going to try to cite them.
Edited by geddarkstorm, 09 January 2009 - 06:25 PM.
