June 22, 2011
Short Telomeres Boost Progerin Aging Protein
Each time a cell divides its chromosome caps (called telomeres) get shorter. When telomeres get really short they interfere with the health of cells and cell division becomes more difficult. Telomere length is an indicator (albeit not perfect) of cell age and cell health. Therefore mechanisms by which telomere length impact cell health and cell death are as important topic of aging research. So it is interesting that NIH researchers have discovered a mechanism by which telomere shortening boosts production of the toxic protein progerin in cells.
National Institutes of Health researchers have identified a new pathway that sets the clock for programmed aging in normal cells. The study provides insights about the interaction between a toxic protein called progerin and telomeres, which cap the ends of chromosomes like aglets, the plastic tips that bind the ends of shoelaces.
The study by researchers from the National Human Genome Research Institute (NHGRI) appears in the June 13, 2011 early online edition of the Journal of Clinical Investigation.
Telomeres wear away during cell division. When they degrade sufficiently, the cell stops dividing and dies. The researchers have found that short or dysfunctional telomeres activate production of progerin, which is associated with age-related cell damage. As the telomeres shorten, the cell produces more progerin.
Progerin is a mutated version of a normal cellular protein called lamin A, which is encoded by the normal LMNA gene. Lamin A helps to maintain the normal structure of a cell's nucleus, the cellular repository of genetic information.
This finding ties the premature aging disease Hutchinson-Gilford progeria syndrome (HGPS) which typically kills children by their early teens (see pictures of progeria children). The same progerin protein that causes cellular damage in progeria syndrome also causes the same sorts of damage as we grow older and our telomeres shorten.
You might think, why not rejuvenate by lengthening telomeres? The problem (see that link) is that telomere shortening is probably a defense mechanism against cancer. So lengthening telomeres (assuming we had a treatment that would do this) might not lower the risk of all-cause mortality. However, throw in some great cures for cancer (the sooner the better) and telomere lengthening will suddenly become a very appealing idea. Another possibility: If we could bioengineer our immune systems to very aggressively police against cancers we could reduce the cancer risk from making our telomeres long again. Immune system rejuvenation along with tweaks to make the immune system more aggressive against cancers could so reduce cancer risk that telomere lengthening would carry far less risk.
Cell therapies using rejuvenated stem cells with long telomeres (carefully checked to assure no cancer-causing mutations) will some day deliver some of the benefits of telomere lengthening. While cell therapies won't replace all the aged cells in bodies they at least will provide youthful cells that will do lots of tissue repair.Similarly, advances in tissue engineering to enable growth of replacement organs from youthful stem cells will allow us swap out organs that have lots of aged cells with short telomeres.
For a sense of how important telomeres are in the aging process see my previous posts Telomere Length Indicates Mortality Risk, Chronic Stress Accelerates Aging As Measured By Telomere Length, Telomere Genes Linked To Longer Life, and Telomere Test For Longevity Estimate.
I've suggested that we could risk immortal cells, if we had the right kind of artificial genetic diversity. Suppose you did SENS style replacement of stem cells, but made those cells immortal. Cancer risk, right? But generate the cells with a huge spectrum of specific vulnerabilities built into them, like programed apotosis triggers. Along comes a cancer, you identify which stem cell it's descended from, activate the apotosis trigger for that cell line, and the cancer dies, along with a tiny fraction of your healthy tissue.
Immortal cells will still mutate, especially during division. The accumulation of errors and loss of imprinting will make them progressively less and less functional, even if they don't become cancerous.
Replacement of cell populations with new error-free clones may be the only way around this without cell-by-cell nanotechnological upkeep. You'd wipe out an old population and refresh with a new one, like changing oil.
According to tasciences (www.tasciences.com), a Geron spinoff, their (expensive) product ta-65 does lengthen telomeres. Although it does send the BS sensors into high alert status, it's association with Geron does "seem" to give it some credibility.
They also claim that cancer causes telomerase, but telomerase doesn't necessarily cause cancer. However, I'm not a molecular biologist and certainly not in a position to say their claims are true or false.
I think that's probably accurate; Defeating telomere shortening is one of the adaptations cancer cells must make to be a threat, so relieving the cells of the need to make that adaptation would increase the number of cancers which were actually threatening, but freedom from telomere shortening isn't actually a cause of cancer, it's just enabling.
I would think you could get around most of the potentially Cancer enabling effects telomere lengthening by not permanently activating Telomerase. A short activation enough to maybe quadruple telomere length when you hit ~35 then maybe every 20 years you get a booster. Most precancerous cells with runaway growth problems should still then divide themselves out of existence in between doses. Permanent reactivation of Telomerase is probably a bad idea until most cancers have a cure.
A study showed that optimal blood levels of Vitamin D will add 5 years to the telomeres life. A number of studies have shown that optimal Vitamin D levels are 60-80% protective against cancer. That's only for folks who do not have high blood sugar.
Just published in PLoS ONE is a study that finds that blood cell (and presumably bone marrow) telomere lengths can fluctuate, sometimes significantly even over a just a few months. The reason is unclear, but perhaps if it can be discovered, telomere length could be increased in other tissues also. See -
"Blood Cell Telomere Length Is a Dynamic Feature"
"Just published in PLoS ONE is a study that finds that blood cell (and presumably bone marrow) telomere lengths can fluctuate, sometimes significantly even over a just a few months. The reason is unclear, but perhaps if it can be discovered, telomere length could be increased in other tissues also. See -
"Blood Cell Telomere Length Is a Dynamic Feature"
Telomere maintenance is clearly a regulated process. The job before us is to identify the regulatory mechanism and learn to modify it.
I think researchers need to work directly on reducing progerin levels as people age also, not just lengthening of telomeres. I may be wrong on this, but I think for men at least, the ever receding hair line with age is probably a marker somehow for this progerin buildup with age. One of the most obvious symptoms of those progeria kids is the rapid balding at a very early age.
Telomerase therapy might be worth it in very old centenarians, if I remember correctly they have something like a 50% probability of death per year.
Rapamycin (the anti-rejection drug used by transplant recipients) also helps degrade progerin, and probably other intracellular debris also. See -
"Drug Reverses 'Accelerated Aging' in Human Cells"
(Also, includes audio link)
Rapamycin, and other related drugs (mTOR inhibitors), increase longevity in some lab studies.