Lost Telomeres, Lost Youth

Shortened Telomeres Explain a lot of Aging
February 18, 2011 Getting older is no walk in the park. The organs slowly give out, energy goes down, diabetes, dementia, and heart attack risks go up and so on. What a mess! Figuring out how and why these things happen has been a surprisingly tough nut to crack. But researchers are finally starting to make some progress. Scientists have had good theories about why slow growing cells like brain, liver and heart suffer from aging. And other theories to explain why fast growing cells like blood and intestinal cells age. Now, in a new study, scientists have tied these theories together in a nice bow.

Blame aging on shortened
Just as scientists might have thought a few years ago, telomeres appear to be the key. Telomeres protect chromosomes from getting damaged whenever a cell divides. But each time a cell divides, it loses a bit of its telomere off the end of its chromosomes. Eventually enough of the telomere is lost that the chromosomes start to get damaged. The cell turns on its DNA repair machinery and slows everything down. This causes fast growing cells to slow down and to eventually age and stop growing. (Chromosome damage can also cause a cell to kill itself.) Slow growing cells should be relatively immune to these effects. But they age too. And it is partly because of that same telomere loss. The researchers found that losing telomeres also affects how mitochondria work. Remember, mitochondria are the power plants of the cell--they turn sugar into energy. And they need to be working at their best for slow growing cells to survive. The researchers propose that telomere loss in slow growing cells causes problems like diabetes and dementia by affecting how the mitochondria work. Add to this the effect telomere shortening has on fast growing cells and scientists start to get a more complete picture of aging at the molecular level. The researchers were able to show that both effects happen for the same reason. Telomere loss turns on the p53 gene. And the p53 gene affects many other genes that affect cell growth and mitochondrial function.
The Master Regulator, p53
The p53 gene is mostly known for its role in cancer. When it is working right, it can prevent cancer cells from growing into a tumor. Cancer happens when certain parts of the DNA in a cell get damaged. The DNA damage leads to the cells growing uncontrollably or refusing to die. This kind of DNA damage turns on the p53 gene which gets to work.

The red spots are telomeres.
When they get too short,
cells can't divide anymore.
The p53 gene first makes lots of p53 protein. This protein then goes on to turn on and off lots of other genes. These p53-controlled genes slow a cell down and get the DNA repair machinery working overtime. The idea is that the slowed-down cell will have time to fix its DNA. Once repaired, the cell can then go about its usual business. In many cancers, the p53 gene itself is damaged. Now the cell has trouble dealing with any other DNA damage. So the unprotected cell eventually turns into cancer. Aging damages DNA too but in a different way--through the chipping away of telomeres at the end of chromosomes. Once telomeres become short enough, p53 kicks into action slowing down the cell for repair. Except that the cell can't repair the telomeres. So the cell ends up in senescence--old and dying. The p53 gene affects other genes too. This study shows that it turns down two PGC-1 genes in certain cells. And that PGC-1 genes are needed in these cells for their mitochondria to work at their best. Slow growing cells need their mitochondria to hum along at optimal efficiency. When they aren't, people end up with age related problems like diabetes and heart disease. So telomere shortening turns on p53 which causes cells to slow down and fix their telomeres. This p53 can also slow down mitochondria. But not always. Other studies have shown that p53 can sometimes make mitochondria more efficient. Things are never cut and dried in biology! Scientists will need to see if p53 works differently in different cell types with regard to mitochondrial activity. It may be that p53 contributes to mitochondria slow down in some kinds of cells and not others. And telomeres and p53 are probably not the whole story either. Damaged mitochondrial DNA (mtDNA) appears to play a key role in aging. It could be that affecting the PGC-1 genes also affects the repair of mtDNA but this has not yet been shown. This study greatly increases scientists' understanding of aging. But they obviously still have a long way to go. Why people need telomeres.

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Just Add Telomerase
From all of this an obvious answer to the aging problem is to fix the telomeres in old cells. Now the fast growing cells can get back to work and the slow growing cells can have their mitochondria humming along. People live forever, end of story. Not so fast, though. Fixing telomeres is not an easy thing to do. And adding telomeres to the ends of chromosomes willy nilly is just what cancer cells want cells to do.

Maybe Ponce de Leon should have
been looking for telomerase.
Telomeres are one of the natural brakes on cancer cells. Each time a cancer cell divides, it loses a bit of its telomere too. Eventually, it would run out of telomeres and die. Cancer cured. One way cancer cells get around this is by turning on a gene called telomerase. Telomerase makes an RNA/protein hybrid that heals telomeres. It is normally on in fast growing cells like immune and stem cells but cancers can hijack it and put it to their own nefarious uses. So any anti-aging therapy that uses telomerase to repair telomeres in old cells must walk a fine line. It needs to repair telomeres in aging but not cancerous cells. This won't be easy! Scientists will need to find some way to distinguish between an old and a cancerous cell. And to only get telomerase to work in the old cells. And to make sure not to reactivate precancerous cells that have petered out because they lost their telomeres. Eventually scientists will learn enough to beat the problem of aging. Or at the very least, make everyone live longer, more productive lives. We all will just have to be patient and try to live long enough to see this research come to fruition.