How Can We Stop Killing Ourselves?

Last week, I wrote aspects of aging that appear to be active self-destruction.  I mentioned four such processes that might make promising targets for anti-aging therapies: inflammation, immune derangement, cell suicide (or apoptosis) and telomere shortening. I promised more detail to follow

We used to think the body wears out with accumulated damage. In order to extend life span, we’d have to deploy some pretty crafty engineering in order to fix things that millions of years of evolutionary selection couldn’t solve.

But the picture of aging as an active process is much more hopeful. It’s far easier to shut down an existing biochemical pathway than to create a new one, and pharmaceutical companies have a history of success on which to build.

 

Inflammation

Inflammation is the best-known and best-studied of the four. Simple anti-inflammatories are already available, and they work. Better approaches are in the pipeline.

Inflammation is the body’s first line of defense against invading microbes, and it also plays an important role in eliminating diseased cells and damaged tissue in wounds and bruises. However, as we get older, inflammation turns against the body. Inflammation in cartilage is the proximate cause of arthritis, and in our arteries, inflammation creates the plaques which can lead to heart attacks and strokes. Inflammation damages DNA, and can turn healthy cells into cancers. Simple anti-inflammatory agents like aspirin and ibuprofen are the best-documented and best-accepted life extension pills we have right now – a cheap and simple way to add about 2-3 years to your life expectancy . (This is my own computation, based on a reported 13% reduction in all-cause mortality.) They work because after age 50, inflammation is doing more harm than good, and generally dialing it down with a “dumb” drug has a substantial benefit. But to make further progress with inflammation, we will need “smart” drugs that can reduce the harmful effects of inflammation without hampering the action of inflammation where it is needed. I’ve recently read that Nigella sativa has some potential in this area. In case you’re not a botanist, Nigella sativa is the black seed baked into some East European breads (not caraway). In different traditions, it is known variously as black cumin seed, kalonji or chernushka.  Among many anti-inflammatory herbs, it stands out because it simultaneously enhances immune function.

 

Immune derangement

Closely related is the problem of immune derangement. Our white blood cells fight invaders and destroy pre-cancerous cells before they can harm us. The smartest white blood cells are called T-cells, where the T stands for thymus. The thymus is a little gland above your breast bone where T-cells are trained to do their job. They are shown samples of all the body’s cell types, and they learn not to attack self, but anything else is assumed to be an invader.

But the thymus shrinks over our life time. It reaches its largest size when we are pre-teens, and by the time we are 50 it is half that size, and shrinking fast. In older people, the thymus is too small to do its job well. The T-cells are no longer learning their lessons, and they get confused. Sometimes they miss a deadly invader, and let it pass; and sometimes they attack perfectly good tissue. (Statisticians call these errors of Type 1 and Type 2.)

Other parts of the immune system are similarly deranged, making errors of both types. Our lives depend on having smart immune systems that can tell self from other. Since it is the immune system that directs inflammation, Type 2 errors might be the more damaging. In 2009, a study of mice made front page news, when it was announced that their life spans could be increased substantially, even starting in “middle age” with a drug called rapamycin . Rapamycin is a powerful immune suppressant, probably not suitable for long-term use in humans, but it points the way toward advances that might preserve immune specificity as we age. Simply maintaining our thymus glands will be a good start. Supplementing with DHEA has been studied  as a possible means of slowing decline of the thymus.

 

Apoptosis

Apoptosis is the biologists’ word for cell suicide. It is vitally important to be able to get rid of cells that are unneeded, or cells that have become diseased or cancerous. Under a signal from the mitochondria, our cells are programmed to dismember themselves in a safe and orderly fashion, to break up DNA into pieces, to cut proteins into individual amino acids that can be reused, then to dissolve the cell wall and allow the cell’s contents to spill into the bloodstream, where it is re-cycled. In the womb, apoptosis is deployed to kill nerves that are extraneously connected, and to dissolve the webs that grow between our embryonic fingers. When we are mature, apoptosis is triggered when a cell is invaded by a virus. One cell that sacrifices itself in this way can prevent the virus from multiplying, and thwart its attack on many other cells. Cells that are pre-cancerous may also detect that something is wrong, and they die via apoptosis before they can cause trouble.

We need apoptosis, and would be more vulnerable without it, but as we get older, apoptosis develops a “hair trigger”, and cells begin to commit suicide when they’re still healthy and useful. In an Italian study, life span of genetically-engineered mice was extended by removing a gene called p66 that promotes apoptosis. Overactive apoptosis is to blame for sarcopenia  – the loss of muscle mass with age. Apoptosis is also implicated in the loss of brain cells that leads to Alzheimer’s Disease.

It should not be difficult to simply instruct the body to down-regulate apoptosis, and there is cause for optimism that this will offer a net benefit.  One hint is that animals that live longer because of caloric restriction are found to have lower levels of apoptosis in muscles and in nerve cells.  But CR animals also show higher levels of apoptosis in organs that are prone to cancer.  If we are lucky, we may find a high-level mechanism that causes apoptosis to be promoted or inhibited according to the body’s need.

 

Cellular Senescence

This may be the most promising target of the four, because the other three require a better balance, with more discrimination between good and bad effects. But there is reason to think that longer telomeres will be an unqualified benefit to the body; in fact there are prominent scientists who think that telomere length might be the body’s primary aging clock.   I’ve written about the promise of telomere research in two earlier posts here and here.

Telomerase is the enzyme that our cells use to extend telomeres, restoring the lost ends. If we could get telomerase into the cell nucleus, it would do its job. But this is not so simple. Telomerase can’t be taken as a pill or even injected, because it is not transported to the cell nuclei where it is needed. However, every cell knows how to make telomerase, because the gene for telomerase is in every cell. The cell only expresses certain genes at certain times, and the telomerase gene remains locked up tight, except in human embryos.

Many of the experts in the field of telomere science believe that it should be possible to find promoters that turn on the telomerase gene. In fact there are herbal extracts available now that seem to work in a limited way to induce telomerase expression (see previous blog). Several companies are hard at work searching for better promoters.

There are other experts who fear that turning on the telomerase gene might be dangerous, that it will lead to higher risk of cancer. The fears are based on the fact that most cancers find ways to turn telomerase on. But while it is true that cancer causes telomerase, it is not true that telomerase causes cancer. People with longer telomeres have longer life expectancies and lower cancer rates. Both in animals and in people, telomerase therapies have not increased cancer risk.

 

The future: regulation of gene expression

Since about 1960, we have understood well the genetic code, which is the language by which DNA is transcribed into proteins. But only about 1% of our DNA consists of genes that are transcribed in this way. Much of the rest controls gene regulation: which genes get turned on where, and when. We are just beginning to learn this parallel language, also coded in the genes. We know that it is a great deal more complicated than the genetic code, with multiple, overlapping signals that both promote and inhibit expression of a gene. When we understand this language, it should be possible to re-program our old cells to transcribe genes as if they were younger. Will that make the cells young again? I can’t wait to find out.

For basic information about healthy living for a long life,
see the author’s permanent page at AgingAdvice.org.