Last week, I wrote that the new view frames aging as an active process in which the body attacks its own healthy tissues. Much of this damage appears avoidable, if only we kept churning out the same hormones we did when we were young, instead of changing to a less effective mix as we get older.  Some of these chemical signals that turn on in old age seem directly to trigger the destruction, as if “on purpose”. There are four processes that seem to be the main culprits: inflammation, immune derangement, cell suicide (or apoptosis) and telomere shortening. They make promising targets for new anti-aging research.

A challenge to evolutionary theory

It has been a surprise for evolutionary biologists, beginning in the 1990s, to discover that there are genes that regulate aging. More curious yet – some of the genes for aging have been around for at least half a billion years, from a time when one-celled eukaryotes (nucleated cells) ruled the earth. Usually, evolution is very good at holding on to what works, and getting rid of genes that are harmful. Aging ought to be in the second category – aging destroys fitness. Why would evolution preserve harmful genes and pass them on?

This sounds like a question for theorists, or even philosophers. But the question has taken on a practical importance now that biochemists know how to turn genes on and off. Should we turn off the aging genes? Would terrible things happen to us as a side-effect – sterility, or maybe cancer? Or would this be the shortcut we’ve all been waiting for – a new and more effective path to life extension?
Discovery of Genes for Aging

Nematode worms, fruit flies, and yeast cells are the most common lab organisms used to study aging because they can be grown in small containers and their life spans are conveniently short. Beginning in the 1990s, geneticists knew how to identify individual genes and remove them – mutate or snip them out from an egg cell, which contains a single copy of the genome that will be replicated into every cell of the adult. Here was a surprise that transformed aging science: for each of the three lab organisms, there were genes that could be removed, permitting the animal to live longer. What is more, these genes were closely related, underscoring the inference that they were no accident, but a surprising and paradoxical product of evolution. A common genetic basis also suggested that what we learned from simpler animals might also apply to humans.

Some of the earliest genes discovered to regulate aging were related to the insulin metabolism, and presumably mediate the mechanism by which aging is slowed by caloric restriction (or shall we say, “aging is accelerated by abundant food”?) In worms, DAF-2 was one of these genes.

It was natural to ask about the metabolic effects of DAF-2: what is its role in the metabolism? The Harvard laboratory of Gary Ruvkun was able to prepare “mosaic” worms that had different genes in different parts of their bodies. Before asking “how”, it would be interesting to know “where” DAF-2 was acting. Ruvkun and team tried mutating DAF-2 just in the muscles. No life extension. They repeated the experiment with DAF-2 mutated in just the digestive system. No life extension. But when DAF-2 was disabled in the nerve cells, that was sufficient to double the worms’ life span. [Ref] The nervous system suggested signaling and active, intelligent control. This finding helped to solidify the new paradigm: life span is actively regulated by the body.

 

Sharpening the evolutionary paradox

Here’s a detail that underscored the evolutionary paradox: The principle that “natural selection can only generate adaptations that are good for an individual’s fitness” is so fundamental to evolutionary theory, that theorists looked for an interpretation of the data that would support this axiom. The axiom might still be true if these preserved genes were selected for some powerful benefit, such that accelerated aging was a side-effect of genes whose primary effect was beneficial. This theory goes by the name antagonistic pleiotropy, and was first proposed by George Williams back in 1957.  (“Pleiotropy” is the word geneticists use to describe a single gene that acts in multiple ways.)

The gene DAF-2 did indeed have benefits, and the long-lived mutants appeared fat and lazy. But the benefits appeared when the gene was turned on in muscle cells, while the life-shortening effects came from the gene’s presence in nerve cells. It is normal for gene expression in different tissues to be separately regulated. Ruvkun emphasized that the costs and benefits were easily decoupled. If he could separate the two effects in a simple lab manipulation, why hadn’t nature learned to do the same over the aeons?

 

Implications for Anti-aging Medicine

The more we learn about the physiology of aging, the clearer it becomes that the standard evolutionary view doesn’t work. Three of the body’s systems that are highly evolved for self-protection morph, as we age, into means of self-destruction. These are inflammation, the immune system, and apoptosis. A fourth system – telomere loss, also called cellular senescence – seems to act like an aging clock, destroying our bodies on schedule. It is common to speak of this as “dysregulation”, as though it were just a mistake. But you have to wonder why natural selection would make such costly mistakes.

Each of these four makes an excellent target for anti-aging research, and when scientists learn to control all four, radical life extension of many decades will be the natural result.

 

Inflammation

Inflammation is the best-known and best-studied of the three, and research is well on its way. 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 . They work because after age 50, inflammation is actually 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 beneficial.

 

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 attack perfectly good tissue; and sometimes they miss a deadly invader, and let it pass. (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 1 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.

 

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 .

 

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.

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. Several companies are 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

As a strategy for research, study of the body’s signaling holds the best promise for big strides in life extension. We can work at fixing what goes wrong, engineering solutions to the damage that appears at many levels, and in many tissues as we age. But if much of this damage is self-inflicted, it will be easier to prevent it than to fix it. The fact that aging is highly regulated suggests it should be possible to modulate aging from the top down by intervening in the regulatory chemistry.

Evolutionary theorists are still adamant that aging could not have been selected as an adaptation, but their theory is holding back progress. One of these days they will have to face the overwhelming evidence that aging has evolved as an active process of self-destruction. Both evolutionary theory and geriatric medicine will be profoundly affected.

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Follow-up on factors besides calories that affect weight 

Two weeks ago, I wrote that the efficiency in absorbing food calories is affected by many factors including gut microbiota.  In Science Magazine this week, an experiment is described in which transfer of bacteria from the intestine of a lean mouse to an obese mouse induced weight loss.  For the “lean bacteria” to take over required a change in diet.