A funny thing happened along the way to testing a carbon nanostructure for toxicity.  The lab rats who got the toxin lived twice as long.  Is there a possibility here for human health?

Three Allotropes of Carbon

When I went to school, they taught us that carbon was found in nature in two elemental forms (or allotropes).  Graphite consists of 2D sheets of carbon atoms that slide over one another so smoothly that graphite is slippery enough to be used as a dry lubricant.

Diamond consists of carbon atoms in a 3D tetrahedral network, so rigid that diamond is the hardest material known to man.

I strongly suspect that a deeper biological mechanism is involved in the health and longevity-producing effects of C60 despite the prevailing wisdom.  As I see it the candidates for these deeper effects of C60 are (1) effects exercised on DNA including impacts on structural configuration, epigenetic gene activation effects, histones and nuclear envelope shape, (2) effects exercised on microtubule structures in cells, (3) effects on mitochondria, and (4) epigenetic impacts such as on histones and DNA methylation.

He goes on to detail his support for all four hypotheses. If you’re interested in this topic, I suggest reading the full text as a next step.

An eminent Russian biochemist has been working fifteen years to get the cell’s most active anti-oxidant into the mitochondria, which is the locus of its action. Called “SkQ” for short, his designer drug administered in food, has been shown to make mice live longer; and topically it can induce regression of eye diseases in rodents, dogs and horses. While the long process of US FDA review has just begun, an eye drop containing SkQ has been approved for sale in Russia, and can now be purchased in Moscow drug stores.
Biochemical background: Ubiquinol in Mitochondria

Mitochondria are “organelles”, hundreds of independent energy factories floating within the cells of all higher life forms. Sugar is “burned” in the mitochondria, and the energy generated is stashed as molecules of ATP, which act like a battery that the rest of the cell can use. Muscle and nerve cells are large consumers of energy, and their function can be limited when mitochondria in aging cells begin to wane. Mitochondria have another role as well: they serve as executioners for diseased or damaged cells. It is the mitochondria that emit peroxides, which trigger a cascade of signals, culminating in cell suicide, or apoptosis. (This story is told colorfully and creatively in a book I highly recommend, called Power, Sex and Suicide by Nick Lane.)

Ubiquinone was named as the enzyme that is “found everywhere”. Every cell needs energy, and every cell relies on mitochondria to supply that energy, and every mitochondrion uses ubiquinone, both to create the energetic molecules of ATP that are exported for use in the cell’s primary functions, and also to clean up the mitochondria’s effluent of peroxides. Peroxides are an example of reactive oxygen species (ROS). ROS are toxic waste that corrodes the body’s delicate chemistry. At higher concentrations, peroxides constitute also a distress signal which can trigger cell suicide and even export a suicide message to neighboring cells.

As we age, we have less ubiquinone and there are dire consequences: less energy in our muscles and nerves; more toxic waste that damages and poisons more delicate chemicals; and over-active cell suicide that destroys healthy cells in our muscles and brains. We lose strength, sensitivity and mental acuity. Ubiquinone is sold as CoQ10, a nutritional supplement that some people take for heart health and oft-imputed anti-aging benefits. But no animal study has ever succeeded in extending life span with CoQ10. Perhaps its value is limited by bioavailability. Only a small portion of ingested CoQ10 makes its way from the stomach into the bloodstream, and a much tinier portion actually reaches the mitochondria where it is needed. This is the issue that Skulachev has addressed in such an innovative way with his molecule, which his friends and students have affectionately dubbed SkQ.

The molecule and how it works

Skuklachev’s molecule is designed like a tugboat pulling a barge on a chain. The barge on the left is a molecule like ubiquinone. The 10-carbon chain is a simple hydrocarbon. And the tugboat on the right consists of a positively charged phosphorus atom, surrounded by ligand residues that delocalize and shield the charge. This works because mitochondria, in nature’s design, are the only parts of a cell to carry a consistent electrical charge. They are continuously pumping protons out through their membranes, maintaining a negative electrical potential within the mitochondria.

The electrostatic attraction is a powerful lure, drawing the positively-charged tugboat into the mitochondria, and dragging the barge in behind. The effect is to concentrate SkQ a million-fold inside, compared to outside the mitochondria. This means that very tiny amounts can be effective antioxidants. SkQ is a very practical drug, inexpensive and non-toxic because it is administered in tiny doses.

Curiously, the “barge” on the left is not the version of CoQ that is used by mammals, but the plant version, called plastoquinone, which is an even more effective anti-oxidant. After comparing plastoquinone to ubiquinone in animal experiments, Skulachev switched to plastoquinone several years ago.

Anti-oxidant or signal molecule?

Readers of this column must be aware that I have been skeptical about anti-oxidants for life extension. It appears that SkQ may be an exception because it is so precisely targeted to mitochondria. There is some precedent for the exception, in that genetic interventions that are targeted to the mitochondria have also been found to extend life span in mice. This study arranges for extra copies of the anti-oxidant called catalase in the mitochondria only. Perhaps the reason for the exception is that to the mitochondria, peroxides not only cause molecular damage, but also can signal cell suicide. This is the theory that Skulachev has promoted.

He should know. In earlier days, Skulachev was responsible for elucidating the electrochemistry of mitochondria in relation to energy generation and programmed cell death.

Life extension in animals

Since 2007, Skulachev’s lab at Moscow State University has been publishing studies which demonstrate life extension, first in flies and other invertebrates then in a variety of different rodents. SkQ has also been shown to delay all the common diseases of aging in rats. The effect on life span is easily discerned, and is large under some circumstances:

Administered as eye drops, the effect has been more dramatic. Rabbits have been cured of glaucoma. Macular degeneration has regressed in horses and dogs.  Experimenting on himself, Skulachev reports that his age-related presbyopia has regressed to the point where he can see without glasses for the first time in many years.

Present and future

SkQ has cleared the Russian equivalent of FDA approval. Clinical trials have begun for SkQ, and preliminary results indicate that 80% of people who were given the drops for cataracts experience an improvement in visual acuity within half a year (unpublished).  As of last summer, SkQ eye drops have become available for sale in Moscow and environs through a partnership with a company named Mitotech, under the brand name Bизомитин, or Visomitin in a more familiar script.  Sales are brisk because Skuklachev is something of a legend in his own country. There is no present timetable for marketing Visomitin in America.

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.

Most people think of aging as passive – something that happens to your body. Random mutations occur faster than the body can fix them. Cholesterol deposits build up in the arteries. Above all, oxidation damages the body’s delicate chemistry, and this affects the ability to fix other damage.

But a new view is emerging, in which aging is an active process. Much of the 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. Worse – some systems actually turn against the body, destroying perfectly good tissue, as if “on purpose”. There are four such processes: inflammation, immune derangement, cell suicide (or apoptosis) and telomere shortening. They make promising targets for new anti-aging research. More on this next week.

What’s up with evolution?

It has been a surprise for evolutionary biologists in recent years 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 eukaryotes (nucleated cells) were new on 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 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, causing 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 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. 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.

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?

Evidence accumulates for active aging

The more we learn about the physiology of aging, the clearer it becomes that the standard evolutionary view doesn’t work. Two of the body’s systems that are highly evolved for self-protection morph, as we age, into means of self-destruction. These are inflammation and apoptosis. It is common to speak of this as “dysregulation”, as though it were just a mistake. But you have to wonder about such costly mistakes. Natural selection ought to be quite efficiently weeding them out.

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.

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. 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. 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.

A third self-destruction mechanism is cellular senescence.  This is the telomere metabolism, which I discussed in two earlier posts here and here.  Unlike inflammation and apoptosis, cellular senescence serves no useful purpose for the body.  (Theorists have proposed a role for telomeres in cancer prevention, but it has turned out that animals and people with short telomeres have consistently higher risk of cancer.)

.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 evolved 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.