About Josh Mitteldorf

Josh Mitteldorf studies evolutionary theory of aging using computer simulations.

The surprising fact that our bodies are genetically programmed to age and to die
offers an enormous opportunity for medical intervention. It may be that therapies
to slow the progress of aging need not repair or regenerate anything, but only
need to interfere with an existing program of self-destruction.

Mitteldorf has taught a weekly yoga class for thirty years. He is an advocate for
vigorous self care, including exercise, meditation and caloric restriction.

After earning a PhD in astrophysicist, Mitteldorf moved to evolutionary biology as a
primary field in 1996. He has taught at Harvard, Berkeley, Bryn Mawr, LaSalle
and Temple University. He is presently affiliated with MIT as a visiting scholar.

In private life, Mitteldorf is an advocate for election integrity as well as
public health. He is an avid amateur musician, playing piano in chamber groups,
French horn in community orchestras. His two daughters are among the first children
adopted from China in the mid-1980s.

Much to the surprise of evolutionary biologists, genetic experiments indicate
that aging has been selected as an adaptation for its own sake. This poses a
conundrum: the impact of aging on individual fitness is wholly negative, so aging
must be regarded as a kind of evolutionary altruism. Unlike other forms of
evolutionary altruism, aging offers benefits to the community that are weak, and
not well focussed on near kin of the altruist. This makes the mechanism
challenging to understand and to model.

more at http://mathforum.org/~josh

The Varieties of Aging in Nature

In 1999, I met Cynthia Kenyon for the first time, and she told me her one-line proof that aging is an evolved trait.  Lifespans in nature range from hours to thousands of years. This shows that natural selection is not constrained, but can implement aging on whatever time scale is appropriate.

A few years ago, Annette Baudisch added another dimension to this proof: It’s not only the duration of life, but the shape of the aging curve that takes on so many various forms.  Misguided theories of aging are based on the human life cycle (and others like it) with Gompertz mortality.  (In the 19th Century, Benjamin Gompertz first noted that risk of death increases exponentially with age.)  Several smart theorists have been seduced into attempting proofs—either from thermodynamics or from evolution—that gradual aging is a necessary consequence of the conditions of life.   

But Baudisch gathered data on hundreds of animals and plants, demonstrating that the exponential shape of the human mortality curve is just one among many possible.  Furthermore, every conceivable shape is paired with every time scale.  Any theory of aging must account for all these ways to age.  Or not to age: Baudisch got her start in research collecting examples of negative senescence.  Given this variety, the only viable theory is, “nature can do whatever she wants”.  More formally, natural selection can mold aging as appropriate to fit every possible niche in every ecology.  


Aging is ancient, but it is not universal.  We are accustomed to think that animals age gradually beginning at maturity, ending with inevitable death, but life is stranger than this.  Some animals and many plants have escaped from aging entirely.  Many more pass through long periods of their lives without aging.  Cicada nymphs mature underground for seventeen years, while not being subject to increasing death rates or aging in any other sense.  Then the cicada emerges, mates, ages and dies all in a single day.  This is a dramatic example of semelparity, in which aging occurs all in a rush after a single burst of reproduction.  In many such cases, the aging can be experimentally decoupled from the reproduction, demonstrating once again that the aging is a separate adaptation.  The simplest example of this is the pansies in your garden.  As long as you snip off the flowers before they go to seed, you can keep the plant blooming all summer.  

Snipping off flowers before they go to seed will keep the plant alive all summer.

Many plants and animals  die when they are done reproducing, as evolutionary theory predicts; but among those that long outlive their fertility, there are some (like C. elegans worms) that don’t tend to their children or grandchildren.  What evolutionary force has provided for their continued life?

A few animals and many plants don’t age at all, but grow larger and stronger and more fertile through their entire lifespans.  Some have been observed to regress from mature states, and start life anew as larvae, with a full life expectancy ahead of them.

 

What does life without aging look like?

Sanicula is a shrub growing in the meadows of Sweden, and one plot in particular has been studied continuously for seventy years. Sanicula has a life expectancy comparable to a human, but sanicula does not age.  For people, the probability of dying gets higher with each passing year, whereas for sanicula, about one shrub in 75 dies each year, irrespective of age.  A 75-year-old plant has no more mortality risk than a 10-year-old plant.  For a person, the life expectancy at birth might be 75 years; the life expectancy for someone 60 years of age might be 18 more years, and for someone 80 years old, perhaps the life expectancy is 7 more years.  For a sanicula, the life expectancy of a seedling is 75 years, and the life expectancy of a 60-year-old shrub is 75 more years.  There are, in fact, a few 200-year-old saniculas, and they have a life expectancy of 75 more years. At this rate, about one plant in a million should live a thousand years.  A thousand-year-old sanicula is no closer to death than a sapling.

It is unknown today whether lobsters age or not.  Lobsters are fished so heavily that they rarely grow larger than a pound, but lobsters weighing more than 5 lbs are still caught occasionally (and usually released). The largest lobster on record was 44 lbs. The reason that the large lobsters are released back into the ocean is not just that they won’t fit on a dinner plate. Lobsters become more fertile as they grow larger, and their young are more viable. A few large lobsters can be the breeding stock for a large area. We don’t have an age record for the oldest lobster ever caught because lobsters don’t have annual rings or layers that broadcast their age. The 44-lb animal was said to be more than one hundred years old, but no one knows for sure.

…and not the largest on record, either.

Clams also can grow larger and more fertile indefinitely. But clams have growth rings that count the years for us. The oldest clam on record (an ocean quahog of the species Arctica islandica) has been tagged at 507 years. Small clams have natural predators, including starfish that latch onto their shells and pull them apart by brute force. But once a clam outgrows the arms of a starfish, it can keep growing indefinitely. Clams have one foot, one mouth, no eyes or ears or stomach, no brain. Giant clams, up to 800 lbs, live the same lifestyle as their smaller relatives, sucking in the seawater, taking in thirty thousand times their weight in water every day, and filtering out plankton and algae, which continue to grow and reproduce inside them. Like giant lobsters, the giant clams provide eggs for a whole community. They have been known to release half a billion eggs in a day.

Giant clams can live hundreds of years.

All of the longest-living species in the world are trees.  There are several reasons for this.  Trees invest a great deal in growth, always trying to project their leaves upward, out of the shade of other trees, to compete for the best light.  The oldest trees tower above the forest, and get first dibs at the sun’s energy.  So there is a powerful evolutionary incentive for trees to live a long time so they can grow taller than their competitors, and the sky is the limit.

As opposed to plants, animals’ life spans are limited by a requirement of ecological stability.  Most plants produce their own food, but all animals depend on other species (either animals or plants) for their food.  Hence it is natural for a plant to live as long as possible and make as many seeds as it can make.  Trees are the best examples of Darwin’s dictate that life is about reproduction.  (Sequoia trees can produce more than a billion seeds.)  But animals can’t get away with reproducing faster than the plants at the base of the food chain.  Animals are evolved to guard the species lower down on the food chain, and they must never reproduces faster than the animals they eat—otherwise, in a very few generations, they will wipe out their food source and their children will starve.

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Do trees age at all?  Some do, and some don’t. Most trees go for long periods of time growing ever larger and less vulnerable to death.  That counts as negative senescence.  Of course, size itself becomes a hazard as a tree becomes the tallest in its grove—the first to be struck by lightning, the most top-heavy and vulnerable to toppling in the wind when erosion weakens the roots’ hold on terra firma. But in addition to this, it seems that most trees have a characteristic age, after which death finally becomes more likely with each passing year. There is some indication that trees become more vulnerable to fungus and disease with old age, but for the most part, old trees succumb to the mechanical hazards of excess size. The very ability to continue growing that offers them the possibility of “reverse aging” over so many decades proves in the end to be their downfall.

 

Instant Ageing; Sudden Death

Semelparous animals and plants reproduce just once in a lifetime, usually followed promptly by death. Sudden post-reproductive death is common in nature, affecting organisms as varied as mayflies, octopuses, and salmon, not to mention thousands of annual flowering plants.

The cause of death in semelparous organisms varies widely.  Theorists once assumed that the animal just wears itself out in a burst of reproductive effort, but this idea has not held up.  The burst of reproduction and the sudden death seem to be separable and independent adaptations. In addition to the example of pansies mentioned above, octopuses can be induced to live beyond their burst of reproduction if their optic gland is surgically removed; and Atlantic salmon, close cousins of the Pacific salmon, also endure treacherous migrations upstream in order to mate, but they don’t necessarily die after laying eggs, and can return to the ocean for another bite at the apple.

Chinook salmon hatch in river pools, often hundreds of miles upstream from the sea. They spend their first year or two in the protected environment of the river, where life is tamer and larger predators rarer. When they have grown large enough to compete, they migrate downriver, out to the ocean to seek their fortunes. They may range up to 2,500 miles from the mouth of the stream where they first entered the sea. They live in the ocean anywhere from two to seven years, growing larger but not weakening or becoming frail with age. When they are ready to reproduce, they find their way back, not to any handy river mouth but to the very same river pool where they were hatched. Their journey is a headlong rush, simultaneously into fertility and death.

Salmon fight rushing water to return to their spawning ground.

By the time the adult salmon reach their spawning ground, their metabolisms are in terminal collapse. Their adrenal glands are pumping out steroids (glucocorticoids) that cause accelerated—almost instant—aging. They’ve stopped eating. Moreover, the steroids have caused their immune systems to collapse, so their bodies are covered with fungal infections. Kidneys atrophy, while the adjacent cells (called interregnal cells, associated with the steroids) become greatly enlarged. The circulatory systems of the rapidly deteriorating fish are also affected. Their arteries develop lesions that, interestingly, appear akin to those responsible for heart disease in ageing humans. The swim upstream is arduous, but it is not the mechanical beating that fatally damages their bodies. It is rather a cascade of nasty biochemical changes, genetically timed to follow on the heels of spawning. The symptoms affect both males and females, despite the uneven share of metabolic work that falls to females, whose eggs may constitute a third of their body mass during the final leg of their trip.

Some organisms are genetically programmed not to eat after reproduction and starve as a result; it’s quicker and surer than traditional ageing. Mayflies entering adulthood have no mouth or digestive system whatever. Elephants chomp and grind so many stalks and leaves during a lifetime that they wear out six full sets of molars. But when the sixth set is gone, they won’t grow another, so old elephants can starve to death.

 

Elephant molars get a lot of wear. The elephant can replace them 5 times but not 6.

Praying mantis males take the prize for the most bizarre and macabre mode of programmed death.  After an elaborate mating ritual, the male fertilizes his mate’s eggs with his bottom half, while the female chomps off his top half.  Sometimes.

 

Octopuses makes an especially good story. They live a short time, a few months to a few years, depending on the species, and they die after reproducing once. After mating, the female guards and cares for her eggs, but if conditions are not right for her brood, she may eat them, and then she has another chance to try again later. Like praying mantisses, the octopus female sometimes cannibalizes the male. If she decides the time is right to deliver her young, not only does she refrain from eating her eggs, she stops eating altogether. The octopus mom guards her eggs from predators, focused and immobile for months on end.  (They are such smart animals, even playful.  How is it that they don’t get bored?)  During this time, her mouth seals over. She may live for years in this state of suspended animation, just guarding her eggs; but when the eggs hatch, she dies within a few days. Her death isn’t from starvation. We know because there are two endocrine glands, called “optic glands” though they are unrelated to the eyes, whose secretions control mating behaviour, maternal care, and death. The optic glands can be surgically removed, and the octopus mom lives longer. If just one optic gland is removed, the female doesn’t eat but still lives an extra six weeks. If both optic glands are removed, then the octopus doesn’t lose her mouth and resumes eating after the eggs hatch. She then regains strength and size and can live up to forty weeks more.

In 2007, Bruce Robison of the Monterey Bay Aquarium Research Institute discovered a deep-sea octopus mom watching over her clutch of 160 eggs in the deep, cold waters off the California coast. He returned periodically to observe the same octopus on the same rock in the same position. From 2007 to 2011, she didn’t eat, and she didn’t move except to slowly circulate the water over the eggs, assuring a fresh supply of mineral nutrients. After four and a half years, the eggs hatched, and the octopus mom disappeared, presumed dead, all within a few days. The empty eggshells were observed, memorializing her effort. It was the longest gestation ever observed.

 

Ageing in Reverse

In 1905, the Dutch biologist Friederich Stoppenbrink was studying the life cycles of Planaria, a kind of flatworm, a fraction of an inch long, common in freshwater ponds. He noted that when the animals didn’t have enough to eat, they systematically consumed themselves, beginning with the most expendable organs (sex), proceeding to the digestive system (not much use in a famine), and then muscles. The worms got smaller and smaller until the most precious part—the brain and nerve cells—were all that remained. Stoppenbrink reported that when he started to feed the worms again, they grew back, rapidly regenerating everything they had lost. What’s more, they looked and acted like young worms, and when their cohorts who had not been starved began to die of old age, the starved-and-regrown worms were still alive and kicking. This trick could be performed again and again. As long as Stoppenbrink kept starving and refeeding the worms, they went on living without apparent signs of age.

The medusoid Turritopsis nutricula achieved its fifteen minutes of fame when it was hailed as “the immortal jellyfish” in science news articles of 2010. The adult Turritopsis has inherited a neat trick: after spawning its polyps, it regresses back to a polyp, beginning its life anew. This is accomplished by turning adult cells back into stem cells, going against the usual developmental direction from stem cells to differentiated cells—in essence driving backward down a one-way developmental street. Headlines called Turritopsis the “Benjamin Button of the Sea.” Here again, life seems to imitate art.

Turritopsis can regress and begin life anew

 

Carrion beetles (Trogoderma glabrum) perform a similar trick, but only when starved. As they play life out on a carcass in the woods, the beetles go through six different larval stages in succession, looking like a grub, and then a millipede, and then a water glider before ending up as a six-legged beetle. A pair of entomologists working at the University of Wisconsin in 1972 isolated the sixth-stage larvae (when they were just ready to become adults) in test tubes and discovered that without food, they regressed to stage-five larvae. If they were deprived of food for many days, they would actually shrink and regress backward through the stages until they looked like newly hatched maggots. Then, if feeding was resumed, they would go forward again through the developmental stages and become adults with normal life spans. They found they were able to repeat the cycle over and over again, allowing them to grow to stage six and then starving them back down to stage one, thereby extending their life spans from eight weeks to more than two years.

Carrion beetle, when starved, reverts to any of its previous larval stages.

Continuous Regeneration

Hydras are radially symmetrical invertebrates, each with a mouth on a stalk, surrounded by tentacles, which grow back when cut off—like the many-headed monster of Greek mythology for which they are named. With their tentacles, they snare “water fleas” and other tiny crustaceans, on which they feed. Some hydras are green, fed by symbiotic algae living beneath their translucent skin.Hydras have been studied for four years at a time, starting with specimens of various ages collected in the wild, and they don’t seem to die on their own or to become more vulnerable to predators or disease. In the human body, certain cells, such as blood cells, skin, and those of the stomach lining, slough off and regenerate continuously. The hydra’s whole body is like this, regenerating itself from stem cell bedrock every few days. Some cells slough off and die; others, when large enough, grow into hydra clones that bud from the stalk-body to strike out on their own. This is an ancient style of reproduction, making do without sex. For the hydra, sex is optional—an occasional indulgence.

One recent article claims that the hydra does indeed grow older, and it shows it by slowing its rate of cloning. The author suggests that perhaps clones inherit their parents’ age. The hypothesis is that only sexual reproduction resets the ageing clock. If this is true, then the hydra’s style of ageing is a throwback to protists, ancestral microbes more complex than bacteria. Amoebas and microbes of the genus Paramecium are examples of these protists, single cells in a vast lineage that has anciently radiated into over one hundred thousand species and includes all the seaweeds, slime moulds, and ciliates and other organisms that do not belong to the animal, fungal, plant, or bacteria kingdoms.

 

Ancient Aging

For paramecium, sex and reproduction are two entirely different functions.  Reproduction takes place by simple mitosis—the cell clones itself. Sex takes place by “conjugation”.  The paramecium sidles up to another paramecium, their two cells merge and then the two cell nuclei merge, mixing their DNA, reshuffling within each chromosome, as genes cross over from one to the other.  Then the two cells separate, but the two cells that come apart are not the two cells that entered.  Each one is a different combination of the two original cells—“half me and half you.”

Here is the connection to aging:  Cells keep track of how many times they have cloned themselves via telomere length.  Each time the cell clones itself, the telomeres becomes a little shorter.  When it becomes too short, the cell languishes and dies.  The telomere can be re-set to full length with the enzyme telomerase, but this only happens during conjugation, not during mitosis.  The result of withholding telomerase is that the individual can clone itself about a hundred times, but at some point, it must share its genes via conjugation, giving up its individual identity.  Telomere shortening is an ancient mode of aging that forces the individual to share genes with the community.

This ancient process was a template for the future evolution of aging. Many higher organisms have telomeres that shorten through our lifetimes, until we die. Telomerase is held back in humans, dogs and horses, but not pigs, mice or cows. In the former animals, telomeres are only reset during reproduction, when a new individual is formed from gamete cells of two different parents.  Just like paramecia.

 

Bees That Can Turn Ageing Off

Queen bees and worker bees have the same genes but very different life spans. In the case of the queen bee, royal jelly switches off ageing. When a new hive begins, nurse bees select—arbitrarily so far as we can tell—one larva to be feted with the liquid diet of royalty. Some physiologically active chemical ambrosia in the royal jelly triggers the lucky bee to grow into a queen instead of a worker. The royal jelly confers upon the queen the overdeveloped gonads that give her a distinctive size and shape. The queen makes one flight at the beginning of her career, during which she might mate with a dozen different drones, storing their sperm for years to come.

Weighted down with eggs and too heavy to fly, the full-grown queen becomes a reproducing machine: she lays at a prodigious rate of about two thousand per day, more than her entire body weight. Of course, such reproductive regality requires a suite of specialized workers to feed her, remove her waste, and transmit her pheromones (chemical signals) to the rest of the hive.

Worker bees live but a few weeks and then die of old age. And they don’t just wear out from broken body parts, the rough-and-tumble worlds through which they fly. We know this because their survival follows a familiar mathematical form, called the Gompertz Curve, which is a well-known signature of biological aging. Meanwhile, queen bees, though their genes are identical to those of the workers, show no symptoms of senescence. They can live and lay for years and sometimes, if the hive is healthy and stable, for decades. They are ageless wonders. The queen dies only after running out of the sperm she received during her nuptial flight. At that point, she may continue to lay eggs, but they come out unfertilized and can only grow into stingless drones. Then, the same workers that formerly attended her assassinate the depleted queen. They swarm about her, stinging her to death.

What does it all mean?

Styles and durations of aging in nature are just about as diverse as they can be.  Aging doesn’t have to exist at all, and individual fitness would be 20-30% higher in most cases if aging just took a walk.  Where mother nature has tempered reproduction and kept aging in the life cycle, it is for the purpose of stabilizing the ecosystem, preventing population overshoot that can lead to extinction.  This theory accounts for some broad facts about aging in nature:

  • that aging is near universal in animals, but not necessarily in plants,
  • that aging slows down when animals are starved (no extra curtailment of life is needed in a famine)
  • that animals can substantially outlive their fertility
  • that predator lifetimes are generally longer than their prey
  • that the genetic basis for aging has been preserved over hundreds of millions of years

Apologia pro Scientia Sua

Were I, like Adam, choiced by evil snake
That fruit of knowledge I might free partake
Or, spurning insight, might forever be,
And dwell in vast, obscure eternity…

By two such options I’d be sorely torn—
’Twas not for blind submission I was born.
Infinity sans knowledge is no prize,
While light that fades to black before mine eyes
Is destiny no man would freely choose,
For what we have is all we have to lose.

Posed thus, ’tis plain: rebellion is my path—
I’ll risk the flaming ire of God’s own wrath,
His knowledge, freely giv’n is not so dear
As what by our own efforts we make clear.

With tools of science I’ll investigate
The logic of this world and mine own fate;
While passions I will equally devote
To quest for health, and death’s own antidote.

— Josh Mitteldorf

Detail from The Last Judgment by Hieronymus Bosch (1450-1516)

A Dead Theory Still Walks

The way evolution works makes it impossible for us to possess genes that are specifically designed to cause physiological decline with age or to control how long we live.”  —from a Scientific American article by Jay Oshansky, Bruce Carnes, and Leonard Hayflick (2004)

Most biologists still think this way, even among people who study aging, even those working on anti-aging medicine.  If you believe this as a matter of bedrock theory, then what do you say when a gene is discovered that cuts life short, but still manages to dominate the gene pool?  You say that the gene has benefits that outweigh its costs.  It is a fertility gene, but it has side effects that kill you slowly.  Or it has survival benefit in the wild that are difficult to study in the laboratory.  This is called the theory of antagonistic pleiotropy.  “Pleiotropy” is the biological term describing a situation where one gene has two or more effects on the phenotype.  In 1910 when the term was invented, this was thought to be a special situation, requiring a special name.  We now know that almost all genes have multiple effects.

In theories of aging, antagonistic pleiotropy (in different variants), is considered the unassailable king of the roost.  It is not questioned.  There is no such thing as an aging gene, so as more and more aging genes are discovered, they carve out more and more excuses and exceptions to preserve their bedrock evolutionary theory.  Just this week, there are two new examples, in worms and in people.  

The First Aging Genes

In the 1980s, Tom Johnson, working at UC-Irvine, was studying aging in the lab worm C. elegans.  Johnson grew worms with a defective gene, which he named age-1 after he discovered that worms without it lived half again as long as normal worms. No one had ever imagined that a single gene could have such an effect on life span. In fact, the best experts in evolution had theorized that “everything ought to wear out at once,” so that no single gene could have any noticeable effect. Johnson’s discovery was the more remarkable because longer life required nothing new but rather the deletion of an existing gene. This implied that the effect of the age-1 gene was to cut the worm’s life short. What was it doing in the genome? How did it get there? And why did natural selection put up with it?

Johnson had a ready explanation. He believed (and still believes, I believe) in antagonistic pleiotropy. The worms without age-1 laid only a quarter as many eggs as other worms. It was easy to see how they had been losers in Darwin’s struggle. In fact, Johnson’s finding looked like a dramatic confirmation of the theory that aging was a side effect of genes for greater fertility, greater individual fitness. Aging had not evolved directly, selected for its own sake, but as a cost of greater fertility, a real-life example of antagonistic pleiotropy.

But a few years later, this story unraveled, and what had been confirmation of theory became a direct contradiction. Johnson discovered that his mutant worms actually had two genes that were different. In addition to age-1, there was another, unrelated gene defect (fer-15) on a separate chromosome. By crossbreeding, he was able to separate the two. Worms with the fer-15 mutation had impaired fertility without extended life spans. Worms with the age-1 mutation had extended life spans with unimpaired fertility. This was a full- fledged Darwinian paradox: the age-1 gene found in nature was the one that gave the worm a short life span. It was the “defective” gene that caused the worm to live longer. Age-1 looked not like a selfish gene but an aging gene. It was just the kind of gene that natural selection ought to eliminate handily. How had this gene survived, and what was it doing in the worm genome?

Age-1 was only the first case of an aging gene in worms.  There are now hundreds of genes known that lengthen life span when they are deleted. In other words, these genes, when present, have the effect of shortening life span. Some of them tend to improve fertility; some don’t. Some have other beneficial side effects, but about half the known life-shortening genes offer nothing in return, or at least nothing that has yet been identified.

Still, the pleiotropic theory is rarely questioned.

 

Fertility in male worms

A recent Nature paper from the Shanghai laboratory of Shi-Qing Cai identifies a pair of C. elegans genes that affect the span of fertility in males.  The group collected worms from many different locations around the world.  They found that in some worms, the males remain fertile almost their entire lives, while other males undergo rapid reproductive senescence.  With some excellent detective work, using database searches and genetic manipulation that would have been impossible a few years ago, they identified the genes rgba-1 and npr-28.  Each exist in two versions in wild populations, even though they have powerful effects on reproductive fitness.  Evolutionary theory tells us that genes with a close relationship to fitness should be subject to strong selection, so that the high-fitness version should promptly wipe out the low-fitness version.  In accord with theory, the authors cite statistical evidence that the high-fitness version of npr-28 has recently displaced the low-fitness version.  But, paradoxically, the low-fitness version of rgba-1 has displaced the high-fitness version.

Do they raise a flag in their article and protest that the theory is all wrong?  No, they are almost apologetic, and don’t dare to suggest that there’s anything wrong with the theory.  Such stark contradictions between empirical findings and the evolutionary theory of aging have become so commonplace that most everyone has become inured to them.  They shrug their shoulders and say, “there must be some hidden benefit associated with the wild-type gene that we have not yet identified.”  Part of the reason that they do this again and again is that this is happening in many different labs.  Perhaps each researcher in experimental genetics has only discovered one or two anomalies—they may be unaware that their finding is part of a larger pattern. 

 

Fertility in male mice

In August, a very similar discovery was made by a research group (Xiao-dong Wang’s) at the National Institute of Biological Sciences, Beijing, where I have been resident the last two summers.  Wang published a groundbreaking study demonstrating programmed reproductive senescence in male mice.  The RIPK1-RIPK3-MLKL signaling pathway in wild-type mice was identified as causing a kind of necrosis in male reproductive organs.  Inhibiting this pathway caused the males to retain fertility longer.   

In their Discussion, they say right off the bat, “The above presented data indicated that the previously unknown physiological function of necroptosis is to promote the aging of male reproductive organs.”  But they don’t challenge the pleiotropic theory.  Instead—quite typically for experimentalists—they speculate on a possible loophole that will save the theory:  Mice sired by older males are less healthy than those sired by younger males.  Aha—maybe this is completely unavoidable, and evolution has had to do what it could to prevent these less healthy pups from coming into the world.  “We therefore propose that necroptosis in testis is a physiological response to yet-to-be-identified, age-related, TNF family of cytokine(s) that transduces necroptosis signal through the canonical RIPK1-RIPK3-MLKL pathway.”  One thing they omit is that cutting off fertility to prevent the births of offspring that are (statistically) less healthy is no more consistent with the orthodox evolutionary theory (based on selfish genes) than are the theories that say aging is an adaptation.  Both require group selection, about which orthodox theory is in denial.

 

An Amish family lacking a death gene

Just this week, Douglas Vaughan’s group at Northwestern University reports identification of a rare genetic “defect” that gives some Amish families longer, healthier lives.  The gene called SERPINE1, encoding PAI-1, is mutated and non-functional in these families.  The result is longer telomeres, better insulin sensitivity, protection from cardiovascular disease, and longer life expectancy.  Conversely, the SERPINE1 must be regarded as an aging gene, having no purpose (we know of) except to hasten the demise of its owner.

What do the authors say about the evolutionary implications of their finding?  Exactly nothing.

In Japan, the life-shortening effects of PAI-1 have been known for several years, and there is already a drug in development that blocks its effect.  The drug is called TM5441, and a quick Google search located two lab houses [one, two] that sell it for the same exorbitant price.

Gericault – the Raft of Medusa

In Defense of Pleiotropy

To be fair, I should point out that these genes that have no other purpose than to cause early death really are the exception.  Almost all genes are pleiotropic in one way or another.  Much more common than pure aging genes like SERPINE1 is the situation where genes are dialed up or dialed down late in life in a way that is detrimental (or fatal).  The canonical example is mTOR, the target of rapamycin gene.  This gene plays an essential role programming the development of a young animal.  But when it is turned on late in life, it promotes aging and shortens lifespan.

My position is that this doesn’t let the theory of antagonistic pleiotropy off the hook.  Epigenetic programming is every bit as much under the control of evolution as gene sequences.  Many genes are turned on and off as needed, and this is a matter of course.  A matter of life and death, in fact.  If mTOR is turned on late in life, I presume that natural selection has deemed it so.

Pleiotropy is real.  Most genes have several functions.  But for the pleiotropic theory of aging to be valid, it must be true that tradeoffs are unavoidable.  In fact, when the theory was put forth by George Williams [1957], epigenetics had not yet been discovered, and there was yet no notion of turning genes on and off.  We now know that this process of gene regulation is an essential part of life in all eukaryotes, and that the timing of gene expression is exquisitely regulated.  It makes no sense to imagine (as Williams did) that once you have a gene you’re stuck with it, even if it kills you.  In fact, there are many genes that are turned on in youth and turned off in old age, and the effect is almost always to pro-aging.  In other words, aging is programmed for the most part not through aging genes like SERPINE1, and certainly not through pleiotropy, but rather through epigenetics.  Essential body systems like inflammation and apoptosis are re-purposed later in life as a means of self-destruction.

This opens onto a larger story, the subject of my book.

Aging in the news this week

In the press this week

  1. High-profile, misleading “proof” that aging is inevitable
  2. Disappointing results from Alkahest trials
  3. NewYorker article on exercise in a pill
  4. Splicing factors rescue senescent cells

  1. Mathematical proof that aging is inevitable

The headlines in the secondary scientific press said

Humans living forever is ‘impossible’ according to science

It’s mathematically impossible to beat aging, scientists say

Aging is Inevitable: Math shows Humans can never be Immortal

Mathematical models of aging are my specialty, but I’m not foolish enough to believe in the models.  I’m skilled and experienced at modeling so that I can adjust the assumptions to make a model do anything I want it to do.  I’ve seen time and again how tiny parameter changes can lead to opposite conclusions.  

Mathematical models can prove something is possible.  “Nature might arrange things in this way…”  But math models can never prove something is impossible.  Nature always has the option of arranging things in a way that’s different from the assumptions in your model.

In fact, the paper purports to be a general proof that aging is inevitable in all multicelled life.  But there are a few animals and many plants that don’t age.  Long periods of negative actuarial senescence (during which the probability of death goes down and down for years at a time) are common in trees, molluscs, and sea animals that keep growing without a characteristic, limiting size.  Turritopsis and Silphidae are capable of regressing to larval stage when starved and beginning life anew with a full life expectancy in front of them.  Annette Baudisch has made a career studying and documenting “negative senescence”.  So the idea that aging is some kind of mathematical certainty has about as much credibility as the authoritative declaration in Scientific American that flight by a heavier-than-air craft was impossible (1904 – more than a year after the Wright Brothers’ first flight).

The paper that appeared last week in PNAS is based on the premise that there is a kind of Darwinian competition among cells in the body.  Cells reproduce and mutate within the life of an organism.  In their model, somatic evolution–genetic change over time among cells in the same body–must navigate a course between Scylla and Charibdis.  The result is that mutations must accumulate, leading either to dysfunctional cells, too weak to do their job, or to cancer cells that have lost their allegience to the body and go on

They call this “aging,” but in fact somatic mutations do not contribute significantly to aging [ref].  Rather, in humans, the causes of aging include runaway inflammation, loss of insulin sensitivity, and thymic involution.  (In my view, most of these changes are driven in turn by programmatic epigenetic changes in gene expression.)  They redefine the term “senescent cells” to mean “cells that lose vigor due to cellular damage”, and then look for somatic mutations that cause the loss of vigor; but in general usage the term usually applies to cells that have critically short telomeres, or have otherwise entered a senescent state through epigenetic changes.  

The bottom line is that Masel and Nelson demonstrate a process that theoretically must kill us in the end, but their proof is silent about how long “in the end” might be, and they offer no evidence that the process they describe has to do with aging as humans (or other animals or plants) experience it.  Whatever “in the end” might mean, it must certainly be longer than 80,000 years, because that is the age of the Pando Grove which, last time I checked, qualifies as a multicelled life form.

Scylla and Charibdis

 

Blowing my stack (forgive me)

No one wants to think that death was handed to us with malice aforethought by evolution/nature/the gods.  In African myth, death was an accident caused by the laziness of a canine messenger of the gods.  In Judeo-Christian tradition, man would have been immortal if only Adam had not tasted the forbidden fruit.  William D Hamilton, one of the most insightful and best-grounded thinkers in evolutionary biology, proved that aging was an inevitable result of natural selection in 1966; forty years on, Baudisch and Vaupel used very similar reasoning to prove the exact opposite–that natural selection could never lead to aging [2004].  There are smart, famous people even today who argue that aging derives from the Second Law of Thermodynamics (Hayflick, of all people, is the man who discovered that cell lines run out of telomere).

We want to think that Nature is beneficient, that evolution has done her best by us and made us as strong and durable as possible.  If we get old and die, it must be because of something beyond evolution’s control.  But it’s just not true.  Natural selection first imposed aging on one-celled protozoans, and some of the same mechanisms that cause aging and programmed death in protozoans are active ingredients in human aging today (including telomere shortening and apoptosis).  Aging and programmed death have a long evolutionary history, and an ancient genetic basis.  We must conclude they exist for a purpose.

William Wordsworth asked, “Who shall regulate with truth the scale of intellectual ranks?”

Winston Churchill told us, “A lie gets halfway around the world before the truth has a chance to get its pants on.”

Arthur C. Clark said, “When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is very probably wrong.”  

Young Paul Nelson may be excused for getting carried away by his mathematics, but his mentor (and my former colleague) Joanna Masel ought to know that what they have done is irresponsible.  These memes have consequences.   Arguably, the small and under-funded community of anti-aging research is the most promising frontier of medical science today, offering a vision that may eclipse multi-billion dollar research programs in cardiovascular disease, cancer and Alzheimer’s disease.  Articles like theirs have power because the people who make funding decisions are not experts, they don’t like to be ridiculed, and they’re easily swayed by general sentiment in the research community = people who are already getting the funding.  

If we do not correct this impression, it is likely to discredit the most innovative and dynamic field of medical research today.

 

  1. Disappointing results from Stanford’s first trials of infusions of young blood

Alkahest is a for-profit spin-off from the Stanford lab of Tony Wyss-Coray, doing research with blood plasma from young animals infused into older animals.  I first wrote about the project two years ago.  The company leapt ahead of animal studies to try infusions of young plasma as a treatment for human Alzheimer’s patients.  Last week, Science Magazine reported on a pre-printed meeting abstract: no change in cognitive trajectory of patients who received the infusions.

The people I know best in the field of young plasma are Irina and Mike Conboy.  When I visited them last Spring, Irina told me she expected Wyss-Coray’s protocol couldn’t work.  The dosage is not sufficient, the duration of treatment is too short, and (according to the Conboys’ research) it is more important to remove pro-aging factors from old blood than it is to add the factors found in young blood.

Wyss-Coray took a chance, and I wouldn’t want to criticize his ambition.  But the research world being what it is, this high-profile failure is likely to set back funding for a promising research field.  Let’s do what we can to make sure that research by Wyss-Coray, the Conboys and Amy Wagers continues apace.

 

  1. New Yorker touts the Exercise Pill

An article in last week’s New Yorker began with a long encomium to the drug GW501516, developed by GlaxoSmithkline some 20 years ago, sold in the grey market as Cardarine or Endurobol.  Looking behind the headline led me to learn about  a family of transcription factors called PPAR.  They seem to be promising targets for life extension drugs that are just beginning to be explored.

“In mice, GW501516, either when combined with exercise or at higher doses by itself, induces some hallmarks of [exercise] adaptation such as mitochondrial biogenesis, fatty acid oxidation, an oxidative fiber-type switch and improved insulin sensitivity via AMP-activated protein kinase (AMPK)” [source]  

Sounds pretty good, doesn’t it?  But

“To its detriment however, tumorigenic effects of GW501516 have been reported and development was discontinued by Glaxo in Phase II clinical trials.”   

How serious is the risk of cancer?  Are there ways to separate the benefits from the hazards, either by combing with other drugs or by chemical modifications to the structure of GW501516?  Is there anyone with a lab who is seeking answers to these questions?  

Cardarine=GW501516

Personally, at age 68 the three main ways that I feel my age are (1) decreased flexibility in yoga postures, (2) decreased speed in running and swimming, and (3) I can’t remember what the third one is.  I have charted my steady progression.  Swimming and running times are 30-35% longer than when I was 40, and increasing year by year on an accelerating schedule.  Exercise is my personal biomarker for age.  For reasons of vanity and vitality as well, I eagerly seek pathways to improved performance.  I also think that the activities of GW501516 and other PPAR agonists suggest potential for life extension, though there seem to be no lifespan studies either in rodents or humans.
Much of my source for what follows comes from a new paper summarizing exercise-mimetic drug state of the art, and references therein.

PPAR stands for Peroxisome Proliferator-Activated Receptor.  Peroxisomes are organelles in every cell that specialize in breaking down fat into short chains that the mitochondria can burn.  Thirty years ago, PPARs were discovered in the context of making more peroxisomes, but we now know that their most important function is to increase insulin sensitivity and signal a switch from burning sugar to burning fat.

Stimulating PPAR-α lowers LDL cholesterol and blood triglycerides.

PPAR-γ is a transcription factor that controls creation of new mitochondria.  (Mitochondria are the source of cell energy, and as we age, we have fewer of them and they become less efficient, linked to all diseases of age. [from my blog last summer: Part 1, Part 2]  Stimulating PPAR-γ improves insulin sensitivity and atherosclerosis.  PGC-1α is a protein that turns on PPAR-γ, indirectly creating more mitochondria.  Activating PPAR-γ has been discussed as an anti-cancer strategy.

Stimulating PPAR-δ (the modus of GW501516) switches the body from a preference for burning sugar to burning fat.  Great for weight loss and also for endurance.  You can double the running endurance of mice with GW501516.  Presumably, it was rather effective in enhancing performance in human long-distance runners before it was banned in 2009.  In calorie-restricted mice and long-lived mutants,    PPAR-δ is overactive.  (I’ve seen PPAR-β referred to only as similar to PPAR-δ. Maybe they’re the same.)

Joe Cohen at Self-Hacked sings the praises of GW501516.  Comments on this blog claim that (1) the increased cancer risk in rats was at very high doses*, and (2) the mechanism in rats doesn’t apply to humans.  Other commenters also minimize the cancer risk, but don’t offer references, and they may well be trolls for the companies that profit from GW501516.

“Although peroxisome proliferators have carcinogenic consequences in the liver of rodents, epidemiological studies suggest that similar effects are unlikely to occur in humans.” [source, ref, ref, ref, ref, ref].  “A number of experimental observations suggest that there is a species difference between rodents and humans in the response to PPAR agonists.” [same source] The article goes on to say that PPAR agonists may be more likely to create cancers in rat livers than human livers because rat livers have 10 times the PPAR expression compared to humans. It may be that tumorogenesis comes from the function for which PPARs were named: multiplying the number of peroxisomes.  But we now know that PPARs promote new peroxisomes in rodents but not in humans.

Here’s what I’ve been able to find out about PPARs, GW501516 in particular, and cancer:

PPAR is upregulated in colon cancer cells.  This shows that cancer causes PPAR, but not that PPAR causes cancer. There are many articles like this one, comprising evidence that activation of PPAR-δ promotes growth of existing tumors of the colon. The evidence is indirect, and gives no suggestion of the magnitude of the risk in humans who have colorectal cancer, let alone whether it in implies a risk for people who don’t have colorectal cancer.

PPAR-δ increases expression of COX2, the opposite of what aspirin and NSAIDs do.  NSAIDs decrease risk of cancer, and this suggests both that PPAR-δ increases risk of cancer and that the effect may be offset with NSAIDs.

There are no studies in humans.  There are many websites selling Cardarine, from which I guess that at least several thousands of people have taken taken it since 2005.  I have seen no sales numbers or estimates of the number of self-experiments, let alone cancer statistics. I have been unable to locate any anecdotes about cancer.

This 2004 review preceded GW501516, and reaches no conclusion.  It does, however, state baldly that PPAR-γ (not δ) is generally anti-cancer and that PPAR-α (not δ) causes cancer in rats but not in humans.

I have been unable to find published reports of the origina Smithkline-Glaxo experiment with rats that led to concern about cancer and abandonment of GW501516.

SR9009 is an unrelated mitochondria-growing drug sometimes mentioned in the same articles as GW501516.  There are no studies suggesting that it is carcinogenic, but that may be because it is much newer and there are so few studies altogether.

I don’t know whether Cardarine is too dangerous for human use, or whether similar drugs can be developed that target PPR-delta more safely.  But I’m outraged that the decision to abandon research on Cardarine has been made by investors in a board room who have no concern for public health and consider only the corporate bottom line.  This is an example of the worst kind of collision between capitalism and medicine–a collision which claims millions of casualties each year in the US alone.

I can’t blame the suits in the board room for doing their job, marching to the tune of those who paid the piper.  But this is emblematic of a gross failure of our regulation system, the FDA, and the reliance on for-profit drug companies to decide on our nation’s research priorities.  We now have (presumably) thousands of people taking a drug which may have large benefits and may have large dangers.  Most of them are motivated by wanting to be more buff or more sexy, and they are paying little heed to long-term consequences.  And because FDA has washed its hands of responsibility, there is no one even keeping records or collecting data to learn from the massive experiment about long-term health effects of GW501516.

Cardarine (GW501516) is available from LC Labs ($2240/g), from Monster Labs ($45/g), and from IRC Bio ($108/g, cheaper in quantity)

 

  1. Splicing Factors rescue senescent cells

I must admit that RNA splicing factors weren’t on my radar until this week, but I find this new experiment pretty convincing.  Eva LaTorre and colleagues from University of Exeter (UK) claim that splicing factors, more than sirtuins, are the pathway by which resveratrol (and analogs) extend life.

Sections of DNA (genes) are transcribed into messenger RNA, which finds its way to ribosomes, where the mRNA is translated into protein molecules.  But there is an in between step (in eukaryotes, but not in bacteria).  The DNA contains not whole (contiguous) genes but pieces of genes that need to be spliced together to assemble instructions for a whole protein.  Large sections of the DNA, called introns, are not intended for coding, and they need to be spliced out.  And, in fact, the pieces can generally be spliced together in different ways to make different useful proteins.  The work of splicing is performed by molecular complexes called splicing factors.  This is a process to which I had not given much thought until reading this article, but apparently it is a crucial step in epigenetics.  Epigenetics, the process of turning genes on and off, seems to get more complex with each passing year.

Resveratrol was identified about 15 years ago as a compound that extends lifespan in many species (but perhaps not in mammals).  Resveratrol has many effects, but the primary mode of action has been thought to be through SIR2 (or SIRT1) or related compounds called sirtuins that are selective gene silencers.  But the LaTorre group set out to show that the anti-aging benefit was through splicing factors rather than sirtuins.  They synthesized variations on the resveratrol molecule and tested them until they found one that promotes slicing factors but has no effect on sirtuins.  

Using this resveratrol analog, they were able to turn senescent cells back into fully functioning cells, with restored telomeres and other epigenetic changes.  They demonstrated that this was accomplished through splicing factors, and without sirtuins.

All this was done in (human) cell cultures, and it the horizons are now open to see what effect such rejuvenation has at the whole body level.

_____________

* Of course, there is no established dosage for GW501516, but pills come in 10mg and 20mg typically, corresponding to ~0.1 to 0.3 mg/Kg.  The highest doses I’ve seen discussed in  humans are ~2mg/Kg daily, nominally the same as the rat dosage.

Digging Deeper in Response to Reader Comments

Thank you, readers, for a lively dialog that has developed at the bottom of this page over the last few weeks, touching on some subjects that I have written about and many that I haven’t written about.  I will take this space to respond to some of what you’ve written about.  Some of my favorite topics include exercise, epigenetics, NSAIDs, and the gut microbiome.  Reports of whole-body rejuvenation with the four “Yakanaka factors” is especially promising. I’m grateful to Dr Paul Rivas for many of the ideas that I’ve expanded on here.


Aspirin, Ibuprofen, Naproxen

Background: COX2 inhibitors were found to reduce pain and inflammation of arthritis, but most COX2 inhibitors also inhibit COX1.  It is the COX1 inhibition that led to stomach damage and ulcer risk.  So in the 1990s, the pharma industry set out to find drugs that would inhibit COX2 without inhibiting COX1.  Only later, it came to light that these drugs elevated risk of heart disease, though they lowered the risk of cancer.  (Merck knew of the dangers of Vioxx before anyone else, but kept the stats under their hat as long as they could.) The worst offender, Vioxx=rofecoxib was taken off the market.  Only after CV statistics made the problem clear, researchers were led to ask, Why?  The problem is endemic.  Turns out that COX2 plays a role in maintenance of arterial health, and generally the NSAIDs increase heart risk to the extent that they inhibit COX2.  It turned out that Vioxx was dangerous because it did too well exactly what it was designed to do.

This story hangs together until we consider aspirin.  Aspirin inhibits both COX1 and COX2, and yet the preponderance of studies appear to show aspirin is associated with reduced CV risk [ref, ref].  This suggests there is a piece of the metabolic puzzle that is still missing.  Aspirin has many mechanisms of action, some of them unique to aspirin.

 

My advice, longstanding, has been to take ¼ to 1 whole aspirin or ibuprofen a day (not both; not to be mixed in the same week) after about age 50 for lowered inflammation and protection from heart disease and cancer.  Evidence for protective effect of aspirin has weakened a bit in recent years, but is still holding up [2016].  For patients who have already had a heart attack, aspirin remains standard protocol, and evidence for this population is strongest.

Readers pointed to this study [2017], which reports elevated risk of heart attack for people taking ibuprofen or naproxen.  The dosages they are looking at are several times higher than the daily dosage used for prevention alone.

All the NSAIDs have powerful effects in reducing cancer risk.  Glossing over the different numbers for different kinds of cancer with different NSAIDs in different studies, it’s a good rule of thumb that taking low-dose NSAIDs daily cuts cancer risk in half. [ref]

Effects on cardiovascular risk are more complicated.  I have been unable to find direct comparisons of aspirin vs ibuprofen and others, but there is “circumstantial” evidence in the literature that aspirin slightly decreases CV risk, while all the others slightly increase risk.  Different studies rank the NSAIDs differently.  There is suspicion of the “coxib” drugs which many people find work well for arthritis, but the latest studies show this seems to be unfounded.  This study [2016] finds Celecoxib (Celebrex) is safer than either ibuprofen or naproxen (Alleve), and results in both lower CV risk and lower all-cause mortality.

There may be other reasons to prefer one or another NSAID.  There are benefits for joint pain and stiffness; there are risks for gastric pain and ulcers.  It’s an individual choice, and I encourage you to experiment on yourself.  You can alternate different NSAIDs, but it’s best to do so week-by-week or month-by-month, rather than daily.  Don’t take aspirin and other NSAIDs in the same week.

 

Does too much exercise cause areterial calcification?

Readers pointed to this study [2017] from Mayo Clinic, in which young adults were followed for 25 years, and those who exercised most hours per week had elevated calcification of their arteries.  Calcification, in turn, is correlated with higher risk of heart disease.

There are several reasons I’m not turning on a dime to change my advice about exercise (which has always been, “the more, the better”).

  1. It’s a new finding.  The study is still in preprint form, and cites no precedent.
  2. It’s based on just 268 subjects.
  3. The people in the high-exercise/high-calcification group did the equivalent of 7 or more hours of jogging each week.  But the study didn’t separate recreational from occupational exercise.  Social class is a really big factor, and it may be that all we’re seeing is that working class people have more CV symptoms than the upper middle class.
  4. The fact that exercise is correlated with calcification and calcification is correlated with increased heart risk does not necessarily imply that exercise is correlated with heart risk.  This is such a common mistake.  (A correlated with B) and (B correlated with C) does not let you conclude that A is correlated with C.  In fact, the paper explicitly cites precedent that people who exercise most have lowest CV risk [ref, ref].
  5. So many benefits of exercise for so many aspects of health have been documented over the years that exercise is one of the solidest pillars of any health and longevity program.

The Copenhagen City Heart Study gave me more pause.  They found that joggers who ran at a moderate pace 2-3 hours per week had longest lifespans.  The benefit was about 6 years of life (a big number compared to every other life extension strategy that’s been studied, with the exception of caloric restriction).  But runners who worked longer and harder than this lost the benefit and, in fact, died early.  There is support for this thesis in other articles as well [ref, ref].  But there are also studies claiming that there is only a law of diminishing returns, and no amount or intensity of exercise that is actually bad for longevity [ref, ref].  

I have not figured out the reason that different studies come to different conclusions, but here is what they agree on:  

  • Exercise has a strong benefit for life expectancy, health, mood and productivity.
  • For low intensity exercise (yoga, walking, hiking, low-speed cycling, low-speed swimming) there is no evidence that too much can hurt you.
  • If there is a threshold above which exercise can increase cardiovascular risk and shorten life expectancy, it is only for intense exercise and long duration, typical of a marathon runner.

My guess (based on disagreement among experts) is that there are individuals for whom a great deal of high intensity exercise is beneficial, and there are others who damage their cardiovascular systems by pushing too far.  Doctors may be able to tell you if you have a heart condition that makes exercise hazardous.  My hope (based on personal experience with yoga) is that we might develop a sensitivity to our bodies, so that we can distinguish the pain of damage from the pain and resistance that always accompanies a strenuous workout.

 

IP6 is a new supplement for me

I’m grateful to Dr Paul Rivas whose comment in this blog led me to read a little about it.  Inositol hexaphosphate (IP6) is a bio-available form of Inositol, which is in the B-vitamin family.  It has a major benefit for certain kinds of anxiety and depression, and minor benefits for blood sugar, insulin sensitivity, and cancer prevention.

 

Extraordinary story of radiation hormesis

A reader referred us to this story in a comment last week.

It would be unethical to intentionally expose people, unknowing, to ionizing radiation.  But in Taiwan 35 years ago, construction steel was accidentally contaminated with Cobalt 60.  The Health Safety Society recommends that 50 millisieverts (mSv) is the maximum safe radiation dosage.  But 1700 people in apartments buildings in Taibei were exposed to this much radiation year after year for a period of 9-20 years until the contamination was discovered and they were evacuated.  These people were studied for adverse possible health effects, but the result was that they had dramatically lower rates of cancer and birth defects.

Hormesis is a word for Improved health and longevity in response to challenges such as low doses of toxins, radiation, heat, cold exercise and fasting.

 

Cancer as atavism

Dr Green has outlined a theory that cancer [his comment] is a state of unconstrained cell growth characteristic of free-living cells half a billion years ago, before there was multicellular life.

First part of theory is cancer is normal growth from prior to 500,000 million years ago, prior to Cambian period. That was before plants and before oxygen rich atmosphere; life was fermentation, unlimited telomerase, no aging, cells were immortal.

This was new to me.  Cyanobacteria have been around for 2.5 billion years, with the capacity to turn CO2 into O2.  But apparently it was not until 800-600 million years ago that the oxygen in the atmosphere approached present levels.

Of more practical interest is Dr Green’s idea that it is epigenetics and not genetics that makes a cancer cell.  If this is true, then an entire anti-cancer industry based on the idea of mutations being the root cause of cancer is misguided.

 

Yamanaka Factors Used for Rejuvenation

I missed this article when it came out almost a year ago.  The “Yamanaka factors” (abbreviated OSKM) are four chemicals which, when applied together, can turn an ordinary differentiated cell (a skin cell, for example) back into the stem cell from which it came.  Pluripotent stem cells replenish all the cell needs in the body.  The offspring of a stem cell can be any kind of cell, hence “pluripotent”.  Up until ten years ago, it was thought that this was a one-way street, and that the process of differentiation was irreversible.  Then the Kyoto laboratory of Shinya Yamanaka reported success in “de-differentiating” cells by adding just four chemicals, initials O, S, K and M.  In other words, these four chemicals turn a regular skin or muscle or organ cell back into the stem cell from whence it came.

Summary of the Yamanaka-factor reprogramming experiment.

De-differentiation rejuvenates the cell, including lengthening of telomeres.  But can the rejuvenation be done without the de-differentiation?  That’s the subject of a Cell paper by Ocampo et al.  They report success in rejuvenating cells in a living mouse, without changing them back into stem cells.  They do this via intermittent doses of the same four Yamanaka factors.  The shorter duration (2-4 days) has the effect of epigenetically reprogramming cells to their younger state, without destroying their differentiated identity.

For several years, I have have been attracted to the idea that aging is essentially an evolved epigenetic program.  The holy grail would be to take cells that are programmed to be old and epigenetically reprogram them to be young.  The hitch in this plan is that to do this directly requires changing methylation at millions of separate sites, in addition to re-programming dozens of other kinds of epigenetic markers (besides methylation), some of which are just being discovered.  These sites are specific to cell type, introducing further complexity.  We have neither the knowledge of where all these sites are, and only rudimenteray ability to alter them with CRISPR and allied techniques.

These results raise the exciting possibility that epigenetic changes supersede/precede other aging hallmarks in the physiological aging process, as well, and may thus constitute a key target for future rejuvenation strategies. – Anne Brunet & Salah Mahmoudi

The finding last year by Ocampo et al offers the possibility that we don’t have to do any of this, that just four chemicals will instruct the body to do it all for us.  Watch closely—this may be the pathway to whole-body rejuvenation that so many researchers have been groping toward.

What about damage to the cells?  The good news is that epigenetically rejuvenated cells seem to be able to repair their damage better than we might do it with artificial interventions.  Somatic DNA mutations were repaired.  Mitochondria were returned to a younger appearance and performance.

Provisos and qualifications:

  • Lifespan increase has been demonstrated in genetically short-lived mice.  For normal lab mice, they report physiological markers of rejuvenation, but didn’t wait to see if the mice would live longer.
  • How do you get OSKM into the mice (or the humans)?  In this experiment, extra copies of the four factors were inserted into the mouse genome before birth in such a way that they were normally turned off, except in the presence of the antibiotic doxycycline.  This provided a convenient way to turn OSKM on and off at will, with injections of doxycycline.
  • In the genetically short-lived mice, the rejuvenation is temporary, only lasting 8 days before progeria asserts itself again.  We don’t yet know whether rejuvenation in normal mice will be short- or long-acting.

Brunet and Mahmoudi end by suggesting that induction of the four factors could be combined with removal of senescent cells, speculating that major life extension could result from synergy between the two.  (They also note that getting the four factors into cells of a living human being is a challenge we don’t yet know how to approach.)

Comparison of Various Rejuvenation Modalities

 

News from the world of telomerase activation

Thanks again to Dr Rivas for this article demonstrating that ashwagandha is a potent telomerase activator.  This article adds to the evidence that cells with the shortest telomeres are the problem, and average telomere length is less important.

 

Gut Microbiome

Once again it is Dr Rivas pointing us to this article.  Stool samples from 1,000 “extremely healthy” people of all ages were analyzed for RNA sequences associated with intestinal bacteria.  Their principal finding was that the composition of the bacteria depended more on health than on age.  There were major differences through childhood, and for people in their 20s, the bacterial colony was in a class by itself.  But after age 30, up through age 100, bacterial ecology of all the healthy individuals tended to look alike.

A recent consensus says that we lose gut diversity with age, possibly as an adaptation, but more likely with negative consequences for health.

 

Tocotrienols

These are variants of vitamin E.  They differ from vitamin E (tocopherol) in the same way that unsaturated fats differ from saturated fats.  They are more reactive, more easily manipulated by the body.  The normal varieyty of vitamin E (alpha tocopherol) does not have lifespan benefits, and may be a net negative.  Gamma tocopherol may be better, or it may be that we need a mixture of tocopherols in combination. The only human studies have been done with alpha tocopherol, and when you buy “vitamin E pills” that’s what you’re getting.

Early research suggests that tocotrienols protect against cancer and reduce inflammation. The body treats them differently from vitamin E, and they have separate activity. Tocotrienols occur naturally in foods including palm oil, wheat germ, and rice bran.  You can buy supplements of mixed tocotrienols, or gamma tocotrienol, or mixed tocotrienols with tocopherols.  

 

Inheriting Telomere Length

Unsurprisingly, telomere length at birth is inherited from parents, and is assumed to be correlated to lifespan.  Surpringly, a baby’s telomere length is inherited more from the father than from the mother.  More surprisingly, older fathers sire children with longer telomeres (though their own telomeres are, presumably, shorter).

 

Low-Dose Naltrexone

Naltrexone is a 35-year-old drug used to block opioid receptors and help people breaking addictions.  Soon afterward, Dr Bernard Birhari discovered naltrexone in low doses as a treatment for auto-immune disorders (allergies, lupus) and as an anti-inflammatory.  There has been some success with LDN as a cancer treatment.  Take LDN at bedtime, as it blocks pleasure receptors.  The theory is that blocking receptors during sleep increases the release of endorphins during the day.  There is anecdotal evidence for LDN as treatment for depression, PTSD, anxiety and sexual dysfunction.  LDN hasn’t been approved or tested for any of these uses, but informal experimentation off-label is gathering a critical mass. Advocacy site for LDN.


Thanks to all of you reading this column, and thanks especially for the intelligent and informative conversation that has grown up underneath this blog.  I hope you’ll please keep the ideas coming!

Air Pollution and Life Expectancy

Increased air pollution cuts victims’ lifespan by a decade, costing billions” blared the headline from Eurekalart last summer.  I spent five months of the last 15 in Beijing, with arguably the worst air quality in the world.  I call Philadelphia my home, with the 10th worst air pollution in the US.  In the past, before good statistics were available, I have been an advocate, board member and even expert witness in support of clean air legislation.  Now I dreaded discovering what air pollution might be doing to my long-term health.  I procrastinated, and left this project on a back burner for a year.  But when I finally chained myself to my desk to research this column, the results were not nearly so bad as my fears.


The above Eurekalert article referred to this research from Denmark, and the summary, it turned out was misleading.  The question it appears to be asking is, “if you live in a city with 10μg per m3 of particulate pollution, how much sooner must you expect to die?”  But in fact, it addresses a different question:  “Assume that air pollution has zero effect on the great majority of people, and that the entire burden of increased mortality comes from a small number of unlucky people.  If you are one of those unlucky people, how much is your life cut short because of air pollution?”  (Even for this unrealistic assumption, I am not convinced that the author did the calculation correctly.)

For context, the study was based on the concentration of the smallest particulate pollution, particles less than 2.5μm in size, which are thought to do the most damage.  A concentration of 10μg/m3 for such particles is a level typical of a large American city on an average day.  Philadelphia has many days each year exceeding this level.  Beijing air on a summer day has 150μg/m3, and winter days are typically 400-600μg.  If my reading of the Danish study is correct, it implies that the average citizen of Beijing loses 500 years of life to air pollution.

 

Questions

Beginning my reading, here are the questions I was curious about:

  • How much life is being lost to air pollution in American cities and Chinese cities?
  • What pollutants are responsible?
  • Is the risk linear with pollution, or is there a threshold?
  • Are sources of pollution predominantly local or regional?
  • Where are the best and worst places to live?
  • What diseases are associated with air pollution?
  • What can be done to mitigate health consequences of exposure to air pollution?
  • Is it better to exercise in polluted air or not exercise at all?

I came away realizing that some of these questions are difficult to address with field studies and epidemiology, and others have not been addressed, even though they are not so difficult.  But generally, I was re-assured that air pollution is not as big a health threat as headlines had led me to fear.

 

How big is the effect overall?

This study looked at day-to-day variations in death rates in Wuhan, a large, polluted city in China’s heartland.  They find that 10% of all deaths are due to respiratory disease, and some large fraction of respiratory deaths are triggered by the day’s SO2 level.  (Sulfur dioxide is a significant pollutant in China, but not America, because so much coal is burned in and near cities.)  This speaks of the  immediate effect only, and corresponds to less than one year of life lost.  But this kind of study can tell us nothing about long-term effect.  Another study in Eastern China (Jiangsu province) compares across cities, so is potentially sensitive to long-term as well as immediate effects.  They find a smaller effect of ozone (O3), corresponding to a few months of lost life.

One of my first discoveries in researching an early ScienceBlog column five years ago was that large differences in mortality correspond to small differences in life expectancy.  The deep cause of this counter-intuitive effect is the steep rise in mortality curves, building a wall of death into actuarial tables.  This is what Benjamin Gompertz realized two centuries ago, but I was a little late to the party.  

These mortality statistics are large enough to detect unambiguously, and a few percent increased mortality (up to 10% in China’s most polluted cities) sounds quite serious.  But when these numbers are translated into life expectancy changes, the results are far less alarming.  10% in the worst Chinese cities corresponds to less than 1 year of life expectancy.  1% – 2% typical of American cities corresponds to about a month of life expectancy.  Much more difficult to quantify is the extent to which the health effects of air pollution are focused on a subset of people who are particularly sensitive, and who will suffer a seriously early death.  This is the question addressed by the headline-grabber I quoted at the top of this column [ref].

The most recent comparison of South and North China (where coal was burned freely for winter heat) is featured in  Eurekalert with the sensational headline, Air Pollution Cuts 3 Years in Northern China, but the research article behind it reports 8 months.

 

My own informal study: Life Expectancy in American Cities

Can we see an effect of pollution on life expectancy in America’s largest cities?  I looked up the data, and found a surprisingly large variation in life expectancy.  Here is a scatterplot of life expectancy plotted against EPA’s measurement of average morning pollution levels for the smallest particles (PM2.5).

There is a correlation that goes in the expected direction, but not statistically significant, and no clear visible trend.  For comparison, look at the plot of life expectancy vs per capita income:

Here there is a statistically significant correlation (p=0.01) and a trend that is visible to the eye.  Across 25 cities, 29% of the variance in life expectancy can be explained by wealth alone.
[Source for pollution data]
[Source for life expectancy data]
[Source for income data]

Mechanism of long-term damage

When mice breathe air with particulate pollution, their arterial walls thicken and stiffen, arterial plaques increase, and inflammation rises over a period of months [ref].  Similar effects in humans would be expected to increase risk of heart disease and ischemic stroke.  Much of this damage is thought to be reversible after ths source of the pollution is removed [ref].

Joel Schwartz of Harvard School of Public Health has persisted through a long career in creating some of the most solid and credible connections between pollution and its health consequences.  This classic study, more than two decades old, uses conservative statistical methods to separate effects of weather from pollution.  (Weather is known to be highly correlated with daily mortality, more so than pollution, and pollution, of course, is correlated with daily weather and also with season.)  The result is a robust conclusion that TSP of 100 μg/m3 increases risk of death by a factor 1.06.  The weakness of this finding is that, since the time of this study, TSP=“total suspended particulates” has gone out of fashion as a measure of pollution.  TSP measures large particles more heavily than small, but we now know that the smallest particles are most damaging.

Air quality in America has improved in the last 20 years, and most days, most places are compliant with EPA limits.  Nevertheless, a difference in mortality rates can be detected between the good days and the bad.  A recent study from Schwartz’s group investigated the question of low-level pollutants.  They are able to detect effects from three pollutants: PM2.5, O3 and NO2, and report a total ~1% increase in daily mortality.

 

Dose-Response

This is a large unanswered question, very difficult to pose in an epidemiological study design.  It is plausible that high exposure for a short time is more damaging than low exposure for a longer time, but the opposite is possible.  It is plausible that the combination of chemical irritants (e.g., O3, SO2, NO2 with micron-size particles is worse than either of the two separately, but we don’t know.  A “latency” is often assumed, such that today’s exposure to bad air can produce hidden damage that shows up a decade later to cause disease or death.  But it is just as plausible that those who are fortunate to escape disease in the immediate aftermath of pollution exposure suffer no long-term consequences.  We do know that hospital admissions and both cardiovascular and pulmonary mortality rise in times of major pollution events.  But smaller day-to-day fluctuations in air pollution also produce smaller fluctuations in a city’s mortality and morbidity rates, and these can be correlated in long-term studies.  

 

Is there a threshold, below which low levels of pollutants cause no problem?

Probably not.  This study by Schwartz found that 1% or 2% of all deaths in Boston are arguably attributed to particulate and ozone pollution, and Boston air is cleaner than most large American cities, and was within EPA guidelines virtually all during the time of the study (2000-2009).  A study across different cities in Eastern China also could find no evidence of a “safe threshold”.  

 

Do filter masks do any good?

Masks are common in China

These cheap, simple respirator masks are a common sight in Beijing.  They are so thin that it is easy to imagine that they can’t be doing much of anything, but apparently this simple measure is quite effective.  This study from University of São Paulo was based on metabolic response to pollution, and found the response was reduced to undetectable levels by wearing a mask.

Also common in China are indoor air purifiers that continually circulate air through a HEPA filter.  The Berkeley Wellness Letter offers some suggestions and emphasizes limitations.  A room air purifier provides less effective protection than a mask.

Room air purifier

 

Can B Vitamins Shield you from Harm?

This study looked at short-term effects of particulate pollution only.  These include elevated heart rate, suppressed immune function, certain epigenetic changes (DNA methylation),  and a decrease in heart rate variability.  (The latter is a somewhat mysterious but apparently robust measure of health that has begun to gain recognition as an indicator in recent years [ref].)  By all these measures, a modest course of B vitamin supplementation for several weeks preceding exposure completely prevented the physiological response.  On the one hand, it’s a very impressive result; on the other hand, what we care most about is long-term damage to the lungs and CV system, and the short-term protection may or may not correspond to long-term protection.

To Exercise or Not to Exercise?

This study finds that the benefits of walking and cycling outweigh the damage done by breathing more polluted air.  The claim is that this is overwhelmingly true in moderately polluted Western cities, and remains true in all but the most polluted cities of the developing world.  The methodology of the study looks good to me, although the data on which it is based are uncertain.  The study doesn’t address high-intensity exercise, which necessarily involves rapid hyperventilation.  It is hard to know if lung damage might be caused at an extra-high rate when the body’s cleansing mechanisms are overwhelmed, as they are in cigarette smoking.  People in China tend to exercise less on high-pollution days, but when they live in high-pollution cities, they make the most of it and exercise indoors, or outdoors when the pollution is as good as it’s going to get [ref].

Early morning Tai Chi, an old Chinese tradition all year ’round

 

The Bottom Line

Mitigating air pollution is an important environmental project, with health benefits that far outweigh the costs.  It is indeed a travesty that our EPA is bowing to pressure from GM and Exxon, decade after decade.   Mitigation is well worth pursuing in the US, let alone in developing Asian cities.  Nevertheless, even in the worst areas of China and India, the air pollution is a major health problem only for a sensitive segment of the population, and overall robs city-dwellers of less than a year off life expectancy.


Two Personal Notes

  1. I fasted for five days last month, coordinated to end on the Jewish fast day of Yom Kippur.  The last two days I took large doses of quercetin, thinking to purge senescent cells.  Fasting is supposed to protect normal cells, while sensitizing senescent cells to toxins.  Quercetin is a supplement commonly found in health food stores, a flavonoid extracted found in onions and green tea.  It has been identified as a senolytic.  Results:  Difficult to say with any certainty, but I did feel an ease and speed in swimming after I began re-feeding, and perhaps an easing of chronic stiffness in my low back.
  2. I have a yoga practice that goes back to 1972 and, I believe, has helped me to retain range of motion.  The place I feel loss of suppleness most is my lower spine, and MRIs showed a loss of discs beginning 20 years ago.  I take daily aspirin, 325 mg at bedtime, and I think I associate this with an easing of flexibility in the low back.  Recently, I’ve noticed that if I substitute naproxen (200 mg) for the aspirin, my low back feels less stiff in the morning.  Naproxen is a stronger over-the-counter NSAID than aspirin, more likely to produce side effects in sensitive stomachs; some studies claim to detect long-term heart risks.  The best reason to prefer aspirin over naproxen is the long history attesting to the safety of aspirin (for most people).  

    I intend to try more controlled experiments over the next few weeks to see if my first impressions of naproxen’s benefit hold up.

 

Is Cancer a Mitochondrial Disease?

“Cancer is a genetic disease.  Its primary cause is mutagens in the environment, abetted by time and bad luck.  A cell is controlled by the chromosomes in its nucleus, and when just the wrong combination of mutations happens to occur, a cell can begin to grow and multiply uncontrollably.  The next crucial step occurs when the cell acquires the ability to travel through the bloodstream and implant somewhere else.  The whole pathway from errant cell to malignant cell proceeds via chance mutations. From inception to metastasis, cancer is driven by genetics.”

This theory of cancer is more than 100 years old, but it didn’t become the dominant view until the 1950s, when, after Watson and Crick, genes assumed an exalted position in the study of biology.  The “somatic mutation theory” continues to dictate the course of cancer research and treatment today.

It is uncontested that cancer cells have abnormal chromosomes.  Dozens of different mutations have been found in malignant cells.  They have been catalogued as different oncogenes, and because they are so different in their functions, cancer has been re-conceived from a single disease to a category containing many different diseases with similar symptoms.

Are mutated genes the root cause of cancer?  Toxins that commonly break DNA (teratogens) are also found to cause cancer (carcinogens).  Radiation, ditto.  “Ionizing” radiation packs enough wallop in each photon to break a chemical bond, and is associated with cancer, while non-ionizing radiation (visible, infrared, and radio waves) is not mutagenic and generally not carcinogenic*.  This has been taken as powerful circumstantial evidence for the prevailing theory.

A direct answer to the question of whether cancer originates in the nuclear DNA is available from an experiment that is simple in principle: Swap nuclei between two cells, one normal and one malignant.  Take the mutated DNA out of a cancer cell and put it in a normal cell, to see if it becomes malignant.  Take the un-mutated DNA out of a normal cell and put it in a cancer cell to see if the cell is rescued and restored to health.

This experiment has been technically feasible for more than 30 years, and indeed Barbara Israel and Warren Schaeffer actually performed both experiments at UVM and wrote them up in 1987 [ref, ref].  The results were exactly the opposite of what was expected: The cell with normal cytoplasm and cancerous nucleus was normal; the cell with normal nucleus and cancerous cytoplasm was cancerous.  This result has been confirmed in other labs [reviewed by Seyfried, 2015].  Still, the genetic paradigm has a stubborn grip on cancer research and treatment to this day.

An alternative theory of cancer as a metabolic disease was put forth by the Nobel polymath Otto Warburg in the 1930s.  The principal proponent of this theory today is Thomas Seyfried of Boston College.  Seyfried cites evidence that damage to the nuclear DNA, conventionally thought to be a root cause of cancer, is actually an effect of the damaged mitochondria and irregular metabolism.  “The metabolic waste products of fermentation can destabilize the morphogenetic field of the tumor microenvironment thus contributing to inflammation, angiogenesis and progression.”

 

Respiration and Fermentation

Every cell in our bodies (and almost every cell in all eukaryotes everywhere) makes uses of energy in the form of ATP, adenosine triphosphate.  ATP is manufactured in the mitochondria, usually by a controlled burning of sugar to form CO2 and H2O. Highly energy-intensive cells such as muscles and nerves have thousands of mitochondria in each cell.  The word “respiration” in this context is used to mean burning sugar in an efficient energy conversion process, yielding 38 ATPs for every sugar molecule.  But when oxygen is scarce, perhaps because you’re breathing as fast as you can or sprinting in deep anaerobic mode, another process can be used to rapidly convert available sugar stock to lactic acid, requiring no oxygen at all, but yielding only 2 ATPs per sugar molecule.  The latter process is called “fermentation”.  (This observation explains the extraordinary effectiveness of interval training (sprints) for weight loss.)

Warburg was among the first to notice [1931] that most cancer cells use fermentation rather than respiration as an energy source.  Metabolic studies pointed to damaged mitochondria in tumor cells that had become inefficient in producing sufficient energy through respiration.  He theorized that impaired mitochondrial function is the root cause of cancer.  In fact, Warburg did some of the early work establishing the role of mitochondria as cellular energy factories.

So most cancer cells are sugar addicts.  They consume enormous amounts of sugar, both because they are actively growing and dividing, and also because they use sugar so much less efficiently than normal cells.  A PET scan can be used to visualize concentrations of sugar in the body, and PET technology is often used to locate tumors.

Sugar is easily made from carbohydrate foods, and when you eat a diet containing carbs, sugar is the fuel of choice.  Ketones are an alternative fuel used by the body when burning fat, either stored fat or ingested animal fat or vegetable oils.  (Medium chain saturated fatty acids like coconut oil seem to be most effective in inducing metabolic ketosis.)  Unlike sugar, ketone bodies cannot be fermented.  They generate ATP energy only through oxidative respiration in the mitochondria.

The logical question:

Are zero-carb diets an effective treatment for cancer?

Some well-known cancer drugs (Gleevec, Herceptin) already target the fermentation metabolism.  Acarbose has been proposed but not yet tried.  But might it be safer and more effective to starve cancer cells by cutting carbohydrates in the diet to zero?  There is a robust literature suggesting, “yes” [e.g., ref, ref, ref, ref, ref, ref, ref] but so far the results have been less than earth-shaking.

A search of ClinicalTrials.gov yields 25 trials of ketogenic diet variants for cancer treatment.  Most are in early stages, 5 have been completed, 2 have results.  In this study, the ketogenic diet, with or without chemotherapy, did not cure glioma.  This small study found modest benefits in a variety of advanced cancers.  These results are consistent with many mouse studies, in which some benefit was recorded from the ketogenic diet, but not a dramatic difference.  The most encouraging results I have found was a study in which 9 of 11 mice treated with a combination of radiation and a ketogenic diet were cured of brain cancer.  Clearly, this is no miracle cure, but it’s too early to give up–we’re just figuring out how to make the diet work, and it has not yet been tried except at late stages, after all else has failed.

Fasting shows more promise than ketogenic diets.  (Perhaps fasting lowers blood sugar even more than ketogenic diets.)  A series of studies by Valter Longo make the case that fasting simultaneously sensitizes cancer cells to chemo or radiation and de-sensitizes normal cells.

Seyfried has proposed a “press-pulse” system based on this vulnerability, targeting the glucose metabolism and the glutamine metabolism with hyperbaric oxygen.  Besides glucose, glutamine is also a major fuel for tumor cells.  Drugs will be required to target glutamine, as glutamine is the most abundant amino acid in the body and can be easily synthesized from glutamate.  Hyperbaric oxygen requires a patient to be enclosed in a pressurized oxygen chamber or room filled with pure oxygen at 2.5 x atmospheric pressure.  There is one highly encouraging case report for the success of this triple combination—hyperbaric oxygen, glucose inhibitors, and low-dose chemo—in which a late-stage, resistant breast cancer is driven to total remission.

Last week, a research paper from Duke U suggested a target for attacking the fermentation metabolism of cancer cells, and a marker for identifying which cancers are likely to be sensitive to it.  The research group of Jason Locasale found a protein called GAPDH which switches to the fermentation metabolism, and a compounded called koninjic acid, extracted from fungi, that inhibits GAPDH.  They have tested koninjic acid extensively in cell lines, and have begun testing in live mice.  Whether such drugs are more effective than simply restricting glucose is a topic for investigation.

Explanatory diagram from the Duke study of GAPDH

 

Mito-targeted Cancer Prevention

 Supplements that promote mitochondrial health include CoQ10, PQQ, mitoQ/SkQ, alpha lipoic acid (ALA), carnitine, and melatonin.  Can they lower risk of cancer?  So far, we have just a few hints; this is a promising area for research.

CoQ10 was studied in the 1990s as a cancer treatment, with some encouraging results [ref].  PQQ has been shown to kill cancer in vitro [ref].  One mouse experiment looked at ALA as part of a cancer treatment [ref].  Use of carnitine remains theoretical [ref].  Most has been written about melatonin [ref, ref, ref], but even here, there is no epidemiological evidence.

 

The Bottom Line

All the evidence for radiation and other mutagens causing cancer might be re-interpreted in terms of mutations to mitochondrial DNA.  (Mitochondria live in the cytoplasm, outside the cell nucleus, but they have a bit of their own DNA and ribosomes for transcribing it.)  Damaged mitochondria can also cause cancer even when their DNA is intact, and Seyfried (after Warburg) makes a strong case that mitochondrial damage is the root cause of cancer.  Inflammation is probably the single worst source of mitochondrial damage. Do we need one more reason to minimize inflammation?  Viruses often target mitochondria for their own ends, and this may explain cases in which viral infections are associated with etiology of cancer.

The insight that mitochondrial damage is the root cause of cancer (preceding nuclear mutations) also has broad implications for cancer prevention.  As for treatment, there have been a few disappointments and also some promising pilot studies, especially in combining glucose deprivation with radiation or chemo to finish the job (“press-pulse”).  This is a research field that deserves much more attention.

__________

*There are exceptions to both these generalizations.  There is controversy whether ionizing radiation at low dosages causes cancer [ref]; and cell phones (non-ionizing) have been linked convincingly to cancer risk, presumably by a different mechanism than breaking chromosomes [my column last year].

I sent a draft of this column to Thomas Seyfried, who was kind enough to edit it in detail and add references of which I was unware.

I was led to this subject by my co-author’s publisher, Chelsea Green, publishers of
Tripping over the Truth, by Travis Christofferson.