Lithium for Life Extension?

Last month, Anna Fels wrote in the Sunday NYTimes suggesting that lithium be added to the drinking water because trace amounts of lithium are associated with lower rates of mental illness, violence and suicide in particular.  What she didn’t say was that communities with naturally-occurring lithium in their drinking water enjoy greater longevity as well.  Though the evidence is still thin, there is a credible mechanism, through inhibition of a chemical signal called GSK-3β.  The dosages we’re talking about are ½ to 2 mg per day, which is less than 1% of the dosage typically prescribed for bipolar disease.


 

Lithium is not a drug, but a chemical element.  It is right above sodium in the periodic table, and the theory is that the body can’t tell the two apart.  Sodium is an essential electrolyte, and the body uses it everywhere.  Nerve signals are propagated as waves of substitution of sodium for potassium.  The theory is that trace amounts of lithium in the body replace sodium, and move a little faster across membranes, because the ions are smaller and lighter.

The only study looking at all-cause mortality compared different regions of Japan.  Drinking water was analyzed and mortality rates were compared in 18 different towns, 1.2 million people in all.

 

394 2011 171 Fig1 HTML Lithium for Life Extension?

Top graph: 18 Japanese towns Bottom graph: Survival curve of lab worms

The top graph shows about 10% decrease in mortality in regions of Japan that had naturally high concentrations of lithium.  Large dots correspond to counties with large populations. Note the log scale on the X axis; the high counties had about 30 times as much lithium in their drinking water compared to the low counties.  10% decrease in mortality corresponds to about an extra year of life, extrapolating boldly.

The bottom graph is a survival curve for lab worms with lithium added to their medium, compared to control worms without.

The most abundant and compelling data is about suicide and violent crime rates in towns with varying amounts of natural lithium in the water.   Twenty different studies in different parts of the world are summarized here.  This same review covers four studies in which lithium was used to treat Alzheimer’s Disease, and all four found benefits, measured by cognitve performance.

 

Lithium in the diet

There is general agreement that animal grazers don’t concentrate lithium, and the best dietary sources are plants.  Which plants are best?  The answer seems to depend on lithium in the soil at the site where the plants happen to be grown.  We can’t characterize some foods as “good sources of lithium” except according to the location in which they were grown.  So it is impractical to figure out how much lithium you’re getting in your diet.  A blood test might be helpful, with the qualification that lithium passes quickly through the body (swept through with sodium), so the test is sensitive to what you happen to have eaten in the last 24 hours.

 

How does it work?

Of course, we don’t know how lithium works, but speculation all centers around a powerful and ubiquitous (if little-known) chemical signal called GSK-3β.  Lithium suppresses the action of GSK-3β.  All that I know about GSK-3 (alpha and beta forms) I learned from this article by James P Watson (not to be confused with the Watson who got the Nobel for DNA).

The alpha and beta forms of GSK-3 are distinct proteins, derived from separate genes.  The nomenclature would lead you to believe that they are different forms of the same thing, but the nomenclature is deceptive.  I’m not going to tell you what GSK stands for, except that the last word is kinase, because the name reflects only the particular circumstances in which GSK happened to have been discovered (in 1980).

If “energy is the currency of the body,” then phosphate groups are the dollar bills.  Kinases are enzymes that activate other chemicals by attaching a phosphate group to them.  The GSK-3s are kinase amplifiers.  They specialize in finding placs where there is already a single phosphate, then adding more to fully activate the substrate.

GSK-3β has been implicated in the formation of amyloid plaques in the brain, which is one theory for the cause of Alzheimer’s Disease.  This was the motivation for trials of lithium against AD, which have shown early signs of success.

The two forms of GSK-3 are involved in many different processes, turning on dozens of genes and turning off dozens more.  The actions are varied and complex, and GSK-3 cannot be characterized as helpful or harmful.  Watson refers to GSK-3α as the “mainly good guy” and GSK-3β as the “mainly bad guy”.  GSK-3β expression increases with age, and it may play a predominantly pro-aging role.  Suppressing it a bit seems to do some good.  GSK-3α does not modulate consistently with age, either up or down.  However, when the GSK-3α gene is knocked down in mice, the mice are not only viable but have lower fat mass and increased insulin sensitivity—harbingers of extended life.  Watson characterizes GSK-3α nevertheless as “mainly good” based on its effect dampening three aging targets: mTOR, Wnt and P53.  P53 controls apoptosis=cell suicide which, I have argued, is on a hair trigger as we age.  Dialing down apoptosis non-selectively has general benefits for preserving muscle and nerve cells, but it also increases cancer risk. TOR is “Target Of Rapamycin”.  Recall that rapamycin is a drug that made headlines three years ago when it was found to extend mouse life span, though fed to the mice late in life.  Rapamycin is a powerful immune suppressor, and may be too dangerous a drug for general human use, but other drugs that dampen TOR signaling may be promising.

 

Speculation on the future

I am convinced that both forms of GSK-3 are key players in aging and other metabolic functions.  However, they may not be good targets for anti-aging intervention because they play on both teams (promoting pro- and anti-aging pathways).  The fact that they need “priming”—a first phosphorylation by a more specific kinase—indicates that they are not an upstream source of aging.  We can find better targets.

Trace doses of lithium might prove to be useful for modestly extending life and protecting against Alzheimer’s.  I’d like to see studies in mice, and larger epidemiological studies, and then clinical trials if warranted.  There has been only one epidemiological study.  It should not be difficult to find some part of the world where people don’t tend to move very often and then correlate local concentrations of lithium in drinking water with local variations in age at death.

 

For early adopters

If you want to experiment with lithium, I think that doses up to 1mg/day are safe.  Just for context, this is a tiny quantity.  One ounce of lithium is a lifetime supply.  Larger doses are not better.  They are toxic.

Lithium is not a standard ingredient in multi-mineral pills. Nor is it a standard blood test.

Lithium carbonate is available as a prescription drug, in pills that cannot easily be divided into 100 doses.  If you felt comfortable with the procedure, I suppose you could dissolve a 500mg pill in a pint of water and take it by the teaspoon.  There are about 100 tsps in a pint.  Lithium carbonate is about ⅙ lithium.  You can also get lithium salts from chemical supply houses.

Google to find on-line sources of supplements with appropriate low doses of organic salts of lithium, like lithium arginate and lithium orotate.  They are not better or more bio-available than the simple carbonate, just more expensive.


Thanks for Michael Eaves for pointing me to sources for this article.

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Anti-aging Oxymorons and         Anti-oxi-morons

The natural foods industry is deep into the anti-aging business, and it’s all based on two lies—one about pesticides and toxins, the other about anti-oxidants.  Neither toxins nor oxidation are the reason that we get old, and we can’t live longer by eating less toxins or more anti-oxidants.  In fact, toxins in small quantities stimulate the body’s longevity pathways, and anti-oxidants can nullify the very real anti-aging benefits of exercise.

People who are fanatical about clean air and organic food don’t live to extraordinary ages.  Animals raised in a super-clean, toxin- and pathogen-free environment actually die earlier than animals raised with bugs and dirt.

Anti-oxidants have been tried in animal experiments and human studies, and they don’t extend life.  In a definitive study, 29,000 Finnish men were given anti-oxidant vitamins in the 1990s, until the experiment was called off for ethical reasons.  It turned out people taking the vitamins were dying at a higher rate than the placebo group.

“Natural anti-aging” is a contradiction in terms, an oxymoron.  There are plenty of good reasons to eat organic.  Support more sustainable farming practices.  The vegetables taste better.  There’s more nutritional value and it might even be healthier, especially for young people.  But natural foods are not part of the recipe for a longer life.

In fact, there is plenty you can do to slow down aging and improve your odds for a long life, but the best practices aren’t particularly “natural”.  Weight loss, fasting and short bursts of vigorous, all-out exercise are high on the list.  There are also some hormones and two prescription drugs* (long out of patent) that seem to work.  The easiest thing you can do to improve your odds is to take tiny doses of aspirin and mega-doses of vitamin D. (Much more here.)

 

What aging really is

Aging is not about the body wearing out, and it’s not about accumulating  toxins.  Aging is something our bodies are doing to themselves.  All the stuff that goes wrong as we get older is no accident, and it’s not a failure of the body.  Aging is suicide on a schedule, programmed into our genes.

  • The stem cells in our body are tasked with renewing our skin and muscle and bones and blood, and even our nerve cells regrow over time.  But the stem cells have replication counters in the chromosomes.  Regular readers of this page are familiar with telomeres and “cellular senescence”.  Telomeres are the body’s primary aging clock; when the counter gets too high, the stem cells get the message to slow down growth and repair, to let the body go to pot.
  • Our immune system is brilliant at distinguishing invaders from self, attacking the former and protecting the latter.  This is done by the T-cells in our blood.  The T in T-cell stands for “thymus”, a little organ behind the breast bone where T-cells are trained to tell the good guys from the bad guys.  But your thymus has been shrinking ever since you were about 10 years old, and by the time you’re 40, it’s only ⅓ what it was when you were a child.  90-year-olds have almost no thymus left, and that has everything to do why 90-year-olds can’t defend against the flu, and why pneumonia is the Old Man’s Friend.
  • The T-cells don’t just fail to defend us against enemies, they make the opposite mistake as well, and attack perfectly good, healthy tissue.  Inflammation is your first line of defense against invading microbes when you’re injured, and it works great when we’re young.  But as we get old, inflammation turns inward.  Healthy cells are destroyed.  Stem cells are re-purposed as cancer cells.  Inflammation has been linked to the Big Four diseases of old age which, together, are responsible for more than 90% of all deaths:  cancer, heart attacks, Alzheimer’s dementia, and stroke.
  • There are more ways in which the body actively destroys itself in old age.  Read some of them here.

These aren’t failures of the body.  They’re mutiny.  We can’t fix these problems by supporting the body with a natural diet.  Instead, we have to trick the body into doing something it wasn’t designed to do.  That’s the very opposite of “natural”.

The reason that medical progress in the diseases of old age has been so slow is that the researchers are all working with the wrong model.  They are stuck in the paradigm of the 20th century, when “natural medicine” was so successful.  The idea was to work with the body, to enhance the body’s natural defenses,  to help the body heal itself rather than to engineer fixes from the outside.

This worked really well for trauma and for infectious disease and all the diseases that young people get.  But it won’t work for the diseases associated with aging, because the body itself is the enemy.  The body is programmed to self-destruct—that’s the very essence of aging.  We can’t fix it by coddling or helping or restoring the body, because the body is divided against itself.  We can’t oppose aging with “natural medicine” because aging itself is natural, designed into our life plan.

 

Why don’t anti-oxidants work?

Every cell in the body generates the energy it needs in hundreds of tiny factories called “mitochondria”.  And it’s true that they generate toxic waste, in the form of ROS, Reactive Oxygen Species aka Free Radicals.  The ROS can attack the body’s sensitive biomolecules and make them dysfunctional.  This much is true, and it has been the basis of one of the oldest and most popular theories, the Free Radical Theory of Aging.

The Free Radical Theory is more than fifty years old, and based on the theory, a substantial industry of anti-oxidant vitamins and supplements has grown up.  If damage from oxidation was the problem, then anti-oxidants should be the solution.  It was a plausible theory when it first came out, but we’ve known for twenty years now that anti-oxidants don’t work.  The only reason this news hasn’t reached the public is that it is bad for sales.  What is more, we now understand why they don’t work.  It turns out that the damage caused by free radicals is completely avoidable, and it occurs when the body dials down its own native anti-oxidant system.  The body has its own anti-oxidants, perfectly adequate to quench the free radicals and keep the damage to levels at which it doesn’t accumulate at all.  Some of these molecules are glutathione, ubiquinone (aka CoQ10), and SOD=superoxide dismutase.  But they are all held back, so we have less of them in old age.  Our defenses against oxidation are crippled by design, and that’s why oxidative damge tends to accumulate.

The deeper reason why anti-oxidants do more harm than good is that the body uses free radicals as a signal that switches on active repair and rebuilding.  Every time you exercise, you generate copious free radicals, and they signal the body to repair damage, and rebuild muscle and bone better-than-new.  Free radicals also signal the body to keep insulin sensitivity high, steering away from diabetes.  When we take anti-oxidants, we interfere with this system, and that’s why anti-oxidants do more harm than good.  Anti-oxidants shut off the signal that tells the body to rebuild tissues and upgrade defenses.

 

Hormesis

It’s an idea with enduring appeal, that the reason we age and die has to do with accumulating  toxins.  And modern life is toxin city—pesticides, fertilizers, plastics, GMOs, and heavy metals.  But, once again, the idea has not panned out.  It is based on a faulty foundation,  a mistaken concept of aging and where it comes from.

Tiny doses of toxins may, in fact, be good for us.  Homeopaths have been telling us this for 200 years, but only in the last decade has hormesis gained acceptance as a medical concept.  Confronted with a challenge, the body jumps to respond, and unexpectedly, the body over-reacts.  We are stronger and live longer in the face of hardships than if we live a protected life.  Dogs exposed to tiny doses of chloroform live longer than dogs that are fed a pure, toxin-free diet.  Rats raised in a germ-free environment don’t live as long as rats who get an average dose of dirt and disease.  And so on…there is a whole literature of hormesis.

 

Paleo diet

This is an idea based on a completely muddled understanding of aging.  But despite this, it happens that it’s not a bad diet.  The Paleo Diet is one of those ideas that works much better in practice than in theory.

Grains are mostly starch, and avoiding starch offers a substantial benefit.  Starch is turned instantly to sugar in the mouth, before it even reaches the stomach.  Less starch and sugar means less insulin, which slows the decline into insulin resistant “type II” diabetes, which is one deep cause of aging.  Raw foods are a good idea precisely because they are difficult to digest.  Raw foods are absorbed slowly and incompletely.  For those of us who enjoy eating or who are addicted to food, raw foods may allow us to eat to satiety, because more of the food goes through us, and less is absorbed.  Raw foods are also less prone to cause a spike in blood sugar, triggering insulin release.

Just try getting fat on a raw food diet, and you’ll see what I mean.

Less starch and more raw foods are the best things about the Paleo Diet.  The theory behind the Paleo Diet is something else again.  It’s based on the idea that our body is evolved to work with the foods that were available while we were evolving, which was, for the most part, before agriculture, in hunter-gatherer societies.  You might be suspicious from the get-go when you realize that life expectancy in hunter-gatherer societies is under 40 years, even when the high rates of infant mortality are factored out.  If the paleo diet worked so well, we would expect to find some extraordinarily old people among native peoples in parts of South America and Borneo where they still live the lives of our ancestors 20,000 years ago.

 

What works?

There is a lot you can do here and now to slow aging and improve your odds for continued good health.  I’ve summarized what I know on the page AgingAdvice.org (a non-commercial web page with no advertising).  If you adopt all these measures, it should buy you an extra decade of health.  Much of it is standard medical advice:

  • weight loss
  • vigorous exercise
  • daily baby aspirin
  • a low-carb, anti-inflammatory diet
  • regular sleep habits

But there may be more effective and easier remedies available soon.  The future of anti-aging medicine is fast upon us.

The good news is that researchers are beginning to realize that aging is an inside job.  There are hormones and biochemical signals that tell the body to self-destruct.  Jamming a chemical signal is something that pharmaceutical companies know well how to do and it’s much, much easier than repairing a body full of random damage.  Some of the hormonal signals have been identified just in the last year or three:  Pro-aging (inflammatory) signals have names like NFκB and TGF-β.   Anti-aging signals include GDF11, melatonin, and the “love hormone” oxytocin.  Researchers at Stanford are beginning this month to test transfusions of blood plasma containing a hormone mix from young donors as a treatment for Alzheimer’s Disease in the elderly.

Telomere regrowth is another area that has the potential to extend life dramatically, and even to roll back the years.  There are several companies now selling herbal supplements that can turn on telomerase modestly.  Researchers are hot on the heels of powerful telomerase activators that might actually turn back the body’s primary aging clock.

Look for tangible progress in anti-aging technologies in the near term.

——————–
* One is glucophage=metformin; the other is deprenyl=selegiline=eldapryl=emsam.

 

pf button Anti aging Oxymorons and         Anti oxi morons

The Carrot and the Stick

Sex is so important to the health of a breeding community that natural selection has arranged to encourage everyone to participate.  There’s a conflict here, because the selfish gene does not want to share.  The strongest and most fertile individuals–anyone who has an advantage in the present environment–is tempted not to dilute her genes by sharing, but to reproduce clonally instead.  Avoid the competition for mates; avoid the energy expense, the dangers and deceptions to which mating is prone; transmit all your genes to the next generation, not just half.

 

Sex is not reproduction.

Sex originally had nothing to do with reproduction, and how the two became bound so tightly together is a subject of ongoing debate in the evolutionary community for a hundred years.  Sex is the sharing of genes.  Your children get half your chromosomes and half from your spouse.  What is more, individual genes within a chromosome can cross over between a mother’s chromosome and  a father’s in an exchange that greatly enhances the possible combinations.  Sex serves a profound evolutionary purpose, boosting evolvability by broadening the competition, making possible trials of many diverse combinations.  Sex is a democratizing force in opposition to the selfish gene, tying together the fate of an entire community.  Any selfish gene that wants to get very far in evolutionary competition has to learn to work well with a variety of other genes in the community.  This puts a damper on the selfish advantage of any gene that provides only a temporary advantage, or whose advantage depends on stealing from others.

In “higher organisms”–that’s you, me, and the cockroach–sex and reproduction have been so tightly integrated that it’s not possible to reproduce without sharing genes. Ultimately, it’s the prospect of reproduction that provides the “carrot” (not what you were thinking?)  In some animals, including humans, sexual activity modestly enhances life expectancy.  That might be a carrot if you think of it as a motivation to have sex, or a stick if you think of early death as punishment for abstience.

In many protozoans, the functions of sex and reproduction are completely separate.  Sex occurs between two protozoans of the same species via conjugation, and it may occur only once in a few hundred lifetimes.  But reproduction is something every protozoan does individually, by dividing in half.

 The Carrot and the Stick

Paramecia conjugating

In conjugation, two cells sidle up to each other and the membranes between them dissolve.  Two cells actually fuse, and then the nuclei of those cells (containing the genetic material) fuse as well.  The identities of the two are thoroughly scrambled to create two new individuals.  Then two cells emerge from conjugation, but the cells that emerge cannot be identified individually with the original cells.  You and I have both become ‘half me and half you’.

 

Sex and the Single Protozoan: What’s in it for Me?

In animals and plants, sex and reproduction have been tied tightly together so that organisms can’t revert to reproduction on their own.  But in protozoans, where is the motivation to participate in conjugation?  What carrot or stick assures that cells take time out from the serious business of reproduction to share their genes?

The carrot is entirely subjective.  Disclaimer: I, myself, have never had personal experience as a protozoan.  But several protozoans whom I know and trust have told me that it is an experience like no other.  I mean, like cosmic, man, really far out.  The feeling of that cell wall dissolving and new cytoplasm pouring in is an experience of a lifetime–once in a hundred lifetimes, actually.  Even though they are merging with just one other individual, what they describe is an experience of sublime oneness with all of creation.  Groovy.

Still, in case the experience itself is not sufficient reward for sharing, nature has provided a stick as well as a carrot.  And that is that if you go for too many generations just reproducing clonally, never sharing genes, then you die.  This is the origin of replicative senescence, another name for telomere shortening.

Every time the cell reproduces, the telomere gets a little shorter (in both daughter cells).  If the daughter cells go on like this for more than a few hundred generations, they run out of telomere.  The remedy: sex=conjugation.  When two cells conjugate, the two cells that emerge have long telomeres again, and a fresh lease on life.  Telomerase is brought out of deep storage to rescue the chromosomes and restore their telomeres to full length.  The cells that emerge begin life anew and can replicate hundreds of times more before their descendants have to worry again about a shortage in the telomere department.

 

Telomerase Rationing Enforces Gene Sharing in Protozoans

The interesting thing is that telomerase is right there in the genome, always available to be expressed.  The cell could, in principle, get out a little telomerase every time it replicated, so it would not lose telomere length at all, ever.  In this sense, it is an artificial shortage.  Telomerase is withheld by evolutionary programming, and the cell is coerced into sharing genes every so often in order to get its hands on the telomerase it needs to continue living and reproducing.  The temptation to cheat must be enormous.  The telomerase gene must be hidden away (by epigenetic programming) so well that a chance mutation can’t create a rogue daughter cell that is “immortal” in the sense that it can go on dividing and dividing, never sharing its genes.

We are the descendants of these cells, a billion years on, and we have inherited the same system of telomerase rationing that the protozoans have to live with.  In protozoans, the artificial shortage of telomerase is the “stick” that enforces the imperative to Share Genes!  In humans (and most other mammals) our stem cells divide during an individual lifetime, and very little telomerase is available, so the telomeres of our stem cells gradually shorten with age, and this is one of the primary aging clocks, one of a handful of deep roots of human aging.

oxytricha trifallax The Carrot and the Stick

Oxytricha trifallax

Last week, ScienceBlog featured an article about one such protozoan that reproduces by simple mitosis without telomerase, and conjugates occasionally to exchange genes and renew its telomeres.  This is the pond-dwelling cilliate Oxytricha trifallax.

 

Two Cell Nuclei

Oxytricha and other protozoans (but not higher life forms) actually have two cell nuclei.  There is a micronucleus that contains the original copy of all the chromosomes.  Then there is the macronucleus that contains many working copies.  In the course of the cell’s metabolism, it is the macronucleus that directs all the cell’s activities.  The original copies of the genes are preserved in the micronucleus, which is only active during reproduction and conjugation.  Genes in the micronucleus are organized strictly onto chromosomes.  Genes in the macronucleus are cut apart for easy access.  The number of copies of each gene is proportional to the amount of activity that that gene needs to contribute to the cell’s metabolism.

During clonal reproduction, chromosomes in the micronucleus are copied to make two identical new micronuclei.  But the macronucleus is simply split in two, half going to each clone.  After reproduction, the micronucleus fortifies the macronucleus with new gene copies.

But conjugation brings a truly fresh start.  After conjugation, the two macronuclei are destroyed and digested!  This is so new instructions can be read from the new library of genetic material, coming from two organisms that are slightly different.  The old macronuclei are destroyed, and new ones are created separately in each daughter cell, with faithful copies of that daughter’s genes.

In Oxytricha,

the level of DNA processing in the formation of a new macronucleus is extraordinary: the original micronucleus chromosomes are fragmented at tens of thousands of positions, 95% of the DNA complexity is lost, and the resulting chromosomes– sometimes referred to as “nanochromosomes”–are amplified to thousands of copies each. Each macronucleus chromosome typically contains a single gene flanked by very short telomeres. The size of these molecules ranges from 0.25 to 35 kb, and each is present at an average of 1000 copies.  [Genome Inst, Washington Univ St Louis]

The ScienceBlog summary referred to a recent article by Laura Landweber’s group at Princeton:

Here, we report the Oxytricha germline [micronucleus] genome and compare it to the somatic [macronucleus] genome to present a global view of its massive scale of rearrangement.  The remarkably encrypted genome architecture contains >3,500 scrambled genes, as well as >800 predicted germline-only genes expressed, and some posttranslationally modified, during genome rearrangements.  Gene segments for different somatic loci often interweave with each other.  Single gene segments can contribute to multiple, distinct somatic loci. Terminal precursor segments from neighboring somatic close to each other, often overlapping.

The message is that the genome evolves by assembling pieces of genes that had been found useful in different circumstances in the past, and that much of the genome is assembly instructions for piecing together parts from different locations to form a functional whole.  Many of the pieces are re-used.

This presages the fact for higher organisms that only 5% of our DNA is genes, and the rest is epigenetic instruction, dictating when and where each gene is to be expressed.


 

Brief Updates

I did another 4-day fast this week.  It seemed easier than my first long fast last spring.  There were no craving or headaches.  I’m not able to run or to swim or do interval training while fasting, but I can bicycle and do yoga and walk for hours on end.  I bicycled more than 20 miles (to attend a conference) on my fourth day, and didn’t feel drained.  I’m not very productive during a fast, and my concentration is pretty diffuse.  Sleep is often interrupted by hunger.  But on the positive side, there’s a calm and peace that comes over me, and it’s easy to be content just being where I am.

Science Magazine had 2 feature articles [Ref1, Ref2] and a summary news article on CRISPR dynamics in E. coli bacteria.  The articles describe how CRISPR RNA is able to locate stretches of foreign DNA, planted there by an invading virus, and excise it from the genome.  I still can’t say that I understand how the cell knows what to look for.

 

 

pf button The Carrot and the Stick

Smart molecules, Really smart molecules, and the “B team”

I like to think about chromosomes as Torah scrolls in the Arc of the cell nucleus.  As the Torah contains the germ of all Jewish law, the chromosomes are repositories of all the information that the cell uses to do its business.  Like the Torah, the chromosome is a copy of a copy of a copy of an ancient document.  Like the Torah, the chromosome is scrolled up most of the time for safekeeping, wrapped around a molecular spool made of protein (histone).  And like the Torah, the chromosome is useless unless it is read; and yet every time it is read, there is a risk of damage.  The Torah can be torn, the chromosome becomes broken.

The DNA consists of two complementary strands.  When one breaks, then repairing the other one is easy— the complementary strand is used as a guide.  But when double-stranded breaks occur, proper repair is a complex problem.

The cell has several redundant methods and a great deal of machinery for repairing double-stranded breaks.  The machinery is very similar, not just in plants and animals, but also in bacteria and archaea.  Evidently, DNA repair evolved very early in the history of life, and has been conserved for well over a billion years.

The person who repairs the Torah is called a Sofer, and he has been apprenticed for years, memorizing more than a thousand rules about calligraphy, materials and fabrication.  DNA is repaired by smart protein molecules, which have no apprenticeship.

DNA Repair Smart molecules, Really smart molecules,  and the “B team”

DNA Repair

Making a mistake in DNA repair can be fatal for the cell, so there’s a lot of motivation to do it right.  If one letter is miscopied, the result is occasionally disastrous, but usually is not so important.  If a letter is missing or an extra one added, however, this can spell big trouble.  DNA is read in three-letter words, and if there is one two-letter word thrown in, the reader just grabs a letter from the next word, which then starts in the wrong place, and so on all the way down the line.  This is called a “frame shift error”.  It’s the difference between ABC  ABC  ABC  ABC…  and ABA  BCA  BCA BCA…  Since ABC has a completely different meaning from BCA, the result is not a small difference in one word, but a monstrosity all along its length.

The best and most reliable mode of repair is called homologous recombination, and is closely related to the process that takes place when sperm and egg combine, and some of their genes are permitted to cross over.  There is a molecule called MRN that clips frayed ends to create a clean break.  There is a molecule called RPA that binds to one strand on each side of the break, and a molecule called Rad51 that makes a local copy of the nucleotide sequence near each broken end, and then goes wandering through the nucleus, looking for a match. When all goes well, the match is found, because there are two almost-identical copies of each chromosome in the nucleus (one inherited from the mother and one from the father). So the unbroken, homologous chromosome is found and unzipped at the point matching the Rad51 template.

From this point there are two different sub-pathways.  I don’t think anyone knows how one is chosen over the other.  But the net effect of each is to “invade” the good copy of the chromosome, cut out one strand only, then use base pairing to repair the single-strand gap.  The excised piece is carried back to the broken spot (how to find it?) and inserted at one end. Meanwhile, another Rad51 molecule has done the same thing for the other broken end.

Now the tricky part: The two broken ends each have one strand extended, and these single strands come together, joining up via complementary pairing.  Another smart molecule called DNA ligase performs ligation=snipping off the excess, and re-joining in just the right place.

This story leaves me breathless, contemplating two mysteries: How did random variation and natural selection manage to discover such smart protein molecules?  And how did resourceful teams of dedicated humans (who can’t, after all, sit inside the nucleus and watch this happen) ever figure all this stuff out?

There is no Sofer, no little man inside the cell nucleus directing the process and applying good judgment when things don’t go as expected.  There are only a handful of molecules that perform the repair.  Smart molecules.  Really smart molecules.

 

The B Team

I’m hoping you find such stories as jaw-dropping as I do, but you may be wondering:  What’s it doing in my aging blog?

I was hoping you’d ask.

Last month, the team of Vera Gorbunova and Andrei Seluanov (University of Rochester) published in PLoS Genetics (summarized and explained here in ScienceBlog) an article about DNA repair in old and young mice.  One very efficient mode, slightly different from that described above, is NHEJ, non-homologous end-joining.  It is the preferred method in young mice.  But when mice get older, they switch to MMEJ=microhomology-mediated end joining, and make more mistakes.  This contributes to misformed proteins and inefficient cell metabolism at best, genome instability and cancer at worst.

“DNA repair by NHEJ declines with age in mice, which could provide a mechanism for age-related genomic instability and increased cancer incidence with age.”

If DNA breaks are accidents that happen with fixed frequency, there’s no reason to assume they would be more common in older than younger mice.  Gorbunova and Seluanov modified the genomes their mice so that every time a DNA break was being repaired, the cell would glow green.  There was a lot more green in the older mice.  They showed that this is because the MMEJ process, used in older mice, had more failures.

Why does the body switch from a better to a worse mode of DNA repair?  Is there something that goes wrong with the highly-efficient NHEJ process over time, so that in old age (when the mice need it most) it’s not available for them?  Or is it programmed death, one more example of a way in which the body gets old and dies on a schedule fixed by evolution?

 

 

pf button Smart molecules, Really smart molecules,  and the “B team”

CRISPR in your Future

CRISPR is a two-year old technology developed at Berkeley, Harvard Stem Cell Inst and elsewhere, that is making genetic engineering faster, simpler, and more accurate in the lab.  Last year, they figured out how to insert and delete genes.  This year there are methods for repressing and perhaps promoting genes (epigenetically, without modifying the genome) using CRISPR-derived technology.  Enthusiasts say they will soon be able to turn genes on and off at will.  It is my belief (I’m not alone) that aging is controlled largely by epigenetics—what genes are turned on, when, and where.  Rapid progress is being made identifying the genes that need to be promoted and the genes that need to be repressed to restore an older person to younger gene expression.  It may be that by the time we are ready with this knowledge, CRISPR will be ready to implement it in living patients. The biggest question mark at this early stage is delivery.  How do you get the CRISPR protein/RNA complex into the cell nucleus?  

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The first generation of genetic engineering was turned to therapeutic use by means of genetically-modified viruses.  Viruses already know how to drill their way into a cell wall, find their way into the nucleus, then copy their own DNA into the chromosomes that they find there.  For therapeutic applications, first a replacement for a defective gene is added to the viral DNA, so that when the virus copies itself into the host DNA, the therapeutic gene will be copied along with it.  Second, the virus is denatured, crippled so that it has a limited lifetime in the host, and won’t keep multiplying at the host’s expense.  (The host is the patient.)

First-generation gene therapies are crude in that there is no ability to control where in the genome the therapeutic gene is inserted, or to turn it on or off.  Adenoviruses replaced the lentiviruses used in early trials because at least they insert the gene in the same place on the same chromosome. Results have been mixed, unexpected side-effects are common, and gene therapies have been considered only for patients with life-threatening conditions.  Nevertheless, there are about 2,000 clinical trials currently approved world-wide.

Zinc finger nucleases and TALEN are second-generation technology.  These are enzymes that contain a protein-based portion which can be engineered to bind to a specific segment of DNA, plus a snipper enzyme that cleaves DNA (both strands) where it binds.  Potentially, a gene can then be removed or inserted.  The principal disadvantages are that they are time-consuming and therefore expensive.  It is not easy to engineer a protein that reliably binds to a particular target stretch of DNA.

CRISPR technology is a candidate for third-generation gene therapy, based on a DNA-splicing protein that evolved in bacteria as a defense against invading viruses.  Viruses (bacteriophages) can infect bacteria and insert their own viral genes into the bacteria’s genome.  CRISPR-associated system protein (called Cas9 enzyme) splices the DNA at just the right place to remove the virus, restoring the integrity of the bacterial DNA.

This nifty defense evolved in bacteria and archaea, but not in animals or plants.  Now, researchers have figured out how to lift the Cas9 enzyme and the template that guides it, modify the template at will, and inject it into the cell of a human or lab animal.

(The acronym stands for Clustered Regulary-Interspaced Short Palindromic Repeats.  What that means, and why there should be little palindromes spread through bacterial DNA are questions for another day, because they don’t really help understand how CRISPR works, its potential and its limitations.)

The big new advantage is in the Guide RNA (gRNA), which can easily be sequenced to match (as a complement) any short stretch of DNA in the genome of a human or test animal.  The Cas9 splicing enzyme then finds the spot that matches the complement of the gRNA, and that’s were it does its job.  Curiously, the gRNA is not targeted as reliably as zinc finger or TALEN, and occasionally latches on to a stretch of DNA that is a near-match, so a gene can be inserted or a chromosome cleaved at the wrong place. One solution to this problem that is being tried is to prepare two gRNAs for the same stretch of two strands of the double helix, and to modify the Cas enzyme so that it only cleaves the DNA if both strands are struck simultaneously.

 

CRISPRi

CRISPR techniques can be adapted for epigenetic control, not cleaving a gene at all, not modifying the DNA permanently, but silencing a gene that we may wish to turn off.  (The “i” is for “interference” and the acronym is intended to be reminiscent of RNAi, or RNA interference, which is another second-generation technology, useful for silencing genes only.)  With CRISPRi, tags are attached to the DNA at a target location such that they interfere with transcription of a gene in progress.  Potentially, CRISPR can be adapted to promote genes as well, but this is more challenging.  It is in the promise of full epigenetic control that the most exciting applications lie, in my opinion.

 

Delivery

This is one of the big issues remaining before CRISPR technology can become a useful therapy. So far, it has been used on cells in culture. It has also been delivered intravenously at high pressure to lab mice, but the therapy only reaches a small proportion of cells.  It can be micro-injected into the cell nucleus, but this is practical only for experiments, one cell at a time.  CRISPR kits are being sold as plasmids, which is their original progeny in bacteria.  Plasmids are small loops of DNA, commonly exchanged by bacteria, but foreign to animal and plant cells.  There are papers describing adenovirus applications that combine with CRISPR to offer both control and penetration, and these are so far in early demonstration stages.

 

Active and Inactive DNA

Sewing thread is made of multiple, tiny fibers twisted together.  The twisted structure has an integrity of its own, but it’s liable to become tangled and knotted, so we keep it wound neatly on a spool until we need it.  The cell does the same thing with its DNA.  The twisted structure is the double helix.  And the DNA strand is so long that it’s liable to become tangled.  (We have about a 6-foot length of DNA in every cell, stored in a nucleus that is less than a thousandth of an inch across.)  The spools are protein molecules called histones, and threads of DNA are wound around them for orderly storage.  Each chromosome is a continuous thread of DNA, and there are many spools along its length.  At any given time, some parts of the thread are open and available, while other parts are tightly-spooled and hidden from chemical activity. Tightly-spooled DNA is called heterochromatin, and it is inactive, not available to be transcribed into proteins.  Unspooled DNA is euchromatin, and this is the active form of DNA, ready to be transcribed.

So what happens if a CRISPR unit (a Cas enzyme) comes along that is targeted to a part of the DNA that’s tightly wound up as heterochromatin?  Not much happens.  The CRISPR process is much less efficient on euchromatin compared to heterochromatin.  Imagine a reader scanning through a book looking for a particular phrase.  The process is much more likely to work if the book is open.  This is another challenge for realizing the potential of CRISPR.

 

Which genes to turn on and turn off?

I wrote a series of blog posts on this question last year.

Hormones that we lose as we age include melatonin, thyroxine, DHEA and (recently announced) GDF11

Hormones that are overexpressed, and we need to repress or block include NFκB, TGF-β and (recently announced) JAK/STAT signals

 

The Right Technology for Anti-Aging Remedies

I’m not ready to have my genes replaced, thank you very much.  I think that there are genes that are associated with longevity, and several together might add a decade or more to life expectancy.  But replacing genes is permanent, and it’s based on a technology fraught with unexpected side-effects.  Besides, my body already knows how to be young.  When it was young, it had the same genes it had now, but the epigenetics—the set of genes turned on and off was somewhat different.  I’m willing to bet that restoring a young epigenetic state to my same old genes will make me young, and that’s why I’m pumped about the CRISPR technology.

 

Read more:

Fore-Cas-t from The Scientist
Kurzweil AI on CRISPR gene therapy
Cas9 as a Versatile Tool for Engineering Biology
Comparison of Zinc Finger, TALEN, and CRISPR
Adenoviral vector delivery ofRNA-guided CRISPR
CRISPR-Cas systems for editing, regulating and targeting genomes
CRISPRi explained at a technical level
On-line discussion of speculating about use of CRISPR as a gene promoter

pf button CRISPR in your Future

Sleep and Longevity

Good quality sleep, 6-8 hours per night but not more, is statistically associated with longevity.  Is there a causal connection?  Experiments with rats and data from people doing shift work suggests that yes, there is. But how to get good sleep, and even what good sleep means varies widely from one person to the next.  Different people need more or less sleep, and different sleep schedules can work with different job schedules and life styles.  Regularity is important, and changing sleep patterns from day to day is not good for you.  Melatonin supplements can be an aid to regular sleep, and melatonin is itself a longevity hormone.  If you are one of those people who wakes after a few hours in bed, you need not fight with your body to sleep through the night.  A scheduled period of waking in the middle of the night can be part of a regular daily cycle, and you may find the midnight time is especially good for inspirational or creative activities.

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George was my partner in piano duets and also my buddy in all things concerning health and longevity.  We did yoga and meditation, jogged and cycled and gently competed, never for speed.  We discovered caloric restriction and got skinny together in the mid-1990s.  George worked nights as engineer at a TV station, and didn’t like to sleep during the day.  Some evenings he caught a couple of hours of sleep before reporting for work, some evenings he would just catch a few winks duing his midnight “lunch” break.  A few weeks past his 60th birthday, George fell asleep in front of his TV and never woke up.

I’ve learned to take sleep seriously as a longevity factor.  Just what to do about it isn’t so clear.  (And yes, TV viewing is a mortality risk independent of lack of exercise.)

Sleeping more than 8 hours per night adds 20% to mortality risk, and sleeping less than 6 hours adds 10% [ref].  The added mortality is not associated with any particular disease.

“Shift work [ref] and chronic jet-lag [ref] reduce mental acuity and increase the risk of a number of medical problems including cancer, digestive diseases including peptic ulcers, and sleep disorders.” [ref]

For some people, sleeping in total darkness helps to maintain continuous sleep.  Light is a strong trigger for depressing melatonin, and some researchers say that even the light that gets through the eyelids reduces melatonin in the blood.  Sunlight or bright blue light can help with morning wakefulness, again in some people more than others.

Melatonin is a natural hormone, available inexpensively without prescription, and used by many people to regulate sleep.  In our natural circadian rhythm, melatonin in the blood peaks at bedtime, and makes us feel sleepy.  Conversely, disappearance of melatonin from the blood precedes waking in the mornoing.  You can try melatonin at bedtime to help get to sleep, or if you’re one of those people who wakes after a few hours in bed, you can try melatonin in the middle of the night.  Mice that are given daily melatonin live longer [ref, ref].  Experiment with the dosage.  ½ mg or 1 mg is plenty for most people, and some people find that too large a dose makes them groggy the next day.  Caution: Melatonin can exacerbate sleep apnea in some people.

From WebMD:

Magnesium apparently plays a key role with sleep. Research has shown that even a marginal lack of it can prevent the brain from settling down at night. You can get magnesium from food. Good sources include green leafy vegetables, wheat germ, pumpkin seeds, and almonds. Check with your doctor before taking magnesium supplements.  Magnesium can interact with many different medications, and too much of it can cause serious health issues.”

Narcotics and alcohol can help you fall asleep, but I think they’re a bad idea, likely to make you sleepy during the day, and need more sleep in the long run.  Not recommended.  I advise avoiding even the new generation of sleep medications (Ambien, Rozerem, etc).

Caffeine can interfere with sleep if taken late in the day, and even if you take it early in the day it might it might not help your energy level in the long run.  Coffee consumption is not associated with increased mortality risk, and may even have a modest longevity benefit [ref].  But habitual consumption of caffeine causes the body to reset to a lower energy level (classic addiction response).  So I use caffeine sparingly, when I’m speaking or writing and I want to assure an enhanced level of alterness and verbal fluency, and I remain sensitive and responsive to very small hits of caffeine.

Finish eating about 3 hours before bedtime, so digestion doesn’t interfere with sleep.  A longer period of fasting before bedtime may be fine, if you are not kept awake by hunger.

 

Apnea

Fifteen years ago, I had no idea that I was stopping breathing frequently during the night until my wife noticed and alerted me.  Sleep apnea is the most common sleep disorder in the world, and increases in prevalence with age.  Statistics are soft because there are more cases unrecognized than on record.

I went in to a clinic, and spent a night there, wired up to a machine that monitored my breathing and heart rate.  I was incredulous when the doctor told me that through the parts of the night when I was asleep, I was in a 3-minute cycle, holding my breath until the CO2 buildup woke me up, gasping as I awoke, gradually calming my breathing, falling back asleep, and beginning the cycle all over.  I didn’t remember any of this, and demanded to see the recording, before I was convinced.

Much later, with focused attention as I was napping during the day, I could observe myself falling into a pattern of holding the breath until I awoke in a panic.  Apnea left me tired sometimes during the day, with occasional bouts of narcolepsy.

Long term risks of apnea include heart disease, stroke and loss of brain cells.  It’s not the oxygen deprivation that is the problem, but the re-oxygenation afterward that causes the damage.

Apnea is a mortality risk, apparently independent of obesity, with which it is strongly associated.  Fat in the neck can cause constriction of the air passage, making it more likely to collapse.  This is “obstructive sleep apnea”.  There is another flavor, “central sleep apnea”, which is unrelated to obesity or the size of the air passage, but comes instead from a failure of the autonomic nervous system.

The standard treatment for apnea, a cash cow for thousands of sleep clinics, is the CPAP machine (continuous positive air pressure), a face mask and pump that pushes air into the lungs.  Many people are helped by CPAP and find it worth the inconvenience and discomfort.  Many more can’t tolerate the CPAP.  (For me, the CPAP made my apnea worse, since I was failing to exhale, rather than to inhale which is more common.  Negative pressure “CNAP” or “INAP” (intermittent negative air pressure) machines do not exist—the acronyms are my own invention.

There are straps that hold the mouth closed and mouthguards that pull the lower teeth out in front of the top teeth.  There are suction devices that pull the tongue out of the mouth (while holding the mouth open enough so you can’t bite your tongue).  There is a surgically-implanted electrical device that stimulates the tongue to push forward at the appropriate point in the breathing cycle.  All of these work for some people.

Further out therapies for apnea include Buteyko breathing, orofacial myofunctional therapy, and singing melismas The latter even has some data behind it.

I’ve kept my apnea under control by re-training myself not to sleep on my back.  It helps, but is not a complete solution.

Tension and anxiety

Some sleep problems are extensions of day problems—anxiety, depression, ennui, overstimulation, work pressures.  These are often better addressed by life changes than by therapies.  But relaxation practices can help: yoga asanas and breathing, meditation, biofeedback, heart rhythm coherence, Alexander technique, martial arts.  Vigorous exercise and time outdoors helps with every aspect of health, longevity, mood, relationships, productivity, creativity…and sleep, too.

Learning to relax has benefits that go well beyond improved sleep.  Many people find that through self-hypnosis or mental relaxation, yoga or meditation techniques, they can relax at night and feel fully rested even on nights when sleep may be elusive.  These same techniques are good for the “power nap”, when a brief submersion of 10-30 minutes can precipitate a boost in alertness, productivity and good humor.

 

Two-phase Sleep

In 1979, I was fortunate to be acquainted with Bryn Beorse, then in the last year of his life, but productive, healthy and quietly charismatic at age 84.  I knew him as a UC Berkeley engineering prof and lifelong advocate of renewable energy from the ocean.  But he was also an unlikely guru, with a small but loving following of meditators and Sufi practitioners.  Bryn told me that his habit and practice was to awake about 1AM and do an hour or two of Sufi exercises and meditations before returning to sleep out the night.  This and other things he said made a lasting impression on me.

Much more recently, I have learned how common it is for people to sleep in 3-4 hour cycles rather than 6-8 hours.  Some say that before the Industrial Revolution, bi-phasic sleep was part of the culture.  A period of wakefulness in the middle of the night is part of the body’s natural rythm for many of us, and if it is so for you, I suggest you might adapt to it rather than fight it.  Use the waking period for something nourishing, sustaining and relaxing.  Yoga or meditation are ideal.  You can read something inspirational, practice singing or playing music, listen to music that contributes to your wellbeing.  For some, it can be a creative time, writing or painting or composing, but I don’t recommend using the time to extend your work day or answer emails.  Creative play is an alternative, but video games less than optimal.  When you feel the first wave of sleepiness return, don’t hesitate to go back to bed.

It’s not so common in America, but through much of Asia and South Europe, mid-day siesta is part of the culture.  People sleep less at night, and nap after lunch.  The right to a two-hour lunch break is written into the Chinese constitution.

Some studies show that sleeping twice a day is more efficient than sleeping once, but the decision will be based on your metabolism and your daily schedule.

 

Bottom line advice

I encourage you to experiment, with the goal of finding a schedule that works best for you.  Check magnesium levels, especially if you have muscle twitches.  Don’t hesitate to take melatonin at bedtime, but avoid sleeping pills.  The body’s biorhythm adapts to a regular pattern, and disruption of that rhythm can be costly.  Good sleep contributes to everything you value about life (as well as its length): alertness, creativity, patience and good humor, productivity, enjoyment and a depth of wellbeing that comes from connecting the inner and the outer life.

pf button Sleep and Longevity

Transfusing Youth: the epigenetic aging clock hypothesis is about to be tested

Just this past Spring, Tony Wyss-Coray of Stanford demonstrated that infusions of blood plasma from young mice can make old mice grow new brain tissue.  Others have demonstrated benefits for muscle and liver health. The old mice are healthier, smarter, better healers for the infusion of hormones and dissolved factors (not blood cells) from the younger mice.  Leapfrogging over years of animal tests and investigations, Wyss-Coray is about to test plasma infusions in people.  

(I’m grateful to Adrian Crisan and a reader who identifies himself only as “Quandry” for alerting me to this story.  This is not what I had planned to write about today, but I’m pumped.)

 

I have argued that much of our age-state may be coded in gene expression—the choice of which genes are active and which are idle.  We go through life with the same 46 chromosomes we got from our parents, the same DNA, the same genes.  But different genes are turned on and off  in different tissues, at different ages.  This is “epigenetics”, and it determines everything about a cell’s behaviors and activities.

The epigenetic state of a chromosome is programmed by several different kinds of decorations to the DNA.  The decorations include methylation, acetylation, and states of tight-winding and unwinding of DNA about molecular spindles called histones.

Does epigentics also determine age?  In other words, would a young person whose DNA state was epigenetically re-programmed to look like an old person’s actually become old?  Could the body of an old person fix itself up to look like that of a young person if its DNA was reprogrammed?  I think it’s a good bet that this will work.

A separate question is whether it works by a local or a whole-body mechanism.  Does changing the epigenetic programming of a single cell make that one cell younger, or does it contribute to a hormone environment that makes the whole body a tiny bit younger?  DNA expression creates proteins that do the cell’s work at home within the cell, and others that circulate through the body as signals, commonly known as “hormones”.  Hormones can affect the decoration of DNA, changing the epigenetics.  But hormones are also a product of epigenetics.  Cause, effect, and cause and effect.  Perhaps this is the basis of a clock, a biological clock that can time development, maturity, puberty and aging.  It’s an idea I find intriguing.

Up until Sunday, I thought that this idea would be explored at a leisurely pace, indirectly as a result of research with a different conceptual basis.  I was delighted to learn from this New Scientist article of trials soon to begin that will test to what extent young hormones can make a person young.  Here is an interview with Wyss-Coray that contains more details.

History of Parabiosis and Plasma Transfusions

About ten years ago, Tom Rando and several students at Stanford picked up and rejuvenated an experimental paradigm that had been used and abandoned in the past.  They sewed together a young mouse and an old mouse so that they shared a common blood supply.  [See my previous blog, and another].  Of course, the arrangement was hard on both mice, and they didn’t live long.  But they lived long enough to determine that the older mouse was receiving benefits from the younger blood:  faster healing, tissues that looked younger under the microscope, enhanced growth of new nerve and muscle cells.

There were many directions to take this research:

  • What were the blood factors that gave the benefit?  (Not just beneficial blood factors, but others as well that we have too much of as we age.)
  • What tissues and processes are affected?
  • Aside from the surgery, what are the costs and risks?
  • The big question: does the youthful blood profile have the power to reprogram cells epigenetically, so that the body remains in a youthful state and produces its own youthful blood profile?

 

Wyss-Coray’s Bold Experiment

Plasma transfusions are old technology.  Donor blood is separated centrifugally (apheresis) into cells and liquid (plasma) and the cells are returned to the donor’s body.  Because there are no cells, there is no issue of blood type compatibility or immune attack.  A lot of the usual regulatory hurdles are avoided, and Phase I safety studies are bypassed.

This is a small trial, less than 20 Alzheimer’s patients, conducted at Stanford but privately funded by Alkahest, Inc.  (I can’t find a web site for them.  Perhaps they are very new.)  It sounds from the article as though they plan on only one transfusion for each patient.  They will measure cognitive performance sensitively, and hope to see a bump in a few days, perhaps lasting a few weeks or months.

If it is true that they’re planning only one transfusion, this is disappointing.  I’m tempted to say something stronger than “disappointing”, like “what could they be thinking?”  They’re not giving these patients new brain cells, after all.  They’re signaling the body in a way that is likely to stimulate growth of new cells and offer other benefits as well.  But this could take weeks or months, and require a youthful hormonal environment that is sustained over that time.  If I were designing the experiment, I would opt for 10 weekly transfusions to 2 patients, rather than a single transfusion for each of 20 patients.

 

The Future of Blood Factors

I predict that Wyss-Coray’s experiment will work marginally or not at all without repeated treatments.  I hope they see enough success to warrant extended trials in a follow-up.  I think that with ongoing treatment, it has the potential to work spectacularly well, and that over a few months’ time we will see patients becoming younger in a number of ways.  If this happens, it will precipitate a rush of interest and new research in the area.  Patients, too, will be clamoring for treatments.  Old people will feel an entitlement to the blood plasma of young donors.

We will quickly run out of donors.  The best thing that could come from this is an intensive effort to test different components of the blood that vary with age.  I predict that the optimum blood environment will be obtained by re-balancing components.  rather than just adding a few magic ingredients.  Some hormones will have to be dialed up, others dialed down in order to make old blood young.  We may hope that there are just a handful of important factors, and not many hundreds or thousands.  It will not be terribly difficult to create the recipe once we know which hormones are the important ones and how much to add or remove.

 

pf button Transfusing Youth: 
the epigenetic aging clock hypothesis is about to be tested