Nobody Dies of Arthritis

directly.  But in practice, the pain of arthritis limits activity and discourages exercise.  The chronic pain of arthritis wears people down, contributing to depression, which is a substantial mortality risk factor.  Limitations on mobility combined with disspiriting effects of pain can destroy the will to live.  There is no cure for arthritis yet, but anti-inflammatories can slow its progress, and one Swiss company claims a cure in the pipeline.

The “commonsense” view of osteoarthritis is that the cartilage that lubricates our joints gradually wears down over time, and when we are old, bone grinds against bone.  Ouch!  In fact, the commonsense view became the medical view which dominated for many years.  But is it really so commonsensical?  Wearing down of the lubricant cartrilage takes place in the course of hours and days, and, in young people, it is rebuilt and replaced as fast as it is worn away.  (Even the association of extreme exertion with early-onset arthritis (Sandy Koufax’s elbow, : Shaquille O’Neal’s foot) is an effect of chronic inflammation rather than physical wear.)  Thirty-year-olds don’t have more arthritis than ten-year olds, but by sixty, almost everyone has symptoms of enlarged joints, degenerated disks or lumbar pain.  What happens over decades is not explained by the sum of tiny deficits in repair from day to day.  Rather it is changes in the metabolism (initiated by epigenetics, and mediated by signal molecules in the blood) that causes a slowing of regeneration and an acceleration of inflammatory damage.

Historically, the medical community distinguishes rheumatoid arthritis–an autoimmune disease–from osteoarthritis, which is accumulated wear on joints.  The emerging view, however, is that there is no fundamental distinction between them, and that the same metabolic forces are at play in both.  The symptoms were always the same, but the distinction was based etiology: osteoarthritis is almost universal in older people, whereas rheumatoid arthritis is traceable to trauma or an autoimmune condition.  We know now that autoimmunity is part of human aging, an icon of the self-destruction program coded in our genes.

Spinal stenosis is a particularly painful and debilitating complication of arthritis in the spine.  Inflamed bone grows until it impinges on the spinal cord, generating numbness or referred pain in the legs and compromising movement.  Fibromyalgia seems to be a generalized inflammation of joints and muscles.


What can be done?

Exercise may be the best treatment.  The cruel paradox is that arthritis makes exercise much less appealing, and so a vicious cycle begins.

“Patients’ fear for disease aggravation and an indefensible traditional approach of rheumatology health professionals to recommend exercise restriction may account for the inactive lifestyle of this population. It is now established that well-designed physical exercise programmes promote prolonged improvements without inducing harmful effects on disease activity and joint damage.” [ref]

Exercise may hurt, but you won’t hurt yourself with exercise.  Cycling and water aerobics are often suggested, not because they are inherently better for arthritis, but because people experience less discomfort and are more likely to stick with the program.

There is no cure for arthritis, but all the emerging anti-aging technologies are expected to slow or turn back the arthritis clock.

I’ve recommended vitamin D for many reasons, especially lowering risk of cancer and preserving the immune system.  In this study, vitamin D supplementation lowered incidence of arthritis by 1/3.  This study found that people with high circulating levels of vitamin D in the blood had risk of arthritis lower by 2/3.  Depending on your metabolism, you may need to take jumbo doses of vitamin D (10,000 – 30,000 IU) to get your blood level up above 90, which I think is ideal. (Here’s a study that looked for a protective effect of vitamin D and didn’t find any. Here’s another study that finds more tentative evidence of a benefit from high blod levels of vitamin D.)

Arthritis may also be one more reason to keep your magnesium intake high.

Glucosamine supplements have been used for more than 20 years, and are well-researched.  On average, they are marginally effective, if taken in sufficient quantity of 3 or more g per day.  Response varies with the individual, and glucosamine is well worth trying.  One study has found a lower all-cause mortality rate in people who take glucosamine.

A dark horse worth trying is boron, a trace mineral for which there is indirect evidence for a powerful benefit [ref].

S-adenasyl methionine (SAMe) is a pro-hormone, sold by prescription in Europe, where it is used as a treatment for arthritis.  Here’s a study that found SAMe worked as well as Celebrex.  My opinion is that SAMe is worth trying, despite thin evidence, because side-effects of SAMe are likely to be salutory.

A study with krill oil produced the best reported results.  Over the first month of treatment with 300mg/day, patients reported substantially less pain and more mobility, and their subjective experience was corroborated by a 30% drop in C-Reactive Protein (CRP) in their blood (a marker of inflammation).

Boswellia is a resin from the sap of a tree, classically known as frankincense.  It is well-known for anti-inflammatory effect, and there are four well-controlled studies that show objective and subjective benefits [1, 2, 3, 4].  (References collected by

Curcumin (from turmeric) is the best known of the herbal anti-inflammatories.  In clinical trials, it has been found to be effective, but not a magic bullet, comparable in benefit to ibuprofen.  Getting an adequate dose absorbed into the bloodstream is always an issue.

Nigella sativa produced benefits for some patients.  It is a tasty black seed, used in rye bread and middle-eastern cooking, known variously as charnoushka, kalonji, or black cumin seed (no relation to cumin).

Here is a review of many herbal anti-inflammatories, with explanation of the role of the signaling by NFkB as a bad actor.  (Full text available from ResearchGate.)  This team of distinguished Indian-Americans, with thousands of publications among them, highlights curcumin, resveratrol, tea polyphenols, genistein (soy), quercetin (onions), silymarin, guggulsterone  boswellia and ashwagandha.  Here is their table, including other candidates that have shown some promise in at least one study.




NSAIDs are effective.  Aspirin and ibuprofen are safe but of small benefit.  COX2 inhibitors (e.g. Celebrex=celecoxib)  are more effective but raise the risk of heart disease.  For some, the tradeoff may be worthwhile.  Celebrex has been marketed by Pfizer for about 20 years, and has been the subject of commercial law suits unrelated to safety.

Steroids (esp dexamethasone) work temporarily and make you feel good for awhile, but are not a long-term solution because of side-effects from upset stomach to diabetes to depression.

Humira, Remicade, and Enbrel are more recent entries into the arthritis marketplace.  They all target tumor necrosis factor (TNF) cytokines, they are all fantastically expensive, and clinical data is yet thin.  Talk to your insurance company.


On the horizon

Two years ago, there was a report from a Swiss pharmaceutical claiming a cure for arthritis in mice.  They combined dexamethasone with targeted immunotherapy, paradoxically using the immune system itself to attack inflamed sites [ref].  Interleukin4 is fantastically expensive, probably one motive for modifying the molecule with an antibody that would seek out inflamed target cells, so the dose can be reduced.  (Of course, lowered dosage also means fewer side-effects.)  The journal article and news reports from 2014 indicated that trials in humans were imminent, but I have been unable to find evidence that this has come to fruition yet.  While you’re waiting, you might write to scientists at ETH, which is a sort of Swiss MIT.


The Bottom Line

As with so many aging conditions, there is no miracle cure, but there are lots of possibilities for treatments that have great benefit for a few, and small benefit for others.  Until we have personalized medicine based on your genetic and epigenetic profile, there is no substitute for personal experimentation.  Many of the recommendations above have beneficial side-effects, or none.  Try them freely, singly or in pairs.  On for a month – off for a month – on for a month – off for a month, keeping a diary of symptoms.  This is a time-consuming exercise, to be sure, but the potential benefit is huge.  Don’t give up if the first few treatments that you try don’t seem to be working; that’s all in the nature of the game.  We’re looking for the treatment that resonates with your metabolism, and you’ll know it when you find it if you can remain objective and scientific.  (That’s the purpose of the diary.)

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Social Correlates of Longevity—Part II

When we think about things we can do to have longer, healthier lives, it’s the metabolism that comes to mind—diet, exercise, supplements.  It’s a surprising fact that (at least until the next generation of anti-aging technology becomes available) the most effective things we can do are not just psychological—they’re social.  Perhaps because we were raised in the most pathologically individualistic culture in the history of humanity, this seems hard to take in.  The message is to embed in your community and your family, to actualize your creative potential, to love the people around you, to celebrate life and connect, only connect*.

Philosophers from Kant to Buber like to distinguish two ways that people may relate to one another.  One is utilitarian, using the person to help you make money or obtain something else that you want.  This kind of relationship needn’t be sinister.  There can be cooperation and mutual benefit, but the relationship is a calculated investment for personal gain.  The second kind of relationship is a core of human friendship or love or companionship or empathy that we value for its own sake, independent of whether we can get anything out of it.

Kant (paraphrased by Popper) said, “Always recognize that human individuals are ends, and do not use them as means to your end.”  Buber said, “If I face a human being as my Thou, and say the primary word I-Thou to him, he is not…He or She, bounded from every other He and She, a specific point in space and time within the net of the world;…but with no neighbour, and whole in himself, he is Thou and fills the heavens. This does not mean that nothing exists except himself. But all else lives in his light.”

Both utilitarian relationships of power and reciprocal relationships of love can contribute to longevity.  There is a longevity bonus attached to social status and power, and a separate correlation with family, sexual contact, and loving connection.



The protective effects of marriage have been known a long time.  Darwin quoted William Farr’s study of the French (1858), finding that marriage (except teen marriage) is associated with better health and lower mortality.  But marriage is difficult to disentangle from economics, access to health care, social standing and a host of other correlates. This paper finds that after correcting for everything under the sun, married men have 7% lower mortality, and women 4% lower, compared to unmarried.  It’s the human connection that counts.  “Although marriage keeps people alive, it does not appear to work through a reduction of stress levels.”  Two kinds of stress must be distinguished.  The stress of poverty or low social station or suffering abuse and contempt of another human is bad for your health and longevity.  But caring for others, taking on responsibility, leading an active, empowered and demanding life can be beneficial [ref].

Both women and men are at highly elevated risk for death during the months immediately following the death of a spouse [ref].


Social correlates of telomere length

It takes a long time to measure the effect of anything on human mortality.  Elissa Epel has pioneered the use of telomere length and telomerase activity as proxies for life expectancy.  She has found telomere loss to be associated with the bad kind of stress—feeling trapped by circumstance, powerless, stuck living in a way that is not what one wants.  Worry shortens your telomeres.  She found telomere connections to a variety of healthy living habits, including exercise, weight loss and meditation.  Suppression of telomerase can be detected from a single experience of humiliation that is tame enough to pass muster with an ethical review board.  This study finds that depression, anxiety and trauma leave their mark on telomere length in men but not women.  Young women also survive adolescence with more of their telomeres intact than young men.  Do men somatize their stress more than women?

Epel and her mentor, Liz Blackburn, have been slow to acknowledge the (now overwhelming) evidence that telomere shortening has a causal relationship to mortality.  They write of telomere length as a “marker” that tells a tale about past stresses and traumas.  They look for a proximate cause in inflammation and oxidative stress, but stop short of asking for a deeper, evolutionary significance.



There have been many studies seeking to connect fertility to longevity in women.  The consensus is a small positive connection—women who have more children tend to live slightly longer.  A message that stands out from this: for women, giving birth after age 40 offers a big bump in longevity, equivalent to setting your aging clock back more than 3 years.  For fathers who have children late in life, the data is thinner, but what data I could find indicate a benefit almost as strong.  The most relevant study I could find was for an Amish population, “a population characterized by large family sizes and close-knit familial units.”  Seven children was average  for these families.  Longevity of both mothers and fathers increased with each additional offspring, up to the 14th child.  But not beyond.

Less clear than the statistics is the interpretation. In my mind, this is all about caring.  When we stay involved in our children’s lives and care about them, there is a benefit for our health, mediated through neurochemistry.  Just my opinion.

(One prominent study finds a negative association between female fertility and longevity, and I have re-analyzed their data to show a positive effect.  The study was co-authored by Tom Kirkwood, best known for the theory that the reason for aging is that the body needs to spend energy on reproduction.  You gotta wonder when the one study that marches to the beat of a different drummer is done by the person whose reputation depends on the contrarian result.)



How could Mother Nature be so politically incorrect?  It is a sad and stubborn fact that, independent of all else, money is a strong predictor of longevity.

In 1980, the poorest one tenth of Americans lived 3 years less than the richest tenth.  By 2000, that gap had widened to 5 years [ref].  It is wider yet today—possibly as much as 14 years for males, 8 for females if this study is to be believed.

You would think there isn’t much difference in access to medicine within the top 1% of family income, but even there, the rich end of the top 1% lives half a year longer than the slightly-less-rich end [ref].

This is a psycho-social effect, connected to prestige and status.  It has little to do with access to health care.  We know this because the wealthy people in poor countries are living longer than the middle classes in wealthy countries, who have comparable incomes and perhaps better access to medical care.



Redeeming Mother Nature’s rep is this study of the Flemish Renaissance which tells us that elite musicians and poets, though poor, lived as long as wealthy non-artists.  Maybe orchestra conductors have just the right combination of leadership and aesthetics to maximize longevity.



A classic study [1943] by an Ohio Medical professor compared lifespans of historical figures in many different fields.  Musicians do better than painters.  Leaders in democracies do better than hereditary monarchs.  Philosophers live longer than poets.  The main conclusion that Lehman puts forward is that late-bloomers live longer than child prodigies**.  This has convinced me that Hillary, Bernie and The Donald don’t really want to be President—they’re in the race for a longevity dividend.




Frequency of sex is a positive predictor of longevity.  The best-known study came from Caerphilly in South Wales [1997].  Men 45-60 who were sexually active had half the mortality rate of men who had sex less frequently.  (I’ve been unable to find corresponding data for women, or more recent data for men.)  The effect seems to be more psychosocial than physiological, because the association is stronger with frequency of intercourse than with masturbation frequency.  (The article in British Medical Journal is written with a British sense of humor, and the authors make a point of debunking folk wisdom and the many religious traditions that associate orgasm with a depletion of vitality, and are especially tough on onanism.)

I think it’s not an accident that the hormone oxytocin is associated with youthful metabolism and is produced in response to intimacy and feelings of closeness.  Oxytocin spikes in an orgasm.



In this study, a crude measure of happiness was associated with a 20% drop in all-cause mortality.  From everything else we’ve seen, this would seem to be unexpectedly low.  If happiness could be more reliably measured and separated from other variables, it might loom even larger.  “For a 70-year-old man of average health, satisfaction of one standard deviation above average promises a 20 months longer life.” [1989]


The Bottom Line

Tilting the odds for a long life is not just a matter of discipline and abstemious living.  A lot of the things you can do to live a long time are things you want to do, or things that will make your life better right now.  Turn off your computer and spend time with a friend.


* “Only connect” is a refrain from E.M. Forster’s novel, Howard’s End
** Lehman emphasizes that much (but not all) of this is a selection effect: If you attained greatness at age 50, that means that you didn’t die before you were 50.

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Social Correlates of Longevity—Part I

Starve yourself.  Exercise until it hurts.  Buy expensive supplements and stay away from the foods you love most.  You may have the impression that living a long time is no fun at all.

But the good news is that the most powerful life extension strategies are things we want to do anyway.  Live in a way that makes you happy.  Connect deeply to friends and lovers.  Spend time with your children.  Enjoy sex more frequently.  Take leadership in your community.  Express yourself artistically.

The very reason that aging evolved is to stabilize death rates for the sake of the community.  How can we be surprised to learn that the biggest factors affecting our life expectancy are not individual life style but social and communal connections?



Human genetics were shaped in a history of competing small tribes.  What I have long wondered about is that a well-functioning tribe needs a lot of loyal followers and one resolute and charismatic leader.

All animals living in a body, which defend themselves or attack their enemies in concert, must indeed be in some degree faithful to one another; and those that follow a leader must be in some degree obedient.
— Darwin, The Descent of Man

Somehow the leaders and followers had to come from the same gene pool.  Selection is simultaneously for strong-willed leaders and compliant followers.  And when we look today at the variety of personalities, we may observe the successful results: most people are indeed content to take their views and opinions from the community around them, to perform faithfully the task allotted to them, to raise few questions.  And yet there are plenty of us—all of my readers, I’m sure—who question authority, think independently, and who are in the habit of pro-active assertion.

How nature has arranged this, I can only imagine.  My guess is that there are infrequent combinations of genes that lead to independent-mindedness.  But there must also be a great deal of phenotypic plasticity.  That’s a five-dollar word describing a phenomenon biologists don’t understand very well.  Each individual is born with the potential to develop in a number of different directions, and adapts epigenetically within a single lifetime to choose one destiny among many.  Somehow, animals and people figure out when leadership is demanded of them, and respond accordingly, and they shut up and obey orders when appropriate, which for most people is most of the time.

The relevance of this to aging is that changes of leadership are disruptive and costly.  Many a tribe must have fallen victim to neighboring tribes during times when old leadership has died or succumbed to senility, while new leadership is distracted by jostling for power.  A beloved leader with a loyal following was and is a great asset to the community.  It would have served the community well if evolution might have arranged for leaders to have a longer life span than followers from the same community, the same pool of genes.

The take-home message:  Cooperative leadership is good for your health.  Earn the love and respect of your neighbors for your contributions to community life.


Glass half empty / Glass half full

Depression is a big risk factor for every disease that has ever been studied, and depression takes years off a person’s life.  The effect is hard to quantify because people who suffer from depression are more likely to have addictive dependencies, less likely to have healthy diets, less likely to exercise, less likely to have supportive social relationships.  The indirect toll of depression makes it hard to measure the direct effect independently.

This study of telomere length in heart patients found that depression accounts for 2½ years of excess telomere attrition.

I think of depression as one side of a continuum, from a full capacity for awareness and open-hearted enjoyment at one end of the spectrum to loss of all vitality and incapacitating numbness at the other end.  But the culture of Western medicine has led to a perspective from which depression is treated as a chemical imbalance in the brain that can be objectively diagnosed, present or absent with no “in between”.

In my view, this accounts for the fact that when psychologists study the health effects of a positive or negative outlook on life, they treat depression as an artifact that warrants separate treatment in their statistics, lest it bias their results.  It is the more remarkable, then, that even after removing from their sample men who are clinically depressed, the authors of this study still find that dispositional temperament accounts for 9 years of life expectancy.  Among a thousand men aged 64-84, those who leanded toward pessimism had more than twice the cardiovascular mortality rates of those who were disposed toward optimism.

9 years of added life is an effect that stands out head and shoulders among the effects that epidemiologists are wont to study.  Points of comparison: If cancer were completely eliminated, it would add 4 years to life expectancy.   Estimates vary for years lost to obesity in America, with a range of 3 to 8 years. Smoking is associated with 10 years of lost life, before subtracting a correction for indirect risk factors that correlate with smoking.


A speculation concerning depression and evolution

Why is depression such a common malady in our culture?  If depression is so bad for us, why has evolution put up with it?  My conjecture is that this is related to the need for phenotypic plasticity in the choice to become leaders or followers.  The genes for leadership must be preserved in the community, and yet most people with genes for leadership must be convinced, nevertheless, to live their lives as loyal followers—else the community would be rent by dysfunctional power struggles.  Depression is nature’s way of keeping too many people with leadership genes from disrupting the authoritarian structures of their community.


Social status

Frequently cited in this regard is a fertile long-term study of health and class in the British civil service system.  The Whitehall Study began in 1967 and continues to this day.

Nearly half a million Brits participate in Her Majesty’s Service, and there are more than 20 grades and subgrades, in a clearly-defined hierarchy of who gives orders and who takes them.  There is a close analogy to grades of military officers.

High-level officers are generally better paid and can afford a more comfortable life.  But medical care in Great Britain is socialized, and disparities in standards of care are relatively small.  There are also differences in family wealth that make the social service grade an independent measure of status, and not merely a surrogate for wealth.

The remarkable finding is that each grade of the service lives longer on average than all the grades underneath it.  Social status is tightly correlated with longevity.




A college education is worth ten years of life to a black male, but only 3 years to a hispanic female.  I don’t think it’s what they learn in school that makes the difference, but the career opportunities and the social connections that come with a college degree that account for the statistics.  I would guess also that there is a good deal of filtering in the process: preferential selection of people with patience and discipline who are inclined  to think about their future. This study attempts to separate the effect of education from filtering for iwhat the author calls “conscientiousness”.  He concludes that both play a role in extending lifespan.  And here is a more recent, drier and more thorough account of differences in life span by race and education, focusing on completion of high school.  A high school diploma seems to be be associated with 5 extra years for a white male, but almost nothing for a black female.


The Bottom Line

To live in a way that is engaged and self-actualized is the best thing you can do for your longevity.  Strong family ties, love, sex, power and money are all good for your longevity.  (Some of these items aren’t in todays blog, but they will be in Part II next week.)


END of Part I

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CRISPR update

I believe that all we have to do to make ourselves younger is to turn on the genes that were expressed when we were young, and turn off the genes that are expressed when we are old. This will require both knowledge and technique; (1) knowing which genes these are, and (2) having a targeted mechanism for turning specific genes on and off in vivo. At this time, our technique is advancing nicely, outpacing the knowledge, thanks to CRISPR / Cas9.

I wrote nearly two years ago that CRISPR was a third-generation technology for editing the genome, which could also be adapted to “edit the epigenome” by turning genes off.  Turning genes on was, and still is more difficult.  The work-around is to add extra copies of the gene, which can be a higher-risk operation, because the body has no evolved mechanisms for deciding when to turn the extra copy on and off.

The older technology of AAV (Adeno-Associated Virus) can be deployed within the living body, transfecting large numbers of cells and inserting a payload gene (of limited size); but there is no control over where in the genome the gene is inserted, and so there is no assurance that it is turned on or off at appropriate times and places.  The newer technology of CRISPR is precisely targeted, can remove or insert a gene, can turn a gene off (but not on).  But so far it is only possible in cell cultures in the lab, and not for large numbers of cells within a living organism.

There are thousands of clinical trials worldwide for AAV gene therapies, and last week the first clinical trial was announced for CRISPR as a cancer therapy.  The protocol is to extract the patient’s own T cells from a blood sample, then modify the cells in lab culture using CRISPR.

The researchers will remove T cells from 18 patients with several types of cancers and perform three CRISPR edits on them. One edit will insert a gene for a protein engineered to detect cancer cells and instruct the T cells to target them, and a second edit removes a natural T-cell protein that could interfere with this process. The third is defensive: it will remove the gene for a protein that identifies the T cells as immune cells and prevent the cancer cells from disabling them. The researchers will then infuse the edited cells back into the patient.

This is a modest first effort in many ways–not just that it is limited to 18 patients and nominally seeks only safety data.  There is great potential for sensitizing the T cells to the patient’s particular cancer.  It would also be logical to combine CRISPR with stem cell therapy.  A patient’s bone marrow stem cells could be harvested, modified with CRISPR, and re-injected, whereupon they would create an ongoing supply of sensitized T cells.  Neither of these ideas will be attempted in this first trial.

The Nature article goes on to recall the tragedy of the first gene therapy trial to kill an 18-year-old patient in 1999, and how gene therapy research lost a decade dealing with safety issues after that.

Hydrodynamic Gene Therapy

This is a kind of brute force method for delivering a genetic payload.  A large volume of dissolved DNA is injected directly into a vein, rapidly enough to raise blood pressure system-wide for a few seconds.  The pressure pushes some of the payload through capillary walls.  This system has been widely adapted for rodent experiments, with a tail vein used as the delivery point.  It has even been tried in humans.  But it is crude and untargeted.  Penetration rates remain low, and collateral damage is unavoidable.


Incorporating CRISPR into Gene Therapy

Of course, what we would really like is the specificity of CRISPR combined with the wide in vitro delivery provided by AAV gene therapy.  The complete machinery for Cas9 to break the DNA strand in a chosen location is too large a payload to fit within the AAV virus.  So marrying CRISPR to AAV has been the subject of some ingenious research just in the last two years.  The first successful experiment was announced this past winter in Nature Biotech.  An MIT-based research team reports that in a single treatment, they are able to make targeted modifications to 6% of white blood cells in a lab mouse.  I’m out of my depth reading about their technique, but from what I understand, there are separate delivery systems for the gene (via AAV virus) and for the targeting (via nano-particles of Cas9 enzyme dissolved in organic fats).  The former makes its way efficiently to the cell nucleus, because that it is what the virus was evolved to do.  The latter must be relied upon to diffuse into the nucleus at random, and the microencapsulation facilitates its transit.

Once inside the nucleus, the Cas9 breaks the chromosome in just the right place, and the virus seizes the opportunity to insert its payload conveniently.  The authors emphasize the importance of eliminating the Cas9 promptly.  If it were part incorporated in the virus, there would be a danger of ongoing, long-term DNA breaks; but the nano-particles containing Cas9 are short-lived.

Here is a recent review of progress in combining CRISPR with viral vectors for gene therapy, written at a technical level.  The Concluding Remarks section speculates on the possibility of combining three separate viruses for delivery of the CRISPR template, the Cas9 enzyme, and the genetic payload.  The obvious problem with such a system is going to be that each of these three viruses has a limited penetration, and it will only be in cells that all three viruses have transfected that the right thing happens (double-stranded break in just the right place, followed by insertion of the payload gene).  In the much larger number of cells that receive one or two of the viruses, there is the probability of damaging side-effects.


A Tangle of Signals

In the fable of the Sorcerer’s Apprentice (and a hundred myths from ancient Africa, Europe and the Orient), the protagonist is attracted to the quick acquisition of power, less interested in the slow acquisition of wisdom.  Exercise of power without wisdom is the classical gateway to tragedy.

And so we see our labs acquiring control over the genome and over gene expresssion proceeding apace, while understanding of the tangle of signaling pathways lags behind.  Many of us are now convinced that aging is controlled by epigenetic signals.  We are beginning to map difference in gene experesssion that occur with age.  But which genes are upstream and which are downstream?  Which are cause and which are effects?  Which are tissue-specific, and which are systemic signal molecules?

It now appears that the technology to modify gene expression will be ours before we know how to use it.

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Rapamycin Redux

Rapamycin is the best anti-aging treatment yet discovered.  Most treatments that work in flies and worms fail when they get to mammals, but rapamycin has consistently extended lifespan more than 20% in mice [review as or 2014].  It works even when administered late in life, and intermittent dosing works as well or sometimes better than daily dosing.

Too bad that rapamycin is too dangerous for general human use.  It is a powerful immune suppressor, used, in fact, to keep kidney transplant patients from rejecting the foreign tissue.  People who take rapamycin are at elevated risk from infectious disease, and who knows but that the immune suppression might inhibit the body’s ability to detect and eliminate incipient tumors.  So there’s a search on for safer “rapalogs” that work through the same TOR (“target of rapamycin”) pathway, but without the side effects, especially with respect to immune suppression.

But what if rapamycin isn’t dangerous?  What if people who take rapamycin don’t get sick any more often, and their cancer risk is actually significantly decreased?  Might rapamycin be a safe and effective anti-aging drug, available now?

Last month, two encouraging reports came out of the research on rapamycin.  One short-term test in marmoset monkeys seemed to show that “immune suppression” was a bogeyman.  There were no adverse effects, even from continuous, long-term administration.  Daily dosage in this test was 1mg/kg, which is the same as used in mice, and 50 times larger than typical human dosages, if calculated with strict scaling by body mass.  (For organ transplant patients, dosages range from 1 to 5 mg per day.)  Scaling of dosage is a not an exact science, and 1 mg per kg of body weight is certainly too large a dosage for our body size.

Marmosets live about 12 years, and there is not yet any data on whether lifespan is affected by rapamycin.

Marmoset monkeys weigh less than a pound.

Mice and some people on rapamycin tend to have high blood sugar, which in humans and mice is associated with risk of all age-related disease.  But the marmosets didn’t have high blood sugar.

Authors of the marmoset paper note that all studies of rapamycin in humans involve people who are sick enough to need an organ transplant, and are taking many other drugs.  We don’t know anything about the effect of rapamycin alone in healthy humans.  Maybe rapamycin enhances the suppression of tissue rejection from other drugs without in itself suppressing the immune system.   This study claims that everolimus actually enhances immune function in elderly humans. (Everolimus, a.k.a. RAD001, is a chemical cousin of rapamycin, a.k.a. Sirolimus, that is used similarly to prevent tissue rejection by organ transplant patients.  Both rapamycin and everolimus act by suppressing the mTOR signal.

Coming down to earth, this study found that in cancer patients treated with everolimus, risk of infection was about double, and in this study, mice infected with influenza and treated with an anti-viral agent did a little worse when rapamycin was added to the cocktail.  But there are other indications that the relationship between TOR and immune response is complex and not yet understood.  Rapamycin seems to inhibit the age-related reactivation of dormant cyto-megalovirus, though it has no direct action against the virus itself..  Already in 2009, it was seen (in mice) that rapamycin can slow the loss of white blood cells that cripples the immune system with age.  In this study, rapamycin was used successfully to aid in treatment of  a mouse model of malaria.  It is the particular action of inflammation against healthy, native tissues that is arguably the greatest source of metabolic damage in aging, and rapamycin may offer a particular protection against this destruction.

Remarkably, animals were protected against ECM [experimental cerebral malaria] even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen and elevated the levels of peripheral parasitemia.



Last month, 40 aging dogs in a limited trial of rapamycin seemed to show improved health without troubling side-effects.  Some dog owners reported a resurgence of puppy-like activity in older dogs.

Cautions from the dog study paper:

The doses used clinically to prevent organ transplant rejection are associated with side effects, such as impaired wound healing, edema, elevated circulating triglycerides, impaired glucose homeostasis, gastrointestinal discomfort, and mouth ulcers (Augustine et al. 2007; de Oliveira et al. 2011).

Triglycerides in the blood spike upward when people first take rapamycin.  Triglyceride levels are associated with increased risk of CV disease, and are in fact a better predictor than any of the many measures of cholesterol [ref, ref].  “Impaired glucose homeostasis” means type 2 diabetes, which is tightly correlated with aging, and probably has a causal relationship to many of the losses and risks associated with age.  It’s a big warning sign, and also a paradox.  At minimum, it suggests that anyone self-experimenting with rapamycin should be taking metformin as well.  Or, maybe the insulin challenge is part of what makes rapamycin work–it wouldn’t be the first time that throwing a challenge at the body had the paradoxical effect of extending lifespan.


The Russian-American biochemist Mikhail Blagosklonny is our foremost enthusiast for rapamycin in humans.  (Read about him in this Bloomsburg article from last year.)

“Some people ask me, is it dangerous to take rapamycin?” Blagosklonny says. “It’s more dangerous to not take rapamycin than to overeat, smoke, and drive without belt, taken together.”  Many colleagues have regarded his advocacy as a bit over-the-top.

It’s rumored that Blagosklonny takes rapamycin himself, but I couldn’t get him to talk about it.  (Actually, I agree with him that it’s one thing for him to experiment on himself, another for him to publicly encourage others to do so.) Blagosklonny writes

  1. Rapamycin suppresses geroconversion: conversion from cellular quiescence to senescence. Geroconversion is cellular basis of organismal aging.
  2. Genetic manipulations that inhibit the TOR pathway extend life-span in diverse species from yeast to mammals
  3. Rapamycin extends lifespan in all species tested
  4. Calorie restriction, which inhibits MTOR, extends lifespan
  5. MTOR is involved in diseases of aging and rapamycin prevents these diseases in animal models

Caveats and Obstacles

Rapamycin is presently the best candidate we have for a drug to extend life in humans.  It is expected to extend “health span” as well as lifespan, lowering incidence of cancer, heart disease and stroke.  But is it “safe and effective” for use in people?  We may never know, because its patent has run out, and there is no company motivated to invest the cost of a human trial.

Proper dosing for human anti-aging purposes is hard to guess.

A short course of Sirolimus (a name brand for rapamycin) can cost thousands of dollars and requires a prescription.  You can buy rapamycin more cheaply from a number of lab supply houses, but only if you provide a delivery address for a university lab, and certify that the purchase is for research purposes only.  It is less pure and quality control is unregulated.


In this recent paper, D. W. Lamming of UWisconsin suggests that the effects of rapamycin can be divided into inhibition of two complexes, mTORC1 and mTORC2.  C1, he says, is good for longevity, while C2 is responsible for the side-effects.  C1 responds quickly, while C2 responds more slowly.  Hence, he suggests that intermittent dosing might be effective at safely increasing life span.  The definition of “intermittent” remains undefined until a variety of schedules can be tested.

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Lamarck Update

I wrote a few weeks ago about newly-discovered dynamics of DNA that make Lamarckian genetic inheritance more plausible than ever.  I wrote that there was now just one step missing from a fully-documented Lamarckian mechanism.  In a comment on that page, a reader pointed me to a paper that fills in that final step.

Almost everyone looking at the process of evolution that has created the vast biosphere is struck initially by how surprisingly efficient the whole process has been.  But quantitative estimates that might tell us whether this intuition is valid are frustratingly elusive.  No one has been able to model or to estimate or even to place a reasonable lower bound on the pace of evolutionary change in a biosphere with the stats of our own Gaia.  The question we would like to be able to ask is whether blind mutation and natural selection constitute a sufficient mechanism to explain all that we see in biology, and the answer is, “no one knows”.  I hasten to add that it is not just religious fundamentalists who are skeptical.  My favorite example is an essay by Carl Woese, but I might have cited a dozen others.

One key to the question (how evolution manages to be as efficient as it is) is the realization that the process of evolution is subject to evolution.  This is “evolution of evolvability” or, as I like to call it, Evolution Squared.  The idea is that in the beginning, evolution may have depended on blind mutation and natural selection, but the process has become vastly more sophisticated and efficient since then, because as nature selects (directly) for increasing fitness, she also selects (indirectly) for those communities that are advancing in fitness more rapidly.  I use the word “communities” advisedly, because evolution isn’t something that happens to an individual; the smallest unit that can evolve is a deme, meaning a local set of animals or plants, all of the same species, that interbreed with one another.

Evolution of evolution has led to many innovations that we see and document, the greatest of which is sexual sharing and mixing of genes.  There is no doubt that the ability to adapt to the environment within an individual’s lifetime and transmmit that adaptation to offspring would be a tremendously useful innovation. This is Lamarckian inheritance, and if it were ever to arise, it would have been copiously rewarded by natural selection for ever increasing fitness.  Is Lamarckian inheritance a reality?

Fifty years after Lamarck, Darwin believed that Lamarck’s mechanism played a role in evolution.  But Darwin’s heirs in the 20th Century decided that Lamarckian inheritance was implausible.  If, for example, a muscle is conditioned and strengthed by constant exercise, how could the information about that muscle ever be communicated to the germ cells, the sperm or egg cells in the gonads that would be the progenitors of the next generation?  Then, in the 1920s, Lysenko’s wild claims about Lamarckian inheritance pulled all credibility out from under the idea, and the scientific community firmly rejected the possibility.

Then, toward the end of the twentieth century, a strange thing happened.  A new kind of semi-permanent inheritance was discovered, and it was fully Lamarckian in its implementation.  This is epigenetic inheritance, the inheritance not of different versions of genes, but of patterns of gene expression.  The choice of which genes are turned on or off is erased from the DNA and reprogrammed with each new embryo.  But through the reprogramming, a selective memory remains; an afterimage of what was found to be useful in the previous lifetime is transmitted to the next generation.

Epigenetic memory lasts a few generations, but it is not as permanent as changes in the DNA sequence (= genetic inheritance).  Could it be that genetic changes are not completely random but, like epigenetic changes, they are subject to Lamarckian influence?  The prevailing skepticism of this idea is rooted in theory, and our understanding of biochemistry.  Remarkably, there has been no thorough experimental exploration, not even a well-designed single trial looking for evidence of Lamarckian inheritance.

But we now know that information about gene expression does get fed back to the germline in the form of epigenetic markers.  From here, it does not seem so implausible that the epigenetic markers may be translated into more permanent changes in the genome.  In this paper from Washington State biologists last year, the last link in the chain is closed.  The authors expose rats to a toxic fungicide, and confirm the previously-observed epigenetic changes in the rats, changes that are transmitted to their offspring.  They then go on to breed the rats for three more generations, and note that there are extra copies of hundreds of genes, some of which are useful in the detox of the fungicide.  These genetic changes appeared in the third generation after exposure, but they were absent in the first generation.  They can’t be written off as mutagenic effects in the fungicide, because they were three generations removed from exposure.

This report does not claim creation of new genes or even new alleles, but it does include permanent changes to the germline DNA.  The emerging view is that gene expression is more important in determining an organism’s structure and function (and fitness) than the precise form of the alleles themselves.  98% of our DNA is not genes but introns, the segments of DNA between genes that collectively determine the timing and circumstance of gene expression.  A curious finding stressed by the authors of this study is that there is zero overlap between the areas of the genome that were epigenetically modified in Generation One after exposure and the areas of the genome that later produced extra copies in Generation Three.  This suggests that the mechanism for this first example of Lamarckian genetic inheritance remains a complete mystery.


Far-reaching implications

I now believe that the remaining pieces of a fully Lamarckian evolutionary mechanism will fall into place.  Books on evolution will have to be rewritten starting from Chapter 1.  Everything that was learned about evolution in the 20th Century will be subject to reinterpretation, and much of it will be deemed irrelevant or naive.  If Lamarckian inheritance pans out, it will turn the science of evolution on its head, and give it a good shake.

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