Thank you, readers, for a lively dialog that has developed at the bottom of this page over the last few weeks, touching on some subjects that I have written about and many that I haven’t written about. I will take this space to respond to some of what you’ve written about. Some of my favorite topics include exercise, epigenetics, NSAIDs, and the gut microbiome. Reports of whole-body rejuvenation with the four “Yakanaka factors” is especially promising. I’m grateful to Dr Paul Rivas for many of the ideas that I’ve expanded on here.
Aspirin, Ibuprofen, Naproxen
Background: COX2 inhibitors were found to reduce pain and inflammation of arthritis, but most COX2 inhibitors also inhibit COX1. It is the COX1 inhibition that led to stomach damage and ulcer risk. So in the 1990s, the pharma industry set out to find drugs that would inhibit COX2 without inhibiting COX1. Only later, it came to light that these drugs elevated risk of heart disease, though they lowered the risk of cancer. (Merck knew of the dangers of Vioxx before anyone else, but kept the stats under their hat as long as they could.) The worst offender, Vioxx=rofecoxib was taken off the market. Only after CV statistics made the problem clear, researchers were led to ask, Why? The problem is endemic. Turns out that COX2 plays a role in maintenance of arterial health, and generally the NSAIDs increase heart risk to the extent that they inhibit COX2. It turned out that Vioxx was dangerous because it did too well exactly what it was designed to do.
This story hangs together until we consider aspirin. Aspirin inhibits both COX1 and COX2, and yet the preponderance of studies appear to show aspirin is associated with reduced CV risk [ref, ref]. This suggests there is a piece of the metabolic puzzle that is still missing. Aspirin has many mechanisms of action, some of them unique to aspirin.
My advice, longstanding, has been to take ¼ to 1 whole aspirin or ibuprofen a day (not both; not to be mixed in the same week) after about age 50 for lowered inflammation and protection from heart disease and cancer. Evidence for protective effect of aspirin has weakened a bit in recent years, but is still holding up . For patients who have already had a heart attack, aspirin remains standard protocol, and evidence for this population is strongest.
Readers pointed to this study , which reports elevated risk of heart attack for people taking ibuprofen or naproxen. The dosages they are looking at are several times higher than the daily dosage used for prevention alone.
All the NSAIDs have powerful effects in reducing cancer risk. Glossing over the different numbers for different kinds of cancer with different NSAIDs in different studies, it’s a good rule of thumb that taking low-dose NSAIDs daily cuts cancer risk in half. [ref]
Effects on cardiovascular risk are more complicated. I have been unable to find direct comparisons of aspirin vs ibuprofen and others, but there is “circumstantial” evidence in the literature that aspirin slightly decreases CV risk, while all the others slightly increase risk. Different studies rank the NSAIDs differently. There is suspicion of the “coxib” drugs which many people find work well for arthritis, but the latest studies show this seems to be unfounded. This study  finds Celecoxib (Celebrex) is safer than either ibuprofen or naproxen (Alleve), and results in both lower CV risk and lower all-cause mortality.
There may be other reasons to prefer one or another NSAID. There are benefits for joint pain and stiffness; there are risks for gastric pain and ulcers. It’s an individual choice, and I encourage you to experiment on yourself. You can alternate different NSAIDs, but it’s best to do so week-by-week or month-by-month, rather than daily. Don’t take aspirin and other NSAIDs in the same week.
Does too much exercise cause areterial calcification?
Readers pointed to this study  from Mayo Clinic, in which young adults were followed for 25 years, and those who exercised most hours per week had elevated calcification of their arteries. Calcification, in turn, is correlated with higher risk of heart disease.
There are several reasons I’m not turning on a dime to change my advice about exercise (which has always been, “the more, the better”).
- It’s a new finding. The study is still in preprint form, and cites no precedent.
- It’s based on just 268 subjects.
- The people in the high-exercise/high-calcification group did the equivalent of 7 or more hours of jogging each week. But the study didn’t separate recreational from occupational exercise. Social class is a really big factor, and it may be that all we’re seeing is that working class people have more CV symptoms than the upper middle class.
- The fact that exercise is correlated with calcification and calcification is correlated with increased heart risk does not necessarily imply that exercise is correlated with heart risk. This is such a common mistake. (A correlated with B) and (B correlated with C) does not let you conclude that A is correlated with C. In fact, the paper explicitly cites precedent that people who exercise most have lowest CV risk [ref, ref].
- So many benefits of exercise for so many aspects of health have been documented over the years that exercise is one of the solidest pillars of any health and longevity program.
The Copenhagen City Heart Study gave me more pause. They found that joggers who ran at a moderate pace 2-3 hours per week had longest lifespans. The benefit was about 6 years of life (a big number compared to every other life extension strategy that’s been studied, with the exception of caloric restriction). But runners who worked longer and harder than this lost the benefit and, in fact, died early. There is support for this thesis in other articles as well [ref, ref]. But there are also studies claiming that there is only a law of diminishing returns, and no amount or intensity of exercise that is actually bad for longevity [ref, ref].
I have not figured out the reason that different studies come to different conclusions, but here is what they agree on:
- Exercise has a strong benefit for life expectancy, health, mood and productivity.
- For low intensity exercise (yoga, walking, hiking, low-speed cycling, low-speed swimming) there is no evidence that too much can hurt you.
- If there is a threshold above which exercise can increase cardiovascular risk and shorten life expectancy, it is only for intense exercise and long duration, typical of a marathon runner.
My guess (based on disagreement among experts) is that there are individuals for whom a great deal of high intensity exercise is beneficial, and there are others who damage their cardiovascular systems by pushing too far. Doctors may be able to tell you if you have a heart condition that makes exercise hazardous. My hope (based on personal experience with yoga) is that we might develop a sensitivity to our bodies, so that we can distinguish the pain of damage from the pain and resistance that always accompanies a strenuous workout.
IP6 is a new supplement for me
I’m grateful to Dr Paul Rivas whose comment in this blog led me to read a little about it. Inositol hexaphosphate (IP6) is a bio-available form of Inositol, which is in the B-vitamin family. It has a major benefit for certain kinds of anxiety and depression, and minor benefits for blood sugar, insulin sensitivity, and cancer prevention.
Extraordinary story of radiation hormesis
A reader referred us to this story in a comment last week.
It would be unethical to intentionally expose people, unknowing, to ionizing radiation. But in Taiwan 35 years ago, construction steel was accidentally contaminated with Cobalt 60. The Health Safety Society recommends that 50 millisieverts (mSv) is the maximum safe radiation dosage. But 1700 people in apartments buildings in Taibei were exposed to this much radiation year after year for a period of 9-20 years until the contamination was discovered and they were evacuated. These people were studied for adverse possible health effects, but the result was that they had dramatically lower rates of cancer and birth defects.
Hormesis is a word for Improved health and longevity in response to challenges such as low doses of toxins, radiation, heat, cold exercise and fasting.
Cancer as atavism
Dr Green has outlined a theory that cancer [his comment] is a state of unconstrained cell growth characteristic of free-living cells half a billion years ago, before there was multicellular life.
First part of theory is cancer is normal growth from prior to 500,000 million years ago, prior to Cambian period. That was before plants and before oxygen rich atmosphere; life was fermentation, unlimited telomerase, no aging, cells were immortal.
This was new to me. Cyanobacteria have been around for 2.5 billion years, with the capacity to turn CO2 into O2. But apparently it was not until 800-600 million years ago that the oxygen in the atmosphere approached present levels.
Of more practical interest is Dr Green’s idea that it is epigenetics and not genetics that makes a cancer cell. If this is true, then an entire anti-cancer industry based on the idea of mutations being the root cause of cancer is misguided.
Yamanaka Factors Used for Rejuvenation
I missed this article when it came out almost a year ago. The “Yamanaka factors” (abbreviated OSKM) are four chemicals which, when applied together, can turn an ordinary differentiated cell (a skin cell, for example) back into the stem cell from which it came. Pluripotent stem cells replenish all the cell needs in the body. The offspring of a stem cell can be any kind of cell, hence “pluripotent”. Up until ten years ago, it was thought that this was a one-way street, and that the process of differentiation was irreversible. Then the Kyoto laboratory of Shinya Yamanaka reported success in “de-differentiating” cells by adding just four chemicals, initials O, S, K and M. In other words, these four chemicals turn a regular skin or muscle or organ cell back into the stem cell from whence it came.
De-differentiation rejuvenates the cell, including lengthening of telomeres. But can the rejuvenation be done without the de-differentiation? That’s the subject of a Cell paper by Ocampo et al. They report success in rejuvenating cells in a living mouse, without changing them back into stem cells. They do this via intermittent doses of the same four Yamanaka factors. The shorter duration (2-4 days) has the effect of epigenetically reprogramming cells to their younger state, without destroying their differentiated identity.
For several years, I have have been attracted to the idea that aging is essentially an evolved epigenetic program. The holy grail would be to take cells that are programmed to be old and epigenetically reprogram them to be young. The hitch in this plan is that to do this directly requires changing methylation at millions of separate sites, in addition to re-programming dozens of other kinds of epigenetic markers (besides methylation), some of which are just being discovered. These sites are specific to cell type, introducing further complexity. We have neither the knowledge of where all these sites are, and only rudimenteray ability to alter them with CRISPR and allied techniques.
These results raise the exciting possibility that epigenetic changes supersede/precede other aging hallmarks in the physiological aging process, as well, and may thus constitute a key target for future rejuvenation strategies. – Anne Brunet & Salah Mahmoudi
The finding last year by Ocampo et al offers the possibility that we don’t have to do any of this, that just four chemicals will instruct the body to do it all for us. Watch closely—this may be the pathway to whole-body rejuvenation that so many researchers have been groping toward.
What about damage to the cells? The good news is that epigenetically rejuvenated cells seem to be able to repair their damage better than we might do it with artificial interventions. Somatic DNA mutations were repaired. Mitochondria were returned to a younger appearance and performance.
Provisos and qualifications:
- Lifespan increase has been demonstrated in genetically short-lived mice. For normal lab mice, they report physiological markers of rejuvenation, but didn’t wait to see if the mice would live longer.
- How do you get OSKM into the mice (or the humans)? In this experiment, extra copies of the four factors were inserted into the mouse genome before birth in such a way that they were normally turned off, except in the presence of the antibiotic doxycycline. This provided a convenient way to turn OSKM on and off at will, with injections of doxycycline.
- In the genetically short-lived mice, the rejuvenation is temporary, only lasting 8 days before progeria asserts itself again. We don’t yet know whether rejuvenation in normal mice will be short- or long-acting.
Brunet and Mahmoudi end by suggesting that induction of the four factors could be combined with removal of senescent cells, speculating that major life extension could result from synergy between the two. (They also note that getting the four factors into cells of a living human being is a challenge we don’t yet know how to approach.)
News from the world of telomerase activation
Thanks again to Dr Rivas for this article demonstrating that ashwagandha is a potent telomerase activator. This article adds to the evidence that cells with the shortest telomeres are the problem, and average telomere length is less important.
Once again it is Dr Rivas pointing us to this article. Stool samples from 1,000 “extremely healthy” people of all ages were analyzed for RNA sequences associated with intestinal bacteria. Their principal finding was that the composition of the bacteria depended more on health than on age. There were major differences through childhood, and for people in their 20s, the bacterial colony was in a class by itself. But after age 30, up through age 100, bacterial ecology of all the healthy individuals tended to look alike.
A recent consensus says that we lose gut diversity with age, possibly as an adaptation, but more likely with negative consequences for health.
These are variants of vitamin E. They differ from vitamin E (tocopherol) in the same way that unsaturated fats differ from saturated fats. They are more reactive, more easily manipulated by the body. The normal varieyty of vitamin E (alpha tocopherol) does not have lifespan benefits, and may be a net negative. Gamma tocopherol may be better, or it may be that we need a mixture of tocopherols in combination. The only human studies have been done with alpha tocopherol, and when you buy “vitamin E pills” that’s what you’re getting.
Early research suggests that tocotrienols protect against cancer and reduce inflammation. The body treats them differently from vitamin E, and they have separate activity. Tocotrienols occur naturally in foods including palm oil, wheat germ, and rice bran. You can buy supplements of mixed tocotrienols, or gamma tocotrienol, or mixed tocotrienols with tocopherols.
Inheriting Telomere Length
Unsurprisingly, telomere length at birth is inherited from parents, and is assumed to be correlated to lifespan. Surpringly, a baby’s telomere length is inherited more from the father than from the mother. More surprisingly, older fathers sire children with longer telomeres (though their own telomeres are, presumably, shorter).
Naltrexone is a 35-year-old drug used to block opioid receptors and help people breaking addictions. Soon afterward, Dr Bernard Birhari discovered naltrexone in low doses as a treatment for auto-immune disorders (allergies, lupus) and as an anti-inflammatory. There has been some success with LDN as a cancer treatment. Take LDN at bedtime, as it blocks pleasure receptors. The theory is that blocking receptors during sleep increases the release of endorphins during the day. There is anecdotal evidence for LDN as treatment for depression, PTSD, anxiety and sexual dysfunction. LDN hasn’t been approved or tested for any of these uses, but informal experimentation off-label is gathering a critical mass. Advocacy site for LDN.
Thanks to all of you reading this column, and thanks especially for the intelligent and informative conversation that has grown up underneath this blog. I hope you’ll please keep the ideas coming!