Isegoria

Amish who carried the null SERPINE1 mutation lived about 10 years longer:

That’s a huge increase in lifespan, arguably much greater than almost any single factor we know in humans.

The carriers of the gene mutation produce less PAI-1, which results in a greater tendency for blood clots to break down. Those who are homozygous (-/-) for the mutation have an even greater tendency to break down blood clots, which results in a bleeding disorder. That’s the immediate consequence of less PAI-1.

However, the heterozygous (+/-) carriers had longer telomeres, which is a sign of slower aging. They also had less diabetes risk, a 0% diabetes rate compared to 7% in non-carriers, even though body mass index was the same. And they had better cardiovascular risk markers, including lower blood pressure and lower carotid artery thickness, a measure of atherosclerosis.

Clearly, PAI-1 does a lot to promote aging, and having less of it appears to result in longer life.

Humans did not evolve to eat modern sugary fruit year round in abundance, Mangan notes, and even in the early modern era it wasn’t a large part of the diet:

In the 18th and 19th centuries, Americans did not eat very much in the way of fruits and vegetables. Meat was abundant, and even the poor ate plenty of it. Fruits and vegetables had a short growing season and were ripe for only a short period of time, and in the absence of refrigeration and transport, spoiled, as Nina Techolz writes:

Even in the warmer months, fruit and salad were avoided, for fear of cholera. (Only with the Civil War did the canning industry flourish, and then only for a handful of vegetables, the most common of which were sweet corn, tomatoes, and peas.)

So it would be “incorrect to describe Americans as great eaters of either [fruits or vegetables],” wrote the historians Waverly Root and Rich­ard de Rochemont. Although a vegetarian movement did establish itself in the United States by 1870, the general mistrust of these fresh foods, which spoiled so easily and could carry disease, did not dissipate until after World War I, with the advent of the home refrigerator. By these accounts, for the first 250 years of American history, the entire nation would have earned a failing grade according to our modern mainstream nutritional advice.

What about apples — fruit, obviously — didn’t Americans eat them? Johnny Appleseed is famous for spreading apple trees around the country. But it turns out that much of the apple crop was turned into apple cider. Not only did cider provide alcohol, but it’s a way to preserve and concentrate apples in the absence of refrigeration and transport.

Fruits (and vegetables) are thought to be healthy due to the phytochemicals, namely polyphenols, that they contain:

However, coffee, tea, red wine, and chocolate all generally provide far more polyphenols than fruit. With the exception of chocolate, they have the added benefit of being entirely sugar-free, and even chocolate can be consumed without sugar or in low-sugar forms such as dark chocolate. So, if you want to consume polyphenols, and you consume coffee, etc., then fruit would be superfluous.

At age 72, Dr. Alan S. Green saw miraculous improvement in health, from feeling old to feeling young, after taking rapamycin once per week:

I attended college on a tennis scholarship and ran a marathon in just under 4 hours at age 40. But by age 70 my main physical activity was reduced to walking my two Shiba Innu dogs in the park. Then by age 72, I experienced angina and shortness of breath on small hills. As a trained pathologist I accepted the reality that I was in rather poor shape. My fasting blood sugar was up, my creatinine blood level was elevated indicating renal insufficiency and I couldn’t fit into any of my pants. I then began trying to learn about aging. I discovered a story more extraordinary and improbable than anything I had ever encountered in my lifetime.

[...]

Based upon empirical medicine principles, I decided rapamycin 6 mg once a week would be an aggressive treatment and 3 mg once every 10 days would be a conservative treatment. I decided to go with aggressive treatment. January 2016, I began the rapamycin-based Koschei formula with intent to take it for one year; in what could euphemistically be called a “proof-of-concept” experiment. I didn’t have to wait one year; by 4 months the results were miraculous. I lost 20 pounds, my waist-line went from 38 inches to 33. I bought a pair of size 32 jeans and didn’t have to wear joggers no more. I could walk 5 miles a day and ride a bike up hills without any hint of angina. Creatinine went from elevated to normal and fasting blood sugar went down. I thought I was Lazarus back from the dead. It’s now over 1 year and I feel great. I’ve also had no mouth sores, the most common clinical side-effect. For me, rapamycin is the world’s greatest medicine.

Dennis Mangan asked Dr. Green a number of questions:

PDM: I note that of the drugs you advocate for anti-aging, metformin, aspirin, and ACE inhibitors/AR blockers are cheap, while rapamycin is more expensive. Does any other drug come close to rapamycin in efficacy or is it indispensable? Of the four drugs, what fraction of anti-aging effect is due to rapamycin in your estimation?

ASG: Rapamycin is only $3.50 for 1 mg if you buy it on line with a prescription from Canada; therefore monthly cost might come to $50-100 a month.

My rough guess of the relative value of each as anti-aging drug would be as follows: rapamycin, ACE inhibitor/AR blocker, metformin, aspirin: 75, 18, 6, 1.

[...]

PDM: I was fascinated to learn about angiotensin disruption for anti-aging, which I’m not sure if I had heard of before, and also that it fits the growth vs longevity paradigm. (On second thought, I had heard of it, but I forgot. Must be the effects of age.) Do you think hypertension is a “normal” manifestation of aging and that everyone can expect to have it to some degree as they age?

ASG: The two best characterized systems which promote aging are the mTOR system and the angiotensin-renin system. Angiotensin II is the primary cause of hypertension; but angiotensin II also promotes atherosclerosis, damage to mitochondria and increase ROS in tissues. I think all older persons probably suffer from higher activity from angiotensin II than is healthy. So probably most old people had some degree of hypertension and they would benefit from being on angiotensin blocker/inhibitor (ARB/ACE). The important thing is to use one that crosses blood-brain barrier.

A couple decades ago, when I first became interested in evolutionary fitness and ketogenic diets, I read that the Eskimos had traditionally lived on a diet almost entirely bereft of carbohydrates — a diet that Vilhjalmur Stefansson tried to promote amongst non-Eskimos in magazine articles and then in his 1946 book, Not by Bread Alone.

But Stefansson Westernized the Inuit diet of raw marine mammals and instead promoted a cooked, all-animal-food-diet, including dairy and eggs — a difference that matters once you realize how marine mammals have adapted to diving and operating with limited air:

Stefansson — who died of a stroke at 82 (though, surprisingly, he lived longer than a lot of other VLC authors) — made the fatal assumption that land mammals and marine mammals are similar. They aren’t. They are entirely different, and the difference is tantamount to different species classification. The Inuit were exploiting unique carbohydrate properties in these marine mammals that aren’t found in land mammals.

It turns out that marine mammals that spend a good deal of their time diving to great depths have significant glycogen stores. Sperm whales make routine dives to 400 meters for 40 minutes and can reach a maximum depth of 2000 meters (6,560 feet, or 1.25 miles). Narwhals make some of the deepest dives recorded for a marine mammal, diving to at least 800 meters (2,600 feet) 18 and 25 times per day every day for 6 months, with many dives reaching 1,500 meters (4,900 feet). Narwhals have been recorded diving to as deep as 1,800 meters (5,900 ft, over one mile). In addition to making remarkably deep dives, narwhals also spend more than 3 hours per day below 800 meters — this is an incredible amount of time at a depth where the pressure can exceed 2200 PSI (150 atmospheres).

During their deep dives these marine mammals run out of oxygen and switch to their unique glycogen-based energy stores. They store large quantities of glycogen in very odd places, but it typically gets concentrated in the skin and organs. Researchers have discovered significant “glycogen pools” in the narwhal’s arterial thoracic retia. Ringed seals have “large quantities of glycogen” in a gelatinous material near their sinuses. A sperm whale’s blubber ranges from 8–30% carbohydrates, mostly believed to be glycogen. The hearts and brains of weddel seals have concentrations of glycogen that are two to three times that of land mammals. Furthermore; in marine mammals, these organs tend to be larger in proportion to the total body weight than in land-based mammals.

In 1973, George and Ronald wrote about the harp seal, “All the fiber types contained considerable amounts of glycogen…it is postulated that the seal muscle is basically geared for anaerobic use of carbohydrate as an adaptation for the animal’s diving habit.”

In a paper on diving marine mammals Hochachka and Storey wrote, in 1975, “In the terminal stages of prolonged diving, however, even these organs must tolerate anoxia for surprisingly long times, and they typically store unusually large amounts of glycogen for this purpose.”

Perhaps what’s most disappointing is that Stefansson never bothered to clearly explain the Inuit’s favorite sweet-tasting whale skin dish (muktuk), that was already known by scientists to be a carbohydrate-rich food. In 1912, the Journal of the American Medical Association (JAMA) had reported, “the skin [of the narwhal] contains a remarkable amount of glycogen, thus supplying sufficient quantities of a carbohydrate to cure the scorbutus. The walrus liver also contains much glycogen.”

So, this idea that we can compare glycogen content of a [grilled, braised, stewed, or otherwise thoroughly cooked, long after dead] cow or human to that of what the Inuit were eating is entirely misguided. We’re talking about marine animals that need large quantities of glycogen to complete their extended deep dives.

It’s well known that glycogen does not survive very long post-mortem. So, it was no coincidence that the Inuit often consumed glycogen-rich foods quickly and froze whatever they couldn’t consume. Peter Freuchen, a Danish doctor and member of the 5th Thule expedition based at Melville Peninsula from 1919-1925, wrote that when a whale was brought to the beach at Repulse Bay everyone feasted on large quantities of the skin until their jaws became too sore to continue.

After a hunt, seals are quickly cut to expose the internal organs. Kristen Borré writes in her 1991 report for the Medical Anthropology Quarterly, that “one of the hunters slits the abdomen laterally, exposing the internal organs. Hunters first eat pieces of liver or they use a tea cup to gather some blood to drink.” This was no coincidence. The parts of the animals with the most glycogen were eaten quickly.

At the time of death, the glycogen and free glucose in beef muscle contains approximately 6g of glucose equivalents per pound. As explained above, diving marine mammals have much more glycogen than land mammals. When we consider that the average Inuit consumed 5 to 10 pounds, or more, of raw fresh or flash-frozen meat per day, it should be clear that they were consuming a lot of glycogen.

But, of course, the Inuit consumed other carbs, too. They consumed berries, seaweed, nuts, corms, and tubers — such as yupik potatoes, boiled polysaccharide-rich seaweed, glycogen-rich winter mussels. See the Disrupting Paleo series for a more indepth discussion of these foods and their importance in the Inuit diet.

What about the glycogen in the foods that weren’t consumed rapidly? If only the Eskimos had access to extremely cold temperatures where they could rapidly freeze chunks of meats immediately after hunting… Hmmm… Kidding aside, the Inuit not only consumed fresh raw meat, blubber and skin that was rich in glycogen, but they also consumed it flash frozen — thus preserving and maximizing its glycogen.

Interestingly, Clarence Birdseye — who invented technology for “flash freezing” — learned about it from the Inuit. According to Wikipedia, “He was taught by the Inuit how to ice fish under very thick ice. In -40°C weather, he discovered that the fish he caught froze almost instantly, and, when thawed, tasted fresh.” He recognized immediately that the frozen seafood sold in New York was of lower quality than the frozen fish of Labrador, and saw that applying this knowledge would be lucrative.

While listening to the audio version of Endurance, about Shackleton’s failed attempt to cross the last uncharted continent on foot, I noted that the famished explorers found penguin liver surprisingly delicious.

Vegetable oils are better called industrial seed oils, P.D. Mangan reminds us, since they’re made from seeds, not vegetables, and require an industrial process to make them in any volume:

The manufacturing process for vegetable oils involves pressing at high pressure, and extracting more oil using solvents such as hexane, a volatile hydrocarbon similar to gasoline. The oils are then refined by heating to a high temperature and adding sodium hydroxide (lye), and finally, degummed, bleached, and deodorized.

Without knowing anything else about it, I already know that I don’t want this industrial substance in my body, much less in the massive quantities most people consume.

[...]

The lipid hypothesis of heart disease, sometimes called the diet-heart hypothesis, holds that dietary saturated fat and high blood cholesterol cause coronary heart disease. Since the beginnings of that idea, mainstream health authorities have urged people to use vegetable oils in order to replace saturated fat with polyunsaturated fat, in the hope that this would reduce the incidence of heart disease. How has that worked out?

A recently published re-analysis of data from the Minnesota Coronary Experiment found that polyunsaturated fats did indeed lower serum cholesterol. Problem is, each 30 mg/dL reduction in cholesterol was associated with a 22% increased risk of death.

The same group re-analyzed the data from the Sydney Diet Heart Study and found that the intervention group that had replaced saturated fat with vegetable oils had a death rate from all causes that was 62% higher than the control group, and 70% higher for cardiovascular disease.

These were randomized controlled studies, which can show causation, as opposed to epidemiological studies, which cannot, and only show association. In epidemiological studies that show an association between intake of polyunsaturated fats and less heart disease, that association could very well be due to the healthy user effect.

Knowing this, deliberately consuming more polyunsaturated fats in the form of industrial seed oils seems positively dangerous to health.

Scientists out of McMaster University recently conducted research on the shortest interval training ever:

To see just how little you can get away with when it comes to interval training for health purposes, the researchers brought in 25 less-than-in-shape young men (future studies will focus on women). They tested their levels of aerobic fitness and their ability to use insulin in the right way to control blood sugar, and biopsied their muscles to see how well they functioned on a cellular level.

Then they split them into a control group, a moderate-intensity-exercise group, and a sprint interval training (SIT) group.

The control group did nothing differently at all.

The moderate-intensity group did a typical I’m-at-the-gym routine of a two-minute warm-up, 45 minutes on the stationary bike, and a three-minute cool down, three times a week.

The SIT group did the shortest interval training ever recorded thus far by science. Participants warmed up for two minutes on a stationary bike, then sprinted full-out for 20 seconds, then rode for two minutes very slowly. They repeated this twice (for a total of three sets). The whole workout took 10 minutes, with only one minute being high-intensity.

All of the groups kept at it for 12 weeks, or about twice as long as most previous studies.

The results?

The control group, as expected, had no change in results.

The two other groups enjoyed results that were basically identical to each other’s. In both, scientists found a 20 percent increase in cardiovascular endurance, good improvements in insulin resistance, and significant increases in the cells responsible for energy production and oxygen in the muscles (thanks, biopsies).

That is remarkable. By the end, the moderate-intensity group had ridden for 27 hours, while the SIT group had ridden for 6 total hours, just 36 minutes of which was arduous.

This means one group spent about 10 total minutes on each workout, while the other spent 50 minutes. The SIT group got the same benefits in a fifth of the time.

I would have assumed that sourdough bread and ordinary white bread were nutritionally very, very similar, but wild yeast strains and bacteria that fill sourdough with sour acids purportedly reduce its glycemic index. Or so scientists thought, until a recent study found otherwise:

In a study led by students Tal Korem and David Zeevi, the Israeli team picked two extremes from the bread world. They hired a local baker to prepare artisanal sourdough from whole-grain flour. They also bought mass-manufactured loaves of white bread, made from refined flour and loaded with preservatives.

The team recruited 20 volunteers and asked half to spend a week eating the white bread and another eating the sourdough. The other volunteers did the same in the reverse order. Before and after each bread-filled week, the team took a census of the bacteria in each volunteer’s gut, as well as measured 20 variables including blood pressure, weight, blood sugar, cholesterol, triglycerides, and various hormones. They found that the bread the participants ate had no significant effect on any of these factors. Even the microbiome, which can shift quickly and extensively after a change in diet, was barely affected by the choice of breads.

The Wall Street Journal reports that weighted bats don’t quicken a batter’s swing — but we’ve known that for decades:

“With 20 college baseball players from one university, I found no difference,” said Dr. Szymanski, who referred to the number of players he studied with 10 differently weighted bats. “Their performance was statistically unchanged.”

Other studies, notably those by Dr. DeRenne, have found that warming up with an overloaded bat, especially with a doughnut, slowed down batters.

“The doughnut is the worst,” said Dr. DeRenne, who tested one weighing 28 ounces. “It changes the balance point in the bat.”

The weight may alter the batter’s swing, especially in younger players who are still developing strength and mechanics.

Sport Science, a television series where athletes and scientists explore the biomechanics of different sports activities, tested the effect with a college player in 2008. Without any added weight, the batter averaged 69 mph on 10 swings and routinely connected with the bat’s sweet spot on balls pitched from a machine. After warming up with a doughnut, the batter’s speed decreased to 68.3 mph on average, and on each swing, the ball missed the bat’s sweet spot by several inches.

The experience of a lone batter in a single test can’t be generalized to others, but the results resembled other studies.

Tibetans have evolved and maintained genetic adaptations that suit them to life above 15,000 feet:

Huff and co-authors published a study in April in PLOS Genetics analyzing for the first time whole-genome sequences for 27 Tibetan individuals. The research identified three new genes that help with mountain living, in addition to confirming two that were previously known. These gene variants give Tibetans the ability to metabolize oxygen more efficiently and protect against Vitamin D deficiency.

[...]

One of the genes that helps Tibetans adapt to high altitude is known as EPAS1. The Tibetan variant of this gene does a surprising thing — it actually lowers the hemoglobin count in your blood at high altitudes. Hemoglobins are a protein in red blood cells that transport oxygen to your body. It’s surprising that Tibetans would have a lower hemoglobin count at high altitudes; normally our bodies respond to lower oxygen pressures by increasing hemoglobins in our blood, allowing for more O2 to reach the muscles. It’s even more surprising because other population groups that have adapted to high altitude environments, including the South American Andes and Africa’s Ethiopian Highlands, have done so in part by raising hemoglobin count.

The Tibetans, however, do things differently. Rather than upping hemoglobin count, their bodies have several adaptations that allow them to use oxygen more efficiently, so they need less of it. This allows them to keep hemoglobin counts relatively low at high altitude, which helps to avoid some of the potential downsides of a high hemoglobin count. Hemoglobins thicken the blood, and the thicker your blood the more likely it is to clot, which increases the risk of heart disease and stroke.