Isegoria

The deregulation of the immune system with age eventually leads to chronic inflammation, or inflammaging, but blood sharing between young and old mice has shown rapid and robust pro-geronic and rejuvenative influences:

Interestingly, the procedure of small animal plasma exchange to dilute the circulating factors in plasma effectively reset the age-elevated systemic proteome and restored youthful healthy maintenance and repair of muscle, liver, and brain, without any added young blood, young plasma, or young factors.

For people, plasma dilution is known as plasmapheresis or therapeutic plasma exchange (TPE); it replaces a patient’s plasma with saline and purified albumin. The blood cells are returned to the patient so that while the cell profile does not change, the circulating blood proteins are diluted, including cytokines, autoreactive antibodies or toxins, and such pathogenic determinants of specific disorders.

Although its full therapeutic benefits are still being discovered, TPE is one of the treatments for autoimmune and neurological diseases such as myasthenia gravis, Alzheimer’s disease, and Guillain–Barre syndrome.

Moreover, TPE has the capacity to relieve the symptoms of long-haul COVID-19, including prevention of pneumonia, reduction of “brain fog,” and attenuation of the cytokine storm and hyper-inflammation.

This came up when eccentric life-extension fanatic Bryan Johnson (“Don’t die!”) shared the news — accompanied by a delightful photo — that he;s no longer injecting his son’s blood:

I am no longer injecting my son’s blood.

I’ve upgraded to something else: total plasma exchange.

Steps:
1. Take out all blood from body
2. Separate plasma from blood
3. Replace plasma with 5% albumin & IVIG

Here’s my bag of plasma. Who wants it?
???? pic.twitter.com/rUScTIDea6

— Bryan Johnson /dd (@bryan_johnson) January 28, 2025

Pilot studies of TPE involving mice and three human patients look promising:

The results demonstrate significant and lasting rejuvenation of both humoral and cellular blood compartments in people who underwent repeated plasmapheresis. The rejuvenative changes are not limited to a reduction of inflammaging but encompass diminished circulatory protein markers of neurodegeneration and cancer, as well as reduced senescence, lower DNA damage, and improved myeloid/lymphoid homeostasis. Mechanistically, these and previously reported positive effects of TPE become better understood through longitudinal comparative proteomics of the blood plasma, demonstrating a youthful recalibration of the canonical signaling pathways, broadly regulating tissue health, and interacting through the node of TPR-4. Lastly, a novel application of Levene’s test to profile the noise of the systemic proteome uncovered several proteins: new biomarkers that collectively quantify a person’s biological age, removing a need for predictions.

Sports scientists have been obsessed with the benefits of heat training, Alex Hutchinson notes:

The extra stress of heat triggers various adaptations that help you handle hot conditions, like more sweating. Some of these adaptations, like increased blood volume, may even give you a boost when competing in cooler conditions. As a result, many top athletes now incorporate elaborate heat protocols into their training.

Dominique Gagnon‘s research suggests that cold training has its own advantages:

Back in 2013, for example, he published data showing that cold-weather exercise relies on a different fuel mix than warmer conditions, burning more fat and less carbohydrate.

[…]

Human metabolism is only about 25 percent efficient — comparable to the internal combustion engine in your car — so three-quarters of the energy in your food is released as heat in the muscles. That means that the temperature inside your muscles can be high even when the rest of you is cool. The advantage of exercising in the cold, then, is that it prevents your muscle cells from overheating and enables them to keep burning more fat for aerobic energy, which relies on the mitochondria in your muscles. In the long run, that should boost mitochondria levels and train your body to become more efficient aerobically.

[…]

In Gagnon’s new study, 34 volunteers trained three times a week for seven weeks, doing interval workouts on an exercise bike. Before and after the training period, they had muscle biopsies, which involve removing a small chunk of muscle from the leg, in order to analyse how much mitochondria was present. Sure enough, the group that trained in 32-degree air [versus 77 degrees Fahrenheit] had a significantly greater increase in several different markers of mitochondrial content.

[…]

Stephen Cheung and his colleagues at Brock University in Canada showed that getting superficially cold, with no drop in core temperature, reduced time to exhaustion in a cycling test by about 30 percent. That involved sitting in a 32-degree room with a light breeze for half an hour before the subjects even started cycling. Staying in the room for longer, so that their core temperature actually dropped by a degree, reduced endurance by another 30 to 40 percent. This is not what Gagnon is aiming for.

The Guardian reviews Gary Taubes‘ Rethinking Diabetes: What Science Reveals About Diet, Insulin, and Successful Treatments

Gary Taubes is probably the most single-minded person I have ever met. In 2002, when he was a little-known science journalist and author of two books on scientific controversies, an article of his was published in the New York Times, headlined: What If It’s All Been a Big Fat Lie? In it, he argued that the low-fat dietary advice of the previous couple of decades wasn’t only incorrect, but actively dangerous and the reason for, as he put it, the “rampaging epidemic of obesity in America”. For Taubes, dietary fat wasn’t a problem at all. Instead, the real danger was carbohydrate, he asserted, sparking a backlash, and fuelling the ongoing conversation about what constitutes a “healthy diet”. He wasn’t the first to assert that carbs were bad (Robert Atkins got there before him), but perhaps because of his serious and scientific background — he has a physics degree from Harvard and studied aerospace engineering at Stanford — he has been a polarising figure, with as many ardent followers as detractors.

[…]

Before the discovery of insulin in the 1920s, diet was the only way to manage diabetes and although various options were tried by early practitioners, low-carb was, says Taubes, among the most popular (with medics, at least). Insulin was a gamechanger. Not only did it almost magically save the lives of children with type 1 diabetes, who would often arrive at hospital comatose and die swiftly afterwards, but it also meant that people with diabetes of both types could eat a more or less normal diet.

[…]

What Taubes would like to see is low-carb diets being offered alongside or instead of diabetes medications. “When insulin therapy started in the 1920s, they had no idea what the long-term side-effects were or what the long-term consequences of living with diabetes were [because most people with type 1 died],” he says. “Then doctors find out that it’s just easier to let patients eat whatever they want and give them drugs to cover them. Then it’s another five, 10 or 20 years before they start seeing the long-term complications, which they think of as long-term complications of the disease.” What he wishes scientists at the time had concluded was: “The reason we’re keeping them alive is insulin therapy. So what we’re seeing is the long-term complications of the disease as controlled by insulin therapy, and the insulin therapy might be causing the complications as much as the disease is.

“By the late 1930s, you have this tidal wave of diabetic complications: the heart disease, the atherosclerosis, the neuropathy, the kidney failure, the blindness, amputations. And nobody ties it back.” By then, the low-carb diet had fallen far from favour. “Nobody wants to eat a diet. So nobody’s being told: ‘Look, if I give you insulin, I’m going to keep you alive until you’re 30, especially if I give you a lot of insulin and you do eat your carbs. But if I tell you not to eat the carbs and we minimise the insulin use — which for type 2 could be no insulin — I might keep you alive as long as anyone else in your family.’”

In the book, which is laden with references, studies and dense historical detail, Taubes mentions case records from the 1700s in which patients on low-sugar diets beg for a medical solution, suggesting that the preference for medication over a highly prescriptive diet has been with us for a long time. “If you’re told, a pill or a diet, we all want the pill. But if you’re told a pill or a diet and the diet will keep you healthy and the pill will give you a chronic degenerative disorder where you’re still going to have these horrible complications, they are just going to be 20 to 30 years later… the pill is going to be easier, because it always is. But if you change the diet, it’s not a hypothetical change: you can put your diabetes into remission, you can stop taking these medications.”

One in five competitive athletes suffers from exercise-induced bronchoconstriction, or EIB:

The numbers are even higher in endurance and winter sports. Puzzlingly, studies have found that athletes with EIB who somehow make it to the Olympics are more likely to medal. What’s so great about wheezing, chest tightness, and breathlessness?

The answer isn’t what you’re thinking. Sure, it’s possible that some athletes get a boost because an EIB diagnosis allows them to use otherwise-banned asthma medications. But there’s a simpler explanation: breathing high volumes of cold or polluted air dries out the airways, leading to an overzealous immune response and potential long-term damage. “It’s well established that high training loads and ventilatory work increase the degree of airway hyper-responsiveness and hence development of asthma and EIB,” explains Morten Hostrup, a sports scientist at the University of Copenhagen and lead author of a new review on EIB in the Scandinavian Journal of Medicine and Science in Sports. In other words, the athletes who train hard enough to podium are more likely to develop EIB as a result.

[…]

Activities with the highest risk involve sustained efforts of at least five minutes, particularly if they take place in cold or polluted air. Cold air doesn’t hold much moisture, so it dries the airways. This affects skiers, runners, and triathletes, among others. Indoor environments like pools and ice rinks are also a problem, because of the chloramines produced by pool water and exhaust from Zambonis.

[…]

Before the 1998 Winter Games, U.S. Olympic Committee physiologists examined Nagano-bound athletes to see whose airways showed abnormal constriction in response to arduous exercise. Almost a quarter of the athletes tested positive, including half the cross-country ski team.

[…]

If you do get an EIB diagnosis, your doctor can prescribe asthma medication, including inhaled corticosteroids like fluticasone and airway dilators like salbutamol. If you’re an elite athlete subject to drug testing, you’ll need to tread carefully, since some of those medications are either banned or restricted to a maximum dosage. Hostrup and his colleagues note that there’s also evidence that fish oils high in omega-3 fatty acids, vitamin C, and even caffeine might help reduce EIB symptoms. And on the non-pharmaceutical side, you can minimize the chance of an attack by doing a thorough warm-up of 20 to 30 minutes, including six to eight 30-second sprints. This can temporarily deplete the inflammatory cells that would otherwise trigger an airway-narrowing attack

Plyometric training can make you a more efficient runner, Alex Hutchinson notes, but there’s still plenty of debate about how it works:

As a result, studies like this one in Sports Biomechanics, published last month by a group led by Aurélien Patoz of the University of Lausanne, don’t garner much attention. They found a 3.9 percent improvement in running economy after eight weeks of either plyometric or dynamic strength training, roughly comparable to what Nike’s original Vaporfly 4% shoe produced. (They also found no evidence that either form of training altered running stride in any significant way, for what it’s worth.)

Why no excitement about a free four-percent boost? As someone who has experimented on and off with various forms of plyometric training over several decades, let me venture a hypothesis: it’s perceived as too complicated, and possibly risky, for most of us.

Does it need to be that complicated?

That’s the question tackled by another recent study, this one led by Tobias Engeroff of Goethe University Frankfurt and published in Scientific Reports. They stripped plyometric training down to its bare bones, tested it on a group of amateur runners—and still found a significant improvement in running economy after just six weeks. The exact size of the improvement depends on how you measure it and at what speed, but was between 2 and 4 percent.

Engeroff’s plyometric program involved nothing but hopping on the spot. Specifically, “participants were instructed to start with both feet no wider than hip width apart and to hop as high as possible with both legs, keeping the knees extended and aiming to minimize ground contact time.” They started by hopping for 10 seconds, resting for 50 seconds, and repeating five times for a total of five minutes. They did this five-minute program daily, decreasing the rest and increasing the number of sets each week: the second week was 6 sets of 10 seconds of hopping with 40 seconds of rest; the sixth and final week was 15 sets of 10 seconds hopping with 10 seconds of rest, still totaling five minutes.

This program was based on the idea that it’s tendon stiffness that boosts running economy. In particular, the stretch and recoil of the Achilles tendon provides between half and three-quarters of the positive work required for running, by some estimates. Engeroff’s short daily program draws on recent research by Keith Baar and others suggesting that connective tissue such as tendons responds best to brief, frequent stimulus rather than longer and harder workouts. Notably, this approach didn’t injure any of the runners.

European explorers found that indigenous peoples ate rotten meat:

From arctic tundra to tropical rainforests, native populations consumed rotten remains, either raw, fermented or cooked just enough to singe off fur and create a more chewable texture. Many groups treated maggots as a meaty bonus.

[…]

Some Indigenous communities feasted on huge decomposing beasts, including hippos that had been trapped in dug-out pits in Africa and beached whales on Australia’s coast. Hunters in those groups typically smeared themselves with the fat of the animal before gorging on greasy innards. After slicing open animals’ midsections, both adults and children climbed into massive, rotting body cavities to remove meat and fat.

Or consider that Native Americans in Missouri in the late 1800s made a prized soup from the greenish, decaying flesh of dead bison. Animal bodies were buried whole in winter and unearthed in spring after ripening enough to achieve peak tastiness.

But such accounts provide a valuable window into a way of life that existed long before Western industrialization and the war against germs went global, says anthropological archaeologist John Speth of the University of Michigan in Ann Arbor. Intriguingly, no reports of botulism and other potentially fatal reactions to microorganisms festering in rotting meat appear in writings about Indigenous groups before the early 1900s. Instead, decayed flesh and fat represented valued and tasty parts of a healthy diet.

[…]

Many travelers such as Landor considered such eating habits to be “disgusting.” But “a gold mine of ethnohistorical accounts makes it clear that the revulsion Westerners feel toward putrid meat and maggots is not hardwired in our genome but is instead culturally learned,” Speth says.

[…]

Fermented fish heads, also known as “stinkhead,” are one popular munchy among northern groups. Chukchi herders in the Russian Far East, for instance, bury whole fish in the ground in early fall and let the bodies naturally ferment during periods of freezing and thawing. Fish heads the consistency of hard ice cream are then unearthed and eaten whole.

Speth has suspected for several decades that consumption of fermented and putrid meat, fish, fat and internal organs has a long and probably ancient history among northern Indigenous groups. Consulting mainly online sources such as Google Scholar and universities’ digital library catalogs, he found many ethnohistorical descriptions of such behavior going back to the 1500s. Putrid walrus, seals, caribou, reindeer, musk oxen, polar bears, moose, arctic hares and ptarmigans had all been fair game.

[…]

“Recognizing that eating rotten meat is possible, even without fire, highlights how easy it would have been to incorporate scavenged food into the diet long before our ancestors learned to hunt or process [meat] with stone tools,” says paleoanthropologist Jessica Thompson of Yale University.

[…]

Instead, Speth speculates, cooking’s primary value at first lay in making starchy and oily plants softer, more chewable and easily digestible. Edible plants contain carbohydrates, sugar molecules that can be converted to energy in the body. Heating over a fire converts starch in tubers and other plants to glucose, a vital energy source for the body and brain. Crushing or grinding of plants might have yielded at least some of those energy benefits to hungry hominids who lacked the ability to light fires.

[…]

Over the last few centuries, they have favored tongue, fat deposits, brisket, ribs, fatty tissue around intestines and internal organs, and marrow. Internal organs, especially adrenal glands, have provided vitamin C — nearly absent in lean muscle — that prevented anemia and other symptoms of scurvy.

Western explorers noted that the Inuit also ate chyme, the stomach contents of reindeer and other plant-eating animals. Chyme provided at least a side course of plant carbohydrates.

The popularity of GLP-1 receptor agonists, like Ozempic and Wegovy, has skyrocketed, because they do help people lose weight:

Though a certain amount of lean loss is inevitable with significant weight reduction (usually about 25% of total weight loss), the goal is to increase the body’s overall proportion of lean mass – in other words, to improve body composition.

[…]

However, from the information we can scrape together based on sub-cohort data, these “miracle drugs” start to look a bit less miraculous. In 2021’s STEP 1 trial — the first trial demonstrating the efficacy of semaglutide as a treatment for adult obesity — a subset of 140 patients underwent DEXA scans for body composition analysis. Among these patients, lean mass accounted for approximately 39% of total weight loss — substantially higher than ideal. In a substudy of 178 patients from the SUSTAIN 8 trial on semaglutide as a diabetes treatment, the average proportion of lean mass loss was nearly identical at 40%, despite lower doses and less total weight loss than in the STEP 1 trial.

Researchers in Finland looked at 17 pairs of identical twins who didn’t have similar exercise habits:

The first thing to note is just how unusual such twin pairs are. The twins in the study were drawn from two previous Finnish twin studies that included thousands of pairs of identical twins. The vast majority of them had similar levels of physical activity. The High Runner mouse line that’s often used in lab studies took mice that loved to run, bred them with each other, and produced mice that love to run even more. I’d like to think that human behavior (and mating patterns) are a little more complex than that, but the twin data certainly suggests that our genes influence our predilection for movement.

Still, they found these 17 pairs whose paths had diverged. There were two different subgroups: young twins in their thirties whose exercise habits had diverged for at least three years, and older twins in their fifties to seventies whose habits had diverged for at least 30 years. On average, the exercising twins got about three times as much physical activity, including active commuting, as the non-exercising ones: 6.1 MET-hours per day compared to 2.0 MET-hours per day. For context, running at a ten-minute-mile pace for half an hour consumes about 5 MET-hours.

All the twin pairs came in for physical examinations, and the results were pretty much what you’d expect. The exercising twins had higher VO2 max (38.6 vs. 33.0 ml/kg/min), smaller waist circumference (34.8 vs. 36.3 inches), lower body fat (19.7 vs. 22.6 percent), significantly less abdominal fat and liver fat, and so on.

[…]

A 2018 case study from researchers at California State University Fullerton looked at a single identical twin pair, then aged 52. One was a marathoner and triathlete who had logged almost 40,000 miles of running between 1993 and 2015. The other was a truck driver who didn’t exercise. In this case, the exercising twin weighed 22 pounds less, and his resting heart rate was 30 percent lower. Most fascinatingly, muscle biopsies showed that the marathoner had 94 percent slow-twitch fibers while the truck-driver had just 40 percent slow-twitch. No one before or since (as far as I know) has shown such a dramatic change in muscle properties.

Alex Hutchinson explains how to hold on to your sprint speed as you age:

Many of the challenges of daily living, once you hit your 70s and 80s and beyond, are essentially tests of all-out power rather than sustained endurance (though both are important).

The problem is that sprint speed starts declining after your 20s, and most endurance athletes have no clue how to preserve it.

[…]

Older sprinters take shorter steps and their feet spend longer in contact with the ground, presumably because they’re less able to generate explosive force with each step. That’s consistent with the finding that older sprinters have less muscle, and in particular less fast-twitch muscle, than younger sprinters.

But it’s not just a question of how much muscle you’ve got. In fact, some studies suggest that you lose strength more rapidly than you lose muscle, which means that the quality of your remaining muscle is reduced. There are a bunch of different reasons for muscle quality to decline, including the properties of the muscle fibers themselves, but the most interesting culprit is the neuromuscular system: the signals from brain to muscle get garbled.

[…]

The authors cover their bases by recommending that your resistance training routine should include workouts that aim to build muscle size (e.g. three sets of ten reps at 70 percent of one-rep max); workouts that aim to build strength (e.g. two to four sets of four to six reps at 85 percent of max); and workouts to build power (e.g. three sets of three to ten reps at 35 to 60 percent of max).

[…]

The authors suggest training to improve coordination through exercises that challenge balance, stability, and reflexes, such as single-leg balance drills. One advantage of this type of training: it’s not as draining as typical “reps to failure” strength workouts, so it may provide more bang for your buck if you can’t handle as many intense workouts as you used to.

[…]

On that note, the standard advice that veteran athletes give you when you hit your 40s is that you can no longer recover as quickly. Strangely, the authors point out, the relatively sparse data on this question doesn’t find any differences in physiological markers of post-workout recovery between younger and older athletes. The main difference is that older athletes feel less recovered—and in this case, it’s probably worth assuming that those feelings represent some kind of reality, even if we don’t know how to measure it.

In The Hungry Brain, neuroscientist Stephan Guyenet references a 1965 study in which volunteers received all their food from a “feeding machine” that pumped a “liquid formula diet” through a “dispensing syringe-type pump which delivers a predetermined volume of formula through the mouthpiece.”

What happens to food intake and adiposity when researchers dramatically restrict food reward? In 1965, the Annals of the New York Academy of Sciences published a very unusual study that unintentionally addressed this question. …

The “system” in question was a machine that dispensed liquid food through a straw at the press of a button—7.4 milliliters per press, to be exact (see figure 15). Volunteers were given access to the machine and allowed to consume as much of the liquid diet as they wanted, but no other food. Since they were in a hospital setting, the researchers could be confident that the volunteers ate nothing else. The liquid food supplied adequate levels of all nutrients, yet it was bland, completely lacking in variety, and almost totally devoid of all normal food cues.

[…]

The researchers first fed two lean people using the machine—one for sixteen days and the other for nine. Without requiring any guidance, both lean volunteers consumed their typical calorie intake and maintained a stable weight during this period.

Next, the researchers did the same experiment with two “grossly obese” volunteers weighing approximately four hundred pounds. Again, they were asked to “obtain food from the machine whenever hungry.” Over the course of the first eighteen days, the first (male) volunteer consumed a meager 275 calories per day—less than 10 percent of his usual calorie intake. The second (female) volunteer consumed a ridiculously low 144 calories per day over the course of twelve days, losing twenty-three pounds. The investigators remarked that an additional three volunteers with obesity “showed a similar inhibition of calorie intake when fed by machine.”

The first volunteer continued eating bland food from the machine for a total of seventy days, losing approximately seventy pounds. After that, he was sent home with the formula and instructed to drink 400 calories of it per day, which he did for an additional 185 days, after which he had lost two hundred pounds —precisely half his body weight. The researchers remarked that “during all this time weight was steadily lost and the patient never complained of hunger.” This is truly a starvation-level calorie intake, and to eat it continuously for 255 days without hunger suggests that something rather interesting was happening in this man’s body. Further studies from the same group and others supported the idea that a bland liquid diet leads people to eat fewer calories and lose excess fat.

This machine-feeding regimen was just about as close as one can get to a diet with zero reward value and zero variety. Although the food contained sugar, fat, and protein, it contained little odor or texture with which to associate them. In people with obesity, this diet caused an impressive spontaneous reduction of calorie intake and rapid fat loss, without hunger. Yet, strangely, lean people maintained weight on this regimen rather than becoming underweight. This suggests that people with obesity may be more sensitive to the impact of food reward on calorie intake.

Only one theory can account for all of the available evidence about the obesity epidemic: it is caused by one or more environmental contaminants:

We know that this is biologically plausible because there are many compounds that reliably cause people to gain weight, sometimes a lot of weight.

[…]

We need a theory that can account for all of the mysteries we reviewed earlier. Another way to put this is to say that, based on the evidence, we’re looking for a factor that:

1. Changed over the last hundred years
2. With a major shift around 1980
3. And whatever it is, there is more of it every year
4. It doesn’t affect people living nonindustrialized lives, regardless of diet
5. But it does affect lab animals, wild animals, and animals living in zoos
6. It has something to do with palatable human snackfoods, unrelated to nutritional value
7. It differs in its intensity by altitude for some reason
8. And it appears to have nothing to do with our diets

Environmental contamination by artificial, human-synthesized compounds fits this picture very well, and no other account does.