Polyphenol Postbiotics

Microbiome Manipulation in Dementia

In see.nf/gutbrain, I present a remarkable case study titled “Rapid Improvement of Alzheimer’s Symptoms After Fecal Microbiota Transplantation” and discuss the contradictory results of dozens of randomized controlled trials on prebiotics, probiotics, and fermented foods for cognitive performance. Unfortunately, some of the most promising findings have been overshadowed by concerns about the accuracy of the data, including oligomannate, a prebiotic that was approved in China in 2019 under conditions to treat mild to moderate Alzheimer’s cases.

Polyphenol Postbiotics

Just as the benefit of fiber lies in supplying good bacteria with prebiotics and the resulting postbiotic metabolic products (short-chain fatty acids), polyphenols can also act as prebiotics and generate beneficial postbiotics. For example, the level of blueberry pigments in the blood rises sharply one hour after consumption, but the next day new, blueberry-derived substances appear in the blood, because the bacteria make new treats from them. Polyphenols from berries can be a never-ending gift.

As I describe in detail in see.nf/urolithins, an important class of postbiotics for aging is the urolithins. Our friendly gut flora forms them in the colon from ellagic acid, which is produced in the small intestine when we eat ellagitannins, the most common form of tannins—natural compounds with a characteristic astringent taste that were part of our ancestors’ diet, such as berries, nuts, acorns, and tree leaves. Because tannins are not bioavailable, they have been treated somewhat like a stepchild in nutrition science or even viewed as “antinutrients”—a view that “changed dramatically” once it was recognized that they can be converted by the microbiome into urolithins, which are now thought to be responsible for some of the positive effects of berries, nuts, and pomegranates.

In C. elegans, urolithins extend lifespan by triggering mitophagy, mitochondrial autophagy, which prevents defective mitochondria from accumulating with age. A decline in mitophagy has been associated in older people with lower muscle mass and poorer physical fitness (slower walking). In older rodents, urolithins were found to counteract the age-related decline in muscle function by improving physical performance and, in humans, to induce a molecular signature of better mitochondrial health and biogenesis in muscle biopsies, similar to after an aerobic training session. This then leads to greater muscle endurance, even without exercise. As with any postbiotic, what matters here, too, is that the necessary microbes are present. Studies show that some people produce only little urolithin, and in others the microbiome cannot produce any urolithin at all.

When people were given pomegranate extract to drink, urolithin producers experienced a significant reduction in LDL cholesterol, whereas non-producers did not. But after a few weeks of supplementation, some transformations occurred—non-producers became producers. That could be an explanation for why vegetarians tend to have more urolithin-producing microbes, since they eat more plants. But some plants contain more than others: Among berries and nuts, boysenberries, marionberries (both American blackberry cultivars), Himalayan raspberries, pomegranates, and walnuts have the highest content of ellagitannins.

Calorie Restriction

Three meals a day (plus snacks!) are new from an evolutionary perspective. In see.nf/fasting, I explain that the history of life on Earth is a history of hunger. If our physiology is so well adapted to recurring scarcity, might it be good to restrict ourselves? During fasting, not only are all resources freed up that would otherwise be needed for digestion and storage, but cells switch into a protective mode that reduces damage from free radicals and inflammation. This is the concept of hormesis: “What doesn’t kill me makes me stronger.” This was perhaps demonstrated most clearly in a series of horrific experiments in which mice were exposed to gamma radiation at Hiroshima levels, strong enough to kill 50 percent of the animals within two weeks. But of the mice that had been intermittently fasted for six weeks before irradiation, not a single one died.

Time to Fast

Benjamin Franklin said: “To lengthen thy life, shorten thy meals.” Could this hormetic strengthening of defenses lead to a longer life? Slowing aging through calorie restriction became a topic during the Great Depression in the 1930s, when average life expectancy seemed to rise unexpectedly. This had already been observed during World War I in Denmark, when the naval blockade restricted food transports and the mortality rate subsequently fell by 34 percent, and later in World War II in Norway, when calorie intake fell by 20 percent and the mortality rate fell by 30 percent. However, the composition of the diet also changed at the time, which makes the picture more complicated, because people had to eat fodder crops like barley rather than the animals that would otherwise have received the feed.

In the lab, restricting calorie intake without malnutrition is one of the most effective nonpharmacologic interventions to extend healthspan and lifespan across a wide variety of species and is “perhaps the most important discovery in the biology of aging to this day.” A simple reduction in food intake can double or triple the lifespan of yeast, fruit flies, and worms and extend the average and maximum lifespan of rats and mice by up to 50 percent. Such experiments can be that simple: Give a few spiders (with the cute name bowl-and-lid spiders) a few flies—one fly per week, and the spiders live an average of 81 days; three flies per week and they live only 64 days; and at five flies per week it’s only 42 days.

The animals in some of these experiments not only live longer but also healthier. The obvious slowing of the aging process, which has been preserved all the way up to primates, is accompanied by resistance to various age-related diseases and prevents or delays autoimmune diseases, cancer, cardiovascular disease, glaucomas, kidney disease, and neurodegeneration. In Part I, I went into many of the theoretical foundations of the life-extending benefits of calorie restriction in detail, from revving up AMPK to autophagy, the “cleaning out the closets,” in which misfolded proteins, defective cellular structures, and senescent cells are removed. An article about the mechanisms by which intermittent fasting prevents cardiometabolic disease bears the subtitle “The janitor is secretly the boss.”

The candle that burns twice as bright burns half as long

Another possible mechanism is slowing metabolism. Because we have been programmed over millions of years of evolution to survive scarcity, as we gradually lose weight we not only unconsciously move less to save energy, but our metabolism adapts as well. Each pound less can reduce resting metabolic rate by seven calories per day. If you want to lose weight by dieting, that’s a curse (see.nf/biggestloser), but in fact a slowed metabolism can be a good thing.

Restricted calorie intake can extend animals’ lifespans, and slowing metabolism could be the mechanism behind it. Maybe that’s why the tortoise lives ten times as long as the hare. (Harriet, a tortoise Charles Darwin took from the Galápagos Islands in the 1830s, lived until 2006.) Maybe slow really does win the race.