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Diseases of all shapes and sizes have been linked to the dysregulation of microRNAs.7118 But the good news is that there is something we can do about it. MicroRNA expression can be modified through diet.7119
In humans, dozens of circulating microRNAs are upregulated as we age, and dozens are downregulated.7129 The blood levels of seven microRNAs may be able to differentiate Alzheimer’s patients from healthy controls with up to 95 percent accuracy.7130 If these dynamics are all just genetic, then microRNA levels could still be useful as biomarkers or diagnostics, but they might be harder to tweak to control our fate. But, no, a study on identical twins who died about a decade apart found they had highly discordant microRNA levels, suggesting that nongenetic factors, such as diet and lifestyle, are
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As we know, one problem with petri dish studies is that sometimes concentrations are used that far exceed that which can be achieved through regular dietary consumption, but a few foods have been put to the test. For example, a study showing that extra-virgin olive oil with a high polyphenol content has a different microRNA impact than lower-polyphenol olive oil suggests that the polyphenols may be playing an active role.7154 Nuts—either one to two handfuls of walnuts a day for a year7155 or a single handful of a combination of almonds and walnuts for eight weeks—also change the levels of an
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There are well-known inflammiRs, inflammatory microRNAs like miR-155, that are suppressed by a variety of flavonoids—genistein in soy, quercetin in apples and onions, allyl isothiocyanate in onion family vegetables, curcumin in turmeric, and apigenin in parsley, celery, and chamomile tea.
Flavonoids have been found to suppress the proliferation of tumor cells by both suppressing oncogenic (cancer-causing) microRNAs and boosting tumor suppressor microRNAs.7159 Long-term soy consumption in breast cancer patients had this effect,
Intercellular microRNA communication is conserved throughout the evolutionary tree of life, raising the possibility of cross-kingdom gene regulation. In the eighteenth century, life was classified as belonging to either the plant kingdom or the animal kingdom.7171 In the nineteenth century, single-celled organisms like amoebas got their own kingdom,7172 and with further improvements in microscopy, bacteria got one as well. (These days we’re up to seven kingdoms—algae and fungi each got their own, as did bacteria-like organisms originally described as extremophiles, living in previously thought
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Recognition of the ubiquitous presence and activity of microRNAs in plants followed soon after their discovery in animals.7179 Cotton plants, for example, use microRNAs to silence the virulence genes of a pathogenic fungus.
Just like we share many microRNAs with other animals, some microRNA sequences in plants have such close overlap with animal microRNAs that scientists suspect they’re actually the same microRNA, conserved through 1.5 billion years of evolution.7181 Regardless, matching up the sequences of plant microRNA to human messenger RNA, there appear to be at least a thousand different human genes that plant microRNAs could target.
Plant-based diets contain thousands of biologically active microRNAs.7183 While the scientific community has historically chalked up the benefits of fruits, vegetables, and herbal medicines to the presence of phytonutrients, it may be their microRNAs playing a role.
As we’ve seen, one way that phytonutrients like polyphenols affect our physiology is by manipulating our microRNA expression, but perhaps plant microRNAs are silencing our genes directly.
The exploration of the potential for cross-kingdom gene regulation with “xeno-microRNAs”7186 from plants is currently considered among the most exciting topics in all of science.
Dietary microRNAs would mean that food may provide information as well as nutrition—information that could effectively switch our genes on or off.
Yes, plant microRNAs have been shown to enter human cells and alter our gene expression,
Researchers found that as many as 5 percent of all detectable microRNAs circulating in people’s bodies may be from plants.
Plant microRNAs have been found throughout the human body, including the brain, breasts, kidneys, liver, and lungs, as well as in breast milk, amniotic fluid, and umbilical cord blood.7216 Are these just incidental findings, or are dietary microRNAs doing anything to us or for us?
Hundreds of different microRNAs have been found in the edible nanoparticles of common fruits and vegetables.
Do we get anything from these trillions of tenants taking up residence in our colon, or are they just squatting? They pay rent by boosting our immune system, making vitamins for us, improving our digestion, and balancing our hormones. We house and feed them, and they maintain and protect their house, our body. Prebiotics are what feed good bacteria. Probiotics are the good bacteria themselves. And postbiotics are what our bacteria make.
The transition from adulthood into old age is accompanied by pronounced changes to the microbiome.7315 Given large interpersonal differences, there is no “typical” microbiome of the elderly,7316 but the trends are in the very direction Metchnikoff described: a shift from the fermentation of fiber to the putrefaction of protein.7317 This deviation from good bugs to bad is accompanied by an increase in gut leakiness, the spillage of bacterial toxins into the bloodstream, and a cascade of inflammatory effects. This has led to the proposal that this microbiome shift is a “primary cause of
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centenarians have up to about a fifteenfold increase in butyrate producers.
centenarians carry more of the good bacteria in their gut.
When we eat a fiber-depleted diet, we starve our microbial selves. Our famished flora, the microbes in our gut, have to then compete for limited resources and may consume our own mucus barrier as an alternative energy source, thereby undermining our defenses.
The most important role a healthy microbiome has for preserving health as we age is thought to be the prevention of systemic inflammation.7376 Inflammaging is a strong risk factor not only for premature death.7377 Those with higher-than-average levels of inflammatory markers in their blood for their age are more likely to be hospitalized,7378 frail,7379 and less independent,7380 and suffer from a variety of diseases, including common infections.
The ultraprocessed foods that make up the majority of our diet7403 aren’t just deficient in fiber but include additives that have been shown to muck with our microbes. Even something as simple as salt can affect our microbiome. Approximately doubling sodium intake by adding a teaspoon of salt to people’s diets not only increases their blood pressure and boosts pro-inflammatory cells7404 implicated in autoimmune disease7405 but it rapidly depletes the gut of the good bacteria
Why can’t we just take a fiber supplement? There are literally thousands of types of fiber in plant foods, and each may support different communities of bacteria in our gut.7527 Unlike whole foods, like brown rice or whole-grain barley, fiber supplements don’t seem to work to improve the richness of the microbiome.7528 What’s more, a combination of brown rice and barley synergistically works better than either alone.7529 That’s the reasoning behind recommendations that people take a “50-food challenge,” eating at least fifty different plant foods a week to achieve a diet diverse enough to feed
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Fiber isn’t the only prebiotic. For example, about 30 percent of the caloric content of human breast milk is made of “indigestible” oligosaccharides.7535 Though we may not be able to digest them, guess who can? Bifidobacterium infantis, good bacteria in the guts of infants. That’s how important the human-bacteria relationship is. We were designed to be a symbiotic species.
Inulin, concentrated in such vegetables as onion and garlic, can have a “huge” bifidogenic effect.7536 Ironically, some people with irritable bowel syndrome actively avoid inulin because it is a type of FODMAP, or fermentable oligo-, di-, and monosaccharides and polyols. Individuals following FODMAP-restricted diets tend to end up with depleted levels of Bifidobacteria, so it’s been theorized that such eating patterns could actually impair long-term gut health.7537 There is “resistant starch”—starches resistant to digestion in our small intestines so they make their way to our colon, where
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As with fiber, you need to eat the prebiotics and have prebiotic-eating bugs to benefit. Those carrying starch scarfers like Ruminococcus can ferment nearly all the resistant starch they eat, whereas those who don’t are only able to take advantage of 20 to 30 percent.7542 How do you foster the growth of more of these good bugs? Eat more foods containing resistant starch! Within just ten days of being randomized to a diet high in resistant starch, the abundance of starch eaters like Ruminococcus can be quadrupled.
The preferred prebiotic of Bifidobacteria is starch, so how can we ferry more starch to our colon?7544 Wrap it in fiber. That is, within intact grains and legumes.
Compare that to even whole milled grains. Ground flour particles can be a hundred times smaller—even smaller than the cells themselves—so nearly every one may be ruptured open, spilling their contents early and leaving our gut flora in the lurch.7548 That’s why we should try to de-flour our diets. Whole grains are good, but intact whole grains (groats) are better. It’s the same reason why eating nuts can alter our microbiome for the better, boosting the growth of good bugs that produce short-chain fatty acids, but there appears to be no prebiotic influence when we eat the same amount of nut
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Another major class of prebiotics are the polyphenols concentrated in fruits and vegetables.7557 Those who discount the power of polyphenols often refer to studies showing their low bioavailability. Up to 85 percent of the polyphenol pigments that make blueberries blue do not get absorbed and end up in our colons, for example,7558 but more advanced detection methods have recently shown that the majority of polyphenols may be absorbed after all.7559 And our colon may be exactly where some of the magic happens.
An interventional trial in which older individuals were randomized to swap out some low-polyphenol snacks for foods like berries and dark chocolate experienced a significant increase in good (butyrate-producing) bacteria and a bolstering of the gut barrier.7567 However, polyphenol-rich beverages probably provide the best proof. Tea leaves and coffee beans have a lot of polyphenols that end up in the brew, whereas the fiber is completely left behind. Both green tea7568 and coffee7569 are bifidogenic. Three cups of coffee a day can raise Bifidobacteria levels in the gut significantly within
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polyphenols from green, black, and oolong tea also boost Bifidobacteria and short-chain fatty acid production.
Just as the benefits of fiber result from both the prebiotic fueling of good bacteria and the resulting postbiotic metabolites (short-chain fatty acids), polyphenols can act as prebiotics and also result in beneficial postbiotics. For example, there is an immediate bump of blueberry pigments in our blood within an hour of consumption, but a day later, new blueberry-derived compounds continue to appear in our bloodstream as our bacteria churn out new goodies from them.7582 In this way, berry polyphenols can be the gift that keeps on giving.
As I detail in see.nf/urolithins, one class of postbiotics important to aging are urolithins, which are created in our large intestine by our friendly flora from ellagic acid, which is formed in our small intestine when we eat ellagitannins,7583 the most common form of tannin,7584 characteristically astringent-tasting natural compounds found in many of our ancestral foods, including berries, nuts, acorns, and tree leaves.
A decline in mitophagy has been linked to low muscle mass and poor physical function (slower walking speed) in the elderly.7588 Urolithins have been found to counter age-related muscle function decline by improving the exercise capacity of older rodents7589 and, in people, induced a molecular signature of improved mitochondrial health and biogenesis in muscle biopsies, similar to what one might see after an aerobic exercise regimen.7590 This then translates into improved muscle endurance even in the absence of any exercise training.7591 Like any postbiotic, though, it depends on having the
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This may explain why vegetarians tend to have a higher abundance of urolithin-producing microbes, their greater intake of plants.7594 However, some plants have more than others. Among berries and nuts, the highest levels of ellagitannins are found in boysenberries, marionberries, yellow raspberries, pomegranates, and walnuts.7595
the CALERIE trial does suggest that even “normal weight” individuals should eat less to improve their health and longevity.
As I note in see.nf/earlytre, studies suggest that prolonged nightly fasting with reduced evening food intake may decrease cancer risk and recurrence.
In general, shifting food intake toward the morning—eating breakfast like a king, lunch like a prince, and dinner like a pauper or skipped entirely—has beneficial cardiometabolic effects, whereas the same eating window pushed toward the evening (skipping breakfast) can have null or negative effects.
one of the ways fasting works is by reducing the levels of the cancer-promoting growth hormone insulin-like growth factor 17763 (see the IGF-1 chapter).
In the year 2000, a new human hormone was discovered. It was the twenty-first documented fibroblast growth factor, so it was named FGF21.7779 Since its discovery, it has emerged as a key agent for promotion of metabolic and artery health, leanness, and longevity.
FGF21 appears to act through multiple aging pathways, boosting AMPK and sirtuin activity,7783 while inhibiting IGF-1 and mTOR signaling.
Exercise boosts FGF21 levels, which may in fact be one of the reasons it’s so good for us.7793 Circulating FGF21 rises immediately after a bout of exercise, peaking an hour afterward and returning to baseline within three hours.
Even without reducing protein intake, FGF21 levels shoot up when people are fed lots of starchy foods.7809 The healthiest sources would likely be legumes and intact whole grains.7810 FGF21 is bumped up by butyrate, the short-chain fatty acid our good gut flora make from fiber,
This suggests slow-digesting starches, such as pasta, beans, and intact grains, could have a similar “pro-longevity” effect.
in FGF21 within a single week, accompanied by a significant increase in insulin sensitivity. The researchers concluded that “dietary protein dilution” promotes metabolic health in humans.7822 Switching men and women from a high-protein diet of 138 g per day down to a more than adequate 67 g7823 also multiplied FGF21 levels in the blood sixfold, but within just four days.7824
FGF21 may help explain the mounting evidence suggesting that a lower protein intake is associated with increased health and survival.
FGF21 levels were found to be markedly higher in those eating plant-based.
Low IGF-1 levels predict survival in people with exceptional longevity.
that the diets with the lowest protein-to-carbohydrate ratios yielded the longest maximum lifespans independent of calories.
