Chapter 168
Does Fitness Beat the microRNAs?
For example, miR-17 (short for microRNA-17) directly extends the lifespan of mice. Transgenic mice created for the purpose of overexpressing miR-17 lived longer and healthier, proving that microRNA not only correlates with a longer life but immediately causes it, among other things by suppressing mTOR. It may be that the results of parabiosis studies are attributable to such longevity miRNAs. Do you remember the crazy experiments in which old animals were rejuvenated by sewing them together with younger cage mates and connecting their circulatory systems? That vividly proved that there are factors in the blood that determine aging. Perhaps microRNAs belong in this category.
In humans, dozens of circulating microRNAs are upregulated with increasing age, and dozens of others are downregulated. Based on the blood levels of seven microRNAs, one can distinguish Alzheimer’s patients from healthy members of a control group with a hit rate of up to 95 percent. If all these dynamics were only genetically determined, microRNA levels could still prove useful as biomarkers or for diagnostic purposes, but it could be harder to optimize them to play fate. But that is not the case—a study of identical twins who died about ten years apart found that their microRNA levels differed markedly from one another, suggesting that non-genetic factors such as diet and lifestyle play a decisive role for the microRNAs that correlate with life expectancy.
Does Fitness Beat the microRNAs?
More than 6000 patents have been filed for the possible use of synthetic microRNA mimetics and inhibitors to combat aging and disease, but so far no such drug has been approved. So what can we do naturally?
Randomized controlled trials showed that exercise can prevent cognitive decline in older adults and improve the cognitive performance of those who already have Alzheimer’s, and one of the reasons could be microRNAs. There are microRNAs whose levels are reduced in Alzheimer’s (for example miR-132 and miR-338) but are increased by physical activity, and conversely there are microRNAs that are overexpressed in Alzheimer’s (miR-7 and miR-766) but are reduced by physical exercise. But the picture is not entirely clear. MiR-146a levels in blood, in the brain, and in cerebrospinal fluid are consistently elevated in Alzheimer’s patients. And although short-term resistance training and long-term basketball training lowered levels of the circulating microRNA, rowing training and marathon running were also found to raise it. So there is still a lot to figure out about what role microRNAs play in how physical activity can improve mental agility.
Modulating microRNAs Through Diet
MicroRNAs also mediate the benefits of polyphenols. A dozen different phytonutrients changed the expression of dozens of microRNAs in vitro. As we know, a problem with petri dish studies is that sometimes they work with far higher concentrations than one can achieve through normal consumption of foods, but a few foods have been examined. For example, a study showing that extra-virgin olive oil with a high polyphenol content has a different effect on microRNAs than olive oil with a lower polyphenol content suggests that the polyphenols may play an active role. Nuts, too—either one to two handfuls of walnuts daily for a year or a handful of a mixture of almonds and walnuts for eight weeks—change the levels of multiple microRNAs in the blood. But to what end?
Some well-known inflammatory microRNAs such as miR-155 are suppressed by a variety of flavonoids—genistein in soy, quercetin in apples and onions, allyl isothiocyanate in vegetables of the onion family, curcumin in turmeric, and apigenin in parsley, celery, and chamomile tea. MiR-155 also plays a role in cancer; for example, it is involved in the development of acute myeloid lymphoma, the deadliest and most common form of leukemia in adults. In a study titled “Slowing the Progression of Acute Myeloid Leukemia (AML) Using Sulforaphane by Regulating miR-155 Levels,” miR-155 levels could not only be lowered in vitro by about 80 percent by a compound from cruciferous vegetables, but this also led to a marked decline in the viability of cancer cells. Unfortunately, broccoli sprouts, the most concentrated source of sulforaphane, have not yet been tested in AML patients to assess their clinical effects.
Flavonoids have been found to suppress the spread of tumor cells by both suppressing oncogenic (cancer-causing) microRNAs and supporting tumor-suppressive microRNAs. In breast cancer patients, long-term consumption of soy had this effect, which may explain why soy consumption appears to prevent the development of breast cancer in women before and after menopause, increase the survival rate of breast cancer patients, and reduce the likelihood that the cancer returns. And it may also explain the upregulation of tumor-suppressive microRNAs in vegetarians and vegans compared to omnivores and the resulting lower cancer risk, although meat consumption also affects microRNAs.
After subjects ate beef or lamb three times daily for a month, rectal tissue samples were taken from them, and these showed a significant upregulation of oncogenic microRNA clusters. If this diet was supplemented with resistant starch, this effect was reduced, but could not be completely eliminated. Likewise, the meat carcinogen PhIP, which is found especially in cooked, grilled, roasted, and fried chicken meat, acts in an estrogen-like way on microRNAs that play a role in the development and progression of breast cancer. MicroRNA modulation has also been cited as an explanation for the fact that saturated fats increase insulin resistance, even though this has so far been demonstrated only in the muscles of rats.
Aside from the possibility that diet-related microRNA changes contribute to the lower rates of cancer and diabetes in people who eat predominantly plant-based diets, they can also contribute directly to life extension. A study of circulating microRNA expression conducted in the Blue Zone of Loma Linda, where healthy Adventist vegetarians live about ten years longer than other Californians, found that about a half dozen microRNAs associated with the aging process were expressed differently in vegetarians and non-vegetarians and may provide mechanisms for the higher life expectancy with plant-based diets. Interestingly, semi-vegetarians and vegans scored better on one of the anti-aging indices than ovo-lacto vegetarians, who avoid meat but eat eggs and dairy products. Semi-vegetarians were defined as people who eat meat at least once a month but no more than once a week. The researchers suspected that the semi-vegetarians ate fewer animal products overall than vegetarians who regularly ate eggs and dairy products.
Xeno-microRNAs
Intercellular microRNA communication has been conserved across the entire evolutionary tree, opening up the possibility of gene regulation across the boundaries of the plant and animal kingdoms. In the 18th century, all life forms were assigned either to the plant or the animal kingdom. In the 19th century, unicellular organisms such as amoebas were given their own kingdom, and with further improvements in microscopy, bacteria got one too. (Today we are up to seven—algae and fungi each got their own kingdom, as did bacteria-like organisms that were originally called extremophiles and live in zones once thought to be uninhabitable, such as in hot springs).
Is it possible that inhabitants of different biological kingdoms communicate with one another using a shared microRNA language? In 2011 it was found that the microRNAs of the microbiome can modulate their host’s gene expression. For example, there are gum-disease pathogens that secrete vesicles full of microRNA that enter host cells, apparently to suppress our immune response. Clever! In 2016 we realized that we have our own microRNA readiness police. Fecal microRNAs produced by intestinal mucosal cells infiltrate the intestinal bacteria and regulate their gene expression and growth; they may be indispensable for maintaining a healthy microbiome. If microRNA manipulations take place between the simplest and the most complex organisms on Earth, what about exchange with something in between—the plant kingdom?