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Since everyone should be striving to get enough folate, there is no benefit to routine genetic testing to see which variant you have, which is why major medical organizations in the field recommend against MTHFR testing.658 The only thing you might do differently if you knew you had a double dose of the less functional enzyme is to be especially careful about alcohol intake. Acetaldehyde, the breakdown product of alcohol, can destroy the folate in our body,659 so those with double T variants should consider restricting their consumption to less than one drink a day.660 As everyone should
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For example, randomized controlled trials have shown that men taking folic acid supplements significantly increase their risk of developing prostate cancer. Randomized trials have also found that those taking folic acid supplements for more than three years are more likely to develop colorectal polyps.668 So, natural sources of folate, like beans and greens, may be best,
Beyond food and supplements, the third way to improve your folate status is to contract out some of the production to your microbiome. A folate transporter in our colon appears to be specially designed to absorb folate670 produced by good bacteria like Bifidobacterium when we feed them fiber.671 Increasing your fiber intake can bolster the growth of little folate factories in your gut.
Our epigenome, characterized by the pattern of DNA methylation, can be thought of as a lens through which our genetic information is filtered.672 Unfortunately, it’s a lens that can become cloudy as it deteriorates with age. Thankfully, epigenetic changes are reversible, so we may be able to polish it back into focus. Caloric restriction, as well as diet and lifestyle improvements, including physical activity, smoking cessation, and shopping more in the produce aisle than at the meat counter, may all slow the epigenetic clock. Getting sufficient levels of methyl-donor nutrients, such as
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To help boost this anti-aging pathway, on a daily basis, consider: restricting calories by 12 percent, which would be cutting about 250 calories out of a 2,000-calorie diet (e.g., skipping a piece of pie or cake every day) meeting the 400 µg recommended daily allowance of folate, which could be achieved with about a cup of cooked lentils or edamame, a cup and a half of cooked spinach or asparagus, or two and a half cups of broccoli, for example
more than 50,000 scientific papers have been published on this “Maillard reaction,” in which proteins can become irreversibly glycated, or bonded with sugar.673 The same reaction can occur at body temperature, leading to an accumulation of advanced glycation end products (AGEs),674 which we now know are one of the main factors contributing to the aging process.
So, even if you have normal blood sugars, some proteins and other molecules in your body are being irrevocably glycated.
whole lifespan. Glycation causes proteins to cross-link together, which stiffens our tissues—most critically, our arteries and the heart muscle itself. This impaired elasticity can result in high blood pressure, peripheral artery disease, heart disease, and even cancer. (Stiffness of breast tissue is associated with an increased risk of cancer.)680 The acronym for advanced glycation end products was chosen intentionally, to emphasize their role in the aging process.
chronic, systemic inflammation. In the search for the mechanism for this response, researchers discovered receptors for AGEs in our body that spark the inflammatory cascade and named them RAGE: receptors for advanced glycation end products.682 RAGE can function as a master switch. When AGE sparks RAGE, a whole host of inflammatory genes are triggered, along with a promotion of further RAGE expression, which leads to a vicious, cyclical feedback loop that can have profound pathological effects.683 As AGEs accumulate in our bones, joints, and muscles, they may contribute to osteoporosis,
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The toxicity of AGE accumulation is underscored by the number of defense mechanisms our body employs to prevent their formation.688 Once they have been formed, though, they’re hard to get rid of, so they gradually accumulate and wreak havoc.689 Over five to six decades, AGE levels in our tissues roughly double.
Across the animal kingdom, the slower the rate of AGE formation, the longer species tend to live. The bowhead whale, for example, who, by living more than two centuries, is probably the longest-living mammal, has exceptionally low rates of AGE accumulation.694 How can we best keep our levels low? AGE formation is heat-dependent.
The burden of AGEs in our tissues appears to be less a matter of how much we make and more a matter of how many AGEs we eat.
Cooking methods do matter. A raw apple has three times fewer AGEs than one that’s been baked,
But don’t lose perspective: A raw apple has 13 units of AGEs compared to a baked apple’s 45 units, while a boiled hot dog has 6,736 units compared to a broiled hot dog’s 10,143. So, a baked apple still has 150 times fewer AGEs than a boiled frankfurter,730 and vegetables, even when grilled, have but a fraction of the AGEs of raw meat.
Population studies have found that those with elevated AGEs in their blood are at greater risk for anemia, artery and cartilage stiffness, cardiovascular disease, chronic kidney disease,736 osteoarthritis,737 and osteoporosis,738 but most of the studies have focused on the adverse effects of AGEs on our muscles, mortality, and minds.
In the influential paper “Oral Glycotoxins Are a Modifiable Cause of Dementia … [in] Humans,” the reduction of food-derived AGEs is suggested as a feasible, effective strategy to combat our dementia epidemic.
The benefits of reducing food quantity can be undone by reductions in food quality. We’ll see this in the next chapter, where the well-being enjoyed by members of the Calorie Restriction Society may be constrained by their relatively high protein intake.
Even though the majority of AGEs in the body come externally through our diet, AGEs are also formed internally. This normally happens at a slow, continuous rate, but it is sped up in the context of high blood sugars.
choosing lower glycemic load carbs, such as legumes (beans, chickpeas, split peas, and lentils), fruits, and intact whole grains.
By 1980, it had already been shown that beans cause an “exceptionally” low blood sugar response, half that of other common foods.765 But two years later, an extraordinary discovery was published: Legumes can benefit your metabolism hours after consumption766 or even the following day. If you eat lentils for dinner, your body reacts differently to breakfast eleven hours later.767 Even if you drink straight sugar water the next morning, your body is better able to handle it if you had lentils the night before. Researchers initially dubbed it the “lentil effect,” but when subsequent studies found
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One reason diabetics suffer nerve and artery damage is due to methylglyoxal, an inflammatory metabolic toxin that forms at high blood sugar levels. Methylglyoxal is the single most potent creator of AGEs.
From a glycemic-index standpoint, breads made from sprouted grains790 with added cracked wheat,791 whole wheatberries,792 or rye berries,793 or made with stone-ground flour are preferable.
If you simply just can’t live without white bread, toasting it,795 using sourdough fermentation if you bake your own,796 and freezing and defrosting it all lower the blood sugar response.
When starch is cooked, then cooled, some of it crystallizes into “resistant” starch—starch that is resistant to being broken down into sugars by the enzymes in our digestive tract, which lowers its glycemic impact.
To minimize the glycemic index of potatoes, simply precook them and either eat them cold or reheated
Randomized controlled trials involving both diabetic and nondiabetic subjects suggest that blood sugar control may be improved by adding two teaspoons of vinegar to a meal, effectively blunting the post-meal blood sugar spike by about 20 percent.805 So, the effects of these high-glycemic foods may be blunted by adding vinegar to rice (like the Japanese do to make sushi) or dipping bread in balsamic vinegar, for example.
vinegar isn’t the only way to help blunt the blood sugar surge. For example, if you eat berries with your meals, they can act as starch blockers by inhibiting the starch-digesting enzyme.807 This then slows the absorption of blood sugars into your system.
On the other end of the culinary spectrum, onions can do the same thing.
You can also drink your spices. Have some ginger tea with two slices of refined flour white bread, and you drop the bread’s glycemic index by nearly 30 percent. Cinnamon tea works even better, with nearly a 40 percent drop in glycemic response.
AGEs are considered “gerontotoxins,”826 meaning aging agents (from the Greek geros for “old age,” as in geriatric), and are implicated in a wide spectrum of age-related diseases. In a sense, we are all slowly being cooked alive. AGEs are formed endogenously at body temperature, especially with high blood sugars, but their buildup in our tissues is largely determined by the AGEs we eat (or smoke), which are formed at much higher temperatures when some foods are cooked at high heat
lower IGF-1 levels may have given the centenarians the advantage.
There is a single IGF-1-lowering gene variant that adds as much as ten years or so to life expectancy if you inherit it from both parents.850 Those lucky enough to be born with genetically lower IGF-1 levels are more likely to live to be nonagenarians.
the dampening of IGF-1 signaling appears to be a human-longevity mechanism.
IGF-1 is one of those key signals for regulating cell growth.
If your IGF-1 levels stay elevated after you’re old enough to vote, your cells will continue to get the message to continue to grow and divide. As you might expect, the higher the IGF-1 in your bloodstream, the higher your risk for developing some cancers, such as breast,870 colorectal,871 and prostate.872 (That doesn’t seem to be the case, though, with lung,873 ovarian,874 or pancreatic cancer.
Those with a tendency to have lower IGF-1 levels are less likely to get cancer in the first place,878 and cancer survivors with lower levels are more likely to survive longer.879 It’s not the original tumor that tends to kill you; it’s the metastases.880 As a growth factor, IGF-1 doesn’t just make tumors grow;881 it helps cancer cells separate from the main tumor, infiltrate surrounding tissues, and invade the bloodstream.882 IGF-1 is what helps breast cancer get into the bone,883 liver, lung, brain, and lymph nodes.884 It’s involved every step of the way, facilitating the transformation of
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So, lowering IGF-1 activity could have the dual benefit of decreasing cancer risk while increasing longevity.
Most malignant tumors are covered in IGF-1 receptors. Without any IGF-1 around, the tumors may not be able to grow and spread.
Fasting is the poster child of unsustainability, though. If you fast long enough, you’re guaranteed to stop aging—because you’ll be dead.
In rodents, calorie restriction alone reduces IGF-1 levels,902 but in humans, unless protein consumption is also reduced, even severe caloric restriction doesn’t work. Researchers were only able to get subjects’ IGF-1 levels to budge after the protein intake of calorie-restriction practitioners was cut from typical American quantities down closer to the recommended daily allowance.903 At intakes far exceeding recommended consumption, protein from plants and animals equally raises IGF-1 levels,904 but at more reasonable levels, animal protein appears to be the main culprit.
Although some IGF-1 is made locally in various tissues, our liver is responsible for approximately 75 percent of the IGF-1 that circulates throughout our body.930 So, what happens when we consume a load of protein? Our liver starts pumping out IGF-1 to tell all the cells in our body that it’s time to grow to use up the excess. With so much extra protein to work with, our liver sends the signal to our cells to be fruitful and multiply.
The problem is that tumors may be some of the new additions spurred by this growth hormone. When you’re a fully grown adult, cell growth is something we want to slow down, not accelerate. The goal, therefore, would be to maintain adequate, but not excessive, protein intake.
What about the few plant proteins that have amino acid profiles similar to animal proteins, like soy? One of soy’s selling points is that it has “high-quality” protein, but when it comes to IGF-1, so-called higher quality may mean higher risk. Is that the case with soy-based protein? We know that the consumption of animal protein is associated with significantly higher levels of IGF-1, while the consumption of non-soy plant protein is associated with significantly lower levels.939 Soy protein falls in the middle, with no significant association with IGF-1 levels either way. This suggests that
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When a dream team of longevity researchers, including Luigi Fontana and Valter Longo, followed a nationally representative sample of thousands of Americans over age fifty for an average of eighteen years, they found that those under sixty-five with high protein intakes had a 75 percent increase in overall mortality and a fourfold increase in the risk of dying from cancer. When the protein sources were split up into plant versus animal, however, the overall mortality risk was found to be limited to the consumption of animal protein.
One of the ways our body tries to protect us from cancer is by releasing a binding protein into our bloodstream to tie up any extraneous IGF-1. Think of it as our emergency brake. Let’s say you’ve managed to downregulate production of new IGF-1 through diet. What about all that excess IGF-1 still circulating from the bacon and eggs you may have eaten the day before? No problem: The liver releases a snatch squad of binding proteins to help take it out of circulation.
After only eleven days of cutting back on animal protein, your IGF-1 levels can drop by 20 percent and your levels of IGF-1 binding protein can jump by 50 percent.
The cancer-suppressing effect seems so powerful that, in a randomized controlled trial, Dr. Ornish and colleagues appeared to be able to slow, stop, and even reverse the progression of early-stage, non-aggressive prostate cancer without chemotherapy, surgery, or radiation—just a plant-based diet and lifestyle program.
A Food That Lowers IGF-1 Are there any foods that actively lower IGF-1? A retrospective966 and snapshot-in-time study suggested that tomato consumption may be associated with lower IGF-1 levels.
Insulin-like growth factor 1 is considered to be of cardinal importance for cancer expansion,989 so downregulating IGF-1 activity not only has the potential to slow the aging process990 but may be a way to turn anti-aging genes against cancer.991 IGF-1 is cranked up on high-protein diets and by animal protein in particular. This helps explain the benefits of more plant-oriented eating,992 as well as why consuming a diet with a relatively low proportion of protein is considered critical for lifelong health.
In recent years, one of the most medically important discoveries was recognizing the potential role of inflammation in many chronic diseases, including at least eight of the top ten leading causes of death.
