How Not to Age: The Scientific Approach to Getting Healthier as You Get Older

by Michael Greger

Another AMPK-boosting zinger is hibiscus,

When we consume vinegar, the acetic acid is absorbed and metabolized, giving us a natural boost in AMPK at the dose you might typically get dressing a salad.

How Not to Diet, I cover how vinegar can diminish both visceral and superficial body fat213 and reduce blood sugars in diabetics on par with antidiabetic drugs214 by improving the uptake of blood sugar by our muscles.215 That’s an AMPK effect also seen with exercise.216 Surprisingly, vinegar plus metformin worked better to control blood sugars than metformin alone, suggesting either additive benefits to further AMPK stimulation (the metformin dose was relatively low) or vinegar benefits above and beyond AMPK.

Vinegar has also been shown to improve artery function218 and to have other AMPK-activation benefits, such as decreasing blood cholesterol and triglyceride levels.

Don’t like the taste of vinegar? Instead of delivering acetic acid through your mouth, you can also supply it to your bloodstream from the opposite direction. You know how vegetables and grains turn sour when they’re fermented? Think sauerkraut or sourdough. That’s because there are good bacteria like Lactobacillus that produce organic acids like lactic acid. Acetic acid is a type of short-chain fatty acid made by the friendly flora in our gut from the fiber and resistant starch we eat. These prebiotics are concentrated in legumes (beans, split peas, chickpeas, and lentils) and whole grains, but fiber can be found throughout the plant kingdom. When we eat whole plant foods, our gut flora can make acetic acid from scratch inside our colons by fermenting fiber. Then, that acetic acid can get reabsorbed back into our bloodstreams. So, we can use the top-down approach to activate AMPK by consuming vinegar or the bottom-up approach by eating fiber.

The sparking of AMPK by colon-produced acetic acid is suspected to play a role in some of the metabolic benefits of a high-fiber diet.

The discovery of AMPK is considered to be one of the most important breakthroughs in biomedicine in the last few decades.231 Because this enzyme is involved in the functioning of the majority of aging-associated regulators, including autophagy, which I discuss next, the importance of AMPK in anti-aging interventions is hard to overestimate.

The drug metformin activates AMPK but carries adverse side effects and may not benefit healthy individuals. AMPK is an energy sensor, so it’s activated when we eat less or move more. Some food components, like saturated fat, can suppress AMPK, whereas others, like fiber, can boost it. There are also specific AMPK-activating compounds in barberries, black cumin, hibiscus tea, and vinegar.

2 teaspoons of vinegar (though never taken straight; sprinkle on food or dilute it in the tea)

Upon realizing there isn’t much food around, our body starts rummaging through our cells in a salvage operation, looking for anything we don’t need—defective proteins, malfunctioning mitochondria, and other stuff that isn’t working anymore. It clears out the junk and upcycles it, turning it into fuel or new building materials, thereby renewing our cells. So, autophagy plays two major roles: nutrient recovery and quality control. The conservation of autophagy machinery over a billion years of biological evolution underscores the importance of this universal recycling program,234 recognized in 2016 with a Nobel Prize awarded for teasing out its secrets.

The buildup of cellular detritus isn’t merely wasteful but harmful, too. Out with the old and in with the new doesn’t just restock the pantry; it also clears away decay. Our ancient ancestors often ate only once a day or went for several days without any food, so our autophagy switches were constantly getting tripped.237 Today, in our three-meals-a-day world, our cells no longer need to look under the couch cushions for sustenance, and the trash heaps just pile higher.

In the modern context of not only having relatively easy access to sufficient nutrients but to food in excess, our baseline rate of autophagy is low238 and slips down even lower as we get older. A decline in autophagic capacity with age has been described in nearly all animals analyzed.239 This can lead to more accumulation of cellular debris, which can then further impair our aging cells. This may be why inadequate autophagy is not just a consequence of aging but is considered to be one of its causes.

As I discussed in the last chapter, we know that the enzyme AMPK activates autophagy. So, anything that suppresses AMPK activation, like saturated fat intake, may also suppress autophagy. Inversely, the enzyme mTOR (see the chapter on mTOR) deactivates autophagy,249 so anything that activates mTOR, like animal protein,250 may also suppress the autophagy process.

Some carbohydrate-rich foods, though, notably french fries and potato chips,252 may inhibit autophagy through another mechanism, acrylamide.

acrylamide is a chemical formed when carbohydrates are exposed to particularly high temperatures that can inhibit autophagy, at least in cells in a petri dish.253 This may explain why high acrylamide exposure is associated with increased mortality.

Any food that activates AMPK should also activate autophagy, so any of the AMPK-boosting foods in the previous chapter should fit the bill. However, autophagy can also be activated directly in pathways independent of AMPK. The most reliable way to kick autophagy into high gear may be to eat less food altogether, but there is a downside to dietary restriction: Starving yourself, as was understated in a major review, “generates discomfort.”257 There is, however, something we can consume that induces autophagy that many find comforting: coffee.

coffee consumption seems protective against the development of fatty liver disease260

A systematic review of the health impacts of coffee concluded that “daily coffee consumption should be encouraged” in patients with chronic liver disease.267 If coffee enhances autophagy, shouldn’t its benefits extend to a wide range of diseases? Yes. Intake is also associated with lower risk of kidney disease,268 along with reduced risk of conditions as varied as gout, type 2 diabetes, skin cancer, and Parkinson’s disease. Decaf was also associated with a range of health benefits.269 The results are all the more remarkable because many of the studies failed to adequately control for smoking and unhealthy food intake, both of which tend to accompany coffee drinking.270 So, coffee drinkers appeared to be healthier in spite of their tendency for less wholesome habits. Does all this translate into them living longer? Apparently so.

Don’t be fooled by “low acid” coffee. It doesn’t help with the acid reflux, heartburn, or stomach upset that plagues some coffee drinkers. The low acid is a reference to low chlorogenic acid—which is exactly what we don’t want. Low-acid coffee producers use a slow roasting process that destroys the autophagy-activating compound. That’s like an orange juice company going out of its way to destroy the vitamin C and then branding its OJ as “low acid.” Technically true, since vitamin C is ascorbic acid, but the OJ maker would be bragging about destroying some of the nutrition, and that’s exactly what low-acid coffee companies are doing.

Milk protein can also undercut the benefits of tea,285 berries,286 and chocolate.287 What about soymilk? In a test tube, phytonutrients in coffee not only bind to proteins in dairy but also in eggs and soy.288 Eggs haven’t been put to the test yet in humans, so the jury’s still out on whether having an omelet with black coffee would impair absorption, but soy appears to have been given the all-clear. Soy proteins initially bind up the coffee compounds in the small intestine, but our good bacteria release them so they can be absorbed down in the lower intestine.289 Other nondairy milks, such as almond-, rice-, oat-, and coconut-based milks, have so little protein that I’d assume there wouldn’t be a binding issue, but they have yet to be directly tested.

The brewing method also affects the impact of coffee on our cholesterol. Watch see.nf/cafestol to see why paper-filtered is preferable.

In 1676, Antonie van Leeuwenhoek, the father of microscopy, was the first person in history to see bacteria. The following year, he saw his own sperm,308 and a year after that, in 1678, he discovered tiny crystals forming in the semen he had left sitting around.309 Centuries later, this compound would be recognized as spermine. It and its precursor spermidine are actually found throughout the body, so their names are just an accident of history. It was independently discovered in brain tissue in 1885 and named “neuridine,” but when it was revealed to be the same as spermine, naming rights defaulted to the indelicate original.

Spermidine plays a key role in regulating cell growth.311 It is positively charged, so it naturally binds to negatively charged molecules like DNA.312 Spermidine fits neatly in both the major and minor grooves of the DNA helix.313 Most spermidine in our body is actively bound to our genetic material,314 stabilizing our genetic code for proper translation.315 Spermidine is also a potent activator of autophagy.

Researchers in Italy found that by the time most people reached their sixties and seventies, their spermidine levels had already fallen to about a third of what they measured in middle age. But those living into their nineties and beyond were somehow able to maintain their youthful spermidine levels, presumably by just making more of it internally. However, we could also replenish declining levels externally with a spermidine-rich diet. The researchers suggested foods like soybeans and mushrooms,324 but, as we’ll learn, wheat germ is an even more concentrated natural source.

a restoration of youthful spermidine levels can improve antibody production in immune cells taken from older adults,333 suggesting that spermidine may help “reverse immune aging.

The reason people who eat more spermidine tend to have less cardiovascular disease336 may be that spermidine can restore autophagy in the cells lining our blood vessels that are responsible for healthy artery function.

Those who consumed the most spermidine didn’t just have lower risk of dying from cardiovascular disease; spermidine intake was associated with a lower risk of all major causes of death, which is what we’d expect from an anti-aging agent. Critically, this survival advantage persisted even after controlling for dietary excellence, meaning it didn’t appear to be just because they were eating more healthful foods in general.

At sufficient doses, wheat germ can also help control cholesterol, triglycerides,450 diabetic blood sugars,451 and pain, fatigue, headache, and mood swings associated with painful periods.452 (Details in see.nf/wheatgerm.) It can also boost Bifidobacteria in the gut. A common constituent of commercial probiotics, Bifidobacteria are considered one of the proxies for a beneficial balance of good bugs in general453

A symbiotic combination of prebiotics and spermidine-producing Bifidobacteria was able to increase spermidine levels in people’s blood. This then translated in a randomized, double-blind, placebo-controlled trial to improve endothelial function,463 thought due to a boost of autophagy.464 Spermidine-producing bacteria are fiber-feeding,465 so prebiotics alone would likely foster the growth of more spermidine producers. Then, even if you miss a day, your colonic colleagues can pick up the slack. Since beans and whole grains are leading sources of spermidine and also the fiber and resistant starch our good bugs eat, they may offer a double dose of cellular spring cleaning.

Autophagy is considered the “primary system for cleaning the body” from the inside out.477 Some food components, like acrylamide, may suppress autophagy, whereas others, like spermidine, can boost the process.

Chlorogenic acids in coffee can also help your cells take out the trash. What’s more, autophagy can be boosted indirectly by amping AMPK or quelling mTOR.

Fifty years ago, microbiologist Leonard Hayflick demonstrated that, contrary to what was believed, human cells in a petri dish do not continue to double forever.478 They only grow and divide about fifty times before entering an irreversible state of arrested replication, known as cellular senescence.479 Senescence comes from the Latin word senex, meaning “growing old.”480 We always have immortal stem cells that can create new cells with a fresh start, but, once they form, they only have about fifty divisions before they, too, are dead in the water. This is a good thing. This natural “Hayflick limit” helps protect the body against cancer by blocking the proliferation of damaged cells.

When we are younger, senescent cells are cleared by our immune system. When our cells reach their limit and are ready to retire, they are programmed to start releasing a cocktail of inflammatory chemicals called the senescence-associated secretory phenotype, or SASP. Inflammation, a process that often carries negative connotations, can sometimes be a benefit. Just like inflammation caused by a splinter draws immune cells out of circulation to a puncture wound, senescent cells make their own funeral arrangements by releasing inflammatory factors to flag themselves for immune clearance.485 There’s a problem, though. As we age, more and more senescent cells are piling up at the very same time that our immune systems are falling into disarray.

The marked extension of healthspan and lifespan through senescent cell clearance sparked a gold rush to identify senolytics, compounds that can eliminate senescent cells.

In 1936, Albert Szent-Györgyi, who won the Nobel Prize the following year for discovering vitamin C, suggested that a class of phytonutrients called flavonols should also be considered a vitamin. (He suggested “vitamin P.”)505 The most common flavonol in the diet is quercetin,506 which is found concentrated in onions, kale, and apples.507 It’s what gives apple peels their bitter taste.508 Researchers had been testing dozens of different compounds on cells scraped from umbilical cords and then irradiated to force senescence. In 2015, they announced their results: Quercetin was a natural senolytic.

A modeling study even suggested that prescribing an apple a day could prevent about as many deaths from vascular disease on a population scale as prescribing everyone a cholesterol-lowering statin drug—and with fewer side effects.

Given the senolytic success of a quercetin cocktail, researchers started screening other flavonoids.537 In doing so, they found one that was nearly twice as potent: fisetin.

Like quercetin, fisetin has been shown to have anti-inflammatory effects in clinical trials,

fisetin is concentrated in strawberries, the richest known dietary source.

fisetin supplements are not recommended.

A third natural senolytic compound has been discovered: piperlongumine,553 found concentrated in a spice commonly sold in Indian grocery stores as pippali (Piper longum, also known as pibo in China and long pepper in Europe).

To help slow this aging pathway, on a daily basis, consider: consuming quercetin-rich foods, beverages, and seasonings, such as onions, apples, kale, tea, and salt-free capers eating fresh, frozen, or freeze-dried strawberries seasoning meals with pippali (long pepper)

Epigenetics, which literally means “above genetics,” layers an extra level of information on top of the DNA sequence, which on its own is only about 750 megabytes of data574 encoding 50,000 genes.575 All our dividing cells are genetically identical, carrying a full complement of our DNA, but each cell doesn’t need to express all our tens of thousands of genes. Our nerve cells don’t need to be pumping out liver enzymes, and our heart cells don’t need to be growing hair. That’s where epigenetics comes in—in effect, it’s what switches genes on and off. There are a multitude of ways our body does this.576 I’ll talk about sirtuins and microRNAs in their own chapters, but the best-known epigenetic regulator is DNA methylation.

We have enzymes that can strategically add methyl groups directly onto our DNA to silence gene expression. A methyl group is a simple, stable configuration of carbon that can be added to flag stretches of DNA as skippable. It’s one of more than a dozen ways DNA can be tagged.

We used to think that once cells matured and had their DNA appropriately methylated to lock them into their specialized functions, that was it.581 But we now know that our “epigenome,” the pattern of methyl markings in our cells, is a dynamic system and responsive to external stimuli. Epigenetics allows organisms to more rapidly adapt to changing environmental conditions.

It can take eons for large-scale shifts in the genetic code to happen, but the genes we already have can be switched on or off within a matter of hours. Epigenetics is how green grasshoppers can turn themselves black after a grassland fire to better camouflage against the charred soil582 and how our body determines the number of active sweat glands we have in our skin based on whether we’re born in the tropics or in a colder setting.583 Epigenetics is good news.

In the Gene Expression Modulation by Intervention with Nutrition and Lifestyle (GEMINAL) study, Dr. Dean Ornish and colleagues took tissue biopsies before and after subjects adopted intensive lifestyle changes for three months that included a whole food, plant-based diet. Beneficial changes in gene expression were noted for five hundred different genes. The expression of disease-preventing genes was boosted, and the oncogenes that promote breast and prostate cancer, for example, were suppressed.585 No matter the genes we may have inherited from our parents, we can affect how those genes affect our health with what we eat and how we live. That’s the power of epigenetics. Same DNA, but with different results.

the control group continued to age at a rate of about one year per year, but in that time, the dietary restriction group only seemed to age by about one month. And they achieved this with only a 12 percent calorie restriction, which is like skipping just one donut a day.

The lifestyle factor most closely associated with slowing aging—even more than exercise—is a marker of fruit and vegetable intake, blood levels of carotenoid phytonutrients like beta-carotene.618,619 So, an “epigenetic diet” would focus on consuming more fruits and vegetables.

In a Nobel Prize–winning discovery,630 stem cell researcher Shinya Yamanaka identified what we now refer to as Yamanaka factors, a small handful of DNA-binding proteins responsible for cellular reprogramming that serve, in essence, to return a cell to factory settings.