“Hell, no,” Richard Isaacson bellows when asked whether some form of is inevitable with age, especially for those genetically tilted toward the disabling of Alzheimer’s disease. Then, in the interest of science, an enterprise customarily cloaked in the conjectural, he restrains himself. Even of the 60 or so thought to influence the risk of Alzheimer’s disease after age 60, he says, none of them makes inexorable what surveys show is the most feared condition in a population living longer and longer. That fact, along with an earthquake of emerging evidence that cognitive impairment shows itself only after decades of decay in the processes that power our brain cells, has given Isaacson, a neurologist at Weill Cornell Medicine and New York-Presbyterian, enough of an edge to open the country’s first Alzheimer’s–prevention clinic.

The quick cascades of molecular events that enable you to toss a word off the tip of your tongue or remember where you parked the car begin at a basic level of body operations, and new methods of capturing their footprints have led to the recognition that cognitive decline is, in the words of science, modifiable. That such a tepid term cloaks a revolutionary possibility reflects the cautionary tale of recent history: Hundreds of trials of hundreds of agents to slow or stop cognitive decline in thousands of patients have been conducted over the past two decades, and every one has been a bust.

It may be that they all targeted the wrong mechanisms of disorder. Recent studies show that the plaques of amyloid proteins that accumulate between brain cells and the tangles of tau proteins that cluster within brain cells, both considered a signature of Alzheimer’s, also occur in many who have no memory loss—and are absent in 35 to 40 percent of those who, by neuropsychological testing, do. There’s no correlation between the presence of plaques and cognitive function. Rather than the trigger for disease, the plaques and tangles may be more peripheral phenomena or downstream effects of other processes.

Although no one can say for sure what causes the changes in the brains of those afflicted, that doesn’t mean those changes are not preventable. “In 2007, I used the term ‘treating prodromal Alzheimer’s disease,’ and no one paid to me,” says Isaacson. “Since 2014, when the clinic was founded, it’s been OK to say ‘Alzheimer’s disease’ and ‘prevention’ in the same sentence,” he told a recent conference at the New York Academy of Sciences.

And here’s the paradox of -edge intervention—it may not entail anything exotic. No magic bullet, rather an array of mostly mundane choices accessible to almost anyone on the planet—primarily diet and moderate amounts of exercise. Much research suggests that at its core, Alzheimer’s disease—and garden variety cognitive decline—may be a metabolic disorder, a perturbation in fuel use by the brain, a process that loses efficiency with age and is inherently influenced by what we eat. After all, our bodies must run on the nutrients we consume, and the flora and fauna we harvest for the table are made from the same molecules that we are, their chemical constituents shuffled and reshuffled inside us—whether they arrive dressed up as duck à l’orange or unadorned as kale salad.

It matters hugely which nutrients we put on the table. In a preliminary study of 166 patients, Isaacson has found that as little as six months of a diet rich in fresh vegetables and light on carbohydrates can attenuate memory decline in those at risk, speed up mental processing, and boost , including inhibitory control and attention. The diet includes fatty fish but no more than one serving of red meat a week—and then only grass-fed. When patients eat is as important as what they eat; meals must leave room for at least a 12-hour carbohydrate fast overnight.

The diet is also a significant shift from standard American fare, which is so rich with red meat, fried foods, and denuded carbohydrates that ketchup was once proposed to constitute a vegetable serving. Even those who follow government-issued dietary guidelines are consuming only what is calculated to avert nutrient deficiencies, points out nutritional Lisa Mosconi, founder and director of the and Brain Fitness Lab at New York University Medical Center. “We don’t know how to eat right for the brain,” she says.

Ciao!

If anyone KNOWs, it’s people who live along the Mediterranean, as scientist Ancel Keys discovered nearly half a century ago. Regions where inhabitants build meals around fresh fruit and vegetables, eat substantial amounts of grain and legumes, and lavish olive oil on their food have the highest concentrations of healthy centenarians, Keys reported in 1970.

The Mediterranean way of eating is an unhurried event of several small courses accompanied by moderate amounts of wine. It features fish more than meat along with soups and sides of leafy vegetables, like swiss chard and chicory in several variations, that do not win popularity contests at American supermarkets. Then, too, a major meal in Italy is typically followed by la passeggiata, a stroll around town that is as much an exercise of fashion as of musculature, and exercise is a proven brain protector.

Over the years, many trials of the Mediterranean diet have established that heart attacks are not an inevitable consequence of aging. And with gathering urgency over the past decade, trials of the diet—sometimes tweaked as new evidence rolls in—are demonstrating that cognitive aging isn’t either.

Because both the heart and the brain are exquisitely intolerant of disruptions in blood supply, what protects one also protects the other. “Vascular factors are as critical in cognitive function and the development of dementia as they are in cardiovascular disease,” says Irwin Rosenberg, head of the Human Nutrition Research Center on Aging at Tufts University. “Nutritional factors are similar for both.” The brain is only 2 percent of the body by weight, but it is so metabolically active that it consumes 25 percent of the body’s fuel. Under ordinary conditions, that fuel is glucose. An array of nutrient-specific transport systems help nutrients cross the heavily guarded blood-brain barrier. Mess with the system and…well, that is exactly what hordes of researchers are desperately trying to figure out.

Mind Control

Had she not been born and raised in Italy, Mosconi would nonetheless be a champion of the Mediterranean approach. Her studies of clinically and cognitively normal men and women in their 40s and 50s show that even in middle age, the brain areas and functions most vulnerable to disruption by Alzheimer’s pathology are already being affected by diet, in ways that implicate typical American consumption patterns. Mosconi doesn’t view Alzheimer’s as a disease of old age: “It’s a lifelong process that starts young and reaches a tipping point only after age 50.”

In one study, Mosconi collected detailed information on food intake from 52 participants consuming their normal diet. She paid special attention to 35 nutrients linked one way or another to cognitive function. At the same time, she used magnetic resonance imaging to assess the volume of gray matter, which is a measure of brain atrophy—that is, cell death. Brain shrinkage—starting in the hippocampus, the seat of memory storage in the medial temporal cortex, and spreading to the frontal lobes, which control executive function—is a hallmark of Alzheimer’s disease. Mosconi also measured the amount of amyloid protein in the brain and glucose uptake by the brain.

Whether or not subjects had risk factors for Alzheimer’s disease, such as a family history of the disorder, Mosconi found a firm correlation: The higher the intake of vitamin B12, vitamin D, and fatty acids, the lower the load of brain amyloid and the greater the brain volume and glucose metabolism. And consumption of foods rich in vitamin E, mono- and polyunsaturated fats, carotenoids, vitamins A and C, and fiber all positively affected glucose metabolism. Conversely, both brain volume and metabolism were lowest among those who consumed the most saturated fats, trans fats, cholesterol, and sodium, Mosconi reported in the Journal of Nutrition, Health and Aging. The protective patterns were linked to a higher intake of vegetables, fruit, whole grains, fish, low-fat dairy food, and a lower intake of sweets, fried potatoes, processed meat, and high-fat dairy foods, including butter.

The same nutrients and their food sources turned out to be brain-protective in a separate study of cognitively normal individuals ages 25 to 72, all of whom were at risk for Alzheimer’s: They either had a first-degree relative with the disease or carried a specific gene—the ApoE4 gene. Apolipoprotein E (ApoE) is one of several transporters of the fats, or lipids, the body deploys to move nutrients around, and it exists in three variant forms. The E4 variant, which is also implicated in heart disease, increases the risk of late-onset Alzheimer’s disease, and it is present in about 20 percent of Americans. Those who have one copy of the ApoE4 variant have two to three times the average risk of Alzheimer’s, while those with two ApoE4 alleles have 15 times the normal risk. But even they are not doomed to develop the disorder. The findings, Mosconi and her colleagues reported in BMJ Open, suggest that “nutritional interventions aimed at preserving brain activity might be particularly useful if instituted in young adulthood in normal individuals at risk for Alzheimer’s disease, before irreversible neuronal loss.”

Critically, Mosconi found strong effects of nutrients only when they came from actual foods, not from supplements. “The beauty of food is that it contains multiple forms of a nutrient. There are eight forms of vitamin E; one isolated form is less effective than all of them together.” Only foods supply a broad array of antioxidants, and a motley army may be needed to combat all the events underlying cognitive decline.

Few in the brain business doubt that the Mediterranean diet is good. But the MIND diet may be even better. Developed by Martha Clare Morris, a nutritional epidemiologist at Rush University Medical Center in Chicago, it bears the formal name Mediterranean-DASH Intervention for Neurodegenerative Delay and incorporates only those foods shown by “compelling scientific evidence” to be neuroprotective.

It prominently features green leafy vegetables and recommends at least one serving of them every day, along with two other vegetable servings. In year-long trials of the diet Morris has conducted to deter decline among those at risk for Alzheimer’s disease, green leafy veggies—good sources of carotenoids, the B vitamin folate, vitamin E, and polyphenols—had the highest positive correlation with brain function. “The rate of decline among those who consumed one to two servings per day was the equivalent of being 11 years younger in age, compared with those who rarely or never consumed green leafy vegetables,” Morris found. Also high on the recommended list are berries (the only fruit to pass the evidence test); cruciferous vegetables; yellow veggies, rich in antioxidant-heavy carotenoids; along with nuts, beans, whole grains, poultry, extra-virgin olive oil, and wine.

Nearly a thousand Chicagoans ages 58 to 98 consumed the MIND diet and were rated based on their adherence to its brain-healthy food groups and avoidance of unhealthy food groups—red meats, butter and stick margarine, cheese, pastries, and sweets. The top scorers wound up testing 7.5 years “younger” in brain age than their nonadherent peers. The diet is powerful enough that even those who stick to it only moderately also benefit, with reduced rates of decline.

On-ramps to Oxidative Stress

Isaacson deploys the MIND diet and adjusts it to the idiosyncrasies of individual biology—more omega-3–rich foods for those at cardiovascular risk because of high triglyceride levels, more vitamin D consumption for people with two copies of the ApoE4 gene. But just as important as what people eat is when: for at least 12 hours overnight, five nights a week, no carbohydrates at all. Carbohydrate restriction shunts the brain onto its backup fuel, ketone. There is evidence that fasting resets the machinery of glucose utilization, starting with the elaborate systems the body has for sensing the availability of nutrients. “The data suggest that the very earliest changes in Alzheimer’s disease are those affecting glucose,” says neuroscientist Gary Gibson, and they occur especially early—in young adulthood—in those who carry the ApoE4 gene. “Glucose changes are very highly correlated with cognitive changes.”

In the brain, glucose powers all nerve cell activity, most intensively in the gray matter of the cortex, and for this key task it is converted, through several oxygen-needy steps, into adenosine triphosphate, or ATP, in the cells’ mitochondria. But glucose also provides the precursors for synthesis of the brain’s neurotransmitters, and it sets in motion processes to clear away waste products and cell debris, a necessary maintenance task for an organ that is a metabolic hothouse.

As Gibson, who is a professor at Weill Cornell Medicine and its Brain and Mind Research Institute, sees it, the mitochondria are the first cause of Alzheimer’s disease. With age, changes in the mitochondria impair oxidative metabolism and create , marked by excess levels of free radicals of oxygen—by themselves a potent agent of damage: to DNA, to fats, to proteins, and to other molecules. Oxidative damage is pervasive in the Alzheimer’s brain, even more so than plaques and tangles, especially in the early stages of the disease, says Gibson. Oxidative , in turn, activates an enzyme that cleaves beta amyloid from its precursor protein, accelerating amyloid production and setting the stage for its accumulation.

But oxidative stress does much more, Gibson says. It impedes debris clearance, promoting the buildup of cell toxins, inflammatory processes, and cell death. And of particular interest to Gibson, it deactivates a mitochondrial enzyme called ketoglutarate dehydrogenase complex (KGDHC).

In animal studies, KGDHC deficiency leads to plaque formation, memory deficits, and diminished neurogenesis, which, Gibson says, suggests that increasing production of the enzyme could be therapeutic. KGDHC production hinges on the presence of vitamin B1, also called thiamine. Clinicians have long known that thiamine deficiency mimics Alzheimer’s memory deficits and changes in . Funded by the National Institutes of Health, Gibson is currently conducting a one-year clinical trial of a thiamine variant, benfotiamine, in 76 patients with mild cognitive impairment or mild Alzheimer’s disease. Benfotiamine is a long-established treatment for neural complications of diabetes.

It may be that oxidative stress gets a pathologic push from the accumulation of iron in the brain. Studies have found high concentrations of the mineral in areas of the brain associated with neurodegeneration, and people at low risk for dementia have no such deposits. Diets rich in red meat may contribute to toxic levels—but so may government rules requiring iron-enrichment of refined grains. While the science sorts itself out, researchers believe it is wise to keep blood hemoglobin levels at the low end of normal—yet another reason to limit consumption of red meat.

Time Out: The Role of Fasting

Getting glucose into the brain in the first place is the job of a transport system that hinges on the insulin. In the brain, the density of insulin receptors is highest in those parts of the organ with the toughest jobs, like the hippocampus and the prefrontal cortex, says Auriel Willette, assistant professor of food science and human nutrition at Iowa State University. The problem is that while insulin is essential for normal brain function, the body tends to become insulin resistant with age. What’s more, many foods in the American diet—refined carbohydrates, beef—promote insulin resistance, as do and inactivity. The brain is so sensitive that even a small degree of insulin resistance (much less than it takes to set off diabetes) may have wide-scale downstream neural effects.

Willette’s work links insulin resistance with neurodegeneration and cognitive decline. In one study, he and colleagues looked at 150 cognitively normal middle-age adults at risk for Alzheimer’s and found that insulin resistance predicted diminished glucose metabolism—especially in the prefrontal and temporal cortices—as measured by PET scans, and it impaired memory on tests of cognitive function. “Insulin resistance confers a nontrivial risk for Alzheimer’s disease in ,” the team reported in JAMA Neurology. Willette contends that the way to interrupt “presymptomatic Alzheimer’s disease” is to target mechanisms involved in insulin signaling.

Enter fasting. Calorie restriction in general, and carbohydrate restriction more specifically, help overcome insulin resistance by forcing the brain off glucose and onto its backup fuel, ketone. Because brain function is so important, it is protected even under conditions of starvation; fat cells are directed to release their booty, and the liver converts free fatty acids into ketone bodies as a glucose replacement. Ketones are particularly efficient; the brain gets more ATP bang for its fuel buck from ketones than from glucose, and studies show that the increased energy boosts cognitive performance. Bypassing glucose helps restore insulin sensitivity.

Since the 1930s, scientists have known that calorie restriction can extend lifespan, and it does so by delaying or preventing age-related chronic conditions like diabetes, heart disease, neurodegenerative diseases, and many cancers. That such disparate disorders respond similarly suggests they are connected through some basic biological processes. The suspicion that there may be shared causes of the diseases of aging constitute what is now known as “geroscience,” and the hunt for those causes has become science’s latest gold rush. Targeting one may tackle them all, paying what has been called a “longevity dividend.” At least with the research that’s publicly funded, the work aims not so much to extend lifespan as to extend “healthspan,” to postpone chronic disease and compress decline into a fast endgame. Research focuses strongly on metabolism—because every cell needs energy and nutrients.

As effective as calorie restriction may be, it’s just too tough to maintain for long. Instead, researchers, working with creatures from single-cell yeast to worms, mice, and men, are exploring regimens that mimic the effects of calorie restriction and trying to figure out how they protect the body and brain. Cell biologist Valter Longo, a professor of at the University of Southern California and the director of its Longevity Institute, is one of them.

Periodic starvation is actually part of life, says Longo, a condition all organisms have faced from the beginning of existence. “We’ve forgotten that, because food is all around us. But fasting is a very carefully evolved process, and it revolutionizes metabolism in the brain. It changes the way the brain functions.” He calls it “a wide-action strategy” that works independently of the genetic hand anyone is dealt.

In humans, as in all other animals, Longo explains, biochemical mechanisms are built in for acquiring and storing food and then, during the lean times, calling on the stored energy for repair and resisting stress. Fasting triggers a host of innate cell-renewal mechanisms, and studies in multiple organisms show that this fasting physiology is tied to the circadian cycle, as is our nutrient-sensing apparatus. At the dawn of life, both energizing and repair facets of metabolism were set in harmony with the day/night activity/rest cycle. Whatever gains we’ve made with our full larders open 24/7 and artificial lighting, we’ve disrupted the activity/rest cycle our metabolism was built on over millions of years of evolution, and we’ve inadvertently kick-started many chronic diseases. But fasting physiology, Longo finds, can be switched back on by intermittent and periodic fasting.

Restricting the timing of food intake to 12 hours daily, without any overt attempt to cut consumption, accomplishes the same thing calorie restriction does: It triggers cellular reprogramming, revitalizing glucose metabolism and signaling pathways, juicing up the complex cascades of molecular signals the body relies on to get nutrients to the brain. Middle-age mice placed on a fasting-mimicking diet for four days twice a month for seven months not only lived significantly longer and lost body fat, they outperformed standard-fed controls on tests of motor coordination and short- and , Longo and the Salk Institute’s Satchidananda Panda recently reported in Cell Metabolism. Studies show that the feeding strategy generates new and functional neurons.

A Metabolic Master

Fasting may not be the only “wide-action” route to cognitive youth. Geroscientists are keen on metformin, an antidiabetic drug in use for the last half century. Data collected on it over the years suggests it curbs cancer risk and preserves cognitive function, while laboratory studies show that it aids glucose metabolism by acting directly on mitochondria to slow oxygen consumption, thereby curbing oxidative stress as well as molecular damage, even to DNA. It’s possible that it also exerts effects by favorably altering the composition of the gut microbiome. A five-year, randomized, double-blind clinical trial of the drug that focuses on its anti-aging effects (called TAME, or Targeting Aging with Metformin) has been approved and is awaiting adequate funding.

Rapamycin is another drug already in use against one disease of aging—cancer—that may mitigate the other ills or, at the very least, provide insights into basic processes underlying them all. Rapamycin works, says geroscientist Matt Kaeberlein, a professor of pathology at the University of Washington, by targeting a central nutrient-sensing pathway that controls cell growth and division. The pathway goes by the very unoriginal name of mTOR, for mechanistic target of rapamycin, and studies show that mTOR activity tends to increase with age. They also show that suppressing mTOR with rapamycin makes animals stress-resistant, extends their lifespan, and improves cognitive function.

“It’s surprising that rapamycin is of benefit for cognitive aging,” says Kaeberlein. “We don’t understand why. Activation of mTOR is needed for learning and memory. It may be a function of dose.” All along the line, rapamycin seems to have two faces, a feature that adds to its scientific allure. Given in high doses, rapamycin kills cancer cells and is used for immunosuppression after organ transplantation—yet it also can boost immune function. It may take only small amounts for positive brain effects.

It turns out that mTOR is a central player in calorie restriction. It also influences mitochondria energetics and the recycling process (called “autophagy”) by which old cells are broken down and their components refurbished for new cells. It’s seen as a metabolic master regulator. Fasting dampens mTOR activity, and rapamycin given to an array of organisms even in midlife—for just three months in mice—extends their lifespan, Kaeberlein finds. It also shifts the composition of the microbiome.

Autophagy is one important means of cell upkeep and renewal, and it’s especially critical in the metabolically active brain. But the body is equipped with another key route to rejuvenation: stem cells. Ongoing studies suggest that one of the most important things that both fasting and rapamycin do is change of stem cells to enhance their function and boost their power of regeneration—paving the way for true revival at the cellular level. With age, says Kaeberlein, “stem cells stop working efficiently. Their environment is not favorable to them.” Exercise, he finds, may also be a way to favorably alter the niche stem cells inhabit.

Kaeberlein admits he’s toying with the idea of taking a low dose of rapamycin for a limited period of time. “There’s enough data showing it is safe in low doses.” He is already overseeing a randomized, blind trial of mTOR suppression by rapamycin in pet dogs.

As experimental science sorts out the processes of aging, Isaacson keeps fine-tuning the elements of his multitarget, brain-protection strategy. Turning the basic science into clinical medicine, he is now adding genetic assessment of the microbiome to the biologic data by which he individualizes diet; the gut microflora not only produce essential nutrients, they also contribute to normal brain development and function. But the diversity of the flora changes dramatically with age, at least among Americans, and those changes may compound cognitive decline. Shifting the composition of the gut flora by upping the intake of garden variety fiber-rich foods, such as greens and beans, becomes an added maneuver to delay brain aging.

There’s a cosmic joke in there somewhere, that the cutting edge of science comes very close to the way hardy Sicilians have been eating for centuries. But of course, that isn’t the same as saying we knew it all along.

Foods to Favor

Sardines, herring for omega-3 fats, vitamin D

for omega-3 fats, vitamin D Leafy greens: Swiss chard, red-leaf lettuce, kale, spinach for B vitamins, vitamin E, fiber, vitamin C, antioxidants (carotenoids, flavonoids)

for B vitamins, vitamin E, fiber, vitamin C, antioxidants (carotenoids, flavonoids) Cruciferous vegetables: cabbage, broccoli, cauliflower for B vitamins, vitamin C, fiber, antioxidants, glucosinolates

for B vitamins, vitamin C, fiber, antioxidants, glucosinolates Yellow vegetables: carrots, squash for carotenoid antioxidants, B vitamins, fiber

for carotenoid antioxidants, B vitamins, fiber Walnuts, almonds for vitamin E, antioxidants, omega-3 fats, vitamin B, fiber

for vitamin E, antioxidants, omega-3 fats, vitamin B, fiber Blueberries, strawberries for antioxidants, vitamin C

for antioxidants, vitamin C Legumes: lentils, chickpeas, beans for B vitamins, fiber

for B vitamins, fiber Extra-virgin olive oil for monounsaturated fats

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