Skipped meals could improve memory, says Buck Institute for Research on Aging researcher

When people and mice go hungry, their stomachs growl and they feel discomfort. But at a metabolic level, frequent food deprivation could boost their memory and even make them live longer.

That’s the hypothesis of John Newman, a new faculty member at the Buck Institute for Research on Aging, based in Novato. The world-class scientific institute has some of the brightest aging-related research minds in the world among its faculty.

Yale-educated Newman, 39, who earned a Ph.D. in biochemistry and medical degree at the University of Washington, is assistant professor of medicine in the geriatrics division of University of California, San Francisco. He worked as a visiting scientist at the Buck for a year and was recently awarded a faculty position, funded by a modest career-development grant from the National Institute on Aging, a division of the U.S. National Institutes of Health.

“It’s like seed funding,” Newman said, the term tech startups use to refer to founding capital.

North Bay Business Journal met with Newman in March as he set up his laboratory on the Buck campus and began hiring post-doctoral students to help with research.

“My current scientific interest lies in investigating ketone bodies as one of the mechanisms of health benefits of fasting and calorie restriction,” Newman said. So far, he studies ketone bodies in mice.

Ketone bodies are produced by the body when glycogen stores are diminished, as happens in fasting or extended periods of exercise, such as running a marathon or cycling 50 miles. When the body runs out of its usual fuel source, glycogen, triglycerides in fat tissue are broken down into fatty acids and carried to the liver, where they are catabolized to acetyl coenzyme A then converted to ketone bodies including acetoacetate, Beta-hydroxybutyrate and acetone. Newman plans to test whether ketones affect age-related diseases, especially focusing on Beta-hydroxybutyrate.

“I have found that a ketogenic diet can increase longevity and health-span measures in mice, including improving age-related cognitive decline,” Newman said. If his hypothesis can be proven, Newman’s research could have gargantuan economic benefits.

According to data from sources including Alzheimer’s Association and National Institute on Aging, Alzheimer’s affects five million Americans - two-thirds of them women - and 44 million globally. The number of patients with Alzheimer’s will triple to 13 million in U.S. by 2050, and to 135 million globally. Dementia care costs $600 billion globally per year. By 2040, Alzheimer’s is expected to consume 25 percent of the Medicare budget.

President Ronald Reagan died after a long battle with Alzheimer’s. The disease dimmed the brains of composer Aaron Copeland, artist Norman Rockwell, writer E.B. White, boxer Sugar Ray Robinson and actors Rita Hayworth, Peter Falk and Charleton Heston.

The disease ruins neurons and incrementally sabotages its victims’ mental acuity. Even a modest reduction in the number of patients or a delay in onset could reap giant savings.

“Geriatrics is not about age,” Newman said. “It’s about you as a person. We specialize in people who are older, who are complicated, have lots of medical problems, complex social or home situations. We think of ourselves as complexivists. We take care of people where medical problems aren’t simple and answers aren’t simple.”

He looks for ways to improve patients’ lives - “staying independent in their own home, doing things they need to do by themselves, staying out of the hospital,” he said.

“Eating less, fasting and restricting calories is the surest, most consistent way to make animals healthier,” Newman said, “and maybe make people healthier. The big idea is not that eating less or fasting makes you healthier,” but that genetic switches triggered by fasting bring health benefits.

“Are ketone bodies one of these molecules that provide health benefits? They are the way the body uses energy when you are fasting. It’s the way the body burns fat.”

Ketone bodies are not just used for energy, but as signals.

“They change the way cells work, the way genes are expressed, affecting inflammation, regulating metabolism,” Newman said, noting “tantalizing clues that could be important for aging.”

Newman tested his theories on laboratory mice, feeding them a ketogenic diet for most of their adult lives of about three years. The diet was largely Crisco, the non-trans-fat formula, mixed with a bit of cocoa butter. The diet had few carbohydrates, with normal protein, fiber and vitamins, but was not low in calories. Not having carbohydrates triggers the liver to produce ketone bodies.

The rodents devoured as much as they wanted. “We had to figure out how to keep them from getting obese,” he said. “We fed them a ketogenic diet every other week,” alternating with a normal diet.

“Is that good for them or bad for them?” he asks. In early findings published in September 2017, he reported, “It’s pretty clearly not unhealthy. There were elements of their health that were better.”

Some mice on ketogenic diets lived modestly longer - about 10 percent longer. The most dramatic improvement for mice was enhanced memory.

“We use a few ways to test their memory,” Newman said of the rodents, using visual spatial cues that orient the animals in a room. “And how well they can recognize new objects. Remembering what they have seen and where they have been,”

Some of the ketogenic mice signed up for college, he joked, displaying a graph that depicts significant memory differences between ketogenic mice compared to mice that ate normally.

He has managed the carefully controlled ketogenic-mouse study for about five years, working with Eric Verdin, president and CEO of the Buck Institute. Parallel studies at U.C. Davis by nutritionist Jon Ramsey yielded similar results.

Positive effects of the ketogenic diet lingered past the period where mice ate mostly fat.

“You don’t have to be on ketone bodies for your memory to be better,” Newman said. “We saw really cool stuff with the initial diet study.”

As he understands more about ketone bodies and carbohydrate restriction, Newman aims to create and test therapies or drugs with minimal side effects - perhaps a supplement or injection that would induce ketogenesis in the body or provide ketone bodies directly.

Diabetics can produce too many ketone bodies, a condition called ketoacidosis. Insulin normally acts as a signal that stops the body from making more ketone bodies. Type-1 diabetes causes lack of insulin. People with epilepsy may benefit from ketogenic diets, Newman said, especially children who cannot tolerate drugs.

“Most new drugs don’t work out,” Newman said. “Everything could have downsides. We’re not too far from figuring out if these approaches could work in people - only a few years away.”

He belongs to a nationwide network of geroscience specialists.

“There is less of a clear road to market than for a heart drug or a cancer drug,” Newman said. “Aging is not a disease. We need to design clinical trials and outcomes in a way that captures the downsides of aging in a quantitative way” that allows targets for drug approvals by the FDA.

“We can narrow down what’s actually going on in the brains of these mice” then design “targeted therapies that we could potentially translate to people,” he said.

Mice don’t get Alzheimer’s disease the way people do, but Newman will look at inflammation in their brains, gene-expression patterns, proteins. He will test whether the ketogenic diet’s benefits can be achieved with short stints, or just later in life.

Restricted diets for seniors that cause weight loss lead to strength loss and deteriorating health, Newman said, so ideal ketogenic therapies would ideally not reduce weight.

As he settles in at the Buck, Newman will continue clinical work and teaching geroscience through UCSF and the San Francisco Veteran’s Administration Health Care System. Few practicing geriatricians also conduct laboratory studies.

His specialty is helping veterans get in and out of the hospital without suffering deleterious effects “in a way that preserves their brain function and mobility,” he said. Just going into the hospital often causes other forms of sickness beyond the initial malady, especially delirium.

“If an older person breaks a leg, it’s a life-changing event,” he said. “Often they never recover even though we are really good at fixing broken bones. It’s not the bone.”

Anesthesia and surgery appear to contribute to delirium, along with “being in bed all the time. It’s a huge problem,” Newman said. “A big risk factor is people whose brains aren’t normal to begin with - they have Alzheimer’s. Their brains are not as resilient as (those of) younger, healthier people. Can we make their brains more resilient, prevent delirium as they heal? Their resilience in the face of terrible medical problems is awe-inspiring,” he said.

“The clinical problems their doctors are trying to treat are so complicated. We become more complicated as we age. We don’t want to, but we do,” he said. “You have to think about every aspect of their health - home environment, family support, access to medical care, to medicines, mental health. You have to address all those elements.”

Scientists who study ketogenic diets sense that a breakthrough might be close. “We really are translating aging biology,” Newman said. “People are starting to test interventions. That’s what I’m most excited about. This is happening. The Buck is going to be the catalyst.”

James Dunn covers technology, ?biotech, law, the food industry, and banking and finance. Reach him at: or 707-521-4257.

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