by Buck Institute

The Buck is awarded three federal grants to target aging to prevent or cure Alzheimer’s disease.

The National Institutes of Health (NIH) new, broader approach to Alzheimer’s disease (AD) is a fortuitous one for the Buck Institute. Over decades the majority of NIH research dollars have been directed to looking at the sticky amyloid plaques and tau tangles which are present in the brains of those affected. Both features are hallmarks of AD, but neither has been conclusively proven to cause the memory- robbing disease. The bottom line: After hundreds of failed clinical trials there is no successful treatment for the neurodegenerative disease, which is the sixth leading cause of death in the U.S.

Now the NIH is turning its attention to investing in geroscience, which focuses on the connection between aging and chronic disease. (The Buck coined the term “geroscience” and got the first federal grant to establish the field in 2007.) The new awards highlight the fact that aging is the largest risk factor for AD and the possibility that targeting the mechanisms of aging is a potential way to tame it. Three federal grants totaling $9.8 million are going to Buck faculty members Gordon Lithgow, John Newman, and Julie Andersen to study Alzheimer’s disease (AD) through the lens of aging.

AD, which currently affects at least five million people and impacts 16 million unpaid caregivers in this country, has defied attempts to cure, prevent or delay it. “These awards are an awesome example of what geroscience is meant to be,” says Buck assistant professor John Newman, MD, PhD. “Take the basic knowledge of aging mechanisms and apply it to a hugely important human disease in a way to make progress in that disease. We are confident that we can make a real difference.”

“These awards are an awesome example of what geroscience is meant to be.”
Assistant Professor John Newman, MD, PhD

Looking at the role of ketone bodies

The Newman lab is focused on harnessing metabolic signals to treat geriatric syndromes of aging. Previous work from the lab showed that a ketogenic diet, which features high fat, normal protein and very low carbohydrates, significantly improved memory in aging mice and increased the animal’s chances of surviving to old age. Eating a ketogenic diet ramps up the production of the ketone body beta-hydroxybutyrate (BHB).

Newman’s five-year $3.8 million grant enables him to delve deeper into the mechanisms of BHB to identify not only what ketones like BHB are doing, but how they’re doing it.

BHB is an energy molecule; aging comes with decreased energy availability in the brain as sugar metabolism slows and mitochondria (our cell’s power plants) lose their efficiency. Newman, who also cares for geriatric patients at the San Francisco VA Hospital, wants to know if ketones can provide a needed energy boost to help brain cells resist damage and stay healthy. BHB also functions as a signaling molecule by binding on to other molecules and changing their activity. Newman says through this signaling, BHB can modulate many basic aging processes, like inflammation and metabolism. He says BHB may be directly interfering in aging pathways that lead to Alzheimer’s progression and could potentially be used to prevent the damage from occurring.

Currently, the key mechanism of how ketones like BHB function is a complete unknown. Newman says understanding these mechanisms can have an important translational effect because there are already some clinical trials underway involving Alzheimer’s patients who are on a ketogenic diet. “Without knowing how ketones work or what we expect them to do, it’s hard to design studies and measure outcomes. We hope this work leads to better-designed ketones that amplify their beneficial effects and make a positive impact on patient lives.”

Testing drugs that have already slowed aging in C. elegans

There are sixty-five compounds that extend lifespan in the tiny nematode worm C. elegans sitting in freezers at the Buck.. The $2.9 million grant awarded to professor Gordon Lithgow, PhD, will enable his team to look at whether some of those compounds, along with drugs that are already approved by the FDA, are efficacious in AD. His team will first examine what 100 selected compounds do in worm models of the disease, then researchers will move screening and testing into human neuronal cell cultures, finally taking the best-of-the-best into mice.

“We’re taking a holistic approach. We think that aging is at the crux and is the actual cause of this disease,” says Lithgow, who is also Vice President for Academic Affairs at the Buck. Referring to failed research efforts that have focused on single targets involving amyloid plaques and tau tangles, Lithgow admits that aging-as-a cause of AD is still a hypothesis. “But at least we are not focusing on a single mechanism of action going in. At this point we don’t care about mechanisms – our job is to identify what works. We’ll dig deeper and make big bets on the compounds that make it into the mice.”

Previous work in the Lithgow lab has shown that Vitamin D, low-dose lithium and a common lab dye called thioflavin T, among others, extends lifespan in the worms. Lithgow says success in the treated worms will be measured by the build-up of toxic protein aggregates in animals genetically bred to develop the hallmarks of AD. “We’re also able to track neuronal death, to see what happens in the presence of the toxic proteins. We’ll be able to screen for chemical compounds that help keep the neurons healthy.”

Lithgow expects that natural compounds found in “healthy” foods (think berries, dark chocolate and nuts) will be tested in this program. He is particularly excited to test a new library of drugs that are either approved by the FDA or have shown promise in clinical trials. “Those compounds have already been found to be safe in humans. If they work in our models of disease they would be able to be fast tracked for pre-clinical research.”

Diving deep into a novel gut/brain connection in order to boost a mechanism that goes south with aging

Professor Julie Andersen, PhD, is beginning the work on her $3.1 million dollar grant at the point where Lithgow hopes to be in five years. She’s looking at a particular compound that shows promise in the fight against AD. After doing chemical screens in mammalian cells and human neurons she identified a compound, dubbed “C1,” that boosts autophagy. Translated from Greek, autophagy literally means “self-eating.” It may sound gruesome but the natural process has great benefits for our cells. During autophagy, cells recycle damaged proteins and mitochondria and use them for nutrition.

“There is an age-related decrease in autophagy in the brain,” says Andersen. “We think the decrease in the cells’ ability to recycle damaged proteins could be causing the accumulation of the different toxic proteins that are hallmarks of both AD and Parkinson’s. Our job is to understand and exploit the mechanisms of C1 to see if we can come up with a treatment. ”

Prior to applying for the recent grant, Andersen’s team showed that C1 reduces the accumulation of AD-related toxic tau proteins in human cell culture and prevents the accumulation of toxic proteins in a mouse model of Parkinson’s disease. Digging deeper into mechanisms, they confirmed that C1 upregulates transcription factor EB (TFEB) a human protein involved in lipid metabolism. Under study in many labs for its ability to boost autophagy, her team further confirmed that TFEB interacts with the bile acid receptor FXR, best known for its metabolic function in the liver where it processes food and fats.

Here’s where Andersen’s grant application stood out. Her group found that the bile acid receptor is also in play in neurons. “It’s another indication of a link between the gut and the brain,” she said, adding another twist to the story. “Everyone has been looking in the liver where boosting FXR prevents inflammation associated with liver disease. Our data shows that inhibiting FXR in neuronal cells boosts autophagy and reduces neurodegeneration.”

For this project Andersen is not worried about the Jekyll and Hyde nature of FXR, saying there would likely be ways to tweak C1 to bypass problems in the liver if the compound is successful in the brain. But Andersen says clinical trials are underway for fatty liver disease that utilize drugs that increase expression of FXR. “There is some concern that those drugs might have negative knock-off effects in the brain. It’s something that needs to be explored.”

Andersen will do studies in human neurons created from skin cells of patients with AD and in mice genetically bred to have the disease. Her team, which includes other Buck faculty, will be tracking the health of mitochondria, the accumulation of toxic amyloid plaques and tau tangles, losses of synapse integrity and in the mice, cognitive function.

The mice are already being fed C1. Andersen expects preliminary results within the next 6 months to a year.

Science is showing that while chronological aging is inevitable, biological aging is malleable. There's a part of it that you can fight, and we are getting closer and closer to winning that fight.

Eric Verdin, MD, Buck Institute President and CEO

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