A ketogenic diet has been used to treat drug-resistant epilepsy in children for decades, and emerging evidence from animal models suggest that a ketogenic diet may have therapeutic benefits for headache, neurodegenerative diseases, sleep disorders, and even potentially brain cancer. Yet we still know relatively little about the mechanisms and impacts of a ketogenic diet or ketosis-inducing interventions such as fasting on the human brain.
To learn more about what we do know about how fasting and ketosis affect the brain, we interviewed Shelly Xuelai Fan, a science writer and a neuroscientist specializing in brain rejuvenation. In 2013, Shelly wrote an article for Scientific American’s MIND blog about the potential advantages of a fat-fueled brain. She has also published research in Nature Neuroscience and Annual Review of Neuroscience.
Shelly practiced a 16/8 intermittent fasting schedule (eating only 8 hours out of the day) for two years during her postdoctoral research, mostly because she didn’t want to stop experiments to eat lunch. Eating lunch made her feel more sluggish in the afternoons, she said, although otherwise she didn’t notice many changes. But inside of her head, intermittent fasting could have been changing how her brain cells reacted to stress, potentially with less oxidative damage to cellular components including DNA.
LifeOmic: Can you tell us about your dissertation and postdoctoral research on brain health and rejuvenation? What kind of questions did you study, and what were some of your most surprising findings?
Shelly: My thesis project focused on developing a new treatment for neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinson’s. All of these diseases have one thing in common: the brain’s cells gradually accumulate toxic proteins, which clog up the cells’ normal molecular machinery. Over time as these proteins accumulate, neurons die. There’s some evidence that getting rid of the toxic proteins helps with neuronal survival and delays symptoms (at least in mice).
I led a project that developed a modular peptide drug for protein knockdown. Once injected into the blood, it tunnels through the blood-brain barrier, grabs onto its target toxic protein and drags it to the cell’s own waste disposal system, an organelle called a lysosome. The peptide can be customized for different types of toxic proteins by swapping out one of its modules, kind of like Lego pieces. In mouse models of both Huntington’s and Parkinson’s disease, the respective peptide drug saved neurons and improved symptoms.
As it happens, there are also natural ways to activate the lysosome, the cell’s own waste disposal system, so that it’s more efficient at getting rid of toxic molecules.
Caloric restriction and exercise are both examples, and that’s partly how I got interested in the effect of exercise on brain health and aging.
My postdoc research focused on how exercise benefits the aging brain. There’s been a paradigm shift in the brain aging field, in that scientists are increasingly aware that the aging process is reversible. For example, there’s plenty of evidence showing that in aged mice, exercise boosts synaptic plasticity and enhances learning and recall, at least for certain types of memories. There’s evidence, at least in mice, that exercise increases the birth of new neurons (a process called adult neurogenesis) that seem to help keep similar memories separate and benefit mood.
“Significant increases in brain volume, in both gray and white matter regions, were found as a function of fitness training for older adults who participated in aerobic fitness training but not for older adults who participated in stretching and toning (nonaerobic)...” — Aerobic Exercise Training Increases Brain Volume in Aging Humans, 2006
The body also heavily influences how healthy the brain stays during aging. My lab previously found that when you inject an old mouse with the blood of young mice, something in young blood helps the aged mouse’s brain function better.
Editor’s Note: Whether exercise and fasting can stimulate pro-youth factors that delay brain aging in humans is still an open question, although there are clearly mechanisms that link these interventions to reduced brain inflammation and oxidative damage.
More reading: Be smart, exercise your heart: exercise effects on brain and cognition, Nature Reviews Neuroscience [PDF here]
LifeOmic: What does it mean, to rejuvenate the brain or “make an old brain young again,” on the cellular level? What is the most compelling research you’ve seen on interventions that delay or reverse brain aging?
Shelly: My lab mainly studies the hippocampus, a brain region crucial for spatial and episodic memory, that is, the memory of autobiographical events. Young blood and other systemic manipulations, such as exercise, caloric restriction and metformin (a type II diabetes drug), seem to revamp the aged hippocampus in two main ways.
First, these treatments boost neuronal communication during learning (synaptic plasticity, evidenced through electrical recordings). At the molecular level, the treatments stimulate the production and/or activation of proteins that support synaptic plasticity, like CREB.
Editor’s Note: CREB (cAMP response element-binding protein) is a transcription factor capable of binding DNA and regulating gene expression. CREB has a well-documented role in neuronal plasticity and long-term memory formation in the brain. There’s evidence that cognitive stimulation, exercise and intermittent fasting (in mice) can enhance brain-derived neurotrophic factor (BDNF) and serotonin signaling, which in turn activate transcription factors like CREB that regulate gene expression involved in neural plasticity, stress resistance and cell survival.
These interventions also lower global brain inflammation, which is thought to benefit cognition.
By far the most compelling research I’ve seen in this area is related to exercise, caloric restriction and young blood. Exercise has by far the most evidence for benefits in aged humans. Caloric restriction as an intervention is relatively hard for humans to follow for long periods of time, and I haven’t yet seen a well-done human study in that domain. There’s actually some controversy on whether caloric restriction works in non-human primates in terms of increasing healthspan (the length of healthy life). Young blood hasn’t yet been rigorously tested in humans for its anti-aging effect (there are some iffy “trials” going on), though a recent study using it for Alzheimer’s disease didn’t show significant benefits. The eventual goal is to isolate out specific “pro-youth” factors from young blood and administer those in a concentrated form.
LifeOmic: How does the aging brain look different, metabolically or on the cellular level, than the young brain?
Shelly: The aged brain looks different in a few main ways (blog post here). One, the cell’s main energy factory, the mitochondrion, declines as we age both in numbers and function. Disrupted brain metabolism has been linked to Alzheimer’s disease, but its role in normal age-related memory decline is less clear. Aged neurons also have trouble sensing nutrients in their environment. This is especially true for glucose, which normally is the brain’s main energy source.
Editor’s note: This is where intermittent fasting comes in as an interesting intervention to improve nutrient signaling or insulin sensitivity.
Aged neurons in the hippocampus and prefrontal cortex also have fewer synapses, although the total number of neurons doesn’t seem to change much with age. Finally, aged brains have little to no neurogenesis and increased inflammation, though if and how these processes contribute to age-related memory decline remains unclear.
Editor’s Note: Animal model research suggests that intermittent fasting, or reduced meal frequency, can increase insulin sensitivity, improve cellular stress responses and reduce oxidative damage in the brain, in ways similar to the impacts of exercise.
LifeOmic: What is synaptic plasticity, and what are the potential ways we can preserve it in the aging brain?
Shelly: Broadly speaking, synaptic plasticity is the brain’s ability to strengthen or weaken connections between pairs of functionally linked neurons. Neurons form functional circuits through specialized nodes called synapses. The synapse is where one neuron talks to another.
One central idea in neuroscience is that learning activates select neurons. These neurons then form a clique of sorts. When one neuron reactivates (for example, when you want to retrieve the memory), there’s a much higher chance that others in that same circuit will also fire. In essence, the synaptic connections strengthen during learning. Similarly, synaptic strength can also weaken. The ability to change synaptic strength is called synaptic plasticity, and scientists believe it underlies our ability to learn and remember things.
I’ve already mentioned a few ways to preserve plasticity in the brain: aerobic exercise such as running and caloric restriction are both more “natural ways” to go about it. Young blood and (more promisingly) metformin represent a more pharmacological approach, which many researchers are focusing on.
LifeOmic: How can we stimulate neurogenesis in the aging brain? In your research and expertise, what interventions are promising (for humans) in stimulating neurogenesis?
Shelly: Running! I used to be a long-distance runner in grad school. I used it for stress management, but fell off the band wagon during my PhD. Later, in the lab, I actually looked at the brains of runner (mice given running wheels) versus sedentary mice (mice that live normally in shoebox cages, so they still scurry around normally). The effect of running on neurogenesis was so astonishing that I picked up running again.
That said, I need to stress that whether humans have neurogenesis or the birth of new neurons cells beyond childhood is debatable. A recent Nature study didn’t find any signs of new neurons in the brain of aged human donors (excellent News and Views here), so it’s possible that exercise and other neurogenesis-stimulating treatments are working in some other way to benefit the aging brain. My bet is on synaptic plasticity and increased blood flow.
LifeOmic: While fasting, the brain starts using ketone bodies for energy to make up for a lack of glucose. How does the brain use ketone bodies, and how is it different from how the brain uses glucose?
Shelly: Normally, the brain mainly uses glucose as its energy source. During conditions of low glucose, as in fasting or a ketogenic diet, the liver makes ketone bodies from acetyl CoA generated by the oxidation of fatty acids. These ketone bodies can cross the blood-brain barrier, and neurons then use them as fuel.
Compared to glucose, burning ketones seem to have several benefits for brain health.
One, they’re highly energy efficient. BHB, a major ketone, provides more energy (or ATP molecules, which are the energy currency of the cell) than glucose per unit of oxygen used in the biochemical reactions inside of our cells. Ketones also stimulate hippocampal neurons to make more energy-producing mitochondria.
Editor’s Note: In other words, ketones prompt our cells and brain cells to become more efficient, as they are sensing hard times ahead.
Second, BHB is an epigenetic regulator. It can boost the expression of certain genes in the brain. Among these is BDNF (brain-derived neurotrophic factor), a major “nutritive” protein that inhibits neuronal death, boosts synaptic plasticity and neurogenesis. Many benefits of exercise on the brain are due to BDNF, and it’s possible that exercise promotes BHB in the blood, which in turn goes into the brain to work its magic.
“It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance.” — Exercise: a behavioral intervention to enhance brain health and plasticity, Trends in Neuroscience
Third, ketones seem to rebalance excitation in the brain. The brain uses two major types of neurotransmitters, glutamate and GABA, to transmit information. Glutamate is excitatory, stimulating neuronal chatter, whereas GABA dampens it. Too much excitation, as in the case of many neurodegenerative diseases, and neurons die in a process called excitotoxicity. In people prone to seizures, ketones lower glutamate transmission while increasing GABA at the synapses. This seems to be great for inhibiting seizures (and potentially for neuroprotection), but you do have to wonder what it does to a normally functioning brain.
Ketones also inhibit the production of free radicals, which contain unpaired electrons that make them highly reactive (and highly dangerous). Increased oxidative stress from free radicals is a major hallmark of aging and neurodegeneration. Free radicals are an unfortunate side effect of glucose metabolism. When you lower glucose consumption, as in the case of a ketogenic diet [or while fasting], it directly lowers the amount of free radicals. What’s more, ketones stimulate the activity of our innate anti-oxidant system to combat these molecules.
LifeOmic: Is it true that ketosis results in improved “mental clarity”?
Shelly: I’m not sure how this can be scientifically measured (for example, should we do tests in the working memory domain or some other types of memory? Or multitasking ability?) To my knowledge, there isn’t any concrete evidence for this, though it’s definitely a popular opinion on r/keto and other forums.
There was a study recently using EEG to tease out brain wave patterns associated with successful versus unsuccessful word recall, and the former (successful recall) was described as a type of “mental clarity,” so looking at brain waves may be a place to start.
Editor’s Note: For people with impaired metabolic functions or mitochondrial dysfunction, ketosis may improve neuronal excitability and reduce inflammation, which may lead to an improvement in cognitive disorder symptoms that could be described by some people as mental clarity. For some, intermittent fasting or a ketogenic diet may also lead to fast loss and improved mood.
LifeOmic: What role can or do metabolic interventions that target the insulin pathway and senescent cells, such as caloric restriction and intermittent fasting, play in healthy brain aging?
Shelly: Targeting the insulin pathway and senescent cells are two very well-documented ways to maintain neuronal metabolism, synaptic plasticity and learning and memory in the aging brain. For example, modulating IGF (insulin signaling) pathways can boost neurogenesis and memory in aged mice, but the trick is figuring out a way to activate those pathways using specific small chemical drugs. Recently there’s been far more interest in exploring senolytics, which are drugs that eliminate senescent cells. In fact, some aging experts believe that this class of drug may be available on the market within the next decade, and these drugs have been shown to increase brain function in aged mice. While not directly related to metabolic manipulation, senolytics do offer very strong proof-of-concept that eliminating senescent cells is a powerful way to keep an aged brain healthy.
At LifeOmic, we are creating a series of LIFE apps that bring precision medicine to you. These apps encourage lifestyle interventions you can use to live healthier including exercise, anti-inflammatory diets, stress management and intermittent fasting. But just as importantly, our apps will also allow you, your doctors and researchers to track the impacts of these interventions and integrate them other health indicators. By signing up for our LIFE apps, you can help bring data to the science of healthy aging.
If you or someone you know are battling brain cancer, check the new OurBrainBank app, which we discovered through Adam Hayden. In a similar vein to our LIFE apps, OurBrainBank is enabling patients and caregivers to document their symptoms, mood and activities, with the data analyzed by researchers to spot insights, accelerate learning and speed up clinical trials.