Why Fast? Part Four – Brain Health

Pretty much every feature of the human body can be found, in some form or another, on other species. Opposable thumbs? Great for building and using tools, but apes have them, too. Even the giant panda has an opposable sesamoid bone that works like a thumb. Bipedalism? Helped us avoid direct mid-afternoon sun and carry objects while moving around the environment (among other possible benefits), but plenty of other creatures walk upright, like birds and Bigfoot. The human foot? Okay, our feet are quite unique, but every other -ped has feet (just different types), and they all work well for getting around. So, what is it that makes us so different from other animals (because it’s got to be something)?

What truly sets us apart from the rest of the animal kingdom is the human brain. Other animals may have brains big and complex enough to help them procure food, shelter, and water while processing and acting on basic sensorial inputs from the environment (“avoid obstacle” or “this smells like food” or “I am thirsty, where’s the water?”), but they do not share the human brain’s capacity for self-reflection and symbolic thought. It is the fleshy thinking mass of fatty furrows and gelatinous valleys sitting atop our spine that gave and gives us art, literature, architecture, agriculture, nuclear power, syntax, philosophy, advertising, society, this laptop on which I type this post, and the smart phone on which you read it. In short, our brains make us human. Without them, we wouldn’t be us.

I don’t know about you, but I enjoy being a human. I like contemplating my own existence, being entertained for hours by strange scribblings on layered sheets of dried and pressed wood pulp, and playing Ultimate Frisbee, and if I’m going to continue to enjoy those things, I need to protect my brain and keep it healthy. And if I want to enjoy myself on this planet and experience all it has to offer until I drop dead, I’m going to need as much brain function as possible (since, you know, the brain handles all that experimenting stuff) as I age. Luckily, fasting appears to offer three main protective and therapeutic benefits to the brain:

Fasting Boosts Neuronal Autophagy

I’ve cited this study before, but I’ll do it again because it’s central to the theme of today’s post: “short-term fasting induces profound neuronal autophagy.” Autophagy, or “self-eating,” is the process by which cells recycle waste material, downregulate wasteful processes, and repair themselves. Brain health is highly dependent on neuronal autophagy. In fact, a recent paper shows that deletion of an “essential autophagy gene” in the hypothalamic neurons of fetal mice resulted in metabolic derangement (more body fat, poor glucose tolerance) and impaired neuronal development. Another study shows that disruption of neuronal autophagy induces neurodegeneration. Simply put, without the process of autophagy, brains neither develop properly nor function the way they should.

Fasting Increases Levels of Brain-Derived Neurotrophic Factor (BDNF)

BDNF is a protein that interacts with neurons in the hippocampus, cortex, and basal forebrain (the parts of the brain that regulate memory, learning, and higher cognitive function – uniquely human stuff). It helps existing neurons survive while spurring the growth of new neurons (neurogenesis) and the development of synapses (lines of communication between neurons). Low levels of BDNF are linked to Alzheimer’s, and supplementary BDNF prevents neuronal death, memory loss, and cognitive impairment in an animal model of Alzheimer’s disease.

Fasting Increases Production of Ketones

Ketone bodies like hydroxybutyrate are famously neuroprotective, and fasting often induces ketosis.

Increased autophagy and BDNF and ketones from fasting sounds awesome, but do they manifest as actual benefits to neurological health? Let’s see what the research says.

No discussion of fasting and neurological health research is complete (or can even be initiated) without including Mark Mattson. Mattson, chief neuroscientist at the National Institute on Aging, has been releasing paper after paper on the neurological effects of intermittent fasting for the past dozen years, and he’s amassed an impressive body of work that suggests IF can induce neurogenesis and protect against brain injury and disease. In the following sections, I’ll discuss the evidence – from Mattson and other researchers – for the beneficial effects of fasting on neurological health across a spectrum of conditions.


The most common type of strokes are ischemic strokes (composing about 88% of all strokes) – cerebrovascular events in which a blood vessel that supplies blood to the brain is blocked by a clot. Without blood, the brain can’t get oxygen or nutrients, and (often permanent) brain damage can occur. In an animal model of ischemic stroke, fasting upregulated BDNF and other neuroprotective proteins, reduced mortality and inflammation, and increased cognitive health and function. However, it’s worth noting that fasting was most effective against stroke in young animals, who enjoyed a four-fold increase in neuroprotective and neurogenerative BDNF. Middle aged mice saw a two-fold increase in BDNF, while older mice saw no increase. Post-stroke cognitive function had a similar relationship to age and feeding status; young and middle-aged fasted mice retained far more than old mice and fed mice. Fasted mice displayed lower levels of inflammatory cytokines, but this effect was also modulated by age. Overall, fasting increased neuroprotective proteins and decreased inflammatory cytokines in young and middle-aged mice, thereby reducing the brain damage incurred by stroke.

Brain Trauma

Research indicates that fasting is also effective against physical trauma to the brain. It’s not that fasting somehow physically repels impending trauma by generating a magical ketone-powered force field; it’s that fasting reduces the oxidative stress, mitochondrial dysfunction, and cognitive decline that normally result from brain trauma. Employing one of these contraptions, researchers induced a “controlled cortical impact” on fasting rats and found that a 24-hour fast (but not a 48-hour fast) was neuroprotective. Perhaps the reduced appetite that commonly accompanies a concussion is a protective mechanism rather than an annoying side effect?

Cervical Spine Injury

“Every other day” fasting was neuroprotective following an injury to a rat’s cervical spine. Despite extensive trauma, fasted rats improved gait pattern, vertical exploration, and forelimb function (all heavily dependent on brain function). Neuronal integrity was preserved, cortical lesion volume was reduced, and corticospinal axon (nerve fiber) sprouting increased. The same team performed a similar study on mice suffering from a spinal cord injury, but had very different results; every other day fasting failed to confer any neuroprotective or functional benefits to the injured mice whatsoever. How can we reconcile these apparently contradictory findings? Well, in the rats who experienced neuroprotection, fasting increased ketone production by 2 or 3 fold. The fasting mice never reached ketosis. Ketosis was key.

Alzheimer’s disease.

In a mouse model of Alzheimer’s disease, both intermittent fasting and 40% (!) calorie restriction conferred cognitive and behavioral benefits when compared to mice on the control diet. IF and CR mice showed higher levels of exploratory behavior, and, when placed in a Morris water maze, found the escape platform sooner than the control mice. However, only IF mice showed evidence of protection against synaptic pathology – a hallmark of the disease.

Huntington’s disease.

Huntington’s disease is also characterized by a depletion in BDNF levels. In a rat model of the disease, intermittent fasting normalized BDNF levels, while regular feeding kept them low. Fasting rats lived longer and even enjoyed better glucose tolerance than ad libitum fed rats. By all accounts, fasting slowed progression of Huntington’s disease.

Age-Related Cognitive Decline

We’ve all had a grandmother who called us by our sibling’s name, or a grandpa who forgot to unwrap the Werther’s Original before popping it into his mouth – these are the innocent, simple, quaint, seemingly unavoidable declines in cognition that accompany the aging process. Well, maybe they aren’t unavoidable. Although most of the research focuses on neurological trauma and disease, there’s evidence that intermittent fasting is good for basic age-related cognitive decline. I find it interesting that this was “late-onset” intermittent fasting, meaning elderly rats who began fasting only after showing signs of decline still wrought cognitive benefits. Contrast that with the stroke study in which older rodents saw almost no benefit from fasting and a picture emerges: as long as they’re not trying to counter a debilitating event, like ischemic stroke or trauma, older brains can also expect to benefit from fasting.


Depression has long been associated with lower BDNF levels as a prognostic of the disease, but it’s only recently that researchers are entertaining the possibility that low BDNF and depression could be causally related. And indeed – antidepressants actually increase BDNF signaling and synthesis in the hippocampus (the part of the brain where depression “happens”). Could fasting help with depression via upregulation of BDNF and promotion of neurogenesis? Perhaps. I’d say it’s worth a shot, especially since skipping a few meals doesn’t require a prescription.

Obviously, since these are mostly rodent studies, and hard-and-fast peer-reviewed evidence of the neuroprotective and neurogenerative effects of fasting in humans doesn’t exist yet, we’re only speculating. But I’d argue they are plausible speculations worth pursuing. The mechanisms are there. Speculations about IF’s other health effects – to general health and cancer and longevity and fat loss – are being borne out by human research. Both the risk and barrier to entry are low. And it makes sense in light of our evolutionary history as hunter-gatherers. In a recent interview, Mattson even couches the neuroprotective effects of fasting in evolutionary terms, noting that during pre-agricultural times of scarcity, people “whose brains responded best – who remembered where promising sources could be found or recalled how to avoid predators — would have been the ones who got the food” and lived to pass on their genes.

As I age, the risk of my uniquely human brain going screwy and sabotaging my selfish desires to remain cognizant and engaged with life until the very end increases. It is not a foregone conclusion – I know too many quick-witted, sharp-tongued folks thirty years my senior – but the chances do increase. Since I don’t want that to happen, and the occasional fast is a nearly risk-free endeavor with proven benefits in other areas, I’ll continue to miss a few meals every now and then. It hasn’t hurt me yet, it just might be one of the factors that allows me to live long and drop dead, and hey, since I’m fat-adapted it’s not even a struggle to do it.

What say you, readers? Do the potential neuroprotective effects of fasting interest you? Why, or why not?

Thanks for reading.

Here’s the entire series for easy reference:

Why Fast? Part One – Weight Loss

Why Fast? Part Two – Cancer

Why Fast? Part Three – Longevity

Why Fast? Part Four – Brain Health

Why Fast? Part Five – Exercise

Why Fast? Part Six – Choosing a Method

Why Fast? Part Seven – Q&A

Dear Mark: Women and Intermittent Fasting

About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

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