Rewiring Brain Activating BDNF with β-Hydroxybutyrate Production Naturally

Dr Mehmet Yildiz

Initiating neurogenesis and enhancing cognitive reserves with simple lifestyle habits based on insights from scientific papers in neuroscience, biology, and cognitive science
Brain ImagingPhoto by Anna Shvets from Pexels

A Scientific Review of Literature for Brain-Derived Neuro Factor and β-Hydroxybutyrate

Neurodegenerative diseases cause suffering for aging people and substantially impact healthcare costs and the economy.

During my cognitive science studies in neuroscience classes at the doctoral level, one of the most exciting topics was neurogenesis and brain plasticity. I got thrilled when I learned that the brain could grow at any age, and we could create cognitive reserves for brain atrophy.

Using this empowering knowledge, my mental health, sensible biohacking, transhumanism, and longevity toolbox included powerful tools like BDNF (Brain-Derived Neuro Factor) and BHP (β-hydroxybutyrate). Moreover, I learned ways to increase BDNF and BHP naturally from scientific studies, which I want to share in the simplest possible way in this article as they are complex.

Brain atrophy is natural and inevitable. As we age, we lose specific mental capabilities. BDNF is a crucial factor in human cognition. β-hydroxybutyrate is a remarkable signaling molecule contributing to the increase of BDNF.

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and depression are examples of brain atrophy. Unfortunately, millions of aging people suffer from these debilitating diseases globally.

One of the measures to mitigate brain atrophy risk is maintaining cognitive reserves. Simple lifestyle changes such as moderate exercise, optimal diet meeting our genetic makeup, stress management, and high-quality sleep can help us create and maintain cognitive reserves.

I introduce BDNF, provide a brief review of relevant scientific resources, and present a few practical ways to increase BDNF based on my experience and observations.

Please note that this article does not provide any medical advice. It reflects the views and findings of scientists cited in the linked scientific papers indexed in Pubmed. There is no illegal drug or supplement advice. BDNF and β-Hydroxybutyrate are natural processes in the brain.

What is BDNF?

BDNF (Brain-Derived Neuro Factor) is a signaling protein for brain plasticity. It is produced by the BDNF genes, which are also in various body parts. BDNF genes are also part of the neurotrophin group of growth hormones.

Neurotrophins are a family of proteins that induce neurons' survival, growth, and functioning. These hormones contribute to the development of neurons in the brain and are essential for the survival of neurons.

BDNF is active in brain regions such as the hippocampus, the cortex, the basal forebrain, and the cerebrum. These regions help us learn and build new memories. For example, BDNF was observed to be reduced in Alzheimer’s patients.

The hippocampus is critical for our learning process. If this region of the brain is damaged, we experience a learning disability. The necessary knowledge is that the hippocampus needs BNDF for coding information. In short, the lack of BDNF can shorten the synaptic strength in this learning region of the brain.

As confirmed by this scientific paper, BDNF is essential to promote the persistence of long-term memory (LTM) storage. The study demonstrates that BDNF induces memory persistence by itself, transforming a non-lasting LTM trace into a persistent one in an ERK-dependent manner. Thus, BDNF is not only necessary but sufficient to induce a late post-acquisition phase in the hippocampus essential for the persistence of LTM storage.

Even though the hippocampus plays a critical role, several other brain regions coordinate learning and skill-building. So, total brain activity is essential for learning and improving our skills.

Impact of BDNF on Neurodegenerative Diseases

Many scientific studies, as compiled by a comprehensive review in Cellular Neuroscience, depict the association of BDNF in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, multiple sclerosis (MS), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SZ), and depression.

There is evidence on the effect of chronic stress on BDNF and its link to psychiatric disorders. For example, this study points out that:

“the hippocampus is altered by prolonged exposure to aversive situations. A wide variety of strategies have been assessed to reduce the deleterious effects caused by chronic stress. Infusions of BDNF in the rat hippocampus before a chronic restraint stress protocol can protect against the deficits in learning.”

To give you a useful perspective on these diseases, I share five prominent scientific papers touching on each condition from my review of the topic in scientific literature.

1 — BDNF and Depression

As highlighted in this study, “depression and suicidal behavior have recently been shown to be associated with disturbances in structural and synaptic plasticity. Brain-derived neurotrophic factor (BDNF), one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons and in synaptic plasticity. Several lines of evidence suggest that BDNF is involved in depression, such that the expression of BDNF is decreased in depressed patients. In addition, antidepressants up-regulate the expression of BDNF.”

2 — BDNF and Alzheimer’s Disease

This study published in Nature points out that “reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer’s disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aβ) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aβ-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established.”

3 — BDNF and Parkinson’s Disease

This study sees BDNF as a Promising Therapeutic Agent in Parkinson’s Disease. “Brain-derived neurotrophic factor (BDNF) promotes neuroprotection and neuroregeneration. In animal models of Parkinson’s disease (PD), BDNF enhances the survival of dopaminergic neurons, improves dopaminergic neurotransmission and motor performance. Pharmacological therapies of PD are symptom-targeting, and their effectiveness decreases with the progression of the disease; therefore, new therapeutical approaches are needed.”

4 — BDNF and Huntington’s Disease

This study discusses the role of a brain-derived neurotrophic factor in Huntington’s disease. “Neurotrophic factors are essential contributors to the survival of peripheral and central nervous system (CNS) neurons, and demonstration of their reduced availability in diseased brains indicates that they play a role in various neurological disorders.

The paper concentrates on the role of brain-derived neurotrophic factor (BDNF) in the survival and activity of the neurons that die in Huntington’s disease (HD) by reviewing the evidence indicating that it involves profound changes in BDNF levels and that attempts to restore these levels are therapeutically interesting.”

5 — BDNF and Overall Neurodegenerative Diseases

As mentioned in this recent scientific review, altered levels of BDNF, both in the circulation and in the central nervous system (CNS), have been reported to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), multiple sclerosis (MS), and ischemic stroke.

How to Increase BDNF and Maintain Cognitive Reserves

After this brief theoretical unpinning, I want to highlight practical ways to increase BDNF and maintain cognitive reserves. As mentioned in this study, “circulating BDNF levels increase with physical activity and caloric restriction, thus BDNF may mediate some of the observed associations between lifestyle and the risk for dementia.”

Caloric restriction — in the form of time-restricted eating (intermittent fasting) — and intense exercise contribute to the formation of β-hydroxybutyrate, which is a powerful ketone producing alternative energy to the brain and several other organs. Therefore, one of my reasons to stay in mild ketosis through time-restricted eating is to improve BDNF.

As this study points out, “Beta-hydroxybutyrate Promotes the Expression of BDNF in Hippocampal Neurons under Adequate Glucose Supply. β-Hydroxybutyrate induces BDNF expression by activating cAMP/PKA/p-CREB signaling and enhances H3K27ac level independent on HDAC.”

When we consume liver glycogen and stay in a caloric deficit, the body produces ketones as an alternative energy source, especially for the brain. Ketones are created from lipids. The brain can’t use fat as an energy source directly; however, it happily uses ketones. This is part of our evolution. During the famine, humans survived by this unique energy source. When adequate glucose does not go to the brain, we experience brain fog. Ketones provide alternative energy.

1 — Intense Exercise

Cardio and high-intensity interval training (aerobic exercises) are criticized in some fitness communities associated with muscle loss. I understand the hesitance in the side effects of excessive cardio, especially for aging adults. However, moderate cardio and HIIT are essential tools to create BDNF.

In the form of weightlifting and calisthenics, resistance training is also important. As confirmed by this study, intense resistance exercise increases peripheral brain-derived neurotrophic factors.

As this study articulates, “it is well established that acute exercise increases circulating levels of BDNF, and numerous studies have sought to characterize this response to improve brain health. Engagement in regular bouts of exercise confers numerous positive effects on brain health across the lifespan. Acute bouts of exercise transiently improve cognitive function, while long-term exercise training stimulates brain plasticity, improves brain function, and helps to stave off neurological disease.”

Exercise reduces insulin resistance and increases β-hydroxybutyrate when incorporated with time-restricted feeding such as intermittent fasting. Ketones as signalling molecules can also reduce oxidative stress and inflammation.

2 — Time Restricted Eating (Fasting)

Fasting is another controversial topic in fitness circles and health communities. While some medical professionals highly recommend fasting, especially intermittent fasting, some experts depict reservations.

For example, this study titled “Fasting and exercise differentially regulate BDNF mRNA expression in human skeletal muscle” confirmed that BDNF gene expression was measured in human skeletal muscle following three intensities of exercise and a 48-hour fast while fasting upregulated BDNF by ∼3.5-fold.

According to another study, “neurobiological evidence suggests that the ketone metabolite β-hydroxybutyrate (BHBA) exerts many neuroprotective functions for the brain. The previous study revealed that BHBA could promote the expression of brain-derived neurotrophic factor (BDNF) at inadequate glucose condition.”

From my experience, intermittent fasting and long-term fasting with medical supervision provided me with significant physical and mental health benefits. In addition, reducing sugar intake helped me produce more β-hydroxybutyrate. In other words, I maintain ketosis allowing my brain to use ketones as an alternative source of energy.

3 — Reversing Insulin Resistance and Metabolic Syndrome

As this study informs, “BDNF serves widespread roles in regulating energy homeostasis in both fetuses and adults, by controlling patterns of fetal growth, adult feeding, and physical activity, and by regulating glucose metabolism in peripheral tissues. Impaired BDNF signaling may be implicated in the etiopathogenesis of the metabolic syndrome.”

I posted several articles related to insulin resistance, metabolic syndrome, and non-alcoholic fatty liver disease related to obesity, type two diabetes, and cardiovascular diseases on NewsBreak.

4 — Dealing with Chronic Stress, Inflammation, & Sleep Disorders

Chronic stress, inflammation, and sleep disorders play a critical role in physical and mental health, including neurodegenerative diseases.

As this study, published in Human Neuroscience, points out, “Yoga, Meditation and Mind-Body Health: Increased BDNF, Cortisol Awakening Response, and Altered Inflammatory Marker Expression after a 3-Month Yoga and Meditation Retreat”.

Sleep is critical for stress management and reducing chronic inflammation. In addition, some studies show association with sleep and low levels of BDNF in the brain.

For example, this critical review points out that “poor sleep quality is related with alterations in the BDNF concentration. Some authors argue that most of the cases show that impaired sleep quality increases the stress and, consequently, the vulnerability to depressive disorders, suggesting that there is a relationship between sleep, depression and BDNF levels.”

As this is a broad topic, I link my articles related to stress, inflammation, and sleep for interested readers.


Our physical and mental health are closely linked. Therefore, for a sustainable and joyful life, we need to look after our mental health by reducing risks for cognitive decline.

A well-known approach to reduce neurodegeneration is increasing and maintaining BDNF. This approach also may help to create and maintain cognitive reserves as we age and contributes to high-quality longevity.

By adopting healthy habits and making lifestyle changes, we can naturally increase our BDNF. Exercise, time-restricted eating, reducing chronic stress and inflammation, and improving sleep quality play an important role in increasing BDNF.

There is sufficient evidence for β-Hydroxybutyrate (BHB) contributing to BDNF and other cognitive capabilities in the medical literature. So, ketosis, naturally increasing BHB, is a compelling option as pointed out in the papers.

My future articles will cover several other factors that can affect BDNF, such as music, heat therapies (sauna), and neurobics (brain exercises).

Thank you for reading my review and perspectives.

I attach a valuable presentation by a reputable neuroscientist reflecting on her years of research sharing her personal story in a TED talk.

Disclaimer: Please note that this article is not health advice. It is for information purposes only. The content reflects my review of credible sources from scientific papers indexed in PubMed which is the US Government's National Library of Medicine.

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I write about important and valuable life lessons. My goal is to delight my readers. My content aims to inform and engage my readers. I'm a technologist, cognitive scientist, and postdoctoral researcher, with four decades of experience.


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