MTHFR is a real gene in the folate pathway, but it often gets treated like it explains everything. This episode keeps the scale right. You’ll learn what the enzyme does, why homocysteine became a popular lab marker, and how to separate association evidence from intervention evidence so you don’t get misled by a number moving without outcomes changing. You’ll also get a simple decision model you can use without spiraling.

You’ll learn:

• What MTHFR actually does inside folate metabolism

• Why folate was historically studied in medicine

• How homocysteine became a biomarker

• Why association studies and randomized trials tell different stories

• What DNA methylation actually means

• Why this is a pathway discussion, not a personality explanation

This episode separates evidence types carefully and keeps claims proportional to data.

Timestamps

0:00 Primary intro

1:05 Why MTHFR gets inflated in conversation

2:00 Folate history and why it mattered in medicine

3:00 One carbon metabolism explained clearly

4:15 What MTHFR enzyme actually does

5:20 B12 as cofactor and why this is a pathway, not a solo gene

6:10 Homocysteine as a biomarker and what association means

7:20 Randomized trials lowering homocysteine and outcome nuance

8:40 DNA methylation defined properly

9:50 What MTHFR does not control

10:40 Mendelian randomization and causality

11:30 Micro protocol and bridge to Part 2

Key Terms

Folate: A B vitamin required for DNA synthesis and red blood cell formation. Named from the Latin “folium,” meaning leaf.

One carbon metabolism: A network of reactions that transfer single carbon units for DNA synthesis and methylation reactions.

MTHFR: Methylenetetrahydrofolate reductase, an enzyme that converts one form of folate into another needed for homocysteine recycling.

Enzyme: A protein that speeds up a chemical reaction.

Homocysteine: An intermediate amino acid in methionine metabolism that can accumulate if recycling is impaired.

Methionine: An essential amino acid involved in protein synthesis and methyl group donation.

Vitamin B12: A vitamin that acts as a cofactor for methionine synthase in homocysteine conversion.

Cofactor: A helper molecule required for an enzyme to function.

Biomarker: A measurable biological indicator, often assessed through blood testing.

Association: When two variables move together statistically; does not prove cause.

Randomized controlled trial: A study design that assigns participants by chance to test cause and effect.

DNA methylation: The addition of methyl groups to DNA that can influence gene expression levels.

Gene expression: The process by which a gene is used to produce a protein.

Mendelian randomization: A genetics based method using variants as natural experiments to estimate causality.

Keywords

MTHFR, folate cycle, homocysteine, methylation, one carbon metabolism, B12, C677T, gene expression, cardiovascular risk, Mendelian randomization

References

NIH Office of Dietary Supplements. Folate Fact Sheet for Health Professionals.

NIH Office of Dietary Supplements. Vitamin B12 Fact Sheet for Health Professionals.

HOPE 2 Investigators. NEJM. 2006.

NORVIT Trial Investigators. NEJM. 2006.

Clarke R et al. Homocysteine and vascular disease. JAMA. 2002.

Recent Mendelian randomization analyses on homocysteine and cardiovascular outcomes, 2018–2023.

Episode 7 Part 2 continues directly from Part 1 and turns MTHFR from a confusing gene label into practical decisions you can use. We walk through homocysteine as a pathway signal, why observational associations are not the same thing as cause, and what randomized trials taught us about lowering homocysteine versus improving real world outcomes. You’ll also learn what common lab terms mean in plain language, including serum B12, serum folate, and RBC folate, and why each test gives a different kind of picture. From there we translate micrograms and kilograms into normal food and bodyweight anchors, then bring in the brain layer with neurotransmitters, methylation, and gene expression kept in proportion. ADHD is addressed as an applied example without making it the headline. We close with a detailed, repeatable protocol focused on labs in context, folate and B12 consistency, protein targets, iron and omega 3 foundations, and sleep stability.

Timestamps

0:00 Primary intro and safety disclaimer

0:37 Bridge from Part 1 and what Part 2 solves

1:45 Homocysteine, association versus causation, and why trials changed interpretation

3:19 Lab terms decoded, serum B12, serum folate, RBC folate

4:53 Units made human, micrograms, folate targets, food examples

5:10 B12 planning, fortified foods, consistency

6:12 Protein targets, kilograms, 1.6 g per kg, meal anchors

8:23 Brain layer, neurotransmitters, methylation, gene expression

8:41 ADHD as an applied example, polygenic meaning many genes

10:30 Ferritin and iron, what it means, food sources, absorption tip

12:22 Omega 3, EPA and DHA, evidence summary, food sources and ranges

13:42 Sleep and stress, how instability amplifies symptoms

14:32 Protocol begins, labs plus food and training anchors

15:30 Two week stability challenge

15:36 Close and final line

17:29 End

Key Terms

Microgram: One millionth of a gram, used for vitamins and minerals because they work in small amounts.

Kilogram: A unit of bodyweight equal to about 2.2 pounds.

Protein adequacy: Consuming enough protein to support tissue repair and training adaptation, often around 1.6 g per kg per day for resistance training contexts.

Polygenic: Influenced by many genes that each contribute small effects.

Ferritin: A blood marker used to estimate iron storage.

Omega 3: A family of fats, including EPA and DHA, studied for brain and behavioral outcomes.

EPA: Eicosapentaenoic acid, an omega 3 fat studied in inflammation and brain related outcomes.

DHA: Docosahexaenoic acid, an omega 3 fat important for neural tissue structure and function.

Keywords

MTHFR,micrograms, kilograms, protein, gene expression, polygenic, ferritin, iron, omega 3, EPA, DHA,

References

Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease. New England Journal of Medicine. 2006.

Bønaa KH, Njølstad I, Ueland PM, et al. Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction. New England Journal of Medicine. 2006.

Morton RW, Murphy KT, McKellar SR, et al. A systematic review, meta analysis and meta regression of the effect of protein supplementation on resistance training induced gains. British Journal of Sports Medicine. 2018.

NIH Office of Dietary Supplements. Folate Fact Sheet for Health Professionals.

NIH Office of Dietary Supplements. Vitamin B12 Fact Sheet for Health Professionals.

Tseng PT, et al. Peripheral iron levels in children with ADHD. Scientific Reports. 2018.

Liu TH, et al. Omega 3 Polyunsaturated Fatty Acids for Core Symptoms of ADHD. Journal of Clinical Psychiatry. 2023.

The Unlocked Podcast is educational content, not medical advice. For personal medical decisions, consult a qualified professional.

A short guided practice to downshift, recover, and ground the nervous system.

This episode is a guided nervous system reset designed to help you downshift from stress, stimulation, or mental overload.

You don’t need a yoga studio, special equipment, or prior experience. This practice can be done seated or lying down, at home, after work, after training, or before sleep.

The breathing and awareness used here are intended to support recovery by gently shifting the nervous system out of a high-alert state and toward a calmer, more regulated one. Over time, practices like this can support better sleep, digestion, emotional regulation, and overall recovery.

This session is not about forcing relaxation or clearing the mind. It’s about giving the body enough space to settle naturally.

You can return to this reset anytime you feel overstimulated, scattered, or in need of grounding.

What You Need

A quiet space where you can sit or lie down comfortably.

A chair, mat, couch, or bed all work.

Optional: a light blanket if the room is cool.

After the Practice

Try to keep the transition gentle.

Hydration is helpful.

If you eat afterward, warm, grounding foods are often more settling than highly stimulating options.

Your biology listens. Live like it.

Episode 5 is a short, high-energy activation episode focused on momentum rather than discipline. Instead of relying on motivation as a prerequisite, this episode explains how movement itself acts as a biological signal that organizes focus, clarity, and drive. The emphasis is on reducing friction, using small actions to shift nervous system state, and creating traction without pressure. This episode is designed to be listened to in real time, especially before work, training, or any task that requires initiation.

Energy Adjustment Options

High-performance days:

Read at a slightly faster pace, with clearer posture cues and more vocal lift in the middle section.

Lower-energy or burnout days:

Slow the pacing slightly, soften the emphasis, and allow longer pauses between sentences to reduce pressure.

Your biology listens. Live like it.

Episode 4 explores ACTN3, a gene tied to fast-twitch muscle fiber structure, and how muscle architecture influences strength, speed, fatigue, and recovery. We move beyond genetic labels and focus on how structure, energy systems, and training signals interact to shape performance over time.

The episode traces the scientific history of ACTN3, beginning with the identification of the R577X variant and early athlete association studies, then moves into mechanistic research using Actn3 knockout models to explain why some bodies respond differently to power and endurance demands.

Rather than treating genetics as destiny, this episode frames ACTN3 as a structural context that influences training cost, energy use, and recovery timelines. We connect muscle architecture to ATP demand, nervous system load, and how training converts into adaptation rather than lingering fatigue.

The practical section introduces a simple one-week “conversion” experiment to help listeners observe how their own system responds to strength-biased versus volume-biased training, without needing a genetic test.

This episode sets the foundation for future discussions on training precision, recovery architecture, and the long-term direction of performance systems, regeneration, and bio-integrated technology.

Timestamps

(0:00 Introduction and framing ACTN3 as structure, not identity

1:10 Muscle architecture overview and why fiber structure matters

2:20 ACTN3 history and the R577X variant

3:35 Athlete association studies and population-level findings

4:55 Mechanistic research and Actn3 knockout models

6:30 Muscle metabolism, ATP demand, and training cost

8:05 Conversion versus fatigue and why recovery timelines differ

9:40 One-week conversion experiment explained

11:30 How this fits into long-term performance systems

13:05 Episode summary and close

Key Terms

ACTN3: A gene that codes for alpha-actinin-3, a structural protein found in fast-twitch muscle fibers.

Alpha-actinin-3: A protein involved in anchoring actin filaments in fast-twitch muscle fibers.

Fast-twitch fibers: Muscle fibers specialized for high-force, high-speed output.

ATP (Adenosine Triphosphate): The primary energy currency used by cells to perform work.

Aerobic metabolism: Energy production that relies more heavily on oxygen-supported pathways.

Conversion: How effectively training effort translates into repeatable adaptation rather than fatigue.

Muscle architecture: The structural arrangement of muscle fibers and contractile elements.

Your biology listens. Live like it.

References

North KN et al. (1999). A common nonsense mutation results in alpha-actinin-3 deficiency in the general population.

Yang N et al. (2003). ACTN3 genotype is associated with human elite athletic performance.

MacArthur DG et al. (2007). Loss of ACTN3 gene function alters muscle metabolism and performance in mice.

MacArthur DG et al. (2008). Structural and metabolic consequences of ACTN3 deficiency.

RSS Footer Disclaimer

The Unlocked Podcast is educational content, not medical advice. For personal medical decisions, consult a qualified professional.

Episode 3 uses COMT as a practical lens for understanding signal duration and clearance in focus and stress physiology. We trace COMT through the mid 20th century discovery era of neurotransmitter inactivation, then connect it to prefrontal cortex function and later human genetics work on functional variation such as Val158Met. The episode stays focused on real world patterns like wired but tired and fog, then gives repeatable experiments around caffeine timing, light timing, sleep stability, training structure, and downshift rituals. The aim is a cleaner signal, steadier attention, and more predictable recovery, especially for high demand lifestyles like students building a business. Key Terms functions as the glossary, and listening again after vocabulary is familiar typically makes the episode land differently.

Timestamps

0:00 Story opener and the real world focus problem

2:35 Bridge into COMT and what clearance means in plain language

4:05 COMT, catecholamines, and signal duration

5:30 Prefrontal cortex, attention control, and performance under stress

6:45 Here’s a little context from the research history, why COMT entered the science story

9:30 Demand and clearance as the practical model

10:45 Wired but tired and fog patterns, how modern life amplifies both 12:20 Repeatable levers, timing, sleep stability, training structure, downshift

14:10 Cybernetics bridge, biology as feedback loops

15:25 Reminder pass, Key Terms glossary cue,

Key Terms

COMT: Catechol O methyltransferase, an enzyme involved in metabolizing catecholamines through methylation related chemistry.

Catecholamines: Neurochemicals involved in alertness, motivation, and stress response, including dopamine, norepinephrine, and epinephrine.

Dopamine: A neurotransmitter involved in motivation, attention, learning, and reward signaling.

Norepinephrine: A neurotransmitter and hormone involved in alertness, arousal, and stress response.

Epinephrine: Also called adrenaline, involved in acute stress response and energy mobilization.

Prefrontal cortex: Brain region involved in planning, working memory, attention control, impulse control, and decision making.

Gene expression: Which genetic instructions are used more or less often under certain conditions, without changing the DNA sequence.

Clearance: How the body breaks down and removes chemical signals over time, shaping how long a stress or focus state stays active.

Signal noise: Excess stimulation and stress input that makes focus, mood, and recovery less stable.

Feedback loop: A system where outputs influence future inputs, central to cybernetics and biological regulation.

Physiology: How the body functions in real time, including nervous system activity, hormones, metabolism, and recovery processes.

Adaptation: A lasting change after repeated signals, where the body becomes better at handling the same demand.

References

MedlinePlus Genetics. COMT gene overview.

Tunbridge EM, Harrison PJ, Weinberger DR. Catechol O methyltransferase, cognition, and dopamine regulation in prefrontal cortex. Review.

McEwen BS. Stress, adaptation, and allostatic load framework.

Goldman Rakic PS. Prefrontal cortex and executive function foundational work.

Axelrod J. Early foundational work on O methylation of catecholamines.

In Episode 2, we use BDNF, Brain Derived Neurotrophic Factor, as a real biological example of how training and environment shape adaptation. BDNF is part of the neurotrophin family, signals that support neurons and plasticity, which matters for learning, mood, and performance. We walk through the research history behind neurotrophins, including the NGF thread, and then bring it into modern exercise science. We cover what studies tend to show about acute exercise effects on peripheral BDNF, what longer training programs suggest about resting peripheral BDNF, and a measurement nuance that changes how results appear, serum versus plasma, and why platelets matter.

The episode closes by connecting BDNF signaling to the real world plateau problem. A lot of the time it is not that the plan is wrong on paper. It is that the recovery environment is unstable. We talk about why sleep timing and stress load shift the background physiology that training signals land inside of, and why that changes whether progress “sticks.”

Your biology listens. Live like it.

Key Terms

BDNF: Brain Derived Neurotrophic Factor. A neurotrophin involved in neuronal support and plasticity.

Neuron: A nerve cell that transmits signals in the brain and nervous system.

Neurotrophin: A family of proteins that support neuron survival and plasticity, includes NGF and BDNF.

NGF: Nerve Growth Factor. A protein that supports survival and growth of certain neurons, important in the research history of neurotrophic signaling.

Purification: Laboratory isolation of a molecule from tissue so it can be studied directly.

Microgram: One millionth of a gram.

Peripheral BDNF: BDNF measured outside the brain, typically in blood.

Serum: The liquid part of blood after clotting.

Plasma: The liquid part of blood when clotting is prevented.

Platelets: Blood components involved in clotting that can store and release proteins like BDNF during sample processing.

TrkB: A high affinity receptor for BDNF, often discussed as a main docking site for BDNF signaling.

Receptor: A cellular docking station that receives a signal and triggers internal responses.

Plasticity: The ability of the nervous system to strengthen connections and improve function through learning and repetition.

Adaptation: A lasting biological change after repeated training signals, where the body becomes better at handling the same demand.

Physiology: How the body functions in real time, including hormones, nerves, muscles, and recovery systems.

Anabolic: A metabolic direction that supports building and repair.

Catabolic: A metabolic direction that supports breakdown or conservation.

Muscle protein synthesis: The process of building and repairing muscle tissue from amino acids.

References

Barde YA, Edgar D, Thoenen H. Purification of a new neurotrophic factor from mammalian brain. The EMBO Journal. 1982.

Dinoff A, Herrmann N, Swardfager W, Liu CS, Sherman C, et al. The Effect of Exercise Training on Resting Concentrations of Peripheral Brain Derived Neurotrophic Factor (BDNF): A Meta Analysis. PLOS ONE. 2016.

Serra Millàs M. Are the changes in the peripheral brain derived neurotrophic factor levels due to platelet activation. World Journal of Psychiatry. 2016.

Lamon S, Morabito A, Arentson Lindgren M, et al. Acute sleep deprivation and anabolic resistance in skeletal muscle, with related hormonal environment changes. Physiological Reports. 2021.

The Nobel Prize in Physiology or Medicine 1986 Press Release. NobelPrize.org. Background context on NGF and growth factor history.

In Episode 1 of The Unlocked Podcast, we start with the foundation: what DNA is, what genes do, and why gene expression is the key to understanding human performance.

Most people grow up thinking DNA is a fixed script. In reality, DNA is an instruction manual, and gene expression determines which instructions are used at any given time.

In this episode, we explain DNA in plain language, break down how genes build proteins, and connect those proteins to outcomes people care about: training results, recovery, stress tolerance, mood, and cognition. We also introduce epigenetics, the science of how your environment can influence gene activity without changing your DNA sequence.

To give you context for why this matters now, we walk through major milestones in genetics, from the discovery of the double helix to the Human Genome Project, and what that progress revealed about regulation, environment, and long term health.

This episode also sets up the direction of the series and the topics we will build into next, including performance genes like ACTN3, BDNF, and COMT, nervous system regulation, recovery loops, and eventually the intersection of biology and technology.

If you have ever felt like you are doing the right things but your results do not match your effort, this episode will give you a clearer framework for how to think about your body and what it responds to.

Your biology listens. Live like it.

Timestamps

0:00 Welcome and what The Unlocked Podcast is about

0:50 DNA in plain language

1:40 Genes, proteins, and why they matter

2:25 What gene expression means

3:10 What epigenetics means

4:05 A short timeline of modern genetics

5:05 Why we start with ACTN3, BDNF, and COMT

Key Terms

DNA: Deoxyribonucleic acid, the molecule that stores genetic instructions.

Gene: A sequence of DNA that helps make a functional product, often a protein.

Protein: A molecule that builds, repairs, and regulates structures and processes in the body.

RNA: Ribonucleic acid, a temporary message copied from DNA.

Gene expression: How a gene’s instructions are used to make RNA and proteins.

Epigenetics: Regulation of gene activity influenced by the environment without changing the DNA sequence.