MTHFR gets blamed for everything online... The real story is that MTHFR variants change how efficiently you make active folate. This then touches methylation, homocysteine, neurotransmitters, and histamine clearance. Bad internet lore abounds. What’s the most confusing MTHFR claim you’ve seen?

1/ One under-discussed root of depression: mitochondria that can’t keep up. When they struggle, ROS rises → inflammatory cytokines rise → mood symptoms follow for some people.

check out the latest Genetic Lifehacks weekly newsletter on histamine, a new tracker, and getting back to homeostasis. geneticlifehacks.substack.co…

Awesome. Thank you! Here's what I was going off of as far as the X algo.

Do me a favor if you happen to see this post. Click the share icon and copy the link. I want to see if that boosts this post or not (reading through the newly released X algorithm :-)

Latest Genetic Lifehacks weekly newsletter. Sign up to get it in your inbox! geneticlifehacks.substack.co…

A new study on the pesticide chlorpyrifos shows that higher exposure (e.g. living next to a field that is being sprayed) increases the risk of Parkinson's disease significantly. Chlorpyrifos is an organophosphate pesticide that is commonly used to control termites, mosquitoes, and roundworms. It is also used on corn and soybeans. Mice exposed to aerosolized chlorpyrifos developed movement problems and lost dopamine-producing neurons. link.springer.com/article/10…

Ooohhhh.... This is an interesting study. Researchers from the University of Arizona have developed a urine test for autism based on gut microbe metabolites. The test has 90% sensitivity and 100% specificity based on the metabolite levels in the urine. For anyone interested in autism, it is worth reading through the introduction section (and the discussion at the end). The researchers go into the changes in the gut microbiome seen in the majority of people with autism, but then also touch on the ones without gut changes usually having rare genetic mutations that are driving the autistic symptoms. Here's a few quotes that I thought were interesting: "In the context of early neurodevelopment, abnormal elevation of certain microbial metabolites—particularly those derived from tryptophan and phenylalanine metabolism—has been associated with adverse effects on gut barrier function, immune signaling, neurotransmitter pathways, and neurobehavioral outcomes" "Among participants with autism spectrum disorder (ASD), 42% exhibited high levels of one or more tryptophan metabolites, 57% had elevated phenylalanine/tyrosine metabolites, and 26% had high levels of both one tryptophan metabolite and one phenylalanine metabolite. 16% of ASD participants showed increased levels of yeast metabolites." 👇

There's a growing trend (by some pro-keto influencers) of using individual Lp(a) studies to argue the risk from high Lp(a) is overblown. The latest example: a study showing visceral fat modifies atherosclerosis risk in people with high Lp(a). It's a real and interesting study showing that high Lp(a) in the presence of a high waist-to-hip ratio (belly fat) increases atherosclerosis risk, while those with high Lp(a) and visceral fat didn't have an increased risk of atherosclerosis. But cherry-picking one study and saying that Lp(a) doesn't matter if you're thin and healthy misses the broader picture. High Lp(a) is more than just atherosclerosis... - High Lp(a) raises heart attack risk even without atherosclerosis - It triples the risk of aortic valve stenosis and calcification of the aortic valves - Inflammation (hsCRP) is another modifier that changes the equation The science on Lp(a) is nuanced. That's not a reason to dismiss it — it's a reason to understand it more deeply. I've updated my Lp(a) article to include the visceral fat research alongside the other modifying factors.👇🔗

Proline is an amino acid that the body uses to make proteins. It is synthesized from the amino acid glutamate in a multistep process. We can also get proline from protein-rich foods, such as gelatin and collagen, which are particularly high in proline. Proline in mitochondrial aging: A 2024 study showed that proline is likely very important in healthy aging and may be able to restore mitochondrial function and ameliorate DNA damage in senescent cells. Mitochondrial dysfunction is thought to be one of the driving factors of aging and the decay of health. Highlights from the study include that increasing proline levels in aging cells: - induces mitophagy (the recycling of damaged mitochondria), which improves cellular energy production - reduces senescent mesenchymal stem cells by promoting mitochondrial function - mitigates DNA damage and inflammatory cytokine expression through its positive effect on mitochondrial function Read the rest of this article here: longevitylifehacks.substack.…

This is an interesting new study on cognitive health in aging - broken out by APOE status. The results showed a more than 50% reduction in the risk of dementia in people eating the most red meat. The kicker is that this result was only true for APOE E4 allele carriers.

Standard-dose naltrexone (50–100 mg) blocks mu-opioid receptors to treat alcohol and opioid addiction, but at low doses (LDN) it flips into a micro-immunomodulator. In this article, I walk through dose-dependent mechanisms (opioid vs TLR4 vs TRPM3), with a table that maps dose → target → clinical use. geneticlifehacks.com/naltrex…

This is an interesting study on how cardiac output and changes in cerebral blood flow are abnormal in ME/CFS. Normally, when going from lying down to standing up, there's a compensatory change in cerebral vasodilation -- the body adjusts so that the brain gets enough blood when you stand up. In 91% of the ME/CFS patients in this study, the brain blood vessels didn't compensate for the change in cardiac outflow in the normal way. This isn't defined as POTS because heart rate didn't rise. However, the researchers concluded that things like more fluids, salt, compression stockings may help with ME/CFS. Study link below. (And yes, I'm updating my ME/CFS Genetic Lifehacks article with this today.)

~ While the reduced folate carrier (SLC19A1) is the dominant folate receptor throughout the body, two other folate receptors enhance folate uptake in a few specific tissues. ~ The folate receptor alpha (FOLR1 gene) is important for the higher folate levels in the cerebrospinal fluid that provide the folate needed in the brain. FOLR2 is important in the immune response. ~ There are a couple of genetic variants and rare mutations that can affect the function of FOLR1 and FOLR2. In addition, antibodies against folate receptor alpha may contribute to cerebral folate deficiency. Check your folate genetic variants👇 geneticlifehacks.com/folr1-a…

~ Pantothenic acid (vitamin B5) is the precursor for coenzyme A, which is fundamental for mitochondrial energy production. ~ Vitamin B5 is especially important in the brain. Post-mortem brain studies show significantly lower vitamin B5 levels in Lewy body dementia, Alzheimer’s, and Huntington’s disease. ~ Rare PANK2 mutations cause pantothenate kinase-associated neurodegeneration (PKAN). ~ Pantothenate produced by gut bacteria increases GLP-1 secretion, and supplementing with pantothenate reduced sugar cravings in diabetics with low levels of this microbe. Check your vitamin B5 genetic variants👇 geneticlifehacks.com/vitamin…

Back to back in my timeline - the exact same tweet about consciousness. Why the focus there?

I'm still totally fascinated by this study from a couple of weeks ago. Population-scale sequencing resolves determinants of persistent EBV DNA The research team looked at whole-genome sequencing from the UK Biobank and All of Us study cohorts (~ 700,000 total). In addition to your human DNA, the whole genome sequencing data can also include persistent viral or bacterial DNA -- including Epstein-Barr virus DNA. About 10% of people had detectable EBV DNA in their blood at the time of the whole-genome sequence sample. People with EBV DNA in their blood were more likely to have autoimmune diseases, COPD, heart disease, depression, or fatigue (e.g. ME/CFS) diagnoses in their electronic health records. The researchers went on to look at how the participants' genetic variants influenced the relative risk of having Epstein Barr virus DNA. They found that variants in the HLA region increased the risk of having circulating EBV risk. 🔗below to full study

“Safe” BPA exposure in pregnancy may not be so safe. A new study shows that low-dose BPA in utero masculinizes female bone marrow, feminizes male bone marrow, and pushes both toward metabolic profiles seen in people with metabolic syndrome.”​ Key findings: Pregnant rats received BPA in drinking water at 0.5 or 50 µg/kg/day – doses at or below levels long considered safe for humans.​ Offspring were studied ~1 year later (no BPA since weaning). In females, BPA shifted 99% of sex-biased genes toward male-like expression In males, 99% shifted toward female-like expression (strong “sex reversal” signature in bone marrow).​ Plasma metabolomics and lipidomics showed sex-specific changes (e.g., altered phospholipids, amino acids, lipoproteins) that significantly overlapped with patterns seen in humans with metabolic syndrome. The authors conclude that developmental low‑dose BPA may promote metabolic syndrome particularly in males, likely via sex‑specific T‑cell–related immune programming.​ Study: ‘Developmental low-dose bisphenol A exposure leads to extensive transcriptome female masculinization and male feminization later in life’ Communications Medicine

This is an interesting study on an increased prevalence of mannose-binding lectin deficiency in people with #MECFS. Mannose-binding lectin is part of the innate immune system. It's produced mainly in the liver and binds to certain viruses, bacteria, and fungi to mark them to be destroyed by the complement system. The study looked at a bunch of immune system parameters -- and reduced MBL was by far the most common abnormality: 32.1% of ME/CFS patients had reduced MBL levels, and 7% met criteria for clinical MBL deficiency (levels <50 ng/mL combined with recurrent/severe infections). The criteria used there is stricter than most studies defining mannose-binding lectin deficiency, so this stands out as important. Mannose-binding lectin levels have a strong genetic component, with multiple variants linked to low MBL levels. This connection for ME/CFS would fit the pattern of infection-triggered onset, with the inability to completely clear certain viruses or fungal infections.

Thiamine insufficiency is common in the elderly and can mimic dementia symptoms, while studies show benfotiamine (a bioavailable form) reduces amyloid-beta plaques, attenuates brain inflammation, and improves cognitive function by modulating pathways like 🧬GSK-3β. This suggests potential preventive or therapeutic roles for B1 in neurodegeneration. geneticlifehacks.com/thiamin…

Kidney stones were long thought to be just calcium oxalate formations - inorganic crystal clumps that need to be broken up and moved out. Researchers at Harvard just looked inside the stones…. and found they have bacterial biofilms as part of their intrinsic structure. In fact, they could even culture the live bacteria. This explains why breaking up the kidney stones sometimes causes illness or even sepsis. And why stones keep recurring for some people. The bacteria may be secreting calcium along with extracellular DNA to form the nucleation sites for the stone.

Your gut has a mucus “shield” that keeps bacteria, viruses, toxins, and digestive enzymes off your intestinal cells — and modern emulsifiers, alcohol, microplastics, stress, and even certain genes can quietly thin that barrier and crank up inflammation risk.​ 👉 Check out: - How mucins like MUC2/MUC5AC and goblet cells build this barrier - Why emulsifiers (CMC, polysorbate 80, carrageenan), mycotoxins, alcohol, and microplastics erode it - Genetics, microbiome, and nutrient “lifehacks” (urolithin A, glutamine, vitamin D/A, zinc, specific probiotics) to support gut mucosal integrity 👇link in comment

New study on TRPM3 ion channel in ME/CFS "Results: Electrophysiological experiments revealed a significant reduction in TRPM3 function in NK cells from individuals diagnosed with ME/CFS compared with controls in all parameters analyzed. Importantly, there was no significant effect of the laboratory sites on the results of this investigation, which confirms TRPM3 as a consistent biomarker for ME/CFS. Conclusion: The current large-sample-size study confirmed previous results regarding TRPM3 ion channel dysfunction in NK cells in ME/CFS, demonstrating involvement of TRPM3 in the pathomechanism of this condition. Therefore, this multiple-site investigation offers strong evidence demonstrating TRPM3 as a potential biomarker for the diagnosis of ME/CFS, given the accumulating evidence." frontiersin.org/journals/med…

Is Reelin the "Master Key" to both your brain health and your vascular system? 🧠💓 Reelin is a multifunctional glycoprotein essential for memory, learning, and keeping the adult brain resilient. However, its impact depends entirely on where it is located in the body: • In the Brain: Higher Reelin levels help maintain synaptic plasticity and protect against neurodegenerative diseases like Alzheimer’s. • In the Blood: Elevated plasma levels are linked to vascular inflammation, clotting risks, and the pathology of Long COVID. • Mental Health: A significant decrease in Reelin is often seen in individuals with schizophrenia and major depression. Genetic variants and environmental factors, such as exposure to certain pesticides, can also disrupt this delicate balance. geneticlifehacks.com/reelin-…

🔥A new, large study on Lp(a) was published in JAMA today. Researchers followed almost 30,000 women for 30 years, showing that Lp(a) levels over 30 mg/dl increase major cardiovascular events. The risk rises with time. High Lp(a) is strongly genetic. Everyone should check their genes for the risk variants. link👇

There's a new review / meta-analysis of studies on building muscle with resistance training. Essentially, it shows that both slow and fast repetitions build muscle almost equally well. So lift weights however you like -- the point is that you have to just do it. journals.lww.com/nsca-jscr/a… Here's more on how your genetic variants influence how quickly you gain muscle mass: geneticlifehacks.com/resista…

This is a study from a couple of months ago showing that resveratrol plus copper helps to shrink glioblastoma. The trial was conducted in patients who were scheduled to undergo surgery for their brain tumors. In the pre-surgical "window", the patients received a high dose of resveratrol and copper four times a day for about 12 days. A problem in glioblastoma is that the dying cancer cells release cell-free chromatin particles that then get taken up in neighboring cells, causing inflammation and double-stranded DNA breaks. The theory is that this increases the risk of recurrence, which is high with glioblastoma. The resveratrol plus copper 4x/day reduced cell-free chromatin particles almost completely. It also significantly reduced immune checkpoints (PD-1, CTLA-4, etc), which then allows the immune system to be activated against the cancer. nature.com/articles/s44276-0… My 2 cents: This may be a significant breakthrough in glioblastoma treatment - and it may point to an important role for resveratrol plus copper for T cell exhaustion in other cancers. Here's another article on the interaction of polyphenols, and specifically resveratrol, with PD-1: pmc.ncbi.nlm.nih.gov/article…

Here's my current supplement stack for longevity (just my personal musings on what I'm taking and why -- not advice!) longevitylifehacks.substack.…

Share this with any older men you know with red, weathered-looking noses. Rosacea comes in several forms. Rhinophyma is the name given to a red, bumpy, thickened nose that is often seen in men over the age of 50. Many people think it is caused by drinking too much alcohol, but it is actually a type of rosacea. I think this is a change that older men overlook because they don’t know what’s causing it — and they likely don’t know that there are readily available treatments for it. Research reveals that the cause of rosacea is a combination of overactivation of inflammatory pathways, changes in tiny blood vessels of the face, and changes in the tight junctions between skin cells. Some people are genetically more prone to rosacea, with genetic variants related to inflammatory pathways increasing the risk -- along with tiny mites, called Demodex, that trigger the inflammation. geneticlifehacks.com/rosacea…

Statin use decreases GLP-1 levels. Gut microbiome connections

Borderline Personality Disorder - BPD - isn't just genetics or just trauma—it's both. 40-60% genetic susceptibility + environmental triggers like childhood trauma. New research shows specific gene variants in serotonin, dopamine & cortisol pathways increase risk. Plus: natural interventions that actually work (DHA/EPA, circadian optimization, magnesium).

Reversing late stage Alzheimer's open.substack.com/pub/longev…

~ Many healthy foods contain oxalates, but dietary intake must be balanced with the metabolism and excretion of oxalates. ~ Genetic variants can disrupt the balance of oxalate excretion from the body, leading to the formation of kidney stones or oxalate crystals. Check out your Oxalate genetic variants 👇 geneticlifehacks.com/green-s…

~ Low levels of B6 are linked to an increased risk of diabetes, cardiovascular disease, neurodegenerative diseases, and cancer. ~ Vitamin B6 is also important for reducing oxidative stress and inflammation. ~ Genetic variants in several B6-related genes can increase your need for vitamin B6.

Magnesium is an essential mineral needed for hundreds of reactions in the body. Some people genetically are more likely to be deficient than others, based on polymorphisms that impact magnesium absorption.

This is an interesting study showing how gut microbes can cause intestinal pain. Essentially, a specific gut microbe produces an enzyme that ends up causing a pain signal from the gut. The researchers found that: Bfp1 is a serine protease released by Bacteroides fragilis Bfp1 activates PAR2 on our gut epithelial cells to "disrupt epithelial integrity, induce nociception, and inflammation" A Bacteroides fragilis protease activates host PAR2 to induce intestinal pain and inflammation

Genetic variants in carnitine-related genes (SLC22A5, CPT1, CPT2) can cause disorders that affect energy production, causing issues from mild fatigue to severe dysfunction. Check your carnitine genes 👇 geneticlifehacks.com/carniti…

Your genes might explain why you're always tired (even when you eat "healthy") Here's what most people don't know about vitamin B1: Thiamine (vitamin B1) isn't just another vitamin. It's the master key that unlocks your cells' ability to produce energy. Without enough of it, your mitochondria literally can't convert food into ATP—the energy currency every single cell in your body runs on. Here's where it gets interesting: genetic variants can dramatically change how much thiamine YOU specifically need. Several genes control thiamine transport and metabolism: - SLC19A2 and SLC19A3 (intestinal absorption) -SLC44A4 (absorbing thiamine from gut bacteria) -TPK1 (conversion in intestinal cells) - SLC25A19 (getting thiamine INTO your mitochondria) If you carry variants in these genes, you could be absorbing or utilizing significantly less thiamine than the person sitting next to you—even eating the same diet. Thiamine deficiency doesn't just cause "beriberi" (the severe deficiency disease). Mild insufficiency shows up as: - Chronic fatigue and brain fog -Irritability and mood issues - Gut problems - Headaches - Difficulty concentrating The #longcovid connection: Recent clinical trials show thiamine significantly shortens long Covid symptom duration. In severe Covid patients, thiamine supplementation reduced mortality rates. Why? Because COVID depletes thiamine. Thiamine modulates immune response (prevents cytokine storms), and it's essential for mitochondrial energy production (which Long COVID disrupts). Your gut microbiome is also important. Certain gut bacteria can either: - MAKE thiamine for you (Bifidobacterium, Lactobacillus) - STEAL it from you (E. coli overgrowth) So if you have SIBO or dysbiosis, you might be thiamine-deficient even with adequate dietary intake. The absorption hacks: Want to maximize thiamine? ✓ Eat yogurt with probiotics (increases plasma thiamine) ✓ Cook rice/potatoes, cool them, then reheat (resistant starch → more microbial thiamine production) ✗ Limit tea/coffee with meals (decreases absorption) ✗ Avoid moldy foods (mycotoxins have anti-thiamine effects) Best food sources: Pork (0.4mg per 3oz) Trout, mussels, tuna Black beans (0.4mg per 1/2 cup) The bottom line: If you struggle with persistent fatigue, brain fog, or Long COVID symptoms—and conventional treatments aren't working—thiamine might be worth investigating. Sometimes the answer isn't complex. Sometimes it's a $10 vitamin your body can't properly absorb or utilize due to your unique genetics. Your genes don't determine your destiny—but they do affect your dietary needs. Understanding this is the difference between guessing and knowing what your body needs.

This is an interesting paper on ME/CFS - Glymphatic System Dysregulation as a Key Contributor to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome The glymphatic system clears metabolites (lactate, glutamate, ROS, amyloid‑β, tau, ammonia) from the brain via CSF–interstitial fluid exchange as we sleep. The authors of the paper propose that glymphatic dysfunction can result from and also exacerbate blood-brain barrier breakdown. This then causes and exacerbates neuroinflammation, oxidative stress, hypoxia, and mitochondrial dysfunction. "AQP4 water channels are the primary pathway for water movement into the brain’s interstitial space, and when dysfunctional, this process is significantly reduced." This caught my eye since AQP4 genetic variants are risk factors for Alzheimer's and schizophrenia.

The gut microbiome can play a role in colon cancer risk. New study shows: "Repeated S. flexneri C.11 exposure-induced DNA damage and inflammatory-to-neoplastic transformation. Three genotoxic cyclodipeptides (CDP1–3) were identified, driving malignant transformation and accelerating colitis-associated tumorigenesis. Mechanistically, S. flexneri C.11 upregulated ERBB3, activating the PI3K-AKT pathway." pmc.ncbi.nlm.nih.gov/article…

This is an important new study on ALS! In ALS, the neuromuscular junction - the connection between nerves and muscles - breaks down. A protein called TDP-43 builds up in the wrong spot in the axons and disrupts how the nerve cells make proteins locally. The researchers discovered that a microRNA (miR-126) prevents TDP-43 buildup normally, but in ALS, there's not enough miR-126. "We found an approximately threefold reduction in the relative abundance of miR-126-5p in patients with sALS compared to healthy donors" The microRNA is normally made in the muscle cells and sent to the neuron via extracellular vesicles. Importantly, when researchers injected miR-126-5p into mice with the genetic form of ALS (SOD1 mutation), they were able to completely prevent ALS. nature.com/articles/s41593-0…

Genetics + Environment = Schizophrenia risk: Twin studies show heritability around 80%—but genes alone don’t determine the fate. Critical environmental factors, like childhood trauma or early infections, play a major role in triggering symptoms.

New study gets to the heart of rheumatoid arthritis. SNORD3, a small nuclear RNA, controls epigenetic signaling of inflammation in RA. science.org/doi/10.1126/scit…

Problems sleeping? Genetics can point the way to individualized solutions for insomnia and sleep issues. Many sleep disorders — insomnia, restless leg syndrome, and more — have a strong genetic component. Gene variants impact your sleep quality, timing, and duration. Here's how your genes make a difference:👇

Got your 23andMe results and thought "cool, now what?" Your DNA can actually tell you: ~ How you process caffeine ~ Your detox pathways ~ Sleep, circadian rhythm & stress genetics ~ Methylation factors Genetic Lifehacks translates your raw data into actionable insights. Your data never leaves your device. geneticlifehacks.com/members…

TNF and glutamate: Excess TNF-alpha in the brain may cause extracellular glutamate to accumulate - excitotoxicity. Genetic connections: Some people have genetic variants that increase TNF above normal in response to a stimulus. Excess glutamate, excitotoxicity connections: #longcovid #MECFS Alzheimer's, Parkinson's Brain fog (cognitive dysfunction) Neurogenic pain References below👇 Image from PMC5011997

Only about 40% of people naturally produce urolithin A—a beneficial compound for mitochondria—even if they eat foods like pomegranate or walnuts. That means 60% of people miss out unless they support their gut microbiome or use a supplement. Gut health really changes how you benefit from polyphenols.