A couple of quick notes for Genetic Lifehacks members before I dive into this week’s newsletter topic.

- A reader contacted me with confusion over the link to the Substack newsletter (clicking on the title in the email) vs. the link to the article on Genetic Lifehacks. I’ll put a clearer article link in from now on. Please feel free to reach out whenever something is confusing!

- For anyone with whole-genome data from Nucleus, I’ve created a quick Nucleus VCF converter. If you test it out, let me know what you think and if you run into any issues with it. (This is specific to Nucleus VCF - other whole-genome conversion options are listed here.)

Gratefully yours,
~ Debbie

Article w/ Genotype Report: Histamine Intolerance

Finding your histamine bottleneck (Learn)

Histamine is something most people associate with allergies and needing an antihistamine during pollen season. But histamine has a lot of different roles in the body - it’s a signaling molecule that triggers stomach acid release when you eat, affects vascular function, is part of the immune response to pathogens, and acts as a neurotransmitter in the brain.

An excess of histamine, though, can lead to symptoms that affect different systems of the body. For some, histamine symptoms can include headaches, brain fog, acid reflux, hives or itching, sinus drainage, stomach or intestinal issues, or even mood changes such as anxiety or irritability.

Histamine intolerance is defined (by me) as having histamine symptoms from an excess of histamine from high-histamine foods, gut bacteria producing too much histamine, or even from your body producing excess histamine in response to certain environmental exposures (e.g. your nose runs when walking down the laundry detergent aisle from the fragrances).

Genetic variants in the genes responsible for the breakdown of histamine can increase susceptibility to having problems with excess. But that isn’t usually the whole picture.

Imagine your histamine levels as a sink that has a small drain - or like a shower drain partly clogged with hair (eww…).

Your inflow is histamine from foods, like fermented foods, leftovers sitting in the fridge for a week, or pizza with pepperoni and tomato sauce.

The drain is the DAO (diamine oxidase) enzyme encoded by the AOC1 gene, which breaks down histamine in the gut from food and from the gut microbiome. In addition, the HNMT enzyme inactivates histamine produced in the brain and in tissues throughout the body. (HNMT needs a methyl group, tying it to the methylation cycle and MTHFR.)

Everything goes OK for a while with inflow and drain capacity being equal, but then, you turn up the faucet with an amplifier of histamine… These amplifiers can be sleep disruption, allergy season, a new medication that blocks DAO (diamine oxidase enzyme), alcohol that blocks DAO, mast cells degranulating due to viral persistence, or even adding in other biogenic amines that utilize DAO. The sink overflows with a histamine mess.

So how can you know what is going on with histamine-related symptoms? That brings us to…

Tracking your inputs and symptoms (Experiment)

I’ve added a Histamine Symptom, Food, & Supplement tracker to the Histamine Intolerance article. (The link is at the beginning of the lifehacks section of the article, if you need to get back to it.)

It’s a tool to get you thinking about how what you eat and which supplements you take (and when) all come together to affect symptoms, which can be frustratingly delayed. It’s fairly easy to identify an immediate food allergy when you break out in hives 10 minutes after eating strawberries. But figuring out acid reflux in the middle of the night from eating three-day-old leftover beef casserole for lunch… that can be less obvious.

Writing down and keeping track of what you experiment with is important for seeing the patterns (and remembering what you actually did…)

So if you’re going to try a low-histamine diet for a week, give the new histamine tracker a try. It can help with planning out which variable you’re going to work on — e.g. low-histamine foods for a week, adding a new supplement like DAO enzymes or quercetin, or trying a new probiotic. Doing just one thing at a time makes it easier to see the patterns and know what really moves the needle.

I want to be clear: The histamine tracker is not a clinical diagnosis scoring system or anything like that. It’s just a way to keep track of what you eat, take, and feel for a week or two.

My goal with Genetic Lifehacks is to give you the information and the tools you need to figure out your individual health issues. If you use the histamine tracker, let me know what you think of it. If you have another idea for a similar type of tool for another topic - let me know that also!

Eating what you want without feeling bad (Optimize)

With histamine intolerance (or with other food-related issues), my goal is always to get my body back to homeostasis. A long-term restrictive diet isn’t optimal, and a low-histamine diet cuts out a lot of healthy foods. When your garden is full of ripe tomatoes and strawberries, you want to be able to eat these higher histamine foods without having histamine-related symptoms.

This is where the experimenting continues. You may find that you really benefit from eating a lower histamine diet only during the season that your pollen allergies are high. Or you may find that you can get by with just taking a DAO supplement when eating out at certain restaurants. If you stop taking a histamine-producing probiotic, your gut microbiome may settle down and stop adding excess histamine to your system. If sleep is the problem, then perhaps a DAO supplement before bedtime would help more than at other times… Optimize for the least food restrictions and lowest number of supplements.

It’s easy to get into the mindset when working on a health issue that taking a food group out of your diet is the ‘cure’ - and that it is the way you have to eat for the rest of your life. (And yes, that could be true in certain cases, like a peanut allergy that causes anaphylaxis or with gluten in celiac disease.) Instead, I would propose that the goal should always be to get your system back to reacting more normally.

New and interesting studies:

Combined DHA and Vitamin D3 for preventing dementia:
New clinical trial showing that the combination of vitamin D3 plus 1g/ day of DHA improved cognitive function in older adults with mild cognitive impairment.

Light exposure and dementia risk:
This is an interesting study from June on how light exposure affects dementia risk. It’s a large study looking at light exposure using a wrist-worn light sensor - ~87,000 people who were dementia free at the beginning of the study, with an average age of 62. They were then tracked for a median of 8.1 years after that initial light study, with 741 developing dementia during that time. The big result was that daytime light exposure over 1,000 lux was linked to a 16% lower risk of dementia. Even longer duration and brighter light were similarly protective. What I found most interesting was that the protective effect from daytime bright light (e.g. sunlight) was strongest in people who had higher nighttime light exposure and in people who were APOE4 carriers.

New on Longevity Lifehacks:

Longevity Lifehacks

Imidazole propionate (ImP) and dementia

Imidazole propionate (ImP) is a metabolite formed when certain types of gut microbes break down the amino acid histidine…

Read more

8 days ago · 24 likes · Longevity Lifehacks

Continuing this week with the newsletter format of Learn, Experiment, Optimize, I’m bringing you some new research connections that I found interesting - and hopefully you will too!

Gratefully yours,
~Debbie

Low vitamin B6, quinolinic acid, and Parkinson’s (Learn):

Vitamin B6 is an essential cofactor in over 100 different reactions in the body. It’s a water-soluble vitamin that we don’t store long-term, so we need to get it regularly in our diet.

Genetic variants can influence how likely you are to need a little more B6 and which form of B6 is likely to work best for you. Here’s the full Genetic Lifehacks article on B6 if you want to check your genes.

While updating the B6 article this week, I came across a 2025 study on Parkinson’s that ties to B6 in a really interesting way.

The study showed that B6 levels are usually lower in people with Parkinson’s (as many studies have shown for decades), and that lower B6 levels cause the amino acid tryptophan to be metabolized into quinolinic acid, which is neurotoxic, in the brain.

Tryptophan can either be used to synthesize serotonin and melatonin, or it can be converted to kynurenine. When inflammation is present, such as in aging or in people exposed to toxins, more tryptophan gets shuttled to the kynurenine pathway. Kynurenine then can either become a neuroprotective kynurenic acid or go down a second path that leads to the formation of niacin - with quinolinic acid as an intermediary there.

When B6 is limited, less kynurenine goes toward kynurenic acid, with more creating 3-HK and ending up as quinolinic acid, which is excitotoxic. It can bind to NMDA receptors and cause overactivation.

In the study, higher quinolinic acid levels in Parkinson’s patients were directly shown to be associated with worse motor-related symptoms.

The authors of the study don’t say that taking vitamin B6 will prevent all Parkinson’s cases, and I don’t want you to think that is the takeaway here. Rather, they show that lower B6 levels are likely involved in part of what is going on with Parkinson’s. There are multiple pathways involved.

Here’s what I found interesting - the connection with the gut microbiome and an environmental risk factor for Parkinson’s.

A 2024 study shows that long-term exposure to organophosphate pesticides changes the gut microbiome in a way that reduces vitamin B6 production.

Backing up a bit - we get vitamin B6 from foods like liver, tuna, chickpeas, salmon, chicken, bananas, and potatoes. But the bacteria in our gut also crank out quite a bit of B6. We can’t survive on the amount from the gut microbiome alone, but some bacteria are giving off B6, which is then absorbed in our gut or used by other gut microbes.

The 2024 study involved people exposed to higher ambient levels of organophosphate pesticides, which are used on crops and on golf courses. (Another recent study had shown that living within a mile of a golf course was associated with “126% increased odds” of Parkinson’s compared to living more than 6 miles from a golf course. The connection to golf is pesticide runoff into the water sources.)

So… we have organophosphate pesticides changing the gut microbiome to reduce B6 production, pesticides linked to increased Parkinson’s (possibly through multiple routes including BChE), and reduced vitamin B6 mechanistically and directly linked to increased quinolinic acid, which causes neuronal damage.

What can you do? (Experiment)

For active Genetic Lifehacks members - check your genes related to vitamin B6 and see how your diet stacks up with the amount of B6 needed. One SNP in the PNPO gene (rs17679445) is found in about 6% of the population, and it reduces the conversion to the active form of B6 (P5P) by 40%. For someone with variants that reduce B6 levels or reduce conversion of B6 to P5P, consider increasing your dietary intake or supplementing with low-dose P5P.

The thing with B6 is that you don’t want to go overboard with high-dose supplements for a long time. There are case studies and anecdotal reports of people ending up with peripheral neuropathy with long-term high-dose B6 supplementation. The upper limit (UL) is set at 100mg/day for adults, which is significantly higher than the RDA of 1.5-1.7mg/day.[ref] So dialing in B6 may mean taking into account whether you have something causing chronic inflammation (and thus using up more B6), looking at your current dietary intake, considering any genetic variants, and then adding either food sources or a low-dose supplement.

The thing to remember with supplements, whether vitamins or flavonoids, is that it doesn’t have to be something you take forever - come back in a few months and reconsider your current status with diet, inflammation, and any positive changes that have occurred. Back off the supplement if it is no longer needed.

As always, let me caution that you should talk with your doctor if you have any questions, are on prescription medications, or have major medical issues before starting any supplement, including something as seemingly benign as a water-soluble vitamin. Definitely talk with your doctor if you’re on Parkinson’s medications because B6 also plays a role in the conversion of dopamine.

Preventing neurodegenerative disease and cognitive dysfunction (Optimize):

The Parkinson’s study was just one example of the many ways that B6 is important in the brain. There are links between optimal vitamin B6 and depression, homocysteine levels, Alzheimer’s, and overall cognitive function.

Read through the full B6 article if you’re interested in the other ways that B6 optimization can help with brain function. And if you’ve got B6 covered, cross it off your list and move on to the Parkinson’s article, brain fog article, depression and inflammation, blood-brain barrier function, etc.

Latest on Longevity Lifehacks:

Longevity Lifehacks

Research roundup: New studies out this week related to health in aging

Here’s a quick overview of a few new longevity-related studies that I found interesting this week…

Read more

14 days ago · 14 likes · 1 comment · Longevity Lifehacks

As I mentioned last week, I’m working on a more consistent format for the newsletter - one that focuses on something new to learn, how you could experiment with the information, and then how to optimize going forward. The feedback was good, so I’m going to stick with the format for now. Let me know if you love it or hate it.

For current Genetic Lifehacks members: If you haven’t run a summary report recently, you may want to check out the new report format. I’ve also added a feature that flags rare or impactful variants at the top of the report so that you won’t miss them.

~ Debbie

Small fiber neuropathy (Learn)

Small fiber neuropathy (SFN) is classically thought of as burning, tingling, or numbness that starts in the hands or feet. It’s caused by damage to the nerve endings in the type C nerve fibers that are unmyelinated and send signals from the tiniest of nerve fibers that are found in your skin.

There’s more to small fiber neuropathy, though.

SFN can also affect nerves in the autonomic nervous system, causing problems with heart rate variability, blood pressure response to standing up, bladder issues, sweating, and even whether your skin wrinkles up in the bathtub.

Genetic research shows that ion channel mutations can be the root cause for some people, and TRP channels can affect the amount of pain. Other causes can include autoimmune attacks on the nerves, high blood glucose (e.g. diabetes), viral infections, toxins, or long-term B12 deficiency.

The thing with small fiber neuropathy is that it can overlap with other conditions - like long Covid, fibromyalgia, neuropathic POTS, chronic Lyme, Sjogrens, and MCAS - adding to the difficulty in diagnosis.

Here’s an example: A new study looked at nerve density in gastric mucosal biopsies in people with long Covid compared to people who didn’t have long Covid (they were getting the biopsy for dyspepsia). The results showed that long Covid patients had significantly reduced nerve density in the gastric mucosa, particularly in the cholinergic nerves. This doesn’t specifically mean that they all have small fiber neuropathy, but it showed that the type C nerve fibers were damaged in the stomach lining in long Covid patients. Other studies using skin biopsies clearly show SFN in long Covid patients who started having neuropathy after Covids.

My point is that damaged small nerve fibers can have multiple causes and multiple outcomes. Systemic infection, systemic autoimmune disease, systemic reactions — all can affect autonomic nerve function, which then affects the whole body. A tingling, burning pain in your hands or feet could be a sign of more than just a single diagnosis.

What can you do if you have SFN? (Experiment)

Here’s where I’m going to say “talk with your doctor for medical advice”. And I really mean it - small fiber neuropathy isn’t a DIY diagnosis. But I would also encourage you to do your due diligence in looking at the current research on SFN, side effects of medications for SFN pain, and options for reversing underlying causes. This gives you the background knowledge to have productive conversations with your healthcare provider.

The thing is - knowing why you have the nerve damage is really important in figuring out how to stop it from progressing and hopefully reverse it. Small fiber nerves regenerate, so stopping the damage is the essential first step. For example, whole genome testing may help you narrow down a rare ion channel mutation, or testing for Lyme may give you insight if you’ve had a tick bite. Treating an autoimmune disease may be your sweet spot, or fixing a long-term vitamin B12 deficiency problem. An excess of B6 - or a lack of B6 - can also be a cause of neuropathy.

The lifehacks section of the SFN article has a bunch of additional options and genetic connections as well for logged-in Genetic Lifehacks members. For example, looking at your genetic variants related to thiamine deficiency, B6 conversion, or B12 deficiency may give you insight as to optimizing B vitamin levels.

What if you just want to maintain healthy nerve function? (Optimize)

To me, the bigger picture here is that maintaining nerve function is important for everyone, especially as we age. Keeping inflammation under control, maintaining good mitochondrial function, and an overall healthy diet and exercise are important for nerve function. For example, DHA and EPA are necessary for the resolution of inflammation. Antioxidants can help to prevent oxidative stress in the axons. Vitamin B12 is important in nerve function, along with vitamin B6 and thiamine.

If you don’t have small fiber neuropathy, you may be thinking - why should I care about this?

One tangential connection here is skin aging and wrinkles. A new study in Cell shows that reduced skin nerve function (the same nerve fiber types as found in SFN) results in less collagen formation, leading to skin aging and wrinkles. So even if you never have SFN, the health of the tiny unmyelinated nerve endings is important in many other ways.

What I’ve been reading this week:

Placebo-controlled trial with plasmalogens:
A new clinical trial looks at the effects of oral plasmalogen supplements on cognitive function in healthy middle-aged and older adults. The results showed that 12 weeks of 1mg/day of a scallop-derived plasmalogen supplement improved standardized verbal memory scores.

MicroRNA variant and chronic low back pain:
This new genetic study found that an miRNA gene (miR-499) variant changes the way that the miRNA affects the expression of SOX5, which is associated with an increased risk of chronic low back pain.

The tagline for Genetic Lifehacks is Learn. Experiment. Optimize. That’s been my personal operating system - learn about a topic, experiment with how it applies to me, and then dial it in by tweaking the experiments to what works best. I’m changing the weekly newsletter to reflect this idea: a short bit of interesting science (Learn), covering some of the ways you could apply this as example scenarios (Experiment), and then looking at ways you can track and make changes (Optimize). The newsletter will still end with links to new research studies that are impactful or just interesting to me.

This newsletter reaches a wide audience, full of people with expertise on a range of topics. If the weekly topic is something in your wheelhouse, I would love it if you would help other readers out by leaving a substantive comment - add a link to a research paper, give a source for testing, share an experience. You do have to have a free Substack account to comment, but if you want to share without an account, just reply to the newsletter email, and I’ll compile and share the responses.

~ Debbie

Plasmalogens and APOE4 (Learn):

Plasmalogens are a special type of lipid that is concentrated in cell membranes, mainly in the brain, heart, and immune cells. They not only keep the cell membrane fluid, but they can also be brought into the cell as a lipid antioxidant.

In the brain, plasmalogens play an important role in neutralizing oxidative stress. This makes them an integral part of brain health, both in aging and in situations of neuroinflammation.

Plasmalogen levels decline with age (about a 40% drop from age 40 to 70), and the levels are even lower in people with Alzheimer’s or other neurodegenerative diseases. Genetic variants (full Genetic Lifehacks article here) can also influence your plasmalogen levels.

What is new here is a 2026 study that ties together low plasmalogen levels in Alzheimer’s patients and the APOE4 allele. (APOE4 is the genetic variant that increases Alzheimer’s risk significantly.) APOE is an apolipoprotein that transports lipids and cholesterol in the brain and throughout the body. While the role of cholesterol transport in the brain has been a focus of APOE research, this lipoprotein also carries phospholipids, including plasmalogens.

A number of studies have shown that circulating plasmalogen levels are significantly decreased in patients with dementia, and clinical trials show that in the early stages of memory loss, supplemental plasmalogens may help. Plasmalogens reduce oxidative stress in the neurons and reduce the activity of an enzyme needed for the formation of amyloid-beta plaque.

The new study showed that APOE4 particles carry substantially less ethanolamine plasmalogen than APOE3 particles. This makes the lower plasmalogen levels in APOE4 carriers a plausible mechanistic link between APOE4 and higher Alzheimer’s disease risk.

Increasing plasmalogen levels (Experiment):

Ok, so what can you do about it if you have APOE4 - or if you have neuroinflammation such as in long Covid, ME/CFS, or long-term depression?

There are supplements that directly provide plasmalogens. The drawback is that they are expensive - like $100-$200/month or more for the supplements that are high quality. (There are cheap options on Amazon that likely don’t do anything… read reviews and do your due diligence.) I personally haven’t tried the high-quality plasmalogen supplements and can’t give you personal experience here. But for someone in early memory decline or with neuroinflammation, it may be worth considering even if costly. Leave a comment below if you’ve used any of the plasmalogen supplements.

Foods that have higher levels of plasmalogens include shellfish, fish, chicken, and beef. Interestingly, a recent study also showed that eating more unprocessed red meat and poultry was beneficial for Alzheimer’s prevention in people with the APOE4 allele. (study, Longevity Lifehacks article with more references) There are also cooking methods that can help to preserve more plasmalogens in meat (see the Lifehacks section of the GL plasmalogens article).

Increasing olive oil consumption and increasing DHA (omega-3 oil) also helps to increase plasmalogens. Other studies show that increasing alkylglycerols can help to boost plasmalogen levels. Shark liver oil is one natural source of alkylglycerols.

Are dietary changes enough? (Optimize)

When it comes to Alzheimer’s disease prevention, studies show that things like a healthy diet with whole foods, fish consumption (DHA), and even olive oil consumption are likely to help reduce risk. But it doesn’t reduce the risk to zero…

Keeping oxidative stress low with antioxidants may pair well with increasing dietary DHA and plasmalogens. Perhaps supplementing DHA from fish or krill oil along with antioxidants plus using olive oil… you get the idea.

This is where each of you is unique and needs to set your own path. For example, if you’re middle-aged and want to prevent Alzheimer’s (with an APOE4 allele), you may want to just dial in your diet. If you’re older, say mid-60s to 70s, you may want to seriously look at plasmalogen supplements or alkylglycerol supplements along with cognitive testing to see where your baseline is before supplementing. You could also talk with your doctor about plasmalogen level blood tests. There used to be a blood test for this through Prodrome Science, but I’m not seeing how to order it now on their site.

Here’s where you come in —

If you have experience with plasmalogen supplements that you want to share, post it below as a comment (substack) or reply to this email, and I’ll share it as a comment here for you. If you know of a testing source, post that as well. Or if you have seen any high-quality research studies on the topic that I’ve missed in the plasmalogen article, please send those my way also.

What I’ve been reading:

Oral bacteria and HPV in head and neck cancer
This new study used a bean lectin (from the Lablab bean) in a chewing gum form to trap the bacteria and HPV virus associated with oropharyngeal cancer. This is an interesting study.

P&G buys supplements maker Thorne
Proctor & Gamble bought out Thorne supplements for $3.8 billion. Also in the article is a mention that Unilever bought out the supplement brand Gruns in April (I had missed that).

Overlapping Persistent Virus-Specific T cell Responses in Long COVID
A new study shows that many long Covid patients have ongoing immune responses to reactivation of latent viral infections. The researchers found that long Covid patients have CD8+ T cells directed against SARS-CoV-2 and also Epstein-Barr virus (EBV) or cytomegalovirus (CMV).

This week I published a new article + genotype report on hypophosphatasia, prompted by questions about the condition from two members. Hypophosphatasia causes inorganic pyrophosphate to build up, interfering with normal bone remineralization. In children with a more severe form, this is noticed in childhood with skeletal and dental problems. The adult form is milder and can cause joint or bone pain, fractures, loss of teeth, and fatigue or generalized pain.

Hypophosphatasia is a rare disease, with the severe form affecting only 2 or 3 in 100,000 children. But statistics like that are misleading, since it is significantly underdiagnosed in the milder adult form. Having one copy of an ALPL mutation may cause symptoms that are misdiagnosed as fibromyalgia, arthritis, or another pain condition. If you’ve had consistently low ALP, check out the article to see if it is something to follow up with your doctor about.

This is a pattern seen over and over: rare mutations cause significant genetic diseases if someone has two copies of the mutations, but for carriers of a single mutation, the effects are more subtle and often end up undiagnosed or misdiagnosed.

The other article + genotype report that got a major overhaul this week is NQO1, which is an enzyme that metabolizes quinones (like CoQ10 and estrogen metabolites) as well as benzene, a carcinogen found in smog, cigarette smoke, and propellants used for spray sunscreen and dry shampoo. About 25% of the population has impaired NQO1 function, which combines with environmental factors to increase the risk of certain cancers.

One interesting line of research that I came across found that the genetic variants that impair NQO1 function significantly increase what the researchers called ‘premature skin aging’ — essentially having a few more wrinkles and older-looking skin. NQO1 plays an important role in combating UV damage and oxidative stress in skin. Check out the lifehacks section of the article for several ways to boost NQO1 in the skin.

Gratefully yours,

~ Debbie

If you’re a Genetic Lifehacks member and love it, would you consider sharing the site with a friend or leaving a TrustPilot review this week?

NQO1 Gene: Metabolism of Quinones, Benzene, and More

Key takeaways:

• The NQO1 gene codes for a phase II detoxification enzyme that breaks down quinones, benzene, and some specific chemotherapy drugs, acting as a reducing agent to make certain substances easier for the body to eliminate.

• It is also important in metabolizing and removing estrogen quinone metabolites, which are linked to breast cancer risk.

• Genetic variants in the NQO1 gene can change its function, increasing or decreasing your risk of cancer or other negative effects from toxins.

In this article, we’ll start with what NQO1 does at the biochemical level, then look at how it protects you from environmental toxins and oxidative stress in the gut, brain, heart, and skin. Next, we’ll dig into common NQO1 genetic variants, and then end with lifehacks that may help if your function is reduced.

Read the full article here

Hypophosphatasia (HPP) and the ALPL Gene

Key takeaways:

• Hypophosphatasia is caused by mutations in the ALPL gene, which reduce the activity of tissue‑nonspecific alkaline phosphatase (TNAP), an enzyme that’s important for bone, tooth, liver, and kidney health.

• Low ALP allows pyrophosphate and active vitamin B6 (P5P) to build up, interfering with normal bone mineralization.

• Single ALPL mutations can be associated with low‑normal ALP and higher rates of bone and dental issues, and may underlie osteoporosis in a subset of patients.

• Adult-onset HPP symptoms can mimic fibromyalgia.

Read the full article here

Check out the latest on Longevity Lifehacks:

Longevity Lifehacks is where I write about longevity research that I find interesting, but that doesn’t quite fit on Genetic Lifehacks. Join me there if you’re interested in healthspan or longevity topics.

From Irreversible to Repairable: Reversing AGEs

A new study published in the journal Nature Communications last week has me optimistic about reversing some of the detrimental effects of aging.

The study, titled “Reversal of protein chemical aging by enzymatic deglycation”, explains that the researchers created an enzyme to undo a previously irreversible hallmark of aging.

Read the full article here

When looking at the inputs into why plants thrive or die, there are the big ones, like water and sunlight, the major nutrients (N, P, K), and the micronutrients. The micronutrients are where things get tricky, and usually I just hope for the best, assuming the soil will have what is needed. But not enough of an essential micronutrient, like zinc or boron, will stunt the plant’s growth and cause subtle changes. They just won’t thrive.

Similarly, without the right balance of micronutrients, we can’t thrive.

Take zinc, for example: While we won’t get yellowing on our leaf edges from a lack of zinc, there are other signs when this essential nutrient is lacking.

Zinc is an essential mineral - completely necessary in small amounts and harmful in large doses. It is absorbed in the intestines using specific transporters, moved throughout the body, and involved in hundreds of cellular reactions.

What does zinc insufficiency look like?
Zinc insufficiency can show up as decreased growth in children, decreased immune function (colds, fungal infections), blood glucose regulation problems (zinc is needed for beta-cell function in the pancreas), and impaired wound healing.

For most of us, though, zinc insufficiency is going to show up as skin problems, hair not growing, white spots on the fingernails, or gut issues. Zinc is essential in cells that turn over quickly, like skin cells, and in the mucosal barrier lining the gut.

An underappreciated role of zinc, though, is in mental health and cognitive function. Studies show that zinc deficiency can play a role in depression, and multiple studies show that children with ADHD or autism are more likely to be low in zinc.

What could cause zinc deficiency?
Zinc is most abundant in shellfish, meats, and seeds. Phytic acid, found in many plant foods, binds zinc and blocks its absorption. This means that vegans and vegetarians are more at risk of zinc deficiency, as are people eating a more limited diet. Worldwide, it is estimated that up to a third of the population isn’t getting sufficient zinc.

Genetic variants that decrease absorption or transport can mean that some of us need a little more zinc than others.

Don’t go overboard:
Before you go out and buy a Costco-sized zinc supplement, the flip side is that a high intake of zinc, such as from higher-dose supplements, can prevent the absorption of copper. This can eventually lead to copper deficiency, causing symptoms such as fatigue, loss of coordination, muscle weakness, brain fog, or even osteoporosis.

Genes can also come into play with copper. Mutations in the ATP7B gene cause an excess of copper to accumulate (Wilson’s disease). Excess copper is a problem - with symptoms ranging from neurological issues to liver problems to infertility. Part of the treatment for Wilson’s disease can be high doses of zinc to deliberately block copper absorption.

Understanding your genetic variants can help you thread the needle between too little zinc, too much zinc, not enough copper, or too much copper.

Resilience:
One of my goals with Genetic Lifehacks is to help you understand the nuances - how your genes interact with the environment - so that you can optimize your body. Having the underlying substrates, such as enough but not too much zinc, gives you the resilience for physical and mental health. You don’t want yellow leaf edges or stunted zucchini growth :-)

New feature this week:
I’ve added a new feature to many of the summary reports — you’ll now see a section at the top that flags any rare or high-impact variants so that you don’t miss them. There’s a lot of information on Genetic Lifehacks, and I don’t want anyone to miss something important and actionable, like variants related to blood clots or iron overload. So if you see something flagged at the top of a summary, be sure to click through to that article.

Happy summer!

Debbie

Zinc, Genetics, and Your Risk for Depression, Infection, or Diabetes

Key takeaways:

• Zinc is an essential micronutrient, acting as a cofactor in thousands of cellular reactions that impact immunity, skin health, wound healing, blood sugar regulation, and brain function.

• Long‑term low zinc intake is common worldwide and can show up subtly as more frequent infections, slower wound healing, skin and hair problems, type 2 diabetes risk, and mood changes such as depression.

• Your genes influence how well zinc is absorbed and transported into cells. Variants in zinc transporter and related genes (SLC30A8, SLC39A2, CA1, and PPCDC) can increase your need for dietary zinc or make you more responsive to supplementation.

• Clinical trials show that the right form and dose of zinc can improve immune resilience, support wound healing, and be beneficial for migraines, PMS, gestational diabetes, and mild cognitive impairment. However, excessive dosing can deplete copper and cause side effects.

Read the full article here

What I’ve been reading this week:

Urolithin A activates mitophagy via the AMPK–mTOR axis and modulates the gut–ceramide axis to ameliorate cardiac remodeling in HFpEF
A new animal study on heart failure with preserved ejection fraction showed that urolithin A could ameliorate at least part of the dysfunction. Urolithin A improved mitochondrial structure and function in the heart muscle.

Skin-innervating glutamatergic neurons modulate aging
A lot of things go on with aging skin, including a loss of collagen. It turns out that at least part of that is due to a lack of glutamatergic neurons stimulating collagen production in the skin.

VMAT2 in Long Covid:
A study using brain scans of long Covid patients (compared with matched, healthy controls) found that VMAT2 levels were significantly lower in certain regions of the brain.

What is VMAT2? It’s the transporter that moves dopamine and other monoamine neurotransmitters into vesicles inside neurons. These vesicles release the neurotransmitter when needed, which is an essential way that neurotransmitter levels are controlled.

VMAT2 is particularly important for packaging dopamine. Excess dopamine in the neuron’s cytosol can oxidize and become neurotoxic, so VMAT2 both regulates how much is released and protects the neuron from the toxicity of free-floating dopamine.

In long Covid, the lower VMAT2 levels in the dopaminergic neurons correlate with the neurological symptoms of apathy, memory decline, and even slowed motor function (speed of physical movements).

My VMAT2 article is now updated and vastly expanded. In it, I explain the genetic variants, the connections to Parkinson’s and neurodegenerative diseases, and the research on PTSD and anxiety. Environmental factors that can decrease VMAT2 include certain pesticides, flame retardants, and heavy metals — as well as chronic cocaine or methamphetamine use.

AGEs and falling apart in aging:
Advanced glycation end products (AGEs) are compounds formed in the body during metabolism (especially glycolysis) and formed in foods by the Maillard reaction - the browning of meat or baked goods. AGEs then irreversibly modify proteins in the body. For example, AGEs are involved in the cross-linking of collagen that causes stiffening of tendons or wrinkling of the skin.

AGEs accumulate with aging, and they cause inflammation through activation of the receptor for advanced glycation end products. All in all, AGEs end up being one of the causes of much of what goes wrong in aging.

What prompted this big article update? There’s a new study out showing an engineered enzyme can now reverse what was thought to be irreversible. The enzyme removes a specific type of advanced glycation end product that builds up and triggers chronic inflammation — essentially reversing decades of aging. Here’s an easy-to-read article on the study.

There are also a bunch of natural supplements that can help reduce the production of AGEs, and genetic variants that can increase or decrease AGEs. I cover all of that in the Advanced Glycation End Products article and genotype report.

Coming next week:
I’m working on a new article about the genetic causes of hypophosphatasia and low ALP levels.

Gratefully yours,

~ Debbie

What I’ve been reading:

Urolithin A for heart failure
A new study (in animals) shows that urolithin A can help to restore mitochondrial function in heart failure. They were able to reverse much of the damage in heart failure with urolithin A in a mouse model of heart failure. I hope they do clinical trials on urolithin A for heart failure soon to determine dosing in humans!

Diverticular disease genome-wide association meta-analysis identifies 257 novel loci, implicates structure and motility (Preprint)
A massive new genetics study involving 157,000 cases of diverticulitis and 1.2 million controls shows that genetic variants in colonic smooth muscle, fibroblasts, and intestinal cells are at the root of susceptibility.

Vagal cholinergic denervation of the gastric mucosa in Long-COVID-19: in vivo evidence of structural autonomic dysfunction
Researchers looked at stomach biopsies from long Covid patients and counted the nerve fibers in them. The patients had persistent gastrointestinal symptoms and dysautonomia after Covid infection. The results showed that the patients had a significant loss of cholinergic nerve fibers in the stomach (about half of the nerve density compared to the healthy controls).

Plasma GDF15 affects long-term dementia risk and alters neuroimmune signaling
From the study: “Growth/differentiation factor–15 (GDF15) is a secreted cytokine strongly associated with dementia risk...” Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer’s disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15’s mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation.

Why? Non-secretors have a strong resistance to certain intestinal viruses, including norovirus and rotavirus, because these pathogens rely on FUT2-dependent blood group sugars to attach and infect the gut.

In a world without modern sanitation and clean water, avoiding deadly diarrheal disease was a huge survival advantage in childhood.

What are FUT2 and secretor status?

The FUT2 gene encodes the fucosyltransferase 2 enzyme, which adds a fucose sugar to precursor molecules in mucus and other secretions. This reaction creates the H antigen that your ABO blood type builds on, but in your bodily secretions rather than on red blood cells.

• If FUT2 is working, you’re a secretor, meaning your ABO blood type sugars show up in your intestinal mucosa, saliva, tears, sweat, lung mucosa, and semen.

• If both FUT2 copies are non-functional, you’re a non-secretor and the blood type sugars aren’t secreted, even though your red blood cell blood type is the same.

About 20% of people of European and African ancestry are non-secretors (much lower for Asian populations). This is not rare or a disease state, but rather a common genetic pattern with pros and cons. (There are Facebook groups and alternative practitioners who tend to paint non-secretor status in a bad light.)

Microbiome tradeoffs: Fewer Bifidobacteria, different diversity

In the gut, secretor status affects the composition of the microbiome.

Secretors tend to have a higher prevalence of Bifidobacteria, often considered “good guys” for gut health, and a greater overall diversity. These microbes can feed both on dietary oligosaccharides (e.g. from wheat) and on the host-derived oligosaccharides (your blood type sugars) in the gut mucosal barrier.

Without the blood type oligosaccharides, Bifidobacteria species usually aren’t able to thrive at higher levels. (Yes, it is a bit gross to think about your gut bacteria munching on your blood type in your gut mucosal layer… I’m bringing you the good stuff this morning :-)

Non-secretors often have:

• Lower levels of Bifidobacteria and, in some studies, very low or even absent Bifidobacteria. (Keep in mind that Bifidobacteria species help with digesting wheat, so this may be why some people feel better going gluten-free.)

• Reduced species richness and altered community composition in the gut microbiome compared to secretors.

Non-secretor changes aren’t just limited to the gut. Studies also show -

• A different lung microbiome and a higher risk of severe exacerbations in COPD.

• A distinct oral microbiome, where FUT2-dependent glycans influence both bacterial attachment and types of bacteria.

So while there can be negatives to being a non-secretor of your blood type, when it comes to the microbiome, there are also benefits (not getting the norovirus on a cruise comes to mind…). Tradeoffs.

The bigger picture here is that many of our genetic variants are due to trade-offs. Some variants may protect against a certain disease while at the same time increasing the risk of a different pathogen. Variants in the inflammatory pathways may increase chronic disease risk, but they allowed your ancestors to survive a cholera outbreak.

Want to dig into your own FUT2 status? I’ve just updated my FUT2 article and genotype report with new studies and the updated report format.

Stay curious!

~ Debbie

What I’ve been reading:

NLRP3 inflammasome as a central target for the pleiotropic effects of GLP-1 receptor agonists
This is an interesting overview of how GLP-1 RAs can decrease NLRP3 and NF-kB activation. This may explain, at least partly, why some people with chronic diseases - including mast cell issues - find low-dose GLP-1s to be helpful.

Immunoadsorption Versus Sham Treatment for Post-COVID Syndrome: A Randomised Sham-Controlled Crossover Trial
Negative results are important in helping to understand what is driving the continuing health problems in long Covid. This clinical trial showed that removing autoantibodies from long Covid patients didn’t help their symptoms. The researchers successfully removed autoantibodies against G protein-coupled receptors (adrenergic and muscarinergic receptors), but this didn’t statistically change any of the symptom scores or other parameters that they were tracking.

New on Longevity Lifehacks Substack:

Brain energy changes in Alzheimer’s connect to the benefits of low-dose lithium
Looking at a new study that shows that glycolytic metabolism changes occur before amyloid-beta and tau deposition — and tying that to one reason that low-dose lithium is likely beneficial for Alzheimer’s prevention.

Lithium is famous (infamous?) for being used at high doses for bipolar disorder, but at much lower doses, recent studies are showing some very interesting findings for both mood and the prevention of neurodegenerative diseases.

Epidemiological studies over the past couple of decades have shown that areas with higher naturally occurring lithium levels in the drinking water (and soil) have statistically lower levels of Alzheimer’s disease, suicide, and aggressive crimes.

You can read all about lithium, supplemental low-dose lithium orotate, and genetic connections here: Lithium Orotate and Vitamin B12: Benefits for Mood and Cognitive Support

Today, I wanted to highlight a Nature study that I just added to that article. The study builds upon more than two decades of studies on lithium and Alzheimer’s disease, and it answers some of the questions on mechanisms. Essentially, the researchers used a mouse model of Alzheimer’s and fed the mice a diet that was deficient in lithium. The low-lithium diet accelerated amyloid‑β deposition, tau phosphorylation, microglial activation, synapse and myelin loss. It did this through increasing the activation of GSK3β, which caused increased neuroinflammation (microglial activation, IL-6, IL-1B, and other inflammatory markers).

What is important about this study is that the researchers showed that low-dose lithium orotate was able to prevent the age-related brain changes almost completely (again, in mice).

Lithium orotate is readily available as an inexpensive supplement. The question that remains is: what is the exact right dose for Alzheimer’s prevention? The answer is likely highly personal — based on your genes (including GSK3B variants) and on your dietary intake of lithium. As you can see from this USGS map, lithium levels in the water vary a lot across the US.

Check out the full article on lithium orotate, genes, and all of the studies on mood, brain function, long covid, and even new studies on Parkinson’s. I also cover the safety concerns for higher doses of lithium, interactions with vitamin B12, and genes that may drive the benefits for depression or mood.

Website updates!

Every article on Genetic Lifehacks is getting updated with a new format for the genotype reports and genetic previews — hopefully making it easier to see and understand your data. You’ll see these changes rolling out across the whole site within the week.

If you’re up for helping out with some beta testing, I have a new format for the summary reports here. You can now filter out the SNPs that aren’t included in your raw data and see the notes specific to your genotype. Test them out, let me know what you think - and most importantly, if you spot any errors, please send me a screenshot!

July sale!

I’m running a two-day sale on memberships - use the coupon code 1776 for 17.76% off any membership or upgrade. If you’re a monthly member, consider upgrading to the annual or lifetime membership. If you are already a lifetime member, consider sharing this coupon code with family or friends.

Happy 4th (a day early) and happy Canada Day (belated) to my friends to the north,

~ Debbie

Lithium Orotate and Vitamin B12: Benefits for Mood and Cognitive Support

Key takeaways:

• For some people, supplementing with low-dose lithium orotate helps with anxiety, depression, and anger issues.

• For others, lithium orotate supplements seem to have little or no noticeable effect on mood.

• Research shows that small amounts of lithium (natural mineral) influence mood, aggression, neuroinflammation, and more.

• Vitamin B12 comes into play here as well, and lithium orotate along with B12 may help with mood and cognition.

In this article, we will explore the potential lithium orotate benefits, backed by research studies, and discuss its impact on mood, anxiety, and cognition.

Read the full article here

A new study came out this week showing that creatine fuels the dendritic cells (immune cells) that patrol the body to detect cancer. Creatine supplementation was shown to improve dendritic cell function and suppress tumor cell growth in a mouse model of melanoma.

This prompted me to update my article on creatine with several recent studies on creatine and cancer.

The studies show a nuanced picture…

Some types of cancer cells theoretically are able to use creatine as a fuel for growth and metastasis, while most studies in humans show that higher creatine levels are protective against cancer.

This new study on creatine fueling dendritic cell function adds to prior studies showing that creatine helps to power CD8+ T cells — both dendritic cells and T cells are important in the way that the immune system protects us against cancer. So while creatine may promote growth or metastasis in active cancers (it’s considered a ‘third line’ fuel for cellular energy after glucose and glutamine), the majority of studies show that higher levels of dietary creatine and creatine supplements are beneficial for the prevention of cancer. (Obviously, if you have cancer, talk with your oncologist before taking creatine or any other supplement! Everyone is unique.)

New format rolling out for Genetic Lifehacks genotype report sections:

I’ve been working on some behind-the-scenes database updates and am rolling out a new format for the genotype report sections. You’ll see a mix of the older format and the new format in articles for the next few weeks as we get every single article updated on the site.

You can see the new genotype report format if you’re logged in as a Genetic Lifehacks member in the updated creatine article.

Here’s an example of what it looks like:

My goal with the new format is to make it easier for you to immediately understand the impact of the genetic variant for your genes.

You’ll also note that the preview section is a bit different — you’ll now see the note specific to your genotype in the preview at the top of the article. Hopefully, this will make it easier to understand your genes at a glance.

I’m also working on better interconnecting articles to help you move to related genes more easily. For example, I clarified the connection between creatine, the methylation cycle, and MTHFR, and added related methylation cycle links.

Substack newsletter and community:

As mentioned in prior newsletters, I’ve moved everyone over to getting the email newsletter through Substack. One benefit here is that you can now leave a comment on this newsletter. So if you have insight on creatine, comment about how you use it — or link us to any interesting studies that you’ve read about creatine below.

Stay well,

~ Debbie

What I’ve been reading this week:

Extracellular vesicles in ME/CFS patients

This new study backs up prior studies showing increased numbers of extracellular vesicles in plasma from ME/CFS patients compared to healthy controls. Extracellular vesicles help with intercellular communication and move proteins and lipids between cells. The study found increased numbers of EVs as well as subtle protein cargo differences that point to possible immune, complement, and coagulation pathway involvement.

Alternate RNA decoding results in stable and abundant proteins in mammals

For anyone deep into genetics, this new study in Nature looks at what is called ‘alternate translation’ events. Essentially, when looking at 1,000 human samples, the researchers found substitutions in amino acids in proteins that were different than what is coded for by the gene. This wasn’t just a one-off; there were thousands of copies per cell of the alternative protein coding. This is an important paper…

Wake-active brainstem GABA neurons signal sleep pressure by upregulating AMPA receptors to drive recovery sleep

This new study in mice shows that sleep deprivation triggers a switch in GABA-related neurons to make them more active during non-REM recovery sleep. This activation of the GABAergic neurons enhances the rebound sleep.

PAI-1 inhibits tPA and uPA, which are the main enzymes that help break down clots through fibrinolysis. That means too much PAI-1 can make clots hang around longer, while too little can increase bleeding risk. Much of the early PAI-1 research focused on clot-related problems, such as heart attacks and stroke.

But the more interesting part is that PAI-1 is also tied to lung fibrosis, brain function, mood, mast cell activation, infertility, neurodegenerative diseases, insulin resistance, and even aging. PAI-1 levels rise with age and are linked to cellular senescence, and stress hormones like cortisol can push PAI-1 higher, too.

Several recent studies have clarified that PAI-1 levels are a driving factor in increased cellular senescence in certain tissue types. Cellular senescence is a state in which the cells no longer divide and instead send out inflammatory signals so that they can be removed by the immune system. This happens throughout life, but in aging, the accelerated rate of senescence overwhelms the immune system’s ability to clear out the cells, leading to chronic, low-grade inflammation. PAI-1 plays an integral role in the increased senescence of fibroblasts, endothelial cells, and even muscle stem cells, positioning it as a driver of everything that goes wrong in aging. Here’s a good overview if you want to take a deeper dive into PAI-1 in aging.

Genetics comes into play here also. Some people also have genetic variants in the SERPINE1 gene, such as the 4G variant, that lead to higher baseline PAI-1. You can see this, plus other variants that increase PAI-1, in the genotype report (logged-in members).

In the Lifehacks section of the article, I go through several natural supplements, like hesperidin and olive leaf extract. (Rabbit trail - olive leaf extract interacts with COMT and may not be a great choice if you have slow COMT.) But what I found most interesting is that omega-6 polyunsaturated fats may increase PAI-1 levels, which is an interesting tie-in with our modern diet high in omega-6s (corn oil, soybean oil, etc) and the increase in chronic diseases that involve higher PAI-1.

It looks like much of the new research on PAI-1 involves drug development of inhibitors, with several in phase II clinical trials. The studies are focusing on lung diseases, Alzheimer’s, and cancer therapy at this point. It will be interesting to see what gets approval. There’s a fine balance, of course, between the benefits of inhibiting PAI-1 to reduce fibrosis, clotting, and plaque formation - balanced with not going overboard and increasing bleeding risk.

Check out the full PAI-1 article for more details.

~ Debbie

PAI-1 (SERPINE1): Genetic Variants, Blood Clot Risk, Fibrosis, and Natural PAI-1 Inhibitors

• Plasminogen Activator Inhibitor (PAI-1) is an enzyme that helps regulate how quickly the body breaks down blood clots and is also involved in fibrosis and tissue remodeling.

• Higher PAI-1 levels are associated with an increased relative risk of heart attack, stroke, blood clots, tissue fibrosis, miscarriage, senescence in aging, and metabolic problems.

• Variants in the SERPINE1 gene can influence your baseline PAI-1 levels, affecting clotting and fibrosis risk.

• Lifestyle, diet, and natural compounds may help to lower elevated PAI-1 levels.

Read the full article here

Interesting studies that I’ve read this week:

Astaxanthin Inhibits STING Carbonylation and Enhances Antiviral Responses
I usually think of astaxanthin as an antioxidant supplement (and the reason flamingos are pink). But this study shows that astaxanthin can enhance the type-1 interferon response to a virus.

Co-exposure to PFAS and hydroxylated PCBs is associated with increased odds of multiple sclerosis
Researchers found that higher PFAS levels, along with specific HLA genetic variants, increased the odds of MS by fourfold.

Human cells can exchange genomic DNA that alters cell behavior
This is a good overview of a new study showing that cells can directly transfer large pieces of genomic DNA to nearby cells through nanotubes.

Folate transporter blocked by mycotoxins:
Fumonisins are a mycotoxin metabolite produced by Fusarium mold species that grow on corn, barley, oats, peanuts, and grapes. To give you an idea of the scope of exposure - the WHO estimates that about 50% of corn products worldwide have fumonisin contamination at low levels, and a US study found fumonisins in 86% of beer brands.

At higher levels, researchers have found that fumonisin exposure reduces both types of folate transporters that are used to bring folate and folic acid into cells. Researchers had noted that in populations with high exposure to fumonisins (eating contaminated grains), there was an elevated rate of neural tube defects, which are caused by a lack of folate in pregnancy. In one study, folate receptor expression was reduced by 43% after exposure to fomonisin B1.

The first question to come to my mind is whether fumonisin exposure from tortillas, oats, and barley is enough to have an effect on folate transport in kids or adults.

While the epidemiological studies showing a higher rate of neural tube defects in areas where pregnant women are exposed to higher levels of fumonisins are interesting, they don’t quantify where the tipping point is.

When could blocked folate transport from a mycotoxin be a problem? Well, the combination of genetic variants that decrease detoxification pathways for that mycotoxin, combined with variants that impact folate receptor function or folate conversion (MTHFR), added to a poor diet, may be the recipe for a significant effect from fumonisin mycotoxins.

Decreased folate transport into cells could then lead to decreased methyl groups.

Which brings me to arsenic...

Arsenic is naturally found in the water in certain areas of the world, and it is also a soil contaminant in areas with past pesticide use, mining, or emissions from certain industries. About 7% of wells in the US have arsenic levels that are of concern, and much of the rice grown in the southern US tests positive for arsenic.

Arsenic detox is methylation cycle dependent:
Arsenic is detoxified using the AS3MT enzyme, which adds a methyl group to arsenic to aid in excretion.

Without enough methyl groups - especially if combined with AS3MT genetic variants - arsenic detoxification is impaired.

Here’s a scenario:

A young mom with AS3MT variants and MTHFR C677T decides to go gluten-free. She ends up eating lots of gluten-free bread that uses rice flour (high in arsenic) and oat flour (fumonisin). She also likes to drink beer and eat tortilla chips (corn and barley containing fumonisin mycotoxins), doesn’t eat green vegetables (low folate diet), and drinks well water that contains arsenic.

People eating gluten-free have nearly double the urinary arsenic concentration because rice flour (used in gluten-free breads, pasta, and pretzels) concentrates arsenic from the soil.

The fumonisin mycotoxins from the corn and oats then decrease the folate transport and eventually limit methyl group production, especially if combined with genetic susceptibility to methylation pathway problems.

So - no folate for the arsenic detoxification pathway due to a combination of genetics, mycotoxins, and diet, combined with a higher-than-normal intake of arsenic from rice flour and well water.

What could go wrong?

Well, arsenic in drinking water is associated with a 10–15% relative risk increase for breast cancer at the population level. But for someone with AS3MT variants, that risk jumps to 2–3 fold. Combine that with a lack of folate for methyl groups, and the risk of breast cancer gets real scary, real fast.

This was a totally fictional scenario - just an illustration of how genes interact with your environment in complex ways. I don’t want any of you thinking that your gluten-free pretzel habit is necessarily going to give you cancer!

Check out the new detoxification genes hub page. I’ve organized all of the articles with genotype reports to make it easier to find where your susceptibility lies.

~ Debbie

What I’ve been reading:

Psilocybin reversing Alzheimer’s symptoms?

This is a fascinating case study. Psilocybin given to a severe Alzheimer’s patient reversed some of the symptoms. The woman had a 10-year history of Alzheimer’s and hadn’t really been able to talk for 5 years. The oral psilocybin-containing mushroom dose restored speech, recognition of family members, and even bladder function over several weeks.

I’m not sure what to think about this one. From Alzheimer’s studies, the damage to certain regions of the brain should be fairly permanent, with marked brain shrinkage in imaging studies.

Latest on Longevity Lifehacks:

SIRT6 and Reversing DNA Changes in Aging

A new study shows that SIRT6 may be key to reversing chromatin changes that happen to DNA in aging.

Norepinephrine levels are kind of a Goldilocks situation -

• too low is associated with brain fog and low drive,

• too high may cause anxiety and a “noisy” brain

• the sweet spot in the middle

In the area of the brainstem called the locus coeruleus, about 30,000 neurons send norepinephrine projections throughout your brain. It’s synthesized from dopamine and released into the synapse of the neurons. Norepinephrine helps you stay alert, attentive, and engaged with the task in front of you. These neurons signal through three main receptor families – α1, α2, and β adrenergic receptors – and each one is more active at different norepinephrine levels.

Genetic variants (of course) affect how much norepinephrine is synthesized, how it is regulated in the synapse, and how the signal is received.

You may immediately be thinking of brain fog or ADHD, but norepinephrine may also play a role in ME/CFS, long Covid, Alzheimer’s, and Parkinson’s.

In ADHD, for example, insufficient norepinephrine tone or rapid reuptake in the prefrontal cortex is tied to problems with focus and task engagement. Several of the ADHD medications act on this pathway, along with influencing dopamine.

In ME/CFS and long COVID, a new study shows that norepinephrine pathway activity is reduced even when dopamine appears normal, and the severity of post‑exertional malaise tracks with how low norepinephrine is. On the other end of the spectrum, in a hyperadrenergic subtype of POTS, norepinephrine levels surge upon standing, and a clinical trial of a NET inhibitor actually made tachycardia and symptoms worse.

You can read the full norepinephrine article, including all the genotype tables and study links, on the site now.

Stay curious!

~ Debbie

Norepinephrine: Focus, stress, genetics, and brain function

Key takeaways:

• Norepinephrine is both a neurotransmitter that helps with focus, attention, and motivation, and a hormone that affects blood pressure, heart rate, and stress response.

• In the brain, most norepinephrine is produced in the locus coeruleus. It activatesα1, α2, and β adrenergic receptors to fine-tune neurological pathways.

• Norepinephrine is synthesized from dopamine by DBH, cleared from the synapse primarily via the norepinephrine transporter (NET/SLC6A2), and then metabolized by MAO‑A and COMT.

• Genetic variants can shift the baseline levels of norepinephrine and the response to drugs.

• Altered norepinephrine signaling is implicated in ADHD, Alzheimer’s, ME/CFS, Parkinson’s, long Covid, POTS, and mood disorders.

Read the full article

What I’ve been reading:

Age-Related ‘Unraveling’ of DNA May Be Reversible, Study Suggests

Researchers have figured out that SIRT6 may be the key to turning back the clock on changes seen in DNA with aging. I’ll dig into this more in a Longevity article soon.

Choline and cognition:
In the brain, choline is essential in a couple of ways. First, it is incorporated into the cell membrane of neurons in the form of phosphatidylcholine. This keeps brain cells flexible and able to function well. Just as important, choline is also used for acetylcholine, a neurotransmitter involved in learning, memory, mood, and muscle control.

We can synthesize some choline with the help of the PEMT enzyme, but we also need choline from the diet. Choline is especially essential in pregnancy, with higher maternal choline intake correlating to higher IQ in the child. The PEMT gene is upregulated by estrogen, increasing choline availability in pregnancy.

Which brings me to a new study on choline and brain function after menopause...

When estrogen levels decrease postmenopause, the PEMT gene is no longer upregulated, leading to lower endogenous choline synthesis.

This new study assessed the effect of supplemental choline on brain function in postmenopausal women. The researchers looked at brain imaging and functional connectivity three hours after the consumption of a choline supplement. The results showed that choline improved functional connectivity under conditions of memory load. The authors conclude that “choline may increase brain functional efficiency in low estrogenic conditions like menopause”. A number of prior studies also show a connection between dietary choline intake and post-menopausal brain function. The choline boost from PEMT expression may be why some women find that HRT helps their brain, and increasing choline may be an alternative for women who don’t want to take hormones after menopause.

This week, I’ve updated and overhauled my article “Which type of choline works best with your genes“.

Whenever I bring up choline, I inevitably get emails from folks who are concerned about TMAO and worried about eating choline-rich foods such as eggs or beef. TMAO is a gut metabolite produced more abundantly when eating choline-rich foods, and higher TMAO levels correlate with increased cardiovascular disease. However, there are questions on the causation here.

Another new study looked at the effect of swapping beans for red meat as a protein source. The study was conducted in healthy adult males, avoiding the effect of estrogen on PEMT. After six weeks, the results showed no differences in TMAO or inflammation levels between groups. However, plasma choline levels did drop in the ‘beans’ arm of the study. That said, this was in healthy men (avg. age 37) and doesn’t mean higher TMAO is benign in someone with diabetes or metabolic syndrome

Other Genetic Lifehacks updates and In the Works:

• Alpha-Gal Syndrome is updated this week, timely for the summer tick season.

• An article on norepinephrine genes is in the works for next week.

• For anyone with a Sequencing.com VCF file, I have a beta version of a converter that you can try out. Keep in mind that it is just an initial version, and you’ll need to check back for updates. This is just for Sequencing VCF file and likely won’t work for other VCF files at this point.

Stay curious!

~ Debbie

Which Type of Choline Works Best with Your Genes?

Key takeaways:

• Choline is an essential nutrient that you get from your diet and also synthesize in your liver, which your body uses in several important ways.

• Choline is needed for brain function and cellular health. It can also be utilized in the methylation cycle as a methyl donor.

• Genetic variants can impact how well you create choline or how you convert between types of choline.

• Studies show that genetic variants significantly impact how much choline you need from your diet in order to maintain adequate supplies.

• Personalize your choline based on your genetic variants: PEMT T/T carriers benefit most from supplementation, while BHMT A carriers may prefer choline over betaine. Slow COMT may also interact with betaine supplements.

Read the full article, see your genes

What I’ve been reading:

Elevated microbially-derived metabolites in autism: a possible diagnostic screening test for a distinct ASD phenotype

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. The specific metabolites covered have interesting links to brain development and function.

However, not everyone who is on a medication will end up with a micronutrient deficiency... It is a triple intersection of genetic susceptibility, length of time on the medication, and diet.

This week, I’ve put together a new article with integrated genotype reports showing the studies on which vitamins and minerals are depleted for specific medications. Keep in mind that genetic variants don’t always mean that you will be deficient in a micronutrient, just like taking a medication doesn’t cause everyone to be deficient. Instead, take the information together with your normal dietary intake, and then consider whether you should get a blood test done to confirm a deficiency or simply increase that micronutrient in your diet.

As always, the article is for educational purposes only. It’s a starting point -- use the information to talk with your doctor about testing or supplementing. Many medications have interactions with supplements, so you should always check with a pharmacist or your doctor before adding a micronutrient supplement.

Wishing you all a happy and healthy Memorial Day,

~ Debbie

Drug Depletions: Medications and Missing Micronutrients

Key takeaways:

• Many common prescription medications can lower specific vitamins and minerals over time.

• Genetic variants can increase your risk of becoming deficient while taking certain drugs.

• Combining your medication list, genotype information, and diet helps you decide which micronutrients to test or prioritize in foods/supplements.

• Always talk with your prescribing physician before changing supplements, since nutrients like potassium or vitamin K can alter how medications work.

Medications can decrease vitamin and nutrient levels

In the US, about two-thirds of adults regularly take at least one prescription medication, with many taking multiple drugs.[ref] These drugs can be lifesaving for blood pressure, reflux, diabetes, mood, and more. But some medications often come with a side effect of quietly draining vitamins and minerals over the months or years of use.

Certain medications can block the absorption of micronutrients in the gut or can increase the depletion of specific vitamins or minerals.[ref] At the same time, common genetic variants can also increase your susceptibility to being low in nutrients like B12, folate, magnesium, or vitamin D, and diet and lifestyle can push you further in either direction.

When you look at medication use + genetics + diet/lifestyle together, it can help you identify where you’re most likely to run low and which micronutrients are worth testing or prioritizing in your diet or supplements.

Researchers sometimes call this “drug-induced nutrient depletion” or “drug–nutrient interactions,” and it can show up as fatigue, neuropathy, bone loss, or mood changes that don’t have an obvious cause. Mild deficiencies from medication use may go unnoticed at first, but over time, they can reduce your resiliency. Lower baseline levels of a nutrient can make the effects show up sooner or be more severe. For example, metformin commonly lowers vitamin B12, and people with certain B12-related variants are more likely to develop neuropathy or anemia unless the deficiency is caught and corrected.

Read the full article, see your genes

New on Longevity Lifehacks:

Topical Supplements for Preventing Skin Aging
Looking at the studies on topical taurine and topical resveratrol for reversing different aspects of skin aging.

What I’ve been reading:

Genome instability triggers intercellular DNA transfer between human cells

Researchers have discovered that fragments of a chromosome in the cytoplasm can trigger cell-cell transfer of that fragment through cytoskeleton-based nanotube structures. The transferred DNA fragments can then be incorporated into the new cell during cellular replication and persist across cell divisions.

Digital addictions:
Have you heard of dopamine fasting? Silent walking? Digital detox?

As someone who is old enough to remember the era before smartphones and ubiquitous internet access, I have to laugh when I see videos of young people talking about how to do a silent walk... (It’s just going for a walk without your phone.)

Digital addiction is a general term covering smartphone addiction, internet usage disorder, and internet gaming addiction. This is a global problem that affects up to a quarter of the population (depending on the study).

Genetic studies show that certain genetic variants - mostly related to dopamine pathways - can significantly increase susceptibility to digital addictions.

Check out the new article + genotype report here.

Updated BBB article:
I keep running across new studies to add to my recent article on blood-brain barrier dysfunction. This week I added a study showing the connection between severe Candida infection and BBB dysfunction.

Histamine in the brain:
While histamine is normally thought of in terms of allergy symptoms, it also acts as a neurotransmitter and neuromodulator in the brain. There’s a great new study out that maps where histamine receptors and enzymes live in the human brain and shows that their strongest expression sits in association and limbic areas, not in the primary sensory cortex. It also draws connections to psychiatric disorders and cognitive function, strengthening the evidence that histamine plays a role in ADHD, major depressive disorder, anorexia, and schizophrenia. This puts histamine as a serious psychiatric target.

I’ve updated my article on histamine receptors and histamine intolerance to further explain the role of histamine in the brain.

Magnesium for the brain:
A new clinical trial comparing magnesium-acetyl-taurate to magnesium threonate showed that magnesium-acetyl-taurate increased brain magnesium levels more effectively than the threonate form. Details in my updated magnesium article + genotype report.

Gratefully yours,

~ Debbie

Dopamine and Digital Addictions (Internet Usage, Gaming, and Smartphone Addictions)

Key takeaways:

• Modern technology constantly stimulates our brains, causing us to feel distracted, anxious, and unmotivated.

• Researchers now think that some people have an addiction to the dopamine hits produced from using social media, smartphones, or internet gaming.

• Genetics plays a role in susceptibility to addictive behavior, including internet and smartphone addiction.

Can smartphones and internet usage be an addiction?

Can people really have an addiction to using their smartphones or to being constantly connected to technology? Researchers paint a pretty compelling picture that this behavior can lead to addiction for some people.[ref]

There are thousands of studies looking into the problem, which is referred to by various names:

• smartphone use disorder (SUD)

• internet usage disorder (IUD)

• internet addiction disorder (IAD)

• digital dependency/addiction

• problematic smartphone use and dependence (PSU)

• internet gaming disorder

• social media addiction

A 2022 review study found that digital addiction is a global problem with a significant prevalence. The results, combining data from 504 studies involving over 2 million participants, showed 27% for smartphone addiction, 17% for social media addiction, 14 for internet addiction, 8% for cybersex addiction, and 6% for game addiction.[ref]

Read the full article, see your genes

New on Longevity Lifehacks:

Boosting NAD+ Function While Inhibiting CD38

What I’ve been reading:

Activated charcoal to prevent gout flare-ups

This 24-week randomized controlled trial involved ~350 gout patients and investigated adding activated charcoal along with gout medication (febuxostat). The activated charcoal + febuxostat group had significantly fewer gout flares than those who just took febuxostat.

Related GL article: Gout and uric acid genes

Old worms, new tricks: dynamical instability explains late-life rejuvenation in C. elegans

This is a preprint showing that lifespan can be doubled by an intervention at the end of life in C. elegans (a worm used in research studies).

Why is this interesting? It shows that it isn’t just damage accumulated in the body (of the worm) that causes death. Instead, it points to a designed deterioration after reproduction that causes systemic instability, leading to death.

GABA: First up is the updated GABA report and article. GABA is the main inhibitory neurotransmitter -- important for calming the brain, reducing anxiety, and modulating the immune response. It’s synthesized from glutamate by the GAD1/GAD2 enzymes using vitamin B6 as a cofactor. GABA affects about 20-25% of neurons, regulating brain impulses and filtering noise.

The new study that prompted my GABA update was actually on the gut microbiomes of habitual coffee drinkers. The researchers found that coffee consumption (decaf or regular) affects the composition of the microbiome in a way that reduces GABA-producing bacteria. The researchers also found coffee drinkers to be more impulsive with greater emotional reactivity, which would go along with less GABA.

I find it totally fascinating to look at the interaction of diet and gut microbes and how that affects the metabolites produced by the bacteria. We get a lot of vitamins (B12, folate, riboflavin, B6, thiamine, and vitamin K) from our gut microbiome, and certain bacteria also produce neurotransmitters (GABA, serotonin, dopamine, etc.) that are then absorbed by the body.

Hantavirus connection: After seeing several news articles on a hantavirus outbreak, I spent some time updating my article on ITGB3. What does a platelet and blood-clotting gene have to do with the hantavirus? It turns out that people with a variant in the gene are less likely to get a severe case of hantavirus.

New Methylation Cycle hub: Also new this week is the methylation cycle hub page. I’ve been working on connecting articles in better ways, and this is an attempt at organizing the methylation cycle genes into a cohesive group.

Transparency on AI: You may notice that some of the wording on the new methylation cycle hub page& sounds like I used AI to write it (or, in this case, to rewrite it). And I want to be totally up front with you on where and why I use AI on the site.

Genetic Lifehacks has had a drop-off in growth over the last year. It’s still growing, just not as fast.

There are a couple of reasons for this:

First, a bunch of AI-generated genetic report sites have popped up, selling reports that are strangely similar to my content (kind of like AI bots have scraped Genetic Lifehacks and other genetic sites for the past few years and now can replicate my content for others to sell as a report). Some of these new sites are ranking much higher than Genetic Lifehacks because they were crafted specifically for AI search.

The other hit on new traffic is that people just aren’t searching and finding the site in the same way. Search has changed, and the way people use the internet has changed a lot over the past few years.

The reality is that I need to adapt Genetic Lifehacks to these new patterns. So I’ve decided to use AI to optimize certain pages and topics in ways that AI search results will like.

In general, AI sites (LLMs) are great at producing what is essentially a regurgitation of the average of a bunch of webpages, and the AI search results seem to prioritize pages that match the consensus.

I won’t be changing the core ways that I write articles and do in-depth research, but you will find some AI-sounding overviews and general articles on Genetic Lifehacks in a few places. Some are just experiments to see what works.

While it may sound like I’m whining about AI (since I am), I do want to admit that these tools can be helpful. I’m now using AI as a copy editor to help me clean up poorly written articles, and I’m cringing at some of the grammar errors I’m finding in old articles (apologies to past readers!).

For those of you using AI to do your own research on genes, I do have a tip!

I’ve been frustrated by the lack of depth in results when using AI for researching genetic topics. The results sound confident and comprehensive but often miss important genes. Many high-quality journals are blocking AI from searching their sites, creating a moat around their information. Thus, AI answers often come from review articles published in lesser journals, rather than original lab research papers. However, from those review articles, you can find original papers to download and then run through AI to make them easier to understand.

Facebook is back: For those of you who follow Genetic Lifehacks on Facebook, you may have noticed it was missing in your feed for a week or so. Some automated Meta bot decided that my content should no longer be shown in feeds due to allegedly violating something in a vague policy. I finally figured out that a couple of older posts about peptides had triggered the automated ban, and I deleted them. Apparently, posting about my articles on BPC-157 or thymosin beta is now forbidden.

From a content creator viewpoint, it’s always eye-opening to see what gets suppressed and makes me wonder what I’m not seeing... Going to have to dust off my tinfoil hat again.

IBS: For anyone dealing with IBS and/or constipation, I’ve updated the IBS article with a recent study showing that genetically reduced thiamine transport is often a cause of slowed gut motility. You can check your genes to see if it is likely a root cause for you.

Stay curious -- and I apologize if this email comes across as if I have low GABA and more emotional reactivity. I admit that I’m a habitual coffee drinker, and my gut microbes may not be making enough GABA this morning.

~ Debbie

GABA: Genetics, Anxiety, and Immune Response

Key takeaways:

• GABA (gamma-Aminobutyric acid) is an inhibitory neurotransmitter that acts to stop a neuron from firing. This is an essential way that the brain regulates impulses.

• Low GABA levels are linked to anxiety and PTSD and may affect immune response.

• Genetic variants can alter your GABA levels and increase susceptibility to mood disorders.

In this article, you’ll get a quick overview of how neurons make GABA, how this connects to anxiety and immune response, and then see your GAD1, GABA receptor, and GABA metabolism gene variants. We will conclude with natural ways to optimize GABA levels.

Read the full article, see your genes

What I’ve been reading:

Anti-Inflammatory and Neuroprotective Polyphenols Derived from the European Olive Tree, Olea europaea L., in Long COVID and Other Conditions Involving Cognitive Impairment

Olive polyphenols may be helpful for neurodegenerative diseases or long Covid. One mechanism highlighted here is that olive leaf suppresses activation of the NLRP3 inflammasome.

Note that Olive Leaf extract may inhibit COMT. Check your COMT variants here.

Gut microbiota reshapes host energy metabolism to modulate depressive behaviors

This is a new metabolomics study in people with depression compared to a healthy control group. The researchers discovered that the gut microbiome differences in the depressed group caused significant disruptions in three core energy pathways: glycolysis, the TCA cycle, and the ornithine cycle. These changes correlated strongly with symptom severity and cognitive impairment, with 14 energy metabolites distinguishing MDD from controls. The depressed patients had elevated lactate, L-glutamic acid, and arginine, but depleted glucose, ornithine, and cAMP.

What if the problem isn’t in your neurons, but in the barrier between your blood and your brain? Too much getting into the brain, or not enough getting out.

The blood-brain barrier (BBB) is the specialized endothelial lining of the small blood vessels supplying your brain with nutrients. The cells there are tightly joined together to protect the brain from toxins and pathogens, and there are specialized transporters to move substances in and out of the brain.

Certain variants in tight junction genes like CLDN5 can lower claudin‑5 levels, making the blood-brain barrier a little less tight - and more vulnerable to inflammatory cytokines and toxins.

Genetic variants can also affect how substances, like medications or amyloid-beta, are transported into and out of the brain.

These variants can increase your susceptibility to neurological conditions, like Alzheimer’s disease, depression, ADHD, or schizophrenia, or to negative effects from psychiatric medications, such as akathisia.

Reading the BBB research and writing this new article deepened my appreciation for how complex and intertwined our bodies’ systems are. Cool stuff.

It also reminded me of how grateful I am to all of you who are Genetic Lifehacks members, supporting my work here. I receive emails all the time from readers who have used Genetic Lifehacks articles to make connections, discover ways to improve their health, or solve long-term problems.

Your support of Genetic Lifehacks makes this possible - so I wanted to pass along my thanks to all of you!

Gratefully yours,

~ Debbie

Blood-Brain Barrier Genes: SNPs, Leaky BBB Risks & Solutions

Key takeaways:

• The blood-brain barrier (BBB) prevents circulating toxins and pathogens from reaching the brain.

• Tight junctions between the epithelial cells and specific transporters keep the brain isolated and protected.

• Certain genetic variants increase your risk of BBB dysfunction.

• Blood-brain barrier dysfunction can be part of the cause of Alzheimer’s, depression, and neurological disorders.

Read the full article here

Interesting new research studies:

Humans with function-disrupting variants in the myostatin gene (MSTN) have increased skeletal muscle mass and strength

A new study on the MSTN genetic variants that increase muscle mass and decrease fat mass.

Updated GL article: Resistance Training Genetics: Personalized Muscle Building

Gut microbiota reshapes host energy metabolism to modulate depressive behaviors

This is a new metabolomics study in people with depression compared to a healthy control group. The researchers discovered that the gut microbiome differences in the depressed group caused significant disruptions in three core energy pathways: glycolysis, the TCA cycle, and the ornithine cycle. These changes correlated strongly with symptom severity and cognitive impairment, with 14 energy metabolites distinguishing MDD from controls. The depressed patients had elevated lactate, L-glutamic acid, and arginine, but depleted glucose, ornithine, and cAMP.

Everyone has their pet theory on the increase in ADHD - it’s the food additives, too much sugar, video games / TV rotting the brain, lead in the pipes, pesticides, prenatal exposure to something, overdiagnosis, etc...

My updated article on ADHD looks at the topic from a genetic perspective, exploring the pathways connected to genetic variants that increase the relative risk of ADHD.

Studies show that there is a strong genetic basis (70-90% heritability), but it is not just one gene. You don’t have the “ADHD Gene,” even if it is fun to say :-) Instead, it’s a combination of genetic variants and environmental interactions. Understanding the genetic susceptibility can lead to more targeted solutions.

This week, I updated the ADHD article and genotype report. Previously, it had focused primarily on neurotransmitter variants and circadian rhythm variants.

What was missing from the article was the well-researched role of the gut microbiome and the gut-brain axis connections.

Here are four things you may find surprising about ADHD:

1. ADHD looks more like a circadian disorder than most people realize:
Up to 73–80% of people with ADHD have measurable circadian rhythm disruptions, including altered expression of core clock genes like PER2, BMAL1, and PER3, along with shifted cortisol and melatonin rhythms.

In adults with ADHD, combining morning bright light with just 0.5 mg melatonin at night shifted melatonin onset almost two hours earlier and cut symptom scores by about 14%. Important here is that symptoms rebounded when melatonin was stopped.

This also means that blue light from screens and LED lights has a bigger impact than most people understand, or want to admit, when it comes to their ADHD symptoms. (Here’s how to shift your iPhone to red at night.)

2. The gut can literally “transfer” ADHD‑like behavior in animal models:
Children with ADHD have distinct microbiomes, including higher Prevotella and reductions in short‑chain–fatty‑acid producers. Several studies now link this to lower microbial vitamin B12 synthesis and altered inflammation, which affects the gut-brain axis.

In a cool study, when researchers transplanted a low‑Lactobacillus sanfranciscensis microbiome from kids with ADHD into mice, the mice developed hyperactivity and inattention. What made the study neat is that those behaviour changes could be reversed with probiotics or with supplemental acetate (a short‑chain fatty acid).

3. Histamine genes tie together eczema, food dyes, and ADHD:
Allergy-adjacent conditions like eczema, allergic rhinitis, and asthma are significantly more common in kids with ADHD, pointing toward overlapping inflammatory and histamine pathways.

A common variant in the histamine‑degrading enzyme gene HNMT (rs1050891) is linked both to higher brain histamine and to hyperactivity triggered specifically by artificial food dyes, making low‑histamine, dye‑free diets a targeted strategy for people with HNMT variants.

4. Saffron supplements rival methylphenidate (Ritalin) in trials:
Multiple clinical trials in children and adults report that 20–30 mg/day of saffron can be as effective as methylphenidate for ADHD symptoms, both by boosting dopamine, serotonin, and norepinephrine signaling and by affecting the gut microbiome.

While these are four distinct pathways, they all intertwine... histamine can be produced in the gut microbiome; saffron can increase short-chain fatty acid producing bacteria; the gut microbiome can influence circadian rhythm - and vice-versa. All of these then interact with the brain and neurotransmitter homeostasis.

The goal of using your genetic data in ADHD is to give you a starting point. For example, if you have a bunch of circadian rhythm variants, start with changing your light exposure (no blue light at night, lots of daylight in the morning). If you have histamine or gut-related variants, start with the lifehacks that are linked to those topics.

Coming soon: I’m working on an in-depth article on the genetic variants and environmental factors that affect the blood-brain barrier. I’m also working on some back-end things that will hopefully facilitate using your genetic data in better ways.

Wishing you all the best,

~ Debbie

ADHD: Causes, Neurochemistry, and How to Check Your Genetic Raw Data

Key takeaways:

• ADHD affects around 5-7% of the population.

• Brain imaging studies show physiological differences in the way certain regions of the brain work in people who have ADHD.

• Many genetic variants come together to increase susceptibility to ADHD. You can check your 23andMe or AncestryDNA data below for these genetic markers.

• Pathways in ADHD genetic susceptibility include circadian rhythm genes, neurotransmitter (dopamine, norepinephrine, histamine) genes, and gut-brain axis genes.

• Environmental factors also play a role, including toxicant exposure.

Read the full article, see your genes

Latest on Longevity Lifehacks:

Research Roundup: Mitigating Sleep Deprivation

Sleep is foundational for longevity. What can you do about a sleepless night?

New research studies that are interesting:

NMN and REM sleep

This study in mice shows that NMN increases the activity of slow-oscillation neurons in REM sleep, which is interesting.

Intestinal interoceptive dysfunction drives age-associated cognitive decline

This new study in Nature shows that age-associated memory problems are partly due to changes in the gut microbiome.

In the mitochondria, taurine acts as an antioxidant and keeps ions balanced. This is why taurine is important in heart rhythm, bone health, and muscle function. Taurine is also conjugated to bile acids, and it helps to keep the skin barrier and intestinal barrier function intact. Interestingly, the gut microbiome also supplies some of our taurine through the deconjugation of bile acids.

Taurine levels drop in aging, and this is one of the reasons that age-related conditions, such as high blood pressure, osteoporosis, heart failure, and cognitive decline, occur.

Sleep deprivation, leaky gut, and taurine:
What I learned this week is that taurine is also important in mitigating the negative effects of sleep deprivation. Chronic sleep deprivation lowers taurine levels in the brain, and it shifts the gut microbiome in a way that decreases taurine production from gut bacteria. This results in a leaky intestinal barrier. In animal models, the combination of less taurine from gut bacteria plus less taurine signaling shows up as a leakier gut and disrupted circadian signaling in the intestine. Importantly, these problems improve when taurine is supplemented. So if you are having problems sleeping or just don’t get enough sleep on a regular basis, consider upping your taurine intake.

The other interesting tidbit about taurine is that topical taurine (in animals) improves skin barrier function, increases ceramide production, and decreases wrinkles. I’ll experiment and let you know if I suddenly develop a youthful, glowing complexion.

Also updated this week:

• LDL Cholesterol - Updated to include more gene-targeted information in the Lifehacks section. I’m working on being more explicit in how natural solutions tie back to your genotypes.

• C15:0 (Fatty 15) - Added a couple of new studies on fatty 15.

• Nattokinase and Lumbrokinase - Updated with new studies, including an interesting one (in animals) on lumbrokinase for cognitive dysfunction due to stress. In addition to being able to break apart fibrin clots, lumbrokinase also cleaves the precursor form of BDNF into the active form.

Interesting article to read:

This recent article in Nature explains that tens of thousands of scientific journal publications from 2025 likely include AI-generated (hallucinated) references. Peer-reviewed studies in academic journals are what I base everything on for Genetic Lifehacks, and I now spend a lot of time double-checking everything that has been recently published.

If you’re digging into research studies on your own, take this as a heads-up to be cautious with studies you find on PubMed. And if you’re using AI searches for anything health-related, be sure to always click through to the referenced study to see if it exists and says what the AI claimed.

Stay curious,

~ Debbie

Taurine: Healthspan, Mitochondrial Function, and Heart Health

Key takeaways:

• Higher taurine levels may be beneficial for healthspan and healthy longevity.

• Taurine is an amino acid that helps mitochondrial energy production, acts as an antioxidant, balances calcium in cells, interacts with bile acids, and is neuroprotective.

• Your body can synthesize some taurine, but you also need to get taurine from food.

• Taurine levels decrease in aging, and supplemental taurine may help prevent the diseases associated with aging (heart disease, osteoporosis, high blood pressure, mitochondrial dysfunction).

Read the full article, see your genes