Autophagy Genes

Autophagy is a general term for cellular pathways that move something from the cytoplasm of the cell into the lysosome for degradation. The term comes from the Greek ‘auto’ (self) and ‘-phagy’ (to eat).  So when you see articles touting ‘autophagy diets’ as the latest and greatest for longevity or beautiful skin, realize that the term is just a general one that applies to a cellular process that goes on all the time in our cells.

Let me see if I can explain a bit of the biology behind this, and then I’ll go into how your genes play a role in autophagy.

Back to high school science class:  Inside almost every cell in the body is an organelle called a lysosome. It is made up of a membrane that surrounds a bunch of different enzymes for breaking down proteins.  This is a way our cells can clean up after themselves, and also how they get rid of foreign invaders like bacteria. Continue reading “Autophagy Genes”

Lithium: A mineral that affects mood, Alzheimer’s disease, obesity, and telomeres

I’ve written before on the topic of supplemental lithium orotate for mood, anxiety, and irritability. (Read the previous article here: A little lithium and B12 makes the world a happier place — for some.)

What about the effects of lithium as a mineral supplement on other aspects of health?

In reading studies on a wide range of other topics over the past three years, several links to lithium have popped up. Topics such as circadian rhythm dysfunction, Alzheimer’s disease, telomere length, type 2 diabetes, and obesity… not the subjects that I expected to lead me back to lithium!

The rest of this article lays out the evidence that increasingly shows the importance of this mineral in our health and longevity. I think it is important to examine the research and look at the long-term effects and safety questions that always come to mind when talking about lithium. There is such a stigma, at least in my mind, around lithium that I’ve hesitated at times to talk with friends and family about it – a hesitation that no one seems to have in recommending other minerals such as magnesium or potassium.

Lithium orotate supplements compared to prescription lithium carbonate:
I want to clarify before getting into the studies on lithium what ranges of dosages the studies are talking about. The prescription medication that most people are familiar with for bipolar disorder is usually in the form of lithium carbonate.

Standard doses of lithium carbonate are around 900-1200mg/day, although this can vary based on the individual. For lithium carbonate, there is about 18.8 mg of elemental lithium per 100mg of lithium carbonate. So a 900mg dose would give about 170mg elemental lithium.[ref]

Lithium orotate usually comes as a 120mg supplement that gives about 5mg of elemental lithium.

The amount of lithium that we get in foods and drinking water varies based on the mineral content of the soil, with estimates of .5 to 3mg per day. A provisional RDA of 1mg/day has been recommended. [ref]  So a 120mg lithium orotate (5mg elemental lithium) supplement would average around twice the normal daily consumption from food and water, while the prescription dosages are closer to 80 to 100 times normal daily intake.

Alzheimer’s Disease:
A new study came out in November 2017 on Alzheimer’s rates and natural lithium levels in the drinking water in Texas. In an article about the study (which is easier to read than the research paper:-), the lead author of the study explains the findings. Water samples from almost all of the counties in Texas were tested for their natural levels of the mineral lithium, which varies depending on the concentration in rock and soil.

The researchers found that Texas counties with higher levels of lithium in their groundwater had less of an increase in Alzheimer’s rates compared with counties that had lower levels of lithium. This isn’t a total surprise since previous studies had linked lithium to a decreased risk of dementia, but it is a great confirmation at a large scale population level.  A lot of the initial studies were observations linking bipolar patients taking large doses of lithium carbonate and having lower rates of dementia.

A sampling of other recent studies on lithium and Alzheimer’s disease:

  • A 2015 review in the Journal of Alzheimer’s Disease analyzed the data from three randomized placebo-controlled clinical trials of lithium for treating patients who had already been diagnosed with Alzheimer’s disease. The trials found that lithium “significantly decreased cognitive decline as compared to placebo”.
  • An October 2017 article in JAMA Psychiatry details a nationwide study in Denmark on the exposure to lithium in drinking water and the incidences of dementia.  This was a large study, with 73,000+ dementia patients and 733,000+ people without dementia as the control. The study found that there was a decreased rate of dementia in those people exposed to naturally higher levels of lithium in their water (measured since 1986).
  • A March 2018 animal study looked into the mechanisms of how lithium chloride lowers the risk of Alzheimer’s. It found that lithium chloride caused an increase in soluble β-amyloid clearance from the brain. In mice genetically bred to be a model of human Alzheimer’s, lithium chloride restored the clearance of soluble β-amyloid to the levels of normal mice. One big thing to note from this study is that lithium chloride did not affect β-amyloid that had formed plaque already.
  • A study in 2015 looked at the effects of microdoses of lithium on a mouse model of Alzheimer’s disease. The study found that small doses of lithium carbonate in the drinking water of mice carrying the genes for Alzheimer’s disease caused “decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in cortex, when compared to non-treated transgenic mice.” This was a follow-up study to the human study in 2013 which showed that microdoses of lithium stopped the cognitive decline in Alzheimer’s patients.

You may be wondering at this point why all doctors aren’t handing out low doses of lithium to everyone at risk for Alzheimer’s. I think the quick answer is that it isn’t the ‘standard of care’ with enough clinical trials backing it up. The cynical side of me also notes that lithium orotate (and aspartate) are cheap, over-the-counter supplements without pharmaceutical companies sponsoring huge trials and pushing doctors to prescribe them. There seems to be a couple of ‘novel’ low-dose formulations in the works by pharmaceutical companies, though. [ref][ref][ref]

Telomeres and aging:
Telomeres are the sequences of DNA that are found at the ends of each chromosome. This sequence protects the ends of the chromosome from deterioration. The common example given is to think of telomeres like the plastic on the end of shoelaces that protects the shoelace from fraying. When cells undergo cellular reproduction (mitosis), a little bit of the telomere is lost, and thus telomere length is considered a biomarker of cellular aging. Shorter telomere length is associated with several age-related chronic diseases including Alzheimer’s.

A recent transgenic mouse study found that lithium carbonate treatment leads to longer telomere length in mice that are bred to have Alzheimer’s disease. Interestingly, the normal mice had no effect on telomere length from lithium.  A meta-analysis of 13 studies found that Alzheimer’s patients have shorter telomeres.

A human study looked at telomere length in patients with bipolar disorder. The study found that patients with bipolar disorder (not on lithium) and their relatives had shorter telomeres lengths than healthy, unrelated people. More interestingly, patients with bipolar disorder who were lithium-treated had longer telomere length than patients with bipolar disorder who were not taking lithium as well as relatives of bipolar patients.

Telomere length is a new field of investigation for researchers looking into so many different topics of aging, longevity, and disease. I don’t think the handful of studies on telomere lengthening from lithium really lead to a conclusion yet; I look forward to seeing what future studies tell us on the topic.

Anti-Inflammatory action of lithium:
Lithium exerts some anti-inflammatory effects on the body as well as pro-inflammatory effects under some conditions. It has been known since the 1970’s that lithium inhibits prostaglandin synthesis and COX2 in some parts of the brain. While there is some debate on the topic, the majority of studies also point to lithium decreasing the production of TNF-α, a pro-inflammatory cytokine.[ref]

A recent cell study looked at the potential of lithium plus caffeine, theobromine, and catechin on the innate immune system and inflammation.  The results showed that stacking lithium with caffeine, theobromine, and catechin was more effective as an anti-inflammatory than using them separately.

Another recent study looked at the anti-inflammatory effects of lithium on cells containing the SOD2 genetic variant rs4880.  The study found that those with rs4880 alanine allele (GG for 23andMe) had more of an anti-inflammatory response than those with the valine allele (AA for 23andMe).  This was a cell study though, so it is hard to know how well this translates to the whole body.

Obesity and Type 2 Diabetes:
What surprised me about the Nov. 2017 study that I referenced above was that Texas counties with higher levels of lithium in their water also had lower levels of obesity and diabetes.  I was surprised by this because one of the side effects of long-term, high dose lithium carbonate usage is an increased risk of hypothyroidism and possible weight gain.

Part of the explanation for the high levels of lithium in water correlating to lower levels of obesity and diabetes may be due to the effects on circadian rhythm. Another possible connection between lithium, obesity, and T2D may be the effect on blood glucose levels. In mice, certain levels of lithium reduced non-fasting blood glucose levels.[ref]

How is lithium affecting our body and brain?
For a long time, it wasn’t really understood how lithium worked for bipolar patients. (Quite a few psychiatric medications have been used for decades without fully understanding the mechanisms by which they work – or don’t work – for people.) Studies over the past decade or two have shed light on the neurobiological mechanisms of lithium and genetic studies have increased that knowledge.

One effect of chronic, low-dose lithium is an increase in BDNF, which is a protein that promotes the growth of nerve cells.[ref]

The American Chemical Society published a great overview the topic in 2014, “Neuroprotective Effects of Lithium: Implications for the Treatment of Alzheimer’s Disease and Related Neurodegenerative Disorders“. One of the effects of lithium is its inhibition of GSK-3β (glycogen synthase kinase-3 beta), which is involved in neuronal cell development and energy metabolism. Genetic mutations of GSK-3β increase the risk of bipolar disease.

Lithium ions compete with sodium and magnesium ions in the body for binding sites in certain circumstances. Lithium’s inhibitory effect on GSK-3β is thought to be due, in part, to binding to a site that is normally occupied by magnesium. For a very thorough overview of the biochemical properties of lithium, including its effect on the activation energy of water within a cell and its effect on mitochondrial function, please read through “Towards a Unified Understanding of Lithium Action in Basic Biology and its Significance for Applied Biology“.

One action of GSK-3β is its inhibition of glycogen synthase, which is an enzyme involved in the reaction that takes excess glucose and turns it into glycogen for storage. Thus inhibiting GSK-3β increases glycogen synthesis and increases insulin sensitivity.[ref][ref]

GSK-3β and Circadian Rhythm:
Our body’s core circadian clock is run by a couple of core genes that are expressed during the day and a couple of core circadian genes that rise at night. It is this daily rise and fall of gene expression that then drives our internal daily cycles of waking and sleeping, temperature, and energy metabolism. GSK-3β is involved in phosphorylation of both the day and night core circadian genes.

Genetic variants that change our circadian rhythm are linked to increased risk for bipolar disorder. People with bipolar disorder who respond well to lithium therapy have changes in their circadian gene expression when they take lithium.[ref][ref][ref][ref]

Alzheimer’s disease is also strongly linked to circadian disruption. [ref]

Prevention of lead toxicity:
A recent article hypothesized that some of the benefits reported for higher lithium levels in the drinking water (lower suicide rate, lower homicide and crime rates) could be due to lithium mitigating the effects of lead toxicity. “Animal studies demonstrated that lithium pre-treatment mitigates lead toxicity.”

Toxicity of lithium:
Lithium is considered by some to be an essential trace element, and a complete elimination of lithium causes a decline in fertility, higher mortality rates, and behavioral abnormalities.[ref] But, like all substances, there is always a toxic upper limit.

Patients taking lithium carbonate or lithium chloride for mood stabilization show a variety of side effects, depending on dosing. Most patients taking prescription lithium carbonate get blood tests done at regular intervals to determine their serum lithium levels. Plasma lithium levels above 1.2 mM cause nausea, diarrhea, and tremor. [ref]  Other side effects noted by patients taking lithium chloride include increased thirst and urination, weight gain, and mental dullness. It was theorized that bipolar patients taking lithium may drink more calories due to increased thirst, thus causing weight gain.[ref] Other side-effects of higher doses of lithium include increased risk of kidney problems and interaction with hypothyroidism.

Lithium orotate, as a supplement, comes in much, much lower doses than the lithium in prescription lithium carbonate. There is one case report, though, of nausea and mild tremor from a teenager taking 18 tablets of a supplement that contained 100mg of lithium orotate.

Side effects of Lithium Orotate:
There aren’t any recent research studies or case reports (other than the one above) on lithium orotate side effects, so this section is n=1 personal experiences and internet hearsay. A couple of people that I’ve talked with have reported that lithium may make them tired or a little sleepy during the day, but this was pretty subjective and could have been due to other reasons. An article from a holistic doctor who suggests lithium orotate to most of his patients notes that very few have any side effects. He does suggest taking lithium orotate before bed instead of during the day. This makes sense in light of the circadian rhythm effects via GSK-3B inhibition. A study from 1986 on using lithium orotate for alcoholism listed minor side effects to the treatment (included more than just lithium orotate -e.g. low carb diet and other supplements) as loss of appetite, mild apathy, and muscle weakness. [ref]


If after reading through all the information about lithium orotate you want to add it to your supplement list, here are a couple of brands that are well regarded by my family: Weyland’s Lithium Orotate and Seeking Health Lithium Orotate.

As with any supplement, I suggest talking with your doctor if you are on medication or if pregnant or nursing.

The study on stacking lithium with caffeine, theobromine, and catechin for an increased anti-inflammatory effect was interesting. If you are considering this combo, a good source of theobromine is cacao nibs.  Catechins and caffeine are found in green tea.




Alzheimer’s and Light at Night: Taking action to prevent this disease (Patrons only)

With the advent of consumer genetic testing from 23andMe, AncestryDNA, etc, it is now easy to know if you are at a higher risk of getting Alzheimer’s Disease (AD). Those with APOE ε3 are at a normal risk for Alzheimer’s, and those who carry an APOE ε4 allele (or two) are at an increased risk. 
This is a touchy subject for some people, so please think it through before you check to see your APOE type. 
One reason for learning your APOE type is to know if it is important to keep up with current research on preventing Alzheimer’s.  
While tons of research money over the last couple decades has been spent on trying to find drugs to stop the tangled accumulation of beta-amyloid plaque without much success, a new direction of research is looking into the tie to circadian rhythm dysfunction. I find this intriguing since the sudden increase in Alzheimer’s disease rate over the past few decades correlates with increasing chronic exposure to blue light at night, a circadian rhythm disruptor. 
It has long been known that circadian disruption is a part of AD. Called ‘sundowning’, Alzheimer’s patients often are more active or confused in the evening /night and sleepy during the daytime.
The chicken-or-egg question comes to mind: Is Alzheimer’s caused by changing circadian rhythms  –or–  is the circadian dysfunction being caused by the disease.
New research out this month may help answer that question.
The rest of this article is for patrons-only through Patreon


Building Up Iron: Check your genes to see how iron affects your health

Hemochromatosis is a fairly common genetic disease that causes iron to build up in the body. Knowing that you carry the genetic variants for hemochromatosis can literally add years to your life since you can prevent the buildup of iron through giving blood.

This is a personal cause for me, and getting the word out to as many people as possible is important because this is one bit of genetic information that can make a huge impact on the quality of life.

23andMe and Ancestry genetic data can tell you if you likely carry the genetic variant for hemochromatosis. Read on to find out how to check your data…

Background: What is hemochromatosis?

“Hereditary (genetic) hemochromatosis (HHC) an inherited disorder of abnormal iron metabolism. Individuals with hereditary hemochromatosis absorb too much dietary iron. Once absorbed, the body does not have an efficient way of excreting iron excesses.  Over time, these excesses build a condition of iron overload, which is a toxic [sic] to cells. Glands and organs, including the liver, heart, pituitary, thyroid, pancreas, synovium (joints) and bone marrow burdened with excess iron cannot function properly.  Symptoms develop and the disease progresses.”  Iron Disorders Institute

The most common type of hemochromatosis is Type 1, or Classic, and is usually caused by variants in the HFE gene.

Check Your 23andMe results for rs1800562 (HFE C282Y) (v.4 and v.5)

  • AA: most common cause of hereditary hemochromatosis, highest ferritin levels
  • AG: increased ferritin levels, check to see if compound heterozygous with rs1799945
  • GG: normal/ wild-type

Check your 23andMe results for rs1799945 (HFE H63D) (v.4 and v.5)

  • GG: can cause (usually milder) hemochromatosis, increased ferritin levels
  • CG: somewhat higher ferritin levels, check to see if compound heterozygous with rs1800562
  • CC: normal / wild-type

Check your 23andMe results for rs1800730 (HFE S65C) (v. 4)

  • TT: can cause (usually milder) hemochromatosis, increased ferritin levels
  • AT: possibly increased ferritin levels
  • AA: normal / wild-type

Iron Buildup in those Heterozygous for Hemochromatosis gene variants:

So you’ve checked your genetic data and found that you are heterozygous (one variant) for one of the HFE variants… While most of the official hemochromatosis sites will say that you are ‘just a carrier’, in actuality, it could be causing problems, just not to the extreme extent that being homozygous for the variant could cause.

Doctors and researchers seem to be focused (rightly so) on the long-term consequences such as liver failure and heart failure of extreme iron overload. But if you know that you genetically susceptible to building up iron, you can take action to avoid the irritations that come with too much iron, such as random joint pain, fatigue, and/or abdominal pain.

Recent studies showing higher disease risk due to HFE variants:

  • increased risk of non-alcoholic fatty liver disease [ref][ref]
  • metabolic syndrome  [ref]
  • cardiovascular disease [ref] including women with heterozygous variants [ref]
  • slightly higher risk of cancer [ref] meta-study [ref] breast cancer[ref] liver[ref]
  • musculoskeletal problems (osteoarthritis like symptoms) [ref]
  • high blood pressure [ref]
  • hyperuricemia (gout) [ref]
  • lung fibrosis  [ref]
  • diabetes[ref]
  • cardiovascular disease in kidney disease patients [ref]
  • increased lead levels [ref] [ref]

The Iron Disorders Institute includes these signs and symptoms of too much iron: chronic fatigue, joint pain, abdominal pain, liver disease, diabetes, irregular heart rhythm, skin color change, hypothyroidism, enlarged spleen, elevated blood sugar and more.


Middle-aged men and menopausal women who are heterozygous or homozygous for any of the HFE variants, should, in my non-medical doctor opinion, go get their serum iron, TIBC, and ferritin levels checked or ask their doctor to test them. In the US, you can order your own labs online through places like Ordering serum iron w/ TBIC and ferritin should give you enough information to know if you are storing too much iron.

If you have slightly elevated iron levels, the simplest way to manage iron levels is to give blood! You will probably feel good, and you will definitely help out someone else with your blood donation. If your iron test levels are really high, go to a doctor. Seriously.

Natural Iron Chelators and Inhibitors:

In addition to giving blood, natural and pharmaceutical iron chelators have been used to reduce iron levels in the body.[ref]

Quercetin, a flavonoid found in fruits and vegetables, has been studied for its iron chelating properties.[ref]  A 2017 study on dendritic (immune system) cells found that quercetin “increase extracellular iron export, resulting in an overall decrease in the intracellular iron content and consequent diminished inflammatory abilities.” And a 2014 study on quercetin concluded: “Potentially, diets rich in polyphenols might be beneficial for patients groups at risk of iron loading by limiting the rate of intestinal iron absorption.” Foods high in quercetin include apples, dark cherries, tomatoes, capers, onions, and cranberries. Quercetin supplements including pure quercetin powder are also readily available.

Another flavonoid, rutin, has also been studied for its iron chelation properties.[ref]  A 2014 study in rats found: “Rutin administration to iron-overloaded rats resulted in significant decrease in serum total iron, TIBC, Tf, TS%, ferritin levels…”  Foods high in rutin include capers, black olives, buckwheat, asparagus, and berries.  Rutin is also available as a supplement and in bulk powder.

Okra: A 2015 study found that okra “dramatically decreases intracellular iron levels in H63D cells compared to untreated cells”.[ref]  Time to make some gumbo!

Dietary phenols such as EGCG from green tea and grape seed extract also have been shown to inhibit iron uptake in the intestinal cells.  [ref]

The jury is still out on curcumin.  In a double-blind, placebo-controlled, randomized, cross-over study, curcumin was found to decrease hepcidin and increase ferritin.[ref]  Other studies, though, refer to curcumin as a possible iron chelator.[ref]

Taurine, in a mouse model of hemochromatosis, was found to protect against liver damage from excess iron.  The study is worth reading and looking into if you are worried about iron-induced liver damage.

Iron Fortified Foods…May, or may not, be a problem for those carrying the hemochromatosis genetic variants.  In the US, white rice and refined wheat products are fortified with iron.

  • A Swedish study looked at the effect of iron-fortified foods on iron absorption in men with hemochromatosis.  The study found that eliminating iron fortification from foods significantly reduced the iron absorbed by the men in the study.  The study also found that the time needed between phlebotomy (to maintain proper iron levels in hemochromatosis patients) was increased significantly.
  • A US study in 2012, though, declared that there is no evidence that dietary iron content made a difference in ferritin concentration.  (I actually don’t agree with their ability to draw that conclusion based on the method of doing the study.)  Basically, they gave 200 people (homozygous for the HFE C282Y variant and high serum ferritin levels) surveys asking for information on the type of diet they had eaten for the last few years as well as alcohol intake.    Then they compared the survey data to their serum ferritin levels to look for a correlation and drew the conclusion that iron intake doesn’t impact hemochromatosis. [ref]
  • A few studies have looked at the impact of the overabundance of iron on obesity.   But while the risk for each of these diseases increases with higher ferritin levels, no one seems to be publishing studies showing that iron fortification is causing them.

The Science behind Iron Overload:

Hepcidin is the iron regulatory hormone produced by the liver. Hepcidin was discovered and named in 2000, and scientists have since figured out that it controls the regulation of iron in the body and responds to lipopolysaccharides to prevent iron-loving bacteria from reproducing rapidly.  [ref]

“Hereditary hemochromatosis is caused by a deficiency of the iron-regulatory hormone hepcidin (Ganz and Nemeth, 2011). Hepcidin is a 25 amino acid peptide secreted by hepatocytes. It controls iron concentrations in extracellular fluid and blood plasma by regulating the amount of ferroportin, the sole known cellular iron exporter. Ferroportin transports absorbed, recycled or stored iron from tissues into plasma (Donovan et al., 2005). Hepcidin binding to ferroportin triggers its degradation, resulting in the decreased transfer of iron to plasma and consequently hypoferremia (Nemeth et al., 2004b). During infections or in response to injection of microbial molecules, hepcidin production is greatly enhanced (Armitage et al., 2011; Rodriguez et al., 2014), stimulated by inflammatory cytokines including IL-6 (Nemeth et al., 2004a; Rodriguez et al., 2014) and possibly activin B (Besson-Fournier et al., 2012). It has been proposed that hepcidin-mediated hypoferremia functions as a host defense mechanism that evolved to restrict iron availability for pathogen growth (Drakesmith and Prentice, 2012; Ganz, 2009) but this has never been demonstrated. Hepcidin was also reported to have direct bactericidal activity in vitro (Krause et al., 2000; Park et al., 2001), but the effect is seen only at unphysiologically high concentrations.” –

Other Genes Involved:

Not everyone who is homozygous for the hemochromatosis variants will develop iron overload.  Diet and lifestyle play a role in the rate at which iron accumulates. Additionally, there are other genes that play a role in ferritin levels and iron levels in the body. Some of these are listed below:

  • BMP2 gene: rs235756 (v.4)-A allele is associated with higher ferritin levels with HFE variants (several studies) [ref] [ref]
  • BTBD9 gene: rs3923809 (v.4 and v.5)-G allele is associated with higher ferritin levels [ref]
  • HBS1L-MYB gene: rs4895441 (v.4 and v.5)- G allele protects against anemia [ref]
  • SLC40A1 gene: rs1439816 (not in 23andME v.4/v.5 data) – C allele may lead to more liver damage [ref] [ref]
  • TMPRSS6 gene: rs855791 (v.4 and v.5)- G allele associated with higher iron stores in men [ref
  • SLC40A1 gene: rs11568350 (not in 23andMe data) (Q248H) – leads to higher ferritin levels

Rare genetic forms of hemochromatosis (mostly non-HFE):

  • Hemochromatosis type 2A: listed in 23andMe as i5001498 (T is the risk allele)(v.4 and v.5)[ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5001502 (A is the risk allele)(v.4 and v.5) [ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5001501 (C is the risk allele)(v.4) [ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5000096 (T is the risk allele)(v.4) [ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5001503 (T is the risk allele)(v.4) [ref]
  • Hemochromatosis type 4: rs28939076 (T is the risk allele)(v.4) [ref]
  • Hemochromatosis type 4: i5006507 (T is the risk allele)(v.4)[ref]
  • Hemochromatosis type 4: i5006505 (A is the risk allele)(v.4)[ref]
  • Hemochromatosis type 2B: listed in 23andMe as i5003867 (T is the risk allele)(v.4) [ref]
  • Hemochromatosis type 1: i5012781 (C is the risk allele)(v.4) [ref]
  • Hemochromatosis type 1: i5012784 (C is the risk allele)(v.4) [ref]
  • Hemochromatosis type 1: rs1800562 (A is the risk allele) (v.4 and v.5) [ref]

Final thoughts…

Bloodletting in 1860. Public domain photo from Burns archive.

It hit me while researching all of this, that the bloodletters of yesteryear probably did some good for the minority of people who were overloaded with iron. Leeches to reduce blood and iron stores were probably effective against bacterial infections from iron-loving bacteria.

Fortification of iron into all wheat product in the US, which began in the 1940’s, is good for children and most women of childbearing age, but it adds to the iron overload burden for some men and older women.  When looking at the forced fortification of foods with iron and folic acid, it really does seem that the policymakers are focused on the majority, at the expense of a minority who genetically are harmed by it.  Since iron can takes decades to build up in the body, it may be that we are now seeing the consequences in the baby boomer generation.


More to read:




SOD1: Genetic Variants in Our Antioxidant Defense System

SOD1 AntioxidantsSuperoxide dismutase 1 (SOD1) is the gene that codes for the copper-zinc superoxide dismutase enzymes which help protect against oxidative stress and detoxify reactive oxygen species.

Three types of superoxide dismutases are part of our built-in antioxidant system:  SOD1, found in the cytosol or fluid in cells; SOD2, a mitochondrial antioxidant; and SOD3, which is extracellular.[ref]

SOD1 binds copper and zinc ions and destroys free radicals.  It is an ‘antioxidant’ that our body produces which converts superoxide radicals into oxygen and hydrogen peroxide.  The hydrogen peroxide then can be broken down by other enzymes.  Reactive oxygen species do have a role in health, but they need to be in balance with antioxidants.

SOD1 variants cause either an increase or decrease of enzyme activity.  Mutations in SOD1 have been linked with several diseases including an inherited form of ALS (Lou Gehrig’s disease). [ref]  More common variants are linked with conditions such as diabetes and hearing damage.

SOD1 Genetic Variants:

SOD1 variants have also been studied in regards to nephropathy (kidney disease) and cardiovascular events in people with type 2 diabetes.  A 2012 study of 3,744 people with diabetes found that rs1041740 was associated with microalbuminuria, which is caused by kidney problems, as well as an increased risk of death due to cardiovascular reasons.  The risk of death from heart disease isn’t limited just to those with type 2 diabetes, as a 2016 study showed an increased risk of death from heart disease for those who were homozygous for the T allele.

In type 1 diabetes, oxidative stress plays a role in kidney disease.  SOD enzymes protect against kidney disease through detoxifying reactive oxygen species.  In a 2011 study of 1,258 type 1 diabetics (Caucasian), the T-allele of rs1041740 was associated with a more than 5 times greater risk of kidney disease. [ref]

Check your 23andMe results for rs1041740:

  • TT: increased risk for kidney problems in diabetes, increased risk of death from heart disease
  • CT: increased risk of kidney disease in T1D
  • CC: normal

Oxidative stress is thought to play a role in Alzheimer’s disease as well, and SOD1 variants have been studied to see if they affect the risk of Alzheimer’s.  For rs2070424, the G allele was found to be protective against Alzheimer’s disease regardless of APOE gene status. [ref] [ref](See my article on APOE and Alzheimer’s to determine your APOE type.)

Check your 23andMe results for rs2070424:

  • AA:  normal
  • AG:  protective against Alzheimer’s Disease (OR=0.47)
  • GG:  higher SOD1 enzyme activity, protective against Alzheimer’s Disease (OR=0.47) [ref] protective against myelomeningocele (neural tube defect) [ref]

Hearing loss is also associated with SOD1 antioxidant activity. In one study, the GG genotype of rs10432782 was associated with higher risk of noise induced hearing loss.  That GG genotype of rs10432782 also showed higher SOD1 activity. [ref]

Check your 23andMe results for rs10432782:

  • TT:  wildtype
  • GG:  higher SOD1 enzyme activity, greater risk of noise induced hearing loss [ref]

Nutrition Plays a Role…

  • There are SOD supplements by Seeking Health made from extramel melon juice.   The reviews seem pretty good, but I haven’t tried it myself.
  • Acai freeze dried powder, in an animal model of SOD1 deficiency, was found to increase healthy aging and reduce oxidative damage.  Freeze dried Acai powder can be found online, and acai juice can be found in most grocery stores.
  • Resveratrol was found to increase SOD1 activity in a couple of studies, but other studies didn’t find much of an effect.
  • Copper and Zinc are needed by the body for normal SOD1 function.  Copper deficiency is associated with reduced SOD activity, but always be sure to do a blood test to make sure that you are deficient in copper before thinking about supplementing with it.

More to Read…
Superoxide Dismutase supplement pill SOD  benefit and risk, by Ray Sahelian, M.D.

Alzheimer’s and APOE type

Alzheimer's DiseaseOne very important gene that has been researched in association with Alzheimer’s disease is the APOE gene, which is involved in carrying cholesterol and other fats in your bloodstream.

Late-onset Alzheimer’s disease (after age 60) is thought to be influenced both by genes and by environmental factors, so keep in mind when looking at your genetic risk that your genes are only one part of the equation when it comes to Alzheimer’s (and many other diseases!).  But knowing your risk can help you to understand the importance of doing all that you can to prevent AD.

Your APOE type is defined as different alleles (ε2, ε3, or ε4), and you will have one APOE allele from each parent.

From the NIH website:

  • “APOE ε2 is relatively rare and may provide some protection against the disease. If Alzheimer’s disease occurs in a person with this allele, it develops later in life than it would in someone with the APOE ε4 gene.
  • APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
  • APOE ε4 is present in about 10 to 15 percent of the population and in about 40 percent of all people with late-onset Alzheimer’s. People who develop Alzheimer’s are more likely to have an APOE ε4 allele than people who do not develop the disease.”

To determine your APOE type from your 23andMe data or other genetic data, you will need to look at the following rsid’s: rs429358 andrs7412.

APOE Allele rs429358 rs7412 Risk of Alzheimer’s
ε2/ε2 TT TT lower than normal
ε2/ε3 TT CT lower than normal
ε2/ε4 CT CT slightly higher than normal
ε3/ε3 TT CC normal
ε3/ε4 CT CC higher than normal
ε4/ε4 CC CC highest risk


Again, your genetic risk isn’t the only factor involved in getting Alzheimer’s Disease.  Some people who have the highest risk factors will never get the disease.

Lifehacks for Preventing Alzheimer’s Disease:

If you are at an increased risk of Alzheimer’s, the key is to use this knowledge to do all that you can to decrease your risk. Below are a few studies that I’ve read through on the topic. This is not an exhaustive list by any means, and I highly encourage you to keep up to date with current information on the topic.

Circadian Rhythms, Sleep, and Melatonin:
From what I’ve read on the topic, number one on my list for preventing Alzheimer’s is to block blue light at night with some nerdy-looking orange glasses.

Quite a few studies have found a link between sleep quality and the risk of dementia or Alzheimer’s. Our natural circadian rhythm causes melatonin to rise in the evening and stay elevated until morning. Light in the shorter, blue wavelengths signals through receptors in our eyes to turn off melatonin production in the morning. Our modern reliance on lights at night, especially from TVs and phones, is disrupting the natural circadian rhythms.

Blue-blocking glasses, worn in the evening for several hours before bed, have been shown to increase natural melatonin production by about 50% in just two weeks. More and more research studies are showing a connection between circadian rhythm disruption, melatonin, insulin regulation, and healthy brain aging.[study][study][study] Trials are also evaluating the use of melatonin supplements for Alzheimer’s[study].

There have been several studies showing that both aspirin and non-aspirin NSAID use reduced the risk of Alzheimer’s Disease.  Keep in mind that these are population-wide studies that don’t take into account genetic differences; you also need to weigh the risk of liver damage from long-term NSAID usage. Two good studies to read:  Nonsteroidal Antiinflammatory Drugs and the Risk of Alzheimer’s DiseaseAnti-inflammatory drugs and risk of Alzheimer’s disease: an updated systematic review and meta-analysis

Cardiovascular Health:
There have been several studies that link cardiovascular health markers to the risk of Alzheimer’s.  One study showed that an elevated homocysteine level is associated with higher risk of Alzheimer’s. Homocysteine levels are often genetically related to your MTHFR genes, methylation, and your B6 and B12 levels. (Overall, though, carrying the MTHFR variant doesn’t seem to be a risk factor for Alzheimer’s unless homocysteine is high)

Additionally,  staying active, eating well, and keeping your blood pressure low should lower your risk of Alzheimer’s.

Alcohol Consumption:
A 2014 study found that for older adults who carry the APOE e4 polymorphism, light to moderate drinking increased their risk for cognitive decline.  From the study: “Light and moderate alcohol consumption during late life was associated with greater decline in learning and memory among APOE e4 carriers, whereas light and moderate alcohol consumption was associated with an increase in learning and memory among non-APOE e4 carriers. There was not a significant interaction between midlife alcohol consumption status and APOE e4 on the trajectory of learning and memory.[ref]”

There have been lots of studies on antioxidants and Alzheimer’s disease; unfortunately, most are contradictory or inconclusive. Eating a healthy diet is, of course, always a good idea. Luteolin, an antioxidant flavonoid, has been studied recently with interesting potential as far as Alzheimer’s.[ref]

One mineral that has been tied to a reduced risk of Alzheimer’s is lithium. Lithium is naturally found in food sources; most people consume to be between .1 and 1 mg per day from food. High doses of lithium, such as prescription doses for bipolar disorder, come with side-effects and long-term health risks — along with a decreased risk of dementia. But what about low doses of lithium as a mineral supplement? One study showed that low doses of lithium helped AD patients to have no decrease in cognitive impairment over 15 months. You can buy lithium in 5mg doses as a supplement. There are interactions between lithium and several prescription drugs, so always check before starting any supplement. Here is another source that looks at several studies on lithium.

More reading: