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Understanding the Heritability of Teeth Cavities

Catherine on April 10, 2025

Disclaimer: This article is for informational purposes only and is not intended for diagnostic use. LifeDNA does not provide diagnostic reports on any traits discussed. Genetics is just one piece of the puzzle; please consult a healthcare professional for comprehensive guidance on any health condition.

Overview

We’ve all heard it before, “Brush your teeth or you’ll get cavities!” While oral hygiene, diet, and dentist visits undeniably plays an important role in dental health, an important question remains, can your genes be partly to blame for your cavities?

Understanding both genetic and non-genetic factors is essential because it gives us a more complete picture of what truly affects dental health. This may help individuals make informed choices, have specific preventive care more effectively, and even lead to personalized dental treatments in the future.

What Are Cavities?

Dental cavities, or caries, are permanent damage to the tooth’s surface caused by bacteria that feed on sugars and release acids. These acids erode tooth enamel and can lead to painful infections if untreated. While brushing, flossing, and reducing sugar intake are key preventive strategies, not everyone with good oral hygiene avoids cavities and not everyone with poor habits gets them.

Genes That Shape Your Teeth

Several specific genes influence tooth development, enamel formation, and salivary composition each of which can affect your risk for cavities.

Multiple studies have revealed that mutations in genes like ENAM (enamelin) and AMELX (amelogenin) are linked to enamel defects that make teeth more vulnerable to decay. Other enamel matrix genes also play a role in determining the thickness and mineralization of enamel. Even minor differences in enamel quality due to genetic variation can significantly influence decay risk.

Genes influencing saliva composition can also influence cavity risk. Saliva does more than just help you chew, it neutralizes acids, remineralizes teeth, and carries protective proteins.

Variants in genes such as MUC7, which influence salivary mucin production, may alter its antimicrobial and buffering properties. Studies conclude that people with specific variants may have reduced protection from acids and harmful bacteria, increasing their risk of developing cavities.

Saliva-related gene expression also appears to differ in individuals with high versus low caries risk, suggesting that personalized saliva profiles—shaped by genetics—might one day be used to predict or prevent cavities.

One of the strongest types of evidence pointing to a genetic link in cavities comes from studies on twins. Identical twins share 100% of their genes, while fraternal twins share about 50%. Comparing dental health between these groups helps researchers understand the role of heredity.

Multiple twin studies have found that genetic factors contribute significantly to an individual’s risk of developing dental caries. Heritability estimates have ranged from 20% to 65%, indicating that a substantial portion of cavity risk could be inherited. The higher similarity in decay rates among identical twins compared to fraternal twins strongly supports the role of genetics.

Immune System Genes and the Battle Against Bacteria

Tooth decay is caused by bacteria—but not everyone’s immune system responds to these invaders in the same way. Some people may be genetically better equipped to fight off harmful microbes in their mouths.

Genetic variation in immune response genes, such as those encoding cytokines and toll-like receptors, can influence caries susceptibility. Polymorphisms in genes like IL1B and TLR2 may lead to stronger or weaker inflammatory responses. Research says that Inadequate immune responses may allow decay-causing bacteria to flourish, while overly aggressive responses could damage oral tissues.

The Role of the Oral Microbiome

Each of us hosts a unique mix of bacteria in our mouths, known as the oral microbiome. While shaped by environment and diet, genetics may also play a role in determining which microbial communities dominate.

Evidence shows that the host genome can influence the composition of the oral microbiome, meaning your genes may indirectly affect your cavity risk by altering the oral environment to be more or less favorable for harmful bacteria.

For example, genetic differences that affect saliva’s mineral content could lead to microbial imbalances that raise your risk of decay.

Can Genetic Testing Predict Cavities?

While multiple studies have proposed integrating genetic risk factors into dental care, current findings may not be strong enough to support widespread predictive testing.

Many of the identified genetic variants have only small effects on their own. Tooth decay likely results from a complex interaction of many genes, each contributing a small part, along with lifestyle and environmental factors as suggested by some recent genome-wide association studies (GWAS).

Nosingle “cavity gene” has been found. Still, as more genetic data is gathered, future breakthroughs may make genetic testing a practical part of oral care planning.

Personalized Oral Health

Gene expression profiles in saliva may serve as non-invasive biomarkers to predict caries risk and allow for proactive, individualized care.

Another key takeaway is the role of education and awareness in applying genetic insights. If people understand that they may be genetically predisposed to cavities, they might be more motivated to take preventive actions.

For parents, this could mean early interventions for children at risk, such as dental sealants or frequent fluoride varnish treatments. It also reduces blame or stigma around dental issues that may not be fully preventable, even with good hygiene.

References:

Understanding Inclusion Body Myositis

Catherine on April 7, 2025

Overview

Inclusion Body Myositis (IBM) is a rare and progressive muscle disorder that primarily affects adults over the age of 50. It causes slow but steady muscle weakness, especially in the arms and legs. While IBM is often mistaken for other types of inflammatory muscle disease, it stands apart due to its unique cellular changes and resistance to most conventional treatments.

While the exact cause of Inclusion Body Myositis remains unknown, researchers have identified several contributing factors that appear to play a role in its development. These include autoimmune activity, abnormal protein buildup, and age-related cellular changes.

You might want to read: The Genetics of Age-related Muscle Mass Loss

Causes of Inclusion Body Myositis

The exact triggers of IBM are not fully understood, but researchers believe it develops due to a combination of immune system issues and underlying cellular defects. Key contributing factors include:

Autoimmune response
IBM is classified as an inflammatory myopathy, which means the body’s immune system mistakenly attacks its own muscle tissue. This autoimmune reaction leads to chronic inflammation and progressive damage to muscle fibers.
Protein misfolding and accumulation
A hallmark of IBM is the buildup of abnormal clumps (inclusion bodies) inside muscle cells. These clumps are made of misfolded proteins that the body fails to clear. The presence of these inclusions is what gives IBM its name and contributes to muscle degeneration.
Genetic susceptibility
While IBM is not typically inherited in a straightforward way, certain genetic aspects(like variations in the HLA-DRB1 gene) may increase the risk. These genetic variants may influence immune function or how cells process and remove damaged proteins.
Age-related changes
IBM mostly affects people over 50, suggesting that aging muscles may be more vulnerable to the underlying disease processes. As we age, the body becomes less efficient at managing inflammation and repairing damaged tissue.

Symptoms of Inclusion Body Myositis

IBM usually progresses slowly over several years, with symptoms that can vary from person to person. Common signs include:

Weakness in the thighs and forearms
IBM tends to affect specific muscle groups, particularly the quadriceps (front thigh muscles) and finger flexors (muscles used to grip). This leads to difficulty rising from chairs or holding objects.
Frequent falls and unsteady walking
Leg weakness often causes people with IBM to lose balance or trip easily. Falls become more common as the condition progresses.
Difficulty swallowing
Involvement of the throat muscles can make swallowing difficult, increasing the risk of choking or aspiration pneumonia.
Wasting or shrinkage of muscles
As muscle tissue deteriorates, visible muscle wasting (atrophy) may occur, especially in the forearms and thighs.
Slow but steady progression
IBM develops gradually over time and may take years before becoming significantly disabling. Unlike other forms of myositis, it typically does not respond to steroids or immunosuppressants.

Genetics on IBM

Research studies have looked at immune-related genes and found that certain variations in the HLA-DRB1 gene may increase the risk of IBM. These variations affect specific amino acid coding positions in the gene, possibly changing its function, which could help explain why some people are more likely to develop the disease. Another gene, CCR5, has also shown a possible link to IBM, suggesting there may be shared genetic features between IBM and other autoimmune diseases. In addition, rare genetic changes have been discovered in genes like VCP, SQSTM1, and FYCO1, which are involved in how the body breaks down damaged proteins. Studies also found large mitochondrial DNA deletions in certain muscle cells, suggesting that mitochondrial damage could be part of IBM as well. Similar findings have been reported by a more recent study on mitochondrial DNA variants in IBM. Altogether, these findings support the idea that IBM is caused by a combination of immune system problems, protein breakdown issues, and mitochondrial dysfunction. Scientists now believe that inflammation in the muscles may come first, leading to a buildup of damaged proteins and mitochondrial changes. Different research approaches have helped uncover these clues, and ongoing global studies are collecting more samples to improve future research. Larger studies that include diverse populations, along with advanced genetic testing methods like whole-exome and whole-genome sequencing, are expected to reveal even more about how genetics contributes to IBM.

How to Care for Someone with Inclusion Body Myositis

While there is no known cure for Inclusion Body Myositis (IBM), supportive care can make a significant difference in a patient’s quality of life. Physical therapy plays an important role in helping maintain mobility and muscle strength through gentle, customized exercises that avoid overexertion. Occupational therapy is also valuable, offering practical tools and adaptations to support daily tasks as fine motor skills decline. As leg weakness progresses, mobility aids such as canes, walkers, or wheelchairs may become necessary to prevent falls and maintain independence.

For those experiencing swallowing difficulties, working with a nutritionist or speech therapist can help modify diets to ensure safe and adequate nutrition. Emotional support is equally crucial—living with a chronic, progressive condition can be isolating, so having access to support groups, therapy, and a strong social network can help ease the psychological burden. Regular visits to a neurologist are essential to monitor progression and manage emerging symptoms. In some cases, patients may also qualify for clinical trials exploring potential new treatments. A coordinated, multidisciplinary approach remains the best strategy for managing IBM over time.

Can You Get Tested for Inclusion Body Myositis?

Diagnosing IBM can be challenging because its symptoms often resemble other muscle diseases like polymyositis or ALS. However, there are several ways to confirm it:

Blood tests
These may show elevated muscle enzymes like creatine kinase (CK), but levels are usually only mildly increased in IBM.
Electromyography (EMG)
This test measures electrical activity in muscles and helps identify patterns consistent with IBM-related muscle damage.
Muscle biopsy
A definitive diagnosis usually requires a biopsy, where a small sample of muscle tissue is analyzed under a microscope. Inclusion bodies and other cellular changes are key markers of IBM.
Genetic and immune testing
While there is no standard genetic test for IBM, some individuals may benefit from genetic screening to identify genetic variants like those in HLA-DRB1. Research is ongoing into the genetic underpinnings of IBM, and new insights may shape future diagnostics.

If you’re experiencing unexpected muscle weakness or other concerning symptoms, speak with a healthcare provider. A neurologist or rheumatologist familiar with neuromuscular disorders is best equipped to assess and guide you through the appropriate tests.

References

https://my.clevelandclinic.org/health/diseases/15700-inclusion-body-myositis

Genetics of Pernicious Anemia

Catherine on April 6, 2025

Overview

Pernicious anemia may sneak up on someone without them realizing that they actually have a serious condition. At first, they might just feel tired or experience brain fog, symptoms easy to brush off as everyday stress or busy life. But underneath, their body isn’t absorbing enough vitamin B12 because of an immune system issue. Genetics may also play a role, making some people more likely to develop this condition. Knowing about these hidden connections can help them get diagnosed and treated sooner.

Recent statistics shows that Pernicious anemia typically affects people between the ages of 60 and 80, especially those of Northern European descent. In the United States, it is estimated to affect about 151 in every 100,000 people. Although it is more common in this group, anyone may develop the condition.

Understanding this condition is important because the early symptoms are often subtle and easy to miss. If this is left untreated, it may lead to serious complications, including nerve damage and cognitive issues. Being aware of the symptoms and risk factors may help people seek timely medical advice and improve their quality of life.

What Is Pernicious Anemia?

Pernicious anemia is a type of megaloblastic anemia, a type of anemia where the body produces unusually large and immature red blood cells that don’t work properly. This happens because the body lacks important nutrients, usually vitamin B12 or folate (vitamin B9) that are needed to make healthy red blood cells. As a result, the blood can’t carry enough oxygen to the body’s tissues, causing symptoms like tiredness and weakness.

The root cause is typically an autoimmune response that attacks the stomach’s parietal cells or intrinsic factor, a protein necessary for vitamin B12 absorption. Without adequate vitamin B12, the body can’t produce healthy red blood cells, leading to symptoms like fatigue, weakness, numbness, and cognitive difficulties.

You may want to read: How Genetics May Affect Vitamin B12 Levels

What Are the Symptoms of Pernicious Anemia?

Pernicious anemia symptoms often develop slowly and may be mistaken for other conditions, especially in the early stages. Because vitamin B12 is involved in red blood cell formation and neurological health, symptoms can affect many systems in the body.

Common Symptoms Include:

Fatigue and Weakness:
As red blood cell production declines, less oxygen circulates through the body, leading to persistent tiredness and a feeling of weakness even after rest.
Pale or Yellowish Skin:
The lack of healthy red blood cells may cause the skin to look pale, while the breakdown of defective red cells can give the skin a slightly yellow tone.
Shortness of Breath and Dizziness:
Low red blood cell count reduces oxygen delivery, making people feel out of breath during activities or even at rest.
Numbness and Tingling in Hands and Feet:
deficiency in vitamin B12 can lead to peripheral nerve damage, causing sensations like pins and needles—especially in the extremities.
Balance and Coordination Problems:
Nerve damage can also impact motor control, resulting in difficulty walking, poor coordination, or frequent falls.
Cognitive Issues:
Many people with untreated pernicious anemia experience brain fog, memory loss, and even mood changes like irritability or depression.
Glossitis and Mouth Ulcers:
Inflammation of the tongue (glossitis) can cause pain, redness, and a smooth appearance. Mouth sores are also common.
Digestive Symptoms:
Some may experience nausea, bloating, or appetite loss, especially if the autoimmune response affects stomach lining function.
Fast Heart Rate or Irregular Heartbeats:
In response to low oxygen levels, the heart may beat faster to compensate, potentially leading to palpitations or arrhythmia.

Causes of Pernicious Anemia

Primary Causes:

The main cause of pernicious anemia is when the body’s immune system makes a mistake and attacks components in the stomach that help absorb vitamin B12. Normally, special cells in the stomach called parietal cells make a protein called intrinsic factor. This protein is needed to help the body take in vitamin B12 from food.

In people with pernicious anemia, the immune system creates antibodies that destroy these parietal cells. Sometimes, the antibodies attack the intrinsic factor protein itself, stopping it from working properly. Because of this, the body can’t absorb enough vitamin B12, which is important for making healthy red blood cells. Also, long-term swelling and damage in the stomach lining, called autoimmune gastritis, often happens along with pernicious anemia and makes the problem worse.

Other Contributing Factors:
Aside from problems with the immune system, other things may raise your chances of getting pernicious anemia. Your genes play a big part, but some people are born with genetic variation that makes their immune system more likely to attack the lining of the stomach. If you have family members with autoimmune diseases like type 1 diabetes or thyroid problems, your risk may be higher too. Age matters as well, and people over 60 get this condition more often.

Genetic Studies on Pernicious Anemia

Researchhas shown that pernicious anemia is closely linked to genetics and the immune system. Researchers analyzed the DNA of over 2,000 people with pernicious anemia and compared it to more than 650,000 people without the condition. They discovered several genetic markers that are much more common in those affected.

Three large European biobanks were used: the Estonian Biobank (EstBB), UK Biobank (UKBB), and FinnGen. In Estonia, 378 cases and over 138,000 controls were identified, with a disease rate of 0.3%. In the UK, 754 cases and 390,000 controls were found, with a rate of 0.2%. In Finland, researchers looked at a broader category called “Vitamin B12 deficiency anemia,” identifying 1,034 cases and 131,000 controls, with a rate of 0.8%. All studies applied a special analysis method that adjusted for factors such as age, sex, and genetics. The combined results from these populations were analyzed together in a meta-analysis to better identify genetic links to the disease.

The meta-analysis pinpointed five specific genetic variants strongly associated with pernicious anemia. These variants are located on Chromosome 1 (rs6679677), Chromosome 2 (rs12616502) , Chromosome 6 (rs28414666), Chromosome 10 (rs2476491) , and Chromosome 21 (rs74203920). Importantly, these findings were consistent across all three biobanks, confirming the genetic basis of this autoimmune form of vitamin B12 deficiency. The genetic markers are near genes involved in immune system function and other autoimmune conditions, suggesting that inherited immunological traits may increase the risk of developing pernicious anemia. Overall, this research confirms that genetics plays a significant role in pernicious anemia..

Management and Treatment

The primary approach to managing pernicious anemia involves restoring and maintaining adequate levels of vitamin B12, typically through intramuscular injections since the body cannot absorb the vitamin naturally due to the lack of intrinsic factor. Once B12 levels stabilize, some patients may switch to high-dose oral supplements under medical supervision. Treatment is ongoing and often lifelong, as the underlying absorption issue remains. In certain cases, antibiotics may be prescribed if intestinal bacteria are interfering with B12 absorption. Many individuals begin to feel better within days of starting treatment, although it may take several weeks for noticeable improvements. Long-term management generally requires regular monitoring and continuous supplementation to prevent recurrence and complications.

LifeDNA and Vitamin B12

LifeDNA offers a personalized Vitamins and Supplements Report based on your DNA to help you understand your body’s unique nutritional needs. This includes insights on Vitamin B and D levels, giving you a clearer picture of what your body may need.

Vitamin B12 is one of the essential nutrients covered in these reports. Since the body doesn’t produce B12 naturally, it must come from food or supplements. Good sources include eggs, red meat, soy, nuts, seeds, shellfish, leafy greens, mushrooms, and bananas. While the recommended daily amount for adults is 2.4 mcg, higher amounts—up to 1000 mcg—may be needed for those with a deficiency. Fortunately, excess B12 is typically excreted through urine, making it safe to take more than the minimum.

References

Genetics and Response to Metformin

Catherine on April 5, 2025

Overview

Metformin is one of the most commonly prescribed medications for type 2 diabetes. It helps control blood sugar, is generally well-tolerated, and it is studied for its potential benefits as an anti-aging and cancer prevention agent. But here’s a little catch you need to know; not everyone responds to metformin the same way.

While metformin works well for some people, others may get more side effects or see little improvement. The answer lies in our genes. In recent years, researchers have begun uncovering how genetic differences affect our response to this medication. If you’re planning on taking Metformin, understanding how your DNA may influence its effectiveness to personalize your treatment plan and improve outcomes is important.

You may want to read: Are You Always Craving Sugary Drinks? Your Genetics May Be the Cause

What Is Metformin?

Metformin is a medication commonly used to help people with type 2 diabetes manage their blood sugar levels. It is often the first treatment doctors recommend because it works well and doesn’t usually cause weight gain or dangerously low blood sugar levels like some other diabetes medicines.

Metformin is approved by the FDA and is most effective when combined with healthy habits like eating well and exercising regularly. By keeping blood sugar levels in a healthy range, metformin can help prevent serious long-term problems such as kidney damage, nerve pain, vision loss, foot or leg amputations, and even heart attacks or strokes.

In addition to diabetes, metformin is also being studied for other health conditions, including polycystic ovary syndrome (PCOS), obesity, and aging.

How Does Metformin Work?

Metformin helps lower blood sugar in three important ways:

It reduces how much sugar the liver makes: The liver naturally produces glucose, but metformin slows this process down so less sugar enters the bloodstream.
It helps the body respond better to insulin: Insulin is the hormone that helps move sugar from the blood into the cells. Metformin makes the body more sensitive to insulin, so sugar is used more efficiently.
It lowers the amount of sugar absorbed from food: After eating, some sugar from food gets absorbed into the blood through the intestines. Metformin helps reduce this absorption, which keeps blood sugar from rising too high.

Why People Respond Differently to Metformin

While metformin works well for many, about 1 in 3 people either don’t get optimal results or experience side effects like nausea, diarrhea, or abdominal pain. For some, this leads to stopping the medication altogether. One major factor is our genetic variation. Your DNA may influence how your body absorbs metformin or your liver and kidneys process it and how sensitive your cells are to insulin.

A seminal genome-wide association study (GWAS) discovered that genetic differences help explain why people respond differently to metformin, the most widely used drug for type 2 diabetes (T2D). Researchers studied over 13,000 individuals from diverse ethnic backgrounds and discovered that a variant in the SLC2A2 gene, which affects the glucose transporter GLUT2, is linked to a significantly stronger response to metformin. People with this variant have reduced GLUT2 activity, limiting glucose processing in the liver—an effect that metformin helps reverse. The variant was also associated with higher body weight, potentially explaining why metformin often works best in overweight patients. These findings support a move toward precision medicine in diabetes care, suggesting that some patients may benefit from higher doses or earlier intervention based on their genetic profile.

Several recent pharmacogenetic studies have demonstrated that variations in genes encoding various cellular transporters are associated with metformin pharmacokinetics, pharmacodynamics and metformin response.

Known Factors Affecting Metformin Response

While genetics provide valuable insight, they represent only one aspect of the overall picture. Several other factors can significantly influence an individual’s response to metformin. However, these factors may also be affected by your genetic make-up.:

Diet and Exercise Habits – What you eat and how active you are can impact blood sugar control and insulin sensitivity, which can affect metformin’s effectiveness.
Other Medications – Some drugs may interact with metformin, either enhancing or reducing its effects.
Liver or Kidney Function – Since metformin is processed by the liver and excreted by the kidneys, impaired function in these organs can alter how the drug works.
Gut Health and Microbiome – A healthy balance of gut bacteria can influence how metformin is absorbed and metabolized.
Age and Hormone Levels – Age-related changes and hormonal shifts (such as during menopause or puberty) can affect insulin response and how the body processes medication.

How Genetics May Affect Metformin Side Effects

Metformin is a commonly used medication, especially for type 2 diabetes and sometimes PCOS. While it works well for many people, some experience uncomfortable side effects—and your genes could be part of the reason why. Let’s look at some of these symptoms and how your body’s natural makeup might influence them.

Unusual Muscle Pain: Muscle pain while taking metformin can be a sign of a rare but serious problem called lactic acidosis. Some people’s bodies process metformin more slowly, which can cause it to build up and lead to this condition. If you’re more sensitive to metformin, your muscles might ache even with normal doses.
Feeling Cold: Feeling cold can also be linked to how your body handles metformin. If metformin builds up in your system or affects your energy levels, you might feel chilly or have trouble staying warm. This is more likely if your body naturally clears the medicine more slowly.
Trouble Breathing: Difficulty breathing is another serious sign that metformin might not be agreeing with you. Some people are more prone to having low energy production in their cells when taking metformin, which can lead to breathing problems—especially if too much of the medicine stays in the body.
Feeling Dizzy, Light-Headed, Tired, or Very Weak: If you feel faint, tired, or unusually weak, your body might be reacting strongly to the effects of metformin. Some people experience drops in blood sugar or shifts in energy levels more easily, depending on how their body processes the medication.
Stomach Pain, Vomiting: Stomach issues like cramps, pain, or vomiting are some of the most common side effects. But some people feel these more intensely. Your genes may make your stomach more sensitive to metformin, leading to stronger reactions even if you’re taking the standard dose.
Slow or Irregular Heart Rate: A very slow or uneven heartbeat can happen if metformin affects the balance of fluids or energy in your body. If your system doesn’t handle the drug efficiently, this kind of side effect can be more noticeable.

Can You Get Tested for Metformin Sensitivity?

Some health and wellness companies offer genetic tests that look at your DNA to see how you might respond to metformin. These tests check for specific genetic differences that can affect how well metformin works for you or whether you might experience side effects.

Although these genetic tests are not yet used by doctors to officially prescribe or adjust metformin, they can still be helpful. Knowing your genetic information can make it easier to talk with your doctor and may help you:

Have more realistic expectations about how metformin might work for you.
Avoid guessing and reduce the time spent trying different treatments.
Lower your chances of experiencing uncomfortable side effects.
Think about other treatment options sooner if metformin isn’t the best fit for you.

References

Genetic Response to Ashwagandha

Catherine on April 3, 2025

Ashwagandha, often referred to as Indian ginseng or winter cherry, is an ancient herb with deep roots in Ayurvedic medicine. Known for its ability to help the body manage stress, improve energy, and enhance focus, it has gained global popularity as a natural supplement. But not everyone experiences the same results when taking ashwagandha—and that’s where genetics come into play.

Recent scientific interest has focused on how our genetic makeup may influence our response to ashwagandha. In this article, we’ll explore what ashwagandha is, its benefits, how it works in the body, and how individual genetic variations—especially in stress, hormone, and neurotransmitter pathways—can shape its effects.

What Is Ashwagandha?

Ashwagandha (Withania somnifera) is an adaptogenic herb, meaning it helps the body adapt to physical and emotional stress. It has been used in Indian traditional medicine for over 3,000 years to promote strength, calm the nervous system, and support immune function.

The active compounds in ashwagandha—known as withanolides—are believed to be responsible for most of its therapeutic effects. These compounds, like the Withaferin A and Withanone, help balance hormones, reduce inflammation, and support brain function.

Ashwagandha is typically available in powder, capsule, or extract form, often standardized to contain a specific percentage of withanolides.

What Are the Benefits of Ashwagandha?

Scientific studies have validated many of the traditional benefits of ashwagandha. Some of the most common and researched advantages include:

Reduces stress and anxiety: Ashwagandha helps lower cortisol, the body’s primary stress hormone, and may ease symptoms of anxiety.
Improves sleep: It promotes deeper and more restful sleep by calming the nervous system.
Supports thyroid health: It may help balance thyroid hormones, particularly in individuals with underactive thyroid function.
Boosts brain function: Ashwagandha enhances memory, attention, and information processing.
Increases energy and stamina: It supports adrenal health, which may lead to better energy levels.
Enhances muscle strength and recovery: Studies show it may improve muscle mass and physical endurance.
Improves male fertility and testosterone levels: Some trials have found it may raise testosterone and support reproductive health in men.

While these benefits are promising, individual experiences and outcomes with ashwagandha can vary. One reason may lie in your genes.

How Does Ashwagandha Work in the Body?

Ashwagandha interacts with multiple systems in the body. It helps regulate the hypothalamic-pituitary-adrenal (HPA) axis—a key stress response system—by reducing excessive cortisol release. It may increase GABA (gamma-aminobutyric acid) signaling, a neurotransmitter that promotes relaxation and reduces nervous activity. Ashwagandha also has strong antioxidant properties that protect cells from oxidative stress. It can influence the balance of thyroid hormones and testosterone, which are vital for metabolism, energy, and fertility. These actions create a wide range of benefits—but how powerfully they work may depend on your individual biology, especially your genetics.

What Is the Genetic Response to Ashwagandha?

Not everyone responds to ashwagandha the same way. Differences in certain genes can affect how your body processes or responds to the herb’s active compounds. Here are a few key genetic pathways that may shape your response:

COMT Gene – Cognitive and Mood Effects

The COMT (catechol-O-methyltransferase) gene affects how your brain breaks down dopamine, epinephrine, and norepinephrine—neurotransmitters related to mood, focus, and stress. Variants in the COMT gene determine whether you clear these neurotransmitters quickly or slowly. Fast COMT (Val/Val) types may experience more cognitive benefits from ashwagandha, such as better focus and stress relief. Slow COMT (Met/Met) types may be more sensitive and experience stronger sedative or calming effects.

NR3C1 and FKBP5 Genes – Stress Response and Cortisol Regulation

These genes are involved in regulating the body’s sensitivity to cortisol, the stress hormone. People with certain Glucocorticoid receptor gene; NR3C1 or Immunophilin (prolyl isomerase 5) gene FKBP5 gene variants may have a heightened or prolonged stress response. Ashwagandha may help normalize cortisol levels, but individuals with dysregulated stress genes may respond more noticeably, finding it especially helpful in calming anxiety or improving sleep.

GAD1 Gene – GABA Production

The GAD1 gene codes for GAD67, an enzyme that helps convert glutamate (a stimulating neurotransmitter) into GABA (a calming one). Low GAD67 activity can lead to a state of excitability or anxiety. Ashwagandha’s ability to support GABA activity may be more beneficial to those with GAD1 variations who experience chronic stress or restlessness.

TH and MAOA Genes – Mood and Hormone Regulation

These genes affect dopamine, serotonin, and other mood-related chemicals. Variations here can influence how ashwagandha impacts mood stability, emotional resilience, and even energy levels. People with MAOA-L (low activity) may experience stronger mood-stabilizing effects from ashwagandha, especially in high-stress environments.

Where Does Ashwagandha Come From?

Ashwagandha is a shrub native to India, parts of the Middle East, and North Africa. Its roots and berries are used for medicinal purposes, although most modern supplements use root extracts. These extracts are standardized to specific withanolide content to ensure consistent potency. Top-quality sources often come from organically grown plants in India and undergo purification to remove contaminants like heavy metals or pesticides.

Can Genetic Testing Help Personalize Ashwagandha Use?

DNA testing companies now offer reports that examine your stress response, mood sensitivity, hormone metabolism, and other traits related to neurotransmitter activity. These insights can help you understand whether ashwagandha may help with stress or make you feel overly calm, how your nervous system processes stimulants and calming agents, and if you’re more likely to benefit from ashwagandha for cognitive or physical reasons. This can be particularly useful if you’ve tried ashwagandha before and noticed very mild—or very strong—effects.

Who Should Be Cautious About Ashwagandha?

While ashwagandha is generally safe, certain people should consult a healthcare provider before using it. This includes pregnant or breastfeeding women, individuals with hyperthyroidism (as ashwagandha may further increase thyroid hormone levels), people taking sedatives or thyroid medication, and those with autoimmune diseases, since ashwagandha may stimulate the immune system.

Personalized Herbal Medicine

As the field of nutrigenomics grows, more people are turning to personalized health solutions based on their DNA. Herbs like ashwagandha may become part of targeted wellness strategies, especially for addressing stress, fatigue, and hormone imbalance. By understanding your genetic makeup, you can make more informed decisions about whether ashwagandha is right for you—and how best to use it.

Ashwagandha is a powerful adaptogenic herb that can reduce stress, improve mood, and support overall health. However, not all bodies respond the same. Your genetic makeup, particularly genes related to stress hormones, neurotransmitters, and hormone regulation, can shape how well ashwagandha works for you. As genetic testing becomes more accessible, it’s now possible to tailor natural supplements like ashwagandha to your unique biology—leading to more effective and balanced wellness outcomes.

The LifeDNA Methylation Genes Report gives you a closer look at how your genes may affect your well-being. One of the key genes it covers is COMT, which helps your body break down brain chemicals like dopamine and adrenaline. These chemicals affect how you handle stress, focus, and mood. Knowing your COMT type can help you understand why you may feel calm or anxious in certain situations. The report also looks at other important genes linked to mental clarity and overall wellness, making it a helpful tool if you want to learn how your body responds to things like stress or calming herbs such as ashwagandha.

References

https://www.webmd.com/vitamins/ai/ingredientmono-953/ashwagandha

The Genetics of Tay-Sachs

Catherine on March 17, 2025

Tay-Sachs disease (TSD) is a rare, inherited neurodegenerative disorder that primarily affects infants, leading to progressive deterioration of the nervous system. It is caused by mutations in the HEXA gene, which encodes the enzyme β-hexosaminidase A (Hex A). The genetic basis of Tay-Sachs disease is well understood, and advances in genetic testing have made early diagnosis and carrier screening possible.

What is Hex A?

β-Hexosaminidase A (Hex A) is an enzyme that acts like a cellular cleanup crew. It helps to break down a fatty substance called GM2 ganglioside inside our brain and in nerve cells. GM2 ganglioside is a fatty substance (glycolipid) found in nerve cell membranes, especially in the brain. It plays a role in cell signaling and communication, but it must be broken down. If not properly degraded, GM2 gangliosides accumulate in nerve cells, leading to neurodegeneration and severe brain dysfunction.

Why Does Hex A Matter?

Prevents Harmful Buildup – If GM2 gangliosides are not broken down, they accumulate inside cells, especially in the brain, leading to damage.
Keeps the Nervous System Healthy – This process is essential for normal brain function, allowing nerve cells to communicate properly.
Linked to Tay-Sachs Disease – When the HEXA gene, which produces Hex A, has a defect, the enzyme doesn’t work. This leads to Tay-Sachs disease, where GM2 gangliosides build up in the brain, causing severe neurological problems and early death.
A Part of the Body’s Cleaning System – Just like how the body gets rid of waste, Hex A helps clean up unnecessary fat molecules in nerve cells to keep them functioning properly.

Genetic Basis of Tay-Sachs Disease

Tay-Sachs disease is an autosomal recessive disorder, meaning that an affected individual must inherit two defective copies of the HEXA gene—one from each parent. The HEXA gene is located on chromosome 15q23-q24 and encodes the α-subunit of β-hexosaminidase A, an enzyme found in lysosomes.

Mutations in HEXA disrupt Hex A activity, leading to the accumulation of GM2 gangliosides in neurons. Over time, this accumulation causes progressive neurodegeneration, which manifests in severe developmental regression, loss of motor and sensory function, and early death in most cases.

There are over 100 known mutations in the HEXA gene that can cause Tay-Sachs, including:

Frameshift mutations – Lead to truncated, nonfunctional proteins.
Splice-site mutations – Affect proper RNA splicing, preventing correct enzyme production.
Point mutations – Some common mutations include the 1278insTATC (common in Ashkenazi Jewish populations) and G269S (associated with late-onset Tay-Sachs).

A 2021 study investigated the genetic causes of Tay-Sachs in three unrelated consanguineous families from Pakistan and Morocco, identifying novel and known HEXA gene mutations. Using whole exome sequencing and targeted gene sequencing, researchers discovered two novel homozygous variants (p.Asp386Alafs13 and p.Trp266Gly) and a previously reported Ashkenazi-associated mutation (p.Tyr427Ilefs5) in a Pakistani patient, marking its first report in this population.

Types of Tay-Sachs Disease

Based on enzyme activity and disease progression, Tay-Sachs disease is classified into three forms:

Infantile Tay-Sachs Disease (Classic Form)
- Most severe form, with onset at 3–6 months of age.
- Symptoms include loss of motor skills, seizures, vision and hearing loss, and progressive paralysis.
- Characterized by the “cherry-red spot” on the retina.
- Death typically occurs by age 4 or 5.
Juvenile Tay-Sachs Disease

- Rarer, with onset between 2–10 years of age.
- Symptoms include ataxia, cognitive decline, and spasticity.
- Progresses more slowly than the infantile form, with survival into adolescence or early adulthood.

3. Late-Onset (Adult) Tay-Sachs Disease (LOTS)

- Mildest form, appearing in adolescence or adulthood.
- Symptoms include muscle weakness, psychiatric disorders, speech and coordination problems.
- Often misdiagnosed as other neurological disorders.

Inheritance and Carrier Frequency

Since Tay-Sachs is an autosomal recessive disorder, an individual must inherit two mutated copies of HEXA to develop the disease. Carriers, who have one normal and one mutated allele, do not show symptoms but can pass the mutation to their children.

While relatively rare in general population (~1 in 250–300 carriers), Tay-Sachs has a high carrier frequency in specific populations:

Ashkenazi Jews (~1 in 27 carriers)
French Canadians and Cajuns (~1 in 30 carriers)
Irish-Americans (~1 in 50 carriers)

The high frequency of recessive mutations in some populations have been attributed to a phenomenon called the ‘founder effect’.

Founder Effect

The founder effect is a type of genetic drift that occurs when a small group of individuals becomes isolated from a larger population, leading to a reduced genetic diversity and an increased frequency of certain genetic traits or mutations. This happens because the new population is derived from a limited number of ancestors, and their genetic variations are passed down, sometimes leading to a higher prevalence of specific inherited conditions.

This effect is seen in isolated or historically endogamous communities, such as the Ashkenazi Jewish population, French Canadians, Amish communities, and certain Finnish and Icelandic groups. Other examples of conditions attributed to the founder effect are Gaucher disease, as well as BRCA1/BRCA2-related cancers which occur at higher rates.

Read our in-depth analysis of Gaucher Disease

Carrier screening through genetic testing is widely available, especially in high-risk populations, allowing for reproductive counseling and prenatal diagnosis.

Diagnosis and Genetic Testing

Enzyme Activity Testing – Measures β-hexosaminidase A activity in blood or white blood cells.
Genetic Testing – Detects HEXA mutations using targeted sequencing or whole-exome sequencing.
Prenatal Testing – Includes chorionic villus sampling (CVS) or amniocentesis for at-risk pregnancies.

With advances in molecular genetics, preimplantation genetic diagnosis (PGD) allows couples carrying HEXA mutations to select unaffected embryos during in vitro fertilization (IVF).

Current and Emerging Treatments

Currently, there is no cure for Tay-Sachs disease, and treatment is primarily supportive care aimed at managing symptoms. However, gene therapy and substrate reduction therapy are being actively researched:

Gene Therapy: Experimental approaches involve delivering a functional copy of HEXA using viral vectors to restore enzyme activity.
Substrate Reduction Therapy: Drugs like Miglustat are being investigated to reduce GM2 ganglioside accumulation.
Enzyme Replacement Therapy (ERT): Early-stage research is exploring the possibility of introducing functional Hex A enzyme.

In 2020 a novel approach to treating Tay Sachs was introduced. Researchers used AAV-delivered CRISPR gene editing to integrate a modified HEXM gene into liver cells of neonatal Sandhoff mice, enabling enzyme production and secretion. After four months, enzyme activity in the blood and brain significantly increased, leading to reduced GM2 ganglioside levels in most tissues, improved motor function, and reduced brain and liver cellular abnormalities.

A 2022 study reported a gene therapy trial for infantile Tay-Sachs disease, focusing on safety as the primary endpoint. Two patients received AAVrh8-HEXA and AAVrh8-HEXB gene therapy. In this therapy a modified virus (AAVrh8) is used to deliver working copies of the HEXA and HEXB genes into nerve cells. These genes help produce functional HexA, the missing enzyme in Tay-Sachs disease, allowing cells to break down GM2 gangliosides (see intro section). Both tolerated the procedure well, with no vector-related adverse events. HexA enzyme activity increased and remained stable in cerebrospinal fluid. One patient showed temporary disease stabilization but later progressed. The other patient remains seizure-free at age 5 on the same anticonvulsant therapy.

Also read about other autosomal recessive disorders:

Cystic Fibrosis
MCAD
Salla Disease

Conclusion

Tay-Sachs disease is a devastating neurodegenerative disorder caused by mutations in the HEXA gene. Its autosomal recessive inheritance pattern and high carrier frequency in certain populations have led to robust genetic screening programs. While no cure currently exists, advances in gene therapy and enzyme replacement therapy offer hope for future treatments. Early diagnosis and genetic counseling remain essential tools in managing this condition and preventing its transmission.

References

Genetics of Salla Disease: Mutations, Inheritance and Gene Therapy

Catherine on March 15, 2025

Salla disease is a rare autosomal recessive lysosomal storage disorder characterized by defective sialic acid metabolism. It falls under the broader category of sialic acid storage disorders (SASD) and is caused by mutations in the SLC17A5 gene, which encodes the sialin transporter protein. This transporter is responsible for the export of free sialic acid (N-acetylneuraminic acid) from lysosomes. Mutations in SLC17A5 lead to an abnormal accumulation of sialic acid within lysosomes, affecting multiple organ systems, particularly the central nervous system.

Sialic acids are important for cell signaling, immune function, and neural development, and their proper export allows cells to recycle them for glycoprotein and glycolipid synthesis. Defective transport impairs cellular function, particularly in the nervous system, leading to severe neurodevelopmental and metabolic disorders.

Genetic Basis of Salla Disease

SLC17A5 Gene and Its Role

The SLC17A5 (a.k.a AST) gene, located on chromosome 6q14-q15, encodes sialin, a protein essential for transporting sialic acid out of lysosomes.

In Salla disease, mutations in SLC17A5 impair this transport, leading to accumulation of sialic acid inside cells and subsequent cellular dysfunction. The disease follows an autosomal recessive inheritance pattern, meaning an affected individual must inherit two defective copies of the SLC17A5 gene—one from each parent.

Common Mutations in SLC17A5

Several mutations in SLC17A5 have been linked to Salla disease, with the most common being:

c.115C>T (p.R39C): A prevalent mutation in Finnish populations, often associated with classical Salla disease.
c.850C>T (p.Q284X): A nonsense mutation leading to a truncated, non-functional sialin protein.
c.1408G>A (p.G470R): A missense mutation affecting protein stability.

Clinical Manifestations

The severity of Salla disease varies based on the residual function of the mutated sialin transporter. There are two primary forms:

Classical Salla Disease (CSD) – Milder form, primarily observed in Finnish populations, presenting with early-onset hypotonia, delayed motor development, progressive neurological deterioration, and intellectual disability.
Infantile Sialic Acid Storage Disorder (ISSD) – A more severe neonatal-onset form, often leading to fatal multi-organ involvement and profound neurodevelopmental impairment within infancy.

Diagnosis and Genetic Testing

Diagnosis of Salla disease is confirmed through:

Urinary Free Sialic Acid Testing – Elevated free sialic acid in urine is a hallmark of the disease.
Molecular Genetic Testing – Identification of SLC17A5 mutations through next-generation sequencing (NGS) or Sanger sequencing.
Brain MRI – May reveal characteristic white matter abnormalities, indicative of leukoencephalopathy.

Genetic Counseling and Inheritance

As an autosomal recessive disorder, parents of an affected child are typically carriers (heterozygous), each having one defective copy of SLC17A5. Carrier parents have a 25% chance of passing the disease to their offspring with each pregnancy, a 50% chance that the child will be an asymptomatic carrier, and a 25% chance of being unaffected.

Also learn about other autosomal recessive disorders:

Cystic Fibrosis

Genetic counseling is highly recommended for families with a history of Salla disease, especially in high-risk populations such as those of Finnish descent.

Potential Therapeutic Approaches

A 2023 study compared two methods, the CRISPR-Cas9-mediated homology-directed repair (HDR) and adenine base editing (ABE), to correct the SLC17A5 c.115C>T (p.Arg39Cys) variant in human fibroblasts. While HDR showed minimal correction with a high rate of undesired mutations, ABE achieved significant correction without detectable errors, effectively reducing free sialic acid levels and offering a glimpse of hope that one day this methodology could be applied to help affected individuals as well.

Learn more about the groundbreaking usage of Gene Editing to cure genetic conditions

Currently, there is no cure for Salla disease, and treatment focuses on symptom management and supportive care, including:

Physical therapy for motor function support.
Speech and occupational therapy for developmental delays.
Seizure management with antiepileptic medications.
Future gene therapy prospects – Research into gene therapy and targeted molecular treatments may provide potential interventions in the future.

Conclusion

Salla disease is a rare lysosomal storage disorder caused by mutations in the SLC17A5 gene, leading to defective sialic acid transport and progressive neurological impairment. While currently incurable, early diagnosis, genetic counseling, and supportive therapies can improve quality of life for affected individuals. Advances in molecular genetics continue to offer hope for future treatments, highlighting the importance of ongoing research in the field of lysosomal storage diseases.

References

A Genetic Deep-Dive into MCAD Deficiency

Catherine on March 14, 2025

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCAD deficiency) is a rare genetic disorder that affects the body’s ability to break down medium-chain fatty acids into energy. This condition primarily impacts energy production, especially during prolonged fasting or periods of increased energy demand, such as illness or physical exertion.

Medium Chain Fatty Acids

Medium-chain fatty acids (MCFAs) are a type of saturated fatty acid that contain 6 to 12 carbon atoms. They are found in various food sources and play a critical role in energy production and metabolism. Unlike long-chain fatty acids (LCFAs), MCFAs are more easily digested, absorbed, and utilized by the body for quick energy.

MCFAs are unique compared to short-chain (less than 6 carbons) and long-chain (more than 12 carbons) fatty acids due to their rapid absorption and metabolism. Some key characteristics include:

Water solubility: MCFAs are more soluble in water than long-chain fatty acids, making them easier to digest.
Direct absorption: Unlike LCFAs, which require bile salts for digestion, MCFAs are absorbed directly into the portal vein and transported to the liver, bypassing the lymphatic system.
Fast energy production: The liver quickly converts MCFAs into ketones, which can be used as an alternative fuel source, especially for the brain and muscles.

MCFAs are naturally present in various food sources, including:

Coconut oil (rich in C8 and C10)
Palm kernel oil
Dairy products (butter, milk, cheese)
Human breast milk
Medium-chain triglyceride (MCT) oil (a purified form of MCFAs, commonly used for therapeutic and dietary purposes)

The most common MCFAs include:

Caproic acid (C6)
Caprylic acid (C8)
Capric acid (C10)
Lauric acid (C12)

How are MCFAs metabolized?

MCFAs are metabolized through a process called mitochondrial beta-oxidation. In this process fats that enter the body from the diet are converted into usable energy.

MCFA metabolism is considered to be more efficient compared to that of LCFAs. This is because MCFAs bypass the lymphatic system and enter the liver quickly through the portal vein. In the liver, they enter the mitochondria without requiring carnitine transport. Inside the mitochondria, MCFAs undergo beta-oxidation. During beta-oxidation MCFAs are sequentially cleaved into acetyl-CoA molecules. Acetyl CoA enters the Krebs cycle and generates ATP, the body’s main energy currency. Additionally, excess acetyl-CoA from MCFAs can be converted into ketones, an alternative fuel source for the brain and muscles, especially during fasting or low-carbohydrate intake.

Understand the Genetics of Saturated Fat Metabolism in more detail

Genetics of MCAD Deficiency

The Role of the ACADM Gene

The ACADM gene provides instructions for producing the enzyme medium-chain acyl-CoA dehydrogenase (MCAD). This enzyme plays a crucial role in beta-oxidizing MCFAs in the mitochondria.

When mutations occur in the ACADM gene, the production or function of MCAD enzyme is impaired, preventing the efficient breakdown of medium-chain fatty acids. As a result, individuals with MCAD deficiency experience an accumulation of fatty acid metabolites in the body, leading to metabolic crisis, hypoglycemia (low blood sugar), and potential organ damage if left untreated.

p.K304E or c.985A>G mutation

The p.K304E mutation accounts for ~80% of MCADD cases in Northern European populations who are homozygous for it. MCAD enzyme needs a molecule called FAD (flavin adenine dinucleotide) to function properly. Normally, MCAD enzymes group together into four-unit structures (tetramers) to work efficiently. A 2023 study examined 12 different MCAD mutations, including p.K304E and 11 otherrare ones. It found that half of these variants had trouble holding onto FAD, with levels dropping below 65% of normal.

Inheritance and Genetic Mutations

MCAD deficiency is inherited in an autosomal recessive pattern. This means that a person must inherit two mutated copies of the ACADM gene, one from each parent, to develop the disorder. Individuals with only one mutated copy are carriers and do not typically show symptoms, but they can pass the mutation to their offspring.

More than 100 mutations in the ACADM gene have been identified, with the most common mutation being the c.985A>G (K304E). Although MCAD deficiency is found only in 1 in 15,000 to 1 in 20,000 births in the whole USA, this specific genetic variant accounts for up to 80% of the cases in individuals of Northern European descent. Other mutations, including frameshift and missense mutations, contribute to the variability in disease severity observed among affected individuals.

Read about another autosomal recessive condition: Cystic Fibrosis

Genetic Screening and Diagnosis

Genetic testing for MCAD deficiency is commonly performed through newborn screening programs in many countries. Screening involves detecting elevated levels of medium-chain fatty acids, particularly octanoylcarnitine (C8), in dried blood spots. Confirmatory diagnosis is done via:

Molecular genetic testing to identify mutations in the ACADM gene
Enzyme activity assays in cultured fibroblasts or leukocytes
Plasma acylcarnitine profile analysis

Early diagnosis is crucial in preventing life-threatening metabolic crises, which can occur in infancy or early childhood. Benefits of early diagnosis of MCADD was reinforced by this large 2022 study in ~200,000 new borns in China between 2016 and 2022. Genetic analysis identified four known and four novel ACADM variants. Five children remained asymptomatic with proper dietary management, while one died due to a vaccination-triggered metabolic crisis leading to hypoglycemia and elevated acylcarnitines. The study highlights that genetic screening is essential for early detection, prevention, and improved prognosis of the disorder.

Implications of Genetic Findings

Identifying specific ACADM mutations can help predict disease severity and guide personalized medical management. Some individuals with milder mutations may experience fewer metabolic episodes, while others with severe mutations may have a higher risk of metabolic decompensation.

A case study published in 2010 follows the clinical history of a female patient. Her metabolic tests showed low urinary hexanoylglycine and suberylglycine, failure to produce ketones after 12 hours of fasting, and low blood carnitine level. This suggested a mitochondrial β-oxidation defect. Enzyme activity analysis confirmed mild MCADD, with octanoyl-CoA dehydrogenase activity reduced to 25% of normal. Other mitochondrial enzymes remained functional. Genetic testing revealed compound heterozygosity with the common c.985A>G (p.K304E) mutation and a novel c.145C>G (p.Q24E) mutation in the ACADM gene, marking the first report of this variant. This case shows that mild MCADD phenotypes, despite retaining some enzyme activity and showing low glycine conjugate excretion, can still lead to metabolic crises, reinforcing the need for early diagnosis and management.

Carrier screening for at-risk populations, especially among those of Northern European descent, can help prospective parents make informed reproductive decisions. Genetic counseling is recommended for families with a history of MCAD deficiency.

Conclusion

MCAD deficiency is a genetic disorder caused by mutations in the ACADM gene, leading to impaired fatty acid metabolism. Understanding its genetic basis has improved early detection, newborn screening, and personalized treatment strategies. With proper management, individuals with MCAD deficiency can lead healthy lives by following dietary recommendations and avoiding prolonged fasting. Advances in genetic research continue to enhance our knowledge of this condition, offering hope for improved interventions in the future.

References

Genetic response to alpha-keto glutarate

Catherine on March 14, 2025

Overview

Your body needs energy to do everything, from moving your muscles to helping your brain think. That energy comes from the food you eat. But before your body can use food for energy, it has to break it down. One important step in this process is called the Krebs cycle (also known as the Citric Acid Cycle).

The Krebs cycle is a series of steps that happen inside your cells. It takes compounds derived from food, such as sugars (glucose), fatty acids and amino acids and turns them into energy. This happens in small organelles inside the cells called the mitochondria, which are often called the powerhouses of the cell. The main job of the Krebs cycle is to make energy in the form of ATP that your body can use. ATP or adenosine triphosphate is the fuel your cells use to work.

This is where Alpha-keto glutarate or AKG comes into play. AKG is an intermediate compound that mediates the conversion of food into adenosine triphosphate (ATP). AKG is gaining the interest of researchers for its wide-ranging benefits from supporting cellular energy to promoting longevity and healthy aging. Beyond energy metabolism, Alpha-keto glutarate or AKG is also involved in regulating gene expression, muscle health, immune function, and even lifespan. Interestingly, the way individuals respond to AKG supplementation may vary based on their genetics. Understanding this will help us know how to keep our cells healthy, how to boost energy naturally, and even how to slow down aging.

What Is Alpha-Ketoglutarate?

Alpha-keto glutarate is a special compound that helps our cells make energy. Our bodies make AKG naturally, but we can also take it as a supplement to help our bodies work better. AKG is important for making other things our bodies need, like building blocks for proteins. However, as we get older, our bodies may not use AKG as well, so taking it as a supplement might not work the same for everyone.

AKG also helps the body make two important substances called glutamine and glutamate. These are used to build proteins, help brain cells talk to each other, and keep your immune system strong. Because AKG is involved in so many body processes, scientists are studying it to see if it can help our cells make energy better, help us heal faster, lower swelling in the body, and maybe even help us live longer, as is suggested by studies in animals.

Alpha-Ketoglutarate Functions & Benefits

Helps Build Proteins and Muscles: AKG helps our bodies make two important amino acids—glutamine and glutamate. These are like tiny tools our bodies use to build proteins and keep muscles healthy. They also stop our bodies from breaking down muscle, which could happen when we’re sick or stressed. Glutamine is very important—it helps our gut, immune system, and muscles. Even though muscles store a lot of glutamine, we can run low during tough times. That’s why taking AKG might help us keep enough glutamine when we need it most.
Helps Us Absorb Iron: AKG can also help our bodies absorb more iron from food, especially when we don’t have enough iron or when we’re growing quickly. Iron is important for healthy blood and energy.
Helps Make Collagen: Collagen is a protein that holds our body together—it’s in our skin, bones, and joints. AKG helps an enzyme (P4H) in our body that makes collagen work properly by helping to produce hydroxyproline, a crucial amino acid needed for strong collagen structure. If this doesn’t happen, our bodies can’t make good collagen, and that can affect how long our skin and bones stay strong and stretchy.
AKG Helps Make and Reuse Proline: Proline is another important part of collagen. Our bodies can produce proline using AKG as a precursor. Most of the time, our bodies actually reuse proline from old collagen that’s been broken down. AKG helps with that too, by supporting an enzyme that recycles proline. This means AKG helps both make new proline and reuse old proline, which is great for keeping our skin and bones healthy.
AKG Affects Hormones and Bone Growth: AKG can help our bodies make more of certain hormones like insulin, growth hormone, and IGF-1. These hormones help us grow, heal, and stay strong. In animal studies, giving AKG increased the levels of proline in the blood. AKG works together with vitamin C and iron to help our bodies make collagen—a protein that builds strong bones and skin. So, AKG plays a part in keeping our bones strong and healthy.
Mitochondrial support: As a fuel for the Krebs cycle, AKG boosts cellular energy production, which is critical for tissues with high energy demands, such as muscles and the brain.
Immune regulation: AKG may help modulate the immune response by supporting T-cell function and reducing inflammatory cytokines.
Detoxification: AKGhelps the liver and kidneys clear excess nitrogen and toxins from the body, improving metabolic balance.

Genetic Response to Alpha-Keto glutarate

A recent study investigated how alpha-keto glutarate (AKG) supplementation affects growth, nutrient use, antioxidant capacity, and gene expression in Nile tilapia when combined with different protein levels in the diet. Researchers tested five diet groups: four with 1% AKG at varying protein levels (20%, 25%, 30%, and 35%) and one control group with 35% protein and no AKG.

After 60 days, the group fed a diet with 30% protein and 1% AKG showed significantly better growth, nutrient utilization, and antioxidant enzyme activity (SOD and CAT) compared to regular diet. Notably, the expression of the growth-related gene IGF-1 was significantly upregulated in this group, indicating a genetic response to AKG that supports growth. Inflammatory markers like TNF-α were lower in the lower-protein AKG groups, suggesting improved immune status.

Interestingly, the 25% protein + AKG group ( achieved similar growth results as the 35% protein control group without AKG , highlighting that AKG may reduce the need for higher protein input in aquafeeds without compromising growth.

The findings suggest that AKG not only supports better physical growth but also activates genes related to growth and inflammation control, offering a promising dietary strategy for more sustainable fish farming.

People with certain genetic profiles may experience greater benefits from AKG supplementation, particularly if their natural AKG metabolism or mitochondrial function is suboptimal. Genetics plays a major role in how well AKG works in the body. With the help of personalized testing and informed supplementation, AKG may offer a science-backed way to enhance vitality and support healthy aging at the cellular level.

Sources of Alpha-Ketoglutarate

While AKG is naturally produced in the body, dietary intake can also support its levels. Foods high in protein, especially those rich in glutamate or glutamine (like meats, eggs, and dairy), may indirectly boost AKG production. However, these dietary sources typically don’t provide a significant amount of free AKG.

Supplemental AKG is often available in the form of calcium alpha-ketoglutarate (Ca-AKG), which is more stable and better absorbed. This form has been used in many aging and mitochondrial health studies, showing promising results.

Who Might Benefit from Alpha-Ketoglutarate?

Because AKG plays a foundational role in energy metabolism and cellular repair, the people who may benefit the most include:

Older adults: looking to preserve muscle, bone, and cognitive function
Athletes or active individuals: recovering from intense training
People with mitochondrial or metabolic dysfunction: including fatigue-related conditions
Those under chronic stress: who may have elevated inflammation and reduced recovery capacity
Biohackers and longevity enthusiasts: exploring ways to slow biological aging

Genetic testing may help identify whether someone has variants that could impair mitochondrial function or AKG metabolism, making supplementation especially useful.

Safety and Precautions of Using AKG

While alpha-ketoglutarate (AKG) is used by some people for conditions like long-term kidney disease and other health issues, it’s important to be careful when using it.

Safety: Taking AKG by mouth appears to be safe for most people when used for up to three years. Using AKG on the skin is also likely safe for up to eight weeks. However, it’s best not to use it for longer periods without checking with a healthcare professional.

Pregnancy and Breastfeeding: There isn’t enough reliable information about how safe AKG is for pregnant or breastfeeding women. To be safe, it’s recommended to avoid using AKG during pregnancy and while breastfeeding.

Other Uses: Although some people use AKG for things like aging skin, improving athletic performance, or helping with liver disease, there isn’t enough strong scientific evidence yet to prove that it works for these purposes.

Before starting AKG, especially if you have health conditions or are taking other medicines, talk to your doctor to make sure it’s safe for you. As more people turn to personalized health strategies, the importance of understanding genetic and biological responses to supplements like AKG is becoming clearer.

Emerging research suggests that tailoring AKG supplementation based on genetic markers could optimize benefits—especially in areas like muscle maintenance, cellular aging, and brain health.

How LifeDNA’s Nutrition Report

LifeDNA’s Nutrition Report doesn’t just help you understand your dietary tendencies—it can also offer insights into how your body might process and respond to key compounds like Alpha-Ketoglutarate (AKG). Because AKG is connected to several metabolic and cellular processes, your genetic profile, especially those genes influencing protein metabolism, mitochondrial efficiency, and nutrient absorption may affect how your body utilizes AKG.

References

An In-Depth Genetic Review of Preeclampsia

Catherine on March 14, 2025

Preeclampsia (PE) is a serious pregnancy complication characterized by the expecting mother’s high blood pressure and signs of organ damage, often affecting the liver and kidneys. It typically arises after 20 weeks of pregnancy and can lead to severe complications for both the mother and baby if left untreated.

Despite extensive research, the exact cause of preeclampsia remains unclear. However, increasing evidence suggests that genetic factors play a crucial role in its development.

This article explores the genetic underpinnings of preeclampsia, highlighting key genetic markers, inheritance patterns, and potential implications for future research and treatment.

Genetic Risk Factors for Preeclampsia

Preeclampsia is considered a multifactorial disorder, influenced by both genetic and environmental factors. Studies have identified several genes and genetic variations associated with an increased risk of preeclampsia.

Maternal and Fetal Genetic Contributions

Research suggests that both maternal and fetal genes contribute to preeclampsia risk. The maternal genome influences how the mother’s body adapts to pregnancy, while fetal genes inherited from both parents affect placental function, which is crucial in preeclampsia development.

In a 2020 study researchers identified placental genetic and epigenetic markers, notably the upregulation of the microRNA MIR138 in preeclamptic placentas of female infants.

Another 2020 study highlighted the role of the complement system in preeclampsia risk. The complement system is an important aspect of immune response. Researchers hypothesized that specific combinations of maternal and fetal complement gene SNPs can contribute to preeclampsia risk. Sequencing factor H (CFH), C3, and CD46 genes revealed nine common SNPs, with two fetal CD46 variants showing significantly higher frequencies in preeclampsia cases.

Other Candidate Genes Associated with Preeclampsia

Several genes have been linked to preeclampsia (PE), including:

FLT1

FLT1 (Fms-related tyrosine kinase 1) gene encodes a protein involved in making blood vessels. Increased levels of soluble FLT1 (sFLT1) are found in preeclamptic women. This leads to poor blood flow to the placenta.

In the same year, another study performed on the Japanese population also found elevated levels of FLT1 mRNA in women with preeclampsia. However, the authors note that a larger study is needed to definitively ascertain this link.

A 2023 RNA sequencing study flagged FLT1 as one of the genes whose expression was upregulated in African-American women with severe preeclampsia.

A 2020 study in Estonian cohorts observed the rs4769613-C variant to be associated with preeclampsia. This SNP is located in an enhancer near FLT1.. The study also notes that identifying this variant in cell-free fetal DNA (cffDNA) from maternal blood could aid in early risk assessment for preeclampsia.

ENG (Endoglin)

ENG is another key gene in blood vessel function, and elevated levels of soluble endoglin contribute to endothelial dysfunction, a hallmark of preeclampsia. Elevated soluble endoglin (sEng) levels are found in the serum, plasma, and urine of preeclampsia patients. The sEng are generated through membrane-bound endoglin are broken away by metalloproteases (a kind of enzyme) and potentially other proteases. A study published in February of this year (2025) showed that thrombin could possibly be responsible for this. Thrombin is the key protein that helps your body in the clotting process.

A 2021 systematic review and meta-analysis of 20 studies involving 1146 preeclamptic and 1675 normotensive pregnant women found that soluble endoglin levels were significantly higher in preeclamptic women during the second and third trimesters. Elevated soluble endoglin levels were observed in both early-onset and late-onset preeclampsia.

A retrospective study, also published in 2021, was performed on 124 women to study the angiogenic and metabolic placental factors in type 1 diabetes, type 2 diabetes, gestational diabetes, preeclampsia, and control groups. The results showed that the genetic expression of the ENG gene was the highest in patients with preeclampsia.

MTHFR

The MTHFR gene, short for Methylenetetrahydrofolate Reductase, is crucial in the body’s metabolic processes. This gene is responsible for producing the MTHFR enzyme, which plays a vital role in processing amino acids, the building blocks of all proteins.

Read our in-depth analysis of the MTHFR gene here.

A 2020 case-control study examined the role of methylenetetrahydrofolate reductase (MTHFR), homocysteine, and MDA levels in 30 preeclampsia patients and 30 healthy pregnant women. Results showed significantly higher homocysteine and MDA levels in preeclamptic women, along with reduced MTHFR activity. This suggests impaired homocysteine metabolism. These findings highlight the role of homocysteine regulation and MTHFR activity in blood pressure control, making them potential targets for preeclampsia prevention and treatment.

A 2023 study investigated the role of polymorphisms in eNOS (-786 T > C, 894 G > T) and MTHFR (1298 A > C, 677 C > T) in preeclampsia among 160 patients and 160 healthy pregnant women in Quanzhou (Han population). Variants eNOS 894 G > T and MTHFR 1298 A > C showed no significant differences. However, the eNOS -786 C allele (OR: 2.07, p = 0.03) and MTHFR 677 T allele (OR: 1.83, p = 0.04) were more frequent in preeclampsia (PE) patients.

Additionally, women with the eNOS -786 CC genotype had lower nitric oxide (NO) levels, while those with the MTHFR 677 TT genotype had higher homocysteine (Hcy) levels, both of which contribute to vascular dysfunction in PE. These findings suggest that eNOS -786 CC and MTHFR 677 TT genotypes may serve as genetic predictors of PE risk.

Interestingly, however, a systematic review, also published in 2023, done on relevant case-control studies between 2000 and 2019, irrespective of ethnic background, showed no statistical significance between the MTHFR 677 T allele and preeclampsia risk.

Another case-controlled study comprising of women from South India showed that preeclampsia was common in women carrying the T variant of MTHFR rs1801133 SNP.

A note on previously implicated genes

The AGT (angiotensinogen) gene, particularly the M235T variant, has been implicated in preeclampsia in some studies. But the association remains inconsistent across different populations.

Findings from a 2021 study suggest that AGT M235T polymorphism does not play a significant role in preeclampsia pathophysiology in the Thai population, despite previous associations with increased blood pressure in pregnancy. Similar findings were recorded in a 2022 study on the Chinese population.

Inheritance Patterns

Preeclampsia exhibits a strong familial component, with women having a higher risk of developing the condition if their mother or sister had preeclampsia.

Maternal inheritance

Daughters of women with a history of preeclampsia are at an increased risk, indicating a hereditary predisposition.

Paternal influence

Some studies suggest that a father’s genetic contribution may also play a role. Men born to preeclamptic mothers have a higher likelihood of fathering pregnancies affected by preeclampsia.

Polygenic inheritance

As seen in the previous sections, rather than a single gene, multiple genetic variants collectively contribute to susceptibility, making preeclampsia a polygenic disorder.

Epigenetics and Preeclampsia

Epigenetic modifications, such as DNA methylation and histone modifications, regulate gene expression without altering the underlying genetic code. Environmental factors, including maternal diet, stress, and exposure to pollutants, can influence these epigenetic changes and potentially contribute to preeclampsia risk.

Abnormal DNA methylation patterns in placental tissues of preeclamptic women can affect genes involved in angiogenesis and immune function. A 2020 epigenetic study showed higher ENG methylation in preeclampsia cases. But more robust studies are needed to establish this link definitively.

MicroRNAs (small RNA molecules that regulate gene expression) show altered expression in preeclampsia, impacting placental function. A 2021 study investigated CD4+ T cells in preeclamptic and healthy pregnant women. Results showed that miRNA-326 was upregulated in CD4+ cells of women with preeclampsia. Similarly, findings from a 2020 study suggests that plasma exosomal miRNA profiling could enhance understanding of preeclampsia pathophysiology and serve as a potential diagnostic tool.

Implications for Diagnosis and Treatment

Understanding the genetic basis of preeclampsia has important clinical implications:

Genetic Screening: Identifying high-risk women through genetic testing could allow for early monitoring and preventive interventions.
Targeted Therapies: Research into genetic pathways involved in preeclampsia may lead to the development of targeted treatments, such as drugs that modulate sFLT1 levels.
Personalized Medicine: Genetic insights can pave the way for individualized treatment approaches, improving maternal and fetal outcomes.

Summary

Preeclampsia remains a major global health challenge, but advances in genetic research are shedding light on its complex origins. While no single gene is responsible for the condition, a combination of maternal, paternal, and fetal genetic factors contribute to its development. Further research, particularly in genomics and epigenetics, holds promise for improving early detection, prevention, and treatment strategies for preeclampsia, ultimately enhancing maternal and neonatal health.