Category Archives: Supplements

Low dose lithium reduces cellular senescence

A recent study shows that low-dose lithium may act as a senolytic.[ref] This has important implications in healthy aging – including preventing mortality from respiratory diseases, such as COVID, and neurodegenerative diseases like Alzheimer’s.

First, let me go into a little background information on lithium and then cellular senescence. Next, I’ll explain the new study on lithium as a senolytic and why this is so cool.

Lithium – naturally occurring mineral:

Lithium is perhaps best known for its use in batteries and as a drug for bipolar disorder.

As a naturally occurring mineral, lithium exists at varying levels in the soil and water throughout the world. According to estimates, people consume about 3mg of lithium a day from food and water, however, the amount varies a lot depending on where your food is grown and the source of your groundwater.

Epidemiological studies show that areas with higher levels of lithium in the groundwater have lower levels of suicide and assaults. Studies also correlate higher levels of lithium in water with lower levels of Alzheimer’s disease. (Read more about lithium and Alzheimer’s prevention.)

Lithium as a drug or supplement:

Lithium carbonate is about 19% elemental lithium. Thus a 300 mg dose prescribed for bipolar disorder would equate to about 57 mg of elemental lithium.

Microdoses of lithium carbonate used in clinical trials for Alzheimer’s disease are in the 300 μg to 30mg range. Elemental lithium would be around 57 μg to 5mg. Still a huge range, but in the ballpark of what a person likely consumes from food, depending on where the food is grown.

Several clinical trials now show that microdoses of lithium may prevent cognitive losses in AD.[ref][ref]

Supplemental lithium orotate is available in 5 mg – 20 mg doses. You can get it on Amazon or through health food stores.

Cellular senescence in aging:

Cellular senescence is a natural process that cells go through when they are at the end of their replicative life. When a cell can no longer replicate safely, it will send out signals for the immune system to destroy the cell. This is a process that occurs throughout life, but in older age, the number of senescent cells multiplies too rapidly for the immune system to keep up.

The signals that a senescent cell gives off are inflammatory cytokines. When all goes according to plan, the inflammatory cytokines cause a quick immune response. But in aging, the accumulated senescent cells give off a lot of inflammatory cytokines, increasing overall inflammation in the body. Uncleared senescent cells can cause harm to their neighboring cells through the signals that the cytokines give off.

A key issue in COVID-19 and other respiratory illnesses in the elderly is the hyperinflammatory response by the body. Excessive inflammatory cytokines lead to cell death and eventually to morality. One reason for the hyperinflammatory response in the elderly seems to be the high burden of inflammatory cytokine-producing senescent cells. (Read about cellular senescence in respiratory illnesses.)

Lithium as a senolytic:

The study on low-dose lithium as a senolytic shows that senescent cells treated with low concentrations of lithium decreased the inflammatory cytokines associated with senescence.[ref] The decrease in inflammatory markers included lower levels of IL-6.  Interleukin 6 (IL-6), an inflammatory cytokine, becomes elevated in COVID-19 in patients with severe disease.

The study results showed that the low-dose lithiums is acting via the same mechanism that high-dose amount act: prescription levels of lithium for bipolar disorder inhibits GSK3B activation.

Conclusion:

More research is needed to determine dosages and the mechanism of action of lithium as a senolytic. It is also not clear, to me at least, whether lithium is clearing out senescent cells, as a senolytic does, or if it is suppressing the cytokines from senescent cells.

In light of the recent FDA approval of a $56,000/year Alzheimer’s drug that doesn’t slow or reverse cognitive decline, I would love to see more trials on microdosing lithium for Alzheimer’s disease. The stark difference between a very cheap mineral supplement that does stop cognitive decline in Alzheimer’s patients vs. the horribly expensive drug that does not actually help…well, words fail me on why the government chooses via the FDA to pay for (via Medicare) a drug that is 1,000 times more expensive and yet less effective.

I would also love to see clinical trials on lithium as a senolytic in elderly people. Other senolytics, such as quercetin, fisetin, luteolin, and dasatinib, have shown efficacy in diseases related to senescence.[ref][ref] Lithium would be an even less expensive, readily available choice – if it is as effective as other senolytics.

 

 

Preventing muscle loss in aging

Kind of like pornography, we all know aging when we see it. There is a specific point when suddenly someone looks old. Like they have crossed some invisible threshold, moving from healthy and older into the twilight area at the end of life.

I’m not talking about gray hair or laugh lines that became more permanent. Nor the middle ages spread or some stiff joints when getting up from a chair.

What causes this indefinable aura of old age? A big component of looking old is the loss of muscle mass that accelerates towards the end of life. Called sarcopenia, the loss of lean muscle mass is something we all instinctively recognize as “old”, whether in our pets or relatives.

Preventing muscle loss

The harsh reality is that we all start losing muscle mass after age 30, and the loss of strength, without intervention, is exponential. Muscle loss starts off really slowly, then suddenly skyrockets towards the end of life.

As we get older, we should focus on preventing age-related muscle loss before it happens. Regaining muscle strength is a whole lot harder in aging.

Why do we instinctively see muscle loss as ‘old’? It is a physical indicator of what is going on inside.

  • Sarcopenia goes hand-in-hand with cognitive decline. A meta-analysis shows that people with sarcopenia are three times more likely to also have cognitive decline.[ref]
  • Sarcopenia also increases the risk of respiratory diseases, heart failure, and overall mortality. For example, the risk of community-acquired pneumonia is almost 4-fold higher in people with sarcopenia.[ref][ref][ref][ref]

Good news: Sarcopenia, the loss of lean muscle, is reversible, even in aging. But often the change in muscle mass shown in the research studies is small, barely enough to overcome the rate of loss.

The key: the best bet is likely a multi-pronged intervention. Instead of just one pill, one diet change, or one exercise, to have a relevant impact multiple changes may be needed.[ref]

Exercise to prevent muscle loss

It seems like a no-brainer that exercise prevents muscle loss. Let’s dive into the research to see exactly what is effective and how much of a result can be experienced.

Tai Chi: A randomized controlled trial showed that older adults (avg. age of 70) increased skeletal muscle mass and improved gait speed after 10 months of Tai-Chi. The increase in the skeletal muscle mass was 1.76% and gait speed improved by an average of 9%.[ref]

Aerobics vs resistance exercise: A trial in older, overweight adults found that while strength increased more in the group lifting weights, both the aerobic and resistance training group lost lean muscle mass over the course of the 6-month long intervention. The exercise wasn’t useless, though, because in that period the control group lost even more lean muscle.[ref]

Resistance training: A 10-week intervention of instructor-led resistance training showed that the males in the group had a slight increase in overall physical performance. Additionally, both males and females in the intervention group had an average increase in lean body mass of about 1kg.[ref]

High-intensity resistance training: Older men (age 72+) participated in high-intensity resistance training twice a week for 28-weeks. Their results were compared to a control group with no exercise. Skeletal muscle mass index increased by 4% in the resistance training group, compared to no real change in the control group. The resistance training group maintained handgrip strength, while the control group had a decrease. Similarly, the training group also maintained walking gait speed, while the control group had a decrease. Interestingly, the researchers note that the resistance training group.[ref]

You may be thinking, “Meh – not all that impressive”. While definitely not the gains found in younger people, the research clearly shows that exercise can help to prevent muscle loss and perhaps increase muscle mass a little bit. Tai Chi stands out for improving walking gait the most, while high-intensity resistance training improved muscle mass in men.

Specific amino acid to prevent muscle loss

Even though many studies have focused on using protein powders or whey supplements, a recent study found that one specific amino acid stands out as important in preventing sarcopenia.

Leucine is an essential amino acid used in the synthesis of proteins. Dietary sources of leucine include meat, dairy, and fish.

A randomized controlled trial in older patients with sarcopenia found that leucine supplementation increased the skeletal muscle index and handgrip strength more than a control group. Both the intervention group and control group (no leucine) did low-intensity resistance training in a post-stroke rehab program.[ref]

Vitamin D to prevent muscle loss

Vitamin D may help to increase muscle mass in older people who are vitamin D deficient.[ref]

A placebo-controlled clinical trial in Vitamin D deficient older people showed 10,000 IU of vitamin D three times per week improved skeletal muscle mass, but not handgrip strength.[ref]

Fighting chronic inflammation to prevent muscle loss

Chronically elevated inflammatory markers are a hallmark of aging. This increase in inflammation is implicated in many of the diseases of aging, such as heart disease, diabetes, neurodegeneration, and sarcopenia.

TNF-alpha is often one inflammatory cytokine elevated in older people. A study on exercise in frail people (avg. age of 81) found elevated TNF-alpha levels at baseline. After three months of exercise, the muscle TNF-alpha levels decreased and muscle protein synthesis increased.[ref]

Quercetin is a supplement that can decrease TNF-alpha. Animal research shows that quercetin can protect against TNF-alpha-induced muscle atrophy.[ref]

In addition to quercetin, the polyphenols resveratrol and curcumin may also help to decrease chronic inflammation. Animal studies also show that these polyphenols may help improve muscle strength and regeneration.[ref]


Stacking interventions

The studies on exercise, vitamins, or nutritional intervention all show they help to maintain muscle and prevent further loss. To be honest, the clinical trial results aren’t all that impressive to me. If I’m going to do high-intensity resistance training several times a week, then I want to see real results.

A single pill or a single type of exercise may not be enough. Instead, attacking age-related muscle loss with several combined interventions seems to be much more efficacious.

Omega-3 plus Weight lifting: A clinical trial that included resistance exercises, such as leg presses and knee extensions, showed that omega-3 supplementation along with weight lifting may give a little extra benefit. The omega-3 supplementation group had a slight decrease in IL-6 (an inflammatory cytokine) and an increase in strength in specific exercises. The placebo group was taking a corn oil supplement, and they actually lost a little strength. While not an overwhelming result, it does show: either omega-3 is good – or – corn oil is bad.[ref]

Resistance training plus nutritional supplement: A clinical trial investigated home-based resistance training with or without a nutritional supplement. The supplement included whey, creatine, vitamin D, and fish oil. The placebo group took collagen, sunflower oil, and sugar. The resistance training including using elastic bands, squats, crunches, and stretches. Both groups gained a little weight, but the placebo group gained some body fat plus muscle while the nutritional supplement group gained mainly muscle mass. The average was about 2 lbs.[ref] My takeaway: supplementing with sunflower oil and 25g of sugar isn’t as good as fish oil and whey protein. I wish the control/placebo was more benign. An additional 6 teaspoons of sugar a day (as well as the seed oil) may have negatively impacted the control group results.

Vitamin D plus leucine: A randomized controlled trial in older people with low skeletal muscle mass showed that supplementing with vitamin D and leucine-enriched whey protein increase chair-stand time and appendicular muscle mass.[ref]

Multi-domain lifestyle intervention for the win: A clinical trial in people who were either pre-frail or with sarcopenia showed combining nutritional, cognitive, and physical intervention reversed sarcopenia after 3 to 6 months. This result was compared to each intervention separately, which improved sarcopenia somewhat but failed to reverse it. The combination also reduced inflammatory markers. The nutritional intervention included leucine and vitamin D, B6, B12, and folate. Cognitive training included learning strategies for recall, doing puzzles, and attending training classes for 12-weeks. The exercise portion of the intervention included resistance exercise and balance training (two 90-minute sessions per week)


Supplements

Leucine is available as a stand-alone supplement or as a part of whey protein supplements.

Vitamin D is readily available via sun exposure, or you can supplement with it when sun exposure isn’t possible. Personally, I prefer to use a vitamin D supplement that doesn’t include soybean oil. There are coconut oil options available with vitamin K2 or without.

As always, the links are not intended to be brand recommendations. Read the reviews and go with the option that best fits your personal needs.

What about exercise? Tai Chi, resistance bands, body-weight exercises all seem to be beneficial. Whether home-based or with a physical trainer, all exercise seems to help. Perhaps a combination or mixed routine would be beneficial?

 

 

Glycine for improving slow-wave (deep) sleep

A recent study on sleep and dementia points out (once again) that sleep is essential for good health in aging. The study found that decreased sleep, such as 6 hours or less per night, during your 50s and 60s increases the risk of dementia in your later decades by 30%.

Quality sleep is foundational for healthspan

Prioritizing sleep is one of those foundational things that everyone needs to do for quality health. Yes, there are the rare mutations that decrease your need for sleep, but if you aren’t one of the 1 in 10000 people who carry the DEC2 mutation, you need to get around 7.5 or 8 hours of sleep a night.

Amount of sleep: The first step, of course, is to plan enough time for sleep. Parents of little ones know how important it is to plan for the right amount of sleep. But somehow as adults, we sometimes tend to disregard the simple math on this. When my Oura ring first told me to start getting ready for bed at 9:15, I was surprised. But since I normally get up around 5:45, Oura was just doing the simple math of subtracting 8 hours and then giving a half-hour buffer to brush my teeth and wind down to sleep.

Sleep quantity is a fairly simple metric…but everyone knows that the quality of sleep also affects how you feel the next day.

When you sleep, your brain activity goes through several stages. You will have segments of light sleep, REM sleep, and slow-wave sleep.

More slow-wave sleep is linked to better response time and accuracy in cognitive tests the next day.[ref] One of the problems with aging is that slow-wave sleep decreases and becomes more fragmented. This slow-wave sleep loss has links to cognitive decline and to higher amyloid-beta levels.[ref][ref] Animal research points to a possible benefit for Alzheimer’s prevention with solid slow-wave sleep.[ref]

How can you increase your slow-wave sleep?

Glycine before bed may help increase your sleep quality and the time spent in slow-wave sleep. Glycine is an amino acid used throughout the body in many different ways. Your body naturally produces glycine (avg. of 45g per day), and you also get some from your diet (avg. 3-5g per day). In the central nervous system, glycine acts as an inhibitory neurotransmitter via glycine receptors in certain types of neurons. Additionally, glycine and glutamate act together in the brain in certain types of excitatory neurons.[ref]

Research on glycine for sleep quality:

Let’s take a look at the studies on glycine for sleep quality:

Improves sleep quality: 3g of glycine before bed improved sleep quality, sleep efficacy, and how quickly the participants got into slow-wave sleep.[ref]

Reduces fatigue the next day: In study participants who were sleep restricted for a few nights, 3 g of glycine significantly reduced fatigue the next day. The glycine did not affect melatonin production nor the expression of core circadian clock genes.[ref]

Drops overnight body temperature: Glycine supplementation before bed also decreases core body temperature. The drop in core body temperature is one of the circadian cues for sleep.[ref]

So what is going on in the brain when you take glycine at night?

When you take glycine as a supplement, it can easily pass across the blood-brain barrier to be used in the brain.

Glycine is a co-agonist with glutamate as a neurotransmitter in certain areas of the brain. NMDA receptors in neurons are activated by glutamate and glycine when certain conditions are met. (The NMDA receptors also activate with certain psychoactive drugs, ketamine, and alcohol.)[ref]

One area of the brain that has NMDA receptors is the suprachiasmatic nucleus, the region of the hypothalamus responsible for your circadian rhythm. Animal research shows that activation of these NMDA receptors by glycine decreases body temperature at night and is sleep-promoting.[ref]

Where can you get glycine?

Collagen and gelatin are excellent dietary sources of glycine. If you drink a hot beverage, such as herbal tea, before bedtime, you could dissolve collagen or gelatin into your tea. Check the label on your collagen or gelatin to see how much glycine is in a scoop.  For example, Zint collagen from grass-fed cows has around 5g of collagen per two-tablespoon serving. It dissolves fairly easily in both cold and warm drinks.

Glycine supplements are also cheap and readily available. You can get it in a powdered form, and the taste is just mildly sweet. Add it to water or another beverage to take glycine powder before bed. Glycine is also available in 1g capsules.  Personally, I like the powdered form so that I’m not taking unneeded cellulose capsules and because it is cheaper per serving.

Our ancestors likely consumed quite a bit more glycine in their diets than we do today. Traditionally, the whole animal was used for food, with the bones and other bits being incorporated into broths and stews. Bone broth is high in glycine due to the gelatin and collagen content. Most population groups have traditional recipes that are high in glycine such as fish head soup, ham hocks, or tripe. Congealed puddings, jellied luncheon meats, and gelatin desserts were also popular.  As a kid, I remember my mom making Knox blocks with grape juice as a treat. Knox gelatin is, of course, high in glycine.

Safety data for glycine:

While glycine is an endogenous amino acid, its role as an excitatory neurotransmitter (along with glutamate) means that there is a limit to what a person should take.

In rats, the toxicity dose (LD50) is 7930 mg/kg. Thus, while it is a fairly safe amino acid to supplement with, like pretty much everything, there is a maximum dose.

Clinical trials of glycine for sleep usually use around 3g/night. Other clinical trials, though, have used doses up to 0.8g/kg in schizophrenic patients (split into 2-4 doses).  For a 150 lb adult, 0.8g/kg would be over 50g. Other clinical trials for patients with schizophrenia used 15g-30g/day. While these doses explain the safety of glycine supplementation at higher amounts, the positive effects on sleep quality are likely found in the 3-5g range.

The one negative effect that I found for glycine is that it may inhibit wound healing. The inhibition of angiogenesis by glycine slows the growth of blood vessels, which could be a negative if you have a wound. On the other hand, this may slow the growth of tumors.[ref]


More to read:

Glycine plus NAC to boost glutathione
A high dose glycine plus n-acetyl cysteine supplement increased glutathione production in older adults. This reduced oxidative stress and increased mitochondrial function.

Supplementing with Glycine and NAC: reduce oxidative stress, increase mitochondrial function

Mitochondrial dysfunction and elevated oxidative stress are part of the root cause of aging.

  • With poor mitochondrial function, cells can’t perform at an optimal level, leading to an increase in ROS (reactive oxygen species).
  • Oxidative stress, due to an increase in ROS, increases the risk of cognitive decline, inflammation, heart disease, and insulin resistance.

So how do young cells fight oxidative stress and keep mitochondrial function in tip-top shape? Glutathione.

Glutathione is an antioxidant produced in your cells to combat excess ROS (reactive oxygen species). It is the body’s first line of defense against oxidative stress.

As we age, we produce less glutathione, and glutathione is used up more rapidly to combat oxidative stress.[ref][ref]

Increasing glutathione:

When trying to mitigate the negative effects of aging, the question is: How can we increase the production of glutathione? 

Glycine, cysteine, and glutamate are the amino acids that your cells need to synthesize glutathione. The limiting factor in producing enough glutathione seems to be the amino acids glycine and cysteine. Glutamate is plentiful.[ref]

Research shows that low levels of glycine and cysteine in older adults lead to a decrease in the production of glutathione.[ref][ref]

Production of glutathione is a multistep process, and glycine and cysteine are needed in different steps of the synthesis. Low levels of either amino acid are enough to decrease glutathione levels, thus supplementing with both glycine and cysteine together is needed to reliably increase glutathione and decrease oxidative stress.[ref]  Studies using only glycine or only cysteine are not all that impressive when it comes to stopping the diseases of aging.

Research studies on cysteine plus glycine in aging:

Supplemental cysteine and glycine have now been shown in several studies to raise glutathione levels and reduce oxidative stress in older adults. Studies show:

  • Supplementing with glycine and cysteine increased glutathione by 94.6% in elderly adults, bringing their glutathione levels back in line with younger people within two weeks.[ref]
  • A long-term study looked at the effects of supplementing with glycine and cysteine in older adults (age 70+) for 6 months. The study participants took 1.33 mmol/kg/day of glycine and 0.81 mmol/kg/day, provided as N‐acetylcysteine [NAC]. The results showed that the supplements corrected the baseline deficiency. It also improved inflammation, insulin resistance, cognition, strength, walking speed, and exercise capacity.[ref]
  • In older adults with HIV, supplementing with cysteine and glycine for 2-weeks corrected their glutathione deficiency. This also improved mitochondria function.[ref]
  • Glycine plus cysteine also increases heart function and decreases inflammatory markers in old mice.[ref]

How much?  

A couple of the studies in older individuals used the following:[ref][ref]

  • 1.33 mmol/kg/day glycine –> about 6g/day for a 130 lb person, divided into two doses
  • 0.81 mmol/kg/day of n-acetyl cysteine –> about 8g/day for a 130 lb person, divided into two doses

Note – the dose seems really high for N-acetyl cysteine. Glycine intake from food is normally in the 2-3 g/day range for a normal diet.

Where do I get it?

Disclaimer: I’m not a doctor…If you have questions about supplements and whether they are right for you, definitely talk with your own doctor. N-acetyl cysteine may interact with medications such as nitroglycerine. It can also lower blood pressure in some people, which could be a problem if you are already on a blood pressure medication.

The studies are using large doses of glycine and n-acetyl cysteine…Your best bet for supplementing may be to buy the powder in bulk. Amazon used to carry NAC in powder and capsules, but they have decided not to sell it any more.  BulkSupplements.com sells powdered NAC, and purebulk.com is another good source. You can also get both NAC and glycine in capsules, but that would be a lot of capsules to take in a day.

Glycine is available in bulk powder on Amazon. It is also available from BulkSupplements and PureBulk.

Don’t want to supplement with glycine? Try incorporating gelatin or collagen into your daily routine. For example, Zint collagen contains 4.5g of glycine per 12g serving (scoop included). You can add it to coffee, smoothies, or soup.

Another good source of glycine is bone broth. The glycine content is going to vary a bit, depending on how you make your bone broth. You could always add a little more gelatin or collagen to your broth if needed.[ref]

Foods high in cysteine include pork, beef, chicken, and tuna. But you would need to eat a whole lot to get to a level that is similar to supplemental n-acetyl cysteine. For example, a 6oz steak contains 587 mg of cysteine.

Exercise can also boost glutathione a little, but not as significantly as the supplemental glycine plus cysteine. The supplement studies (above) showed about a 95% increase in glutathione. Compare this to a study showing that  40 minutes of aerobic exercise, 6-days a week, increased glutathione levels by about 25%.[ref]

Personally, I like to supplement with things initially in order to isolate the variables and see what the effect is at a known dose. Supplementing long-term, though, can get expensive and I often lose motivation. At that point, I branch out and try incorporating foods or lifestyle changes.  For example, after trying supplemental NAC and glycine for a while, I may switch to bone broth, collagen, and beef, along with exercise. And then cut back on the supplements to see what happens.

 

Lithium orotate: A natural mineral that affects mood, Alzheimer’s disease, and aging

I read a lot of studies on health and genetics, and I keep finding research on the mineral lithium popping up. Topics such as circadian rhythm dysfunction, Alzheimer’s disease, telomere length, type 2 diabetes, and obesity…all linking to lithium?

The rest of this article explains the research showing the importance of this mineral in our health and longevity.

There is a stigma, at least in my mind, around lithium, and I’ve hesitated at times to write about it. Funny, isn’t it, that no one has hesitation about talking about other minerals such as magnesium or potassium. I’ll let you read through the research overview and decide for yourself.

Recent scientific research on lithium and health

Minerals are needed by the body in the right amount, and it is important to look at the safety and health effects before supplementing with any mineral.

Lithium is a mineral that can be naturally found in food and drinking water. It is also available in low-dose supplemental form (lithium orotate).

Is Lithium Orotate the same as lithium (prescription)?

First, let’s look at the different types and amounts of lithium being referenced in the research studies. Quite a range exists – from natural levels found in water to high levels in prescription meds.

For a lot of people, lithium brings to mind the prescription medication for bipolar disorder. This is almost always in the form of lithium carbonate.

Prescription doses of lithium carbonate are around 900-1200 mg/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. Thus, a 900mg dose would give about 170 mg elemental lithium.[ref]

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

The amount of natural lithium that we get in foods and drinking water varies based on the mineral content of the soil, with estimates of .5 to 3 mg/day.

A provisional RDA  of 1 mg/day is recommended.[ref]

Breaking this down, for an average person, a standard lithium orotate (5mg elemental lithium) supplement would be 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 and Lithium:

A 2017 study investigated Alzheimer’s rates and natural lithium levels in the drinking water in Texas.[ref] In an article about the study (much quicker read than the full paper), the lead author of the study explains the findings.

Essentially, 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.

Alzheimer’s rates have risen everywhere, but the researchers found that Texas counties with higher levels of lithium in the groundwater had less of an increase in Alzheimer’s rates compared with counties that had lower levels of lithium.

The study results are not a total surprise since previous studies linked lithium to a decreased risk of dementia, but it is a great confirmation at a large scale population level. Additionally, observational studies show patients taking prescription lithium are at a lower risk of dementia.

Research 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 Alzheimer’s patients. The trials found that lithium “significantly decreased cognitive decline as compared to placebo“.[ref]
  • 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 a decreased rate of dementia in people with naturally higher levels of lithium in their water (measured since 1986).[ref][ref]
  • 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.[ref]
  • A study in 2015 looked at the effects of microdoses of lithium on a mouse model of Alzheimer’s disease. The study found small doses of lithium carbonate in the drinking water of mice carrying the genes for Alzheimer’s disease caused a “decreased number of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF density in the 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.[ref][ref]

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. Lithium is a cheap, natural mineral with no money in it for funding clinical trials. There seems to be a couple of ‘novel’ low-dose formulations in the works by pharmaceutical companies, though.[ref][ref][ref]

Telomeres, aging, and lithium:

Telomeres are the sequences of DNA 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 shortens. Thus, telomere length is considered to be a biomarker of cellular aging. Shorter telomere length has associations with several age-related chronic diseases including Alzheimer’s.

A recent transgenic mouse study found lithium carbonate treatment leads to longer telomere length in mice bred to have Alzheimer’s disease.[ref] Interestingly, the normal mice had no effect on telomere length from lithium. Couple this information with a meta-analysis showing that Alzheimer’s patients have shorter telomeres.[ref]

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 treated with lithium had longer telomere lengths than non-lithium-treated patients with bipolar disorder as well as relatives of bipolar patients.[ref]

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 can really lead to a conclusion on aging. But I look forward to seeing what future studies tell us on the topic.

The anti-Inflammatory action of lithium:

Lithium exerts anti-inflammatory effects on the body — as well as pro-inflammatory effects under specific conditions. Since the 1970s, it’s been known 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.[ref]

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 the rs4880 alanine allele (G/G for 23andMe) had more of an anti-inflammatory response than those with the valine allele (A/A for 23andMe).[ref] This was a cell study though, so it is hard to know how well this translates to the whole body.

Obesity, Diabetes, Thyroid, and Natural Lithium:

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]

Suicide levels decrease as natural lithium increases:

A number of studies have investigated the link between lithium in drinking water and its effect on overall mood — such as aggression (violent crime rate) and suicide.

A meta-analysis of 15 different studies shows that areas with higher lithium concentrations in their drinking water have lower suicide rates.[ref]


How is lithium affecting our body and brain?

For a long time, exactly how lithium worked for bipolar patients was not understood. (Quite a few psychiatric medications were 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 of the neuroprotective effects of lithium.[ref] 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. The thought on lithium’s inhibitory effect on GSK-3β might be due, in part, to binding to a site normally occupied by magnesium. For a comprehensive 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,  read “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 runs by a couple of core genes 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 drives our internal daily cycles of waking and sleeping, temperature, and energy metabolism. GSK-3β is involved in the phosphorylation of both the day and night core circadian genes.

Genetic variants that change our circadian rhythm have links with an 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]

The link between Alzheimer’s disease and circadian disruption is strong.[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.”[ref]

Toxicity of lithium:

Many consider lithium to be an essential trace element. Its complete elimination from the body causes a decline in fertility, higher mortality rates, and behavioral abnormalities.[ref]

But, like all substances, there is a toxic upper limit.

Patients taking lithium carbonate or lithium chloride for mood stabilization show a variety of side effects, depending on dosing. (e.g. around 170 mg elemental lithium). Most patients taking prescription lithium carbonate need blood tests done at regular intervals to determine their serum lithium levels. Plasma lithium levels above 1.2 mM cause nausea, diarrhea, and tremors.[ref]

Other side effects noted by patients taking prescription levels of 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 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.

If you have questions on any mineral supplement, talk with your doctor or health care provider for medical advice. 

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. 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]


Lifehacks:

If you have medical questions, talk with your doctor – especially if you are on any medications or if pregnant or nursing – before supplementing with lithium orotate. 

Supplement Doses: Lithium orotate is available as a natural supplement in many health food stores and online (Amazon). You can get it in doses from 5 mg to 20 mg.

Anti-inflammatory: 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.

Where to buy:

Lithium orotate is relatively inexpensive as a supplement. It is available on Amazon as well as in a few health food stores.

TNF-alpha and Inflammaging

TNF-alpha (tumor necrosis factor alpha) is a proinflammatory cytokine upregulated in aging. TNF-alpha acts as a signaling molecule in our immune system and is important in our innate immune response. But chronically elevated TNF-alpha is one cause of the diseases of aging. Inhibiting chronic inflammation is one tool available for longevity and healthspan.

This article will dig into the role of elevated TNF-alpha in the disease of aging as well as natural solutions for decreasing TNF-alpha and resolving inflammation.

Elevated TNF-alpha in aging:

TNF-alpha acts as a signaling molecule. Activated immune cells, such as macrophages, mast cells, B cells, and lymphocytes produce TNF-alpha. Its production also occurs in other cells, such as smooth muscle cells, in response to an injury.[ref]

TNF-alpha is a signal that calls in the troops to cause cell death. This is great when it involves tumor cells (get the name – tumor necrosis factor), but not great when we are talking about chronic inflammation.

Researchers have known for several decades that elevated TNF levels are a prognostic marker for mortality in the elderly.[ref][ref]

Genetics studies show that genetic variants associated with lower inflammatory cytokine production, including lower TNF-alpha levels, are linked to longevity.[ref]

One source of elevated TNF-alpha in aging is from B cells. A type of white blood cell, B cells are responsible for the body’s antibody response. In aging, a subset of B cells become inflammatory, secreting TNF-alpha among other cytokines.[ref]

Senescent cells, which are no longer able to function properly or reproduce, give off inflammatory cytokines, including TNF-alpha.[ref] Cellular senescence increases considerably with aging. Additionally, higher levels of inflammatory cytokines, such as TNF-alpha, can cycle back to increase cellular senescence.[ref]

Elevated TNF-alpha also plays a role in the pathogenesis of neurological diseases including Alzheimer’s, ALS, and Parkinson’s disease.[ref]

Production of TNF:

TNF-alpha is a cytokine that can either be on the membrane of a cell (in immune cells) or released from all types of cells in the soluble form.

TNF-alpha is a ‘pyrogen’, meaning it can cause fevers, signal cell death, and inhibit viral replication.

TNF-alpha receptors:

The signal from TNF-alpha received by several different receptors causes different actions to happen in a cell.

TNFR1, tumor necrosis factor receptor 1, is found on most types of cells throughout the body. When activated by TNF-alpha, it can signal to increase NF-κB, another important inflammatory cytokine in the important pathway for resisting infection. TNFR1 also signals for the initiation path for cellular death (such as for killing off tumor cells).

The TNFRSF1A gene codes for TNFR1, and variants in TNFRSF1A can cause periodic fever syndrome, a genetic auto-inflammatory disease.  Elevated TNFRSF1A levels are associated with schizophrenia, bipolar disorder, and dementia or cognitive impairment in aging.

TNFR2 (tumor necrosis factor receptor 2), on the other hand, interacts with T-cells in controlling the immune response. Dysregulation here is one factor in autoimmune diseases such as Crohn’s, MS, lupus, and type 1 diabetes.[ref]

The TNFRSF2A gene encodes the TNF receptor 2 protein found only on immune cells. It doesn’t initiate cell death. So to some extent, TNFR2 is playing more of a modulatory role in the immune response.

Why would you want to decrease TNF-alpha?

While TNF-alpha is essential for removing cells with DNA mutations that could cause cancer, chronically elevated TNF-alpha is not good and plays a causal role in many of the diseases of aging.

Quite a few studies show elevated TNF-alpha levels present in mild cognitive impairment (MCI) and Alzheimer’s disease. Animal studies show that once chronic brain inflammation is occurring, there is an upward spiral of TNF-alpha induced, which may stimulate amyloid-beta plaque formation.[ref] Note that chronically elevated TNF-alpha is just one of the players here — I don’t want it to seem like this is the only thing going on in the pathogenesis of Alzheimer’s disease.

Animal studies also elucidate the role of elevated TNF-alpha in the brain inflammation involved in Parkinson’s disease.[ref]

Higher levels of TNF-alpha due to genetic variants have links to gum disease, inflammatory bowel disease, asthma, COPD, heart disease, septic shock, and arthritis.[ref][ref][ref][ref][ref][ref][ref][ref][ref][ref] If you have your genetic data from 23andMe or AncestryDNA, check your TNF gene variants here.

Always keep in mind that it is a balancing act between not wanting chronic inflammation and the need for a good response to kill potentially cancerous cells.

Anti-TNF drugs:

TNF-alpha inhibitors approved by the FDA include:

  • infliximab (Remicade)
  • adalimumab (Humira)
  • certolizumab pegol (Cimzia)
  • golimumab (Simponi)
  • etanercept (Enbrel)

The inhibitors are used for autoimmune diseases such as rheumatoid arthritis, psoriasis, and IBD, which are all associated with increased TNF-alpha and too much cell death.[ref]

Note that one side effect of TNF-alpha inhibitors is an increased risk for certain cancers.

Natural TNF-alpha inhibitors:

Talk to your doctor or pharmacist if you are on any medications before beginning supplements.

Many of these natural TNF-alpha inhibitors have the added benefit of being anti-cancer molecules as well. This may be one advantage of using natural polyphenols for reducing elevated TNF-alpha over stronger pharmaceutical options.

Quercetin:

Quercetin is a flavonoid found in fruits and vegetables such as apples, onions, and blueberries. Many studies show that quercetin supplementation can decrease TNF-alpha levels.[ref][ref]

Quercetin has poor bioavailability, with only about 2% absorption for oral doses. Studies show absorption occurs in the upper section of the small intestines.[ref]

Quercetin can impact iron absorption — good if you are high in iron, but a problem if you are needing more iron. If you are low in iron, you may want to make sure to time your quercetin away from iron-rich meals or iron supplements.

Quercetin is better absorbed with fat. A study found a ~40% increase in bioavailability when taking a quercetin supplement along with a high-fat meal (15g of fat in their breakfast).[ref]

Curcumin:

Curcumin is a polyphenol found in turmeric (a spice). Many studies have shown both in humans and animals that curcumin is a natural inhibitor of TNF-alpha. It works to block the release of TNF from macrophages and it works to inhibit some of the downstream inflammatory effects when TNF-alpha binds to either TNF receptor.[ref]

Curcumin bioavailability improves 3-fold when taken with piperine, a component of black pepper. A clinical trial in people with NAFLD showed that 500 mg/day of curcumin + 5mg of piperine lowered TNF-alpha levels. Another clinical trial using 1,000 mg/day of curcumin + 10 mg piperine showed a significant reduction in TNF-alpha levels in people with diabetes. Final example – a clinical trial of 1,000 mg/day of curcumin in people with metabolic syndrome also showed a significant reduction in TNF-alpha levels.[ref][ref][ref]

Curcumin doesn’t absorb well in the intestines and quickly metabolizes once absorbed. The piperine allows it to stick around longer in the body, and nanoparticles and other complexes make it more bioavailable.[ref]

Cannabinoids:

Studies point to a role for cannabinoids in reducing TNF-alpha.[ref][ref]

Cannabidiol (CBD), a non-psychoactive component of cannabis and hemp, may also be an option for decreasing the release of TNF-alpha. [ref][ref][ref]

Luteolin:

Cell studies show that luteolin, a flavonoid, suppresses the release of TNF-alpha.[ref] Animal studies also show that luteolin can decrease the transcription of TNF-alpha.[ref] There are just a few human studies using luteolin as an anti-inflammatory. One study in children with autism showed that a supplement containing luteolin (100mg) and quercetin (70mg) reduced TNF-alpha levels.

Hesperidin:

One more anti-inflammatory flavonoid is hesperidin and it is found in citrus fruit. Animal and cell studies show that hesperidin decreases TNF-alpha levels.[ref][ref][ref]

Hesperidin doesn’t absorb well in the stomach or small intestines. Instead, the colon’s microbiome converts it to the more bioavailable aglycone hesperetin for easier absorption. It is possible the metabolites give the health benefits, rather than the original hesperidin molecule.[ref]

 

Targeting cellular senescence with natural compounds

Cellular senescence is a natural process that stops the reproduction of cells. While senescence happens throughout life, in aging, an accumulation of excess senescent cells seems to be at the heart of many age-related diseases.

What is cellular senescence?

Senescence is when a cell can no longer divide and has been damaged — but yet the cell remains in place and doesn’t go through cell death.

Senescence has dual outcomes:

  • On the one hand, stopping cellular reproduction in cells that have been damaged (DNA mutations, wounds, or tissue damage) is vital. This allows for wound repair and stops cancer from DNA mutations in the wrong genes. Stopping cancer is good!
  • On the other hand, senescent cells give off inflammatory and dangerous signals that increase chronic inflammation and negatively impact the health of surrounding cells. Chronic inflammation is bad.

Cellular senescence happens throughout your lifespan, but in aging, the rate of cellular senescence outpaces the ability of the body to eliminate the senescent cells.

Radiation, toxins, cellular stress, and cancerous mutations can all increase the number of senescent cells.

So what makes senescence so bad during aging? Why are damaged cells that just sit there and don’t grow – or die – bad? The answer is the dreadful SASP.

What is SASP?

One of the biggest issues with senescent cells is that they give off signals known as “Senescence Associated Secretory Phenotype’ or SASP.

If the senescent cell lingers longer than it should, these inflammatory signals cause damage to other surrounding cells and cause an overall increase in chronic inflammation in the body.

Naming names: SASP initially may consist of factors that are immunosuppressive such as TGF-β1 and TGF-β3, but as time goes on, the signals given off are more proinflammatory including TNF-alpha,  IL-1β, IL-6, and IL-8.  But not all senescent cells give off the same signaling molecules or export the same exosomes. Additionally, alterations in microRNAs, proteases, and an increase in reactive oxygen species are associated with SASP.[ref]

Estimations state that 30-70% of senescent cells develop a SASP signature.[ref]

While it is possible to target individual inflammatory cytokines, such as reducing TNF-alpha, the bigger picture when it comes to inflammation in aging is to clear out the senescent cells that are giving off the inflammatory signals.

What does increased senescence cause?

Here is a partial list of chronic diseases of aging that are caused, at least in part, by cellular senescence:[ref][ref]

  • frailty
  • macular degeneration
  • skin conditions such as psoriasis and non-healing wounds
  • COPD
  • dementias
  • atherosclerosis
  • chronic kidney disease
  • cancers
  • osteoarthritis
  • degenerative disc disease
  • idiopathic pulmonary fibrosis

Why is senescence such a problem in aging?

Younger people can keep senescence in balance, with their immune systems clearing out the cells in a timely fashion.

I don’t know that the question of why senescent cells accumulate so rapidly starting around age 60 has been fully answered yet in research.

Some researchers think that the body reaches a threshold at which it can no longer clear out enough senescent cells and accumulation starts to occur rather rapidly. Contributors to cellular senescence include DNA damage (toxins, radiation), cellular stress from reactive oxygen species, lipid toxicity, hypoxic stress, inflammation, and more.[ref]

The aging of the immune system is at least part of the picture in the inability to clear senescent cells. But part of the change to the immune system in aging is due to senescence. So it is a bit circular to point to the aging immune system as the cause of increased senescence, when the increase in senescent cells causes aging in the immune system.[ref]

Senolytics: targeting the senescent cells

Senolytics are drugs or natural compounds that decrease the burden of senescent cells. These molecules cause senescent cells to undergo apoptosis or cell death, while not killing healthy cells.

While we have known about cellular senescence since the 1960s, the science showing that these cells can be targeted and removed by certain molecules is less than a decade old.[ref]

One of the first senolytic drugs developed/discovered is dasatinib, which is a tyrosine kinase inhibitor used as a type of chemotherapy for leukemia. Specifically, dasatinib inhibits EFNB1 (ephrin B), a type of tyrosine kinase.

Of note here, not all tissue types have the same type of SASP, and some of the senolytics may better target specific tissue types than others.

It takes weeks to months for senescence cells to develop and to start giving off a SASP signature signal. So senolytics are often used only periodically instead of on a continual basis.[ref] The goal is to give your body’s natural ability to clear out senescent cells a periodic boost.

In most research studies, senolytics are used at high doses but just for a few days. This may then be repeated after a couple of months. Clinical trials are still ongoing to determine the more effective schedule and dosing.[ref]

Natural senolytics:

Until pharmaceutical senolytics go through clinical trials and are readily available for treating aging as a disease, many of us are left with relying on natural plant compounds that act as senolytics.

Heads-up:  Talk with your doctor before starting any supplements. Many natural substances can interact with pharmaceutical drugs, so check for interactions with any medications that you are on.

Quercetin:

One of the first natural substances investigated as a senolytic was quercetin. Many studies stack quercetin with dasatinib for a synergistic effect — attacking senescence in multiple ways.

Quercetin is a flavonoid found in apples, onions, and many other fruits and vegetables in small amounts.

A recent (small) clinical trial investigated the effect of a combination of dasatinib (100mg/day) and quercetin (1,000 mg/day) in patients with chronic diabetic kidney disease. The study participants received dasatinib + quercetin for three days. After 11 days post-treatment, biopsies of adipose and skin cells along with blood samples were examined. The results showed a decrease in senescent cells after 11 days in adipose tissue and blood, but no statistical effect in skin cells.[ref]

Another recent (small) clinical trial used 100 mg/day of dasatinib plus 1,250 mg/day of quercetin in patients with idiopathic pulmonary fibrosis. Again, the participants took the combination for three days and then were tested later for improvements. The one statically significant improvement was in physical function (walking speed and chair-stand times).[ref]

Animal studies on quercetin plus dasatinib show promise for heart disease, lung function, and osteoporosis. Three-day courses of the combined senolytics increased cardiac ejection fraction and decreased vascular calcification. Additionally, when given intermittently, the combination increased pulmonary function, and a reduction in pulmonary fibrosis occurred.[ref]

Interestingly, animal studies also show that quercetin plus dasatinib may reduce intestinal senescence as well as inflammation.[ref]

Of note with quercetin: it seems to be much more effective in conjunction with dasatinib, and there are questions surrounding the efficacy of quercetin alone as a senolytic.

Fisetin:

Fisetin is another naturally occurring flavone that works well as a senolytic. It acts as a selective BCL-x inhibitor.

Fisetin has shown in studies to selectively induce cell death in some types of senescent cells, but not all. For one, it doesn’t target senescent adipocytes (fat cells).[ref]

A study investigating ten natural compounds for their senolytic capacity found that fisetin was the top candidate as far as reducing the relative number of senolytic cells. Importantly, fisetin reduced senolytic cells without reducing healthy cells. Additionally, the study showed that either acute oral or chronic lower-dose fisetin reduced senescence and aging phenotype in mice.[ref]

Importantly, animal studies also show that fisetin extends lifespan while reducing age-related problems.[ref] Extending healthspan is the goal for senolytics, so it is good to see that a natural senolytic can have this benefit (in animals).

In the epithelial cells of the lungs, an animal study shows that fisetin inhibits senescence and reduced pulmonary fibrosis.[ref]

Another animal study showed that fisetin reduces atherosclerotic plaque and downregulates the expression of PCSK9 (important in cholesterol levels).[ref]

There is currently a clinical trial underway with the Mayo Clinic in older women using fisetin with a goal of reducing frailty and inflammation. The dosage being used is 20 mg/kg/day (oral) for two days a month with the trial lasting two months.[ref]

Piperlongumine:

Piperlongumine is a component of the fruit of the Piper longum (long pepper) plant.

There isn’t as much research on piperlongumine as the other natural compounds, but what is available is intriguing.

Several studies have shown that piperlongumine acts as a senolytic, selectively killing senescent cells. Interestingly, it works via targeting oxidative stress response proteins, which are elevated in senescent cells and cancer cells.[ref]

A 2018 mouse study showed that oral administration of piperlongumine increased neuronal plasticity and neurogenesis.[ref]

Piperlongumine may also act as an immunosuppressant for TH17. This may be beneficial for people with imbalanced T-cell differentiation, such as in autoimmune diseases, but of concern in other situations. Of note, the study showed the effect only when thiols were not present.[ref] Additionally piperlongumine may also act as an anti-clotting agent.[ref]

Curcumin:

Curcumin, a component of the spice turmeric, is a readily available supplement that has some senolytic properties.

A study looking at the senolytic properties of curcumin and one of its metabolites, o-Vanillin, shows that it can clear senescent cells from intervertebral discs.[ref]

Animal studies show that curcumin, at higher doses, can act as a senolytic – in certain tissues.[ref]

Note that curcumin can act as a blood thinner.

Phloretin:

Phloretin (Dihydronaringenin) is a flavonoid that has been investigated for its anti-cancer possibilities.[ref] It is a polyphenol found in apples and is metabolized to produced phloridzin.  

Phloretin has shown in several cell and animal studies to have senolytic effects.[ref]

This seems to be a compound with potential, but with a lot more research needed.

EGCG:

Epigallocatechin gallate, EGCG, is a bioactive compound found in green tea.

While EGCG is not a senolytic, a cell study shows the EGCG increases SIRT3 activity, which may delay cellular senescence. The study used senescent adipocytes (fat cells).[ref]

Combining natural compounds as senolytics:

A recent cell study showed that the combination of resveratrol, curcumin (bioCurcumin), and liposomal β-caryophyllene significantly reduced several components of senescent cells including reducing L-1β, IL-6, and TNF-α expression levels and increasing SIRT1.[ref]

In different tissue types, senescent cells may need to be targeted with different compounds. Some senescent cell types can be targeted via BCL-2, which is also what quercetin acts upon. Other cell types are better targeted via PI3 kinase delta or BCL-xL. Thus, a combination of different senolytic compounds may give a better overall response.

 

Side effects from natural senolytics:

Gastrointestinal side effects are possible from higher doses of many of the natural senolytics.[ref]

Quercetin and fisetin both inhibit COMT and could lead to irritability, anger, or anxiety in people with COMT genetic variants. Maybe.

Anecdotally, fisetin at higher doses may cause a flu-like feeling.

Seriously, check for interactions if you are on any medications. High doses of supplements can interact with many medications.

Fisetin reduces blood sugar levels in animals. If you tend to have problems with hypoglycemia, you may want to be cautious with fisetin.[ref]

Where to find natural senolytics:

The amounts of these natural flavonoids used in the trials, whether human or animal, are much higher than what you could get from eating fruits and vegetables.

Quercetin is readily available at most health food stores and online via Amazon. Read the reviews and pick out your favorite brand of capsules or as a powder. Just as a warning – quercetin is a yellow powder that stains, so use caution if trying to create your own capsules with it.

Research shows that eating a meal that contains fat along with the quercetin supplement can increase bioavailability.[ref] Transdermal absorption of quercetin (mixed with oil/fat) is possible.[ref] Again, quercetin is yellow, and it stains the skin with a nice jaundice-like hue.

Dasatinib is a prescription medication in the US. It may also be available as a research chemical from some online peptide stores, but the question of quality and purity is one that you should investigate thoroughly before going down that path.

Fisetin is available as a supplement from several manufacturers either in capsules or as a powder. High-dose fisetin is used as a senolytic for just a few days at a time. Your better bet for higher doses may be to use the powdered form of fisetin. Note that the Mayo clinical trial (no results yet) is using a dose of 20 mg/kg/day for two days in older women.

While not commercially available (that I can find), a liposomal formulation of fisetin may be many times more bioavailable.[ref] Other studies also point to fisetin encapsulated in fat being more bioavailable.[ref] While no human studies seem to be available on this, it may be that fisetin is more absorbable if taken along with fat.

Fisetin can also be applied topically and has been studied in animals for reversing photoaging.[ref][ref]

Piperlongumine seems to only be available as a research chemical. Long peppers are available as a food, but I don’t know that it would be possible to consume enough to make a difference as a senolytic. Apparently, long pepper is quite spicy.

Phloretin is available as a very expensive skincare product. I have no idea how well it works for skincare. Phloridzin, the metabolite of phloretin, is available in apple polyphenol supplements, but at low dosages (5% of supplement weight).

 

 

Alzheimer’s prevention through targeting the liver

Preventing Alzheimer’s is at the top of the list for many people when considering longevity and healthspan. Genetics, as well as environmental factors, play into the susceptibility to this disease of aging. While most focus is on the brain, recent research shows points to another key player in Alzheimer’s prevention: the liver!

Bile acids, Alzheimer’s, the liver, and brain health:

Alzheimer’s disease is due to neurodegeneration in the brain. A buildup of amyloid-beta plaque and tau tangles are characteristics of the Alzheimer’s brain, but not everyone with amyloid-beta plaque ends up with dementia symptoms.

The biggest genetic risk factor for Alzheimer’s is the APOE E4 allele, which is a lipoprotein involved in cholesterol transport. But even without the APOE E4 risk factor, Alzheimer’s prevention should be at the top of the list for almost everyone. To put this into perspective, in the UK in 2018, Alzheimer’s was the number one cause of death in women (2nd biggest cause of death for men).[ref]

While many decades of clinical trials, animal studies, and theories surround the amyloid-beta hypothesis of Alzheimer’s disease, not much progress has been made on this front.

Newer research is branching out and looking at Alzheimer’s disease from different perspectives — as a mitochondrial disorder, like type-3 diabetes or glucose dysregulation in the brain, as a response to viral pathogens, due to the gut microbiome, or a lack of serine.

But the genetic link from the APOE E4 allele solidly remains. And this ties into cholesterol transport, metabolism, and the gut microbiome. (Cholesterol is essential to the brain and about 25% of the total cholesterol in the body is in the brain.[ref])

Now some researchers are pointing towards the liver as the organ that we need to look at for Alzheimer’s prevention.[ref]

Before we dive into the research on the liver and bile acids in Alzheimer’s prevention, let’s do a very quick overview of amyloid-beta…

Quick background overview: Amyloid-beta in the brain and periphery

Amyloid-beta, a peptide formed from the amyloid precursor protein (APP), breaks apart to form the amyloid-beta peptide. This naturally occurring peptide exists in plaques in the brains of people with Alzheimer’s.

Amyloid-beta normally circulates in the plasma, cerebrospinal fluid, and the brain interstitial fluid, and clears out of the brain during sleep via the lymphatic system. (Yep – sleep is important in Alzheimer’s prevention)

One theory suggests Alzheimer’s possibly misfolds the amyloid-beta that doesn’t clear out like it should instead of forming the plaques that eventually cause neurons to die.

While I’ve often pictured amyloid-beta similar to the gunky plaque building up before you get your teeth cleaned (but in the brain), in actuality, a natural production and clearance occur of the amyloid-beta peptides and it goes on all the time from the brain. Amyloid-beta moves from the interstitial fluid around the brain and transports across the blood-brain barrier and into the bloodstream.[ref]

The question then arises as to how to keep brain levels of amyloid-beta in check, and how the flow of amyloid-beta across the blood-brain barrier affects the balance of amyloid-beta in the brain.

Research in animals shows that reducing amyloid-beta in the bloodstream may reduce brain amyloid-beta.[ref] Studies also show that cholesterol is linked with Alzheimer’s, and statins slightly reduce the risk of Alzheimer’s. Cholesterol doesn’t cross the blood-brain barrier, but some cholesterol metabolites do.[ref]

This brings us around to the liver and bile acids…

Bile acids:

A recent study took a deep dive into the changes in postmortem brain samples of Alzheimer’s patients and cognitively healthy controls of a similar age. The study determined bile acids are altered in the brains of Alzheimer’s patients.[ref] This adds to several previous studies that also found altered bile acid metabolites in Alzheimer’s brains.[ref][ref]

Certain bile acid metabolites are neuroprotective and other bile acids are neurotoxic in the brain.[ref] On the neuroprotective side is TUDCA, which we will come back to in the Lifehacks section.

High neurotoxic bile acid metabolites are could be playing a role in the cognitive decline in Alzheimer’s.[ref] Or it could be the alteration in the ratio of the different metabolites.

Stay with me hereThis all ties together in Alzheimer’s disease with cholesterol metabolism, the liver, cell signaling, and the gut microbiome.

Digging deeper into bile acids:

Quick background science: Bile acid production takes place in the liver and then transports to the gallbladder for storage as bile until needed. Bile gets released in response to eating foods containing fat and then emulsifies that fat for absorption by the intestines. Bile acids are a component of bile, which I think of as acting kind of like a detergent to break up fat from foods.

Bile acids are derived from cholesterol, and bile acid production is linked with cholesterol homeostasis. So one role of bile acids is to keep cholesterol levels in balance. Bile acids also act as cellular messengers, and secondary bile acid production occurs from the gut microbiome.

There are two primary bile acids, cholic acid (CA) and Chenodeoxycholic acid (CDCA). These two primary bile acids are conjugated with either glycine or taurine, making them into bile acid salts that are better at breaking up fats.[ref]

Once the bile acids break down fats and complete their job, the intestines reabsorb them. The bile acids then recycle back to the liver to be reused. About 10% reach the colon and break down into secondary bile acids by the gut bacteria.

CA (cholic acid), converts into the secondary bile acid, deoxycholic acid (DCA) by bacteria in the colon. CDCA, the other primary bile acid, converts into lithocholic acid (LCA) and ursodeoxycholic (UDCA). They can then get reabsorbed in the colon and taken back to the liver to be reused.[ref]

So that is what happens with most of the bile acids produced in the liver…into the intestines (usually by way of the gallbladder), doing their job with fats, and then eventually recirculated and reused.

But…some bile acids ‘spill over’ into circulation and act as signaling molecules for regulating energy. Additionally, bile acid receptors exist in the brain and link to Alzheimer’s disease.[ref]

To get a little more complicated, cholesterol doesn’t cross the blood-brain barrier but instead, the brain synthesizes it. That cholesterol can break down in the brain cells into primary bile acids using a little bit of a different pathway than liver cells use (called the alternative pathway).[ref] But, bile acid metabolites, such as TUDCA and UDCA, can cross the blood-brain barrier.

In brain samples from Alzheimer’s patients, several studies now show a reduction in CA (primary bile acid, cholic acid) and an increase in the secondary bile acids produced by bacteria.[ref][ref] Remember – some of those secondary bile acids are neurotoxic.

In addition to the primary bile acid to secondary bile acid ratio being altered in Alzheimer’s, that ratio also links to increased cognitive decline. So the ratio gets worse as cognitive performance goes downhill.[ref]

What causes a decrease in the primary bile acids and an increase in gut microbe-derived secondary bile acids?  I’m not sure that the research gives us an answer there yet. The gut microbiome changes in aging[ref]…and the biggest risk factor for Alzheimer’s is age. So that may be part of the answer to the changes in bile acid metabolites. Additionally, there are links between liver dysfunction and Alzheimer’s…Perhaps both?

One more role of bile acids: Connective tissue growth factors

In the area of the brain with the amyloid-beta plaque and neurofibril tangles, researchers find higher levels of connective tissue growth factors. These growth factors possibly play a role in amyloid-beta plaque production. A secondary bile acid, TUDCA, downregulates the connective tissue growth factors.[ref]

More about the liver in Alzheimer’s prevention:

This link with the liver and Alzheimer’s isn’t just about bile acids, though.

A low-density lipoprotein receptor (LRP1), found in the liver and the brain, also may be important in Alzheimer’s prevention:

  • To cross the blood-brain barrier, LRP1 (low-density lipoprotein receptor-related peptide 1) must transport amyloid-beta.
  • Additionally, LRP1 bound to amyloid-beta circulates in the bloodstream and prevents it from crossing back into the brain.
  • In the liver, LRP1 clears out systemic amyloid-beta.[ref]

Additional studies on LRP1 show that its effect on Alzheimer’s may be due not only to clearing out peripheral amyloid-beta but also due to APOE.[ref]

Thus, the APOE E4 genetic connection comes into play here also. APOE, an apolipoprotein, involves the transport and metabolism of cholesterol. In the liver, LRP1 and the LDL receptor work together in clearing out APOE particles.

LRP1 is important in regulating liver fat in a high cholesterol diet. Animal studies show that decreased LRP1 causes increased liver disease.[ref]

Thus, the liver and LRP1 come together in several ways to impact Alzheimer’s prevention: clearing out amyloid-beta in the peripheral circulation, acting on APOE E4, and regulating cholesterol (and thus impacting bile acids). Beyond the liver, LRP1 is also important in the blood-brain barrier.[ref]

This story of LRP1 isn’t clear, though, as just increasing LRP1 everywhere to get rid of amyloid-beta plaque. A lot of research on the LRP1 receptor in brain tissue shows conflicting results.[ref] To me, it seems that the research focused at the cellular level on brain cells with LRP1 may be missing the benefit of LRP1 helping to remove amyloid-beta in the peripheral circulation.


Lifehacks:

What can you do to alter bile acid metabolism in the brain? Or to clear out more amyloid-beta via the liver?

Gut health is important because gut microbiome changes have links to healthy aging. So one aspect is to feed your gut microbes healthy, whole food.  To be frank, that is more of a baseline that everyone should be doing at a minimum, rather than what I would qualify as a ‘lifehack’.  Research on probiotics may someday point to specific ways of altering the gut microbiome to prevent Alzheimer’s, but we aren’t there yet.

Supplements: The usual “talk with your doctor” advice applies here before starting any supplements, especially if you are in poor health or on prescription medications. 

Supplemental bile acids:

TUDCA is a bile acid metabolite that is readily available as a supplement. It is often marketed for gallstones or liver health (if you need to know which section of the health food store to look in).

In a mouse model of hereditary Alzheimer’s disease, six months of TUDCA supplementation prevented the Alzheimer’s pathology that should have happened in these mice.[ref]

Other studies show that TUDCA prevents cognitive impairment in animal models of Alzheimer’s disease.[ref]

Another mouse study using transgenic mice as an Alzheimer’s model found that TUDCA could reverse the amyloid-beta deposits in the brain. One thing noted was that TUDCA stopped the GSK3β hyperactivity, which is part of the formation of tau tangles. Most encouraging was the TUDCA partially rescued synaptic loss.[ref]

Of note here, TUDCA can cross the blood-brain barrier.[ref]

Mouse studies don’t always translate to humans in Alzheimer’s research, but the mechanism of action here is promising.

Another bile acid, UDCA, is a similar molecule to TUDCA but not conjugated with taurine (the T in TUDCA). UDCA is available as a prescription medication in many countries including the US. Cell studies using neuronal tissue from Alzheimer’s patients show that UDCA increases mitochondrial function.[ref]

Is TUDCA relatively safe to take? There are numerous human clinical trials on TUDCA, just none relating to Alzheimer’s disease. Instead, the trials have focused on the treatment of liver diseases, gallstones, and ALS with good safety profiles.[ref][ref][ref][ref]

Supplements: TUDCA is readily available at health stores and online. Here is one that I’ve used, but read through the reviews and choose one that you are comfortable with.

Targeting LRP1:

Withanolides, from ashwagandha, upregulates LRP1 in the liver and increases amyloid-beta clearance. In an animal model of Alzheimer’s disease, this decreased amyloid-beta in the brain and also reversed behavioral deficits.[ref][ref][ref][ref]

Supplements: Ashwagandha is also readily available as a supplement. Look for one that includes the percentage of withanolides, the active ingredient that impacts LRP1. Here is one example with a higher withanolide concentration, but shop around if you are interested in other formulations or simpler Ashwagandha powders to add to smoothies.

Cannabinoid receptor agonists have also shown to upregulate the expression of LRP1 in the blood-brain barrier and enhance the clearance of amyloid-beta across the BBB in animal studies.[ref]

Avoiding Fatty Liver Disease:

Non-alcoholic fatty liver disease (NAFLD) occurs by an increased fat accumulation in the liver. Estimates show that almost half of adults in the US have fatty liver. With the link between liver function and Alzheimer’s, it would make sense that NAFLD would be associated with AD. Indeed, research shows that NAFLD has an association with decreased cognitive performance (for everyone) and with Alzheimer’s disease.[ref][ref][ref]

For more information on NAFLD and lifehacks for reversing it, please read: Fatty Liver: Genetic variants that increase the risk of NAFLD

Luteolin: neuroprotective and anticancer flavonoid

Luteolin is a flavonoid found in herbs and vegetables. Research shows that it has numerous anti-inflammatory and antimicrobial effects. Additionally, some research shows that luteolin may help to stop the proliferation of certain cancer cells.

The goal here is to simply present a balanced view of the studies and clinical trials on luteolin as a supplement. You can decide if it is worthwhile to add it to your arsenal of natural supplements.

Luteolin:

You will find the flavone luteolin in parsley, carrots, artichokes, celery, thyme, chamomile tea, olive oil, oranges, and oregano.

Flavonoids, such as luteolin, are produced by plants as a cellular defense against microorganisms or UV radiation. Many of these molecules also bring cellular health benefits to us when we consume them.[ref]

A quick note to prevent confusion: luteolin is different than lutein (yellow plant pigment used for macular degeneration).

Neuroprotective effects of luteolin:

O-glycosylation of amyloid precursor protein is required for the production of amyloid β, which builds up in plaques in the brains of Alzheimer’s patients. Inhibiting this process, at least in theory, could decrease amyloid β in the brain. Let me emphasize, this is theoretical and not proven in human studies.

Luteolin selectively inhibits the type of O-glycosylation (Mucin-type O-glycosylation) involved in amyloid β formation.[ref]

Animal studies show luteolin inhibits neuroinflammation by controlling microglia activation.[ref]

In a mouse study of Alzheimer’s, luteolin protects against amyloid β memory dysfunction and also increases levels of endogenous antioxidants including Mn-SOD, Cu/Zn-SOD, and glutathione.

Let me emphasize here, though, that mouse and cell studies don’t always pan out when it comes to Alzheimer’s research…

Luteolin as an anti-inflammatory:

In cell studies, luteolin inhibits TNF-alpha and IL-6 released via suppressing NF-κB.[ref]

Other studies point to luteolin reducing IL-6 (an inflammatory cytokine) production in response to bacterial infections.[ref]

Luteolin and apigenin (another flavonoid) have shown to inhibit IL-31 and IL-33 in microglial cells.[ref] IL-31 is an inflammatory cytokine produced by activated T lymphocytes and it plays a role in chronic inflammatory diseases.

Antihistamine properties of luteolin:

Luteolin can act as a mast cell stabilizer and reduce histamine release.[ref][ref] This may be of benefit to anyone dealing with mast cell activation syndrome or histamine intolerance.

The ‘brain fog’ term applies to the inability to think clearly or concentrate. Some researchers think that brain fog is due to inflammation and histamine release. They theorize that luteolin should be helpful for brain fog, pointing to studies on it improving attention in kids with autism.[ref]

Luteolin and sleep:

Animal studies show that luteolin has a sleep-inducing effect – at least when given along with a sleep drug.

Interestingly, this hypnotic effect was driven by interactions with the adenosine receptor. (The build-up of adenosine and binding with the adenosine receptor drives us to need to sleep each night.) Additionally, luteolin increased sleep time and non-REM sleep.[ref]

I also wanted to point out that histamine is an alerting neurotransmitter, so it makes sense that if luteolin decreases high histamine levels it may help some with sleep. Think Benedryl (antihistamine) making you sleepy…

Luteolin as an antimicrobial:

Cell studies show that luteolin is antimicrobial.

  • It stops the growth of Staphylococcus aureus.[ref]
  • Luteolin acts as an antiviral agent against one of the causes of encephalitis (Flaviviridae virus).[ref]
  • In trials for SARS-CoV-1, luteolin blocks viral entry into host cells. Some researchers theorize it may also be helpful for SARS-CoV-2, but clinical trials are needed.[ref]
  • Cell studies also show that luteolin has antiviral activity against the flu virus (H1N1).[ref]

Luteolin inhibits cell proliferation in cancer:

First, let me plainly state that I’m not implying that anyone should treat their cancer themselves using a supplement. (That would be ludicrous.) Instead, the research overview presents general information on cancer prevention.

The consumption of fruits and vegetables has links to a reduced risk of cancer in epidemiological studies. But epidemiological studies that ask people what they eat and then associate that with an outcome are really just vague pointers towards a possible link. Perhaps people who naturally eat a lot of vegetables also have genetic variants in their taste receptors (likely) — and those variants also impact cancer (less likely).

Many cell studies have shown that luteolin induces apoptosis (cell death) in cancer cells. Additionally, it induces cell cycle arrest – stopping the cancer cells from reproducing. Various studies point to a couple of ways that luteolin stops cancer cell proliferation including through inhibiting the IGF1 receptor and via acting on GSK-3β. Recent studies also show that luteolin downregulates mTOR and upregulates P53 (tumor suppressor gene).[ref][ref][ref][ref]

While it is great that luteolin works to stop a number of different types of cancer cells from proliferating in a petri dish, the question remains as to whether this works at levels that can be obtained in vivo. In other words, can you take enough supplemental luteolin to actually make a difference – without side effects?

Clinical trials on luteolin for cancer prevention are lacking.

What about just eating foods rich in flavonoids? A trial that looked at cancer prevention from the consumption of flavonoid-rich vegetables, including luteolin content, found no difference in cancer risk among women who consumed the most flavonoids compared to the least.[ref] Another trial, specific to ovarian cancer, also found no difference in cancer risk with higher consumption of luteolin (or other flavonoids). Likely, supplemental doses would be needed to see any effects.

Luteolin for skin and sunburns:

A clinical trial found that a nanoparticle formula containing a luteolin-rich plant extract decreased UVB-induced erythema (e.g. sunburns). The formula seemed to work when applied before UVB exposure and, to some extent, after exposure. After exposure, the luteolin-rich plant extract was as effective as hydrocortisone cream.[ref]

Luteolin in ApoB levels:

When it comes to cholesterol, you want the right amount and the right type. The answers surrounding how much and what type, though, are still not entirely clear.

In general, apoB-containing lipoproteins, such as LDL and chylomicron remnants, have links to plaque buildup in the arteries (not good).[ref]

Luteolin acts on HNF4α, a nuclear transcription factor, in regulating the secretion of apolipoprotein B (apo B) containing lipoproteins.[ref] What this means is that luteolin is acting upstream of the production of cholesterol in the liver — regulating the production.

 


Absorption and Metabolism of luteolin:

Luteolin can be absorbed transdermally because it is a relatively small molecule.

Luteolin can absorb orally and then show up in the bloodstream after an hour to an hour and a half.[ref] It has a half-life of 5-7 hours.[ref]

Studies on colon cancer cells show that liposomal luteolin is much more effective than free luteolin.[ref]

Drug interactions?

Research points to luteolin inhibiting CYP2B6, CYP2C9, and CYP2D6.[ref] A lot of common prescription medications use those CYP450 enzymes in breaking down the drug. Caution is warranted if you are taking prescription medications at the same time as luteolin. Talk to your doctor or pharmacist.


Where to get luteolin:

A quick note of common sense: Talk to your doctor or pharmacist before taking luteolin if you have any questions. Luteolin may have estrogen interactions, so I would definitely err on the side of caution and avoid it while pregnant or trying to conceive.[ref]

Food sources, such as celery and parsley, contain luteolin, but to achieve the levels used in research studies, you would need to supplement.

Here are a couple of options for supplemental luteolin (read the reviews — not a plug for any particular brand here):

Supersmart Luteolin 100 mg

 

Monoherb Luteolin 100 mg

Metformin: Longevity research and genetics

A decades-old diabetes drug now holds promise for increasing healthspan. Research shows that metformin may reduce the risk of some of the diseases of aging, thus increasing the number of years someone is healthy.

What is metformin?

Metformin, also known as Glucophage, is the most commonly prescribed medication for reducing blood glucose levels. Metformin prescriptions target people with diabetes, prediabetes, and sometimes PCOS (polycystic ovarian syndrome).

Beyond diabetes, there are also many studies pointing to other positive benefits for metformin as a longevity or healthy aging medication.

How does metformin work?

Metformin has a couple of mechanisms of action:

  1. It decreases glucose production in the liver, which is especially important for overnight blood glucose regulations.
  2. It increases the uptake of glucose in muscles and other parts of the body.

Let’s take a close look at all three of these actions of metformin:

Decreases glucose production in the liver:
When glucose levels in the body fall, such as when fasting or even overnight when sleeping, the liver can produce glucose through a process called gluconeogenesis. This keeps glucose levels in the right range all day and night for people without diabetes.

The research on exactly how metformin decreases gluconeogenesis (glucose production) in the liver isn’t fully elucidated. There seem to be several possibilities:

  • First, metformin may act partially in the mitochondria, inhibiting complex I in the electron transfer chain. This would alter the ratio of AMP (adenosine monophosphate) to ATP (adenosine triphosphate), which triggers AMPK.  AMPK does a bunch of things, including decreasing gluconeogenesis.[ref]
  • Second, metformin may be altering the way mitochondria use lactate for energy. A January 2020 paper contends that metformin works through decreasing glucose 6-phosphate (G6P).[ref][ref]

New research also questions whether metformin reduces glucose production in the liver for people without type 2 diabetes. The studies indicate that glucose production in the liver may not decrease – and may possibly increase a bit to counteract the drop in blood glucose levels.[ref][ref]

Increases glucose uptake:
Blood glucose levels remain tightly regulated, and the release of insulin by the pancreas facilitates the uptake of glucose into cells. For most cells, glucose can’t cross the cell membrane without a transporter. The glucose transporters are known as GLUT1 through GLUT4, with different transporters in different cell types. The GLUT4 transporters are found in muscle tissue and fat cells. When blood glucose levels are high, the GLUT4 transporters are located in the cytosol of the cell (inside the cell), but when glucose levels fall, insulin levels rise. Insulin then binds to a receptor on the cell membrane, causing a cascade of actions that results in the GLUT4 transporters moving to the cell membrane. There, they can move glucose into the cells.

Metformin is thought to work in a way that keeps the GLUT4 transporters available on the cell surface so that the skeletal muscle cells can take up more glucose without needing more insulin.[ref]

Altered microbiome composition:
Research also shows that metformin alters the composition of the gut microbiome, promoting Akkermansia muciniphilia, a bacteria associated with a lower risk of obesity and a lower risk of inflammatory conditions in the intestines. The altered gut microbiome composition may also be a mechanism through which metformin helps with diabetes. Additionally, metformin has shown to increase short-chain fatty acid metabolism in the intestines.[ref][ref][ref]

PCOS and metformin:

Polycystic ovarian syndrome (PCOS) is characterized by insulin resistance and altered androgen hormone production. Studies show that metformin may be beneficial for women with PCOS. One study found that 12 weeks of metformin decreased testosterone levels and improved glucose effectiveness.[ref]

Metformin for Longevity and Aging:

Many researchers are now looking at aging as a disease. In fact, the World Health Organization recently added it to its classification system as a disease. With this idea in mind, let’s take a look at the use of metformin to prevent chronic diseases in aging.

Animal studies have repeatedly shown that metformin can increase lifespan. Most of the studies show that starting metformin in middle age or earlier can increase lifespan and healthspan.[ref][ref][ref]

But humans aren’t the same as mice, and the results of animal studies sometimes don’t hold true for people.

Human studies on metformin show:
A large meta-analysis found that people with diabetes and also taking metformin had lower all-cause mortality than non-diabetics. They also had lower cardiovascular disease and cancer rates. That is pretty amazing. The study also showed that diabetics taking metformin had lower rates of cancer than diabetics using other types of diabetes medications.[ref]

Another meta-analysis using data from over 1 million patients found significant reductions in both all-cause mortality and cardiovascular events. (20% for all-cause mortality and over 30% for cardiovascular events).[ref]

Other studies show a reduction in all-cause mortality and cancer-related mortality in people who take metformin.[ref]

Not all human studies show fantastic results:
In a study of heart attack patients, 4 months of metformin did not have beneficial long-term effects.[ref] Other studies show a possible impact that negates the benefits of aerobic exercise.[ref]

How can metformin extend healthspan?

One mechanism (other than decreased blood glucose levels) for a positive effect on healthy aging is that metformin may activate SIRT1. The sirtuins are a family of enzymes that are important for regulating cellular homeostasis, and SIRT1 (sirtuin 1) is important in healthy aging. A link exists between the activation of SIRT1 and lower rates of cardiovascular and metabolic diseases.[ref][ref]

Another mechanism through which metformin has shown to act is in the way that mitochondria use fatty acids for energy. The ACAD10 gene codes for an enzyme needed in beta-oxidation and animal studies show that metformin acts through the inhibition of mTORC1 to upregulate ACAD10.[ref]

Impact on muscles:

A Dec 2019 randomized crossover trial shows that 4 days of metformin doesn’t impact skeletal muscle activity. Interestingly, the authors note that metformin caused the participants to feel like exercise took more exertion. Thus, it may cause people to want to exercise a little less.[ref]

In another study in older adults (age ~62), 3 months of metformin seemed to attenuate the benefits of aerobic exercise.[ref]

Potential negative side effects from metformin:

Most importantly, there is an increased risk of lactic acidosis in people taking metformin. This may be more of a risk for people with underlying kidney problems.[ref]

Some people have gastrointestinal side effects from metformin. People with SLC22A1 variants (below) are more likely to have gastrointestinal problems.[ref]

Metformin metabolism and excretion:

Metformin circulates unbound because its metabolism doesn’t occur in the liver. Instead, the kidneys clear it from the body facilitated by SLC22A2 kidney cells. (more on this below)[ref]


Genetic variants associated with metformin response:

Like almost every drug or supplement, individuals respond differently to metformin. Below you can find some of the genetic variants associated with the altered response to metformin.

Note: This article is also cross-posted on GeneticLifehacks.com.

If you have genetic data from 23andMe or AncestryDNA, check out the genetics section of this article on Genetic Lifehacks.   


Lifehacks:

If you are interested in metformin for longevity, talk with your doctor about whether getting a prescription for it is right for you.

Alternatively, there is an online website that sells 3-month prescriptions of metformin, after you interact with their telemedicine doctor. The website is called qualytude.com. Read through the information and be sure to understand the terms of the website.

Longer-term use of metformin increases the risk of vitamin B12 deficiency.[ref] Consider supplementing with vitamin B12, especially if you don’t eat a lot of foods that contain B12.

Berberine is a natural supplement that is often touted as a natural alternative to metformin in terms of blood sugar control. Read more about berberine.