Category Archives: Longevity

Senolytics for COVID and other respiratory illnesses?

New research on COVID-19 shows the important role of cellular senescence in the high mortality rates in the elderly.

Elderly people are much more vulnerable to the flu, respiratory infections, and sepsis than middle-aged or younger adults. We all know that when grandma gets the flu in the nursing home, it is a serious matter. And we instinctively know that frailty is key – not all 75-year-olds are going to have the same vulnerability.

New research from the Mayo Clinic explains why the mortality risk from viral infections skyrockets in the elderly.

While the SARS-CoV-2 virus is new to the human population, COVID-19 deaths follow a similar pattern to other respiratory viruses that are commonly fatal in elderly or frail individuals: a weak initial immune response fails to kick the virus’s butt. But this is followed by a huge outpouring of an inflammatory response, and the heightened inflammatory cytokines end up causing cell death in the lungs and epithelial cells.[ref][ref]

It turns out that senescent cells play an active role in the hyperactive inflammatory response to respiratory pathogens.

Cellular senescence and hyper-inflammatory responses

Senescence describes cells that can no longer function and replicate. It is a response to DNA damage, wounds, oxidative stress, and other cellular insults.  Cellular senescence happens throughout life, and your immune system is responsible for clearing out the senescent cells. This is a really important way that the body prevents cancer and out-of-control cellular replication.

One cause of aging is that the number of senescent cells exceeds the capacity to clear them out. The scales tip towards more and more senescent cells with the immune system no longer able to keep up with clearing them out.

So why are senescent cells a problem in aging? 

Senescent cells give off inflammatory signals so that they can be cleaned up and cleared out by the immune system. Sometimes likened to ‘zombie cells’, the senescent cells not only don’t function, but they also impact surrounding cells due to the inflammatory signaling.

Thus, one problem with too many senescent cells in old age is they increase chronic inflammation – a sterile inflammatory response not due to a virus or pathogen. Cellular senescence can happen in all the tissues of the body, including immune system cells. Immunoscensence (too many senescent immune cells) is part of the reduced ability of an elderly person in fighting off pathogens.

But the senescent immune cells causing reduce immune response isn’t the whole story behind why the elderly are so much more likely to die from a viral or bacterial illness — especially in COVID-19.

Our immune system is pretty cool and able to recognize and fight off tons of different invaders through multiple lines of defense.

One way our immune systems recognize the bad guys is through pathogen-associated molecular patterns (PAMPs). These molecular markers reside on the surface of bacteria or viruses — and recognized by the immune system as always belonging to an invading bacteria or virus. It’s like a general ‘bad guy’ flag that the immune system attacks without knowing who exactly the bad guy is.

The lipopolysaccharides (LPSs) found on the cell membrane of gram-negative bacteria is an example of PAMPs. The immune system knows that LPS = bacteria, and it launches an immediate immune response without needing to know the specific bacteria.

COVID-19 and Pathogen-associated molecular patterns

Quick background:
The SARS-CoV-2 virus enters cells by attaching a spike protein to the ACE2 receptors.

Researchers at the SALK institute discovered that the spike protein alone causes the immune system to react -even without the accompanying SARS-CoV-2 virus invading cells.[ref]

Other research also shows that SARS-CoV-2 activates the PAMP response system.[ref] This isn’t new, nor unique to COVID. The pathogen pattern recognition receptors recognize the positive-sense RNA viruses in general, including other coronaviruses such as SARS and MERS.[ref][ref][ref]

Back to the new COVID-19 research:
This recent paper in Science by researchers at the Mayo Clinic shows that senescent cells significantly increase their inflammatory signals in response to activation of  PAMP. The senescent inflammatory signals are collectively known as SASP or senescence-associated secretory phenotype.

Specifically, the SARS-CoV-2 spike protein-1 activates the PAMP pathways and increases inflammatory signaling (SASP) from senescent cells. 

With senescent cells accumulating in the elderly added to an increase in inflammation when senescent cells are exposed to the spike protein, the hyper-inflammatory response seen in the elderly begins to make sense.

From the study: “certain inflammatory/SASP factors released by senescent human lung cell types, including IL-1α, IL-1β, IL-6, MCP-1, TNFα and MMP-1, are central to the pathological cytokine storm seen in some COVID-19 patients”.

In a nutshell, the spike protein identifies as a PAMP and causes senescent cells to pump out more and more inflammatory cytokines. These senescent cells produced cytokines then exacerbated the systemic inflammatory response. The hyper-inflammatory senescent cells then caused other surrounding cells to become senescent.[ref]

It seems to be a triple whammy in COVID – increased inflammation, more cellular senescence, and then an increased ability for the virus to enter the cells. For SARS-CoV-2, in addition to the ACE2 receptor, TMPRSS2 is necessary for cleaving the spike protein and required for the virus to enter a cell and replicate. Senescent cells upregulate TMPRSS2 in the surrounding healthy cells – thus increasing the ability of the virus to infect other cells.

From cell study to animal research:

The Mayo Clinic researchers went further than just showing that different senescent cell lines are activated by the spike protein.

The problem with elderly mortality isn’t limited just to SARS-CoV-2. The flu, pneumonia, common cold viruses, etc — all are much more likely to be deadly to someone who is elderly and frail.

Thus, the next part of the research study involved looking at the response in elderly mice to exposure to multiple microbes, including a beta-coronavirus, similar to SARS-CoV-2 but able to infect mice.

Lab mice live a sheltered life and aren’t exposed to all the bacteria and viruses to which mice in the wild or pet mice are constantly exposed. Pet store mice, especially, carry a lot of diseases.

When you expose old lab mice to mice from a pet store, they get sick and die from the various diseases carried by pet store mice. This is something that invariably happens within a couple of weeks of co-housing the mice. (Young lab mice don’t die from the exposure, just elderly lab mice.)

The researchers in the Science study found that the high number of senescent cells in the old mice was the key to mortality upon exposure to the high microbial load. The pre-existing senescent cells reacted to the pathogens, spreading high levels of inflammation.

But…it wasn’t all pathogens that caused this hyper-inflammation in the senescent cells. Through immunizing the old mice with the mouse version of the coronavirus, the researchers showed that the main driver of death in the old mice was actually the mouse beta-coronavirus.

Stopping the hyper-inflammatory response

In COVID-19 patients, a lot of emphasis has been on suppressing the body’s own immune response so that it doesn’t kill the patients.

In the elderly mice, the researchers were able to decrease mortality by half using senolytics, drugs that increase the clearance of senescent cells.

Giving senolytics after exposure to the mouse coronavirus cut the elderly lab mouse death rate from 100% dead within two weeks to about 50% mortality in two weeks.

The senolytic used in this part of the study was fisetin, a natural polyphenol compound, and it was given on days 3, 4, 11, and 12 after exposure to the viruses. This was followed by a second trial using quercetin plus Dasatinib, another senolytic cocktail used in research. The results with Dasatinib and quercetin were similar – 50% of the old mice surviving pathogen exposure compared to a 100% death rate in the control group.

Next step for the researchers: pretreating the elderly lab mice with senolytics before exposure to the coronavirus pathogen. The senolytic was given in two doses, several days before the exposure to the pathogens. The results showed pretreatment with senolytics reduced the mortality rate by about half, similar to giving the senolytics after exposure.

Prior research on cellular senescence and susceptibility to infection

While the Mayo Clinic study in Science is a fascinating look at how cellular senescence influences COVID-19 susceptibility, previous research shows this is not unique to the ‘novel’ coronavirus.

A higher burden of senescent cells is a key component to COPD and idiopathic pulmonary fibrosis (IPF).[ref] These two diseases are also linked to a significantly increased risk of pneumonia in older individuals.

In general, elderly people are at a 4-fold greater risk of pneumonia compared with non-elderly.

In older individuals, chronic low-grade inflammation, which includes elevated TNF-alpha and IL-6 levels, significantly increases the risk of pneumonia. Animal studies show that infusing young mice with TNF-alpha and IL-6 to the levels of old mice causes a similar susceptibility to pneumonia.[ref]

One big cause of chronically elevated TNF-alpha and IL-6 is the accumulation of cellular senescence and the inflammatory signals that the senescent cells give off (SASP).

Rapamycin is a drug that is being investigated for its impact on longevity and healthspan. Rapamycin is not a senolytic, per se, but instead suppresses the SASP signals from senescent cells. Animal studies show that rapamycin reduces mortality from pneumonia in aging animals via reducing lung damage from inflammatory cytokines, rather than working as an antibiotic.[ref]

In terms of COVID-19 research, cancer patients who have had chemotherapy have a higher rate of mortality than the general public.[ref] Certain chemotherapy agents induce a higher rate of cellular senescence.[ref]

Conclusion:

To me, the research on cellular senescence in COVID shows a clear picture of explaining a mechanism of hyper-inflammatory response. It makes sense of the high morbidity in frail people and in the comorbidities seen in those who are vulnerable to COVID-19.

The bigger picture here is that a high burden of cellular senescence adds to an inflammatory response. While inflammation is essential for healing wounds and fighting infection, an excessive inflammatory response will kill you. Thus, reducing the excess of senescent cells in aging may help to reverse chronic diseases as well as reduce mortality for pathogen infections. Clinical trials are underway on using senolytics in preventing diseases of aging.[ref]

If you want to know more about fisetin as a senolytic, check out this article on natural senolytics and this article specific to fisetin.

Some researchers hypothesize that microdoses of lithium act as a senolytic and may help with COVID.

Animal studies show an interesting link with NAC (n-acetyl cysteine) and reduced cellular senescence, but human trials are lacking there.[ref]

 

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?

 

 

Alpha-ketoglutarate for longevity

Alpha-ketoglutarate is a key molecule produced in your cells. Recently, research studies have shown that it may play a key role in healthy aging, including increasing healthspan and lifespan.

What is alpha-ketoglutarate?

Alpha-ketoglutarate (αKG) is a molecule that cells produce. It has several important functions in the body:[ref]

  • It is involved in the Krebs cycle for energy production
  • αKG is important in epigenetic regulation of the production of other molecules in the cells
  • It is involved in stem cell proliferation and formation of bone cells
  • αKG is important in regulating inflammation

All of these come together as essential in preventing the diseases of aging.

The key, before we get further into the science, is that αKG (alpha-ketoglutarate) levels are decreased in aging. In fact, there is a 10-fold decrease in αKG between ages 40 and 80.[ref]

ΑKG in Energy Production via the Krebs Cycle:

The Krebs cycle is part of the process for creating cellular energy in the mitochondria.

Quick background: Mitochondria are organelles within cells that can create ATP from either sugar or fats. Each cell can have hundreds to thousands of mitochondria, depending on the need for cellular energy. ATP (adenosine triphosphate) is the molecule that is produced in cells to store energy. The ATP bonds can easily be broken to release energy whenever and wherever it is needed inside the cells. No ATP, no energy = no life

Important here is that the alpha-ketoglutarate produced in the Krebs cycle can be used for ATP, or it can cross out of the mitochondria and be used elsewhere. Alpha-ketoglutarate can also be used by the cells to make glutamine, which can be used as a neurotransmitter.[ref]

Epigenetics: alpha-ketoglutarate and DNA methylation

TET proteins and αKG are important in methylation

Centenarians, people living to 100+, have differences in their DNA methylation. Essentially, methylation is one way that cells can turn off or on different processes.

The processes needed to be kept switched on in aging include the sirtuins, DNA repair enzymes, insulin signaling pathways, FOXO genes, telomere extension, and cellular antioxidants that decrease oxidative damage.

Alpha-ketoglutarate levels impact the transcription of the FOXO genes. This is the same pathway that calorie restriction impacts for extending lifespan. αKG is also a cofactor for DNA and histone demethylation enzymes.[ref]

Research studies on alpha-ketoglutarate

OK, so αKG is important for cellular energy production – and – it is necessary for DNA methylation regulation. Additionally, αKG decreases a bunch as we age.

What happens if we correct the decrease in αKG that naturally happens with aging?

Supplementing alpha-ketoglutarate increases lifespan in animals (mice, worms). This has been known for a decade or so. Researchers using C. elegans found that increasing αKG extended the lifespan of the animal.[ref]

A recent study in mice showed that alpha-ketoglutarate extended lifespan of about 10%. More importantly, though, it significantly improved healthspan.[ref]

Healthspan is the years that you remain healthy in aging. The last few years of life are often plagued with frailty, dementia, and severe chronic disease — healthspan is the time during aging when someone remains healthy.

The trial showed that the mice had less time where they were frail or had diseases of aging at the end of life.

How does alpha-ketoglutarate increase healthspan?

Supplementing with αKG, starting at mid-life and beyond, may increase energy production in the mitochondria and positively impact DNA methylation.

  • Animal research shows αKG supplementation prevented the increase in cytokine levels that are normally associated with aging in female mice.[ref]
  • αKG reduces the senescent cell inflammatory signaling, which is the problem with cellular senescence in aging.
  • Supplemental αKG induces the browning of fat in mice.
  • A positive effect on macrophages and shifting towards anti-inflammatory type was noted with αKG.
  • Giving female animals αKG during their reproductive years preserves ovarian function.

Suppressing inflammation: One of the causes of aging is an increase in chronic inflammation. The research on αKG in mice showed that female T-cells cells produce higher IL-10 (an anti-inflammatory molecule) with supplementation. The researchers theorize this is one of the main ways that frailty was reduced in the animals.[ref]

Reducing senescence phenotype: While αKG doesn’t clear out senescent cells, it does reduce the negative aspect of cellular senescence: constantly increased inflammation.[ref]

Brown fat: One reason, among many for increased inflammation in aging, is the alterations to adipocytes (fat tissue). As we age, fat cell turnover decreases, and existing fat cells become more dysfunctional and give off inflammatory cytokines.[ref]

A positive aspect of αKG is that it may cause white adipose tissue (fat) to become beige or brown fat. Brown fat is the good fat. It contains lots of mitochondria, causing it to look ‘brown’ under a microscope. These mitochondria are producing heat, burning off excess fat.

Mouse studies show that increasing αKG through supplementation increases the “beige-ing” or browning of fat.[ref] In aging, DNA methylation is involved in the reduction of brown fat. Thus αKG may be impacting fat storage, energy production, and inflammation via the positive methylation changes.

Macrophages and inflammation: One component of the immune system is a cell type called macrophages. Dual purposed immune cells, macrophages can either become pro-inflammatory (M1) or anti-inflammatory (M2). Higher levels of inflammatory cytokines, such as TNF-alpha or interferon-gamma, cause macrophages to activate to an M1 (inflammatory) type. Higher levels of alpha-ketoglutarate, though, can promote the MT anti-inflammatory type of macrophage.[ref]

Reproductive years extended: Animal research shows that αKG extends the time that the animals are fertile. One reason for this was that αKG prevented the shortening of telomeres in the ovaries.[ref]

Why would this be important in aging? For women, many of the deleterious effects of aging occur with the decrease in estrogen after menopause.

Osteoporosis and alpha-ketoglutarate:

αKG promotes bone development in animal studies and in a study of postmenopausal women. One way that αKG impacts bone strength is through producing needed proteins for the type of collagen found in bones. Another way is via regulating histone methylation of genes involved in bone formation.[ref]

Human clinical trials on alpha-ketoglutarate

You’ll notice that the above trials are all in animals. While animal research is great for finding an effect on longevity in short-lived animals, it doesn’t always correlate to the same effect in humans.

And honestly, who cares about mice living longer…

Currently, there are no longevity trials in humans for αKG. So we really can’t know the effect of αKG on aging in humans. Instead, we can look at the trials that have been done — mostly on athletes to see if αKG could enhance performance.

Male athletes training with low oxygen (e.g. high altitude) were given alpha-ketoglutarate as a supplement. The supplement didn’t change athletic performance, but it did improve blood oxygen levels.[ref]

Male athletes (ages 30-50) were given arginine alpha-ketoglutarate supplement 3 times per day for a total of 12 g/day. The results showed some improvement in specific exercises, such as bench press. Importantly, it was well-tolerated and safe.[ref]

Another trial of male athletes found that 12g/day of arginine alpha-ketoglutarate had little effect on nitric oxide or blood flow.[ref]

To me, the trials on well-trained, fairly young male athletes weren’t all that impressive, but they likely already had sufficient alpha-ketoglutarate levels due to age and athletic training.

Supplementing with αKG

My first question on a supplement is always “Is it safe”.

The answer is going to be different for each individual, but the FDA considers alpha-ketoglutarate as “GRAS” or generally regarded as safe.

When it comes to supplements for longevity, I also always want to think about whether they can promote the growth of cancer. The answer here is that alpha-ketoglutarate has several anticancer properties including blocking the formation of new blood vessels for tumors.[ref]

αKG is not readily available in the diet, at least not at significant levels. Thus, the effects seen in clinical trials are at levels found in supplements.

Supplements of alpha-ketoglutaric acid are available in capsules. Ornithine alpha-ketoglutarate is also available. Shop around to find your favorite brand or reviews that you’re comfortable with.

A commonly used bodybuilding supplement, arginine plus alpha-ketoglutarate is available in powdered form, which is more economical for higher doses. Arginine boosts nitric oxide and theoretically improves workouts (studies aren’t great there). The flavor is mild and it easily mixes into a beverage or smoothie.

Ornithine alpha-ketoglutarate is also available as a powder. (I haven’t tried it, so I can’t comment on the flavor or ease of dissolving.)

Other ways of increasing αKG

There are a few diet and lifestyle hacks that can increase your endogenous production of alpha-ketoglutarate:

  • ketogenic diet[ref]
  • metformin, a commonly used diabetes drug, increases alpha-ketoglutarate in clinical trials[ref]

Side effects of αKG, supplement interactions

Supplements that contain arginine plus αKG may decrease your blood pressure. Be sure to check the interaction with blood pressure medications.

If you are using arginine plus αKG: check for interactions with blood thinners, erectile dysfunction, nitrates, anticoagulants, diabetes medications.

Conclusion:

While the human trials for longevity are non-existent, the safety profile for alpha-ketoglutarate seems good. The questions remain, though, as to what levels of supplementation are needed to achieve increases in healthspan.


References:

Asadi Shahmirzadi, Azar, et al. “Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.” Cell Metabolism, vol. 32, no. 3, Sept. 2020, pp. 447-456.e6. PubMed, doi:10.1016/j.cmet.2020.08.004.
—. “Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.” Cell Metabolism, vol. 32, no. 3, Sept. 2020, pp. 447-456.e6. PubMed, doi:10.1016/j.cmet.2020.08.004.
Campbell, Bill, et al. “Pharmacokinetics, Safety, and Effects on Exercise Performance of L-Arginine Alpha-Ketoglutarate in Trained Adult Men.” Nutrition (Burbank, Los Angeles County, Calif.), vol. 22, no. 9, Sept. 2006, pp. 872–81. PubMed, doi:10.1016/j.nut.2006.06.003.
Chitalia, Vipul. “α-Ketoglutarate-A New Currency of Longevity.” Science Translational Medicine, vol. 6, no. 244, July 2014. PubMed Central, doi:10.1126/scitranslmed.3009803.
Cuyàs, Elisabet, et al. “Metformin Induces a Fasting- and Antifolate-Mimicking Modification of Systemic Host Metabolism in Breast Cancer Patients.” Aging, vol. 11, no. 9, May 2019, pp. 2874–88. PubMed, doi:10.18632/aging.101960.
Kössler, Florian, et al. “5-Hydroxymethylfurfural and α-Ketoglutaric Acid Supplementation Increases Oxygen Saturation during Prolonged Exercise in Normobaric Hypoxia.” International Journal for Vitamin and Nutrition Research. Internationale Zeitschrift Fur Vitamin- Und Ernahrungsforschung. Journal International De Vitaminologie Et De Nutrition, vol. 91, no. 1–2, Jan. 2021, pp. 63–68. PubMed, doi:10.1024/0300-9831/a000606.
Liu, Shaojuan, et al. “The Regulatory Role of α-Ketoglutarate Metabolism in Macrophages.” Mediators of Inflammation, vol. 2021, Mar. 2021. PubMed Central, doi:10.1155/2021/5577577.
Mancuso, Peter, and Benjamin Bouchard. “The Impact of Aging on Adipose Function and Adipokine Synthesis.” Frontiers in Endocrinology, vol. 10, Mar. 2019. PubMed Central, doi:10.3389/fendo.2019.00137.
Sharma, Rishi, and Arvind Ramanathan. “The Aging Metabolome—Biomarkers to Hub Metabolites.” Proteomics, vol. 20, no. 5–6, Mar. 2020. PubMed Central, doi:10.1002/pmic.201800407.
Tian, Qiyu, et al. “Dietary Alpha‐ketoglutarate Promotes Beige Adipogenesis and Prevents Obesity in Middle‐aged Mice.” Aging Cell, vol. 19, no. 1, Jan. 2020. PubMed Central, doi:10.1111/acel.13059.
Wells, Jana, et al. “Efficacy and Safety of a Ketogenic Diet in Children and Adolescents with Refractory Epilepsy—A Review.” Nutrients, vol. 12, no. 6, June 2020. PubMed Central, doi:10.3390/nu12061809.
Willoughby, Darryn S., et al. “Effects of 7 Days of Arginine-Alpha-Ketoglutarate Supplementation on Blood Flow, Plasma L-Arginine, Nitric Oxide Metabolites, and Asymmetric Dimethyl Arginine after Resistance Exercise.” International Journal of Sport Nutrition and Exercise Metabolism, vol. 21, no. 4, Aug. 2011, pp. 291–99. PubMed, doi:10.1123/ijsnem.21.4.291.
Zdzisińska, Barbara, et al. “Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use.” Archivum Immunologiae et Therapiae Experimentalis, vol. 65, no. 1, 2017, pp. 21–36. PubMed Central, doi:10.1007/s00005-016-0406-x.
—. “Alpha-Ketoglutarate as a Molecule with Pleiotropic Activity: Well-Known and Novel Possibilities of Therapeutic Use.” Archivum Immunologiae et Therapiae Experimentalis, vol. 65, no. 1, 2017, pp. 21–36. PubMed Central, doi:10.1007/s00005-016-0406-x.
Zhang, Zhenzhen, et al. “Α‐ketoglutarate Delays Age‐related Fertility Decline in Mammals.” Aging Cell, vol. 20, no. 2, Feb. 2021. PubMed Central, doi:10.1111/acel.13291.

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).

 

 

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.