All posts by Debbie Moon

Methylene Blue: Mitochondrial function, cognitive benefits?

Methylene blue (Methylthioninium chloride) has been used in pharmacology for over a century. It is a fascinating compound that was first synthesized as a blue dye. In 1891, it was discovered that it could treat malaria. It is also used as a stain for microscope slides.[ref]

Currently, methylene blue is an FDA-grandfathered drug. It is used to treat carbon monoxide, methemoglobinemia, and cyanide poisoning.

What does methylene blue do?

The biochemical processes going on in our cells rely on moving electrons, such as in oxidation-reduction (redox) reactions. Uniquely, methylene blue can accept electrons and also transfer electrons to oxygen, forming water.

In the mitochondria, the electron transport chain is responsible for producing ATP, which is used for cellular energy. Within the electron transport chain, methylene blue can act as an artificial electron donor at low doses. Essentially, it adds a little boost and helps to reduce the production of reactive oxygen species in the mitochondria.[ref]

Response curve

More is not better. With methylene blue, the dose matters quite a bit. Doses that range from 0.5 – 4 mg/kg seem to have positive benefits in studies. But going above 10mg/kg decreases the biochemical response. At higher doses, methylene blue can take away electrons in the electron transport chain — slightly reducing energy production in the mitochondria.[ref]

Methylene blue response curve (rats) — read the full study PMC2867617

Long term, higher doses, such as what is used for malaria treatment, can cause urine, skin, and the whites of the eyes to become bluish.[ref]

G6PD deficiency: Caution with MB

Before I go any further in this article, I want to throw out a caution flag…

G6PD deficiency is a genetic disorder that causes red blood cells to be broken down too quickly when eating certain foods or taking certain medications, including methylene blue. People with African heritage are at a higher risk of having G6PD deficiency. Malaria studies show that methylene blue at higher doses causes “a slight but clinically non-significant haemoglobin reduction.”[ref] Nonetheless, caution is definitely warranted in taking methylene blue if you have G6PD deficiency. Check your genetic data here — or talk to your doctor about full genetic testing if you suspect G6PD deficiency. 

OK – Back to discussing the studies and clinical trials on methylene blue.

Methylene Blue: Visible results in the brain

An MRI brain of study participants showed low doses of methylene blue (280 mg) increased response during vigilance tasks. The results also showed a 7% increase in correct responses to memory tests. The study participants were adults aged 22-62, and they were compared with a healthy control arm that received a placebo blue food coloring.[ref] It is interesting to see that the methylene blue has enough impact to show up as significant on an MRI.

The blood-brain barrier keeps many medications and toxins out of the brain. But methylene blue not only can cross the blood-brain barrier, but it preferentially accumulates in the brain out of the bloodstream.[ref]

Methylene blue has been used in several trials to prevent neurological impairment. For example:

A study showed that the chemo drug cisplatin impairs learning (animal study). The neurological side effects of the drug are caused by inflammation and mitochondrial damage in the brain. The study found that methylene blue could prevent memory impairment (in animals).[ref]

Other studies point to the role of mitochondrial energy and reduction in oxidative stress as being the primary benefits of neuroprotection. Again, this is mainly in animal studies, but the results show neuroprotective effects of MB in many neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and stroke.[ref]

Inducing autophagy:

One way that methylene blue may be neuroprotective is by inducing autophagy (recycling of damaged cellular components). In animal studies of brain injury, methylene blue increase neuronal survival through inducing autophagy and decreasing cell death.[ref]

Alzheimer’s protection:

One issue in an Alzheimer’s brain is mitochondrial dysfunction. Methylene blue can reduce the production of free radicals in the mitochondria in the brain.

The results of the trials have varied.

No benefit: A phase III clinical trial using a stabilized, reduced form of methylene blue tested the benefits in people with mild to moderate Alzheimer’s disease. The participants were divided into three groups: 75mg twice a day, 125 mg twice a day, or a control group taking 4 mg twice a day. The results showed that there were no treatment benefits from 75mg or 125 mg when compared to a control group taking 4mg.[ref]

Lower dose: Another randomized clinical trial in dementia patients may hold the key. The trial used a 200mg/day dose with an 8mg/day control group dose. There was no treatment benefit for 200mg/day. But there were significant improvements in brain atrophy with the 8mg/day dose. The results showed that 200mg/day resulted in worse clinical outcomes, while 8mg/day was likely beneficial. The conclusion was that a trial with a maximum dose in the 20-60mg/day range was needed.[ref]

Revised analysis: A revised analysis of the Alzheimer’s trial data found that the 4mg/ twice per day dose that was used as the control group may be beneficial, especially as add-on therapy with other Alzheimer’s drugs.[ref]

Inhibiting viral replication:

Methylene blue has long been known to have antiviral activity. It corrupts the integrity of viral DNA or RNA, which gives it broad-spectrum antiviral properties. Additionally, methylene blue can target the viral envelope, such as in HIV.[ref]

  • At low concentrations, methylene blue inhibits the replication of H1N1 (flu virus) and SARS-CoV-2.[ref]
  • Both in vitro and in vivo studies showed that methylene blue can inhibit viral growth and replication in the Zika virus.[ref]
  • Methylene blue was shown early on in the COVID-19 pandemic to stop the replication of SARS-CoV-2 in cell studies.[ref] Further studies show that methylene blue is able to stop the spike protein on the SARS-CoV-2 virus from binding to the ACE2 receptor.[ref]
  • A clinical trial in hospitalized severe COVID-19 patients found that methylene blue shortened hospital stays and improved blood oxygen levels (compared to a control group). The study, though, used a combination of methylene blue, N-acetyl cysteine, and vitamin C.[ref]

Dosing and Buying:

Where to get methylene blue: Yes, methylene blue is available at the pet store to treat fish diseases, but it isn’t guaranteed to be pure.

Instead, pharmaceutical-grade methylene blue may be your better option. You can buy it from many health food stores, nootropics stores online, or on Amazon. Look for a USP grade that is made for human consumption. Here is one option on Amazon — in a glass dropper with a 1% solution that will last a long time. A 1% solution will provide 0.5mg of methylene blue per drop.


Clinical trial dosing covers a wide range. For example:

  • In a trial of bipolar patients, the placebo group got a 15mg/day dose, and the active group received 195mg/day.[ref]
  • In the MRI study (above), the participants received a dose of 280mg (4mg/kg with an average of 70 kg), which showed improvements in memory tests and changes in the brain MRIs.[ref]
  • A study involving adults with claustrophobia used a dose of 260mg of methylene blue. The results showed methylene blue helped with the retention of cognitive training.[ref]

On the other hand, online forums and nootropics websites often recommend very low doses in the range of 0.5mg/day for cognitive benefits.

There is a huge span between 0.5mg and 280mg. The dementia clinical trial that found a benefit in the control dose (8mg/day) was very interesting.

The problem with placebo groups with methylene blue is that urine turns blue at a certain dose, so the placebo arm is often dosed with lower levels of methylene blue. The question then arises whether lower doses are really a control — of whether, with the U-shaped dose curve if low doses are actually the better option.

In addition to blue pee, methylene blue stains anything it touches. If you use liquid methylene blue, be careful with it on your countertops and sinks. Vitamin C may help to remove the stain.


In addition to the caution around G6PD deficiency, at higher doses, methylene blue may interfere with MAOA, which is the enzyme that breaks down neurotransmitters such as serotonin. High levels of serotonin can make you sick and possibly result in death. There are a few case studies of methylene blue being used in hospital settings (injected) that resulted in serotonin syndrome.[ref]

If you have any questions on any supplement, always check in with your doctor or pharmacist.


Methylene blue is an interesting option for mitochondrial function and Alzheimer’s prevention.

I would love to see more clinical trials that dial in the dosages better since it seems that many clinical trials were over-shooting the optimal dosage. Realistically, the money for clinical trials is likely not available for an intervention that only costs pennies.

Genetics and Healthspan: Teasing out what is important

Genetic studies, especially large genome-wide association studies, can be informative when looking at what is really important for healthspan. Essentially, these types of studies look to see which genetic variants are linked to outcomes — real-life people, real outcomes, and large data sets.

A new study recently published in Nature Medicine estimated the effects of genetic variants on DALYs (disability-adjusted life years). DALYs measure ‘lost healthy life years’ — or the opposite side of healthspan.

This Sept. 2022 publication shows that a common genetic variant in the LPA gene had the strongest effect on DALYs for an individual. Additionally, a combination of genetic variants that increased pain was also tied to reduced healthy years.

Other genes that impacted healthy years included HLA genes, heart-related genes, and APOE (Alzheimer’s). Among the heart-related genes, NOS3 (nitric oxide synthase) and PCSK9 (LDL cholesterol levels) were top hits.

Interestingly, a variant in the CHRNA5 gene also was statistically significant. The variant is linked to nicotine dependence, showing that people more susceptible to nicotine dependence are likelier to smoke more and longer.

Rare mutations, such as in cancer-related genes, were also considered. For example, carrying a BRCA1 mutation (breast cancer risk factor) was associated with an average loss of 4 healthy years.

The study used data from the UK Biobank (400,000+ people) and the FinnGen (300,000+ people) biobank. So it is important to note that the participants were skewed toward European Caucasian background.[ref]

What did previous genetics studies show?

A previous study looked at healthspan and genetics, with some overlapping genes. The study cohort was from the UK, using the UK Biobank information on genetics combined with health records.[ref]

The top reasons for the end of healthspan were cancer, diabetes, and heart attacks. While cancer topped the list for ending healthspan, the study found that genetics wasn’t a significant player (except for cigarette smoking). Instead, genetic variants related to heart disease (heart attack, chronic heart failure), stroke, and diabetes were the strong hits for healthspan.

Surprisingly, this study did not find a link between healthspan and APOE genetic variants related to Alzheimer’s disease.

The most significant impact factor found was in the LPA gene, which encodes lipoprotein (a). Lp(a) levels are highly genetic — and a big risk factor for heart attacks. (If you’ve done genetic testing, go to Genetic Lifehack’s LPA article to check your data.)

Another large impact on healthspan was found in the TCF7L2 gene, which is highly associated with an increased risk of diabetes.

A variant in the MC1R gene was also linked to reduced healthspan. MC1R encodes melanocortin, which is involved in skin and hair color. But, variants in the gene are also linked to susceptibility to certain pathogens. Variants in the HLA genes were also linked to healthspan. The HLA-DQ1 gene has variants related to a number of autoimmune diseases, including type 1 diabetes and celiac disease.


These healthspan genome-wide studies really drive home the importance of metabolic health (avoiding diabetes) and heart health. Additional signals seem to indicate that the immune response is also essential.

Spermidine and Healthspan

From extending healthspan to improving vaccine efficacy in older adults, spermidine is a biogenic amine with many possible anti-aging benefits. I’ll dig into the research on the topic, explore the clinical trials, and explain why increasing spermidine can sometimes be a bad idea. This one ‘supplement’ is essential to go beyond the headlines and understand both the pros and the cons.

Spermidine: Longevity superstar?

Researchers have known for over a decade that spermidine supplementation can increase lifespan in many model organisms, including c.elegans and mice. Experiments have repeatedly shown both life and healthspan extension of up to 25%.[ref][ref][ref]

In 2012, researchers found that spermidine and other polyamine levels are significantly lower in older people (ages 60-80) when compared with younger adults. Interestingly, though, this pattern didn’t hold for healthy centenarians and nonagenarians. The long-lived people had relatively higher spermidine and spermine levels than the 60 to 80-year-old group.[ref]

These tantalizing clues to spermidine’s role in longevity and healthspan have prompted a plethora of research studies with exciting results.

But first, let’s go over some of the background science to make all of this make sense.

What is spermidine?

Spermidine is a polyamine, which means that it is an organic compound with two amino groups.

This biogenic amine has many roles in the body:[ref]

  • Polyamines are essential for cell growth and proliferation, stabilizing DNA and RNA transcription.
  • Spermidine is important in inducing autophagy in cells that are damaged and need to be recycled.  Autophagy is necessary for aging, both for recycling cellular components and clearing out damaged parts of the cell.
  • In addition to regulating autophagy, spermidine downregulates IL-6, an inflammatory cytokine, in the aging brain.[ref]
  • Spermidine is also a potent modulator of circadian clock gene expression.[ref]

In animal studies, spermidine supplementation extends lifespan a bit, but it also decreases heart disease. Researchers have found that the cardioprotective effects are through increasing autophagy in cardiac muscle cells.[ref]

Important here: Spermidine and polyamine levels decrease in aging. Higher spermidine levels have links to healthy longevity, but there are some trade-offs as well.

Now let’s dig into the science…

Creation of spermidine in the body:

The spermidine synthase enzyme catalyzes the production of spermidine from putrescine and decarboxylated S-adenosylmethionine (SAMe). What does this mean? The enzyme is essential for the reaction, and the substrates needed are putrescine and SAMe.

Spermidine conversion PMC6637774

What is putrescine?

Putrescine is a polyamine produced by the breakdown of amino acids. It is named putrescine because it is responsible for the foul odor in decaying flesh. In living people and all eukaryotic organisms, cells need putrescine for division.

A 2012 study shows that low putrescine levels are likely the driving factor for low spermidine levels in aging.[ref] This makes targeting an increase in putrescine one way to increase spermidine.

So how do we get putrescine?  Putrescine can synthesize in a couple of ways. One way that may be ‘hackable’ is that arginine can convert into ornithine and then putrescine.

Arginine -> Ornithine -> Putrescine

Utilize your gut microbes: Researchers found that a probiotic (Bifidobacterium animalis subsp. lactis ) plus arginine increases putrescine production in the gut.[ref] After completing the animal studies showing the increase in putrescine, the researchers took it one step further in human studies. They found that the specific Bifido in yogurt plus arginine improved endothelial function and reduced the risk of atherosclerosis. The yogurt plus arginine increased both putrescine and spermidine levels.[ref]

What is SAMe?

S-adenosylmethionine (SAMe) is the other essential component needed for the body to make spermidine. SAMe is the primary methyl donor in the body, shuttling methyl groups created in the methylation cycle for many reactions. Methyl groups are created in the body from consuming either folate- or choline-rich foods.

Spermidine and the hallmarks of aging:

Spermidine inhibits several of the hallmarks of aging.[ref][ref]

  • epigenetic changes
  • impaired proteostasis
  • mitochondrial dysfunction
  • stem cell dysfunction
  • impaired intercellular communication


Clinical trials on spermidine supplementation for aging:

The correlation between low spermidine levels and diseases of aging, such as dementia or Alzheimer’s, has been shown in several trials.[ref] The question, though, is whether increasing the polyamine will prevent or reverse diseases of aging.

Spermidine clinical trials for dementia or Alzheimer’s:

Clinical trials on spermidine in the elderly show varying results. The differences in outcomes may be from the age at the start or the degree of cognitive impairment in dementia trials.

Supplemental spermidine in older adults with cognitive decline found no difference after 1.2 mg/day for three months. The supplement was safe and well-tolerated. It just wasn’t a miracle cure for dementia in three months.[ref]

Another clinical trial in older adults with memory problems, though, did find that it helped moderately with cognitive function.[ref]

A double-blinded study in nursing home patients found that spermidine supplementation improved cognitive performance in people with mild dementia.[ref]

Overall, the study results point to a supplement that may be worth trying, but one that is likely not a complete miracle pill for dementia.

Spermidine supplementation may improve vaccine efficacy in older people:

Autophagy is important in T cell function, and both decrease with aging. The decrease leads not only to decreased immune function but also leads to vaccines not being as effective.

A study in 2020 showed that “Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors’ cells, in which spermidine biosynthesis has been inhibited.” [ref] This research in older adult T cells follows animal research studies showing that older animals have an improved T cell response when supplemented with spermidine.[ref]

Spermidine and spermine levels in Parkinson’s:

A 2019 study shows lower levels of spermine and spermidine in people with Parkinson’s disease than in an age-matched cohort. Interestingly, a metabolome analysis showed higher levels of acetylspermidine and N-acetylputrescine, which are metabolites of spermidine.[ref]

Here is an in-depth look at spermidine biosynthesis and metabolism:

CC image source


Spermidine and cancer: caution is needed

In cancer, spermidine seems to be a double-edged sword.

On the one hand, researchers find that it enhances autophagy to prevent cancerous mutations from replicating.[ref] High intake of spermidine-rich foods is associated with better outcomes in very early cancer cases.[ref]

But once a tumor starts to grow, higher levels of polyamines help to promote growth. Blocking the formation of polyamines is, therefore, a target of cancer researchers.[ref] In fact, a polyamine-reduced diet showed benefit in prostate cancer in a clinical trial.[ref]

Heart disease and spermidine:

Animal studies show that supplemental spermidine in their food increases lifespan, in part, through enhancing heart health.

The researchers have found that adding spermidine to the food of lab animals decreased the age-associated decline in heart function. The spermidine-fed mice had reduced blood pressure and no decline in the cardiac muscles. Researchers determined that spermidine prevented the decline in autophagy in cardiac muscles that usually causes heart problems in aging.[ref]

It may seem odd that autophagy is significant for preventing heart problems. Autophagy is a cell survival strategy that helps cells survive damage from inflammation, nutrient deprivation, and reactive oxygen species. Autophagy is essential for pruning out damaged mitochondria and encouraging the formation of new powerhouses for the cell. On the other hand, over-activation of autophagy can lead to cell death. Thus, like everything in the body, it is a matter of balance.

In the heart, autophagy is essential for keeping the heart muscles functioning well. In animals with genetic modifications to reduce autophagy, cardiac hypertrophy or dilated cardiomyopathy occurs at an early age. Spermidine is important in autophagy, and counteracting the decrease in aging helps prevent declining heart function in the elderly.[ref]

Animal research also shows that spermidine increases the viability of heart muscle cells after a heart attack.[ref]

A human research study found that older adults who consume more spermidine in foods were more likely to have lower all-cause mortality and decreased heart disease.[ref]

Spermidine for hair growth?

Animal studies show that spermidine supplementation suppresses heart problems in aging and decreases age-induced hair loss.[ref]

Spermidine is needed for normal hair growth. In fact, one way to stop excess hair growth in women is to apply a topical inhibitor of the enzyme that makes putrescine and spermidine.

A placebo-controlled human trial found that spermidine supplements for three months prolonged the anagen phase in hair. The anagen phase is the active growth phase of hair, so prolonging it can theoretically keep the hair around longer.[ref]

How can you increase spermidine?

For many, an effort to increase spermidine levels in aging may help to improve healthspan. Granted, animal studies are a lot more impressive on this than human studies.

Which foods contain spermidine?

Spermidine is found in the following foods:[ref][ref][ref]

  • blue cheese
  • aged cheeses
  • mushrooms
  • soy, such as tempeh (not soy milk)
  • natto
  • peas and broccoli
  • wheat germ and whole grains

High heat cooking, such as grilling or frying, may reduce spermidine content in meat. Boiling vegetables also reduces their polyamine content, except peas and peppers still retain their polyamines after cooking.[ref][ref]

Fermentation increases polyamines (as well as histamine – so not a great option for people who are histamine intolerant).

Supplements for increasing spermidine:

The body needs putrescine and SAMe for creating spermidine.

Putrescine is the limiting factor for many older people in producing spermidine.

The clinical trial mentioned above with arginine plus the probiotic, Bifidobacterium animalis subsp. lactis is intriguing. It seems like a solid way to increase putrescine and spermidine.[ref]

Additional evidence from animal studies also shows that a probiotic, Bifidobacterium lactis LKM512, plus arginine increases spermidine. The animals also had improved longevity and protection from age-induced memory impairment.[ref]

Arginine is an amino acid that is readily available as a supplement. has some in-depth research on arginine if you would like to read more about it.

L-citrulline is often used instead of arginine in supplements because the body can convert it to arginine. For the purposes hereof, wanting the gut microbiome to produce putrescine, you should probably go with arginine instead of l-citrulline.

I don’t have a good brand recommendation on specific probiotics. Read the labels and reviews – and look for ones like this one or this one with Bifidobacterium animalis subsp. lactis.

SAMe is integral in the methylation cycle as a source of methyl groups. The body needs choline and/or folate for creating the methyl groups and regenerating SAMe. Eating choline-rich foods or folate-rich foods can help to ensure that you have enough SAMe.  It is also available as a stand-alone supplement and marketed for depression. SAMe can profoundly impact mood, so I recommend talking with your doctor before supplementing with it if you have mood issues or questions about medication interactions.

Riboflavin, or vitamin B2, is a cofactor for the FAD-dependent enzymes essential for converting other polyamines into spermidine.[ref] If you think you are low on riboflavin or don’t get enough in your diet, it is available as a stand-alone supplement or as part of a B-complex.

What about directly taking spermidine? 

Spermidine supplements are also available. They usually are based on fermented wheat germ extract. I haven’t tried them, personally, since I don’t eat wheat. Studies in older adults show that spermidine supplements are likely safe and well-tolerated.[ref]

My final thoughts:

Spermidine seems like an excellent option for boosting autophagy and increasing healthspan. But the links with cancer growth are a good reminder that one-size-fits-all supplement recommendations may put you on the wrong path. Talk with a health care professional if you need help.



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Glymphatic brain clearance system – draining the brain

The glymphatic system, which was identified in 2012, is the network that clears out waste products from the brain and central nervous system.

Essentially, this system is the way that fluid surrounding the brain and spinal column moves out of the brain, carrying waste products with it. The glymphatic system is found in the areas alongside the arteries that bring in blood and oxygen and the veins that take the blood back to the heart.

The interstitial and cerebrospinal fluid that makes up the glymphatic system moves by the pulsing of the arteries in the brain. [ref][ref][ref]

Pretty cool, huh.

The brain works hard all day, producing metabolites or by-products in many of its processes. The glymphatic system then moves the metabolites out of the brain – like a wastewater system cleaning everything up. The corollary for the rest of the body is the lymphatic system, which also moves fluids around.

Exactly how the glymphatic system works is a hot new research topic, so there are still a lot of unanswered questions here. I’ll cover the highlights of what is currently known and why it is important in healthy aging.

Let’s start with some background …

Why is the glymphatic system important?

Decreased glymphatic function is linked to neurodegenerative disorders in aging, such as dementia, Parkinson’s, and Alzheimer’s disease. No one wants neurodegeneration when aging…

Causes of glymphatic dysfunction include:[ref]

  • decreased cerebral spinal fluid
  • decreased flexibility in the arteries
  • changes in the glial cells that make up the glymphatic vessels

Animal studies show that glymphatic function decreases dramatically in the aged. In animals, there is an 80-90% reduction in glymphatic function in aged animals compared to young.[ref]

What is the glymphatic system cleaning out?

One big thing that the glymphatic system clears is soluble amyloid-beta.[ref] Other waste metabolite proteins include alpha-synuclein and tau proteins.[ref]

Much of the research focuses on the above proteins because they are linked to neurodegeneration in aging. But the glymphatic system clears out many metabolites. The brain is a big energy user and thus waste produce.

Where does it come from?

The fluid in the glymphatic system comes from cerebral spinal fluid and interstitial fluid. Certain areas of the brain produce cerebral spinal fluid, which is important in the glymphatic system as well as in the spinal column and nervous system. Interstitial fluid is the fluid between blood vessels and cells.

When looking at interstitial fluid in the brain, a protein type known as aquaporin is important. Aquaporins are the cell membrane transport proteins that control the flow of water through membranes due to osmosis. Think back to high school chemistry and moving water across a membrane to balance out salts.

AQP4: While there are several different aquaporins in the nervous system, spinal cord, and sensory organs, AQP4 (aquaporin 4) is the important one in the glymphatic system. AQP4 on astrocyte membranes controls a large part of glymphatic function. Astrocytes are a type of brain and spinal cord cell that support the function of the neurons. Astrocytes do a lot – including producing nutrients and cholesterol for neurons as well as interacting with the blood-brain barrier. The AQP4 membrane protein on astrocytes is controlling the flow of water into and out of the brain. [ref]

Where does it go?

Initial research pointed to a flow of brain metabolic waste into the veins of the brain.[ref] The blood then takes the waste out to be taken care of in other parts of the body such as the kidneys and liver.

Other research shows that the glymphatic system drains into the cervical lymph nodes. [ref]

Thus, good blood flow and lymph drainage are important here.

Sleep is essential for cleaning out the brain:

Did you know that we can go a lot longer without food than we can without sleep? All animals sleep, and for a long time, scientists weren’t exactly sure why.

In 2013, a landmark study on sleep was published in Science. The study explains how metabolites are cleared from the brain during sleep via the glymphatic system. It is an answer to the age-old question of “why do we sleep?” Laying down and sleeping is absolutely essential for brain function.

Recent research answers questions on whether it is just the lying down and resting or whether more processes are involve.

A 2020 study explains that there is a circadian rhythm to glymphatic function, and the mid-point of sleep is when the peak flux takes place. Your circadian clock is the molecular clock that drives the body’s 24-hour rhythm. For example, hormones like cortisol and melatonin rise and fall at certain times of the day. Similarly, circadian rhythm seems to drive glymphatic function. [ref]

Sleep posture and glymphatic transport:

Glymphatic transport is increased during sleep… and most of us sleep laying down. It would make sense, then, that body position matters in the glymphatic system.

fMRI studies give researchers a glimpse into the glymphatic transport system. Researchers were able to visualize how body posture matters for glymphatic transport. They found that: [ref]

  • Upright (standing, sitting) posture has the slowest clearance from the brain.
  • Laying on the back has better clearance than being upright.
  • The best glymphatic transport is while laying on the side.

My take away: Sleep on my side whenever possible

What can you do to improve glymphatic function?

Let’s take a look at several lifestyle factors that are important in glymphatic function…

Sleep QUALITY is imperative in glymphatic function

Researchers have known for a while that people with disturbed and fragmented sleep have higher than normal amyloid-beta levels. [ref] Sleep dysfunction and Alzheimer’s go hand in hand.

New research on the glymphatic system shows why the quality of sleep is so important in brain function. Deep, slow-wave sleep is when the most glymphatic flux takes place. [ref] Thus, if deep sleep is impaired due to aging, getting up a lot in the night (prostate problems?), or other sleep issues, the glymphatic system is not going to work as well.

(Learn how glycine may help increase deep sleep.)

Are you wondering how much time you spend in slow-wave deep sleep? Sleep trackers such as the Oura ring, woop strap, or Apple watch can help you quantify it.

I don’t know that any sleep tracker is truly accurate. Instead of obsessing over the exact amount of time spent in slow wave sleep, I use my sleep tracker (an Oura ring) to determine how different interventions impact my sleep – tracking whether it trends up or down.

Breathwork and the glymphatic system:

Ultra-fast fMRI study shows that breathing – and not breathing – affects the glymphatic system. The researchers found that voluntary breath-holding increases pulses in certain regions of the brain. When you hold your breath, CO2 levels increase, which causes dilation in the blood vessel in the brain. This is a dynamic process. Initially during a breath-hold, the pulses in the brain decrease, but then there is a compensation reaction that causes an increase in blood flow and oxygen. The fMRI showed that the cardiovascular pulses in the brain (moving the glymphatic system) increased in certain brain regions with breath holds. [ref]

Breathing well is important for oxygenation in the brain — and for the glymphatic clearance.

Breath training, such as the Wim Hof method or yoga breathing, may be something to look into for brain health.

The flip side here is that decreased respiration in older individuals could be contributing to decreased glymphatic movement. Additionally, sleep apnea could be having a negative impact on glymphatic waste removal during sleep. Sleep apnea increases the relative risk of Alzheimer’s.

A recently published study (June 2021) directly shows the connection in Alzheimer’s patients between brain activity during sleep and the glymphatic system’s ability – or inability – to clear out amyloid-beta. [ref]

Alcohol, glymphatic flux, and AQP4

I mentioned above that AQP4 – aquaporin 4 – is important for glymphatic clearance. AQP4 is a transporter that moves water and solutes from astrocytes into the glymphatic system. [ref]

Low-level alcohol consumption may help? A mouse study showed that low levels of alcohol consumption increase glymphatic function. But higher levels of alcohol consumption decreased AQP4 and decreased glymphatic clearance. [ref] This may explain why moderate

Diabetes and brain health

Recent animal studies show that in type-2 diabetes models the glymphatic clearance is decreased by 3-fold. This is one explanation of the connection between diabetes and the progression of neurological diseases in aging. [ref]

More of a stretch…

Going out on a limb here, the following are a few more options that research points to:

Transcranial magnetic stimulation – in rats – increase brain drainage via increasing glymphatic flow. [ref]

Lymphatic massage: The research about the glymphatic system draining into the cervical lymph nodes sent me off on a rabbit trail of looking into lymphatic massage. It turns out that there is an animal study showing that boosting the lymphatic system (mouse massage therapy?) helped with elderly cognitive function. [ref]

Here’s a video on self-massage for the cervical lymphatic system:

Omega-3 fats show promise in research on concussions and brain injuries. Mouse research shows that omega-3 fatty acid supplementation increased glymphatic clearance after a brain injury.[ref] Perhaps this is part of the protective role of fish oil in Alzheimer’s disease.


The research on the glymphatic system points to a solid reason to prioritize sleep quality for brain health.

How you go about doing this individually will vary.

There are all kinds of websites and books on ‘sleep hygiene’. Essentially, it boils down to blocking blue light from screens for an hour or two before bed and going to bed at a reasonable hour so that you can get enough sleep. Everyone is unique in what it takes to turn off the brain and go to sleep (or stay asleep). If you can’t sleep when it is hot, get a fan or air conditioner. If noise bothers you, try a white noise machine or move to a quiet place.

The key here is that it is worth putting a little time and effort into prioritizing sleep quality – but don’t obsess about it to the point of being stressed. For me, a Ken Burns documentary, especially that one on the Civil War, will lull me into a very deep sleep. So I encourage you to find your own Ken Burns documentary… In other words, have a plan for how to get back to sleep if you are an early waker, or know what makes you sleep if you have trouble drifting off.

Low dose lithium reduces cellular senescence

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

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

Lithium – naturally occurring mineral:

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

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

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

Lithium as a drug or supplement:

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

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

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

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

Cellular senescence in aging:

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

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

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

Lithium as a senolytic:

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

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


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

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

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



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]


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]


Clinical trial showing reversal of early Alzheimer’s

A pre-print study posted in May 2021 shows positive results in a clinical trial with the goal of reversing early Alzheimer’s disease.

This is big!

An attitude of acceptance that Alzheimer’s is a non-reversible fate prevails in medical practices, and a positive clinical trial showing marked improvement in many participants is wonderful to see.

The clinical trial used Dr. Dale Bredesen’s protocols for Alzheimer’s prevention, much of which he has outlined in his book, The End of Alzheimer’s.

Why am I writing about a pre-print? This study seems to be of very high quality and backed by a lot of other research. It comes together showing a personalized approach to Alzheimer’s prevention is the right approach. I’ll update this article whenever the preprint is published in a major scientific journal.

Clinical trial to reverse Alzheimer’s

Let’s take a look at the clinical trial:

The study involved 25 patients (ages 50-76) with either Alzheimer’s disease or mild cognitive impairment. The Montreal Cognitive Assessment (MoCA) was used to quantify the degree of cognitive impairment.

The researchers evaluated the participants for “markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure (metals, organic toxicants, and biotoxins), genetic predisposition to cognitive decline, and other biochemical parameters associated with cognitive decline.“

Researchers then used this information to create a personalized protocol for each patient.

The study participants were then followed for 9-months, with cognition tests every three months.

Genetically, the participants covered a range of APOE types (E2/E3, E3/E3, E3/E4, and E4/E4). If you have 23andMe genetic data, you can check your APOE type here, if you want to know.

Before we get into the results, a couple of things stand out about the trial…

First, it is awesome to see a study using so many different parameters and personalized targeted interventions. But, it is important to note that the participants were younger than many Alzheimer’s patients. Additionally, the study participants were almost all college graduates, with almost half of the cohort having a graduate degree. Both of these factors make it more likely to have a positive outcome than a general population group. This was a proof-of-concept clinical trial, so I would assume that the researchers chose the participants carefully.

Treatment interventions:

The protocol for all participants included:

  • All participants were encouraged to exercise (aerobics and strength training) for 45 minutes a day for 6 days a week.
  • Sleep hygiene was encouraged, and sleep apnea was treated.
  • Everyone ate a diet that included a lot of organic high-fiber vegetables (raw and cooked) and pastured eggs and meat. The diet was ‘mildly ketogenic’ and avoided processed foods, gluten, and dairy.
  • The participants used biofeedback, heart-rate variability training (HeartMath), and brain training.

Individual protocols included:

  • Hormone replacement when needed.
  • Thyroid supplement for participants with less than optimal thyroid function.
  • Vitamin D, omega 3, B-vitamins, CoQ10, and minerals were supplemented for people who had suboptimal levels.
  • Gut healing protocols for people with leaky gut, inflammation, infection, or impaired digestion.
  • Anti-inflammatory herbs for people with systemic inflammation. Low-dose naltrexone was prescribed for some.
  • Anti-virals were prescribed for Herpes simplex and an herbal protocol given for active Epstein-Barr virus. For tick-borne infections, herbal antimicrobials and immune system support were given.
  • Detoxification protocols were used for people with heavy metals, biotoxins, and organic pollutants (e.g. phthalates, organophosphates). This was done with binding agents, sauna, herbs, and restricting mercury-containing fish.

Results of the intervention:

A caregiver questionnaire showed that 84% of patients improved (mild to marked improvements). This is a great result since caregivers are likely to have a keen eye for either improvements or declines.

What about the Montreal Cognitive Assessment? 76% of participants improved their scores, 12% declined in scoring, and 12% remained the same.

You may be thinking, “Why didn’t everyone improve?” Good question, but important here is that most people without intervention would have shown a decline in cognitive scores over 9 months. So 76% improving scores and 12% remaining the same is pretty impressive.

The results are not broken out by APOE genotype, though, which is something that I would be interested in seeing. I would be most interested in knowing if any of the E4/E4 carriers were able to improve. But in the discussion section of the study, the researchers report that “both groups—the ApoE4+ group and the ApoE4- group—showed statistically significant improvements in MoCA and NCI (Neurocognitive Index)


Research on Alzheimer’s disease shows that there are likely many different contributing factors to the pathology. A single intervention – drug, lifestyle change, etc – is unlikely to be effective. Instead, this proof-of-concept clinical trial points to the efficacy (and common sense) of using multiple interventions that target many different factors that contribute to the risk for Alzheimer’s disease.

Want more information? Check out Apollo Health. This healthcare group is implementing Dr. Bredesen’s protocol with testing, nutritional plans, supplements, cognitive training, medical practitioners, and health coaches.

The time to prevent Alzheimer’s is in the decades before symptoms begin.

Interested in how your genetic variants could play into the different risk factors for Alzheimer’s? Check out the following Genetic Lifehacks articles:



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)


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.


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.


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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.
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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.