Instead of selling you on the latest and greatest (because I honestly don’t know which is the greatest), I’m going to explore some studies on how topical taurine or topical resveratrol may be theoretically helpful.

Taurine and skin aging

Taurine is a sulfur-containing amino acid. Your body naturally synthesizes it from other amino acids - cysteine and methionine, and you can get it from your diet (seafood, dairy, and meat contain taurine) or energy drinks.

Studies show that taurine is important in heart health, muscle function, digestion (bile acids), and nervous system functionality. You can read more on general reasons why taurine is important for longevity here.

But let’s look specifically at the studies on skin health (because I’m tired of looking old).

Taurine levels are fairly high in the skin and help to modulate skin moisture content. It plays a role in regulating the tight junctions between cells, which prevents moisture loss and regulates the inflammatory response.[ref]

However, studies also show that taurine levels in the skin decline with aging1. (I write that phrase ‘declines with aging’ a lot… sigh.)

Let’s take a look at some of the studies on increasing taurine to reverse the effects of skin aging.

Oral taurine for skin health:
In animal studies, higher taurine levels (added to their water) helped to prevent UV-induced wrinkles. It also helped to reduce wrinkles that were already established. Importantly, the oral taurine was able to reverse the decreased skin taurine levels.2 Another recent animal study used a mouse model of accelerated skin aging. The results showed that oral taurine supplementation prevents a lot of the negative effects of skin aging. 3

Topical taurine mitigates estradiol decrease:
A 2025 study in animals showed that topical taurine can help to mitigate the skin effects of decreased estradiol in menopause. When estrogen levels drop, skin becomes drier with more wrinkles, and taurine was shown to upregulate zonulin, claudin-11, and other tight junction proteins along with type III collagen in a way that mimics the effect of estradiol.4

Genetic connection to skin aging:
A Mendelian randomization study found that genetic variants that are associated with increased taurine levels are also associated with decreased skin aging effects.5

Increases hyaluronic acid and ceramides:
Low taurine causes problems in the skin. A study using skin cultures found that increasing taurine levels directly results in an increase in ceramide synthesis, filaggrin (tight junctions), and hyaluronic acid synthesis. Together, these point to higher taurine levels enhancing skin barrier function and increasing moisture.6

Plaque psoriasis case study:
A study involving two cases of unresponsive psoriasis showed that N-bromotaurine plus regular taurine in olive oil healed the pustular plaques. The study noted that the addition of taurine cut the healing time in half compared to N-bromotaurine alone.7

Resveratrol for age spots:

The other problem with aging skin is dark spots - unkindly known as liver/age spots or medically known as solar lentigo or hyperpigmentation.

Melanin is the pigment in the skin that gives it its color, and excess melanin causes age spots. Tyrosinase is the enzyme involved in converting tyrosine eventually into melanin. Overactive or overproduction of tyrosinase causes excess melanin, usually due to UV damage.

Resveratrol is theoretically beneficial for dark spots because it directly inhibits tyrosinase. It also regulates the inflammatory processes to prevent oxidative damage, which then decreases melanocyte stimulation.8

Resveratrol is a fairly small molecule (228 Daltons), which means that it should be able to penetrate the skin barrier. It is also lipophilic (lipid soluble) and not very water soluble.910

• Animal studies show that resveratrol can effectively decrease hyperpigmentation through inhibiting melanin synthesis.11

• A human clinical trial using resveratrol in nanoliposomes showed that it had ‘anti-aging and skin-brightening effects’. 12

Of note, though, several dermatology websites claim that there are better options for age spots - mainly retinoic acid.

DIY topical taurine and resveratrol: My experiment

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• NAD+ is a coenzyme in every living cell that powers mitochondrial energy production, DNA repair, immune function, and cellular stress response

• Levels decline 50% or more by age 60 due to increased consumption by CD38 (inflammation), PARP (DNA repair), and decreased production

• This decline drives multiple problems of aging: fatigue, cognitive decline, metabolic dysfunction, and increased disease risk

I recently came across a couple of studies on simultaneously boosting NAD+ and, at the same time, decreasing CD38 with natural supplements.

What is NAD+?

Let’s start with a little background science on NAD+, and then I’ll get into the studies on CD38 inhibition.

NAD+ (nicotinamide adenine dinucleotide) is used by all plants and animals in cellular processes, including ATP (cellular energy) production. It is a niacin derivative necessary for multiple cellular functions -- without it, cells can't produce energy..

Cellular energy: In cellular metabolism, NAD+ shuttles electrons in redox reactions for ATP production. The majority of ATP production comes from processes in the mitochondria (the powerhouse of the cell). This is where NAD+ is essential - shuttling electrons in the Krebs cycle and electron transport chain.

Much of the focus on NAD+ is for cellular energy, but there’s another important role for NAD+….

CD38: Immune system using up NAD+
CD38, and a similar molecule, CD157, consume a lot of NAD+ in the body - especially in aging.1 CD38 is found as a surface receptor on immune cells. Both CD38 and CD157 are also involved in the immune response and neuroinflammation in the brain.2

CD38 uses up NAD+ by acting as an enzyme that catalyzes the degradation of NAD+ in order to use the metabolites as messenger molecules.

How do we get NAD+?

There are two main ways we get NAD+

• It can be synthesized from niacin, which can be obtained from your diet or through the conversion of tryptophan. This is called de novo synthesis.3

• NAD+ can be synthesized in a salvage pathway that recycles NR (nicotinamide riboside) or NMN (nicotinamide mononucleotide) to NAD+.

How CD38 and inflammation result in NAD+ depletion in aging:

CD38 is key to the decline of NAD+ in aging by depleting levels. Increased inflammation - inflammaging - causes increased CD38, which uses up more NAD+, causing a parallel decline in NAD+ levels. Increased cellular senescence in aging also causes increased CD38, with a subsequent decrease in NAD+.4

Here’s what it looks like:

T cells, immune cells, endothelial cells, and smooth muscle cells all can produce CD38, and it is upregulated by proinflammatory cytokines, cellular senescence, steroid hormones, and in response to bacterial infections. CD38 is also upregulated in fibrosis.56

CD38 does a lot, including activating T cells, regulating calcium ions in the brain, inhibiting sirtuins, and limiting NAD availability in bacterial infections. So you don’t want to completely inhibit CD38, just prevent the excess rise in it.7

Boosting NAD+ while simultaneously inhibiting CD38:

A 2024 study on skin aging showed that simultaneously inhibiting CD38 while boosting NAD+ was better for skin health than either alone. The combination increased sirtuin activation, improved autophagy, and boosted mitochondrial functionality.8

There are two supplements to boost NAD+ levels in aging: NR or NMN. Which one is better is a matter of ongoing debate — and commercial interests — among researchers with financial stakes in each.

• NR (nicotinamide riboside): TruNiagen is the patented version with good quality control, testing, and clinical trials. It is also expensive.

• NMN (nicotinamide mononucleotide): There are multiple sources for NMN, and I suggest going with a brand name that you trust and that has 3rd party testing. I usually go with a powdered form of NMN because I don’t like to take too many capsules. I don’t mind the taste, but some people find it hard to handle.

Drop your favorite NR or NMN recommendation on this in the comments. I would love to know what works for all of you. The Amazon links above are just examples of what I’ve used - not necessarily a recommendation of the best.

There are several natural supplements that inhibit CD38.

Apigenin is a flavonoid that is a mild inhibitor of CD38. Animal research shows that apigenin decreases CD38 levels along with an increase in NAD+ levels.9 Apigenin is readily available as a supplement.

Quercetin is a flavonoid that inhibits CD38, and studies on it show that it may be synergistic with supplemental NAD.10 Quercetin can be found in capsules or powdered form, but note that it is yellow and will stain when using the powder.

Luteolin is another flavonoid that can inhibit CD38.11 It is also available as a supplement.

Enoxolone is another natural compound that has been shown to inhibit CD38.12 It is a component of licorice and derived from glycyrrhizic acid.

Researchers are looking at CD38 inhibitor drugs as well. For example, a small molecule referred to as 78c is a CD38 inhibitor that increases lifespan in mice by about 10%.13

So, how much difference does this actually make?

Multiple clinical trials show some benefits for heart health or specific biomarkers from NR or NMN, but the results aren’t spectacular. Personally, I find that it gives me a little more energy throughout the day. So this is one supplement that I keep in my rotation that I think likely has some benefits, but I don’t want to oversell this as the one thing that will cure death and aging. Adding a CD38 inhibitor makes sense, but talk with your doctor if you have questions on whether a supplement is right for you.

The reality is that a stack with an NAD+ booster and CD38 inhibitor is just one tool that may add some benefits for healthy aging.

When you form a clot to stop bleeding, your body continually breaks it down and remodels it. The breakdown process is called fibrinolysis. PAI-1 prevents this breakdown from happening too quickly by blocking the enzymes (tPA and uPA) that would normally dissolve the clot. This balance is crucial: too little PAI-1 results in excessive bleeding, while too much PAI-1 prevents clots from dissolving, increasing the risk of heart attacks, strokes, and microvascular clot formation.

PAI-1 levels rise with age, starting after middle age and correlating with increased cardiovascular risk and frailty. This makes PAI-1 a protective protein when balanced and a harmful aging accelerator if elevated.

To get a little more technical, PAI-1 is a serine protease inhibitor (serpin), and the SERPINE1 gene codes for it. Common variants in the SERPINE1 gene can make you a little more or less susceptible to having clot-related problems like strokes or heart attacks. Rare mutations in SERPINE1 can cause PAI-1 to be significantly impaired, and looking at how these mutations affect longevity is really interesting.

PAI-1 is primarily produced in the endothelial cells lining blood vessels, but is also produced in platelets and released upon platelet activation. Fat cells and the liver can also produce PAI-1. Inflammatory cytokines (TNF-alpha) can increase PAI-1 levels, as can high blood glucose or low oxygen (hypoxia). PAI-1 is also elevated significantly in infections, such as Covid or sepsis.

Beyond blood clots, or rather, preventing blood clots, PAI-1 has more recently been discovered to play a role in promoting fibrosis, such as liver or lung fibrosis. This is because PAI-1 can prevent the degradation of urokinase plasminogen activator, which is involved in breaking down fibrosis in tissues. This leads to higher levels of fibrosis with higher PAI-1 levels.

Since PAI-1 levels naturally increase with age, what happens if PAI-1 is inhibited?

How does PAI-1 tie into longevity?

Genetic studies on rare mutations can show what the extreme - a significantly increased function or decreased function of a gene - does to the body.

2017 Amish study on PAI-1 mutation:
A null mutation in SERPINE1 protects against biological aging in humans, Science, 2017

Researchers studied 177 members of the Berne Amish community, including 43 carriers of a rare null mutation in SERPINE1 (encoding PAI-1, plasminogen activator inhibitor-1), to determine if reduced PAI-1 affects human aging.

Here’s what they found:

• Lower PAI-1: Circulating PAI-1 levels were 50% lower in heterozygous mutation carriers and completely undetectable in homozygotes.

• Longer telomeres: Heterozygous carriers showed 10% longer telomere length compared to noncarriers after adjusting for age, sex, and family structure.

• Better metabolic health: They also had 28% lower fasting insulin levels and zero diabetes prevalence versus 7% in noncarriers.

• Extended lifespan: Analysis of 56 deceased relatives with known genotypes revealed carriers lived a median of 85 years versus 75 years in noncarriers—a 10-year lifespan extension.

This 2017 study shows multiple benefits for lower PAI-1 levels over the course of a lifetime from carrying one copy of a non-functioning mutation. Mice with the same mutation as seen in the Amish study above also live longer.

PAI-1 inhibitor drugs and mechanisms have been studied in multiple contexts - from preventing clot-related heart attacks and strokes to decreasing pulmonary fibrosis to increasing the release of hematopoietic stem cells. Inhibiting PAI-1 also helps to prevent T cell exhaustion by inhibiting the PD-1 checkpoint. Overall, studies on PAI-1 inhibitors show that they have anti-thrombotic effects, anti-fibrotic effects, anti-inflammatory effects, anti-aging effects, and immune checkpoint inhibitory effects.

The obvious drawback to inhibiting PAI-1 is that excessive inhibition could increase bleeding risk; however, the animal studies show that PAI-1 inhibitors don’t extend bleeding time as much as antiplatelet drugs.

So, where is the research at today?

New study: Silencing of PAI-1 using siRNA-lipid nanoparticles reduces thrombosis and prolongs life span in murine models

There’s a brand new study out showing that using one dose of a small interfering RNA (siRNA) that targets PAI-1 could reduce plasma PAI-1 levels by 90% for 10 days. There was no ‘overt toxicity’ noticed in the mouse study, but obviously, that is a long way from human trials. The study also looked at the effect of inhibiting PAI-1 in aged mice and found that it prolonged lifespan in a fast-aging mouse model.

Checking your PAI-1 variants:

If you have genetic raw data, you can check to see whether you have higher or lower PAI-1 activity based on your genes. Keep in mind that in addition to genetic variants, factors such as hypoxia, high TNF, or high blood glucose can also increase PAI-1 levels.

Natural PAI-1 inhibitors:

These studies bring me to the idea that inhibiting PAI-1 is likely beneficial in longevity — assuming that the individual doesn’t have a risk of excessive bleeding.

As always, this is just an overview of natural supplements shown in literature to have an effect. Talk with your doctor if you are unsure whether a supplement is a good idea for you.

Hesperidin is a natural flavonoid found in citrus fruits and readily available as a supplement. It is a natural TNF inhibitor. A cell study found that hesperidin significantly decreased PAI-1 levels.

Resveratrol: In cell studies, resveratrol inhibits the upregulation of PAI-1. A randomized placebo-controlled trial of resveratrol showed that 350 mg/day for one year resulted in decreased PAI-1 levels.

Olive oil and oleuropein: Olive oil is a mild PAI-1 inhibitor. Olive leaf extract is also a good source of oleuropein.

Aspirin is a COX inhibitor that affects platelet aggregation and clotting in several ways. One effect of aspirin (650 mg) is a reduction in PAI-1 levels. The reduction peaked at 2 hours.

Vitamins C and E are natural ways to attenuate PAI-1 expression in animals with high cholesterol.

Baicalin (skullcap): The herbal supplement baicalin has been shown in animals to reduce PAI-1 levels and airway inflammation caused by cigarette smoke.

References:

Chen, Xiangqi, et al. “Endothelial H2S-AMPK Dysfunction Upregulates the Angiocrine Factor PAI-1 and Contributes to Lung Fibrosis.” Redox Biology, vol. 70, Apr. 2024, p. 103038. DOI.org (Crossref), https://doi.org/10.1016/j.redox.2024.103038.

Ferraresso, Francesca, Chad W. Skaer, Zimu Wei, Woosuk S. Hur, Hongyin Y, et al. “Age-Associated Increases in PAI-1 Silenced with siRNA-Lipid Nanoparticles Reduces Thrombosis and Prolongs Lifespan.” Blood, vol. 147, no. 18, Apr. 2026, pp. 2053–63. PubMed Central, https://doi.org/10.1182/blood.2025029834.

Ferraresso, Francesca, Chad W. Skaer, Zimu Wei, Woosuk S. Hur, Hongyin Yu, et al. “Silencing of PAI-1 Using siRNA-Lipid Nanoparticles Reduces Thrombosis and Prolongs Life Span in Murine Models.” Blood, vol. 147, no. 18, Apr. 2026, pp. 2053–63. PubMed, https://doi.org/10.1182/blood.2025029834.

Giménez-Bastida, Juan Antonio, et al. “Hesperetin and Its Sulfate and Glucuronide Metabolites Inhibit TNF-α Induced Human Aortic Endothelial Cell Migration and Decrease Plasminogen Activator Inhibitor-1 (PAI-1) Levels.” Food & Function, vol. 7, no. 1, Jan. 2016, pp. 118–26. PubMed, https://doi.org/10.1039/c5fo00771b.

Khan, Sadiya S., et al. “A Null Mutation in SERPINE1 Protects against Biological Aging in Humans.” Science Advances, vol. 3, no. 11, Nov. 2017, p. eaao1617. DOI.org (Crossref), https://doi.org/10.1126/sciadv.aao1617.

Moon, Deborah. “Plasminogen Activator Inhibitor-1 (PAI-1): Regulator of Clotting.” Genetic Lifehacks, 27 July 2023, https://www.geneticlifehacks.com/plasminogen-activator-inhibitor-1-pai-1/.

Mousa, Shaker A., et al. “Effect of Single Oral Dose of Aspirin on Human Platelet Functions and Plasma Plasminogen Activator Inhibitor-1.” Cardiology, Nov. 2008, pp. 367–73. DOI.org (Crossref), https://doi.org/10.1159/000175993.

Ohkura, Naoki, and Riyo Morimoto-Kamata. “Antithrombotic Natural Products That Inhibit Plasminogen Activator Inhibitor 1 (PAI-1).” BPB Reports, vol. 7, no. 2, 2024, pp. 51–55. J-Stage, https://doi.org/10.1248/bpbreports.7.2_51.

Orbe, J. “Vitamins C and E Attenuate Plasminogen Activator Inhibitor-1 (PAI-1) Expression in a Hypercholesterolemic Porcine Model of Angioplasty.” Cardiovascular Research, vol. 49, no. 2, Feb. 2001, pp. 484–92. DOI.org (Crossref), https://doi.org/10.1016/S0008-6363(00)00260-1.

Smokovitis, A., et al. “Great Variation in the Response of Tissue Plasminogen Activator Activity, Plasminogen Activator Inhibition and Plasmin Inhibition to Endotoxin, Aspirin and Endotoxin after Administration of Aspirin.” Thrombosis Research, vol. 50, no. 4, May 1988, pp. 495–505. DOI.org (Crossref), https://doi.org/10.1016/0049-3848(88)90198-3.

Tzekaki, Elena E., et al. “Oleuropein Is a Natural Inhibitor of PAI-1-Mediated Proliferation in Human ER-/PR- Breast Cancer Cells.” Breast Cancer Research and Treatment, vol. 186, no. 2, Apr. 2021, pp. 305–16. Springer Link, https://doi.org/10.1007/s10549-020-06054-x.

Zagotta, Ivana, et al. “Resveratrol Suppresses PAI-1 Gene Expression in a Human in Vitro Model of Inflamed Adipose Tissue.” Oxidative Medicine and Cellular Longevity, vol. 2013, 2013, p. 793525. PubMed, https://doi.org/10.1155/2013/793525.

Zhang, Hu, et al. “Baicalin Ameliorates Cigarette Smoke-Induced Airway Inflammation in Rats by Modulating HDAC2/NF-κB/PAI-1 Signalling.” Pulmonary Pharmacology & Therapeutics, vol. 70, Oct. 2021, p. 102061. PubMed, https://doi.org/10.1016/j.pupt.2021.102061.

———. “Baicalin Ameliorates Cigarette Smoke-Induced Airway Inflammation in Rats by Modulating HDAC2/NF-κB/PAI-1 Signalling.” Pulmonary Pharmacology & Therapeutics, vol. 70, Oct. 2021, p. 102061. PubMed, https://doi.org/10.1016/j.pupt.2021.102061.

Just two weeks of sleep restriction to 6 hours or less a night caused significant decreases in cognitive performance. Moreover, the study participants weren’t aware that they had significant cognitive deficits over the study period. They thought they were doing ok with six hours of sleep, but the tests proved otherwise.

The reality is that we all have periods in life when we are likely to be chronically sleep deprived — whether due to insomnia, work schedules, stress, traveling, or a health or pain issue.

Problems sleeping can happen at any age, but they are much more common as we get older.

While getting sleep back on track is essential, there are also some new studies on ways to mitigate the negative consequences of sleep deficits.

Sometimes you just need to solve the immediate issue of getting your brain back on track now, and then work towards figuring out how to consistently sleep well. That’s what this research roundup is all about - what to do the morning after a sleepless night, when your brain and body are crying out for help.

Creatine supplements:

Study: Single-Dose Creatine Reduces Sleep Deprivation-Induced Deterioration in Cognitive Performance, Nutrients April, 2026

This new study is a follow-up to a 2025 study on the impact of a high dose of creatine after sleep deprivation (21 hours awake). The study participants were healthy adults aged 20-40 who normally sleep at least 7 hours a night. The study was a double-blind, randomized, prospective trial where participants essentially did the sleep deprivation twice, 7 days apart, with a placebo for one test and creatine for the other.

The participants were given 0.2 g/kg body weight of creatine (or placebo) and then had cognitive tests later to see if the creatine could help mitigate sleep deficits. The results showed that creatine improved cognitive performance compared to a placebo. Creatine helps in maintaining ATP regeneration in the brain, keeping the brain functioning a little better in logic and cognitive processing speed.

This study was a follow-up to a prior study that had used 0.35g/kg bw creatine, which, for a 70 kg (154 lb) person, would be 24.5 g of creatine, which is a lot.

In this new study, using 0.2 g/kg (14g for a 70 kg person) showed positive results with an improvement of up to 12%, but the effect wasn’t as pronounced as the higher dose.

My thoughts: Creatine isn’t right for everyone, but if you don’t have a medical reason not to take creatine, it is worth considering. Look for one in a powdered form without additives, like this (Amazon link as an example - buy the brand you like best). I can get 14g to dissolve in a cup of coffee or smoothie on a morning after a sleepless night.

Here’s more on creatine and longevity.

Taurine:

Study: Taurine Prevents Impairments in Skin Barrier Function and Dermal Collagen Synthesis Triggered by Sleep Deprivation-Induced Estrogen Circadian Rhythm Disruption Cells 2025

Another consequence of sleep deprivation is both intestinal barrier dysfunction and skin barrier dysfunction. You see this in the mirror after a sleepless night…

Read more

It turns out that isn’t what the term means. So let me give a bit of a definition before diving into the recent research study on reversing some of the damage in heart failure.

Heart failure is a chronic condition, not usually meaning imminent death as it sounds. It’s defined by several biomarkers showing that the heart muscle isn’t pumping enough blood to fully meet the body’s needs. There are different types of heart failure based on whether it is on the left side, right side, systolic, or diastolic. There are multiple causes, with high blood pressure, leaky heart valves, atherosclerotic plaque, smoking, heart attack, or chronic AFib being common ones.

Ejection fraction is one measurement used to diagnose heart failure. A healthy heart has an ejection fraction of around 60%, while people with heart failure can have a reduced ejection fraction (<40%) or a preserved ejection fraction (>50%). Along with ejection fraction, heart failure measurements include the thickness of the heart muscle, the size of the heart, and the flow of blood through the heart valves. 1

Along with having a terrible sounding name, heart failure is usually talked about as chronic and progressive — which sounds pretty doom and gloom. The heart keeps working harder, trying to meet the needs of the body for oxygen and blood flow, and the heart muscle keeps enlarging for a while. The enlarged heart then takes up space in the lungs.

It turns out that there’s an interesting way that heart function can be improved, and for some people, heart failure can be reversed.

Cardiac resynchronization study:
A study in the European Heart Journal showed that a therapy called cardiac resynchronization therapy (CRT), which is an implanted device used for specific types of heart failure, can actually reverse the enlargement of the heart and reverse the cardiac remodeling. 2

What I found interesting, though, was the ‘why’.

The researcher found that this cardiac resynchronization device increased fatty acid uptake in the cardiac muscle cells. The heart muscle needs a lot of energy, and it relies on converting fatty acids into energy more than most organs in the body.

In heart failure, researchers are finding that the heart shifts to using glucose as an energy source instead of fatty acids. The CRT study showed that the device caused the heart muscle cells to revert back to using more fatty acids and more ketones for energy. This then allowed the heart muscle to remodel in a positive way and regress back to almost normal size. In six months, the left ventricular volume reduced by almost 50%.

Before I get into more clinical trials, let me caution:
If you have questions on whether any diet or supplement is right for you, please be sure to talk with your doctor for advice that is appropriate for your situation. Everyone is unique. What works for someone else may not be right for you.

Ketones for the heart:
In the heart muscle cells, ATP can be produced using glucose (from carbs) or ketones (from fats). The heart muscle relies on ketones during stress, exercise, or heart failure. Utilizing ketones gives more energy while using less oxygen. In heart failure, it is energy-deprived, and there’s a distinct shift to the heart needing more ketones.34

Other studies have looked at the effect of shifting the fuel for the heart to be fatty acids or ketones using supplemental ketones.

Ketone supplements are referred to in several ways: beta-hydroxybutyrate, beta-hydroxybutyrate salts, exogenous ketones, or 1,3-butanediol. You can get ketones as a drink mix, drinkable shots, or capsules. Be sure to watch for added caffeine — a lot of these are marketed for pre-workout energy boost and can contain caffeine. (The Amazon links above are so that you can see the variety of products - not specific brand recommendations. Read reviews, talk with your doctor, etc.)

Ketogenic diet:
You can also shift your body to make more ketones through a ketogenic diet that is very low in carbohydrates and high in fats. However, cardiologists don’t recommend a ketogenic diet for heart failure patients. For one, a high-fat diet can increase cholesterol significantly for some people, which for someone with atherosclerosis could be a bad idea. It can also be stressful for some people, which is also not a good idea for heart failure. In general, the consensus from cardiologists seems to be that there’s not enough of a proven benefit and too many risk factors to recommend it for everyone with HF.5 6

Medium chain triglycerides (MCT):
Fatty acids are categorized as long-chain, medium-chain, or short-chain, depending on their carbon chain length. Medium-chain triglycerides are unique in that they can be used more easily by cells for energy (don’t need cofactors or additional enzymes). Coconut oil is one source of medium-chain triglycerides, or you can get it as MCT oil.

Clinical trials in heart failure patients:

The cardiac resynchronization study showed that shifting the heart back to using ketones for six months improved heart function and decreased heart size. That implanted device isn’t an option for everyone, so let’s look at the clinical trials using exogenous ketones or MCT oil to boost blood ketone levels. (Animal studies clearly show that ketones help with heart failure - but I’m not going to include them since there are multiple clinical trials in humans.)

Let’s take a look at some of the clinical trials using different forms of ketones in heart failure patients:

A 2019 randomized crossover trial found that short‑term IV 3‑hydroxybutyrate (3‑OHB) acutely improves cardiac output and left-ventricular function in heart failure with reduced ejection fraction patients (and in healthy controls). The researchers did three-hour IV infusions with different doses of ketones and then did a crossover with the patients receiving placebo infusions. The ketone infusions increased left ventricular ejection fraction by 8% (end of 3-hour infusion). The infusions raised ketone levels to ~3.3 mmol/L.7

A 2025 study showed that medium-chain triglycerides (0.5g/kg MCT) increased cardiac output by 16% and left ventricular ejection fraction by 5%. It also increased blood ketone body levels by ~1mmol/l. 8

A 2025 clinical trial in heart failure patients used (R)-1,3-butanediol, which is another form of ketone that elevates ketone levels longer. The heart failure with reduced ejection fraction patients took 0.5 g/kg of (R)-1,3-butanediol or a taste-matched placebo. (This stuff tastes pretty bad…) The results showed that the ketone metabolite supplement raised ketone levels by ~1.4 mmol/l and increased left ventricular ejection fraction by 3%.

A 2024 trial in patients with heart failure and type 2 diabetes looked at the effect of 2 weeks of exogenous ketones. The trial used a pretty hefty dose - 25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol, four times a day, which raised ketone levels by 10-fold over baseline. After 2 weeks, the treatment increased cardiac output by 0.2 L/min and reduced cardiac filling pressures and ventricular stiffness.9

Another 2024 clinical trial in heart failure with reduced ejection fraction patients involved taking ketone esters four times a day (25 g; KE4 pro, Ketone Aid). Ketone ester treatment decreased NT-proBNP (heart failure measurement) by 18% and increased left ventricular ejection fraction statistically.

One more option for increasing ketones is a diabetes medication called an SGLT2 inhibitor. This type of medication is now recommended for heart failure patients, even without diabetes. The SGLT2 inhibitor increases the amount of glucose that exits the body via urine, and it also slightly increases overall ketone levels. It is thought that the increase in ketones is at least part of why SGLT2 inhibitors are cardioprotective. These medications are prescription only and something to consult with your doctor about.10

Conclusion and my observations:

Again, this information is simply presented for informational purposes. If you know someone with heart failure, pass the article along so that they can talk with their doctor.

The MCT oil study surprised me with the effect size and improvement in heart function from 0.5g/kg/day. If I did my math right, that is a couple of tablespoons a day for an average adult for a significant improvement in heart function. Again, this may be too much saturated fat for some people, but for someone who isn’t sensitive to saturated fat, swapping in coconut oil for other types of fats may make sense.

Bigger picture - to me - is that the progressive negative effects seen in heart failure can actually be reversed. That impressed me.

Healthspan is all about staying healthy in aging, and ketones for the heart may be one option to keep in mind.

💥💥 The results showed that people with APOE E4 (Alzheimer’s risk allele) who ate the most red meat were at a more than 50% decreased relative risk of Alzheimer’s! What?!? 💥💥

I know that some of you are steak lovers and cheering this finding, while others are shaking their heads, thinking of the studies showing that plant-based diets are best for longevity. And all of you are smartly thinking that there is more to this story.

First, if you want to know how to check your APOE type from 23andMe raw data, read the Genetic Lifehacks article on APOE. Be sure to carefully think it through before looking at your APOE status. Not everyone wants to know, and that is totally OK.

Let’s dig into the details of the study, look at the findings, and then check for any weaknesses in the data. If you don’t care about the study details - skip to the end for the interesting part on why APOE E4 may be an ancient adaptation to a time before agriculture and plant-heavy carbohydrates dominated.

First: Who did the study and why…

The study, published in JAMA Network Open, was done by researchers in Sweden at the Karolinska Institute. Of note here - it’s a good journal, peer-reviewed study, and from a world-renowned research institute.

The researchers looked at data from 2157 older adults who had been followed for more than 15 years for the Swedish National Study on Aging and Care–Kungsholmen.

Who was in the study:

The study participants are Swedish, urban, and aged 60+ and dementia-free at the start of the study period. They were followed for 15+ years.

Importantly, the researchers broke out the participants by APOE genotype, with about 25% of the participants carrying an E4 allele.

APOE E3/E4 and E4/E4 individuals are at a significantly increased risk of Alzheimer’s and dementia, compared to people with the typical E3/E3 genotype. So this study was powered to see if there is an effect on dementia risk or on cognitive decline from meat consumption, broken out by APOE type.

Study participants filled out extensive food-frequency questionnaires at multiple time points over the 15+ year period. This gave researchers data on the frequency of foods eaten over the past year.

The researchers also measured global cognition and checked for dementia diagnoses over the time frame.

What did they find?

The meat intake data was broken out into quintiles (top 20% is Q5 and bottom 20% is Q1). In looking at total meat intake and cognitive function, there was a link between the E4 allele, higher meat consumption, and slower cognitive decline.

In APOE E4 carriers (APOE E3/E4 and E4/E4):

• People in the highest meat-intake group (Q5) had slower cognitive decline over 10 years than those in the lowest.

• They also had better episodic memory trajectories.

In non-E4 genotypes (E3/E3 or E3/E2), there was no clear association between higher meat intake and cognitive trajectories.

Not all meat is the same. Importantly, when the researchers divided out processed meat from unprocessed meat consumption, processed meat consumption was associated with worse cognition scores. Higher unprocessed red meat consumption was driving the benefit for APOE E4.

Higher unprocessed meat intake was also linked to lower all-cause mortality in E4 carriers (HR 0.85; 95% CI 0.73–0.99; P = .04).

To me, the all-cause mortality benefit is an important point. There are studies showing that APOE E4 allele carriers who eat a lot of saturated fat are at a higher risk of heart disease. Not all studies show this, but there’s enough of a signal there that I was worried that higher red meat intake may be preventing dementia by causing everyone to die early from heart disease. Not the case here.

But, but… What about…

I know some of you are thinking of a million things that could cause this correlation. Perhaps people who eat more meat are rich with better healthcare, or are better educated?

Covariates, including education, physical activity, smoking, alcohol, multimorbidity, and diet quality, were all adjusted for in the study. It really does seem to be a well-done study, and the Swedish healthcare system is generally good. However, there still could be some residual confounding variables, such as early-life factors or something more nuanced in their lifestyle that isn’t taken into account.

I don’t want to overhype this, though. A social media headline about this study claimed that eating lots of meat completely abolishes the increased risk of Alzheimer’s from the E4 allele. That claim is a bit of a reach, in my opinion.

The dementia association in E4 carriers was calculated to be about half the risk for the top meat consumers compared to the lowest quintile. However, that calculation was based on relatively few dementia events within the E4 groups. It was statistically significant, but a larger cohort and longer study period are needed to truly know the effect size here.

How much meat did they eat?

The meat intake for the lowest quintile (Q1) was about 220g/week, and the middle (Q3) was around 510 g/week. That’s a couple of small servings of meat in a week for Q1. For the upper quintile (Q5), it was around 930g/week - essentially eating meat every day.

The upper quintile consumed quite a bit more meat than the Nordic guidelines for red meat consumption.

Here’s a breakdown of meat consumption (created in Claude using the data from the study):

Why would APOE E4 benefit from meat consumption?

What I found most interesting was the theory of why APOE E4 allele carriers benefited from more unprocessed meat.

APOE is a lipoprotein that carries cholesterol, and it transports lipids in the brain. The APOE E4 type leads to lower plasma APOE levels. In the brain, APOE also helps to regulate the clearance of beta-amyloid.

The E4 allele is thought to be the ancestral human APOE type, with the E3 and E2 alleles being more recent and more adapted to agriculture. Over the course of history, researchers think there was a ‘hypercarnivore’ phase for a long period when <30% of calories came from plants. Then that shifted to swing back to more of a plant-based omnivorous diet.

The lower APOE levels with E4 could then correspond to being adapted to a diet higher in meat and cholesterol and lower in plant sterols.

Here’s how the authors of the study break it down, including different theories and prior assumptions from other studies:

If you want to read more and see the studies on the benefits of APOE E4, check out the Genetic Lifehacks APOE article. The protection against parasites, such as Giardia and Cryptosporidium, would have been a real benefit for our ancestors.

Conclusion:

This study clearly shows a statistical connection between better cognitive function and more meat consumption in people with APOE E4 alleles. Or, to be more precise, in older Swedish adults with APOE E4. The increased risk of Alzheimer’s for E4 allele carriers varies quite a bit by ancestry group, with Asians and European Caucasians being at a much higher increase in relative risk than people with African ancestry.[ref] I would love to see this type of study carried out in people with different ancestry and in different parts of the world.

What do you think? Will this cause you to eat more unprocessed red meat? Let me know in the comments below.

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This ‘Research Roundup” for paid subscribers looks at three new studies on the gut microbiome that showed somewhat counterintuitive results.

1) Depleting the microbiome benefits the brain in aging:

A preprint from researchers at Harvard showed that, in animals, depleting the gut microbiome with antibiotics rejuvenated several of the hallmarks of brain aging.

The researchers gave old mice a 30-day cocktail of broad-spectrum antibiotics to deplete gut bacteria. This actually resulted in gene expression changes that were consistent with reversing the age-associated brain and vascular changes seen in old age. There was an increase in vascular density and higher levels of Claudin-5, which suggests improved blood-brain barrier integrity. There was also an improvement in myelin production and neurogenesis. In addition, there was a decrease in inflammation.

What was driving these improvements? The researchers found that eotaxin-1 was significantly reduced in the brain and in the plasma after antibiotics. Adding back in eotaxin-1 during antibiotic treatment blocked many of the key benefits of gut bacterial depletion. Essentially, gut eosinophils (a type of white blood cell) increase with age. The antibiotics decreased the eosinophil levels, but adding eotaxin-1 back in caused increased eosinophils and increased inflammation for the gut-brain axis.

What is eotaxin-1? It is a chemokine - an immune signaling protein- that recruits eosinophils and other types of white blood cells to the site of inflammation. It is also called CCL11. As we age, eotaxin-1 levels rise, and higher levels are linked to reduced neurogenesis and memory loss.

The researchers suggest that targeting eotaxin-1 is a better option than using broad-spectrum antibiotics. There are so many nutrients that our gut microbes provide for us, like B vitamins and l-arginine, that it is hard to imagine a benefit from depleting the microbiome.

However, it is interesting that some ancient civilizations, such as the Nubians and the Egyptians, seasonally consumed fermented beer that contained high levels of the antibiotic tetracycline. Tetracycline causes bones to fluoresce under UV light at a specific wavelength, so researchers know from bones that are several thousand years old that tetracycline was regularly consumed.

2) Intestinal dysfunction causes cognitive decline in aging due to medium-chain triglycerides

Read more

Viral causes of Alzheimer’s:
Tau tangles and amyloid beta are integral to the Alzheimer’s pathology, but just having amyloid-beta alone isn’t the whole story. Researchers have shown that amyloid beta plays a role in the brain's innate immune response to viral, fungal, and bacterial pathogens. It’s not just a toxic accident in the brain, but a way to trap viral particles.[ref]

A recent study from Harvard researchers takes this one step further and shows that one reason tau tangles form is to protect the brain from herpes simplex 1 (HSV1) virus. Tau acts specifically to fight viral infections, but in the process combines with amyloid-beta to form the plaque that causes Alzheimer’s.

From the study: “The combined antimicrobial activities of Aβ and phosphorylated tau resulting in Aβ plaques and neurofibrillary tangles, along with neuroinflammation, suggest that AD neuropathology may have evolved as an orchestrated innate immune host defense response to microbial infection in the brain.”[ref]

Your first thought may be: If Alzheimer’s is caused by a virus, can we just take an antiviral medicine to prevent it? You aren’t the only one thinking that…

A phase I clinical trial, published in JAMA in December 2025, tested this idea using the antiviral valacyclovir. The study involved 120 participants who were herpes simplex seropositive and who had early stages of Alzheimer’s. The results showed that taking valacyclovir, an anti-viral medication, was actually associated with a slightly worse outcome on the Alzheimer’s tests than the group receiving a placebo.[ref]

So it seems that valacyclovir is not the answer for someone who has Alzheimer’s.

Perhaps it is the timing? Treating herpes simplex with valacyclovir in elderly people who were in the beginning stages of Alzheimer’s may have been too late.

A large retrospective study in Taiwan looked at herpes simplex infection data and treatment data going back to the year 2000. The researchers compared data for over 8000 people with herpes simplex to an age and sex matched group of more than 25000 people without the virus, and then looked at who ended up with an Alzheimer’s diagnosis. They divided up the herpes simplex positive group into those who were treated with antivirals vs. those who weren’t treated.

The results showed that the untreated HSV-positive group was at a 2.5X increased risk of Alzheimer’s. However, the group that had taken anti-viral medications for herpes simplex was at a significantly reduced risk of Alzheimer’s. What’s unknown here from the insurance data and retrospective study is which specific anti-herpes medications were used in Taiwan to treat the virus.[ref] However, the implication is that treating herpes during the initial infection seems to greatly reduce Alzheimer’s risk.

If amyloid beta is part of the brain's immune defense against pathogens, then the next question is: how are those pathogens getting into the brain in the first place? A fascinating new study explains an unexpected route of entry.

Bacteria moving into the brain:

You may be wondering how pathogens get into the brain since we have a nice blood-brain barrier protecting the noggin.

A massive study this week showed that some bacteria take the gut-brain axis highway by hitching a ride on the vagus line.[ref]

Background context: A wave of research over the past decade has firmly established a connection between changes to the gut microbiome and changes to the brain. The gut microbiome shifts can be measured a decade before the onset of Parkinson’s and predict the disease. Even neurodevelopmental disorders, such as autism, often have measurable differences in the gut microbiome.

This new study involved mice fed a high-fat diet — specifically, it’s the high-fat, high-cholesterol diet that is used in studies to give mice atherosclerosis. It’s not what mice would normally eat. Shortly after the diet change, the gut microbiome composition shifted substantially, and intestinal barrier function was reduced.

The researchers checked to see if gut bacteria were escaping into the bloodstream and organs, but didn’t find that happening. Instead, they found that certain gut bacteria were moving up the vagus nerve into the brain.

The blood-brain barrier was still intact, and genome sequencing using DNA barcoding clearly showed that low levels of bacteria in the brain were the same bacteria as were in the gut.

Giving the mice antibiotics then caused big shifts in the composition of the gut microbiome. However, microbes still moved to the brain, just different ones than were seen in the initial study setup. Partially cutting the vagus nerve, though, decreased bacterial translocation to the brain significantly.

Taking it another step, the researchers used different mouse genetic strains that are used for modeling Alzheimer’s, autism, and Parkinson’s. Again, when fed the high-fat diet, they were able to show specific gut bacteria translocating to the brain through the vagus nerve.

The study was extensive and meticulous, as is needed for proving a novel finding. I would encourage you to read through it here (I’m not doing it justice with this explanation!).

Wrapping up:
I don’t have a lot of answers here, just musings on the very interesting studies. The blood-brain barrier blocks bloodborne pathogens and toxins, constantly protecting the brain. But it seems that pathogens are still sneaking in, and some may be using nerve pathways to get there. Recently making headlines are studies showing that the shingles vaccine may also decrease dementia risk. While I’m sure there are many variables involved there, including healthy user bias, it is interesting in that the shingles (chicken pox, varicella-zoster) virus can stick around for decades, remaining dormant in the nerve ganglion.

Finally, I’d like to circle back to a couple of previous articles. I recently wrote about the theory that motor neurons are the hard limit on lifespan. I’ve also written about the role of gut barrier integrity in preventing autodigestion. Both ideas come together here again in the role of the gut microbiome and gut barrier to protect against the translocation of viruses and bacteria into the brain.

It seems to be frailty. People in their 90s and 100s tend to die of ‘old age’, when frailty eventually leads to an inability to get around, slowed movement, slowed breathing, and peaceful passing in their sleep.

But why does frailty eventually cause the hard limit on lifespan?

A recent article from Unaging caught my attention. In it, the author argues that motor neuron breakdown is what sets the cap on human lifespan at around 120 (assuming you don’t die of heart disease or cancer).

In the article, the author explains that longevity interventions like diet and exercise reduce all-cause mortality, but the effect is based on reducing mortality at age 60 or 70. When looking at much older individuals (90s, 100s), then those interventions aren’t important. At that age, frailty - the inability to walk across the room - takes over as the limiting factor, and that may be due to motor neuron loss. Centenarians rarely die of cancer or heart disease; instead, they are more likely to die of ‘old age’.

One metric that is often used in studies on old age is grip strength. Poor grip strength is predictive of increased mortality rate, which I took to mean that I should do some hand exercises to prevent death. Turns out that motor neuron failure is what is decreasing grip strength and predicting death — not the lack of using one of those hand grip exercisers.

Let’s take a look at what studies show on this, and then see if there are any possible solutions.

What are motor neurons?
First, some background science (skip ahead if you know this). Motor neurons are the long nerve cells that carry signals from the central nervous system (brain, spinal cord) to your muscles and glands. They are why you move, breathe, and have a heartbeat.

The two main types of motor neurons are upper and lower motor neurons. They have a large cell body (called the soma) and a long axon that carries the signal. These are some of the longest cells in the body, with some lower motor neurons reaching over 3 feet in length.

• Upper motor neurons (brain) have their cell bodies in the motor cortex of the brain and send long axons down through the brainstem and spinal cord. They don’t directly contact muscles, but instead fire the lower motor neurons.

• Lower motor neurons (brainstem/spine) are in the brainstem and the spinal cord’s ventral horn. Their axons exit the spine and directly innervate skeletal muscle fibers at the neuromuscular junction.

The lower motor neuron, plus the muscle fibers that it controls, is called a motor unit. These range from the neurons and muscles that handle fine movements (fingers, eyes) to the large motor units that control gross movement of the legs.

What causes motor neuron loss?
Motor neurons are vulnerable to degradation in part because they are really large cells that need constant energy. This means that proteins, ATP, and cellular waste end up getting transported long distances. They are also highly excitable with lots of glutamate receptors, making them vulnerable to excitotoxicity, or damage from excessive stimulation. Finally, they have a lot of mitochondria for energy production, but a relatively low calcium-buffering capacity.

Moreover, these big neurons have a very limited capacity for regeneration. There’s some regrowth of peripheral neurons, but it is slow. Nearby neurons can also branch out and cover a lost neuron.

What’s the evidence for motor neuron degeneration as the hard limit on lifespan?

Sarcopenia is the loss of muscle mass that happens in aging. It’s the shrinking, weakness, and shakiness that is the picture, in my mind, of frailty in the elderly. Research now points to the loss of motor neurons as a key component of sarcopenia.

Motor neuron loss happens throughout adulthood, but for a long while, the nearby surviving neurons sprout new branches to cover the muscle. This seems to work up to about 70 or 80 for most people, when a tipping point is reached, and too many motor neurons have been lost.

Motor neuron loss —> sarcopenia:
Researchers now think that the loss of motor neurons is the driving cause, or at least initiation, of sarcopenia. The loss of muscle mass then causes frailty, falls, and even a diminished ability to breathe due to the loss of diaphragm muscle strength.12

There’s an interesting study (in mice) that showed that inhibiting autophagy caused neuromuscular dysfunction in old age — and that could directly be measured by the diaphragm function decreasing.3

A large Japanese study in adults over age 65 found that sarcopenia approximately doubled the risk of death in both men and women. The researchers broke out the results, looking at low muscle mass by itself compared to low muscle mass along with slow gait and reduced grip strength. Low muscle mass by itself wasn’t correlated to all-cause mortality. Instead, it is the combination of gait and grip changes, along with muscle weakness, that increases mortality, illustrating the role of motor neurons instead of strength.4

ALS, Lou Gehrig’s disease —> motor neuron loss:
ALS is the first thing many people think about when they hear the term “motor neuron”. It’s a motor neuron degeneration disease that causes muscle weakness, paralysis, and eventually respiratory failure.

ALS can be due to genetic mutations in about 10-15% of cases, and looking at the genetic cause (SOD1 mutations) sheds light on the argument for motor neuron loss being the limiting factor for lifespan.

Researchers used a mouse model with the SOD1 gene knocked out to show that sarcopenia is initiated in motor neurons. This leads to neuromuscular junction disruption, which then causes mitochondrial dysfunction and reactive oxygen species (ROS) production in muscles. This creates a feedback loop that further disrupts the neuromuscular junction and leads to muscle fiber loss.5

Metabolic connection:
Motor neurons also innervate organs, such as the pancreas. This ties the theory to both the idea of pancreatic digestive enzymes causing autodigestion and also the links to insulin and metabolic changes affecting aging and lifespan.

All together, the evidence is fairly compelling that motor neuron degeneration is a limiting factor for lifespan, if you don’t die of heart disease or cancer first. I don’t know that I am totally convinced that it is the only limiting factor, but it is a plausible theory.

So what can we do to maintain our motor neuron health?

To me, it makes sense to protect and try to restore motor neuron function, whether it increases my lifespan or not. Motor neuron health is undeniably integral to healthy longevity, and preventing the neurodegeneration and breakdown of the axonal sheath may be beneficial for multiple reasons.

First, there’s research going on right now with small-molecule drugs that can protect motor neurons. Keep an eye on research trials for drugs for motor neuron diseases, such as for ALS.

Slowing decline:

There are a number of interventions that slow the degeneration of motor neurons — note that this is just slowing and not preventing or reversing.

Keto: A ketogenic diet in old mice showed significantly increased motor neuron unit number estimates and improved grip strength. Interestingly, the improvement was in motor unit connectivity, not raw muscle strength, which again points to the role of motor neurons being the linchpin here.6

Thiamine: Vitamin B1, or thiamine, plays an essential role in mitochondrial ATP production, which is essential for maintaining motor neuron function. Low thiamine may play a role in motor neuron degeneration and motor neuron diseases.78 Benfotiamine is the form that is better absorbed and utilized by the body.

Creatine: Motor neuron loss in ALS may be helped with creatine supplementation, at least in animals. Creatine helps to enhance ATP production, and it may also limit excitotoxicity from glutamate.9

Vitamin B12: A phase III clinical trial in ALS patients showed that methylcobalamin injections slowed the clinical progression of the disease.10

Environmental factors: Oxidative stress and excess ROS are thought to play a primary role in motor neuron diseases. A number of environmental factors, including pesticide and heavy metal exposure, may damage motor neurons. Several herbicides, including glyphosate and 2,4-D, are linked to an increased risk of motor neuron diseases. Similarly, the pesticides carbaryl and chlorpyrifos also increase the relative risk.1112 Thus, avoiding herbicide and pesticide exposure as much as possible is a good idea.

Viruses, including polio and enterovirus-A71, are known to directly trigger degeneration in motor neurons. Avoiding polio is also a good idea.

L-Carnitine: Another protector of mitochondrial energy is L-carnitine, which is a cofactor used in the beta oxidation of long-chain fatty acids. A mouse study using a model of ALS showed that L-carnitine increased survival time.13

Final thoughts:

A study of a lady who had reached the ripe age of 117 showed that she didn’t have heart disease, cancer, or dementia — but she had been in a nursing home for a while due to deteriorating mobility. In the end, she passed away peacefully, and it was likely due to respiratory muscle failure. It’s likely that motor neurons to her diaphragm eventually failed, and she simply stopped breathing in her sleep.14

If researchers can prove that motor neuron degeneration is the hard limit for lifespan, then it seems like this is a solvable problem. While we don’t have the solutions right now, here’s a lot of current research on motor neuron diseases that has me hopeful. In the meantime, improving mitochondrial function and avoiding exposure to environmental neurotoxins may be the best bet. If motor neuron degradation can be solved, then heart disease and cancer become the bottleneck again. This then implies that the longevity roadmap is essentially a sequence of bottlenecks to clear.

What do you think? What does aging look like if we solve heart disease, cancer, and motor neuron degeneration?

Researchers from Washington University in St. Louis tested out this idea in mice that have Alzheimer’s mutations, and they used CAR-T cells to do this in a nifty way. (Study in PNAS, 2026)

CAR-T cells are currently used in immunotherapy for cancer. They are T cells that are collected from the patient’s body and modified in a lab to have what is called a chimeric antigen receptor (CAR) that targets a specific protein. Then they are then multiplied in the lab, and then reintroduced back into the body. For cancer patients, the CAR T cells are engineered to have whatever specific proteins are on that patient’s tumor cells.

For Alzheimer’s, the researchers engineered the CAR-T cells to recognize amyloid-beta plaque by using antibody fragments from current anti-amyloid drugs (Lecanemab and Aducanumab). They showed that these CAR-T cells could effectively clear amyloid from the dura, which is the thick outer membrane of the brain where lymphatic drainage occurs and the immune cells get activated. By clearing the amyloid in this area, they reduced the deposition of amyloid beta plaque, but they didn’t clear out plaques that were already in the brain.

You don’t want a constantly active (or permanent) CAR expression on T cells because it could cause chronic immune activation or autoimmunity. So the researchers did a transient technology with multiple infusions over several weeks in the mice.

This is a long way from being ready for humans, but as a proof-of-concept, it is pretty neat. The CAR-T immunotherapy for cancer has been developed and refined over the past two to three decades. There are clinical trials underway for autoimmune diseases. The infrastructure is in place, and a lot has been learned.

However, taking it to this level for targeting amyloid in the brain will need a lot more research and trials. Plus, CAR-T therapy in cancer is still really expensive, and they need to balance not triggering damage to the brain. The Aducanumab antibodies by themselves have some serious risks, like brain hemorrhaging. No one wants brain hemorrhaging as a side effect.

With those drawbacks, why do I think this is a nifty study?

My excitement here is that I think prompting the immune system to clear out amyloid-beta plaque is a plausible idea. In the long run, CAR-T may end up not being the best option, but I think this is heading along the right path in promoting the right type of T cell response.

Prior studies:
The focus for decades has been on amyloid-beta deposits as initiating the progression of Alzheimer’s disease. But amyloid-beta alone is insufficient to cause Alzheimer’s — there’s been something missing, and it looks like T cell abnormalities may be the key.

Here’s what’s known about T cells and Alzheimer’s:

• A 2023 study in Nature Neuroscience used a 3D human neuroimmune axis model to show that CD8+ T cells selectively infiltrate Alzheimer's cultures and trigger increased microglial activation, neuroinflammation, and neurodegeneration. They also found that T cell infiltration induces interferon-γ and neuroinflammatory pathways in microglial cells.

• A 2024 study showed that exhausted microglia cells may be at the root of APOE4 Alzheimer’s. This study directly links the immune response, or really a perturbed immune response, to the Alzheimer’s pathology.

• In a 2024 study in PNAS, researchers showed that age-related memory CD8 T cells can generate neurodegeneration with the features of Alzheimer’s mice, upstream of amyloid-beta and tau. Essentially, they could use antigen-specific CD8 T cells to induce plaque and tau tangles. Interferon-gamma was also necessary here.

• A 2025 study by Swiss researchers showed that even in very early stages of Alzheimer’s, there is altered T cell reactivity that can be detected in asymptomatic people. This pattern is different than the T cell activity seen in early symptomatic patients.

• All of this makes sense with the many studies on how brain injuries accelerate neurodegenerative disease.

Brain aging and T cells: Zooming out beyond Alzheimer’s
There’s a bigger picture here, as well, when looking at brain aging, biological age, and T cells.

Another new study in Alzheimer's & Dementia (January 2026) also explores T cells in the brain. The researchers calculated biological age and age acceleration from blood DNA methylation data in 704 older adults. They also looked at associations with clinical Alzheimer’s diagnosis and antemortem biomarker levels. What they found was that eight biomarkers were associated with age acceleration (including tau), and notably, that methylation levels in CD4 and CD8 T cells are associated with age acceleration. Methylation is a kind of off switch for genes, with higher methylation levels in T cells reducing function. Interestingly, the associations with brain aging and T cell changes were a stronger indicator for Alzheimer’s among APOE E3 individuals than those with APOE4.

Where does this leave us?
I freely admit that I don’t fully understand all of the ins-and-outs of the changes in T cells in the brain in aging. However, I have enough understanding to be excited that researchers seem to be making great progress over the last couple of years on putting together more of the puzzle pieces for Alzheimer’s.

The bigger picture is that the brain may be the rate-limiting organ for longevity. A new theoretical paper published in January in Cureus makes the argument that the brain is the biological bottleneck for overall healthspan. When brain function starts to deteriorate, everything goes downhill. As the authors put it: “progressive disruption of neural networks governs functional decline across multiple physiological systems, regardless of peripheral biological age.” The authors of the paper call it a "Brain-First Longevity Framework". Essentially, working on your metabolic health or cardiovascular health doesn’t matter much if your brain is declining faster than the rest of the body.

The authors of that paper mention that treating neurological conditions should be a priority — chronic migraines, major depressive disorder, psychosis, TBI, chronic pain, or sleep disorders shouldn’t be ignored since they cause constant stress on neural circuits. Looking for other studies on this, a 2025 study showed that chronic migraines are associated with accelerated brain aging — a 4-year-older brain age than chronological age.

The practical takeaway here is that treating neurological disorders - depression, migraines, concussions, pain - should be prioritized. It’s easy to be passive about treating a migraine that occurs just once a month or so, but the damage could be cumulative in terms of brain longevity.

Autonomic network regulation is also part of the brain’s core functions - heart rate variability, blood pressure stability, and vascular tone. Heart rate variability is something that can be easily measured and tracked with an Apple watch, Oura ring, Whoop strap, and Garmin trackers. I’m not currently using any of these, so I don’t have a lot of practical buying advice. (Drop your favorites in the comments if you use one of these!)

The other takeaway is that depression, stress, and anxiety should be dealt with so that they don’t degrade your neural networks over time. For example, chronic psychological stress compromises the blood-brain barrier, increases neuroinflammation, and accelerates T cell aging.

So I’ll leave you with the hope that researchers are on the right track for solving Alzheimer’s disease, and the practical takeaway that you should prioritize brain health for longevity and healthspan.

An unsolvable longevity health problem (so far) is that the thymus shrinks and declines with age, decreasing your overall immune response. The thymus is a small organ located just behind the breastbone where T cells are produced and mature.

T cells are a type of white blood cell that fight both infections (bacteria, viruses) and cancerous cells. The decline in response to pathogens means that the flu kills you when you’re old. Similarly, an inability to nip cancerous mutations in the bud means that cancer incidence increases dramatically with aging.

There are multiple types of T cells - some regulate the immune response and protect against autoimmune attacks, while others directly kill off cells that need to be removed.

Photobiomodulation - red light therapy - is one way to help boost T cell function in aging (or at any age). It is exactly what it sounds like: exposure to light in the red wavelengths at a strong intensity. And the clinical trials on it show that it can significantly improve immune function.

Background terminology:
When looking at light therapy, the things to consider include wavelength, intensity, and time of exposure.

Wavelength: The color of the light - wavelength - is important for interacting with cytochrome c in the mitochondria to produce ATP. In the study on mitochondrial ATP production, the researchers used 810nm light. Other studies show that around 610 nm, 760 nm, and 820 nm have an effect.

• Red light: 600-700 nm (visible), penetrates 1-2 cm

• Near-infrared (NIR): 700-1100 nm (invisible)

  • 800-850 nm penetrates 2-4 cm

  • 1064 nm penetrates even deeper

Irradiance (power density): Studies measure this in different ways, which makes it confusing. But irradiance is power (usually mW) divided by area (usually in cm²).

Energy density (Fluence): This is the amount of light energy per unit area times the duration. It comes out to be Joules/cm² in terms of units and is usually in the range of 2-70 J/cm².

U-shaped curve: Some studies show that there is essentially a U-shaped curve in reference to the dose and response. Low levels aren’t going to do anything, too high of levels can be a negative — thus the need for the right wavelength, energy density, and duration. 1

Clinical trials, immune response:

Let’s take a look at what randomized clinical trials (most with sham control) show for photobiomodulation for immune-related conditions: 2

• 45%reduction in pain and stiffness for rheumatoid arthritis patients (810 nm wavelength, 10 J/cm², 3x weekly for 12 weeks)

• 65% faster wound healing for chronic wounds (660 nm wavelength, 4 J/cm², daily for 4 weeks)

• 40% reduction in asthma exacerbation and improved pulmonary function (904 nm wavelength , 6 J/cm², 2x weekly for 8 weeks)

• 55% improvement in psoriasis inflammation (633 nm wavelength, 12 J/cm², Daily for 8 weeks)

• 30% reduction in relapse rate for MS (670 nm, 5 J/cm², 3x weekly for 16 weeks)

• 30% reduction in ICU length of stay (635nm and 880 nm, 90-second intervals over thighs, legs, arms for 15 minutes)3

Let’s just let that last one sink in for a minute — almost a third less time in the ICU is significant in a lot of ways, including cost. I wonder why every hospital isn’t putting in a red light therapy room.

Mitochondrial health:

Mitochondria are the ‘powerhouse’ of the cells, supplying the ATP needed for most cellular reactions. Researchers in 2024 showed that light at specific wavelengths can enter the mitochondria and excite specific molecules in the electron transport chain to produce ATP directly. It’s not a huge amount (you still need to eat food), but it is a measurable increase. 4

In addition to producing ATP, photobiomodulation affects the mitochondrial production of reactive oxygen species (ROS). In cells, ROS needs to be at the right level. Excess ROS causes oxidative stress and can kill the cell, but a low level of ROS is needed as a signaling mechanism to promote antioxidant defense and immune activation. 5

Positive T cell changes:

Looking specifically at the changes in T cells, a study involving an animal model of COPD showed that photobiomodulation reduced inflammation in the lungs, reduced mucous, and improved bronchoconstriction. This was in conjunction with positive changes to CD4+ and CD8+ T cells. 6

In a mouse model of familial Alzheimer’s, researchers found that photobiomodulation promoted CD4+ T cells and a positive brain immune response.7

Rabbit trail: Making people smarter

While I had planned to write only about the immune modulating effects of photobiomodulation, I also wanted to mention that there are a bunch of new studies on photobiomodulation through the skull to improve memory and cognitive function.

• Targeting the prefrontal cortex with a low-level laser on the forehead above the right eyebrow improved memory and cognition for 5 days.8

• The military is also interested in photobiomodulation. A study using transcranial photobiomodulation (1,070 nm, 15 minutes) resulted in a decrease in anxiety, stress, and depression while simultaneously improving cognitive performance. 9

What to buy?

This is where a great article on photobiomodulation would hold all the answers and tell you the exact best product to buy. I don’t have all the answers.

If you belong to a gym or fitness center, check to see if they have full body red light therapy available. I know people that swear by the full body red lights.

What I ended up buying a few years ago for a muscle injury was from hooga. It was a flexible wrap with 660nm and 850nm wavelengths. I like the flexibility of the wrap format, and at the time it was a moderate price (~$50). But… it looks like hooga no longer makes it. (Here’s something similar for reference.)

Can you help me out?
If you have a red light or photobiomodulation device that you like and recommend, can you post it in the comments? Also important, if you had a red light device that wasn’t high quality or didn’t work for long, I would love the heads up on that as well.

I would also like opinions on whether a whole body setup is worthwhile or if the small flexible wraps are good enough. And if anyone has tried the new helmets for boosting IQ, let me know if it works! The one that I was looking at is around $2K, so I doubt that I will be trying it out any time soon.

We call it reaching developmental milestones in childhood — baby teeth erupt, crawling, walking, permanent teeth coming in, puberty hitting — growth happens at a consistent, programmed rate around the world.

In middle age, we no longer call it reaching a milestone when the need for reading glasses happens, hair turns gray, menopause, blood pressure creeps up, etc.

What controls that rate?
Fundamental questions of aging and lifespan extension include: What controls and drives aging? Why is there a hard limit on lifespan?

When looking at animals, maximum lifespan is consistent for animals in the same species and conditions (e.g. horses live 25-30 years, field mice live 1-2 years). We wouldn’t expect to find a 100-year-old horse, but it’s reasonable for a tortoise. Every animal has consistent developmental milestones, and a fairly consistent maximum lifespan and reproductive span. A mouse 2 years, a naked mole rat 30 years.

On a practical level, understanding the rate of aging, the constraints, and whether we can turn back the clock are important to me as I contemplate retirement planning.

There are a lot of smart people trying to figure this out. I’m going to present some of the competing frameworks here. Please forgive any errors in my understanding of this and any missteps in my thinking.

Programmed Aging vs. Damage Accumulation:

Overarching theories on aging fall into two camps: 1

• Damage accumulation: Random cellular damage gradually accumulates until repair systems can't keep up, causing aging in each organ and tissue. Within this, the question is whether the inability to repair is due to epigenetic control being damaged.

• Programmed aging: Other theories look at aging as a program that controls gene expression through development, adulthood, and then actually causes programmed aging.

Hallmarks of Aging: Damage happens and accumulates
In 2013, researchers put together a list of what they considered the ‘hallmarks of aging’. This was updated in 2023 (article in Cell) with additional systemic hallmarks that drive aging. The hallmarks include cellular senescence, telomere shortening, chronic inflammation, mitochondrial dysfunction, genetic damage, etc. — all the tangible changes that are seen at a cellular level in aging.

These are all independent causes, and each hallmark needs a separate fix (although some interrelate). The different types of damage are fundamentally causing aging. Evolutionary biologists talk about there not being any selection pressure to live past our reproductive span.

This still leaves me with the question: Why do all these things happen together around the same time? Aging happens in bursts; it isn’t linear.

Information theory of aging: Epigenetic control that gets damaged
In 2019, David Sinclair published a book called Lifespan: Why We Age and Why We Don’t Have To. In it, he lays out his information theory of aging in which he argues that epigenetic changes are like software that becomes corrupted over time — like a scratched-up CD. In a 2023 article in Nature, Dr. Sinclair updates this idea of being able to reverse the epigenetic changes and reset cells to a younger age.

This puts aging under epigenetic control - like a program, but the program gets randomly damaged to cause aging. Fixing it is just a matter of restoring the epigenetic information back to what it was at a prior time point. Cleaning the scratches on the CD.

This leaves me with the question: Why was the epigenetic information lost? I understand the software vs. hardware analogy, but I just don’t quite buy it. Especially since aging isn’t a linear progression.

Programmed gene expression: Centralized control sets lifespan
Other researchers argue that there’s an overarching program that controls gene expression throughout the body that sets the pace for development through to old age. This program then controls embryonic and early development, shifts to a different profile for maintaining health during the reproductive years, and then shifts again to a late period that either allows or actually causes the destruction of normal functions.

A recent article argues that the brain is the rate-limiting organ. It regulates the rest of the physiological systems in the body, with perhaps the hypothalamus as the central controlling pacemaker for both aging and lifespan.

Questions that aren’t answered:

To me, the question is whether there’s a centralized, overarching control that allows the breakdown of the body at a certain age, or whether damage just builds up randomly.

It seems like damage causes epigenetic changes, and that epigenetic changes cause damage. Partially reprogramming cells with Yamanaka factors (Yang, 2023) can extend cellular lifespan. Is this because it is restoring information or that it is improving multiple hallmarks?

Are the ‘hallmarks’ of aging the cause or the consequence? Does accumulated damage drive aging, or does aging (perhaps pre-programmed) drive the accumulation of damage?

The overarching idea of a program that controls development and aging for an organism makes sense to me. Developmental stages, reproductive years — all of that is experientially true. What I don’t quite have my mind wrapped around is the idea that part of the program is a deliberate stopping of repair mechanisms, such that we go downhill towards death.

Why is this even important?

A recent preprint from researchers at the Weizmann Institute of Science showed statistically what I think is something that most people instinctively know: Lifestyle and dietary interventions for longevity only extend lifespan by about a year. Yeah, the study was a bunch of statistics, averages, and the use of the word stochastic. It may not be true for each individual. However, it’s consistent with what larger studies show.

Is it worthwhile to spend extensive time and money on ‘longevity’ if the payoff is living to 83 instead of 82? (Yes, I know that healthspan is important, too, but that’s not what I’m pondering here.)

What do we know for sure?

I’ve put a lot of questions in this article, without a lot of answers. Sometimes, taking a look at what is known can help clarify what still needs to be figured out. Here are some “knowns” that may be helpful to think about:

Not linear:
Aging happens in bursts rather than at a steady linear rate. Think about the changes from infancy to age three or four, the momentous changes in puberty, that feeling in your early 40s that you’re no longer what you were a few years ago, and then the jump towards being ‘old’ that happens in the early 60s. If you want to read the research on it, this paper by Shen et al. (2024) lays it out in excruciating detail.

Organs age at different rates:
A recent study in Nature aging looked at how organ-specific aging predicts disease onset and mortality. Using proteomic data from the UK Biobank, the researchers developed 10 organ-specific aging algorithms that demonstrated that organs age at different rates within individuals. Brain aging had the strongest link to mortality.

Similar animals have vastly different lifespans:
Even among mammals of the same size, there can be almost 10-fold differences in lifespan (such as mice vs. naked mole rats). Then there’s the hydra, which is biologically immortal.

Immortal cells:
Certain cell lines and tissue cultures in labs can be maintained for decades. They don’t age like cells in the body do. An example is a mouse fibroblast cell line, 3T3, that researchers have been using since 1962. Why do those same tissues or cell types get old and die in the body? (If you want an interesting book on the HeLa cell line that has been used since the 50s, check out The Immortal Life of Henrietta Lacks. It’s a good read on a lot of levels.)

Where does this leave me?

The idea that inflammaging can be tackled with anti-inflammatories, that DNA damage can be avoided if we eat clean and avoid toxins, that mitochondrial dysfunction can be avoided with the right supplement, or that we can get a whole body glow up with some young plasma — all of that is tangible, understandable, and feels like taking the right steps. (OK, maybe not the young plasma. I’m not going to do that.)

Extending healthspan is worthwhile, and that is what addressing the hallmarks of aging or even reprogramming cells in a specific tissue will do. I’m going to keep on with this pursuit. I want to be as healthy as possible in middle age and don’t want to be debilitated in old age.

The reality, though, is that none of these ‘longevity lifehacks’ is likely to move the needle more than a few years in the end.

I’m ok with that, to some extent. But I am unsatisfied with not having the answers to why we age, what controls the timing, and what imposes the hard limit on lifespan.

I can’t help but wonder what happens when the control system - centralized or decentralized - is understood well enough to be manipulated. I’m planning and saving for retirement, with goals and financial analysis based on both a realistic lifespan and then stretching that a few years (a fudge factor, so that I don’t outlive my retirement money).

The societal implications of manipulating lifespan are huge, but on a personal level, I’m disquieted and don’t know how to balance the uncertainty with action.

Suggested reading:

https://www.frontiersin.org/journals/human-neuroscience/articles/10.3389/fnhum.2025.1695510/full

https://www.biorxiv.org/content/10.64898/2025.12.22.695887v1 - maximum lifespan mechanistic model of aging

https://en.nagoya-u.ac.jp/news/articles/is-aging-an-act-of-genetic-sabotage-for-the-greater-good-scientists-find-a-gene-that-turns-off-food-detection-after-reproduction/

https://www.nature.com/articles/s43587-025-01016-8

https://yurideigin.medium.com/death-becomes-her-or-why-aging-is-an-epigenetic-program-c55a32fd8c74

https://www.cell.com/cell/fulltext/S0092-8674(22)01570-7?

https://www.mdpi.com/2073-4425/12/5/611

https://pmc.ncbi.nlm.nih.gov/articles/PMC6555444/

https://pmc.ncbi.nlm.nih.gov/articles/PMC6413751/

Disclaimer: I’m not a doctor. In no way should you take this as medical advice. Talk with your personal doctor if you have questions about your supplements, health, or need medical advice.

My approach to supplements:

I like to use supplements as a targeted way to isolate a variable and see what happens when I increase it. For example, there are many ways to get vitamins and minerals in the diet. I often will supplement with one specific vitamin or mineral to see if I notice a difference, and then if I do, I try to make the necessary dietary changes to incorporate it that way.

Below is a roundup of what I’m doing, along with links to the details on why. "Some links below are Amazon affiliates for reference. Choose what's best for you and buy local when possible.

Powdered supplements - preferred over vegetarian capsules:

I don’t necessarily want to consume a lot of methylcellulose capsules because I’m unsure of the effect on the gut mucosal barrier. (Here’s why) Thus, I try to get supplements in a powdered form when possible.

Powdered supplements are a good option for things that don’t taste terrible and that don’t stain. I also have my own capsule maker and put the stuff that stains or tastes terrible (e.g. quercetin, NAC) into an empty gelatin capsule.

Currently, I take the powdered supplements with little or no flavor in a glass of water along with an electrolyte flavored drink mix — or — I dump them into a bowl with some yogurt.

Note that I’m not including doses here, for the most part. I often take less than the suggested dose on the package, but it depends on what I’m eating and on how my stomach feels (one or two of the supplements seem to make my stomach feel a bit off at higher doses).

Here’s what I’m taking and why:

• Yogurt: Based on the study of a 116-year-old supercentenarian, which found that one of her longevity superpowers was a gut microbiome with abundant bifidobacteria. She had a lifelong habit of eating a lot of yogurt every day. So I make my own yogurt in an Instant Pot using a small container of plain yogurt as a starter and also adding a bifidobacteria probiotic to the mix. To my morning bowl of yogurt, I add blueberries, homemade granola, and several powdered supplements.

• Proline: This amino acid was found to be lower in people as they age, and also a key to preserving mitochondrial function.

• Arginine + Alpha Ketoglutarate: Arginine is another amino acid that becomes more essential in aging. It not only may help with preventing Alzheimer’s, but it also powers T cell function to boost the immune response against cancerous cells. Alpha-ketoglutarate is also included in my powdered arginine supplement, with many positive benefits for longevity.

• Resveratrol: Resveratrol has many benefits for aging, such as promoting heart health, decreasing gingivitis, and inhibiting COX1/2. (more here, here, here, and here) Note that I tend to switch between anti-inflammatory supplements, so I sometimes leave out resveratrol and take hesperetin or quercetin instead.

• Creatine or methylfolate: There are many studies on creatine for brain health, including a recent one on supplemental creatine for Alzheimer’s prevention. About 40% of methyl groups (which methylfolate provides) are used to synthesize creatine, so I tend to either supplement with creatine or a low dose of methylfolate. I also try to get plenty of folate and choline in my diet.

• Glutamine: This one is because I’m convinced that gut barrier function is essential for healthy aging. I don’t want to cause damage to my organs through my own digestive enzymes escaping into the circulation (autodigestion study).

• NMN: I am currently taking powdered NMN, but at times switch to nicotinamide riboside. NMN is usually less expensive and has the advantage of a powdered form.

Things that I take in capsules or tablets:

These are supplements that I take fairly regularly, but usually not every day. I could give a long, rational explanation of mitigating the risk of toxicity in a supplement by pulse dosing or spacing out the doses… In reality, I’m usually busy on the weekends and forget to take them. During the week, I tend to alternate days on what I take because I’m not convinced that I always need them every day (and I’m cheap… supplements get expensive).

Urolithin A: This is the exception to my “I’m cheap” statement. I get the expensive brand of urolithin A, because testing showed that the cheap brands on Amazon don’t contain much, if any, urolithin A. Here’s why I take urolithin A for mitochondrial function.

Curcumin or quercetin: I have multiple reasons for taking curcumin (or quercetin when I run out of curcumin), including to block NLRP3 overactivation to reduce inflammation and prevent Alzheimer’s.

Fish or Krill oil: DHA and EPA are essential for the synthesis of pro-resolving lipid mediators to prevent chronic inflammation. This is something that I’m brand-specific on (based on ConsumerLab and other testing results), and I buy it in stores rather than online. I take DHA/EPA whenever I am not regularly eating fish.

What about you?

I would love to know which supplements you’re excited about for longevity this year. Drop a comment below and include the ‘why’ for the supplement. I'd especially love to hear about supplements I haven't tried or new research I should know about.

Caveat first: It’s a mouse study, and Alzheimer’s studies in mice have traditionally not translated well to humans. But this study uses multiple genetic models of different ways of causing Alzheimer’s in different strains of mice. Plus, the mechanism here is one that makes sense.

Let’s dig into the study:

The researchers used a compound called P7C3-A20 to restore NAD+ levels in the brains of different mouse models of Alzheimer’s. They were able to prevent or reverse behavioral and physiological changes of Alzheimer’s, depending on when the compound was given (mid-life or after the onset of Alzheimer’s). The compound also reversed deterioration of the blood-brain barrier.1

NAD+ (Nicotinamide Adenine Dinucleotide) is a co-enzyme used in every cell in the body for ATP production in the mitochondria. Its levels naturally decline with age, leading to fatigue and age-related issues.

NAD+ is also a co-substrate for sirtuins, which are proteins that help to regulate DNA repair and cellular metabolism.

The study showed that NAD⁺ dysregulation correlates with the severity of Alzheimer’s disease, and there is more dysregulation in AD brains than is normal for the NAD+ decline found in aging.

Importantly, the study found that “pharmacologically normalizing NAD⁺ homeostasis with P7C3-A20 restores brain resilience and enables recovery from advanced disease across diverse mouse AD models”.

What is this magic compound, P7C3-A20?
It’s a research chemical that has been studied for about 15 years for restoring normal NAD+ metabolism in the brain after TBI, ischemic stroke, Alzheimer’s, or Parkinson’s. It does so without elevating NAD+ above normal levels. 23

The compound has been tested in mice, rats, and monkeys in an oral form, but I didn’t find any human clinical trials on it. It works by activating nicotinamide phosphoribosyltransferase (NAMPT), which increases intracellular levels of NAD. 4

What are the current options today?

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are currently available as supplements and can increase NAD+ levels. A number of animal studies have shown that NMN or NR holds promise for preventing Alzheimer’s (but not to the extent of P7C3-A20).56

A clinical trial in adults with mild cognitive impairments found that multiple supplements, including nicotinamide riboside, NAC, L-serine, and L-carnitine, resulted in cognitive improvements.7

What about just nicotinamide (niacin)? A phase IIa clinical trial in older adults with mild cognitive impairment did not show significant results after 48 weeks with nicotinamide supplementation, indicating that it isn’t a lack of dietary niacin.8

Conclusion:

The current options of NR and NMN to increase NAD+ seem to help some with Alzheimer’s prevention in early stages, but the compound P7C3-A20 seems to hold more benefits specific to brain function. I’m hopeful that it, or another similar compound that normalizes NAD+ in the brain, will be trialed in humans soon.

8

Yulug, Burak, et al. “Combined Metabolic Activators Improve Cognitive Functions in Alzheimer’s Disease Patients: A Randomised, Double-Blinded, Placebo-Controlled Phase-II Trial.” Translational Neurodegeneration, vol. 12, no. 1, Jan. 2023, p. 4. PubMed, https://doi.org/10.1186/s40035-023-00336-2.

To understand aging, it needs to be defined. In 2013, there was a proposal of 9 “hallmarks” of aging, including DNA damage, telomere shortening, and more.

These hallmarks are a scientific framework that identifies the key biological processes that drive aging. In 2023, the hallmarks were updated to 13 and now include inflammaging as a cause of aging. The idea of the hallmarks of aging framework is that these 13 biological processes cause aging — and that altering the processes should reverse aging.

New study, casting doubts on a ‘hallmark’ of aging:

There’s a new study out that casts doubt on whether inflammaging - chronic inflammation in old age — is actually a cause of aging. The study, titled Nonuniversality of inflammaging across human populations, was published in the journal nature aging in 2025.

Researchers compared inflammatory markers (cytokines) in blood samples from four populations:

• Two industrialized populations, InCHIANTI (Italy) and SLAS (Singapore Longitudinal Aging Study).

• Two indigenous, nonindustrialized populations, Tsimane (Bolivian Amazon) and Orang Asli (Malaysia).

Chronic inflammation in industrialized populations:

The researchers found that the Italian and Singapore (industrialized) populations fit the profile of chronic inflammation that increased with age. They looked at CRP, IL-6, TNF, sTNF-RI, sTNF-RII as the inflammatory markers, and they found that there was a strong association with the chronic diseases of aging, such as kidney disease, diabetes, and heart disease. The results were fairly similar between Italy and Singapore.

No inflammaging in indigenous populations:

When the researchers looked at and normalized the data across other population groups, a pattern emerged. The non-industrialized, indigenous population groups from the Bolivian Amazon (Tsimane people) and Malaysia (Orang Asli group), had little to no increase in the inflammatory markers with age and no association with chronic disease.

However, these indigenous populations had high levels of specific inflammatory cytokines due to frequent infections.

The researchers found that 40-80% of the indigenous populations had parasitic worms. Fungal infections, respiratory infections, and gastrointestinal infections were also common.

So CRP may be high, but that didn’t correlate with IL-6 or TNF. Different cytokines were active depending on specific infections, and none of them seemed to drive inflammaging.

What this means…

The study suggests that inflammaging is not universal biology, not inevitable, but rather a consequence of industrialized lifestyles (diet, pollution, sedentary behavior, etc.). There’s also an evolutionary mismatch between our modern environment and our immune systems. We may be built for periodic worms.

Why does this matter?

The hallmarks of aging are a framework, a foundation for a lot of new research on reversing aging. It’s important that they are understood and correct as far as causality, and the findings from industrialized populations may not be universal.

The indigenous population data show that high inflammation is not always harmful inflammation. Infection-driven inflammation is different from metabolic, lifestyle, or environment-driven inflammation. Even at an older age, the immune system can have high activity without triggering chronic diseases of inflammation.

This study highlights that evolution shaped immunity for high-pathogen environments, not modern sterile ones. It concludes: “Inflammaging, as measured in this manner in these cohorts, thus appears to be largely a byproduct of industrialized lifestyles, with major variation across environments and populations.”

Making connections and changing my perspective:

I’ve written a lot in the past about tamping down chronic inflammation in aging. If elevated inflammatory cytokines aren’t a biological process that is part of aging, then the focus should be on preventing the cause of inflammation rather than taking supplements that suppress certain cytokines.

My article on T cell exhaustion in cancer immunotherapy being exacerbated by sucralose consumption is a perfect example…

You want a strong, continuing immune response to fight cancer (most types of cancer, anyway). Immunotherapy drugs help boost the T cell response to the tumor. That’s great, until the T cells become exhausted and stop responding. Researchers recently found that l-arginine is a key amino acid for T cell metabolism, and that sucralose consumption changed the gut microbiome in a way that decreased l-arginine production. This represents a modern, industrialized lifestyle change (sucralose consumption) that limits the power of your immune response to cancer.

A lot of things in our modern environment - microplastics, pesticides, phthalates, PFAS, artificial sweeteners, food additives, antibiotics, dishwashing detergent - alter our gut microbiome. And the gut microbiome composition is integral to the balance of our immune response throughout the body.

Tamping down chronic inflammation is likely still important to reducing chronic diseases, like heart disease, diabetes, and arthritis. But balancing that with a robust immune response is also important. The resolution of inflammation as an active process that relies on pro-resolving mediators is likely a key component. The omega-3s, DHA and EPA, are necessary for the synthesis of pro-resolving mediators.

In the end, chronic inflammation may be aging us in modern societies, but it’s not an inevitable biological process—it’s largely shaped by how we live and what we are exposed to.

So what’s actually happening here?
It turns out that when epithelial (skin) cells are damaged, subcutaneous fat cells release fatty acids to help in tissue regeneration through epithelial stem cells.

In hair follicles, the transition from the resting phase to the actively growing (anagen) phase involves the activation of epithelial stem cells. Building on prior observations that skin injuries or burns can trigger local hair regrowth, the researchers looked at how subcutaneous adipose tissue promotes hair regrowth. They found that adipose tissue in proximity to epithelial stem cells helps the cells meet the energy demand during stress by releasing monounsaturated fatty acids.

I have to admit that I’m skeptical here: It seems hard to believe that putting monounsaturated oil on your head could regrow hair.

Let’s take a look at what other studies show:

Read more

Background on Arginine:
Arginine is a semi-essential amino acid that is used in the body for protein synthesis and nitric oxide synthesis. It is also the precursor for other amino acids, including proline and creatine.

Semi-essential, in amino acid terms, means that most of the time the body can produce enough arginine to meet its needs. For arginine, this means that the body can synthesize it from glutamine via citrulline. In the lining of the small intestine, glutamine (or glutamate) is converted to citrulline, which is then carried in the bloodstream to the kidneys, where it is converted to arginine. In times of physical stress, such as for significant wound healing, sepsis, burns, or trauma, or when in kidney failure, arginine is essential to get from the diet. Arginine is also a key amino acid needed for optimal T cell function in cancer or chronic infections.

The New Study:
The study looked at the interaction of arginine with amyloid-beta plaque. The researchers used cell models and then used animal models of multiple types of familial Alzheimer’s mutations. The animals were treated with arginine added to their water starting at a relatively early age. Compared to a control Alzheimer’s model group, the arginine groups had significantly less amyloid-beta accumulation and a substantial decrease in inflammatory cytokine levels. Wildtype mice (no Alzheimer’s mutations) showed no significant changes from arginine consumption (no changes in weight, no changes in normal inflammation levels, no behavior changes, etc). The researchers note that arginine can help to prevent aggregation of polyglutamine proteins in certain diseases, including spinocerebellar ataxia.1

What Else Is Known About Arginine and Alzheimer’s?

You may be thinking, “So what?” that the amino acid prevents amyloid beta buildup in mice. A lot of things are effective in mouse models of Alzheimer’s disease (AD)…

There are several reasons that this study stands out: studies showing reduced arginine in Alzheimer’s disease patients, immune system changes, gut microbiome connection, and dietary connections.

First, it’s been known for a while that arginine and the metabolites of arginine are altered in the brain samples of Alzheimer’s patients. One of the downstream metabolites of arginine is spermidine, which is also decreased in AD.2 3

Arginine, Diet, and Mild Cognitive Impairment
A nifty study from 2021 looked at the effect of diet on amino acid composition in the cerebrospinal fluid of people with mild cognitive impairment (MCI) and a normal control (NC) group. The trial involved a diet high in saturated fat and high glycemic index (called the High Diet) compared to a diet low in saturated fat and with a low glycemic index (called the Low Diet). The participants with MCI eating the High Diet had a significant decrease in arginine levels in their cerebrospinal fluid. A couple of other amino acids, including valine and isoleucine, were also altered by diet and only in the MCI group.4

This ties together the epidemiological studies showing that a high fat/high glycemic index diet increases the risk of Alzheimer’s disease with decreased arginine in the brain.

Immune System and T Cell Exhaustion:
Arginine is also the limiting factor in powering T cells, and not enough arginine can increase T cell exhaustion.5 I wrote about it recently — explaining a study on how sucralose changes the gut microbiome in a way that limits arginine production. The lack of arginine then increases T cell exhaustion in cancer patients undergoing immunotherapy.

The question is: Are T cells plaing a role in Alzheimer’s disease?

T cells are a type of white blood cell, part of the adaptive immune system. They can be activated by antigens, such as those from a virus, bacteria, or cancer, and then act to kill off the bad/infected cells. T cells have surface receptors that can downregulate the response, called checkpoints. When T cells have been stimulated continually by an antigen for a while, they can become exhausted. In the exhausted state, the checkpoint proteins are increased, and the T cells no longer mount the normal immune response.

A number of studies have shown that amyloid beta plaque may form in response to a persistent viral infection in the brain, such a herpes simplex virus (HSV1 or HSV2).6 7

T cell activation has been studied in the brain for Alzheimer’s disease for a couple of decades or more, and higher T cell response toward amyloid-beta is found in older adults with Alzheimer’s disease.8

Multiple clinical trials are currently going on for several types of vaccines that stimulate the immune system against the amyloid-beta or tau protein in the brain. This isn’t a new idea, with vaccine trials for Alzheimer’s dating back decades. One of the prior clinical trials found that some patients ended up with meningoencephalitis from the vaccine due to an excessive inflammatory response, so the goal is to not overstimulate the immune response. 910111213

T cell exhaustion, in the context of the brain, could mean that a persistent infection is no longer kept in check by the immune system or that persistent antigen stimulation is occurring. One conundrum with Alzheimer’s is that some people with amyloid-beta buildup have no cognitive impairment, while others will have dementia. In a study involving cerebral spinal fluid samples from people with amyloid-positive brains but who were cognitively normal compared with amyloid-positive plus cognitive impairment, the researchers found T cell exhaustion only in those with cognitive impairment.14

Dietary Sources of Arginine:
Arginine is found in protein-rich foods, such as meat, fish, dairy, nuts, and seeds. It is also made by a healthy gut microbiome. (Again, a connection to AD risk from altered gut microbes.)

Arginine Supplements:
Arginine is also available as a supplement in powdered form* or in capsules. The advantages of powder are that you can vary your dose, starting low and increasing. However, without clinical trials to know how much is effective. Arginine can decrease blood pressure, so talk with your doctor if you have any questions or are on any medications.

Supporting Arginine Production Through the Gut Microbiome
The recent study showing that sucralose (an artificial sweetener) altered the gut microbiome in a manner that reduces arginine production is a good reminder that gut health is important and complex.

Lactobacillus rhamnosus GG is a probiotic that has been shown in clinical trials to both enhance gut barrier function and specifically to stimulate gut arginine metabolism. You can get L. rhamnosus GG as a standalone probiotic or as part of a probiotic multistrain complex. 15

Conclusion:
Is arginine a key supplement that everyone should take to prevent Alzheimer’s? We really need more studies than just mouse and cell studies to know. I kind of doubt that it is the one single supplement that will cure all, but it makes sense that T cell exhaustion and arginine could be part of the problem. The arginine connection nicely ties in the gut microbiome and the immune system, both of which have decades of studies on them in terms of their connection to AD.

Background:
Exosomes are tiny vesicles that cells release to communicate with one another. The outer membrane of the vesicle is formed from the cell’s membrane, which encapsulates the payload inside the cell and then is released outside the cell.

Exosomes are formed and released from multiple tissues in the body as a way that cells can communicate both with nearby cells and with the whole body through circulating in the blood.

Researcher classify exosomes by where they are formed (e.g., from neurons vs. from the pancreas), by their size (tiny or even tinier), and by what they carry (neurotransmitters, lipids, mRNA, microRNAs, proteins, and more).

In the brain, exosomes carry signals for neurogenesis, synaptic plasticity, stress response, and even neurotransmitters.

The Alzheimer’s connection:

Read more

A new study in Nature aging shows that urolithin A, as a supplement, may hold the key to slowing inflammaging.1

Background:
Urolithin A is a natural compound that gut bacteria produce by metabolizing specific polyphenols, called ellagitanins, which are found in pomegranates, berries, almonds, and walnuts.

About 40% of the population hosts the right type of gut microbes for converting ellagitanins to urolithin A. However, supplemental urolithin A at 500 mg/day has been shown to raise plasma levels by about 6-fold more than pomegranate juice (assuming you have the right gut bacteria).2

In regard to mitochondrial health, urolithin A has been shown to increase mitophagy, the process by which damaged or defective mitochondria are broken down and recycled. It also increases mitochondrial energy production - but only when mitochondria are under stress. 3

The intervention:
The new study that has longevity science abuzz involved 50 adults (aged 45–70) who took either 1,000 mg/day of urolithin A (UA) or a placebo for 4 weeks.

What did they find?
Urolithin A increased the number of naive, less-exhausted CD8+ T cells, which are the type of immune cell important for fighting infections and cancer. CD8+ T cells are also called cytotoxic T cells and are a type of white blood cell (lymphocytes). Urolithin A also increased natural killer cells and monocytes, while decreasing cytokines (IL-6, TNF, IL-1β). The urolithin A arm of the study also showed improved fatty acid oxidation capacity, which means the immune cells could better use fats for energy due to improved mitochondrial function.

Essentially, urolithin A causes a broadly beneficial reprogramming of immune cells, shifting gene expression toward a healthier state with more energy available.

Why is this important:
T cell exhaustion and dysregulated immune response could arguably be the number one cause of death (I’m lumping together cancer and infectious diseases).

Quality caution on urolithin A supplements:
There are multiple brands of urolithin A supplements on Amazon — some expensive and some relatively cheap. It turns out that the relatively inexpensive urolithin A supplements from brands that I had never heard of don’t actually contain much urolithin A….

SuppCo testing company also tested urolithin A supplements from brands ordered off Amazon. They found four brands that had their labeled amount: CodeAge liposomal*, Timeline Mitopure, Pure Encapsulation Renual (out of stock right now), and Neurogan Health. The other, less expensive brands had little to no urolithin A in them. You can read the full SuppCo report here.

These supplements are expensive (~$50/month) and are more likely to be helpful for someone who is older or who is dealing with a health problem. Personally, I added a couple to my Amazon wish list and am going to check for Black Friday sales.

Want to know more about urolithin A?
Check out the Genetic Lifehacks article that goes into clinical trials for athletic performance, osteoarthritis, and muscle decline in older adults.

Let me give you a little background on BPIFB4 first, and then we’ll dive into the details of the new study.

Background: What does BPIFB4 do?

About a decade ago, the BPIFB4 gene was discovered in a genome-wide association study to be associated with longevity. Researchers in Italy were looking at people aged 95+ to see what was genetically different, and they found a variant in the BPIFB gene that they called the longevity-associated variant (LAV-BPIFB4 — researchers love acronyms). The discovery spurred research into what the BPIFB4 protein actually does in our bodies and whether it might hold the key to extending not just lifespan, but healthspan.12

BPIFB4 is a secreted protein that modulates the immune response and keeps inflammation in check. Found both in respiratory secretions and circulating through our bloodstream, BPIFB4 helps defend against airborne pathogens while simultaneously fine-tuning our immune system’s responses.

Long-lived people were more likely to have more BPIFB4 due to the longevity-associated variant. (Check your BPIFB4 genes here.)

Frailty in Aging:

As we age, frailty creeps in - decreased stamina, speed, activity, strength, and weight. People who are frail are more likely to have adverse events.

Here’s where BPIFB4 is important: people carrying gain-of-function mutations in this gene show significantly lower rates of frailty in old age. The flip side is equally telling - people with mutations that decrease BPIFB4 function have markedly higher frailty risks.

Atherosclerosis and Heart Disease:

BPIFB4 also influences blood vessel health. Plaque building up in the arteries causes atherosclerosis, leading to heart disease, high blood pressure, increased heart attacks, and strokes.

A key factor in causing atherosclerosis is chronic, systemic inflammation. Gene therapy studies on BPIFB4 in mice show that it may be able to improve cardiovascular disease. Researchers used adenovirus viral vectors to transfer the longevity variant of BPIFB4. The animals undergoing the gene therapy showed reduced inflammation associated with cellular senescence and improved NAD+ levels, which typically decline with age. Intriguingly, the increased BPIFB4 variant found in humans is also associated with higher NAD+ levels.3

Other recent studies show that the LAV-BPIFB4 version improves vascular health by increasing endothelial nitric oxide synthase as well as acting on two protein kinases.4

So we have several things going on with higher BPIFB4 levels: less frailty, less heart disease, and more NAD+ to boost mitochondrial health.

New study:

Researchers had previously created a genetically edited mouse version of the LAV-BPIFB4 variant and found that it reduced the risk of cardiovascular disease and inflammation.

The new study on BPIFB4 used an oral version of the longevity-associated variant of BPIFB4 as a recombinant protein. While small, the study showed that oral administration of BPIFB4 prevented atherosclerosis and preserved the integrity of blood vessels. Moreover, the mechanism here was that it reduced IL-1α, IL-1β, TNF-α, and IL-6 (pro-inflammatory cytokines) even in metabolically unhealthy mice fed a high-fat diet. 5

Why is this cool? No one wants to be gene-edited like a mouse, so the fact that an oral version of the protein survives the stomach and could be absorbed is potentially a huge breakthrough. As usual, more studies are needed!

While we wait…

While we wait to see if BPIFB4 orally has positive effects in humans, here are a few ways to target the same pathways for healthy aging.

NMN or NR: One benefit of BPIFB4 for longevity is the increase in NAD+ levels, which decline in aging. Nicotinamide riboside* or NMN can also increase NAD+ levels.[ref][ref][ref]

Curcumin or quercetin can help to tamp down inflammation.[ref][ref] For anyone with genetic testing, check your COMT gene to make sure that you don’t have interactions with this supplement.