Thread by @ChrisMasterjohn

The 3 things @bryan_johnson is missing from his longevity routine, coming from a PhD with over 20 years of research into nutrition science and biomarkers.

A thread 🧵👇

Johnson’s goal is to use the research of his team on promising published anti-aging strategies to incorporate them into his own stack, test them on himself, and use the vast resources at his disposal to bring the best anti-aging hacks to the masses.

He has gone to some crazy lengths to find longevity secrets.

He injected himself with one liter of his son’s blood six times before determining it had no discernible benefit (though he still donates his own blood to his dad).

He’s committed to sleeping alone, and his diet is extremely regimented.

He spends millions of dollars on his self-experimentation, but he is well aware of and empathetic to the fact that others do not have these resources.

His hope is he can use them on himself to find strategies that will benefit all of humanity as we move into a future where death can be transcended through science.

I love that Johnson is open-minded, data-driven, action-oriented, and responsive to criticism.

I love his philosophy of automating the little things in life to achieve bigger things. Let the data tell me what to eat so I can spend my time building businesses, expanding philosophy, or creating art.

Let’s do the dirty work in our generation so that our children can dream bigger dreams.

But, does living a long and healthy life require to lose our life trying to save it? Do we have to commit most of our time and resources toward finding a way to age incrementally more slowly?

Many people may ask, how can I get the 80/20 of this? What are the small number of high-impact things that can give me the most important results?

You may want to lengthen your lifespan and healthspan without losing the opportunity to eat freely of enjoyable foods, sleep with your partner, or spend most of your money or your day managing your health.

Understanding this is actually critical, because harmful processes that occur with aging accelerate over time. It is quite possible that each day we go without optimizing what is accessible to us gets us closer to the point of damage becoming irreversible.

So, let’s start this discussion right now before the opportunity to live better escapes us.

In this analysis, I look for things Johnson is doing that may be holding his results back, blind spots in the data he is collecting, and accessible ways to simplify his approach.

This analysis draws on his monthly notes:



his current results and protocol:



And posts of his on this platform.protocol.bryanjohnson.com/Monthly-Notes
protocol.bryanjohnson.com/#bryan-johnson…

A central finding is that he is missing three types of datasets: 1) functional markers of nutrients, 2) markers of bottlenecks in energy metabolism...

...and 3) ranked and sorted genetics to find the small number of mutations with high impact that are unique to him rather than focusing broadly on any of his genetics that seem relevant.

These missing datasets prevent him from recognizing some aspects of his protocol or things he should add to his protocol that are highly unique to him.

Paradoxically, better understanding this would actually help him spread high-impact strategies to the masses, because everyone has things that are highly unique to them, so everyone should have a strategy for figuring out what they are.

One principle that emerges from this is Johnson is focused on restricting his energy intake, without focusing on optimizing his body’s ability to make that energy flow down the paths of least resistance and into the most health-promoting investments.

Let’s start with his caloric restriction.

Johnson would agree with me that his 25% caloric deficit was too extreme. He recently concluded the same:

https://twitter.com/bryan_johnson/status/1732484916619997503

His 25% caloric deficit lowered his testosterone, which led him to supplement testosterone with a patch.

The combination of the caloric deficit and negative feedback on testicular activity from the supplemental testosterone gave him a sperm profile of 3% normal, 81% immotile, and 6 times lower functional sperm counts per ejaculation than he has currently.

These metrics indicate infertility:

clearblue.com/how-to-get-pre…

Shifting from a 25% caloric deficit to a 10% caloric deficit allowed him to stop the testosterone patches, and his sperm profile improved to 11% normal, 38% immotile, and 6 times greater numbers of functional sperm per ejaculation.

His current profile is average for a healthy, fertile male:

onlinelibrary.wiley.com/doi/10.1111/an…

Johnson says his thyroid markers (TSH, T4, T3) are healthy, but that his body temperature lowered four degrees to 94.9F on his protocol:

https://twitter.com/bryan_johnson/status/1730233810602660345

But calorie restriction raises free fatty acids:

pubmed.ncbi.nlm.nih.gov/14207771/

Free fatty acids reduce thyroid hormone transport into cells and binding to the hormone’s nuclear receptor:

pubmed.ncbi.nlm.nih.gov/11355745/

Johnson does not list free fatty acids (nonesterified fatty acids, FFA or NEFA) in his measurements:

protocol.bryanjohnson.com/#routine-measu…

Thus, the calorie restriction appears to have decreased his sensitivity to thyroid hormone, put him in a hypothyroid state despite normal levels of the hormones, lowered his body temperature proportionally...

...and contributed to — in combination with negative feedback from exogenous testosterone — the reversible cessation of his fertility.

So, we can conclude from his experiments — and I think he would agree — that we don’t need to endure a 25% caloric deficit to lengthen our lifespan and healthspan. Indeed, it is at least harmful to aspects of healthspan.

The question that remains is whether his 10% caloric deficit is an important contributing to his anti-aging results.

While many papers claim that caloric restriction consistently lengthens life across species, this is biased by using strains of each species that benefit from the restriction, and mouse data suggest the response is genetically determined and extremely inconsistent.

In an analysis of 41 strains of mice, some strains had their life lengthened by calorie restriction but more strains had their life shortened by caloric restriction:

ncbi.nlm.nih.gov/pmc/articles/P…

There was no correlation between lifespan under ad libitum (eat as much as they want) and calorically restricted conditions.

This means there are genetic determinants of longevity under ad libitum conditions that are different from the genetic determinants of longevity under calorie restricted conditions...

...and there is currently no way to predict the effect of calorie restriction in anyone without testing it directly.

If we cannot generalize from one mouse to another on this strategy, then we certainly cannot generalize from non-humans to humans or from one human to another.

One thing that is overwhelmingly clear is that energy is needed to invest in both fertility and longevity, but that too much detracts from both.

Energy is needed to regenerate tissues, to keep telomeres long, to repair DNA, to defend against oxidative stress.

But too much energy stored as fat becomes a stress. As adipose mass crowds out the vascularization needed to deliver oxygen and nutrients to fat cells, it elicits an inflammatory stress response that calls on the immune system to remodel the adipose tissue.

This diversion of energy into inflammation comes at the expense of investing energy in fertility and longevity.

See here for references and further discussion of that topic:

chrismasterjohnphd.substack.com/p/026-when-fat…

Both underweight and overweight is associated with mortality, and the association with underweight is not explained by smoking status or preexisting illness:

pubmed.ncbi.nlm.nih.gov/17670912/

When body composition is considered more precisely, fat mass increases mortality and fat-free mass decreases mortality:

pubmed.ncbi.nlm.nih.gov/33437985/

However, the lowest-fat individuals are not the ones who live the longest. The longest-living cohort by fat mass are individuals in the second-lowest quartile.

They have an average fat mass index of 7.3 kilograms (kg) per square meter, an average fat mass of 20.7 kg, and a bodyweight of 72.8 kg, which would seem to indicate a body fat percentage around 28%, although the ratio of two means is not the same as the mean of two ratios.

This pools males and females, so this undoubtedly is reflecting the need for females of higher body fat than males.

But the point is that the evidence does not indicate you need to be insanely low body fat to have a long life. It indicates that you need to have good muscle mass and not have excessive fat mass.

This is probably very simple to determine: if you can get your muscle mass up and fat mass down enough to bring your high-sensitivity C-reactive protein (hs-CRP) maximally suppressed, you have probably done all you need to in optimizing your body composition for longevity.

But why is there such enormous genetic variation in the effect of calorie restriction in mice? This is not explained by the simple need to have a healthy body composition.

There is room for debate, but my contention would be that since energy is needed to invest in longevity, some mice need to maximize their ATP production to maximize their lifespan.

On the other hand, since intake of normal macronutrients generates neurotoxins and cardiotoxins when there are bottlenecks in metabolism from nutrient deficiencies toxins...

...and genetic impairments, some mice benefit more from restricting the sources of these endogenous toxins than they do from maximizing their ATP production.

In “How I Found My Health “Super Unlock” After 20 Years of Research and 20,000 Genes Tested,” I used data from the One Million Exome study looking at the genetics of almost one million people from all over the world to estimate that each person...

...has one to six genetic bottlenecks in their metabolism that could interfere with ATP synthesis or increase toxin accumulation from macronutrients.

Read that article here:

chrismasterjohnphd.substack.com/p/unlocking-pe…

One approach Johnson could use from among the tools he already has in his kit to determine whether he is benefitting from calorie restriction...

...is to go off his caloric deficit for a period of time and see how the 25% caloric deficit, the 10% caloric deficit, and a 0% caloric deficit affect before-and-after measurements of the epigenetic age clocks he uses.

Johnson primarily uses DunedinPACE now, which is not based merely on cross-sectional data, but is actually based on serial measurements over time and longitudinal correlations with greater rates of loss of health with aging:

pubmed.ncbi.nlm.nih.gov/35029144/

The clocks were recently criticized by @PeterAttiaMD as being cross-sectional in nature without the ability to assess the effects of interventions:

peterattiamd.com/how-accurate-a…

@PeterAttiaMD TruDiagnostic, which offers a clock including DunedinPACE, argued that this view is outdated, and the fact that calorie restriction slows the clock shows that it is sensitive to interventions:

trudiagnostic.com/blogs/news-for…

@PeterAttiaMD I come down in the middle. As I reviewed above, calorie restriction is not a solid, robust means to a longer life. There is enormous genetic variation in the response to it.

@PeterAttiaMD However, DunedinPACE has enough longitudinal data behind it that I think it is very interesting to use as a possible indicator of the effect of an intervention.

@PeterAttiaMD I just got my first TruDiagnostic sample drawn yesterday so that I can enter Johnson’s “Rejuvenation Olympics” here:

rejuvenationolympics.com

@PeterAttiaMD However, I believe what Johnson is missing on this is measures of energetic bottlenecks.

@PeterAttiaMD The inclusion of respiratory chain function, amino acids, organic acids, acylcarnitines, and acylglycines in his program — all of which are missing from his description of his routine markers —

@PeterAttiaMD would help determine whether his primary energetic bottlenecks are more related to producing sufficient energy or to accumulation of metabolic toxins.

@PeterAttiaMD This is not just relevant to assessing whether restriction of energy intake is helping or hurting, but also to optimizing the flow of energy down the path of least resistance.

@PeterAttiaMD It is hard to tell from Johnson’s data whether his energy metabolism is optimized in this way. In principle, optimizing energy metabolism should lead to broad-spectrum investment of energy in the regeneration of all tissues across the board.

@PeterAttiaMD Johnson engages in numerous tissue-specific anti-aging strategies that could mask whether his energy metabolism is systemically optimized, as well as certain strategies that could “hack” the biological clocks in a way that further takes clarity away from this.

@PeterAttiaMD For example, he uses the Jinfiniti intracellular NAD test, and uses nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) to bring those levels up. This supplementation alone can lower the rate of aging on biological clocks:

pubmed.ncbi.nlm.nih.gov/37994989/

@PeterAttiaMD Is that creating systemic cross-tissue slowing of the rate of aging?

@PeterAttiaMD NAD+ is likely improving DNA repair by improving the use of PARP enzymes to use it as a label in the DNA repair process. This is probably having a systemic effect. However, it is not getting to the root cause of the DNA damage, which is oxidative stress.

@PeterAttiaMD I’ve written more about the limitations of the Jinfiniti test here:

chrismasterjohnphd.substack.com/p/why-you-shou…

@PeterAttiaMD I’ve covered the antioxidant defense system in detail in this course:

chrismasterjohnphd.substack.com/p/the-antioxid…

@PeterAttiaMD The antioxidant system runs on the fuel of energy metabolism, so any individual bottlenecks in energy metabolism will impair it.

@PeterAttiaMD Thus, is Johnsons’ low rate of aging on the biological clock a sign that his energy is optimally invested in longevity, or is he simply compensating for the lack of this optimization by replacing NAD as it gets depleted with supplements?

@PeterAttiaMD I am not arguing that replacing the NAD is not beneficial. Rather, I am arguing that it doesn’t necessarily solve the primary bottlenecks in energy metabolism that lie under the hood and are driving the increased accumulation of DNA damage with age.

@PeterAttiaMD The reason this is important is because energy has to be invested in a lot of other things! These include maintain excellent skin and hair, regenerating tissues, optimizing immune function, keeping blood vessels healthy, and preventing tissue from becoming cancerous.

@PeterAttiaMD Johnson uses a custom hair formulation that includes caffeine, finasteride, minoxidil, azelaic acid, diclofenac, tea tree oil, rosemary oil, ginkgo biloba, biotin, and melatonin.

@PeterAttiaMD He has said by his genetics he should be bald already, and that he is unsatisfied with the effect size of this formulation.

@PeterAttiaMD However, he has gotten his baldness index down to age 26 and his gray/white index down to age 41, both of which are younger than his chronological age of 46.

@PeterAttiaMD While his genetics may predispose him to problems with his hair, this really is biasing the effect of poor energy metabolism into the hair.

@PeterAttiaMD For example, minoxidil acts by mimicking the effects of ATP to open up channels that improve delivery of nutrients into the hair follicle. Optimizing ATP production would be a way to improve the hair while also improving everything else in the body.

@PeterAttiaMD He uses tretinoin on his skin, which mimics the effect of the NAD+-dependent activation of vitamin A to retinoic acid.

@PeterAttiaMD Johnson uses the Jinfiniti intracellular NAD+ test, but the activation of vitamin A to retinoic acid requires a high ratio of NAD+ to NADH.

@PeterAttiaMD The best way to make an inference about this ratio is to look at the ratio of lactate to pyruvate and the ratio of beta-hydroxybutyrate to acetoacetate, but Johnson doesn’t include these markers.

@PeterAttiaMD If one of the limitations to his energy metabolism is in the mitochondrial respiratory chain, this could lead to a failure to activate vitamin A.

@PeterAttiaMD The intracellular NAD+ and the blood levels of vitamin A — both of which he measures — would not capture this, so he would not be able to see why his skin health is dependent on tretinoin.

@PeterAttiaMD He uses the iTear100 to stimulate the nerves to increase tear production, filled his gum pockets with a mixture of platelet-rich plasma, platelet-rich fibrin, and bone...

@PeterAttiaMD ...and the “Project Babyface” he initiated in March of 2023 is not clearly described but seems to have been the injection of fat into his face to make up for what was lost in caloric restriction.

@PeterAttiaMD Johnson’s tissues are not universally young in age based on his measurements. His brain measurements are very close to his chronological age, raging from 37-48.

@PeterAttiaMD His VO2 max is very young (18), his HRV (40) and RHR (37) are younger than chronological, but he has size and volume measurements in his heart ranging 52-70+. Four skin measurements are teenage, two are 31 and 41, but three are 50-70.

@PeterAttiaMD His eye pressure is age 38, but his choroidal thickness is age 51 on the left and age 70 on the right, and his eyelash length, which he says is genetically short, is age 70+.

@PeterAttiaMD His ear function is generally higher than his age: pinna is 30 and left ear extended high frequency (EHF) is 32, but right ear EHF is 60, left ear normal frequency is 51, and right ear normal frequency is 61.

@PeterAttiaMD None of these detract from major achievements he has made in getting some of these numbers down, and in getting incredibly fit.

@PeterAttiaMD However, this gives me the impression that his energy metabolism is not fully optimized to flow into broad cross-tissue investment in longevity...

@PeterAttiaMD ...but rather his physical training program gives him a great VO2 max, his topical treatments give him much-better-than-his-genetics hair and skin, and his NAD+ precursor supplementation improves his rate of DNA repair.

@PeterAttiaMD With all that said, I definitely think his diet and supplements, in combination, are leading to good status of many nutrients, and this will offer protection against all sorts of damage that occur with age.

@PeterAttiaMD Still, he is missing important markers.

His routine markers include blood concentrations of nutrients. However, he does not include amino acids, organic acids, or enzyme activities that can be used as functional markers of nutrient status.

You can have optimal concentrations of riboflavin in your blood, but you can have elevated glutaric acid that goes down with riboflavin supplementation due to an increased genetic need. He tests the riboflavin, but not the glutaric acid.

You can have optimal concentrations of thiamin in your blood, but you can have low activity of thiamin-dependent enzymes due to a genetically increased need for thiamin that raises alanine, glutamate, and lactate. Johnson tests the thiamin, but not the amino acids or lactate.

In his monthly notes, he describes lowering his calcium alpha-ketoglutarate supplementation from 4 grams to 2 grams due to a possible contribution to a slight increase in his resting heart rate.

He was using this supplement, which should reflect a decrease from 2.9 to 1.45 grams of total alpha-ketoglutarate:

vitality-pro.com/product/caakg-…

This could easily be explained by the alpha-ketoglutarate failing to be cleared by the thiamin-dependent enzyme alpha-ketoglutarate dehydrogenase ...

...and potentially backing up the B6-dependent clearance of glutamate to alpha-ketoglutarate, or even reversing that reaction to generate glutamate.

Elevated glutamate levels could lead to increased neurostimulation, leading to increased resting heart rate. These could have been detected using a plasma amino acid analysis.

There are many other examples. Each nutrient has functional markers that tell you wether the nutrient is doing its job:

the tryptophan metabolites xanthurenate, quinolinate, and kynurenate for B6, the leucine metabolite beta-hydroxyisovalerate for biotin, methylmalonic acid for B12, and so on.

Johnson is right to measure nutrient concentrations in his blood but should also measure functional markers to see whether those nutrients are doing their jobs.

There are some areas where I think his team’s interpretation of his measurements are probably holding back his health.

For example, he uses urea as a marker of longevity, which almost certainly reflects the contribution of poor kidney health to mortality, but then lowers his urea by restricting his protein.

I’m sure his kidneys are healthy but this is “hacking” the urea measurement with a tool that does not reflect longevity.

In May of 2023, his plasma selenium came in at 416, he considered slightly high using the reference range of 100-340 mcg/L. He adjusted his Brazil nut intake down as a result.

However, the sweet spot for plasma selenium is around 120, which is optimal for cancer protection, and higher levels are clearly associated with an increased risk of diabetes and possibly associated with an increased risk of cancer.

Thus these levels are not slightly high, but dangerously high.

References on selenium:



pubmed.ncbi.nlm.nih.gov/11568452/
pubmed.ncbi.nlm.nih.gov/17620655/

Johnson has described aspects of his genetics in podcasts but has not released any kind of comprehensive review of their contribution to his protocol.

I believe he would benefit by ranking and sorting them according to the few that have the highest impact.

In my experience analyzing dozens of whole genome samples, everyone has heavily skewed mutations with fewer than 10 and often as few as 1 being orders of magnitude more severe than the rest.

These could be contributors to increased nutrient needs that would raise functional markers of deficiency without altering blood levels of the nutrients.

These could be creating idiosyncratic bottlenecks with huge returns on investment to address that impact whether caloric restriction is hurting or harming his anti-aging protocol and how he can best optimize energy to flow down the path of resistance.

What he is missing, then, is three things: ranked and sorted genetics, functional markers of nutrient status, and screening for bottlenecks in energy metabolism.

Johnson wants to bring longevity to the masses, to raise the healthspan and lifespan of the whole human race.

I support that goal, and I believe that idiosyncrasies that make us each unique are universal.

While there are aspects of Johnson’s protocol that will always be unique to him, deriving an approach to help each person figure out their own unique bottlenecks is something that can benefit everyone.

The most impactful things Johnson is doing that we can all copy without signing our money and life away are eating a highly nutritious diet, maintaining a health body composition, and systematically testing nutrient status.

The three things missing from this recipe that we should all embrace are including ranked and sorted genetics, functional markers of nutrient status, and comprehensive screening for impairments in energy metabolism.

The thing I think we can all dispense with is the extreme 25% caloric deficit. Most of us should go without even a 10% caloric deficit, and we probably don’t need to be as extreme as he is about the regimented diet schedule or the extremely lean body composition.

I have resources on nutrient testing in the “lab tests” section of my web site:

chrismasterjohnphd.substack.com/p/lab-tests

I hope this analysis advances the longevity conversation forward, I welcome any feedback from Johnson, and I hope this proves useful to Johnson and to anyone searching for the 80/20 of longevity.