Longevity and Healthy Aging: Two Competing Visions (Part 4 of 5)

Bio-Hacking with supplements, off-label prescription drugs, and technology. The trans-human forever young you. Or not.

Bio-Hacking You

Previously, in the first three posts of this series on Longevity and Healthy Aging, we covered the major topics of Healthspan, Exercise, and Metabolic Health and Diet as discussed by our four medical doctors, Sullivan (2016), Luks (2022), Hyman (2023), and Attia (2023), and as confirmed or challenged by other qualified experts and peer-reviewed sources.

Despite salient differences when it comes to their visions of Longevity, so far we have found vast areas of agreement among our four medical doctors on Healthspan, Exercise, and even Metabolic Health and Diet. This changes considerably when it comes to our next area of concern: Bio-Hacking with supplements, off-label prescription drugs, and technology. We lose common ground. We rediscover (at least) two competing visions of Longevity, and hence also on how to extend Healthspan. Our previous consensus on healthy aging has evaporated.

The Longevity Promise Spectrum

On one end of the spectrum, the goal is better years — but not really more. You have a certain natural Lifespan even under ideal conditions, and you want to extend your Healthspan towards the very end of your Lifespan. On the other end of the spectrum, aging itself is a disease in the process of being overcome and so human life expectancy itself can be significantly expanded — the new limitations yet unknown.

We quoted earlier the declaration by Hyman (2023): “I plan to live to be 120, maybe even 180, in good health, savoring the miraculous gift of this life every day.” He holds that living to “150 or 200” is “not beyond current scientific possibility” and things are only improving. In this, Hyman (2023) is strongly influenced by and largely follows David Sinclair, PhD, Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for Biology of Aging Research at Harvard Medical School.

The Pied Piper of Immortality

American Exile has chosen not to directly review Professor Sinclair’s Lifespan: Why We Age — and Why We Don't Have To (2019) in this series of articles because (in our opinion):

• He has received far too much attention already — although he has thus far delivered comparatively little in practical terms for human longevity.

• His major popular statements seem a wonderous mix of promise, potential, extrapolated lab results from mice, counterfactuals and carefully crafted legalese so no actual commitment is made even though the majority of his public readers and listeners seem convinced that Sinclair has the Grim Reaper on the ropes and heading for the canvas.

In other words, Professor David Sinclair, PhD, is both a world-class researcher and a smooth operator. He has no shortage of admirers and no shortage of funding. He also has some high-level detractors. Charles Brenner, PhD, Alfred E. Mann Family Foundation Chair in Diabetes and Cancer Metabolism at the City of Hope National Medical Center, publishes research in largely the same areas as Sinclair and takes exception to several of Sinclair’s claims. Brenner’s (2022: 10.1016/j.archger.2022.104825) “A Science-Based Review of the World’s Best-Selling Book on Aging” should be required reading for any discussion of Sinclair’s claims.

Of Mice and Men

In contrast to the academic researcher Sinclair, PhD, all the practicing or formerly practicing medical doctors cited in this post — Sullivan, Luks, Hyman, Attia, and Palmer — have successful real-world results with formerly unhealthy people. They have case studies of and testimonials from former patients. Likewise, the majority of research studies they cite are of humans, not rodents. Sinclair is the Pied Piper leading cohorts of lab mice to significantly extended lifespans — all good. But your author advises caution before you sell everything to follow Sinclair on the road to immortality.  Nonetheless, we must discuss some of his work in this section as he has influenced Hyman (2023) and Attia (2023) among many others.

The Bio-Hacking Spectrum

We can also view the Bio-Hacking spectrum as a continuum of minimalist to maximalist — and this largely tracks our first distinction of better years vs. better years & (potentially) MANY more years.

Three Levels of Supplement Usage

We can start with how our experts seem to understand and employ supplements. Using the minimalist to maximalist spectrum, we have three overlapping levels —areas of our spectrum that blend into each other:

1. Supplements for general nutritional purposes — and particularly, for correcting diet deficits. For example, a multi-vitamin or a B-complex vitamin or Omega 3 fish oil.

2. Supplements for enhanced performance or enhanced healing, designed to support the increased metabolic and perhaps anabolic demands of a stressed body. The stress might be transient and beneficial — such as exercise-induced stress. Or, the stress might result from a chronic condition being treated. For example, creatine monohydrate for strength training, and Coenzyme Q10  for someone on statins or who has symptoms of congestive heart failure.

3. Supplements intended to help up-regulate or down-regulate specific metabolic pathways processes in order to change the default (and often, normatively “healthy”) state of homeostasis. Two targeted outcomes are increased autophagy (the body cleaning out damaged cells) and increased mitophagy to result in new and healthier mitochondria (mitochondrial biosynthesis). For these purposes, the supplements seem invariably at some point combined with off-label usage of prescription medications. Please see, for example,  the supplement list(s) cited shortly below as used by Hyman (2023) in his breakfast smoothie and his “advanced longevity stack.” Or, the similar list provided by the highly informed and obviously healthy bio-hacker behind “My NHM Experiment.”

These three levels as stated do overlap and readily blur into one another, but nonetheless this mapping of the spectrum has some use.

Third Level Transhumanism

The third level treats aging itself as a disease. Hence it is NOT good enough to be a normatively healthy 60-year-old, for example. You must hack your metabolism (and more) to reverse aging — you must achieve a new and improved state of homeostasis, one typically not available through diet, exercise, and healthy living. You are reversing biological time across your body (or so intend to) — and this cannot be accomplished by purely natural means.

Hence supplement usage level three, maximalist Bio-Hacking, participates in Transhumanism. Supplement usage level one, minimalist Bio-Hacking, does not; and supplement usage level two, particularly when it concerns enhanced performance, bridges the divide.

Our Experts Across the Bio-Hacking Spectrum

Luks (2022) and Hyman (2023) provide excellent examples of the minimalist and maximalist approaches to supplement usage; Sullivan (2016) and Attia (2023), largely likewise occupy the minimalist and maximalist parts of the spectrum, respectively, but we will save that comparison for our discussion of technology.

Minimalist Luks

You will not find health and weight loss in a supplement bottle,” Luks (2022) declares, so “save your money.” Luks (2022) is not against supplements per se — he is against “magic bullets” and “magical supplements.” “We are all too easily fooled,” Luks (2022) holds, into “trying highly restrictive and unsustainable diets, or experimenting with supplements and unproven medications to improve our strength and lifespan without results or evidence of efficacy.”

In contrast, Luks (2022) argues that we know what works and we can start doing all that right now:

Some of the significant factors critical to maintaining a long healthspan are a combination of lifestyle, sleep, diet, and movement [exercise] and avoiding toxic habits like smoking. Many non-physical factors are also important, such as stress management, optimism, laughing, being socially connected, and feeling a sense of purpose and community.

Supplement usage for Luks (2022) should be based primary upon your biomarkers as determined by a comprehensive blood panel, and any existing conditions you might have:

Make sure you know your biomarkers. If something is off, ask what you can do to correct it. For example, your cardiologist might recommend vitamin B or folate supplements if you have high homocysteine. ... See an expert, assess your risk, and define a prevention strategy that works for you. Creatine may have a role in improving our brain’s energy systems.

In addition to recognizing the potential value of creatine, a supplement that other medical experts swear by, Luks (2022) also thinks “supplements such as flavanols (cocoa), fish oil, extra virgin olive oil (EVOO) plus the Mediterranean diet” have demonstrated some promising results with improving “memory, cognition, and muscular performance.”

But proper nutrition first, supplements second when indicated by your biomarkers or advised by a qualified health professional. Go slow with Bio-Hacking yourself. Start with a healthier diet, regular movement, exercise, and staying socially connected.

Luks (2022) does believe the research on longevity is promising — but the proven efficacy is not there yet:

Over the next decade, researchers will have supplements or medications and targeted therapeutics that will improve our healthspan meaningfully.

Maximalist Hyman — the Future is Now

For Hyman (2023), that next decade is now. We turn next to the ingredient list —including optional ingredients — for [capitals his] “DR. HYMAN’S HEALTHY AGING SHAKE” which “provides support for muscle synthesis, mitochondrial health and repair, microbiome support, detoxification support, and hormone and adrenal support” as well as healthy aging.

• 30 grams (2 scoops) goat whey from organic or regeneratively raised goats; or, Vegan alternative, 42 grams (2 scoops) Garden of Life Sport Organic Plant-Based Protein

• 1 packet Mitopure by Timeline

• 5 grams (1 scoop) creatine by Thorne

• 9 grams (1 scoop) Gut Food by Farmacy

• 1 tablespoon MCT oil or Brain Octane oil

• 1 teaspoon Stamets 7 Mushroom Powder

• 8 to 12 ounces unsweetened macadamia milk or other nut or seed milk without emulsifiers or sweeteners — Elmhurst recommended

• 1 handful frozen berries

To which you should freely add:

• 1 scoop or packet Athletic Greens

• 1 tablespoon each Organic Pomegranate and Cranberry Concentrate

• 1 teaspoon matcha powder by Navitas

Hyman (2023) intends his “HEALTHY AGING SHAKE” as either a breakfast alternative  or for post-workout recovery. To understand how practical this might prove or not for many people, let’s just consider the set-up costs using Hyman’s recommended brands. Also, please note that we cannot purchase just one tablespoon of this or one teaspoon of that. Your author will also choose the one-time purchase price, and the not the generally discounted subscription price when available, on the basis that a newcomer would likely try this first before committing to it.

Wise Investment or Budget Buster?

Here goes! Naked Goat protein powder at $70 for 30 servings (60 scoops) or $2.33 a serving; or, the Vegan Garden of Life protein powder at $41 for 19 servings or $2.16 a serving. Timeline Mitopure Powder at $125 for a one-month supply (30 servings) or $4.17 a serving. Throne Creatine at $40 for 90 servings or $0.44 a serving. Gut Food by Farmacy at $99 for 30 servings or $3.63 per serving. Brain Octane Oil at $44 for 63 tablespoon servings or $0.70 a serving. Stamets 7 Mushroom Powder at $23 for 33 teaspoons servings or $0.70 a serving. Elmhurst unsweetened nut milk around $7.34 per single quart (32 ounce) bottle with four 8-counce servings at $1.84 per serving. Frozen organic berries at roughly $7 per 32-ounce pack of 6 servings or $1.16 per serving.

We have not gotten to optional ingredients yet, but let’s do a total. Your set-up costs for the non-Vegan shake: roughly $415. Some of your items contain more than a month’s supply, some less. Your cost per shake (the per serving cost for all your items): roughly, $14.97. Your savings on the Vegan version, insignificant.

A solution for whom?

Who is this for? A single mother and wage-earner trying raise her two children? A senior citizen who must work at an Amazon Warehouse or a Wal-Mart to make ends meet? As Victor Davis Hanson (2021) has reminded us:

Fifty-eight percent of Americans have less than $1,000 in the bank. A missed paycheck renders them destitute, completely unable to service sizable debt. Most of what they buy, from cars to electronic appurtenances, they charge on credit cards.

Yet many of these Americans — the above 58% — are the ones suffering from, or at risk at of suffering from, largely preventable chronic diseases. Likewise, many of these American are on the SAD (Standard American Diet). They need to improve their health and extend their Healthspans. Chronic illness can be financially devasting to these Americans on the individual level, and chronic illness also imposes a horrific public health burden. Back to our breakfast shake as a solution — or not.

Finish the HEALTHY AGING SHAKE!

Let’s add in the optional ingredients — for which Hyman (2023) instructs “include as many as you can.” Athletic Greens (AG1) at $99 for a 30-day supply or $3.30 per serving; Lakewood Organic Pomegranate Concentrate at $16.67 per single bottle of 12.5 ounces or roughly 32 tablespoons at $0.52 per serving; Lakewood Organic Cranberry Concentrate at $13.90 per single bottle of 12.5 ounces or roughly 32 tablespoons at $0.43 per serving; and Matcha powder by Navitas at $21 for 85 grams or roughly 42 teaspoons at $0.50 per serving. Our set-up costs have risen by over $150 to about $566; our cost per shake is now around $19.72.

With the optional ingredients, consuming one “DR. HYMAN’S HEALTHY AGING SHAKE” per day would cost about $7200 a year. Minimum wage differs per US state, but the 2023 Federal minimum wage is $7.25 per hour or $58 for an 8-hour day and so roughly $15,080 per year.

Obviously, Hyman (2023) is targeting a higher end clientele — and likely people who are well-educated, who already eat and well and exercise, who do regular doctor visits, and more. We would have great difficulty separating out the benefits from his shake versus those from those of the healthy user effect and of the placebo effect. But for Americans conditioned to poly-pharmacy, poly-supplementation feels natural.

Wait, there’s more — much more!

That’s just “DR. HYMAN’S HEALTHY AGING SHAKE” — your daily breakfast and/or workout recovery shake. Hyman (2023) also shares with us the “advanced longevity stack I recommend daily.”

The advanced daily longevity stack

Are you ready for this? Not just any daily longevity stack, but the “advanced longevity stack” (Hyman, 2023):

NMN or NR, 1,000 mg a day; Fisetin, 500 to 1,000 mg a day; Quercetin and other flavonols; Pterostilbene, 100 mg once or twice a day; Curcumin, 500 to 1,000 mg a day; Epigallocatechin gallate (EGCG), 500 to 1,000 mg a day; Glucoraphanin; Urolithin A (but covered in Mitopure if you do the shake); Branched-chain amino acids; Creatine, 5 to 10 grams daily (but also covered if you do the shake).

But wait. If you want to go ALL-IN, do add (Hyman, 2023):

RegenerLife by Natural Factors, 1 scoop or 4 capsules a day; Acetyl-L-carnitine, 500 to 1,000 mg a day; N-acetylcysteine, 600 mg twice a day; PQQ, a derivative of coenzyme Q10, 100 to 200 mg a day; and Alpha-lipoic acid, 300 to 600 mg a day.

When you combine all of this, it seems near-impossible to determine which supplement is doing exactly what and how, and what the possible interaction effects are between all the supplements. Because these generally get treated by body as food sources, however, the risk is reduced. Oh, and how much would the “advanced longevity stack” set you back? Well, if you have the ask the price, peasant …

Poly-supplementation as a replacement for poly-pharmacy?

American Exile has already covered the failure of poly-pharmacy: yes, poly-pharmacy has failed in delivering better health outcomes. It may for many people add a few marginal (sickly, diseased, dysfunctional) years to Lifespan: it does NOT improve Healthspan. Furthermore, a nationwide cohort study by Chang, et alia (2020: 10.1038/s41598-020-75888-8) found that poly-pharmacy was “associated with a higher risk of hospitalization and all-cause death among elderly individuals.” So we are not even sure that poly-pharmacy helps extend Lifespan. Over the next decade, American Exile might yet be covering the failure of poly-supplementation. Or not. We will report what the data reveals.

Bio-Hacking with Off-label Usage of Prescription Drugs

We stated earlier that Luks (2022) and Hyman (2023) provide excellent examples of the minimalist and maximalist approaches to supplement usage. To cite one more Luks-ism supporting the minimalist position: “It doesn’t matter what supplement you take if you remain insulin resistant and at risk for type 2 diabetes.”

But we also noted that Bio-Hacking with supplements at the third level, the maximalist level as exemplified by Hyman (2023) and many others, at some point typically gets combined with off-label usage of prescription medications. In other words, the maximalist approach to longevity combines both poly-pharmacy and poly-supplementation. What could go wrong?

Brenner (2022: 10.1016/j.archger.2022.104825) asserts that Sinclair “has popularized a stack of drugs and supplements with significant potential to harm the general public,” and astutely reminds us that “polypharmacy is associated with greater mortality when controlled for comorbidity and age.” So that could go wrong: greater mortality risk or a shorter and sicker life.

We will go down that rabbit-hole soon enough, and meet David Sinclair (as well as rejoin Hyman and Attia) in this new wonderland. But let’s take a step back for a moment.

Deep Breath Before the Plunge

For too many Americans, what Hyman (2023) proposes in terms of supplement usage is NOT a viable option: neither affordable nor practical. But even if only 1/5 of the American public could implement Hyman’s proposed routine in whole or part, that is still over 67 million people. Not a bad start, assuming Hyman (2023) is on to something that justifies the hassle and expense.

Likewise, for the daily cost of “DR. HYMAN’S HEALTHY AGING SHAKE” alone, some people manage to daily feed small families. But for some Americans, $20 or so is not unreasonable for a meal or for a daily indulgence. Your author has spent far too much time (in his opinion) in conversation with people who consider themselves aficionados of small-batch bourbon, or of fine cigars, or of cannabis, or of cheesecake, et cetera. Is it better to go to a high-end bar and have two shots of fancy liquor, or to save your money for a home-made longevity smoothie?  Smoothie, please.

Your author respects the bio-hacker behind “My NHM Experiment.” This person obviously does regularly exercise and seems to have his general health well in order. Your author has also explored the content provided by many other bio-hackers using supplements for improved Healthspan and potentially extended Lifespan. These people have taken responsibility for and taken charge of their health. Almost invariably, they are doing all the right things which Luks (2022) would recommend —but they are also adding complicated and expensive supplement stacks into the mix. Well, their money and their bodies, so their decision.

American Exile is NOT anti-supplements

Let’s take one more step back before we go down further into the third level rabbit hole where poly-supplementation meets poly-pharmacy. The quality of your supplement depends on the manufacturer and the supply chain. Consumer Lab provides independent testing and reviews, and regularly flags poor quality products or contaminated products — even those from big-name manufacturers. Even if you are taking a supplement of proven value, please do a careful background check on your supplement source.

American Exile is NOT against supplement. On a daily basis, your author uses creatine, fish oil, a high-quality multi-vitamin, and glucosamine plus chondroitin. Depending on bio-markers and other factors, your author has also cycled in zinc, or/and magnesium, or/and extra B-vitamins. But the more complex a supplement routine becomes, the more expensive and more problems with compliance.

But why so many?

Two of the most desired outcomes from longevity supplement stacks are autophagy and mitochondrial health and repair. The question is not only “what else” but “what PRIMARILY” helps your body with both autophagy and mitochondrial health and repair? EXERCISE. Second only to or perhaps co-equal with exercise, good general nutrition: DIET. We know exercise and healthy nutrition work: we do not know how well the various longevity stacks work, but at best their contributions are minor compared to those from regular exercise and a healthy, low-glycemic diet. In other words, get your metabolic house in order before you start spending a small fortune on supplements — otherwise, your longevity stacks will likely largely be going to waste and possibly “waist” as well. Health comes first; optimization for performance, second. If what you are doing is contra-indicative to health, who needs longevity?

But again, your money and your body. So your informed decision. Still in your author’s opinion a better enthusiasm than whiskey or cigars, et cetera. But in regard to maximalist bio-hacking with supplements, American Exile agrees with Luks (2022) that we just do not know enough yet and will likely have much more clarity within a decade from now. But let’s cut Hyman (2023) a break. He states unequivocally:

Bottom line: The most important thing you can do for healthy aging is to balance your blood sugar and keep your insulin levels low and your cells insulin-sensitive, which means eating a low-sugar, low-starch diet with plenty of good-quality fats and protein, and a boatload of phytochemical- and fiber-rich fruits and vegetables.

So there it is. Eat clean. Get moving. Build strength. The foundation for any supplement usage.

In the Wonderland of Poly-Supplementation/Poly-Pharmacy

Time for the plunge: deep into third level rabbit hole where poly-supplementation meets poly-pharmacy.  

Sinclair (2019) posits the “Information Theory of Aging.” Our DNA is constantly under attack from “epigenomic noise,” and as a result, cells “lose their identity and malfunction” and the chaos which then ensues “materializes as aging”:

It’s why our hair grays. It’s why our skin wrinkles. It’s why our joints begin to ache. Moreover, it’s why each one of the hallmarks of aging occurs, from stem cell exhaustion and cellular senescence to mitochondrial dysfunction and rapid telomere shortening.

For Sinclair (2019), “aging and the diseases that come with it are the result of multiple ‘hallmarks’ of aging”:

1. Genomic instability caused by DNA damage

2. Attrition of the protective chromosomal endcaps, the telomeres

3. Alterations to the epigenome that controls which genes are turned on and off

4. Loss of healthy protein maintenance, known as proteostasis

5. Deregulated nutrient sensing caused by metabolic changes

6. Mitochondrial dysfunction

7. Accumulation of senescent zombielike cells that inflame healthy cells

8. Exhaustion of stem cells

9. Altered intercellular communication and the production of inflammatory molecules

The big promise (Sinclair, 2019): “Address one of these [hallmarks of aging], and you can slow down aging. Address all of them, and you might not age.” Forever Young, as Hyman (2023) titled his own book.

Addressing the Hallmarks of Aging

How do we address the hallmarks of aging? In part, it seems according to both Sinclair (2019) and Hyman (2023), we must hack the insulin signaling pathway, and the mTOR and AMPK metabolic pathways, to start. For this, we might make off-label usage of the prescription drugs rapamycin (Sinclair, Attia, and Hyman) and metformin (Sinclair and Attia) for now — until better drugs are developed.

Encouraging Autophagy, Repressing the mTOR pathway

Down-regulating the mTOR pathway can promote and provoke autophagy — essentially, the cleaning out of and recycling of old cells. But we do not want mTOR down-regulated or silenced for too long — because we need it up-regulated or activated for protein synthesis, building muscle, building tissue, etc.

Hence biohackers will cycle low-doses of the drug rapamycin, which down-regulates mTOR, to induce autophagy and cell clean-up. This is an off-label usage of rapamycin. Attia (2023) both engages in the practice described above, cycling rapamycin, and apparently offers the same medication on a controlled schedule for interested and select patients/clients.

Overcoming Insulin Resistance, Activating the AMPK pathway

Up-regulating or activating the AMPK pathway — as Hyman (2023) describes it — “improves your cells’ ability to produce energy, reverses insulin resistance and improves blood sugar control, enhances stress resistance, and improves your cells’ housekeeping functions.” The well-known diabetes drug metformin works in part by activating the AMPK pathway. Attia (2023) discusses the possible longevity benefits in some detail. Sinclair (2019) in much greater detail.

As a result, many bio-hackers are experimenting with off-label usage of metformin as a longevity drug. Hyman (2023) so far does NOT do so. He uses diet and nutritional timing instead to up-regulate the AMPK pathway. The sense of timing is important.

We do not want the AMPK pathway always turned on either. It inhibits anabolic pathways needed for the building of cells, tissues, and organs. Given that at some point your cells must reproduce for your life to continue, anabolism leading to biosynthesis and growth is also vital.

Any Noteworthy Objections to Bio-Hacking Off-Label?

So does a bio-hacker know better than their own body as to whether or not they should be a catabolic or anabolic state? There’s more. Remember Chris Palmer, MD? That one — the practicing and board-certified Psychiatrist, Director of the Department of Postgraduate and Continuing Education at McLean Hospital, and Assistant Professor of Psychiatry at Harvard Medical School.

In reviewing the literature, Palmer finds (2022) that taking metformin might well work AGAINST improving mitochondrial health. To cite just one example (2018: 10.1111/acel.12880), Palmer notes:

improvements in muscle mitochondrial function were abrogated in the people taking metformin. The metformin group had no overall change in whole-body insulin sensitivity, even though the placebo group experienced improvement. These researchers summarized their findings in the title of their study: “Metformin Inhibits Mitochondrial Adaptations to Aerobic Exercise Training in Older Adults.”

Palmer (2022) is concerned enough that he declares:

So, in all the studies looking at the effects of exercise for weight loss, diabetes, or mental disorders, we would need to know if any of those participants were taking metformin. If they were, they were likely being set up for failure to improve their mitochondrial function, and this might be the reason some of the studies showed no benefit.

If you have poor mitochondrial health, you have poor metabolic health — to start. Palmer (2022) is not the only expert expressing possible concerns about metformin in this regard.

Brenner (2022: 10.1016/j.archger.2022.104825) is also highly unamused by Sinclair’s passion for metformin:

it is no surprise that the book includes Sinclair’s daily regimen, which includes 1 gram of type 2 diabetes drug metformin in addition to aspirin, resveratrol and three vitamins.  … The regimen is potentially damaging for individuals without type 2 diabetes as there is strong evidence that metformin use blunts the beneficial effects of physical activity (Konopka et al., 2019).

And we still have the risks posed by poly-pharmacy whereas we know exercise (physical activity) works and produces benefits across the metabolic landscape (Sullivan, 2016).

Still in Wonderland with mTOR and AMPK

We will stick with discussing the well-studied mTOR and AMPK  pathways: your author will not be wading to the quagmire of claims by Sinclair (2019) and Hyman (2023) that revving up sirtuin activity will improve gene transcription and help reverse the damage done by epigenomic noise. Simply, too many other high-level researchers deem the sirtuin solution as speculative even if promising; and some have far harsher things to say. Nothing approaching a consensus.

Why bio-hack the mTOR and AMPK pathways? To put your body in survival mode so it engages in house-cleaning, recycling, and repair. What else does this?  Hormesis: good stress, the kind that comes from exercise, intermittent fasting, and other activities which challenge but do not overwhelm your metabolism.

For example, your author recently went on a back-packing and hiking trip with some friends from the boxing gym. We did not take a case of beer. We did bring some fresh food and some prepared food to cook for the weekend, and after the first day, we drank boiled water from the mountain streams.

By the end of this trip, which turned into a vigorous but enjoyable challenge, your author was in a catabolic state and 3.3 kilograms lighter as indicated by scale on Monday morning. During this time, your author was neither hungry nor meaningfully dehydrated: he was burning fat and cleaning the crap out his body.

Think of it as “outdoor activity-based intermittent fasting,” a phrase which American Exile should cynically trademark and license. A system reset: autophagy and mitophagy, resulting in improved mitochondrial and metabolic health. The minor loss in muscle mass was easily corrected by your author upping the protein in his diet and returning to the gym on his regular schedule to hit the weights, hard and heavy.

But even more moderate physical challenges — good ol’ exercise — will put your body into repair mode. Get some of that autophagy and mitophagy work done.

The Miracle Diabetic Weight-loss Drug that Fails

Too many people want shortcuts at home, not long hikes in the fresh air outdoors — they want exercise in a pill. If bio-hacking with a drug intended to treat diabetes sounds familiar, welcome to Ozempic — the TikTok-celebrity craze! Does Ozempic (semaglutide) help you lose weight. YES! But does our elite bio-hacker to the elites, Peter Attia, MD, recommend it for his clients/patients?  NO! In fact, HELL NO!

Why not? Well, you don’t want to just lose weight. You want to improve your body composition. You want lose unhealthy fat. You do NOT want to lose lean muscle mass. All our medical doctors, ALL — Sullivan, Luks, Attia, and Hyman— agree that the loss of lean muscle mass, sarcopenia, is bad as in really bad for your Healthspan and Lifespan. You want to retain and even add to your lean muscle mass.

When his clients/patients are out to lose weight, Attia knows that some muscle mass will also be lost. Designing their programs, he strives for a 3 to 1 ratio of fat loss to lean tissue loss. (Otherwise, a rough 2 to 2 ratio seems more typical). But for Ozempic usage, Attia observed that people lose body mass at 1 to 3 ratio of fat to lean tissue.

Since the majority of lean tissue mass is muscle, the Ozempic ratio is just a disaster for older adults. Given the importance of lean muscle mass as we age, this is like spending 10 health dollars to get back maybe 3 health dollars. Losing lean muscle mass sets you up for poor metabolic health, lowers your basal metabolic rate, leaves you weaker and more fragile, and so on: “tik-tok” goes your mortality clock.

Exiting Poly-Supplementation/Poly-Pharmacy Wonderland

Attia knows these things because he makes extensive use of technology and has an entire team: a neurologist, a body movement specialist, and so. Using active glucose monitoring technology, he and his clients can track some changes in their metabolism in real time. Using scheduled Dexa scans, comprehensive blood panels, and more, Attia and his clients/patients can track their progress both in a timely manner and in extreme detail.

If a program redirect or intervention is indicated, team Attia is all over it. If you regularly fly international business class or by private jet, you no doubt expect this level of personal service. If you cannot afford this level of service, you might well be setting yourself up for a world of hurt by bio-hacking your metabolism with off-label prescription drugs. But even with team Attia or the equivalent in your corner, you still run risks because of the poly-pharmacy and unforeseeable down-stream consequences. Your body and your money, your decision. We know that exercise and good nutrition work.

One final note on Attia here: in practice, he is a maximalist bio-hacker. But he does not promise his clients/patients extreme extended longevity or “forever young”— he works to ensure that they have better years. So philosophically, in that sense, he is positioned between Sullivan (2016) and Luks (2022) at one end of the spectrum, and Hyman (2023) and Sinclair (2019) at the other end.

Between the three of them, Sinclair (2019), Attia (2023), and Hyman (2023) have received a great deal of media attention for their writings on longevity. The work of Brenner, a world-class researcher on human metabolism and related matters, is far less known. Hence to be contrarian, American Exile will give the last expert word on this particular topic to Brenner (2022: 10.1016/j.archger.2022.104825):

Today, at least on social media, longevity followers appear to include a significant proportion of young adults, suggesting that anti-aging fad diets, drugs and practices are being adopted in ways that could add many years of exposure to drugs that lack an evidentiary basis for their off-label adoption.

In your author’s opinion, many more years of drug usage is not the solution for people seeking improved health or an extended Healthspan. Your author knows many people who are poly-pharmaceutical — who take multiple prescriptions for chronic conditions. Your author does not know of one single person — not one — who has become healthier from doing so.

Finally, for this subtopic, Sinclair (2019), Attia (2023), and Hyman (2023) go into much greater detail about bio-hacking with supplements and off-label usage of prescription drugs. The discussion above does NOT comprehensively represent their claims or positions. Moreover, your author has an obvious bias towards minimalism in medical treatment.

Bio-Hacking with Technology

The extensive data-tracking and hence safeguards that Attia (2023) wisely builds into his programs brings us to the final subtopic in this discussion of Bio-Hacking: technology. In the one corner, we seem to have the steak and eggs caveman Sullivan, MD, PhD, former emergency room doctor turned PBC (professional barbell coach), and in the opposing corner, the former investment banker and now bleeding edge practitioner to the elites, Attia, MD, celebrity maximalist bio-hacker. Attia did some boxing in his youth and Sullivan is a Krav Maga blackbelt as well as a former USMC officer, so this has all the makings of a good fight — but the contrast is unfair to both our medical doctors.

A cursory reading of Sullivan (2016) might lead one to mistakenly believe that all you need is chalk, a notebook and pen, perhaps lifting straps, and perhaps a good ol’ school weight belt for heavy lifts.

A more careful reading of Sullivan (2016) tells a different story: get your annual check-up. Get a blood panel. Get any additional screenings as indicated. Take your prescribed medications — although you ideally would want to taper down or even off some to all of them, pending tangible progress and the appropriate all-clear. Take charge of your own health but listen to and work with qualified medical professionals rather than with practitioners of the mystic healing arts.

Sullivan as of 2016 — now 7 years ago — had not much use for fitness trackers, let alone real-time glucose monitoring. Although he seems to incorporate Sullivan’s base package, Attia (2023) further offers his clients/patients a high-end sports performance or even a NASA astronaut-like package of health data collection and monitoring. Once again, we have a socio-economic divide in regard to feasibility and affordability.

Good News, Bad News

Good news: the prices are coming down for comprehensive blood panels. More good news: fitness trackers and metabolic trackers are becoming more common and more affordable.

Bad news: if you rely on health insurance, you are likely still shit out of luck (SSOOL) and so paying out of pocket if you can afford it. More bad news: your doctor might be relatively clueless about all this as their Med School curriculum did not spend much time on exercise and nutrition. (Your doctor did learn how to write prescriptions). So even if you have some user-friendly tech, you still might have problems finding support for translating your new-found data into effective actions.

A Middle Ground?

Do we have a middle ground? Sorta, kinda. Your author turns to both Luks (2022) and then your author’s own personal experiences.

“Fitness trackers can change your life — if you let them,” Luks (2022) proclaims based upon his experience as a doctor and a consumer. Although “no single technology is right for everyone,” Luks (2022) has conversed with many people who use fitness trackers and found that “their tracker will cause them to modify their lifestyle to hit certain achievable goals.”

Although the information provided by various and now increasingly affordable trackers always comes with a margin of error, Luks (2022) is optimistic:

The research is becoming clear. The more we move, the longer we live. The more we know about our weight, body fat percent, heart rate, and blood pressure, the better we will be able to help our doctors help us. Any physician will tell you, we have seen many patients able to stop their blood pressure medications, diabetes medications, and more because they put a little effort into their health-related activities, so yes, if the tracker gets you moving, it can truly change your life.

Your author’s experience is generically similar to that of Luks. Family members, friends, and associates with fitness trackers are almost always more active and committed to health and well-being than those without. Moreover, the tracker crowd believes that the trackers help them.

For low-cost technology which provides actionable information for you to improve your health and extend your Healthspan, please know that you can go far indeed with an annual checkup, a comprehensive blood panel (perhaps twice a year), and a fitness tracker. If you do not travel in Attia’s rarified socio-economic strata, consider taking the steak and eggs caveman Sullivan bio-technology package and adding a fitness tracker.

Do the work — the results will follow. If you wish to go upscale, the last third of Hyman (2023) reads like an advertisement for various services and products with which he has some affiliation. Huberman lab provides links to sponsors, et cetera. Your money, your decision.

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Necessary Disclaimer: American Exile does not offer medical advice, and none of our five posts in this series on Longevity should be understood as such.

Sources are cited in text. The six primary books and one key essay discussed above: Sullivan (2016), The Barbell Prescription: Strength Training for Life After 40; Sinclair and LaPlante (2019), Lifespan: The Revolutionary Science of Why We Age – and Why We Don’t Have To; Luks (2022), Longevity…Simplified. Living A Longer, Healthier Life Shouldn’t Be Complicated; Palmer (2022), Brain Energy: A Revolutionary Breakthrough in Understanding Mental Health—and Improving Treatment for Anxiety, Depression, OCD, PTSD, and More; Hyman (2023), Young Forever: The Secrets to Living Your Longest, Healthiest Life; Attia (2023), Outlive: The Science & Art of Longevity; and Brenner (2022), “A Science-Based Review of the World’s Best-Selling Book on Aging.”