Top Health Mitigations
Medical Advancements in Managing the Diseases of Prosperity
My previous health-related column made universal recommendations for optimizing health and longevity. Many people, however, will have difficulty implementing high-effort solutions such as those I discussed. No one, however, should write themselves off to a short life with an early disability. Medicine has significantly advanced in managing the diseases of prosperity. Even very unhealthy lifestyle factors can be successfully mitigated with today’s medicine. I have a loved one in my extended family who has had a diagnosis of congestive heart failure for over a decade. Despite being in her late 70s and a smoker, modern medicine has managed to keep her alive and sharp and able enough to enjoy many extra years of life. It’s truly miraculous what has happened in the management of these diseases.
If you have lifestyle risk factors, the most important thing you can do is take advantage of free preventative care and pursue annual blood testing. Do not avoid the doctor because you don’t want bad news, or because you need to lose weight. Especially if you’re significantly overweight, you’ll want to start tracking your numbers in your 20s. If you are developing diabetes or any other problem, earlier intervention is much preferred to slow the cumulative damage that is done to the body. You do not have to lose weight to benefit, because there are well-tolerated, well-studied medicines that can slow or reverse these conditions with no other lifestyle interventions.
Your doctor will probably focus on a few numbers, and though I have yet to experience any of these risk factors, if I ever do, this is how I would attack them.
Cholesterol & Statins
This is the bugaboo of outdated 1980s medicine that caused an entire generation of people to consume heart-destroying trans fats instead of natural fats like butter and lard. The medical consensus is now much more mixed on what cholesterol indicates. Much of it is genetic, and low cholesterol isn’t necessarily a panacea. People like me, with low cholesterol, might be more subject to depression. Cholesterol is the “mother molecule” to all of the body’s hormones. And there’s not much evidence anything can be done to change it. After decades of telling patients to avoid cholesterol-rich foods like eggs, we now know that consumption of cholesterol has little to do with total levels since much of it is made by the body itself. Attempts to directly lower it, with statins, show no benefit to patients and may cause harm:
Tracking Insulin Resistance with Hemoglobin A1c
If there’s one blood test you’ll want to insist your doctor order, it’s Hemoglobin A1c. This marker is a cumulative tracker of glucose metabolism and is the most reliable indicator of insulin resistance. The result looks something like this:
If you get into the pre-diabetes zone, there are some excellent, cheap drugs that can delay diabetes for years. One of the most amazing is Metformin.
Metformin
Metformin is a cheap, safe, and amazing drug that can often treat diabetes without the need for external insulin. Its mode of action is to reduce blood glucose levels, restoring insulin sensitivity. Metformin is so effective at what it does that many anti-aging researchers and Silicon Valley health optimizers without diabetes take it daily for its health benefits. Normally, diabetics have a huge increased risk of cancer, heart disease, and other bad health outcomes. However, diabetics treated with metformin had overall lower mortality than non-diabetics!
Metformin's effect on blood glucose makes it similar in its effects to fasting, but in the painless form of a pill. Metformin, by increasing insulin sensitivity and lowering blood sugar, can also make traditional dieting more effective and tolerable - more stable blood sugar means less hunger when cutting calories. One study showed huge decreases in BMI in metabolic syndrome patients.
The only caveat with metformin is that it should not be taken by men who are trying to have children. A recent study linked metformin use in men to increased birth defects in their sons.
PDE5 Inhibitors
This class of drugs, the best of which is tadalafil (Cialis), were initially developed to treat high blood pressure. A quickly discovered side effect in the 1990s was that it improved circulation in certain extremities. Pfizer, the patent owner, promptly made a mint. These drugs work by increasing blood levels of nitric oxide, which relaxes and widens the walls of blood vessels. Interestingly, this is also a side effect of sun exposure.
Men taking PDE5 inhibitors, like those with more sun exposure, show a similar decrease in all-cause mortality. This is despite the fact that men who get treated specifically for ED skew less healthy anyway. It seems a reasonable hypothesis that the common cause in both is the increased levels of nitric oxide. PDE5 inhibitors give much of the same benefit, and now with many generics on the market, the cost is very reasonable. These drugs are among the most widely used in human history, so we know their safety profile very well and the risk/reward ratio is very much in the patient’s favor if you have pre-existing risk factors (high blood pressure, overweight, obesity, etc). We’re talking about a 33% reduced chance of dying from a cardiovascular event - rarely seen in medicine.
These drugs could slow aging in a thousand subtle ways. If you have risk factors already, getting more blood flow to distant tissues served only by capillaries (say the skin of the face) can only be a good thing, though I can only recommend taking any prescription drug if there are pre-existing risk factors like high blood pressure, overweight/obesity, or insulin resistance. Doctors give these drugs out like candy to anyone who requests them, men or women, so a little bit of embarrassment is worth it.
Testosterone Optimization
Over the last 30 years, there has been a well-documented decline in testosterone and sperm quality among Western men. Explanations for this vary, ranging from obesity to widespread use of Roundup and insecticides. Regardless, the consequences of lower testosterone are well known: increased death, depression, and anxiety. Low T lowers muscle mass and increases the risk of obesity. One wonders how much the general androgyny, increased incidence of paraphilias, and sexual confusion of our society has been driven by environmental pollution of synthetic estrogens - when women are less womanly, and men are less manly, sexual polarity, a glorious part of God's creation, is dimmed in its brilliance.
Unfortunately, due to liver toxicity, testosterone cannot be taken as a pill. It must be injected or absorbed as a gel. These are most highly advertised, especially on-patent exogenous testosterone medications. Better, cheaper, and safer alternatives are out there, and they work by increasing the body's own natural testosterone production instead of relying on an external supply. Exogenous testosterone may also cause infertility.
The oldest drug known to stimulate increased testosterone production is Clomid. A generic drug with a stellar safety record, it is equally effective as expensive exogenous testosterone, and rather than harming fertility, it can double sperm count. A similar drug that complements Clomid is anastrozole, another cheap generic drug with no major safety issues despite decades of use by millions of people. Whereas Clomid stimulates endogenous production, anastrozole slows the natural process whereby testosterone degrades into estrogen (both men and women have both hormones but in vastly different amounts). It is often prescribed as an adjunct if estrogen levels are high.
New research, however, indicates Clomid may have some problems. Specifically, it is a mixture of two stereoisomers*, enclomifene and zuclomifene. The latter seems to have pro-estrogenic effects that work against the effects of the active isomer, enclomifene, and most troubling, has a much longer half-life (10 days vs. 10 hours). Overall, Clomid is still pro-testosterone but many studies are now showing that enclomifene alone is more effective. Enclomifene, purified from Clomid, is currently available from several compounding pharmacies.
(Hat tip to my new substack friend Chris Demuth, Jr., linked to by my intellectual brother-by-another-mother CBS, for recently sending me down the enclomifene rabbit hole.)
*Chemistry nerd time. A stereoisomer is a molecule with the exact same formula and structure but is asymmetrical such that it can have left and right-hand mirror image configurations. Amazingly, these two configurations can have different effects on the body. Ibuprofen is the most widely used stereoisomeric drug. One of the isomers is medically active, while the other is inert.
Low testosterone is usually diagnosed as a level below 250 ng/dl. Some doctors are more progressive, considering treatment of levels near 300 as "low normal." The ideal range seems to be north of 500, but this depends on the total free testosterone, a complex calculation involving another blood test. Many general practitioners lack experience in this area, leading to an overly cautious reluctance to prescribe, but most urologists now recognize the benefits of testosterone optimization and know which blood levels to check.
While pharmaceutical reps are pushing the on-patent gels, an ethical urologist, or an affordable telemedicine specialist, is happy to prescribe Clomid, enclomifene, and/or anastrozole as a first-line therapy. Low T is so common that any man suffering from depression or anxiety should have his levels checked first before considering any psychiatric intervention. Given the toxic environment causing population-wide endocrine disruption, no man should feel ashamed of such an intervention.
GLP-1 Receptor Agonists: Real Miracle Weight Loss Drugs
In my last column on health, I covered the benefits of weight loss while acknowledging the obvious difficulty most people experience when attempting it with diet and exercise alone. A new class of drugs has come online, GLP-1 receptor agonists, originally for treating diabetes, that are showing near-miraculous effects. Numerous studies have shown these to be the first drugs for weight loss that are as effective as bariatric surgery, leading to a long-term weight loss of about 21%. They will quickly become first-line treatments for the obesity epidemic and are already being used off-label by Hollywood stars looking for an edge in maintaining an optimal camera-ready weight. Amazingly, the effects on the brain are far-ranging, with patients reporting a loss of desire for other addictive behaviors, such as consuming alcohol.
If you struggle with weight and especially if you have elevated HA1c levels, these drugs could be life-changing, are now FDA-approved, and merit a discussion with your doctor. Early intervention, before diabetes and excess weight can damage internal organs, will yield the most benefits.
I’m cautiously optimistic about the future of drugs like this. An entirely different class of molecules, called leptin sensitizers, may target weight with even fewer side effects by targeting the brain damage done by overeating due to exposure to excess leptin (notably, these results are consistent with the most convincing theory of obesity, in terms of accounting for all of the data, presented by Stephen Guyenet in The Hungry Brain). In mice, a novel leptin sensitizer in early-stage trials reduced weight in obese mice by 45% in 21 days, the most dramatic effect ever observed in an animal model.
Nicotine for Depression
Anxiety and depression are all too common artifacts of modern life. We live in a very different world than our ancestors and our mind's biology does not always respond in the best way to the unique stressors we face. Surging cortisol was useful when the occasional bear might attack you, but constant exposure to stress and the fight-flight-freeze response can overload the mind's capacity to cope.
About 12 years ago, I found myself moderately depressed, despite having financial security and a wonderful family. My children and employees, both growing populations, needed me to upgrade to better mental hardware and expand my personal capacities from that of a somewhat pessimistic intellectual introvert to someone who could lead, influence, and encourage others. I exercised regularly and lost a bunch of weight but those interventions, while helpful, still seemed inadequate. I began a search for a natural product that would actually work to alleviate my depression and generally sour disposition without significant risks of side effects.
Pharmaceutical anti-depressants have significant, unpredictable side effects, in some individuals triggering violent or suicidal behavior, hence the "black box" warnings mandated now by the FDA. Most of them, if they ever work, stop working at some point. There’s considerable uncertainty if they work any better than a placebo. I also saw studies showing that a natural chemical, nicotine, has been shown to be at least equally effective in treating depression in non-smokers. Now, you might be asking yourself why nicotine would be included as an option in an anti-aging regime - doesn't nicotine cause cancer?
The harmful effects of smoking are well-documented but stem almost entirely from the smoke, not the nicotine. Smokeless tobacco, for example, is 98% safer than cigarettes, including for oral cancer. We have massive population-wide data sets on the effects of nicotine alone, as Sweden made it a national policy in the 1970's to convince smokers to switch from cigarettes to smokeless tobacco. Swedish data shows that those who switched had no statistically different lifespans than non-smokers. "The life expectancy of a 35-year-old ST user was 35.9 additional years, only 0.04 years (ie, 15 days) less than a nontobacco user but 7.8 years greater than an active smoker."
This is despite the generally lower socioeconomic status of tobacco users, which would normally depress lifespan as an independent factor! Smokeless tobacco users are also ingesting huge amounts of nicotine - as much as 20 mg over an entire dipping session, compared to 1 mg per smoked cigarette. The Duke study with nicotine patches involved at most 21 mg evenly spread across a 24-hour period, so a much smaller dose, and because it was a patch, no oral cancer or gum disease risk, though those risks are statistically non-existent with snus, the steam-processed smokeless tobacco popular in Sweden (American smokeless products, like Skoal, are baked at higher temperatures and thus have more carcinogens).
The risks, then, with medicinal-grade nicotine delivered in a patch are fairly low. The even dosage lessens the chance of addiction, as there is no acute behavior associated with a high (the effects are not immediate when the patch is put on, there is a 5-10 minute delay), nor an opportunity to spike blood levels like with cigarettes or smokeless. Nicotine itself is not as addictive as smoking, and arguably no more addictive than a prescription antidepressant, which always causes dependence as well, requiring a tapering-off period. Either way, a scientific consensus is emerging that nicotine by itself is as benign as caffeine.
What we do know is that depression and anxiety are significantly associated with mortality and that prescription antidepressants have significant risks and side effects, including weight gain (again more mortality) and loss of libido. Nicotine has been with us for a long time and the side effects are well known - it does not cause suicidal ideation, weight gain (it suppresses appetite!), or loss of libido. For this reason, I recommend that anyone suffering from depression or anxiety try nicotine as a first-line option.
Nicotine also is not known to cause anhedonia, or loss of pleasure, like drugs of abuse such as alcohol or methamphetamine- it has a strange feedback loop in the brain where it increases overall dopamine without affecting dopamine sensitivity. As a result, most nicotine users do not significantly increase the dosage over time. From my personal experience, it seems to strengthen the reward-seeking circuits of the brain while suppressing the pain-avoidance circuits. Depressed people, in my view, tend to have the pain-avoidance circuits on overdrive, so nicotine can bring balance to the mind. On the other hand, nicotine could make a person who is a natural risk-taker and thrill-seeker strengthen those behaviors. Psychologists often use a master analogy that all of their patients either need a screw loosened (depressed, overly cautious people) or tightened (anti-social risk-taking types). Nicotine is a chemical tool to loosen the screw and cope with the state of the world. Michael Pollan describes the related stimulant, caffeine, this way: “Caffeine helps us to cope with the world caffeine helped us to create".”
Tucker Carlson, an enthusiastic nicotine user, speaks well of its effects:
Tucker here overstates the expense if you shop around. Patches on Amazon cost as little as $1.50 per day, and non-prescription Zyn (discussed below) runs about $5 per can, with a can lasting 2-3 days.
I’d describe its subjective effects as helping focus and shutting down the internal dialogue. Depressed people tend to have a problem with rumination, or overthinking things. Nicotine shuts that problematic circuit down, and more importantly, allows me to focus on the work in front of me. I now completely understand why many men in unpleasant or dangerous occupations are enthusiastic smokeless users. It just helps you get the job done and not really care about the unpleasantness involved. At the same time, nicotine makes me less jittery than coffee, which I’ve cut to only once a day in the morning, except for an espresso shot on afternoons I lift weights.
While I began using oral lozenges and the patch, I now prefer the smooth flow of Zyn nicotine pouches, of which I am a proud investor in Swedish Match, its manufacturer. Zyn is now very popular as a nootropic and mood stabilizer among people who would never use smokeless tobacco because of the yuck factor. It does not stain or yellow teeth, there’s no spitting, and the flavors are not tobacco-like in any way.
Nicotine must be started gradually as the body adapts to the stimulus. Habitrol 1 mg lozenges or 7 mg patches are a great way to start, but the effective terminal dose is about 20 mg per day, so as the body acclimates higher dosage products can be attempted.
My friend at CBS has a theory that society needs to be re-nicotinized. It’s strange that the government is promoting and tolerating cannabis, a stupefying drug linked to schizophrenia and psychosis while continuing to persecute a drug that is the most effective natural nootropic we know, all the while featuring “side effects” that raise testosterone and suppress the desire to overeat. The government is ok with us being fat, dumb, and passive on pot, but a drug that energizes and motivates us must be subject to the strictest regulation. I’m only half-kidding when I say that the reason we can’t go to the moon anymore is because there aren’t enough chain-smoking engineers at NASA anymore.
One prescription alternative that works by a similar chemical pathway as nicotine is the atypical antidepressant Wellbutrin. It has been called the "Happy, Skinny, Sexy Pill" because it is the only antidepressant shown to cause weight loss and an increase in libido. Wellbutrin is often prescribed to ease nicotine withdrawal because it stimulates some of the same brain circuits. I’ve never used it, but it’s the only conventional antidepressant that doesn’t scare me.
The most common cause of male depression and anxiety today is low testosterone, and should be ruled out before trying any direct antidepressant; see the section above.
Be A High Agency Person
Whether you’re looking to optimize your health or get ahead of known risk factors, I challenge you to be a high-agency individual rather than a victim of circumstance. Even if you have risk factors, medical interventions like the ones cited above can extend and enhance your life. There really has never been a better time to a) either become healthy due to the dispersal of expertise on the subject or b) use medical science to mitigate the effects of modern afflictions. There’s no need to despair, and no shame, in needing and getting help.
That’s all I have for this Tom File. Thanks so much for reading!
The statin study is almost worthless because they compare placebo to pravastatin?! The statins predominantly used in outpatient medicine in the US are atorvastatin and rosuvastatin. Both are much more effective at lowering LDL/increasing HDLs than pravastatin. They are particularly effective in reducing risk of cardiac events in certain groups (e.g., diabetes). You’ve been fooled into a bad take. Please correct or at least tell more of the story.