Smash Notes
Exercise, Nutrition, Hormones for Vitality & Longevity | Dr. Peter Attia
My guest this episode is Dr. Peter Attia, M.D., who trained at Stanford University School of Medicine, Johns Hopkins Hospital and the National Institutes of Health (NIH). Dr. Attia is host of The Drive podcast and is a world expert on behavioral approaches, nutritional interventions, supplementation and pharmacological techniques to improve lifespan…
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Notes
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Peter Attia calls lipoprotein little a the single most prevalent genetic driver of atherosclerosis. A person is born with the level, and the check only needs to happen once. Somewhere between eight and twelve percent of the population has a high enough lipoprotein little a that it is contributing to atherosclerosis. A guest on Peter Attia's podcast suggested the share could reach twenty percent. Most physicians do not know what lipoprotein little a is. Not checking a twenty-year-old leaves money on the table, since lipoprotein little a can contribute to a lot of the early atherosclerosis seen in people.
Everybody should be screened early in life. How often blood gets tested after the one lipoprotein little a result comes down to the state of interventions. Peter Attia does not think it makes sense to do blood tests for the sake of doing blood tests. A blood test is for the most part a look at a window in time. A few checks over the course of a year help when a level is unsure. If a result does not look great, Peter Attia says it might make sense to recheck the result without reacting to it. Typically, patients might have blood checked two to four times a year while an intervention is underway, such as whether a drug had the desired outcome, or whether someone put on three pounds of muscle and lost three pounds of fat.
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On Huberman Lab, body fat is the least interesting of the four results a DEXA scan produces and ranks fourth for health. Bone mineral density, visceral fat, and the metrics used to compute appendicular lean mass index and fat-free mass index are significantly more important than body fat.
Bone mineral density speaks to the risk of osteoporosis and osteopenia. It does not sound very sexy to fifty-year-old men. A fifty-year-old woman who is just about to go through menopause or has just gone through menopause is at enormous risk for osteopenia and ultimately osteoporosis, because estrogen is the single most important hormone regulating bone mineral density.
The bone loss is a huge cause of morbidity. Over the age of sixty-five, a fall that breaks the hip carries about thirty to forty percent one-year morbidity.
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On Huberman Lab, a study done in Australia took older women who looked to be in their sixties or seventies and who had never lifted weights, and put them on a strength training protocol. The women had osteopenia, and some probably already had osteoporosis. The lifting is remarkable to watch, and bone health is improving at that age.
The women are doing good mornings, doing deadlifts, and picking heavy things up off the ground. The speaker is unsure of the exact figure and wants to say one woman was picking up 50 to 60 kilos off the ground. The sums of weight are staggering for women who have never done anything.
The goal is to avoid ever getting to the point of having to lift heavy for the first time. Strength training is an essential part of existence, so it is never too late to start, and training should never stop.
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Peter Attia defines the marginal decade as the last decade of life and says everyone will have one. He calls that the only fact he can state with absolute certainty. There is no immortality and no hidden elixir. Outside sudden death or an accident, he says most people know when they are in the marginal decade. He adds that a person might not know the day it begins, and that someone old enough to be asked probably has a sense of already being in it.
The practice runs the exercise very early. About 50 questions prompt patients to lay out, in more detail than they have ever considered, everything that should happen in the marginal decade. Peter Attia does not fix the calendar. He says the years could run from 87 to 97 if things are going well, or the span might be 79 to 89. Until a person can say what they want to be doing in that last decade, he says the rest of the planning is abstract and nonsense, and a program cannot be designed to get them there.
Asked what high bone mineral density gives men and women apart from falling, breaking a bone, and dying a year later, he calls the question the inverse. The person still has to articulate what that last decade should include, including someone who would move more slowly or sit in a wheelchair only to avoid a fall. He compares the standard to an Ironman, where the objective is already taken for granted.
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On Huberman Lab, cardiorespiratory fitness shows a profound link to all-cause mortality. People in the bottom 25 percent of maximal oxygen uptake for age and sex have roughly a 2x difference in risk versus people at the 50th to 75th percentile, and a 5x, 400 percent, difference versus the top 2.5 percent.
The comparison stays inside age and sex. Against the 50th to 75th percentile, the bottom 25 percent lines up with about a 2x difference in risk. Against the top 2.5 percent, called the elite level for a given age, the bottom quarter lines up with a 5x difference, a 400 percent difference in all-cause mortality. Dr. Peter Attia says that is probably the single strongest association seen for any modifiable behavior. Elite means the maximal oxygen uptake number for the age group, and a person does not have to be a world-class athlete to reach it.
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Going from completely sedentary to 15 metabolic equivalent hours a week produces probably a 50 percent reduction in risk, equal to half the benefit of going all the way. On Huberman Lab, nothing told to patients matters more for Alzheimer's prevention than exercise, and the small recommendations usually offered are not enough for the maximum benefit.
A metabolic equivalent is the energy of quiet sitting, about one metabolic equivalent. Sitting and talking uses about 1.3. Walking really briskly uses about five, so 15 metabolic equivalent hours a week is three one-hour brisk walks. The largest share of benefit comes from going from nothing to something, and that first step is what brings the 50 percent reduction. Personal skepticism on Huberman Lab puts the true reduction a bit under 50 percent, while the studies miss further upside. Exercising past 15 metabolic equivalent hours still adds benefit, though each added hour accrues more slowly.
Health span sits outside the risk numbers. It is the functional question of the marginal decade: picking up a great grandkid who comes running, getting up off the floor, and playing on the floor with a kid before standing up alone.
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Peter Attia has cycled nicotine on and off for the last 10 years and calls it a concentration enhancing substance. He used the gum, then stopped liking the gum, and moved to small lozenges. Nicotine is addictive and people need to be wary of the addiction. Peter Attia experiences no addiction: he can take it every day for 30 days, stop, and feel no withdrawal.
About a year earlier he went through the details of his own use. David Sinclair mentioned a company, and Peter Attia ordered a lifetime supply before learning, the next week, that the company name was unrelated. What arrived was a small patch, which suited him better than the gum he had hated for its taste. Dose is the limit. One cigarette is about one milligram of nicotine, while many lozenges deliver four to eight milligrams in one shot. For someone new to nicotine, four milligrams is a lot of nicotine in one bolus.
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On Huberman Lab, half a recommended dose of armodafinil, prescribed by a doctor, was a powerful stimulant. Four hours into a talk in Hawaii, a co-speaker pointed out spit at the corner of the mouth, no blink for three minutes, and only two people left in the audience. The host never took any more of it.
The host had gone to Hawaii to give the talk and took that half dose. Focus tightened until the setting fell away and the host forgot the context. The host already described a tunnel-vision tendency, and said that half dose was all it took. For later cognitive work, and sometimes before workouts, the host uses 300 milligrams of alpha-GPC. Subjectively, alpha-GPC narrows focus in a nice way, with use held to no more than once or twice a day and no more than once or twice a week.
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On Huberman Lab, a low dose of progesterone through the last half of the luteal phase, and sometimes through the entire luteal phase, makes all premenstrual syndrome symptoms vanish. The enormous reduction of progesterone so quickly is described as probably impacting the brain in a susceptible woman, and the symptoms are stated as a legitimate effect because progesterone for the seven days makes the symptoms go away.
Progesterone does nothing for 14 days in the follicular cycle, then rises and dominates the luteal cycle. At about 21 days the body has figured out whether she is pregnant. Most of the time she is not, so progesterone and estrogen start crashing, the uterine lining sheds, and the menses begins. The last seven days of the cycle are when a susceptible woman develops premenstrual syndrome symptoms. Stabilizing progesterone for the seven days, or for the whole luteal phase on a low dose, clears every one of the symptoms.
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On the show, the relative risk increase of breast cancer in the estrogen plus synthetic progesterone group versus placebo was 25 to 27 percent. The only headline said HRT increases risk of breast cancer by 27 percent. The absolute risk increase was 0.1 percent, a difference between five cases per thousand and four cases per thousand, one case in a thousand. The breast cancer headline turned out not to be true.
Preliminary results were first made available before peer review and before publication, and a huge press announcement said women receiving CEE plus MPA in the group with a uterus had a higher incidence of breast cancer. Going from four in a thousand to five in a thousand is a 25 percent increase, and stating the relative change alone is a completely inappropriate context. A relative risk change is never to be given without an absolute risk beside it.
Headlines of that sort are nothing short of criminal because they distort people's thinking and steer the course of science and medicine for decades.
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On Huberman Lab, estrogen plus synthetic progesterone reached one breast cancer case in a thousand and just hit statistical significance at a p-value of 0.05. Estrogen alone, given versus placebo to women without a uterus, went the opposite direction: a 24 percent risk reduction of about one in a thousand, with a p-value of 0.06 or 0.07. On Huberman Lab, the pattern suggests synthetic progesterone was playing more of a role than anything else.
Two findings in the combined arm were negative: a small increase in the risk of heart disease and a small increase in the risk of breast cancer. The breast cancer increase just reached a p-value of 0.05, one in a thousand cases. In women without a uterus, estrogen alone did not reach statistical significance. The p-value was 0.06 or 0.07, and the result was a 24 percent risk reduction, about one in a thousand.
Oral estrogen, no longer used, does increase coagulability and the ability of the blood to clot a little bit. Topical estrogen and patches of estrogen do not show the clotting rise. With estradiol, the risk of heart disease goes down.
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On the show, hormone replacement therapy for a woman is preferred from her gynecologist, with an endometrial ultrasound every year and a pap smear every year, so the cervix and the endometrium can be checked and the lining is not too thick. When a woman still has her uterus, estrogen solves most of the problems. The next decision is whether she can tolerate progesterone, because not all women can.
Systemic progesterone is a hundred to two hundred milligrams. For some women that dose is a life-saving intervention: they start sleeping better, their hair gets thicker, and they feel better. For some women it drives them crazy. On the show, that reaction is probably the reciprocal of what shows up in women with premenstrual syndrome. Oral progesterone then stops, and a progesterone-coated intrauterine device supplies local progesterone in the uterus for protection while estrogen stays systemic.
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On Huberman Lab, insulin suppresses sex hormone binding globulin. As insulin comes down, sex hormone binding globulin goes up, and if testosterone has not gone up with it, free testosterone falls. Helping a person get metabolically healthy can lower free testosterone in the short run, all things equal.
A patient can show a total testosterone of 900 nanograms per deciliter, about the 70th percentile on the scale they look at, with free testosterone at 8 nanograms per deciliter, less than 1 percent free. A man should be about 2 percent free, closer to 16 to 18 nanograms per deciliter. Sex hormone binding globulin in that situation is really high, probably in the 80 to 90 range, above an upper range around 55 or 56. Estradiol, insulin, and thyroxine are the three hormones that run sex hormone binding globulin, and estradiol is the most important. Higher estradiol means higher sex hormone binding globulin. Somebody on a very low carbohydrate diet who drops water and weight raises sex hormone binding globulin if insulin goes down, and then has less free testosterone.
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On Huberman Lab, a clinician stopped using Anavar to lower SHBG. The question was whether Anavar was still used because Anavar is too potent. The reply was that Anavar is simply too complicated for patients. Anavar cannot be taken orally, so each dose has to sit under the tongue, like a troche.
One patient was told about 87 times and still swallowed the Anavar tablets. The dose was 10 milligrams three times a week. The clinician first said three months of swallowing, then corrected the span to two months. Two months of swallowing Anavar every time tripled his liver function test. After the liver function test tripled, Anavar was not worth the hassle of chasing perfection.
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Peter Attia gives patients who arrive on a long supplement list a homework exercise: answer seven questions for every supplement. He calls the exercise another Peter principle. The result is sobering. A lot of patients come back and report that they cannot produce any reason, along a rigorous line of thinking, for taking 80 percent of the supplements.
At intake, Attia asks which drugs and supplements a person takes. Some say they take nothing and want Attia in charge of the plan. Others need extra pages of documentation because they travel with a suitcase of pills that rattles through an airport. Attia hands them a spreadsheet. The spreadsheet walks through the logic of why the patient takes each molecule. After patients work through the spreadsheet, many say they have no defensible reason for 80 percent of the list.
Attia uses the seven questions to force an explicit reason for each molecule. Patients who finish the spreadsheet often find that a rigorous line of thinking leaves 80 percent of what they walked in taking without a justification.
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Peter Attia says the only purpose of fixing testosterone is to give someone the capacity to work harder, recover more from workouts, and experience more muscle protein synthesis. Extra testosterone with the same nutrition, no exercise, and time spent on the couch brings no benefits.
As an adult, his most extreme physique was at 38. A DEXA scan put him at 7% body fat, with a fat-free mass index of 23.2 to 23.3 kilograms per meter squared. He was huge, strong, and totally ripped while testosterone was in the toilet. He exercised about 26 hours a week, swimming and cycling, and was grossly overtrained. He looked like twice the man he is today, and he says today his testosterone is probably twice as high as it was then.
Giving testosterone alone does little. Attia says it probably helps insulin resistance without any other change, and he calls that a waste of the gift, which is the ability to do more work and capture the benefit through muscle protein synthesis.
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On Huberman Lab, dietary cholesterol plays no role in serum cholesterol and has no bearing on it. Ancel Keys acknowledged the finding in the 1960s, and the American Heart Association acknowledged it another 60 years later. Saturated fat is a separate molecule, and saturated fat consumption raises LDL cholesterol in many people.
Cholesterol in food is esterified, and an esterified cholesterol molecule cannot pass into circulation the way non-esterified body cholesterol can. On Huberman Lab, the body probably de-esterifies ten to fifteen percent of dietary cholesterol. Small amounts do reach circulation, yet they remain a small fraction of the total body pool. Saturated fat is a fully saturated long-chain fatty acid with no double bonds and can sit alone, in a triglyceride, or in a phospholipid. Fat in food is saturated, monounsaturated with one double bond, or polyunsaturated with two or more double bonds.
The observation that eating saturated fat raises cholesterol is generally correct, so serum cholesterol and LDL cholesterol move with saturated fat even though dietary cholesterol does not set the serum level.
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On Huberman Lab, semaglutide is catabolic across the board, so patients lose fat and also lose muscle. Semaglutide is not a miracle drug, and the dose in the main trial sits above the amount many clinic patients need.
The trial ran for one year, or maybe a little over that, maybe 60 weeks. About 16 weeks went into getting patients comfortably up to 2.4 milligrams weekly, and patients stayed on 2.4 milligrams. In clinic use, enough benefit usually shows between one and two milligrams, and people move along a little quicker. Some patients cannot tolerate semaglutide because of nausea. Dr. Peter Attia says nausea might be part of how semaglutide works, as appetite suppression taken to an extreme. Most of the effect of semaglutide is central, not peripheral. Dr. Peter Attia would bet 80 percent of the effect is in the hypothalamus. Semaglutide also improves insulin sensitivity in the periphery, but Dr. Peter Attia does not think the peripheral improvement accounts for much of the benefit. Coming off semaglutide brings a weight regain. Newer versions seem to preserve the weight loss even off semaglutide.
Dr. Peter Attia says the work is still in super early days and asks whether a person will cycle semaglutide or stay on semaglutide indefinitely, and whether resistance will show up.
Related notes
- How Did Powerlifting Build Strength Without Bigger Muscles?
- How Did Fadogia Agrestis Lift Andrew Huberman's Testosterone?
- What Testosterone Dose Sits Between Normal and Blasting?
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