Outlive by Peter Attia — a Reflection
I am sure glad a book like this exists. I don’t believe there is a book this committed to explaining many of the ailments that currently exist in US society (a stretch to say modern society). As a Huberman lab podcast listener, it was obvious I needed to read this book when it came out.
And 2.5 months after I had placed a hold (before its official release date), it landed in my hands in the local King County library. The timing could not have been better, after completing Spring Quarter amid oncoming PA school application deadlines, I needed something to inspire me. It did not take much after finishing the introduction and then reading the first sentence of Part I: “I’ll never forget the first patient whom I ever saw die” before I went into the usual cruise control of reading the book in Attia’s monotonous voice. It’s pleasant, but frankly, I prefer Huberman’s narration.
The book is called Outlive and the first sentence is “I’ll never forget the first patient whom I ever saw die.” Strangely, he never called out this irony himself in the book. The book’s title is something to examine itself. Who or what are we trying to outlive? How can we know how long we are *expected* to live?
In the “Acknowledgments” section, Attia acknowledges how his work was close to never being published. He credits Bill Gifford, another coauthor, and Michael Ovitz for pushing Attia to finish the project. This sort of project does not get done alone, especially with the heavy amount of research permeating much of the text’s first two parts. It is a testament to the amount of effort made in the mission to educate.
In general, I highly recommend the book to those who have yet to develop chronic diseases. Importantly, all of us will inevitably age and our bodies are not immune from further decline, whether it be cognitive, physiological, or physical. The point is to ward off chronic disease for as long as we can, to preserve as much quality of life as we can before we end up having to deal with these problems anyway. It serves as a guide for paying attention to values we can track over time, usually studied during our annual wellness checks. Growing old is difficult enough and at the very least, we should study ahead trends that we see in our blood to discover our baselines and understand what those values mean to us, in case we are predisposing ourselves to some future complication. It would not hurt to read this book, keep it, and the next time you get your blood tests ready, refer to the book to contextualize your health.
The point is to be active and curious in understanding how we can optimize ourselves so we can live not only long but well. Today, it is MUCH easier to get ahead of habits that may be directing us to future complications than it was for our parents and grandparents. Most of us only have one annual wellness check, and it does not give us a good picture of our health, given that many of the complications discussed in the book can appear only after a few months. Shifting our perspective from not solely responding to a disease onset helps protect our future selves from habits that lead us to our demise.
A separate but important point discusses the difference between what is healthy versus what is average. Average, in this country specifically, may have us end up with a HgbA1c value that is close to a prediabetic level for our age and give us no cause for concern. Yet, we should encourage ourselves to strive for not average, but healthy levels. The goal is to Outlive and for all of us, we want to live for as long as possible. The average gets us further from this goal.
As such, it helps to preview some vocabulary that is in the book, with some context. These concepts do not necessarily speak to the solutions to longevity, but they are related subjects in the field. Of course, the book discusses them a bit more, along with resveratrol which I have written about before in a post done here.
Part A:
Reviewing the biochemistry and associated literature in this book will take too darn long to sift over and if you have read this book, would you want to sit through another lengthy post describing something you can read about anyway? Fear not, I hope this very inexhaustive summary functions as a sparks note version:
a) HbA1c levels = measures the amount of glycosylated Hemoglobin in our blood, estimating the average level of blood glucose over the past ninety days. If the result is >6.5, that rounds out to an average blood glucose level of 140 mg/dL, compared to normal which is 5.1 corresponding to a glucose level of 100 mg/dL averaged over the past ninety days.
Attia makes the point that the different thresholds that signify nondiabetic versus prediabetic versus diabetic are arbitrary and unhelpful when it comes to how medicine responds to these values. After all, if prediabetes is a 5.7 value and your blood shows a 5.6 level, should we not at least be the least bit concerned?
b) ApoE = a gene that has a known effect on Alzheimer’s Disease (AD) risk. It stands for apolipoprotein E. It is related to cholesterol metabolism and glucose metabolism. There are three variants: e2 (protective variant), e3 (most common), and e4 (two copies of this variant can significantly enhance the risk of AD by a factor between 2 and 12) (68).
2019 meta-analysis: people who carried at least one copy of ApoE e2 without e4 were 30% more likely to reach extreme old age, compared to the standard e3/e3 combination (68). Extreme old age is defined as 97 for men and 100 for women!
ApoE plays an important role in shuttling cholesterol around the body and the brain. The book explores this function in further detail, explaining that neurons require very large amounts of cholesterol (and glucose) to function properly. The e4 allele encodes a defect in both cholesterol and glucose metabolism, so there would be reduced efficiency in moving cholesterol into and out of the brain (198).
c) FOXO3 = A family of transcription factors that govern a “variety of cellular repair tasks (69).” Three SNPs in FOXO3 were strongly associated with healthy aging and longevity. FOXO3 also helps prevent cells from becoming cancerous, presumably by halting the cell from advancing in cell cycle checkpoints when the cell should not.
Interestingly, FOXO3 can be activated through exercise or slight deprivation of nutrients. It is still not well understood exactly how FOXO3 displays “youthful patterns of gene expression, more closely resembling a control group of people in their twenties (when undergoing genetic testing of Spanish centenarians) (70).”
d) Rapamycin = Has many diverse applications. Slows down the process of cell growth and division. Is also used for transplant patients for immunomodulatory purposes in accepting new organs, and to treat athlete’s foot (initially, rapamycin was thought to be only immunosuppressive in the context of organ transplants, but one study showed that this depended on the dose of rapamycin (84)). Interacts directly with mTOR, which stands for mechanistic target of rapamycin. Can trigger autophagy (discussed in AMPK section)
e) mTOR = “The job of mTOR is basically to balance an organism’s need to grow and reproduce against the availability of nutrients.” When food is plentiful, mTOR activates and the cell goes into growth mode, whereas mTOR is suppressed when nutrients are scarce. When suppressed, mTOR causes cells to recycle cellular components, slowing down cell division and replication (77).
mTOR is two separate complexes that have different functions, mTORC1 and mTORC2. mTORC1, if inhibited, may lead to “longevity-related benefits (85).”
Generally, mTOR and Rapamycin’s relationship is reproducible. It reflects the relationship between caloric consumption and how the cell responds to nutrient availability. In caloric restriction, we see that the cell must ration the remaining nutrients which are available and initiate cellular processes that make use of a limited supply of resources.
f) AMPK = AMP-activated protein kinase which is an enzyme that senses a deficiency in nutrients to activate a specific cellular pathway to initiate mitochondrial biogenesis. It will also release energy stored in fat and produce glucose in the liver.
Mitochondrial biogenesis is important to replace the older mitochondria impacted by oxidative stress and genomic damage. It turns out that restricting the amount of nutrients available triggers newer mitochondria to be produced that will be able to pump more ATP with the fuel it does have (82). (Mitochondria can produce up to 32 ATP from just one glucose molecule. Imagine having more mitochondria!)
AMPK also inhibits mTOR, but the actual pathway is less food = less Amino acids → AMPK↑ → mTOR↓ → growth processes are shut down → autophagy is activated. Autophagy signifies a state where the cell goes into stress-resistant and fuel-efficient mode.
Autophagy represents the breakdown of old proteins and cellular structures to build new ones. Using lysosomes that have hydrolytic enzymes that break down the cellular compartments, our cells can continuously refurbish themselves, while breaking up aggregates that can accumulate from used proteins over time. Deficiencies in autophagy are risk factors for Amyotrophic Lateral Sclerosis (ALS), AD, and Parkinson’s. As we age, autophagy declines (83).
g) apoB (apolipoprotein B) = First off, an apolipoprotein wraps around a lipoprotein particle that carries cholesterol around the body. It depends on what lipoprotein it is (LDL, HDL, vLDL, IDL) since different apolipoproteins attach to different lipoproteins and they are not equivalent (as you will learn the difference between apoB and apoA and apo(a)). ApoB’s general function relates to LDL particles, which are more fat-dense and less protein-dense compared to HDL particles, as they are carried around the body. The more apolipoprotein B is present in the blood, the higher the incidence of atherosclerosis. Another thing to note is that LDL particles are unable to cross the endothelium, whereas HDL with ApoA can cross the endothelial barriers. As such, this inability can contribute to atherosclerosis due to plaque buildup caused by a stickiness to the endothelial wall, instead of traversing the endothelium.
As page 120 points out:
LDL particles stick in the arterial wall and subsequently become oxidized, meaning the cholesterol (and phospholipid) molecules they contain come into contact with a highly reactive molecule known as a reactive oxygen species, or ROS, the cause of oxidative stress. It’s the oxidation of the lipids on the LDL that kicks off the entire atherosclerotic cascade.
Attia mentions that the main factor here is the ApoB particle mainly since apoB also is attracted to higher lipid density lipoproteins (LDL and vLDL). So, checking the amount of apoB in our blood does illuminate a lot about our atherosclerotic risk. With more aggregates and clumps, macrophages will then be attracted to respond to the fatty streaks in our blood, causing a foamy/soapy substance in our blood vessels; as you can imagine, this will lead to more resistance and an increased risk of stroke. Other processes take place, including calcification as the body’s response to such a plaque formation, and the smooth muscle cells work to form a barrier around the plaque as well. But you can read that in the book (120–125).
h) Lp(a) = formed when an LDL particle is fused with apo(a), NOT apo(A) that marks HDL particles (128). The apo(a) wraps loosely around the LDL, picking up bits of oxidized lipid molecules when traveling around the bloodstream. So, Lp(a) is part of the apoB particle family (complex enough for ya?).
Lp(a) also get stuck in the endothelium and with the extra cargo it brings along from picking up the oxidized lipids, would more likely get stuck (128).
It turns out, Lp(a) is “the most prevalent hereditary risk factor for heart disease.” (129) Attia recommends testing Lp(a) if people have a history of premature heart attacks in the family. Lp(a), if high, can lead to “tiny, bony particles in the valve leaflets, which leads to stenosis or narrowing of the aortic outlet.” (129)
Reducing these levels is tricky since Lp(a) is not found to be responsive to exercise or other behavioral interventions. PCSK9 inhibitors seem to lower apoB, thereby lower Lp(a), except it is not completely conclusive that heart attacks are reduced based on that regimen. PCSK9, if uninhibited, will degrade LDL receptors that are attached to the liver, leading to more LDL circulating in your blood but not entering the liver to be degraded. Degrading PCSK9 will lead to more LDL absorption, hopefully in the liver where it can be broken down (Cleveland Clinic).
I could go on with other important metrics but at this rate, it is better to read the book.
Part B:
If there was any criticism I had, it would be how slow Part III was out of the gate. But it still introduces exercise science, which outlines exercise as the best treatment for most of these chronic conditions. The final two chapters of Part III drive home very important points related to sleep and the importance of psychological health. This makes sense since these two subjects are perhaps the most controllable facets of our lives that we can establish actionable habits to fix. Not to say these are easy problems to fix…
While I did mention that Part III seemed slow, the content still provides many necessary details regarding different muscle fibers, VO2max, diabetes control, nutrition (sorry, nutritional biochemistry), lean muscle mass, stability, strength, breathing, caloric restriction, diet, sleep, and mental health. Part III relies on the information you learn in Part II. Part II represents biochemistry and biology; Part III represents the application, to answer the question of why we should care.
To finish the book, appropriately, Attia draws attention to the importance of sleep and mental health. While the topic of mental health is thrown around quite often these days, I think it would be more apt to consider the last chapter as how to approach adversity. Not necessarily how to solve one’s problems, but how to approach each issue considering the significance of these issues impacting one’s health. The sleep chapter also serves as an appropriate summary of Matthew Walker’s book “Why We Sleep,” except Attia shares more personal advice to better maximize sleep quality. It also explains the impact of poor sleep that will compound developing health issues that may transform to early-onset dementia or other cognitive health decline conditions.
Part III consolidates all this knowledge into personal takeaways for the reader. Personally, it meant a lot to read about Attia’s struggles in archery. While I have never shot with a bow and arrow, I play tennis a lot and both sports ask a tremendous amount from a player’s mental endurance. I have had my share of rage fits in the past: smashing rackets to the ground, swearing loudly, hitting tennis balls as hard as possible to a nearby fence (a little tamer and provides some freedom of expression!) but as Attia describes on page 407
Only when I at least entertained the notion that maybe I was not a monster was I able to start chipping away at the narrative that had nearly destroyed my life and everyone in my wake.
The last time I was on the court, I remembered this line. When I was almost to the point of throwing a rage fit, I took what I learned from that chapter and gave myself some time to process everything, before continuing again. Sure enough, my forehand improved 3x afterward.
References
Attia, P. (2023). Outlive. Penguin Random House USA.
Cleveland Clinic. (2022, Feb 17). PCSK9 Inhibitors. Cleveland Clinic. https://my.clevelandclinic.org/health/drugs/22550-pcsk9-inhibitors
