Outlive Reflection

My interest in the topic of longevity was piqued after reading David Sinclair’s Lifespan two years ago, so I was excited to dig back into the subject with Peter Attia’s Outlive. While both books are very scientific, Outlive comes off as a more conservative, sober analysis of what is currently known in the field. Sinclair has claimed that the first person to live to 150 has likely already been born, while Attia believes we might be able to add a “bonus decade” to our lives if we commit to certain practices. I hope Sinclair is right, because then I’ll feel a lot better about spending 6+ years in grad school. 

Attia begins by distinguishing between fast and slow causes of death. The fast causes include things like infectious diseases and acute health emergencies, which modern medicine has made great progress on treating and curing. However, we have made little progress on treating slow causes of death, like type 2 diabetes, heart disease, cancer, and neurodegenerative disease, which he refers to as the “four horsemen” of chronic disease. In order to address these conditions, he believes we need a more proactive approach, which he calls Medicine 3.0. 

Medicine 1.0 was practiced for most of human history and involved guesswork and a lot of quackery. Medicine 2.0, or the era of modern medicine, arrived in the mid-1800s with the germ theory of disease and the application of the scientific method to solve medical problems. But Medicine 2.0 has always been reactive by nature, waiting for people show acute symptoms before intervening. Medicine 3.0 is characterized by assessing risk on much longer time horizons, engaging patients in healthy habits, closely tracking biomarkers, and applying preventative care more liberally.

He is correct to point out that the main way we pay for healthcare in the US, the “fee-for-service” system, is much better suited to Medicine 2.0 practices. In order to transition to the Medicine 3.0 approach, we first need to better align the financial incentives of providers with patients’ long-term health interests, likely through some value-based payment models. However, even in this new paradigm, it’s not necessarily going to be the case that all preventative care will be cost-effective. Attia describes the benefits of new technologies like DEXA scans and continuous glucose monitors, but shrugs off critics who say they are not worth the cost for all patients. If they are cost-effective, or even cost-saving in the long run, then he should show that. I’m going to venture to guess that his practice, Early Medical, doesn’t take many low-income patients on Medicaid.

The second part of the book describes in great detail the four horsemen of chronic disease, but for the sake of brevity, I’ll only provide a few key points for each. He begins with type 2 diabetes and related metabolic dysfunction, as they are key underlying risk factors for the other three. Here he argues that metabolic dysfunction, or the body failing to properly convert food into energy and get rid of waste, is the key issue, while obesity (being overweight) is simply one symptom of the underlying problem. In other words, it’s better to be metabolically health and obese than metabolically dysfunctional at a “normal” weight. The most concerning form of metabolic dysfunction is insulin resistance, which involves cells ignoring insulin’s signals to take up glucose out of the blood, resulting in the glucose being stored as excess fat. Poor diet and lack of exercise contribute to these problems, but genes play an important role as well.

Atherosclerotic disease, which includes heart disease and stroke, is the leading cause of death in the US, but Attia believes that it could drop to 10th place with more proactive treatment. While most of these deaths occur after 65, and most doctors/patients don’t address the risk until one’s 40s or 50s, the damage to arteries can start building up as early as one’s teens. The key to prevention as he sees it is to mitigate the build up ApoB and Lp(a) particles, which ride along with LDL - the “bad” cholesterol. Effective interventions include lowering triglycerides, managing insulin, eating more good fats (olive oil, macadamias, avocados), and using statins. While HDL, the “good” cholesterol, has some positive effects, it has not been shown to causally improve atherosclerotic disease.

Despite Nixon declaring a war on cancer back in 1971, little real progress has been made and it remains the 2nd leading cause of death in the US. What makes cancer tricky is that it’s difficult to detect early on, it’s generally not linked to specific genetic markers, and our current treatments, such as chemo, are not very effective or precise. Most deaths from cancer come from metastatic cancers, which spread beyond the original organ into the rest of the body, making them very difficult to treat. For this reason, he strongly believes we should do more aggressive early screening so that the cancer can be caught and treated before it spreads. Little can be done to prevent cancer, besides avoiding smoking and becoming diabetic. However, he is optimistic about new diagnostics and treatments coming down the pipeline, including immunotherapies where one’s T-cells are reprogrammed to target specific cancer cells.

Neurodegenerative diseases like Alzheimer’s (6M people in US), Lewy body dementia (1.4M), and Parkinson’s (1M) are associated with the build up of certain particles in the brain, but the causal pathways are not well understood. The scientific community has long assumed that amyloid beta caused Alzheimer’s, but no drug that reduces its build up has had any effect on cognitive activities. Attia proposes an alternative theory, where the calcification of blood vessels and capillaries causes Alzheimer’s via reduced blood flow, and amyloid beta is simply a byproduct. People with the e4 variants of the APOE gene are at notably higher risk, but other genes can lower the risk. While researchers are still hesitant to suggest that neurodegenerative diseases can be prevented, he is convinced that exercise, getting good sleep, and maintaining a healthy metabolism and good mental health can be effective.

So what can be done about these four horsemen? Attia focuses the rest of the book on his recommendations for exercise, diet, sleep, and mental health. Exercise is quite clearly the “most powerful longevity drug.” It can improve our circulatory system, metabolism, immune system, robustness to injuries, and even our memory. His highest priority is aerobic fitness, which includes both zone 2 training (70-85% of your max heart rate) and VO2 max training (max oxygen intake at peak exercise effort). He cites VO2 max as the single most powerful marker of longevity. He also emphasizes the importance of functional strength and stability training, as falls are the leading cause of accidental death over the age of 65 and back pain is the leading cause of disability in the world. Indeed, as I’ve grown older I’ve come to recognize that even minor injuries can derail a good exercise habit, so investing in injury prevention is likely worthwhile.

Attia presents a number of charts showing how various measures of health and fitness across a population tend to decline as we age. From these data he reasons that if you want to be at a certain fitness level later in life, you need to be far above this level in the decades earlier. While this is likely broadly true, it would be interesting to see the rates of decline broken down by fitness and exercise levels early in life. Do people who are healthy and exercise regularly in their thirties follow the same trajectory as unhealthy/inactive people, just at different levels? How does continued exercise through midlife modify this trajectory? I’m sure exercise at any age is helpful, but I’m not sure if his point about the necessity of doing the work ahead of time is proven by the data he presents.

Moving into nutritional biochemistry (his preferred term for diet), things become much less clear cut. This is largely because nutrition research relies on epidemiological association studies, which are popularized in the media, but almost never produce causal evidence. Nutrition basically comes down to eating the right amount of calories, getting sufficient protein and essential fats, obtaining the vitamins and minerals you need, and avoiding pathogens. Beyond this we know relatively little with complete certainty. However, we can be fairly sure that the Standard American Diet (SAD), which is characterized by added sugar, highly refined carbs with low fiber content, processed oils, dense caloric food, and junk food, is bad for longevity.

Attia categorizes diets as being focused on calorie restriction, dietary restriction, time restriction, or some combination of those three. Calorie restriction has the strongest evidence for enhancing longevity (particularly avoiding cancer) and simply involves counting how many calories you are eating without much regard to what or when you are eating them. Dietary restriction (limiting certain foods) receives the most attention, research, and debate, but probably has the least generalizable findings. Finally, time restriction (various lengths of fasting) has some positive effects at the cellular and metabolic levels, but more long-term research on humans is likely needed. His main concern with all three of these strategies is that they may lower your consumption of protein, which he views as by far the most important macronutrient, particularly for maintaining strength and stability at older ages. While current guidelines recommend 0.8 grams of protein per kilogram of body weight per day, he thinks the minimum should be 1.6g/kg, or 130-180g per day for someone weighing 180lbs. 

Interestingly, this subject is where he and David Sinclair appear to diverge the most. Sinclair’s top recommendations for improving longevity (not just diet) are to eat less often and be more vegan. As someone who is mostly vegan, I’m inclined to side with Sinclair, but admittedly he bases most of his reasoning on studies of cells and animals, rather than at the human level. I see Attia’s point about getting enough protein, but I’m not sure that I’m convinced of its utmost importance. After all, most elderly homes are filled with thin women who likely erred on the side of eating less food/protein than he recommends. I would love to see the two of them get together and hash this one out.

The last two chapters discuss sleep and mental health, which as you can imagine are important for many facets of health and longevity. I will not discuss them further here, but I will acknowledge that his brutally honest description of his own mental health challenges was the most moving part of the book. To bring this reflection to a close, this book taught me a great deal about science, medicine, and life. It is densely packed with useful information - so much so that I reviewed all 400 pages a second time, took detailed notes, and wrote this long-a** post about it. Any book about longevity is going to be biased by the author’s predispositions, but I have great respect for Peter Attia and how he went about writing this. I just hope I live long enough to see all of these longevity puzzles worked out.