59 pages • 1 hour read
Peter AttiaOutlive: The Science and Art of Longevity
Nonfiction | Book | Adult | Published in 2023A modern alternative to SparkNotes and CliffsNotes, SuperSummary offers high-quality Study Guides with detailed chapter summaries and analysis of major themes, characters, and more.
Part 2, Chapters 4-6Chapter Summaries & Analyses
Part 2, Chapter 4 Summary: “Centenarians: The Older You Get, the Healthier You Have Been”
Attia starts Chapter 4 by pondering whether there are specific types of healthy behaviors that lead people to become centenarians. He points to examples of recent centenarians, such as Richard Overton, Henry Allingham, Jeanne Calment, Mildred Bowers, and Emma Morano, who all had unhealthy behaviors (e.g., smoking and drinking alcohol) but remained happy and healthy well past the age of 100. Given their unhealthy behaviors, luck may have played a role in their advanced age.
These anecdotes, coupled with recent research into centenarians, suggest there are no unifying healthy behaviors among this group. Instead, luck and genes may play some role. Attia notes, “being the sister of a centenarian makes you eight times more likely to reach that age yourself, while brothers of centenarians are seventeen times as likely to celebrate their hundredth birthday” (62). Most of us, however, do not have centenarians in our family history. Attia still believes we can live healthier longer even without centenarian genes.
A key observation about centenarians is that if they develop Horsemen diseases, they do so much later in life compared to the average person. Centenarians also retain high cognitive functions and the ability to do daily tasks (e.g., clip their own toenails and cook meals for themselves). Male centenarians also tend to be in better health than female centenarians, perhaps due to men generally having more muscle mass which is correlated to extended lifespan. Supercentenarians (those who live to age 110) and semi-supercentenarians (those who live to between the ages of 105-109) tend to have better health than individuals who live to 100 years old, suggesting “the older you get, the healthier you have been” (65). These individuals remain biologically younger than their peers for decades.
Researchers have tried to identify longevity genes. However, centenarians have little in common genetically. In fact, most people carry problematic genes (e.g., genes related to Alzheimer’s) because natural selection does not remove them. The reason is that these genes show up in midlife and beyond. Since these genes do not impact reproductive fitness, the genes continue to be passed on. There are still likely genes that help people live longer, but the research suggests “no two centenarians follow the exact same genetic path” (67).
Attia still believes genetic screening is important because there are potential longevity genes, such as the three variants of APOE which have a known effect on neurogenerative diseases (Chapter 9). Knowing whether we have certain genes can help us inform our strategy for longevity.
Ultimately, Attia hopes to replicate the centenarian effect. The goal is to compress morbidity or shrink the period of decline in later years while extending healthspan. He wants everyone to have a briefer period of morbidity.
Part 2, Chapter 5 Summary: “Eat Less, Live Longer: The Science of Hunger and Health”
In Chapter 5, Attia focuses on the molecule rapamycin, which comes from Easter Island, the world’s most isolated land mass located in the southeastern Pacific Ocean. Rapamycin has done “something that no other drug had ever done before: extend maximum lifespan in a mammal” (74). Rapamycin slows down the process of cellular growth and division, which is responsible for aging, by acting on mTOR (mechanistic target of rapamycin). mTOR is a protein found within cells of all life forms.
The mTOR protein helps “balance an organism’s need to grow and reproduce against the availability of nutrients” (77); mTOR activates growth mode in cells when food is plentiful. Food scarcity suppresses mTOR, leading to cell division and growth slowing or stopping so organisms can conserve energy. Based on research, it appears caloric restriction and mTOR appear important to our understanding of longevity.
Caloric restriction (and exercise) seems to activate an enzyme called AMP-activated protein kinase (AMPK). AMPK stimulates the creation of new mitochondria, which are organelles that produce energy in cells. These new mitochondria replace old and damaged mitochondria, helping cells produce more energy (called ATP). AMPK also prompts glucose production in the liver and the release of energy housed in fat cells, which serves as fuel for the new mitochondria.
AMPK also inhibits mTOR’s cellular growth regulation activity. This causes cells to go into autophagy, a cellular recycling process. During this process, the body breaks down and reuses old cell parts, enabling cells to “run more cleanly and efficiently and helps make them more resistant to stress” (83). Autophagy declines as humans age. Impaired autophagy might drive age-related diseases. Thus, giving rapamycin to aging humans might help invigorate autophagy, extending lifespan.
Rapamycin does have serious side effects, including potential immunosuppression. Clinical trials are trying to determine whether the lifespan-extending benefit of this molecule outweighs its risks. Attia believes so.
Part 2, Chapter 6 Summary: “The Crisis of Abundance: Can Our Ancient Genes Cope With Our Modern Diet?”
Metabolic health is the focus of Chapter 6. When someone is metabolically healthy, their body processes nutrients and sends them to the right place. In contrast, when an individual is metabolically unhealthy, the nutrients end up where they are not needed. Hormones, particularly insulin (produced in the pancreas), help the body decide where to put energy from food.
The body can store energy for near-term use, such as when carbohydrates are converted into glycogen, which typically goes to the skeletal muscle and liver. Energy can also be stored for long-term use. Here, energy is stored as fat. Subcutaneous fat, located just below our skin, is “the safest place to store excess energy” (97). Attia underscores that subcutaneous fat helps maintain metabolic health since it absorbs extra energy and stores it for later use. It becomes an issues when someone reaches capacity to store excess energy in their subcutaneous fat (likely because they are sedentary). This energy still needs a home. It begins to infiltrate organs, becoming visceral fat, which is dangerous. Visceral fat drives inflammation. Genes influence fat-storage capabilities.
When excess fat moves to the muscles, it causes serious issues, including insulin resistance. While insulin resistance appears to start in muscles, it also occurs in fat and the liver. Insulin resistance is when cells no longer respond to insulin’s signals, impairing cells’ ability to take up glucose from the blood. Insulin resistance impairs our ability to store energy as anything other than fat, which leads to more fat accumulation. High fasting blood glucose numbers on a blood test indicate that a person has high insulin and blood glucose levels (signs of hyperinsulinemia).
Hyperinsulinemia is associated with type 2 diabetes, which is known as a “disease of civilization” since it is associated with modern times. Nearly half of the US population either has prediabetes or diabetes. Diabetes puts people at greater risk for cancer, heart disease, and neurogenerative diseases. The Horsemen diseases are a result of a mismatch between our evolutionary and modern environments (See: Background).
There are five important criteria related to metabolic dysfunction: high blood pressure, high lipid in the blood (triglycerides), low HDL cholesterol, obesity, and elevated fasting glucose. Metabolic dysfunction also increases the risk of the other three Horsemen diseases. Metabolic syndrome means an individual meets three or more of these criteria. Attia finds value in this concept because “it helps us see these [metabolic] disorders as part of a continuum and not a single, binary condition” (108). Monitoring biomarkers related to metabolism helps Attia spot early signs of trouble in his patients.
Part 2, Chapters 4-6 Analysis
In this section, Attia draws on several anecdotes and research studies to help explain key biological concepts around The Importance of Living Better for Longer. One is the discovery of rapamycin. Locals on Easter Island have long touted the healing benefits of their soil. A Canadian scientific and medical expedition team brought back the first soil samples in 1964. These samples eventually ended up with Canadian biochemist Suren Sehgal, who worked for a pharmaceutical company in Montreal. When the company closed, they ordered Sehgal to destroy the samples. He disobeyed and brought them with him to his next job in New Hampshire, where he was the first to scientifically prove the healing properties of this molecule.
Attia raises the concept of luck several times in this story. In many ways, the story of rapamycin is another example. It was luck that the soil ended up with a scientist who refused to listen to company orders. Had Sehgal complied with these orders, the world might not have known about the scientifically-proven healing properties of rapamycin for many more years. This could have delayed the discovery of critical treatments for cancer.
Another is the scientific study that first demonstrated that rapamycin extends mouse lifespans in 2009, even when given late in life. Attia repeatedly notes that studying longevity in humans is difficult because of timescale, replicability, and study-size challenges. Researchers use animals, such as mice, rather than humans to overcome these challenges. The results from this 2009 study were especially compelling because they used many genetically-diverse mice (nearly 2,000) and the study has been replicated. The conclusion from these studies (and others on fruit flies and yeast) suggested that rapamycin might have similar lifespan-extending impacts on humans.
Attia continues to tackle myths around biological concepts. Here, he takes issue with the focus on the obesity epidemic. Modern medicine equates obesity with being unhealthy. While being obese does put people at greater risk of acquiring one of the Horsemen diseases, obesity’s relationship to health is complex. Multiple studies have found that “not everyone who is obese is metabolically unhealthy, and not everyone who is metabolically unhealthy is obese” (93). Medicine 2.0 treats obesity and metabolic health as if they are the same when they clearly are not: Obesity is one of five criteria that indicate problems with metabolic health.
Attia continues to build on his theme Proactive Versus Reactive Medicine. Throughout the book, Attia recommends a battery of tests that readers should do. One of these tests is the DEXA scan, which measures bone density and body composition (body fat and muscle mass). Attia has his patients complete a DEXA scan yearly. To him, the visceral fat number is far more important than total body fat. Having even just a little bit of visceral fat causes health problems, including cardiovascular disease and type 2 diabetes. Attia argues that knowing your visceral fat number helps an individual create a plan that addresses visceral fat if it is an issue. Understanding key biomarkers will enable people to reach their longevity goals.
