Why this book:  I had heard David Sinclair interviewed by Peter Attia and was impressed with the interview. I have just read The Longevity Paradox, and wanted to see what Sinclair had to say that might fit with, or contradict what Gundry had said in his book (they are pretty much in synch.)   Also, Sinclair and his views were among the original sources of my interest in the new longevity, about which I wrote in my essay a few years ago.

Summary in 4 Sentences: This book makes 4 important claims: First that aging is a disease and the symptoms of aging as we now know it,  are not pre-determined and can be delayed by decades or potentially indefinitely. Second, that research is progressing rapidly to better understand the biological processes of aging, and scientists are finding ways to arrest these process.   Three, there are cultural and institutional impediments to progress in this field, given that our medical system is invested in treating diseases, rather than preventing them and promoting vitality and longer health span. And Four, that it is inevitable that significantly increased life and health spans will be available to those who can afford the coming medicines and treatments,    but that change will cause some significant social disruptions, and the world is not ready.  

My Impressions: This is a wonderful book, exciting to read, even if I didn’t understand ALL  the bio physiology.  He explains why and how he is certain that in the next few decades, life expectancy for those living in healthy societies will increase by 50% and more.  Don’t believe it?  He uses the analogy of how in less than a century, we went from the Wright brothers to putting a man on the moon.  Or from a pocket calculator and a walky-talky to a cell phone connected to the whole world and the knowledge of the ages. Sinclair’s enthusiastic belief in this vision of significantly increased life and health span is infectious, but he doesn’t shy away from the challenges his prognosis presents. Lifespan is written in three parts: 

Part 1 WHAT WE KNOW (THE PAST).  In Part 1, he introduces us to some of the research that has led to the key bio-physiological bases for his predictions.  A key player in the Longevity drama is our sirtuins.  He describes how sirtuins ” order our bodies to ‘buckle down’ in times of stress, and protect us against the major diseases of aging: diabetes and heart disease, Alzheimer’s disease and osteoporosis, even cancer.   They mute the chronic overactive inflammation that drives diseases such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis and asthma. They prevent cell death and boost mitochondria, the power packs of the cell.” p 24  Activating and energizing our sirtuins is one of the keys to increasing our longevity and health span.  Sirtuins are a key player throughout the book.

He goes on to explain how our genes work in this process,  using analogies, such as, that our genome is like a grand piano, each gene is a key on the piano, and the pianist that plays this piano is the epigenome which determines which genes are expressed, when and how. The epigenome is very much influenced by our environment and things we do, choices we make, how we live, what we eat,  and our lifestyle decisions.  So the epigenome is fundamental to who we are. He states it directly, “Studies of Identical twins place the genetic influences on longevity at between 10 and 25 percent which, by any estimation, is surprisingly low.  Our DNA is not our destiny.” p37  The “epigenome” is actually more important. 

Much of the rest of Part 1 is Sinclair making the case that aging is something that we have assumed is the way it has to be, but aging can be hacked and “cured.”   He notes that while lifespans have increased, “health spans”  have not – we have kept unhealthy, unhappy people alive for decades longer than in the past. This is not acceptable.  He notes that many of the diseases that afflict the aged can be dramatically mitigated if not “cured,” by better understanding the microbiological processes by which we deteriorate.  He gives us numerous examples of research with mice and other mammals which have had amazing results, and that some of these insights are already moving into therapy for humans. 

PART 2. WHAT WE’RE LEARNING (THE PRESENT) This is a heavy chapter which outlines the many lines of research that are supporting his thesis that aging can be “cured” and he explains the steps that anyone can and should take to extend not just their lifespan, bur more importantly, their health span. 

He discusses the research about why creating healthy stress to the body creates long term resilience -stresses such as fasting, exercise, High Intensity exercise, heat stress, cold stress – anything which stimulates the body at the cellular level to make itself stronger and more resilient to prepare for such future stresses.  Our bodies have to be nudged, or even shoved to adapt, to become stronger and more resilient.  He writes that “ A bit of adversity or cellular stress is good for our epigenome because it stimulates our longevity genes.” (p112)

We learn that a molecule called “NAD is the central regulator of many major biological processes, including aging and disease” and serves as fuel for sirtuins to do their good work.  He talks about NAD boosters that are having a positive impact on many people,  resveratrol, MTOR inhibitors, NMN molecules, metformin as an anti-cancer drug that many are taking off label. He writes that an extensive study of metformin in 41,000 users between ages 68 and 81 “concluded that metformin reduced the likelihood of dementia, cardiovascular disease, cancer, frailty, and depression , and not by a small amount.” (p125)

 We learn about senescent cells – what he calls “zombie cells” that “might as well be radioactive waste.” Our bodies create senescent cells, that are still alive, but no longer reproducing, and as they live on without doing any work, they release tiny proteins called “cytokines” that cause toxic inflammation in our bodies. He notes that inflammation is also a driving force in heart disease, diabetes, and dementia, and cause other cells to become senescent, releasing more cytokines.  Inflammation is so much a part of age-related diseases, scientists and doctors often refer to “inflammaging.”   He  shares how research is developing “senolytic” drugs which may be able to kill senescent cells , by “inducing the death program the should have happened in the first place.”(p153)

He notes how our biology is designed for us to live long enough to reproduce and raise our young. After that our evolutionary/biological work is done. Some of what has evolved to help us survive and thrive while we’re young and reproducing and raising children,  is no longer useful and becomes counterproductive as we age.  Scientists are exploring how to identify and modify these biological mechanisms that have outlived their usefulness and can inhibit health and well-being once we’re beyond our reproducing and child rearing years.  For example, senescent cells are not normally a problem for young people.  But they apparently are an important part of the aging process for those of us who are older.  

MEDICAL INNOVATION:

Pharmacogenetics – the increasing realization that medication acts differently among people of different genotypes, including often having very differently effects on men and women.  “Eventually , every drug will be included in a huge and ever expanding database of pharmacogenteic effects.  It won’t be long before prescribing a drug without first knowing a patient’s genome will seem medieval.” (p184) 

With a simple blood test, doctors will be able to scan for circulating cell-free DNA.. and diagnose cancers that would be impossible to spot without the aid of computer algorithms…We’re going to get ahead of symptoms. Way ahead.  We’re even going to get ahead of “feeling bad,’  Many diseases, after all, are genetically detectable long before they are symptomatic.” p186

We will have clothing with sensors that can track biomarkers, and other devices that will send alerts to doctors if there is something amiss with your heart rate or breathing pattern. He predicts that bio tracking will help stop acute and traumatic preventable deaths by the millions. Bio tracking will “see you when you’re sleeping and know when you’re awake..<will> be able to identify through the data when  you are feeling sad, driving too fast, having sex, or had too much to drink. “p198  There are clearly problems which accompany the advantages of such bio tracking – someone will have to keep and store and regulate access to the data.  Who will that be? Who do we trust?  Are we willing to give up that privacy?  He has a whole section on how bio tracking will be key to defeating the next pandemic (this book was written before the COVID 19 pandemic)

He writes that”Once you recognize that there are universal regulators of aging, in everything from yeast to roundworms to mice to humans… and once you realize that it’s all one disease, it all become clear:  Aging is going to be remarkably easy to tackle.  p147-8

PART 3. WHERE WE’RE GOING (THE FUTURE) In this final part of his book, Sinclair gives warning – there are serious problems that accompany the opportunity to live decades, perhaps even centuries longer.  And he looks at social and political trends internationally that are related to, and will impact the movement toward increasing health and life span.

He writes, “Most people, upon coming to the realization that longer human lives are imminent, also quickly recognize that such a transition cannot possibly occur without significant social, political, and economic change. ..there can be no evolution without disruptions.”  (p219)

He points out problems with the American medical system that does not seriously promote healthy living, and is surprised at a general American unwillingness to look at and seriously consider systems that seem to better promote health and well being. The US is ranked 24th internationally on a rating of a Human Capital Index – a measure of knowledge, skills, and health that people in a nation accumulate over their lives.  China was 25th.” (p275)

This section is a fascinating potpourri of issues that he is concerned with, that are related to his work in defining aging as a disease and improving life and health span.  Problems/issues which he identifies and explores include:

• Environmental sustainability of increasing affluence and longevity across the globe. Environmental degradation continues, as does over-consumption and increasing waste.  He quotes environmental writer George Monbiot that “consumption bears twice as much responsibility for pressure on resources and ecosystems as population growth.”  (p283)
• 100 year old politicians? As people get older and healthier, they tend to hold on to power and influence.  It may be much more difficult for younger people to bring in new ideas, and influence positive disruption when octogenarians, nonagenarians or centenarians won’t give up positions of power and influence. 
• Social Security – The expected retirement age will have to evolve.  Do we push the retirement age out to 75 or 80 or beyond?   There is no economic model which allows for large numbers of people living 40+ years beyond their retirement age. 
• Increasing the gap between rich and poor.  Currently “the richest 10% of Americans live 13 more years than the poorest 10%.”  (p231) That gap will increase dramatically, as the wealthier have access to genetic testing, gene editing, and other tools for maximizing health and life span that the poor do not.  This will have predictable disruptive social consequences.  The Rich-Poor gap will be even more dramatic internationally. 
• Older work force. There willl be more older workers, and they are different from younger workers – offering different value and liabilities in the work place.   With more older workers remaining longer in the work force, our culture will have to more actively confront the issues of age-discrimination in the work place.
• The medical profession is NOT focused on disease prevention, or helping people to live well. “Research aimed at prolonged vitality is rather paltry; the biggest checks are still being written to supporting initiatives aimed at recognized diseases.”  (p268)  “Effective longevity drugs will cost pennies on the dollar compared to the cost of treating the diseases they will prevent. “ p273)
• Individual  choice. How do we attack preventable causes of aging, such as poor diet, poor lifestyle, obesity, lack of exercise, etc that are based on individual choice?  Each individual has choices to make daily that impact their health and longevity.  “The most critical daily decisions that affect how long we live are centered around the foods we eat.” p190
• He also argues for death with dignity, and argues against spending enormous sums to keep people alive, but miserable, when the prognosis is clear. 
• GMOs To solve our food shortages and other crises, we need to accept the strong evidence that GMOs are safe. 
• CRSPR gene editing will bring changes that affects longevity that we can’t yet predict.

CONCLUSION: He writes that “Although I’m very  optimistic about the prospects for prolonged vitality, I’m not that optimistic. I don’t know any reputable scientist who is. One hundred years is a reasonable expectation for most people alive today. One hundred twenty is our known potential and one that many people could reach – again, in good health if technologies in development come to fruition. If epigenetic reprogramming reaches its potential, or someone comes up with another way to convince cells to be young again, 150 might even be possible for someone living on this planet with us right now. And ultimately there is no upward biological limit, no law that says we must die at a certain age… But these milestones will come one at a time, and slowly. Death will remain a part of our lives for a very long time to come, even as the time of it is pushed out in the coming decades.”  p 247-8

 So, what does David Sinclair do? Since he is on the cutting edge of longevity research, he is often asked this question – what does HE do to increase his own health and life span.  Below is a copy of page 304, of Lifespan where he answers that question: 

Since reading this book, I’ve added NAD+ (an NMN Booster), Vit K, and Resveratrol to the supplements I take.  And in the other areas, I’m pretty close to what David Sinclair does.  Metformin, which he argues should be a standard longevity enhancing drug for most people, still requires a prescription, primarily for diabetes.  He notes that a large portion of those who study longevity are taking metformin – off label.  They either are doctors, or know doctors who will prescribe it for them. It is very inexpensive.