In Lifespan: Why We Age – and Why We Don’t Have To, David Sinclair Ph.D., Harvard Medical School professor and Co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging, tells a story about what we’ve learned and where we’re headed with regards to aging, the one malady that affects us all. With the book, Sinclair is clearly trying to get a message out, if we look at aging as a disease, it opens a floodgate of potential funding into research and treatments that would have a dramatic impact on all-cause mortality. Advances made in aging could provide breakthroughs for some of the most heavily funded and researched diseases, cardiovascular disease, cancer, Alzheimer’s, and Parkinson’s. Lifespan isn’t quite a manifesto, but Sinclair is clearly aiming to give us a jumpstart on the future by bringing us up to speed and setting the stage for what’s at stake.
The Information Theory of Aging
Sinclair backs up his call to have aging classified as a disease by revealing what he terms the Information Theory of Aging. The IToA model starts with a perfect expression of the epigenome from our youth. Over time, several factors (environmental, exposure to toxins, etc.) break the individual strands of DNA. If the breaks proliferate, the regulation of DNA packaging in the cell degrades, causing a loss of cell identity (eg., a skin cell showing up in muscle tissue). When cell identity breaks down, it becomes senescent (an irreversible state of deterioration), and the accumulation of senescent cells leads to disease (eg., a bunch of skin cells in muscle tissue become a tumor). Disease leads to death.
Sinclair asserts there is no program in humans dictating aging as manifest destiny, we just haven’t identified how to eliminate or correct the degradation at a whole organism level. Sinclair believes (and has evidence to support) we carry a stored copy of our original cellular epigenetic information. When the stored pattern is delivered to a cell and triggered using a common virus in the lab, it sheds its accumulated methyl groups and resets to a youthful state. Sinclair describes a series of experiments in his lab where they used this technique to successfully reset the epigenetic state of retinal cells damaged from aging or trauma and restore youthful vision in mice.
Sit with that for a second.
Sinclair writes, “Surviving cancer or heart disease doesn’t substantially increase the average human lifespan, it just decreases the odds of cancer or heart disease.”
Stated a different way, ending cardiovascular disease for everyone adds just 1.5 years to our average lifespan and curing cancer only adds 2.1 years, because all other causes of death still increase exponentially. If Sinclair is right and researchers in his lab and elsewhere continue to have success on this front, the implications are staggering, way beyond simply treating or reversing disease (or resorting to cybernetic upgrades).
Sinclair devotes a significant amount of the book to address the social, ethical, and material impact of millions (or billions) of people living much longer. He falls on the side of optimism for the future but stresses the need to solve concurrent issues of consumption, modern health treatment, and environmental issues.
What Can We Do Now?
We have a long way to go before we start thinking of ourselves as Dorian Gray, but Sinclair gives us ways to slow down aging, describing the three pathways into longevity and giving five ways to influence them. If optimized, these pathways could add twenty years or more to our health span (how long we live with a high level of functionality and vitality), and that extra time could place us in a future where therapies based on IToA are available.
3 Longevity Pathways - mTOR, AMPK, Sirtuins (SIRT1-7)
While the optimal blend of activation or suppression of the longevity pathways still needs a ton of research, there is evidence showing that intervening on these three fronts can increase health, reverse disease, and potentially lengthen lifespan. Interventions include fasting, diet, exercise, cold exposure, and limiting exposure to toxins and chronic stress states, along with supplements like NR/NMN, metformin, Rapamycin, and Resveratrol.
Here are a few podcasts that can help you go deeper,
- Tim Ferriss Podcast #193 - Learn all about mTOR.
- David Sinclair on The Drive #70 - Peter Attia avoids rehashing everything from the book, spending more time on the science, and allowing Sinclair to describe the difference between cellular reset and stem cells.
- HVMN Podcast - Geoffrey Woo’s book review touches on what he agrees with, what he doesn’t, and what is missing in the conversation with ketones.
- Vamsi Mootha on The Drive #66 - A fascinating companion conversation to Lifespan with Mootha’s research on mtDNA, NAD, and exercise.
My interest in anti-aging began after spending years battling an off-the-rails autoimmune response that was so challenging that doctors, where I lived in Oregon, told me they couldn’t help me anymore. I moved to California, and when my Stanford doctors could do little to explain my astronomical inflammation, I realized to survive, I was going to need to solve the puzzle myself. As sick as I was, my doctors never expected to see me well (telling me this directly), working from the assumption they would continue to remove my digestive system bit-by-bit until I would eventually succumb to complications from malnutrition.
One day while on a webinar with Dean Kalish, a Functional Medicine practitioner and creator of the Kalish Institute, who was describing how cellular health and dysfunctional neurotransmitters are upstream issues for inflammation and dysfunctional gut, a light bulb went off. Whether causal or corollary, it is impossible to have chronic disease and inflammation without significant cellular/mitochondrial damage. I turned my focus to anti-aging because that is where the most cutting edge research and treatment for inflammation and cellular health is happening. I began measuring, tracking, and implementing my own protocols based on dozens of biomarkers, genetic information, and microbiome data.
After more than half a decade hacking my Crohn’s with strategies not even on the radar of GI doctors or experts on leaky gut and IBD, I was declared in deep remission, confirmed by biopsy. I can draw a straight line from remission through the pathways described by Sinclair,
- reducing mTor and stimulating autophagy by fasting and training as a cyclist
- activating sirtuins with training, ketosis, fasting, and repairing my body’s ability to synthesize protein
- activating AMPK by training, ketosis, and improving protein synthesis
One area of Sinclair’s book that I disagree with is the characterization and over-simplification of amino acids and protein consumption. Amino acids are what our body uses to transcribe and build cells and manage nearly every process. Some amino acids the body can produce, and some have to be eaten. Eating protein is our primary source of amino acids, and requirements vary based on general health, injury, and activity level. Deficiencies in specific amino acids lead to cell dysfunction and disease, as described by the IToA model. Eating more protein from plants or meat won’t solve the problem. A significant factor in reversing my Crohn’s and extreme inflammation was solving systemic amino acid deficiencies while supporting my body’s energy production and protein synthesis. We shouldn’t treat protein as a black-and-white, right-or-wrong subject, but like other areas of biohacking, test and gain an understanding of our needs and design protocols to address them.
I put together an effective supplement protocol to support the strategies above with methylation support, amino acids, a mineral-rich marine algae (Aquamin), Alaskan salmon oil, and a patch to support mitochondrial health with CoQ10/PQQ/NR/Resveratrol. I also have interventions to increase the oxygenation of my blood, increase ketones, boost iron levels, accelerate healing, and more in my back pocket, as needed.
At the end of Geoffrey Woo’s review (linked above), he offers a challenge to put the efficacy of Sinclair’s approach with Rapamycin, NMN, Metformin, and Resveratrol against a cyclical ketogenic diet, plus cardio and strength training. Why choose? I haven’t taken Rapamyacin or Metformin (I have recommended them both to my father), but I have significant N of 1 data showing supplementation for cellular health can have a profound effect on health and energy. Having lost seven years to chronic illness, I value the time I have and wouldn’t want to burn a decade to prove the point either way.
Bringing It Back Around
I hadn’t been as excited for a non-fiction book since reading The Gene, by Siddhartha Mukherjee. Like Mukherjee, David Sinclair weaves a story of personal significance backed up by deep domain expertise and experience with the subject. For the average reader, Lifespan should be mindblowing, if not hard to believe. For people who have experience with the aging pathways, Lifespan is a rally-cry to shine more light on the work and its potential impact (I’ve never flipped to the notes section of a book so much). I recommend buying the physical book, as it offers details like beautiful illustrations, and a “Cast of Characters” at the back with thumbnail portraits drawn by Sinclair, himself.
Aging and death unite us all, and no matter where you fall on the ethical position of life extension, we are already all beneficiaries of advancements that have pushed the mid-life crisis from our 30’s to our late 40’s or 50’s. If we get it right, Sinclair’s and other’s work, in the field of anti-aging, has the potential to be the tide that raises all boats.