Book Summary: Lifespan by David Sinclair

A book summary of the key ideas from Lifespan: Why We Age – and Why We Don’t Have To by David Sinclair, along with informal notes and the view from the blog.

Book Summary: The Key Ideas

#1: Aging is a disease: We must move away from treating age-related diseases and focus on their root. Reclassifying aging as a disease is a critical first step in this shift in approach.

#2: The Information Theory of Aging: The loss of analog information in the epigenome is the universal cause of aging.

#3: The longevity genes: Research is increasingly focusing on understanding the role of some specific longevity factors, such as sirtuins, NAD, and TOR.

#4: Activating the survival network: Research shows some day-to-day practices, such as calorie restriction, intermittent fasting and cold exposure, can activate our longevity genes and potentially extend lifespan.

#5: Chemical and technological routes to longer life: Several existing drugs and future technologies offer the potential to extend lifespan and reduce age-related diseases.

#6: Implications for our future: A longer-living global population poses a potential economic, political and environmental earthquake. Human innovation is capable of countering these dangers.

Book Notes: The Key Ideas in Detail

Premise of the Book

  • David Sinclair is an award-winning academic in the field of aging.
  • The book provides an introduction to the new science of aging, as well as providing insights on how we might be able to extend our lifespans right now.

Key Idea #1: Aging is a disease

  • Sinclair believes we’re wasting money and time on what he calls “whack-a-mole” medicine.
  • We’re pursuing cures for individual diseases like cancer, heart disease and Alzheimer’s, but these don’t get at the real root of the problem: aging.
  • As Sinclair puts it:

“There is nothing more dangerous to us than age. Yet we have conceded its power over us. And we have turned our fight for better health in other directions.”

  • Stopping the progression of one disease doesn’t make it any less likely that a person will die of another. While lifespans have increased because of this approach, increases in health span haven’t kept pace.
  • Failure to define aging as a disease is also stunting research funding to understand the biology of aging.
  • By defining aging as a disease, laboratories would grow, and innovation and competition would flourish as labs compete for funding.
  • Countries that move to this definition first will have a first-mover advantage.

Key Idea #2: The Information Theory of Aging

  • Traditional aging theories pointed to our bodies’ natural selection and DNA mutation as universal causes of aging.
  • But these theories have been largely disregarded as universal causes because free-radical damage doesn’t actually lead to aging and clones have proven that DNA damage does not cause it.
  • The scientific perspective has instead coalesced around 8-9 hallmarks of aging, as opposed to a universal cause. These include telomere shortening, genomic instability, and mitochondrial dysfunction.
  • Address one of these hallmarks of aging, and you can slow aging. Address all of them, and potentially you can stop it.

The Information Theory of Aging:

  • Despite the focus on these hallmarks of aging, Sinclair believes there is a single cause of aging: loss of information.
  • Unlike past theories, which focused on the loss of robust, digital information in the form of DNA, Sinclair believes aging is caused by the loss of analog information.
  • This analog information resides in what is known as the epigenome, and because it’s analog, it is prone to epigenetic “noise”. In other words, changes in our genes and enzymes can provoke the hallmarks of aging.
  • It’s our genetic, primordial survival kit, evolved over millions of years, which helps regenerate cells, fight disease and protect our immune system. But loss of information in this “survival kit”, as Sinclair calls it, is also the cause of our aging.

Key Idea #3: The longevity genes

  • Much of recent aging research has focused on several longevity factors which may hold the key to understanding and stemming the loss of analog information: sirtuins, NAD, and target of rapamycin (TOR).
  • Sirtuins: These are a family of proteins that regulate cellular health. The seven sirtuins in the cell play a variety of roles have been linked to the aging process, inflammation, energy efficiency and DNA repair. They play a key role keeping cells in balance, but they can only function in the presence of nicotinamide adenine dinucleotide (NAD). Research is increasingly showing how sirtuins can become “distracted” and “overworked” when dealing with too many DNA repairs, precipitating quicker aging.
  • NAD: Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme found in every cell in the body. NAD helps turn nutrients into energy and works like a personal assistant for proteins that regulate other cellular functions, such as sirtuins. It’s involved in hundreds of metabolic processes, but levels of NAD decline with age.
  • TOR: This is a complex of proteins that regulates growth and metabolism. Like sirtuins, TOR has been found in every organism in which scientists have looked for it. TOR provides a distress signal when DNA repair is required and plays an important role in digesting old proteins.
  • AMPK: This is a metabolic control enzyme, evolved to respond to low energy levels, activating glucose and fatty acid uptake and oxidation when cellular energy is low.
  • The critical point among the science jargon is that we find these same genes in every organism on the planet – trees, yeast, worms, whales, humans, etc – but some of these live an exceptionally long time and others not. Scientists want to understand why.

Key Idea #4: Activating the survival network

  • The commonality of these longevity genes is that they are all activated in response to biological stress. Some activation may be key to delaying aging but overworking them leads to a loss of epigenetic information and aging.
  • The key, Sinclair believes, is to activate our survival network of longevity genes just enough and in just the right way.

Things we can do:

  1. Eat less: Countless studies have shown significant increases in lifespans of mice and other mammals when calories are restricted over a large portion of their lives. Long-term calorie restriction may therefore increase lifespan, but it’s not an appealing solution.
  2. Intermittent fasting: There is emerging evidence that we can cheat this process through periodic calorie restriction, regularly skipping a meal or fasting for a few days.
  3. Lower protein, vegetable-rich diet: The reduction of amino acids (found in meats) leads to the inhibition of mTOR (which can help protect mitochondria from damage). Evidence on the reduced risk of heart disease, cancer and other diseases is now widely accepted.
  4. Exercise: More frequent exercisers have larger telomeres in studies. Exercise appears to shift cells into survival mode, raising NAD levels which in turn activates the survival network, growing oxygen-carrying capillaries in muscles. High-intensity interval training appears to be the most effective form.
  5. Cold exposure: Exposure to cold activate sirtuins, which in turn activates brown fat in our backs and shoulders. The presence of higher levels of this “brown fat” is associated with lower age-related disease.

Things that overwork our epigenome:

  • Smoking and passive smoking; pollution, PCBs and other chemicals in plastics; solvents and pesticides; food treated with sodium nitrate such as beer, cured meat, and cooked bacon; radiation from x-rays, gamma rays and UV light.
  • Sinclair recognises the impossibility of avoiding all these things, noting that the epigenome is set up to deal with a certain level of DNA breakages. The balance is ensuring we limit the damage as much as possible.

Key Idea #5: Chemical and technological routes to longer life

  • Sinclair next turns his attention to some of the research on chemical compounds and technological solutions that may have the potential to extend life.

Existing drugs and compounds:

  • Rapamycin: This lowers immune response and is used to facilitate organ transplant acceptance. Mice given small dosages in the final months of their lives lived 9%-14% longer.
  • Metformin: This is a diabetes drug which has also been linked to longer lifespan. In 25 out of 26 studies of rodents treated, metformin showed potential as a protector against cancer. It’s less toxic than rapamycin, but similarly mimics aspects of calorie restriction.
  • Resveratrol: This is a natural molecule found in red wine, grapes and berries – albeit in low quantities. Research has shown a positive impact on heart health, as well as 20% life extensions in mice.
  • NAD boosters: These are the emerging compounds of interest. Two variants (NR and NMN) both show promising signs, while research has also found that they may prolong fertility. No human trials have been conducted yet.

The future:

  • Sinclair outlines a range of other exciting new paths, such as senolytics, which aim to kill off senescent cells, potentially rapidly rejuvenating us.
  • He also turns his attention to exciting research on the Nobel-prize winning discovery of Yamanaka factors, before explaining how personal DNA screening and biotrackers will allow us to anticipate and pre-empt diseases before they take hold.

Key Idea #6: Implications for our future

  • Even if all of this promising research only extends lifespans by a decade, the corresponding population growth could push our planet to breaking point.
  • There would be more crowding, more environmental degradation, more consumption, and more waste. Politicians could potentially serve for 50 or even 100 years with outdated views. Social security, healthcare, and the work environment would need to be completely reconsidered. And the rich would get access to the cutting-edge treatments first, widening inequalities further.
  • But population growth brings with it innovation. Sinclair believes human ingenuity means there shouldn’t necessarily be a maximum capacity to the planet.
  • He also argues we’d get an enormous “peace dividend” from ending the war on age-related diseases, saving trillions on healthcare. According to Sinclair, there is no cheaper way to address the healthcare crisis at its core than to address aging.

You can buy the book here or you can find more of our book notes here. For further interesting health-related reads, check out How to Change Your Mind by Michael Pollan and Count Down by Shanna Swan.

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