Aging & Longevity

Six Intriguing Ideas from David Sinclair’s Book, Lifespan: Why We Age — and Why We Don’t Have To

In his book, Harvard’s Dr. David Sinclair presents concepts such as the Information Theory of Aging — how modifications to our DNA may cause aging.

By Bennett M. Sherman

Key Points:

Dr. Sinclair presents six key ideas in Lifespan: Why We Age — and Why We Don’t Have To:

  • Aging is a disease: Instead of treating age-related diseases, we must focus on their root cause — aging.
  • The Information Theory of Aging: According to this theory, aging results from the progressive loss or corruption of epigenetic information stored as molecular modifications on DNA — epigenetic changes.
  • Longevity-promoting factors: More and more research is focusing on longevity factors that may slow age-related epigenetic changes, such as sirtuins, nicotinamide adenine dinucleotide (NAD+), and target of rapamycin (TOR).
  • Activating the survival network: Some everyday practices like calorie restriction, cold exposure, and intermittent fasting may activate longevity genes — referred to as the survival network — and possibly extend lifespan.
  • Chemical and technological routes to a longer life: Several existing compounds and future technologies have the potential to extend lifespan and alleviate age-related diseases like the NAD+ precursor nicotinamide mononucleotide (NMN).
  • Implications for our future: A longer-living global population may pose a geopolitical and economic conundrum and have adverse impacts on the environment; however, Dr. Sinclair believes human innovation may counteract these dangers.

Dr. David Sinclair, a Harvard professor and award-winning expert on aging, wrote a popular book on aging titled Lifespan: Why We Age — and Why We Don’t Have To. In his book, published in September 2019, he covers six groundbreaking ideas.

Reclassifying Aging as a Disease

The first thought-provoking idea Sinclair writes about is reclassifying aging as a disease. The rationale behind this conception comes from the fact that researchers currently look for cures for individual age-related diseases like cancer and Alzheimer’s disease. With this “whack-a-mole” approach to medicine, in the sense that we attack diseases individually, we do not get to the root problem. Behind each age-related disease are common aging processes that take a toll on our bodies.

As Dr. 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.”

The thing is that stopping the progression of one age-related disease does not make it less likely we will die of another. While lifespans have increased with the “whack-a-mole” approach to confronting each disease on its own, we still do not get more years where we live disease-free (no increased healthspan). Thus, targeted research on aging itself may hold the key to alleviating multiple aging-associated diseases and prolonging human lifespans.

The Information Theory of Aging

The second key idea presented in Dr. Sinclair’s book is the Information Theory of Aging. For this theory, Dr. Sinclair proposes that the single underlying cause of aging is the loss of information contained within chemical modifications on DNA from the progressive corruption and deterioration of this information. He refers to the information contained in chemical modifications on DNA as epigenetic information. According to this theory, the age-related loss of epigenetic information provokes the so-called hallmarks of aging, physiological characteristics that arise because of aging or which may cause aging.

Techniques for restoring epigenetic information seen during youthful years are in the works. Already, in aged mice, activating certain genes called Yamanaka factors has been shown to extend remaining lifespan by 109%. Through the application of these Yamanka factor-activating gene therapies or future pharmaceuticals which also activate them, humans may one day have a chance to revert their epigenetic information to more youthful states. In doing so, we may have new ways to rejuvenate tissues and cells, making certain organs younger.

Factors that May Hold the Key to Age Reversal

The third critical idea presented in Dr. Sinclair’s book is the concept of longevity factors. These molecules, namely sirtuins, NAD+, TOR, and AMP-activated protein kinase (AMPK), may also hold the key to reversing aging.

  • Sirtuins: Proteins within cells that come in seven different varieties: SIRT1-7. Fascinatingly, they have been linked to inflammation, metabolism, and DNA repair, all of which play roles in driving aging as we get older. Sirtuins also depend on NAD+ to perform their tasks.
  • NAD+: This molecule is found in every cell of the body that is critical for cellular function and energy generation. Concentrations of cellular NAD+ have been shown to decline with age. Proteins like sirtuins and poly(ADP-ribose) polymerases (PARPs) depend on NAD+ for DNA repair and cellular maintenance..
  • TOR: This is a protein complex that regulates metabolism and growth. TOR sends a distress signal when cells require DNA repair and plays a crucial role in digesting old proteins — a process called autophagy. Somewhat surprisingly, suppressing TOR, referred to as the mammalian target of rapamycin (mTOR) in mammals, with a compound called rapamycin has been shown to extend mouse lifespan. These data suggest this protein’s critical role in aging.
  • AMP-activated protein kinase (AMPK): This is an enzyme with key roles in aging processes, according to Dr. Sinclair. As a metabolic control enzyme, it evolved to respond to low energy levels. With low energy levels, AMPK triggers the cellular uptake of sugar (glucose). Interestingly, some data suggests that activating AMPK extends lifespan in organisms like worms.

    Practicing Routines that Activate Survival Networks

    The fourth idea Dr. Sinclair provides is a series of routines that activate the body’s survival networks. Reaping some activation of these survival networks, according to Dr. Sinclair, may delay aging.

    Accordingly, Dr. Sinclair provides a list of five things we can do to induce just enough biological stress to activate our survival networks:

    • Eating less: Research has shown that restricting calories over a large portion of mice’s lifespan significantly prolongs their lives. Long-term calorie restriction may also extend human lifespan, according to Dr. Sinclair. However, clinical trials need to be done to confirm this notion.
    • Intermittent fasting: As an alternative to cutting calories, timing when you eat may confer similar pro-longevity benefits. One way to practice intermittent fasting entails limiting your intake of food to an eight-hour window each day, fasting for the remaining 16 hours.
    • A low-protein, vegetable-rich diet: Limiting protein intake to reduce the consumption of certain protein building blocks — amino acids — in your diet has been linked to TOR inhibition. Suppressing TOR may help to prevent cell powerhouse (mitochondria) damage, according to Dr. Sinclair, thus improving their function.
    • Exercising: Research has shown that regular exercisers have longer protective caps composed of repetitive DNA sequences at the ends of chromosomes — telomeres. The age-associated shortening of telomeres has been dubbed a hallmark of aging, either occurring because of aging or partially contributing to it. Moreover, exercise has been associated with increasing the beneficial longevity factor NAD+.
    • Cold exposure: Cold exposure includes activities like bathing in ice water. According to Dr. Sinclair, cold temperatures activate sirtuins. Cold exposure may also increase levels of brown fat tissue in the back and shoulders. Higher levels of brown fat have been associated with lowering the risk of age-related diseases like cardiovascular problems and diabetes.

      Compounds that May Extend Lifespan

      The fifth conception that Dr. Sinclair presents is that we may already have compounds that have lifespan-prolonging benefits. He lists four of them:

      • Rapamycin: The FDA has already approved this compound to prevent tissue rejection in organ transplant recipients. Interestingly, some aged people have repurposed this molecule for its potential age-slowing properties. Rapamycin has anti-inflammatory properties and has been shown to extend mouse lifespan by 9% to 14% when given in the later stages of life.
      • Metformin: This drug, used to treat diabetes, has also been linked to a longer lifespan. Furthermore, research in rodents suggests that metformin confers anti-cancer benefits.
      • NAD+ boosters: Two variants of NAD+-boosting molecules continue to grow in popularity — NMN and NR. Research suggests that they promote physical function in humans and prolong female fertility in rodents. Human trials are in the works to confirm NMN’s and NR’s potential pro-longevity benefits.

        Future Implications for a Population Boom of Aged People

        The final conceptions that Dr. Sinclair discusses in his book are implications for our future if we see a significant leap in our average lifespans. Even if new technologies, supplements, and drugs extend our lives only by a decade, the population surge could push our planet to a breaking point.

        A population upsurge of aged people could lead to overcrowding, overconsumption of the globe’s resources, and more waste. What’s more, politicians could possibly serve for 50 to 100 years with outdated views. Social security would need to be restructured, and people may even need to retire at later ages. Finally, the rich would likely have first access to age-slowing interventions, thus exacerbating social inequalities.

        According to Dr. Sinclair, a world population surge from increased average lifespans may bring new innovation, though. Because of human ingenuity, Sinclair does not believe there should necessarily be a maximum capacity to our planet. He also thinks that overcoming age-related diseases with new anti-aging technologies would save trillions on healthcare and possibly give new incentives for more peaceful resolutions to global conflicts.

        Possible Benefits from Longer Lifespans

        Dr. Sinclair’s book Lifespan: Why We Age — and Why We Don’t Have To presents these six conceptions that provide a glimpse into what longevity researchers are aiming for. According to these ideas, not only may we find ways to live longer in the future, but we also already have potential age-slowing compounds and technologies under investigation. If we treat the root of all aging-associated diseases — aging — with the new discoveries that aging researchers are looking for, we may also reap prosperity from spending less on healthcare as we get older.


        Book Summary: Lifespan by David Sinclair. Hustle Escape (2020).


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