Lifespan: Why We Age and Why We Don't Have To

“Aging is a disease, and that disease is treatable.” - David Sinclair

This article is a summary of the book Lifespan: Why We Age–and Why We Don't Have To, co-written by David Sinclair, PhD, a professor of genetics at Harvard Medical School, and science journalist Matthew LaPlante.

Published in September 2019, this book is a comprehensive explanation for why we age based on information theory and a conclusion that aging is a disease, and that disease is treatable.

Chapter layout

The book is laid out in three sections: past, present, and future. Casual conversations between Sinclair and LaPlante are interspersed between the sections, giving a sense of the conversational process they used to write the book.

  1. What we know – The past. Evolution and former theories of aging. Problems with our current healthcare system and how it treats aging. Hallmarks of aging and their single upstream cause, loss of analog information.
  2. What we're learning – The present. Habits that affect aging through hormesis. Molecules that can change the epigenetic landscape. Novel treatments and ongoing mouse and human studies.
  3. Where we're going – The future. Implications for the planet of longer-living humans. A message of hope and a humanitarian push to reclassify aging as a disease and increase funding.

Hallmarks of aging

Researchers can reliably measure the hallmarks of aging, such as DNA damage, telomere shortening, mitochondrial dysfunction, senescent cell accumulation, and stem cell exhaustion, among others.

While some of these are already being treated to extend lives, and tackling each of these may add several years to your life, they won't cure aging.

There have been various theories of aging in the past, mostly focused on single causes, but working on these problems hasn't significantly increased the maximum lifespan of humans.

Past theories of aging

  • DNA mutations – Changes in genetic code are not a major cause of aging. If old cells lost crucial genetic information, and that was the cause of aging, we wouldn't be able to clone new animals from older animals. Clones would be born old. But old animals retain all the requisite information to make a new, young animal.
  • Free radicals – The belief that reactive oxygen species, or chemically reactive molecules in the body, contribute to the aging process still drives much of the popularity of antioxidants. Sinclair believes that free radicals are not a major factor in aging until later in life and that it's surprisingly simple to undo their effect.

Information theory of aging

What if there was a single cause of aging upstream of all the hallmarks of aging? Sinclair believes that there is – loss of information.

Genetic code can be thought of as digital information. Like digital information, it's based on a limited set of options, base-4 data, the four nucleotides of DNA. It's actually a reliable way to store and copy information. DNA can survive boiling water and forty thousand years in neanderthal bones. So the loss of information isn't in the genetic code.

Rather, the loss is in the epigenome, or the expression of genetic code that instructs newly divided cells what they should be. If the genome were a computer, the epigenome would be the software. If the genome were a piano, the epigenome would be the concerto.

When a caterpillar turns into a butterfly the genetic code of that insect doesn't change, only the expression of its genes does – the epigenome. This information can be thought of as analog information, and when cells forget what they're supposed to be bad things happen.

Sirtuins

When damage to genetic code occurs, such as double-strand breaks of DNA, epigenetic signallers rush to address the damage. These signallers are called sirtuins.

Sirtuins are a family of seven proteins that control cellular health. They keep kidney cells from acting like liver cells from acting like nerve cells, and vice-versa.

When the sirtuins leave their normal responsibilities they can sometimes get lost or return to other places. This is like distracting the pianist – sometimes the wrong notes get played. Cells stop doing what they're supposed to do, wrinkles form, and aging occurs.

Epigenetic changes cause aging

This is why it's important to avoid damage to genetic code. Not necessarily because the damage itself is bad, but because the repair process can cause cells to lose their identity. These are the analog scratches on the digital DVDs. Epigenetic changes cause aging.

It's why our hair greys, skin wrinkles, and joints ache. It's why hallmarks of aging occur – stem cell exhaustion, cellular senescence, mitochondrial dysfunction, and rapid telomere shortening.

AMPK and mTOR

Two powerful signaling hubs work together with sirtuins to control aging and longevity.

AMPK – A master regulator of cellular energy that controls hunger and energy expenditure. AMPK activation increases catabolic processes in the body that mimic calorie restriction, which is known to reliably increase longevity. It's currently a therapeutic target for the treatment of diabetes, obesity, and cancer.[1][2]

mTOR – A downstream target of AMPK that coordinates responses such as cell growth, cell death (apoptosis), and inflammation. When you inhibit mTOR, animals live longer. Researchers believe this is because inhibition may preserve stem cell function and induce recycling of damaged cells (autophagy). There is cross-talk between mTOR and AMPK, and both appear to play a significant role in the metabolism of obesity and type-2 diabetes.[1][3]

Strategies for living longer

To live longer you must change the epigenetic landscape. Fortunately, there are established ways to help cells that have lost their identity get reprogrammed.

The three most powerful methods are to activate sirtuins, activate AMPK, and inhibit mTOR. There are molecules known to affect each one of these pathways, but there are also practical habits that can affect all at once.

Hormesis

Hormesis is the favorable biological response to low exposures of stressors. It's kind of like prank calling the pentagon – it kicks the system into action, activating all the defenses, but ultimately there is no war. This is why healthy stressors like exercise, fasting, and cold exposure are good for you and protect against disease.

One simple intervention that has existed for thousands of years in human culture and is known to extend lifespans in animals is calorie restriction. Fasting, or calorie restriction, is defined as a reduction in nutrient intake without malnutrition. It is a powerful way to activate sirtuins, AMPK, and inhibit mTOR.[3]

In addition, cold or heat shock on the body is known to induce hormesis. This means that hot saunas, cryotherapy, and cold showers stress the body in healthy ways to increase resilience.

Promising compounds

Several anti-aging compounds are known to affect the three pathways discussed above to undo epigenomic changes and help delay or reverse aging.

  • Resveratrol – Found in grape skin, resveratrol is known to activate one type or sirtuin, however, it is not very potent in humans. Pterostilbene is a more potent version of resveratrol but increases LDL cholesterol, so may not be suitable for all people.
  • NAD – Sirtuins can only function in the presence of NAD, a coenzyme found in all living cells. NAD precursors such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) increase NAD in the body and therefore activate all seven types of sirtuins.
  • Metformin – A drug that is prescribed to treat diabetes due to its effect on lowering blood sugar. Metformin mimics aspects of calorie restriction, activates one type of sirtuin, and also activates AMPK.
  • Rapamycin – A drug that reduces immune response and is therefore prescribed for donor transplants to increase organ acceptance by the body. It is known to inhibit mTOR and is currently the only known pharmacological treatment that increases lifespan in all organisms studied. Analogous molecules to rapamycin, called rapalogues, are being studied that might have wider tolerance.[3]

Final thoughts

There is much more to the book beyond the cutting-edge science. Entire chapters are dedicated to the potential effect on society of longer-living humans. It also covers Sinclair's personal anti-aging routine.

In the future, Sinclair believes that families will be monitored by biosensing wearables, small devices at home, and implants that will optimize their health and save lives by suggesting meals and detecting infections and diseases.

The book closes by making an emotional, humanitarian push to reclassify aging as a disease so that we can treat it like a problem that can be solved.