PDF Summary:Lifespan, by David Sinclair

For all of recorded history, people have seen aging as an inevitable fact of life. Biologist and geneticist David Sinclair disagrees: He believes that old age is a deadly disease, and he’s dedicated his life to curing it.

Sinclair is a professor of genetics and co-director of the Paul F. Glenn Center for Biology of Aging Research at Harvard University. He argues that it’s not only possible—but inevitable—that we’ll learn to overcome the aging process. New medicines and technologies will increase our maximum lifespan and years of health until eventually humans won’t have a maximum lifespan—we’ll stay young and healthy forever.

In Lifespan, Sinclair discusses why aging happens, how we can prevent it, and how we might create a world where nobody has to die of old age. This guide explains Sinclair’s ideas and provides background information to make complex biological concepts more accessible to the average reader.

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However, age is the single biggest risk factor for numerous conditions, ranging from heart disease to cancer to Alzheimer’s. Therefore, if we could prevent—or better yet, reverse—the effects of aging, then average life expectancy and quality of life would both skyrocket.

The Healthspan Question

Sinclair uses the term healthspan, meaning how long a person stays healthy (in the same sense that lifespan means how long a person stays alive). Healthspan is a relatively new concept and still somewhat controversial: Some researchers argue that there’s no clear definition of what “healthy” means, and no concrete way of measuring “health,” and therefore it’s not appropriate to use the term in scientific literature.

However, even those who say that “healthspan” shouldn’t be used scientifically acknowledge that it’s useful when talking to the general public, who are generally more concerned with understanding broad ideas.

Killing Senescent Cells to Preserve Other Cells

As we get older, our cells start to shut down, which causes a lot of the deterioration that we experience as we age. Sinclair believes that destroying those cells before they cause too much damage can significantly extend both life and health.

Cells that are no longer able to divide, or that suffer genetic or epigenetic damage too severe to repair, can enter senescence: They don’t function anymore, but they also don’t die when they should (leading some researchers to refer to them as “zombie cells”). Furthermore, senescent cells can cause other cells to enter senescence, so the process only accelerates once it’s begun.

Sinclair says that senescent cells send out chemicals that cause inflammation in surrounding tissue, which is associated with symptoms of aging. Therefore, it seems likely that senescent cells are responsible for many of the negative effects of old age.

Researchers found that destroying senescent cells in mice extended their remaining lifespans by a third or more and reversed many of the effects of aging; in theory, the same principle should apply to humans. To that end, researchers began testing senolytics (“senescence destroyers”) on people in 2018, though Sinclair says it could be years before we have any conclusive results about their effectiveness and safety for human patients.

The State of Senolytics

The Mayo Clinic began human trials of senolytics in 2018, as Sinclair said. Four years later (as of this guide’s publication), Mayo Clinic’s website shows that at least one trial is currently in phase 2: assessing safety, effectiveness, and best practices for the treatment.

Phase 3 involves testing the treatment on large numbers of people and comparing it to current treatments. After this, the product will be ready to go to market. An optional phase 4 trial would later study the long-term effectiveness and safety of the new treatment.

Protecting Health With Technology

While the focus of Sinclair’s work is undoing the damage caused by aging, he also believes that technology will extend our years of health by letting us recognize and treat diseases before the symptoms even begin. Improved DNA sequencing techniques will allow us to find genetic markers and risk factors for numerous conditions, while biometric devices (like smartwatches) can track our vital signs and warn us of potential problems. Furthermore, Sinclair believes that having access to this detailed information will allow experts to design diets, exercise programs, and treatment regimens that are custom-tailored to your genetics and lifestyle.

(Shortform note: Sinclair’s vision of using technology to prevent disease isn’t hypothetical; geneticists can already use DNA analysis to determine if someone’s at risk for cancer, Parkinson’s, and numerous other diseases. Also, when Sinclair says biometrics, he just means taking information about your vital signs like heart rate and blood pressure. It’s the same data that doctors collect in the medical office, so it’s not unreasonable to imagine relying on wearable tech like smartwatches instead of visiting a doctor in person.)

Of course, sharing such intimate personal data comes with enormous privacy and security concerns. Sinclair says we’ll each have to decide how much we’re comfortable with sharing, but he personally believes it’s more than worth the risk—much like how our cell phones collect tons of data about us, but we still use them. In fact, Sinclair shares that he uses biometric devices himself, and that the insight he gains from them is worth the potential risks.

(Shortform note: While Sinclair is talking about using biometrics to track our vitals, biometric technology—including tech that’s already widely used—encompasses a lot more than heart rate and blood pressure. Biometric security devices can use everything from your fingerprints to the sound of your voice to determine that you are who you say you are. The main security risk with biometric data is that it can’t be altered; if a hacker got your password you could simply change it, but if a criminal had your fingerprint, there would be no way to lock him out of the system while still allowing yourself to access it.)

On a less personal level, Sinclair says that improved technology such as new vaccines and 3D-printed organs—which don’t force you to wait and hope that a match becomes available—will enable us to avoid diseases and recover from grievous injuries or surgeries more easily.

(Shortform note: Scientists are currently working on creating functional organs in a lab using 3D-printing technology, but the process is still in its infancy. Experts say that we might be as much as 30 years away from the sort of organs-on-demand that Sinclair envisions.)

Clearing Epigenetic “Noise” With Sirtuins

When it comes to repairing epigenetic damage, Sinclair’s work focuses on sirtuins—enzymes that regulate the epigenome. He believes he can reverse many of the effects of aging by bolstering our sirtuins because they’re involved in everything from repairing DNA to suppressing inflammation—all of which they accomplish by activating or deactivating certain genes in response to certain stressors.

We’ve already discussed Sinclair’s theory that DNA damage doesn’t directly cause aging. Now he adds that sirtuins have to move away from their usual functions in order to repair DNA damage. As we age and start suffering from more and more problems, this leads to two issues: First, the sirtuins aren’t able to get back to their positions before they have to rush out to repair more damage. Second, sometimes they don’t return to the correct positions. These two things lead to epigenetic chaos—genes that should be active are deactivated, and vice versa.

Therefore, manipulating sirtuins to work more effectively—which scientists have done in mice with drugs like resveratrol—helps combat the effects of aging and extends life. The next step, Sinclair says, is to find drugs that cause the same effects in humans.

(Shortform note: Sirtuins are a relatively new area of study, and while initial research results look promising, there isn’t yet much evidence that we can effectively manipulate them in humans or that we’d get the desired results by doing so. A scientific review from 2020 summed up the results of many different studies on sirtuins in organisms ranging from yeasts to primates. In short, it says that sirtuins are “promising targets” for therapies to treat everything from age-related diseases to cancer, but there are still few (if any) studies using human subjects.)

Turning Back the Clock With Yamanaka Factors

Sinclair believes that the true cure for aging may be a set of four genes, called Yamanaka factors, that reverse aging in cells—not just the effects of aging, but aging itself. Shinya Yamanaka, the stem cell researcher who discovered these genes’ potential, showed that they could cause adult cells in a petri dish to revert to immature stem cells. Those stem cells could then re-mature into young, healthy cells of any type.

Sinclair believes that it will someday be possible to use Yamanaka factors, along with other treatments, to completely undo epigenetic damage and even revert senescent cells into healthy ones, thereby resetting people’s biological clocks. He even says it might become possible within our lifetimes, though he admits that’s an optimistic prediction.

The author acknowledges that this sort of genetic de-aging therapy is a work in progress: He suspects that it’ll take at least another decade to develop methods that are both safe and effective for humans. However, Sinclair’s own laboratory has made great strides already, and he truly believes that this procedure (or one like it) will someday keep us young and healthy indefinitely.

(Shortform note: Chemist and biologist Joanna Wysocka showed that a particular group of embryonic cells—called the neural crest—naturally use Yamanaka factors to turn back into stem cells. These cells of the neural crest, which were at one point locked into becoming skin, were then able to turn into bone or muscle tissue instead. This suggests that, not only are the Yamanaka factors theoretically effective on living humans, but are in fact already a part of our development.)

Part 3: A World Without Aging

In the final part of Lifespan, Sinclair imagines what it might look like to live in a world where people live forever. He speculates on how we might create such a world, and he discusses the potential pros and cons of doing so.

Causes for Concern

In imagining a world where people never die, Sinclair starts by outlining some of the potential problems. Some of his chief concerns are:

• Stagnating scientific and social advancements. Sinclair says that progress doesn’t happen by winning over the opposition, but because the (usually older) opposition eventually dies off—if people start living for hundreds of years, that won’t happen.
• Widening wealth gaps as rich people live longer and invest more in politics to get even richer at everyone else’s expense. To make matters even worse, the wealthy will almost certainly have access to life-extending treatments long before poor and working class people do.
• Overpopulation leading to starvation, mass poverty, and worsening climate change

Should We Live Forever?

In Antifragile, Taleb says that people living forever would be a serious detriment to the species.

In brief, Taleb’s theory of antifragility—becoming stronger after being damaged—is that an antifragile system must be made up of fragile parts. An unexpected or stressful event destroys some of those fragile units, and then the rest of the system responds by not just repairing the damage, but by becoming strong enough to withstand that event in the future. A simple example is lifting weights: The exercise damages your muscles, which then become stronger as they heal.

If we consider the human race to be a system, and each person to be a part of that system, Taleb’s theory means that individuals living forever (in other words, losing their fragility) would paradoxically make the human race fragile. Perhaps some unexpected shock to the system—a disease, a war, or a natural disaster—would leave us unable to respond and recover thanks to Sinclair’s theorized stagnating science and social issues. Or, perhaps we’d simply wipe ourselves out through overpopulation.

Speculation aside, Taleb (and many others) would argue that we should not only ask can we live forever, but should we?

Causes for Optimism

Despite the risks, Sinclair says that there are numerous reasons for us to be optimistic about living forever. In short, he believes that people can and will overcome any of the previously mentioned problems through human ingenuity and grit.

Scientific and Economic Boosts

Sinclair imagines a world where people have the wisdom and experience of the elderly with the strength and energy of the youth. He believes that, with such people driving society, our rates of productivity and advancement would skyrocket—the exact opposite of the stagnation he talked about in the previous section.

(Shortform note: There is a correlation between increased life expectancy and increased productivity, which supports Sinclair’s idea here. On the other hand, correlation is not causation: it’s equally possible that some outside factor like improved technology explains both the increased life expectancy and the increased productivity. In short, both this idea and the possible stagnation from the previous section are just speculation on Sinclair’s part.)

Sinclair also says that people staying healthier for longer will be a boon to the economy. As it stands now, elderly people stop contributing to the economy at the same time that they become expensive to care for, which places an enormous burden on the economy. Therefore, keeping people healthier for longer will create more wealth; that wealth, in turn, will fund research and treatments to keep more people healthier for longer.

(Shortform note: Sinclair lives in the US and writes from an American perspective. It’s worth noting that, globally, the US ranks 46th in average life expectancy yet has the highest per capita spending on health care—in other words, nations where people tend to live longer still manage to spend far less per person than the US does. This suggests that there are other factors at work than simply how many elderly people live in the nation. Thus, age alone might not be the economic burden that Sinclair thinks it is, and rejuvenating treatments might not provide the boost he expects.)

Overpopulation Concerns May Be Overblown

Estimates of the maximum human population that Earth can support range anywhere from 8 billion (which we’ve already reached) to 16 billion. Sinclair says that a few estimates even place the maximum at around 100 billion people.

More to the point, most of those estimates don’t account for technological and societal advancements. In other words, they estimate the current maximum population that Earth could sustain, but by the time we reach that number, the true maximum could be far higher.

In fact, Sinclair says we should question the idea that there even is a maximum human population—it seems obvious that there must be a limit, but there’s no solid evidence to prove it. Perhaps technology will keep pace with our ever-growing population, offering ways to house and feed more people than we’d ever thought possible. For example, we could imagine floating cities, food replicators like those on Star Trek, and the possibility of colonizing other worlds.

Why Is There Such Uncertainty?

The enormous range of estimates for Earth’s maximum sustainable population—ranging from 500 million people to over a trillion—is the result of the wide array of techniques used to come up with those estimates.

For example, the first known estimate of Earth’s carrying capacity came from the Dutch biologist Antoni van Leeuwenhoek, who simply took the population density of Holland and multiplied it by the estimated area of livable land on Earth. He concluded that Earth could support 13 billion people.

Later studies tried to take more variables into account, such as the availability of food and fuel in different places. Still more advanced studies used dynamic modeling, trying to predict not only the available resources but how those resources would impact each other—for example, someplace with rich farmland might pollute its water with fertilizer and pesticide runoff. Naturally, the more variables a model tries to take into account, the more guesswork is involved in the final answer. Those layers of uncertainty lead to these wildly different estimates of Earth’s maximum population.

Sinclair also points out that the last two centuries saw the biggest population boom in history, but at the same time we greatly improved quality of life for most people in the world: better education, better health care, better living conditions, and so on. Therefore, there’s no reason to assume that further increasing the population will reverse that trend.

Furthermore, even as our population increases, the environmental impact of each individual is going down. We’ve made great strides in reducing air and water pollution, and we’re moving toward using cleaner energy sources. There’s little doubt that we’ll continue making such advancements.

(Shortform note: Sinclair is severely downplaying the environmental impact of an ever-increasing human population; while it might be true that each individual will cause less harm as technology continues to advance, the overall harm we cause is still enormous. For example, a study from 2015 calculated (using very conservative estimates) that vertebrate species are currently going extinct 100 times faster than the natural extinction rate. It would take some truly incredible advances in clean energy production, agriculture, and waste management to offset the damage if our population keeps growing.)

Finally, birth rates have much more impact on the total population than death rates. Sinclair says that, globally, about 55 million people die each year—which sounds like a lot, but it’s nowhere near as many as are born each year.

(Shortform note: Again, Sinclair might be overly optimistic here. In 2020, the global population experienced roughly 140 million births and 60 million deaths, for a total increase of about 80 million people. If anti-aging technology had prevented or greatly reduced those 60 million deaths, the overall increase in population could have been nearly twice what it was—140 million people instead of 80 million—which is much more significant than Lifespan makes it sound.)

How to Create the Best Future

The point of all this speculation is to (somewhat) predict and prepare for the future. Sinclair believes it’s inevitable that we’ll cure the disease of aging, so his final goal in Lifespan is to propose ideas for how we could prepare society for people living forever.

The overall idea is that we have to stop thinking about long-term issues as “somebody else’s problems.” We need to take accountability for the future—not just the near future, but 100 or 200 years down the road—and encourage others to do the same. For example, many people aren’t concerned about climate change because they expect to be dead before the worst effects hit us; if those people thought they’d have to personally experience the drought, famine, deadly heat, and extreme storms that climate change will bring, they would probably push harder for solutions.

To that end, Sinclair says we’ll have to fight for major advancements in almost every aspect of society. We’ll need more efficient ways of producing and transporting food, a health care system that doesn’t accept the effects of aging as inevitable, and a commitment to reducing our consumption and waste production by breaking our addiction to “stuff”—in other words, we need to live sustainably, taking only what we need.

In summary, Sinclair believes that we can not only cure the disease of old age, but also create a world that’s able to support an undying human population in safety and comfort. It will require major changes in how we think about almost every aspect of society, but Sinclair says that it’s not only possible, but necessary to do so.

What Is Sustainability?

When Sinclair talks about preparing for a future where people live forever, he’s really talking about sustainability—meeting our present needs while ensuring that people in the future will also be able to meet theirs.

Over the last few decades, as people have become more conscious of our impact on the future, sustainability has become a big enough concern that some of the world’s largest companies have named it as one of their top priorities. They’ve also developed clearer pictures of what sustainability means, and commonly break it down into three key areas:

• Environmental sustainability. This is what most people think of when they hear “sustainability.” In short, it means reducing your impact on the environment by using water and fuel as efficiently as possible, minimizing your waste output, and replenishing what natural resources you can (planting food or trees, recycling whenever possible, and so on).

• Social sustainability. Basically, supporting the community you live and work in. On a corporate level, this often means making sure that products come from ethical sources, that the workplace is safe, and that employees can enjoy a good work/life balance. On an individual level it could mean doing volunteer work, running fundraisers for local causes, or hosting social events.

• Economic sustainability. This area of sustainability is all about managing risks, following the rules, and ensuring long-term profitability without sacrificing the other aspects of sustainability. This is almost purely a corporate concern, but if you were to adapt it for the individual, you could say that it’s about doing worthwhile work, investing responsibly (making sure that you’re supporting good causes with your investments, not just looking for maximum returns), and not turning to illegal practices for a quick buck.

If Sinclair is right that people could someday live for hundreds of years, then sustainability will become a more important (and personal) issue than ever before.