PDF Summary:Jellyfish Age Backwards, by Nicklas Brendborg

Why do people get sick and die from old age, while some other organisms don’t? Is there a way to prevent aging in humans, or even to reverse it? In Jellyfish Age Backwards, biotech researcher Nicklas Brendborg uses Turritopsis dohrnii—the immortal jellyfish—as an entry point to explore the latest research on longevity. Brendborg weaves together cutting-edge science, evolutionary biology, and practical insights about diet, exercise, and lifestyle factors to explore how people can live the longest and healthiest lives possible.

In this guide, we’ll present two competing theories about why we suffer the effects of old age. We’ll then discuss various anti-aging strategies, including lifestyle changes and medical interventions. Our commentary will provide background information and scientific research that supports (or opposes) Brendborg’s assertions. We’ll also compare this book with other prominent anti-aging guides, like David Sinclair’s Lifespan. Finally, we’ll provide some actionable ideas to help you extend your life and enhance your health.

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Strategy #1: Calorie Restriction

Brendborg begins by discussing calorie restriction: dramatically reducing how much you eat.

He says that, based on various studies and observations, people who have cut their calorie intake by anywhere from around 10-25%—while still making sure to get all the nutrients they need—have shown remarkable health improvements. Some of the benefits include losing weight, reduced blood pressure, and improved immune responses.

However, by their very nature, such studies take a long time to conduct. Therefore, it’s too soon to say for sure whether calorie restriction ultimately leads to a longer lifespan in humans.

(Shortform note: Part of the reason why calorie restriction—even severe calorie restriction—can be beneficial is because it addresses a modern-day problem: People have evolved to eat too much and too unhealthily. This is because fatty and sugary foods—valuable sources of calories—were rare for our ancestors, so humans evolved to eat all the fat and sugar they could find. However, those behaviors are a serious mismatch with the modern world where fat and sugar are readily available—now, if we eat like our genes compel us to, we’re likely to give ourselves health problems like obesity, high blood pressure, and diabetes.)

While there isn’t yet a consensus about whether calorie restriction makes you live longer, Brendborg says that researchers do have theories about the health improvements they’ve recorded so far. Calorie restriction appears to trigger various cellular maintenance mechanisms, most notably autophagy.

Autophagy, which literally means “self-eating,” is the body’s way of breaking down damaged or mutated cells and recycling their components. This is not just an efficient use of resources, it’s also a way for the body to repair itself. This cellular recycling process is sort of like repairing a machine by swapping out damaged components for new ones. Although autophagy happens naturally throughout your life, it declines as you get older. Promoting autophagy through calorie restriction (or other methods, as we’ll discuss) seems to counteract this decline, which may help you maintain healthier cells into old age.

(Shortform note: Another way calorie restriction may improve health is by boosting sirtuin activity. As David Sinclair explains in Lifespan, sirtuins are a group of enzymes that regulate gene expression (which genes are active and when). However, as we age, sirtuins stop performing their gene regulation duties as effectively—so genes that should be active are not, and vice versa. Researchers have found that fasting activates sirtuins, leading to numerous health benefits, including increased cancer-fighting abilities. Therefore, like autophagy, this is another cellular maintenance mechanism that you can force your body to engage through calorie restriction.)

Strategy #2: Intermittent Fasting

Brendborg notes that severe calorie restriction is an unrealistic approach for most people—they’d find that any benefits to their health and lifespan aren’t worth the discomfort of constant hunger. However, intermittent fasting (IF) may offer similar benefits while being much more sustainable for the average person.

IF is a dietary strategy that limits when you eat, rather than how much you eat. For example, common methods include setting an eight-hour window each day during which you’re allowed to eat (say, between 9:00 am and 5:00 pm), and alternate-day fasting: eating normally one day, then eating little or nothing the next day, and repeating that pattern indefinitely.

According to Brendborg, recent research has suggested that the life-extending benefits of calorie restriction may actually be due to longer periods of fasting between meals, rather than eating fewer calories overall. In other words, autophagy and other maintenance processes trigger after you go for a long enough time without eating, even if you still eat the same amount of food overall.

(Shortform note: Research supports Brendborg’s argument: Intermittent fasting has health benefits that are comparable to the benefits of calorie restriction. However, contrary to Brendborg’s idea that the time between meals is the key point, many researchers believe that IF is effective because it’s basically a simplified version of calorie restriction. By limiting when you eat to specific time windows, you naturally consume less overall, creating a calorie deficit. If that’s the case, then IF’s main advantage is simplicity—you can get the same results without needing to count calories and carefully track everything you eat. As a result, many people find intermittent fasting more sustainable than traditional kinds of dieting.)

Healthy Stressors

The second lifestyle strategies Brendborg shares have to do with healthy, positive forms of stress—mild hardships that strengthen the body instead of weakening it. In biology this is called hormesis: a phenomenon wherein small amounts of a stressor can be beneficial, while larger amounts of that same stressor are harmful or even fatal.

To give an example, many medicines follow this pattern. Taking the recommended dose of, say, a cough medicine will produce the intended effects (clearing up congestion and relieving your cough), but taking too much could make you seriously sick.

(Shortform note: The study of exactly how and why hormesis works is still ongoing, but some researchers believe that it happens—at least in part—because the body responds to stress and injury by producing more of certain types of proteins. Some of these proteins work to repair damaged cells, while others protect cells from further damage. As a result, after recovering from whatever stress caused that response, you become more resilient and better able to heal yourself in the future.)

Strategy #1: Exercise

The most obvious form of healthy stress is exercise, and the fact that exercise helps you live longer is hardly a new discovery. However, Brendborg emphasizes that the health and longevity benefits of exercise seem to have no hard limits. This means that, regardless of your age or your fitness level, working out will continue to boost your health and lifespan.

(Shortform note: Some people are put off by the idea of exercise, thinking that it only refers to strenuous or complicated workout plans. However, exercise can actually be very simple—even just going for regular walks has numerous benefits, such as helping you lose weight and improving your cardiovascular health. In The Nature Fix, Florence Williams adds that walking in natural settings like forests and parks also has significant mental health benefits, like reducing feelings of stress and anxiety.)

Brendborg explains that more exercise is better as a general rule, but it’s crucial to remain aware of how your body feels and performs. Remember: Exercise is a form of stress, meaning it actually hurts you. The health benefits of exercise come from the recovery period, when your body rebuilds itself to be stronger than it was before. And while the benefits of exercise have no limits, there is a limit to how much your body can handle. If you overwork yourself, you’ll reach a point where the damage outweighs the benefits—for example, you might tear a muscle by trying to lift weights that are too heavy for you. So, if you’re in pain or find that you seem to be getting weaker instead of stronger, it’s probably time to rest and recover.

(Shortform note: While more exercise gives greater benefits, it actually doesn’t take a lot to significantly improve your health. Researchers have found that just 150 minutes (two and a half hours) of moderate exercise each week increases life expectancy by about seven years, and that physically active people in their 70s had hearts, lungs, and muscles that were comparable to those of some 40-year-olds. If you have a health condition that limits how much you can exercise—or makes you wonder if you should be exercising at all—a physical therapist or personal trainer can help you come up with a fitness plan that works for you.)

Strategy #2: Plant Compounds

Brendborg says that another way to benefit from hormesis is to take advantage of the natural defense mechanisms found in many edible plants. Much like the benefits of exercising, the health benefits of fruits and vegetables have been common knowledge for a long time, but most people assume these plants are valuable because they’re nutritious.

(Shortform note: Experts tout the nutritional value of fruits and vegetables because they’re associated with greater longevity. Studies consistently find that the more fruits and vegetables you eat, the lower your risk of dying from various age-related conditions, including heart disease. Eating more fruits and vegetables may also help you maintain the kind of calorie restriction Brendborg recommends, since these plants are rich in fiber—which makes you feel fuller for longer.)

However, some scientists (including Brendborg) think hormesis also plays a role in their value. For example, pineapples contain an enzyme that breaks down proteins, which is why your mouth might feel strange after eating it—the enzyme isn’t dangerous enough to harm humans, but it may induce hormesis. Similarly, most fruits and vegetables contain compounds called polyphenols that are mildly toxic to humans; the relatively small amounts you ingest won’t hurt you in any noticeable way, but the author says that it’s still enough to trigger hormesis.

(Shortform note: Although pineapple enzymes and polyphenols may benefit us through hormesis, we may lose out on this benefit when we cook those foods. This is because high heat denatures proteins (changes their shapes, making them useless) and causes many types of molecules to break down. As a result, substances in food that would have caused the minor damage Brendborg describes here can lose their potency, denying us the benefits of hormesis.)

A Warning: Other Kinds of Hormesis Are Too Risky

Brendborg acknowledges that exercise and eating your vegetables might not be new or exciting ways to extend your life, but they’re effective and safe. He then discusses a couple of other possible ways to become stronger and more resilient through hormesis—however, he insists that these are too dangerous to try. He explains that hormesis is dangerous by nature, and it’s very easy to do more harm than good. Additionally, there’s no ethical way to conduct studies that involve intentionally hurting people. Therefore, the methods he discusses have never been rigorously tested for safety or effectiveness in humans.

With that said, two other possible ways to induce hormesis include:

1) Poisons: Brendborg discusses studies performed on roundworms, where researchers found that low doses of arsenic (a deadly poison) and paraquat (a powerful herbicide) actually extended the worms’ lifespans. The test subjects also became more resilient against other toxic substances. However, higher doses of those poisons killed the roundworms, as expected.

(Shortform note: While taking even small doses of powerful poisons like arsenic is extremely dangerous, many people all over the world regularly drink alcohol, which is a much milder type of poison. Furthermore, there is an ongoing debate over whether regularly drinking small amounts of alcohol might be beneficial. Many researchers say that drinking one or two glasses of wine every day has health benefits ranging from reduced stress to improved heart health. On the other hand, the World Health Organization (WHO) released a statement in 2023 arguing that no amount of alcohol is good for your health—even the small amount in a glass of wine increases your risk for several kinds of cancer.)

2) Radiation: Studies of radiation exposure, such as accidental exposures among nuclear plant workers, have shown that low doses of radiation can produce unexpected health benefits. Some of these benefits included lower cancer rates and longer average lifespans among those exposed.

(Shortform note: Ionizing radiation, meaning radiation that’s strong enough to be harmful, is known to cause cancer and other health conditions even at low doses. This is because it contains enough energy to strip electrons away from atoms—in other words, to ionize them—which creates highly unstable atoms and free radicals. Those unstable elements then cause cellular damage, such as mutations.)

Medical Strategies to Combat Aging

We’ve discussed lifestyle changes that you can do on your own to improve your health and extend your lifespan. In this final section, we’ll go over some medical interventions that hold promise for treating the symptoms of old age—or even reversing the aging process.

Strategy #1: Medications

Brendborg starts by discussing various drugs that may be able to slow the aging process.

The first of these drugs is metformin, a diabetes treatment that has shown promise for extending a person’s life even if they are not diabetic. This is because insulin resistance tends to increase with age, meaning your body gets less efficient at processing sugar, and therefore is less able to regulate your blood sugar levels. Insulin resistance is the exact problem that drugs like metformin are designed to treat, meaning that this could be a way to treat one of the symptoms of aging.

However, Brendborg is somewhat skeptical about giving metformin to healthy people because it may make exercise less effective, which is counterproductive to a long and healthy life. Exercise and metformin both boost your ability to metabolize sugar, but for reasons that scientists don’t fully understand, these two methods seem to interfere with each other rather than supporting each other as one would expect.

(Shortform note: A 2021 clinical review of various trials of metformin concluded that it’s unclear whether metformin is effective in humans as an anti-aging drug. However, the researchers noted that metformin does extend healthspan (the years of life spent in good health) by reducing the risk of conditions ranging from diabetes to dementia. They add that these benefits appear to be side effects of processing and regulating sugar more effectively—which is what metformin is primarily used for. However, as noted above, some studies do suggest that combining exercise and metformin treatment lowers the effectiveness of both.)

There are also drugs that promote autophagy, the cellular recycling mechanism we discussed in the Dietary Restrictions section. Remember that autophagy naturally declines with age, so enhancing it (using dietary choices, medications, or both) is an effective way to combat that part of the aging process.

One of these autophagy-boosting drugs is rapamycin, an immunosuppressant that’s normally used to prevent the body from rejecting a transplanted organ. Another is spermidine, a compound found naturally in many foods like whole grains and legumes. Spermidine has the advantage of not needing a prescription, since it’s readily available as a dietary supplement.

(Shortform note: Using unproven medications and supplements like Brendborg describes can be dangerous, and there’s a very real chance of doing more harm than good. Rapamycin in particular is known to have serious side effects, ranging from body aches and blurred vision to deafness and seizures. Furthermore, at least one recent study suggests that rapamycin may accelerate aging rather than slowing it. On the other hand, spermidine is not known to have any serious side effects, and some research suggests that it does have real and significant anti-aging properties, similar to those of calorie restriction.)

Finally, Brendborg points out that the development and testing of anti-aging drugs faces significant challenges. This is because, by the very nature of the work, it takes a long time to determine whether anti-aging treatments have been effective. Researchers must either wait decades to see if middle-aged test subjects live longer than expected, or test drugs on elderly subjects with less time for the treatments to work.

(Shortform note: By FDA protocols, clinical trials for new medications—or new uses for existing medications—are already time-consuming, possibly lasting upwards of six years before a drug can be approved for widespread use. Furthermore, the FDA estimates that only 25%-30% of drugs even make it to the last stages of trials, let alone being released to the public. As Brendborg notes, this problem is exponentially worse for anti-aging drugs, where researchers might have to wait decades at each stage of trials to see if the test subjects actually live longer than average.)

Strategy #2: Cellular Engineering

If aging is the result of changes to the DNA, as the theories we discussed earlier suggest, then the best way to reverse aging would be to undo those changes at the cellular level. In fact, Brendborg says that scientists have already discovered a couple of ways to do this. Unfortunately, both of these methods greatly increase the risk of cancer, and there’s currently no safe way to use them on people.

The first method is telomerase activation. Recall our earlier discussion of telomeres, the protective DNA caps that get shorter each time a cell divides. An enzyme called telomerase is able to rebuild those telomeres, so boosting telomerase could let cells avoid senescence and keep dividing forever.

(Shortform note: In The Telomere Effect, the authors explain that artificially boosting telomerase is dangerous because having too much telomerase could cause your cells to divide rapidly and uncontrollably—which is to say, it could cause cancer. However, they also say that there are natural and safe ways to boost your telomerase, and you can accomplish this just by living a healthy lifestyle. Some of the natural telomerase boosters they discuss are a healthy diet, good sleep habits, regular exercise, and an environment that’s as clean and free of pollution as possible.)

Brendborg says the second method uses a set of four genes, which are called Yamanaka factors after the scientist who discovered them: Shinya Yamanaka. Researchers have used the Yamanaka factors to revert adult cells to embryonic stem cells, literally resetting those cells’ biological clocks. They can then regrow into young, healthy cells of any type.

(Shortform note: Biologist Joanna Wysocka showed that a group of embryonic cells called the neural crest naturally use Yamanaka factors to turn back into stem cells. These cells, which had already begun developing into skin cells, were then able to turn into bone or muscle instead. Therefore, the Yamanaka factors aren’t just theoretically effective on living humans, they’re already a natural part of our development. Unfortunately, like with telomerase, artificially introducing more Yamanaka factors carries a very high risk of cancer.)