by Jamie Metzl
Although the idea that we have some kind of Wizard of Oz inside us turning knobs to determine how long we live seems strange to many people, it really shouldn’t feel so strange. Somewhere in our biology we have the ability to turn back time on a cellular level, kind of like the immortal jellyfish, evidenced every time we reset the genetic clock by making a baby.
But even if we better understand the underlying mechanisms of aging and believe that reprogramming our biology to extend our healthy life spans is possible, the question of how we to do it remains.
When reading a book about science, the last thing most people want is yet another reminder to get off their duffs. But the hard science of longevity makes abundantly clear that smart lifestyle choices are the best first way to hack our own epigenetic signals.*
Repeated studies have shown that these types of behavior changes also can lengthen our telomeres, the stretches of DNA at the end of our chromosomes. The telomeres serve to protect the integrity of the genetic data inside the chromosome, like plastic tips protect shoelaces. Our telomeres get slightly shorter each time our cells divide, becoming less and less able to protect our genetic data from harmful mutations. Although it’s not entirely clear whether shortened telomeres are a cause or an effect of aging, shorter telomeres are associated with faster aging and higher risks of age-related disease.30
But even if we don’t live like the people in blue zones, we still need to recognize that our biology and our lifestyle choices are not different things in the context of our health and longevity. Instead, they are the interconnected points along the spectrum of ourselves. Our lifestyle choices help realize the potential of our biology. Our biology helps determine the extent to which these types of choices can help us. And because we are humans, most of us are looking for new ways to beat the system.
We know that our bodies have a built-in genetic survival mechanism that has protected our ancestors in past times of scarcity and stress that can potentially be exploited for our advantage. Because much of the preliminary research on the genetics of extending life and health span seeks to understand how the human body responds to calorie restriction and scarcity, it’s logical to ask if we shouldn’t all just start living on a calorie-restricted diet. It could conceivably help, but I don’t necessarily recommend it. Even though the animal studies are pretty convincing, it’s yet not fully proven that calorie restriction extends human life and health span, possibly because testing this hypothesis on humans is so difficult.
Nevertheless, calorie-restriction societies have popped up around the United States and world over the past couple of decades, bringing together people committed to significantly cutting their calorie intake in the hope of extending their lives. For most everyone else, however, cutting calories to about 1,500 calories a day for men and 1,800 for woman (compared to the USDA recommended two thousand calories for active adult women and twenty-five hundred for active adult men) over the course of an entire life is hardly an appealing prospect and might not even be as healthy overall as a balanced diet.†
But a recent study found that significantly reducing calories just five continuous days a month, for two months a year, might elicit the same conserving resources response from the body and give people the same health benefit as cutting calories every day.31 The case, based on animal studies for intermittent fasting, is not as compelling as continuous calorie restriction, but fasting once in a while or for blocks of time each day might seem a more palatable way for most people to get at least some of the potential benefits of calorie restriction without feeling miserable all the time.
Perhaps a more appealing option, at least for some people, is exercise. I’m an Ironman triathlete and ultramarathoner and one of those crazy people who think doing these types of activities is actually fun.* For most people, however, exercise is a chore. If offered a pill that elicited the same protective genetic and metabolic response in their bodies as if they had exercised, most people would not only just say yes, they would pay huge sums of money or raid their local pharmacy to get it. But by triggering the same cellular shift to repair-and-conservation mode, exercise does all of those things for free.
A recent comprehensive study followed more than 650,000 people for an average of 10 years and analyzed nearly 100,000 death records in an attempt to quantify the input versus output benefits of exercise. The study found that 75 minutes a week of moderate exercise, like brisk walking, led to almost 2 years of added life expectancy compared to sitting on your couch. The benefits went up from there. Adding 2.5 to 5 hours of exercise a week added 3.5 years. An hour a day, or 450 minutes a week, added 4.5 years to life expectancy.32
Even with these odds, not everyone is willing to restrict calories or exercise religiously, and even those who do both will still likely want whatever additional benefits might help them live even longer and healthier lives. The good news for all of us is that drugs mimicking the function of the genes we wished we’d inherited or the impact of the calorie restriction or exercise we wished we’d done will soon likely be available thanks in part to the new tools of the genetic revolution.
One reason that, unlike the naked mole rats, our ability to repair damaged DNA declines as we get older is that the levels in cells of a molecule called nicotinamide adenine dinucleotide, or NAD+, decreases as animals like us age. The NAD+ molecules amplify the activity of a group of seven special genes called sirtuins to augment their ability to repair damaged DNA. The more NAD+ in the cells, the better able they are to fix these problems.
An obvious approach to potentially fixing this problem might be inserting NAD+ molecules into cells, but the NAD+ molecule is too large to make it through the cell’s outer membrane. Instead, scientists figured out a way to use smaller, precursor molecules called nicotinamide mononucleotide, or NMN, and nicotinamide riboside, or NR, that are small enough to make it through. Once in, the NMN and NR bind with a molecule already inside the cell and make NAD+.
When Harvard scientist David Sinclair and his colleagues genetically engineered older mice to express higher sirtuin levels, or used NMN to increase their NAD+ levels, they found the mice had better organ function, endurance, disease resistance, blood flow, and longevity than other mice the same age.33 In many ways, boosting the NAD+ levels tricked the mouse’s cells into shifting from growth to repair mode. Although human trials are only just beginning, the market for NMN and NR pills, sold in the United States as unregulated supplements, is exploding.
Another drug that shifts the balance of cellular activity from growth to repair mode is the seeming wonder drug metformin. Doctors have prescribed metformin since the 1950s, but the history of its essential ingredient actually goes back much further. In its earlier incarnation, medieval herbalists used a plant known as French lilac, or goat’s rue, to treat a multitude of ailments, including frequent urination, today recognized as a telltale sign of diabetes. In 1994, the U.S. Food and Drug Administration approved metformin as a treatment helping diabetics keep their blood sugar levels in check. Because it’s been around so long, metformin is known to be relatively safe, is not patent protected, and costs about five cents a pill. Today, Americans fill about 80 million metformin prescriptions every year.
With so many people taking the drug, doctors around the world began first observing and then studying some of the surprisingly positive effects metformin was having beyond controlling diabetes. A 2005 study found that metformin reduced the risk of cancer among diabetics.34 In a 2014 study comparing metformin to another diabetes drug, researchers found that the metformin-taking diabetics didn’t just live longer than the other diabetics taking the other drug but also lived longer than the control patients who didn’t have diabetes at all.35 The same year, a Singaporean study concluded that metformin halved the risk of cognitive impairment among older diabetics.36 A slew of mouse studies also showed the same types of miraculous results. Male mice given the drug lived an average of 6 percent longer than those who weren’t, and all mice taking metformin had fewer cancers and
less chronic inflammation than the controls.37
The combined force of these findings pushed scientists toward the inevitable hypothesis that metformin was not just impacting a few individual diseases but instead having a systemic effect on entire organisms. It was, in effect, making regular people more like the centenarians with their genetic predispositions for longer and healthier lives or the people living in blue zones. This makes logical sense. Insulin tells our cells it’s time to grow. When we have too much of it, either by gorging at the dessert bar or being a diabetic, our cells overinvest in growth at the expense of repair. When we moderate our insulin uptake through diet, exercise, calorie restriction, or metformin, our cells shift back into repair mode, like Cynthia Kenyon’s Daf-mutated roundworms. This helps us reduce oxidative stress like the quahog clams and better fight disease and live longer and healthier like the naked mole rats.
To answer the question of whether metformin might be a systematic drug that helps enhance healthy life spans among nondiabetic populations, Nir Barzilai and his collaborators are now exploring how metformin might delay the onset of multiple age-related diseases and stem decline in older people’s physical performance, cognitive clarity, and quality of life. Proving for the first time that a single drug like metformin can target multiple diseases of aging simultaneously would revolutionize the field of aging.
NAD+ boosters and metformin may be among the first drugs that target aging, but they will certainly not be the last. Another drug that’s proven to extend the life of all animals tested in studies around the world is the miraculous drug rapamycin.
In 1965, Wyeth Pharmaceutical scientists visited tiny Easter Island in the Pacific looking for soil bacteria that might have antifungal properties. Among the thousands of samples they collected, one contained unique bacteria that secreted a compound allowing the bacteria to absorb as many soil nutrients as possible while stopping other competitive funguses from growing. The scientists named the compound rapamycin in recognition of the island’s local name, Rapa Nui.
Rapamycin’s natural ability to slow the proliferation and growth of targeted cells made it an ideal immunosuppressant, perfect for preventing people’s immune systems from rejecting transplanted organs. But then doctors started noticing that animals and some human transplant patients taking rapamycin seemed to be healthier than similarly situated animals and people taking other drugs. They soon figured out that rapamycin regulated the metabolism of cells and triggered the same kind of shift-to-repair-mode signaling as happens when calories are scarce and which we also saw with metformin. They named the protein targeted in this process mTOR, or mammalian target of rapamycin.
With almost every study, the list of rapamycin’s almost magical capacities increased. By regulating cell growth, rapamycin proved extremely useful in treating specific diseases where out-of-control metabolism and cell-growth was the problem, including cancer, diabetes, heart and kidney diseases, neurological and genetic disorders, and obesity.38
The quahog clam can live over five hundred years because it slows its metabolism and shifts the energy of its cells from growth toward repair mode, so it makes sense that by essentially triggering the same shift a drug like rapamycin could impact longevity. In studies run on species after species—yeast, flies, worms, mice, and rats, to name but a few—ingesting rapamycin led to about 25 percent longer lives across the board, an astounding feat.39 Leading longevity and rapamycin expert Matt Kaeberlein is now launching a major multiyear effort to study the life and health-span impact of rapamycin on companion dogs as a step toward better understanding how the drug might work on humans.40
In spite of all this promise, there’s a good reason why scientists weren’t immediately hailing rapamycin as the human fountain of youth. Having our immune systems suppressed when we are getting organ transplants is making the best of a bad situation. We benefit from the transplanted organ but pay the price by turning off our immune system, making us more vulnerable to dangerous viruses and bacteria we would otherwise be able to fight off. Rapamycin also can have other dangerous side effects for immune-suppressed people, including anemia, hyperglycemia, cataracts, and testicular degeneration.41 It’s still not clear whether healthier people taking rapamycin would experience the same risks.
Researchers are now working hard to try to find way of delivering rapamycin or a derivative that can maximize the compound’s remarkable benefits while minimizing its downsides.42 Pharmaceutical behemoths like Novartis and start-ups like Boston’s resTORbio and PureTechHealth are racing to develop drugs using rapamycin to help shift our cells toward repair mode and potentially enhance our health and longevity.
Before human trials are completed, it’s not a good idea for people to start taking NMN, NR, metformin, or rapamycin on their own in an effort to extend their life or health spans. Having said that, I’ve been surprised by how many of the NMN and NR researchers are themselves taking NMN and NR, how many metformin researchers are taking metformin, and even how many rapamycin researchers secretly confess that they are experimenting on themselves by taking rapamycin. And I do think it’s likely that many people around the world will within a decade be taking some type of antiaging drug using some or all of these ingredients or derivatives of them, as well as other compounds yet to be identified.43 Ideally, this pill will be personalized and different for different people, based on gender, age, genetic profile, metabolic status, microbiome diversity, and other factors. But this won’t be the only option.
When we are young and relatively healthy our cells divide regularly to replace themselves, but as we get older, or face other stresses, some of our cells stop dividing. Rather than just dying and getting flushed out of our systems, these zombie-like “senescent” cells secrete molecules, causing increasing levels of inflammation and tissue damage. The older we get, the more of these senescent cells we accrue. That’s not entirely a bad thing, however, because senescent cells also help repress the growth of cancer cells and tumors, which are an increasing danger as we age.
We probably wouldn’t want to get rid of all of our senescent cells and lose their benefits, but pruning the level of senescent cells in our bodies, it now appears, might help us function a bit more like when were younger and healthier. After scientists genetically engineered and then activated a transgenic “suicide gene” to pare senescent cells in mice, the mice not only lived 25 percent longer but also regrew lost hair, had stronger muscles and better functioning organs, and experienced increased insulin sensitivity and lower rates heart disease and osteoporosis.44 Not bad. In August 2018, a team of researchers at England’s University of Exeter used three different novel compounds to prune senescent cells in the mitochondria of mice, which then showed significant signs of cellular rejuvenation.45
With this research as a backdrop, the race is now on to develop and test a new class of drugs called senolytics, designed to prune senescent cells to treat specific diseases of aging and potentially expand both health span and life span. Few humans will sign up, at least for now, to have “suicide genes” genetically engineered into their genomes, but many of us would take a pill that had the same effect, if it were available. With this in mind, Dutch scientists have designed a chain of amino acids that bump up our body’s ability to clear out senescent cells. Interestingly, these amino acids influence the same Daf-16 genes Cynthia Kenyon identified in her roundworm studies. Older mice given the compound regrew the luxurious fur of their youth and were able to run twice as far as they could just weeks before.46
A related potential approach to countering aging involves manipulating the way our cells recycle their own biomass to extract energy and remove harmful proteins, a process scientists call autophagy. Autophagy serves younger organisms well but can malfunction and cause age-related diseases later in life. A new class of potential treatments for some age-related diseases and for aging itself, therefore, involves the targeting of specific steps of the autophagy process to help older cells start behaving as if they are younger.
If you are already amazed by how many potential ways there may be to hack aging, buckle up. We are just getting started.
Baby-making is so commonplace that we can often miss the clue about human aging right in front of our eyes. Every time a child is conceived something in our cells is already resetting the biological clock.
Each of our cells, as we know, contains the genetic blueprint of our entire genome. That’s why it would be possible to clone a person from a single one of their cells. But we would be in big trouble if each of our thirty trillion cells kept aspiring to be its own person. The reasons this doesn’t happen is that, as we’ve seen, the epigenetic signals in our cells control which of our genes are turned on and which are turned off. As we develop from the single cell of a fertilized egg into the complex beings we become, these epigenetic marks choreograph our cells to become specialized, adult cells like heart cells, skin cells, and so on, each performing their specific functions.