Space-age technologies, designer drugs that target the hallmarks of aging, and life-changing longevity research are already in the works. Because of these innovations, people will stay healthy for an additional ten to twenty years, and the most common side effect will be living to one hundred and beyond. The time line still needs to be determined, but chances are, children who are in elementary school now will live long enough to meet their great-great-grandchildren. New technologies not only are changing the ways we treat illness and disease but are also providing us with revolutionary options for early detection of diseases and, better yet, early detection of the hallmarks of aging, which precede sickness and disease. New technology, including artificial intelligence, is making it possible for us to study thousands of data points at a time rather than having to take the traditional and painstaking approach of studying only one or two. And that leap forward is allowing us to determine more accurate biomarkers for aging, which will affect everything from when we need to start getting certain diagnostic tests to drug dosage.
One of the reasons we’re able to make such great strides forward with research is that artificial intelligence allows us to process massive amounts of data.
We call this data omics, and it’s transforming our ability to solve aging riddles that would otherwise take years if not decades to figure out. Instead of theorizing and setting out to find certain answers, we look at the data produced by the technology and find the answers there in an unbiased fashion.
Whole exome sequencing—the sequencing of the part of the genome made up of exons—is such an omic, where we have all the important sequences of most of the centenarians’ genes that account for hundreds of millions of DNA letters multiplied by three thousand subjects. This is billions of data points, and we’re asking the technology to tell us all the differences between the exomes of centenarians and their offspring and those of the control group. This narrows our search considerably, but there are still hundreds of thousands of differences in the DNA sequence between those with exceptional longevity and our control group. As a result, many of the points identified are going to be false positives, because if you have thousands of people in a study, some of the distinctions between the groups will occur just because of chance. That means some results may initially seem significant, but once we correct the results, not all of them will turn out to be statistically significant. At the same time, though, it’s inevitable that we will eliminate some of the distinctions that actually are significant—in other words, false negatives, which are actually positive.
After correction, we still had about thirty thousand significant differences between centenarians and the control group, so we have assigned each of these differences to a pathway. This is important because it’s less about what individual SNPs or variants do and more about what the pathways do. All the tens of thousands of differences are assigned to their own pathways, and now we’re looking at the knowledge that we have from each pathway. And some of the pathways that are most significant are the signaling pathways for insulin, IGF, and mTOR. In other words, what we have learned from animal research lines up with these pathways. And thanks to Alan Shuldiner, vice president of Regeneron Pharmaceuticals, who performed the sequencing for free, we saved millions of dollars.
The technology that creates omics is also helping us to find longevity secrets that are hidden in proteins. In animal studies, we and other researchers learned that the blood of younger animals was somehow restoring youthfulness in older animals, but the question we needed to answer was which proteins were responsible for this “magic.”
This is one of those questions that would have taken us a very long time to explore just a few years ago because we could only study several proteins at a time. But SomaLogic invented a method to measure five thousand proteins as quickly and accurately as we were able to measure one or two. Rather than measuring the proteins of centenarians, who are at the end of their lives, we wanted to find out first what the differences were between the centenarians’ offspring and the control group. And thanks to Tony Wyss-Coray, one of SomaLogic’s founders and a professor of neurology at Stanford, we were able to look at these five thousand proteins in one thousand members of our LonGenity study, who are all age sixty-five to ninety-five. We examined if we could find proteins that could be biomarkers of aging. You can imagine that this is a huge amount of data, and because of Tony, what could have cost millions of dollars was done for us at no cost.
The technology identified 585 proteins whose levels increased or decreased significantly with age. So there are definitely proteins that are associated with biological age. And that’s not even the best part of what we learned from the data. The results were so statistically significant that we know we can repeat this analysis many times and get the same results. To be classified as statistically significant, the probability value of a hypothesis—a measure of the probability of finding the same or more extreme results by chance—needs to be less than 0.005, and our results were between 10−40 and 10−80. Adding to our excitement, some of the proteins that were identified are very large, and their levels increase severalfold with aging, so they are among the first we’re studying.
We also found out that the five proteins we had previously identified as being most significant in terms of aging were barely significant compared with the top fifty that SomaLogic identified. And when we compared the results of the five hundred centenarians’ offspring and the five hundred people in the control group, whose members were the same chronological age, we found something truly remarkable. The levels of only 235 of the 585 proteins changed significantly in the offspring, and this is because the offspring were biologically younger than the members of the control group. It’s possible that if we retest them several years from now, the offspring will have just as many significant proteins as the control group, but for now, they are biologically younger. Not only that, but in the offspring, we found twenty-five proteins that are unique to them, and we think they may be protecting them from the hallmarks of aging. So far, we know that at least three of the proteins are protective. One of them, klotho, is typical in centenarians’ offspring and not in the control group, and a company called Unity recently invested $250 million to commercialize this protein.
Many of the proteins associated with aging are the result of the breakdown of tissues, and we also see proteins that we and other researchers have linked with aging in longevity pathways such as GH/IGF-1. Many of these broken-down proteins may serve as excellent biological markers for the treatment of aging because if we succeed, the breakage should stop and we should see a decrease in the levels of these proteins. We want to see that the levels decrease with treatment before we embark on long, expensive studies that may not produce the effects we’re hoping for.
And we are also working with Yale University pathologist Morgan Levine to create an instrument like a clock that will predict biological age based on a set of specific proteins. We expect it to be as good as or better than measuring methylation for estimating biological age. When we have standardized biomarkers for aging, we will need to show only the change in markers to get approval for a treatment instead of needing five years to show hard evidence. For example, no matter what method we use to lower cholesterol or blood pressure, we will prevent cardiovascular diseases, so aging will be about biomarkers that show change. The signature of our proteins that show biological age is, of course, much more predictive of mortality than the frailty index or chronological age.
As genetic tests become more refined and less expensive, we can personalize medical treatments in ways that were not even conceivable in the past. This is one of the most exciting new frontiers because we know that the same drugs and treatments can have varying effects on men and women, young and old—there isn’t any one thing that’s good for everyone under all circumstances. But there may be drugs that target one hallmark of aging better than another.
We are also making advances in beginning to personalize diabetes treatments, and an NIH-funded study being conducted at several centers is exploring what the best treatments are for different people. So it won’t be long before we will also be using personalized medicine to treat all the hallmarks of aging.
One of the best examples of personalized medicine already under way is the treatment for various types of cancer. Each type of cancer now has a different recommended treatment, and as research progresses, scientists will be able to customize these targeted approaches even more, which should lead to higher survival rates. One of the new immune treatment therapies is melanoma itself. My father may have unknowingly benefited from this approach long before it officially became a treatment.
When Dad was in his forties, he developed a persistent cough, and a chest x-ray showed a mass in his right lung that the radiologist suspected was a tumor. It was 1968, and surgeons in Israel did not have the capacity to perform this surgery, so he and my mother traveled to Sloan Kettering. I was thirteen at the time, and when he returned home, he looked fine. But one day soon after, he took me aside and said, “I don’t know how much time I have to live, so I hope you will take care of your mother and sisters.” He never offered information about a diagnosis or the surgery, so I didn’t know why he suspected that his time might be coming to an end, but over the years, every now and again, he would give me this goodbye talk. After a while, I stopped believing that it was anything more than a father saying what he thought he should impart to his son.
It wasn’t until I was a fellow at Sloan Kettering that the mystery was solved. As it turned out, my father’s cancer was metastasis of melanoma that invaded most of his right lung and the chest cavity. His right lung had been surgically removed, and the surgeon removed all the cancer he could see in the chest cavity. It looked so bad that the surgeon didn’t recommend follow-up treatment because he didn’t think my father would live more than a few months. To everyone’s surprise, he lived to be eighty-four years old, and when he did die, it was not from cancer. As it happens, one in one thousand people with melanoma have or develop an immunological capacity to deal with it. In my father’s case, he must have had an ability to clear the cancer that was left after the surgery.
In the years to come, in addition to advanced technology—and also because of it—doctors will have much more information about their patients and aging in general. This will dramatically increase the accuracy of diagnoses and decrease the incidence of medical errors and negative drug interactions. Add those advantages to early detection, genetic testing, epigenetic assessment, aging clocks, personal health monitoring devices, and greater understanding of nutrition and exercise, and the result is decades more of good health and life.
We have a grant to identify the mechanism for resiliency to Alzheimer’s disease in our centenarians, and we discovered they have a mutation in a gene called ABCA1, which is involved in a cholesterol disease called Tangier. It happens that ABCA1 is already a target for drug development to treat Alzheimer’s, but we have other candidates as well.
At the same time, a member of our resiliency consortium, Catherine Kaczorowski, head of the Jackson Laboratory in Bar Harbor, Maine, a Nathan Shock Center of Excellence in the Basic Biology of Aging, is studying why some people who have a family history of Alzheimer’s and brain changes associated with this disease do not lose their cognitive abilities. She’s working to identify biomarkers of resilience that protect mice—including those that have a genetic predisposition for cognitive decline—from neurodegenerative diseases, including Alzheimer’s. Rather than studying the factors that make mice and people susceptible to Alzheimer’s, Kaczorowski is focused on finding the genetic and molecular mechanisms associated with the regulatory pathways that lead to resilience, and we’re collaborating with her to make mice that are protected from Alzheimer’s disease so she can study them. While this may sound far-fetched, the drug humanin has prevented age-related cognitive decline in mice, and there’s good reason to believe it may benefit human cognition, too. You may recall that our centenarian Frieda had the highest humanin level on record, and she was mentally sharp long after she turned one hundred.
The race to find ways to keep people vital and healthy for as long as we live is inspiring scientists all over the world to explore uncharted territories with thousands of pursuits that may or may not pan out. I’m hopeful that some of their innovations will prove to be effective in double-blind clinical trials but until then, I’m sharing a few examples of ventures that I provided consultation for but have no financial stake in. I’m not yet convinced that they will change the face of aging, but I want to make the point that some of the “crazy” things being pursued might be crazy enough to work.
For example, in a relatively new realm of research, scientists are looking at how particular foods affect particular genes and other aspects of cell metabolism. There are also many biological extracts derived from plants—including metformin, which comes from the French lilac—that will be faster and easier to test because of new technology.
I suspect that nature has many potent forces that can be harnessed to target aging and associated diseases, and I’m betting that many of them will be totally unexpected. A company called Regenera Pharma is testing a botanical that appears to have helped animals and humans with a variety of age-related problems. Zadik Hazan, founder and chief scientific officer at Regenera, started the company with the mission to help people restore the function that’s lost as a result of neurological diseases. We offered to test this drug at our center to see if it really targeted aging, and we couldn’t demonstrate a significant effect on longevity, but we could show some other beneficial effects, such as reduced inflammation. Mice are not always great predictors of how a drug will work in people, though, and now Regenera has a leading drug candidate. This candidate, RPh201, is purified plant sap from the mastic gum plant, which is already being used in some foods and medicines. The drug is being tested for its regenerative activity and functional recovery benefits and has shown promising results in preclinical models and may have properties that protect against stroke, vascular dementia, and other neurological conditions. A double-blind study is under way to evaluate the effectiveness and safety of RPh201 in about 230 people who have been diagnosed with nonarteritic anterior ischemic optic neuropathy (NAION), which is a stroke of the optic nerve that impairs vision to the point of blindness. The participants will be studied to measure the drug’s impact on visual function, so it will be a while before we know the results, but the potential is exciting.
There’s also a lot of excitement around many innovative treatments that are being offered to slow and reverse the physical and cognitive decline currently associated with aging. For example, my rather recent mentor and friend Sami Sagol, who has studied the science of aging with great interest and invested in academia and the business of aging, invested in a hyperbaric center run by Shai Efrati, a smart and energetic doctor at Yitzhak Shamir Medical Center, in central Israel. Sami wanted to hear what I thought of this investment because of my understanding of aging and my training in hyperbaric medicine, which I received as an Israeli naval physician. He didn’t realize when he approached me that my mother had been treated for deep infections with hyperbaric medicine and that some of my diabetic patients with infections had also benefited from this treatment. When diabetics with wounds are treated in hyperbaric chambers, the bacteria are exposed to oxygen and killed.
Sami’s hoping that this therapy can also be beneficial for age-related diseases and particularly for cognitive decline. For the treatments at Shai’s center, patients sit inside a chamber that looks like a submarine and is furnished like the business-class section of an airplane. They receive a high-oxygen treatment in a pressurized “cabin.” The people who have started to have cognitive problems are treated weekly or biweekly for a few months, and they are reporting that they feel much better and that their cognitive functions are improving.
Shai says that by giving people nearly 100 percent oxygen under pressure, it can reach cells that oxygen doesn’t often reach in older people. As we age, there are areas of the body, particularly the brain, that do not get enough blood supply and, therefore, not enough oxygen. If oxygen is successfully delivered to those areas, it can repair tissues and might even stimulate stem cells to initiate a process that’s rejuvenating.
I can’t help but be curious about whether there is a strong placebo effect with the treatment, but the possibilities are worth more exploration. I look forward to the results of controlled studies that eliminate the placebo effect and test the effects of high and low doses of oxygen.
In 1962, John B. Gurdon showed in a petri dish that cellular age could be reversed, and in 2006, Shinya Yamanaka discovered that a particular set of four genes could reprogram adult cells to become immature cells that could in turn develop into any type of cell. He laid the groundwork for scientists to grow new blood cells tissues and organs that are already being transplanted into people. In 2012, Gurdon and Yamanaka were jointly awarded the Nobel Prize in Physiology or Medicine for their work.
The “Yamanaka factors” have profound implications for aging, but they’re not something we can simply ingest. They need to be delivered directly to cells, and one of the ways this is done is by putting these factors’ information on a virus—modulated to remove the harmful aspects—and directing the virus to attack the cell. The challenge with the Yamanaka factors is that one of them is highly carcinogenic, but my buddy David Sinclair, founder of Iduna, found that he can take an old cell and make it young again by using only the three factors that are not carcinogenic. He delivers those three factors with a virus to the crushed optic nerves of mice, and this restores partial eyesight to mice with previously nonresponsive optic nerves. The viruses infect the nerve cells and transcribe the three factors so that they change the cells into cells that behave like stem cells. The same procedure has reversed glaucoma in mice. This research has far-reaching implications for repairing crushed nerves all over the body, including the spine. And in the future, we may even have a virus that can rejuvenate all cells from time to time, which would mean staying healthy and young for an extraordinarily long time.
In the meantime, researchers are exploring drugs that can deactivate the harmful results of a certain type of virus that wreaks havoc as we age. People are often surprised to find out that much of our DNA is composed of the DNA of viruses that infiltrated our own DNA a very long time ago. The virus DNA, called retrotransposons, was integrated into DNA and caused horrific mutations, but it also helped to create more diversity within species.
It is believed that the diversity of dogs, a subspecies of the wolf, is due to the integration of viruses in wolves. Fortunately, those integrated viruses remain inactive and do not reproduce. But recent research by my friend John Sedivy, a molecular and cellular biologist at Brown University, and neurosurgeon Sanjay Gupta has shown that a virus transposon called LINE-1 wakes up with aging and behaves like a live flu virus. Our immune systems recognize it as an invader and increase inflammation. Antiviral treatments, such as those administered to HIV patients, can quiet it down, and we’ve learned that LINE-1 is also kept silent by a stress response protein called Sirtuin 6 (Sirt6), which also helps to repair DNA, maintain telomeres, and lower inflammation. The exciting part of this story is that researchers are working toward creating specific drugs with Sirt6 that can keep the LINE-1 silent throughout our lives.
In the years to come, we will see a wide array of advancements in genetic engineering and with them a confounding number of ethical questions. One of the things we can already do in animals is replace the APOE4 gene with a mutation that protects them from Alzheimer’s, and we will probably be able to do this in humans someday, but should we? If a woman is pregnant and genetic testing shows that her daughter will be born with the BRCA1 gene, the ability to have that gene removed or replaced could sound like the right thing to do. If we can manipulate genes in a way that will ensure good health, it will be beneficial for individuals, society, and the economy. But what about adding in genes that can make a child more athletic, more artistic, or more musical? What if there is a gene that will give a child a higher IQ? These are a few of the questions we will face in the future, and governments will need to create new laws and negotiate with each other to regulate genetic engineering. Otherwise, it could become an arms-race scenario, with each country attempting to out-engineer the others, except in this case they would be engineering people. My friend Jamie Metzl has explored some longevity possibilities like these in Hacking Darwin.
For now, our best bet and safest course of action is to charge ahead in our quest to develop drugs that temper or stop the activity of undesirable genes and mimic the actions of beneficial variations and mutations so that we can all be young until we die. Our DNA blueprint to be young isn’t harmed or diminished by age, so slowing aging is just the first step. In time, we should be able to stop certain aspects of aging and reverse others.
If that sounds like an impossible dream, here’s something that might change your mind—the ability to reverse aging is already contained within the human body. If we take the sperm of a seventy-year-old man and the egg of a fifty-year-old woman, we can determine the age of the sperm and the egg, and those ages will be about the same chronological ages of the donors. But we know that if you fertilize the fifty-year-old egg with the seventy-year-old sperm, the new cells that divide and begin the life of the fetus start at age zero. This is one of the most stunning and promising discoveries for the science of longevity, and the race to unravel this mystery is well under way.
Tomorrow will be brighter and healthier!