In the decades that I have been studying the cholesterol levels of centenarians’ plasma, I have also been studying aging in animals that get different types of diseases than people but age similarly. All animals age in similar manners—skin, hair, skeletal bones, and muscle all change shape and function, and diseases are contracted more frequently. Finding out what is and is not fundamental to aging in a wide variety of organisms was crucial for cracking the code of human longevity. Studying different organisms has helped us to put together a true picture of what aging necessarily is for humans—and what elements are inessential and can be avoided. For example, my friend Steven N. Austad, author of Why We Age, studied clams that were five hundred years old and small invertebrate organisms called hydra that don’t seem to age at all. And Vera Gorbunova and her husband, Andrei Seluanov, investigate why the naked mole rat lives up to twenty times longer than any other rodent.
By comparing the results of our animal studies with the information we collected from centenarians, we are progressively cracking the code of how to slow aging for us all. Yet humans are special, and our cholesterol metabolism is different from that of many animals, particularly rodents. As it turned out, our first clue about the link between cholesterol and longevity came from centenarians. Cholesterol is a type of fat that is in our blood and builds every cell of our bodies. Without it, we would not develop and would probably die, but many people still think of it as a harmful substance that we only get from eating certain foods like meat, eggs, fish, and dairy products. These foods do contain cholesterol, but you might be surprised to hear that it’s your body weight that has the biggest effect on your blood levels of cholesterol. You also may not know that the liver is central in coordinating the metabolism of cholesterol and moving it through the body. Cholesterol is also leaving our bodies through the secretion of bile that begins in the liver. This coordination is important for thousands of biological functions, mainly for cells’ membrane layer and production of hormones such as vitamin D. But despite being a vital organic molecule, cholesterol has managed to earn a questionable reputation.
The lipid panel that is part of a standard annual checkup shows the levels of HDL and LDL cholesterols, which make up most of our cholesterol. The lipid panel also shows the level of triglycerides (TG), which makes up about 20 percent of total cholesterol. In clinical practice, your doctor may be more concerned with the ratio between the LDL and the HDL than with the individual numbers. If the ratio is smaller than 3:1, your doctor may not be worried about your LDL number even if it’s higher.
Before these numbers were commonly broken out in test results, the total cholesterol number was misleading, and fat became our archenemy because it was linked to high cholesterol, which increases our risk for cardiovascular disease. But we need fat for our brains and other organs to function, so the total cholesterol number is not nearly as relevant as the individual levels of each type of cholesterol. For example, when we have high LDL, we have a greater risk of heart disease because it combines with fat, calcium, and other substances to form plaque in our arteries. This buildup, called atherosclerosis, constricts the flow of oxygen-rich blood to the heart and other organs. When we decrease LDL, we get less heart disease and significantly lower our chances of dying from symptoms of the disease, including heart attacks. On the other hand, having high levels of HDL seems to protect us from heart disease. And women tend to have higher levels of HDL than men, so that may also be a factor in why they live longer than men on average. Although when people ask me why husbands often die before their wives, I say, “Because they want to.” I’m kidding, of course, and statistics show that married men live longer, on average, than men who are not married.
We often see high levels of triglycerides in people who are obese, and being obese increases the risk of type 2 diabetes, heart disease, and strokes. Type 2 diabetes patients have varying levels of LDL, but they usually have high triglycerides and low HDL. Not surprisingly, most of the cholesterol studies conducted to date have explored the connection between cholesterol and cardiovascular disease, and the conclusions have led to the development of the class of drugs called statins that were designed to prevent heart attacks. Statins, such as Lipitor and Crestor, lower bad cholesterol by moderating how much of it the liver produces, how much circulates in the bloodstream, and how much is secreted through the bile duct and into our intestines.
When statins were tested in clinical trials, they prevented heart attacks and death from heart attacks by 25–30 percent, compared with people not taking them. On the other hand, statins usually did not change overall mortality even though heart diseases play such a large role in mortality. How can these drugs prevent the major contributor to death but not result in less death overall? I was an author of one of the first three studies showing that people who are on statins have a 30 percent higher risk of developing type 2 diabetes than people who aren’t, and some research has suggested that using statins also increases the likelihood of suicide. I was also concerned that lowering LDL cholesterol too much would be harmful to the neurons in the brain, some of the richest cholesterol-containing cells in our bodies. While extremely low LDL has recently been associated with bleeding strokes, the literature generally does not suggest negative effects, maybe because its anti-atherosclerosis effects are in balance with the need for cholesterol for better brain function in the elderly. Whatever the case, while there can be drawbacks to taking statins, overall they are making a big difference for millions of people who have not been able to lower their LDL cholesterol levels without them.
So from the standpoint of being a specific drug treatment that targets a specific human disease, statin therapy is helpful, but on average, it does not increase longevity in humans or animals, and it may be unnecessary and even unsafe in people eighty or older who have cardiovascular disease. Statin therapy is very different from aging therapy, which is what we are most interested in at Einstein. That’s why when we looked at cholesterol in SuperAgers and their offspring, we looked at it through a different lens.
When we began finding centenarians for our Longevity Genes Project, we conducted basic tests similar to those you would undergo at an annual checkup, which include measuring electrolyte and glucose levels, checking kidney functions, and drawing blood to do a lipid panel. In a diverse population, men’s HDL cholesterol levels average about 45 mg/dl and women’s average about 55, but the centenarians’ offspring sometimes had HDL levels over 100! The centenarians themselves had HDL levels in the 50s, which isn’t considered high, but when you take into account that HDL decreases by about five points every eight years starting at middle age, their HDL would have been expected to be around 20. For example, Eva Fleischer’s mother, Muti, was 102 and had HDL cholesterol of 62, which is at the upper end of the average range for a woman at that age, and Eva herself had HDL cholesterol of 142 mg/dl. Now that our study has grown, we have many people with HDL that’s above 100, which is a remarkable phenotype because very few people have HDL that’s 80 or above. If a man’s HDL is 60 and a woman’s HDL is 70, it’s considered fabulous.
An interesting side story involving this data is that when HDL is measured in the general population, the average across all ages is always about 45 for men and about 55 for women. But how is this possible if, individually, it goes down five points every eight years when we follow up with the same subjects? My explanation is that when the HDL goes down, it stops protecting against the consequences of aging, and people die. The average is maintained in the population because HDL is a survival factor. While centenarians have average HDL levels, we know from their offspring that their HDL was probably much higher when they were seventy or eighty. And we are worried that those with lower HDL may be at risk for dying in the coming year or so.
The connection between high HDL and exceptional longevity was clear, but we didn’t know what caused it. To find out, we began by looking more closely at the centenarians’ blood. How might it be different from those in the control group? What we found astonished us. These fatty cholesterol molecules are often packaged into larger clusters and transported through the body in the blood. In the case of the centenarians and their offspring, they didn’t only have more HDL but had much larger HDL and LDL particles than average. Larger HDL and LDL particles are associated with decreased risk of hypertension, cardiovascular disease, and metabolic syndrome. In fact, it is believed that small particles easily oxidize and are a ready template for initiating the first steps of atherosclerosis. And as it turned out, some people in the control group who did not have hypertension or cardiovascular disease also had HDL and LDL particles that were significantly larger than average.
Part of the reason for the higher HDL levels in our centenarians is that they are packed on specific carriers—APOA—that transport more cholesterol than normal away from the arteries. While centenarians’ LDL levels are usually normal, their LDL tends to be in formations that are larger than average, and they have their own specific carriers—APOB—to move the “loads.” These larger forms undergo less oxidation than smaller ones, so they are less likely to form the plaque that causes atherosclerosis. So it’s confusing, because it is hard to tell whether the cholesterol profile of centenarians is because of their total HDL, the ratio of LDL to HDL, the large HDL particle sizes, the large LDL particle sizes, or a combination of some or all of the above. Whatever the reason, centenarians with one or more of these characteristics have less heart disease, less chance of Alzheimer’s, greater cognitive function, and—of course—longer lives. Whatever the case, the bigger question was: What was responsible for these differences?
We continued to search for the answer, but the high levels of good cholesterol were so consistent that now when I see patients with high HDL and longevity in the family, my thought is that they are “at risk” of living a long time. While most of my time is devoted to research and educating people about our findings, I have volunteered at the Bronx’s Montefiore Diabetes Clinic for the past twenty-seven years, and one patient of mine stands out regarding cholesterol levels. She was a fifty-eight-year-old woman who, despite her diabetes, seemed to be in remarkably good health. One strange piece of the puzzle was that she had an HDL cholesterol level far above normal. For a woman of her age, especially with her illness, we would expect her HDL cholesterol levels to be 35 to 45. Instead, she clocked in at 100! She looked at least a decade younger than her age, while her husband was a decade younger than she was but looked much older. In my experience, the difference between chronological and biological aging was never more striking than in this couple, who looked like they were twenty years apart but the younger-looking one was actually older.
“I know this sounds strange,” I said when I met her, “but I have to ask—do you have any unusually old people in your family?”
Her eyes widened. “Well, yes!” she said. “My mother is 96 years old and doing well. And her father lived to 114. How did you know?”
I told her about our longevity study and said that centenarians and their families have unusually high levels of HDL cholesterol, especially when compared with their average LDL cholesterol levels. By this point, I was quite comfortable treating this phenomenon as a real indicator of longevity.
After seeing similar cholesterol results in hundreds of centenarians and offspring, we were convinced that whatever was responsible for their differences could be inherited. So we began looking for cholesterol genes that might have significant mutations that were doing good instead of harm. But we ran into some unanticipated resistance from the IRB because the members were concerned about what we would do if we discovered people who had harmful mutations that caused diseases. If we happen to see one, there isn’t anything we can do about it.
Discovering mutations and variants is exciting, but the findings are given the same weight as the findings of association studies until we can validate them in other populations or do functional studies on cells or animals to prove that the mutations are important.
Once we got approval from the IRB for our study, we began looking at a variety of genes that are associated with the creation and transportation of cholesterol, and we discovered that two genes that modulate HDL cholesterol and triglycerides had functional variants, meaning that the genes functioned differently because of the mutation. And many of our centenarians had one or two genetic variants that affect the clustering of the cholesterol particles:
Both of these variations are giving us insights into cardiovascular health and longevity, and we’re delighted that our findings have helped two pharmaceutical companies develop inhibitor-type drugs. One of the reasons for failures in drug development is that we assume we know what to expect in humans based on what we learn from mice. For pharmaceutical development, it is important to first find people who have mutations or variants in the gene that the company wants to target. They want to see variants or mutations that either cause a disease or prevent it. Furthermore, if the mutation or the variant causes the exact effect that the company wants to mimic, they will want to see if there are downsides to the variant, so there’s a need to gather data on safety. In our case, both variants were more common in centenarians than in the unrelated control group, and that was a good sign that they were safe. The pharmaceutical companies were not really interested in the variants’ potential for the treatment of aging but in their potential for the prevention of coronary heart diseases. In the near future, though, we will have pharmaceuticals that mimic these variants so that everyone can enjoy the health benefits and the extra years.
The cholesteryl ester transfer protein gene plays an essential role in regulating cholesterol. However, the function of the variants causing a decrease in CETP action is not fully understood. On one hand, like a shuttle bus, it transfers the cholesteryl ester from the coronary vessels of the heart and out of the body through the bile and intestines. The mutation inhibits the carrier from disposing of the cholesterol, so why would you want to develop a drug that stops the shuttle of bad cholesterol? On the other hand, because the load of cholesterol is not getting off its transporter, the particles become bigger and bigger, and this may be the pivotal effect. Maybe the fact that the particles become larger and packed together prevents damage to the vessels. So while a decrease in CETP can have both benefits and drawbacks, the good appears to outweigh the bad.
There are indications that the mutation in CETP may protect us from heart disease, which is wonderful, but at Einstein, we wanted to know if it goes so far as to protect us from aging and therefore from more than one disease. If we could determine that it does, we could say that CETP is a longevity gene, not a disease gene. So we looked at this mutation to see what other age-related diseases it might affect, and we found that it is associated with protection from hypertension. Granted, one could argue that hypertension is part of cardiovascular disease, but it is also an age-related condition.
We also looked at all the subjects in our study who had the variants to see if they had less prevalence of cancer than those without the variants. As it turned out, they did not, maybe because we don’t have that many cancers in our SuperAgers population, but we saw that the people with this mutation developed cancer an average of ten years later than people without the CETP mutation. Though that was just an observation—without enough subjects and statistical power to call it significant—it gave us the sense that the variants we were finding that led to high HDL would also provide other protections from other age-related diseases and therefore are targeting a basic biology of aging.
But the biggest prize for us will always be cognitive preservation. Is there a link between the mutation and cognitive decline? Our own data showed that centenarians with the CETP mutation had experienced a small fraction of the cognitive decline of centenarians who did not have the mutation. Moreover, we had a couple of subjects who had a major gene risk for Alzheimer’s called APOE4. The textbooks suggest that carriers of the gene will have dementia at age seventy and be dead at eighty, but our subjects did not have dementia and were still alive at one hundred. Both of these subjects had the CETP mutation.
To validate our findings regarding the link between the mutation and cognitive decline, we collaborated with Richard Lipton, a professor of neurology, epidemiology, and population health who is leading the Einstein Aging Study. This study recruited hundreds of people between the ages of forty-five and sixty-five and followed their cognition over three decades. The researchers looked for changes in cognition and attempted to formulate physical or biological tests that could predict decline. They genotyped the CETP variant of the CETP gene in the participants and demonstrated that those who had it experienced 70 percent less incidence of Alzheimer’s and cognitive decline. The study subjects were mostly white, but there were also some Jews and some blacks, and the protective factors for black people were the most striking. There is no other example of a single variant that extends this magnitude of protection against cognitive decline or Alzheimer’s disease.
But our findings have not been confirmed by all the studies that have been done. For example, in a study of centenarians conducted in southern Italy, there wasn’t a greater presence of the CETP variants in the centenarians than in the rest of the population, so we did not get validation from that study. In northern Italy, however, the same study was done with a group of Italian centenarians who were genetically different from those in the south, and the results were similar to ours, showing that there was greater longevity and protection against Alzheimer’s disease among those with the variants. But then David Bennett, the star of Alzheimer’s disease research at Rush University, tested our variant in his study and showed that, if anything, the people with the CETP mutation in his study had cognitive function that was not as good as the cognitive function in the control group. The difference was relatively small, but we are seeing that we get different results in different populations.
What we’ve learned is that when you have a single variant and you look at it in isolation, you can’t always validate it, because populations are not made of a single variant; they are made from many variants, and some cancel each other out. For example, in our study, the centenarians and their offspring who had the CETP variant and high HDL levels are likely to have longevity, but if you have a population that has the mutation but doesn’t have high HDL, they probably will not have longevity. So it is not enough to look at the variant—we have to look at the phenotype of the variants, which in this case is HDL.
Not long after we made the discovery about the CETP variant, Pfizer began developing a CETP inhibitor that was intended to work the same way the variant worked in our centenarians. The study was shut down soon after it began, because people who had taken the drug experienced a substantial increase in blood pressure and therefore more cardiovascular events instead of fewer. It turned out that the drug had more than one action, so it was not only inhibiting the CETP but also affecting other systems. Once it was understood that this was not a mechanistic error but a bad drug development, Merck & Co. considered continuing the development of its own CETP inhibitor, and the company was receptive to seeing our results. I imagine that it received input from more studies than ours, but our study is the only one that showed that people with this mutation live to be one hundred, which at least means that targeting CETP is very safe.
I suggested that Merck also do a cognitive function assessment of people with the CETP variation. The assessment did not indicate that the people in the study were protected against cognitive decline, but that may have been because they were a much younger population than we tested in our study, and they used a test that is much less sensitive for people that age. So we’re not sure if the CETP variant preserves cognitive function or not. Because our centenarians had these mutations before they were born, maybe the effects we’re seeing began when they were children or in their twenties or forties and fifties. If that’s the case, then giving the drug to people in their sixties or older may not work. To find the answer to when the drug might optimally be taken, we need to study cognition longitudinally, because even with very sophisticated tests, we usually don’t see cognitive decline in people until they are seventy or older even when they have been diagnosed with Alzheimer’s.
But what’s even more significant than the individual studies is that when we have a group of people with variants or mutations that protect from or cause certain diseases, pharmaceutical companies can use this knowledge to develop drugs that target those genes to either inhibit their functions or activate them to prevent or treat diseases. The best example of this so far is a gene called PCSK9. Human research studies showed in 2003 that a gain-of-function mutation—a mutation that results in new or stronger protein function—causes familial hyperlipidemia, abnormally high levels of fats in the blood. Amazingly enough, by 2006, there was a study that showed that a loss-of-function mutation—a mutation that results in less or no protein function—brought an 88 percent reduction in coronary heart diseases. Then, in 2012, The New England Journal of Medicine published a study looking at a population who had the protective variant for PCSK9. It found that the effects of inhibiting the enzyme over a longer time reduced the risk of cardiovascular disease without creating the adverse effect of blocking this pathway. Then in 2018, The New England Journal of Medicine published the phase-three study on the PCSK9 inhibitor evolocumab (Repatha) and alirocumab (Praluent). In one of the studies, among patients who had a previous acute coronary syndrome and were treated with statins, the risk of recurrent ischemic cardiovascular events—in which blood flow to the heart is obstructed—was lower among those who received evolocumab than among those who received a placebo.
With this valuable genetic information, researchers didn’t need to spend years doing animal research, so it took relatively little time for alirocumab to be developed as the new therapy for people who cannot tolerate statins or need additional help.
THE BENEFITS OF CETP PERSONIFIED
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Irving Kahn didn’t work until the end of his life. He just worked until he was 108. In late 2014, just a year before he died at 109, he finally retired as chairman of the Wall Street investment firm Kahn Brothers, which he founded in 1978 with two of his sons and which manages between $800 million and $900 million in assets. Until then, he reviewed every proposed transaction and had the final word on investment policy from the firm’s corner office. The idea of not working was unthinkable to Irving.
“If you took it away from me, I’d try to buy it back,” he said during one of my visits with him. Age 104 at the time, he also told me that his exceptional longevity had its advantages in the business world. “You know what’s rotten and what’s fresh and what’s good or bad, and you can participate at a higher level of successful choices. That’s me.”
“Work is his life,” his son Thomas, company president, said at the time. “He’s always been an absorber of information. Ever since I was a child, he would bring home annual reports and read them at the dinner table, and that’s what he still does.” The family believes that work also probably did more than anything else to help Irving through his grief after the death of his wife, Ruth, in 1996 after sixty-five years of marriage.
Thomas thinks his father’s passion for work came from an appetite for knowledge. Irving read three newspapers a day and constantly added to his personal library of thousands of books, most of them about scientific developments and possibilities.
“The important thing is to keep the brain going, you see,” he said.
Speaking of the brain, Irving was a progressive thinker when it came to social issues and philanthropy. One of his favorite causes was the Jewish Foundation for Education of Women, for which he was a trustee emeritus. He also founded the New York City Job and Career Center in 1986 to help prepare high school students for the workforce.
Hand in hand with his social consciousness was a sense of his own empowerment, which he ultimately credits to his parents. Irving’s mother had her own shirtwaist business, and his father taught him to ride a bike by giving him a single push. “He said, ‘Stay on this street and hold on to the handlebars,’ and gave me a push. Well, here I was out in the middle of the street … What could I do? So I learned how to ride pretty quickly.” His father used a similar approach to teach Irving how to swim. “He pushed me in the water and said, ‘Would you rather die or rather swim?’”
It wouldn’t be much of an exaggeration to say Irving had been his own man ever since. He began his Wall Street career in 1928, and despite having only a year’s experience by the time of the stock crash in 1929, he managed to turn a profit while so many others lost everything.
As speculation ran rampant that summer, Irving realized that short selling was the road to success. Under that strategy, he would profit from a fall in the price of a stock rather than a rise. His first stock trade was a short sale in a copper mining company, and an in-law lent him the money for it despite his certainty that Irving would lose his shirt by betting against the bull market.
Well, Irving proved him wrong by almost doubling his money when the crash hit.
Before long, though, he adopted the much more conservative approach known as value investing, which he learned from the creator of the concept, Benjamin Graham, at Columbia University in the 1930s. (Warren Buffett was also a disciple of Graham’s, and Irving and Buffett would ride the subway to his lectures together, Thomas says.) Under the value investing strategy, investors assess a stock’s actual value and buy shares only if they are available for a significantly lower price. It’s the strategy that saw Kahn Brothers through the crash of 2008 and multiple sell-offs over the past forty-plus years. And it saw Irving through more than eight decades of crashes, beginning with the big one.
In a 2014 interview with The Daily Telegraph of London, Irving summed up the philosophy that has been Kahn Brothers’ guiding light:
There are always good companies that are overpriced. A disciplined investor avoids them. As Warren Buffett has correctly said, a good investor has the opposite temperament to that prevailing in the market. Throughout all the crashes, sticking to value investing helped me to preserve and grow my capital. Investors must remember that their first job is to preserve their capital. After they’ve dealt with that, they can approach the second job, seeking a return on the capital … Our goal has always been to seek reasonable returns over a very long period of time. I don’t know why anyone would look at a short time horizon. In my life, I invested over decades … I prefer to be slow and steady.
The value investing strategy that Irving helped to pioneer seems to reflect his practical approach to life in general. He led a modest lifestyle and didn’t see the sense in spending more on life’s necessities than was necessary. His wardrobe was a good example. To the office, he would wear a purely functional oxford shirt with a conservative tie, and he’d put on a bright blue fleece vest if he felt a chill. He also went to bed at eight and got up at seven like clockwork, and he was diligent about taking his vitamins.
When asked if he thought his sensible approach to life had something to do with his longevity, he’d say, “Maybe.” When asked if he thought it was likelier genetic, he’d say no and politely explain that he wasn’t interested in the reason for his longevity. Fortunately, though, he was willing to participate in Einstein’s Longevity Genes Project.
Thomas backs the argument for genetics, saying Irving’s diet was far from healthy, including many more cheeseburgers than salads. And then there was Irving’s older sister, Helen Reichert, who lived to be 110 and smoked for more than ninety of those years. (So again, we see centenarians being protected from habits that are very unhealthy for most people.)
When Irving died, the obituary headlines called him the world’s oldest stockbroker, and the stories all mentioned that he was one of the few people who have celebrated their one-hundredth birthdays by ringing the opening bell at the New York Stock Exchange.
In addition to the CETP mutation, in 2006, we discovered that some of our centenarians had a mutation in the APOC3 gene, which is found on triglyceride-rich lipoprotein, and that these centenarians had lower triglycerides and higher HDL cholesterol. The association of this mutation with longevity is so powerful that even among centenarians, it appears to add a year to their lives on average. Triglycerides increase our risk for cardiovascular diseases and are typically high in people who are obese or have type 2 diabetes. These types of study results are why controlling cholesterol is becoming one of the top ways to target aging (even if we can’t formally call it that just yet) while increasing overall health.
My colleague Alan Shuldiner made similar discoveries with the link between APOC3 and longevity in an Amish population in 2008. He found that the Amish have a mutation in the same gene but in a different location. The people in his study who had this loss-of-function mutation had fewer heart attacks and lived longer than average, but none of them made it to one hundred. In 2014, two additional populations with the same mutation demonstrated about a 40 percent reduction in coronary heart diseases. So there has been a lot of validation of the protective nature of mutations in APOC3, and fortunately, the company Ionis developed a drug that inhibits APOC3 and changes the lipid panel to lower triglycerides and raise HDL. It completed a phase-three trial in 2015, so this drug will soon be available. Just to be clear, as with Merck’s development of a CETP inhibitor, Ionis is not developing this drug to target aging—they’re interested in targeting diseases. But the fact that centenarians have this mutation is a good indication that it’s safe.
Our research and treatments are the greatest possible argument for preventive medicine. Just like managing the flu or rickets, targeting aging is good for society, our economy, and our politics. As former U.S. senator Claire McCaskill noted when we met with her about the dividends of having people stay healthy longer, even reducing adult diabetes by a “modest” percentage could evaporate our national debt. The longer and healthier we all live, the better, safer, and more prosperous we can be as a society.
The Italians like to toast, “Cent’anni,” which has come to mean “May you live for a hundred years.” The comparable Jewish blessing is “May you live until 120,” which is the number of years that Moses lived. Once, such sentiments were just wishful thinking, but perhaps now they will become the new normal. For now, though, we can stick to the humbler but wonderfully joyful Hebrew toast: l’chaim—to life.