Unlocking the Mysteries of Aging

There’s a lot of research being done right now on the best way to understand the processes by which we age. Here’s our first story.

There are numerous ways to try to unlock the mysteries of aging. You could study long-lived individuals like centenarians and supercentenarians, particularly long-lived smokers, perhaps, to uncover the secrets to their resilience. Or, you could go in the opposite direction and study short-lived people—tragic, accelerated aging syndromes like progeria, where children age at eight to ten times the normal rate––wrinkling, balding, and then typically dying around age 13 of a heart attack or stroke.

Or, you could study long-lived animals. There are mammals, such as the bowhead whale, that can live hundreds of years. There are oysters and clams whose hearts can beat more than a billion times over its five-century lifespan. What accounts for the 10,000-fold range of lifespan in the animal kingdom?

Most of the aging pathways identified as the hallmarks of aging were established using so-called “model organisms,” such as yeast, worms, flies, and mice—simpler species that may nonetheless offer insights, due to the remarkable conservation of common aging mechanisms throughout the eons of evolutionary time. Aging used to be considered simply too complex to study––a constellation of internal and external influences too complicated to disentangle. But then, the game changer, the discovery that a single gene mutation could dramatically prolong the lifespan and youthful state of a tiny worm known as C. elegans.

C. elegans has since wormed its way deep into the study of longevity. It seems we shared a common ancestor about a half billion years ago, and, to this day, we still share about half of their genes. With a lifespan of only two to three weeks, their fast turnover allows researchers to rapidly assess the effects of genetic or dietary tweaks, unlike humans, who are described as “not an easy-to-study system both for ethical as well as for practical reasons.”

Even simpler, the single-celled organism Saccharomyces cerevisiae, otherwise known as brewer’s or baker’s yeast. In 1959, it was discovered that yeast cells are not immortal, dividing only a finite number of times. They are even more evolutionary divergent, though. We haven’t shared a common ancestor with brewer’s yeast for more like a billion years, and only have about 30 percent of their genes in common at this point, but their microscopic size and even faster turnover allows for high-throughput systems able to screen for more than a thousand different compounds a day for potential lifespan-extending properties. And, even if those yeast longevity compounds fail to translate to extending human life, yeast researchers argue they could still be useful for brewing extra beer.

Yeast have a lifespan that can be measured in days; worms in weeks; fruit flies—another common model—in months––compared to mice that can live for years. But, mice and men were one as few as 75 million years ago, arising in the mammalian explosion shortly after the resolution of the asteroid v. dinosaurs matchup. Mice share about 85 percent of their genes with humans. Granted, it’s an important 15 percent.

Humans are not just more complex anatomically than rodents, but more complex even on a cellular level. Extrapolating data from lab animals is infamously fraught with difficulty. Fewer than one in ten cancer drugs that seem to work in mice even make it into human clinical trials, and hundreds of seemingly promising Alzheimer’s drugs have similarly been lost in the translation. As one review in the journal Trends in Biotechnology put it: “Humans Are Not Huge Worms or Big Mice.” We are, however, big primates.

Rhesus monkeys are also used in aging research, though they can live up to 40 years, stretching research timelines. Their DNA is 93 percent identical to humans, though as similarity increases, so too do ethical concerns regarding experimentation. One might expect research on dogs to perhaps be most sensitive, but there are citizen science initiatives in which family dogs are enrolled in noninvasive studies to study––for example, the genetics of why some so-called “Methuselah dogs” reach ages of twenty-five or more. But 99.9 percent of other dogs do not. For example, mixed-breed dogs live more than a year longer than same-size purebred dogs, who can be plagued with certain genetic disorders. Aged pooches suffer many of the same ravages of aging: arthritis, cancer, cataracts, kidney problems, muscle loss, etc. Advances in canine longevity might not only be applicable to human aging, but have the intrinsic value of enhancing the quality and quantity of life of the more than 70 million companions we share our homes with in the U.S. alone.

In our next story, we look at ways to boost the longevity hormone FGF21?

In the year 2000, a new human hormone was discovered. It was the 21st documented fibroblast growth factor; so, they called it FGF21. Since its discovery, FGF21 has emerged as a key agent for promotion of metabolic and artery health, leanness, and longevity. Inject it into fat monkeys, and they lose body weight without reducing food intake, and not just a little—a 27 percent drop in body fat eating the same amount. In mice, it increases their lifespan 30 to 40 percent, comparable to lifelong caloric restriction, but again was achieved without decreasing food intake. The researchers conclude that FGF21 could potentially be used as a hormone therapy to extend lifespan in mammals, which has gotten big pharma salivating, raising the question, “Can aging be ‘drugged’?”

And that’s not all it can do. The idea that one drug can treat obesity, diabetes, dyslipidemia (like high cholesterol), and hypertension all at once might have seemed impossible a few years ago, but is now a tantalizing and exciting prospect. The reason you can’t just give people straight FGF21 is that it gets rapidly broken down in the body; so, you’d have to get injections like every hour or two around the clock. So, drug companies are trying to patent a variety of longer-acting FGF21 look-alikes. And indeed, give people a little PF-05231023, and they can lose about 10 pounds in 25 days, along with dramatic drops in triglycerides and cholesterol.

But then, the side effects of these new-fangled drugs started cropping up. Okay, so what about this: we package the FGF21 gene into a virus, and then inject the virus and have it stitch extra FGF21 genes into our DNA. Or you can just lace on your running shoes. Exercise boosts FGF21 levels, which may in fact be one of the reasons exercise is so good for us.
Which works better, though, aerobic exercise—eight weeks of running training—or resistance exercise—eight weeks of weights? The answer is both, but the resistance exercise edged out the running, a 42 percent increase in FGF21 versus a 25 percent increase in the aerobic exercise group.

Okay, but what can we do with food? Yeah, you could try engineering and injecting it, but wouldn’t it be easier to just stimulate our own endogenous, natural production through diet? One way is through no diet at all. You may have noticed it’s been dubbed the starvation hormone. That’s because fasting induces FGF21, but not just a day or two.

Physiologically, FGF21 expression is markedly increased in response to fasting/starvation. But, unlike mice, which show an increase after just six hours of fasting, humans don’t get a notable surge in FGF21 until after a week. Fasting can quadruple FGF21, but it takes 10 days of fasting, which is the very poster child of an unsustainable eating pattern.

Finally today, what can physicians do to promote healthy, life-extending, lifestyle changes? Here’s the story.

A pivotal paper published in Europe more than a decade ago, entitled “Healthy Living Is the Best Revenge,” found that adhering to just four simple healthy lifestyle factors compared to none could potentially have a strong impact on the prevention of chronic diseases. We’re talking nearly 80 percent less chronic disease risk––slashing diabetes risk by 93 percent, dropping heart attack risk by 81 percent, cutting stroke risk in half, and cancer by 36 percent. Think about what that means. The potential for preventing disease and death is enormous. In the U.S. alone every year, there are a half million heart attacks, a half million strokes, a million new cases of diabetes, and a million new cancer diagnoses. The message is clear: adopting a few healthy behaviors can have a major impact. What are those four fabled factors? Never smoking, not being obese, averaging about a half hour of exercise a day, and adhering to healthy dietary principles, like lots of fruits, vegetables, and whole grains, and less meat. Follow those four simple rules and boom! Enjoy nearly 80 percent reduced risk of major chronic diseases.

What does that mean for mortality risk? A similar batch of four health behaviors combined predicted a four-fold difference in total mortality, with an estimated impact equivalent to 14 years in chronological age, meaning the individuals were dying at such a reduced rate that it was as if they were 14 years younger. “Finally, a Regimen to Extend Human Life Expectancy.” This commentary was in reference to this study, where a similar analysis of the impact of healthy lifestyle behaviors on life expectancies was made, but this time it looked directly at the U.S. population, which is particularly important, since Americans have a shorter life expectancy compared with residents of nearly all other high-income countries. The researchers concluded that adopting a healthy lifestyle could substantially reduce premature mortality and prolong life expectancy in U.S. adults. Okay, but by how much? They estimated that adherence to a low-risk lifestyle could prolong life expectancy at age 50 years by 14.0 years in women and 12.2 years in men. So, if you’re 50 right now, instead of only living to 79 if you’re a woman, and 75½ if you’re a man, taking just basic care of yourself could propel you to an average life expectancy of 93 if you’re a woman and 87½ if you’re a man.

The bottom line is it’s never too late to turn back the clock. A midlife switch just to the basics, like at least five daily servings fruits and vegetables, walking even like 20 minutes a day, maintaining a healthy weight, and not smoking results in a substantial reduction in mortality even in the following few years. We’re talking a 40 percent lower risk of dying in the subsequent four years. So, making the necessary changes to adhere to a healthy lifestyle could be considered extremely worthwhile, and middle age is certainly not too late to act.
As an aside, realizing the 12 to 14 years of added life study was based on data from health professionals, that got me excited about all the potential knock-on effects. If health professionals start getting healthier, they can become role models for more healthful living and potentially save more lives than just their own. But that may have just been wishful thinking. Practicing what you preach can sometimes backfire. Evidently, “displays of excellence can paradoxically turn off the very people they are trying to inspire.”

You’d assume that not being a hypocrite and trying to walk the walk would just lead to positive consequences, inspiring confidence in others. Don’t you want a dance instructor who can dance, a music teacher who can play, and a health professional who’s healthy? But this simple intuition fails to take into account concerns about making other people feel inadequate. Like you know how vegetarians are the targets of a surprising amount of hostility and ridicule. That’s because they may come off as morally superior and make people feel like they’re being looked down upon.

There was an elegant demonstration of this phenomenon in this study where “Principled deviants who take the high road threaten others’ moral self-worth.” This is what they did. Research subjects were asked to complete a racist task by an experimenter, and those moral rebels who refused to obey were cheered by observers but were disparaged by participants who had themselves gone through with it, and for whom the rebels’ stance thus an implied indictment of their spinelessness. Isn’t that interesting?

So, when doctors portray themselves as “the picture of health,” patients might think they’re being holier-than-thou and unintentionally alienate people, potentially turning off the very patients who most need their help. You can see how someone with a weight issue might feel threatened and judged by a physician triathlete. But what are we supposed to do? We want healthy practitioners. Physicians who smoke are less likely to tell their patients to quit smoking, physicians who are overweight are less likely to counsel their patients about weight, and physicians who don’t work out are less likely to talk about exercise. What we can do to make patients more comfortable is emphasize that our role is to help people meet their own personal health goals, whatever they may be. Studies show that when doctors do this, taking this approach, it increases the appeal of fitness-focused physicians to overweight patients. So, we can then display exemplary behavior, while at the same time not inadvertently alienate the very people who would benefit most from our guidance.