Live Long and Prosper

Legend says that Ponce de León was looking for the Fountain of Youth when he landed in Florida in the 1500s. Although the story is likely apocryphal, centuries later countless others are still seeking the secret to youthfulness. Despite detox diets and sham pills that promise the contrary, we still follow the inexorable march of Father Time, year by year, decade by decade.

We still grow old.

Ask a doctor about how to stay young, and you’ll likely hear familiar truisms: Exercise regularly, eat your fruits and vegetables, and don’t smoke. But now science is starting to give us more detailed answers about what happens when we age and how things like diet affect us at the cellular, molecular and genetic levels.

As we get older, wear and tear makes us more prone to diseases like diabetes, cancer and Alzheimer’s. “Statistically speaking, age is the most potent risk factor for many of these diseases,” says Pinchas Cohen, dean of the USC Davis School of Gerontology. By teasing apart how aging relates to disease, USC researchers are learning what it takes to live longer and, more importantly, to live healthier.

“For us, the goal is really to make life disease free,” says Lucio Comai, a professor of molecular microbiology and immunology at the Keck School of Medicine of USC. His research quest starts with a particularly rare and debilitating genetic disease—one that causes time to seemingly speed up.

Aging fast

Those with Werner syndrome have a normal childhood, but when they reach puberty, things start to go awry. First, there’s no growth spurt. In their 20s, they go bald or their hair turns gray. By their 30s and 40s, they develop cataracts, type 2 diabetes or cancer. Their bones weaken and arteries harden. In short, they get old. Fast.

The syndrome occurs when people carry a mutation in an important gene. The mutation causes the loss of the normal version of what’s called the Werner protein.

Comai and his colleagues are studying how the healthy Werner protein protects cells against age-related wear and tear. It seems to help keep the genome stable —including protecting the telomeres, the fragile regions of DNA at the end of chromosomes whose deterioration has long been linked to aging.

The hypothesis is that as we age, the Werner protein deteriorates over time, Comai explains. Because it stops working like it used to, we become more vulnerable to diseases. “Our goal is to really understand the details, because that’s how you design a drug,” he says. “We think we’re halfway there.” Such a drug that boosts the protein might help people stay healthier.

“This is fantasy right now, but that’s our ultimate dream,” Comai adds. Still, a long life won’t be as simple as making more of this protein—too much could actually increase the likelihood of cancer.

Protect and repair

A variety of threats can damage cells as we age, says Kelvin Davies, the James E. Birren Chair in Gerontology at USC Davis, where he is also dean of faculty and research. Even psychological and emotional stress can cause harm.

Much of the deterioration of our cells over a lifetime is due to what’s called oxidative stress, the consequence of molecules known as free radicals that wreak havoc in cells. While some free radicals come into the body from drugs, alcohol, radiation and air pollution, most are byproducts of normal metabolism as cells turn food and oxygen into energy.

These free radicals, or oxidants, are harmful because they have a lonesome, unpaired electron hanging around the fringes of the molecules. Electrons love to be in pairs, so in a quest for balance, the free radical will strip an electron away from another molecule, such as DNA or a protein, damaging that molecule in the process.

In every cell of your body, free radicals damage some 1,000 sites in your DNA every day, Davies says. But your body can fix about 99 percent of the damage, thanks to several layers of defense and repair systems.

You’ve probably heard of antioxidants such as vitamins E and C, which are abundant in fruits and vegetables and can’t be produced naturally in your body. They’re good for you because they disarm free radicals. (Nevertheless, antioxidants are overhyped, and most people don’t need supplements, Davies says. “You’re better off eating lots of fruits and veggies like your mother told you.”)

But antioxidants can only do so much, and some free radicals eventually get through, crippling or killing cells. Damage to DNA, in particular, can cause cancer. In fact, free radicals are involved in just about every major disease, from heart attacks to Alzheimer’s. There’s even a well-respected theory that free radicals may cause aging and determine lifespan.

Fortunately, antioxidants are just one way the body mitigates damage. Cells sometimes slow down their other activities to focus on protecting and repairing themselves, and they can adapt to stress by turning on extra protective genes, Davies explains.

Hundreds of genes and enzymes are involved in protecting cells and adapting to stress. Over the past few years, Davies and his colleagues have identified these adaptive pathways and discovered a handful of master genes that control this protective system, he says, “like a conductor of an orchestra.” One such gene is NRF2.

“The more we look, the more involvement we find that it has with adaptation, stress resistance, longevity and lifespan,” he says. As it turns out, NRF2 works less effectively as we age.

Researchers like Davies want to reverse this slowdown—and find out if doing so extends youthfulness. Can they find ways to boost NRF2 or remove the roadblocks that keep it from working well? So far, he says, they’ve found tantalizing clues. Eating fewer calories, for example, improves the NRF2 response, although no one knows yet exactly how that happens. Other researchers are testing the potential of drugs that can make the body act like it’s getting too little food.

Fasting for youth

Cutting calories has been one of the most intriguing ways to promote longevity. Just ask Valter Longo, director of the USC Longevity Institute, whose research on periodic fasting and protein restriction has thrust him into the news.

Here’s how fasting works. By default, your body is always geared toward reproducing, since you never know when a suitable mate will come along. But if you restrict your calories, your body will focus its resources on protecting itself—an evolutionary adaptation for when food is scarce.

“Fasting is probably the most powerful beneficial intervention you could do to a human being.”

Valter Longo

That’s one idea, anyway. There are countless factors and biological processes involved, and no one knows exactly how cutting calories may extend lifespan. But thanks to experiments on mice, worms, fruit flies and yeast, scientists know that organisms that consumed fewer calories than on a normal diet—in some cases, 40 percent less—lived much longer. On the other hand, much longer studies involving rhesus monkeys proved less conclusive, probably because they ate very little over a long time, which might have counterbalanced fasting’s protective effects, Longo says.

Regardless, Longo acknowledges that it’s impractical to nibble at every meal and constantly feel hungry. It’s hard enough to ignore that last french fry, let alone skip a third of your calories. “Nobody’s ever going to do it,” he says.

Instead, periodic fasting may be a better strategy. “Fasting is probably the most powerful beneficial intervention you could do to a human being,” Longo says. Cutting calories for a few days shifts the body from ready-to-mate mode into standby and maintenance: You save energy and your cells get a chance to regenerate.

In particular, Longo has found that fasting helps rejuvenate the immune system, which weakens with age, making the elderly more susceptible to disease. While fasting, your body gets rid of old and damaged immune cells, but once you eat again, your immune system comes back renewed. The team is now planning a clinical trial to see if fasting can help elderly people combat the flu by renewing their immune systems.

His quest for answers has even whisked him a continent away—to remote villages in Ecuador.

In 2005, he contacted an Ecuadorean physician who was studying a group of people with an intriguing genetic mutation—one that’s similar to mutations that Longo’s team had discovered among yeast and mice with unusually long lifespans. These Ecuadoreans were all under 4 feet tall—and they were remarkably youthful and free of cancer or diabetes. The reason: A genetic mutation blocked the activity of a growth hormone. That got Longo thinking.

Levels of that same growth hormone rise when people eat a high-protein diet.When Longo and his partners studied a large group of Americans’ eating habits over two decades, they found that eating lots of animal-based protein like meats and dairy products during middle age raised the chance of cancer and early death. In another study, they showed that a low-protein diet mitigated symptoms of Alzheimer’s disease in mice.

It’s early, but the data are promising: Periodic fasting seems to dampen the growth hormone’s activity. Soon the team will publish a study that tested a fasting regimen among volunteers. For five days a month, over three straight months, people were asked to follow a carefully designed, extremely low-calorie diet—about 700 to 1,100 calories per day, far lower than the 2,000 to 2,500 recommended for most adults.

Longo already thinks periodic fasting is the way to go, and he follows the fasting plan himself—as do others in his lab, and his family and friends, he says. But he warns that no one should do it without medical supervision and food proven to provide adequate nutrients. (In response to cancer patients asking him if they could eat something instead of fasting, Longo has started a USC spinoff company called L-Nutra that prepares and sells the meals. To avoid a conflict of interest, he’s not allowed to be involved in the collection or analysis of the data in the human studies.)

“The concept is that there isn’t a single recipe for staying healthy longer.”

Pinchas Cohen

While drugs may someday treat aspects of aging, they may also carry side effects, Longo says. So fasting will likely be the best option, since your whole body can adjust accordingly. “You are in tune with the diet,” he says. And fasting, he points out, is something people have been doing for thousands of years as part of necessity or religious practice, which he suspects was likely also done for its mental and physical health benefits.

USC Norris Cancer Center, the Mayo Clinic and other hospitals are even testing whether careful fasting can help protect cancer patients and sensitize their cancer cells to treatment.

“This is not a fad,” Longo says. “This is our history. Now, finally, it’s met with the clinical, scientific evidence that’s necessary to do it right.”

Holistic precision

Much of what science is learning about aging is consistent with what social scientists see outside the lab. Murali Nair, a clinical professor in the USC School of Social Work, has met some of the world’s oldest citizens in nations from Japan to India. Getting to know several dozen centenarians taught Nair that most of them, whether they’re rich or poor, share a lifestyle that he says the rest of us should emulate.

They eat regularly and relatively little, mostly vegetables, fruit and nuts. They remain physically, socially and mentally active. They maintain a positive outlook on life and have some sense of spirituality and faith in something greater than themselves. They also all believe in random acts of kindness. “We have advanced technology in extending our lives, but modern medicine alone is not enough,” Nair says. We need a holistic approach that shows better appreciation of our body, mind, spirit and the environment.

Aging is complex, involving every biological organ and system. Lifestyle, environment and genetics all come into play. As a result, no one ages the same way, and we all have different susceptibilities to diseases and different responses to diet, exercise and drugs. The solution to such diversity may be what Cohen, of USC Davis, has dubbed “personalized aging.”

“The concept is that there isn’t a single recipe for staying healthy longer,” Cohen says. “Each of us should find the best strategy that’s scientifically driven.”

Doctors are already beginning to target cancers at the genetic level. Cohen proposes a similar approach to delay aging. By sequencing your genome while you’re healthy, doctors could determine your risk of age-related diseases like diabetes or Alzheimer’s. If you show a high risk for disease, then doctors could identify drugs or lifestyle changes that might work particularly well for your genomic profile.

Today, doctors can already reasonably assess risk for some diseases, and they’ll only get more accurate over time, Cohen says. But no one completely knows which treatments and strategies are best suited for each person’s individual genome. That will likely take decades.

“We’re not even halfway there,” Cohen says. Until then, we have yoga and broccoli.