Helping You Raise the Bar...Without Hurting Yourself!
What if You Didn't Have to Grow Old?

by Tom McGrath



There are many reasons a major leaguer can fall into a batting slump: losing his timing at the plate, bailing out on pitches, thinking too much about dinner after the game. But the funk that Tampa Bay Rays outfielder Rocco Baldelli fell into over the past two seasons was on a whole different level.

The dude's mitochondria were letting him down.

No bells ringing for you? Let me help you out: sophomore year in high school... specifically, biology class... the unit on cells... the discussion of the cell's power source...

Mitochondria! Yes!

Although Baldelli didn't realize it when his muscle soreness started or when his injuries began to pile up, his mitochondria were in serious trouble. And they weren't just causing a slump at the plate, they were causing a slump in his life. Early last year, he couldn't work out for more than a few minutes without becoming exhausted. He had cramping and other strange sensations in his limbs. By the start of the season last April, things were so bleak that the Rays had put him back on the disabled list.

Fortunately, this is a story with a pretty happy ending. Doctors eventually determined that Baldelli was suffering from mitochondrial myopathy — damage to those power plants. He began a course of treatment, and by early August the Rays were on the verge of making their first trip to the playoffs. He played well in the regular season, and in the postseason, as TV announcers struggled to pronounce "mitochondria," he stepped up his performance even more, hitting two postseason home runs and driving in one of the runs that sent the Rays to the World Series.

But don't let Baldelli's struggle spook you too much. His disease, however scary, is rare. And even though damaged mitochondria can do bad things to you, as Baldelli will attest, the opposite is also true: Strong, healthy mitochondria can make you strong and healthy now, and maybe for a very, very, very long time.

"Expanding lifetimes for another hundred, some say a thousand years, is... science fiction," says David Sinclair, Ph.D., his Australian drawl rising softly. "We can't even extend the life of a mouse that far.

How could we do it for ourselves? I don't know of anything we're doing yet that would allow us to accomplish that."

Yet.

It's Friday afternoon and I've come to Sinclair's lab at Harvard medical school to talk to him not only about the prospects for supercharging our mitochondria, but also about the long-term effects of keeping these cellular power plants humming. Sinclair, a slight, intense man of 39, dismisses the idea of adding centuries to our lives, but he's more optimistic about the possibility of adding a few decades of, say, competitive softball.

"In the future, people will be thinking, 'When I'm 80, I'll still be playing tennis...and at 90 I'll still be around to see my great-grandkids graduate from college,' " he says.

Over the past couple of decades, researchers have gained an increasing understanding of just how crucial mitochondria are to, well, just about every aspect of human health and fitness. On the positive side, for example, research shows that properly functioning mitochondria pave the way for an array of benefits — from muscle growth and increased energy to greater endurance and a great head of hair. On the negative side, damaged mitochondria are associated with an equally wide array of diseases and conditions — from diabetes, heart disease, and obesity to the type of neuromuscular disorder that sucked the spirit out of Rocco Baldelli.

As your mitochondria go, apparently, so goes the rest of you.

That's why Sinclair has been trying to pinpoint a genetic way to keep our mitochondria charged up. Currently, he and a group of researchers are focused on enzymes called sirtuins, which, when activated, have been shown to invigorate mitochondria. Sinclair himself has made several of the most recent, high-profile breakthroughs involving sirtuins. In 2003, he discovered that the sirtuin known as SIR2 could be activated with resveratrol, a compound best known for its presence in red wine. In subsequent studies, he and other researchers found that giving lab mice large amounts of resveratrol not only made them healthier and more energetic, but in some cases extended their lives by up to 30 percent. (Don't reach for the Beaujolais just yet, though — you'd have to drink at least 35 bottles a day for an equivalent dose). Then, last year, Sirtris Pharmaceuticals—the company Sinclair cofounded to develop antiaging drugs — announced that it had cooked up a chemical compound that's a thousand times more potent than resveratrol.

What does all this mean? In the short term, it means lots of enthusiasm for what Sinclair and his colleagues are doing. Pharmaceutical giant GlaxoSmithKline, for example, is so bullish on Sirtris that in June 2008 it bought the company for $720 million. Meanwhile, Sinclair himself believes that a sirtuin-activating, mitochondria-boosting drug could be on the market within a decade and possibly within 5 years.

If that happens, the impact on all of us is potentially profound. For starters, it would be a step toward a whole new type of treatment for some of the most common and debilitating human diseases, including heart disease, diabetes, and even cancer. Just as significant, though, is the fact that the drugs could allow us to remain healthy, active, and energetic years beyond what we're capable of now. So both Father Time and the Grim Reaper are in the crosshairs.

And for Sinclair, it seems, that is precisely the point. "We have such a short time on the planet — on a geological scale, we're around for a second," he says. "And our loved ones are not going to be around forever. I'd like to do something about that. I think aging is the curse of mankind."

He leans forward in his chair. "It's really not fair for conscious beings to be aware of their own mortality."

Mitochondria are tiny, but their effects are large. You can easily see the difference between an animal whose mitochondria are working perfectly and one whose mitochondria are worn out.

Sinclair beckons me over to his computer.

Onto the screen pops a video of two mice running side by side on two tiny treadmills. The mouse on the left — which Sinclair explains was part of the control group in a recent study, one that was fed a diet of pellets — is struggling like an overweight chain smoker trying to run the New York City Marathon. The mouse on the right, whose mitochondria were fired up with megadoses of resveratrol, is sprinting forward gleefully.

So how exactly do mitochondria turn one mouse into a near-superhero while leaving another looking like a rodent version of Jack Black? The answer goes back to the role mitochondria play in cells. The main function of mitochondria is to transform nutrients that enter cells into supplies of the energy molecule ATP — something they accomplish through a complex process called aerobic respiration. ATP, in turn, provides the energy the cells need to function. (The number of mitochondria in a cell varies, depending on how much energy the cell requires. Heart cells, for example, have thousands of mitochondria, while skin cells have only one mitochiondrion each.)

Now when your mitochondria are functioning properly, good things happen. Your body runs the way it's supposed to — your heart beats, your neurons fire, your muscles contract, your eyes see, and your liver, kidneys, and other organs operate as they should. You are, in essence, a perfectly tuned piece of physiology.

Unfortunately, at least two factors stand in the way of properly functioning mitochondria. The first is genetic mutation. Mutations may be inherited, or caused by diet and lifestyle, or simply random. And they're associated with a vast array of conditions ranging from neuromuscular ailments to dementia, atherosclerosis, and diabetes. In such cases, the genetically damaged mitochondria fail to process all the nutrients in the cell, leading to an energy crisis within the cell. Without enough power to function, the cell falters... and presto, bad stuff happens.

The second force working against your mitochondria is, simply, time. The great paradox of mitochondria is that even as they're providing energy to your body, they're essentially sowing the seeds of their own destruction. During aerobic respiration, by-products, such as free radicals, leak out. Over time, they harm both the mitochondria and other parts of the cell. The result: damage that looks a lot like aging.

The link between mitochondria and aging was most definitively established in a 2004 study published in the journal Nature. In the study, researchers at Stockholm's Karolinska Institute developed a strain of mice with damaged mitochondrial DNA. For the first 25 weeks (until young adulthood) the mice were normal. But then they suddenly began to show signs of premature aging. They displayed the sorts of symptoms you typically see at a 50th high-school reunion: creaky joints, failing mojo, even baldness. Typically, wild mice live for about 2 years (100 weeks), while pet or lab mice live for 3 years or so (150 weeks). All of these mice were dead by 61 weeks.

Is there anything you can do to help your mitochondria withstand the ravages of time? The happy answer is yes. Exercise, for example, is known to have a major impact on mitochondrial function. In a 2003 study, Mayo Clinic researcher Kevin Short, Ph.D., put 65 healthy nonexercisers on a bicycle-training program 3 days a week. Not only did their aerobic capacity increase significantly, but their mitochondria were pumping out more ATP-boosting enzymes as well.

Alas, you can't exercise your way to immortality, which is why David Sinclair and others are trying to find a pharmacological way to keep those mitochondria revving. The mouse who's a stud on the treadmill and his resveratrol-stoked brethren, for example, had significantly less heart disease and diabetes and lived 30 percent longer than their resveratrol-deprived friends. "They were healthier, fitter mice, all thanks to resveratrol in their food," says Sinclair.

David Sinclair may be on the brink of a mitochondria-boosting drug, but the quest actually began more than 70 years ago, long before he was born. In the 1930s, a group of researchers made a fascinating finding: Significantly reducing an organism's calorie intake lengthens its life. From an evolutionary standpoint, this makes sense. It suggests that organisms that could slow their own aging during food shortages were able to survive and reproduce, while organisms that couldn't saw their genetic lines die off. Still, while scientists have repeatedly shown that caloric restriction works in all sorts of organisms, they never really understood exactly how this magic took place.

In the early 1990s, an MIT researcher named Lenny Guarente, Ph.D., decided to take a crack at solving the caloric-restriction riddle. As career moves go, it was pretty risky, given that the study of aging had long been seen as a backwater of science. "There were a lot of claims that turned out to be wrong," Guarente says as we chat in his MIT office, which is just across the Charles River from David Sinclair's lab. Now 56, Guarente is bald and has dark, deep-set eyes. "Aging was also seen as too complicated, too chaotic" to solve, he continues. "And evolutionary theory holds that it should be that way. Aging occurs late in life, when natural selection has waned. The things that happen haven't been selected for and honed."

Guarente was undeterred by his colleagues' skepticism, though, and with the help of a couple of graduate students, he studied aging in yeast. (That's about as simple an organism as you can think of.) In 1996, he and his team discovered that a strain of yeast that lived longer than its counterparts had a mutation in a particular set of genes — namely, its sirtuin enzymes. Eventually, Guarente added an extra copy of one of those genes, SIR2, to a normal yeast cell, and found that — voila — it extended the cell's life span by 50 percent.

It was around this time that Guarente was joined in the lab by Sinclair, then a 27-year-old Australian who'd just earned his doctorate in biology at the University of Sydney. The two had met by accident — they'd sat next to each other at a scientific forum in Sydney — but as soon as Sinclair heard what Guarente was working on, he wanted to join him. "I basically told Lenny, 'I'm coming to your lab whether you like it or not,'" Sinclair remembers. "I didn't want to do anything else with my life."

Over the next few years, Guarente and his team made two more significant discoveries. In 1999, one of Guarente's lab assistants found that adding an extra copy of the SIR2 gene had a similar effect on roundworms. Guarente says this was a pivotal moment for him, because the finding suggested that the same process was at work in a variety of organisms.

The other breakthrough, equally crucial, was the discovery of a link between SIR2 and caloric restriction — the life-extending diet that had first been recognized back in the 1930s. While previous theories had speculated that caloric restriction worked by slowing an organism's metabolism, Guarente's research suggested the exact opposite was happening — slashing calories actually activated SIR2, which in turn revved up the cell's mitochondria and kept them young and vital.

In the nearly 10 years since then, Guarente and Sinclair, as well as a number of other Guarente protégés, have been researching sirtuin. Sinclair founded his own lab at Harvard in 1999, and he's made significant advances there, including the discovery that resveratrol can activate SIR2. He's also created a new chemical compound that's a thousand times more potent than resveratrol. In 2006, Sinclair and his team launched the first human studies of this new compound, and he's clearly excited by the results.

"The trials have shown that blood glucose levels are lowered in people with diabetes, as we saw in the mice," he says. "So far, we are seeing the same kind of improvements in glucose metabolism in humans that we saw in the mice. And we've seen no evidence of toxicity or side effects."

How much time does he think the drugs might potentially add to human life? "It's feasible that we could help people live 5 or 10 years longer in a healthy state," he says. "Ultimately, they could have a far greater effect on healthy longevity based on what we know about caloric restriction in animals and its ability to keep animals healthy for an additional 30 percent longer."

Not everyone is convinced that Sinclair is onto the next big thing. Some scientists argue that studies of mice don't guarantee that resveratrol will work — or be safe — in humans. A handful of others are skeptical of any significant life-extension benefits, arguing that from an evolutionary perspective, humans may have already reached their maximum life span.

Sinclair acknowledges that plenty of obstacles are still ahead, but he has faith that he's on the right track. "Caloric restriction works in every organism, and so far, these molecules have worked in every organism," he says. "I'm hoping humans are not the planet's only exception. People who think that are usually disproven when it comes to biology."

So what will these sirtuin-activating, mitochondrial-boosting drugs look like if they ever hit the market? The drugs that Sirtris is now working to develop will be targeted at specific diseases and not the aging process itself, largely for practical reasons. In order for a drug to be approved by the FDA, its manufacturer must show it has a measurable effect. To demonstrate an impact on aging would take at least 10 to 20 years, something no drug company has the time, resources, or interest in doing. Diabetes, in contrast, can be tested relatively quickly.

"It's probably never going to be sold as an antiaging drug," Sinclair says. "But if a drug comes to market and is capable of doing what we see in mice, then there will also be approved trials by doctors to treat other ailments. And the hope is that people will then start to see the other benefits." Included in those other benefits are nearly all the things you see when mitochondria are working properly: abundant energy, improved memory, reduced chance of heart disease and cancer — the list goes on.

Sinclair says that sometimes people complain about what he's doing, but he insists they simply don't understand it.

"I occasionally get letters from people saying, 'I'm 75, I can barely walk, I'm in pain — the last thing I want is a pill that extends my life.' " His voice falls to a near-whisper. "I think they miss the point. People think we're extending the final years of life, when what we're actually doing is increasing the years of youth. So it's keeping people out of nursing homes, not keeping them alive longer in nursing homes."

Given all of that, the more intriguing question might be this: What impact could these drugs have on society? Sinclair believes that reducing levels of age-related diseases would create a huge economic benefit to society. "If you make people live longer in a healthy way, it's far cheaper," he says. "I've read that if you reduce one disease — cancer, for example — by 10 percent, the savings to the United States would be about $5 trillion. Well, we're talking about drugs reducing disease maybe more than 10 percent — and many of them at once."

The more profound impact may be on each of us individually. On a practical level, you'd no longer be able to retire at 65. On the positive side, you'd have more years to enjoy the things you love, and probably watch your great-grandchildren grow up. And on a deeper level, perhaps the very arc of your life would be affected. In a world where 95 is the new 65, and 65 the new 40, would we stop going to school in our early 20s, or would we extend education another decade or so? Or go for repeated educations and careers? And how about marriage — would most of us still marry before we're 30? Would one spouse remain the ideal, or would we slap a 50-year expiration date on marriage and change partners later in life?

It's a lucky thing that mitochondria give us energy; we're going to need plenty.

For Sinclair, any complications pale in comparison to the benefits. "When I was working for my Ph.D., my mom got lung cancer. The doctor said, basically, say goodbye to your mom — there's only a 5 percent chance she'll survive. It was pretty traumatic for her and us kids. And for a time I wasn't going to come to the United States because I figured I might never see her again. But I resolved that if I was going to leave her, I would devote myself to making practical use of discoveries.

"Fortunately, she's still alive. But that was a turning point in my life. People probably think I'm just spinning it, but I'm only doing this because I want to help people and prevent them from dying. Or delay it, at least."

Despite his heroics in baseball's postseason, Rocco Baldelli isn't cured — and he knows it. He's said that he sleeps twice as much as he used to, and he takes a daily cocktail of medications to combat his condition. His baseball future is unclear, as well: A few days after the Rays lost the World Series, Baldelli became a free agent.

"I don't anticipate that the state of my health will be changing," he told a sportswriter recently.

But that doesn't mean he's without hope. Sinclair and the team at Sirtris are currently conducting trials of their resveratrol formulation on a number of conditions, including Baldelli's disease. Results of that study are expected in the first half of 2009, and as any Tampa Bay Rays team member knows, miracles do happen sometimes.
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