Scientists believe they may have found a common link in diseases from cancer to Alzheimer's to heart disease. Here's the story behind the search for THE SECRET KILLER
By David Stipp

(FORTUNE Magazine) – Actuaries, not economists, are the truly dismal scientists. Consider some actuarial projections about the graying America of 2050: One in 26 of us will have Alzheimer's disease, compared with one in 64 people today. The annual incidence of strokes will almost double. Ditto for cancer. The diabetes rate will nearly triple. As for other diseases of aging, don't ask.

But an almost surreal turn of events in medicine is beginning to cast doubt on those gloomy predictions. Evidence is growing that drugs able to lower the risk of almost every major disease of aging aren't far off. In fact, a slew of studies suggest that rough drafts of those miracle pills are no farther away than your local grocery. They include aspirin, ibuprofen, and similar "nonsteroidal anti-inflammatory drugs," commonly referred to by their acronym, NSAIDs (pronounced "en-sedz").

Over the past decade one galvanizing report after another has suggested that regular users of NSAIDs are less afflicted by aging diseases than are nonusers. In a 2001 study a Dutch team found that NSAID takers had an 80% lower risk of Alzheimer's disease. A recent review of aspirin's effects found that long-term users had 32% less risk of heart attacks. Other reports indicate that NSAIDs can cut the risk of colon cancer by nearly half, of lung cancer and prostate cancer by two-thirds, and of breast cancer in women by half.

And it's not just NSAIDs that seem to help. A second series of surprise findings involves statins, the cholesterol-lowering drugs with names like Lipitor and Crestor. It now turns out that statins may lower the risk of Alzheimer's, diabetes, stroke, possibly cancer, and even depression--as well as heart disease, of course.

What's perhaps most exciting about these revelations is the light they shed on the aging process--and on how we might retard one of its most damaging aspects. Both NSAIDs and statins reduce inflammation, the immune response that causes pain, redness, and swelling at infection sites. That gives weight to the theory that much of what goes wrong as we age stems from smoldering, low-level inflammation in places like arterial walls and the brain. "We've spent billions of dollars and decades of work trying to treat diseases of aging after they appear," says Andrew Dannenberg, a cancer researcher at New York--Presbyterian Hospital. "But the diseases don't just happen in one day. There's a long underlying process, and I fundamentally believe inflammation is an important part of it." Says Claudio Franceschi, scientific director at the Italian National Research Center on Aging in Ancona and coordinator of a massive, ongoing study on centenarians: "Inflammation is probably the background and driving force behind all major age-related diseases."

Franceschi was one of the first to voice that sweeping theory, which he calls "inflammaging." He began formulating it a decade ago when he and colleagues discovered that as people age, key immune cells become increasingly inflammation-prone. Recently the group has identified genetic variants in male centenarians that appear to mitigate the pro-inflammatory effect of aging. They and other researchers also have shown that frail, sickly oldsters are more likely to carry pro-inflammatory gene variants than their healthy peers. Elevated levels of pro-inflammatory proteins in the blood have been linked to heightened risk of osteoporosis, loss of lean muscle mass after middle age, anemia in the elderly, and cognitive decline after 70.

All that is enough to bring on a Ponce de Leon moment: Perhaps NSAIDs and statins at least partly mimic centenarians' genetic resistance to inflammation-driven aging diseases! If so, the drugs might qualify as the first credible semblance of anti-aging medicines. That's a leap, but not an Evel Knievel one. Though the apparent health benefits of anti-inflammatories haven't yet been rigorously vetted, some medical experts aren't waiting to start popping them. "I take an aspirin every day, and I do it because I think I'm reducing my aging," says a gerontologist who asked not to be named. If statins were as cheap as aspirin, everyone would be on them, says a physician, echoing a view that's becoming a kind of underground mantra in medicine. (The most frequently prescribed statins typically sell for about $3 a pill.)

If you're thinking of following suit, you'll be wading into murky waters (see box, "What Should You Do?"). There are frustratingly few guides on which anti-inflammatory pill to take, what is the right dose, or whether the pros outweigh the side-effect cons. Doctors generally tell healthy people not to take NSAIDs daily, for example, in part because they can cause serious gastrointestinal bleeding.

The lack of data is not surprising. Patents on drugs like aspirin and ibuprofen expired long ago, so there's no financial incentive for any company to fund costly trials on them. The National Institutes of Health is sponsoring some research on the preventive powers of off-patent, anti-inflammatory drugs. But no organization is planning to definitively test whether taking an anti-inflammatory drug regularly after age 40 or so lowers the risk of multiple diseases that may not appear for decades. That would require a clinical trial of unprecedented size, duration, and cost--a medical Mars shot.

Okay, so we may never know for sure whether anti-inflammatories work as broad preventives. But we may soon find out whether certain ones benefit patients known to be at risk for specific diseases. Trials on those what-ifs are already underway, led by pharma companies that have patent-protected anti-inflammatory drugs. Pfizer and Merck, for example, are funding trials on whether their COX-2 inhibitors--NSAID-like drugs thought to pose less risk of gastrointestinal bleeding--can prevent various precancerous conditions from evolving into full-blown tumors.

Makers of statins are also jumping in, thanks to the emergence of a simple blood test for a pro-inflammatory substance called C-reactive protein, or CRP. CRP levels shoot up when tissues are inflamed, and chronically elevated CRP has been linked to a panoply of risks, including heart attack. In fact, CRP is an even better indicator of cardiovascular risk than LDL cholesterol is, according to studies led by physician Paul Ridker at Brigham and Women's Hospital in Boston. Ridker's data indicate that $20 CRP tests can spot people at high risk of heart attack, stroke, and diabetes whose traditional risk-factor levels give no cause for alarm. Such patients might represent a huge new market for statins.

Studies on low-grade inflammation are also clarifying longstanding mysteries. Fat tissue is a strong producer of pro-inflammatory molecules, says Bente Pedersen, a researcher at University Hospital in Copenhagen. That may at least partly explain why obesity is linked to so many diseases of aging, from colon cancer to Alzheimer's, and why eating very low-calorie diets has been shown to extend animals' lives by a third or more. Exercise, on the other hand, appears to suppress low-level inflammation. Among other things, that may partly account for a 2001 study indicating that dedicated exercisers have half as much risk of Alzheimer's as couch potatoes.

Still, many medical experts caution that the inflammation hubbub resembles earlier fads that failed to measure up in rigorous trials, like hormone-replacement therapy for postmenopausal women. They argue that few, if any, of the studies linking low-grade inflammation to aging diseases actually prove that inflammation causes those diseases. Low-level inflammation may be a symptom, rather than an inducer, of inner decay. Thus, taking anti-inflammatory drugs to ward off diseases of aging may be like gobbling aspirin to avert headaches from a swelling brain tumor.

Skeptics also note that NSAID doses way below those customarily seen as anti-inflammatory have been linked to reduced risk in some studies. Suppressing the fiery inflammation that plagues rheumatoid arthritis sufferers, for instance, requires doses two to three times higher than those for quelling headaches, which in turn require doses higher than the chronic ones that seemingly can lower risk of aging diseases. That raises questions about the idea that NSAIDs' benefits, if real, have to do with inflammation.

So is the inflammatory buzz justified?

Perhaps the best reason to think so is the way that researchers studying different diseases of aging, knowing virtually zip about one another's work, have arrived at remarkably similar conclusions on the central role of inflammation in their ills of interest. It is as if detectives investigating murders in different cities suddenly found that their disparate sets of clues were all pointing to a single serial killer.

The culprit in this medical whodunit has been described as the immune system's startle response to injury and infection. Inflammation rapidly releases molecules that induce pain, summon blood-borne immune cells, and make local blood vessels leaky to facilitate the movement of defending cells to a trouble site. The scene gets ugly as those defending cells spew enzymes that actually liquefy infected tissue to stop germs from spreading.

The high risk posed by infections in eons past caused that first-line response to evolve with a hair trigger that helps to speedily stop the advance of invading germs. But it can also make for mistakes. During infections inflammation can spin out of control, leading to high fever, a drastic drop in blood pressure, coma, and death. That may well be how the SARS virus, which caused the scary epidemic earlier this year, kills people.

What's more, naturally occurring molecules that look a little strange to the immune system apparently can spark symptomless, low-level inflammation. Examples of those unwelcome oddballs include oxidized fatty particles in the blood (the LDL cholesterol that may form as an excess of cheeseburgers is turned into clogged arteries) and clumps of sticky proteins secreted by neurons (precursors to Alzheimer's). Making things worse, countless clashes with germs over the decades cause some of our immune cells to get increasingly trigger-happy, posits Italy's Franceschi. That's probably why blood markers of inflammation rise with age.

Once underway, smoldering inflammation may feed on itself. Tumors even twist the inflammation induced by their presence to their own deadly ends. In order to metastasize, for instance, they apparently use so-called adhesion proteins that immune cells engender on surrounding cells in order to move about. The proteins act like a rock climber's anchor bolts.

All this slowly unfolding damage didn't matter much in the bad old days. Life was too short. But now most of us live long enough to fall prey to its cumulative effects. Our pro-inflammatory spare tires and sedentary ways don't help.

In recent years scientists have learned how inflammation abets different diseases, depending on the tissue type and trigger involved. But long before those details came into focus, telltale patterns of disease risk pointed to hidden inflammation. In the early 1980s, researchers discovered that recovering heart-attack patients with unremittingly high C-reactive protein, the blood marker of inflammation, should get their wills together fast--they tend to suffer fatal second attacks within days. Other studies hinted that covert inflammation might contribute to first heart attacks. A 1988 report, for instance, showed that men who took an aspirin every other day had 44% less risk of first heart attacks than nontakers.

The hints grew stronger in the mid-1990s with the advent of highly sensitive blood tests for C-reactive protein. Using one such test, Boston's Ridker and his colleagues in 1997 riveted attention with a study in which they divided male subjects into four groups based on their CRP levels. Those in the group with the highest levels turned out to have three times the heart-attack risk of those in the lowest-CRP group. Further, the men with high CRP benefited more from regularly taking aspirin, in terms of lower heart-attack risk, than those with low CRP. The Boston researchers subsequently showed that statins reduced CRP (not just LDL cholesterol) and that their anti-inflammatory effect was tied to lower cardiac risk regardless of cholesterol levels.

Meanwhile, similar discoveries were coming to light in cancer and Alzheimer's research. In 1983 a Colorado surgeon named William Waddell reported a remarkable finding in patients with an inherited form of colon cancer: Intestinal polyps, a precursor to the disease, disappeared in several patients who were taking an NSAID named sulindac. That led to other studies of cancer incidence among NSAID takers. Many of the studies showed lessened risk in regular users of the drugs.

The cancer story quickened in the mid-1990s when researchers began investigating the effects of COX-2 inhibitors, the chemical cousins of NSAIDs designed to cause fewer side effects. In an elegant 1996 study Japanese researchers showed that a COX-2 inhibitor shrank intestinal polyps in bioengineered mice predisposed to colorectal cancer. Human trials led in 1999 to FDA approval of Celebrex, a COX-2 inhibitor now owned by Pfizer, to treat polyps in people with an inherited form of colon cancer.

The Alzheimer's part of the story also came alive in the 1980s. One of its heroines, W. Sue Griffin, a researcher at the University of Arkansas for Medical Sciences in Little Rock, reported in 1989 that a molecular booster of inflammation is found at abnormally high levels in the brains of Alzheimer's victims. Then Patrick McGeer and his colleagues at the University of British Columbia in Vancouver reported that arthritis patients, who tend to be heavy NSAID users, have a strikingly low occurrence of Alzheimer's. The plot thickened in 1994 when a team led by John Breitner, now at the University of Washington in Seattle, reported exciting data: Among elderly twins, some of whom had Alzheimer's, those who had used NSAIDs were very likely to be the later-affected or unaffected member of a pair. Over the past few years attention has turned to statins--it seems that chronic use of the drugs can cut Alzheimer's risk by nearly 80%.

We're now in the the acid-test phase. Studies have been launched to establish whether certain high-risk patients truly get more gain than pain from regularly taking anti-inflammatory drugs. Boston's Ridker is leading a closely watched trial on whether statins lower cardiovascular risk in people with low cholesterol but high CRP levels. His team is enrolling 15,000 volunteers to test the idea with Crestor, a statin made by AstraZeneca. Another study, funded by the National Institute on Aging, is testing whether naproxen, a generic NSAID, or Celebrex, Pfizer's COX-2 inhibitor, reduces Alzheimer's risk in people with a family history of the disease. In yet other trials COX-2 inhibitors are being tested as preventives in patients with precancerous signs of colon, bladder, skin, and other tumors.

Answers from these trials are several years away. While settling many questions, they won't address the key issue for many of us: If we're at normal risk of aging diseases, should we take low-dose anti-inflammatories as insurance?

Well, here's a thought. Each year we spend more than $15 billion in the U.S. on vitamins, antioxidants, memory-boosting herbs, and similar vigor preservers. If actuarial projections are any indication, our main gain from this expenditure is the world's costliest pee. Taking an aspirin every day or two poses a little risk (check with your doctor first), and it won't necessarily do you more good. But it costs about a penny a pill. Do the math.

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