Fortune Magazine Story on NSAIDS, Statins, Aging

ANTI-AGING:
The Secret Killer
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 that link.
by
David Stipp
E-mail: [EMAIL PROTECTED] 
Fortune Magazine (October 27, 2003)
Actuaries, not economists, are the truly dismal scientists. Consider
some actuarial projections about the graying America of 2050: 1 : 26
of us will have Alzheimer's Disease, compared with 1 : 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 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.

        OK, 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 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.