The Older, the Wiser

Some fortunate folks stay mentally sharp well into their 90s. Scientists are learning their secrets in hopes of helping the rest of us keep our minds fit as we age.

Irving Kahn works 8 hours a day, 5 days a week, at his Madison Avenue investment advisory firm. This would hardly be noteworthy, except for his age: 99. When scientists gave him a mental fitness exam two years ago, Kahn showed no signs of cognitive decline. "I don't seem to have that problem," Kahn says.

Kahn has the good fortune to be intellectually spry as he approaches his 100th birthday. But he is not alone. Although only one in 10,000 people lives to be 100, studies suggest that up to a third of centenarians are doing well cognitively, and most of the rest have dodged any mental impairment until well into their 90s. Contrary to popular belief, "there is not an inexorable decline in mental function in older people," says neurologist David Bennett, who runs two longitudinal studies of aging at Rush University Medical Center in Chicago, Illinois. "If you follow [older] people over time, a lot do get worse, but most stay the same--and some get better."

A growing body of research is geared toward determining what keeps some people’s minds nimble into old age, and how to reproduce that success in the rest of us. Some scientists have identified genes that are associated with successful aging of the brain and hope to find drugs with similar effects. Others have discovered that simpler solutions like mental exercises also might prevent dementia, including the most devastating sort that accompanies Alzheimer's disease. Buttressed by these findings, Bennett speculates: "Cognitive, physical, and social factors may delay the onset of Alzheimer's disease."

Either way, attempts to halt cognitive decline are essential if people are ever going to take any kind of life-extending medicine, opines S. Jay Olshansky, a biodemographer at the University of Illinois, Chicago. Olshansky warns that treatments that lengthen the lives of lower creatures such as worms or fruit flies might not extend the useful life of the human brain in tandem with the rest of the body. "The worst scenario is having a body that goes on indefinitely but a mind that dies," Olshansky says.

Gerontologist Nir Barzilai and his colleagues at Albert Einstein College of Medicine in New York City are working to avert that scenario. They have been looking for genes in humans that are associated with both extreme longevity and mental stamina. The researchers have studied more than 300 Ashkenazi Jews with an average age of 98 along with their 70-ish children and, as a comparison group, the children's spouses. Kahn, the 99-year-old investment adviser, is one of the subjects, as are his 104-year-old sister and 98-year-old brother.

Several years ago, the researchers found a genetic mutation that was dramatically more prevalent in the Ashkenazi Jewish centenarians than in younger cohorts. The genetic alteration--which hinders the activity of a protein called CETP (cholesteryl ester transfer protein)--appears to work by boosting blood concentrations of the "good" high-density lipoprotein (HDL) and the size of HDL particles in centenarians (see "Small Isn't Always Beautiful").

Now, at a 10 March meeting jointly sponsored by Einstein and Montefiore Medical Center, also in New York City, Barzilai reported that the mutant CETP gene also augurs well for mental fitness in his centenarians. The altered gene was highly predictive of a participant's score on a test of memory and reasoning called the Mini-Mental State Examination. Nearly one-third of the high scorers among the 200 centenarians tested had the CETP mutation, whereas only 5% of those scoring below the researchers' cutoff had the same variant. "This is really significant. It is not a coincidence," Barzilai says.

The latest CETP results explain the researchers' earlier observation that high HDL concentrations and more massive HDL particles appear to be directly associated with good cognitive function among the oldest old. Why altering HDL would affect cognition, however, Barzilai cannot yet say. "I don't understand how [the CETP variant] is working," he admits.

Nevertheless, a drug might soon be available that mimics the gene's effects. Researchers at Pfizer Inc. are testing a medication called torcetrapib that inhibits CETP. By boosting HDL concentrations and particle sizes, the drug is meant to reduce the risk of cardiovascular disease. The Pfizer team has not yet tested torcetrapib's effects on the brain, but Barzilai thinks the drug might help stave off cognitive decline in the same way that the CETP mutation seems to.

Nothing points to a direct role for CETP in Alzheimer's disease or any other specific brain pathology. However, recent data suggest that any genes or behaviors that help thwart cognitive decline might do so even when neurodegenerative disease is present. Bennett and his colleagues examined postmortem brain samples from 180 elderly clergy members who had taken mental function tests as part of the Rush-based Religious Orders Study. The researchers saw clear signs of pathology--such as the plaques and tangles that riddle the brains of people with Alzheimer's disease--even among people who had shown no cognitive impairment before they died. Of the 37 people who had shown mild impairment, half had brains that showed clear signs of Alzheimer's disease, and many of the rest had brains bearing signs of stroke. Individuals who avoid losing cognition despite physical deterioration must possess some type of protective factors, Bennett says: "Now you can think about preventing cognitive decline despite the physical presence of pathology."

The protection need not come from genes or drugs, Bennett says. He thinks that what people do with their minds can also be important to keeping them in good condition. Bennett and his colleagues have shown that formal schooling has a "whopping effect" on how much the encroachment of Alzheimer's disease--as measured in the brain after death--influences the person's cognitive function in life. The scientists found that the longer a person went to school, the less any Alzheimer's pathology in their brains affected their minds.

Staying in school is probably not the only way to keep your mind active. "We think education is a proxy for lifelong cognitive experiences," says Bennett. For Kahn, remaining at work rather than retiring might have helped keep his brain in shape. The would-be centenarian recommends putting off retirement until at least age 70, a prescription he says should help us stay both intellectually and financially fit.

Ingrid Wickelgren is a freelance writer in northern New Jersey who hopes that her brain will still be working at 99, even if she's not.