Outer Limits
Explorers on Aging’s New Frontiers
By Matt Windsor
 Have you heard the one about the elderly patient and his doctor? The patient says, “Doc, I’ve been golfing, and my right knee hurts.” The doctor says, “What do you expect? It’s 85 years old.” And the man replies, “So is my other knee, and it’s fine!”
As a geriatric researcher and advocate for the elderly, Richard Allman, M.D., loves this joke. “It makes the point that aging isn’t a disease,” he says. “The man’s knee doesn’t hurt because he’s old; it hurts because there is something wrong with the bone, or the cartilage, or the joint—and you might be able to fix it.”
Since 1900, medical advances have boosted the average American’s life expectancy from 45 into the high 70s and beyond. “There are people in their 90s going to work every day,” Allman says. But as we climb into uncharted territory, we’re only beginning to understand what happens to a body during a century on Earth: Muscles disappear, memory fails, and conditions such as heart disease, Alzheimer’s, and diabetes run rampant.
Richard Allman explains why aging isn't the enemy
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Allman on the puzzle of geriatrics
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The rise in life expectancy has happened so fast that physicians don’t know enough about these new populations to figure out how to help them. In the words of Allman’s colleague Andrew Duxbury, M.D., “what we know about the physiology of a healthy 90-year-old can fit on the head of a pin.”
UAB’s Center for Aging is turning that pinhead into a beachhead. As director of the center and the Division of Gerontology, Geriatrics, and Palliative Care, Allman leads more than 185 faculty members with research interests ranging from incontinence to cell senescence. Their work is aggressively translational and squarely pragmatic—designed to quickly jump from lab to clinic to living room.
New Hope for Old Problems
Not all research begins in a lab, of course. Since 1999, Allman’s own work has focused on the UAB Study of Aging, which enrolled 1,000 older adults in rural and urban counties around Birmingham, divided equally between race and gender. Participants were initially surveyed on baseline socioeconomic, health, emotional, and cognitive status, with changes tracked every six months.
| “What we know about the physiology of a healthy 90-year-old can fit on the head of a pin.” — Andrew Duxbury |
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The study’s goal is to understand how aging impacts independent mobility—or “life-space”—which is an important aspect of quality of life. Results so far offer valuable lessons, explains Allman. Specific diseases, such as diabetes, have been shown to be key predictors of life-space decline—as have depression, low levels of cognitive function, and lack of transportation. This data will help tailor programs for the elderly to have maximum impact.
The Study of Aging has also identified 10 symptoms leading to life-space decline that are easily overlooked during doctor visits—embarrassing or seemingly inconsequential signs such as loss of appetite, incontinence, pain, and unsteadiness. “These are things we would consider geriatric syndromes,” Allman says. “Many of them, if identified, can be treated and prevented.”
Muscle Man
One way to prevent and even reverse life-space decline is regular physical activity. Walking is usually recommended, but Center for Aging scientist Marcas Bamman, Ph.D., says an appropriate weight-training regimen can help older adults maintain mobility, raise levels of good cholesterol in the blood, and improve bone density and normalize blood glucose.
As our bodies age, we lose muscle mass, reducing strength and power, which, along with a consequent loss of bone mass, causes unsteadiness, falls, and fractures. It’s a growing concern as people live longer, Bamman says. “When you’re 78 years old, losing 40 percent of your limb muscle is a real problem.”
His lab attacks this problem at all levels. Earlier studies proved that weight training is the best way to rebuild muscle in older adults, though the process is not as efficient as it is for younger people. That led Bamman to explore molecular changes in aging muscle, focusing on the components necessary to bulk up: new proteins and additional nuclei for the expanding cells. He says the solution appears to be in helping muscle cells recruit the extra nuclei they need to grow. Bamman also suspects the three-times-a-week training regimen for adults is too frequent to allow older bodies to recover; he is now conducting trials to determine the optimum routine for seniors.
Free and Clear
Incubator for Investigators
The next great innovation in aging research may already be at UAB. That’s why Center for Aging director Richard Allman, M.D., invests much of his time in mentoring junior faculty members and helping them start their own research careers. He is also co-director of the Southeast Center for Excellence in Geriatric Medicine, a joint project with Emory University that provides pilot grants, salary support, and encouraging ears to junior faculty and senior fellows committed to academic careers in geriatrics. Allman notes this investment has paid amazing dividends—offering a return of more than 1,000 percent. “Our funding since 1998 has been $2.3 million,” he says, “and with that our trainees and faculty have generated $36.7 million in external support.” |
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Like Bamman, investigators in the Center for Aging’s Atherosclerosis Research Unit (ARU) move from proteins to patients and back. Atherosclerosis is a leading contributor to heart disease—the number-one cause of death for all geriatric patients—as well as stroke and even Alzheimer’s disease. But ARU scientists may be approaching several breakthroughs.
Most people are aware of cholesterol’s good and bad carriers: high- and low-density lipoprotein (HDL and LDL). Yet even atherosclerosis researchers don’t fully understand what HDL and LDL do as they ferry lipids out of the bloodstream. Statins, the widely prescribed class of cholesterol-lowering drugs, effectively reduce LDL levels, but “they probably only prevent half of heart disease, and that’s where HDL comes in,” says ARU director Jere Segrest, M.D., Ph.D.
More than 30 years ago, he discovered HDL’s elemental secret; to get water-hating fats to move through water-based blood plasma, it folds into a unique shape called the amphipathic helix.
Segrest, who also directs UAB’s Center for Computational and Structural Biology, specializes in unraveling the auto-origami of body proteins, which can morph into a dizzying array of shapes. “If you know a protein’s structure, you have the possibility of figuring out exactly how it interacts with other molecules,” Segrest explains. “Then you can design drugs to accelerate it, slow it down, or whatever else you want to do.”
Good Cholesterol Made Better
Building on Segrest’s discovery, ARU scientists G.M. Anantharamaiah, Ph.D., and David Garber, Ph.D., have designed two potentially revolutionary HDL-mimicking drugs. Oral HDL, a peptide developed with a UCLA research team and currently in phase-2 trials, has been shown to inhibit atherosclerosis, and animal tests suggest it could also correct several lipid-associated disorders—inhibiting Alzheimer’s disease and the flu virus, reducing inflammation, and improving cognitive function. “And we have shown that if you mix Oral HDL with statins, you can actually regress atherosclerosis in mice,” Anantharamaiah says. More recently, he and colleagues produced a second peptide that can lower plasma cholesterol levels by staggering margins and reduce lesions associated with lipid buildup in the arteries; laboratory tests are ongoing.
Other ARU scientists have proved that cholesterol is not just a heart problem. Researcher Ling Li, Ph.D., has demonstrated that a high-cholesterol diet and genetic hypercholesterolemia tend to exacerbate Alzheimer’s disease development in mice. But her early studies also show that statins can prevent Alzheimer’s disease and restore lost cognitive function. Even more significant, the same neuroprotective and neurorestorative effects were found in aging mice. “That means that statins may not only be useful in disease situations, but also in normal aging,” says Li. She is now trying to decipher what cellular or molecular mechanism produces these effects.
Li tests many of her hypotheses using computer simulations designed by Segrest. His detailed models rely on trillions of calculations to accurately reproduce the chaos of the human bloodstream, fully taxing UAB’s array of high-performance computers. But the university’s processing power recently jumped when Segrest and other researchers acquired the IBM Blue Gene computer cluster, which he says is among the world’s fastest machines.
Supercomputer modeling is a long way from house-to-house surveys, but Allman notes the Center for Aging must pursue every option. “There’s a lot to learn,” he says. “We know much more now than we did 10 years ago, but it’s much more important today—because 10 years from now, a flood of people will wash up in every doctor’s waiting room in America. And I’ll be there, so they better know how to take care of me!”
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