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Seeking Biomarkers of Aging and Diseases of Aging

October 2, 2007

Conference Overview

An agitated woman is talking to her doctor. “Every day I walk for 30 minutes, I drink 8 glasses of water and I eat 5 fruits and vegetables,” she says. “But I’m still getting older!”

Like the woman in the cartoon, no one has yet discovered the secret to halt the aging process. At a one-day conference organized by the American Federation for Aging Research (AFAR), however, more than 200 representatives from academia and industry agreed to collaborate toward a more coordinated effort to understand the complex biological phenomenon that, as one attendee said, has made patients of us all. “Can we stop aging? No, but maybe we can slow it down a bit,” said Donald Ingram, PhD, Head of the Nutritional Neuroscience and Aging Laboratory at Louisiana State University.

Held at the University Club in New York City, the October 2 meeting focused on using biological measures, or biomarkers, as sensitive indicators of aging and as tools for extending healthy lifespans and targeting age-related diseases with effective interventions. With the deliberate inclusion of both academic researchers and pharmaceutical industry leaders, a theme of public-private collaboration prevailed throughout the day. Several speakers asked how such a partnership might provide a smoother bridge from basic to applied science. Others urged a more collaborative approach toward establishing a consensus definition of biomarkers, developing agreed-upon validation criteria, fighting spurious anti-aging claims and promoting a more consistent drug approval process.

The challenge for researchers has been finding a measure that in less than the full lifespan of an organism – whether in “Uncle Harold” or a fruit fly – can reliably predict survival or the rate of change – Richard Sprott, PhD

A basic challenge is finding biomarkers that can predict what people often know intuitively, said the Ellison Medical Foundation’s Richard Sprott, PhD, who as executive director oversees the foundation’s grant-making programs for aging research. Everyone may sense, for example, that a 40-year-old “Uncle Harold” will never make it to 70. On the other hand, everyone may have known for decades that “Aunt Matilda” would surpass that same milestone physically and cognitively intact. The challenge for researchers has been finding a measure that in less than the full lifespan of an organism – whether in “Uncle Harold” or a fruit fly – can reliably predict survival or the rate of change.

Especially disappointing was the failure of the National Institute on Aging Biomarker Program to produce a panel of such biological markers despite a 10-year effort. But Dr. Sprott and other speakers said scientists nevertheless learned valuable lessons and that a combination of newly available tools and open dialogue may yet “dramatically change the trajectory” of the research.

Examining sets of genes that turn on and off in age-dependent and age-independent patterns should yield some useful biomarkers permitting the aging process to be measured on an individual rather than a population-wide basis. – Stephen Helfand, MD

Brown University neurologist and molecular biologist Stephen Helfand, MD, struck an equally optimistic tone with his assertion that researchers do have a relatively good concept of biomarkers. In fruit flies, he said, researchers can separate chronological age from physical age by raising the flies in higher or lower temperatures. As the flies age, researchers can look at how genes of interest turn on or off by attaching “reporter” genes for pigment production or even lethal toxins and then recording when and where coloration appears or whether a mutation that delays toxin production keeps certain flies alive. Examining sets of genes that turn on and off in age-dependent and age-independent patterns should yield some useful biomarkers, Dr. Helfand said, permitting the aging process to be measured on an individual rather than a population-wide basis.

Richard Miller, MD, PhD, associate director of the Geriatrics Center at the University of Michigan, sounded a cautionary note, however, by suggesting that a chief impediment to biomarker research has been an overly broad use of the term, especially as a synonym for age-sensitive traits or risk factors for death. A biomarker, he proposed, should be thought of as a surrogate for something that’s hard to measure, just as the “Walk on this line please, sir” test can be a surrogate for blood alcohol levels. The big question for biomarkers, he said, is whether researchers can use them to meaningfully estimate the difficult-to-measure biological age of normal people.

To be validated, a biomarker must predict the outcome of multiple, age-sensitive tests, after statistical adjustment for age – Richard Miller, MD, PhD

Risk factors for death – having had a heart attack last week, perhaps, or being tied to the railroad tracks – are easy to identify. “We have tons,” Miller said, “but they’re terrible biomarkers of aging.” So too are most age-sensitive traits, like having gray hair or fond memories of Elvis performing live in Vegas. Neither indicates whether a person is a dynamic senior citizen and others that might, like grip strength, are unproven as biomarkers. To be validated, he said, a biomarker must predict the outcome of multiple, age-sensitive tests, after statistical adjustment for age.

Long-term studies are providing the first tantalizing suggestions that caloric restriction might provide a significant survival advantage for primates – and perhaps point toward intervention strategies in which drugs mimic the effects of fewer calories. – Richard Weindruch, PhD

Multiple studies that came out of the National Institute on Aging Biomarker Program consistently confirmed that restricting calories led to longer average lifespans among mice and rats, according to Pennsylvania State University professor of health and human development Gerald McClearn, PhD. Although the difference varied widely depending on the inbred mice and rat strains used, that conclusion in rats had been reached as far back as 1935, noted Richard Weindruch, PhD, a professor of geriatrics and gerontology at the University of Wisconsin. Long-term studies with rhesus monkeys, he said, are now providing the first tantalizing suggestions that caloric restriction might provide a similarly significant survival advantage for primates – and perhaps point toward intervention strategies in which drugs mimic the effects of fewer calories.

Biomarkers of caloric restriction in male rhesus monkeys – such as lower insulin levels and lower body temperatures – have successfully predicted survival in humans too, Louisiana State University’s Ingram asserted. But what about the low-calorie diets themselves? Dr. Weindruch noted that Okinawans reportedly eat 40 percent fewer calories than Japanese mainlanders and have the highest percentage of centenarians in the country. Higher calorie diets are also linked to an increased risk of developing a range of cancers as well as Alzheimer’s and Parkinson’s disease. And among a group of people who have voluntarily reduced their caloric intake, emerging evidence suggests the dieters enjoy an increased resistance to cardiovascular disease.

Several speakers agreed that no one factor can be expected to be a superb predictor of lifespan, let alone a predictor of biological age. But having several dozen could allow scientists to home in on useful predictors. Finding them, of course, will depend upon funding, and keynote speaker Richard Hodes, MD, director of the National Institute on Aging, noted that NIA and overall National Institutes of Health funding had remained flat, and in fact had eroded due to inflation in the ability to support biomedical research.

Even so, new fields such as epigenetics, or the study of changes in gene expression and regulation that aren’t limited to the genetic sequence, are revealing new age-dependent patterns, Dr. Hodes said. And collaborative public-private partnerships like The Biomarkers Consortium, whose goal is to seek out and validate biological markers of aging, are enabling government, industry and philanthropy to explore and develop mutually beneficial tools.

Supporting the Next Generation of Researchers

As highlighted by the four winners of the AFAR-GE Healthcare Junior Investigator Award for Excellence in Biomarker Research, a new generation of scientists is lending a capable hand. One winner, Carolina Ibáñez-Ventoso, PhD, from Rutgers University, led a study that identified 50 microRNA molecules – tiny pieces of RNA – which may modulate aging in roundworms. Another award-winning study led by Stuart Chambers, PhD, from Baylor College of Medicine in Houston produced a comprehensive “molecular portrait” of aging in a class of stem cells that replenish blood and the immune system throughout an individual’s life.

Krishnamurthy Janakiramam, PhD, from the University of North Carolina at Chapel Hill, explored a pair of tumor suppressors that seem to work by preventing cells from performing their routine maintenance, thereby contributing to aging. “It’s a double-edged sword,” he said. And Ying Liang, PhD, from the University of Kentucky in Lexington, led a study that identified a new gene coding for a potential tumor suppressor whose expression also changes with age.

Industry Weighs In

What’s the industry’s outlook for biomarker research? Ihor Rak, MD, vice president of Global Clinical Development for AstraZeneca’s Neuroscience Therapy Area, said the industry hopes to use biomarkers to provide initial confidence to invest in a potential treatment and then the means to get that treatment approved. It’s about “reducing risk, reducing risk, reducing risk,” agreed Joan Amatniek, MD, a director at Ortho-McNeil Janssen Scientific Affairs. Drug development for Alzheimer’s disease, she noted, is a particularly high-risk area of research, in part because of the huge variation in how the disease manifests itself and develops over time. “Having a biomarker that says, ‘Yes, this is the pathology, yes, we followed it and yes, this is how [the therapy] worked,’” she said, would be enormously helpful.

Kenton Zavitz, PhD, senior director of clinical affairs for Myriad Pharmaceuticals, said biomarkers can be used for a diagnosis earlier in the disease process when intervention is still possible, to track the progression of a disease and to understand how the underlying course of a disease may be changed by therapeutics.

Isro Gloger, PhD, a director in the Discovery Technology Group at GlaxoSmithKline in the United Kingdom, said filling in the gaps for age-related disease knowledge at a basic level and advancing the validation process for legitimate biomarkers at the industry level will require not only mutually agreed-upon definitions and validation criteria but also a new willingness to share samples. Luigi Ferrucci, MD, PhD, director of the Baltimore Longitudinal Study on Aging at the National Institute on Aging, another conference speaker, agreed with the assessment, adding that collaboration from the very onset will be vital for designing the trials required to win approval from the Food and Drug Administration.

Meanwhile, the public is being flooded with unproven claims that aging can be slowed through supplements, anti-aging clinics and other interventions. The pharmaceutical leaders pledged their support in fighting the rampant “quackery,” but conceded that the public is often suspicious of their motives, underscoring the need for a public-private partnership that involves regulatory agencies and perhaps even Congress. As Michael Berelowitz, MD, Global Medical Head of Worldwide Development at Pfizer and a professor of medicine at Stony Brook University concluded, “We’ve got to figure out a way to work together in a way that’s seen to be in the best interest for humanity.”

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AFAR gratefully acknowledges the underwriters of this conference which include: Anonymous, Applied Biosystems/MDS SCIEX, AstraZeneca, The Ellison Medical Foundation, GE Healthcare, GlaxoSmithKline, The Glenn Foundation for Medical Research, Merck, Myriad Pharmaceuticals, Inc., Nestlé SA, Ortho-McNeil Neurologics, Inc., Pfizer, sanofi-aventis, and the 2007 Dorothy Dillon Eweson Lecture Series.

Funding for this conference was also made possible by 1R13AG31693-01 from the National Institute on Aging, National Institutes of Health. The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

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