Written by Steve Sandstrom • Photo Illustration by Jason Johnson
Scientists like to ask questions. Two years ago while working in the lab of Andrzej Bartke, Ph.D., professor emeritus and SIUC distinguished scholar of internal medicine and physiology, researcher Yimin ‘Julia’ Fang, Ph.D., posed a challenging one. She wondered why rapamycin, a drug that had been rigorously tested and proven beneficial in longevity studies and in organ transplant procedures, was causing negative metabolic effects in some medical research.
Rapamycin, also known as Sirolimus, was discovered as a product of a bacteria from Easter Island, known as Rapa Nui. It was approved by the FDA in 1999 and is marketed under the trade name Rapamune™ . Widely used in combination with other drugs, rapamycin suppresses rejection of tissue for organ transplants and is used as a heart stent coating. It is especially popular for kidney transplants because of its low toxicity to these organs.
Rapamycin also affects aging. Tests showed the drug suppressed an enzyme called the target of rapamycin (TOR) in yeast, worms and flies. TOR is important in nutrition signaling and the regulation of growth and aging. Changes to its corresponding gene affect longevity.
Because its life-extending properties looked promising, the NIH included rapamycin in a longevity intervention testing program on mice. NIH researchers and other groups have found rapamycin increased the lifespan of the animals.
Unexpectedly, a large number of additional studies of rapamycin produced detrimental effects, including insulin resistance. “Effects were more like metabolic syndrome— harmful changes — rather than the metabolic profile of a long-living animal,” Dr. Bartke says.
Research had already shown that rapamycin could extend longevity. What accounted for the poor metabolic effects?
Dr. Fang wanted to solve the paradox of why rapamycin would make an animal become disease-prone and die instead of becoming healthier and live longer than normal mice. ”Most of the studies on the effects of rapamycin look at the very short-term treatment of the drug. Life-extension studies used the drug for a much longer period,” Dr. Fang says. “My hypothesis was that the contradictory findings may be due to differences in the duration of treatment, and longer rapamycin treatment may change the metabolic parameters controlled by insulin signaling toward a beneficial profile.”
Dr. Fang tested animals on three different terms, comparing what happens to mice receiving drug treatments for two, six and 20 weeks. Her experiments measured metabolic changes within the animals: glucose tolerance, respiratory activity, lipids, etc.
As she studied the animal data, it became apparent that, as Dr. Fang puts it, “the switch had been tripped.” With two weeks of treatment, the animals developed the unfavorable metabolic characteristics reported by other labs. But the detrimental effects of rapamycin — hyperinsulinemia, insulin resistance and hyperlipidemia — were only observed during the early stages of the treatment.
But then, it happened: At six weeks of treatment, the effects subsided, became insignificant or disappeared. After 20 weeks, the negative effects actually reversed. Longevity indicators were there, including reduced fat and insulin levels, increased oxygen consumption and ketogenesis and better insulin sensitivity. “Now instead of seeing these detrimental effects on metabolism, we saw beneficial, positive effects that fit with longer life,” Dr. Bartke says.
Beyond solving a scientific contradiction, Dr. Bartke believes more is at stake. Since these metabolic characteristics are considered to be regulators of aging and longevity, doubts cast on their effects could undermine future aging research experiments. “This was really an important issue to resolve, especially to us. And Dr. Fang provided the answer.”