Could Rapamycin Help Humans Live Longer?
In the 1990s, pharmacologist Dave Sharp of the University of Texas’s Barshop Institute for Longevity and Aging Studies in San Antonio was studying mice with pituitary dwarfism—a condition in which the pituitary gland fails to make enough growth hormone for normal development. The puzzle, Sharp explains, was that research had shown that these hormone-deficient dwarf mice lived longer than normal mice. “I wondered, why is being small connected with longer life?” he says.
Yeast research led by molecular biologist Michael Hall at the University of Basel in Switzerland was to provide Sharp with an unexpected lead. In 1996, a team led by Hall (who would go on to win a Lasker award in 2017 for the work) revealed a new intracellular signaling pathway, mediated by the protein targets of a compound called rapamycin. Using this drug to block the “target of rapamycin” (TOR) proteins in yeast had the same effect as starvation did: treated yeast cells were smaller, but longer-lived than normal cells (Cell, 7:25-42, 1996). For Sharp, it sparked an idea. “Maybe TOR is a nutrient response system, connecting diet restriction and growth-factor restriction,” he recalls thinking. “I proposed that if you fed mice rapamycin, they would live a long time.”
Back then, the hypothesis was unconventional. Rapamycin, a compound first identified in the 1970s in a soil sample from Easter Island, has been used for decades to suppress the immune system in transplant patients; it seemed counterintuitive that it could prolong life, Sharp notes. “Nobody would read my proposals,” he says. “They’d just laugh. You know, ‘An immunosuppressant extending lifespan?’”
But research since then has lent support to Sharp’s theory. Studies in the early 2000s showed that the drug could make nematodes and fruit flies live longer, while research by Sharp and others suggested that TOR signaling is downregulated in long-lived dwarf mice. And a collaboration between Sharp and the Barshop Institute’s Randy Strong, the principal investigator for the National Institute on Aging’s Interventions Testing Program, led to a landmark mouse study that identified rapamycin as the first drug to extend lifespan in mammals (Nature, 460:392-95, 2009). By fine-tuning dosage and delivery systems over the next five years, the pair increased longevity in male mice by 23 percent and in females by 26 percent, compared to control animals (Aging Cell, 13:468–77, 2014).
In the 1990s, pharmacologist Dave Sharp of the University of Texas’s Barshop Institute for Longevity and Aging Studies in San Antonio was studying mice with pituitary dwarfism—a condition in which the pituitary gland fails to make enough growth hormone for normal development. The puzzle, Sharp explains, was that research had shown that these hormone-deficient dwarf mice lived longer than normal mice. “I wondered, why is being small connected with longer life?” he says.
Yeast research led by molecular biologist Michael Hall at the University of Basel in Switzerland was to provide Sharp with an unexpected lead. In 1996, a team led by Hall (who would go on to win a Lasker award in 2017 for the work) revealed a new intracellular signaling pathway, mediated by the protein targets of a compound called rapamycin. Using this drug to block the “target of rapamycin” (TOR) proteins in yeast had the same effect as starvation did: treated yeast cells were smaller, but longer-lived than normal cells (Cell, 7:25-42, 1996). For Sharp, it sparked an idea. “Maybe TOR is a nutrient response system, connecting diet restriction and growth-factor restriction,” he recalls thinking. “I proposed that if you fed mice rapamycin, they would live a long time.”
Back then, the hypothesis was unconventional. Rapamycin, a compound first identified in the 1970s in a soil sample from Easter Island, has been used for decades to suppress the immune system in transplant patients; it seemed counterintuitive that it could prolong life, Sharp notes. “Nobody would read my proposals,” he says. “They’d just laugh. You know, ‘An immunosuppressant extending lifespan?’”
But research since then has lent support to Sharp’s theory. Studies in the early 2000s showed that the drug could make nematodes and fruit flies live longer, while research by Sharp and others suggested that TOR signaling is downregulated in long-lived dwarf mice. And a collaboration between Sharp and the Barshop Institute’s Randy Strong, the principal investigator for the National Institute on Aging’s Interventions Testing Program, led to a landmark mouse study that identified rapamycin as the first drug to extend lifespan in mammals (Nature, 460:392-95, 2009). By fine-tuning dosage and delivery systems over the next five years, the pair increased longevity in male mice by 23 percent and in females by 26 percent, compared to control animals (Aging Cell, 13:468–77, 2014).
Yeast research led by molecular biologist Michael Hall at the University of Basel in Switzerland was to provide Sharp with an unexpected lead. In 1996, a team led by Hall (who would go on to win a Lasker award in 2017 for the work) revealed a new intracellular signaling pathway, mediated by the protein targets of a compound called rapamycin. Using this drug to block the “target of rapamycin” (TOR) proteins in yeast had the same effect as starvation did: treated yeast cells were smaller, but longer-lived than normal cells (Cell, 7:25-42, 1996). For Sharp, it sparked an idea. “Maybe TOR is a nutrient response system, connecting diet restriction and growth-factor restriction,” he recalls thinking. “I proposed that if you fed mice rapamycin, they would live a long time.”
Back then, the hypothesis was unconventional. Rapamycin, a compound first identified in the 1970s in a soil sample from Easter Island, has been used for decades to suppress the immune system in transplant patients; it seemed counterintuitive that it could prolong life, Sharp notes. “Nobody would read my proposals,” he says. “They’d just laugh. You know, ‘An immunosuppressant extending lifespan?’”
But research since then has lent support to Sharp’s theory. Studies in the early 2000s showed that the drug could make nematodes and fruit flies live longer, while research by Sharp and others suggested that TOR signaling is downregulated in long-lived dwarf mice. And a collaboration between Sharp and the Barshop Institute’s Randy Strong, the principal investigator for the National Institute on Aging’s Interventions Testing Program, led to a landmark mouse study that identified rapamycin as the first drug to extend lifespan in mammals (Nature, 460:392-95, 2009). By fine-tuning dosage and delivery systems over the next five years, the pair increased longevity in male mice by 23 percent and in females by 26 percent, compared to control animals (Aging Cell, 13:468–77, 2014).
In the 1990s, pharmacologist Dave Sharp of the University of Texas’s Barshop Institute for Longevity and Aging Studies in San Antonio was studying mice with pituitary dwarfism—a condition in which the pituitary gland fails to make enough growth hormone for normal development. The puzzle, Sharp explains, was that research had shown that these hormone-deficient dwarf mice lived longer than normal mice. “I wondered, why is being small connected with longer life?” he says.
Yeast research led by molecular biologist Michael Hall at the University of Basel in Switzerland was to provide Sharp with an unexpected lead. In 1996, a team led by Hall (who would go on to win a Lasker award in 2017 for the work) revealed a new intracellular signaling pathway, mediated by the protein targets of a compound called rapamycin. Using this drug to block the “target of rapamycin” (TOR) proteins in yeast had the same effect as starvation did: treated yeast cells were smaller, but longer-lived than normal cells (Cell, 7:25-42, 1996). For Sharp, it sparked an idea. “Maybe TOR is a nutrient response system, connecting diet restriction and growth-factor restriction,” he recalls thinking. “I proposed that if you fed mice rapamycin, they would live a long time.”
Back then, the hypothesis was unconventional. Rapamycin, a compound first identified in the 1970s in a soil sample from Easter Island, has been used for decades to suppress the immune system in transplant patients; it seemed counterintuitive that it could prolong life, Sharp notes. “Nobody would read my proposals,” he says. “They’d just laugh. You know, ‘An immunosuppressant extending lifespan?’”
But research since then has lent support to Sharp’s theory. Studies in the early 2000s showed that the drug could make nematodes and fruit flies live longer, while research by Sharp and others suggested that TOR signaling is downregulated in long-lived dwarf mice. And a collaboration between Sharp and the Barshop Institute’s Randy Strong, the principal investigator for the National Institute on Aging’s Interventions Testing Program, led to a landmark mouse study that identified rapamycin as the first drug to extend lifespan in mammals (Nature, 460:392-95, 2009). By fine-tuning dosage and delivery systems over the next five years, the pair increased longevity in male mice by 23 percent and in females by 26 percent, compared to control animals (Aging Cell, 13:468–77, 2014).
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