"Long before it's in the papers"
June 04, 2013


Already-approved drug tied to longer, healthy life in mice

May 25, 2013
Special to World Science  

The first drug to suc­cess­fully ex­tend the life­span of nor­mal lab mice al­so does so in a way that pro­longs their healthy ex­ist­ence, ac­cord­ing to a new stu­dy.

Re­search­ers hope the drug, ra­pa­my­cin, may al­so serve to pro­long life and ward off aging-related dis­eases in people, especially as it’s al­ready tested and ap­proved for an­other hu­man use: to pre­vent trans­plant re­jec­tion.

A pop­u­lar strain of lab mice known as C57BL/6, used in the new study by Yi­qiang Zhang and col­leagues at the Uni­ver­si­ty of Tex­as Health Sci­ence Cen­ter at San An­to­nio. (Im­age cour­te­sy FDA)

But obstacles remain before any hu­man use of ra­pa­my­cin as a longevity boost­er. It’s un­clear what dosages and reg­i­mens might be required for such a pur­pose. Con­cerns about side ef­fects linger. And mouse stud­ies have used a spe­cial encap­sula­tion method that’s not cur­rent­ly used in human con­sump­tion of the drug.

A biotech firm has sprung up in San An­to­nio, Tex­as in hopes of ex­ploit­ing new com­mer­cial pos­si­bil­i­ties for ra­pa­my­cin, and its of­fi­cials have said that clin­i­cal tri­als are ex­pected soon.

In the new stu­dy, mice were fed ra­pa­my­cin as part of their di­et start­ing when they were 19 months—the equiv­a­lent of about 60 hu­man years—old. The meas­ured life­span in­creases were more mod­est than in some pre­vi­ous stud­ies. Com­pared to un­treated mice, the life­span of the treated ro­dents went up by about 3 per­cent on av­er­age, al­though the dif­fer­ence rose to 7 per­cent for mice who made it to old­er ages to beg­in with.

Pre­vi­ous stud­ies had yielded more dra­mat­ic re­sults. 

A study in the July 2009 is­sue of Na­ture, us­ing a si­m­i­lar meth­od­ol­o­gy but dif­fer­ent mouse strains, had found in­creases as high as about 10.5 per­cent for old­er mice on ra­pa­my­cin com­pared to un­treated. An­oth­er piece of re­search found that if treat­ment was started when the mice were about half as old, then the av­er­age sur­viv­al in­crease jumped to about 14 per­cent. That study ap­peared in the Feb­ru­ary 2011 is­sue of The Jour­nals of Ger­on­tol­o­gy: Bi­o­log­i­cal Sci­ences.

The new stu­dy, in the May 16 on­line edi­tion of the same jour­nal, fo­cused on the health ef­fects in ad­di­tion to the life­span ef­fects. “Whether the life-ex­tending ef­fects of ra­pa­my­cin treat­ment are re­flected in ex­tended health has not yet been ex­ten­sively in­ves­ti­gat­ed,” wrote the au­thors, re­search­ers with the Uni­vers­ity of Tex­as Health Sci­ence Cen­ter at San An­to­nio.

The au­thors in­clud­ed scientists who have li­censed ra­pa­my­cin-related tech­nolo­gies to the biotech company, Ra­pa­my­cin Hold­ings Inc.

They al­so wrote that they in­ves­t­i­gated the health ef­fects in great­er de­tail be­cause “in­creas­ing life span with­out sim­ul­ta­ne­ously in­creas­ing health span is a fool’s er­rand.” They found that treat­ed mice enjoyed health ben­e­fits in­clud­ing in­creased stride length and bet­ter re­sults on a test of en­dur­ance.

Rapamycin’s lifespan bene­fits to mice have tended to be greater for fe­males, which received life­span boosts up to 80 per­cent greater than the males depending on the stu­dy. 

The in­ves­ti­ga­tors in the new study used ra­pa­my­cin that had been “mi­cro­en­cap­su­lated” by a spe­cial meth­od in or­der to re­sist de­grada­t­ion when mixed with the ro­dent chow. This is­n’t the same way ra­pa­my­cin, a pre­scrip­tion drug, is nor­mally tak­en in hu­man clin­i­cal use, al­though it is tak­en oral­ly.

Ra­pamycin is thought to ex­ert its ef­fects on life­span by sup­pressing the ac­ti­vity of a chem­i­cal path­way in the body known as mTOR, which helps to gov­ern growth and sur­viv­al re­sponses in cells. 

Ra­pamycin al­so helps pre­vent trans­plant re­jec­tion by blocking cer­tain im­mune sys­tem cells, lead­ing to con­cerns of harm­ful im­mune-sup­pressing side ef­fects. But these have not proved prob­le­matic in the mouse stud­ies, ac­cord­ing to scien­tists.

Very few sub­stances have been found to re­liably pro­long life­span in lab an­i­mals. Be­fore ra­pamycin, the one con­sid­ered per­haps most prom­is­ing was res­ver­a­trol, found to ex­tend life­span in round­worms, yeast and cer­tain fish. But such ben­e­fits in lab mice, seen as an im­por­tant stepping-stone to­ward hu­man stud­ies, were re­ported only for mice that were obese.

Ra­pamycin is so named be­cause it was dis­cov­ered com­ing from soil bac­te­ria at East­er Is­land, al­so known as Rapa Nui.

* * *

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The first drug to successfully extend the lifespan of lab mice also does so in a way that prolongs their healthy existence, according to a new study. Researchers are hoping the drug, called rapamycin, may also be useful in humans to prolong life and ward off aging-related diseases. But although it’s already FDA-approved as a drug to suppress transplant rejection, it’s unclear what dosages and regimens might be required for any effects on longevity. And concerns about side effects remain. A biotech firm has sprung up in San Antonio, Texas to exploit commercial possibilities for the substance, and its officials have said that clinical trials are expected soon. In the new study, mice were fed rapamycin as part of their diet starting when they were the equivalent of 60 human years old. The measured lifespan increases were more modest than in some previous studies. Compared to untreated mice, the lifespan of the treated rodents went up by 3 percent on average, although the difference rose to 7 percent for mice who made it to older ages to begin with. Previous studies had yielded more dramatic results. A study in the July 2009 issue of Nature, using a similar methodology but different mouse strains, had found increases as high as about 10.5 percent for older mice on rapamycin compared to untreated. Another piece of research found that if treatment was started when the mice were the equivalent of about 30 human years in age, then average survival went up 10% for males and 18% for females. That study appeared in the February 2011 issue of The Journals of Gerontology: Biological Sciences. The new study, in the May 16 online edition of the same journal, focused on the health effects in addition to the lifespan effects. “Whether the life-extending effects of rapamycin treatment are reflected in extended health has not yet been extensively investigated,” wrote the authors, researchers with the University of Texas Health Science Center at San Antonio. The authors included researchers who have licensed rapamycin-related technologies to the biotech company, Rapamycin Holdings Inc. They also wrote that they investigated the health effects in greater detail because “increasing life span without simultaneously increasing health span is a fool’s errand.” They identified health benefits including increased stride length and better results on a test of endurance. The investigators used rapamycin that had been “microencapsulated” using a special method in order to resist degradation when mixed with the rodent chow. This isn’t the same way rapamycin, a prescription drug, is normally taken in human clinical use, although it is taken orally. Rapamycin is thought to exert its effects on lifespan by suppressing the activity of a chemical pathway in the body known as mTOR, which helps to govern growth and survival responses in cells. Rapamycin also helps prevent transplant rejection by suppressing certain immune system cells, leading to concerns of harmful immune-suppressing effects. But these have not proved significant in the mouse studies, according to the University of Texas group. Very few substances have been found to reliably prolong lifespan in lab animals. Before rapamycin, the one considered perhaps most promising was resveratrol, found to extend lifespan in roundworms, yeast and certain fish. But such benefits in lab mice, seen as an important stepping-stone toward human studies, were seen only for those that were obese. Rapamycin is so named because it was discovered coming from soil bacteria Easter Island, also known as Rapa Nui.