• Late-life rapamycin administration regimens enhanced male mouse survival significantly.
  • Continuous rapamycin administration enhanced female mouse survival.
Rapamycin dosing regimens enhance mouse lifespan in a sex-specific manner.

Life expectancy differences between males and females point to variations in aging. How these aging-related differences tie into responsiveness to compounds that combat aging remains incompletely understood. Along these lines, not much is known about sex-specific differences in optimal dosage regimens to achieve maximal age-mitigating compound efficacy.

Harrison and colleagues from the Jackson Laboratory in Maine published a study in Aging Cell that indicated late-life rapamycin dosage regimens extend mouse lifespan in sex-specific manners. They found that administering male mice every other month with rapamycin beginning at age 20 months and giving rapamycin continuously from age 20 to 23 months was as effective at improving survival as continuous exposure starting at age 20 months. Intermittent and continuous exposure increased female survival, but intermittent was not as effective as a continuous exposure. The findings move us closer to understanding the sex-specific effects of varying rapamycin dosage schedules and improving sex-specific treatment regimens.

Rapamycin May Improve Lifespan by Suppressing Cell Proliferation

Clinicians use an immune-dampening compound called rapamycin (Sirolimus) to prevent human organ transplant rejections and for rare lung disease (lymphangioleiomyomatosis) treatment. Rapamycin suppresses mammalian cell proliferation by targeting a master regulator enzyme of cell growth aptly called the mammalian target of rapamycin or mTOR, although its specific effects remain incompletely understood. Studies have shown rapamycin extends lifespan in yeast, worms, and flies, and some researchers believe the compound may provide a means to improve human health during aging and extend lifespan.

Late-life Rapamycin Dosing Schedules Produce Sex-Specific Lifespan Enhancements

To see if variations in the timing of rapamycin administered to middle-aged mice would lead to different survival outcomes, Harrison and colleagues compared three dosing regimens. The first dosing regimen consisted of treating the mice with 42 parts per million (the equivalent of 7 mg/kg body weight per day) rapamycin concentrations in food given at 20 months until death, which significantly increased male and female survival. The second dosing regimen consisted of the same rapamycin treatment only for three months at 20  months of age; this second rapamycin treatment scheme facilitated improved survival in males only. Finally, a third dosing schedule of repeated rapamycin treatment every other month starting at age 20 months had positive survival effects in both sexes, however, this approach did not work as well as continuous rapamycin exposure in females.

All three dosing regimens led to a similar 9%-11% median male lifespan increase, extending lifespan about 1/3 from the beginning of administration. On top of this, the researchers saw that continuous rapamycin administration after age 20 months and every other month after this age increased the maximum lifespan of more males. But giving males continuous rapamycin from ages 20 months to 23 months did not significantly increase these numbers. Nevertheless, the three dosing regimens produced no significant differences in their ability to extend the median male lifespan.

(Strong et al., 2020 | Aging Cell) Three rapamycin dosing regimens produced significant male mouse lifespan extensions. Forty-two parts per million (the equivalent of 7 mg/kg body weight per day) rapamycin doses administered continuously at 20 months, every other month beginning at age 20 months, and every day from age 20 to 23 months facilitated significantly extended (9%-11%) median lifespan.

In contrast, each of the three treatment protocols gave distinctly different survival benefits in females. Providing rapamycin continuously, every other month, and for 3 months starting at age 20 months facilitated 15%, 8%, and 4% increases in median lifespan, respectively. The most effective lifespan-extending dosing regimen, continuous administration, facilitated about a 40% female lifespan extension from the beginning of administration at 20 months. When testing for changes in maximum lifespan, Harrison and colleagues saw that the first two treatment regimens induced longer lives but treatment from age 20 to 23 months did not.

(Strong et al., 2020 | Aging Cell) Rapamycin extended female mouse median lifespan in a dosing schedule-dependent manner. Rapamycin continuously administered after age 20 months (green circles) produced a 15% improvement in median lifespan, administered every other month after age 20 months gave an 8% increase, and given continuously between age 20 and 23 months produced a 4% enhancement.

Four Drugs with No Effect on Mouse Lifespan

Harrison and colleagues gave mice other potential longevity-enhancing food treatments. They tested four compounds: 17-DMAG (30 parts per million for 6 months) due to evidence suggesting it protects mouse neurons and reduces inflammation, β-GPA (3300 parts per million for 6 months) due to its potential longevity-enhancing effects of lowering blood glucose and  MitoQ (100 parts per million for 7 months) as a cell stress-reducing antioxidant, and antibiotic minocycline (300 parts per million for 6 months) due to its roundworm and fly lifespan extension potential. Although none of these treatments resulted in significant longevity enhancements, it remains possible that providing other treatment concentrations or dosing regimens may produce lifespan-enhancing outcomes.

(Strong et al., 2020 | Aging Cell) None of the scientist-administered drugs besides rapamycin enhanced median mouse lifespan. Molecules DMAG, minocycline, β-GPA, and MitoQ administered to males and females produced no significant median lifespan extensions.

Developing an Optimal Clinical Dosing Strategy

The team of researchers said they don’t have a ready explanation for the sex differences in survival-related dosing regimen effects.  “It is possible, in addition, that some of the rapamycin effects involve alteration in microbial populations within the GI tract, which could show variable time courses of drug‐induced reconfiguration and recovery,” said the authors.

An optimal rapamycin clinical strategy development with minimal side effects may require careful refinement and adjustment for sex-specific rapamycin efficacy on survival. “Developing clinical strategies for optimal benefit in long‐term rapamycin treatment, with minimal side effects may require careful stepwise refinement and adjustment for sex‐specific effects,” concluded the authors. Clinical trials must still determine whether rapamycin can improve human longevity and if so whether these sex-specific differences apply.