Highlights:

  • In addition to prolonging median lifespan, the rapamycin and trametinib combo prolongs maximum lifespan by 32% for females and 26% for males. 
  • While the combo improved several aspects of health, it also led to side effects such as testicular degeneration and fatty liver. 

In these latter stages of modern human civilization, modern medicine has allowed us to live longer than our ancestors. Today, scientists are working tirelessly to generate medicines that alleviate the suffering caused by diseases unknown in the past. Meanwhile, some researchers are attempting to find ways of maximizing human life expectancy without such suffering. In doing so, they have discovered compounds that prolong the lifespan (length of life) and healthspan (length of life in good health) of mice. 

Furthermore, in the search for lifespan maximization, German scientists have tested whether combining known life-extending compounds can reap additive benefits. By doing so, the researchers have achieved one of the greatest lifespan extensions to date. Their findings suggest that combining compounds targeting complementary cellular pathways may bring us closer to the Fountain of Youth. 

Additive Life-Prolonging Effects of Rapamycin + Trametinib 

The researchers began the administration of rapamycin, trametinib, or a combination of the two when the mice were 6 months of age, roughly equivalent to approximately 30 years of age in humans. Rapamycin, at a dose of 42 mg/kg, was fed to the mice on alternate weeks while 1.44 mg/kg of trametinib was fed to the mice every day.  

By itself, trametinib led to a median lifespan extension of 7.2% for females and 10.2% for males. Additionally, there was no effect on maximum lifespan for males and a 15.8% increase for females. Working more potently, rapamycin alone led to median lifespan extension of 17.4% for females and 16.6% for males. Additionally, it extended maximum lifespan by 16.5% in females and 18.3% in males. 

Still, combined treatment of rapamycin and trametinib increased median lifespan by 34.9% in females and 27.4% in males. It also increased maximum lifespan by 32.4% in females and 26.1% in males. These findings reveal that combining rapamycin and trametinib has additive life-prolonging effects on mice. 

(Gkioni et al., 2024) Additive Lifespan-Extending Effects of Rapamycin and Trametinib. While, compared to control (black), rapamycin (purple) and trametinib (green) extended both female and male lifespan, combining rapamycin with trametinib (orange) extended lifespan further.

Healthspan and Side Effects

The researchers also measured the health of the mice to determine their healthspan in response to combined rapamycin and trametinib treatment. There were very few effects that were not sex-specific, which included the following: 

  • Reduced body weight 
  • Reduced liver tumors 
  • Prevention of increased brain glucose uptake 
  • Reduced kidney inflammation 
  • Reduced spleen pathology 

There were also effects that were significant for one sex but only trended towards significance in the other. The authors say, 

“The combination treatment attenuated the decline in heart function with age, delayed tumour growth and overall tumour load, and reduced brain and peripheral inflammation, suggesting improved health at old age.”

These findings suggest that, in addition to prolonging lifespan, the combination of rapamycin and trametinib improves healthspan. However, regarding adverse side effects, the researchers reported a reduction in the anti-inflammatory molecule IL-10, and the occurrence of fatty liver disease and testicular degeneration. These side effects call for further investigation into how the combination of rapamycin and trametinib may trigger adverse health effects.

Maximizing Human Lifespan with Combination Prescription Drugs 

Rapamycin and trametinib are both Food and Drug Administration (FDA)-approved drugs. Rapamycin is usually prescribed after organ transplantation to prevent rejection by the immune system. Trametinib is specifically approved for BRAF-mutant melanoma — a deadly type of skin cancer. However, scientists are finding that certain FDA-approved drugs can target multiple ailments, delay aging, and prolong the lifespan of rodents and other animals.

Other combinations of FDA-approved drugs have been shown to prolong the lifespan of mice. The authors say, 

“The combination of rapamycin with metformin increased mouse lifespan by 26% and 23% in females and males, respectively, while coadministration of rapamycin and acarbose led to a 28% and 34% increase in median lifespan in females and males, respectively.” 

Metformin and acarbose are both FDA-approved anti-diabetes drugs that have long been investigated for their anti-aging effects. The authors point out that it may be interesting to combine more than two drugs (i.e., rapamycin, trametinib, and acarbose). By targeting different cellular pathways, combining multiple drugs may fight disease and delay aging. However, more studies will be needed to determine if these drug combinations interact to produce unwanted side effects. Furthermore, studies in humans will be necessary to realize the full potential of these drug combinations.