Two-drug combinations extend mouse lifespan by 30%

Combining two existing cancer drugs together can extend the lifespan of mice by about 30%, while improving elderly health, thus providing new hope for human lifespan research.

The combination of rapamycin and trametinib is not only longer than both drugs, but also reduces chronic inflammation and delayed tumor development without additional side effects.

Scientists at the Max Planck Institute for Aging Biology show that although rapamycin alone increased their lifespan by 15-20% and tramitinib by 5-10%, together they achieved extraordinary results: a real additive benefit that extends lifespan to around 30% of male and female mice.

Beyond simple addition

What is particularly fascinating about this discovery is not only the numbers, but also the mechanism. The researchers found that combining these FDA-approved drugs would produce entirely new biological effects that neither were achieved separately.

“Although rapamycin and trastuny act on the same network, this combination achieves new effects, which may not be due to the dose increase,” the research team noted. Gene expression analysis revealed changes in activity triggered only by drug combinations, not by individual treatment.

These drugs target different branches of the IGF-MTORC1-RAS nutritional induction network, a biological pathway associated with species aging. Rapamycin blocks MTORC1 signaling, while Trametinib inhibits the Ras-Mek-erk pathway. Both pathways have been widely communicated, suggesting that simultaneous inhibition may prevent compensatory responses that limit the effectiveness of a single agent.

Health benefits beyond longevity

This combination treatment achieved an impressive health improvement in aging mice. Key findings include:

• Reduce inflammation: Significant reduction in brain, kidney, spleen and muscle inflammation, as well as lower circulating proinflammatory cytokines
• Cancer Protection: Sexual liver tumors are fewer, male spleen tumors are reduced
• Brain Health: Age-related increase in obstruction-associated decrease in brain glucose absorption and activation of microglia density
• Heart function: Age-related cardiac performance decline

Perhaps most importantly, this combination avoids many of the side effects associated with individual treatments. Rapamycin causes hepatic steatovenous disease, hyperglycemia and testicular degeneration, but tramini does not produce obvious harmful effects and does not worsen complications of rapamycin.

Inflammation connection

Chronic inflammation associated with age is called “inflammation” and is the main driver of health deterioration in the elderly. This drug combination is specifically designed for multiple organ systems.

In the brain, combined treatment mice exhibit reduced density of activated microglia and astrocytes whose excessive activity contributes to neurodegeneration. The treatment also blocks typical age-related brain glucose absorption, a marker of excessive neural activation, often associated with cognitive decline.

Tissue analysis showed that reduced expression of inflammatory genes, including CD5 antigen-like (CD5L) and CC motif chemokine ligand 8 (CCL8), were associated with inflammatory conditions and cancer progression. The researchers observed these changes in the kidneys, spleen and muscle tissue.

Drug administration and translation challenges

The study used a relatively modest dose of tramitinib – 1.44 mg per kg diet – supplemented at a plasma level of 0.1 ng/ml in mice. For comparison, human cancer patients usually receive 2 mg per day to reach plasma concentrations of 5.5-7.5 ng/mL.

This dose difference suggests that the concentration of lifespan effect may be much lower than the concentration required for cancer treatment. As the researchers noted, “Anti-cancer effects require higher curtinib doses than life span.”

This discovery opens interesting possibilities for human application, although significant issues remain regarding optimal dose and management schedules.

Gender-specific responses

The study showed that the gender differences in treatment response were significant, especially at the molecular level. Female mice showed a more significant decrease in inflammatory cytokines, while males showed a stronger transcriptional response in spleen tissue, despite lower plasma levels of curvetinib.

“While we don’t want a similar life span like the humans we find in mice, we hope the drugs we are investigating can help people with longer health and disease extensions later in life,” said Dame Linda Partridge, co-dean professor from the UCL Institute for Healthy Aging.

The way forward

Both drugs have been approved by the FDA for cancer treatment, which may accelerate clinical testing for lifespan applications. The research team plans to optimize the route of trastuny administration and management to maximize health benefits while minimizing side effects.

“Trametinib, especially in combination with rapamycin, is a good candidate for testing as a drug therapy device in clinical trials,” explained Sebastian Grönke, one of the authors of the study.

This work is based on growing evidence that targeting multiple nodes in a biological network associated with aging may be more effective than a single sports track approach. Previous studies of fruit flies have shown similar additive effects when combined with rapamycin, trastuny and lithium and achieved median life span expansion of up to 48% by triple therapy.

What will happen next? The researchers hope their results will inspire human trials, although they acknowledge the long timeline required for humans to live long. At the same time, they focus on refining the methods in animal models, which have the potential to identify more effective drug combinations.

The broader meaning goes beyond personal therapy. This study shows that a complex understanding of biological network interactions can guide rational drug combination strategies beyond experimental approaches to achieve precise lifespan interventions.