In a paper published in Developmental Cell, scientists from Yale University have demonstrated how targeting multiple pathways related to aging with different drug combinations can slow aging down and extend healthy lifespan in C. elegans .
There is growing interest in pharmacological interventions directly targeting the aging process. Pharmacological interventions against aging should be efficacious when started in adults and, ideally, repurpose existing drugs. We show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved aging pathways and mechanisms using drug combinations. Using this approach in C. elegans, we were able to slow aging and significantly extend healthy lifespan. To identify the mechanism of these drug synergies, we applied transcriptomics and lipidomics analysis. We found that drug interactions involved the TGF-b pathway and recruited genes related with IGF signaling. daf-2, daf-7, and sbp-1 interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and this is required for healthy lifespan extension. These data suggest that combinations of drugs targeting distinct subsets of the aging gene regulatory network can be leveraged to cause synergistic lifespan benefits.
The idea behind Dr. Gruber’s study was to test whether combinations of drugs known to extend healthspan and/or lifespan in animal models could work in synergy and produce even more pronounced effects. The team chose rifampicin, rapamycin, psora-4, metformin, and allantoin. Some of these, namely rapamycin and metformin, are well-known for their connection to lifespan, though their original purposes were somewhat different—rapamycin is used to prevent organ transplant rejection, whereas metformin is a 50-year-old, off-patent drug used to treat type 2 diabetes.
The researchers used C. elegans nematodes as test subjects; their intent was to see which drug combinations, if any, would provide the largest health and lifespan benefits without causing toxicity. While some combinations did turn out to be toxic or no more effective than the single drugs, others proved significantly more effective when used together; In particular, the combination of rapamycin, rifampicin, and allantoin achieved an 89% extension of mean lifespan, whereas rifampicin, psora-4 and allantoin resulted in a 96% increase of mean lifespan—all of which were without any toxicity.
It is also very important to note is that all treated worms of all ages didn’t just live longer; rather, they spent a larger portion of their extra lifespan in good health, which constitutes even more evidence that interfering with the aging processes is a promising avenue to obtain significant health gains. Interestingly, comparable effects were observed when testing similar drug cocktails in fruit flies; nematodes and fruit flies are significantly far apart, evolutionarily speaking, which, according to the researchers, suggests that the aging mechanisms targeted by these drug combinations must trace all the way back to an ancient common ancestor of the two species. This is good news for humans, as it increases the likelihood that similar interventions might work in us as well.
An ever-more recognized therapeutic avenue
It is heartening to see that more and more researchers recognize the importance of treating aging to extend human health and lifespan. “If we can find a way to extend healthy lifespan and delay aging in people,” Dr. Gruber said, “we can counteract the detrimental effects of an aging population, providing countries not only medical and economic benefits but also a better quality of life for their people.”
Dr Gruber also recognised the economic benefits that would derive from even a modest slowdown of aging: “We would benefit not only from having longer lives but also spend more of those years free from age-related diseases like arthritis, cardiovascular disease, cancer, or Alzheimer’s disease. These diseases currently require very expensive treatments, so the economic benefits of being healthier for longer would be enormous.”
Naturally, this study is only a proof of principle, and subsequent studies will aim to design even more effective interventions than those tested here; another objective is to figure out how exactly these drugs interact to slow aging down so that computer simulations of these interactions can be developed and allow researchers to test far more drug combinations. Eventually, this work might lead to safe and effective interventions to slow down aging in humans—a moment that we are all looking forward to.
 Admasu, T. D., Chaithanya Batchu, K., Barardo, D., Ng, L. F., Lam, V. Y. M., Xiao, L., … Gruber, J. (2018). Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling. Developmental Cell.