Better together: Drug cocktails that synergistically enhance lifespan
Microscope image of the  Caenorhabditis elegans  worms used in the study. Image provided by Dr Jan Gruber, Yale University.

Microscope image of the Caenorhabditis elegans worms used in the study. Image provided by Dr Jan Gruber, Yale University.

Aging is controlled by a relatively modest number of evolutionarily conserved pathways. In a wide range of model organisms ranging from yeast to mice, interference with any one these pathways—by gene mutation or drug treatment—can dramatically extend lifespan. New data shows that targeting more than one aging pathway with a cocktail of drugs can yield synergistic effects, extending longevity beyond what can be achieved by a single drug alone.

Using the nematode Caenorhabditis elegans, a workhorse of research in biogerontology, a group led by Jan Gruber at Yale-NUS College in Singapore identified several trios of compounds that both lengthened lifespan and slowed aging. (The apparent redundancy in that last sentence is important: in addition to lengthening life, successful anti-aging interventions must preserve youthful vigor…otherwise, one might argue, what’s the point?)

The compounds were chosen because each one has a significant effect on lifespan. In combination, however, the effects were dramatic, increasing median and maximum lifespan by almost a factor of two. Importantly, the regimens were successful even though treatment began after the worms reached adulthood—a key criterion for pharmacological approaches to slowing aging.

The drugs selected for the study target key players in major longevity pathways: adenosine monophosphate-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), caloric restriction (CR), c-Jun N-terminal kinases (JNK), and mitochondrial metabolism. Surprisingly, even when two of the drugs targeted the same pathway, CR, it was still possible to achieve synergistic lifespan extension, implying that these pathways may have a richer molecular architecture than currently thought.

Biochemical experiments revealed that the successful cocktails had a wide range of effects, but all altered lipid metabolism—in particular, increasing the levels of monounsaturated fatty acids in the worms’ bodies. For more on the fascinating connection between aging and lipids, check out this recent review by Anne Brunet and co-workers on how lipid metabolism interacts with chromatin modifications to delay aging.

The discovery has obvious implications for possible interventions in human aging, argued the authors. In a press release, Gruber said:

“Many countries in the world, including Singapore, are facing problems related to ageing populations,” “If we can find a way to extend healthy lifespan and delay ageing in people, we can counteract the detrimental effects of an ageing population, providing countries not only medical and economic benefits, but also a better quality of life for their people.”

Of course, the use of such cocktails in humans may not yield an effect of the same magnitude. Interventions that yield dramatic effects on simple model organisms rarely confer the same degree of benefit in species evolutionarily closer to humans. As Judy Campisi of the Buck Institute for Research on Aging pointed out in a recent interview in MIT Technology Review (emphasis mine):

If you look at C. elegans, a little worm, the world record for extending the life span of that animal is 10-fold. For humans that would be unbelievable, right? A thousand years. But if you go up the evolutionary scale just a little bit, to the fruit fly Drosophila, it’s maybe twofold. And then if you go to a mouse, most of the really high-profile papers extend its life span maybe 20%, sometimes 30%. So think about the difference between a mouse and a human. We’re something like 97% genetically identical, meaning we have the same genes. And yet there’s a 30-fold difference in our life span. So it seems to me that in order for evolution to evolve a 30-fold difference in life span with so few really clear genetic differences, evolution maybe had to tweak hundreds, if not thousands, of genes. It’s unlikely at the present time that we will find a single drug that’s going to be able to do what ­evolution did.

That said, the authors of this study aren’t using single drugs, but cocktails that have broad effects on gene expression, perhaps beginning to satisfy Dr. Campisi’s criterion for the scope of intervention required.

Admasu et al. “Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling.” Developmental Cell Volume 47, Issue 1, 8 October 2018, Pages 67–79.e5 • DOI • Sci-Hub

Admasu et al. “Lipid profiling of C. elegans strains administered pro-longevity drugs and drug combinations”. Sci. Data. 5:180231 (2018) • DOI