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Targeting drug-drug interactions to maximize healthspan

Tesfahun Dessale Admasu (2, 5), Krishna Chaithanya Batchu (1), Diogo Barardo (1), Ng Li Fang (1), Vanessa Yuk Man Lam (1), Linfan Xiao (1), Amaury Cazenave-Gassiot (2, 3), Markus Wenk (2, 3), Nicholas Tolwinski (1, 4) and Jan Gruber (1, 2)

  1. Science Divisions, Yale-NUS College, Singapore

  2. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

  3. Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore

  4. Department of Biological Sciences, National University of Singapore, Singapore

  5. Department of Biochemistry, College of Medicine and Health Science, University of Gondar, Ethiopia

A growing number of pharmacological intervention have been developed that extend lifespan and healthspan by targeting these pathways. However, lifespan benefits of most drugs, especially when drug treatment is imitated in adult animals only, do not produce benefits of the magnitude as ageing mutations. This is true even for drugs thought to target the same conserved ageing pathways.

Our question was if the limits in efficacy of adult-onset pharmacological interventions were due to an intrinsic limit in lifespan plasticity of adult animals. To answer this question we explored interactions between drugs believed to target distinct ageing pathways.


For our pilot study, we selected 5 candidate compounds, based on magnitude of previously reported lifespan effect, proposed mode of action and translational potential. We then carried out a systematic screen of all possible pairs within this set for lifespan benefits in C. elegans.

We identified two synergistic drug combinations that resulted in healthy lifespan extension beyond benefits seen with any of the single drugs. Lifespan benefits of our best drug combination were comparable to typical ageing mutations, even when treatment was only initiated in adult animals. This result demonstrates that combining drugs targeting distinct subsets of aging regulatory genes may be a promising strategy to engineer interventions with synergistic lifespan benefits.