Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population. Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of structurally related compounds. A prototypic member, 1,8-diaminooctane (VL-004), exceeds Spd in its ability to induce mitophagy and protect against oxidative stress. VL-004 activity is mediated by canonical aging genes and promotes lifespan and healthspan in C. elegans. Moreover, it enhances mitophagy and protects against oxidative injury in rodent and human cells. Initial structural characterization suggests simple rules for the design of compounds with improved bioactivity, opening the way for a new generation of agents with a potential to promote healthy aging.
Bibliographical noteFunding Information:
We thank members of the Gross laboratory for critical reading of the manuscript, comments and advice. We thank the Japan National Bioresource Project for the Nematode C. elegans and the CGC, which is funded by the National Institutes of Health Office of Research Infrastructure Programs (P40 OD010440), for providing some of the strains. We thank N. Tavernarakis and E. Cohen for C. elegans and bacteria strains. This research was supported by a grant from Vitalunga Ltd, the Cleveland Clinic Center for Transformative Nanomedicine, and the ISRAEL SCIENCE FOUNDATION (grant No. 989/19). Graphical Abstract was generated with BioRender.com.
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- Caenorhabditis elegans
- mitochondrial autophagy
- oxidative stress