Distinct designer diamines promote mitophagy, and thereby enhance healthspan in C. elegans and protect human cells against oxidative damage

Vijigisha Srivastava, Veronica Zelmanovich, Virendra Shukla, Rachel Abergel, Irit Cohen, Shmuel A. Ben-Sasson, Einav Gross

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageAmerican English
Pages (from-to)474-504
Number of pages31
JournalAutophagy
Volume19
Issue number2
DOIs
StatePublished - Feb 2023

Keywords

  • Aging
  • Caenorhabditis elegans
  • diamine
  • healthspan
  • lifespan
  • mitochondrial autophagy
  • mitophagy
  • oxidative stress
  • spermidine

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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