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

doi:10.1080/15548627.2022.2078069

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^*

^*Corresponding author for this work

Department of Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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 language	American English
Pages (from-to)	474-504
Number of pages	31
Journal	Autophagy
Volume	19
Issue number	2
DOIs	https://doi.org/10.1080/15548627.2022.2078069
State	Published - Feb 2023

Bibliographical note

Funding 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.

Publisher Copyright:
© 2022 Informa UK Limited, trading as Taylor & Francis Group.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/15548627.2022.2078069

Cite this

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

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.",

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author = "Vijigisha Srivastava and Veronica Zelmanovich and Virendra Shukla and Rachel Abergel and Irit Cohen and Ben-Sasson, {Shmuel A.} and Einav Gross",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2022 Informa UK Limited, trading as Taylor & Francis Group.",

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AU - Srivastava, Vijigisha

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AU - Shukla, Virendra

AU - Abergel, Rachel

AU - Cohen, Irit

AU - Ben-Sasson, Shmuel A.

AU - Gross, Einav

N1 - Funding 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. Publisher Copyright: © 2022 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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.

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KW - diamine

KW - healthspan

KW - lifespan

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

Abstract

Bibliographical note

Keywords

UN SDGs

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