FOXO-regulated OSER1 reduces oxidative stress and extends lifespan in multiple species

FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.

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Publication Details

Journal
Nature Communications
Published
2024-08-21
DOI
https://doi.org/10.1038/s41467-024-51542-z
Citations
27
Primary Topic
Genetics, Aging, and Longevity in Model Organisms
Type
article
Field-Weighted Citation Impact
6.15

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article

FOXO-regulated OSER1 reduces oxidative stress and extends lifespan in multiple species

Zilu Ye, Kaare Christensen, Xiaoling Tong, Jesper Velgaard Olsen et al.
27 citations
Nature Communications
Genetics, Aging, and Longevity in Model Organisms
6.15
article

FOXO-regulated OSER1 reduces oxidative stress and extends lifespan in multiple species

Zilu Ye, Kaare Christensen, Xiaoling Tong, Jesper Velgaard Olsen, Marianne Nygaard, Fangyin Dai, Lene Juel Rasmussen, Héctor Herranz, Wei Qi Guinevere Sew, Vilhelm A. Bohr, Yuan Li, Xin Chen, Jiangbo Song, Zhiquan Li, Lei Zhou
article en
27 citations

Abstract

FOXO transcription factors modulate aging-related pathways and influence longevity in multiple species, but the transcriptional targets that mediate these effects remain largely unknown. Here, we identify an evolutionarily conserved FOXO target gene, Oxidative stress-responsive serine-rich protein 1 (OSER1), whose overexpression extends lifespan in silkworms, nematodes, and flies, while its depletion correspondingly shortens lifespan. In flies, overexpression of OSER1 increases resistance to oxidative stress, starvation, and heat shock, while OSER1-depleted flies are more vulnerable to these stressors. In silkworms, hydrogen peroxide both induces and is scavenged by OSER1 in vitro and in vivo. Knockdown of OSER1 in Caenorhabditis elegans leads to increased ROS production and shorter lifespan, mitochondrial fragmentation, decreased ATP production, and altered transcription of mitochondrial genes. Human proteomic analysis suggests that OSER1 plays roles in oxidative stress response, cellular senescence, and reproduction, which is consistent with the data and suggests that OSER1 could play a role in fertility in silkworms and nematodes. Human studies demonstrate that polymorphic variants in OSER1 are associated with human longevity. In summary, OSER1 is an evolutionarily conserved FOXO-regulated protein that improves resistance to oxidative stress, maintains mitochondrial functional integrity, and increases lifespan in multiple species. Additional studies will clarify the role of OSER1 as a critical effector of healthy aging.

Nature CommunicationsVol. 15(1)
University of Copenhagen (DK), Southwest University (CN), University of Southern Denmark (DK), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Novo Nordisk Foundation (DK), Odense University Hospital (DK), Suzhou Institute of Systems Medicine (CN), Ministry of Agriculture (CA), Institute on Aging (US), National Institute on Aging (US), Ministry of Agriculture and Rural Affairs (CN)
European Commission, National Natural Science Foundation of China, AXA Research Fund, Chongqing University, Linköpings Universitet, Novo Nordisk, Nordea-fonden, Danmarks Frie Forskningsfond, Chinese Academy of Medical Sciences, Natural Science Foundation of Chongqing, Science for Life Laboratory, Novo Nordisk Fonden, National Institutes of Health, Forsknings- og Innovationsstyrelsen, Danish Agency for Science and Higher Education, European Regional Development Fund, Interreg
Openalex Percentile: Top 2%
Genetics, Aging, and Longevity in Model Organisms
6.15
DOIOpen Access PDFOpenAlex
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