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Destabilizing heterochromatin by APOE mediates senescence
Hongkai Zhao1,2, Qianzhao Ji3,4, Zeming Wu1,4,5,6
1State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Nature Aging
|April 28, 2023
Summary
Apolipoprotein E (APOE) accumulation drives cellular senescence in aging stem cells. Deleting APOE enhances cellular resistance to aging, revealing APOE as an epigenetic aging mediator.
Area of Science:
- Molecular Biology
- Gerontology
- Cell Biology
Background:
- Apolipoprotein E (APOE) is crucial for lipid homeostasis and linked to longevity and Alzheimer's disease.
- The precise role of APOE in the aging process remains largely unelucidated.
- Understanding APOE's function in aging is vital for developing interventions against age-related diseases.
Purpose of the Study:
- To investigate the mechanistic role of Apolipoprotein E (APOE) in cellular senescence and aging.
- To explore APOE-driven processes in stem cell homeostasis and aging using various cellular models.
- To identify APOE as a potential therapeutic target for ameliorating aging-related conditions.
Main Methods:
- Utilized human genetic, stress-induced, and physiological cellular aging models.
- Employed mesenchymal progenitor cells (MPCs) to study APOE's effects on aging.
- Used CRISPR-Cas9 gene editing to delete APOE and assess its impact on senescence.
Main Results:
- APOE accumulation was identified as a key driver of cellular senescence in aged human MPCs.
- CRISPR-Cas9-mediated deletion of APOE conferred resistance to cellular senescence in human MPCs.
- Mechanistically, APOE destabilizes heterochromatin by promoting the degradation of nuclear lamina and KRAB-associated protein 1 via autophagy-lysosomal pathways.
Conclusions:
- APOE accumulation is a significant contributor to cellular senescence and aging.
- APOE acts as an epigenetic mediator, influencing heterochromatin stability and cellular aging.
- Targeting APOE presents a potential strategy for mitigating aging processes and related diseases.
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