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Exceptional Longevity Modifying Allele APOE2 Promotes DNA Signaling Pathways Resisting Cellular Senescence in Human Neurons.

Overview

Authors: Cristian Gerónimo‐Olvera1, Stephen M. Scheeler1,2, Carlos Galicia Aguirre1,2, Genesis Vega‐Hormazabal1, Daniela Garcia1, Long Wu1, Natalia Murad1, Kevin Schneider1, Kenneth A. Wilson1, Nikola T. Markov1, Sicheng Song3, Jesse Simons1, Akos A. Gerencser1, Emily Parlan1, Sean D. Mooney3, Eric Verdin1,2, Judith Campisi1,2, Tara E. Tracy1,2, David Furman1, Simon Melov1,2, Lisa M. Ellerby1,2
ORCID iDs: Eric Verdin, David Furman
  1. Buck Institute for Research on Aging Novato California USA
  2. University of Southern California, Leonard Davis School of Gerontology Los Angeles California USA
  3. Department of Biomedical Informatics and Medical Education University of Washington Seattle Washington USA
Institutions: Buck Institute for Research on Aging (United States); University of Southern California (United States); University of Washington (United States)
Journal: Aging cell, volume 25, issue 5, article e70494
Dates: received 7 July 2025; accepted 10 April 2026; published online 8 May 2026; in print May 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1111/acel.70494 · PMID 42103698 · PMCID PMC13156074 · OpenAlex W7160658088
Open access: gold, a free copy (OpenAlex)
Status: data only
Categories: genetics / omics (modality), human (organism), Alzheimer's / dementia (population), cellular / molecular (subfield)
Methods: Spectral & time-frequency, Statistics, Preprocessing
Keywords: aging, APOE2, DNA damage, exceptional longevity, neurons, senescence
MeSH: Apolipoprotein E2*, Cellular Senescence*, Longevity*, Neurons*, Signal Transduction*, Alleles, Animals, DNA Damage, DNA Repair, Humans (* major topic)
Topic: Alzheimer's disease research and treatments (Physiology, Medicine), according to OpenAlex
Funding: National Institute on Aging (1RO1AG061879, 5P01AG066591, T32 AG000266); Paul F. Glenn Center for Biology of Aging; CatalystX award from Alex and Bob Griswood
Citations: not cited yet (Europe PMC); 74 references in the paper

Abstract

Genome‐wide association studies (GWAS) have identified APOE2 allele as linked to exceptional longevity, with carriers exhibiting a reduced risk of Alzheimer's disease (AD). Apolipoprotein E (APOE), a glycoprotein involved in lipid transport, has three major alleles. However, alterations in lipid metabolism alone do not fully explain APOE2's protective effects. In contrast, APOE4 is the strongest genetic risk factor for AD. To investigate how APOE2 promotes neuronal longevity and confers neuroprotection, we generated human isogenic APOE iPSC‐derived models of both inhibitory GABAergic and excitatory neurons. In GABAergic neurons, APOE alleles differentially influenced endogenous DNA damage, DNA repair, and neuronal motility. Single‐cell RNA sequencing revealed APOE4‐specific gene expression signatures associated with AD, whereas APOE2 GABAergic neurons were enriched for DNA repair and signaling pathways. Consistent with this, APOE2 neurons exhibited significantly lower levels of DNA damage. APOE4 GABAergic neurons exhibit increased expression of repetitive ribosomal RNA, which is associated with DNA damage and cellular senescence. To determine whether the effects extended to excitatory neurons, we used a separate human model of Ngn2‐induced glutamatergic neurons, and found that APOE2 excitatory neurons were more resistant to cellular senescence and DNA damage than isogenic APOE3 and APOE4 neurons. Similarly, we found human APOE2‐targeted replacement mice exhibited less nucleolar enlargement and increased nuclear Lamin A/C, Hmgb1, and H3K9me3 compared to APOE4 counterparts. Together, our findings identify DNA repair and suppression of senescence‐associated processes as key mechanisms by which APOE2 is associated with neuronal resilience, providing mechanistic insight into its association with exceptional longevity and protection against AD.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

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Data

Data links

Data Availability Statement

The data that support the findings of this study are available in NCBIs Gene Expression Omnibus at https://www.ncbi.nlm.nih.gov/geo/. These data were derived from the following resources available in the public domain: GSE143276, https://www.ncbi.nlm.nih.gov/geo/.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 21 authors, 6 keywords, 10 MeSH terms, 3 funders, 73 references.

Cite

This paper

Gerónimo‐Olvera, C., Scheeler, S. M., Aguirre, C. G., Vega‐Hormazabal, G., Garcia, D., Wu, L., Murad, N., Schneider, K., Wilson, K. A., Markov, N. T., Song, S., Simons, J., Gerencser, A. A., Parlan, E., Mooney, S. D., Verdin, E., Campisi, J., Tracy, T. E., Furman, D., . . . Ellerby, L. M. (2026). Exceptional Longevity Modifying Allele APOE2 Promotes DNA Signaling Pathways Resisting Cellular Senescence in Human Neurons. Aging cell, 25(5), e70494. https://doi.org/10.1111/acel.70494

BibTeX

@article{geronimoolvera2026exceptional,
author = {Gerónimo‐Olvera, Cristian and Scheeler, Stephen M. and Aguirre, Carlos Galicia and Vega‐Hormazabal, Genesis and Garcia, Daniela and Wu, Long and Murad, Natalia and Schneider, Kevin and Wilson, Kenneth A. and Markov, Nikola T. and Song, Sicheng and Simons, Jesse and Gerencser, Akos A. and Parlan, Emily and Mooney, Sean D. and Verdin, Eric and Campisi, Judith and Tracy, Tara E. and Furman, David and Melov, Simon and Ellerby, Lisa M.},
title = {{Exceptional Longevity Modifying Allele APOE2 Promotes DNA Signaling Pathways Resisting Cellular Senescence in Human Neurons}},
journal = {Aging cell},
year = {2026},
month = may,
volume = {25},
number = {5},
pages = {e70494},
publisher = {Wiley},
issn = {1474-9718},
doi = {10.1111/acel.70494},
url = {https://doi.org/10.1111/acel.70494},
pmid = {42103698},
pmcid = {PMC13156074}
}

RIS

TY - JOUR
AU - Gerónimo‐Olvera, Cristian
AU - Scheeler, Stephen M.
AU - Aguirre, Carlos Galicia
AU - Vega‐Hormazabal, Genesis
AU - Garcia, Daniela
AU - Wu, Long
AU - Murad, Natalia
AU - Schneider, Kevin
AU - Wilson, Kenneth A.
AU - Markov, Nikola T.
AU - Song, Sicheng
AU - Simons, Jesse
AU - Gerencser, Akos A.
AU - Parlan, Emily
AU - Mooney, Sean D.
AU - Verdin, Eric
AU - Campisi, Judith
AU - Tracy, Tara E.
AU - Furman, David
AU - Melov, Simon
AU - Ellerby, Lisa M.
TI - Exceptional Longevity Modifying Allele APOE2 Promotes DNA Signaling Pathways Resisting Cellular Senescence in Human Neurons
T2 - Aging cell
J2 - Aging Cell
PY - 2026
DA - 2026/05/01
VL - 25
IS - 5
SP - e70494
SN - 1474-9718
PB - Wiley
DO - 10.1111/acel.70494
UR - https://doi.org/10.1111/acel.70494
LA - en
ER -

CSL-JSON

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