The DOI matches its Crossref record; 78 of the 79 references it cites were found in a registry or an index.
Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease
Open accessAbstract
The concept of senescence as a phenomenon limited to proliferating cells has been challenged by growing evidence of senescence-like features in terminally differentiated cells, including neurons. The persistence of senescent cells late in life is associated with tissue dysfunction and increased risk of age-related disease. We found that Alzheimer's disease (AD) brains have significantly higher proportions of neurons that express senescence markers, and their distribution indicates bystander effects. AD patient-derived directly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecular biomarker signatures, indicating a specific human neuronal senescence-like state. AD iN single-cell transcriptomics revealed that senescent-like neurons face oncogenic challenges and metabolic dysfunction as well as display a pro-inflammatory signature. Integrative profiling of the inflammatory secretome of AD iNs and patient cerebral spinal fluid revealed a neuronal senescence-associated secretory phenotype that could trigger astrogliosis in human astrocytes. Finally, we show that targeting senescence-like neurons with senotherapeutics could be a strategy for preventing or treating AD.
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“However, features of premature senescence associated particularly with DNA double-strand breaks (DSBs) and p16 expression also have been described in post-mitotic cells such as neurons[16, 18, 29].”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [29]
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“but no AD hallmark neuropathology was shown.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [24]
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“These severely affected donors had lower transcription and reduced chromatin accessibility that may correspond to senescent states97, or global epigenome dysregulation that is indicative of cell identity loss98.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [97]
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“Recent studies have directly induced neurons from individuals with AD through NGN2/ASCL1 overexpression.”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [24]
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“These neurons exhibited several age-associated dysregulations such as instability of mature neuronal fate, increased cellular senescence, and metabolic shifts (11, 24, 25)”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [24]
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Cites
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The senescence-associated secretory phenotype: the dark side of tumor suppression
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DNA methylation and its basic function
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The single-cell transcriptional landscape of mammalian organogenesis
Cao, J., Spielmann, M., Qiu, X., Huang, X., Ibrahim, D. M., Hill, A. J., Zhang, F., Mundlos, S., Christiansen, L., Steemers, F. J., et al. (2019) · Nature · doi:10.1038/s41586-019-0969-x · Cited by 4,490
Telomere measurement by quantitative PCR
Cawthon, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.10.e47 · Cited by 3,550
Single-cell transcriptomic analysis of Alzheimer’s disease
Mathys, H., Davila-Velderrain, J., Peng, Z., Gao, F., Mohammadi, S., Young, J. Z., Menon, M., He, L., Abdurrob, F., Jiang, X., et al. (2019) · Nature · doi:10.1038/s41586-019-1195-2 · Cited by 2,568
Reactive astrocyte nomenclature, definitions, and future directions
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An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.11.012 · Cited by 2,045
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Bartkova, J., Rezaei, N., Liontos, M., Karakaidos, P., Kletsas, D., Issaeva, N., Vassiliou, L.-V. F., Kolettas, E., Niforou, K., Zoumpourlis, V. C., et al. (2006) · Nature · doi:10.1038/nature05268 · Cited by 1,986
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Items 201–207 of 207
Viteri, J. A., Kerr, N. R., Brennan, C. D., Kick, G. R., Wang, M., Ketabforoush, A. H. M. E., Snyder, H., Moore, P. J., Darvishi, F. B., Dashtmian, A. R., et al. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2026.107610 · Cited by 1
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Poynter, C. L., Sánchez-Carbonell, M., Kendall, R. L., Garcia, M. A., de Melo, D. M., McPeck, R. N., Mirita, C., Brown, J. M., Campen, M. J., Holian, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.18.752710
Metabolomic Biomarkers of Cellular Senescence in Neurodegenerative Disease
Slocum, D. L., Duka, D., Antonelli, L., & Logan, R. (2026) · IntechOpen eBooks · doi:10.5772/intechopen.1018049
Yang, Z., Sun, H., Zhang, F., Ji, W., 梁又德, Wang, M., Yan, M., Zhao, Z., & Fu, L. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103408
Huang, J., Ji, L., Jin, H., Shi, Z., Song, X., Cai, Y., & Tong, X. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103398
Metadata
- Authors
- Herdy, J. R., Traxler, L., Agarwal, R. K., Karbacher, L., Schlachetzki, J. C. M., Boehnke, L., Zangwill, D., Galasko, D., Glass, C. K., Mertens, J., & Gage, F. H.
- Affiliations
- Salk Institute for Biological Studies (US)
- Universität Innsbruck (AT)
- University of California San Diego (US)
- Corresponding author
- Herdy, Joseph R.
- Gage, Fred H.
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2022-12
- Volume
- 29
- Issue
- 12
- Pages
- 1637-1652.e6
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC10093780
- OpenAlex
- W4310496865
- Cited by
- 208
- References
- 79
- Citations by year
- 2026: 59 · 2025: 63 · 2024: 63 · 2023: 23
- FWCI
- 23.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- California Institute for Regenerative Medicine
- American Heart Association (H2020, 19PABH134610000, 19PABHI34610000)
- BrightFocus Foundation (A2019562S, ERC-STG-2019-852086, H2020-MSCA-IF-2017-797205)
- Waitt Foundation
- European Commission (H2020-MSCA-IF-2017., H2020, 797205, H2020‐MSCA‐IF, H2020-MSCA)
- Austrian Science Fund (FWF-I5057)
- National Institutes of Health (P30 014195, RT2-01927, 1s10od023689-01a1, H2020, AG062429, AG051449)
- University of California, San Diego
- Horizon 2020 Framework Programme (H2020-MSCA, H2020-MSCA-IF-2017)
- National Institute on Aging (K99AG056679, R01AG056306, R01AG057706, R01AG056511, T32AG000216, P30AG062429, RF1AG056306, P01AG051449, R37AG072502)
- National Cancer Institute (S10-OD023689, P30014195)
- National Institute of General Medical Sciences (T32GM007198)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- neuronal senescence, Alzheimer's disease, senescence-associated secretory phenotype, senotherapeutics, astrocyte activation, neuroinflammation, senescence markers
- MeSH terms
- Aged, Alzheimer Disease, Astrocytes, Brain, Humans, Neurons, Oncogenes
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