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Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts
Open accessAbstract
Aging is a major risk factor in many forms of late-onset neurodegenerative disorders. The ability to recapitulate age-related characteristics of human neurons in culture will offer unprecedented opportunities to study the biological processes underlying neuronal aging. Here, we show that using a recently demonstrated microRNA-based cellular reprogramming approach, human fibroblasts from postnatal to near centenarian donors can be efficiently converted into neurons that maintain multiple age-associated signatures. Application of an epigenetic biomarker of aging (referred to as epigenetic clock) to DNA methylation data revealed that the epigenetic ages of fibroblasts were highly correlated with corresponding age estimates of reprogrammed neurons. Transcriptome and microRNA profiles reveal genes differentially expressed between young and old neurons. Further analyses of oxidative stress, DNA damage and telomere length exhibit the retention of age-associated cellular properties in converted neurons from corresponding fibroblasts. Our results collectively demonstrate the maintenance of age after neuronal conversion.
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“emphasizing the necessity of partial de-differentiation for rejuvenation (Box 1) to occur [22][23][24][25] .”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [23]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Direct cellular reprogramming retains age-related signatures stored in pre-reprogrammed non-neural somatic cells such as fibroblasts, including the epigenetic age, telomere length, and gene expression changes (22, 23).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [22]
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“Conversely, other works have shown that aging-associated DNA methylation patterns and biomarkers persisted when cells were transdifferentiated (Box 1) to different cell types, emphasizing the necessity of partial de-differentiation for rejuvenation (Box 1) to occur [22][23][24][25] .”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [23]
In the citing paper
“Fibroblast-derived iNs preserve substantial signatures of human aging, including transcriptomic, nuclear pore, mitochondrial, epigenetic, and other aspects of aging (Herdy et al., 2019; Huh et al., 2016; Kim et al., 2018; Mertens et al., 2015a; Traxler et al., 2019).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Huh et al., 2016
In the citing paper
“Clearly, iN DNAm ages reflect the adult and old chronological ages of their donors, whereas pluripotent stem cells and their derivatives reflect pre-natal DNAm ages (Figure 7H; Huh et al., 2016; Kim et al., 2014; Lo Sardo et al., 2017).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Huh et al., 2016
In the citing paper
“Clearly, iN DNAm ages reflect the adult and old chronological ages of their donors, whereas pluripotent stem cells and their derivatives reflect pre-natal DNAm ages (Figure 7H; Huh et al., 2016; Kim et al., 2014; Lo Sardo et al., 2017).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Huh et al., 2016
In the citing paper
“AD iNs did not display signs of accelerated epigenetic aging over control iNs (Figures 7I and 7J; Figure S6; Horvath, 2013; Huh et al., 2016).”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Huh et al., 2016
In the citing paper
“Cellular aging features (Huh et al., 2016; Mertens et al., 2015a, 2018; Tang et al., 2017; Victor et al., 2014) and adult-like neuronal identity of iNs (Luo et al., 2019) are likely critical for the emergence of such phenotypes in sporadic AD neurons, because erasure of aging signatures and re-gaining of fetal identity represents a potent rescue in this study (Miller et al., 2013; Ocampo et al., 2”
From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Huh et al., 2016
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Citations
Cites
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CDKN1A protects medium spiny neurons from Huntington's disease pathology
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Modeling human neurodegeneration with iPSCs: opportunities, limitations, and the challenge of aging
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Decline in mitochondrial health and lysosomal acidification in human neurons during normal aging
Legault, E. M., Gamez, J. P. I., & Drouin‐Ouellet, J. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1903701
Metadata
- Authors
- Huh, C. J., Zhang, B., Victor, M. B., Dahiya, S., Batista, L. F., Horvath, S., & Yoo, A. S.
- Affiliations
- Washington University in St. Louis (US)
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States
- University of California, Los Angeles (US)
- Corresponding author
- Yoo, Andrew S
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-09-20
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5067114
- OpenAlex
- W2521543069
- Cited by
- 213
- References
- 57
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 23 · 2023: 22 · 2022: 17 · 2021: 33 · 2020: 29 · 2019: 17 · 2018: 26 · 2017: 11
- FWCI
- 9.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Drug Abuse (R25 DA027995)
- National Institutes of Health (K99/R00, 4R00HL114732-03, 1U34AG051425-01, 5R01, AG042511-02, DP2NS083372-01)
- Washington University in St. Louis (DDRCC, NIDDK P30 DK052574)
- Ellison Medical Foundation (AG-NS-0878-12)
- Cure Alzheimer's Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Keywords
- neuronal aging, fibroblast-to-neuron conversion, epigenetic clocks, DNA methylation, age-related gene expression, oxidative stress, DNA damage, telomere length, neurodegenerative diseases, human neurons
- MeSH terms
- Aging, Cytological Techniques, DNA Damage, Fibroblasts, Humans, Neurons, Telomere, Oxidative Stress, Gene Expression Profiling, MicroRNAs, Epigenesis, Genetic, Cell Transdifferentiation
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