Longevity-associated SMAD3 non-coding centenarian variant impairs a cell-type specific enhancer to reduce inflammation Article Swipe
Jiping Yang
,
Archana Tare
,
Lei Zhang
,
Seungsoo Kim
,
Seungjin Ryu
,
Qinghua Guo
,
Yizhou Zhu
,
Xizhe Wang
,
Xifan Wang
,
Adam D. Hudgins
,
Di Guan
,
Chen Jin
,
Hyun‐Kyung Chang
,
Gil Atzmon
,
Sofiya Milman
,
Nir Barzilai
,
Jan Vijg
,
Laura J. Niedernhofer
,
Paul D. Robbins
,
Yousin Suh
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.05.17.540984
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1101/2023.05.17.540984
Given the pro and anti-geronic roles of the TGF-β superfamily in aging, we hypothesized that human longevity involves genetic variation in TGF-β signaling genes. Here we utilized a candidate functional genomic approach to identify and characterize functional variants in TGF- β signaling associated with human longevity. Targeted sequencing of 113 genes involved in aging- associated TGF- β signaling in an Ashkenazi Jewish centenarian cohort identified genetic variants robustly associated with human longevity. In particular, a centenarian-enriched intronic variant residing in a cell-type specific enhancer in SMAD3, a critical receptor-regulated TGF- β signal transducer, was identified. This non-coding SMAD3 variant (rs8040709) altered binding of ELK1, a member of the ETS family of transcription factor important for enhancer activity in certain cell types, resulting in reduced SMAD3 expression. Analysis of the variant in cell types derived from gene edited iPSCs demonstrated the variant reduced SMAD3 expression, senescence and inflammation in endothelial cells. In addition, heterozygosity in SMAD3 improved healthspan and reduced senescence in the Ercc1 -/Δ progeroid mouse model of accelerated aging. Taken together, these experiments demonstrate that variants in a cell type specific enhancer of SMAD3 resulted in reduced expression, senescence and inflammation and contributes to human longevity. Thus, SMAD3 represents a validated targeted for drug development for extending human healthspan.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2023.05.17.540984
- https://www.biorxiv.org/content/biorxiv/early/2023/05/18/2023.05.17.540984.full.pdf
- OA Status
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- Cited By
- 1
- References
- 41
- Related Works
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- OpenAlex ID
- https://openalex.org/W4377098339
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4377098339Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2023.05.17.540984Digital Object Identifier
- Title
-
Longevity-associated SMAD3 non-coding centenarian variant impairs a cell-type specific enhancer to reduce inflammationWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
-
2023-05-18Full publication date if available
- Authors
-
Jiping Yang, Archana Tare, Lei Zhang, Seungsoo Kim, Seungjin Ryu, Qinghua Guo, Yizhou Zhu, Xizhe Wang, Xifan Wang, Adam D. Hudgins, Di Guan, Chen Jin, Hyun‐Kyung Chang, Gil Atzmon, Sofiya Milman, Nir Barzilai, Jan Vijg, Laura J. Niedernhofer, Paul D. Robbins, Yousin SuhList of authors in order
- Landing page
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https://doi.org/10.1101/2023.05.17.540984Publisher landing page
- PDF URL
-
https://www.biorxiv.org/content/biorxiv/early/2023/05/18/2023.05.17.540984.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.biorxiv.org/content/biorxiv/early/2023/05/18/2023.05.17.540984.full.pdfDirect OA link when available
- Concepts
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Centenarian, Biology, Enhancer, Longevity, Genetics, Progeria, Gene, Transcription factor, SenescenceTop concepts (fields/topics) attached by OpenAlex
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1Total citation count in OpenAlex
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2024: 1Per-year citation counts (last 5 years)
- References (count)
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41Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.contributes | 194 |
| abstract_inverted_index.demonstrate | 175 |
| abstract_inverted_index.development | 206 |
| abstract_inverted_index.endothelial | 149 |
| abstract_inverted_index.experiments | 174 |
| abstract_inverted_index.expression, | 144, 189 |
| abstract_inverted_index.expression. | 126 |
| abstract_inverted_index.healthspan. | 210 |
| abstract_inverted_index.identified. | 95 |
| abstract_inverted_index.particular, | 74 |
| abstract_inverted_index.superfamily | 10 |
| abstract_inverted_index.transducer, | 93 |
| abstract_inverted_index.anti-geronic | 5 |
| abstract_inverted_index.characterize | 36 |
| abstract_inverted_index.demonstrated | 139 |
| abstract_inverted_index.hypothesized | 14 |
| abstract_inverted_index.inflammation | 147, 192 |
| abstract_inverted_index.transcription | 112 |
| abstract_inverted_index.heterozygosity | 153 |
| abstract_inverted_index.receptor-regulated | 89 |
| abstract_inverted_index.centenarian-enriched | 76 |
| cited_by_percentile_year.max | 94 |
| cited_by_percentile_year.min | 90 |
| corresponding_author_ids | https://openalex.org/A5080863597 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 20 |
| corresponding_institution_ids | https://openalex.org/I129975664, https://openalex.org/I78577930 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8100000023841858 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.44030757 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |