Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation
Open accessPreprint — published as 10.7554/elife.90579 · Paper page
Abstract
Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.
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- Authors
- Mitchell, W., Goeminne, L. J. E., Tyshkovskiy, A., Zhang, S., Chen, J. Y., Paulo, J. A., Pierce, K. A., Choy, A. H., Clish, C. B., Gygi, S. P., & Gladyshev, V. N.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Gladyshev, Vadim N.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2023-06-30
- PMC
- PMC10327104
- OpenAlex
- W4382654481
- Cited by
- 2
- References
- 13
- Citations by year
- 2024: 1 · 2023: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health
- National Institute on Aging
- National Institute of General Medical Sciences (GM 67945, R01GM067945, R01GM132129, GM132129)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- National Institute of Biomedical Imaging and Bioengineering (EB016652, T32EB016652)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular rejuvenation, aging, Yamanaka factors, fibroblasts, epigenome, transcriptome, proteome, phosphoproteome, metabolome, mitochondrial oxidative phosphorylation, epigenetic clocks, biological age, cellular respiration, mitochondrial membrane potential, aging reversal
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