Gene Therapy Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice.
Open accessPreprint — published as 10.1089/cell.2023.0072 · Paper page
Abstract
Aging is a complex process best characterized as the chronic dysregulation of cellular processes leading to deteriorated tissue and organ function. While aging cannot currently be prevented, its impact on lifespan and healthspan in the elderly can potentially be minimized by interventions that aim to return these cellular processes to optimal function. Recent studies have demonstrated that partial reprogramming using the Yamanaka factors (or a subset; OCT4, SOX2 , and KLF4; OSK) can reverse age-related changes in vitro and in vivo . However, it is still unknown whether the Yamanaka factors (or a subset) are capable of extending the lifespan of aged wild type mice. Here, we show that systemically delivered AAVs, encoding an inducible OSK system, in 124-week-old mice extends the median remaining lifespan by 109% over wild-type controls and enhances several health parameters. Importantly, we observed a significant improvement in frailty scores indicating that we were able to improve the healthspan along with increasing the lifespan. Furthermore, in human keratinocytes expressing exogenous OSK, we observed significant epigenetic markers of age-reversal, suggesting a potential reregulation of genetic networks to a younger, potentially healthier state. Together, these results may have important implications for the development of partial reprogramming interventions to reverse age-associated diseases in the elderly.
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Expression of OSK throughout the entire body of mice extends their lifespan.
“In fact, expression of OSK throughout the entire body of mice extends their lifespan [26].”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [26]
The Results report that systemically delivered, inducible OSK extended median remaining lifespan in 124-week-old mice by 109%. But the authors chose AAV9 for distribution to “most tissues”; they do not establish OSK expression throughout the entire body. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredDeveloping a chemical alternative to mimic OSK's rejuvenating effects could lower costs and shorten timelines in regenerative medicine development.
“Developing a chemical alternative to mimic OSK’s rejuvenating effects could lower costs and shorten timelines in regenerative medicine development [26, 28–31].”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [26]
The Results and Discussion report rejuvenation-related effects of OSK in aged mice and human keratinocytes. The Discussion also says that using three separate vectors increases manufacturing and clinical-development complexity. It does not discuss a chemical alternative or say that one would lower costs or shorten development timelines. (LLM, conf=0.87)
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- Authors
- Macip, C. C., Hasan, R., Hoznek, V., Kim, J., Metzger, L. E., Sethna, S., & Davidsohn, N.
- Corresponding author
- Davidsohn, Noah
- Venue
- Cellular Reprogramming
- Publisher
- openRxiv
- Published
- 2023-01-05
- Volume
- 26
- Issue
- 1
- Pages
- 24-32
- ISSN
- 2152-4971 (ISSN-L)
- PMC
- PMC10909732
- OpenAlex
- W4392017897
- Cited by
- 95
- References
- 46
- Citations by year
- 2026: 33 · 2025: 26 · 2024: 21 · 2023: 15
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Cellular Reprogramming (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- United States Special Operations Command
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- partial reprogramming, Yamanaka factors, gene therapy, adeno-associated virus vectors, lifespan extension, healthspan, aging, frailty, aged mice, keratinocytes, epigenetic reprogramming, aging reversal
- MeSH terms
- Aged, Aging, Animals, Humans, Longevity, Male, Genetic Therapy, Keratinocytes, Mice, Cellular Reprogramming
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