In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.
Open accessAbstract
Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.
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Numerous tissues, including brain, kidney, and muscle, have been reprogrammed without causing cancer.
“Numerous tissues, including brain tissue, kidney, and muscle, have now been reprogrammed without causing cancer [7, 8, 22, 24, 25].”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [22]
The section “Cyclic In Vivo Induction of Reprogramming Factors Does Not Lead to Tumor Formation” reports no signs of cancer in the organs analyzed after cyclic OSKM induction in mice. The paper also reports effects in kidney and skeletal muscle, but our copy does not establish cancer-free reprogramming of brain tissue. Its finding is limited to the tested mouse protocol and organs, not numerous tissues generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTeratoma formation has been observed in partially reprogrammed animals, particularly when c-Myc is used.
“Teratoma formation has been observed in partially reprogrammed animals, particularly when c-Myc is used in the partial rejuvenation cocktail (Abad et al., 2013; Ocampo et al., 2016; Ohnishi et al., 2014; Senís et al., 2018)”
From Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice (2024) · cites this paper as Ocampo et al., 2016
In “Cyclic In Vivo Induction of Reprogramming Factors Does Not Lead to Tumor Formation” (page not provided), the authors report teratomas in mice given cyclic OSKM induction with two copies of the reprogramming cassette. They do not establish that teratomas occur particularly because c-Myc is included: their comparison varies cassette copy number, not c-Myc use, and the single-copy protocol showed no tumors. (LLM, conf=0.87)
Experimental — accuracy not yet measuredCyclic expression of Yamanaka factors Oct4, Sox2, Klf4, and Myc alleviates symptoms and extends lifespan of progeroid mice and other aspects of aging.
“The cyclic expression of Yamanaka factors Oct4, Sox2, Klf4 and Myc (OSKM) (Takahashi and Yamanaka, 2006) alleviates the symptoms and extends the lifespan of progeroid mice and other aspects of aging (Ocampo et al., 2016; Sarkar et al., 2020).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Ocampo et al., 2016
In a HGPS mouse model, cyclic transgene-mediated expression of OSKM alleviates symptoms and extends lifespan.
“In a premature ageing mouse model of Hutchinson-Gilford progeria syndrome (HGPS), cyclic transgene-mediated expression of these four genes alleviates symptoms and extends lifespan, raising the possibility that OSKM might counteract normal ageing, too16.”
From Reprogramming to recover youthful epigenetic information and restore vision (2020) · cites this paper as [16]
Continuous expression of all four Yamanaka factors in normal mice often induces teratomas or is fatal within days, ostensibly due to tissue dysplasia.
“Continuous expression of all four factors in normal mice, however, often induces teratomas17–19 or is fatal within days16, ostensibly due to tissue dysplasia18.”
From Reprogramming to recover youthful epigenetic information and restore vision (2020) · cites this paper as [16]
It is possible to safely improve tissue function in vivo by pulsing OSKM expression or by continuously expressing OSK.
“But work by the Belmonte lab, our lab, and others have confirmed that it is possible to safely improve the function of tissues in vivo by pulsing OSKM expression [22, 23] or by continuously expressing only OSK, leaving out the oncogene c-MYC [7, 8].”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [22]
Expressing all four Yamanaka factors in mice has toxic effects.
“in light of the toxic effects of expressing all four Yamanaka factors in mice [22]”
From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [22]
Cyclic induction of Yamanaka factors in transgenic mice partially ameliorated aging phenotypes and extended lifespan in the 4F-progeroid model.
“This paradigm partially ameliorated aging phenotypes and extended the lifespan in the 4F-progeroid model (Ocampo et al., 2016)”
From Gene Therapy-Mediated Partial Reprogramming Extends Lifespan and Reverses Age-Related Changes in Aged Mice (2024) · cites this paper as Ocampo et al., 2016
Senescent cells have shown beneficial effects as tumour suppressors, during embryo development, and in liver and skin repair or reprogramming.
“By contrast, senescent cells have shown beneficial effects as tumour suppressors, during embryo development, and in liver and skin repair18–21 or reprogramming22–24.”
From Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration (2023) · cites this paper as [24]
The citation falls on the claim that senescent cells have beneficial effects in reprogramming. The Introduction (p. 1719) discusses reprogramming as a way to ameliorate age-associated cellular phenotypes, while the Discussion describes senescence as a possible outcome when aging hallmarks are not erased. Neither passage addresses whether senescent cells themselves benefit reprogramming; searches for that relationship found no such passage. (LLM, conf=0.74)
Experimental — accuracy not yet measuredShort-term cyclic expression of Oct4, Sox2, KLF4, and c-Myc in LAKI 4F mice suppressed the ageing phenotype, prevented VSMC degeneration, and reversed bradycardia without observed tumorigenesis.
“Short-term cyclic expression of Oct4, Sox2, KLF4, and c-Myc in LAKI 4F mice suppressed the ageing phenotype, prevented VSMC degeneration, and reversed bradycardia without observed tumorigenesis.193”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [193]
HGPS fibroblasts present biomarkers of aging and senescence.
“To determine if sEV-Ys within the CM had the potential to ameliorate biomarkers of aging, we took advantage of primary fibroblasts derived from patients with a severe form of premature aging, HGPS, which present biomarkers of aging and senescence (Figure S2A) (Burtner and Kennedy, 2010, Ocampo et al., 2016, Liu et al., 2011).”
From Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage (2020) · cites this paper as Ocampo et al., 2016
During earlier stages of aging or tissue damage, when there are still plenty of proliferating cells, these can 'repair' tissue dysfunction by ameliorating the senescent phenotype of damaged cells through soluble factors and via sEVs.
“during the earlier stages of aging or during tissue damage, when there are still plenty of proliferating cells, these can “repair” tissue dysfunction by ameliorating the senescent phenotype of damaged cells through soluble factors (Mosteiro et al., 2016, Ocampo et al., 2016) and via sEVs as shown in this study.”
From Small Extracellular Vesicles Have GST Activity and Ameliorate Senescence-Related Tissue Damage (2020) · cites this paper as Ocampo et al., 2016
Recent studies have demonstrated cellular and functional rejuvenation by transient epigenetic reprogramming.
“Epigenetic alteration is a hallmark of ageing4, and recent studies have demonstrated cellular and functional rejuvenation by transient epigenetic reprogramming17,51,52.”
From Measuring biological age using omics data (2022) · cites this paper as [51]
Erasure of aging signatures and re-gaining of fetal identity represents a potent rescue in this study.
“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 Ocampo et al., 2016
Reprogramming factors reset chromatin modifications in old cells.
“Studies so far have shown that reprogramming factors ‘reset’ chromatin modifications in old cells228 and rejuvenate the DNA methylation and transcriptome in several organs of old mice (pancreas, liver, spleen and blood)233.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [228]
Beneficial effects of partial reprogramming are observed in stem and progenitor cells in muscle and pancreas.
“Beneficial effects of partial reprogramming are observed in stem and progenitor cells in muscle and pancreas228.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [228]
Cyclical induction of OSKM can restore youthful properties to aged cells and tissues, including stem and progenitor cells, without loss of cellular differentiation characteristics.
“In contrast, cyclical induction of OSKM can restore youthful properties to aged cells and tissues, including stem and progenitor cells, without loss of cellular differentiation characteristics228.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [228]
Reprogramming factors promote tissue regeneration in aged mice.
“Besides amelioration of cellular aging hallmarks, reprogramming factors promote tissue regeneration in aged mice8,10.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [8]
Partial reprogramming by short-term expression of reprogramming factors ameliorated aging hallmarks without tumor formation.
“Our lab showed that partial reprogramming by short-term expression of reprogramming factors ameliorated aging hallmarks without tumor formation8, opening a possible application of this approach in vivo.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [8]
Partial reprogramming promotes skeletal muscle regeneration in 12-month-old mice.
“We have shown that partial reprogramming promotes skeletal muscle regeneration in 12-month-old mice8, but these studies were performed by expressing OSKM systemically (i.e., in all cell types)8.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [8]
Systemic OSKM induction could promote muscle regeneration in 12-month-old systemic 4F mice.
“We previously showed that systemic OSKM induction could promote muscle regeneration in 12-month-old systemic 4F mice8.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [8]
Systemic OSKM induction has been shown to mitigate the decline of Pax7+ cells in progeria mice after 6 weeks of cyclic induction of OSKM.
“Systemic OSKM induction has been shown to mitigate the decline of Pax7+ cells in progeria mice after 6 weeks of cyclic induction of OSKM8.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [8]
The increase in activated SCs accelerated muscle regeneration, which may partly explain the previous observation that muscle regeneration was promoted in aging systemic 4F mice.
“The increase in activated SCs accelerated muscle regeneration, which may partly explain our previous observation that muscle regeneration was promoted in aging systemic 4F mice8.”
From In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche (2021) · cites this paper as [8]
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Self-citation
- Authors
- Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., Li, M., Lam, D., Kurita, M., Beyret, E., Araoka, T., Vazquez-Ferrer, E., Donoso, D., Roman, J. L., Xu, J., Rodriguez Esteban, C., Nuñez, G., Nuñez Delicado, E., Campistol, J. M., Guillen, I., Guillen, P., & Izpisua Belmonte, J. C.
- Affiliations
- Salk Institute for Biological Studies (US)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 167
- Issue
- 7
- Pages
- 1719-1733.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5679279
- OpenAlex
- W2565424224
- Cited by
- 988
- References
- 58
- Citations by year
- 2026: 148 · 2025: 118 · 2024: 112 · 2023: 128 · 2022: 105 · 2021: 110 · 2020: 71 · 2019: 73 · 2018: 62 · 2017: 58 · 2016: 2
- FWCI
- 33.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Deposito de Investigacion Universidad de Sevilla (University of Seville) (submittedVersion, cc-by-nc-nd)
- Funders
- Glenn Foundation for Medical Research
- Muscular Dystrophy Association
- Leona M. and Harry B. Helmsley Charitable Trust (#2012-PG-MED002, MED002)
- Uehara Memorial Foundation
- Moxie Foundation
- NOMIS Stiftung
- National Institutes of Health
- University of California, San Diego
- Japan Society for the Promotion of Science
- National Cancer Institute (P30CA014195)
- 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
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- partial reprogramming, cellular aging, OSKM, Oct4, SOX2, KLF4, c-Myc, premature aging, lifespan extension, epigenetic remodeling, metabolic disorders, muscle damage, in vivo reprogramming
- MeSH terms
- Kruppel-Like Factor 4, Aging, Animals, Diabetes Mellitus, Type 2, Humans, Metabolic Diseases, Pancreas, Transcription Factors, Aging, Premature, Models, Animal, Lamin Type A, Epigenesis, Genetic, Mice, Sarcopenia, Induced Pluripotent Stem Cells, Cellular Reprogramming
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