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Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state
Open accessAbstract
Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a unique opportunity to derive patient-specific stem cells with potential applications in tissue replacement therapies and without the ethical concerns of human embryonic stem cells (hESCs). However, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. Here we demonstrate, using an optimized protocol, that cellular senescence is not a limit to reprogramming and that age-related cellular physiology is reversible. Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs. Finally, we show that senescent and centenarian-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. These results provide new insights into iPSC technology and pave the way for regenerative medicine for aged patients.
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“However, induction of pluripotency in iPSCs resets the age signatures of the donor cells to a fetal stage (7–9).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Telomere length decreases with age due to cell proliferation in the absence of telomerase enzymes and is restored upon complete iPSC reprogramming (Lapasset et al., 2011).”
From Multi-omic rejuvenation of human cells by maturation phase transient reprogramming (2022) · cites this paper as Lapasset et al., 2011
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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“The rejuvenation of aging hallmarks has been extensively described during cellular reprogramming to pluripotency in vitro (Lapasset et al., 2011;Liu et al., 2011;Mahmoudi and Brunet, 2012;Rando and Chang, 2012), but the dynamics of this process remain poorly understood.”
From In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. (2016) · cites this paper as Lapasset et al., 2011
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“Several groups, including ours, have observed an amelioration of age-associated cellular phenotypes during in vitro cellular reprogramming”
From In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. (2016) · cites this paper as Lapasset et al., 2011
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“iPSC reprogramming reverses many age-associated changes, including telomere attrition and oxidative stress (Lapasset et al., 2011).”
From Multi-omic rejuvenation of human cells by maturation phase transient reprogramming (2022) · cites this paper as Lapasset et al., 2011
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“Early reports using cells derived from old donors to generate iPS cells demonstrated beneficial effects on senescence phenotypes and telomere length [26][27][28] .”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [26]
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“but protocols relied upon rejuvenation through re-differentiation after iPS cell formation 20,26,28 .”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [26]
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“Early experiments in human cells were somewhat encouraging as they provide evidence that some of the biomarkers of aging (that is telomere lengths) were responding to the epigenetic reprogramming”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [26]
In the citing paper
“Of note, senescent cells from elderly people could be reverted to a pluripotent state only by the additional over-expression of NANOG and LIN2 in addition to Oct3/4, Sox2, c-Myc, and KLF4.196”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [196]
In the citing paper
“A growing body of evidence, including the present study and a prior report of reprogramming of senescent human fibroblasts into induced pluripotent stem cells (iPSCs; ref. 48), suggests that near-senescent or senescent cells can be induced back into a proliferative state.”
From p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes (2013) · cites this paper as [48]
In the citing paper
“Reprogramming cells from elderly humans (as old as 101 years of age) into pluripotent cells erases many of the hallmarks of aging and restores a youthful gene expression profile that is maintained during differentiation (Lapasset et al., 2011; Mertens et al., 2015).”
From The Aging Epigenome (2016) · cites this paper as Lapasset et al., 2011
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Citations
Cites
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BackgroundKashpur, O., Smith, A., Gerami‐Naini, B., Maione, A. G., Calabrese, R., Tellechea, A., Theocharidis, G., Liang, L., Pastar, I., Tomic‐Canic, M., et al. (2018) · The FASEB Journal · doi:10.1096/fj.201801059 · Cited by 53
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Reversibility of irreversible aging
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“Somatic cell reprogramming requires cell cycle progression, while senescence entry represents an important barrier to cell reprogramming [7].”
BackgroundReprogramming aging and progeria
Freije, J. M., & López-Otín, C. (2012) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2012.08.009 · Cited by 46
“However, the recent implementation of an optimized reprogramming protocol has demonstrated the feasibility of deriving fully functional iPSCs from senescent and centenarian human cells, providing additional evidence of the reversibility of aging at the cellular level [80 ].”
BackgroundHuman iPSC-Based Modeling of Central Nerve System Disorders for Drug Discovery
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“This is because the epigenetics of patient somatic cells is restored back to the embryonic stage during iPSC-reprogramming [6,192,193].”
BackgroundAge reprogramming: cell rejuvenation by partial reprogramming
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“For example, iPSC-derived fibroblasts showed an extended replicative potential (Suhr et al. 2009; Lapasset et al. 2011) and improved mitochondrial function (Suhr et al. 2010; Lapasset et al. 2011) when compared to the parental fibroblasts used for iPSC reprogramming.”
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“Mitochondrial morphology, distribution, and function are rearranged to a state comparable to ESCs [4,8–10] or to a state in between that of ESCs and somatic cells [11].”
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“Recent papers have indicated that reprograming somatic cells into pluripotent cells might facilitate the rejuvenation [39, 40].”
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“The difficulties in modeling late-onset disease phenotypes may be related to the reset of donor age in human pluripotent stem cells (hPSCs) following reprogramming (Suhr et al., 2010; Lapasset et al., 2011; Mahmoudi and Brunet, 2012; Frobel et al., 2014).”
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“Not surprisingly, the age of human cell donor has little effect on the ability to reprogram the cells to a pluripotent state.(30,39) In fact, human iPSCs (hiPSC) derived from cells with telomerase activity defects and non-critically short telomeres still can be reprogrammed to a pluripotent state.”
BackgroundDifferentiation reveals latent features of aging and an energy barrier in murine myogenesis
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Mechanistic Insights Into MicroRNA-Induced Neuronal Reprogramming of Human Adult Fibroblasts
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“Furthermore, unlike iPSCbased reprogramming methods, direct neuronal conversion bypasses an embryonic intermediate (Lapasset et al., 2011; Miller et al., 2013), thereby retaining the age signatures of starting fibroblasts including the epigenetic clock (Horvath, 2013), ageassociated changes in transcriptome and microR…”
BackgroundGATA6 regulates aging of human mesenchymal stem/stromal cells
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Epigenetic rejuvenation by partial reprogramming
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“combination with Nanog and LIN28.[3] For example, B-lymphoblastoid cell lines derived from a supercentenarian (114-year-old donor) were reprogrammed, and the iPSCs exhibited complete erasure of the ageassociated transcriptomic signature and resetting of telomeres.”
BackgroundInfluentialMid-old cells are a potential target for anti-aging interventions in the elderly
Kim, Y. H., Lee, Y., Park, S. S., Park, S. H., Eom, S. Y., Lee, Y., Lee, W. J., Jang, J., Seo, D., Kang, H. Y., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-43491-w · Cited by 44
Sirt6 Promotes DNA End Joining in iPSCs Derived from Old Mice
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Chanoumidou, K., Hernández-Rodríguez, B., Windener, F., Thomas, C., Stehling, M., Mozafari, S., Albrecht, S., Ottoboni, L., Antel, J., Kim, K.-P., et al. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.03.001 · Cited by 39
“’’ While iPSC reprogramming is accompanied by cell rejuvenation and erasure of aging signature (Lapasset et al., 2011; Meissner et al., 2008), directly converted cells maintainmany features of aging (Huh et al.”
BackgroundKondo, H., Kim, H. W., Wang, L., Okada, M., Paul, C., Millard, R. W., & Wang, Y. (2015) · Aging Cell · doi:10.1111/acel.12411 · Cited by 39
LncRNAs regulating stemness in aging
Sousa‐Franco, A., Rebelo, K., da Rocha, S. T., & de Jesus, B. B. (2018) · Aging Cell · doi:10.1111/acel.12870 · Cited by 38
Myc determines the functional age state of oligodendrocyte progenitor cells
Neumann, B., Segel, M., Ghosh, T., Zhao, C., Tourlomousis, P., Young, A. M. H., Förster, S., Sharma, A., Chen, C. Z.-Y., Cubillos, J. F., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00109-4 · Cited by 41
Hsu, Y., Wu, Y., Tsai, C.-L., & Wei, Y. (2018) · Experimental Biology and Medicine · doi:10.1177/1535370218759636 · Cited by 39
“It has been shown that the efficiency of reprogramming from somatic cells to generate iPSCs declines with age of the donor.(79,80) It is thus important to identify regulatory factors that can overcome aging during the reprogramming processes.”
BackgroundBcl-xL as a Modulator of Senescence and Aging
Mas‐Bargues, C., Borrás, C., & Viña, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041527 · Cited by 39
Emerging Roles of Vitamin B12 in Aging and Inflammation
Simonenko, S. Y., Bogdanova, D. A., & Kuldyushev, N. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25095044 · Cited by 41
“Such cells have comparable telomere lengths and can be re-differentiated into rejuvenated tissue-specific cells [177].”
BackgroundKim, J., Khalid, O. S., Namazi, A., Tu, T. G., Elie, O., Lee, C., & Kim, Y. Y. (2014) · Stem Cells · doi:10.1002/stem.1675 · Cited by 37
Cellular reprogramming for understanding and treating human disease
Kanherkar, R. R., Bhatia‐Dey, N., Makarev, E., & Csoka, A. B. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2014.00067 · Cited by 37
“Indeed, even centenarian fibroblasts can be rejuvenated, and young fibroblasts cultured to senescence can be reprogrammed to a pluripotent state (Lapasset et al., 2011; Villeda et al., 2011; Loffredo et al., 2013).”
BackgroundInduced Pluripotent Stem Cells in Huntington’s Disease Research: Progress and Opportunity
Tousley, A. R., & Kegel-Gleason, K. B. (2016) · Journal of Huntington s Disease · doi:10.3233/jhd-160199 · Cited by 37
Aged induced pluripotent stem cell (iPSCs) as a new cellular model for studying premature aging
Petrini, S., Borghi, R., Doria, V., Restaldi, F., Moreno, S., Novelli, A., Bertini, E., & Compagnucci, C. (2017) · Aging · doi:10.18632/aging.101248 · Cited by 36
“It is accepted that iPSCs can be maintained and propagated indefinitely in culture, maintaining the ability to re-differentiate into fully rejuvenated cells [18, 19].”
Epigenetic Clock: Just a Convenient Marker or an Active Driver of Aging?
Ashapkin, V. V., Kutueva, L. I., & Vanyushin, B. F. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-25650-0_10 · Cited by 41
de Luzy, I. R., Lee, M. K., Mobley, W. C., & Studer, L. (2024) · Nature Aging · doi:10.1038/s43587-024-00586-3 · Cited by 37
“In essence, donor somatic cells undergo cellular rejuvenation by an erasure of their age-associated signatures, including markers of cellular senescence 58–61 (Fig.”
Strategies for modeling aging and age-related diseases
Jothi, D., & Kulka, L. A. M. (2024) · npj Aging · doi:10.1038/s41514-024-00161-5 · Cited by 39
“In addition, the rejuvenation that occurs during reprogramming can reset the aging characteristics of the donor cells 31 .”
BackgroundChiang, C.-H., Wu, W.-W., Li, H.-Y., Chien, Y., Sun, C.-C., Peng, C., Lin, A. T. L., Huang, C.-S., Lai, Y.-H., Chiou, S., et al. (2015) · Cell Transplantation · doi:10.3727/096368915x686986 · Cited by 36
Microglia in Alzheimer's Disease: A Role for Ion Channels
Thei, L., Imm, J. L., Kaisis, E., Dallas, M. L., & Kerrigan, T. L. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00676 · Cited by 37
Santarella, F., Sridharan, R., Marinkovic, M., do Amaral, R. J. F. C., Cavanagh, B., Smith, A., Kashpur, O., Gerami‐Naini, B., Garlick, J. A., O’Brien, F. J., et al. (2020) · Advanced Healthcare Materials · doi:10.1002/adhm.202000307 · Cited by 37
Cellular senescence and neurodegeneration
Holloway, K., Neherin, K., Dam, K. U., & Zhang, H. (2023) · Human Genetics · doi:10.1007/s00439-023-02565-x · Cited by 40
To Clone or Not to Clone? Induced Pluripotent Stem Cells Can Be Generated in Bulk Culture
Willmann, C. A., Hemeda, H., Pieper, L. A., Lenz, M., Qin, J., Joussen, S., Sontag, S., Wanek, P., Denecke, B., Schüler, H. M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065324 · Cited by 37
“One important feature of pluripotent cells is their escape from replicative senescence [19,20].”
BackgroundWagner, W. (2012) · Stem Cell Research & Therapy · doi:10.1186/scrt145 · Cited by 36
“Senescence is not an inevitable fate - it may be advantageous Cellular senescence is not an inevitable fate of all cells in culture: pluripotent cells, such as embryonic stem cells and induced pluripotent stem cells, can bypass the ‘Hayfl ick limit’ [10].”
BackgroundNeural cell state shifts and fate loss in ageing and age-related diseases
Traxler, L., Lucciola, R., Herdy, J. R., Jones, J. R., Mertens, J., & Gage, F. H. (2023) · Nature Reviews Neurology · doi:10.1038/s41582-023-00815-0 · Cited by 37
Potential Clinical Implications of Senotherapies for Cardiovascular Disease
Suda, M., Katsuumi, G., Tchkonia, T., Kirkland, J. L., & Minamino, T. (2023) · Circulation Journal · doi:10.1253/circj.cj-23-0657 · Cited by 37
Malavolta, M., Costarelli, L., Giacconi, R., Piacenza, F., Basso, A., Pierpaoli, E., Marchegiani, F., Cardelli, M., Provinciali, M., & Mocchegiani, E. (2014) · Nutrition Research · doi:10.1016/j.nutres.2014.02.006 · Cited by 35
“Although the senescence program is considered a barrier for efficient cell reprogramming, induced pluripotent stem cells, functionally indistinguishable from embryonic stem cells, have been obtained from in vitro senescing cells [32].”
BackgroundTelomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes
Harley, J., Santosa, M. M., Ng, C. Y., Grinchuk, O. V., Hor, J., Liang, Y., Lim, V. J. W., Tee, W., Ong, D. S. T., & Ng, S. (2023) · Biogerontology · doi:10.1007/s10522-023-10076-5 · Cited by 37
“It is widely accepted that the reprogramming of somatic cells into hiPSCs resets the cellular age resulting in an embryonic-like state which persists in downstream differentiated neural cells (Lapasset et al. 2011; Huh et al. 2016).”
BackgroundPartial cellular reprogramming: A deep dive into an emerging rejuvenation technology
Paine, P., Nguyen, A. T., & Ocampo, A. (2023) · Aging Cell · doi:10.1111/acel.14039 · Cited by 41
“…using pluripotent transcription factors in vitro demonstrated a restoration of telomere size, gene expression profile, oxidative stress, and mitochondrial metabolism in both human cen-tenarian fibroblasts and senescent cells (Lapasset et al., 2011; Lee et al., 2020; Yagi et al., 2012).”
BackgroundAging of Stem and Progenitor Cells: Mechanisms, Impact on Therapeutic Potential, and Rejuvenation
Nurković, J., Volarević, V., Lako, M., Armstrong, L., Arsenijević, N., & Stojković, M. (2015) · Rejuvenation Research · doi:10.1089/rej.2015.1676 · Cited by 34
“81 In iPSC clones derived from human dermal fibroblasts, mitochondrial biogenesis and ROS stress defense mechanisms were analogous to those observed in ESCs.”
Apoptosis: Reprogramming and the Fate of Mature Cells
Cheung, H., Liu, X., & Rennert, O. M. (2012) · ISRN Cell Biology · doi:10.5402/2012/685852 · Cited by 32
“The derived iPSCs reset telomere length and are indistinguishable from normal hESCs [60].”
In vivo reprogramming for tissue regeneration and organismal rejuvenation
Taguchi, J., & Yamada, Y. (2017) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2017.07.008 · Cited by 34
Human induced pluripotent stem cells as a research tool in Alzheimer's disease
Robbins, J. P., & Price, J. (2017) · Psychological Medicine · doi:10.1017/s0033291717002124 · Cited by 34
“Studies indicate that during reprogramming to an embryo-like iPSC state the original age of the somatic cells is lost (Meissner et al. 2008; Lapasset et al. 2011).”
BackgroundKhatiwala, R. V., Zhang, S., Li, X., Devejian, N. S., Bennett, E. V., & Cai, C. (2018) · Stem Cell Reviews and Reports · doi:10.1007/s12015-018-9815-z · Cited by 34
Age reprogramming and epigenetic rejuvenation
Singh, P. B., & Newman, A. G. (2018) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0244-7 · Cited by 35
Reprogramming: Emerging Strategies to Rejuvenate Aging Cells and Tissues
Alle, Q., Le Borgne, E., Milhavet, O., & Lemaitre, J.-M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22083990 · Cited by 35
“recently developed an in vitro strategy based on the use of mRNA to allow the expression of the 6 OSKMNL reprogramming factors in young and old human cells [186], whose effectiveness in erasing aging hallmarks leading to a rejuvenated phenotype had previously been established by the work of our team [128].”
BackgroundMethodSelf-citationSteg, L. C., Shireby, G. L., Imm, J. L., Davies, J. P., Franklin, A., Flynn, R. J., Namboori, S. C., Bhinge, A., Jeffries, A. R., Burrage, J., et al. (2021) · Molecular Brain · doi:10.1186/s13041-021-00810-w · Cited by 32
Manukyan, M., & Singh, P. B. (2012) · Genes to Cells · doi:10.1111/j.1365-2443.2012.01595.x · Cited by 35
Context‐dependent roles of cellular senescence in normal, aged, and disease states
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Vedova, L. D., Baron, G., Morazzoni, P., Aldini, G., & Gado, F. (2025) · Pharmaceuticals · doi:10.3390/ph18020138 · Cited by 40
“In actuality, even the second phase is not to Indeed, recent studies demonstrated that in some cases, SCs can reenter the cell cycle in tumors [30] or be reprogrammed into pluripotent stem cells [31]. be considered irreversible anymore.”
Understanding telomere diseases through analysis of patient-derived iPS cells
Batista, L. F. Z., & Artandi, S. E. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.07.006 · Cited by 35
Human induced pluripotent stem cells: A disruptive innovation
Vos, J. D., Bouckenheimer, J., Sansac, C., Lemaı̂tre, J.-M., & Assou, S. (2016) · Current Research in Translational Medicine · doi:10.1016/j.retram.2016.04.001 · Cited by 37
“Human iPSCs can be obtained from somatic cells of aged donors and even centenarians, and, importantly, the crucial markers of ageing are reversed by cell reprogramming [34,35].”
BackgroundMa, W., Wang, W., Zhao, L., Fan, J., Liu, L., Huang, L., Peng, B., Wang, J., Xu, B., Liu, H., et al. (2025) · Bone Research · doi:10.1038/s41413-025-00416-1 · Cited by 37
iPSCs, aging and age-related diseases
Isobe, K., Cheng, Z., Nishio, N., Thanasegaran, S., Tanaka, Y., & Ito, S. (2014) · New Biotechnology · doi:10.1016/j.nbt.2014.04.004 · Cited by 33
Wen, Y., Wani, P., Zhou, L., Baer, T., Phadnis, S. M., Pera, R. A. R., & Chen, B. H. (2013) · Stem Cells Translational Medicine · doi:10.5966/sctm.2012-0092 · Cited by 32
Squillaro, T., Severino, V., Alessio, N., Farina, A., Bernardo, G. D., Cipollaro, M., Peluso, G., Chambery, A., & Galderisi, U. (2015) · Cell Cycle · doi:10.4161/15384101.2014.995053 · Cited by 32
“This is in good agreement with studies showing that NANOG may reverse the effect of organismal aging on MSC and which appears to have a key role in maintaining stemness and blocking senescence.(18,22,23) We decided to analyze in depth the effect of BRG1 silencing and up-regulation on the expression of NANOG, given its…”
BackgroundResult
Metadata
- Authors
- Lapasset, L., Milhavet, O., Prieur, A., Besnard, E., Babled, A., Aït-Hamou, N., Leschik, J., Pellestor, F., Ramirez, J.-M., De Vos, J., Lehmann, S., & Lemaitre, J.-M.
- Affiliations
- Institut de Génomique Fonctionnelle (FR)
- Hôpital Arnaud de Villeneuve (FR)
- Hôpital Saint Eloi (FR)
- Institut de Génétique Humaine (FR)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-11-01
- Volume
- 25
- Issue
- 21
- Pages
- 2248-2253
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC3219229
- OpenAlex
- W2114840727
- Cited by
- 570
- References
- 31
- Citations by year
- 2026: 30 · 2025: 41 · 2024: 46 · 2023: 49 · 2022: 53 · 2021: 49 · 2020: 38 · 2019: 40 · 2018: 49 · 2017: 33 · 2016: 33 · 2015: 30 · 2014: 29 · 2013: 25 · 2012: 23
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-07-BLAN-0076)
- Institut National de la Santé et de la Recherche Médicale
- Institut National Du Cancer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- cellular senescence, induced pluripotent stem cells, direct reprogramming, aging, telomere length, oxidative stress, mitochondrial metabolism, gene expression profiles, redifferentiation, rejuvenation, regenerative medicine
- MeSH terms
- Aged, Aged, 80 and over, Animals, Cell Differentiation, Cell Line, Cells, Cultured, Humans, Mitochondria, Rejuvenation, Transcription Factors, Mice, SCID, Telomere, Mice, Inbred NOD, Cellular Senescence, Mice, Induced Pluripotent Stem Cells, Cellular Reprogramming
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