Diverse partial reprogramming strategies restore youthful gene expression and transiently suppress cell identity

Roux, Antoine E.; Zhang, Chunlian; Paw, Jonathan S.; Zavala-Solorio, José; Malahias, Evangelia; Vijay, Twaritha; Kolumam, Ganesh; Kenyon, Cynthia; Kimmel, Jacob C.

doi:10.1016/j.cels.2022.05.002

Cited by 44 publications

(30 citation statements)

References 84 publications

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“…7F-Esrrb, ( 11 )). This is consistent with results of ( 22 ) reporting that induction of only SK factors decreases aging score without loss of mesenchymal identity. Such results support the possibility of decoupling reprogramming-induced rejuvenation from the changes involved in the loss of somatic identity.…”

Section: Discussionsupporting

confidence: 93%

“…7F-Esrrb, (11)). This is consistent with results of (22) reporting that induction of only SK factors decreases aging score without loss of mesenchymal identity.…”

Section: Discussionsupporting

confidence: 92%

“…6C) demonstrate that reprogramming may act as a longevity intervention but not in all aspects. Of note, these results are generally consistent with those obtained from single-cell analysis (22). Namely, we observed that the reprogramming suppressed genes were associated with inflammatory response.…”

Section: Discussionsupporting

confidence: 90%

“…After obtaining NES scores for each cell line, we aggregated them using average and applied t-test to assess significance of the aggregated score. As a positive control, we performed a similar analysis in 2 models of overexpression of MYC , known to partially induce the pluripotency program in cells ( 9, 22 ). The latter treatment showed a significant upregulation of pluripotency genes (p-value < 8.94e-5), while it did not result in a significant reduction of cellular tAge.…”

Section: Resultsmentioning

confidence: 99%

“…Recent in vitro experiments ( 19, 20 ) show that the decrease in epigenetic age of reprogrammed cells measured by epigenetic aging clocks ( 21 ) occurs mostly prior to the stabilization phase when the pluripotent state is established. However, even a short-term use of OSKM factors has been shown to produce the detectable subpopulation of cells where late-stage pluripotent genes are expressed ( 22 ). Therefore, independent interventions that would support Reprogramming-Induced Rejuvenation (RIR) without inducing pluripotency may be of a high clinical value.…”

Section: Introductionmentioning

confidence: 99%

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Longevity and rejuvenation effects of cell reprogramming are decoupled from loss of somatic identity

Kriukov

Khrameeva

Dmitriev

et al. 2022

Preprint

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Partial somatic cell reprogramming has been touted as a promising rejuvenation strategy. However, its association with mechanisms of aging and longevity at the molecular level remains unclear. We identified a robust transcriptomic signature of reprogramming in mouse and human cells that revealed co-regulation of genes associated with reprogramming and response to lifespan-extending interventions, including those related to DNA repair and inflammation. We found that age-related gene expression changes were reversed during reprogramming, as confirmed by transcriptomic aging clocks. The longevity and rejuvenation effects induced by reprogramming in the transcriptome were mainly independent of pluripotency gain. Decoupling of these processes allowed predicting interventions mimicking reprogramming-induced rejuvenation (RIR) without affecting somatic cell identity, including an anti-inflammatory compound osthol, \emph{ATG5} overexpression, and \emph{C6ORF223} knockout. Overall, we revealed specific molecular mechanisms associated with RIR at the gene expression level and developed tools for discovering interventions that support the rejuvenation effect of reprogramming without posing the risk of neoplasia.

show abstract

Section: Discussionsupporting

confidence: 93%

“…7F-Esrrb, (11)). This is consistent with results of (22) reporting that induction of only SK factors decreases aging score without loss of mesenchymal identity.…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Longevity and rejuvenation effects of cell reprogramming are decoupled from loss of somatic identity

Kriukov

Khrameeva

Dmitriev

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan

Matteini,

Montserrat‐Vazquez,

Florian

2024

FEBS Letters

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Aging is associated with a global decline in stem cell function. To date, several strategies have been proposed to rejuvenate aged stem cells: most of these result in functional improvement of the tissue where the stem cells reside, but the impact on the lifespan of the whole organism has been less clearly established. Here, we review some of the most recent work dealing with interventions that improve the regenerative capacity of aged somatic stem cells in mammals and that might have important translational possibilities. Overall, we underscore that somatic stem cell rejuvenation represents a strategy to improve tissue homeostasis upon aging and present some recent approaches with the potential to affect health span and lifespan of the whole organism.

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Transcriptomic reprogramming for neuronal age reversal

et al. 2023

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Aging is a progressive multifaceted functional decline of a biological system. Chronic age-related conditions such as neurodegenerative diseases are leading causes of death worldwide, and they are becoming a pressing problem for our society. To address this global challenge, there is a need for novel, safe, and effective rejuvenation therapies aimed at reversing age-related phenotypes and improving human health. With gene expression being a key determinant of cell identity and function, and in light of recent studies reporting rejuvenation effects through genetic perturbations, we propose an age reversal strategy focused on reprogramming the cell transcriptome to a youthful state. To this end, we suggest using transcriptomic data from primary human cells to predict rejuvenation targets and develop high-throughput aging assays, which can be used in large perturbation screens. We propose neural cells as particularly relevant targets for rejuvenation due to substantial impact of neurodegeneration on human frailty. Of all cell types in the brain, we argue that glutamatergic neurons, neuronal stem cells, and oligodendrocytes represent the most impactful and tractable targets. Lastly, we provide experimental designs for anti-aging reprogramming screens that will likely enable the development of neuronal age reversal therapies, which hold promise for dramatically improving human health.

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Diverse partial reprogramming strategies restore youthful gene expression and transiently suppress cell identity

Cited by 44 publications

References 84 publications

Longevity and rejuvenation effects of cell reprogramming are decoupled from loss of somatic identity

Longevity and rejuvenation effects of cell reprogramming are decoupled from loss of somatic identity

Rejuvenating aged stem cells: therapeutic strategies to extend health and lifespan

Transcriptomic reprogramming for neuronal age reversal

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