The Fountain of Youth by Targeting Senescent Cells?

Keizer, Peter L.J. de

doi:10.1016/j.molmed.2016.11.006

Cited by 111 publications

(112 citation statements)

References 95 publications

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“…In skeletal muscle stem cells, termed “satellite cells”, FOXO3 enhances stem cell self-renewal via the activation of Notch signaling, maintaining an available pool of satellite cells that have divided but retain their undifferentiated state 38 . In fact, FOXO proteins play a dual role, and in situations of cellular damage, they can induce cell cycle arrest and senescence while independently repressing stemness signaling 54 . Yet, in humans, despite consistent associations between FOXO3 genetic variants and exceptional longevity 40– 46 , a possible link between FOXO3 and healthy aging remains unclear.…”

Section: Foxo3 and The Genetics Of Longevitymentioning

confidence: 99%

Recent advances in understanding the role of FOXO3

et al. 2018

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The forkhead box O3 (FOXO3, or FKHRL1) protein is a member of the FOXO subclass of transcription factors. FOXO proteins were originally identified as regulators of insulin-related genes; however, they are now established regulators of genes involved in vital biological processes, including substrate metabolism, protein turnover, cell survival, and cell death. FOXO3 is one of the rare genes that have been consistently linked to longevity in in vivo models. This review provides an update of the most recent research pertaining to the role of FOXO3 in (i) the regulation of protein turnover in skeletal muscle, the largest protein pool of the body, and (ii) the genetic basis of longevity. Finally, it examines (iii) the role of microRNAs in the regulation of FOXO3 and its impact on the regulation of the cell cycle.

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Section: Foxo3 and The Genetics Of Longevitymentioning

confidence: 99%

Recent advances in understanding the role of FOXO3

et al. 2018

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“…The ability of SASP-associated pro-inflammatory cytokines to regulate stemness and nuclear reprogramming raises the notion that a SASP-impaired local environment could interfere with tissue rejuvenation by imposing the so-called “stem-lock” state (de Keizer, 2017). Chronic inflammatory conditions via exposure to IL-1, which normally functions as a key “emergency” signal and a master regulator of SASP by inducing downstream effectors such as IL-6, has been shown to impair tissue homeostasis and to induce an aged appearance of the hematopoietic system by restricting stem cell differentiation (Pietras et al, 2016).…”

Section: Aging and Cancer: Two Sides Of Reparative Cellular Reprogrammentioning

confidence: 99%

“…Activation of adult stem/progenitor cells and proliferation of remaining differentiated cells are well-established mechanisms for the replacement of lost cells following injury. A physiological version of OSKM-induced reprogramming might operate as an evolutionary conserved, bona fide epigenetic strategy to provide self-repair and resistance to damage and disease (Cooke et al, 2014; Jessen et al, 2015; de Keizer, 2017). …”

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confidence: 99%

Senescence-Inflammatory Regulation of Reparative Cellular Reprogramming in Aging and Cancer

Menendez

Alarcón

2017

Front. Cell Dev. Biol.

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The inability of adult tissues to transitorily generate cells with functional stem cell-like properties is a major obstacle to tissue self-repair. Nuclear reprogramming-like phenomena that induce a transient acquisition of epigenetic plasticity and phenotype malleability may constitute a reparative route through which human tissues respond to injury, stress, and disease. However, tissue rejuvenation should involve not only the transient epigenetic reprogramming of differentiated cells, but also the committed re-acquisition of the original or alternative committed cell fate. Chronic or unrestrained epigenetic plasticity would drive aging phenotypes by impairing the repair or the replacement of damaged cells; such uncontrolled phenomena of in vivo reprogramming might also generate cancer-like cellular states. We herein propose that the ability of senescence-associated inflammatory signaling to regulate in vivo reprogramming cycles of tissue repair outlines a threshold model of aging and cancer. The degree of senescence/inflammation-associated deviation from the homeostatic state may delineate a type of thresholding algorithm distinguishing beneficial from deleterious effects of in vivo reprogramming. First, transient activation of NF-κB-related innate immunity and senescence-associated inflammatory components (e.g., IL-6) might facilitate reparative cellular reprogramming in response to acute inflammatory events. Second, para-inflammation switches might promote long-lasting but reversible refractoriness to reparative cellular reprogramming. Third, chronic senescence-associated inflammatory signaling might lock cells in highly plastic epigenetic states disabled for reparative differentiation. The consideration of a cellular reprogramming-centered view of epigenetic plasticity as a fundamental element of a tissue's capacity to undergo successful repair, aging degeneration or malignant transformation should provide challenging stochastic insights into the current deterministic genetic paradigm for most chronic diseases, thereby increasing the spectrum of therapeutic approaches for physiological aging and cancer.

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“…This is in part because for long the underlying causes of organismal aging were simply too elusive to comprehend, let alone modify. The chronic build-up of DNA damage has now evidently been established as a major cause for aging, but to counteract the genomic damage that has occurred over a lifetime is an entirely different challenge altogether [2]. One approach to overcome this issue, is to eliminate those cells that are too damaged to faithfully perform their duty and to replace them by fresh and healthy counterparts.…”

Section: Maintenance and Repair Of An Aging Life Cyclementioning

confidence: 99%

“…Comparable to formation of rust on old equipment, like a bicycle (Figure 1), they accumulate during aging and especially at sites of pathology. They develop a chronic secretory profile that is thought to impair tissue renewal and contribute to disease development, for instance by keeping neighboring cells "locked" in a permanent state of stemness [2]. Senescence can be beneficial in a transient setting, but the genetic removal of senescent cells over a prolonged period of time was found to be safe and to potently extended health-and lifespan of naturally aging mice [3].…”

Section: Maintenance and Repair Of An Aging Life Cyclementioning

confidence: 99%

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The Fountain of Youth by Targeting Senescent Cells?

Cited by 111 publications

References 95 publications

Recent advances in understanding the role of FOXO3

Recent advances in understanding the role of FOXO3

Senescence-Inflammatory Regulation of Reparative Cellular Reprogramming in Aging and Cancer

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