The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration

Senescence is a form of cell cycle arrest induced by stress such as DNA damage and oncogenes. However, while arrested, senescent cells secrete a variety of proteins collectively known as the senescence-associated secretory phenotype (SASP), which can reinforce the arrest and induce senescence in a paracrine manner. However, the SASP has also been shown to favor embryonic development, wound healing, and even tumor growth, suggesting more complex physiological roles than currently understood. Here we uncover timely new functions of the SASP in promoting a proregenerative response through the induction of cell plasticity and stemness. We show that primary mouse keratinocytes transiently exposed to the SASP exhibit increased expression of stem cell markers and regenerative capacity in vivo. However, prolonged exposure to the SASP causes a subsequent cell-intrinsic senescence arrest to counter the continued regenerative stimuli. Finally, by inducing senescence in single cells in vivo in the liver, we demonstrate that this activates tissue-specific expression of stem cell markers. Together, this work uncovers a primary and beneficial role for the SASP in promoting cell plasticity and tissue regeneration and introduces the concept that transient therapeutic delivery of senescent cells could be harnessed to drive tissue regeneration

Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium

Paracrine cellular senescence exacerbates biliary injury and impairs regeneration

Senescence has been suggested as causing biliary cholangiopathies but how this is regulated is unclear. Here, the authors generate a mouse model of biliary senescence by deleting Mdm2 in bile ducts and show that inhibiting TGFβ limits senescence-dependent aggravation of cholangiopathies

Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8 + T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing

Induction and transmission of oncogene-induced senescence

Senescence is a cellular stress response triggered by diverse stressors, including oncogene activation, where it serves as a bona-fide tumour suppressor mechanism. Senescence can be transmitted to neighbouring cells, known as paracrine secondary senescence. Secondary senescence was initially described as a paracrine mechanism, but recent evidence suggests a more complex scenario involving juxtacrine communication between cells. In addition, single-cell studies described differences between primary and secondary senescent end-points, which have thus far not been considered functionally distinct. Here we discuss emerging concepts in senescence transmission and heterogeneity in primary and secondary senescence on a cellular and organ level

Senescence and aging – causes, consequences, and therapeutic avenues

Aging is the major risk factor for cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. Although we are far from understanding the biological basis of aging, research suggests that targeting the aging process itself could ameliorate many age-related pathologies. Senescence is a cellular response characterized by a stable growth arrest and other phenotypic alterations that include a proinflammatory secretome. Senescence plays roles in normal development, maintains tissue homeostasis, and limits tumor progression. However, senescence has also been implicated as a major cause of age-related disease. In this regard, recent experimental evidence has shown that the genetic or pharmacological ablation of senescent cells extends life span and improves health span. Here, we review the cellular and molecular links between cellular senescence and aging and discuss the novel therapeutic avenues that this connection opens

Exercise and bone health across the lifespan

With ageing, bone tissue undergoes significant compositional, architectural and metabolic alterations potentially leading to osteoporosis. Osteoporosis is the most prevalent bone disorder, which is characterised by progressive bone weakening and an increased risk of fragility fractures. Although this metabolic disease is conventionally associated with ageing and menopause, the predisposing factors are thought to be established during childhood and adolescence. In light of this, exercise interventions implemented during maturation are likely to be highly beneficial as part of a long-term strategy to maximise peak bone mass and hence delay the onset of age- or menopause-related osteoporosis. This notion is supported by data on exercise interventions implemented during childhood and adolescence, which confirmed that weight-bearing activity, particularly if undertaken during peripubertal development, is capable of generating a significant osteogenic response leading to bone anabolism. Recent work on human ageing and epigenetics suggests that undertaking exercise after the fourth decade of life is still important, given the anti-ageing effect and health benefits provided, potentially occurring via a delay in telomere shortening and modification of DNA methylation patterns associated with ageing. Exercise is among the primary modifiable factors capable of influencing bone health by preserving bone mass and strength, preventing the death of bone cells and anti-ageing action provided

Investigating senescence in cellular plasticity and tissue regeneration

Cellular senescence has mainly been associated with tumor suppression and aging, mediated through cell intrinsic cell-cycle inhibition and arrest. However, through secretion of specific proteins, termed the senescence-associated secretory phenotype (SASP), senescent cells can have paradoxical effects, promoting proliferation, invasion or paracrine senescence in neighbouring cells. Additionally, emerging studies showed that cellular senescence is also implicated in complex biological processes such as embryonic development, tissue repair and wound healing. Unexpectedly, we found that primary mouse keratinocytes undergoing oncogene-induced senescence exhibit an increase in stem cell gene expression. Interestingly, this signature can also be induced in normal cells upon transient exposure to the SASP. However, prolonged exposure to the SASP leads to paracrine senescence in vitro as a possible mechanism to counteract the aberrant regenerative stimulation. Together this work suggests that the SASP is a regenerative mechanism that instructs stemness and plasticity, but if left unperturbed can have detrimental effects seen during aging and tumor formation.La senescencia celular ha sido generalmente asociada a la supresión de tumores y al envejecimiento mediante mecanismos intrínsecos de inhibición del ciclo celular y arresto proliferativo. Sin embargo, mediante la secreción de proteínas específicas llamadas SASP, las células senescentes pueden tener efectos paradójicos, promoviendo la proliferación, la invasión o la senescencia en células circundantes de forma paracrina. Además, estudios recientes han demostrado que la senescencia celular está implicada también en otros procesos biológicos como el desarrollo embrionario, la reparación de tejidos y la cicatrización de heridas. Inesperadamente, encontramos que los queratinocitos primarios de ratón a los que se les induce senescencia mediante sobreexpresión de un oncogén, experimentan un incremento en la expresión de genes de células madre. Cabe notar que esta signatura también aparece en células normales expuestas al SASP. No obstante, una exposición prolongada al SASP in vitro induce senescencia de forma paracrina posiblemente como mecanismo para contrarrestar el exceso de estimulación regenerativa. En conjunto este trabajo sugiere que el SASP es un mecanismo regenerativo que induce propiedades de células madre y plasticidad, pero si persiste puede tener efectos perjudiciales promoviendo el envejecimiento y la formación de tumores

Investigating senescence in cellular plasticity and tissue regeneration

Cellular senescence has mainly been associated with tumor suppression and aging, mediated through cell intrinsic cell-cycle inhibition and arrest. However, through secretion of specific proteins, termed the senescence-associated secretory phenotype (SASP), senescent cells can have paradoxical effects, promoting proliferation, invasion or paracrine senescence in neighbouring cells. Additionally, emerging studies showed that cellular senescence is also implicated in complex biological processes such as embryonic development, tissue repair and wound healing. Unexpectedly, we found that primary mouse keratinocytes undergoing oncogene-induced senescence exhibit an increase in stem cell gene expression. Interestingly, this signature can also be induced in normal cells upon transient exposure to the SASP. However, prolonged exposure to the SASP leads to paracrine senescence in vitro as a possible mechanism to counteract the aberrant regenerative stimulation. Together this work suggests that the SASP is a regenerative mechanism that instructs stemness and plasticity, but if left unperturbed can have detrimental effects seen during aging and tumor formation.La senescencia celular ha sido generalmente asociada a la supresión de tumores y al envejecimiento mediante mecanismos intrínsecos de inhibición del ciclo celular y arresto proliferativo. Sin embargo, mediante la secreción de proteínas específicas llamadas SASP, las células senescentes pueden tener efectos paradójicos, promoviendo la proliferación, la invasión o la senescencia en células circundantes de forma paracrina. Además, estudios recientes han demostrado que la senescencia celular está implicada también en otros procesos biológicos como el desarrollo embrionario, la reparación de tejidos y la cicatrización de heridas. Inesperadamente, encontramos que los queratinocitos primarios de ratón a los que se les induce senescencia mediante sobreexpresión de un oncogén, experimentan un incremento en la expresión de genes de células madre. Cabe notar que esta signatura también aparece en células normales expuestas al SASP. No obstante, una exposición prolongada al SASP in vitro induce senescencia de forma paracrina posiblemente como mecanismo para contrarrestar el exceso de estimulación regenerativa. En conjunto este trabajo sugiere que el SASP es un mecanismo regenerativo que induce propiedades de células madre y plasticidad, pero si persiste puede tener efectos perjudiciales promoviendo el envejecimiento y la formación de tumores