Suppression of p16 alleviates the senescence-associated secretory phenotype

Buj, Raquel; Leon, Kelly E.; Anguelov, Marlyn A; Aird, Katherine M.

doi:10.18632/aging.202640

Cited by 47 publications

(28 citation statements)

References 111 publications

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“…The importance of these and other SASP factors has been verified in multiple biological contexts. [56][57][58][59][60][61][62][63] Interestingly, the control of the SASP itself by RELA/p65, which we detected in two sequencing datasets of aging women, has recently been experimentally verified in U2OS osteosarcoma cells. 64 Transcriptome-wide state-of-the-art technologies such as scRNA-seq will help shape our understanding of not just aging, but also therapeutics that potentially target fundamental mechanisms of aging, such as senolytics.…”

Section: Discussionmentioning

confidence: 55%

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

Saul

Kosinsky

Atkinson

et al. 2021

Preprint

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Although cellular senescence is increasingly recognized as driving multiple age-related co-morbidities through the senescence-associated secretory phenotype (SASP), in vivo senescent cell identification, particularly in bulk or single cell RNA-sequencing (scRNA-seq) data remains challenging. Here, we generated a novel gene set (SenMayo) and first validated its enrichment in bone biopsies from two aged human cohorts. SenMayo also identified senescent cells in aged murine brain tissue, demonstrating applicability across tissues and species. For direct validation, we demonstrated significant reductions in SenMayo in bone following genetic clearance of senescent cells in mice, with similar findings in adipose tissue from humans in a pilot study of pharmacological senescent cell clearance. In direct comparisons, SenMayo outperformed all six existing senescence/SASP gene sets in identifying senescent cells across tissues and in demonstrating responses to senescent cell clearance. We next used SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from publicly available human and murine bone marrow/bone scRNA-seq data and identified monocytic and osteolineage cells, respectively, as showing the highest levels of senescence/SASP genes. Using pseudotime and cellular communication patterns, we found senescent hematopoietic and mesenchymal cells communicated with other cells through common pathways, including the Macrophage Migration Inhibitory Factor (MIF) pathway, which has been implicated not only in inflammation but also in immune evasion, an important property of senescent cells. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Moreover, using this senescence panel, we were able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways associated with these cells, which may be particularly useful for evolving efforts to map senescent cells (e.g., SenNet). In addition, SenMayo represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.

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Section: Discussionmentioning

confidence: 55%

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

Saul

Kosinsky

Atkinson

et al. 2021

Preprint

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“…Although we did observe an increase in IL6 , IL1B , and CXCL8 expression ( Fig. 1 K ), which are known to be transcriptionally regulated ( Aird et al, 2016 ; Buj et al, 2021 ; Capell et al, 2016 ; Orjalo et al, 2009 ), H3K79me3 occupancy was not enriched at these loci ( Fig. 1 L ).…”

Section: Resultsmentioning

confidence: 67%

DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

Leon

Buj

Lesko

et al. 2021

Journal of Cell Biology

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Oncogene-induced senescence (OIS) is a stable cell cycle arrest that occurs in normal cells upon oncogene activation. Cells undergoing OIS express a wide variety of secreted factors that affect the senescent microenvironment termed the senescence-associated secretory phenotype (SASP), which is beneficial or detrimental in a context-dependent manner. OIS cells are also characterized by marked epigenetic changes. We globally assessed histone modifications of OIS cells and discovered an increase in the active histone marks H3K79me2/3. The H3K79 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) was necessary and sufficient for increased H3K79me2/3 occupancy at the IL1A gene locus, but not other SASP genes, and was downstream of STING. Modulating DOT1L expression did not affect the cell cycle arrest. Together, our studies establish DOT1L as an epigenetic regulator of the SASP, whose expression is uncoupled from the senescence-associated cell cycle arrest, providing a potential strategy to inhibit the negative side effects of senescence while maintaining the beneficial inhibition of proliferation.

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“…p16 is a key mediator of cell senescence and was increased in skin during aging via oxidative stress and SASP [ 32 , 33 ]. Also, p16 controls stem cell (SC) self-renewal in several tissues, and its deregulation may lead to aging.…”

Section: Discussionmentioning

confidence: 99%

p16INK4a Plays Critical Role in Exacerbating Inflammaging in High Fat Diet Induced Skin

Liang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Long term high fat diets (HFD) promote skin aging pathogenesis, but detailed mechanisms remain unclear especially for inflammaging, which has recently emerged as a pathway correlating aging and age-related disease with inflammation. p16INK4a (hereafter termed p16) inhibits the cell cycle, with p16 deletion significantly inhibiting inflammaging. We observed that HFD-induced p16 overexpression in the skin. Therefore, we investigated if p16 exacerbated inflammaging in HFD-induced skin and also if p16 deletion exerted protective effects against this process. Methods. Eight-week-old double knockout (KO) ApoE-/-p16-/- mice and ApoE-/- littermates were fed HFD for 12 weeks and their skin phenotypes were analyzed. We measured skin fibrosis, senescence-associated secretory phenotype (SASP) levels, and integrin-inflammasome pathway activation using histopathological, RNA-sequencing (RNA-seq), bioinformatics analysis, and molecular techniques. Results. We found that HFD contributed to inflammaging in the skin by activating the NLRP3 inflammasome pathway, increasing inflammatory infiltration, and promoting apoptosis by balancing expression between proapoptotic and antiapoptotic molecules. p16 knockout, when compared with the ApoE-/- phenotype, inhibited skin fibrosis by ameliorating inflammatory infiltration and proinflammatory factor expression (Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)), and also alleviated inflammaging skin progress induced by HFD in the ApoE-/- mouse model. RNA-seq showed that p16 KO mice inhibited both integrin-inflammasome and NF-κB proinflammatory pathway activation. Conclusions. p16 deletion or p16 positive cell clearance could be a novel strategy preventing long term HFD-induced skin aging.

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Suppression of p16 alleviates the senescence-associated secretory phenotype

Cited by 47 publications

References 111 publications

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues

DOT1L modulates the senescence-associated secretory phenotype through epigenetic regulation of IL1A

p16INK4a Plays Critical Role in Exacerbating Inflammaging in High Fat Diet Induced Skin

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