Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan

Grosse, Laurent; Wagner, Nicole; Emelyanov, Alexander; Molina, Clement; Lacas‐Gervais, Sandra; Wagner, Kay-Dietrich; Bulavin, Dmitry V.

doi:10.1016/j.cmet.2020.05.002

Cited by 240 publications

(195 citation statements)

References 44 publications

Supporting

Mentioning

175

Contrasting

Unclassified

Order By: Relevance

“…A follow-up study then confirmed a significant reduction of spontaneous tumour formation after selective removal of senescent cells [46]. Paradoxically, a very recent report has demonstrated a slow process of senescence accumulation during a lifespan of p16-knock in mice whose p16high hepatic senescence cells appear to have important structural and functional roles [47]. Removal of liver cells with p16high led to liver and perivascular fibrosis, impairing the health of the animals.…”

Section: Paracrine Transmission Of Senescencementioning

confidence: 83%

Induction and transmission of oncogene-induced senescence

Rattanavirotkul

Kirschner

Chandra

2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

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.

show abstract

Section: Paracrine Transmission Of Senescencementioning

confidence: 83%

Induction and transmission of oncogene-induced senescence

Rattanavirotkul

Kirschner

Chandra

2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

show abstract

“…Aging and senescence are associated with decreased fatty acid oxidation resulting in increased hepatic fat accumulation (9). While p16 expression is a widely used marker of senescence, recent evidence suggests that a senescence-associated increase in liver p16 expression may not be related to its expression in hepatocytes (37,38). It is also possible that increased p16 may impact these metabolic pathways prior to the onset of outright senescence in a chronic setting.…”

Section: Discussionmentioning

confidence: 99%

CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway

Deleye

Cotte

Hannou

et al. 2020

Journal of Biological Chemistry

View full text Add to dashboard Cite

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

show abstract

“…On the other hand, senescent cells play pivotal roles in homeostatic maintenance, developmental process, and tissue repair [25][26][27] . Indeed, Grosse et al recently reported that elimination of Ink4a-high senescent cells resulted in liver and perivascular tissue fibrosis 56 . Therefore, there is still controversy over safety of senolytic drugs that kill senescent cells.…”

Section: Discussionmentioning

confidence: 99%

Senescent cell death as an aging resistance mechanism in naked mole-rat

Kawamura

Oka

Takamori

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractNaked mole-rats (NMRs) are the longest-lived rodents, showing minimal aging phenotypes. An unsolved paradox is that NMRs exhibit low intracellular anti-oxidant defence despite minimal aging. Here, we explained a link between these “contradicting” features by a phenomenon termed “senescent cell death (SCD)”—Senescence induced cell death in NMR cells due to their inherent vulnerability to reactive oxygen species and unique metabolic system. In NMR skin, we observed few senescent cells during aging or after ultraviolet irradiation, suggesting suppression of senescent cell accumulation in NMR tissue. We discovered that senescent NMR-fibroblasts induce SCD through retinoblastoma protein activation accompanied by autophagy dysregulation, increased oxidative damage and accelerated H2O2-releasing metabolic pathways. During senescence, NMR cells showed resistance to metabolic remodelling unlike mice. Our findings provide mechanistic insights into how extraordinary aging resistance is accomplished in NMR. This will contribute to the development of senolytic drugs to regulate age-related diseases.

show abstract

Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan

Cited by 240 publications

References 44 publications

Induction and transmission of oncogene-induced senescence

Induction and transmission of oncogene-induced senescence

CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway

Senescent cell death as an aging resistance mechanism in naked mole-rat

Contact Info

Product

Resources

About