p21 as a molecular driver of fasting
Metabolic Syndrome Group
The exact molecular mechanisms driving the fasting-mediated protection from chemotherapy toxicity and fasting-mediated enhanced and anti-tumor immune response have not yet been described. Recently, our laboratory has participated in a project uncovering a possible mechanism for this protection: we described a strongly increased transcription of the cell cycle inhibitor p21 (also known as Cip1 or CDKN1a) upon short-term fasting in different mouse tissues 1.
Importantly, we have later verified that this mechanism is conserved in humans: our laboratory has carried out a clinical trial at IMDEA Food subjecting 20 healthy human volunteers to 36 hours of fasting, and obtaining blood samples to measure p21 mRNA levels in peripheral blood mononuclear cells (PBMCs) before and after fasting, and 24 hours after refeeding. As shown, we could observe a significant increase in p21 mRNA levels after the fasting period, that were recovered back to normal after 24 hours of refeeding.
Importantly, this behavior was parallel to several target genes of the fasting-responsive nuclear receptor PPARa (PDK4 and CPT1a) 2 , indicating that p21 is also a fasting-regulated gene in humans.
1. Lopez-Guadamillas, E., Fernandez-Marcos, P. J., Pantoja, C., Muñoz-Martin, M., Martínez, D., Gómez-López, G., Campos-Olivas, R., Valverde, A. M. & Serrano, M. p21Cip1 plays a critical role in the physiological adaptation to fasting through activation of PPARα. Sci. Rep. 6, 34542 (2016).
2. Bouwens, M., Afman, L. A. & Müller, M. Fasting induces changes in peripheral blood mononuclear cell gene expression profiles related to increases in fatty acid beta-oxidation: functional role of peroxisome proliferator activated receptor alpha in human peripheral blood mononuclear cells. Am. J. Clin. Nutr. 86, 1515–23 (2007).