To describe the effects of medically supervised prolonged water-only fasting on circulating markers of cellular senescence.

Aging is driven by programs of cellular senescence. Fasting has moderated markers cellular senescence in preclinical studies.  Thus, we hypothesize fasting may exert beneficial effects on components of senescence associated secretory phenotype (SASP), an indirect measure of senescence.

The FAST-SASP was a single arm pilot study enrolling human subjects electively undergoing a medically supervised prolonged water-only fast for up to 40 days at a residential health center. Whole blood samples were assessed for SASP analytes via immunoassay using existing methods, Myriad RBM™. Primary analysis was median change in SASP components across time points; baseline, end of fast (EOF), and end of refeeding (EOR) with nonparametric methods. Fasting protocol feasibility and adverse event reporting were safety endpoints. The protocol was approved by the local investigational review board.

Complete samples were available for 20 subjects. Mean age was 62 years, mean fast duration was 14 days, mean refeeding was 6 days. Tumor Necrosis Factor Receptors Type 1 (TNFR1) & 2 (TNFR2) increased across study endpoints (baseline v EOF v EOR) 1.38 x10³pg/ml v 1.49 x10³pg/ml v 1.97 x10³pg/ml (p <0.0001) and 2.03x10³pg/ml v 2.5 x10³pg/ml v 2.9 x10³pg/ml (p<0.0001). Urokinase plasminogen activator receptor (uPAR) increased from baseline to EOR, 13.9 x10²pg/ml v 18.1 x10²pg/ml (p<0.0001). Interleukin-8 (IL-8) was elevated with fasting, 4.4pg/ml v 7.4pg/ml (p=0.0015). Osteoprotegerin (OPG) was increased from baseline to EOR, 948pg/ml v 1253 pg/ml (p=0.0002).

Prolonged fasting and refeeding upregulated senescent associated proteins TNFR 1&2, uPAR, IL-8, and OPG. We speculate that prolonged fasting may provoke an inflammatory state necessary for apoptotic clearance or autophagy of senescent cells and holds potential as a clinical therapeutic for aging. These preliminary findings require confirmation and further exploration in larger mechanistic studies.