Researchers Report Crocin I Delays Cellular Senescence In Vitro via SIRT1/PKM2 Pathway and Lactate Regulation

In vitro research demonstrates that saffron-derived Crocin I delays cellular senescence by modulating the SIRT1/PKM2 axis, highlighting metabolic and lactate homeostasis as promising targets for therapeutic rejuvenation.

A study published in Experimental and Therapeutic Medicine reported that Crocin I, an active compound in saffron, delays cellular senescence in WI-38 human embryonic lung diploid fibroblasts and HK-2 human renal proximal tubule epithelial cells in vitro.

The researchers established a replicative senescence model (passaged to over 55 population doublings) and premature senescence models induced by AAPH and hydrogen peroxide.

Crocin I treatment at concentrations between 10 and 40 µM reduced senescence-associated β-galactosidase positive staining, lowered intracellular reactive oxygen species (ROS), and downregulated the aging markers p53 and p21.

RNA sequencing and molecular docking identified Pyruvate Kinase M2 (PKM2) as a target of Crocin I, which acts by enhancing the expression of SIRT1, leading to decreased PKM2 expression, lower pyruvate kinase activity, and reduced cellular lactate accumulation.

Senescent cells typically exhibit metabolic reprogramming characterized by elevated glycolysis and excessive lactate accumulation.

This study clarifies a mechanism where SIRT1-mediated regulation of PKM2 directly counters these glycolytic shifts, demonstrating that restoring lactate homeostasis can delay cellular senescence.

By identifying the specific SIRT1/PKM2 pathway as the mediator of Crocin I's effects, the research provides a scientific foundation for designing synthetic small molecules targeting metabolic senescence checkpoints.

The discovery that cellular senescence can be modulated metabolically via the SIRT1/PKM2 axis could diversify target selection for companies in the senotherapeutic field.

While traditional senolytics aim for direct apoptotic clearance, metabolic reprogramming represents a non-lethal alternative strategy to manage or suppress senescent cell phenotypes.

This mechanism reinforces industry interest in SIRT1 activators and NAD+-related pathways, potentially affecting early-stage pipeline positioning for metabolic aging therapeutics.

Preclinical studies in mammalian aging models to verify if the metabolic and anti-senescence benefits of Crocin I translate in vivo.

Further characterization of the precise acetylation sites on PKM2 regulated by SIRT1 under Crocin I administration.