Curcumin and butyrate induce fibroblast senescence without the emergence of fibrosis biomarkers

Background: Small molecules have emerged as valuable tools to modulate cellular homeostasis and the changes associated with aging. In particular, the phytochemical curcumin elicits cytoprotective effects that promote human health and longevity. The short-chain fatty acid butyrate provides anti-fibrotic activities, but can also induce cellular senescence. Rationale: The impact of curcumin and butyrate on living cells are not fully understood. To obtain this information, our work focuses on fibroblasts. We selected fibroblasts as cellular model, because they (i) are present in different tissues and organs, (ii) contribute essential functions that derail during organismal aging, and (iii) are prime targets for therapeutic interventions that ameliorate aging-related pathologies. Methods and results: A panel of quantitative assessments determines how curcumin and its nanoformulation (nano-curcumin), either alone or in combination with butyrate, modulate fibroblast physiology. Several experimental approaches and biomarkers demonstrate that curcumin (i) diminishes fibroblast viability, and (ii) promotes cellular senescence in a concentration-dependent fashion. Specifically, curcumin and nano-curcumin increase the activity of senescence-associated β-galactosidase and reduce the abundance of lamin B. When combined with butyrate, both curcumin and nano-curcumin enhance cell death and senescence. Free curcumin decreases the levels of Nrf2, a transcription factor that is upregulated upon oxidative stress. Neither curcumin nor nano-curcumin changes the abundance of the transcription factor NFκB, which is critical for inflammatory responses. Free curcumin, butyrate and nano-curcumin/butyrate combinations significantly diminish the abundance of the lysine deacetylase SIRT1, which is a key regulator of cellular senescence. Notably, none of the compounds or their combinations elevates biomarkers of fibrosis. Conclusions: This study defines the cellular and molecular changes produced in fibroblasts by curcumin, nano-curcumin, alone or together with butyrate. Collectively, our results set the stage to explore curcumin/butyrate-based treatments to control the cellular activities that are contributed by fibroblasts.