Citrinin delays muscle aging and extends lifespan in C. elegans and prevents senescence in C2C12 through SKN-1/Nrf2 activation.

Abstract

Sarcopenia, a condition characterized by the loss of muscle mass and function with aging, is linked to various health issues including diabetes and increased risk of falls and fractures. Currently, there is no FDA-approved treatment exists for sarcopenia. Citrinin, a natural compound present in daily dietary sources such as grains, has not been well characterized for its biological effects on muscle aging. Here, we found that citrinin exhibits beneficial effects in delaying muscle aging in both Caenorhabditis elegans (C. elegans) and mouse muscle cells (C2C12). Citrinin attenuated the decline of muscle activities in aged C. elegans, including pharyngeal pumping, body bending, maximum velocity, and locomotor abilities. It also prevented myosin protein loss in C. elegans muscle cells. Citrinin activated SKN-1 (the C. elegans ortholog of mammalian Nrf2), which mediated the prevention of myosin protein loss and the decline in muscle activities. Additionally, citrinin extended the median lifespan of C. elegans via SKN-1. Furthermore, we found that IRE-1 mediated the effects of citrinin on SKN-1 activation and that citrinin delayed aging through the IRE-1/SKN-1 pathway. However, citrinin prevented muscle aging in a UPR^ER (unfolded protein response of the endoplasmic reticulum) independent manner. In addition, in C2C12 cells, citrinin reduced the number of β-galactosidase-positive stained cells, prevented nuclear expansion, and decreased p21 expression under etoposide-induced senescence conditions, while also activating Nrf2. These findings suggest that citrinin is a potential candidate compound for preventing muscle aging by inducing well-conserved stress response mechanisms from C. elegans to humans. Thus, we propose that citrinin may have positive effects on promoting healthy aging in humans.