MPK-1/ERK is required for the full activity of resveratrol in extended lifespan and reproduction.

Dong Suk Yoon,Yoorim Choi,Jin Woo Lee,Dong Seok Cha,Myon‐Hee Lee

doi:10.1111/acel.12867

Abstract

Resveratrol (RSV) extends the lifespan of various organisms through activation of sirtuin. However, whether RSV‐mediated longevity is entirely dependent upon sirtuin is still controversial. Thus, understanding additional mechanisms concerning the genetic requirements for the biological activity of RSV needs to be clarified to utilize the beneficial effects of RSV. In this study using Caenorhabditis elegans as a model system, we found that MPK‐1 (an ERK homolog) signaling is necessarily required for RSV‐mediated longevity of sir‐2.1/sirtuin mutants as well as for wild‐type worms. We demonstrated that MPK‐1 contributes to RSV‐mediated longevity through nuclear accumulation of SKN‐1 in a SIR‐2.1/DAF‐16 pathway‐independent manner. The positive effect of RSV in regulating lifespan was completely abolished by RNA interference against mpk‐1 in the sir‐2.1 and daf‐16 mutants, strongly indicating that the MPK‐1/SKN‐1 pathway is involved in RSV‐mediated longevity, independently of SIR‐2.1/DAF‐16. We additionally found that RSV protected worms from oxidative stress via MPK‐1. In addition to organismal aging, RSV prevented the age‐associated loss of mitotic germ cells, brood size, and reproductive span through MPK‐1 in C. elegans germline. Therefore, our findings not only provide new mechanistic insight into the controversial effects of RSV on organismal longevity, but additionally have important implications in utilizing RSV to improve the outcome of aging‐related diseases.

Highlights

Increasing evidence has shown that small molecules can affect the lifespan positively or negatively in a variety of organisms, including humans (Hubbard & Sinclair, 2014; Kennedy & Lamming, 2016)
To investigate whether MPK‐1 is involved in RSV‐mediated longevity, we examined the lifespan of WT worms in the absence or presence of RSV
Subsequent studies have suggested that RSV‐mediated longevity may be independent of sirtuin and may not stimulate sirtuin activity to promote longevity (Hu, Liu, Wang, & Liu, 2011)

Summary

| INTRODUCTION

Increasing evidence has shown that small molecules can affect the lifespan positively or negatively in a variety of organisms, including humans (Hubbard & Sinclair, 2014; Kennedy & Lamming, 2016). Sirtuin‐independent/indirect pathways or other RSV targets might be involved in RSV‐mediated longevity (Viswanathan, Kim, Berdichevsky, & Guarente, 2005); (c) SRT1720, known as a specific sirtuin activator which can ameliorate type 2 diabetes and metabolic diseases, can extend the lifespan and improve the health of mice (Mitchell et al, 2014). It was reported that mitogen‐activated protein kinase‐1 (MPK‐1, known as human ERK homolog) extended the lifespan of Caenorhabditis elegans through SKN‐1 (the mammalian nuclear factor erythroid‐ related factor; Okuyama et al, 2010). It has not yet been determined whether the RSV‐mediated lifespan extension in C. elegans can be regulated through MPK‐1 activity. We found that RSV‐mediated MPK‐1 activation increased reproductive span as well as delayed germline aging by maintaining mitotic germ cells

| RESULTS

| DISCUSSION

| EXPERIMENTAL PROCEDURES