Research Article: MPK‐1/ERK is required for the full activity of resveratrol in extended lifespan and reproduction

Date Published: December 21, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Dong Suk Yoon, Dong Seok Cha, Yoorim Choi, Jin Woo Lee, Myon‐Hee Lee.


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.

Partial Text

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). In particular, caloric restriction mimetics, including resveratrol (RSV), rapamycin, and metformin, have been shown to exert beneficial effects on longevity and health (Lamming, Sabatini, & Baur, 2012). Rapamycin was the first chemical identified which extends lifespan in mammals through the inhibition of mammalian target of rapamycin (mTOR; Harrison et al., 2009). Metformin, which can extend the lifespan of C57BL6 mice and short‐lived tumorigenic mice (Anisimov et al., 2005; Martin‐Montalvo et al., 2013), exerts its effects through inhibition of the mTOR signaling pathway (Dowling, Zakikhani, Fantus, Pollak, & Sonenberg, 2007). However, the mechanisms of RSV remain controversial even though its positive effects on longevity have been reported over the past decade. RSV was first identified as an activator of sirtuin (mammalian SIRT1/nematode SIR‐2.1, a family of NAD+‐dependent deacetylases; Figure 1a, Model I) and has been found to extend the lifespan of various organisms by mimicking dietary restriction and to improve the health of mice on a high‐fat diet (Baur et al., 2006; Wood et al., 2004). In addition, Herranz et al. (2010) reported the anti‐aging features of Sirt1 by showing its suppressive effects on aging and metabolic disease using Sirt1 transgenic mice. Thus, sirtuin activation has been thought to comprise an important mechanism of RSV‐mediated longevity. However, recent studies have highlighted the SIR‐2.1‐independent effects of RSV‐mediated longevity (Figure 1a, Model II). For example, (a) caloric restriction extends the lifespan independently of sirtuin in worms (Lee et al., 2006); (b) RSV has multiple targets including STAT3, JNK, AMPK, and ERK (Pirola & Frojdo, 2008). Among these, AMPK (5′‐AMP‐activated protein kinase) has been relatively well‐established as a target of RSV (Dasgupta & Milbrandt, 2007). RSV activates AMPK as its central target and acts indirectly on SIRT1 (Um et al., 2010). Therefore, 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). However, a contradictory effect of SRT1720 on longevity has additionally been reported, as SRT1720 cannot extend the lifespan and does not mimic the effect of RSV on lifespan extension in worms (Zarse et al., 2010). Therefore, the effect of RSV on lifespan extension may not function entirely in a sirtuin‐dependent manner. Moreover, it is necessary to identify other pathways or factors that respond to RSV (Figure 1a, Model III).

Resveratrol was originally identified as an activator of sirtuin and its invertebrate homologs, and has been shown to extend lifespan in both invertebrates and vertebrates (Bhullar & Hubbard, 2015; Pallauf, Rimbach, Rupp, Chin, & Wolf, 2016). However, 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). Therefore, the effects of RSV on longevity seem to be controversial. In this study, we provide important new insights into the effects of RSV on longevity and GSC aging using C. elegans. Previous findings have shown that RSV can extend the lifespan of yeast, worms, and mice in a sirtuin‐dependent manner (Wood et al., 2004). This positive effect of RSV‐mediated sirtuin activation on lifespan extension has been explored in various research fields, such as stem cell aging, diabetes, and cancer (Buhrmann, Shayan, Popper, Goel, & Shakibaei, 2016; Cote et al., 2015; Liu et al., 2012). For these reasons, the effects of RSV‐mediated sirtuin activity cannot be overlooked, although some studies reported that the role of RSV as a sirtuin activator still remains controversial and other alternative pathways need to be found and characterized. Viswanathan et al. (2005) reported that the RSV effect on C. elegans longevity is completely dependent upon sir‐2.1, but independent of daf‐16. Nevertheless, they suggested that RSV inhibits SIR‐2.1 activity to prevent sir‐2.1‐mediated abu‐11 repression. Other studies have shown that SRT1720, a sirtuin‐specific activator, did not extend the lifespan of C. elegans (Zarse et al., 2010). In this study, we observed that RSV partially induced the lifespan extension of C. elegans by sir‐2.1(ok434) mutation. RSV has multiple putative targets, including STAT3, JNK, AMPK, and ERK, among others (Pirola & Frojdo, 2008). Of these, AMPK has been relatively well‐established as an RSV target (Dasgupta & Milbrandt, 2007). One study showed that RSV activates AMPK as its central target and acts indirectly on SIRT1. Additionally, RSV‐mediated AMPK activation is dependent on SIRT1 (Um et al., 2010). Furthermore, RSV cannot induce SIRT1 activation in the absence of AMPK. Hence, it is thought that AMPK is a mediator of RSV‐induced sirtuin activation. In contrast, Dasgupta and Milbrandt (2007) showed that neuronal activation of AMPK by RSV does not require the presence of SIRT1. Thus, it is controversial whether RSV‐mediated AMPK action is dependent upon the presence of SIRT1. In C. elegans, lifespan can be regulated by aak‐2, a gene encoding the AMPK protein (Apfeld, O’Connor, McDonagh, DiStefano, & Curtis, 2004). SIR‐2.1 extends the lifespan of C. elegans via both aak‐2‐dependent and aak‐2‐independent mechanisms (Curtis, O’Connor, & DiStefano, 2006). DAF‐16 is known to be a longevity factor in C. elegans (Lin, Hsin, Libina, & Kenyon, 2001). However, it was reported that RSV‐mediated lifespan extension was not dependent on DAF‐16 (Viswanathan et al., 2005). Thus, it is possible that RSV functions through an additional mechanism to extend the lifespan of C. elegans in a SIR‐2.1‐independent manner. Our results show that mpk‐1 is required for the RSV‐mediated lifespan extension in C. elegans. Knockdown of mpk‐1 in sir‐2.1(ok434) mutant worms completely abolished RSV‐mediated lifespan extension, indicating that MPK‐1 operates independently of SIR‐2.1 in RSV‐mediated lifespan extension. MPK‐1 was first identified as a longevity factor in C. elegans by Okuyama et al. (2010). They reported that active MPK‐1 phosphorylates key residues required for nuclear import of SKN‐1, which is required for normal lifespan (An & Blackwell, 2003). They additionally showed that MPK‐1 extended the lifespan of C. elegans independently of bar‐1 (β‐catenin human homolog), hsf‐1 (Heat shock protein human homolog), and sir‐2.1, which are known as regulators related to daf‐16‐dependent lifespan regulation (Essers et al., 2005; Hsu, Murphy, & Kenyon, 2003). Our lifespan results support this mechanism in that double mutation of sir‐2.1 and mpk‐1 completely abolished the RSV‐mediated lifespan extension, thereby indicating that mpk‐1 contributes to the RSV‐mediated lifespan extension independently of sir‐2.1. Our findings suggest that both sir‐2.1 and mpk‐1 are required for RSV‐mediated lifespan extension and that MPK‐1 is a longevity determinant which acts independently of SIR‐2.1 in C. elegans.

The authors declare that they have no conflict of interests.

DSY and M‐HL performed study conception and design. DSY, DSC, YC, JWL, and M‐HL carried out experiments. DSY, DSC, YC, JWL, and M‐HL conducted analysis and interpretation of data. DSY drafted the manuscript, and M‐HL reviewed the manuscript.




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