Extension of Lifespan in C. elegans by Naphthoquinones That Act through Stress Hormesis Mechanisms

Abstract

Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap‘n’collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway.

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

“…The screen resulted in several hits, and one naphthoquinone from the genus Plumbago (plumbagin) was demonstrated to induce a 15-fold increase in Nrf-2 transcriptional activity and exhibited neuroprotective activity in a mouse model of stroke (Son et al, 2010). Analogs of plumbagin were synthesized and screened and several demonstrated exhibited neuroprotective activity Son et al, 2013) and extended lifespan in C. elegans by a hormetic mechanism (Hunt et al, 2011). This provides a proof-of-principle example for the approach of developing phytochemical "toxins" as potential therapeutic agents.…”

Hormesis: why it is important to biogerontologists

“…Numerous toxic agents as well as ionizing radiation can induce hormetic dose responses, many of which can result in beneficial effects at low doses. While the therapeutic applications of such exposures are most likely quite limited due to other undesirable properties of these agents, it suggests the possibility of finding non-toxic agents that could activate the key pathways of these hormetic agents, in effect, mimicking their effects, thus the concept of hormetic mimetics (Hunt et al 2011;Mattson and Cheng 2006;Sonneborn 2010).…”

Effects of caloric restriction on oxidative stress parameters

“…Possible explanations are alteration of the insulin-like growth factor 1 (IGF-1) signaling (Bluher et al 2003;Ristow and Schmeisser 2011), sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) (Colman et al 2009), activation of the NF-E2-related factor 2/Kelchlike ECH-associated protein 1 (Nrf2/Keap1) (Birringer 2011), or inhibition of stress-induced apoptotic cell death (Cohen et al 2004). The effect of CR on oxidative stress (OS) parameters in organism and hormesis might have a role in anti-aging mechanism of CR (Hunt et al 2011).…”

“…These effects were observed in humans as well (Calabrese et al 2007;Gems and Partridge 2008;Colman et al 2009;Marques et al 2009). CR, irradiation, cold, heat, hyperbaric oxygen and chemicals such as paraquat or juglone have been proved as hormetic stressors (Marques et al 2009;Hunt et al 2011).…”