Abalone peptide increases stress resilience and cost‐free longevity via SKN‐1‐governed transcriptional metabolic reprogramming in C. elegans

Abstract

A major goal of healthy aging is to prevent declining resilience and increasing frailty, which are associated with many chronic diseases and deterioration of stress response. Here, we propose a loss‐or‐gain survival model, represented by the ratio of cumulative stress span to life span, to quantify stress resilience at organismal level. As a proof of concept, this is demonstrated by reduced survival resilience in Caenorhabditis elegans exposed to exogenous oxidative stress induced by paraquat or with endogenous proteotoxic stress caused by polyglutamine or amyloid‐β aggregation. Based on this, we reveal that a hidden peptide (“cryptide”)—AbaPep#07 (SETYELRK)—derived from abalone hemocyanin not only enhances survival resilience against paraquat‐induced oxidative stress but also rescues proteotoxicity‐mediated behavioral deficits in C. elegans, indicating its capacity against stress and neurodegeneration. Interestingly, AbaPep#07 is also found to increase cost‐free longevity and age‐related physical fitness in nematodes. We then demonstrate that AbaPep#07 can promote nuclear localization of SKN‐1/Nrf, but not DAF‐16/FOXO, transcription factor. In contrast to its effects in wild‐type nematodes, AbaPep#07 cannot increase oxidative stress survival and physical motility in loss‐of‐function skn‐1 mutant, suggesting an SKN‐1/Nrf‐dependent fashion of these effects. Further investigation reveals that AbaPep#07 can induce transcriptional activation of immune defense, lipid metabolism, and metabolic detoxification pathways, including many SKN‐1/Nrf target genes. Together, our findings demonstrate that AbaPep#07 is able to boost stress resilience and reduce behavioral frailty via SKN‐1/Nrf‐governed transcriptional reprogramming, and provide an insight into the health‐promoting potential of antioxidant cryptides as geroprotectors in aging and associated conditions.

In silico and in vivo discovery of antioxidant sea cucumber peptides with antineurodegenerative properties

“…As previously, we used paraquat, a potent ROS generator, at a high dose (50 mM) to cause a lethal oxidative stress for rapid survival assay and at a low dose (2 mM) to generate a mild, nonlethal oxidative stress for ROS determination. 10,13 As shown in Fig. 3C, the survival rate of the wild-type nematodes pretreated with the UF<3K peptides was considerably increased when exposed to 50 mM paraquat as compared to the control nematodes exposed to paraquat alone, particularly for the 2.0 and 4.0 mg mL −1 peptide treat-…”

“…Since behavioral dysfunction is a major symptom of many neurodegenerative diseases, we then examined the effect of the peptide on locomotion-related behavior as previously. 10,47 We found that both crawling speed and body bends of the polyQ nematodes were improved on Day 7 of adulthood after the peptide treatment (Fig. 5C).…”

“…Selected peptides were synthesized by Shanghai Top-Peptide Biotechnology Co. Ltd (Shanghai, China) using solid-phase synthesis methods with >95% purity as described previously. 10,17 In silico analysis of sea cucumber peptides…”

“…HSF-1 (heat shock factor 1), 6,10,43 respectively, in C. elegans (ESI Fig. S2B †), demonstrating its potent antioxidant activity.…”

“…9 Using the model animal Caenorhabditis elegans, we have recently found that an octapeptide (SETYELRK) identified from abalone protein hydrolyzate not only increases organismal survival resilience against oxidative stress but also rescues Aβ-and polyQ-mediated behavioral impairments. 10 Intriguingly, many of these naturally derived peptides are cryptic peptides (cryptides), i.e., functional peptide fragments hidden in the structures of natural proteins inactive when encrypted in their parent proteins but active upon release. 5,11 Very often, a large repertoire of cryptides, which as a whole can be referred to as "cryptome", is obtained after the peptides are released by hydrolysis from natural bioresources.…”