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. 2022 Nov 24:13:1034515.
doi: 10.3389/fphar.2022.1034515. eCollection 2022.

Alpiniae oxyphylla fructus extract promotes longevity and stress resistance of C. elegans via DAF-16 and SKN-1

Man Xiao  1 , Bocen Chen  1 , Kun Niu  2 , Ziyu Long  1 , Fan Yang  2 , Yiqiang Xie  2
Affiliations

Alpiniae oxyphylla fructus extract promotes longevity and stress resistance of C. elegans via DAF-16 and SKN-1

Man Xiao et al. Front Pharmacol. .

Abstract

Background: Alpiniae Oxyphylla Fructus (AOF) is Traditional Chinese medicine and a dietary supplements for centuries, which posseses cardiotonic, neuroprotective, antioxidant, warming the kidney and nourish the spleen, these biological fuction is related to potential anti-aging properties. However, little is known about their effects on aging. This work aimed to investigate the effects of extracts of AOF on longevity and stress resistance in Caenorhabditis elegans (C. elegans) and the mechanisms that underlie its effects. Methods: Wild-type (WT) strand of C.elegans (N2)worms were cultured in growth medium with or without AOF. First, we examined the effects of AOF on lifespan, reproduction and healthspan assay, stress resistance and oxidative analysis, lipofuscin levels. Second, The levels of ROS and MDA, the antioxidant enzyme activities were examined to explore the underlying mechanism of AOF. Finally, the expression of the longevity-related genes were investigated to further understand the AOF's underlying mechanism. Results: The lifespan of C. elegans was prolonged by 23.44% after treatment with high-dose AOF (100 ug/ml). AOF alleviated aging-related declines in C. elegans health and enhanced resistance to heat shock. Furthermore, AOF decreased reactive oxygen species and malondialdehyde, increased the activities of superoxide dismutase and catalase, and reduced accumulation of fat. AOF upregulated the expression of sod-3, gst-4, daf-16, and skn-1 but downregulated the expression of daf-2 and age-1 and accelerated the translocation of DAF-16 into the nucleus. The extended lifespan induced by AOF was reversed in daf-16(mu86) and skn-1(zu135) mutants, indicating that this gene is involved in AOF-regulated longevity. Conclusion: Our findings demonstrated that AOF extends lifespan and healthspan and enhances stress via boosting the activity of the antioxidant enzyme and controlling the expression of genes associated with insulin/IGF signaling and SKN-1 pathways. As a result, this work suggested AOF as a possible candidate to reduce the signs of aging by activating and inhibiting target genes.

Keywords: Alpiniae oxyphylla fructus (AOF); Caenorhabditis elegans (c. elegans); aging; insulin/IGF signaling pathway (IIS); lifespan.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Metabolites in AOF. Total ion current pattern of (A) positive ions and (B) negative ions detected by UHPLC-QTOF-MS of AOF. 1: citrate; 2: lauryl sulfate; 3:Benzene-1,2,4-triol; 4: 5,9-dihydroxy-5,7,7-trimethyl-4,5a,6,8,8a, 9-hexahydro-1H-azuleno [5,6-c]furan-3-one; 5: isorhamnetin; 6: D-gluconic acid; 7: 6-gingerol; 8: D-(+)-malic acid; 9: (+)-nootkatone; 10: alpha-cyperone; 11: choline [M]+; 12: germacrone.
FIGURE 2
FIGURE 2
KEGG pathway analysis of AOF metabolites.
FIGURE 3
FIGURE 3
Effects of AOF extract concentration on the survival of wild-type C.elegans N2. Data are the mean ± SD (n = 3).
FIGURE 4
FIGURE 4
Effect of AOF treatment on reproduction in C.elegans. Data are the mean ± SD (n = 3),p > 0.05 for all AOF groups vs Blank groups.
FIGURE 5
FIGURE 5
Effect of AOF treatment on the motility of wild-type C.elegans N2. Data are the mean ± SD (n = 3), *p < 0.05, **p < 0.01.
FIGURE 6
FIGURE 6
Effect of AOF treatment on (C) elegans N2. (A) heat-shock survival at 35°C, and (B) a representative image of the nuclear HSF-1:GFP fraction in (A), Blank group and (B), 100 μg/ml AOF group,and (C) the transcriptional levels of hsf-1、hsp-70, and (D) paraquat-induced oxidative stress survival. Data are the mean ± SD (n = 3). **p < 0.01.
FIGURE 7
FIGURE 7
Effect of AOF treatment on lipofuscin accumulation in C.elegans (A–B). Data are the mean ± SD (n = 3). **p < 0.01.
FIGURE 8
FIGURE 8
Antioxidant effects of AOF treatment of (C) elegans. (A) Effect of AOF on ROS-mediated fluorescence. (B–D) Effect of AOF on the activities of antioxidant enzymes (B) SOD and (C) CAT, and (D) the level of MDA. Pro = protein. Data are the mean ± SD (n = 3). **p < 0.01.
FIGURE 9
FIGURE 9
The role of the DAF-2-DAF-16 signaling pathway in the anti-aging effects of AOF. (A) Relative expression of aging-related genes in (C) elegans. (B) A representative image of DAF-16:GFP expression in (A), control group and (B), 100 μg/ml AOF group. (C) Effect of AOF on the lifespan of daf-2, daf-16, or age-1 mutant worms. (D) The relative SOD-3 mRNA expression in daf-16 mutants. (E) Fluorescence intensity of sod-3:GFP after AOF in (A), control group and (B), 100 μg/ml AOF group.Data are the mean ± SD (n = 3). **p < 0.01.
FIGURE 10
FIGURE 10
The role of SKN-1 in the anti-aging effects of AOF. (A) A representative image of SKN-1:GFP in strain skn-1(zu135) for (A), control group and (B), 100 μg/ml AOF group. (B) The expression of skn-1 in the AOF treatment group vs control group. (C) Effect of AOF on the lifespan of the skn-1(zu135) mutant. (D) The relative GST-4 mRNA expression in skn-1(zu135) mutants. (E) Fluorescence intensity of GST-4:GFP after AOF in (A), control group and (B), 100 μg/ml AOF group.Data are the mean ± SD (n = 3). **p < 0.01.
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