Abstract
Aging is related to the lowered overall functioning and increased risk for various age-related diseases in humans. Tectochrysin is a flavonoid compound and rich in a traditional Chinese Medicine Alpinia oxyphylla Miq., which has antioxidant, anti-inflammatory, anti-cancer, anti-bacterial, anti-diarrhea, hepatoprotective, and neuro-protective effects. Therefore, we tested if tectochrysin had an effect on aging in Caenorhabditis elegans (C. elegans). Our results showed that tectochrysin could extend the lifespan of C. elegans by up to 21.0%, delay the age-related decline of body movement, improve high temperature-stress resistance and anti-infection capacity, and protected worms against Aβ1-42-induced toxicity. Tectochrysin could not extend the lifespan of the mutants from genes daf-2, daf-16, eat-2, aak-2, skn-1, and hsf-1. Tectochrysin could increase the expression of DAF-16 regulated genes. The extension of lifespan by tectochrysin requires FOXO/DAF-16 and HSF-1. Overall, our findings suggest that tectochrysin may have a potential effect on extending lifespan and age-related diseases.
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Introduction
Aging is a natural phenomenon that occurs in -most living organisms. In humans, aging is associated with lowered overall functioning and increased risk for various age-related diseases (Castillo-Quan et al. 2015). Hence, researchers are keen on finding effective components that can promote healthy aging and extend lifespan. The natural decline of function occurring with aging could be prevented and / or reversed through various ways such as gene modifications, dietary interventions, and hormetic mechanism (Kunugi and Mohammed Ali 2019). Accumulating evidence indicated that traditional herbs could promote healthy aging and lengthen healthy lifespans, such as Ginseng Radix et Rhizoma (Biswas et al. 2017), the extract of Aralia chinensis L (Zhang et al. 2015), Notoginseng radix et rhizome (Feng et al. 2015), Dendrobium candidum Wall. ex Lindl (Russo et al. 2019), Calycophyllum spruceanum (Benth.) (Peixoto et al. 2018), and Curcuma longa (Bielak-Zmijewska et al. 2019).
Alpinia oxyphylla Miq. is a traditional Chinese herbal medicinal against diarrhea, salivation, and diuresis (Zhang et al. 2018b). Accumulating evidence has demonstrated that the extracts from the Alpinia oxyphylla Miq. also exert significantly neuroprotective, antioxidant (Shi et al. 2006), anti-inflammatory (Shi et al. 2020), anti-tumor (He et al. 2010), and anti-diabetes effects (Xie et al. 2018). Flavonoids are the main active constituents of Alpinia oxyphylla Miq. (Chen et al. 2014). Tectochrysin (TEC) (Fig. 1a) is a flavonoid compound and rich in Alpinia oxyphylla Miq. Tectochrysin showed improved spatial memory performance in amnestic mice induced by Aβ1-42 (He et al. 2019). Tectochrysin could reduce pro-inflammatory mediator production by directly inactivating p-MEK1/2 (Hou et al. 2018). Tectochrysin could activate aryl hydrocarbon receptor (AhR, which mediates the toxicological effect) (Amakura et al. 2011). Tectochrysin exhibited its anti-diarrhea effect partially by affecting proteins NHE3 and AQP4 (Zhang et al. 2013). Given the multiple biological activities of tectochrysin, we were wondering if tectochrysin could affect the aging process. Because of its short lifespan, amenability to genetic manipulation, clear genetic background, and a proportion of homologous genes in humans, C. elegans is an excellent model for screening chemicals with longevity modulation effects (Ma et al. 2018). Here, we investigated if tectochrysin could extend the lifespan of Caenorhabditis elegans. We found that tectochrysin could improve anti-stress ability, extend lifespan, and improve the symptoms of geriatric diseases in C. elegans.
Methods
Strains and chemicals
All strains were obtained from Caenorhabditis Genetics Center (CGC) and maintained at appropriate temperature as described previously (Brenner 1974), unless otherwise stated. strains used in this study were as follows: N2 (Bristol, wild type), DA1116 eat-2(ad1116) II., MQ887 isp-1(qm150) IV., CB1370 daf-2(e1370) III., TJ356 daf-16(zls356) IV., CF1038 daf-16(mu86) I., RB754 aak-2(ok524) X., EU1 skn-1(zu67) IV., PS3551 hsf-1(sy441) I., CF1553 muIs84 (sod-3::gfp), SJ4100 zcIs13V (hsp-6::gfp), SJ4005 zcIs4V (hsp-4::gfp), and CL4176 dvls27 (myo-3/Aβ1-42 /let UTR, rol-6). All strains grew and were maintained on NGM plates seeded with Escherichia coli OP50. The CL4176 strain is temperature-sensitive maternal effect lethal, and maintains at 15 °C and shifts to 25 °C at L3 stage in the paralysis assay (Xu et al. 2019).
Tectochrysin was purchased from Shanghai Yuanye Bio-Technology Co., Ltd, and dissolved in ddH2O. NGM plates containing tectochrysin were equilibrated overnight before use.
Lifespan assay
All strains were cultured for 2–3 generations without starvation, and lifespan analysis was conducted at 20 °C, unless otherwise stated. For each experiment, at least 60 worms were used. Late L4 larvae or young adults were transferred to NGM plates (9 cm, diameter) containing inactivated OP50 (60 °C for 35 min) and 50 μM of 5-fluoro-2′-deoxyuridine (FUDR, Sigma) to prevent self-fertilization. The day L4 larvae or young adults were transferred to experimental plates and were defined as experiment day 0. To ensure that tectochrysin retained its potency throughout the entire experiment, worms were transferred to fresh plates with or without tectochrysin every other day. Worms that did not respond to a mechanical stimulus were scored as dead, as described previously (Apfeld and Kenyon 1999). Worms were censored, if they crawled off the plate, displayed extruded internal organs, or died because of hatching progeny inside the uterus. The lifespan assay included at least three independent replicate experiments. Statistical analyses were carried out using SPSS packages. Kaplan–Meier lifespan analysis was carried out and p value was calculated using log-rank test.
Phenotypic assays
About 100 Late L4 larvae or young adult worms [wild-type C. elegans (N2)] were transferred to each plate with or without 200 μM of tectochrysin for 5 days or 10 days. Before the phenotype analysis, worms were transferred to fresh plates with inactivated OP50 every other day, and maintained at 20 °C.
In pathogen resistance assay, plates were seeded with live Pseudomonas aeruginosa (PA14) and cultured over-night before use. Worms were transferred to fresh NGM plate with live PA14, incubated at 20 °C, monitored every day, and scored as dead when they did not respond to the gentle touch with platinum wire pick (Pees et al. 2017).
In thermo-tolerance assay, worms were transferred to fresh plates with or without 200 μM of tectochrysin, and incubated at 35 °C, monitored every 2 h, and scored as dead when they did not respond to the gentle touch with platinum wire pick (Wilson et al. 2006).
In oxidative stress assay, worms were transferred to NGM plates containing paraquat (Sigma) and cultured at 20 °C (Zheng et al. 2017). Worms were monitored each day and scored as dead when they did not respond to the gentle touch with platinum wire pick. Kaplan–Meier lifespan analysis was carried out and p value was calculated using log-rank test.
Body bending assay was conducted as described previously (Huang et al. 2004). 3 worms were gently transferred to the plate with a drop of M9 buffer and left to acclimatize for 15 s at room temperature each time. Visualizing under a microscope, the complete body bending, defined as the maximum bend of the part of worm just behind the pharynx from one end to the opposite direction in a forward sinusoidal pattern, was manually counted for 20 s. The reverse bend in the same direction was not included in the count. In pharyngeal pumping assay, worms were transferred to fresh NGM plates. Visualizing under a microscope, the number of Pharynx pumping per 20 s was counted using a hand counter. The data was represented by histogram. The p value was obtained by t-test (Peixoto et al. 2019).
Each phenotype analysis included at least three independent replicate experiments. All the phenotype analyses except thermo-tolerance assay, were performed at 20 °C.
DAF-16::GFP localization assay
In each experiment, at least 30 worms of transgenic strain TJ356 daf-16(zls356) IV. were used to analyze the localization of DAF-16::GFP in the same condition as described for lifespan assay. L4 larvae worms were transferred to the plates with or without 200 μM of tectochrysin. Worms were cultured for 24 h at 20 °C. The location of DAF-16::GFP signal was monitored using a fluorescent microscope (Leica, DM6B). Live images were taken from at least 30 worms per group. The accumulation of fluorescent signal in nuclei was scored as described previously (Rezaizadehnajafi and Wink 2014). The assay included at least three independent replicate experiments. The p value was calculated using t-test.
Fluorescence intensity quantification assay
In fluorescence intensity quantification assays, we used SJ4005 zcIs4 (hsp-4::gfp), SJ4100 zcIs13(hsp-6::gfp), and CF1553 muIs84 (sod-3::gfp) to analyze whether tectochrysin affect the expression of genes: hsp-4, hsp-6, and sod-3, respectively. We observed the distribution of green fluorescent protein and measured the fluorescence intensity in these transgenic strains SJ4005, SJ4100, and CF1553, respectively. Each plate contains 50 μM of FUDR to inhibit egg hatching, as in lifespan assays. About 100 Late L4 larvae or young adult worms (mutants) were transferred to the plates with or without 200 μM of tectochrysin, maintained at 20 °C with dead OP50 for 10 days. Then we took photos by fluorescence microscope (Leica DM6B). Live images were taken from at least 30 worms per group. At last, we used Image J to quantify the intensity of fluorescence. The assay included at least three independent replicate experiments (Peixoto et al. 2016).
Paralysis assay
Transgenic mutant strain CL4176 dvls27 (myo-3/Aβ1-42 /let UTR, rol-6) that carries human amyloid-β protein was used for paralysis assay (Xu et al. 2019). Worms were cultured on NGM plates seeded with dead OP50 until L3 larvae at 15 °C. Then worms were transferred to fresh NGM plates with or without 200 μM of tectochrysin, and were transferred to 25 °C incubator to induce Aβ1-42 expression. Worms were scored every 6 h for paralysis by tapping two times on their head using platinum wire pick till death of the last worm. Worms that did not show any movement were considered as paralyzed.
Chemotaxis assays
Many organisms use chemotaxis to seek out food sources, avoid noxious substances, and find mates. C. elegans has impressive chemotaxis behavior. To analyze whether C. elegans use chemotaxis to avoid tectochrysin, we performed chemotaxis assays (see Fig. 5c) using wild-type N2 worms as described previously (He et al. 2017; Margie et al. 2013). About 200 synchronized C. elegans were placed in the center of an assay NGM plate (diameter: 3.5 cm), which contained 200 μM of tectochrysin plus 2% tetramisole hydrochloride to paralyze the worms on one side of the plate (A side), and H2O as solvent control plus 2% tetramisole hydrochloride on the opposite side of the plate (B side). After incubation at 20 °C for 1 h, Chemotaxis index (CI) was scored [CI = (number of worms on A side − number of worms on B side)/number of worms on A side + number of worms on B side].
Quantitative RT-PCR assays
About 2,000 synchronized young adult worms were transferred to six NGM plates (9 cm, diameter) with or without 200 μM of tectochrysin and cultured at 20 °C for 24 h. Total RNA was extracted using RNAiso Plus (Takara) and converted to cDNA using High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). The quantitative RT-PCR was performed using Power SYBR Green PCR Master Mix (Applied Biosystems) in Quantstudio 6 Flex system. The relative expression levels of genes were carried out using 2−ΔΔCT method and normalized to the expression of gene cdc-42 (Lee et al. 2010). The p values were calculated using t-test. Partial quantitative RT-PCR primers were as follows:
cdc-42, 5′-CTGCTGGACAGGAAGATTACG-3′ (F)
5′-CTCGGACATTCTCGAATGAAG-3′ (R).
hsp-6, 5′-GGATGCTGGACAAATCTCTG-3′ (F)
5′-ACAGCGATGATCTTATCTCCA-3′ (R).
hsp-60, 5′-AAGGATATGGGAATTGCGACGGGA-3′ (F)
5′-TGTGCTCGATTCGCTTCTCGATCT-3′ (R).
hsp-16.2, 5′-CTGCAGAATCTCTCCATCTGAGTC-3′ (F)
5′-AGATTCGAAGCAACTGCACC-3′ (R).
sod-3, 5′-AGCATCATGCCACCTACGTGA-3′ (F)
5′-CACCACCATTGAATTTCAGCG-3′ (R).
irg-1, 5′-AAGCAGCATGCGTATTTTCA-3′ (F).
5′-GCAGCTTCTCCTTTTTCTCC-3′ (R)
F35E12.5, 5′-ACACAATCATTTGCGATGGA-3′ (F)
5′-GGTAGTCATTGGAGCCGAAA-3′ (R).
Statistical analysis
Data is presented as the means ± SEM unless specifically indicated. Statistical analyses included t-tests or log-rank test. All figures were generated using GraphPad Prism 6, SPSS 23 or MS Office 2010.
Results
Tectochrysin extends the lifespan of C. elegans
To determine the prolongevity property of tectochrysin, we treated wild-type C. elegans (N2) with a serial concentration of tectochrysin ranging from 0 to 500 μM. We found that animals raised at 20 °C on NGM plates containing 200 μM of tectochrysin displayed the largest lifespan extension by up to 21.0% (p < 0.0001). Tectochrysin exhibited a smaller but not significant lifespan extension effect with concentrations higher or lower than 200 μM (500 or 50 μM, Fig. 1b, c). The body movement of C. elegans decreases with aging (Newell Stamper et al. 2018). In this study, we selected the frequency of body bending as a measure that indicates nematode movement behavior as previous study (Zhang et al. 2018a). As shown in Fig. 1d, we found that upon treatment with tectochrysin, body movement was significantly increased at 5 days and 10 days of adults (p < 0.0001), suggesting tectochrysin could slow down the decline of body movement.
Tectochrysin improves stress resistance of C. elegans
C. elegans with extended lifespan resulted from genetic and non-genetic manipulations often present increased stress resistance (Denzel et al. 2019). Therefore, we examined the effect of tectochrysin on stress resistance to heat, oxidative, and pathogenic bacteria in C. elegans. As shown in Fig. 2a, tectochrysin treatment suppressed the lethality of heat stress in wild-type C. elegans (N2) and extended the lifespan of C. elegans to 35.8% (p < 0.0001). The molecular chaperone heat shock proteins can repair misfolded proteins, activate unfolded protein reaction and contribute to cellular homeostasis (Govindan et al. 2018; Tan et al. 2015). We found that the mRNA level of genes hsp-6, hsp-60, and hsp-4 were higher in worms treated with tectochrysin (p < 0.05) (Fig. 2b). Furthermore, to test if tectochrysin regulate the expression of proteins HSP-4 and HSP-6, we fed tectochrysin to transgenic strains SJ4005 zcIs4V (hsp-4::gfp) and SJ4100 zcIs13V (hsp-6::gfp) expressing the fusion protein HSP-4::GFP and HSP-6::GFP, respectively. As shown in Fig. 2c, tectochrysin treatment showed increased expression of proteins HSP-4 and HSP-6 by SJ4005 zcIs4V (hsp-4::gfp) (p < 0.0001) and SJ4100 zcIs13V (hsp-6::gfp) (p < 0.0001), respectively.
Paraquat is a free radical generating compound that can induce acute oxidative stress in cells. To analyze the anti-oxidative effect of tectochrysin, we measured the lifespan of wild-type C. elegans (N2) exposing to 20 mM of paraquat. As shown in Fig. 2d, tectochrysin treatment improved the survival rate of C. elegans exposed to paraquat and extended the lifespan to 20.9% (p < 0.05).
The pathogenic bacteria pseudomonas aeruginosa (PA14) was used to activate the immune response in C. elegans (Kurz and Tan 2004). To analyze the anti-pathogenic effect of tectochrysin, we measured the lifespan of wild-type C. elegans (N2) exposing to PA14. We found that tectochrysin suppressed the lethality of wild-type C. elegans feeded with PA14, and extended the lifespan of C. elegans to 17.8% (p < 0.0001) (Fig. 2e). Genes irg-1, F55G11.4, F08G5.6, and F35E12.5 are immune responded (Kumar et al. 2019). To test if the anti-pathogenic effect of tectochrysin was associated with immune response, we measured the mRNA expression levels of these immune related genes in worms treated with tectochrysin. We found that the mRNA level of immune-related genes was significantly increased in C. elegans treated with tectochrysin (p < 0.05) (Fig. 2f). These results showed that tectochrysin could improve the health span of worms and increase their resistance to heat, oxidative, and pathogenic bacterial stress.
Heat shock factor 1 (HSF-1), an essential nuclear protein, is associated with heat-stress response, immunity and aging in C. elegans (Li et al. 2018; Seo et al. 2013). We found that tectochrysin could not extend the lifespan of hsf-1 mutant PS3551 hsf-1(sy441) I. (p > 0.05) (Fig. 2g).
Tectochrysin decreases Aβ-induced toxicity in C. elegans
Alzheimer's disease (AD) is one of the major diseases in elderly population (Hou et al. 2018). The accumulation of peptide Aβ, which produced from amyloid precursor protein (APP) by proteolytic cleavages, is a key pathological event in the development of AD, causing synaptic dysfunction, neuronal death, and cognitive deficits (Jagust 2018). The CL4176 strain contains the transgene encoding human peptide amyloid-β (Aβ1-42) is the genetic disease model of AD (Shanmuganathan et al. 2019). The expression of peptide Aβ could be induced at 25 °C and lead to paralysis of worms. We analyzed the body paralysis and lifespan of the CL4176 strain treated with tectochrysin. Before 48 h, the number of paralysis of worms treated without tectochrysin was higher than that of the treatment group. After 48 h, the number of paralysis of worms treated without tectochrysin was lower than that of the treatment group (Fig. 3a). We found that tectochrysin treatment significantly delayed the time of body paralysis in the CL4176 strain (p < 0.0001) (Fig. 3b) and extended the lifespan of the CL4176 strain by up to 14.8% (p < 0.05) (Fig. 3c), suggesting tectochrysin decreased the Aβ1-42-induced toxicity in C. elegans.
The effect of tectochrysin on the lifespan extension in C. elegans depends on FOXO transcription factor homologue DAF-16
Multiple signaling pathways, such as the insulin/IGF-1, TOR, AMPK, JNK and germline signaling, regulate aging and longevity (Yen et al. 2011). Mammalian FOXO transcription factor homologue DAF-16 could integrate different signals from these pathways to modulate aging and longevity. Via activated, DAF-16 shuttles from cytoplasm to nucleus and regulates the expression of downstream genes (Sun et al. 2017; Tissenbaum 2018). We tested if DAF-16 played a role in the effect of tectochrysin on lifespan extension. We observed the nucleus accumulation of DAF-16 in C. elegans under treatment of tectochrysin (p < 0.0001) (Fig. 4a). So we further investigated if tectochrysin regulated the expression of the downstream genes of daf-16. We found that the mRNA expression level of the downstream genes of daf-16, including sod-3, hsp-16.2, and dod-3, was significantly increased in C. elegans treated with tectochrysin (Fig. 4b). Among the downstream target genes of DAF-16, sod-3 is involved in both stress resistance and longevity (Rangsinth et al. 2019). We examined expression level of sod-3 at protein level in transgenic strain CF1553 expressing SOD-3::GFP fusion protein. We found that the expression of SOD-3 was significantly increased in C. elegans treated with tectochrysin (p < 0.0001) (Fig. 4c). Furthermore, to study whether tectochrysin extended lifespan depended on daf-16, we measured the lifespan of the null mutant of daf-16 with tectochrysin treatment. Our result showed that tectochrysin could not extend the lifespan of daf-16 mutant CF1038 daf-16(mu86) I (Fig. 4d).
Gene daf-2 encoding the insulin/insulin-like growth factor (IGF-1) receptor, regulates PI3-kinase/AKT pathway and FOXO/DAF-16 (Kuningas et al. 2008). Gene skn-1, related to fat metabolism and oxidative stress, can be activated by DAF-16 (Park et al. 2009). We further measured the lifespan of the null mutant of skn-1 and daf-2 with tectochrysin treatment. Our results showed that tectochrysin could not extend the lifespan of mutants CB1370 daf-2(e1370) III. and EU1 skn-1(zu67) IV. (Fig. 4e, f).
Tectochrysin could not extend the long-lived mutants from genes involved in energy processing
Among many genetic and environmental interventions to delay aging so far, dietary restriction (DR) shows consistent lifespan extension with positive effects on health span ranging from C. elegans to monkeys (Colman et al. 2014; Lakowski and Hekimi 1998). Reducing pharyngeal pumping often leads to the decrease of food intake in worms (Chamoli et al. 2014). Firstly, to analyze whether worms avoid tectochrysin, we performed chemotaxis assay. We found worm did not avoid tectochrysin (Fig. 5a, b). Further, we also found that under the treatment of tectochrysin, the pharyngeal pumping in worms didn’t reduce significantly until the 5th day of adult (Fig. 5c). Furthermore, we measured the lifespan of eat-2 mutant treated with tectochrysin. The result showed that tectochrysin failed to extend the lifespan of long-lived eat-2 mutant DA1116 eat-2(ad1116) II. (Fig. 5d). Further, the low-energy sensing AMP-activated protein kinase AMPK/aak-2 played a role in longevity induced by a DR regimen (Greer and Brunet 2009). While the gene isp-1 encoding Rieske iron-sulfur polypeptide 1 is involved in mitochondrial electron transport and can activate the AMPK pathway by decreasing the level of ATP (Curtis et al. 2006). Our results showed that tectochrysin could not further extend the lifespan of the long-lived mutants RB754 aak-2(ok524) X. and MQ887 isp-1(qm150) IV (Fig. 5e, f).
Discussion
Tectochrysin is a main component of a traditional Chinese medicine Alpinia oxyphylla Miq., which has an effect for Center-Supplementing Qi-Boosting, is prescribed for diarrhea and loss of appetite (Zhang et al. 2018b). Tectochrysin also has antibacterial, antifungal, anti-cancer, anti-inflammatory, and anti-oxidation effects (Lee et al. 2003). But the anti-aging effect of tectochrysin is unknown. Here we found that tectochrysin could extend the lifespan of C. elegans, increase the stress resistance, and decrease Aβ-induced toxicity in C. elegans.
In C. elegans, increased lifespan is associated with increased expression of small heat shock proteins (HSPs) (Olsen et al. 2006). We found that tectochrysin could increase the expression of hsp-4, hsp-6, and hsp-60 at mRNA level, while increase the expression of hsp-4 and hsp-6 at protein level. The expression of hsp-4 and hsp-6 are the positive markers of unfold protein reaction (UPR), which can respond to the stress conditions (Jovaisaite et al. 2014). Heat shock factor 1 (HSF-1), an essential nuclear protein, is associated with heat-stress response, immunity and aging in C. elegans (Li et al. 2018; Seo et al. 2013). We found that tectochrysin could not extend the lifespan of hsf-1 mutant, suggesting tectochrysin required hsf-1 to extend the lifespan of C. elegans.
FOXO/DAF-16 contributes to the regulation of development, lifespan, and stress resistance in worms. Thus we investigated if tectochrysion extended the lifespan of worms depending on DAF-16. Our result showed that tectochrysin didn’t extend the lifespan of the daf-16 mutant CF1038 daf-16(mu86) I. Meanwhile, the increased nuclear translocation of DAF-16::GFP was further identified in transgenic strain TJ356 daf-16(zls356) IV exposed to tectochrysin. Furthermore, daf-16 related genes: sod-3, dod-3, and hsp-16.2 were also up-regulated following the tectochrysin treatments at the mRNA level. SOD-3 encodes a Fe/Mn superoxide dismutase, which contributed to the oxidative stress resistance, and reduced with aging (Rangsinth et al. 2019). We found that tectochrysin could slow down the decline of the expression of SOD-3 with aging in worms. Above results suggest that tectochrysin extends the lifespan of C. elegans via DAF-16. The insulin-like receptor DAF-2 regulates the activity of DAF-16 in worms. Furthermore, tectochrysin could not significantly extend the lifespan of daf-2 mutant CB1370 daf-2(e1370) III. This result suggests that either tectochrysin regulates IIS pathway to extend the lifespan of C. elegans, or the effect of tectochrysin on the lifespan extension is not strong enough to distinguish from the extremely long lifespan of CB1370 daf-2(e1370) III.
We found worm did not avoid tectochrysin. Under the treatment of tectochrysin, the pharyngeal pumping in worms didn’t reduce significantly until the 5th day of adult. Tectochrysin couldn’t extend the lifespan of mutants from genes aak-2, eat-2, and isp-1. These results suggested that the effect of tectochrysin on the lifespan extension might be not strong enough to distinguish from the lifespan of these long-lived mutants.
Hormesis is biological phenomena characterized by dose–response relationships displaying low-dose stimulation and high-dose inhibition. It is classically described by an inverted U-shaped or J-shaped dose response curve (Calabrese and Baldwin 2002). Meanwhile, lifespan extension from stress hormesis by thermal stress and oxidative stress also occurred in C. elegans. (Cypser and Johnson 2003; Heidler et al. 2010). Previous studies found that many compounds, such as metformin, curcumin, and tubers extract, regulated the aging process through hormesis (Govindan et al. 2018; Piskovatska et al. 2020; Stępień et al. 2020). The dose–response curve of tectochrysin is an inverted U-shaped. In C. elegans, we also observed increased resistance to stress and lifespan extension by supplementing with tectochrysin. Meanwhile, tectochrysin increased the mRNA level of heat-shock response, immune, and DAF-16 related genes. Given these results, we speculated tectochrysin might partly extend nematode life through hormesis. However, the cellular mechanisms involved in hormesis are still unclear and need further investigation.
In summary, we found that tectochrysin could delay the progress of age-related disease by reducing Aβ1-42-induced toxicity and increase stress resistance in C. elegans, and extend the lifespan of C. elegans via FOXO/DAF-16. It is worth to investigate the beneficial effect of tectchrysin, especially the lifespan extension and treatment for age-related disease of tectochrysin in mammals.
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Acknowledgements
We thank the Caenorhabditis Genetic Center (CGC) for providing the worm strains, which is funded by NIH Office of Research Infrastructure Program (P40OD010440). Financial supports were received from the Natural Science Foundation of China (Grant Nos. 81771516 and 81671405) and the Science and Technology Cooperation Project of Luzhou and Southwest Medical University (2016LZXNYD-Z05).
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The study was conceived and designed by H.-R.L and G.-S.W. Material preparation, data collection and analysis were performed by M.L., L.T. Q.Z., and Z.-L.Y. The first draft of the manuscript was written by M.L, and then the manuscript was revised by J.-N.C., X.-G.Z., H.-R.L and G.-S.W. All authors commented on previous versions of the manuscript. All the authors have read and approved the final version.
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Lu, M., Tan, L., Zhou, XG. et al. Tectochrysin increases stress resistance and extends the lifespan of Caenorhabditis elegans via FOXO/DAF-16. Biogerontology 21, 669–682 (2020). https://doi.org/10.1007/s10522-020-09884-w
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DOI: https://doi.org/10.1007/s10522-020-09884-w