Neural Regeneration Research

: 2021  |  Volume : 16  |  Issue : 6  |  Page : 1062--1067

Astaxanthin alleviates pathological brain aging through the upregulation of hippocampal synaptic proteins

Ning Liu1, Liang Zeng2, Yi-Ming Zhang3, Wang Pan4, Hong Lai3,  
1 1Department of Human Anatomy, College of Basic Medicine, China Medical University, Shenyang; Department of Radiology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China
2 Department of Human Anatomy, College of Basic Medicine, Shenyang Medical College, Shenyang, Liaoning Province, China
3 Department of Human Anatomy, College of Basic Medicine, China Medical University, Shenyang, Liaoning Province, China
4 Department of Neurobiology of Jinzhou Medical University, Jinzhou, Liaoning Province, China

Correspondence Address:
Hong Lai
Department of Human Anatomy, College of Basic Medicine, China Medical University, Shenyang, Liaoning Province


Oxidative stress is currently considered to be the main cause of brain aging. Astaxanthin can improve oxidative stress under multiple pathological conditions. It is therefore hypothesized that astaxanthin might have therapeutic effects on brain aging. To validate this hypothesis and investigate the underlying mechanisms, a mouse model of brain aging was established by injecting amyloid beta (Aβ)25–35 (5 μM, 3 μL/injection, six injections given every other day) into the right lateral ventricle. After 3 days of Aβ25–35 injections, the mouse models were intragastrically administered astaxanthin (0.1 mL/d, 10 mg/kg) for 30 successive days. Astaxanthin greatly reduced the latency to find the platform in the Morris water maze, increased the number of crossings of the target platform, and increased the expression of brain-derived neurotrophic factor, synaptophysin, sirtuin 1, and peroxisome proliferator-activated receptor-γ coactivator 1α. Intraperitoneal injection of the sirtuin 1 inhibitor nicotinamide (500 μM/d) for 7 successive days after astaxanthin intervention inhibited these phenomena. These findings suggest that astaxanthin can regulate the expression of synaptic proteins in mouse hippocampus through the sirtuin 1/peroxisome proliferator-activated receptor-γ coactivator 1α signaling pathway, which leads to improvements in the learning, cognitive, and memory abilities of mice. The study was approved by the Animal Ethics Committee, China Medical University, China (approval No. CMU2019294) on January 15, 2019.

How to cite this article:
Liu N, Zeng L, Zhang YM, Pan W, Lai H. Astaxanthin alleviates pathological brain aging through the upregulation of hippocampal synaptic proteins.Neural Regen Res 2021;16:1062-1067

How to cite this URL:
Liu N, Zeng L, Zhang YM, Pan W, Lai H. Astaxanthin alleviates pathological brain aging through the upregulation of hippocampal synaptic proteins. Neural Regen Res [serial online] 2021 [cited 2021 Sep 29 ];16:1062-1067
Available from:

Full Text


At present, most developed countries and some developing countries in the world are faced with aging populations. With increasing aged populations, the aging of the brain has gradually become clearer. Brain aging refers to the aging phenomenon that occurs gradually in brain tissue morphology, structure, and function, leading to learning, cognitive, and memory dysfunctions (Baghel et al., 2019). How to effectively delay cognitive dysfunction caused by brain aging has therefore become a hot topic in related fields. The mechanisms of brain aging are multifactorial; however, it is generally considered that oxidative stress is the leading cause of brain aging.

Recent studies have demonstrated that silencing information regulator 2-related enzyme 1 (sirtuin 1 or SIRT1) plays a vital role in nerve development, repair, and protection (Toklu et al., 2017; Yerra et al., 2017). SIRT1 substrates include histones, non-histones (involved in apoptosis, neuronal protection, organ metabolism, cell aging, and tumorigenesis, for example), and various transcription factors (Ma et al., 2016; Yan et al., 2016; Lin et al., 2017). SIRT1 can regulate intracellular reactive oxygen species levels and protect cells from oxidative stress injury (Liu et al., 2019). Nicotinamide (NAM) can inhibit the expression of SIRT1 (Hwang and Song, 2017; Pan et al., 2020). Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α), a relatively newly discovered protein in the oxidative stress system, plays an essential role as a transcriptional regulation factor that can induce the expression of cellular antioxidant enzymes. PGC-1α is a core control factor that regulates mitochondrial biosynthesis. Studies have shown that SIRT1 is an upstream protein of PGC-1α that can adjust the initiation and sustained response of PGC-1α in the oxidative stress state (Guo et al., 2014; Tan et al., 2015). Thus, SIRT1 possesses the positive biological effect of stimulating PGC-1α (Thirupathi and de Souza, 2017; Visioli and Artaria, 2017).

Astaxanthin (AST) affects the quenching and scavenging of singlet oxygen in vitro (Jackson et al., 2004). Furthermore, AST can reduce lipid peroxidation and protein damage in diabetic rats, decrease the oxidation of apolipoproteins, and be used as an inhibitor to prevent arteriosclerosis and ischemic brain injury (Marin et al., 2011; Song et al., 2014; Ma et al., 2015). In human lymphocytes, oxidative stress caused by a fatty acid mixture and mitochondrial damage can be reduced by AST, which can maintain and improve DNA function (Wolf et al., 2010; Campoio et al., 2011; Park et al., 2011).

Based on the aforementioned observations, we aimed to determine whether hippocampal synaptic proteins are involved in the potential protective mechanisms by which AST regulates oxidative stress in the hippocampus of aging mice.

 Materials and Methods


Sixty specific-pathogen-free male Institute of Cancer Research mice, aged 6 months, were purchased from Liaoning Changsheng Co. Ltd., Benxi, China (license No. SCXK 2015-0003). These mice had free access to water and food and were kept at 55 ± 5% humidity, 22 ± 2°C, and in a 12-hour light/dark cycle. The experimenters alleviated the suffering of the mice as much as possible during the experiments and complied with the regulations and ethical standards of China Medical University. The study was approved by the Institutional Animal Care and Use Committee, China Medical University (approval No. CMU2019294) on January 15, 2019. This study followed the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.

Pseudo-aging model establishment

The mice were randomly divided into control, amyloid beta (Aβ), Aβ + AST, and Aβ + AST + NAM groups (n = 15 per group). The mice in the control group did not receive any treatment. The mice in all three Aβ groups received right lateral ventricle injections of Aβ25–35 (5 μM, 3 μL/injection, six injections given every other day; Sigma, Milwaukee, WI, USA). The mice in the Aβ + AST and Aβ + AST + NAM groups were then treated with AST (0.1 mL/day, 10 mg/kg; Sigma) by oral gavage for 30 consecutive days from 3 days after completing the Aβ25–35 injections. The mice in the Aβ + AST + NAM group were also intraperitoneally injected with NAM (500 μM/day, Sigma) for 7 consecutive days after the AST treatment [Figure 1].{Figure 1}

Morris water maze

Two weeks after the mouse models were prepared, the Morris water maze test (Liu et al., 2011) was used to assess spatial memory and learning. The maze (Zhenghua Biological Instrument Equipment Co. Ltd., Huaibei, China) consisted of a circular stainless-steel tank (120 cm in diameter and 35 cm in height), which was divided into four quadrants by four fixed points on its perimeter. The tank contained an escape platform of 10 cm3 that was the same color as the rest of the tank (to eliminate any vision-related false-positive results). The platform was placed in a constant quadrant of the tank throughout the trials and was kept 1.5 cm below the water surface. In brief, groups of mice were familiarized with the maze environment on day 1, when they were allowed to swim freely for 2 minutes in the tank (without the platform). The experiment was then implemented four times per day for 5 consecutive days. Each mouse was placed in the water, facing the wall, and the position of the drop point was changed in every test. Each mouse was given 120 seconds to find the submerged platform, and was permitted to stay on the platform for 20 seconds. If the mouse failed to find the platform, it was carefully driven onto the platform and allowed to remain there for 20 seconds. The escape latency time was recorded for each test, which was taken as the learning capability of the mouse. The probe experiment started on day 6, and was performed with the platform removed. Mice were permitted to swim freely in the tank for 120 seconds. The times that the mouse swam across the platform location were counted by a computer, and this measurement was taken as the spatial memory acquisition ability of the mouse.

Tissue preparation

After the behavioral trials, mice (n = 15 per group) were anesthetized with sodium pentobarbital (50 mg/kg, intraperitoneal injection) and decapitated. The hippocampi were quickly removed and divided into two equal parts. One part of each hippocampus was embedded in paraffin and prepared as 5-μm sections for immunofluorescence. The other part of each hippocampus was immediately put into liquid nitrogen and conserved at –80°C, to be used in western blot assays.

Immunofluorescence staining

Brain-derived neurotrophic factor (BDNF) is a hippocampal synaptic protein (Low et al., 2015; Kandola et al., 2019). Synaptophysin (SYN) is closely related to the synaptic structure and function of vesicle protein adsorption, and is recognized as a significant symbol of synaptic plasticity (Cheng et al., 2011; Ma et al., 2019). The paraffin-embedded sections were dewaxed with xylene and rehydrated through graded alcohol solutions. Sections were then washed in phosphate-buffered saline (PBS; 0.1 M, pH 7.2) and placed in citrate buffer (0.1 M, pH 6.0), and were then heated in a water bath (80–90°C) for 10 minutes for antigen retrieval. The sections were then cooled for 30 minutes and placed into PBS for 3 minutes. After rinsing with PBS, the sections were incubated with 5% bovine serum albumin for 30 minutes at 37°C. They were then incubated at 4°C overnight with rabbit anti-SYN (1:500; Cat# 17785; PTG, Houston, TX, USA), rabbit anti-BDNF (1:500; Cat# 25699; PTG), rabbit anti-SIRT1 (1:500; Cat#13161; PTG) and rabbit anti-PGC-1α (1:500; Cat# 20658; PTG). After five rinses with PBS, the sections were incubated for 1 hour at 37°C with biotinylated goat anti-rabbit IgG (1:1000; Cat# 00001-2; PTG). They were then rinsed three times with PBS before being incubated with 4',6-diamino-2-phenylindole and hydrogen peroxide in PBS for 10 minutes. Next, the sections were washed with PBS and coverslipped with glycerin. The optical densities of the immunopositive cells and the average optical densities were recorded and analyzed using ImageJ software (version 1.52a; National Institutes of Health, Bethesda, MD, USA).

Western blot analysis

Hippocampal tissue was first mixed at a ratio of 1:5 with lysis buffer. Next, to homogenize the tissue, the mixture was centrifuged at 12,000 × g for 30 minutes at 4°C. The supernatant was then collected and the protein concentration was measured using a bicinchoninic acid protein assay kit (Pierce Biotechnology, Rockford, IL, USA). The protein samples were segregated using 12% sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred onto polyvinylidene difluoride membranes (Millipore, Boston, MA, USA). The membranes were blocked for 3 hours with Tris-buffered saline with 0.1% Tween-20 and 5% dried skim milk, and they were then incubated with primary antibodies overnight at 4°C. The primary antibodies were rabbit anti-BDNF (1:500), rabbit anti-SYN (1:500), rabbit anti-SIRT1 (1:500), rabbit anti-PGC-1α (1:500), and mouse anti-glyceraldehyde-3-phosphate dehydrogenase (1:1000; Cat#10494; PTG). Next, the membranes were incubated with biotinylated goat anti-rabbit IgG (1:1000; Cat# 00001-2; PTG) at room temperature for 1 hour, and enhanced chemiluminescence (Pierce Biotechnology) and a ChemDoc XRS with Quantity One software (BioRad, Hercules, CA, USA) were used to analyze the bands. Band intensities were analyzed using ImageJ software.

Statistical analysis

All statistical analyses were performed using GraphPad Prism 6 (GraphPad Software Inc., San Diego, CA, USA). All data are expressed as the mean ± standard deviation. The two-tailed independent samples t-test was used for comparisons between two groups. Differences were taken to be statistically significant at P < 0.05.


AST improves cognitive function in aging mice

The Morris water maze results illustrated that the escape latencies and trajectories had different degrees of change in the different groups [Figure 2]A. The average escape latency of mice in the Aβ group tended to increase, indicating that spatial memory and learning abilities were decreased. The average escape latency of the Aβ group was significantly longer than that of the control group (P = 0.0027). However, the average escape latency of the Aβ + AST group was considerably shorter than that of the Aβ group (P = 0.0034), and was not significantly different from that of the control group (P = 0.2968). In contrast, the average escape latency of the Aβ + AST + NAM group was significantly longer than that of the Aβ + AST group (P = 0.0035), and was not significantly different from that of the Aβ group (P = 0.4051). In the probe trial, there were differences between groups in the number of times the mice crossed the platform [Figure 2]B. The number of times crossing the platform was significantly lower in the Aβ group than in the control group (P = 0.0081). However, the number of times crossing the platform was higher in the Aβ + AST group than in the Aβ group (P = 0.0142), but was not significantly different from that of the control group (P = 0.3041). In contrast, the number of times crossing the platform was lower in the Aβ + AST + NAM group than in the Aβ + AST group (P = 0.0279), and was not significantly different from that of the Aβ group (P = 0.5170).{Figure 2}

AST restores the immunoreactivities of hippocampal synaptic proteins in aging mice

Immunofluorescent staining results revealed that, compared with the control group, BDNF (P = 0.0003) and SYN (P = 0.0018) immunoreactivities in the pyramidal cells of the hippocampal CA3 region were significantly lower in the Aβ group. Compared with the Aβ group, the Aβ + AST group had stronger BDNF (P = 0.0334) and SYN (P = 0.0021) immunoreactivities. However, compared with the control group, the Aβ + AST group had no significant differences in BDNF (P = 0.0622) or SYN (P = 0.0813) immunopositivity. Compared with the Aβ + AST group, the fluorescence intensity of SIRT1 (P = 0.0031) was weaker in the Aβ + AST + NAM group, and this was accompanied by a lower fluorescence intensity of PGC-1α (P = 0.0020). However, the SIRT1 (P = 0.0979) and PGC-1α (P = 0.1413) immunoreactivities were similar between the Aβ + AST + NAM and Aβ groups. These findings indicate that NAM may reduce SIRT1 and PGC-1α expression, while AST may enhance SIRT1 and PGC-1α expression. This may ultimately decrease the degree of oxidative stress, thus improving learning and memory abilities in mice [Figure 3].{Figure 3}

AST restores the expression of synaptic proteins in the hippocampus of aging mice

Western blot results revealed that the expression levels of SYN (P = 0.0001) and BDNF (P = 0.0015) were considerably lower in the Aβ group than those in the control group. However, AST treatment increased the expression levels of SYN (P = 0.0005) and BDNF (P = 0.0044) in Aβ mice, to levels that were not significantly different from those in the control group (SYN, P = 0.0932; BDNF, P = 0.0844). The expression levels of SYN (P = 0.0049), BDNF (P = 0.0029), SIRT1 (P = 0.0011), and PGC-1α (P = 0.0214) were markedly lower in the Aβ + AST + NAM group than in the Aβ + AST group [Figure 4].{Figure 4}


Oxidative stress is currently considered to be the leading cause of brain aging (Popa-Wagner et al., 2020); however, the precise mechanisms of oxidative stress-induced impairment of memory, learning, and cognition are not well understood. Using the Morris water maze test, previous studies illustrated that brain aging leads to considerably decreased memory, learning, and cognitive functions (Macklin et al., 2017; Haider and Tabassum, 2018; Ishola et al., 2019). In the present study, the Morris water maze results demonstrated that injections of Aβ25–35 into the lateral ventricles of mice resulted in decreased spatial memory and learning abilities. The mice in the Aβ group had shorter travel distances and longer escape latencies, and their swimming trajectories were dispersed. AST treatment improved and enhanced the spatial memory and learning abilities of these mice.

BDNF is an important protein for central nervous system development and neuronal survival, differentiation, growth, and development. It can prevent nerve damage and death, improve the pathological state of neurons, and promote the regeneration of damaged neurons and the differentiation of biological effects. SYN exists in the synaptic vesicle membranes of presynaptic components, and indirectly reflects the number, distribution, and density of synapses, meaning that it is often used as a marker of synaptic density. As well as being a marker of synapse density, SYN can also reflect the efficiency of synaptic transmission. Furthermore, BDNF and SYN, as markers of presynaptic and postsynaptic components, are also markers of synaptic plasticity. They are involved in the formation and reconstruction of synapses, and their decreased expression can be taken to mean synaptic loss. Both BDNF and SYN are important for the structure, function, and plasticity of synapses. As the brain ages, synaptic plasticity changes, resulting in reductions in learning and memory abilities. In the present study, the immunofluorescence and western blotting results indicated that the protein expression levels of SYN and BDNF in the hippocampus of the Aβ group were decreased, which may have led to the decreased learning, memory, and cognitive abilities of this group. AST has been shown to improve oxidative stress-induced learning, memory and cognitive function during the brain aging process in our previous study (Zhang et al., 2019).

The SIRT1/PGC-1α signaling pathway plays a role in the regulation of oxidative stress. This signaling pathway has also been reported to be associated with synaptic plasticity (Harris and Winder, 2018; Wang et al., 2018; Li et al., 2019; Yan et al., 2019). NAM is an inhibitor of the SIRT1/PGC-1α signaling pathway, and can negatively regulate this pathway (Hwang and Song, 2017; Orlandi et al., 2017; Shen et al., 2017; Chandrasekaran et al., 2019; Pan et al., 2020). The results of the present study revealed that the hippocampal protein expression of SYN was significantly reduced in the Aβ25–35 model of aging, and BDNF was also considerably reduced in this model. These results indicate that this signaling pathway may affect the spatial learning, memory, and cognitive functions of mice; this is similar to the findings of other studies (Liu et al., 2019; Wahl et al., 2019; Wang et al., 2019a; Zhong et al., 2019; Liang et al., 2020). Furthermore, the immunofluorescence and western blotting results in the current study indicated that the expression of PGC-1α, a pivotal protein of this signaling pathway, was decreased in the mouse hippocampus in the Aβ and Aβ + AST + NAM groups. This finding indicates that the expression of the SIRT1/PGC-1α signaling pathway decreased significantly in these groups, which may be related to alterations in the expression of synaptic-related proteins and the spatial memory, learning, and cognitive capacities of mice. This research therefore provides a further experimental basis for the previously reported correlations between the SIRT1/PGC-1α signaling pathway and learning, memory, cognitive, and antioxidant abilities (Sun et al., 2018; Wang et al., 2019b, c).

AST plays a vital role in antioxidative and anti-aging processes, and protects synaptic proteins; however, the precise underlying molecular mechanisms remain to be explored. As can be seen from our experimental results, the spatial learning, memory, and cognitive functions of mice can be decreased by injecting Aβ25–35. Through the SIRT1/PGC-1α signaling pathway, AST can protect synaptic proteins, increase the expression of SYN and BDNF proteins, and improve learning, memory, and cognitive abilities (El-Agamy et al., 2018; Han et al., 2019; Kanazashi et al., 2019; Zhou et al., 2019).

In conclusion, the SIRT1/PGC-1α signaling pathway is closely related to learning, memory, cognitive, and antioxidant abilities, as well as the increased expression of SYN and BDNF, which are synapse-associated proteins. AST can increase the expression of the SIRT1/PGC-1α signaling pathway. These experimental results indicate that AST influences the SIRT1/PGC-1α signaling pathway to regulate the expression of synaptic proteins in the hippocampus, such as SYN and BDNF, thus improving learning, memory, and cognition in aging mice and inhibiting oxidative stress-induced brain aging. The mechanisms of brain aging remain unclear; however, the results of the present study demonstrate that AST acts through the SIRT1/PGC-1 signaling pathway to regulate the expression of SYN and BDNF. Further studies are needed to fully elucidate the cellular and molecular mechanisms mediating the functional improvements in relation to oxidative stress. For example, the roles of SYN, BDNF, SIRT1, and PGC-1α in the aging process can be examined using in vitro experiments. We will continue to investigate whether AST upregulates the expression of other synaptic proteins through the SIRT1/PGC-1 signaling pathway, and explore relevant trials to select the appropriate dose of AST for clinical applications. This study may provide a reliable theoretical basis for the prevention and treatment of brain aging and senile dementia, as well as for the further development and clinical application of AST.

Author contributions: Study design and manuscript writing: NL, HL; experiment implementation: NL, LZ, YMZ; data analysis: NL, WP. All authors approved the final version of the manuscript.

Conflicts of interest: The authors declare that there are no conflicts of interest.

Financial support: This study was supported by the National Natural Science Foundation of China, No. 8177051488 (to HL). The funder had no roles in the study design, conduction of experiment, data collection and analysis, decision to publish, or preparation of the manuscript.

Institutional review board statement: The study was approved by Institutional Animal Care and Use Committee, China Medical University, China (approval No. CMU2019294) on January 15, 2019.

Copyright license agreement: The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement: Datasets analyzed during the current study are available from the corresponding author on reasonable request.

Plagiarism check: Checked twice by iThenticate.

Peer review: Externally peer reviewed.

Open peer reviewer: Evandro Fei Fang, University of Oslo and Akershus University, Norway.

Additional file: Open peer review report 1[SUPPORTING:1].

Funding: This study was supported by the National Natural Science Foundation of China, No. 8177051488 (to HL).


1Baghel MS, Singh P, Srivas S, Thakur MK (2019) Cognitive changes with aging. Proc Natl Acad Sci India Sect B Biol Sci 89:765-773.
2Campoio TR, Oliveira FA, Otton R (2011) Oxidative stress in human lymphocytes treated with fatty acid mixture: role of carotenoid astaxanthin. Toxicol In Vitro 25:1448-1456.
3Chandrasekaran K, Anjaneyulu M, Choi J, Kumar P, Salimian M, Ho CY, Russell JW (2019) Role of mitochondria in diabetic peripheral neuropathy: Influencing the NAD(+)-dependent SIRT1-PGC-1α-TFAM pathway. Int Rev Neurobiol 145:177-209.
4Cheng F, Vivacqua G, Yu S (2011) The role of a-synuclein in neurotransmission and synaptic plasticity. J Chem Neuroanat 42:242-248.
5El-Agamy SE, Abdel-Aziz AK, Wahdan S, Esmat A, Azab SS (2018) Astaxanthin ameliorates doxorubicin-induced cognitive impairment (Chemobrain) in experimental rat model: impact on oxidative, inflammatory, and apoptotic machineries. Mol Neurobiol 55:5727-5740.
6Guo P, Pi H, Xu S, Zhang L, Li Y, Li M, Cao Z, Tian L, Xie J, Li R, He M, Lu Y, Liu C, Duan W, Yu Z, Zhou Z (2014) Melatonin Improves mitochondrial function by promoting MT1/SIRT1/PGC-1 alpha-dependent mitochondrial biogenesis in cadmium-induced hepatotoxicity in vitro. Toxicol Sci 142:182-195.
7Haider S, Tabassum S (2018) Impact of 1-day and 4-day MWM training techniques on oxidative and neurochemical profile in rat brain: A comparative study on learning and memory functions. Neurobiol Learn Mem 155:390-402.
8Han JH, Lee YS, Im JH, Ham YW, Lee HP, Han SB, Hong JT (2019) Astaxanthin ameliorates lipopolysaccharide-induced neuroinflammation, oxidative stress and memory dysfunction through inactivation of the signal transducer and activator of transcription 3 pathway. Mar Drugs 17:123.
9Harris NA, Winder DG (2018) Synaptic plasticity in the bed nucleus of the stria terminalis: underlying mechanisms and potential ramifications for reinstatement of drug- and alcohol-seeking behaviors. ACS Chem Neurosci 9:2173-2187.
10Hwang ES, Song SB (2017) Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cell Mol Life Sci 74:3347-3362.
11Ishola IO, Jacinta AA, Adeyemi OO (2019) Cortico-hippocampal memory enhancing activity of hesperetin on scopolamine-induced amnesia in mice: role of antioxidant defense system, cholinergic neurotransmission and expression of BDNF. Metab Brain Dis 34:979-989.
12Jackson HL, Cardounel AJ, Zweier JL, Lockwood SF (2004) Synthesis, characterization, and direct aqueous superoxide anion scavenging of a highly water-dispersible astaxanthin-amino acid conjugate. Bioorg Med Chem Lett 14:3985-3991.
13Kanazashi M, Tanaka M, Nakanishi R, Maeshige N, Fujino H (2019) Effects of astaxanthin supplementation and electrical stimulation on muscle atrophy and decreased oxidative capacity in soleus muscle during hindlimb unloading in rats. J Physiol Sci 69:757-767.
14Kandola A, Ashdown-Franks G, Hendrikse J, Sabiston CM, Stubbs B (2019) Physical activity and depression: Towards understanding the antidepressant mechanisms of physical activity. Neurosci Biobehav Rev 107:525-539.
15Li N, Li Y, Li LJ, Zhu K, Zheng Y, Wang XM (2019) Glutamate receptor delocalization in postsynaptic membrane and reduced hippocampal synaptic plasticity in the early stage of Alzheimer’s disease. Neural Regen Res 14:1037-1045.
16Liang D, Zhuo Y, Guo Z, He L, Wang X, He Y, Li L, Dai H (2020) SIRT1/PGC-1 pathway activation triggers autophagy/mitophagy and attenuates oxidative damage in intestinal epithelial cells. Biochimie 170:10-20.
17Lin QQ, Geng YW, Jiang ZW, Tian ZJ (2017) SIRT1 regulates lipopolysaccharide-induced CD40 expression in renal medullary collecting duct cells by suppressing the TLR4-NF-κB signaling pathway. Life Sci 170:100-107.
18Liu D, Ma Z, Xu L, Zhang X, Qiao S, Yuan J (2019) PGC1α activation by pterostilbene ameliorates acute doxorubicin cardiotoxicity by reducing oxidative stress via enhancing AMPK and SIRT1 cascades. Aging (Albany NY) 11:10061-10073.
19Liu HL, Zhao G, Cai K, Zhao HH, Shi LD (2011) Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation. Behav Brain Res 218:308-314.
20Low WC, Rujitanaroj PO, Wang F, Wang J, Chew SY (2015) Nanofiber-mediated release of retinoic acid and brain-derived neurotrophic factor for enhanced neuronal differentiation of neural progenitor cells. Drug Deliv Transl Res 5:89-100.
21Ma Q, Geng Y, Wang HL, Han B, Wang YY, Li XL, Wang L, Wang MW (2019) High frequency repetitive transcranial magnetic stimulation alleviates cognitive impairment and modulates hippocampal synaptic structural plasticity in aged mice. Front Aging Neurosci 11:235.
22Ma Y, Li W, Yin Y, Li W (2015) AST IV inhibits H2O2-induced human umbilical vein endothelial cell apoptosis by suppressing Nox4 expression through the TGF-β1/Smad2 pathway. Int J Mol Med 35:1667-1674.
23Ma Y, Gong X, Mo Y, Wu S (2016) Polydatin inhibits the oxidative stress-induced proliferation of vascular smooth muscle cells by activating the eNOS/SIRT1 pathway. Int J Mol Med 37:1652-1660.
24Macklin L, Griffith CM, Cai Y, Rose GM, Yan XX, Patrylo PR (2017) Glucose tolerance and insulin sensitivity are impaired in APP/PS1 transgenic mice prior to amyloid plaque pathogenesis and cognitive decline. Exp Gerontol 88:9-18.
25Marin DP, Bolin AP, Macedo Rde C, Sampaio SC, Otton R (2011) ROS production in neutrophils from alloxan-induced diabetic rats treated in vivo with astaxanthin. Int Immunopharmacol 11:103-109.
26Orlandi I, Pellegrino Coppola D, Strippoli M, Ronzulli R, Vai M (2017) Nicotinamide supplementation phenocopies SIR2 inactivation by modulating carbon metabolism and respiration during yeast chronological aging. Mech Ageing Dev 161:277-287.
27Pan S, Leng J, Deng X, Ruan H, Zhou L, Jamal M, Xiao R, Xiong J, Yin Q, Wu Y, Wang M, Yuan W, Shao L, Zhang Q (2020) Nicotinamide increases the sensitivity of chronic myeloid leukemia cells to doxorubicin via the inhibition of SIRT1. J Cell Biochem 121:574-586.
28Park JS, Mathison BD, Hayek MG, Massimino S, Reinhart GA, Chew BP (2011) Astaxanthin stimulates cell-mediated and humoral immune responses in cats. Vet Immunol Immunopathol 144:455-461.
29Popa-Wagner A, Dumitrascu DI, Capitanescu B, Petcu EB, Surugiu R, Fang WH, Dumbrava DA (2020) Dietary habits, lifestyle factors and neurodegenerative diseases. Neural Regen Res 15:394-400.
30Shen C, Dou X, Ma Y, Ma W, Li S, Song Z (2017) Nicotinamide protects hepatocytes against palmitate-induced lipotoxicity via SIRT1-dependent autophagy induction. Nutr Res 40:40-47.
31Song X, Wang B, Lin S, Jing L, Mao C, Xu P, Lv C, Liu W, Zuo J (2014) Astaxanthin inhibits apoptosis in alveolar epithelial cells type II in vivo and in vitro through the ROS-dependent mitochondrial signalling pathway. J Cell Mol Med 18:2198-2212.
32Sun W, Qiao W, Zhou B, Hu Z, Yan Q, Wu J, Wang R, Zhang Q, Miao D (2018) Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition. Metabolism 88:61-71.
33Tan M, Tang C, Zhang Y, Cheng Y, Cai L, Chen X, Gao Y, Deng Y, Pan M (2015) SIRT1/PGC-1α signaling protects hepatocytes against mitochondrial oxidative stress induced by bile acids. Free Radic Res 49:935-945.
34Thirupathi A, de Souza CT (2017) Multi-regulatory network of ROS: the interconnection of ROS, PGC-1 alpha, and AMPK-SIRT1 during exercise. J Physiol Biochem 73:487-494.
35Toklu HZ, Scarpace PJ, Sakarya Y, Kirichenko N, Matheny M, Bruce EB, Carter CS, Morgan D, Tümer N (2017) Intracerebroventricular tempol administration in older rats reduces oxidative stress in the hypothalamus but does not change STAT3 signalling or SIRT1/AMPK pathway. Appl Physiol Nutr Metab 42:59-67.
36Visioli F, Artaria C (2017) Astaxanthin in cardiovascular health and disease: mechanisms of action, therapeutic merits, and knowledge gaps. Food Funct 8:39-63.
37Wahl D, Gokarn R, Mitchell SJ, Solon-Biet SM, Cogger VC, Simpson SJ, Le Couteur DG, de Cabo R (2019) Central nervous system SIRT1 expression is required for cued and contextual fear conditioning memory responses in aging mice. Nutr Healthy Aging 5:111-117.
38Wang J, Dong ZH, Gui MT, Yao L, Li JH, Zhou XJ, Fu DY (2019a) HuoXue QianYang QuTan Recipe attenuates left ventricular hypertrophy in obese hypertensive rats by improving mitochondrial function through SIRT1/PGC-1α deacetylation pathway. Biosci Rep 39:BSR20192909.
39Wang K, Sun W, Zhang L, Guo W, Xu J, Liu S, Zhou Z, Zhang Y (2018) Oleanolic acid ameliorates Aβ25-35 injection-induced memory deficit in Alzheimer’s disease model rats by maintaining synaptic plasticity. CNS Neurol Disord Drug Targets 17:389-399.
40Wang W, Shang C, Zhang W, Jin Z, Yao F, He Y, Wang B, Li Y, Zhang J, Lin R (2019b) Hydroxytyrosol NO regulates oxidative stress and NO production through SIRT1 in diabetic mice and vascular endothelial cells. Phytomedicine 52:206-215.
41Wang Y, Hong Y, Zhang C, Shen Y, Pan YS, Chen RZ, Zhang Q, Chen YH (2019c) Picroside II attenuates hyperhomocysteinemia-induced endothelial injury by reducing inflammation, oxidative stress and cell apoptosis. J Cell Mol Med 23:464-475.
42Wolf AM, Asoh S, Hiranuma H, Ohsawa I, Iio K, Satou A, Ishikura M, Ohta S (2010) Astaxanthin protects mitochondrial redox state and functional integrity against oxidative stress. J Nutr Biochem 21:381-389.
43Yan S, Wang M, Zhao J, Zhang H, Zhou C, Jin L, Zhang Y, Qiu X, Ma B, Fan Q (2016) MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis. Int J Mol Med 38:201-209.
44Yan XS, Yang ZJ, Jia JX, Song W, Fang X, Cai ZP, Huo DS, Wang H (2019) Protective mechanism of testosterone on cognitive impairment in a rat model of Alzheimer’s disease. Neural Regen Res 14:649-657.
45Yerra VG, Kalvala AK, Kumar A (2017) Isoliquiritigenin reduces oxidative damage and alleviates mitochondrial impairment by SIRT1 activation in experimental diabetic neuropathy. J Nutr Biochem 47:41-52.
46Zhang YM, Zeng L, Zhao HH, Lai H (2019) The effect of astaxanthin on damaged hippocampal formation induced by formaldehyde in mice. Jiepou Kexue Jinzhan 25:207-209,212.
47Zhong J, Ouyang H, Sun M, Lu J, Zhong Y, Tan Y, Hu Y (2019) Tanshinone IIA attenuates cardiac microvascular ischemia-reperfusion injury via regulating the SIRT1-PGC1α-mitochondrial apoptosis pathway. Cell Stress Chaperones 24:991-1003.
48Zhou Y, Baker JS, Chen X, Wang Y, Chen H, Davison GW, Yan X (2019) High-dose astaxanthin supplementation suppresses antioxidant enzyme activity during moderate-intensity swimming training in mice. Nutrients 11:1244.