Hui-Chuan Kuo, Data curation, Formal analysis, Resources, Validation, Writing – original draft,# 1 Sih-Yu Tong, Data curation, Formal analysis, Methodology, Writing – original draft,# 2 Ming-Wei Chao, Data curation, Formal analysis, Methodology, Resources, Writing – original draft,# 3 and Chia-Yi Tseng, Conceptualization, Formal analysis, Investigation, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing 2
Yasmina Abd‐Elhakim, Editor
Abstract
Lingzhi has long been regarded as having life-prolonging effects. Research in recent years has also reported that Lingzhi possesses anti-tumor, anti-inflammatory, immunomodulatory, hepatoprotective, and anti-lipogenic effects. The D-galactose (D-gal, 100 mg/kg/day)-induced aging Long-Evans rats were simultaneously orally administered a DMSO extract of Ganoderma tsugae (GTDE, 200 μg/kg/day) for 25 weeks to investigate the effects of GTDE on oxidative stress and memory deficits in the D-galactose-induced aging rats. We found that GTDE significantly improved the locomotion and spatial memory and learning in the aging rats. GTDE alleviated the aging-induced reduction of dendritic branching in neurons of the hippocampus and cerebral cortex. Immunoblotting revealed a significant increase in the protein expression levels of the superoxide dismutase-1 (SOD-1) and catalase, and the brain-derived neurotrophic factor (BDNF) in rats that received GTDE. D-gal-induced increase in the lipid peroxidation product 4-hydroxynonenal (4-HNE) was significantly attenuated after the administration of GTDE, and pyrin domain-containing 3 protein (NLRP3) revealed a significant decrease in NLRP3 expression after GTDE administration. Lastly, GTDE significantly reduced the advanced glycosylation end products (AGEs). In conclusion, GTDE increases antioxidant capacity and BDNF expression of the brain, protects the dendritic structure of neurons, and reduces aging-induced neuronal damage, thereby attenuating cognitive impairment caused by aging.
Introduction
Aging, a slow and progressive process of physiological change, is an inevitable natural phenomenon that is irreversible. The rate at which aging occurs is affected by complex interactions among genetics, the environment, diet, and lifestyle habits. Aging is often accompanied by a decline in physiological function, which decreases activities of daily living (ADL) and, consequently, increases healthcare and social resource demands [1, 2]. Several theories have been postulated to explain the process of aging, with the most renowned being the free radical theory of aging (FRTA) proposed by Dr. Denham Harman in 1956 [3]. According to the FRTA, aging is caused by free radicals in the body, which induce lipid peroxidation, protein oxidation, and DNA damage. Previous literature has reported that oxidative stress plays a key role in the pathogenesis of neurological or neurodegenerative diseases associated with aging [4, 5], such as Parkinson’s disease [6] and Alzheimer’s disease [7]. Studies have also shown that reactive oxygen species (ROS) promote the inflammatory response through the upregulation of pro-inflammatory mediators, which leads to the formation of inflammasomes in cells. The over-accumulation of inflammasomes in neurons may lead to neuronal death and degeneration [8–10]. Therefore, the prevention of oxidative stress has become a major direction for research on the delay of aging and the treatment of neurodegenerative diseases.
D-galactose (D-gal) is a reducing sugar that produces ROS when it is metabolized in the body [11]. It interacts with free amines on proteins and peptides via non-enzymatic glycation, producing advanced glycosylation end products (AGEs) that indirectly stimulate the production of ROS and, ultimately, cause oxidative stress [12, 13]. Research has shown that AGEs promote the formation and deposition of neurofibrillary tangles and amyloid plaques, which are neuropathological hallmarks of Alzheimer’s disease [14]. Long-term processing of D-gal causes oxidative stress [15], neuronal apoptosis [16], and inflammatory response [17], thereby accelerating aging and resulting in reduced learning ability, memory, and motor ability in animals [18, 19]. Therefore, D-gal-induced animal aging models can be used for the simulation of the characteristics of natural aging in the brain or age-associated neurodegenerative diseases. Models have been recognized internationally and widely used for research on aging mechanisms [20]. D-gal has also been adopted in the present study for the construction of an aging rat model.
Lingzhi (also known as Reishi) is an edible medicinal mushroom that has been regarded as a herb with health-promoting and life-prolonging effects in East Asian countries for several centuries [21]. It contains various bioactive compounds such as polysaccharides, triterpenes, adenosine, and small-molecule proteins. Studies have indicated that Lingzhi has various effects, including anti-tumor [22], anti-inflammatory [23], hypolipidemic [24], hypoglycemic [25], antioxidant [26], immunomodulatory [27], hepatoprotective [28] and anti-atherosclerotic [29] effects. A recent study has demonstrated the medical usage of Lingzhi in vivo and clinical studies [30]. In the present study, Songshan Lingzhi (Ganoderma tsugae), a type of Lingzhi widely used in Asia, was selected for the treatment of D-gal-induced aging rats. The hydroxyl radical-scavenging effect and metal ion chelating ability of G. tsugae give rise to superior antioxidant effects [31, 32]. Moreover, there is currently no research to apply it to the nervous system. In the present study, we established a D-gal-induced Long-Evans rat aging model through subcutaneous injections of D-gal (100 mg/kg/day). The rats were subsequently orally administered a DMSO extract of Ganoderma tsugae (Songshan Lingzhi, a common type of Lingzhi) (GTDE, 200 μg/kg/day) for 25 weeks. We aimed to investigate whether the administration of G. tsugae attenuated oxidative stress and memory deficits in D-gal-induced aging rats.
Introduction
Aging, a slow and progressive process of physiological change, is an inevitable natural phenomenon that is irreversible. The rate at which aging occurs is affected by complex interactions among genetics, the environment, diet, and lifestyle habits. Aging is often accompanied by a decline in physiological function, which decreases activities of daily living (ADL) and, consequently, increases healthcare and social resource demands [1, 2]. Several theories have been postulated to explain the process of aging, with the most renowned being the free radical theory of aging (FRTA) proposed by Dr. Denham Harman in 1956 [3]. According to the FRTA, aging is caused by free radicals in the body, which induce lipid peroxidation, protein oxidation, and DNA damage. Previous literature has reported that oxidative stress plays a key role in the pathogenesis of neurological or neurodegenerative diseases associated with aging [4, 5], such as Parkinson’s disease [6] and Alzheimer’s disease [7]. Studies have also shown that reactive oxygen species (ROS) promote the inflammatory response through the upregulation of pro-inflammatory mediators, which leads to the formation of inflammasomes in cells. The over-accumulation of inflammasomes in neurons may lead to neuronal death and degeneration [8–10]. Therefore, the prevention of oxidative stress has become a major direction for research on the delay of aging and the treatment of neurodegenerative diseases.
D-galactose (D-gal) is a reducing sugar that produces ROS when it is metabolized in the body [11]. It interacts with free amines on proteins and peptides via non-enzymatic glycation, producing advanced glycosylation end products (AGEs) that indirectly stimulate the production of ROS and, ultimately, cause oxidative stress [12, 13]. Research has shown that AGEs promote the formation and deposition of neurofibrillary tangles and amyloid plaques, which are neuropathological hallmarks of Alzheimer’s disease [14]. Long-term processing of D-gal causes oxidative stress [15], neuronal apoptosis [16], and inflammatory response [17], thereby accelerating aging and resulting in reduced learning ability, memory, and motor ability in animals [18, 19]. Therefore, D-gal-induced animal aging models can be used for the simulation of the characteristics of natural aging in the brain or age-associated neurodegenerative diseases. Models have been recognized internationally and widely used for research on aging mechanisms [20]. D-gal has also been adopted in the present study for the construction of an aging rat model.
Lingzhi (also known as Reishi) is an edible medicinal mushroom that has been regarded as a herb with health-promoting and life-prolonging effects in East Asian countries for several centuries [21]. It contains various bioactive compounds such as polysaccharides, triterpenes, adenosine, and small-molecule proteins. Studies have indicated that Lingzhi has various effects, including anti-tumor [22], anti-inflammatory [23], hypolipidemic [24], hypoglycemic [25], antioxidant [26], immunomodulatory [27], hepatoprotective [28] and anti-atherosclerotic [29] effects. A recent study has demonstrated the medical usage of Lingzhi in vivo and clinical studies [30]. In the present study, Songshan Lingzhi (Ganoderma tsugae), a type of Lingzhi widely used in Asia, was selected for the treatment of D-gal-induced aging rats. The hydroxyl radical-scavenging effect and metal ion chelating ability of G. tsugae give rise to superior antioxidant effects [31, 32]. Moreover, there is currently no research to apply it to the nervous system. In the present study, we established a D-gal-induced Long-Evans rat aging model through subcutaneous injections of D-gal (100 mg/kg/day). The rats were subsequently orally administered a DMSO extract of Ganoderma tsugae (Songshan Lingzhi, a common type of Lingzhi) (GTDE, 200 μg/kg/day) for 25 weeks. We aimed to investigate whether the administration of G. tsugae attenuated oxidative stress and memory deficits in D-gal-induced aging rats.