Abstract
Aging is well-characterized by the gradual decline of cellular functionality. As redox balance, proteostasis, and telomerase systems have been found to be associated with aging and age-related diseases, targeting these systems by small compounds has been considered as a promising therapeutic approach. Cycloastragenol (CA), a small molecule telomerase activator obtained from Astragalus species, has been reported to have positive effects on several age-related pathophysiologies, including ischemia, glucose intolerance, diabetes, and neurodegenerative diseases. Although CA has received intense attention as a promising compound for aging and age-related diseases, the mechanisms underlying CA activity related to redox balance, proteasome, and telomerase has not yet been reported. Here, we presented that CA increased Nrf-2 activity leading to upregulation of cytoprotective enzymes and attenuation of oxidative stress-induced ROS levels. Furthermore, CA enhanced telomerase activity by increasing not only the expression of hTERT but also its nuclear localization via the Hsp90-chaperon complex. CA alleviated the oxidative stress-induced mitochondrial hTERT levels while increasing the nuclear hTERT levels. Additionally, the proteasome activity and assembly were increased by CA. Strikingly, our data revealed that CA-mediated neuroprotection requires both Nrf-2 and hTERT induction. In conclusion, this study is the first report describing the effect of CA on these aging-related three major cellular pathways and their interrelationships. As the proteasome activator effect of CA is dependent on induction of telomerase activity, which is mediated by Nrf-2 system, CA has a great potential for healthier aging and prevention or treatment of age-related diseases by positively affecting these three cellular pathways.
Competing Interest Statement
The authors have declared no competing interest.
ABBREVIATIONS
- Nrf-2
- nuclear factor erythroid 2-related factor 2
- Keap-1
- Kelch-like ECH-associated protein 1
- ARE
- Antioxidant Response Elements
- TERT
- telomerase reverse transcriptase
- TERC
- Telomerase RNA Component
- CA
- Cycloastregenol
- DMF
- Dimethyl fumarate
- 18α-GA
- 18α-Glycyrrhetinic acid
- 6-OHDA
- 6-hydroxydopamine
- GA
- geldanamycin
- DTT
- dithiothreitol
- H2DCFDA
- 2’-7’-Dichlorodihydrofluorescein diacetate
- ROS
- reactive oxygen species
- H2O2
- hydrogen peroxide
- HO-1
- heme oxygenase 1
- GR
- glutathione reductase
- GCLC
- Glutamatecysteine ligase catalytic subunit
- CHIP
- C terminus of Hsc70-interacting protein
- Hsp90
- Heat shock protein 90
- FKBP52
- FK506-binding protein 52
- HEKn
- neonatal human primary epidermal keratinocytes
- IB
- immunoblotting
- IP
- immunoprecipitation