RESUMEN
Aging is a complex process of impaired physiological integrity and function, and is associated with increased risk of cardiovascular disease, diabetes, neurodegeneration, and cancer. The cellular environment of the aging brain exhibits perturbed bioenergetics, impaired adaptive neuroplasticity and flexibility, abnormal neuronal network activity, dysregulated neuronal Ca2+ homeostasis, accumulation of oxidatively modified molecules and organelles, and clear signs of inflammation. These changes make the aging brain susceptible to age-related diseases, such as Alzheimer's and Parkinson's diseases. In recent years, unprecedented advances have been made in the study of aging, especially the effects of herbal/natural compounds on evolutionarily conserved genetic pathways and biological processes. Here, we provide a comprehensive review of the aging process and age-related diseases, and we discuss the molecular mechanisms underlying the therapeutic properties of herbal/natural compounds against the hallmarks of brain aging.
RESUMEN
In an increasingly aged global population, achieving healthy life expectancy through natural and safe drug interventions is highly desirable. Here we show that total ginsenosides (TGGR), the main active components in the traditional Chinese medicine, ginseng, promote longevity across species. In Drosophila, an intriguing effect of TGGR on lifespan was the relatively narrow treatment window to elicit long-term benefits. TGGR administration during early adulthood, and especially during midlife, was sufficient to extend lifespan in both sexes. TGGR did not increase lifespan by reducing food intake or reproductive capacity; rather, TGGR increased the fertility of male Drosophila. TGGR augmented healthspan readouts associated with youth and with healthy aging, such as motility, intestinal barrier integrity, and biorhythm homeostasis. TGGR treatment also improved some types of stress resistance in both sexes, including increased tolerance to starvation and oxidation, and shifting "aged" gene expression patterns toward "healthy" patterns seen in the young. Gene expression, pharmacological and genetic epistatic analyses demonstrated that TGGR effects require normal expression of genes involved in insulin, TOR and MAPK signaling. The positive effects of TGGR on both healthspan and lifespan, coupled with its mechanism of action via evolutionarily conserved signaling pathways, demonstrate it to be a promising anti-aging drug.
RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Historical literature and pharmacological studies demonstrate that ginseng, one of the most popular herbal medicines in China, holds potential benefits for Parkinson's disease (PD). AIM OF THE STUDY: Studies in Drosophila melanogaster (Dm) have highlighted mitochondrial dysfunction upon loss of PTEN-induced putative kinase 1 (PINK1) as a central mechanism of PD pathogenesis. Using PINK1B9 mutant Dm, we aimed to explore the therapeutic action of ginseng total protein (GTP) on PD and provide in-depth scientific interpretation about the traditional efficacy of ginseng. MATERIALS AND METHODS: We first used gel chromatography to purify GTP and confirmed its molecular weight by SDS-PAGE. Effects of GTP on PINK1B9 mutants, which were supplied with standard diet from larvae to adult stages, were assayed in flies aged 3-6 (I), 10-15 (II), and 20-25 (III) days. Parkinson-like phenotypes were analyzed by evaluating lifespan, dopaminergic neurons, dopamine levels, and locomotor ability. Mitochondrial function was assessed by evaluating ATP production, respirometry, and mitochondrial DNA. In addition, reactive oxygen species were measured using dihydroethidium and 2',7'-dichlorodihydrofluorescein diacetate staining. PD-related oxidative stress was simulated by paraquat and rotenone, and mitochondrial membrane potential was measured using JC-10 reagent. Protein and mRNA expression was detected by Western blot and real-time quantitative reverse transcription polymerase chain reaction, respectively. RESULTS: This study demonstrates for the first time that GTP treatment delays the onset of a Parkinson-like phenotype in PINK1B9 Dm, including prolongation of lifespan and rescue of climbing ability, as well as rescue of the progressive loss of a cluster of dopaminergic neurons in the protocerebral posterior lateral 1 region, which was accompanied by a significant increase of dopamine content in the brain. In addition, GTP notably reduced the penetrance of abnormal wing position, indicating a strong inhibitory effect on indirect flight muscle degeneration. We further showed that GTP could promote maintenance of mitochondrial function and protect mitochondria from PD-associated oxidative stress by activating the mitochondrial unfolded protein response (UPRmt). CONCLUSIONS: GTP protected against mitochondrial dysfunction and neurodegeneration by inducing UPRmt in the Dm PINK1B9 model of PD. Our results suggest that GTP is a promising candidate for PD, and reveal a new mechanism by which ginseng is neuroprotective.