RESUMO
BACKGROUND: Chronic inflammation and metabolic dysfunction are key features of systemic aging, closely associated with the development and progression of age-related metabolic diseases. Bazi Bushen (BZBS), a traditional Chinese medicine used to alleviate frailty, delays biological aging by modulating DNA methylation levels. However, the precise mechanism of its anti-aging effect remains unclear. In this study, we developed the Energy Expenditure Aging Index (EEAI) to estimate biological age. By integrating the EEAI with transcriptome analysis, we aimed to explore the impact of BZBS on age-related metabolic dysregulation and inflammation in naturally aging mice. METHODS: We conducted indirect calorimetry analysis on five groups of mice with different ages and utilized the data to construct EEAI. 12 -month-old C57BL/6 J mice were treated with BZBS or ß-Nicotinamide Mononucleotide (NMN) for 8 months. Micro-CT, Oil Red O staining, indirect calorimetry, RNA sequencing, bioinformatics analysis, and qRT-PCR were performed to investigate the regulatory effects of BZBS on energy metabolism, glycolipid metabolism, and inflammaging. RESULTS: The results revealed that BZBS treatment effectively reversed the age-related decline in energy expenditure and enhanced overall metabolism, as indicated by the aging index of energy expenditure derived from energy metabolism parameters across various ages. Subsequent investigations showed that BZBS reduced age-induced visceral fat accumulation and hepatic lipid droplet aggregation. Transcriptomic analysis of perirenal fat and liver indicated that BZBS effectively enhanced lipid metabolism pathways, such as the PPAR signaling pathway, fatty acid oxidation, and cholesterol metabolism, and improved glycolysis and mitochondrial respiration. Additionally, there was a significant improvement in inhibiting the inflammation-related arachidonic acid-linoleic acid metabolism pathway and restraining the IL-17 and TNF inflammatory pathways activated via senescence associated secretory phenotype (SASP). CONCLUSIONS: BZBS has the potential to alleviate inflammation in metabolic organs of naturally aged mice and maintain metabolic homeostasis. This study presents novel clinical therapeutic approaches for the prevention and treatment of age-related metabolic diseases.
RESUMO
Bazi Bushen (BZBS), a traditional Chinese medicine, has been proven effective in the treatment of age-related disease in mouse models. However, whether its therapeutic effects are due to antiaging mechanism has not yet been explored. In the present study, we investigated the antiaging effects of BZBS in naturally aging mice by using behavioral tests, liver DNA methylome sequencing, methylation age estimation, and frailty index assessment. The methylome analysis revealed a decrease of mCpG levels in the aged mouse liver. BZBS treatment tended to restore age-associated methylation decline and prune the methylation pattern toward that of young mice. More importantly, BZBS significantly rejuvenated methylation age of the aged mice, which was computed by an upgraded DNA methylation clock. These results were consistent with enhanced memory and muscular endurance, as well as decreased frailty score and liver pathological changes. KEGG analysis together with aging-related database screening identified methylation-targeted pathways upon BZBS treatment, including oxidative stress, DNA repair, MAPK signaling, and inflammation. Upregulation of key effectors and their downstream effects on elevating Sod2 expression and diminishing DNA damage were further investigated. Finally, in vitro experiments with senescent HUVECs proved a direct effect of BZBS extracts on the regulation of methylation enzymes during cellular aging. In summary, our work has revealed for the first time the antiaging effects of BZBS by slowing the methylation aging. These results suggest that BZBS might have great potential to extend healthspan and also explored the mechanism of BZBS action in the treatment of age-related diseases.