The authors of a recent study describe Ginkgolide B, a compound with senotherapeutic potential that improved muscle health, metabolism, frailty, inflammation, and senescence metrics and increased lifespan in female mice [1].
From East Asia to the clinic
Ginkgolide B is a compound that can be extracted from Ginkgo biloba, an East Asian tree known as the maidenhair tree. Previous research indicates that Ginkgolide B may offer many health benefits, such as improvements in osteoporosis and muscle regeneration in aged mice [2-7].
Therefore, these researchers hold that Ginkgolide B’s good safety, tolerability, and pharmacokinetic profile in humans [8, 9] and promising beneficial effects seen in model organisms make it a good candidate for healthspan and lifespan studies.
Extending lifespan
The researchers tested Ginkgolide B’s impact on female mouse lifespan. They started Ginkgolide B administration at 20 months (equivalent to 70- to 80-year-old humans). Ginkgolide B significantly extended the median lifespan by 8.5% and “extended the mean maximal lifespans of the 10% and 20% longest-lived mice by approximately 55” days.
Additionally, the researchers observed a reduced incidence of tumors; however, even the Ginkgolide B-treated mice with tumors still had longer lives, suggesting that Ginkgolide B extends lifespan not only by reducing tumors but through its beneficial impact on multiple organs and molecular processes.
Strengthening muscle
Apart from increasing lifespan, an increase in healthspan was also observed.
First, the researchers tested the impact of Ginkgolide B on muscle mass and strength. Ginkgolide B treatment improved female mice’s muscle strength, exercise capacity, and balance. It also reversed aging-related muscle wasting symptoms, such as a decreased skeletal muscle-to-body ratio, alterations to protein content in muscle, and muscle atrophy markers in aged skeletal muscle. Ginkgolide B also led to enlargement in the thigh’s main (femoral) artery and capillary density, which allowed for increased accessibility of oxygen and nutrients in muscles. However, it didn’t improve fatigue resistance or muscle recovery rate.
On the molecular level, Ginkgolide B treatment reversed several age-related changes associated with declining physical performance and muscle contraction; for example, it reduced aging-related increases in intramuscular lipid infiltration and collagen deposition.
Since the researchers focused on female mice, they also investigated sex hormones’ role in age-dependent muscle functioning. They surgically removed the mice’s ovaries, resulting in estrogen-deficient mice. Loss of estrogen led to muscle deterioration and decreased physical performance. Ginkgolide B treatment restored those functions in a dose-dependent manner, with high doses of Ginkgolide B almost completely restoring measured muscle functions.
Improved aging markers
Apart from declining muscular health, aging results in changes to metabolism, increased frailty, the chronic, low-grade inflammation known as inflammaging, and declining organ health. Ginkgolide B treatment helped alleviate those symptoms, such as by reducing the frailty index by 64.8% and benefiting the heart, kidney, spleen, and liver.
After two months of Ginkgolide B treatment, the body composition of aged mice resembled that of young mice. Similarly, it reversed disruption in biochemical measurements, such as serum triglyceride and total cholesterol levels, in aged mice and improved glucose tolerance and disruptions in glucose metabolism-related genes in skeletal muscle and liver.
Treatment with Ginkgolide B also positively impacted the inflammatory profile of aged mice, making it similar to that of young mice. The researchers also observed changes in the profiles of immune cells in aged mice, such as decreases in pro-inflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages.
Inflammaging, among other aging-related processes, is linked to senescent cells. The researchers observed that Ginkgolide B treatment positively impacted the expression of several senescence-associated markers, such as the senescence-associated secretory phenotype (SASP) along with DNA damage, cell cycle, cell size, and cell proliferation in different organs and in cell culture models of induced senescence.
Molecular pathways
The authors of this study also examined aging-induced molecular changes by conducting multiple analyses of gene expression in the mouse leg muscle using either bulk expression data or expression data from single nuclei.
The results indicated that both aging and Ginkgolide B impacted gene expression. Ginkgolide B treatment had slight but measurable impacts in this area, partially reversing some of the changes that are brought about by normal aging in mice.
An analysis that focused on the hallmarks of aging showed that multiple genes related to these hallmarks are disrupted during normal aging. Ginkgolide B “partially restored intercellular communication, cellular senescence, nutrient sensing deregulation and mitochondrial dysfunction.”
Further gene expression analysis was performed separately for different subtypes of nuclei. The authors observed that one of the subtypes, called Runx1+ type 2B myonuclei, which appear in muscle cells, had the most significant alterations to gene expression. They refer to this subtype of cells as having a “host of age-related and GB-rescued signatures at the single-nucleus level.”
These myonuclei were enriched with apoptosis and ROS markers during aging, which were reversed by Ginkgolide B treatment. The authors hypothesize that the enrichment of apoptosis markers suggests that age-related apoptosis in Runx1+ type 2B myonuclei contributes to muscle degeneration.
The authors conducted further database searches and experiments to find a molecular pathway linking Ginkgolide B treatment and Runx1, a transcription factor that controls the expression of multiple genes. They identified miR-27b-3p, a microRNA whose levels are decreased in aged muscles and restored by Ginkgolide B treatment. Restoration of miR-27b-3p levels leads to reduced expression of Runx1.
Senotherapeutic potential
The researchers concluded that Ginkgolide B has a strong senotherapeutic potential, even when started late in life, and can help address aging-related conditions that current senotherapeutics fail to address, such as sarcopenia. However, the obtained results should be investigated in different mouse strains and eventually in humans to confirm their therapeutic value.
Literature
[1] Lee, C. W., Wang, B. Y., Wong, S. H., Chen, Y. F., Cao, Q., Hsiao, A. W., Fung, S. H., Chen, Y. F., Wu, H. H., Cheng, P. Y., Chou, Z. H., Lee, W. Y., Tsui, S. K. W., & Lee, O. K. (2025). Ginkgolide B increases healthspan and lifespan of female mice. Nature aging, 5(2), 237–258.
[2] Wu, T., Fang, X., Xu, J., Jiang, Y., Cao, F., & Zhao, L. (2020). Synergistic Effects of Ginkgolide B and Protocatechuic Acid on the Treatment of Parkinson’s Disease. Molecules (Basel, Switzerland), 25(17), 3976.
[3] Zhao, Y., Xiong, S., Liu, P., Liu, W., Wang, Q., Liu, Y., Tan, H., Chen, X., Shi, X., Wang, Q., & Chen, T. (2020). Polymeric Nanoparticles-Based Brain Delivery with Improved Therapeutic Efficacy of Ginkgolide B in Parkinson’s Disease. International journal of nanomedicine, 15, 10453–10467.
[4] Yao Y. (2020). Ginsenosides reduce body weight and ameliorate hepatic steatosis in high fat diet‑induced obese mice via endoplasmic reticulum stress and p‑STAT3/STAT3 signaling. Molecular medicine reports, 21(3), 1059–1070.
[5] Zhu, B., Xue, F., Zhang, C., & Li, G. (2019). Ginkgolide B promotes osteoblast differentiation via activation of canonical Wnt signalling and alleviates osteoporosis through a bone anabolic way. Journal of cellular and molecular medicine, 23(8), 5782–5793.
[6] Lee, C. W., Lin, H. C., Wang, B. Y., Wang, A. Y., Shin, R. L., Cheung, S. Y. L., & Lee, O. K. (2021). Ginkgolide B monotherapy reverses osteoporosis by regulating oxidative stress-mediated bone homeostasis. Free radical biology & medicine, 168, 234–246.
[7] Wang, B. Y., Chen, Y. F., Hsiao, A. W., Chen, W. J., Lee, C. W., & Lee, O. K. (2023). Ginkgolide B facilitates muscle regeneration via rejuvenating osteocalcin-mediated bone-to-muscle modulation in aged mice. Journal of cachexia, sarcopenia and muscle, 14(3), 1349–1364.
[8] Shen, C., Jin, X., Wu, M., Huang, X., Li, J., Huang, H., Li, F., Liu, J., Rong, G., & Song, S. (2020). A sensitive LC-MS/MS method to determine ginkgolide B in human plasma and urine: application in a pharmacokinetics and excretion study of healthy Chinese subjects. Xenobiotica; the fate of foreign compounds in biological systems, 50(3), 323–331.
[9] Shao, F., Zhang, H., Xie, L., Chen, J., Zhou, S., Zhang, J., Lv, J., Hao, W., Ma, Y., Liu, Y., Ou, N., & Xiao, W. (2017). Pharmacokinetics of ginkgolides A, B and K after single and multiple intravenous infusions and their interactions with midazolam in healthy Chinese male subjects. European journal of clinical pharmacology, 73(5), 537–546.
