Withanolide and withanoside derivatives

AlexKChen · December 21, 2025, 6:33am

Ksm66 is one example of many, but they seem to be in nightshades and tomatillo might be another example?

RapAdmin · December 21, 2025, 4:55pm

Prompt:

What is the scientific and clinical evidence behind any health benefits of Withanolide and withanoside derivatives

Evidence Level: Preclinical (High Confidence), Clinical (Inferred/Low Confidence).
Data:
- C. elegans Models: Withanolide A extends lifespan by approx. 20% via the Insulin/IGF-1 signaling pathway (IIS), specifically requiring DAF-16 (FoxO) activation.
- ALS Mouse Models: Withaferin A treatment reduced damaged proteins in the spinal cord by 39% and extended lifespan by ~5.6% in aggressive ALS models.
- Metabolic Health: Withaferin A sensitizes the brain to Leptin (the satiety hormone), causing a 20–25% weight reduction in diet-induced obese mice.

Evidence Level: Clinical (Moderate).
Data:
- Withanoside IV: In murine Alzheimer’s models (A$\beta$25-35 injected), oral administration prevented the loss of axons and dendrites.
- Human Trials: Extracts standardized for high withanolide glycosides have shown improvements in cognitive processing speed and memory in mild cognitive impairment (MCI). The proposed mechanism is the metabolization of glycosides into sominone, which then crosses the blood-brain barrier (BBB).

Evidence Level: Preclinical (High), Clinical (Early Phase).
Data:
- NF-κB Inhibition: Withaferin A is a potent inhibitor of NF-κB, the master regulator of inflammation. By blocking this pathway, it reduces the chronic, low-grade inflammation (“inflammaging”) associated with cancer progression and metabolic disease.
- ROS Generation: Paradoxically, while antioxidant in healthy cells, WA induces toxic Reactive Oxygen Species (ROS) specifically in cancer cells, triggering apoptosis (cell death) in breast and ovarian cancer lines.