Ginsenoside Rg3 from ginseng extended lifespan and protected neurons in C. elegans
Ginsenoside Rg3 from ginseng extended lifespan and protected neurons in C. elegans
A team at Shanghai Jiao Tong University fed ginsenoside Rg3 to Caenorhabditis elegans worms. The authors suggest that the lifespan extension and neuronal protection involve lysosomes, cellular compartments that break down unwanted material, and the lipids in their membranes.
The paper was published in Aging Cell on 10 October 2026. Two of the 14 authors work at Sirio Pharma, which provided additional funding. Neurons do not divide and must remove damaged proteins through autophagy, the process by which cells break down and recycle their own components. This clearance declines with age, and the authors tested whether Rg3 could help maintain it.
The work builds on two papers published in 2023. In PLoS Biology, a team in China showed that the enzyme VPS-34 slows the conversion of the lipid PI(3)P to PI(4)P in aging motor neurons, and that partially suppressing VPS-34 reduced age-related motor decline in worms and mice. In Cell, a team in Berlin found in cell experiments that switching between these lipids regulates lysosomal activity: during starvation, PI(3)P disappears from lysosomes, their digestive activity increases, and mTORC1, a cellular nutrient sensor, is inhibited.
Rg3 had previously been reported to protect neurons in disease models, but its effects on aging at the organism level remained unclear. A total ginsenoside extract extended worm lifespan by 14 % in 2021, although Rg1, Re and Rb1 were identified as its main active components.
Worms fed Rg3 lived longer than controls, even when treatment began only on day 5 of adulthood. The researchers also examined feeding and reproduction: the effect persisted when worms were fed heat-killed bacteria, and offspring numbers were unchanged. Rg3 also extended lifespan in mutants affecting five known longevity pathways, but had no benefit when bec-1, which initiates autophagy, was suppressed or in mutants of vha-3, a component of the lysosomal proton pump.
RNA sequencing revealed changes in the expression of 753 genes, with genes involved in phosphoinositide metabolism (lipids such as PI(3)P and PI(4)P), autophagy and neuronal maintenance particularly well represented. This prompted the researchers to examine neurons: Rg3 reduced aggregates of Q40, an aggregation-prone protein containing a long glutamine tract. In a model expressing human α-synuclein, whose aggregation is associated with Parkinson's disease, more worms retained their dopaminergic neurons when treated with Rg3.
The researchers tracked neuronal lipids using fluorescent sensors that label PI(3)P and PI(4)P as spots. The number of PI(3)P spots increased with age, whereas Rg3 reduced their number on days 5 and 10 of adulthood. Rg3 increased the number of PI(4)P spots, some of which overlapped with acidic cellular compartments, including lysosomes.
The 753 genes with altered expression included genes encoding two core components of TORC1, the worm counterpart of mTORC1: their expression decreased, while expression of pifk-1, which encodes an enzyme that produces PI(4)P, increased. TORC1 activity also decreased, as indicated by reduced phosphorylation of its target RSKS-1. HLH-30, the worm counterpart of human TFEB, activates lysosomal and autophagy genes after entering the nucleus; in the authors' model, active TORC1 keeps it outside the nucleus. With Rg3 treatment, HLH-30 accumulated in intestinal cell nuclei, and expression of its target genes increased.
When pifk-1 was suppressed, Rg3 neither induced nuclear accumulation of HLH-30 nor reduced Q40 aggregates; when hlh-30 was suppressed, both the reduction in aggregates and the improvement in mobility were lost. Suppressing let-363 (the gene encoding the TOR kinase itself) together with pifk-1 reduced aggregates compared with suppressing pifk-1 alone, and Rg3 provided no further reduction. The authors therefore concluded that TORC1 inhibition at least partly bypasses the requirement for PIFK-1.