Next, we aimed to determine whether compounds that we predicted to be anti-NeuronAge, i.e. neuroprotective, could indeed prevent the age-related functional decline of aging neurons. We chose two compounds, that were among the most strongly anti-correlated with NeuronAge patterns, BRD-K13195996 and vanoxerine (Figure 6B). The chemical identity of the phenolic compound BRD-K13195996 is 3-Hydroxy-4,5-dimethoxybenzoic acid, which is related to 4-Hydroxy-3,5-dimethoxybenzoic acid that is known as syringic acid. Syringic acid is a naturally occurring secondary compound derived from edible plants and fruits, among those olives, walnuts, and grapes – and furthermore red wine and honey 64. A correlation between the anti-oxidative properties of syringic acid and reduced neurotoxicity following bisphenol A insult has recently been shown65, yet no clear mechanism is reported so far66. Given the dietary availability of syringic acid, we chose to test its effect on rapidly aging neurons in C. elegans. Vanoxerine is a potent dopamine uptake inhibitor and has been developed as cocaine-abuse medication 67, and, moreover, vanoxerine was observed to impede colorectal cancer stem cell functions by repressing G9a expression 68. Vanoxerine was so far not reported to exhibit neuroprotection or anti-aging effects.
We applied either compounds to nematodes for a 24 h short-term treatment. We assessed neurite degeneration in ASJ and ASK neurons (exemplarily for the old predicted neurons) and observed a significantly reduced deterioration for both compounds, with Cohen’s h ranging from 0.8 to 0.97, i.e. large effect sizes (Figure 6C). Applying either of the compounds to nematodes showed no significant adverse effects an OLL neurons (Supplement Figure 4A). This indicates that both compounds interfere with the physiological degeneration process of the old predicted neurons and are able to restore a healthy neuron state.
Next, we assessed whether our NeuronAge compound predictions could also identify neurotoxic compounds and hence serve for compound risk assessment. We tested the 5-HT1A serotonin receptor antagonist WAY-100635, for which so far no adverse effects on neuron health have been reported, in nematode I2 and OLL neurons (as representatives of healthy young neurons). We observed that WAY-100635 induced significant neurite deterioration in I2 (p-value=0.02, Cohen’s h=-0.76) but not in OLL (p-value=0.08, Cohen’s h=-0.34) neurons (Figure 6C). This indicates that WAY-100635 does not have an indiscriminate effect on all neurons but is more selective, potentially depending on surface receptor expression, presentation, or specific neuronal metabolism patterns.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10780450/
Food products [mg/100 g]
Thyme 11.70 ± 0.42 [49]
Oregano 3.75 ± 5.30 [49]
Sage 3.35 ± 4.74 [49]
Rosemary 1.03 ± 1.79 [50]
Cloves 0.79 ± 0.00 [51]
Walnut 33.83 ± 13.96 [52]
Black olive 33.10 ± 32.13 [53]
Green olive 6.00 ± 8.49 [52]
Cauliflower 1.13 ± 0.02 [52]
Date (dried) 6.06 ± 3.81 [54]
Date (fresh) 2.45 ± 4.10 [54]
Currant 0.34 ± 0.13 [55]
Grape seed (Cabernet Sauvignon) 122.87 ± 0.25 [56]
Pumpkin pulp (C. maxima ‘Bambino’) 2.67 ± 0.05 [57]