I find it really intriguing that so many aphrodisiacs are effective in my case. Mastic gum is no exception as it is a traditionally known aphrodisiac. It is however not clear if all of these supplements' aphrodisiac properties are only due to an increase in testosterone. I can only guess there is a convergence between aphrodisiacs and the mechanisms of anti-inflammatory pathways. Of course I have no clear proof of this, but one still has to wonder about the coincidence.
A most likely explanation to this probable connection lies in the overexpression of the NRF2 pathway. Although in the past I thought that NRF2 may not play a significant role in my problems recently I had to realize that it must be one of the factors at its core. This is nothing new of course as NRF2 has a central role in the anti-oxidant response mechanism, however I feel its function lacks proper emphasis and discussion.
A guy who cured himself from CFS made a great article about NRF2.
https://mybiohack.com/blog/nrf2-cirs-sensitivitiesA lot of the things he highlights about NRF2 reminds me of things what POISers were talking about on the site. Although he wanted to point out some of the drawbacks regarding NRF2 activation, most of the article describes its beneficial effects. He lists loads of NRF2 agonist supplements, most of which helped me, though with varying efficacy. Most importantly NRF2 activation can decrease pro-inflammatory cytokines, which must be an important aspect of its effects. It is also indicated that
NRF2 activation can play a role in libido enhancement and sexual organ protection, however it is less clear if this can be generalized.
Although not in the list, but Giloy/Guduchi also potently activates NRF2 and acts as an aphrodisiac.
https://www.researchgate.net/publication/354468485_Tinospora_cordifolia_Willd_Miers_Protection_mechanisms_and_strategies_against_oxidative_stress-related_diseasesMastic oil and its constituents all induce NRF2.
https://www.mdpi.com/2076-3921/10/1/127/htmThere is abundant evidence that saffron also activates the NRF2 pathway.
https://www.researchgate.net/profile/Arian-Khoshandam/publication/361822359_Interaction_of_saffron_and_its_constituents_with_Nrf2_signaling_pathway_A_review/links/62ebcdb80b37cc34476dd64b/Interaction-of-saffron-and-its-constituents-with-Nrf2-signaling-pathway-A-review.pdfIt may also explain why exercise intolerance develops as (premature-) aging turns NRF2 signaling defective which impairs proper responses to exercise.
https://www.frontiersin.org/articles/10.3389/fphys.2017.00268/fullIt was a bit surprising to see Lansoprazole as an activator as it also helped me in the past. Well there are a number of other interesting inducers, but too many to list them here, so check at the link.
Some controversies do exist though. For one apigenin, quercetin and luteolin may work dose-dependently, so their effects are less predictable. Another one is that fenugreek was indicated as an inhibitor, but it is also a source of dioscin and diosgenin both of which clearly increase NRF2 expression. Needless to say this also makes maca an NRF2 inducer.
https://saudijournals.com/media/articles/SJBR_410_318-323.pdfIt also seems contradictory that testosterone is indicated to reduce NRF2 while a number of supplements that increase NRF2 are actually testosterone boosters like damiana, mangosteen, maca, tribulus, zinc, beta-ecdysterone, tongkat ali and probably more.
He also proposes a regime based on hormesis which means an intermittent intake of a combination of NRF2 inducers that may act in synergy for an increased benefit, however the episodic intake may help to avoid the potential pitfalls of prolonged NRF2 overexpression.
Another good deal of NRF2 inducers can be found at Table 1. in the following article. It is quite a good thing that it also details many trace elements, vitamins and amino acids.
https://www.mdpi.com/1422-0067/21/12/4484/htmWell this latter review provides much more information than just about NRF2. It puts our whole problem in a context as I believe that premature aging (senescence) of sexual organs is the most likely cause of POIS.
It is common knowledge that covid-19 causes pro-inflammatory cytokine storm and it was discussed earlier that NRF2 agonist agents may serve to ameliorate this state.
https://poiscenter.com/forums/index.php?topic=3733.msg40429#msg40429NRF2 signaling can be also connected to the earlier model of metabolic syndrome.
https://www.nature.com/articles/s41598-017-08899-7Some additional information that could serve to complement this:
1. Prolonged endurance exercise can significantly reduce Serca2a expression if NRF2 is deficient.
https://www.frontiersin.org/articles/10.3389/fphys.2017.00268/full2. Combined PPARA and NRF2 upregulation causes the downregulation of SREBP-1c and NF-kB.
https://onlinelibrary.wiley.com/doi/abs/10.1002/mnfr.2017004793. PGC-1alpha potentiates the function of NRF1 and NRF2.
https://www.sciencedirect.com/science/article/pii/S15504131110021174. NRF2 activation inhibits TGFbeta signaling.
https://openheart.bmj.com/content/8/1/e001663.full5. AP-1 subunit c-Jun can activate NRF2-induced transcription, while c-Fos can suppress it.
PPARG and estrogen receptor alpha can directly bind to NRF2 and suppress its activity.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369905/6. Estrogen can cause oxidative stress. SULT1E1 inactivates 17beta-estradiol. Oxidative stress induces SULT1E1 through Nrf2 activation. Estrogen also activates Nrf2 as control.
https://cancerci.biomedcentral.com/articles/10.1186/s12935-019-0826-x
