ABSTRACT
The circadian rhythm of the universe controls the cycle of planetary life, which is in direct control over the process of aging itself, which is inevitable. “Adult-onset aging” is degenerative by nature, and in today’s modern society, it is exacerbated by environmental pollutants and extended human life expectancy; rendering an epidemic of the age-related central nervous system (CNS) neurological diseases (NDs), including Parkinson’s disease (PD) and Alzheimer’s disease (AD). Individual vulnerability to these insults is a function of two critical physiological capabilities of the human body which can be modified by drugs/nutrients and include (a) the ability to neutralize oxidative toxins and (b) the ability to remove damaged oxidized biomass, where both events are codependent and play a principal role in predicting lifespan (senescence) and severity of age-related diseases. These capabilities center around the defense system referred to as the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) and Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1)-Nrf2- (antioxidant response element)).
The well-known basic schema of Nrf2/Keap1 involves an oxidant/electrophile adduct modification made on Keap1, which then dissociates from Nrf2, allowing Nrf2 to translocate to the nucleus to evoke an expression of >200 defense genes via the (“antioxidant response element” [ARE]), also referred to as the electrophile response element (ERE). ARE/ERE defense genes in effect boost biological xenobiotic, antioxidant, autophagy, and proteasomal/ubiquitination responses. In this chapter, we discuss the upstream controls over Nrf2/Keap1, which center on either induction or degradation of the Nrf2 transcript through Cysteine (Cys) modifications on Keap1, serine (Ser) residues in the Nrf2 (Neh) domains 1–7 or the age-related rise in Nrf2 suppressors such as Bach-1.
A second theme discussed in this chapter is the inextricable interdependent relay between Nrf2/Keap1 and autophagy (macrophagy – mTOR), which work together like a wheel driven by a bicycle chain with modifications controlled by the pedal. Just like any other universal system (biological or environmental), trash collection, processing, and recycling (autophagy) of waste materials into new-purpose materials maintain order and health. In biological systems, waste systems are carried out by lysosomes (incinerators), which contain hydrolases in an enclosed acidic environment where the trash (autophagosomes) is filled with damaged cellular debris and organelles. The speed of waste removal by autophagy is directly tied to nuclear Nrf2 concentration (and vice versa); this is reported across almost every study in the literature, with the primary focus of current research centered on the p62/sequestosome cargo receptor carrier serving as a prime control over Keap1 in the “Nrf2/p62/SQSTM1 self-propelling axis”. Losses in Nrf2/SQSTM1/p62 create an Nrf2/autophagy shutdown and are associated with AD and PD.
Lastly, in this chapter, we include a critical review of nutraceutical Nrf2-activating compounds, addressing inherent methodological flaws (false positives) observed by Nrf2/Keap1/ARE “protective” activating natural compounds in vitro (auto-oxidation), which can worsen, rather than protect against cell damage by Nrf2-inducing heavy metal toxins. We also discuss concerns about studies conducted in immortal cancer cell lines. A contradiction occurs concerning aging (senescence) and cancer cells (immortality) reflected precisely by a complete inversion of the Nrf2 p62/SQSTM1 axis, widely described in the literature. Lastly, we provide a brief review and a list of Nrf2-activating nutraceuticals reported primarily in animal models with an expansive range of oxidative injuries.
