Healthspan and Lifespan is Determined by Redox Chemistry Cellular Homeostasis

Thioredoxin/TXNIP  ratio may be the servocontrol or lynchpin of redox homeostasis.  Intermittent fasting, Nrf2 activation, keto diet and molecular hydrogen H2 allow restoration of Thioredoxin CAPACITY to signal rapid transcription and post translation modification changes that prevent oxidative damage and senescent or apoptotic changes.

Diabetes or insulin resistance results from lowered ratio of Thioredoxin/TXNIP.

Insulin resistance syndrome is the root cause of virtually all degenerative diseases.

Because of the lower respiratory quotient of triglyceride versus carbohydrate (0.7 versus 0.95), ketogenic diets restore health and resilience for 2/3 of adult patients in early adulthood and speculative every aged person.

Aging reduces proteostasis which reduces redox signaling which causes degenerative changes.  Spermidine (wheat germ) uniquely improves proteostasis by virtue of its spermidine content.

4. Conclusions and Future Directions

Binding to target DNA and triggering the expression of gene transcription involved in essential biological pathways, transcription factors are integral players in the proper cellular and organismal function and survival. Any dysregulation or dysfunction in a transcription factor can lead to a broad range of diseases including cancer, autoimmune disease, cardiovascular disease, neurological disease, and diabetes [108]. Maintenance of ROS levels is essential for organismal well-being and are controlled by enzymatic and non-enzymatic antioxidant defenses that scavenge oxidative aggression. ROS induce PTMs on protein thiols which in turn calibrate protein activities towards an adequate cellular response. Here we discussed the role of PTMs in regulating oxidative stress-responsive TFs. We described TFs that are participating in rapid redox reaction such as inter-disulfide exchange, that way titrating a response to changing redox level. As depicted in Fig. 5, PRDX1, as well as PRDX2, perform such relay function with FOXO3 and STAT3, respectively. Given the requirement of reducible disulfide bridges in the relay partners, it is conceivable to assume that with a rise in H₂O₂ levels, the relay is shut off due to non-reducible thiol modifications that prohibit further regulation of TFs by redoxins. The high-affinity redoxins have for ROS may be the key to this mechanism. For example, the rate constant for reactions between H₂O₂ and PRDXs ranges between 3.0 x 10⁵ – 1.0 x 10⁸ (M^-1s^-1) [109], [110], in times of stress when H₂O₂ levels are high, a PRDX can quickly scavenge the H₂O₂, becoming oxidized, and in turn can promptly oxidize a target transcription factor. Depending on the manner in which the transcription factor is regulated that is activation or inactivation, this fast action can result in the fact up-regulation or down-regulation of target genes that may be key in to the stress response or reestablishing redox homeostasis. The redoxin-driven regulatory pathways may be critical sensors able to differentiate systems operating in a healthy state from systems affected by oxidative stress. By gaining a deeper understanding of the various mechanisms by which signaling during oxidative stress affects TF activity will provide a better understanding of disease pathologies related to disturbed redox homeostasis, such as cancer and neurodegenerative condition

https://www.sciencedirect.com/science/article/pii/S2213231718307055

Redoxins as gatekeepers of the transcriptional oxidative stress response

Barbara L.Hopkins^acdCarola A.Neumann^bcd

Abstract

Transcription factors control the rate of transcription of genetic information from DNA to messenger RNA, by binding specific DNA sequences in promoter regions. Transcriptional gene control is a rate-limiting process that is tightly regulated and based on transient environmental signals which are translated into long-term changes in gene transcription. Post-translational modifications (PTMs) on transcription factors by phosphorylation or acetylation have profound effects not only on sub-cellular localization but also on substrate specificity through changes in DNA binding capacity. During times of cellular stress, specific transcription factors are in place to help protect the cell from damage by initiating the transcription of antioxidant response genes. Here we discuss PTMs caused by reactive oxygen species (ROS), such as H₂O₂, that can expeditiously regulate the activation of transcription factors involved in the oxidative stress response. Part of this rapid regulation are proteins involved in H₂O₂-related reduction and oxidation (redox) reactions such as redoxins, H₂O₂ scavengers described to interact with transcription factors. Redoxins have highly reactive cysteines of rate constants around 6-10^-1s^-1 that engage in nucleophilic substitution of a thiol-disulfide with another thiol in inter-disulfide exchange reactions. We propose here that H₂O₂ signal transduction induced inter-disulfide exchange reactions between redoxin cysteines and cysteine thiols of transcription factors to allow for rapid and precise on and off switching of transcription factor activity. Thus, redoxins are essential modulators of stress response pathways beyond H₂O₂ scavenging capacity.