DetOXify Reactive Oxidants to Prevent Nerve Pain and Loss of Function

A study of neuropathy in C eligans has implications for pain and nerve function loss

Here a chemical reaction with a compound increased by increased glucose levels in the cell leads to nonenzymatic glycosylation (like crispy caramelized sauteed onions) and damage of nerves both sensory and motor.

The enzyme that detoxifies nerve metabolic toxins can be unregulated by nrf2 activators.

Hydrogen rich water.

Alpha Lipoic acid.

Ursolic acid.

Sulforaphane.

I suspect this same antioxidant nrf2 pathway activation could reduce pain or nerve hypersensitivity caused by cytokines and likely would prevent nerve damage and neurodegenerative disease (or slow them.). Perhaps arthritis knee pain would decrease!

I think hydrogen rich water is the most effective and most likely to act across the blood brain barrier.  It is also extremely inexpensive at $2.50 per month using 3 hydrogen sticks lasting 6 months and requiring 1 part white vinegar to 3 part water soak once a month to remove magnesium hydroxide and restore hydrogen production efficiency.

http://stke.sciencemag.org/content/9/457/ec286

Reducing nerve-damaging reactive metabolites

1. Annalisa M. VanHook

+ Author Affiliations

If not degraded or modified, reactive metabolites damage cells. One group of reactive metabolites is the α-dicarbonyls (α-DCs), which damage proteins, lipids, and DNA through a nonenzymatic form of glycosylation (glycation). Methylglyoxal (MGO) is an α-DC that accumulates with age and damages nerves and arteries. MGO also accumulates in patients with neurodegenerative disorders and in diabetic patients. In diabetic patients, the accumulation results from increased glycolytic flux, which produces excess MGO. Chaudhuri et al. found that Caenorhabditis elegans lacking the glyoxalase GLOD-4, an enzyme that metabolizes and detoxifies MGO, exhibited MGO accumulation, reduced motility, and neuronal damage. Similar to diabetic patients, who initially experience hypersensitivity and then later loss of sensation, worms deficient in glod-4 were initially hypersensitive to touch but eventually lost sensitivity to touch. Treating wild-type C. elegans with MGO or rearing them on a high-glucose diet phenocopied loss of glod-4. Genetic experiments revealed that accumulation of α-DCs activated the nociceptive transient receptor potential ion channel TRPA-1, which stimulated signaling through the calcium/calmodulin-dependent kinase II (CaMKII) homolog UNC-43 and the p38 mitogen-activated protein kinases PMK-1 and SEK-1 to stimulate activity of the transcription factor SKN-1. SKN-1 is homologous to vertebrate Nrf2, which stimulates the expression genes involved in antioxidant and xenobiotic responses. MGO-induced activation of SKN-1 stimulated the transcription of glod-4 as well as djr-1.1 and djr-1.2, which encode homologs of the human glyoxalase DJ1. Screening a library of natural products for compounds that rescued the phenotypes of glod-4 mutants identified podocarpic acid, a component of the resin of some conifers. Treating glod-4 mutants with podocarpic acid or the NRF2 activator α-lipoic acid stimulated activation of SKN-1 and reduced the accumulation of MGO in a manner that depended on TRPA-1. Experiments in human and rat cultured cells indicated that this α-DC detoxification pathway is conserved in vertebrates and that podocarpic acid can reduce the neurotoxic effects of MGO. This study not only delineates the pathway through which α-DCs induce the machinery necessary for their detoxification, it also demonstrates the usefulness of C. elegans for identifying compounds that could be developed into therapeutics for human patients.

Telomerase first in health, telomere length is second priority

In humans, circulating telomerase activity rather than telomeres length is inversely associated with the major cardiovascular disease risk factors.  See below.

In the nucleus, telomerase promotes telomere "stability."

In the cytoplasm, telomerase has preservation of mitochondria and antioxidant maintenance as its priority and hTert is actually blocked from translocating to the nucleus.

Beta hydroxybutyrate from lifestyle choices causes telomerase et al of the starvation gene set to be expressed.  Telomerase, BDNF, p53-pgc etc.

E.g..  Weekly 24 hour fasting improved age related heart failure EF from 30% to 60% over 8 weeks in mice.  BDNF of 30% increased to 100% of normal.  BDNF is a proxy biomarker for the starvation gene set expression and by extension telomerase.  Therefore fasting weekly increased beta hydroxybutyrate gene transcription of restorative genes including telomerase, a major biomarker of cardiovascular mortality.

Number needed to treat in the mouse study to restore EF and presumptively to reduce "hospitalization and mortality?"

One.

Conclusion of article wrongly emphasizes eating however when we eat and by extension when we do not eat alone produces beta hydroxybutyrate, a ketone from low insulin intervals and increased fat metabolizing intervals.  Insulin stores glucose and inhibits lipolysis.

80% of metabolic health is when we eat or how well we metabolize fats and produce beta hydroxybutyrate.  Insulin sensitive, exercise, fasting and ppar alpha agonists (such as ursolic acid) consuming persons are metabolically healthy and age slower than their opposites.

It appears logical to the extreme to promote 12 hours daily fasting, 24 hour weekly fasting, exercise and possibly ursolic acid 200mgs  for secondary prevention of cardiovascular disease.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761710/

Nutrition and lifestyle in healthy aging: the telomerase challenge

In contrast to stem cells which constitutively express low levels of telomerase, normal somatic human cells repress its expression immediately after birth [-]. Thus, for a long time, telomere length has been considered as an indicator of cellular senescence, and a potential biomarker of human aging, but studies supporting this role are still contradictory and inconclusive [,,]. More recent genetic studies in animal models have demonstrated that short telomeres rather than average telomere length are associated with age-related diseases and, their rescue by telomerase is sufficient to restore cell and organismal viability [30,31]. In humans, circulating telomerase activity rather than telomeres length is inversely associated with the major cardiovascular disease risk factors [32]. Thus, another concept is coming up, the “telomere stability”, a quite different concept from telomere length. For example, patients with Alzheimer's disease do not invariably have shorter telomeres, but their telomeres have significant signs of dysfunction [33-38]. Improving the activity of telomerase enzyme -that can add length back to shorter telomeres, and, in the meantime, protect longer telomeres to ensure stability- seems a way to actually turn back the biological clock. Telomerase has also extra-telomeric functions influencing various essential cellular processes, such as gene expression, signaling pathways, mitochondrial function as well as cell survival and stress resistance [40,41]. Therefore, the presence of active telomerase in stem cells, and potentially in all cells, may be helpful for longevity and good health.

Lifestyle factors known to modulate aging and age-related diseases might also affect telomerase activity. Obesity [42], insulin resistance [43,44], and cardio-vascular disease processes [45,46], which are related to oxidative stress and inflammation, have all been linked to shorter telomeres. Smoking, exposure to pollution, lower physical activity, psychological stress, and unhealthy diet significantly increase the oxidative burden and the rate of telomere shortening [47-53]. So, what a better way to counteract the “biological clock” by reactivating telomerase trough diet and lifestyle interventions? There is a recent paper showing that with intensive lifestyle modification, with a low fat diet, regular physical activity, and mental stress reduction (by yoga and meditation), telomerase activity increases significantly in peripheral blood mononuclear cell (PBMC) [54]. Again, people living in the Mediterranean countries have longer and healthier life as compared with people living in other industrialized countries, and we previously demonstrated that they have also claim longer telomeres and higher telomerase activity in PBMC [55]. It is still unclear if there is a single nutrient or a factor responsible of Mediterranean diet anti-aging properties or the whole, single ingredient foods and lifestyle are the key to “healthspan”.

Today, researchers are struggling to find a compound or an “elixir” for long life, while common people are taking dietary supplements with the intent to preserve mental, physical, and emotional health into old age. Most dietary supplement programs include combinations of vitamins, antioxidants, and other constituents, some of which have been shown to have significant health benefits in controlled clinical studies. Specific nutrients provide all the necessary building blocks to support telomere health and extend lifespan. This is the case of folate [56,57], vitamins (B, D, E, C) [58] zinc [59] and polyphenol compounds such as resveratrol [60], grape seed extract and curcumin [61]. Several foods -such as tuna, salmon, herring, mackerel, halibut, anchovies, cat-fish, grouper, flounder, flax seeds, sesame seeds, kiwi, black raspberries, green tea, broccoli, sprouts, red grapes, tomatoes, olive fruit- are a good source of antioxidants. These, combined with a Mediterranean type of diet containing fruits, vegetables and whole grains would help protect our chromosome ends [62-70].

In conclusion, what we eat, how we eat and how much we eat, together with lifestyle significantly, can affect our telomerase/telomere system with a great impact on healthspan. “Similes cum similibus curantur” and in nature is still hidden the secret of healthy and long life whereas telomerase could represent the distinctive target.

Starvation Genes Improve and Restores the Failing Heart

In this sepsis induced cardiomyopathy model, carvedilol improves recovery by improving the telomere-p53-pgc signaling.

These 3 gene products are alsoincreased by ursolic acid presumptively by beta hydroxybutyrate.  They are among the 44 starvation genes.

I have previously written how telomerase angiotensin 1-7 are starvation genes that promote metabolically healthy flow mediated dilation which improves small vessel circulation to the healing heart post insult.

See bolded below

http://circ.ahajournals.org/content/134/Suppl_1/A17642.short

Abstract 17642: Carvedilol Improves Prognosis in Sepsis-induced Cardiomyopathy Through the Activation of “telomere-p53-pgc Signaling"

Abstract

Background: Stress-induced cardiomyopathy is a complication of severe sepsis. It is characterized by left ventricular dilatation and depressed ejection fraction. Recent meta-analysis suggested that the mortality depends on the heart hyperkinetic. However, the crucial mechanism of sepsis induced cardiomyopathy and the treatment are still unknown. It has been reported that telomere length has inverse correlation to severity of heart failure and infectious disease. Moreover, it is suggested that dysfunction of “telomere-p53-PGC axis” reduces a mitochondrial function, and as a result, it develops to heart failure.

Purpose: We investigated the therapeutic potential of carvedilol which improves prognosis in preclinical models of severe infection, the murine cecal ligation and puncture (CLP) model to induce peritonitis.

Methods and Results: C57BL/6 male mice were evaluated blood pressure, heart rate and cardiac function followed by CLP surgery and 1mg/kg carvedilol (BB) or saline (CT) was administered for 7days after surgery. 7days after induction of sepsis, BB significantly attenuated blood pressure (101.7±6.0 vs 109.8±57.4mmHg, p<0.05) and heart rate (405.6±18.0 vs 431.6±13.2bpm, p<0.05) as compared to CT. BB also reduced LV dilatation (LVEDV; 53.5±18.5 vs 66.9±15.1uL, p<0.05) and LVEF depression. (61.1±9.9 vs 53.3±7.9%, p<0.05). Kaplan-Meier analysis showed that the 7days mortality significantly reduced in BB group. Telomere shortening of white blood cells seen for sepsis was attenuated in BB by Q-FISH analysis (10.9±1.4 vs 6.8±1.4 telomere fluorescence unit; TFU, p<0.01) Moreover, as compared to CT, BB showed higher expression of tert, PPARγ co-activator (PGC)-1 alpha which promote mitochondrial biogenesis and lower expression of p53 by PCR in heart tissue. Body weight loss was reduced in BB group.

Conclusions: Carvedilol improved sepsis induced cardiomyopathy through the attenuation of telomere shortening due to the enhancement of telomere-p53-PGC axis and reducing mortality resulting from sepsis.