Nrf2 Reduces Senescent Associated Phenotype; Improves Resilience of Somatic and Stem Cells

Not only does removing senescent cells reduce damage and increase resilience of non-senescent cells, REDUCING the senescent associated phenotype or the expression of destructive enzymes works to improve non- senescent cell function and resilience.

This is one of many studies showing that phytochemicals, in this case Apigenin, REDUCE the SASP phenotype and improve tissue function and resilience.

Sulforaphane shows similar affects.  

Hydrogen rich water shows similar effects. 

Wheat germ/spermidine shows similar effects.  

Melatonin shows similar effects.

All through different entry points but all can be blocked by autophagy blockade.

Which pathway is the driver? 

Nrf2 is the driver.

When autophagy is increased genes such as BDNF and other "starvation gene set" are increased by upregulated transcription, and perhaps by turning these genes back on through the combination of HDAC inhibition and de-methylation of cytosine gene promoter sites.  This reverses oxidative stress and decreased energy related epigenic switched off genes.

The anti-aging anti inflammatory Nrf2 pathway suppresses p38-MAPK, and NF-κB. 

All of the above activate Nrf2 and suppress downstream p38-MAPK, and NF-κB. 

Activate the Nrf2 pathway reduce SASP and increase resilience through appropriate autophagy control and signaling.

One either gains and maintains resilience via autophagy signaling and action OR one loses resilience and drift to senescent somatic and stem cells.  The latter leads to degenerative changes, senescent cells or the consequences of senescence- loss of function or malignant transformation.

https://link.springer.com/article/10.1007/s11357-017-9970-1

Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells

April 2017

Apigenin (4′,5,7,-trihydroxyflavone) is a flavonoid found in certain herbs, fruits, and vegetables. Apigenin can attenuate inflammation, which is associated with many chronic diseases of aging. Senescent cells—stressed cells that accumulate with age in mammals—display a pro-inflammatory senescence-associated secretory phenotype (SASP) that can drive or exacerbate several age-related pathologies, including cancer. Flavonoids, including apigenin, were recently shown to reduce the SASP of a human fibroblast strain induced to senesce by bleomycin. Here, we confirm that apigenin suppresses the SASP in three human fibroblast strains induced to senesce by ionizing radiation, constitutive MAPK (mitogen-activated protein kinase) signaling, oncogenic RAS, or replicative exhaustion. Apigenin suppressed the SASP in part by suppressing IL-1α signaling through IRAK1 and IRAK4, p38-MAPK, and NF-κB. Apigenin was particularly potent at suppressing the expression and secretion of CXCL10 (IP10), a newly identified SASP factor. Further, apigenin-mediated suppression of the SASP substantially reduced the aggressive phenotype of human breast cancer cells, as determined by cell proliferation, extracellular matrix invasion, and epithelial-mesenchymal transition. Our results support the idea that apigenin is a promising natural product for reducing the impact of senescent cells on age-related diseases such as cancer.

BDNF for All of God's Children, especially ADHD

In this abstract methylphenidate, like opioids, reduced BDNF the memory chemical which was already lower in the evening in ADHD children.

I propose that this decline reduces the effectiveness of stimulant therapy AND combined treatment with stimulant and lifestyle and supplements to increase BDNF would be superior. Lower levels of BDNF were seen in comorbid hyperactivity and conduct disorders. Could these commodities too inattention reduce with elevated BDNF?

It may be that the BDNF gene is epigenically turned down.  If so then melatonin, vitamin D, hydrogen rich water and sulforaphane could reverse the turned off gene and increase BDNF production.

With regard to the paradox of no effect on depression, stimulants in addition to exercise are treatments for depressant.  This treatment may be a cover up like prednisone in rheumatoid joint destruction relieving only symptoms.

https://link.springer.com/article/10.1007/s00213-016-4460-1

BDNF concentrations and daily fluctuations differ among ADHD children and respond differently to methylphenidate with no relationship with depressive symptomatology

January 2017

Abstract

Rationale

Brain-derived neurotrophic factor (BDNF) enhances the growth and maintenance of several monoamine neuronal systems, serves as a neurotransmitter modulator and participates in the mechanisms of neuronal plasticity. Therefore, BDNF is a good candidate for interventions in the pathogenesis and/or treatment response of attention deficit hyperactivity disorder (ADHD).

Objective

We quantified the basal concentration and daily fluctuation of serum BDNF, as well as changes after methylphenidate treatment.

Method

A total of 148 children, 4–5 years old, were classified into groups as follows: ADHD group (n = 107, DSM-IV-TR criteria) and a control group (CG, n = 41). Blood samples were drawn at 2000 and 0900 hours from both groups, and after 4.63 ± 2.3 months of treatment, blood was drawn only from the ADHD group for BDNF measurements. Factorial analysis was performed (Stata software, version 12.0).

Results

Morning BDNF (36.36 ± 11.62 ng/ml) in the CG was very similar to that in the predominantly inattentive children (PAD), although the evening concentration in the CG was higher (CG 31.78 ± 11.92 vs PAD 26.41 ± 11.55 ng/ml). The hyperactive–impulsive group, including patients with comorbid conduct disorder (PHI/CD), had lower concentrations. Methylphenidate (MPH) did not modify the concentration or the absence of daily BDNF fluctuations in the PHI/CD children; however, MPH induced a significant decrease in BDNF in PAD and basal day/night fluctuations disappeared in this ADHD subtype. This profile was not altered by the presence of depressive symptoms.

Conclusions

Our data support a reduction in BDNF in untreated ADHD due to the lower concentrations in PHI/CD children, which is similar to other psychopathologic and cognitive disorders. MPH decreased BDNF only in the PAD group, which might indicate that BDNF is not directly implicated in the methylphenidate-induced amelioration of the neuropsychological and organic immaturity of ADHD patients.

Joseph Thomas (Tony) Liverman, Jr.

A Strategy for Joy, Happiness, Longevity and Primary and Secondary Wealth.

This article merges psychology and medicine writ large to include lifestyle changes.

If money is secondary property that is accumulated by investing primary property the self assets or gifts and TALENTS, the strategic goal should be the accumulation of TALENTS to share or employ for self and others.

BDNF levels are like assets or bank.  Sensitivity to BDNF is like thrift and explains why some individuals can endure and thrive after losing everything, a stressful event that diminishes BDNF asset levels.

BDNF decreases with aging and disease.  It is inversely proportional to addiction, depression and cognitive impairment.  It is directly proportional to joy, happiness, sobriety and longevity.

This strategic frame of why, how and what allows one to augment their counseling and their healthcare toward wholeness with themselves, others and God which implies goodness congruent with the divine design.  This entire blog is directly or indirectly about increasing BDNF and sensitivity to BDNF.

Below is a link to an article:. The Grim Biology of Poverty. I would suggest a subtitle- A Strategy for Joy, Happiness, Longevity and Primary and Secondary Wealth.

http://nautil.us/issue/47/Consciousness/why-poverty-is-like-a-disease

Cell Transfiguration to Ageless Health is an Epigenic Process

Here, an HDAC3 inhibitor (histone deacetylase inhibitor) restores the acetylation of Peroxisome Proliferation–Activated Receptor and Klotho increases and protects kidneys (other tissue and organs!)

Exercise and fasting also performs this function via the action of beta hydroxybutyrate, an HDAC(3) inhibitor.

Aging methylates the Klotho promoter gene.  Hydrogen rich water or endogenous H2S can demethylate the CGG promoter site of Klotho after histone is removed by the HDAC inhibitor.  

The sequential combination action of HDAC and hydrogen turns genes on.  Aging, loss of the solubility ATP provides, may be caused by ATP loss for one of two reasons.  Protection from cell energy failure or cell solubility failure.  (Please note that pioglitazone, a peroxide proliferation gamma agonist promotes fatty acid oxidation, producing beta hydroxybutyrate and restores Klotho gene promoter switch to on.)

Beta hydroxybutyrate, unlike some HDAC inhibitors, also serves as the starvation gene set promoter which increases mitochondrial biogenesis and ATP is directly proportional to mitochondria volume. Thus cell energy and solubility increase and the cell appears to be younger.

Summary: beta hydroxybutyrate AND hydrogen turns genes back on that promote health and youthful epigenic restoration.  

Aging, inflamaging turns genes off.

Restoring gene switches to on optimally occurs when antioxidant capacity is also optimum and proteostasis is optimum.  

Therefore, sulforaphane (antioxidant capacity) and wheat germ (proteostasis) completes the transfiguration into youthful dynamic cells and in numerous species and human cells increases healthspan and lifespan by 30%!

Beta hydroxybutyrate is downstream of Peroxisome Proliferation–Activated Receptor γ and had a direct effect that is also provided by sodium butyrate which is 3% of butter.  The French version of the Mediterranean diet before Paula Dean is full of this HDAC inhibitor!

http://www.sciencedirect.com/science/article/pii/S0085253817301588

Klotho restoration via acetylation of Peroxisome Proliferation–Activated Receptor γ reduces the progression of chronic kidney disease

Klotho is an anti-aging protein mainly expressed in the kidney. Reduced Klotho (1) expression closely correlates with the development and progression of chronic kidney disease (CKD). Klotho is also a downstream gene of Peroxisome Proliferation–Activated Receptor γ (PPARγ), a major transcription factor whose functions are significantly affected by post-translational modifications including acetylation. However, whether PPARγ acetylation regulates renal Klotho expression and function in CKD is unknown. Here we test whether renal damage and reduced Klotho expression in the adenine CKD mouse model can be attenuated by the pan histone deacetylase (HDAC) inhibitor trichostatin A. This inhibition up-regulated Klotho mainly through an enhancement of PPARγ acetylation, stimulation of PPARγ binding to Klotho promoter, and PPARγ-dependent increase in Klotho transcription, with a substantial control of the regulation occurring via PPARγ acetylations on K240 and K265. Consistently trichostatin A–induced reversal of Klotho loss and renoprotective effects were abrogated in PPARγ knockout mice, supporting that PPARγ is an essential acetylation target for Klotho restoration and renal protection. Intriguingly, the kidneys of adenine-fed CKD mice displayed deregulated HDAC3 up-regulation. Selective HDAC3 inhibition effectively alleviated Klotho loss and kidney injury, whereas the protective effects were largely abolished when Klotho was knocked down by siRNA, suggesting that aberrant HDAC3 and Klotho loss are crucial components involved in the renal damage of mice with CKD. Our study identified an important signaling cascade and key components contributing to the pathogenesis of CKD. Thus, targeting Klotho loss by HDAC3 inhibition has promising therapeutic potential for the reduction of CKD progression.