Bioenergetics Nrf2 and Spermidine; Mitochondria and Endoplasmic Reticulum

Hydrogen rich water reduces senescence by reducing ROS directly and indirectly by activating Nrf2.  Nrf2 activation slows cell aging in trisomy 21.

Mitophagy ultimately removes ROS producing mitochondria and replaces them with efficient cleaner mitochondria.

It is oxidative damage by ROS that damages the MAM mitochondrial associated membrane shared with the endoplasmic reticulum. That blocks the local production of melatonin and other antioxidants that protects the marriage of mitochondria and endoplasmic reticulum.  This results in less exchange of "goods and services" needed to safely produce energy.

Consequences?

Metabolic failure triggers SENESCENCE or CANCER. Both are age and and disease related.  Both lead to stem cell failure and decline.

Reversal from Nrf2 activators and spermidine restores metabolic success and REVERSES aging, carcinogenesis and stem cell failure, the ultimate cause of death.

p53 leads either to restoration or senescence and apoptosis depending on energetic capability/ROS ratio signaling.

Highlights

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Hydrogen alleviates the senescence process of BMSCs in vivo.

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Hydrogen decreases the intracellular ROS levels.

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Hydrogen reduces the expression of senescence-related proteins p53 and p21.

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Hydrogen alleviates senescence of BMSCs via ROS/p53/p21 pathway.

https://www.sciencedirect.com/science/article/abs/pii/S0753332218328403

Hydrogen alleviates cellular senescence via regulation of ROS/p53/p21 pathway in bone marrow-derived mesenchymal stem cells in vivo

Senescence has become a hot point issue in recent decades and requires urgent attention. As a novel and effective antioxidant, hydrogen has been proved to alleviate cellular senescence in endothelial cells in vitro. However, the effects and mechanisms of hydrogen on senescence in vivo are still unclear. In the present study, 12-month-old Sprague Dawley (SD) rats were intraperitoneal administration of hydrogen-rich saline (HRS, 10 ml/kg). Subsequently, bone marrow-derived stem cells (BMSCs) were harvested for the detection of hydrogen antisenescence effects and mechanisms. The results showed that the number of senescence-associated β-galactosidase (SA-β-Gal) positive cells was reduced in BMSCs from rats treated with HRS. BMSCs in rats treated with HRS possessed a better proliferation ability, showed more effectively tri-lineage differentiation potential, and had less percentage of cells in G1 cell cycle arrest than the control cells. Additionally, HRS administration inhibited the production of intracellular reactive oxygen species (ROS) and decreased the expression of senescence-related proteins p53 and p21. Our results revealed that hydrogen could alleviate cellular senescence in vivo. And the underlying mechanism of antisenescence effects of hydrogen in BMSCs was via the ROS/p53/p21 signaling pathway. Thus, hydrogen could be a new and convenient strategy for alleviating senescence and for therapy of age-related diseases.

RESILIENCE is Two Sides of a Reciprocal COIN

There are two models of premature aging; progeria and trisomy 21.

What protects rapidly aging cells protects our  shower aging cells.

Nrf2 slows aging and cell senescence in trisomy 21.

Nrf2 slows aging in every cell.

Therefore Nrf2 is one target of the coin of RESILIENCE.

The flip side is reducing autoimmunity that results from inflamaging.

Tails is increasing Vagal tone and activating the cholinergic anti inflammatory pathway via slow paced breathing with or without augmentation by facial cooling.

RESILIENCE includes Nrf2 activation and autoimmunity deactivation.

https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12812

Nrf2 stabilization prevents critical oxidative damage in Down syndrome cells - Zamponi - - Aging Cell - Wiley Online Library

Mounting evidence implicates chronic oxidative stress as a critical driver of the aging process. Down syndrome (DS) is characterized by a complex phenotype, including early senescence. DS cells display increased levels of reactive oxygen species (ROS) and mitochondrial structural and metabolic dysfunction, which are counterbalanced by sustained Nrf2‐mediated transcription of cellular antioxidant response elements (ARE). Here, we show that caspase 3/PKCδdependent activation of the Nrf2 pathway in DS and Dp16 (a mouse model of DS) cells is necessary to protect against chronic oxidative damage and to preserve cellular functionality. Mitochondria‐targeted catalase (mCAT) significantly reduced oxidative stress, restored mitochondrial structure and function, normalized replicative and wound healing capacity, and rendered the Nrf2‐mediated antioxidant response dispensable. These results highlight the critical role of Nrf2/ARE in the maintenance of DS cell homeostasis and validate mitochondrial‐specific interventions as a key aspect of antioxidant and antiaging therapies.

Joseph Thomas (Tony) Liverman, Jr.

Save the astrocytes; Save the Neuron, Brain and Person

How does sunlight help cognition and mood?

Sunlight makes UCA urocanic acid which ASTROCYTES converts into  glutamate and then lactate that increases the energy of the neuron via the lactate shuttle.

Urocanic acid is made from L-histidine in the stratium corneum of the skin (sweat) and functions as an endogenous sunscreen, hence it arises from sunlight.

Interestingly, the loss of astrocyte function and structure, damages neurons and is associated with neurodegenerative diseases including depression and dementia.  Activated inflammatory astrocytes are named CA-1  and they increase in percentage in the focal areas of disease.  For example the basal ganglia in Parkinson's disease.

Astrocytes are the "canaries in the mine" because they produce lactate for neurons.  They empty themselves of energy and thereby increase their vulnerability to oxidative stress.  Urocanic acid-glutamate-lactate increases neuron function, hence improved mood and cognition derived from sunlight!

In dementia, NMDA inhibitors (namenda) block glutaminergic overdrive which might be viewed as a normal function of astrocytes that converts glutamate into lactate and neuronal energy.  Namenda also improves depression but does not save astrocytes.  Saving astrocytes is 

1. the job of Nrf2 activation which reduces the activation of astrocytes into CA-1.  It is also 

2. the job of the cholinergic anti-inflammatory pathway that is activated by vagal nerve stimulation. (See DrLiverman. blogspot.com/smokingcessation....)

Sulforaphane is concentrated in astrocytes and provides protection for themselves and their offspring.  Save the astrocytes; save the neuron/brain/person.  Sulforaphane is the most potent Nrf2 activator known. Sulforaphane is concentrated in broccoli sprouts and broccoli sprout extract.

https://www.sciencedirect.com/science/article/pii/S0092867418305075

Highlights

Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes.

Jo

Telomerase and Antioxidant Capacity Increases Resilience Which Increases IQ

Long telomeres and increased antioxidant capacity is associated with longevity.

Here they are directly proportional and reflect RESILIENCE.

Telomeres are lengthened by telomerase.

Telomerase can only enter the nuclear pore when the cytoplasm is not under oxidative stress.  When there is adequate antioxidant capacity- superoxide dismutase and glutathione telomeres can be repaired.

One can use relative telomere length as a proxy for innate resilience.

I hypothesis that telomere length is directly proportional to HRV index and predicts children who maintain their synaptic connections or brain network which is a predictor for higher IQ, higher income etc.

We likely can improve educational and intellectual success by improving resilience.

Resilience can be predicted by HRV index.

Resilience and brain network preservation is greater than pedagogy for maxims educational attainment.

Nuclear DNA integrity and mitochondrial DNA integrity is therefore permissive when adequate antioxidant capacity and proteostasis is high.

Proteostasis is a function of spermidine.

This blog is aligned with longevity which is directly proportional to RESILIENCE.

This study in mice also explores the resilience of siblings raised in the same environment and discovered resilience is a function of oxidative capacity and telomerase.

https://www.sciencedirect.com/science/article/pii/S0047637417301653

Telomere length, sibling competition and development of antioxidant defense in wild house mice

Antioxidants and telomere length are potential biomarkers for individuals’ exposure and ability to cope with environmental stressors. However, intraspecific variations in antioxidant alterations due to natural, life cycle related stress, have been rarely estimated. We investigated those changes in wild-derived house mice in a longitudinal study with natural sibling competition as a stressor. Blood was used for telomere length measurements at 8-weeks age and for several selected antioxidants at 8-weeks and 6-months age. Our results show that most of the antioxidants increase during that time, indicating that antioxidant-system continues to develop after early development and sexual maturation. In addition females had higher antioxidant-levels than males. Mice with longer telomeres had also higher superoxide dismutase-activity and more glutathione than mice with shorter telomeres, meaning that long telomeres are associated with better antioxidant defense at maturation and during later life. Sibling competition at early age affected superoxide dismutase-levels at 6-months, but only in females. Females, which were lighter than the average of the litter had low superoxide dismutase –activity in later adulthood, indicating delayed negative effect of sibling competition on antioxidant defense. Our results highlight that sex and developmental stage are crucial in intraspecific comparisons of the antioxidant status and its alterations