Retinoids: Vertebrae Analouges To Juvenile Hormone Of Insects?

[LeeLemonoil]

Calcitox-aging counterbalanced by endogenous farnesol-like sesquiterpenoids: An undervalued evolutionarily ancient key signaling pathway


This is a hypothetic publication from a belgian biologist obviously working mostly in insect-research but he seemingly found some potentially substantial implications and similarities on vertebra/human health with this one.
Curiously, it touches many aging- and health-paradigmas also described in a way how Dr. Peat views this field and unlike many an ignorant "mainstream" scientist.

The Vitamin-A bits come in the second half of the full article, but the entire rational is very worth our attention.


Calcitox-aging counterbalanced by endogenous farnesol-like sesquiterpenoids: An undervalued evolutionarily ancient key signaling pathway

Cells are powerful miniature electrophoresis chambers, at least during part of their life cycle. They die at the moment the voltage gradient over their plasma membrane, and their ability to drive a self-generated electric current carried by inorganic ions through themselves irreversibly collapses. Senescence is likely due to the progressive, multifactorial damage to the cell's electrical system. This is the essence of the “Fading electricity theory of aging” (De Loof et al., Aging Res. Rev. 2013;12:58–66). “Biologic electric current” is not carried by electrons, but by inorganic ions. The major ones are H+, Na+, K+, Ca2+, Mg2+, Cl− and HCO3−. Ca2+ and H+ in particular are toxic to cells. At rising concentrations, they can alter the 3D-conformation of chromatin and some (e.g. cytoskeletal) proteins: Calcitox and Protontox. This paper only focuses on Calcitox and endogenous sesquiterpenoids. pH-control and Ca2+-homeostasis have been shaped to near perfection during billions of years of evolution. The role of Ca2+ in some aspects of aging, e.g., as causal to neurodegenerative diseases is still debated. The main anti-Calcitox mechanism is to keep free cytoplasmic Ca2+ as low as possible. This can be achieved by restricting the passive influx of Ca2+ through channels in the plasma membrane, and by maximizing the active extrusion of excess Ca2+ e.g., by means of different types of Ca2+-ATPases. Like there are mechanisms that antagonize the toxic effects of Reactive Oxygen Species (ROS), there must also exist endogenous tools to counteract Calcitox. During a re-evaluation of which mechanism(s) exactly initiates the fast aging that accompanies induction of metamorphosis in insects, a causal relationship between absence of an endogenous sesquiterpenoid, namely the farnesol ester named “juvenile hormone,” and disturbed Ca2+-homeostasis was suggested. In this paper, this line of thinking is further explored and extended to vertebrate physiology. A novel concept emerges: horseshoe-shaped sesquiterpenoids seem to act as “inbrome” agonists with the function of a “chemical valve” or “spring” in some types of multi-helix transmembrane proteins (intramolecular prenylation), from bacterial rhodopsins to some types of GPCRs and ion pumps, in particular the SERCA-Ca2+-pump. This further underpins the Fading Electricity Theory of Aging.

 

[LeeLemonoil]

Concernig Farnesol:

Farnesol Has an Anti-obesity Effect in High-Fat Diet-Induced Obese Mice and Induces the Development of Beige Adipocytes in Human Adipose Tissue Deriv... - PubMed - NCBI
Farnesol Has an Anti-obesity Effect in High-Fat Diet-Induced Obese Mice and Induces the Development of Beige Adipocytes in Human Adipose Tissue Derived-Mesenchymal Stem Cells.
Kim HL, et al. Front Pharmacol. 2017.

Abstract
Brown adipocytes dissipate energy as heat and hence have an important therapeutic capacity for obesity. Development of brown-like adipocytes (also called beige) is also another attractive target for obesity treatment. Here, we investigated the effect of farnesol, an isoprenoid, on adipogenesis in adipocytes and on the browning of white adipose tissue (WAT) as well as on the weight gain of high-fat diet (HFD)-induced obese mice. Farnesol inhibited adipogenesis and the related key regulators including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein α through the up-regulation of AMP-activated protein kinase in 3T3-L1 murine adipocytes and human adipose tissue-derived mesenchymal stem cells (hAMSCs). Farnesol markedly increased the expression of uncoupling protein 1 and PPARγ coactivator 1 α in differentiated hAMSCs. In addition, farnesol limited the weight gain in HFD obese mice and induced the development of beige adipocytes in both inguinal and epididymal WAT. These results suggest that farnesol could be a potential therapeutic agent for obesity treatment.

 

[Vinero]

The main anti-Calcitox mechanism is to keep free cytoplasmic Ca2+ as low as possible. This can be achieved by restricting the passive influx of Ca2+ through channels in the plasma membrane

So this means that calcium antagonists like magnesium, adamantane, androgens and progesterone are very helpful anti-aging supplements that prevent cell death by excessive calcium influx.

 

[LeeLemonoil]

Not only that. The FxR interacts closely with the retinoidreceptor, steroids and is crucial in bile acid metabolism. Progesterone also is a modulator of that action.
@haidut @paymanz @Travis @burtlancast
this is perhaps another not yet explored physiological angle very much in line with Dr.Peat's work

Look at this stuff:
A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice. - PubMed - NCBI


A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice.
https://www.ncbi.nlm.nih.gov/pubmed/2859638In summary, our results indicate that FXR and TGR5 are up-regulated by caloric restriction and may act as caloric restriction mimetics. Indeed, 2-month treatment of aged mice with the FXR-TGR5 dual agonist INT-767 could reverse age-related kidney disease, including age-related impairments in mitochondrial biogenesis and mitochondrial function. Our studies therefore indicate that FXR and TGR5 agonists may play an important role in prevention and/or reversal of age-related decline in renal function.
FxR-agonists increase mito-function and genesis while reversing (!) age-related decline in kidney function. Also mimics calorie-restriction effects not unlike Glycine.


Faresol against Candida, yeasts and Caries!
Farnesol inhibits development of caries by augmenting oxygen sensitivity and suppressing virulence-associated gene expression inStreptococcus mutans. - PubMed - NCBI

 

[Travis]

Not only that. The FxR interacts closely with the retinoidreceptor, steroids and is crucial in bile acid metabolism. Progesterone also is a modulator of that action.
@haidut @paymanz @Travis @burtlancast
this is perhaps another not yet explored physiological angle very much in line with Dr.Peat's work

Look at this stuff:
A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice. - PubMed - NCBI


A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice.
https://www.ncbi.nlm.nih.gov/pubmed/2859638In summary, our results indicate that FXR and TGR5 are up-regulated by caloric restriction and may act as caloric restriction mimetics. Indeed, 2-month treatment of aged mice with the FXR-TGR5 dual agonist INT-767 could reverse age-related kidney disease, including age-related impairments in mitochondrial biogenesis and mitochondrial function. Our studies therefore indicate that FXR and TGR5 agonists may play an important role in prevention and/or reversal of age-related decline in renal function.
FxR-agonists increase mito-function and genesis while reversing (!) age-related decline in kidney function. Also mimics calorie-restriction effects not unlike Glycine.


Faresol against Candida, yeasts and Caries!
Farnesol inhibits development of caries by augmenting oxygen sensitivity and suppressing virulence-associated gene expression inStreptococcus mutans. - PubMed - NCBI

You should find out if the farnesoid X receptor (FXR) is why 13‐cis‐retinoic acid (isotretinoin) is the only retinoid particularly useful for acne; neither 9‐cis‐, 11‐cis‐, or all‐trans‐retinoic acid is very useful. But what is interesting is the fact that the most useful one, isotretinoin, doesn't bind either the retinoid X receptor (RXR) or the retinoid acid receptor (RAR). This is as puzzling as its true, and it can only mean that it's working somewhere else. I had previously assumed that that it was binding with the liver X receptor (LXR), but perhaps not; perhaps it could really be working through the farnesoid X receptor (FXR)?

 

[haidut]

Not only that. The FxR interacts closely with the retinoidreceptor, steroids and is crucial in bile acid metabolism. Progesterone also is a modulator of that action.
@haidut @paymanz @Travis @burtlancast
this is perhaps another not yet explored physiological angle very much in line with Dr.Peat's work

Look at this stuff:
A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice. - PubMed - NCBI


A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice.
https://www.ncbi.nlm.nih.gov/pubmed/2859638In summary, our results indicate that FXR and TGR5 are up-regulated by caloric restriction and may act as caloric restriction mimetics. Indeed, 2-month treatment of aged mice with the FXR-TGR5 dual agonist INT-767 could reverse age-related kidney disease, including age-related impairments in mitochondrial biogenesis and mitochondrial function. Our studies therefore indicate that FXR and TGR5 agonists may play an important role in prevention and/or reversal of age-related decline in renal function.
FxR-agonists increase mito-function and genesis while reversing (!) age-related decline in kidney function. Also mimics calorie-restriction effects not unlike Glycine.


Faresol against Candida, yeasts and Caries!
Farnesol inhibits development of caries by augmenting oxygen sensitivity and suppressing virulence-associated gene expression inStreptococcus mutans. - PubMed - NCBI

Androsterone is a potent agonist of FXR. Incidentally, back in the 1940s it was studied extensively for reversing kidney aging. See below thread.
Androsterone Is A Potent Agonist / Activator Of The Farnesoid X Receptor (FXR)
The Anabolic Effects Of Androsterone

 

[paymanz]

Interesting

 

[Steven Bussinger]

I'm not well read on calcium, so forgive me for asking a question that comes from overly simplistic understanding, but I thought calcium was supposed to be an extremely important resource to the human body? Why is it so toxic?

 

[LeeLemonoil]

The essence of female-male physiological dimorphism: differential Ca2+-homeostasis enabled by the interplay between farnesol-like endogenous sesquiterpenoids and sex-steroids? The Calcigender paradigm.
De Loof A1.
Author information
Abstract
Ca(2+) is the most omnipresent pollutant on earth, in higher concentrations a real threat to all living cells. When [Ca(2+)]i rises above 100 nM (=resting level), excess Ca(2+) needs to be confined in the SER and mitochondria, or extruded by the different Ca(2+)-ATPases. The evolutionary origin of eggs and sperm cells has a crucial, yet often overlooked link with Ca(2+)-homeostasis. Because there is no goal whatsoever in evolution, gametes did neither originate "with the purpose" of generating a progeny nor of increasing fitness by introducing meiosis. The explanation may simply be that females "invented the trick" to extrude eggs from their body as an escape strategy for getting rid of toxic excess Ca(2+) resulting from a sex-hormone driven increased influx into particular cells and tissues. The production of Ca(2+)-rich milk, seminal fluid in males and all secreted proteins by eukaryotic cells may be similarly explained. This view necessitates an upgrade of the role of the RER-Golgi system in extruding Ca(2+). In the context of insect metamorphosis, it has recently been (re)discovered that (some isoforms of) Ca(2+)-ATPases act as membrane receptors for some types of lipophilic ligands, in particular for endogenous farnesol-like sesquiterpenoids (FLS) and, perhaps, for some steroid hormones as well. A novel paradigm, tentatively named "Calcigender" emerges. Its essence is: gender-specific physiotypes ensue from differential Ca(2+)-homeostasis enabled by genetic differences, farnesol/FLS and sex hormones. Apparently the body of reproducing females gets temporarily more poisoned by Ca(2+) than the male one, a selective benefit rather than a disadvantage.

 

[LeeLemonoil]

This De Loof guy is a genius of the Ray Peat calibre I'd wager


Seems my urge and intutiton when reading the OP-Study was somewhat correct.
His propsitions are much more clever than current prevalent dogma and are clos(er) to what Peat thinks

Arnold De Loof | Evolution scientist | The Third Way of Evolution

 

[LeeLemonoil]

The Fading Electricity Theory of Ageing: the missing biophysical principle?
De Loof A1, De Haes W, Boerjan B, Schoofs L.
Author information
Abstract
Since a few years convincing data are accumulating showing that some of the premises of the master integrative theory of ageing, namely Harman's Reactive Oxygen Species or free radical theory, are less well founded than originally assumed. In addition, none of the about another dozen documented ageing mechanisms seems to hold the final answer as to the ultimate cause and evolutionary significance of ageing. This review raises the question whether, perhaps, something important has been overlooked, namely a biophysical principle, electrical in nature. The first cell on earth started to be alive when its system for generating its own electricity, carried by inorganic ions, became operational. Any cell dies at the very moment that this system irreversibly collapses. In between birth and death, the system is subject to wear and tear because any cell's overall repair system is not 100 percent waterproof; otherwise adaptation would not be an option. The Fading Electricity Theory of Ageing has all necessary properties for acting as a universal major integrative concept. The advent of novel methods will facilitate the study of bioelectrical phenomena with molecular biological methods in combination with optogenetics, thereby offering challenging possibilities for innovative research in evo-gero.

 

[LeeLemonoil]

The cell's self-generated "electrome": The biophysical essence of the immaterial dimension of Life?
De Loof A1.
Author information
Abstract
In the classical "mind-body" wording, "body" is usually associated with the "mass aspect" of living entities and "mind" with the "immaterial" one. Thoughts, consciousness and soul are classified as immaterial. A most challenging question emerges: Can something that is truly immaterial, thus that in the wording of physics has no mass, exist at all? Many will answer: "No, impossible." My answer is that it is very well possible, that no esoteric mechanisms need to be invoked, but that this possibility is inherent to 2 well established but undervalued physiological mechanisms. The first one is electrical in nature. In analogy with "genome," "proteome" etc. "electrome" (a novel term) stands for the totality of all ionic currents of any living entity, from the cellular to the organismal level. Cellular electricity is truly vital. Death of any cell ensues at the very moment that it irreversibly (excluding regeneration) loses its ability to realize its electrical dimension. The second mechanism involves communication activity that is invariably executed by sender-receiver entities that incessantly handle information. Information itself is immaterial (= no mass). Both mechanisms are instrumental to the functioning of all cells, in particular to their still enigmatic cognitive memory system. Ionic/electrical currents associated with the cytoskeleton likely play a key role but have been largely overlooked. This paper aims at initiating a discussion platform from which students with different backgrounds but all interested in the immaterial dimension of life could engage in elaborating an integrating vocabulary and in initiating experimental approaches.

 

[LeeLemonoil]

Calcitox-aging counterbalanced by endogenous farnesol-like sesquiterpenoids: An undervalued evolutionarily ancient key signaling pathway.
De Loof A1.
Author information
Abstract
Cells are powerful miniature electrophoresis chambers, at least during part of their life cycle. They die at the moment the voltage gradient over their plasma membrane, and their ability to drive a self-generated electric current carried by inorganic ions through themselves irreversibly collapses. Senescence is likely due to the progressive, multifactorial damage to the cell's electrical system. This is the essence of the "Fading electricity theory of aging" (De Loof et al., Aging Res. Rev. 2013;12:58-66). "Biologic electric current" is not carried by electrons, but by inorganic ions. The major ones are H+, Na+, K+, Ca2+, Mg2+, Cl- and HCO3-. Ca2+ and H+ in particular are toxic to cells. At rising concentrations, they can alter the 3D-conformation of chromatin and some (e.g. cytoskeletal) proteins: Calcitox and Protontox. This paper only focuses on Calcitox and endogenous sesquiterpenoids. pH-control and Ca2+-homeostasis have been shaped to near perfection during billions of years of evolution. The role of Ca2+ in some aspects of aging, e.g., as causal to neurodegenerative diseases is still debated. The main anti-Calcitox mechanism is to keep free cytoplasmic Ca2+ as low as possible. This can be achieved by restricting the passive influx of Ca2+ through channels in the plasma membrane, and by maximizing the active extrusion of excess Ca2+ e.g., by means of different types of Ca2+-ATPases. Like there are mechanisms that antagonize the toxic effects of Reactive Oxygen Species (ROS), there must also exist endogenous tools to counteract Calcitox. During a re-evaluation of which mechanism(s) exactly initiates the fast aging that accompanies induction of metamorphosis in insects, a causal relationship between absence of an endogenous sesquiterpenoid, namely the farnesol ester named "juvenile hormone," and disturbed Ca2+-homeostasis was suggested. In this paper, this line of thinking is further explored and extended to vertebrate physiology. A novel concept emerges: horseshoe-shaped sesquiterpenoids seem to act as "inbrome" agonists with the function of a "chemical valve" or "spring" in some types of multi-helix transmembrane proteins (intramolecular prenylation), from bacterial rhodopsins to some types of GPCRs and ion pumps, in particular the SERCA-Ca2+-pump. This further underpins the Fading Electricity Theory of Aging.

 

[LeeLemonoil]

Longevity and aging in insects: Is reproduction costly; cheap; beneficial or irrelevant? A critical evaluation of the "trade-off" concept.
De Loof A1.
Author information
Abstract
The most prevalent hypothesis concerning the relationship between reproduction and longevity predicts that reproduction is costly, particularly in females. Specifically, egg production and sexual harassment of females by males reduce female longevity. This may apply to some short-lived species such as Drosophila, but not to some long-lived species such as the queens of ants and bees. Bee queens lay up to 2000 eggs a day for several years, but they nevertheless live at least 20 times longer than their sisters, the sterile workers. This discrepancy necessitates a critical reevaluation of the validity of both the trade-off concept as such, and of the current theories of aging. The widely accepted oxidative stress theory of aging with its links to metabolism and the insulin/IGF-I system has been disproven in Caenorhabditis elegans and mice, but not in Drosophila, necessitating other approaches. The recent spermidine/mitophagy theory is gaining momentum. Two major mechanisms may have been largely overlooked, namely epigenetic control of longevity by imprinting through DNA methylation as suggested by recent data in the honey bee, and especially, a mechanism of which the principles are outlined here, the progressive weakening of the "electrical dimension" of cells up to the point of total collapse, namely death.

 

[LeeLemonoil]

@Travis

I know, but if you can spare some time ... this guy is worth the time reading

 

[Anabolic]

I raise huge amounts of mealworms for longevity experiments (kidding, they're feed for chooks + reptiles) and my research shows that the "mealworm frass" (droppings) are high in farnesol, and I regularly see Lemuria (largest adult beetle with dye spot for observation) eating the frass. He is also stronger and larger than the other marked beetles that aren't frass eaters. Also, his legs, antennae, and mouth parts are much thicker than the others.

 

[Travis]

@Travis

I know, but if you can spare some time ... this guy is worth the time reading

It certainly looks like it. From your post №13 we hear:

'[...] "Biologic electric current" is not carried by electrons, but by inorganic ions. [...]' ―de Loof​

Which is fine if that's his particular definition of 'biologic electric current,' but it's false when viewed under our general understanding of words. All current ultimately comes from the unique organization of the cell: the enzymes, the structural proteins, and the two-electron charge carriers such as NADH and CoQ₁₀ which are the focus of biological current by many including the late Albert Szent-Györgyi. One-electron charge carriers such as flavin also play a role, as does Förster resonance energy transfer inside of microtubules. Although Ca²⁺ undoubtedly has many fundamental roles, both K⁺ and Na⁺ can perhaps be seen merely as spectator ions: They follow electric gradients already in place, being most affected by the mitochondrial membrane potential of −180·mV. But this negative electric potential of the mitochondria does come from electrons: enzymes strip off hydride ions (∶H⁻) from glucose and place them on NAD⁺ ⟶ then becoming NADH. The hydride ion—a hydrogen having two electrons in its orbit—then transfers through chains consisting of CoQ₁₀ molecules held stationary in the mitochondria, then often through flavin, and eventually to heme where the empty d-orbitals of the catalytic iron at its centre provides the positive redox potential to take electrons from hydrogen ⟶ forming a proton (H⁺) and two electrons (2e⁻). To dispense with acidity and redistribute pH, these protons (H⁺) are captured through the reverse hydrolysis of ADP ⟶ forming ATP (vide infra).

ADP⁻ + PO₄²⁻ + H⁺ ⟶ ATP²⁻ + H₂O​

The ATP has a greater negative charge than ADP, and as such is repelled by the mitochondrial membrane potential (ψ = −180·mV) towards the plasma membrane where the reverse reaction occurs: reforming ADP and a proton (H⁺), the acidity of which is then carried away by the extracellular fluid to the kidneys, down the drain, or to a tree, or even to a fire hydrant in domesticated species of Canis.

The heme is now fully charged with two electrons; this energy then flows by Förster resonance energy transfer inside of microtubules to other heme groups elsewhere before it's given to molecular oxygen (O₂) ⟶ forming H₂O. The Förster resonance energy transfer provides the means for nerve conduction, vision, and consciousness; this is done by first separating charges (∶H⁻ = H⁺ + 2e⁻) and then recombining them, a process which can only be made possible through the unique structure of NAD⁺.

 

[LeeLemonoil]

Thanks @Travis

@Anabolic

that bug is obviously on Beetle-juice then ...

Thanks for the curious info, surely no coincidence that the strongest insect feasts on farnesol-contianing stuff

 

[Steven Bussinger]

I raise huge amounts of mealworms for longevity experiments (kidding, they're feed for chooks + reptiles) and my research shows that the "mealworm frass" (droppings) are high in farnesol, and I regularly see Lemuria (largest adult beetle with dye spot for observation) eating the frass. He is also stronger and larger than the other marked beetles that aren't frass eaters. Also, his legs, antennae, and mouth parts are much thicker than the others.

Start shoving that stuff in capsules to eat!

 

[LeeLemonoil]

Farnesol is also antagonistic at certain Serotonin-receptors and increases appetite in chemotherapy patients

https://www.ncbi.nlm.nih.gov/pubmed/30135179
Parapheromones suppress chemotherapy side-effects.

Abstract
The cytotoxic drugs used in chemotherapy often are accompanied by nausea and vomiting. Despite use of antiemetic drugs, chemotherapy-induced nausea and vomiting (CINV) remains a significant side effect for cancer patients and is associated with serotonin type3 receptor (5-HT3R) activation in the brain stem. Farnesol and nerolidol are sesquiterpene alcohols found in essential oils of plants such as rose, citronella, and lemon grass and used as anti-mite parapheromones. Medicinal plants often are effective in treating gastrointestinal disorders including CINV, although the mechanism of action remains unclear. In the current work, the antiemetic efficacy of the naturally occurring racemic mixture of farnesol (m-farnesol) and nerolidol (m-nerolidol) against cisplatin CINV was tested using the pica behavior of rats. Animals treated with m-farnesol or m-nerolidol consumed smaller amount of kaolin than saline treated control animals. This result is consistent with antiemetic efficacy of farnesol and nerolidol. Unexpectedly, m-farnesol but not m-nerolidol treated animals consumed more food and lost less body weight than controls. Thus, farnesol effectively reduced appetite suppression and weight loss induced by cisplatin. In separate experiments, isomers of farnesol and nerolidol were tested on 5-HT-induced responses of acutely isolated nodose neurons with patch-clamp methods. All of the tested constituents inhibited 5-HT3R-mediated current in a non-competitive manner. Thus, both of the farnesol and nerolidol may exert antiemetic efficacy by inhibiting 5-HT signaling in cranial visceral afferents resulting in interruption of emetogenic signaling. However, nerolidol failed to suppress cisplatin-induced anorexia and weight loss suggesting that additional mechanisms may contribute.