Purportedly Xenohormetic Phytochemicals

[Sibiriak]

Mccoy: A recent article from Blagosklonny (Oncotarget 2017)  proposing a multi-drugs approach to longevity. That looks more and more esimilar to Baba Yaga's concoctions, to which on the other side the author freely inspires.

 

An alternative would be a multi-phytochemical approach (possibly with low-dose aspirin or ibuprofen), combined with CRON, optimal EX, CE, IF, etc.

 

We've already discussed many of these phytochemical agents (including adaptogens). The following article utilizes Blagosklonny's Hormesis A vs Hormesis B framework (which I referenced in the adaptogen thread, post #12) and his hyperfunctions model to conceptualize the anti-aging mechanisms of EVOO polyphenols.

 

 

Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil

 

A new family of gerosuppressant agents

 

http://dx.doi.org/10.4161/cc.23756

[mccoy]

Excellent work from the Spanish Bioactive Food Components Platform. Fascinating view of the xenohormetic properties of secoiridoids in EVOO.

 

Sure by extrapolating this article to all other food xenohormetics we can build a powerful and safe arsenal against degenerative aging processes

[Sibiriak]

Molecules 2015, 20, 6544-6572

Longevity Extension by Phytochemicals

 

http://www.mdpi.com/1420-3049/20/4/6544/pdf

In this review, we discuss recent progress in understanding mechanisms underlying such longevity-extending and health-improving effects of phytochemicals on heterotrophic organisms across phyla. We also propose a hypothesis in which phytochemicals that have been released by plants into an ecosystem create xenohormetic, hormetic and cytostatic selective forces that may drive the evolution of longevity regulation mechanisms in heterotrophic organisms inhabiting this ecosystem. [emphasis added]

 

[...] lifespan-prolonging abilities of these phytochemicals rely on cellular proteins integrated into several evolutionarily conserved signaling pathways known to regulate longevity in organisms across phyla [...]. These nutrient-, energy- and stress-sensing pathways include the following: (1) the IIS pathway [...]; (2) the TOR pathway [...]; (3) the sirtuin-governed protein deacetylation module of the longevity signaling network integrating the IIS and TOR pathways [...]; (4) the OSR-1/UNC-43 (CaMKII)/SEK-1 (p38 MAPK) stress-responsive signaling pathway [...]; and (5) the non-selective autophagy pathway for degradation of various cellular organelles and macromolecules [...] (Table 1).

 

Moreover, these lifespan-prolonging phytochemicals postpone the onset of several longevity-defining cellular processes called “the cellular and molecular hallmarks of aging” [...]. Out of the nine commonly accepted cellular and molecular hallmarks of aging [...], lifespan-prolonging phytochemicals are known to delay the development of the following seven common traits of aging in evolutionarily distant heterotrophic organisms: (1) genomic instability [...]; (2) epigenetic alterations [...]; (3) loss of proteostasis  [...]; (4) deregulated nutrient sensing [...];   (5) mitochondrial dysfunction  [...] ;  (6) cellular senescence [...];  and (7) altered intercellular communication...  [emphasis added]

[mccoy]

Interesting article on rapamycin and mTORc1+2 coauthored by David Sabatini

 

http://sabatinilab.wi.mit.edu/pubs/2013/Lamming.pdf

[Sibiriak]

Use of phytochemicals (xenohormetics) are integrated into a general "intermittent bioenergetic challenges" strategy to prevent age-related neurodegenerative diseases:

 

 

Late-onset dementia: a mosaic of prototypical pathologies modifiable by diet and lifestyle

https://www.nature.com/articles/npjamd20153

https://www.crsociety.org/topic/11800-als-cr-updates/page-10

[emphasis added]

 

Figure 3.

 

Intermittent bioenergetic challenges forestall  ILOD [idiopathic late-onset dementia] by stimulating adaptive stress response pathways. (a) As with other species, humans evolved in environments where there was competition for food, mates and other resources. Accordingly, selection favored individuals whose brains functioned best when they were hungry, physically active and under stress. In response to the challenges (exercise, dietary energy restriction/fasting, intellectual challenges and consumption of noxious phytochemicals) neurons experience mild bioenergetic and oxidative stress.

 

The neurons respond adaptively by activating signaling pathways that improve their ability to cope with more severe stress and resist disease. These neuroprotective pathways are triggered by calcium, reactive oxygen species (ROS) and increased energy demand,  and involve kinases such as AMP-activated kinase (AMPK), and transcription factors such as cyclic AMP response element binding protein (CREB). The latter pathways increase autophagy, and induce the expression of genes encoding neurotrophic factors, antioxidant enzymes and  DNA repair enzymes.

 

During the challenges there is a reduction of mTOR (mammalian target of rapamycin) activity and protein synthesis. Once the challenge is over (e.g., food has been acquired) there is a recovery period that involves eating, relaxing and sleeping. During the recovery period mTOR activity, protein synthesis and mitochondrial biogenesis increase, and the growth of axons and dendrites, formation of new synapses and neurogenesis (the production of new neurons from stem cells) occur. Because of the adaptive stress responses induced during the challenge period levels of oxidative stress, DNA damage and protein aggregation are reduced.

 

This model predicts that individuals  who regularly engage in cycles of challenges and recovery periods during their adult life will exhibit optimal brain function and will be relatively resistant to the development of ILOD. (b) An example of a lifestyle that includes intermittent challenges as a means of optimizing brain health. In this case the person fasts (water or non-caloric beverages only) on the first day, while engaging in intellectual challenges (light bulb) and physical exercise (running). On the next day the subject eats several meals,runs, relaxes and engages in critical thinking [such as picking apart arguments by Dean P. and M.R. in the CR Society forums].

[mccoy]

I subscribe conceptually to the cyclical model, which seems to fit better into the ancestral mechanisms of cycles of challenges and recovery periods (lack of food, adversities and so on versus abundance of food and easier life).

 

Whereas constant CR by definition implies no cycles. mTOR is constantly downregulated, maybe unnaturally, since the ancestral situation was not that of a constantly moderate paucity of food.

 

This is a criticism which I pose to the previously illustrated hyperfunctions model by Blagosklonny (he puts CR within the interventions). 

[Sibiriak]

Two examples of possible  phytochemical pro-oxidant  hormetic effects:   low-dose green tea catechins and low-dose resveratrol.

 

Effects of single dose and regular intake of green tea ( Camellia sinensis ) on DNA damage, DNA repair, and heme oxygenase-1 expression in a randomized controlled human supplementation study

https://www.researchgate.net/publication/260446579_Effects_of_single_dose_and_regular_intake_of_green_tea_Camellia_sinensis_on_DNA_damage_DNA_repair_and_heme_oxygenase-1_expression_in_a_randomized_controlled_human_supplementation_study

 

As noted, bioavailability of tea catechins is very low, and there is extensive and rapid conjugation and metabolism of catechins in humans—factors that restrict catechin concentrations in human plasma to nanomolar levels [5, 14]. Still, it is possible that catechins, or their metabolites, accumulate in tissues with regular intake of tea, enhancing direct antioxidant protection against oxidation-induced DNA damage and mutation.

 

Alternatively, or in addition, there could be acute, subtle pro-oxidant effects triggered by catechins (and perhaps other phytochemicals). Regular, small, postingestion “pro-oxidant waves” could induce cytoprotective ARE-triggered adaptations, such as enhanced DNA repair and increased HMOX-1 [8–13]. To date, the hypothesized effects of pro-oxidant phytochemicals on redox tone and cellular adaptive response have not been demonstrated to occur in humans. Here, we present the results of a randomized, placebo-controlled, single-blinded human intervention trial of crossover design.

 

The genoprotective effect of regular intake of green tea was demonstrated in our previous study of middle-aged adults who took tea for 4 wk [4], but this current study is the first human trial to show a significant acute genoprotective effect of green tea, and is the first study to show that hOGG1 activity is enhanced by green tea. This finding of enhanced DNA repair by a dietary factor has important implications for our understanding of the function and molecular effects of phytochemicals and their role in cancer prevention. To our knowledge, there is only one other study that has shown increased hOGG1 activity in a human supplementation trial,  and which was with kiwi fruit taken for 3 wk or longer [16]. Of particular interest in this current study with green tea is the finding that hOGG1 activity had increased significantly (and DNA damage had decreased significantly) as early as 1 h postingestion.

 

In conclusion, results show that drinking green tea leads to a significant acute decrease in oxidation-induced lesions in DNA and increased activity of hOGG1 in lymphocytes, and these changes are maintained, and are more marked for hOGG1 activity, in fasting samples collected after 7 days of regular intake of green tea. The doses of tea used in this study were not large, and could be incorporated easily into the daily diet.

 

 

Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress

http://www.sciencedirect.com/science/article/pii/S0891584916303793?via%3Dihub

 

Abstract

 

Resveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of this natural product remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to its generation of oxidation products such as reactive oxygen species (ROS). At low nontoxic concentrations (in general <50 µM), treatment with resveratrol increased viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, resveratrol treatment led to mild, Nrf2-specific gene expression reprogramming. For example, in primary epidermal keratinocytes derived from human skin this coordinated process resulted in a 1.3-fold increase of endogenously generated glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61 mV mmol GSH per g protein. After induction of oxidative stress by using 0.78% (v/v) ethanol, endogenous generation of ROS was consequently reduced by 24% in resveratrol pre-treated cells.

 

In contrast to the common perception that resveratrol acts mainly as a chemical antioxidant or as a target protein-specific ligand, we propose that the cellular response to resveratrol treatment is essentially based on oxidative triggering. In physiological microenvironments this molecular training can lead to hormetic shifting of cellular defense towards a more reductive state to improve physiological resilience to oxidative stress.

 

Polyphenols represent a large collection of natural products featuring health-beneficial effects [1]. Resveratrol (3,5,4′-trihydroxy-trans-stilbene, RSV), an antimicrobial phytoalexin originally found in white hellebore (Veratrum grandiflorum O Loes) and later in red grapes and other plants, is one of the most prominent polyphenols. Early studies indicated cancer chemo-preventive properties of RSV [2]. Over the last 15 years, numerous studies claimed additional benefits including cardio-protective and anti-aging effects [3]. Consequently, a number of products based on RSV have been developed for dietary and dermatological application [4,5]. Nevertheless, the efficiencies of RSV treatments and underlying mechanisms of action remained largely controversial. For example, RSV had been suggested to modulate estrogen receptor activity [6], or to act as a caloric mimetic by directly increasing the enzymatic activity of the histone deacetylase sirtuin 1 (SIRT1) [7]. Recently, it was shown that inhibition of phosphodiesterase 4 (PDE4) by RSV increased intracellular amounts of the hunger signalling molecule cAMP [8]. Notably, the reported interaction of RSV with these and further target proteins was in many cases low and unspecific. In general, most of these studies assumed a proportional dose-response relationship of compounds, i.e. a conventional pharmacological (linear) threshold model [9].

 

However, in contrast to the standard pharmacological model, hundreds of studies reported (in many cases probably unconsciously) beneficial effects of RSV at “low” but detrimental outcomes at “high” doses. In general, this potentially counterintuitive bi-phasic property of RSV was widely ignored [10]. The large body of data would nevertheless hint to hormesis, a dose-response relationship that is characterized by low-dose stimulation and high-dose inhibition, consistent with the Arndt-Schulz law, Hueppe’s rule and other terms describing a beneficial stimulation (of poisons) at low doses [11,12]. General acceptance of the hormesis concept for therapeutic application seems to remain minor, due to generally faint stimulatory effects and the lack of mechanistic explanation of hormetic phenomena.

 

Interestingly, polyphenols including RSV are considered as antioxidants mainly owing to chemical properties such as scavenging of free radicals or due to indirect effects in a given biological system. Depending on the chemical context RSV and other polyphenols can also become pro-oxidative [1], a fact that seems to be often ignored. Depending on the reaction conditions RSV can be (auto-) oxidized to generate semiquinones and the relatively stable 4′-phenoxyl radical; finally this oxidation process can lead to production of reactive oxygen species (ROS) [13,14]. Oxidative reactions of polyphenols are influenced by changing pH, particularly the presence of hydroxyl anions or organic bases [15,16]. Additionally, metal ions (e.g. iron II ions) facilitate oxidative reactions and generation of radicals via the Fenton reaction [17].

 

The here presented study aimed to explore new aspects and connect fragmented pieces of the chemical and resulting biological properties of RSV to contribute to a comprehensive understanding of the purported health-beneficial effects of RSV.

 

In general, hormetic induction of cellular fitness by pro-oxidative polyphenols such as RSV might represent a powerful approach to protect cells against physiological stress and to inhibit age-related diseases.

[mccoy]

The comments on oxydation remind be about the present controversi on the antioxydants theory. Some biologists (like Navdeep Chandler) affirm that oxydative compounds like peroxide are used for signaling in cell metabolism. It may be that here as well a balance is needed in the amount of such compounds.

 

http://www.feinberg.northwestern.edu/faculty-profiles/az/profile.html?xid=11123

 

 

 

 

Historically, reactive oxygen species (ROS) have been thought to be cellular damaging agents, lacking a physiological function. Accumulation of ROS and oxidative damage have been linked to multiple pathologies, including neurodegenerative diseases, diabetes, cancer, and premature aging. This guilt by association relationship left a picture of ROS as a necessary evil of oxidative metabolism, a product of an imperfect system. Yet few biological systems possess such flagrant imperfections, thanks to the persistent optimization of evolution, and it appears that oxidative metabolism is no different. More and more evidence suggests that low levels of ROS are critical for healthy cellular function. We are testing whether mitochondrial release of H2O2 has evolved as a method of communication between mitochondrial function and other cellular processes to maintain homeostasis (e.g. stem cell function and immune responses) and promote adaptation to stress (e.g. hypoxia).

 

[Sibiriak]

Mccoy: Some biologists (like Navdeep Chandler) affirm that oxydative compounds like peroxide are used for signaling in cell metabolism. It may be that here as well a balance is needed in the amount of such compounds.

 

 

Some articles related to ROS signalling, the need for balance, and other issues:

 

Antioxidants in Translational Medicine

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657516/

PMCID: PMC4657516

 

(Lots of diagrams!)

 

Abstract

Significance: It is generally accepted that reactive oxygen species (ROS) scavenging molecules or antioxidants exert health-promoting effects and thus their consumption as food additives and nutraceuticals has been greatly encouraged. Antioxidants may be beneficial in situations of subclinical deficiency and increased demand or acutely upon high-dose infusion. However, to date, there is little clinical evidence for the long-term benefit of most antioxidants. Alarmingly, recent evidence points even to health risks, in particular for supplements of lipophilic antioxidants.

 

Recent Advances: The biological impact of ROS depends not only on their quantities but also on their chemical nature, (sub)cellular and tissue location, and the rates of their formation and degradation. Moreover, ROS serve important physiological functions; thus, inappropriate removal of ROS may cause paradoxical reductive stress and thereby induce or promote disease.

 

Critical Issues: Any recommendation on antioxidants must be based on solid clinical evidence and patient-relevant outcomes rather than surrogate parameters.

 

Future Directions: Such evidence-based use may include site-directed application, time-limited high dosing, (functional) pharmacological repair of oxidized biomolecules, and triggers of endogenous antioxidant response systems. Ideally, these approaches need guidance by patient stratification through predictive biomarkers and possibly imaging modalities

 

 

Polyphenols and DNA Damage: A Mixed Blessing

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5188440/

PMCID: PMC5188440

 

Abstract

Polyphenols are a very broad group of chemicals, widely distributed in plant foods, and endowed with antioxidant activity by virtue of their numerous phenol groups. They are widely studied as putative cancer-protective agents, potentially contributing to the cancer preventive properties of fruits and vegetables. We review recent publications relating to human trials, animal experiments and cell culture, grouping them according to whether polyphenols are investigated in whole foods and drinks, in plant extracts, or as individual compounds. A variety of assays are in use to study genetic damage endpoints.

 

Human trials, of which there are rather few, tend to show decreases in endogenous DNA damage and protection against DNA damage induced ex vivo in blood cells. Most animal experiments have investigated the effects of polyphenols (often at high doses) in combination with known DNA-damaging agents, and generally they show protection. High concentrations can themselves induce DNA damage, as demonstrated in numerous cell culture experiments; low concentrations, on the other hand, tend to decrease DNA damage.

 

 

 

Polyphenols as dietary supplements: A double-edged sword

 

https://www.researchgate.net/publication/49616946_Polyphenols_as_dietary_supplements_A_double-edged_sword

 

Abstract

 

Increased consumption of fruits and vegetables is associated with a lower risk of chronic disease such as cardiovascular disease, some forms of cancer, and neurodegeneration. Pro-oxidant-induced oxidative stress contributes to the pathogenesis of numerous chronic diseases and, as such, dietary antioxidants can quench and/or retard such processes. Dietary polyphenols, ie, phenolic acids and flavonoids, are a primary source of antioxidants for humans and are derived from plants including fruits, vegetables, spices, and herbs. Based on compelling evidence regarding the health effects of polyphenol-rich foods, new dietary supplements and polyphenol-rich foods are being developed for public use. Consumption of such products can increase dietary polyphenol intake and subsequently plasma concentrations beyond expected levels associated with dietary consumption and potentially confer additional health benefits. Furthermore, bioavailability can be modified to further increase absorption and ultimately plasma concentrations of polyphenols.

 

However, the upper limit for plasma concentrations of polyphenols before the elaboration of adverse effects is unknown for many polyphenols. Moreover, a considerable amount of evidence is accumulating which supports the hypothesis that high-dose polyphenols can mechanistically cause adverse effects through pro-oxidative action. Thus, polyphenol-rich dietary supplements can potentially confer additional benefits but high-doses may elicit toxicity thereby establishing a double-edge sword in supplement use.

 

Geroprotective and Radioprotective Activity of Quercetin, (-)-Epicatechin, and Ibuprofen in Drosophila melanogaster

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179547/

PMCID: PMC5179547

 

 

Our data support an idea that quercetin and (-)-epicatechin consumption in proper low doses can increase life span of Drosophila melanogaster. Furthermore, it can increase the resistance of flies to oxidative stress and ionizing radiation. The possible explanation of observed effects is the hormetic response. Ibuprofen can also stimulate cellular protective mechanisms and induces the resistance of the organism to oxidative and genotoxic stress. Obtained results demonstrate the high potential of the using of these chemicals as geroprotective and adaptogenic drugs.

 

 

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[mccoy]

It would be interesting to know how to determine the safe threshold for natural polyphenols. Probably only massive doses of the natural ones can be detrimental.

 

In some situations, though, the 'body intelligence' can warn us. I've been warned in the past after the massive use of freshly picked tomatoes. After about one-2 months, my body refused tomatoes and was irritated even by their smell and by walking close to the plants (I was growing them in my garden).

 

My interpretation is that the freshly picked tomatoes have an high concentration of solanin or tomatin, a phytotoxin which has hormetic/xenohormetic properties. Especially so in stressful conditions (little water, no fertilizers, no pesticides as in my case).

Maybe the stress caused the release of some other specific xenohormetic compound. Such compounds are often of phenolic nature.

 

Since I was eating them everyday in large amounts, I started to go out of the hormetic zone, into the toxicity zone. The safety mechanism of the body prevented me to introduce further toxins by mere physical repulsion and nausea. 

[Sibiriak]

It might be important to distinguish between phytochemicals that have a  desirable hormetic effect at certain dosages, eg. a desirable pro-oxidant effect,  and those that have a desirable non-hormetic effect at certain dosages, eg. a desirable antioxidant effect (some could have both types of effects.)

 

And one could also distinguish between antioxidants that turn pro-oxidant under certain conditions and those that  do not-- astaxanthin, for example.

 

Potential Anti-Atherosclerotic Properties of Astaxanthin

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771988/

PMCID: PMC4771988

 

It is well known that the activity of carotenoids can be shifted from antioxidant to pro-oxidant according to their concentrations, high oxygen tension, or interactions with other co-antioxidants [14]. Martin et al. divided 17 carotenoids into three classes: (1) those without significant antioxidative properties; (2) those with good antioxidative but also pro-oxidative properties; and (3) those with strong antioxidative and without any pro-oxidative properties. Astaxanthin was categorized as class (3), whereas β-carotene and lycopene were identified as class (2) .

[Sibiriak]

Mccoy: It would be interesting to know how to determine the safe threshold for natural polyphenols. Probably only massive doses of the natural ones can be detrimental.

 

That's likely true, although there may be a few exceptions. 

 

In terms of supplemental extracts (which I think can be valuable if judiciously chosen and of high quality),  in most cases taking  low to moderate dosages over an extended period of time would seem  to be the best approach for general longevity/anti-aging goals (as opposed to intensive treatment of specific afflictions.)

 

Brain Bioavailability of Grape Seed Polyphenols [2009]

 

Study Abstract

The present study explored the bioavailability and brain deposition of a grape seed polyphenolic extract (GSPE) previously found to attenuate cognitive deterioration in a mouse model of Alzheimer's disease (AD). Plasma pharmacokinetic response of major GSPE phenolic components was measured following intragastric gavage of 50, 100, and 150 mg GSPE per kg body weight. Liquid chromatography-mass spectrometry (LC-MS) analysis identified gallic acid (GA), catechin ©, and epicatechin (EC) in plasma of rats gavaged acutely with GSPE. Additionally, 4-methylgallic acid (4-OMeGA), 3'-methylcatechin (3'-OMeC), and 3'-methylepicatechin (3'-OMeEC) were identified as circulating metabolites of GSPE phenolic constituents. C_{max} for individual GSPE constituents and their metabolites increased in a dose-dependent fashion (with increasing GSPE oral dose). Repeated daily exposure to GSPE was found to significantly increase bioavailability (defined as plasma AUC_{0-8h}) of GA, C, and EC by 198, 253, and 282% relative to animals receiving only a single acute GSPE dose. EC and C were not detectable in brain tissues of rats receiving a single GSPE dose but reached levels of 290.7 ± 45.9 and 576.7 ± 227.7 pg/g in brain tissues from rats administered GSPE for 10 days. This study suggests that brain deposition of GA, C, and EC is affected by repeated dosing of GSPE.

 

From press release:

The polyphenols found in red wine are thought to help prevent Alzheimer's disease, and new research from Purdue University and Mount Sinai School of Medicine has shown that some of those compounds in fact reach the brain.Mario Ferruzzi, a Purdue associate professor of food science; Connie Weaver, Purdue's head of foods and nutrition; and Elsa Janle, a Purdue associate professor of foods and nutrition, found that the amount of polyphenols from grapeseed extract that can reach a rat's brain is as much as 200 percent higher on the 10th consecutive day of feeding as compared to the first. Many previous experiments, in which absorption was measured after single or sporadic doses, often found very little, if any, of the bioactive polyphenols reaching brain tissues. However, more chronic exposure appears to improve absorption.

 

"This shows that reasonable and chronic consumption of these products may be the way to go, rather than single, high doses, similar to drugs," said Ferruzzi, who collaborated on the research with Mount Sinai's Dr. Giulio Pasinetti. "It's like eating an apple a day, not a case of apples over two days every month."

 

A paper detailing the findings was published in the early online version of the September issue of the Journal of Alzheimer's Disease. Polyphenols, compounds found in the skins and seeds of grapes, are thought to prevent the formation of beta-amyloid protein, which creates the plaque in the brain that causes Alzheimer's disease. Alzheimer's is a progressive brain disease that destroys memory and cognitive skills and affects as many as 4.5 million Americans, according to the National Institute on Aging. 

 

Pasinetti, the Aidekman Family Professor in Neurology and director of the Center of Excellence for Novel Approaches to Neurotherapeutics, said discovering how polyphenols are absorbed and distributed to the brain can impact researchers' understanding of the amount of grape products or red wine a person would need to consume to most effectively combat Alzheimer's disease.

 

"The most important thing is that when we follow the repetitive administration of this compound, we were able to observe the transfer of the compound to the brain," Pasinetti said. "This may help us figure out the proper concentration necessary to get these chemicals to the brain."

 

Ferruzzi said the study dealt with polyphenols, but also could be important for determining proper doses of other compounds or drugs for patients. Testing of a pharmaceutical, for example, could show that the drug is too potent when given repetitively; whereas that might not be apparent if the drug is administered on non-consecutive days or weeks."It could become important in terms of side effects," Ferruzzi said. "You could be overdosing because the body is adapting and absorbing or metabolizing these compounds differently over time."

 

Pasinetti is the principal investigator for the Center of Excellence for Research and Complementary and Alternative Medicine in Alzheimer's Disease grant from the National Institutes of Health that funded the work. Ferruzzi said further studies will focus on the mechanisms that control absorption of compounds during chronic consumption.

http://www.wellnessresources.com/studies/brain-bioavailability-of-grape-seed-polyphenols

 

Full text here:

 

Bioavailability of gallic acid and catechins from grape seed polyphenol extract is improved by repeated dosing in rats: Implications for treatment in Alzheimer’s Disease

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801429/

PMCID: PMC2801429

[mccoy]

Yes, from the above it would appear that the concept of 'antioxydants' as currently used in divulgative nutrition literature is an overly simplified one.

 

In the meanwhile, I found this exceptionally good and polyphenols rich organic wine, produced near my place. It's dense and spicy, you can taste the tannins and they let the grapes 'season' with their skins for 15 days. Lots of natural resveratrol, I'm reasonably sure.

I'm using it as a medicine, total about 2 drinks a week or less, in moderate amounts, just as outlined above. It's not at all costly, considering its qualitites. I reccomend it for those who have an opportunity to try it: Rosarubra Montepulciano d'Abruzzo

 

This is an example on how the hormetic/xenohormetic diet can be very enjoyable at times! Rapamycin sure doesn't taste that good!

 

 

[Sibiriak]

It's great to be Italian!!

[mccoy]

This is an article posted by Al Pater in his valuable updates and which in my opinion deserves further discussion.

 

Very interesting in that it compares the hormetic effects due to environmental pollutants and those due to phytochemicals.

 

Evolutionarily adapted hormesis-inducing stressors can be a practical solution to mitigate harmful effects of chronic exposure to low dose chemical mixtures.
Kim SA, Lee YM, Choi JY, Jacobs DR Jr, Lee DH.
Environ Pollut. 2017 Nov 7;233:725-734. doi: 10.1016/j.envpol.2017.10.124. [Epub ahead of print] Review.
PMID: 29126094
http://sci-hub.cc/10...pol.2017.10.124

 

 

 

The article is exceedingly interesting and suggests strategies to manipulate the hormetic curve of environmental pollutants by exposure to natural hormetic and xenohormetic stressors. It also expounds the novel (to me) concept of mitohormesis (caused by exercise, CR, IF).

 

A reccomended read to those like me whose attention is focused upon the ongoing war between our system and the destructive hostile external and internal mechanisms, and how to implement the best defensive strategy. 

 

Conceptual framework for coping with chronic exposure to low dose chemical mixtures. In human, dose-response relationship between synthetic chemicals and the risk of diseases may consist of (1) potentially harmful sub-hormetic zone, (2) beneficial hormetic zone and (3) harmful toxicity zone. Harmful effects in the sub-hormetic zone would be the result of “chronic exposure to low-dose chemical mixtures”, such as persistent organic pollutants (POPs). Chronic glutathione (GSH) depletion and/or diverse endocrine disruption are possible mechanisms of harm. With increasing doses of synthetic chemicals, the over-compensation of various adaptive responses can lead to the beneficial hormetic zone. As avoiding low dose chemical mixtures is practically impossible in modern society, two methods for persons who are within the harmful sub-hormetic zone can be suggested: (1) moving to a beneficial hormetic zone of synthetic chemicals with increasing dose of chemicals (situation A) or (2) performing behaviors which induce mitohormesis or xenohormesis, which can induce biological responses similar to those of the beneficial hormetic zone (situation B). In situation B, the dose-response curve itself shifts down without change of chemical dose. Thus, apart from the person in the sub-hormetic zone, any person in any zone can experience benefits of hormesis. Relying on protection through hormesis induced by synthetic chemicals cannot be recommended to humans due to impossibility of controlling degree of exposure and many uncertainties regarding safety. Behaviorallyinduced hormesis can be actively used by the public to help counteract the harmful effects of low-dose chemical mixtures. Examples of mitohormesis- or xenohormesisinducing stressors are calorie restriction, intermittent fasting, exercise, cognitive challenging and phytochemicals. As humans evolved with repeated exposure to these stressors, their hormetic effects can be seen as the result of an evolutionarily adaptive process and therefore as safe.

 

 

[mccoy]

The strategies outline on the above posted article fit well into the multi-stratgy phytohormetical approach which was cited by Sibiriak in the original post.

 

Hormesis+xenohormesis→ various phytochemicals

Mitohormesis→ Proper exercise, CR, IF...

 

The (xeno)hormetic/mitohormetic strategy so implemented causes teh occurrance of adaptive overcompensation systemic mechanisms in the body.

 

The adaptive threshold rises as in the above posted figure. This shifts the subhormetic, detrimental region of environmental pollutants into the hormetic, beneficial region. 

 

Apparently, the suggestions to adopt a xenohormetic diet and behaviour as an health and longevity boostign strategy are becoming ever stronger.

[Sibiriak]

This is an article posted by Al Paper in his valuable updates

 

 

 

"Al Paper"  would be an appropriate nickname!       Thanks for pointing out that article.  I'm away from home and I've haven't been checking his posts as regularly as I usually do.

[mccoy]

By The way the pun was unintentional, I couldn't have thought such a good one on purpose.

 

 

I corrected the mistake.

[mccoy]

MUSHROOMS:

 

That's a favourite of Gordo, and a source of beneficial compounds cited in the Superimmunity book by Joel Fuhrman.

 

Gluthatione and ergothioneine appear to be two beneficial compounds very rich in mushrooms. Top of the list are th ePorcini mushrooms, a valuable culinary species well known in Italy. well, I didn't know, but now I'll make sure to eat frequently of this species, which is widely available in the dried and frozen forms, whereas in the right season it's also available as the fresh fungus.

 

Mushrooms: A rich source of the antioxidants ergothioneine and glutathione

[Sthira]

How do we vegans feel about consuming mushrooms? I admit I love them ferociously, I eat them and eat them, I steam them, steam them up with guilt and olive oil, I mean, kingdom fungi are more closely related to kingdom animalia than they are to plants.

 

..... I wander around after the rains gathering wild mushrooms in the mist; few city folk here dare to chance it, or even notice they exist. If anyone around my ridiculous circus of a life notices I'm gathering mushrooms from the abandoned fields and busy street sides, they might say: "Aren't you AFRAID of DEATHCAPS"

 

I'm like, nope.

 

Do mushrooms have moms and faces and feel pain? Are mushrooms on no-no lists, dear vegans, or am I awful?

[mccoy]

There is another issue regarding mushroom consumption: radioactivity, since, even like fish is a natural accumulator of mercury, mushrooms seem to be natural accumulators of radionuclides.

 

We might even hypothesize that the hormetic effects of mushrooms are mainly caused by radiation hormesis rather than by gluthatione and other phytochemiclas. But it risks to be a potentially disastrous faustian bargain

 

Food Chem. 2014 Jul 1;154:14-25. doi: 10.1016/j.foodchem.2013.12.083. Epub 2014 Jan 3.

Radioactivity in mushrooms: a health hazard?

Guillén J1, Baeza A2.

[mccoy]

Reading the article it stands out that mushrooms also concentrate heavy metals. I hate to be a party pooper but at this point some caution is in order. Shiitake mushrooms in Japan after fukushima displayed exceptionally high concentrations of radio caesium.

[mccoy]

Very interesting info on the xenohormetic nature of resveratrol. Grape Infections boost its content.

 

Since resveratrol is a deviation of the flavonoids metabolism in reaction to infections (mainly a defense against molds), its content is not known a priori (/except that it's definitely higher in red wines) but determined mainly by infections.

As underlined in another thread, organic grapes are more liable to be attacked. I don't know about climate as hinted in another thread on alcohol.

 

This is a classic example of xenohormesis, a toxic compound created by the plant in reaction to a stressor, which is then used to its own advantage by another organisms (like the human being)

 

This phenomenon keeps being fascinanting to me, especially so its evolutionary angle.

 

 

The note has been translated by google from Italian

 

 

 

RESVERATROL
In reality it is not a true polyphenol, even if it has the structure with benzene rings and an OH group, it is a trihydroxystilbene, it derives from the deviation of the flavonoid metabolism when the plant is attacked, it is therefore a substance that the plant produces in response to a 'infection. Normally the plant tends to produce flavonoids, if there is an infection, the molecule of resveratrol has an inhibitory action especially against molds, so the plant modifies the metabolism of flavonoids, produces more stilbenic derivatives with a defense function against attack.
If the grapes are infected, they also contain quantities of a few milligrams per liter of finished wine, precisely because the plant tends to break this substance as a response to an infection, whether it has an attack of powdery mildew, or botrytis that of peronospora to the bunch and not to the leaf. He re-launched the image of wine given its anti-radical anti-radical function. The antioxidant function is however lower than many dimers of gallate-catechins.