ResCu: Resveratrol (Res) and Copper (Cu)
A pro-oxidant combination of two GRAS supplements, resveratrol and copper (ResCu), blocks a newly identified aging pathway identified as double-stranded breaks (DSBs) in DNA, caused by cell-free chromatin particles (cfChPs). ResCu blocks this pathway, down-regulates multiple biological hallmarks of aging, and appears to be beneficial in cancer, Alzheimer's disease, COVID-19, sepsis, and neurodegeneration.
Source:[20] Click [√] to Enlarge
Extensive research from Dr. Indraneel Mittra, and colleagues, conducted at India's Tata Memorial Centre indicates that a combination of two nutraceuticals—resveratrol (R) and copper (Cu)—generates free radicals (ROS) that can help ameliorate various diseases an improve markers that correlate with advancing aging, by inactivating cell-free chromatin particles (cfChPs). The generation of oxygen radicals through this combination deactivates cfChPs, offering potential therapeutic benefits. As detailed on this page, copper can have unwanted side effects, primarily memory impairment in older individuals or in anyone with a pre-existing neurological condition such as Alzheimer's disease. We are recommending that copper be substituted with an alternative metal-oxide that has the same capacity to generate reactive oxygen species (ROS) molecules in the presence of resveratrol.
We have hypothesised that repeated and lifelong assault on healthy cells by cell‐free chromatin particles (cfChPs) derived from the dying cells may be the underlying cause of ageing. In support of this hypothesis, admixing Resveratrol (Res) with Copper (Cu), leads to generation of oxygen radicals by virtue of the ability of Res to reduce Cu (II) to Cu (I). Oxygen radicals that are generated in the stomach upon oral administration of R–Cu are apparently absorbed to have systemic effects in the form of deactivation / eradication of extracellular cell free chromatin. Prolonged oral administration of R–Cu, down-regulated multiple biological hallmarks of ageing and neurodegeneration by virtue of its ability to deactivate cfChPs. Our results suggest that ResCu may qualify as an ideal anti-ageing agent since it has the potential to simultaneously retard or delay the many conditions that are associated with ageing.[3]
Fig 10. Click [√] to Enlarge
For an anti-aging agent to be globally applicable, it should be both inexpensive and non-toxic—criteria that R-Cu meets. R-Cu can be easily administered orally, and both R and Cu are already approved for human use. An illustrated summary of the study design and the mechanisms through which R-Cu-generated oxygen radicals eradicate cfChPs from the brain microenvironment, leading to a reduction in aging hallmarks, is provided in Figure 10.
◉ Summary:
Reactive Oxygen Species (ROS) are short-lived molecules containing an unpaired electron, making them highly reactive as they seek another electron to stabilize. ROS when artificially generated in extracellular spaces, can have therapeutic effects. Multiple studies have now demonstrated that prolonged oral administration of R-Cu to aging mice can reduce multiple biological hallmarks of aging and neurodegeneration by deactivating cell free chromatin particles (cfChPs). R-Cu may be an ideal anti-aging agent, as it is inexpensive, non-toxic, and has the potential to simultaneously retard or delay various conditions associated with aging.
Two studies from Prof. Mittra's group used mouse models to demonstrate the benefits of R-Cu administration in prevention of ageing and sepsis. The first of these indicated that the cfChPs that are released from the billions of cells that die in the body every day and damage healthy cells is the underlying cause of ageing, and prolonged oral administration of R-Cu leads to the downregulation of multiple biological parameters of ageing including neurodegeneration, which is associated with Alzheimer's disease. The other study showed how cfChPs trigger sepsis after bacterial infection in mice; administering R-Cu prevented this pathological process, including the prevention of fatality.
ResCu from Chronic Immune Stimulation / Inflammation
Click [√] on Image to Enlarge
Source: [12] [2015] Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes
The graphical illustrations above demonstrates the mechanistic steps involved in oxygen radical induced down-regulation of aging and cancer hallmarks. (A) cfChPs released from dying cancer cells induce DNA damage and inflammation, and up-regulate cancer hallmarks in surviving cancer cells. (B) Oxygen radicals generated upon oral ingestion of R-Cu are systemically absorbed from the stomach to reach TE leading to eradication of extra-cellular cfChPs and down-regulation of cancer hallmarks in surviving cells. Oxygen radicals also enter into the surviving cancer cells; but their cellular entry leads to activation of intracellular anti-oxidant enzymes which detoxify and eliminate the offending agents. SOD, superoxide dismutase; GPx, glutathione peroxidase; TME, tumor microenvironment. [1]
BACKGROUND
It has now been determined that aging is a disease, and that diseases we associate with aging (Atherosclerosis, Diabetes, Alzheimer’s and Neurodegeneration, Cardiovascular, Osteoporosis, Cancer, Sarcopenia and Systemic inflammation / Inflammaging), are all directly caused by aging. Individual treatments that are effective against a multitude of these diseases are in all probability addressing, or at a minimum, positively impacting a root molecular cause of aging.
Two, very safe nutritional supplements; 1) Resveratrol and 2) copper or magnesium, at very low does, down‑regulate multiple biological hallmarks of aging and neurodegeneration in mice. That is just the main headline of a very long list of what this combination appears to accomplishe.
◉ C A U T I O N ! There is a growing body of evidence suggesting that copper may play a role in the development of Alzheimer's disease. Alzheimer's disease is a neurodegenerative disorder characterized by the progressive loss of memory and cognitive function. Copper is an essential metal that is involved in various biological processes, including neurotransmitter metabolism, antioxidant defense, and the formation of the protein amyloid-β, which is a hallmark of Alzheimer's disease.
Studies have shown that increased levels of copper in the brain can lead to the accumulation of amyloid-β, which can then trigger the formation of toxic aggregates that contribute to the progression of Alzheimer's disease. Copper has also been shown to disrupt the function of the blood-brain barrier, which is a protective barrier that helps to prevent the influx of toxic substances into the brain. This disruption can result in increased levels of copper in the brain and further contribute to the development of Alzheimer's disease.
On the other hand, copper deficiency has also been linked to Alzheimer's disease, as copper is essential for maintaining normal brain function and preventing oxidative damage.
It is important to note that the relationship between copper and Alzheimer's disease is complex and still not fully understood, and more research is needed to fully understand the role of copper in the development of this disease. However, the current evidence suggests that maintaining normal levels of copper in the brain may be an important factor in preventing or slowing the progression of Alzheimer's disease.
Refs
Individuals who are older than 65 are more likely to have developing and often undiagnosed neurological disease. If you have any neurological complications that cause any kind of memory deficits, it may be important to replace the copper in their therapy with the alternative provided in the next paragraph. Regardless of your age, if you chose to implement the ResCu protocol it is important to stop this therapy if you notice any decrease in your memory. Several days of curcumin, (3000 mg, twice a day for three days) which will act as an effective cheating agent will aid in resolving this problem if it is caused by directly by copper [5].
Copper Substitutions
Refs
Some common oxidants include copper (II) oxide (CuO), copper (II) peroxide (Cu2O2), and copper (II) perchlorate (Cu(ClO4)2). These compounds can be substituted with other metal oxides that display similar redox properties, such as iron (III) oxide (Fe2O3), chromium (III) oxide (Cr2O3), manganese (IV) oxide (MnO2) and Magnesium Oxide (Mg02). These metal oxides can release oxygen when they are reduced, providing they are in the presence of a suitable reducing agent. Each of these alternatives have their own toxicity profiles and the extreme titration employed in the ResCu protocol for the copper component should be employed for these potential substations.
A Review of the Role of Curcumin in Metal Induced Toxicity
Curcumin, a bioactive substance in turmeric, is widely used as a dietary supplement. Most studies have shown that curcumin protects against metal-induced lipid peroxidation and mitigates adverse effects on the antioxidant system. This review article provides an analysis to show that curcumin imparts promising metal toxicity-ameliorative effects that are related to its intrinsic antioxidant activity.
Copper-Induced Toxicity
⫸ Copper’s redox nature makes it essential for many biological processes, but at the same time renders it toxic effects due to the generation of the most dangerous ROS, hydroxyl radical (•OH) [118]. An imbalance of Cu ions in the central nervous system engages in many neurodegenerative diseases pathogenesis, the most common is amyotrophic lateral sclerosis, Alzheimer’s, and Parkinson’s diseases [132,133,134,135]. For Cu toxicity, the same chelating treatment is used as for other metal poisonings [136].
Curcumin as an Effective Chelator in Copper induced toxicity
Through quantum chemical computations, it was discovered that due to the proton loss of the CUR enol form, the β-diketone part is the main site of chelation in the CUR-Cu(II) complex [137] (Table 5). In studies conducted with CUR administration, CUR had ameliorating effects on the CuO nanoparticles toxicity in terms of the antioxidant, immunomodulatory, anti-apoptotic, and anti-inflammatory effects on the rats’ kidneys [138]. Moreover, considering the role of oxidative damage in mediating Cu toxicity, CUR suppressed neurotoxicity through its anti-radical and antioxidant properties [82]. CUR’s neuroprotective properties provide the basis for studying its effectiveness in several neurodegenerative diseases involving Cu, such as Alzheimer’s disease. Through the ability of CUR to penetrate the blood–brain barrier, CUR can block amyloid beta-peptide, a key disease factor that accumulates in the brain, and reduce its levels as well as remove the metal ions in the brain [139]. Thus, CUR as a restorative remedy for oxidative stress caused by Cu ions might be useful for therapeutic treatment, including neurodegenerative diseases. ⫷[19]
Copper Chelator Induced Efficient Episodic Memory Recovery in a Non-Transgenic Alzheimer’s Mouse Model
Here we report the capacity of a new copper-specific chelating agent, a bis-8-aminoquinoline PA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model.
ALZHEIMER’S DISEASE IS, AT LEAST IN PART, A COPPER-2 TOXICITY DISEASE
There is good evidence that copper toxicity plays a major role in the pathogenesis of Alzheimer’s, with the size of the free copper pool intimately tied to cognition and cognition loss. Studies in AD animal models show that tiny amounts of inorganic copper in drinking water greatly enhance Alzheimers-type pathology and memory loss. Studies in humans show that those ingesting supplement pills containing copper, if they also eat a high fat diet, suffer rapid loss of cognition. Drinking water copper, and pill copper are both divalent copper, or copper-2. A recent study shows that food copper is primarily copper-1. There is an intestinal transport system specific for copper-1, and this copper goes to the liver, and is put into safe channels. Because mammals, including humans, ingested only copper-1, their systems evolved to safely handle copper-1. With development came copper plumbing and supplement pill ingestion, and copper-2 is now ingested. Some of it bypasses the liver, ends up in the blood free copper pool, and is toxic to cognition.[]
[2020] Impact of N-Truncated Aβ Peptides on Cu- and Cu(Aβ)-Generated ROS: CuI Matters!
In-depth characterizations and ROS production studies of Cu (CuI and CuII) complexes of the Aβ4–16 and Aβ11–16 N-truncated peptides. Our findings show that the N-truncated peptides do produce ROS when CuI is present in the medium, albeit to a lesser extent than the unmodified counterpart. In addition, when used as competitor ligands (i.e., in the presence of Aβ1–16), the N-truncated peptides are not able to fully preclude Cu(Aβ1–16)-induced ROS production.
[2013] The Risks of Copper Toxicity Contributing to Cognitive Decline in the Aging Population and to Alzheimer's Disease
Copper toxicity is the major cause of the epidemic of mild cognitive impairment and Alzheimer's disease engulfing our aging population. This epidemic is recent, exploding in the last 50-60 years. The disease was virtually unknown 100 years ago. And it involves only developed countries that use copper plumbing. Something in our environment associated with development is poisoning the minds of our aged. The epidemic is associated with the use of copper plumbing, and the taking of copper in multi-mineral supplements. Food copper (organic copper) is processed by the liver and is transported and sequestered in a safe manner. Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly. This copper is potentially toxic because it may penetrate the blood/brain barrier. I review a web of animal and human data that tightens the noose around the hypothesis that copper toxicity is causing the epidemic of Alzeimer's disease and loss of cognition in our aging population.
Copper Perturbation in 2 Monozygotic Twins Discordant for Degree of Cognitive Impairment
⫸ The cases reported support the hypothesis of a major involvement of copper and oxidative abnormalities in AD. Alzheimer disease (AD) is a heterogeneous neurodegenerative condition, and biomarker research has focused on a variety of possible disease-related mechanisms.1 Among these, the depletion of vitamins with direct or indirect antioxidant effects and the increase in homocysteine and in compounds involved in lipid peroxidation are thought to reflect oxidative changes with a potential pathogenetic significance in AD, according to the oxidative stress hypothesis of this condition.2-4 Abnormalities of trace metal metabolism also seem to be a primary neurochemical event in the genesis and progression of the disease.5,6 We have previously reported that copper levels measured in the peripheral circulation discriminate between patients with AD and normal control subjects,7,8 as well as patients with vascular dementia.9 In this study, we compare putative markers of oxidative stress in a pair of 73-year-old female monozygotic twins discordant for AD, and we discuss the potential role of copper abnormalities in the pathogenesis of AD in agreement with proposed models of biometal-related neurodegeneration.6⫸⫸ Cu in the research described here utilizes copper as the oxidative soucre. ⫷
[2023] A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study)
Abstract
It has been reported that chemotherapy toxicity is primarily not due to the drugs themselves, but is caused by cell-free chromatin particles (cfChPs) that are released from chemotherapy-induced dying cells. cfChPs from dying cells are readily internalized by healthy cells, wherein they inflict dsDNA breaks and activate inflammatory cytokines. cfChPs can be deactivated by oxygen radicals that are generated upon admixing the nutraceuticals resveratrol (R) and copper (Cu). Pre-clinical studies have shown that administration of R-Cu can reduce chemotherapy toxicity via the generation of oxygen radicals which deactivate cfChPs released from chemotherapy-induced dying cells. We investigated if R-Cu would reduce toxicity of docetaxel-based multi-agent chemotherapy in advanced gastric cancer. This single-arm phase II study was designed to assess the efficacy of orally administered R-Cu in ameliorating toxic side effects, as per National Cancer Institute Common Terminology Criteria for Adverse Events v4.03, in patients with advanced gastric cancer receiving docetaxel-based multi-agent chemotherapy. The primary objective was to reduce the proportion of patients experiencing grade ≥ 3 toxicity from 90 to 70%. Between October 2019 and April 2021, 30 patients, with a median age of 54 years, were enrolled of whom 73% were male. R-Cu treatment did not reduce the overall cumulative incidence of grade ≥ 3 toxicity (77%), or of ≥ 3 haematological toxicity (73%). However, the incidence of non-haematological toxicities comprising hand-foot syndrome (N = 4), diarrhoea (N = 3) and vomiting (N = 1) were markedly reduced (13%). Median progression-free survival (PFS) was 8 months (95% CI: 5.9–10.1), and overall survival (OS) was 16 months (95% confidence interval: 6.3–28.3). A marked reduction in non-haematological toxicities was seen in patients receiving R-Cu compared to historical data without adversely affecting PFS or OS. (292).[2]
The lowest dose of R-Cu (Dose level I) comprised of 5.6mg of R and 560ng of Cu (molar ratio 1:10-4). This dose was arrived at by direct conversion of dose of R and Cu that we have used in our pre-clinical studies (R = 1mg/Kg and that of Cu 0.1µg/Kg) using a standard conversion formula (14). Dose levels II and III were approximately 10 fold and 100 fold higher than dose level I; dose level IV comprised of doses of R and Cu that have been recommended by the respective vendors for use as health supplements. Toxic side effects related to R-Cu treatment was monitored using CTCAE v3.03 guidelines.
◉ Clinical and Laboratory Result of NS-ROS Treatments by Species and Category
◉ ROS are highly reactive molecules that can damage biomolecules such as DNA, proteins, and lipids.
◉ Artificially generated extracellular ROS can have wide-ranging therapeutic effects.
◉ R-Cu generates oxygen radicals that can deactivate or eradicate extracellular cfChPs.
◉ cfChPs can cause extensive damage to host cells and may be an underlying cause of aging.
◉ Prolonged oral administration of R-Cu to aging mice reduces multiple biological hallmarks of aging and neurodegeneration.
◉ R-Cu is a promising anti-aging agent due to its low cost, non-toxicity, and potential to retard or delay various aging-associated conditions.
◉ ResCu reduces toxicities associated with advanced cancers post chemotherapy
◉ ResCu reduces systemic metabolic dysfunction in ageing mice.
◉ ResCu dramatically reduces the incidences of death in severe COVID-19.
◉ ResCu reduces telomere abnormalities in ageing brain cells.
◉ ResCu reduces amyloid deposition in ageing brain and restores of BDNF levels.
◉ ResCu reduces DNA damage, apoptosis and inflammation in ageing brain cells.
◉ ResCu reduces senescence in ageing brain cells.
◉ ResCu reduces aneuploidy in ageing brain cells.
◉ ResCu reduces mitochondrial dysfunction in ageing brain cells.
◉ ResCu prevent fatality in mice following bacterial endotoxin induced sepsis (8)
Mice
[2022] A pro‑oxidant combination of resveratrol and copper down‑regulates multiple biological hallmarks of ageing and neurodegeneration in mice
◉ R–Cu reduces telomere abnormalities in ageing brain cells.
Telomeres play a central role in cellular changes associated with ageing. Telomere attrition, telomere loss and telomere aggregation are cardinal features of ageing.
R–Cu treatment restored telomere length to a significant degree in female mice (p < 0.001), but not in male mice.
Aggregation of telomeres, which was significantly increased in ageing mice of both sexes, but was significantly reduced following R–Cu treatment only in female mice.
Overall, with respect to telomere abnormalities, R–Cu was found to be effective in restoring telomere abnormalities in female, but not in male mice.
◉ R–Cu reduces amyloid deposition in ageing brain and restores of BDNF levels in serum.
Increased amyloid deposition observed in aging mice, is associated with Alzheimer's disease
One year of R-Cu treatment led to a significant reduction in extracellular amyloid in both sexes
BDNF levels were reduced in aged mice of both sexes
R-Cu treatment for one year restored serum BDNF levels nearly to those seen in young mice in both sexes
◉ R–Cu reduces DNA damage, apoptosis and inflammation in ageing brain cells.
DNA damage, apoptosis, and inflammation in brain cells are hallmarks of aging
R-Cu treatment reduced DNA damage, as shown by lower γ-H2AX levels in both sexes
R-Cu treatment reduced apoptosis, as indicated by decreased active caspase-3 levels in both sexes
R-Cu treatment significantly lowered inflammation, as evidenced by reduced NF-kB levels in both sexes
◉ R–Cu reduces senescence in ageing brain cells.
Senescence is the hallmark of biological ageing characterized by gradual deterioration of cellular functions
R-Cu treatment significantly reduced DNA-SCARS, a classical hallmark of senescence, in both sexes
R-Cu treatment significantly reduced co-localizing signals of 53BP1 and PML, markers of SAHF, in both sexes
R-Cu treatment significantly reduced levels of p16INK4a, another marker of senescence, in both sexes
◉ R–Cu reduces aneuploidy in ageing brain cells.
Telomere loss resulting in fusion of chromosomes in ageing mice can cause aneuploidy resulting in abnormal number of chromosomes.
We observed a ~ 15 fold increase in aneuploidy in ageing mice with respect to both chromosomes for both chromosomes in both sexes.
R–Cu treatment markedly reduced aneuploidy with respect to both chromosomes in both sexes.
◉ R–Cu reduces mitochondrial dysfunction in ageing brain cells.
Mitochondrial DNA integrity and functionality decrease with age resulting in accumulation of oxidative damage caused by reactive oxygen species
Overexpression of TOMM20 is associated with increased mitochondrial volume in aging brain cells
R-Cu treatment significantly restored mitochondrial volume in both male and female mice
◉ R–Cu reduces systemic metabolic dysfunction in ageing mice.
Metabolic ageing involves dysregulation of physiological processes leading to insulin resistance and lipid accumulation brought about by low grade chronic inflammation.
Serum glucose levels were elevated in aging mice and reduced by R-Cu treatment in both sexes
Serum cholesterol levels were elevated in aging female mice and reduced by R-Cu treatment in both sexes
CRP levels, an inflammation marker, were elevated in aging mice and reduced by R-Cu treatment in both sexes
Aging Markers in Mouse Study
◉ ResCu reducessignificant reduction in blood levels of glucose
◉ ResCu reducessignificant reduction in cholesterol
◉ ResCu reducessignificant reduction C‑reactive protein.
◉ Aging mice showed significant reduction in SOD levels in brain cells
◉ R–Cu treatment led to marked increase in SOD levels that were similar to that detected in young control mice
A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer
◉ Aging mice showed significant reduction in SOD levels in brain cells
◉ R–Cu treatment led to marked increase in SOD levels that were similar to that detected in young control mice
R–Cu treatment led to reduction of several biological hallmarks of ageing in brain cells which included telomere attrition, amyloid deposition, DNA damage, apoptosis, inflammation, senescence, aneuploidy and mitochondrial dysfunction.
R–Cu treatment did lead to an increase in SOD activity in serum of ageing mice, restoring them to levels similar to those seen in young control mice
◉ Telomeres play a central role in cellular changes associated with ageing32 . Telomere attrition, telomere loss and telomere aggregation are cardinal features of ageing32,33. W
R–Cu treatment did lead to an increase in SOD activity in serum of ageing mice, restoring them to levels similar to those seen in young control mice
◉ Telomeres play a central role in cellular changes associated with ageing32 . Telomere attrition, telomere loss and telomere aggregation are cardinal features of ageing32,33. W
DNA damage and chronic inflammation are two cardinal features of aging addressed by ResCu.
“Aging: is the result of genetic mutations that corrupt our DNA, creating a junkyard of damaged cellular tissue that leads to deterioration, disease and death.” David Sinclair 01/11/2023
◉ There may be some promise of preventing death in bacterial infections that have progressed to Sepsis. See Ref [8]
(WikiLink: Chromatin) - (Last Revision: 01/10/2023)
◉ The DNA double helix in the cell nucleus is packaged by special proteins termed histones. The formed protein/DNA complexes are called chromatin.
◉ Epigenetics describes all reversible, environmental, psychological, physiological and heritable processes that regulate gene expression without altering the DNA sequence. Cell free chromatin from dead and apoptotic cells, when incorporated into healthy cells produces damage and induces inflammatory responses causing systemic signaling that drives aging.
◉ Billions of cells die in the body every day, releasing cell‑free chromatin particles (cfChPs) which them enter into the extracellular compartments of the body, including into the circulation via the plasma. This cell free chromatin becomes readily internalized by healthy cells, wherein they inflict double stranded DNA (dsDNA) breaks, activating apoptotic pathways and inducing inflammatory cytokines.
◉ The results are more cells die and more cfChPs are released producing a self-perpetuating feed-back loop.
◉ Mittra et al., propose that extranuclear cell‐free chromatin particles (cfChPs) act as continuously arising endogenous mediators of inflammation by their ability to inflict double strand DNA (dsDNA) breaks in healthy cells, which may have wide-ranging systemic effects. This negative system has been proposed as a newly identified process that may be a root cause of inflammation and aging.
◉ Emerging evidence indicates that cfChPs play an essential role in ageing, sepsis, the development of cancer, and chemotherapy-related toxicity. Administration of ResCu leads to the downregulation of multiple biological parameters of ageing including neurodegeneration, which is associated with Alzheimer’s disease. The other study showed how cfChPs trigger sepsis after bacterial infection in mice; administering ResCu prevented this pathological process, including the prevention of fatality.
◉ Although resveratrol has poor bioavailability, oral, simultaneous administration of Resveratrol either Copper (ResCu) or Magnesium Oxide (ResMag) leads to the generation of reactive oxygen species (ROS) in the gut. The released free radicals are readily transported into the bloodstream making the poor bioavailability of the core constituents irrelevant.
⫸ These oxygen radicals are readily absorbed and have systemic effects in the form of deactivation of extracellular cell‑free chromatin particles (cfChPs). The cellular genomes are, however, protected from damage as the entry of oxygen radicals triggers the cells to activate their anti-oxidant defence mechanism which detoxifies the invading agents (8). (See illustration in Overview Below) Clinical and Pre-clinical studies have shown that oral administration of small quantities of ResCu can have remarkable therapeutic effects in conditions associated with elevated levels of extracellular cfChPs (2, 6–8). For example, ResCu administered orally can prevent toxic side effects of chemotherapy (6), and radiotherapy (2), and prevent fatalities in mice following bacterial endotoxin induced sepsis (7). We have also shown that prolonged oral administration of ResCu to ageing mice can down-regulate several biological hallmarks of ageing and neurodegeneration (8) ⫷ [1]
Although the aging study were conducted in mice [3], four human studies have been conducted with ResCu. Three in cancer (n = 70) [1,4] and one in SARS COVID-19 (n = 30) [6]. In the COVID study, the recipients of ResCu demonstrated a >50% reduction in their risk of death. The cancer studies substantiated the down-regulation of 21/23 cancer biomarkers representing the 10 hallmarks of cancer, including 5 immune checkpoints. It also demonstrated the ability to mitigate the negative side effects and toxicities of chemotherapy. It should be noted that it failed at reducing grade 3 and greater toxicities directly associated with the cancer.[2] The ability of ResCu to deactivate cfChPs raises the prospect of a novel and non-toxic form of cancer treatment which eliminates the requirement of killing of cancer cells, and instead induces healing by down-regulating cancer hallmarks and immune check-points. [1,2]
SAFETY: It is noteworthy that the amount of Resveratrol present in the lowest dose (level I) was ~90 times less, and that of Cu ~4500 times less, than those that are recommended by the respective vendors for use as health supplements. Thus, small quantities involved in the combination of Res and Cu can generate sufficient oxygen radicals to have profound effects in terms of down-regulation of cancer hallmarks and immune checkpoints by targeting a hitherto unknown constituent of TME. [4] The literature contains a warning for anyone that has been diagnosed with or may have the symptoms of Alzheimer's disease, about the injection of copper. This warning is discussed below. If you are 60 years of age or older, I would strongly recommend that you substitute magnesium Oxide for the copper oxide. The dosage required are identical.
Prolonged oral administration of R–Cu to ageing mice down-regulated multiple biological hallmarks of ageing and neurodegeneration by virtue of its ability to deactivate cfChPs. Our results suggest that ResCu may qualify as an ideal anti-ageing agent since it has the potential to simultaneously retard or delay the many conditions that are associated with ageing.[3]. Extended treatment at the lowest study does for 21 days did not result in any drug related adverse events.[4]
Dosage, Timing and Interval of ResCu Administration
No major side effects have been reported in long-term clinical trials. In fact, resveratrol has been found to be safe and well-tolerated at up to 5 g/day (5,000 mg), either as a single dose or as fraction of multi-day dosing schedules [13].
The beneficial effects demonstrated by ResCu in multiple studies were all accomplished incorporating miniscule doses, (the authors description, not mine). The effective dose of Resveratrol used in this study; (5.6 mg) was nearly 100 times less than the recommended doses of resveratrol when used as a health supplements. The effective dose of Copper (560ng) was nearly 10, 000 times less than recommended daily allowance when utilized as a nutritional supplement. [4]
Resveratrol was admixed in the gut with Copper and administered twice a day on an empty stomach. Reduction in inflammatory cytokines: salivary TNF - α (p = 0.012) and IL—1β (p = 0.009) in dose level I (resveratrol = 5.6 mg and copper = 560 ng), but not in (higher doses) dose level II was observed.[4]
ResCu Dossage Calculation Sheet
Reduction of the nutritional supplements in this published research, down to the minuscule amounts advocated can be difficult to accurately reproduce. Tritration of both agents can easily be accomplished by first putting each into separate solutions.
The authors utilized 20 ml of water/drug as the total final volume administered for each agent.
➲ Resveratrol (H) (5.6 mg) was suspended in 20 mL of water and administered orally, followed by 20 mL of water as wash down.
➲ Copper (H) (560 ng) in 20 mL of water-based solution was administered orally immediately afterwards, followed by 20 mL of water as wash down.
Resveratrol is normally provided in dosages of 200 to 250 mg. That translates into one capsule equalling 33 - 41 doses.
Copper is normally provided in dosages of 2 to 5 mg. That translates into one tablet equalling 3361 - 8403 doses.
IMPORTANT! It is very important to take only the exact, low dosage recommended by the published literature. 5.6 mg of Resveratrol and 560 ng of Copper or Magnesium. Be extremely careful when dividing, measuring and titrating the doses of each Res-Cu components. There are several ways of accomplishing this. One is to take the raw materials to a local compounding pharmacy and they can accomplish the dilution for you. The second method is described below.
Resveratrol* is provided in various forms in dosages ranging between 200 and 250 mg.
We are utilizing “Renue by Science,” brand, pure trans-resveratrol, provided in a 100 gram, free-powdered form. Trans-resveratrol is the more biologically active and is the predominant form found in nature.
Copper** Copper is normally provided in dosages of 2 to 5 mg. Use pill cutter or crush and weigh to obtain correct amount.
We are utilizing “Mag-Ox,” as a replacement oxide for copper. Mag-Ox is provided in a 483mg tablet and is available here: http://www.magox.com.
◉ (A) Resveratrol: Dissolve (B) 200mg of Res into (D) 70 mLs of filtered or distilled water. Each (1) mL of the resulting solution will contain (E) 2.86 mg of Res. Add (F) 2ml of Res solution to 19 mLs of filtered or distilled water. The final 20 ml solution will contain (G) 5.71mg of Resveratrol.
◉ (A) Copper or Magnesium: Dissolve (B) .25 mg of Coppers into (D) 420 mLs of filtered or distilled water. Each (1) mL of the resulting solution will contain (E) 595ng of Copper. Add (F) 1ml of Res solution to 19 ml of filtered or distilled water. The final 20 ml solution will contain (G) 595 ng of Copper.
To obtain the starting copper amount of .25 mg a tablet splitter can be utilized or the tablet can be crushed and weighed and divided using a nanogram scale.
Both agents were put into solution (D) utilizing a stick blender in a stainless steel container.
If you would like a copy of the active dosage calculation excel sheet shown above, please use the links at the bottom of this page.
Long-term duration studies of this combination have not been done. Although the author describes the doses as minuscule, the chemical reaction produced in the gut when ResCu is admixed is designed to produce reactive oxygen species (ROS) and that safety profile will be distinct and unique from either of the two base supplements.
Multiple other strategies have employed administering free oxygen radicals as a treatment modality for a large number of diseases and wound healing. This has been primarily accomplished through the use of hyperbaric oxygen therapy (HBOT), where an individual is placed in a compressed environment containing pure oxygen. HBOT has a long history of providing treatments for over 50 years with a very high safety profile and therapeutic index.
As we do with every age-regressive intervention on this site, we strongly advocate the you consultation with your physician if you decide to implement ResCu as an anti-aging intervention or cancer preventive.
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Epigenetics describes all reversible, environmental, psychological, physiological and heritable processes that regulate gene expression without altering the DNA sequence. Cell free chromatin from dead and apoptotic cells, when incorporated into healthy cells produces damage and induces inflammatory responses causing systemic signaling that drives aging.
Click [√] to Enlarge
By National Institutes of Health - http://commonfund.nih.gov/epigenomics/figure.aspx Public Domain, https://commons.wikimedia.org/w/index.php?curid=89191872
The biggest risk factor to implementing this strategy is the daily dosing of copper. As indicated by multiple publications from Dr. Mittra’s team, minuscule doses of copper are all that’s required. Far below the minimum daily recommended dose. It should also be noted that higher doses of copper were less effective. Copper toxicity information can be found on multiple sties. Wikipedia provides a brief overview here. Curcumin provides a good copper chelation agent in the event that you notice a reduction in memory or concentration. If you are sensitive to copper, magnesium provides an excellent alternative and dose not have the memory problems associated with its use.
Because no long term human clinical data of this combination is currently available, It may be prudent to pulse this therapeutic modality, taking it twice a day for 6 days and skipping one day in each week.
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ResCu in the News
◉ Indian Researchers from ACTREC Discover Novel Therapeutic Agent for a Host of Diseases
◉ Exploiting the synergy of nutraceuticals for cancer prevention and treatment ~ EurekaAlert
◉ Exploiting the synergy of nutraceuticals for cancer prevention and treatment ~ ScienMag
◉ Indian Researchers from ACTREC Discover Novel Therapeutic Agent for a Host of Diseases ~ Benzinga
Related Research
Epigenetic Reprogramming vs Chromatin Inactivation
David Sinclair, a professor of genetics in the Blavatnik Institute at Harvard Medical School and codirector of the Paul F. Glenn Center for Biology of Aging Research is approaching this this same problem/target with a different strategy. Dr. Sinclair is resetting the epigenetic programming of all cells of an organism using OSK transcription factor reprogramming. His most recent paper provides strong evidence that it is the cell's reaction to DNA breaks, rather than actual mutations, that drives the aging clock. “The act of repairing DNA breaks induces chromatin reorganization and a loss of cell identity that may contribute to mammalian aging.”
Dr. Mittra is attempting to intercept and inactivate the primary pathogenetic/aging process causing these DNA breaks: cell free chromatin. The underlying target is the same genomic degeneration caused by information loss via chromatin and double stranded breaks. The interventional action of Dr. Sinclair’s group is probably going to be more effective from a global age-regression perspective, but is also likely to be 5 to 6 years away from being available to the general public. On the other hand you can go buy Resveratrol and Copper supplements at any health food stores or online today.
[2023] Loss of epigenetic information as a cause of mammalian aging
Jae-Hyun Yang 29, Motoshi Hayano 29, Patrick T. Griffin, Andreas R. Pfenning, Luis A. Rajman, David A. Sinclair 30
Published:January 12, 2023 DOI:https://doi.org/10.1016/j.cell.2022.12.027
“We believe ours is the first study to show epigenetic change as a primary driver of aging in mammals,” said the paper’s senior author, David Sinclair, professor of genetics in the Blavatnik Institute at Harvard Medical School and co-director of the Paul F. Glenn Center for Biology of Aging Research.
Non-mutagenic DSB repair, causes the epigenetic landscape to erode and cells to drift into adjacent Waddington valleys, where they malfunction and cause aging, consistent with the Information Theory of Aging.
The team’s extensive series of experiments provide long-awaited confirmation that DNA changes are not the only, or even the main, cause of aging. Rather, the findings show, chemical and structural changes to chromatin — the complex of DNA and proteins that forms chromosomes — fuel aging without altering the genetic code itself.
The Illustration below and Dr. Sinclair’s most recent research (On Left) demonstrate the connection to the potential anti-aging impact of ResCu.
Click [√] to Enlarge
Abstract/Summary
All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called “ICE” (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.
Another current paper incorporating the same approach.
Here, we show that systemically delivered AAVs, encoding an inducible OSK system, in 124-week-old mice extends the median remaining lifespan by 109% over wild-type controls and enhances several health parameters. Importantly, we observed a significant improvement in frailty scores indicating that we were able to improve the healthspan along with increasing the lifespan. Furthermore, in human keratinocytes expressing exogenous OSK, we observed significant epigenetic markers of age-reversal, suggesting a potential reregulation of genetic networks to a younger, potentially healthier state. Together, these results may have important implications for the development of partial reprogramming interventions to reverse age-associated diseases in the elderly.
[1] [2023] A pro-oxidant combination of resveratrol and copper down- regulates hallmarks of cancer and immune checkpoints in patients with advanced oral cancer- Results of an exploratory study (RESCU 004) Abstract in Notes below.
[6] [2021] A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing
[7] [2020] Resveratrol and Copper for treatment of severe COVID-19: an observational study (RESCU 002)
[9] [2019] Cell-free chromatin- A newly described mediator of systemic inflammation
[10] [2018] Resveratrol: A Double-Edged Sword in Health Benefits
[13] [2015] Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes
[14] [2009] Dietary Administration of High Doses of Pterostilbene and Quercetin to Mice Is Not Toxic
[15] [2011] Clinical Trials of Resveratrol
[16] [1998] Resveratrol as a New Type of DNA-Cleaving Agent
[17] [2023] Alzheimer’s Disease is at Least in Part, A Copper-2 Toxicity Disease
[19] [2023] A Review of the Role of Curcumin in Metal Induced Toxicity
[20] [2023] Exploiting the synergy of nutraceuticals for cancer prevention and treatment
Hyperbaric Oxygen Therapy (HBOT)
A great deal of research has been accomplished on the impact of HBOT in disease and aging controls by genetics and epigenetics.
⫸Hyperbaric oxygen therapy (HBOT) refers to a therapeutic method that employs the physical advantages enveloped in the application of 100% oxygen in high-pressure (more than 1 ATA) environment for therapy. HBOT mainly aims to treat decompression sickness and CO poisoning. Lately, HBOT use and research had widened to a range of medical fields, most are involved in regenerative processes with physiological implications that have the potential to reverse age related processes and perhaps be beneficial to healthy aging and longevity.
We hypothesized that HBOT can cause regeneration and aging deceleration in adult humans through utilization of DNA Cytosine methylation. To explore this hypothesis, we performed an epigenome screening employing a novel technology (EPIC array) to monitor epigenomic changes in five elderly humans before and after HBOT treatment, followed by pipeline interrogation (Epigenome Wide Association Studies (EWAS)) to identify candidate epiloci. Six candidate genes (ROCK1, HAND2, IHH, FOXG1, EPHX3, SGCE) were identified to be differentially methylated.
We furtherly validated the six candidate genes by applying Sequenom EpiTYPER MassArray on blood samples from 17 elderlies before and after HBOT treatment. Statistical analysis revealed that four of the six candidate genes (ROCK1, HAND2, IHH, FOXG1) showed significant differences in general methylation and five of the genes (ROCK1, HAND2, IHH, FOXG1, EPHX3) showed significant changes in specific epiloci following HBOT, all of which reinforce the results obtained using EPIC array and point to epigenetic changes that occurs following HBOT treatment in elderly human.⫷ [H3]
These changes in methylation can point to molecular networks stimulated by HBOT, which have the potential to cause regenerative effects, reverse age-related processes or even cause aging deceleration and return to homeostasis.
The increase In free oxygen radicals is the primary proposed mechanism of benefit from HBOT. ResCu appears to accomplish the same effect as HBOT, but in a safer, non invasive manor utilizing oral supplements.
⫸The mechanism of the anti-inflammatory effect of HBO results from the inhibitory effect of such therapy on the synthesis of inflammatory mediators, such as: nitric oxide, prostaglandin E2, TNF-α, interleukin 1β, interleukin 12, interferon γ, as well as the reduction of mRNA expression and type 2 cyclooxygenase. influence on the synthesis of pro-inflammatory cytokines, the consequence of HBO treatment is an increase in the release of anti-inflammatory cytokines, mainly interleukin 10 [4,5].⫷[]
Link is to a Google Scholar Search of: Epigenetic Effects of HyperBaric Ooxygen Therapy
[H1] [2022] Hyperbaric oxygen therapy for healthy aging: From mechanisms to therapeutics
[H3] [2021] The effect of Hyperbaric Oxygen Treatment (HBOT) on human aging methylome
A comprehensive review was undertaken in the above thesis:
[H7] [2010] Hyperbaric oxygen treatment induces antioxidant gene expression
[H8] [1989] Genetic effects of hyperbaric oxygen therapy
[H10] [2022] POSSIBLE APPLICATIONS OF HYPERBARIC OXYGEN THERAPY- NARRATIVE REVIEW
Produces a reduction in IL-1 and increases IL-10.
Miscellaneous
◉ lmmune checkpoint proteins are key regulators of immune response against threats while preserving self-tolerance. The classic immune checkpoint consists of co-inhibitory receptors (CTLA-4, PD-1, TIGIT, LAG-3), which inhibit T-cell function and co-stimulatory receptors (GITR, 4-1BB, OX40, CD40) which stimulate T cell activation. Research on the co-inhibitory receptor CTLA-4 (cytotoxic T-lymphocyte antigen 4) and PD-1 (programmed cell death protein 1) showed significantly improved survival rates of patients with metastatic solid tumors after inhibition of these receptor pathways. Therefore, antibody drugs against immune checkpoints for cancer, tumors and other diseases therapeutics is a key mode in cancer therapy.
◉ Here we report a surprising observation that DNA and RNA cleaving and/or degrading activity of R-Cu increases as the ratio of R to Cu is sequentially increased (i.e., the concentration of Cu is sequentially decreased with respect to a fixed concentration of R). The activity was lost when the Cu concentration was reduced to very low levels.[9]
◉ Recent research has shown that cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body everyday can enter into healthy cells, integrate into their genomes and induce dsDNA breaks and apoptotic responses. Genomic integration of cfCh activates NFjB suggesting a novel mechanism of induction of systemic inflammation. Since DNA damage and inflammation are underlying pathologies in multiple devastating acute and chronic disease conditions, the discovery of agents that can inactivate cfCh may provide therapeutic possibilities.[6]
◉ Thirty of these patients received, in addition to standard care, resveratrol and copper at doses of 5.6 mg and 560 ng, respectively, orally, once every 6 hours, until discharge or death. These doses were based on our pre-clinical studies, and were nearly 50 times and 2000 times less, respectively, than those recommended as health supplements.[5]
◉ Abstract: It is estimated that 10–50 DNA double-strand breaks (DSBs) occur in a nucleated human cell per cell cycle. We reviewed the present state of knowledge and hypothesized that the currently accepted mechanisms cannot explain such high frequency of DSBs occurring daily under normal physiological conditions. We propose an alternative model that implicates illegitimate genomic integration into healthy cells of cell-free chromatin (cfCh) particles released from the billions of cells that die in the body every day. Repeated genomic integration of cfCh may have catastrophic consequences for the cell, such as DSBs, their faulty repair by nonhomologous end joining (NHEJ) followed by apoptosis with release of more cfCh which would integrate into genomes of surrounding cells. This can creates a vicious cycle of cfCh integration, DSBs, NHEJ, and more apoptosis, thereby providing a potential explanation as to why so many billions of cells die in the body on a daily basis. We also recount the recent observation that cfCh integration and the resulting DSBs activate inflammatory cytokines. This leads us to propose that concurrent DSBs and induction of inflammation occurring throughout life may be the underlying cause of ageing, degenerative disorders, and cancer. Finally, we discuss the prospect that agents that can inactivate/degrade cfCh may hold the key to making healthy ageing a realizable goal.[1]
