276 replies to this topic

[Slobec]

I just posted a video you may want to watch on the  NAD subforums: a lecture by dr. Sinclair where states that he takes 1 gram of RSV (apparently orally) every morning.

And metformin in the evening   https://www.frontier...2018.00657/full

[Castiel]

So how is a phytosomal form different to a liposomal one?

 

I've had some success dissolving resveratrol in 95% alcohol before making a lipsomal mix. I expect some is actually in the liposomes and some is just in emulsion, as you suggest.

 

Castiel - to get even 2.4uM you needed 5g, and when I've tried this it's not been pleasant for my digestion! Some form of liposomal resveratrol is the way to go IMO.

 

I've had some very promising results using liposomal resveratrol from Actinovo in combination with some other supplements. I intend to make some of my own lipsomal resveratrol and then report back when I have more to say.

 

 

So was browsing around the web and came across this interesting graph from the age-reversal forum 8 months ago.   I think it regards the revgenetics nitro formulation.

 

 https://forum.age-re...art-Web (1).gif

 

200micromole in plasma for 20 Min, over 30micromole for nearly an hour, and what seems like about 5 micromole for nearly 2 hours.

 

Now several questions pop to mind.  1.) is it true? 2.) is this in mice or humans, and at what mg/kg?   If true how safe would this be with biopiperine or multiple capsules?   If this is with 1 capsule, is that a safe long term dosage?

 

Viewing the patent more carefully should answer some of these questions.  I went over it quickly and it seems some of it talks about mice, so not sure if it is in mice or humans.

 

The article from engadin in the other thread suggests prolonged 100uM rather than lengthen shorten lifespan in yeast, iirc.  10uM lengthens lifespan of yeast. https://www.biorxiv....9411v1.full.pdf That is yeast, so obviously not human, but the fact that happens is a note for potential precaution on too high a sustained level.

Edited by Castiel, 09 September 2020 - 08:14 PM.

[Castiel]

Also browsing around came upon resvida resveratrol

 

https://www.dsm.com/..._2014_Final.pdf

 

That formulation also appears to achieve over 5micromole/L with relatively low dose.

Also browsing around came upon resvida resveratrol

 

https://www.dsm.com/..._2014_Final.pdf

 

That formulation also appears to achieve over 5micromole/L with relatively low dose.

[QuestforLife]

It's been so long since I looked into the resveratrol bioavailability stuff, I'll have to do another deep dive soon.

I do remember that in the studies I looked at people were taking grams of the stuff and struggling to reach the levels you're talking about Castiel.

In the splicing study where they rejuvenated cells that were in a senescent culture, remember that this might not be readable across to human in Vivo benefits. It might have been that the senescent cells were stopping otherwise healthy cells from doing their normal job,and the 24 hours of resveratrol freed the cells that were still proliferation competent. It would be good to see a mechanism outlined for the increase in telomeres though.

[Castiel]

It's been so long since I looked into the resveratrol bioavailability stuff, I'll have to do another deep dive soon.

I do remember that in the studies I looked at people were taking grams of the stuff and struggling to reach the levels you're talking about Castiel.

In the splicing study where they rejuvenated cells that were in a senescent culture, remember that this might not be readable across to human in Vivo benefits. It might have been that the senescent cells were stopping otherwise healthy cells from doing their normal job,and the 24 hours of resveratrol freed the cells that were still proliferation competent. It would be good to see a mechanism outlined for the increase in telomeres though.

 

It said 2.5g to 5g with regular resveratrol in other studies was merely reaching 2.4micromol peak.   But the revgenetics and resvida formulations at least seem to claim they can achieve far higher peaks on lower dose.   It would be high levels but still for a few hours, not 24 hours.   

 

Yet if their claims are true, significantly higher doses using their formulations could be used, but higher than recommended might be risky.   But it seems the right dose(and it wouldn't be too big) could potentially achieve over 5micromole for many hours.

 

But would such higher dose be safe?   What about bioavailability boosters like quercetin or piperine?   Again safety would need to be checked in some study.   But these formulations if their claims are true appear to allow for in vivo concentrations similar to the in vitro ones at relatively low doses.

Edited by Castiel, 20 September 2020 - 09:55 PM.

[QuestforLife]

I took a look at that Revida study

https://www.nmcd-jou...0078-5/fulltext

They did indeed achieve the claimed plasma concentrations: ~1232ng/ml or ~5.4uM an hour after the highest dose of 270mg.

If you wanted and were brave enough to try and sustain that level for 24 hours you could dose 270mg resvida every 2-3 hours.

Resvida is an old product, the paper is from 2011. Is it still sold?

[Castiel]

I took a look at that Revida study

https://www.nmcd-jou...0078-5/fulltext

They did indeed achieve the claimed plasma concentrations: ~1232ng/ml or ~5.4uM an hour after the highest dose of 270mg.

If you wanted and were brave enough to try and sustain that level for 24 hours you could dose 270mg resvida every 2-3 hours.

Resvida is an old product, the paper is from 2011. Is it still sold?

 

There are some supplements in amazon that claim to use resvida resveratrol.

 

One of them is 370mg per pill, iirc.   But the price for that one seems too good to be true.   Others are 100mg per pill.

 

But didn't the cells show signs of division at 17hrs with 5uM? 

 

In the 25uM experiment the htert activity peaked at 6 hours, and was already quite a bit lower by 12 hours. 

https://www.ncbi.nlm...4421/figure/F1/

 

I think it doesn't necessarily have to be sustained for 24hours.   We need more experiments, but it seems reasonable that 6 to 12 hours might be enough time to stimulate significant activity.   The graph in the link for 25uM shows that 1 hour is not enough, but that when it lasts for even 6 hours there's already significant telomerase activity.

Edited by Castiel, 03 October 2020 - 08:56 PM.

[Iporuru]

An interesting presentation at the 2020 Aging Research and Drug Discovery conference by Richard Faragher, co-author of the OP study

 

In the presentation he also mentions his recent study Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibroblasts

 

"Resveratrol alters the cytokinetics of mammalian cell populations in a dose dependent manner. Concentrations above 25–50 µM typically trigger growth arrest, senescence and/or apoptosis in multiple different cell types. In contrast, concentrations below 10 µM enhance the growth of log phase cell cultures and can rescue senescence in multiple strains of human fibroblasts. To better understand the structural features that regulate these effects, a panel of 24 structurally-related resveralogues were synthesised and evaluated for their capacity to activate SIRT1, as determined by an ex-vivo SIRT1 assay, their toxicity, as measured by lactate dehydrogenase release, and their effects on replicative senescence in MRC5 human fibroblasts as measured by their effects on Ki67 immunoreactivity and senescence-associated β galactosidase activity. Minor modifications to the parent stilbene, resveratrol, significantly alter the biological activities of the molecules. Replacement of the 3,5-dihydroxy substituents with 3,5-dimethoxy groups significantly enhances SIRT1 activity, and reduces toxicity. Minimising other strong conjugative effects also reduces toxicity, but negatively impacts SIRT1 activation. At 100 µM many of the compounds, including resveratrol, induce senescence in primary MRC5 cells in culture. Modifications that reduce or remove this effect match those that reduce toxicity leading to a correlation between reduction in labelling index and increase in LDH release. At 10 µM, the majority of our compounds significantly enhance the growth fraction of log phase cultures of MRC5 cells, consistent with the rescue of a subpopulation of cells within the culture from senescence. SIRT1 activation is not required for rescue to occur but enhances the size of the effect."

[QuestforLife]

An interesting presentation at the 2020 Aging Research and Drug Discovery conference by Richard Faragher, co-author of the OP study

 

In the presentation he also mentions his recent study Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibroblasts

 

 

 

Very interesting new paper. After the Op study came out in 2017 I followed the work of Latorre and Harries with interest but have been slightly disappointed with the direction of their research since. Now I find Faragher was the better bet. 

 

One of the open questions from the original paper was the importance of SIRT1; it was suggested that sirtuin activation was not important because one of the analogues had no sirtuin activity despite still having beneficial effects on the senescent cell culture. I note this has now been elucidated - sirtuin activation is not required but does enhance the effect (see Fig 4). The 'effect' I am talking about is the re-entry of (arrested) Phase G0 cells back into the cell cycle, which is measured via the increase in the Ki67 protein (indicating preparation for division). The paper also highlights the importance of dosage, with 25uM of the analogues being mainly beneficial via the increase in Ki67, but 100um being mainly harmful via increases in necrosis (measured by lactate dehydrogenase release) and correlated induction of senescence.  

[APBT]

In the presentation he also mentions his recent study Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibroblasts

 

 

FULL TEXT:  https://sci-hub.do/1...522-020-09896-6

[Iporuru]

Through R.G.A. Faragher's commentary in British Journal of Dermatology Oxytosin as a novel antidegenerative? (what a strange spelling of oxytocin!) I found this interesting paper: Oxytocin alleviates cellular senescence through oxytocin receptor-mediated extracellular signal-regulated kinase/Nrf2 signalling.

 

We found that OT suppressed senescence-associated secretory phenotype-induced senescence in NHDFs, and its effect depended on the age of the donor’s NHDFs [normal human dermal fibroblasts]. The inhibitory effects of OT required signalling by OT receptor-mediated extracellular signal-regulated kinase/Nrf2 (nuclear factor erythroid 2-related factor 2). The age-dependent antisenescence effects of OT are closely related to hypermethylation of the OT receptor gene (OXTR).

We next investigated the molecular mechanism underlying the inhibitory effects of OT on cellular senescence. The positive effects of OT on tissue homeostasis and regeneration are regulated by OXTR-mediated ERK1/2 phosphorylation. To determine whether OXTR-mediated ERK1/2 activation underlies the protective effects of OT against cellular senescence, we altered OXTR levels or ERK activity. Indeed, OXTR knockdown or treatment with a MAPK kinase (MEK) inhibitor completely abolished the ability of OT to prevent SASP-induced cellular senescence, as indicated by increased SA-b-Gal-positive rate (Fig. 3a–c), upregulated levels of p21 and p16 (Fig. 3d) and diminished cell proliferation (Fig. 3e). These results suggest that the protective effects of OT against SASP-induced cellular senescence are mediated by the OXTR-mediated ERK signaling pathway. Several studies have reported that activation of ERK/Nrf2 signalling reduces cellular senescence. The function of Nrf2 is decreased in replicative senescence, and its silencing leads to premature senescence (…). OT enhanced nuclear accumulation of Nrf2 in a dose-dependent manner. This was reversed by OXTR silencing or treatment with a MEK inhibitor. Furthermore, evidence for the direct involvement of Nrf2 in the antisenescent effects of OT was provided by Nrf2 knockdown experiments. Knockdown of Nrf2 completely abrogated the beneficial effects of OT on SASP-induced senescence (Fig. 4c, d). These results suggest that OT suppresses SASP-induced cellular senescence via Nrf2 activation through OXTR–ERK signalling.

[Iporuru]

Strange – the authors of the oxytocin paper quoted above state that activation of ERK/Nrf2 signalling reduces cellular senescence. In the following paper, by the same team as the OP study, the authors found that inhibition of AKT and ERK pathways led to up-regulation of splicing factor expression, reduction in senescent cell load, and partial reversal of multiple cellular senescence phenotypes in a dose-dependent manner. Seems contradictory.

 

FOXO1 and ETV6 genes may represent novel regulators of splicing factor expression in cellular senescence

 

 

We then assessed the impact of chemical inhibition or targeted knockdown of direct downstream targets of the ERK and AKT pathways on splicing factor expression, cellular senescence, and proliferation kinetics in senescent primary human fibroblasts. Components of the ERK and AKT signaling pathways demonstrated altered activation during cellular aging. Inhibition of AKT and ERK pathways led to up-regulation of splicing factor expression, reduction in senescent cell load, and partial reversal of multiple cellular senescence phenotypes in a dose-dependent manner. Furthermore, targeted knockdown of the genes encoding the downstream targets FOXO1 or ETV6 was sufficient to mimic these observations. Our results suggest that age-associated dysregulation of splicing factor expression and cellular senescence may derive in part from altered activity of ERK and AKT signaling and may act in part through the ETV6 and FOXO1 transcription factors. Targeting the activity of downstream effectors of ERK and AKT may therefore represent promising targets for future therapeutic intervention.

Some studies have suggested that the use of MEK or PI3K inhibitors could prevent the induction of cellular senescence and aging (25, 26).The relationship between these pathways is opaque, however; there is crosstalk between them as well as effects of dose, cell type, and context (27). Activation of ERK and AKT signaling by classic aging stimuli such as DNA damage, inflammation, or growth factors may therefore induce dysregulation of splicing factor expression and alternative splicing, and thereby influence cellular senescence.

Inhibition of MEK/ERK and PI3K/AKT pathways rescue cellular senescence phenotypes. No increase in apoptotic index was noted at either dose (Fig. 2F), indicating that the rescue from senescence we noted was not due to selective killing of senescent cells (senolysis). Contrary tour previous work (12) [the OP paper], no restoration of telomere length was observed in treated cells (data not shown).

… the drop in the number of senescent cells did not arise from renewed proliferation of the growth-arrested cells in the culture but represented a partial reversal of senescence. This is in accordance with our previous findings using small molecules (12).

We therefore assessed the expression of an a priori list of 20 age and senescence-associated splicing factor genes derived from our previous work (12) in response to low (1 mM)- and high (10mM)-doseAKTand ERKinhibitors (SH-6 and trametinib, respectively). Treatment with both trametinib and SH-6 at low dose (1 mM) was associated with upregulation of multiple splicing factors (Fig. 3 and Table 2). Effects were more marked for MEK/ERK-inhibited cells than for AKT-inhibited cells.

… we noted a partial rescue of senescence and an increase in splicing factor gene expression in late passage human primary fibroblasts after targeted gene knockdown of either FOXO1 or ETV6.

 

[Iporuru]

Tocotrienols to the rescue!

 

Tocotrienols can alter the levels of splicing factors (like resveratrol and resveralogues), suppress SASP, inhibit the activity of TGF-β which is a trigger of cellular senescence, prevent cell cycle arrest, elongate telomere length and restore telomerase activity in senescent fibroblasts.

 

Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence

 

Tocotrienols (T3) have been shown to represent a very important part of the vitamin E family since they have opened new opportunities to prevent or treat a multitude of age-related chronic diseases. The beneficial effects of T3 include the amelioration of lipid profile, the promotion of Nrf2 mediated cytoprotective activity and the suppression of inflammation. All these effects may be the consequence of the ability of T3 to target multiple pathways. We here propose that these effects may be the result of a single target of T3, namely senescent cells. Indeed, T3 may act by a direct suppression of the senescence-associated secretory phenotype (SASP) produced by senescent cells, mediated by inhibition of NF-kB and mTOR, or may potentially remove the origin of the SASP through senolysis (selective death of senescent cells).

 

Importantly, T3 are recognized among those compounds that are able to activate the nuclear factor erythroid-2-related factor 2 (Nrf2).

 

Another relevant aspect of T3 is their ability to suppress transforming growth factor β (TGF-β) signaling, a cytokine characterized by a pleiotropic role in the inflammatory processes. The suppression of TGF-β signaling with a single drug (an Alk5 Type I receptor kinase inhibitor) was found to simultaneously enhance neurogenesis and muscle regeneration in old mice. Similarly, T3 have been reported to inhibit the activity of TGF-β in human intestinal fibroblasts from Crohn’s disease patients and healthy controls [35] as well as the expression of TGF-β in the kidney of diabetic rats [75] and the transduction of TGF signaling in human prostate cancer cell lines.

Incubation of human senescent fibroblasts at various passages with a T3 rich extract was shown to reverse the senescent morphology, to decrease the activity of SA-β-gal as well as the amount of damaged DNA and cells in G0/G1 phase, and to increase telomere length and the number of cells in the S phase [36]. Given that overexpression of the telomerase reverse transcriptase (TERT) do not revert the senescent phenotype in human fibroblasts [4], it is likely that restoration of telomerase activity is not involved in the reversal of the senescent status shown by T3.

 

There are at least three major mechanisms that can contribute to explain the effects of T3 on senescent cells:

 

1) The elimination of the excess of ROS or other triggers of cellular senescence.

Considering that T3 have a high antioxidant potential and that they are able to modulate the Nrf2 mediated antioxidant response, the modulation of the redox status of the cells could explain both the delay of onset and the reversal of the senescent phenotype observed “in vitro” after T3 treatment. Accumulating evidence also suggests that T3 can inhibit the activity of TGF-β [5, 35, 75] that is another trigger of cellular senescence [31] and may contribute to exhaustion of stem cells in neurogenic and myogenic niche [94].

The alteration of splicing factor expression is another mechanism by which T3 could delay or reverse the senescence phenotype. It has been recently demonstrated that small molecules (such as resveratrol analogues) are able to modulate the expression of splicing factors with a subsequent rescue of multiple aspects related to cellular senescence including increased telomere length, re-entry into the cell cycle and restarted proliferation [33]. In this context, it has been reported that T3 are capable to correct aberrant splicing of IkappaB kinase complex-associated protein (IKAP) in cells derived from patients with familial dysautonomia [2] and to modulate the expression of a specific set of miRNAs in HeLa cells involved in the alternative splicing of pro-apoptotic proteins, such as the X-box binding protein 1 (XBP-1) [10]. Hence, alteration of splicing factor levels may be an additional mechanism by which T3 can reverse cellular senescence.

 

2) Inhibition of pathways that are responsible for SASP production (NF-kB and mTOR)

In analogy with the effects of Rapamycin, a mixture of naturally occurring T3 and tocopherols extracted from palm oil/palm fruits as well as purified γ-T3 has been reported to negatively modulate mTOR pathways in breast cancer cells [57, 83]. Moreover, T3 have been reported to suppress the activation of NF-kB in several experimental models

 

3) Selection of “healthy cells” by senolysis.

Selective cell death of non-proliferating senescent cells (also termed senolysis) can be responsible for a decrease in the percentage of senescent cells and a relative increase of healthy proliferating cells, thus resembling a rejuvenating effect. This could offer an additional explanation of the effects observed “in vitro” after T3 treatment of senescent cells.

 

Tocotrienol-Rich Fraction Prevents Cell Cycle Arrest and Elongates Telomere Length in Senescent Human Diploid Fibroblasts

 

This study determined the molecular mechanisms of tocotrienol-rich fraction (TRF) in preventing cellular senescence of human diploid fibroblasts (HDFs). Primary culture of HDFs at various passages were incubated with 0.5 mg/mL TRF for 24 h. Telomere shortening with decreased telomerase activity was observed in senescent HDFs while the levels of damaged DNA and number of cells in G₀/G₁ phase were increased and S phase cells were decreased. Incubation with TRF reversed the morphology of senescent HDFs to resemble that of young cells with decreased activity of SA-β-gal, damaged DNA, and cells in G₀/G₁ phase while cells in the S phase were increased. Elongated telomere length and restoration of telomerase activity were observed in TRF-treated senescent HDFs. These findings confirmed the ability of tocotrienol-rich fraction in preventing HDFs cellular ageing by restoring telomere length and telomerase activity, reducing damaged DNA, and reversing cell cycle arrest associated with senescence.

 

Shortening of telomere length were observed with senescence of HDFs. Telomere length in senescent HDFs was significantly decreased compared to untreated young HDFs (). Protective effects of TRF against telomere shortening was observed in senescent HDFs. Similar TRF treatment had no effect on telomere length in young HDFs.

 

Our previous study had shown that both γ-tocotrienol and α-tocopherol protected against oxidative stress-induced telomere shortening in HDFs derived from differently aged individuals. The restoration of telomerase activity induced by α-tocopherol caused significant increase in telomere length especially in skin fibroblast obtained from old donor.

 

[QuestforLife]

Tocotrienols to the rescue!

 

Tocotrienols can alter the levels of splicing factors (like resveratrol and resveralogues), suppress SASP, inhibit the activity of TGF-β which is a trigger of cellular senescence, prevent cell cycle arrest, elongate telomere length and restore telomerase activity in senescent fibroblasts.

 

Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence

 

 

 

I can't help but be somewhat sceptical of this study - amazing (albeit in vitro) effects, low doses (low nano molar range by my calculations) which suggest this should be achievable in humans - do we have any user reports to encourage us this is a viable avenue? Perhaps someone has tried a tocotrienol Vit E supplement with resveratrol and got synergistic benefits? 

Edited by QuestforLife, 09 October 2020 - 10:59 AM.

[Iporuru]

Where have we heard about the combination of tocotrienols and oxytocin before? In this thread: https://www.longecit...e-7#entry884660

 

The Conboys found: "TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. Interestingly, the combination also diminished the numbers of cells that express the CDK inhibitor and marker of senescence p16 in vivo. Summarily, simultaneously re-normalizing two pathways that change with age in opposite ways (up vs. down) synergistically reverses multiple symptoms of aging."

 

Besides, tocotrienols have been found to reduce VCAM1 (vascular cell adhesion molecule) is an important aging factor in old blood.

 

So, tocotrienols and oxytocin should be a useful adjunct to the resveratrol/H₂S rejuvenating protocol. Probably also a MEK inhibitor (myricetin, EGCG, apigenin, astaxanthin, honokiol)

Edited by Iporuru, 09 October 2020 - 11:30 AM.

[QuestforLife]

Where have we heard about the combination of tocotrienols and oxytocin before? In this thread: https://www.longecit...e-7#entry884660

 

The Conboys found: "TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. Interestingly, the combination also diminished the numbers of cells that express the CDK inhibitor and marker of senescence p16 in vivo. Summarily, simultaneously re-normalizing two pathways that change with age in opposite ways (up vs. down) synergistically reverses multiple symptoms of aging."

 

Besides, tocotrienols have been found to reduce VCAM1 (vascular cell adhesion molecule) is an important aging factor in old blood.

 

So, tocotrienols and oxytocin should be a useful adjunct to the resveratrol/H₂S rejuvenating protocol. Probably also a MEK inhibitor (myricetin, EGCG, apigenin, astaxanthin, honokiol)

 

Yes, I tried oxytocin with various tgf-B inhibitors but didn't have anything significant to report. I'd need to do a more detailed review of the literature to see if tocotrienols are a better bet than what I tried (acetyl 11 keto B boswellic acid (AKBA) and sartans). At the time I kind of concluded the magnitude of tgf-B inhibition with Alk5i was probably not replicable with nutraceuticals. 

[Iporuru]

I'd need to do a more detailed review of the literature to see if tocotrienols are a better bet than what I tried... 

 

I haven't researched that yet, but I have studied the MEK/ERK pathway and found that some nutraceuticals can be as strong or even stronger than pharmaceuticals:

 

 

Our investigation demonstrated that luteolin similar to PD98059, which acts as a specific inhibitor of MEK, an up stream kinase regulating ERK1/2, and wortmannin, a PI3K inhibitor, inhibited the invasiveness induced by HGF. In conclusion, the luteolin inhibited HGF-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K–Akt pathways. https://pubmed.ncbi....h.gov/16458870/

 

 

Importantly, quercetin exerted stronger inhibitory effects than PD098059, a well-known pharmacological inhibitor of MEK. https://www.ncbi.nlm...les/PMC2276321/

 

 

AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors. To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. https://www.ncbi.nlm...les/PMC3284441/

 

 

In the case of molecules in MEK/ERK signaling pathway, the expression of Ras, Raf, MEK and ERK1/2 was decreased significantly in resveratrol groups with a dose-dependent manner. Conclusions: PD98059 and resveratrol can effectively inhibit the proliferation of SW620 through inhibiting the MEK/ERK signaling pathway. https://www.scienced...99576451500231X

 

Edited by Iporuru, 09 October 2020 - 04:16 PM.

[QuestforLife]

I haven't researched that yet, but I have studied the MEK/ERK pathway and found that some nutraceuticals can be as strong or even stronger than pharmaceuticals:

All good information but in vivo there are hurdles to realising the potential of these substances. Luteolin and quercetin are both terribly absorbed, although taking them together and in a fatty meal will improve things somewhat. But I wonder if there is a good reason the liver is so keen to remove these substances.

From this point of view tocotrienols are more promising as the concentrations used in vitro look very achievable and the body doesn't seem hell-bent on eliminating these compounds.

Edited by QuestforLife, 09 October 2020 - 05:16 PM.

[QuestforLife]

I've posted some detailed thoughts on the action of resveratrol and tocotrienols on telomeres here:

https://www.longecit...-11#entry899109

[Castiel]

  But I wonder if there is a good reason the liver is so keen to remove these substances.
 

 

From the point of view of programmed aging it could be seen that these compounds might interfere with the aging program, and cause population collapse or extinction of a species that eats the plants.  The liver is protecting the aging program and ensuring the animal's health worsens and it can die on schedule, protecting the species from extinction.

 

 

With regards to the tocotrienols they sound very promising indeed.

 

 

 

bioenhanced full spectrum palm tocotrienol complex is shown to upregulate the gene expressions of the “Yamanaka Transcription Factors”

http://tocotrienol.o...r-growth-study/

 

David Sinclair is looking for gene editing, iirc, to enable the yamanaka factors and reverse epigenetic aging.   But here we have a supplement that some claim can do that without any genetic modification.

Edited by Castiel, 11 October 2020 - 10:09 PM.

[zorba990]

Interesting that anabolic steroids increase the expression of oxytocin greatly:

Chronic exposure to anabolic steroids induces the muscle expression of oxytocin and a more than fiftyfold increase in circulating oxytocin in cattle
https://journals.phy...mics.00226.2010

I'm sure there are safer ways to up regulate though.

C-tactile afferents: Cutaneous mediators of oxytocin release during affiliative tactile interactions?
https://pubmed.ncbi....h.gov/28162847/
"Low intensity, non-noxious, stimulation of cutaneous somatosensory nerves has been shown to trigger oxytocin release and is associated with increased social motivation, plus reduced physiological and behavioural reactivity to stressors. However, to date, little attention has been paid to the specific nature of the mechanosensory nerves which mediate these effects. In recent years, the neuroscientific study of human skin nerves (microneurography studies on single peripheral nerve fibres) has led to the identification and characterisation of a class of touch sensitive nerve fibres named C-tactile afferents. Neither itch nor pain receptive, these unmyelinated, low threshold mechanoreceptors, found only in hairy skin, respond optimally to low force/velocity stroking touch. Notably, the speed of stroking which C-tactile afferents fire most strongly to is also that which people perceive to be most pleasant. The social touch hypothesis posits that this system of nerves has evolved in mammals to signal the rewarding value of physical contact in nurturing and social interactions. In support of this hypothesis, we review the evidence that cutaneous stimulation directly targeted to optimally activate C-tactile afferents reduces physiological arousal, carries a positive affective value and, under healthy conditions, inhibits responses to painful stimuli. These effects mirror those, we also review, which have been reported following endogenous release and exogenous administration of oxytocin. Taken together this suggests C-tactile afferent stimulation may mediate oxytocin release during affiliative tactile interactions."

Edited by zorba990, 11 October 2020 - 10:29 PM.

[QuestforLife]

I can't help but be somewhat sceptical of this study - amazing (albeit in vitro) effects, low doses (low nano molar range by my calculations) which suggest this should be achievable in humans - do we have any user reports to encourage us this is a viable avenue? Perhaps someone has tried a tocotrienol Vit E supplement with resveratrol and got synergistic benefits? 

 

Aribadabar pointed out I made a mistake in my calcs, the in vitro effects are a low milli Molar not nano molar doses. So not so simple to get the effects in vivo.

 

To get 0.5mg/ml in your whole body (liquid), you need over 25grams, assuming it was all absorbed. 

Edited by QuestforLife, 12 October 2020 - 01:27 PM.

[Turnbuckle]

Splicing factors as mentioned in the OP might rescue cells from senescence, but they can't reverse epimutations that are responsible for aging. Thus this is the wrong approach. You don't want to rescue cells that are telomerically and epigenetically old. You want them to get recycled and replaced. 

Edited by Turnbuckle, 14 October 2020 - 01:11 PM.

[QuestforLife]

Splicing factors as mentioned in the OP might rescue cells from senescence, but they can't reverse epimutations that are responsible for aging. Thus this is the wrong approach. You don't want to rescue cells that are telomerically and epigenetically old. You want them to get recycled and replaced.

We don't know that. To my knowledge there hasn't been an in vitro study with resveratrol where they've looked at epigenetic age, like they have with rapamycin (https://pubmed.ncbi....h.gov/31136303/).

But it is likely splicing factors can have a profound effect not only on telomere mediated senescence but also other epigenetic changes related to aging.

Of course things are more complex in Vivo and we have the various effects on stem cell replacement as well as effects on normal somatic cells. What you are aiming at is accelerated replacement by epigenetically younger cells. But other approaches are possible, for example pushing some somatic cells into a younger state directly.

[Turnbuckle]

We don't know that. To my knowledge there hasn't been an in vitro study with resveratrol where they've looked at epigenetic age, like they have with rapamycin (https://pubmed.ncbi....h.gov/31136303/).

But it is likely splicing factors can have a profound effect not only on telomere mediated senescence but also other epigenetic changes related to aging.

Of course things are more complex in Vivo and we have the various effects on stem cell replacement as well as effects on normal somatic cells. What you are aiming at is accelerated replacement by epigenetically younger cells. But other approaches are possible, for example pushing some somatic cells into a younger state directly.

 

 

There is no evidence resveratrol reprograms the epigenetic code. Certainly not de novo. It may do some demethylation, but if that is random, it will make cells epigenetically older. The OP paper suggested that cells gained "some features of youth.  They are able to grow, and their telomeres - the caps on the ends of the chromosomes that shorten as we age -  are now longer, as they are in young cells." But if you extend the life of epigenetically old cells, you are ultimately hurting yourself.

[Castiel]

Splicing factors as mentioned in the OP might rescue cells from senescence, but they can't reverse epimutations that are responsible for aging. Thus this is the wrong approach. You don't want to rescue cells that are telomerically and epigenetically old. You want them to get recycled and replaced. 

artificially causing mice to have extra long telomeres prolongs lifespan and healthspan and reduces cancer.   That is cells that would normally have gone senescent remain dividing.   Also human centenarians with longer telomeres tend to be healthier and live longer, iirc.

 

According to Dr. Michael Fossel, telomeres might be upstream of epigenetic aging, restoring telomeres might reverse epigenetic aging, though that is still a controversial position

[Castiel]

There is no evidence resveratrol reprograms the epigenetic code. Certainly not de novo. It may do some demethylation, but if that is random, it will make cells epigenetically older. The OP paper suggested that cells gained "some features of youth.  They are able to grow, and their telomeres - the caps on the ends of the chromosomes that shorten as we age -  are now longer, as they are in young cells." But if you extend the life of epigenetically old cells, you are ultimately hurting yourself.

 

Whether resveratrol alters epigenetics is an open question.   Epigenetics control gene expression, and it is known that resveratrol significantly alters gene expression.   It basically prevents many of the changes in gene expression associated with aging, in a way very similar to CR

 

It is said that CR alters over 800 longevity genes, not sure how many of those resveratrol also alters but

 

 

. The researchers report a “striking transcriptional overlap” of CR and resveratrol (99.7 percent of gene expression changes correlating by direction) in heart, skeletal muscle, and brain (neocortex), and show that both regimens prevent age-related cardiac problems.

https://www.alzforum...ti-aging-elixir

 

 

 

We observed time-dependent expression changes in >1,600 transcripts as early as 6 hours after treatment with resveratrol

https://www.ncbi.nlm...les/PMC3889115/

 

 

 

Surprisingly, resveratrol opposed 947 (92%) of age-related changes in gene expression, and 522 of these represented highly significant differences in expression between the old control and old resveratrol groups (P≤0.01). Thus, resveratrol at doses that can be readily achieved through dietary supplementation in humans is as effective as CR in opposing the majority of age-related transcriptional alterations in the aging heart. Because the collection of such alterations in gene expression is a biomarker of aging, our results imply that similar to CR, middle-age onset resveratrol supplementation at low doses is likely a robust intervention in the retardation of cardiac aging.

https://www.ncbi.nlm...les/PMC2386967/

 

Note that this was a low dose and some other organs received lower changes, could be due to less effectiveness in part in some other organs, or due to absorption not being as good in other organs due to too low a dose.

Edited by Castiel, 15 October 2020 - 06:31 PM.

[Turnbuckle]

 Also human centenarians with longer telomeres tend to be healthier and live longer, iirc.

 

 

 

 

A correlation does not imply causation. If centenarians have longer telomeres, it may mean that their stem cell pools are in better shape and replaced senescent cells to a greater degree than other people. Such replacement cells would have longer telomeres and a lower epigenetic age, so lengthening telomeres alone would do nothing to their epigenetic age except raise it.

 

I have experienced this latter effect myself. Telomerase enhancers rapidly raised my epigenetic age. And that's easy to understand, as eliminating senescence and the resulting apoptosis allows epigenetically old cells to continue to get older, and blocks replacement by epigenetically young stem cells.

 

As for centenarians, super-centenarians have been found to have lower epigenetic age than expected, which is suggestive of more stem cell activity, or better fidelity of the epigenetic code during replication. See Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. But as for telomere length correlating with healthy old age, perhaps not. See Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians.

Edited by Turnbuckle, 15 October 2020 - 07:08 PM.

[QuestforLife]

There's no doubt in my mind continued proliferative ability of cells is a requirement for healthy life extension, but it may not be as simple as elongating telomeres because of the complexities of somatic cell replacement. Various people including myself have experienced an increase in telomere length at the same time as a similar increase in epigenetic age. But as I've pointed out in various places and at various times, this is not necessarily the same as the increase in epigenetic age experienced with increasing biological age. This is obvious when you consider that a lack of proliferative ability in stem cells would also lead to a slowing in the somatic cell replacement rate.

Back to the subject of resveratrol. We know certain genes, i.e. OSKM, can reverse epigenetic aging when turned on, and we know these are regulated by other genes, which in turn can be spliced in different ways to adjust expression. So absolutely splicing factors can reverse epigenetic age as measured per methylation as well as extend telomere length. We don't know that resveratrol does this, of course. But it is possible. In theory.

Edited by QuestforLife, 15 October 2020 - 08:58 PM.

[Castiel]

A correlation does not imply causation. If centenarians have longer telomeres, it may mean that their stem cell pools are in better shape and replaced senescent cells to a greater degree than other people. Such replacement cells would have longer telomeres and a lower epigenetic age, so lengthening telomeres alone would do nothing to their epigenetic age except raise it.

 

I have experienced this latter effect myself. Telomerase enhancers rapidly raised my epigenetic age. And that's easy to understand, as eliminating senescence and the resulting apoptosis allows epigenetically old cells to continue to get older, and blocks replacement by epigenetically young stem cells.

 

As for centenarians, super-centenarians have been found to have lower epigenetic age than expected, which is suggestive of more stem cell activity, or better fidelity of the epigenetic code during replication. See Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. But as for telomere length correlating with healthy old age, perhaps not. See Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarians.

How about the fact that mice which are artificially made to have extra long telomeres from birth, which would keep cells that would otherwise go senescent dividing, live longer have less cancer and are healthier.

 

As for telomerase enhancers, are there any strong enhancers?   

 

I've heard that treatment with telomerase causes rejuvenated gene expression of all but a few genes.   Not only do the cells look younger and behave younger, and are indistinguishable from younger cells under the microscope, but their gene expression is almost identical to young cells.

 

We don't know all negligible senescence species do, but we do know that many perhaps all lengthen telomeres constantly.

 

edit: looking at the  paper on telomere length vs inflammation I notice that the telomeres measured were around 3kb, or in other words short telomeres.   This is not talking about 8-15kb telomeres as a young human vs 3kb, but 3kb vs 3kb.  Short vs short, so surely slight differences on short telomeres might not make much difference.

Edited by Castiel, 16 October 2020 - 06:21 AM.