Thursday, 7 February 2019

Pterostilbene for Neuromodulation – worth a look?

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A common criticism of this blog is that it is mainly about prescription drugs rather than OTC supplements.
Today’s post is about a supplement that is highly regarded by our reader Ling.
Pterostilbene is like a super potent version of resveratrol.  

Resveratrol is quite well known and has long been put forward as having some potentially highly beneficial health effects, but in practise it is just too poorly absorbed to have much effect in humans.
Pterostilbene is found in blueberries.  Also found in blueberries is Anthocyanin, which is worth a mention in this post, it is what gives blueberries their colour; very often it is the colour in a food that underlies part of its health benefit. This is why eating a mixed colour diet is a wise idea.
Aronia is extremely rich in anthocyanins and Aronia juice is very common where I live. We even have a bottle of the dark coloured juice in the kitchen.
The purple colour in beetroot is betanin, a so-called betacyanin and may well have anti-Alzheimer’s effects, inhibiting plaque formation.
Anthocyanin is put forward as one reason certain Japanese who eat large amounts of purple sweet potato do not suffer much cancer or dementia and live a very long time.

Today we are mainly looking at pterostilbene, but if you want Anthocyanins, to avoid dementia, just eat blue and purple coloured fruit and vegetables on a very regular basis.
Ling has proposed pterostilbene as a PDE4 inhibitor, but as is often the case, it has numerous other effects, so it would be hard to know which is the main reason it might be therapeutic.  

Known biological effects of Pterostilbene                                                                                   
Here is an excellent graphic that highlights many of the effects of Pterostilbene, other than on PDE4.

The regular readers of this blog will note that the great majority of the above signalling molecules are implicated in autism.

The proposed effects on the brain are highlighted in the next graphic

The source paper is here: -  


Based on the evidence presented, PTE (Pterostilbene) is more bioavailable and better at evoking molecular and functional events than RES (Resveratrol) in vivo

Although clinical trials are underway to assess the effects of RES in diseases such as dementia and AD, pre-clinical and clinical studies on PTE have yet to be conducted. Furthermore, the biological effects of many of the structural analogues of RES and PTE are unknown, and no studies have identified the metabolites of RES or PTE in brain tissues. There is a need for future studies to identify means of enhancing the efficacy and bioavailability of these compounds and to analyse the metabolites of these compounds in thebrain. Altogether, the evidence from a variety of studies strongly suggests the potential of RES and PTE as promising bioactive agents to improve brain health and prevent neurodegeneration

Most research, but not all, concerns aging and dementia. 

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a natural dietary compound and the primary antioxidant component of blueberries. It has increased bioavailability in comparison to other stilbene compounds, which may enhance its dietary benefit and possibly contribute to a valuable clinical effect. Multiple studies have demonstrated the antioxidant activity of pterostilbene in both in vitro and in vivo models illustrating both preventative and therapeutic benefits. The antioxidant activity of pterostilbene has been implicated in anticarcinogenesis, modulation of neurological disease, anti-inflammation, attenuation of vascular disease, and amelioration of diabetes. In this review, we explore the antioxidant properties of pterostilbene and its relationship to common disease pathways and give a summary of the clinical potential of pterostilbene in the prevention and treatment of various medical conditions.

Resveratrol is a natural phytoestrogen with neuroprotective properties. Polyphenolic compounds including resveratrol exert in vitro antioxidant, anti-inflammatory, and antiamyloid effects. Resveratrol and its derivative pterostilbene are able to cross the blood-brain barrier and to influence brain activity. The present short review summarizes the available evidence regarding the effects of these polyphenols on pathology and cognition in animal models and human subjects with dementia. Numerous investigations in cellular and mammalian models have associated resveratrol and pterostilbene with protection against dementia syndromes such as Alzheimer's disease (AD) and vascular dementia. The neuroprotective activity of resveratrol and pterostilbene demonstrated in in vitro and in vivo studies suggests a promising role for these compounds in the prevention and treatment of dementia. In comparison to resveratrol, pterostilbene appears to be more effective in combatting brain changes associated with aging. This may be attributed to the more lipophilic nature of pterostilbene with its two methoxyl groups compared with the two hydroxyl groups of resveratrol. The findings of available intervention trials of resveratrol in individuals with mild cognitive impairment or AD do not provide evidence of neuroprotective or therapeutic effects. Future clinical trials should be conducted with long-term exposure to preparations of resveratrol and pterostilbene with high bioavailability.

Low-dose pterostilbene, but not resveratrol, is apotent neuromodulator in aging and Alzheimer's disease.

Recent studies have implicated resveratrol and pterostilbene, a resveratrol derivative, in the protection against age-related diseases including Alzheimer's disease (AD). However, the mechanism for the favorable effects of resveratrol in the brain remains unclear and information about direct cross-comparisons between these analogs is rare. As such, the purpose of this study was to compare the effectiveness of diet-achievable supplementation of resveratrol to that of pterostilbene at improving functional deficits and AD pathology in the SAMP8 mouse, a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD. Furthermore we sought to determine the mechanism of action responsible for functional improvements observed by studying cellular stress, inflammation, and pathology markers known to be altered in AD. Two months of pterostilbene diet but not resveratrol significantly improved radial arm water maze function in SAMP8 compared with control-fed animals. Neither resveratrol nor pterostilbene increased sirtuin 1 (SIRT1) expression or downstream markers of sirtuin 1 activation. Importantly, markers of cellular stress, inflammation, and AD pathology were positively modulated by pterostilbene but not resveratrol and were associated with upregulation of peroxisome proliferator-activated receptor (PPAR) alpha expression. Taken together our findings indicate that at equivalent and diet-achievable doses pterostilbene is a more potent modulator of cognition and cellular stress than resveratrol, likely driven by increased peroxisome proliferator-activated receptor alpha expression and increased lipophilicity due to substitution of hydroxy with methoxy group in pterostilbene                                                                                                        

Effect of resveratrol and pterostilbene on aging and longevity.

Over the past years, several studies have found that foods rich in polyphenols protect against age-related disease, such as atherosclerosis, cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes (T2D), hypertension and Alzheimer's disease. Resveratrol and pterostilbene, the polyphenol found in grape and blueberries, have beneficial effects as anti-aging compounds through modulating the hallmarks of aging, including oxidative damage, inflammation, telomere attrition and cell senescence. In this review, we discuss the relationship between resveratrol and pterostilbene and possible aging biomarker, including oxidative stress, inflammation, and high-calorie diets. Moreover, we also discuss the positive effect of resveratrol and pterostilbene on lifespan, aged-related disease, and health maintenance. Furthermore, we summarize a variety of important mechanisms modulated by resveratrol and pterostilbene possibly involved in attenuating age-associated disorders. Overall, we describe resveratrol and pterostilbene potential for prevention or treatment of several age-related diseases by modulating age-related mechanisms.

One area of autism research concerns targeting mTOR signalling. This is covered in the paper below

and was the subject of this blog post from 2015

Targeting the PI3K/Akt/mTOR signaling pathway by pterostilbene attenuates mantle cell lymphoma progression.

Mantle cell lymphoma (MCL) is an aggressive and mostly incurable B-cell malignancy with frequent relapses after an initial response to standard chemotherapy. Therefore, novel therapies are urgently required to improve MCL clinical outcomes. In this study, MCL cell lines were treated with pterostilbene (PTE), a non-toxic natural phenolic compound primarily found in blueberries. The antitumor activity of PTE was examined by using the Cell Counting Kit-8, apoptosis assays, cell cycle analysis, JC-1 mitochondrial membrane potential assay, western blot analysis, and tumor xenograft models. PTE treatment induced a dose-dependent inhibition of cell proliferation, including the induction of cell apoptosis and cell cycle arrest at the G0/G1 phase. Moreover, the PI3K/Akt/mTOR pathway was downregulated after PTE treatment, which might account for the anti-MCL effects of PTE. Synergistic cytotoxicity was also observed, both in MCL cells and in xenograft mouse models, when PTE was administered in combination with bortezomib (BTZ). The antitumor effects of PTE shown in our study provide an innovative option for MCL patients with poor responses to standardized therapy. It is noteworthy that the treatment combining PTE with BTZ warrants clinical investigation, which may offer an alternative and effective MCL treatment in the future.

And finally, PDE4
Inhibiting PDE4 has some very useful anti-inflammatory benefits. It may also improve myelination and indeed cognition.  PDE4 inhibitors are currently used to treat severe asthma and in clinical trials for Multiple Sclerosis (MS) and cognitive enhancement.
There are different sub-types of PDE4.
Inhibiting one of the subtypes has the tendency to make you want to vomit.  This is currently the drawback that limits the use of PDE4 inhibiting drugs.
A selective PDE4 inhibitor is required.
As Ling has found, research does indeed show that pterostilbene is a PDE4 inhibitor.

The molecular basis for the inhibition of phosphodiesterase-4D by three natural resveratrol analogs. Isolation, molecular docking, molecular dynamics simulations, binding free energy, and bioassay.

The phosphodiesterase-4 (PDE4) enzyme is a promising therapeutic target for several diseases. Our previous studies found resveratrol and moracin M to be natural PDE4 inhibitors. In the present study, three natural resveratrol analogs [pterostilbene, (E)-2',3,5',5-tetrahydroxystilbene (THSB), and oxyresveratrol] are structurally related to resveratrol and moracin M, but their inhibition and mechanism against PDE4 are still unclear. A combined method consisting of molecular docking, molecular dynamics (MD) simulations, binding free energy, and bioassay was performed to better understand their inhibitory mechanism. The binding pattern of pterostilbene demonstrates that it involves hydrophobic/aromatic interactions with Phe340 and Phe372, and forms hydrogen bond(s) with His160 and Gln369 in the active site pocket. The present work also reveals that oxyresveratrol and THSB can bind to PDE4D and exhibits less negative predicted binding free energies than pterostilbene, which was qualitatively validated by bioassay (IC50=96.6, 36.1, and 27.0μM, respectively). Additionally, a linear correlation (R(2)=0.953) is achieved for five PDE4D/ligand complexes between the predicted binding free energies and the experimental counterparts approximately estimated from their IC50 values (≈RT ln IC50). Our results imply that hydrophobic/aromatic forces are the primary factors in explaining the mechanism of inhibition by the three products. Results of the study help to understand the inhibitory mechanism of the three natural products, and thus help the discovery of novel PDE4 inhibitors from resveratrol, moracin M, and other natural products.

Based on Ling’s recommendation, I have ordered some Pterostilbene and I am curious to see its effects. It is another substance that might be helpful for older adults, if not for your case of autism.
It is clear that in most cases resveratrol is a substance whose effect is limited to the test tube rather than humans. As a “super-resveratrol” we should take a closer look at Pterostilbene.
Eating large amounts of fruits, vegetables and berries with anthocyanins and betacyanins is going to do you no harm and does look a way to possibly secure a long healthy future, like those Japanese centenarians in Okinawa.


  1. A couple other things about Pterostilbene and Resveratrol should be mentioned which suggests they may be more like apples and carrots than apples and oranges to use an analogy.

    First off, reveratrol has a very short half-life in vivo, however, there was one paper I read a while back that suggested the immediate resveratrol metabolite called resveratrol sulfate was even more potent than resveratrol itself and stayed around in the body much longer before being broken down into something else and excreted.

    Secondly, much of the pooly absorbed resveratrol may exert it's positive health effects, not directly in the body but instead on its interaction with the microbiome. Figuring out which species of bacteria metabolize resveratrol to something else used on the body or else another metabolite used by another bacteria species, etc. is like trying to find a needle in a haystack, but researchers in this space seem to be rapidly improving their abilities in finding needles in haystacks. So at this time I can't say how or if there is a strong connection, but there has been strong speculation that microbiome interactions are one of the primary benefits or oral resveratrol.

    When people talk about Pterostilbene being a superior form of Resveratrol, they are really just talking about their relative effects on SIRT1. The molecules really seem to do many different things in vitro with resveratrol doing a lot more, probably because it has been studied more aggressively.

    My advice is they are both good general purpose supplements with no real downsides and taking both could very well be synergistic, though I have yet to see a study looking at this possibility since all of them to date I have seen merely compare and contrast the two polyphenols.

    There is a strong synergy between resveratrol and spermidine on mTOR inhibition so who knows what synergies pterostilbene has with resveratrol or any other molecule dealing with cellular metabolism.

  2. My own list of all the possible effects of pterostilbene is probably even longer than the one you provided in the picture above Peter, and they are only partly overlapping. It's hard to tell exactly which ones are most important in our case, but I think PDE4 inhibition and enhanced production of certain heat shock proteins might be the answer here.

    We have used it for.. I don't know, 9 months perhaps, without any downsides. Eventually we saw a small change in appetite (less), but that was enhanced before so maybe pterostilbene just normalized things. I haven't heard about anyone vomiting from pterostilbene, so I guess it is more selective regarding the PDE4 effect than rolipram.

    I have tried pterostilbene myself, but I didn't experience any notable effect. For my daughter, it really deserves its place in her daily polypill. So for some it makes a big cognitive change, and for others it will eventually just contribute to a longer healthspan.

    It should be good for both diabetes, colorectal cancer and proteinopathies, and eventually for some hypo-NMDA states. It is a calorie restriction mimetic too.


    1. Ling, it would be useful if you could provide some further information.

      How would you describe the beneficial cognitive effects? What dose are you using? Did you try different doses, if so what was the effect? How long did it take to show effect? Have you tried making a pause to see if the beneficial effect is then lost? Did you also try Resveratrol? Since once effect is against ROS, have you tried other antioxidants like NAC?

  3. I've actually reported on Pterostilbene twice here in this blog, first time at
    and second time here:
    I found a third report in my notes, that I don't think I ever published here:
    "The dose was increased after 5 months of use:
    Age: 3y 5m Weight: 16 kg
    Changing the dose to once daily and upping it to 12.5 mg after several months of use. Saw once again a small cognitive lift within first three weeks. More interest in surroundings and wants to explore more. Started to have an interest in playing board games, which is way above her cognitive level. Plays and plays and plays and wants us to participate. While there still are very few speech sounds, she is using her voice and signs to us more frequently. No obvious side effects at this dose.”

    What I want to add to these reports is that the side effect I mention with toe walking could be something else - last time I saw this I thought it was due to another intervention but in the end it turned out to be teething issues.

    To be honest, I am not sure which dose would be the best. As low as ½ mg/kg and day gave an effect. Upping the dose gives better results, at least short term. I have used as much as 1 mg/kg and day. There was one very unreliable Internet source that I used telling that the cognitive effect of pterostilbene should be at doses between 0.4mg-1.5mg/kg and day, and at least part of that statement seems true.

    We haven't tried Resveratrol and I don't think I will. Ibudilast however could have an additional effect with regards to PDE inhibition.

    Fisetin is the best antioxidant we've used so far, better than Sulforaphane and I think ALA too. Didn't try NAC yet long enough to tell.


    1. Thanks for all the updates Ling.

      Some people do trawl through this blog looking for information, so to make it easier, here are links and the full text of Ling's previous reports on Pterostilbene.

      30 January 2018 at 15:19

      And here is my report on Pterostilbene.

      The brand was Life Extension PteroPure 50 mg and my daughter is 2½ year and weighs around 15 kg.

      We started out with a dose of 2 * 5 mg daily, morning and evening. It was not very easy to get out one tenth of a small capsule, so the dosing was probably a bit uneven. After 2 weeks use we noticed that she was doing "speech sounds" like "mmm" and "mmmaa". At 3 weeks her daycarers surprisingly announced that she had said both "ma-ma" and "pa". This was the same day I decided to change dosing to around 1 mg/kg/day (= 16 mg and easier to dose). After this, she was still using her new sounds occasionally, but we also saw side effects creeping up. Staring spells became more frequent and toe-walking suddenly appeared. After 6 weeks we pulled off and all effects and were lost (speech sounds, toe-walking, staring spells).
      I'm not sure what conclusions to draw from this, but dosing seems to be important.

      18 June 2018 at 22:29

      Time for some reporting!

      My daughter, 3 years and 15 kg, has been on a second round of pterostilbene for 5+ weeks. The dose has been low: 7.5 mg per day and divided into two doses. (According to some sources, 6.5 mg is the lowest dose where pterostilbene has any cognitive effect.)

      The aim was to target PKA via PDE-inhibition with the hope of inducing SATB2 and L-LTP/memory as one important downstream effect.

      Disclaimer: Three weeks before starting pterostilbene we also started vegEPA (fish oil), so this could potentially
      affect the result.

      First three weeks:
      We saw nothing special, only a "good baseline". At the time we were trying to make her learn colours, and for the first time it seemed like she understood what we meant.

      Around day 21:
      There was a sudden cognitive lift, with more presence, happening at the same time as in round 1.

      After 4 weeks:
      She made my jaw fall to the ground one day by throwing a frisbee 4 meters.
      At a couple of occasions she was overhearing and reacting to simple things in our "parental" discussions. Totally unheard of.
      At one evening we were lying in the dark and she pointed and signed what the colours on her blanket where out of memory.
      She discovered her own shadow and has had a lot of fun with it.
      She is opening drawers and doors to check what's behind them.
      At this point I noticed that she had much dryer skin than before (vegEPA effect?).

      Summary after 5 weeks:
      Language comprehension is much better
      Memory is slightly better (very hard to measure but she knows her colours now and maybe even a letter or two)
      More presence - but far from enough
      More exploratory behaviour
      More play and interaction with her sister
      No expressive language gains
      No obvious ongoing cognitive lift after day 21, plateauing?

      All in all - a similar experience to Ponstan/mefenamic acid (but maybe stronger). I guess that I have hit a path where the SATB2 protein is induced, close to CREB.
      Unfortunately this is either not enough or not targeting the place where SATB2 works as a transcription factor, because then I would also see expressive language changes.
      A big question for me is if I should try to work even harder on this pathway (adding Ponstan to pterostilbene) or try another synergistic path like PKC or CamKII.

    2. Interesting stuff Ling. I have tried Fisetin personally for a month with a lot of skepticism due to it along with Resveratrol supposedly being poorly absorbed in oral form and oddly noticed some skin elasticity improvements. Of course it could be other things, but it kinda makes me go humm...

      My interest in Fisetin piqued after recently reading about its properties as a superior senolytic to quercetin and dasatinib and then reading some papers to see its other useful properties including its hypothetical use in neuroprotection. Unfortunately, it's price also peaked at the time so I only ordered one bottle. The price has come down a lot in the last couple of months so I may trial this with my son on your recommendation.

    3. It's interesting to read the concerns of Fisetin's bioavailability on the longevity forums given the obvious effect I see in my daughter. Maybe these people already have the affected functions upregulated by other substances, and so doesn't note any change.

      I think one common denominator is the unfolded protein response, which seems to upregulate protection from oxidative stress, mitochondrial function and heat shock proteins. One effect from Fisetin mimics Sulforaphane (both act on NRF2), and if I remember it right this was implicated for people with the fever effect (doesn't apply to my daughter though). But then Fisetin has other properties too, promoting bone for example and suppressing mast cells. Maybe I should try it for allergy this season?
      As I reported previously, Fisetin had an effect on energy levels (mitochondria), irritability and trichotillomania (oxidative stress) and language (in combination with Bacopa).

      I think a weeks trial is what you need to see any effect. I use 33 mg once daily for a 16 kg-ish kid, which probably is a little low. Have tried 50 mg daily without any problems for 3 consecutive days, one researcher recommended 2-4 mg/kg and day for adults.

      I do hope it helps your son too!

    4. The concerns over the bioavailability were from the actual research group that looked into Fisetin's use recently as a potent senolytic. I think I even posted the study here not long ago.


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