Friday, 15 August 2014

More from Prof. Robert Ko on the BFT debate with Dr. John

Professor Robert Ko
AUGUST 2, 2014

Dr. John, please find below my answers to your questions.

Respectfully, Robert

1. What is the clinical evidence that Glissandra effects anti-aging benefits on skin? How are they documented?

已經證明，以防止在體內和在體外通過太陽能光照射引起的氧化損害。

lol - okay even us scientists need to have a sense of humour!

Seriously though, Glissandra has been shown to protect against oxidative damage induced by solar light irradiation both in vivo and in vitro.

  • That would qualify as antioxidant. Yet (based on what you have said) first it raises ROS (reactive oxygen species). Would you then say it is an a pro-oxidant first (ROS contributor) but then upon adaptation to repeated ROS stress (the signal) it becomes antioxidant (ROS quencher) with time?
  • Yes. Glissandra serves as a pro-oxidant which generates signaling ROS that can activate Nrf2-mediated expression of antioxidant genes. The dependency on cellular enzyme (CYP) to metabolically generate ROS is self-limiting such that pathological events will not occur.
Two clinical trials using Visual anti-aging assessments were conducted. The duration of the studies were 8 weeks. Data collected were tabulated and analyzed.

 North American Trial

Visual anti-aging assessments from 35 subjects of diverse ethnicities, with ages ranging from mid 20’s to late 60’s, from both genders.

South East Asia Trial

Visual anti-aging assessments from 28 subjects of Asian ethnicity with 17 subjects with age <45, 8 subjects with age 45-55, 3 subjects with age 55-65, from both genders.

  • Visual trials with or without controls? Single arm studies without histology are extremely weak on the evidence scale. There are literally tens of thousands of such studies in the world of aesthetics, all generally saying the same thing. Are we to believe them all? It would help immensely to have some validation with split face, controls, serial histology, tape stripping for gene expressions or cytokines, etc.
  • The development of Glissandra as skincare product is based on the over 20 years of research on its Schisandra berry-derived active component, which has been shown to be able to enhance the mitochondrial structural and functional integrity in various tissues, particularly under conditions of oxidative stress. Topical application of the active component at certain critical concentrations was found to produce similar biological effects on animal skin tissue and cultured human fibroblasts. With the strong belief that the enhancement of Skin Qi - cellular energy status can increase the vitality of skin cells, we suggest the development of Glissandra as skincare product. The pre-market testing conducted on human subjects, though having low scientific merit as implicated, is instrumental to collect users feedback prior to the product launch. Surprisingly, Glissandra produces many unexpected beneficial outcomes in human subjects. As far as the basic research is concerned, the "Proof-of-Principle" testing outcomes support the postulated application of the active component in skincare product. 
Both studies documented dramatic effects on various signs of skin aging from end users.


  • Define dramatic. I consider plastic surgery to be dramatic? Compare to that.
  • Professor Robert Ko AUGUST 15, 2014

  • Many obvious improvements on skin before and after use which may not be as dramatic as those of "successful" plastic surgery. However, we believe that Glissandra offers a natural way to enhance the vitality of skin cells rather than doing spot fixing as in the case of plastic surgery.
2. How is the active delivered? What vehicle? In what doses? Continuous vs discontinuous? How deeply does it penetrate?

The active is delivered by passive diffusion. The active is lipophilic, and is readily absorbed by skin.


  • Have you measured it? What you describe defies known stratum corneum absortion dynamics. The stratum corneum (SC) is a radically different biomembrane compared to other membranes in the body in function and composition. The SC is less permeable for lipophilic compared to the water-soluble compounds. Diffusion alone is rarely enough. Most botanically-derived substances e,g, antioxidants, vitamins) have great difficulty getting past the stratum corneum. Retinoids are an exception. But the stratum corneum would seem to be a weak place to carry out hormesis, due to its rapid turnover (memory effects) and the transformation of cells from metabolically active to organelle stripped as they mature from basement membrane to surface. Some measure of penetration seems to me to be crucial to support the hypothesis.
  • Professor Robert Ko AUGUST 15, 2014
  • Given the low molecular weight and high lipophilicity of the active component of Glissandra, its bioavailability to skin tissue/cells should not be an issue. Whether or not  hormetic response can be triggered in Stratum Corneum would also be dependent on the concentration of the hormetic agent. As long as mitochondria are present in the cells, Glissandra can produce the effect.  After all, "dramatic" effect were observed in human users. 
3. How is Glissandrin transported into cells to affect mitochondrial functions? By which known mechanism?

Glissandrin is readily transported via diffusion into the cytoplasm and then mitochondria . The active compound is metabolized by cytochrome P-450 enzymes (in both cytosolic and mitochondrial compartments), with resultant generation of signaling ROS which in turn activate the MAPK/Nrf2 pathway. The consequent increased expression of antioxidant genes can enhance the mitochondrial antioxidant capacity and thus the mitochondrial ATP generation.


  • That is a concept that may works in cell cultures, but not in vivo. Nearly everything that happens in skin depends on active trans[port or some sort of receptor-triggered event cascade. Since the outer layers of the stratum corneum is metabolically speaking remarkably hypoactive, you need to explain how this would all work NOT in a culture of keratinocytes or fibroblasts, but in intact live human skin.
  • PROFESSOR ROBERT KO AUGUST 15, 2014

  • Sorry. I don't see why the active component of Glissandra cannot elicit  cellular responses in skin cells, either cultured or intact (in vivo), via the CYP-catalyzed ROS-mediated MAPK/Nrf2 signaling pathway.
4. What cell populations in skin is it affecting?

As the active compound of Glissandra is bioavailable to all tissues in the body, it is reasonable to assume that Glissandrin is bioavailable to all types of skin cells.

  • You speak of “all tissues of the body” as though Glissandra is being ingested and transported via the circulation. That paradigm doesn’t hold for topically applied substances. First you have to show its site of deepest penetration/action (epidermis, dermis, subdermis), and if epidermal only, what layer (stratum corneum vs deeper epidermis). Very few substances get past the stratum corneum in physiologically active quantities. That is the function of skin – to keep things out. We have to assume that topical Glissandra is not arriving via the circulation.
  • You need to demonstrate what cells it is acting on and how it gets there.
  • PROFESSOR ROBERT KO AUGUST 15, 2014

  • Topical application of Glissandra produces beneficial effect on skin tissues but not other tissues in the body. Oral administration of the active component of Glissandra was found to enhance the mitochondrial structural and functional integrity in various tissues.
5. If there is ROS signaling – what is the signal cascade? What other well known biochemicals are affected?

The signaling cascade involves the redox-sensitive MAPK/Nrf2 pathway. The activation of Nrf2 increases the expression of antioxidant genes such as enzymes in the glutathione antioxidant systems and superoxide dismutase, etc.

  • PROFESSOR ROBERT KO AUGUST 15, 2014

  • Chronic UV exposure at a desirable (safe) dose can produce a similar hormetic antioxidant response. Whether or not the extent of UV exposure can be effectively controlled within a safe limit is questionable, not to mention a sunburn which is a manifestion of overdose. As mention earlier, the prooxidant effect of the active component of Glissandra is self-limiting (ie. safe).
6. As with other mitochondrial stressors is there a shift toward anaerobic glycolysis?

Glissandra differs from other metabolic stressors in that it won't increase the cellular energy demand and thus a shift toward anaerobic glycolysis.

  • Let’s focus on the ROS production and disposal, and its consequences. If Glissandra increases ROS production, what is the ROS disposal mechanism, and why is it good to keep applying an ROS stimulus (as a hormetic signal) after the hormesis has taken place? Why continue to use daily an ROS generating topical? Why would that not risk micro-inflammation, which would then become chronic, with other (undesirable) adaptations? Why not a sensitizing dose and then a booster say every 2-3 weeks?

  • Thanks for indulging our curiosity.
  • PROFESSOR ROBERT KO AUGUST 15, 2014

  • A good question indeed. The signaling ROS is reduced by GSH (Glutathione), with resultant change in cellular GSH redox status, which in turn trigger the redox-sensitive signaling pathway and elicit antioxidant response. GSH will be regenerated from its oxidized form through glutathione redox cycling. Recurrent application of Glissandra is essential to keep this cycle working and set the cellular antioxidant machinery on a "ready" mode. 

  • I look forward to continuing to share our science with you and your readers.
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Saturday, 2 August 2014

Questions from Dr. John and the answers from Prof. Robert in the BFT debate

  • drjohn
    JULY 29, 2014 AT 5:01 PM · REPLY
    Welcome to the debate, it is a pleasure to have you here.
    Now to start I need to explain to our readers that this discussion involves evolving theory in the realm of cell biology that even the average PhD would have difficulty understanding unless they are actively involved in researching these topics. Once we set the stage I will endeavor to focus in on what we call the translational research. Basic facts & hypotheses are translated to prototypes and products, and are tested for clinical utility in a way that affirms or dismisses the underlying theories. At the end of the day we realize that what interests most folks is insight into things that work, and why they work. Theory without tangible application interests scientists, not consumers.
    The hyptotheses we are talking about here have to do with mitochondria, the energy factories present within cells of all types. It turns out the mitochondria are very important determinants of cell fate (cell death or survival from stress or injury), and thus are a center of focus for theories of aging. Now, it may be important to point out that whole organism aging and skin aging (or the appearance of same) at times may diverge, and thus manipulations of one don’t necessarily correlate with changes in the other. In simple human terms,living to 110 does not mean your skin will look young at 50. In some ways, the opposite may be true. So, we need to carefully dissect theories and experiments that have to do with theories of aging, mitochondrial energetics and ROS, tissue survival, etc, to make sure at the end of the day that the chain matches up.
    As clinicians we often think backwards. Start with the problem and potential solution, then track backwards to find physiologic explanations that make sense. Let’s start with some basic questions for Dr. Ko from which we can work backwards.
    1. What is the clinical evidence that Glissandra effects anti-aging benefits on skin? How are they documented?
    2. How is the active delivered? What vehicle? In what doses? Continuous vs discontinuous? How deeply does it penetrate?
    3. How is Glissandrin transported into cells to affect mitochondrial functions? By which known mechanism?
    4. What cell populations in skin is it affecting?
    5. If there is ROS signaling – what is the signal cascade? What other well known biochemicals are affected?
    6. As with other mitochondrial stressors is there a shift toward anaerobic glycolysis?
    Thanks in advance.
Professor Robert Ko
August 2, 2014

Dr. John, please find below my answers to your questions.

Respectfully, Robert

1. What is the clinical evidence that Glissandra effects anti-aging benefits on skin? How are they documented?

已經證明，以防止在體內和在體外通過太陽能光照射引起的氧化損害。

lol - okay even us scientists need to have a sense of humour!

Seriously though, Glissandra has been shown to protect against oxidative damage induced by solar light irradiation both in vivo and in vitro.

Two clinical trials using Visual anti-aging assessments were conducted. The duration of the studies were 8 weeks. Data collected were tabulated and analyzed.

North American Trial

Visual anti-aging assessments from 35 subjects of diverse ethnicities, with ages ranging from mid 20’s to late 60’s, from both genders.

South East Asia Trial

Visual anti-aging assessments from 28 subjects of Asian ethnicity with 17 subjects with age <45, 8 subjects with age 45-55, 3 subjects with age 55-65, from both genders.

Both studies documented dramatic effects on various signs of skin aging from end users.

2. How is the active delivered? What vehicle? In what doses? Continuous vs discontinuous? How deeply does it penetrate?

The active is delivered by passive diffusion. The active is lipophilic, and is readily absorbed by skin.

3. How is Glissandrin transported into cells to affect mitochondrial functions? By which known mechanism?

Glissandrin is readily transported via diffusion into the cytoplasm and then mitochondria . The active compound is metabolized by cytochrome P-450 enzymes (in both cytosolic and mitochondrial compartments), with resultant generation of signaling ROS which in turn activate the MAPK/Nrf2 pathway. The consequent increased expression of antioxidant genes can enhance the mitochondrial antioxidant capacity and thus the mitochondrial ATP generation.

4. What cell populations in skin is it affecting?

As the active compound of Glissandra is bioavailable to all tissues in the body, it is reasonable to assume that Glissandrin is bioavailable to all types of skin cells.

5. If there is ROS signaling – what is the signal cascade? What other well known biochemicals are affected?

The signaling cascade involves the redox-sensitive MAPK/Nrf2 pathway. The activation of Nrf2 increases the expression of antioxidant genes such as enzymes in the glutathione antioxidant systems and superoxide dismutase, etc.

6. As with other mitochondrial stressors is there a shift toward anaerobic glycolysis?

Glissandra differs from other metabolic stressors in that it won't increase the cellular energy demand and thus a shift toward anaerobic glycolysis.

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Tuesday, 29 July 2014

The debate focuses on mitochondrial decay and mitohormesis

More from Craig on Glissandra
JULY 26, 2014 AT 7:09 PM · REPLY
What have scientists found to fight the leading cause of skin aging – mitochondrial decay?
In our previous post, entitled “Theories of Aging”, we discussed how oxidative damage is regarded in the scientific community as the primary cause of aging, and how mitochondria play a significant role in this by being a major source of free radicals.
Now, scientists have made a breakthrough in fighting the leading cause of skin aging: Schisandrins have been proven to effectively reverse mitochondrial decay.
A recap of our previous discussion
Mitochondrial decay in aging refers to a progressive disruption to mitochondrial
structural integrity and functional ability over time. Consequently, cells experience impaired energy production, a decline in normal function, and accelerated free radical generation. This is the phenomenon of cellular aging, which makes the cell more prone to apoptosis, or programmed cell death – much like cell suicide.
Skin aging – the signs of which are commonly manifested in wrinkles, fine lines, age spots, loss of suppleness, and deterioration of skin tone – has been proven to involve mitochondrial dysfunction.
The mitochondria–free radical connection
Research has shown that mitochondria are a major source of free radicals. Deteriorating mitochondria instigate a vicious cycle of exacerbated oxidative stress. Consistent with these findings is the concept that “manipulating the signaling pathways that regulate cellular antioxidant defense” and “controlling the intracellular levels of free radicals” is preferred over “altering individual antioxidant components by extrinsic supplementation”.
In simpler terms, this means that it may be more effective to combat aging by treating the source of free radical production rather than by “cleaning up” free radicals after they are generated. This theory is supported by recent studies that have found that scavenging free radicals through the supplementation of certain antioxidants could be ineffective or even harmful in the long run.i ii
i Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention – Systematic Review and Meta-analysis, Bjelakovic et al; Journal of the American Medical Association 2007; 297(8):842-857 (doi:10.1001/jama.297.8.842).
ii Vitamins in Aging, Health, and Longevity, David R Thomas; The Division of Geriatric Medicine, Saint Louis University Health Sciences Center, Saint Louis, MO, USA.

  • drjohn
    JULY 26, 2014 AT 10:40 PM · REPLY
    So far the discussion has centered on theories of aging, with which I have no particular bone to pick. But this is not the crux of the debate. Glissandra claims that it’s mechanism of action is related to hormesis, a construct that says simply “what doesn’t kill you you makes you stronger”. However, i would be quick to add “what doesn’t kill you quickly may lead to chronic inflammatory disorders and slow death”. It’s all about the timing, dosing, signaling, molecular interactions, etc. In other words, the devil is in the details.
    Let me also say that I am a believer in hormesis and it’s therapeutic potential as a basic physiologic principle. The best known application may be exercise. It stresses physical systems, but they then recover and are stronger the next time challenged. Simple enough. But consider what would happen if you exercised all the time. I once had a patient who was obsessed with body fat and literally exercised herself to death. Exercise requires both a period of intense activity, and a period of recovery, to be beneficial. So, let me take a leap of logic and presume that this product causes a metabolic stress to the mitochondria of skin cells. But, it is not applied for an hour 3 times a week, it is applied twice daily, every day, assuming a constant rate of diffusion / absorption over that 12 hours from the cream. Toughens skin up (those cells that don’t die from the damage)? But wait – no recovery period. Won’t that just lead to chronic “cell danger response” signaling, and inflammation, with no down time to adapt? Maybe if the product sellers said to use it for a few days a month and then stop ….. at least that would match the paradigm.
    Also, this theory it does not comport well with what we know about the skin in responding to chronic oxidative stress. The most salient example? UV stress. We experience it daily, chronically, and the damage to skin accumulates over time. Yes, we have adaptive responses (e.g. repairing DNA damage every night, kill off and replace the worst damaged cells, create more melanin as a filter to sunlight). But even sunlight is only for half the day. But the adaptations don’t completely compensate for the stresses. Over time, the the system deteriorates. Skin ages. Too much of this stress and it also gets cancer. As the theory goes, what doesn’t kill you may toughen you. Perhaps the flip side is true – what doesn’t toughen you may end up killing you.
    I remain open to hormesis as a potentially beneficial mode of action for a dermal therapeutic, but would need to see specific evidence that ties a cyclical cellular stress to an adaptive (anti-inflammatory) response that is ultimately beneficial and does not lead to chronic inflammation and its consequences like disease, cancers, and aging itself.

Professor Robert Ko
JULY 29, 2014
Dr. John,
Thank you for your thoughtful question.
Glissandra (ie schisandrin B) differs from other conventional hormetic agents in that it has a wide range of effective doses which are non-toxic to normal cells. Schisandrin B is chemically transformed in various cells by cytochrome P-450 enzymes and thus produces signalling reactive oxygen species (ROS) which do not cause pathogenic oxidative stress. Instead, the ROS will elicit a glutathione antioxidant response, particularly in mitochondria, which results in mitohormesis - a process that can be induced by blocking insulin signaling, dietary restriction and physical exercise, which are all shown to be effective to prolong a healthy lifespan. Schisandrin B work in the same way in skin cells. The safeguard of mitochondrial function and antioxidant defense is beneficial to retard the skin aging caused by intrinsic (ROS) and extrinsic factors (solar radiation).
I look forward to our continuing to share more science behind our Glissandra products line.
Robert
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