1036 replies to this topic

[QuestforLife]

Regarding my senolytic protocol of Azithromycin+Doxycycline+liposomal Vit C, I had a runny nose during the cycle (and stomach upset from the vitamin C).

On the 3rd day of 3 I replaced the vitamin C with Nicotinamide.

A few days later my knees became very unstable. This effect has been reported by others using fisetin, I believe.

Crazily a skin cream with the same senolytics in it (applied to the face) seem to have the same effect on me (unstable knees).

I've not had problems in any other joints from it. A few years ago I injured one of my knees, and then had instability in it for a while. But this protocol affects both knees.

I am currently trying to determine if the same thing happens if I avoid nicotinamide.

Edited by QuestforLife, 09 October 2019 - 06:29 AM.

[QuestforLife]

Good cells and bad cells

 

I should make clear that I am not necessarily talking about senescent cells.

 

With aging there appears to be selection for cells that can survive but are not doing their job properly. Here are some examples. In the base of the epidermis stem cells that are less easily stressed resist asymmetric division and differentiation, eventually leading to their dominance of the stem cell compartment and failure of the upper layer of the skin to renew itself [https://doi.org/10.1...86-019-1085-7].This explains why various skin treatments that stress the skin and increase turnover, like retinoids, can work. It can be addressed more effectively by (cyclical) ROCK treatment. I suspect that a similar effect occurs in the endothelial lining, also addressed the same way. Another example. VSELs (very small embryonic like stem cells) reside in all adult tissues as a leftover from embryonic development [DOI: 10.1161/CIRCRESAHA.118.314287]. They are pluripotent but largely inactive, requiring ever increasing amounts of stimulation to support tissue. It may be possible to stimulate them via nicotinamide, sex hormones or ROCK inhibitors. Another example. With age human skin fibroblasts lose their respiratory ability via epigenetic downregulation of the serine catabolism pathway [DOi: 10.1038/srep10434]. It is my assessment that this is due to selection pressure. Fibroblasts are increasingly required to create collagen with age (when collagen recycling starts to fail), but the rate of collagen synthesis can only be increased at the cost of reduced antioxidant defences. The cells that heed this call are more likely to die due to increased oxidative stress. Cells that produce less collagen are the ones with lower glycine production. As glycine production is dependent on serine catabolism, and this pathway has been shown to be vital to assemble complex I of the electron transport chain it is clear that these cells will have respiratory defects. With age fibroblasts that don’t make collagen and have lost respiration are being selected for. The best way to treat this is probably with large amounts of glycine [https://doi.org/10.1007/s00726-018-2611-x].

 

In each of the examples given above there is a common thread. Stress causes differentiation of progenitor cells or harder work in somatic cells . This is an intentional response to support tissues. But it will over time select for cells that are resistant to stress AND resistant to responding to that stress.  With age ever greater stress is required to renew tissues. Although this gives us some confidence that exercise, CR, IF, autophagy inducers, etc. will slow aging this has a practical limit. Other treatment options are required.

Edited by QuestforLife, 09 October 2019 - 09:43 AM.

[Andey]

Have you noticed any effect on blood pressure while off cycle of losartan? That could be a proxy for endothelial health.

[QuestforLife]

Have you noticed any effect on blood pressure while off cycle of losartan? That could be a proxy for endothelial health.

 

I noticed a pressure drop after a previous cycle of ~15-20 points from systolic but this was unusual and didn't last more than a week or two and has not reoccurred since I dropped the dose of losartan from 25 to 12.5mg.

 

I'm inclined to think diastolic is the more important measure, and in me that has barely changed since I've been 16. 

[Kentavr]

I noticed a pressure drop after a previous cycle of ~15-20 points from systolic but this was unusual and didn't last more than a week or two and has not reoccurred since I dropped the dose of losartan from 25 to 12.5mg.

I'm inclined to think diastolic is the more important measure, and in me that has barely changed since I've been 16.

An important point:

When you take statins, the production of endogenous coenzyme Q10 decreases (statins block the production of both cholesterol and coenzyme Q10).

When taking statins, I recommend that you also use Ubiquinol.

[QuestforLife]

An important point:

When you take statins, the production of endogenous coenzyme Q10 decreases (statins block the production of both cholesterol and coenzyme Q10).

When taking statins, I recommend that you also use Ubiquinol.

I took Q10 the first couple of cycles, but I've not found it necessary at 5mg atorvastatin for 20 days, probably because the chloresterol lowering effects are weak at that dose and duration.

Fortunately ROCK is inhibited at a much lower dose that is required for chloresterol lowering.

[Kentavr]

I took Q10 the first couple of cycles, but I've not found it necessary at 5mg atorvastatin for 20 days, probably because the chloresterol lowering effects are weak at that dose and duration.

Fortunately ROCK is inhibited at a much lower dose that is required for chloresterol lowering.

Secondly, Statins damage mitochondria.

Ubiquinol protects mitochondria from damage, and also reduces the risk of myopathy:

https://www.ncbi.nlm...ubmed/23624330/

[QuestforLife]

Secondly, Statins damage mitochondria.

Ubiquinol protects mitochondria from damage, and also reduces the risk of myopathy:

https://www.ncbi.nlm...ubmed/23624330/

 

It's an interesting study in vitro, but I lift weights and do HIIT training and this protocol has not stopped me making gains, in fact if anything it has improved my performance. 

 

But take Q10 if you wish.  

 

My guess is that it whether or not you need it will depend on your baseline chloresterol level.

[QuestforLife]

Some future additions to the protocol

 

Telomerase Activation
A recent paper has found some fairly potent telomerase activators, related but not the same as cycloastragenol – namely various triterpenes, the most effective being a 95% purity extract of the triterpenes in Gotu Kola, at peak effectiveness providing about 17% of HELA in immune cells (compared to about 3% for TA-65). This was at a very low concentration (0.02mg/ml). Ten times the concentration was slightly less effective, whilst 100 times the concentration gave almost no telomerase benefit (without causing any outright harm). Given that the strongest triterpene content Gotu Kola supplement I can find has 20% triterpenes, getting the same results in vivo seems plausible. I couldn’t find any bioavailability or half-life information for humans, but on the bright side, various health benefits for Gotu Kola are reported by users on Amazon. The study also confirms the small but apparently robust benefits of Vitamin D for telomerase. [doi:  10.3892/mmr.2019.10614].
Stem Cell mobilisation
AFA (Aphanizomenon Flos-Aquae), Fuciodan and Sea Buckthorn Berry extract all have some evidence for increasing the release of stem cells from the bone marrow [DOI: 10.1016/j.carrev.2007.03.004, 10.1016/j.exphem.2007.02.009, http://dx.doi.org/10.2147/CIA.s186893]. Ordinarily this would be done to increase healing after injury, or for general health, for the former there is some evidence of effectiveness [DOI: 10.19080/NTAB.2017.01.555564, DOI: 10.15406/mojcsr.2015.02.00023]. I think combining this with the Statin-Sartan Protocol, which is hypothesized to partially block differentiation whilst selecting for the expansion of the smallest, more multipotent cells, would be highly synergistic. AFA seems to be the most effective of the proposed substances, and this supplement also has fucoidan (https://www.stemenhance.co.uk/cerule-stemenhance-ultra).

[QuestforLife]

My ideas on aging are moving apace.

The selfish cell lives longer

Arguments for the evolution of aging depend on a non aging (selfish) individual being bad for the group.

I think I see a parallel in the cells that survive in the aged body. Whenever I look into an aspect of aging, I always see the same thing. The cells that survive are the ones that are the worst for the body. Everyone seems to assume that a mysterious process called aging is causing these cells to fail with age. But what if it is a selection process that leaves the most selfish cells alive?

I can give concrete examples(discussed in this thread before, references not repeated). Briefly, epidermal stem cells respond to stress signals through asymmetric division producing a replacement stem cell plus epidermal skin cell. But naturally some stem cells are more resistant to stress and instead with the appropriate growth signal they divide symmetrically, with two(more stress resistant) stem cells spreading out and eventually coming to dominant the epidermis. In this way skin replenishment requires ever greater stress signals and fails. Another example. Fibroblasts produce collagen from glycine at a limited rate that necessities recycling of most of the collagen produced. But eventually more collagen has to be made and this requires diversion of glycine from glutathione production and a rise in ROS (the glutathione level decline with age is secondary to declines in the blood levels of glycine and cysteine).This means the cells that produce most collagen are the most likely to die. Again, you’re always left with the most selfish cells.

[JamesPaul]

"Given that the strongest triterpene content Gotu Kola supplement I can find has 20% triterpenes, getting the same results in vivo seems plausible."

 

Nootropics' gotu kola product is said to be 35% to 45% minimum triterpenes.  The label says < 3 ppm lead, < 2 ppm arsenic, and < 1 ppm cadmium. I'd like to find lower amounts.

https://nootropicsde...coated-tablets/

 

Nature Restore's product contains 0.35 ppm lead, 0.676 ppm cadmium, 1.39 ppm arsenic. It's standardized to 10% triterpenes. From an amazon.com answer, “The label reads that "Every batch is tested for strength, heavy metals and pesticides with ISO 17025 third-party labs and passes all CA Prop 65 Safe Harbor Levels.”

https://www.amazon.c...s/dp/B01G7UQMIA

I'd like to find the lowest ratio of heavy metals to a percent standardization.  Is the 20% product findable on amazon and does the company provide a certificate of analysis?

[QuestforLife]

"Given that the strongest triterpene content Gotu Kola supplement I can find has 20% triterpenes, getting the same results in vivo seems plausible."

 

Nootropics' gotu kola product is said to be 35% to 45% minimum triterpenes.  The label says < 3 ppm lead, < 2 ppm arsenic, and < 1 ppm cadmium. I'd like to find lower amounts.

https://nootropicsde...coated-tablets/

 

Nature Restore's product contains 0.35 ppm lead, 0.676 ppm cadmium, 1.39 ppm arsenic. It's standardized to 10% triterpenes. From an amazon.com answer, “The label reads that "Every batch is tested for strength, heavy metals and pesticides with ISO 17025 third-party labs and passes all CA Prop 65 Safe Harbor Levels.”

https://www.amazon.c...s/dp/B01G7UQMIA

 

I'd like to find the lowest ratio of heavy metals to a percent standardization.  Is the 20% product findable on amazon and does the company provide a certificate of analysis?

 

I ended up going for a 10% powder from a reputable seller: (https://www.amazon.c...0?ie=UTF8&psc=1).

 

On request they supplied the following (attached) certificate of conformity. 

 

Arsenic 0.019 ppm

Cadmium 0.001 ppm

Lead Less than 0.005 ppm

Mercury Less than 0.001 ppm

 

Which is the same amount in micrograms (ug) I'll be getting every time I take a 1g dose. This seems a lot better than the figures you quoted. Maybe higher purity triterpenes also concentrates metal contamination?

Attached Files

•  1571308185_GotuKola.pdf   94.68KB   147 downloads

[JamesPaul]

I ended up going for a 10% powder from a reputable seller: (https://www.amazon.c...0?ie=UTF8&psc=1).

 

On request they supplied the following (attached) certificate of conformity. 

 

Arsenic 0.019 ppm

Cadmium 0.001 ppm

Lead Less than 0.005 ppm

Mercury Less than 0.001 ppm

 

Which is the same amount in micrograms (ug) I'll be getting every time I take a 1g dose. This seems a lot better than the figures you quoted. Maybe higher purity triterpenes also concentrates metal contamination?

Those levels look very good.  I also wonder if concentrating the terpenes results in concentrating the heavy metals.

 

They don't ship to the US when their product is purchased via amazon, but they do ship to the US when a product is purchased from the timehealth.co.uk website.

 

Thank you!

Edited by JamesPaul, 18 October 2019 - 04:12 AM.

[QuestforLife]

My ideas on aging are moving apace.

The selfish cell lives longer...

 

Helpful cells die young; why selection for selfish cells dooms the body to aging

I wanted to talk some more about this idea, as many I’ve explained it to don’t seem to get it. If we take a given tissue in youth the cells appear to be ‘good’ by some metric, but with age the cells of the same tissue appear to be ‘bad’ by the same metric, be this telomeres or mitochondria, epigenetics, etc.; more generally we can take ‘good’ to mean good at performing the task for the body that cell type is assigned.  But currently it is proposed that some process leads these cells to change from being ‘good’ to ‘bad’ with time. What I am proposing turns this on its head by claiming that there are already many ‘good’ and ‘bad’ cells present in a youthful organism and it is aging that selects the bad ones. I suggest that within a given tissue a young body has a range of functionality within its cells, let us assume for the moment that this is epigenetic in nature as all cells have the same genes. Assume this follows a standard bell curve. This functionality reflects the subservience of the cell to the body in which is lives. Note that the way that cells perform this function will be different from tissue to tissue, we discuss here the generalised case (specific examples have been given already). Just as a member of a tribe must put the tribe above its own life, so the cell must put its own life on the line for the good of the body. The health of the body is contingent upon this. But the sacrifice of an honourable cell precludes it from passing on its ‘honourable’ epigenetic state; over time the more selfish cells will predominate. In the case of stem cells this is compounded – future repairs must rely on the cells that did not respond to the previous signalling. In the case of proliferating somatic cell a limit on telomeres and telomerase means that the best ‘die young’ from proliferative exhaustion. In the case of non-dividing cells the same still holds true, as often the cell ‘doing its duty’ for the body endures higher net ROS in the mitochondria and a greater chance of destruction. By this view aging is not one or even a handful of processes inherent to cells, but a range of issues that is revealed by the narrowing of the options that a body has to call on.

[JamesPaul]

How do I delete this post?

 

Edited by JamesPaul, 19 October 2019 - 02:02 PM.

[JamesPaul]

QuestForLife, is it possible to preferentially renew the stem cell pool with a greater proportion of "non-selfish" cells by giving a weak signal to stimulate symmetric stem cell division, which, according to Turnbuckle, is more likely to result in two daughter stem cells?  If I understood Turnbuckle's posts correctly, symmetric cell division is more likely when mitochondria are fused.  That state can be promoted by ingesting stearic acid or BroccoMax.

 

This thought is based on the notion you expressed that the non-selfish cells are more sensitive to weak signals to divide and help the body, whereas the selfish cells are not likely to respond and divide unless given a really strong signal.

 

Later a signal for stem cell division could be given when conditions promote asymmetric division, in order to spend money from the bank if needed, so to speak.

 

Edited by JamesPaul, 19 October 2019 - 02:23 PM.

[QuestforLife]

Regarding the stem cell pool, is it possible to preferentially cause the "non-selfish" cells to divide symmetrically by giving the body a weak signal stimulating stem symmetric cell division (more likely to result in two daughter stem cells), and then later a signal for asymmetric cell division (more likely to result in one daughter stem cell and one differentiated cell)?

This thought is based on the notion you expressed that the non-selfish cells are more sensitive to signals to divide and help the body, whereas the selfish cells are not going to respond unless given a really strong signal to divide.

I'm still thinking about ways to do this. Greater and varied stimulation is one way but this will not work forever. Combining this with a stem cell protocol (aka Turnbuckle) should make the stem cells you've woken up go further (via symmetrical division as you say). Another way is de-differentiation combined with telomerase activation (aka my protocol) as this should reset unco-operative cells back to a useful state. At the moment my protocol is mainly aimed at turning somatic cells back into progenitors and then proliferating them before letting them differentiate. But if you combined it with freeing stem cells from the bone marrow (with AFA) you should be able to expand and make the resultant stem cell pool even more multipotent and effective.

The other half of the equation is senolytics, of course. It might be possible to clear old cells even if they aren't technically senescent, if they have damaged mitochondria.

Another idea is a long fast or other autophagy inducers. They might reset the sensitivity of some stem cells.

All just ideas at this point I'm afraid, but you could sum it up as reprogram, reset or destroy.

Edited by QuestforLife, 19 October 2019 - 02:18 PM.

[JamesPaul]

QuestForLife, are you aware that a recent article,

 

“Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat “Aging-Related Disorders”,” M. Janić et al., Int J Mol Sci. 2019 Apr; 20(8): 1844. Published online 2019 Apr 14. doi: 10.3390/ijms20081844

https://www.ncbi.nlm...les/PMC6514706/

 

says

 

“Some statins in therapeutic doses were shown to induce SIRT1 expression, for example, simvastatin in endothelial progenitor cells [14]. On the other hand, atorvastatin and rosuvastatin reduced its expression in patients with coronary artery disease [15].”

14. Du G., Song Y., Zhang T., Ma L., Bian N., Chen X., Feng J., Chang Q., Li Z. Simvastatin attenuates TNFα-induced apoptosis in endothelial progenitor cells via the upregulation of SIRT1. Int. J. Mol. Med. 2014;34:177–182. doi: 10.3892/ijmm.2014.1740. [PubMed] 

15. Kilic U., Gok O., Elibol-Can B., Uysal O., Bacaksiz A. Efficacy of statins on sirtuin 1 and endothelial nitric oxide synthase expression: The role of sirtuin 1 gene variants in human coronary atherosclerosis. Clin. Exp. Pharmacol. Physiol. 2015;42:321–330. doi: 10.1111/1440-1681.12362. [PubMed]

 

I have to say that I find it interesting that taking fluvastatin is associated with lower-than-average diabetes risk, while atorvastatin is associated with higher-than-average diabetes risk:

 

“Could Statins Raise Diabetes Risk?” Margaret Steele, May 23, 2013

https://www.webmd.co...diabetes-risk#1

This article says that “Certain statins -- the widely used cholesterol-lowering drugs -- may increase your chances of developing type 2 diabetes, a new study suggests. The risk was greatest for patients taking atorvastatin (brand name Lipitor), rosuvastatin (Crestor) and simvastatin (Zocor), the study said....people taking Lipitor had a 22 percent higher risk of new-onset diabetes, Crestor users had an 18 percent increased risk and people taking Zocor had a 10 percent increased risk, relative to those taking pravastatin (Pravachol), which appears to have a favorable effect on diabetes.”

“...the study...was published online May 23 [2013] in the journal BMJ.”

and

“Fluvastatin (Lescol) was associated with a 5 percent decreased risk of diabetes and lovastatin (Mevacor) a 1 percent decreased risk. In previous research, Crestor was associated with a 27 percent higher risk of diabetes, while Pravachol was linked to a 30 percent lower risk.”

Edited by JamesPaul, 25 October 2019 - 03:21 AM.

[QuestforLife]

Thanks for this JamesPaul. Although I have to say I'm not convinced the beneficial mechanism is SIRT1 upregulation. I think it's more likely that the benefits are due to ROCK inhibition, and I find it strange Janic has not made that connection.

Having said that I would like to try fluvastatin rather than atorvastatin, but I've yet to find a source for it.

[Fafner55]

"Given that the strongest triterpene content Gotu Kola supplement I can find has 20% triterpenes, getting the same results in vivo seems plausible."

 

Nootropics' gotu kola product is said to be 35% to 45% minimum triterpenes.  The label says < 3 ppm lead, < 2 ppm arsenic, and < 1 ppm cadmium. I'd like to find lower amounts.

https://nootropicsde...coated-tablets/

 

Nature Restore's product contains 0.35 ppm lead, 0.676 ppm cadmium, 1.39 ppm arsenic. It's standardized to 10% triterpenes. From an amazon.com answer, “The label reads that "Every batch is tested for strength, heavy metals and pesticides with ISO 17025 third-party labs and passes all CA Prop 65 Safe Harbor Levels.”

https://www.amazon.c...s/dp/B01G7UQMIA

 

I'd like to find the lowest ratio of heavy metals to a percent standardization.  Is the 20% product findable on amazon and does the company provide a certificate of analysis?

 

Here's a SWAG for an oral dose of Gotu Kola triterpenes that might activate telomerase at the 0.02- 0.2 µg/ml concentrations reported by

“Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives” (2019) https://www.ncbi.nlm...les/PMC6755196/

• The bioavailability of triterpenes is not well established but if they are similar to steroidal hormones then one can assume 6%. (estrogen 2-10%, ≈5%; testosterone, 6.8+/-3.3% due to first-pass metabolism). 
• Assuming the adult human body contains 40 L of fluids,  0.02- 0.2 µg/ml concentration converts to 0.8-8 mg. At 6% bioavailability, the oral dose is then 13.3-133 mg.
• Nootropics Depot Gotu Kola extract is nominally 40% triterpenes. For this concentration, a high concentration oral dose is adjusted to (13.3-133 mg)/0.4 = 33.3-333.3 mg.
• 120 mg Nootropics Depot 40% is within range. Take 3x/day.

[JamesPaul]

Thanks for this JamesPaul. Although I have to say I'm not convinced the beneficial mechanism is SIRT1 upregulation. I think it's more likely that the benefits are due to ROCK inhibition, and I find it strange Janic has not made that connection.

Having said that I would like to try fluvastatin rather than atorvastatin, but I've yet to find a source for it.

 

You're welcome, QuestforLife.  I understand your reply. 

 

I happened to see the following source for fluvastatin.  I don't know who Tocris would sell to, though, because their site says "Tocris products are intended for laboratory research use only, unless stated otherwise."

 

https://www.tocris.c...tin-sodium_3309
 

Edited by JamesPaul, 03 November 2019 - 09:30 PM.

[QuestforLife]

I have to say that I find it interesting that taking fluvastatin is associated with lower-than-average diabetes risk, while atorvastatin is associated with higher-than-average diabetes risk:

 

“Could Statins Raise Diabetes Risk?” Margaret Steele, May 23, 2013

https://www.webmd.co...diabetes-risk#1

This article says that “Certain statins -- the widely used cholesterol-lowering drugs -- may increase your chances of developing type 2 diabetes, a new study suggests. The risk was greatest for patients taking atorvastatin (brand name Lipitor), rosuvastatin (Crestor) and simvastatin (Zocor), the study said....people taking Lipitor had a 22 percent higher risk of new-onset diabetes, Crestor users had an 18 percent increased risk and people taking Zocor had a 10 percent increased risk, relative to those taking pravastatin (Pravachol), which appears to have a favorable effect on diabetes.”

“...the study...was published online May 23 [2013] in the journal BMJ.”

and

“Fluvastatin (Lescol) was associated with a 5 percent decreased risk of diabetes and lovastatin (Mevacor) a 1 percent decreased risk. In previous research, Crestor was associated with a 27 percent higher risk of diabetes, while Pravachol was linked to a 30 percent lower risk.”

 

One thing you have to bear in mind with this protocol, is that you are aiming to take the statin at a sub-therapeutic dose. If you read the various papers I posted upthread from Janic et al., you'll see that higher dosing is LESS effective (at reversing arterial age) and dosing for too long is also LESS effective (at reversing arterial age). 

 

I've hypothesised that this is due to ROCK inhibition, which statins achieve at a lower dose than their cholesterol lowering effect. In some of the Janic studies you do see a small drop in chloresterol, but this is not something to aim for (unless you are taking statins for this reason). 

 

With all this in mind it is not suprising that atorvastatin is often associated with worse side-effects, as it is the most powerful statin in terms of easy absorption and long half life. That is why I only take 5mg/day of atorvastatin during a 20 day protocol, rather than 10mg/day of fluvastatin for 30 days as done by Janic. 

 

I do not believe that fluvastatin has anything special about it that means it is the only one that would work for reversing arterial age. But I could be wrong and that is why I intend to try fluvastatin in the future. 

Edited by QuestforLife, 04 November 2019 - 11:22 AM.

[Turnbuckle]

My ideas on aging are moving apace.

The selfish cell lives longer...Briefly, epidermal stem cells respond to stress signals through asymmetric division producing a replacement stem cell plus epidermal skin cell. But naturally some stem cells are more resistant to stress and instead with the appropriate growth signal they divide symmetrically, with two(more stress resistant) stem cells spreading out and eventually coming to dominant the epidermis. In this way skin replenishment requires ever greater stress signals and fails. Another example. Fibroblasts produce collagen from glycine at a limited rate that necessities recycling of most of the collagen produced. But eventually more collagen has to be made and this requires diversion of glycine from glutathione production and a rise in ROS (the glutathione level decline with age is secondary to declines in the blood levels of glycine and cysteine).This means the cells that produce most collagen are the most likely to die. Again, you’re always left with the most selfish cells.

 

 

Typically in the epidermis (and in many other tissues), stem cells don't go straight to somatic cells. They first become transit amplifying cells, which do most of the dividing--

 

During normal homeostasis, tissue stem cells often exist in two distinct states: a quiescent state in which they are not making tissue and a primed state in which they are either actively making tissue or more readily activated when needed. Once activated, tissue stem cells produce shorter-lived progenitors (sometimes called ‘transit-amplifying cells’) that divide rapidly several times, but then progress to terminally differentiate to form their respective tissue. 

http://lab.rockefell...s/research/stem

 

 

Skin cells do become epigenetically older with chronological age, but considering that skin cells might live only a few weeks before dying, where does this aging actually occur? And it seems to me that it can only happen in this transit stage, and only if there are insufficient primed stem cells to replace them. If somatic cells skipped the transit stage, they would always be as epigenetically as young as stem cells. So the problem has to lie with the decline of active stem cells to replace transit cells, which then have to divide more times to make up for it.

[QuestforLife]

Update Report November 2019

I am currently running my second SES (Statin-Epitalon-Sartan) 20 day cycle.
I’ve made some changes to the protocol:
1. Epitalon 10mg subQ injection, reduced to every other day (from every day, total over 20 days 100mg)
2. Addition of AFA (stemEnhance Ultra) 1 capsule a day (I found 2 capsules a day too tiring)
3. 500mg powder of 10% triterpenes from Kota gola for additional telomerase activation
4. I’ve added Vit D (with K) because of the season (everyone around me has a cold) and for additional telomerase activation

 

Some observations:
1. My weight training has jumped up a level; I’ve hit new personal bests on deadlift and bench press and more impressively, I seem to be able to lift more often, sometimes with only a 1-day break. I also experienced weight training benefits last time I took epitalon.
2. Again, I’m suffering from allergies. Last time I blamed it on hayfever season, this time it could be a cold.

 

Other experiments since the last update
I been experimenting with high dose glycine in order to increase collagen synthesis [https://www.ncbi.nlm...bmed/30006659].This is in addition to hydrolysed collagen powder. In the past I healed a knee injury with collagen powder where glycine alone failed. My hair and nail growth also noticeably improved since using collagen powder.

This time I went as high as 45g/day glycine. Glycine seems to give me an energy boost, and a slight increase in libido. Notable were the increased intensity of orgasms.  I did high dose glycine for 2-3 months, varying from 10g/day to 45g/day. Towards the end of this period I began to suffer very mild acne on my face, and worse acne on my back. After taking a dose of 10mg rapamycin (I do this once every 3 or 4 months) the acne on my back became very bad. This is unusual for me. I hypothesize that the glycine in my skin has gone up to the extent that it is helping otherwise small infections grow. Combining this with suppression of the innate immune system with rapamycin was disastrous. Is there any support for this theory? Some. [https://news.stanfor...ion-111412.html, https://rapamycintherapy.com/, see ‘Neutrophil Dysfunction].

 

I was forced to go on antibiotics and 3 weeks later the acne on my back has subsided, although not completely gone. I tried to reintroduce glycine at 5-10g/day but almost immediately got new eruptions, even without rapamycin.  I’ve not taken pure glycine since as a result, but have continued with the collagen powder, which contains 2.5-3g of glycine.

 

I (warning!) speculate that the excess glycine I’ve been taken is being mostly diverted to glutathione production (I also take NAC), and that is what has given me the benefits, with possibly only a small contribution to collagen. I suspect the figure of 95% collagen recycling rate (from https://www.ncbi.nlm...ubmed/20093739)is too low and consequently the glycine deficit is not as high as has been supposed. Collagen powder probably gives better results than pure glycine because it also contains proline and lysine in the right quantities. There might also be an effect from actual collagen peptides making it into the blood and fooling the body that it needs to incorporate new collagen. When you look at the above reference, it is also interesting that bone and muscle require the most collagen, skin’s requirement is relatively minor. Hydrolysed collagen may be working to target the skin more efficiently (speculation on my part).

I hope in the future to add back in 5-10g/day of glycine if I can do this without causing acne.

 

Senolytics

 

Interestingly I used azithromycin to control the acne I got from high dose glycine, using it for 3 days a week at 500mg per dose (due to the long half-life). Just as an experiment on the final day of azithromycin per week I also took 100mg of doxycycline. As I expected, this caused fatigue, although this has diminished after doing it 3 times over consecutive weeks. Have I destroyed some senescent cells? Possibly [https://www.ncbi.nlm...pubmed/31002656, https://www.ncbi.nlm...bmed/30428454].

 

The downside of using antibiotics is you kill helpful bacteria in the gut. In the 3 weeks I’ve been using azithromycin, I now find eating cheese uncomfortable. I’m lactose intolerant, but cheese is normally okay for me. I’ll now have to rebuild this capacity. In the future if I use AZ-DOX as a senolytic I’ll need to use much lower dosing and keep the protocol short. I think 250mg/day of AZ and 50mg of DOX, for a maximum of 3 days, should be about right.

 

Mitovitan

 

I experiment with a new skin serum every few months. I’ve been really surprised by how good mitovitan has been. Even using a small amount once or twice a day keeps my skin moist and healthy looking. I’d buy again (which is an extreme rarity for me and skin creams). I’ll probably buy the concentrate form next and make myself a stronger serum to see if I can get even better results. Interesting that this recent paper [https://www.embopres...mbj.2019101982]supports a role for senescent melanocytes inducing ROS in neighbouring keratinocytes underlying skin aging.

 

In conclusion, I’m reminded of the importance of cautious trial and error experimentation over theory. The things that work are generally not what you’d expect based a priori understanding.

[QuestforLife]

Typically in the epidermis (and in many other tissues), stem cells don't go straight to somatic cells. They first become transit amplifying cells, which do most of the dividing--

 

 

Skin cells do become epigenetically older with chronological age, but considering that skin cells might live only a few weeks before dying, where does this aging actually occur? And it seems to me that it can only happen in this transit stage, and only if there are insufficient primed stem cells to replace them. If somatic cells skipped the transit stage, they would always be as epigenetically as young as stem cells. So the problem has to lie with the decline of active stem cells to replace transit cells, which then have to divide more times to make up for it.

 

My example for the epidermis was taken from here: (https://www.nature.c...1586-019-1085-7). I posted about it before so I won't go into detail again now.

 

But my basic idea is that stem cells are activated by a given stimulation, and therefore a population of stem cells will over time become insensitive to that particular stimulation. 

 

How important this is for aging is anyone's guess. But my guess is that it is important. 

[Turnbuckle]

My example for the epidermis was taken from here: (https://www.nature.c...1586-019-1085-7). I posted about it before so I won't go into detail again now.

 

But my basic idea is that stem cells are activated by a given stimulation, and therefore a population of stem cells will over time become insensitive to that particular stimulation. 

 

How important this is for aging is anyone's guess. But my guess is that it is important. 

 

 

That work may be specific to skin, and explains how the useful pool of epidermal stem cells is steadily reduced. Apparently the ability for these cells to produce collagen 17 is reduced by UV exposure, but can be restored with a couple of substances--

 

The good news is that there may be a way to increase or preserve levels of collagen 17 in stem cells, staving off this process of skin aging. Nishimura showed that two experimental chemicals, Y27632 and apocynin, applied topically can increase collagen 17 levels in cells and even promote wound healing.

https://www.scientif...kin-treatments/

 

 

Y27632 is more powerful than apocynin, but is several thousand times more expensive.

[QuestforLife]

Y27632 is more powerful than apocynin, but is several thousand times more expensive.

Fortunately there are cheap generic drugs that also target ROCK.

Unfortunately this is most certainly not the only mechanism of skin aging, but that's another story...

[QuestforLife]

Update Report November 2019

I am currently running my second SES (Statin-Epitalon-Sartan) 20 day cycle.
I’ve made some changes to the protocol:
1. Epitalon 10mg subQ injection, reduced to every other day (from every day, total over 20 days 100mg)
2. Addition of AFA (stemEnhance Ultra) 1 capsule a day (I found 2 capsules a day too tiring)
3. 500mg powder of 10% triterpenes from Kota gola for additional telomerase activation
4. I’ve added Vit D (with K) because of the season (everyone around me has a cold) and for additional telomerase activation

 

Some observations:
1. My weight training has jumped up a level; I’ve hit new personal bests on deadlift and bench press and more impressively, I seem to be able to lift more often, sometimes with only a 1-day break. I also experienced weight training benefits last time I took epitalon.
2. Again, I’m suffering from allergies. Last time I blamed it on hayfever season, this time it could be a cold.

 

 

Only 3 days later but another update.... I am feeling AWESOME on this protocol. Just awesome. 

 

The other day I completed my deadlift and benchpress session in under 30 minutes. That's a first. And I equalled the personal bests I set only a few days beforehand.

 

I'm getting serious wood every night and morning (always a nice feeling for a man who's 40+) 

 

I'm looking good in the mirror (despite cutting my glycine intake right down - I'm still on collagen powder in the AM). 

 

I've recovered rapidly from the azithromycin induced lactose intolerance.

 

The glycine/rapamycin induced acne has almost completely resolved.

 

Only very slight downside is I'm still having occasional allergy-like sneezing outbreaks. 

 

I'm unsure what has made this protocol superior to the previous iterations but something has clicked. 

[QuestforLife]

An exciting new triterpene product: Zen in a Jar - Reishi Spore Triterpene Crystals (45g) https://www.amazon.c...i_SeBYDbRGGR1W3

Very pure, certificate of conformity attached.

This is not isolated from Gotu Kola but from Reishi. Nevertheless, looks interesting.

Attached Files

•  Reishi Spore Triterpene Crystal Powder -CoA.pdf   1.43MB   129 downloads

Edited by QuestforLife, 11 November 2019 - 06:51 PM.

[QuestforLife]

Feedback on completed SES (statin-epitalon-sartan) cycle

Components

• Epitalon 10mg subQ every other day (PM)
• Atorvastatin 5mg (AM)
• Losartan 12.5mg (AM, except last week, when also took 12.5mg PM)
• AFA extract, 1 tab (PM)

Other supplements taken not part of this protocol
• 10K IU Vit D and Vit K (winter months)
• 25mg B6 (have a homozygous deficiency)
• Collagen and protein supplements (general workout stack)

Other additions to protocol (reasons given)
• Increased AFA to 2 tabs per day – increased to optimise benefits; rejected due to tiredness
• Added 1 sea buckthorn extract tab to 1 AFA tab – increased to optimise benefits; rejected due to tiredness
• Added losartan PM dose – wanted to further repress TGF-B concurrent with AFA dose; caused no issues, possibly reduced muscle soreness further
• 100% pure triterpenoid extract from Reishi spores – added for potential telomerase benefits; rejected due to immune reaction (previous acne in remission re-inflamed)

Observations
Side effects
• Increasing the stem cell supplementation from 1 to 2 tabs per day caused fatigue and (eventually) decreased libido.
• Towards the end of the cycle (last 5 days) had occasional muscle cramps, probably due to atorvastatin accumulation. Shorten to 15 days?
• Triterpenoids caused immune flare up
Positive effects
• Greatly decreased recovery time from weight sessions (only 1-day off day required, usual 2-3 days)
• Increased strength (several new personal bests established during 20 day cycle)
• Decreased workout time (same number of reps and sets in a shorter period)
• Muscle soreness greatly decreased without seeming to compromise muscle building
• 1 muscle injury sustained during protocol healed in less than 1 day (usual 3 days)
• Libido increased
Other supplements of future interest for this protocol
• Eurycoma longifolia
• Boswellia extract
• Oxytocin
• Forskolin

Future protocols
I’m considering a workout-only protocol (twice a week), using most of the same substances (without epitalon). The advantages of this is that it would give me regular feedback on effectiveness.
Future Testing
• Blood work to be done at the end of the week. Should give me sufficient data for PhenoAge calculator as well as to show up any obvious problems.
• Lifelength follow up telomere testing next week.
• Results will be posted to Longecity.

 

Alternatives to Atorvastatin and Losartan
This is something people have asked me about. Statins in particular are much maligned and misunderstood, and I may have to devote a post in the future to this as I believe their side effects are directly related to their benefits – in the same way as mTOR inhibition can be good (in short bursts) but bad chronically. Event Sartans have their detractors. But this is for another day. In the meantime, it is worth considering alternatives from more natural products. It may be that these can be used more consistently without side effects.

Alternatives to Statins
For Rho kinase inhibition in place of statins the most promising compound appears to be Eurycoma longifolia, an ancient aphrodisiac. In this recent in-vitro study (https://www.hindawi....m/2019/4341592/) an aqueous extract of EL (concentrated 25x from the root) shows similar ROCK inhibition to the potent pharmaceutical Y-27632.  Of course it has limited bioavailability, 10% according to this paper using rats (https://www.ncbi.nlm.nih.gov/pubmed/16206032), but a 50mg/kg dose achieved a peak serum concentration of 330ng/ml, which corresponds to about quarter of the most effective dose achieved in the in-vitro paper. There is some information in the abstract of the rat study that appears incorrect.  A 1.96mg/kg concentration of eurycomanone is claimed in their extract (called F2), but this is so low it could not possibly have led to a 330ng/ml serum concentration. I assume they actually meant 1.96mg/g, which would correspond to a 20:1 concentrated extract, consistent with the other paper (25:1). The equivalent dose for 85kg human (me) comes out to be 1.4mg. Tongkat Ali supplements commonly have around 10 times this amount per tablet (I have found one with 12mg at 3% eurycomanone and a larger 2% tablet with almost 14mg). Given peak effectiveness at inhibiting ROCK in vitro was 1-10ug/ml, we will likely achieve a concentration in this range and get the full 60-80% ROCK inhibition with 1 tablet.  This might be a too strong an inhibition for our requirements, but I am comforted by the short half life of about 1 hour. Caution is nonetheless warranted but my conclusion is that this supplement is definitely worth trying.
Alternatives to sartans

To replace the TGF-B inhibition of losartan my top pick is Boswellia extract, an ancient Indian remedy for inflammatory conditions. Certain extracts such as the proprietary ‘aflapin’ (or apresflex) have proven to be effective in relieving arthritis sufferers (https://www.ncbi.nlm...pubmed/22022214), asthma and are might even be effective against cancer.  The mechanism is believed to be via 5-LOX inhibition (which will lower TGF-B). The supplement is widely available and looks like low hanging fruit to me.
So in the near future I will be experimenting with Tongkat Ali and Boswellia extract, possibly combined with a stem cell stimulant like AFA or Buckthorn Berry Extract (BBE).