Excellent points and approach.
I’m wondering in regard to timing on increasing HGH which should activate MTORC2 I believe - and please correct me if I’ve got this wrong - but I’ve wondered what experiences people have with inhibition of MTORC1 (e.g. use of Rapamycin) while simultaneously stimulating MTORC2 with HGH. This situation could never occur in nature generally, but I’m sure there are a number of people doing this.
What is everyone’s assessment of logic for doing this or avoiding this, and the timing of the 2 agents if you are going to use them.
For example, during the 72 hours after taking Rapamycin, hold doses of HGH to allow a true unopposed MTOR1 affect, and then until next dose of Rapamycin take HGH (or other secretagogue) to build back stronger with activation of MTORC2.
I’d love to hear some thoughts and logic behind approach on this issue?
MTORC1/MTORC2: subjective opinion: while MTORC1 and MTORC2 have distinct roles, there is a level of interplay between these pathways. MTORC1 primarily regulates protein synthesis and autophagy, while MTORC2 is involved in cell survival, cytoskeletal organization, and metabolism. There is significant cross-talk between MTORC1 and MTORC2. Inhibition of MTORC1 can lead to a compensatory activation of MTORC2 and vice versa. This interplay is part of the body’s mechanism to maintain cellular and metabolic homeostasis. When you disrupt this balance, such as by inhibiting MTORC1 with rapamycin, it could potentially lead to a compensatory or exaggerated response in MTORC2 activity, especially when further stimulated by exercises like HIIT.
Context of hGH, mentioned above: It’s important to note that the hGH discussed above is the natural surge post-exercise, not synthetic injections. This distinction is crucial because the natural release of hGH due to anaerobic exercises like resistance training is a physiological response with potentially different effects and implications than exogenous hGH administration.
Food for thoughts in terms of practical advice: The idea of postponing anaerobic training until rapamycin levels have sufficiently decreased (48 hours? 76 hours?) is a sound one in light of consideration above (activating MTORC2 and inhibiting MTORC1 might send conflicting signals within the cells, leading to unpredictable or less understood cellular responses). This approach allows for a period where MTORC1 activity is inhibited without overlapping with the activation of MTORC2, which is stimulated by anaerobic exercises.
You somewhat mirror my thoughts on this. The issue remains a lack of evidence, and acting on theory. Unfortunately, we often make errors when we think we understand mechanism and activity as to how things actually play out.
As someone who advises patients and prescribes, it is a real challenge, and there is obviously “shared decision making” that occurs. There is no option.
So we (my wife and I) took our Rapamycin on the 20th, and from my perspective, I think things that stimulate MTORC2 should not be pursued vigorously until at least 72 hours there after. We’ve opted for an 8 day cycle, and might go to a 9 day cycle.
So for folks who inject HGH or something that stimulates secretion of HGH, I’d say likewise, hold the dose of those items for 72 hours post Rapamycin - but this is my theoretic approach to this issue.
There is marginal evidence from the TRIIM trial that maybe a year or more of HGH with other agents might be good and regenerate the Thymus and T cells. Impressive MRI’s on that paper. However, HGH seems to also have a lot of risks (including the wallet biopsy for payment) and it might create risk of other health issues.
But can you get an even better outcome with cyclic MTORC1 inhibition then activation of MTORC2?
This is the question in my mind and a question in how we personally manage our longevity regimen, which often times has to be separate from how I advise patients, as I must be more conservative - but flexible.
I am in the land of melatonin hectodoses (not really megadoses and perhaps more so decidoses). Melatonin is thought to stimulate the production of HGH.
I am probably one of the least frequent users of Rapamycin at a maximum frequency so far of 21 days, but I have not thought to vary melatonin usage around Rapamycin dosing.
Several months later, I’m still contemplating what you wrote, @Joseph_Lavelle
I’ve been experimenting with berberine on days when I focus on cardio and AMPK activation. This leads me to wonder about the necessary duration for berberine to start influencing AMPK. Given that the half-life of berberine is approximately 5 hours, but its effect on glucose levels only becomes apparent after a month of supplementing, what does this imply for its timing for AMPK pathway? Should we begin taking berberine a day (or days) before our cardio-focused days to amplify effect on AMPK? Any thoughts on that in absence of any in-vivo evidence?
@SilentWatcher it is clear you have moved beyond me in your thinking about this. I will watch for your findings. I’ll say that I doubt the berberine and curcumin supplements have a large effect on mTOR. The big mTOR levers for me are the rapamycin, exercise and type, staying below or above the mTOR threshold of leucine (volume and quality of protein), and insulin (volume and type of food plus good sleep and stress management). The rest is on the other side of the 80/20 equation, but I’m always interested in learning more about easy to implement tactics.
A new element for me is I’ve started lifting in the early AM, and the next morning I fast until an early dinner, after which I do easy cardio. This is designed to increase the variation of diet based stimulus of mTOR.
@Joseph_Lavelle, thank you for your comment(s). I don’t believe I am much further ahead. However, after considering your feedback and that of @DrFraser, the following strategy came to my mind, which I am now pursuing.
GlyNAC supplementation: Aims to regulate glutathione homeostasis, potentially without disrupting the body’s natural response to training.
Training Days with Anaerobic Sessions (weight lifting):
Elevated protein intake on the day of and the day after training: This strategy is key for activating mechanistic target of rapamycin complex 2 (mTORC2), amplifying effect of strength exercise, leading to an automatic increase in IGF-1, which is crucial for muscle building.
GlyNAC supplementation: As above, it helps in managing glutathione levels without negatively impacting the training response.
Rest Days (days without training) – 2-4 times a week:
NRF-2 activators: Including Sulforaphane, Moringa, Astaxanthin, Lutein, Zeaxanthin, and Ashwagandha, these compounds are known for their role in oxidative stress management and overall cellular defense mechanisms.
Rest Days with mTORC1 Inhibition – once every two to three weeks:
Intermittent mTORC1 inhibition: Utilizing rapamycin in individually tailored dosages to intermittently inhibit mTORC1.
Training pause: Avoid training 1-2 days after dosing to prevent interaction between mTORC1 and mTORC2 pathways.
Blood sugar optimization/AMPK activation: administer Metformin 1-2 days before and after the rapamycin dose. The glucose-regulating effects of Metformin become significant only after three days of administration.
My current schedule: aerobic session day / rest day / anaerobic session day / rest day …
Looks great. Perhaps consider that easy (zone 0-1) aerobic workouts do not require recovery or a rest day. They ARE the rest day (active recovery). They also help lower blood glucose after a meal, and get you out of sympathetic activation (stress mgmt). I try not to have any days with no movement; it means I have to be careful not to beat myself up too much in any workout (HIIT workouts are short). I even when I feel very sore, and long warmup can bring me around to get a nice and easy spin. Good luck.
On your anaerobic training days I would add 5g creatine pre workout and 6g taurine + 2g AKG intra-workout. All relatively inexpensive and with proven health benefits. Here 's an article about taurine;
Good point, @Joseph_Lavelle .That supports a point, that the regulation of metabolic pathways, such as mTOR (mechanistic target of rapamycin), AMPK (AMP-activated protein kinase), IGF (Insulin-like Growth Factor), NRF2 (Nuclear Factor Erythroid 2–Related Factor 2), and several others pivotal for longevity, relies more significantly on appropriate physical stimuli rather than solely on pharmacological interventions and magic pill.
This doesn’t imply that more physical activity is necessarily better. But, for instance, for my personal observation (n=1), a 30-minute walk after lunch (slow carb meal) can reduce the postprandial glucose peak comparably to the administration of 50mg of acarbose, highlighting the potent physiological impact of moderate exercise.
Interesting article about taurine, thank you, @Ludovic .
Unfortunately, I am the one experiencing insomnia after creatine supplementation, and currently, I have no definitive explanation. My understanding is that supplementing with creatine spares the body’s production of S-adenosylmethionine (SAMe), a crucial methyl group donor involved in various bodily functions, including the synthesis of creatine. Since over 40% of SAMe is used to synthesize 1-2g of creatine daily, supplementation can lead to elevated levels of SAMe, which is associated with insomnia in some individuals. Additionally, creatine acts as an adenosine agonist. Adenosine plays a vital role in sleep regulation, and its signaling pathways can influence sleep patterns. Unfortunately, I have not been successful in mitigating these effects with glycine and niacin.
You can train fasted to force the maximum adaptations.
BTW you get even more AMPK activation when you train fasted at higher intensities.
That’s what I do. I even run marathons, trail runs and sprint sessions fasted.
Takes a few months for the body to adapt though.
@SilentWatcher I like your strategy, do you continue with the same approach?
I have a question, out of curiosity: wouldn’t it be somewhat ineffective to take NRF-2 activators (such as sulforaphane, moringa, astaxanthin, lutein and zeaxanthin) on rest days, considering that oxidative stress tends to peak during and after exercise?
@Sergi, thanks for engaging with my strategy. You’re touching upon a nuanced aspect of exercise physiology. Research suggests that exercise-induced oxidative stress is not purely detrimental but plays a crucial role in training adaptations. The body’s response to this stress, through endogenous antioxidant production, is a key part of strengthening its defense systems against oxidative damage (Merry & Ristow, 2016). By allowing the body to encounter the natural oxidative stress from exercise without the immediate introduction of external antioxidants, we might be fostering these beneficial adaptations more effectively.
Introducing NRF-2 activators on rest days is based on the premise that they can support recovery and bolster the body’s antioxidant defenses without interfering with the exercise-induced signaling pathways that drive adaptation. This approach is informed by the understanding that the timing of antioxidant supplementation can significantly impact its effects on exercise adaptation. For example, consuming antioxidants immediately before or after training might attenuate the beneficial adaptations to training, while their consumption during recovery periods may not have the same impact (Paulsen et al., 2014).
Therefore, my strategy is to balance the body’s natural adaptive responses to exercise-induced stress with targeted support during recovery, based on my current understanding of oxidative stress and exercise physiology.
@SilentWatcher Thank you very much for the clarification.
Regarding GlyNAC, some people are of the opinion that the limiting material for glutathione synthesis is glycine, not cysteine, arguing that adults usually have enough cysteine, mainly from broken down muscle tissue, so adding NAC may be unnecessary and may have risks such as cancer (https://www.science.org/doi/10.1126/scitranslmed.aad3740) or thyroid problems. Glycine intake would be the factor that prevents the anti-thyroid effects of NAC and also protects against melanoma
Any opinions on this? In my case, I am refraining from using NAC for the time being and prefer to use native whey protein and collagen which already contains glycine to ensure glutathione synthesis.
I think cycling is definitely the way forward as it’s clear a lot of stuff that’s beneficial work against each other too so you’re definitely on the right track here.
Couple of comments:
Ashwaganda and Astaxanthin as AMPK activators (mTOR inhibitors). Possibly others on that list too.
NAC has been shown to abolish the beneficial effects of increases in oxidative stress from AMPK activation in numerous studies. It’s an extremely powerful anti-oxidant.
@murraci, I appreciate your feedback. I tried to verify your statement with studies and it seems to be accurate. But what does it really mean?
This suggests that Ashwagandha and Astaxanthin should be excluded on days with strength training and the resting days that follow (to avoid interfering with mTOR activation and the natural oxidative stress of exercise). On days with cardio exercise, they still interfere with natural oxidative stress as NRF2 activators; however, on resting days after cardio, when AMPK is activated, they could potentially amplify the effect.
Hmm, this suggests that NAC should be excluded on days of cardio, especially if AMPK levels are high, leaving its intake only for days of strength training (AMPK low, MTOR high).
This would obviously trigger the need for a strategic pivot. Any comments other opinion?
Remember AMPK activation causes mTOR deactivation. That’s precisely how rapamycin works too. So those supplements would work for both cardio and rest days IMO. I think you’d only really want to avoid them the day of and the day after resistance training. Muscle synthesis remains elevated for 30+ hours after training so you I guess you’d want to steer clear of mTOR inhibitors in that time. You also don’t want too many autophagy-focused days either. I personally wouldn’t go for more than 3 per week. All about balance innit.
NAC is a difficult one as a few studies have shown it to inhibit mTOR. That is very confusing to me though given what it is composed of and I strongly suspect systemically it’s a mTOR activator when present in plasma. So I think it’s probably safe to take on resistance training days with creatine, lots of protein, particularly leucine, etc.
This is all subject to more studies coming out but where I’m currently at.
Agreed. I tend to think of glycine as a “can’t go wrong” aid while “NAC” is the Uber strong chemical that is amazing when you need it but don’t do too much. Glycine every night and NAC when tired or feel something (illness) coming on or 1x/week otherwise to boost glutathione.
