Thank you for this point - I have just digested it now :)!
I am currently analyzing the best possible exercise mode for activating AMPK, and it seems that with depleted glycogen, it works in the best way. At the same time, I have a fear of gluconeogenesis/muscle breakdown when running in a fasted state. What is your experience / opinion on that?
@SilentWatcher this episode speaks to your question. It is a very good discussion of the I science and lack of certainty behind fasted exercise.
I don’t exercise fasted (fasting then exercise) to avoid the higher stress / longer recovery. If I want more stress I’ll just go harder.
Dear @Joseph_Lavelle, thank you for the link to the podcast. Indeed, it is a high-quality discussion. The part about the triggering of aerobic pathways in prolonged intervals of HIIT was particularly interesting for me personally. Now, it is clear that nothing is clear 
I am a bit lost. On one hand, cardio shows some edge over HIIT with respect to the activation of AMPK: the MICT group demonstrated a greater magnitude of increase in p-AMPK compared to the HIIT group (MICT = moderate-intensity continuous training).
So, what does this mean for the exercise strategy of activating AMPK? Is alteration the key, with changing exercise regimes provoking adaptations? Any opinion on that?
@SilentWatcher Im sure you already knew to follow a program including: endurance / cardio / zone 1 / 2 (of 5), HIIT (hard enough to not feel well), resistance training (to failure or at least close), plus other mobility stuff (change of direction sports, balance, etc). Lots to do. Hard to prioritize. I try to touch everything every week. But when I can’t I don’t let 2 weeks pass. And progressive overload is the key… get stronger over a long period of time. Injuries will cost you big time.
65% of VO2peak is very low for a trained endurance athlete and far from their VT1 (zone 2 limit) so it’s expected that it’s not going to be a stimulus for anything.
For instance my VT1 (zone 2 limit) is at 76% of VO2peak which is far from 65%of VO2peak.
We can see that when we look at the lactate during the exercise:
The current “optimal” (a moving target for sure) protocol for cardio is to train mostly in zone 2 (around VT1) with 2 days of interval training in zone 4/5 (above VT2) like the 4x4 method or sprints, etc. depending on your goals.
65% of VO2peak will be too much for untrained individuals and not enough for trained athletes.
Here’s a small update. Alternating between “AMPK days” and “mTOR days” has allowed me to build lean muscle mass and burn fat. Since June, I’ve lost 3kg while increasing my weights in squats and bench press.
Reminder, I am following an intermittent path of mTOR/AMPK activation:
“Activating longevity pathways” - AMPK Days (aerobic training, low carb/moderate protein, supplements activating AMPK):
Maintaining muscle mass - mTOR Days (anaerobic training, moderate carb/high protein, supplements supporting a healthy anabolic regime):
How many AMPK days? Many studies on intermittent fasting, which activates AMPK, use protocols lasting 1-5 days. I am tending currently towards 4 days, which should be long enough to enjoy the advantages of this regime.
How many mTOR days? To maintain healthy muscle mass, muscle synthesis stays elevated for 36 hours, and research shows muscles are more sensitive to dietary protein for about 48 hours after exercise. Therefore, I’m tending towards 3 consecutive days in this mode.
Interesting effect: REM sleep and deep sleep improved significantly and continues to improve. Deep sleep:
REM sleep:
Do you measure lactate during training? If you do, I wonder which equipment you usevto dial in zon2?
Yes, I used an EDGE Lactate meter but it’s too cumbersome so now I use a Moxy muscle oxygen sensor which gives information in real time.
Revisiting Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin:
When simvastatin was administered 24 hours after ingestion of the last dose of grapefruit juice, the Cmax and AUC(0-infinity) were increased 2.4-fold (P < .01) and 2.1-fold (P < .001), respectively, compared with control. When simvastatin was given 3 days after ingestion of grapefruit juice, the Cmax and AUC(0-infinity) were increased 1.5-fold (P = .12) and 1.4-fold (P = .09), respectively, compared with control. Seven days after ingestion of grapefruit juice, no differences in the Cmax or AUC(0-infinity) of simvastatin were seen.
→ it seems that at least 48 hours after GFJ+rapamycin should be free of statins/ezetimibe or any other meds, affected by CYP3A4 (vs dosage reduction??). Unfortunately no dedicated ezetimibe study available.
This is why a low dose statin is best.
Thanks for sharing your regimen.
Some questions I ask myself:
If you follow a 3 day routine focused on mTOR and protein synthesis remains elevated 36/48 hours after the last workout, mTOR activation extends to 4 days. So you do two days of training?
In those 4 days of AMPK, would you take the Nrf2 activators every day, or every other day? I ask this because of the suggestion not to activate this pathway continuously, although I understand that being 4 days, it would be a controlled activation.
I think it is very difficult to combine everything but it is a very successful approach and I like it. 
Hi Sergi,
here what I am following:
Day1 (mTOR): weights lifting
Day2 (mTOR): weights lifting (antagonistic muscles with respect to day 1 in order to avoid overtraining)
Day3 (mTOR): recovery
Day4 (AMPK): cardio
Day5 (AMPK): recovery + AMPK/NRF2 boosters
Day6 (AMPK): cardio
Day7 (AMPK): recovery + AMPK/NEF2 boosters
I personally never take NRF2 boosters (quercetin/astaxanhin/lutein/sulforaphan……) on the day of cardio, as they obviously interfere with body’s natural response to exercise. My rapa days are normally located in the middle of AMPK cycle, in order to amplify overall effect (with corresponding adjustments to supps and Rex meds) - currently I am dosing rapa once a 3 weeks.
Critical opinion is always welcome.
@SilentWatcher Working each muscle group 1x per week….Do you just kill it each time? 10-15 sets per muscle group each day? How do you make sure to get enough stimulus?
I lift 3X/week whole body each time; 4-5 sets each WO per muscle group. Last couple sets to near failure or failure. This is a load I can barely recover from in 36 hours, and I deload once in a while or whenever I feel beat. I always skip a muscle group in a workout if I have a tweak that day.
Thanks for the clarification. It seems like this could be a good balance for maintaining muscle or making progress, depending on the person, and at the same time perform the AMPK days
@Joseph_Lavelle, good point. But, training each muscle group once a week is not something completely new. While higher frequency training (2-3x per week) is often recommended for hypertrophy, the difference in results is not as significant as some might think. A meta-regression analysis of non-volume-equated studies here showed that while higher frequencies might offer a slight advantage, the overall difference between training each muscle group once versus three times a week is modest.
For individuals over 40, like myself, balance between recovery (mTOR-driven) and stress (AMPK-driven) states is crucial. This is why I aim to spend less than 50% of my time in an anabolic state: Here some additional considerations for 4/3 split:
@Sergi, if you follow this path and have any insights or some ideas how to improve, I’d appreciate hearing about them. The key is to continuously adapt based on how your body responds and the goals you’re aiming to achieve.
Thanks. I’m familiar with this research which says…
“ that resistance training frequency does not significantly or meaningfully impact muscle hypertrophy when volume is equated”
But it isn’t easy to equate volume when lifting 1x vs 3X per week. I aim for 10 set of near failure work each week….perhaps up to 15 sets overall per muscle group.
My plan is to include as much muscle building activity as I can recover from. I think this will provide superior “younging” results to frequent low calorie periods aimed at autophagy.
What research have you found on that topic?
BTW, Here’s a paper specifically about older lifters
Excellent discussion, I’ve enjoyed your rationale and process. Would you mind summarizing your daily supplements and RX with the daily activities(e.g. weights, zone 2, HIIT and rucking) on your AMPK vs MTOR days? There is a lot of back and forth and I certainly don’t want there to be an N of 1 here. I’d like to try this as well, it is very logical.
Thanks in advance for your help and passing along your knowledge.
I like your critical perspective. I’ll think about it.
Look here: Efficient Combination of Longevity Strategies - #32 by SilentWatcher - I made some minor adjustments, but it is overall approach…
@Joseph_Lavelle, an observation in the context of our discussion about the needed ratio of AMPK/mTOR days: why are TOP 7 out of the “leaders board 2023” 17 ITP interventions clear AMPK activators / mTOR inhibitors?
What does this say about crucial pathways ratio needed for prolonging healthspan?
@SilentWatcher Good point. My thinking is that autophagy is critical but you can have too much. I also think that muscle (resistance training) and mitochondrial building activity (endurance training) is not anabolic for other organs…instead it signals an energy depletion.
In general, my goal is to signal to my body to adapt to an environment where it needs to handle a lot of activity and strength needs. I believe this will keep me youthful and even return me to a more youthful phenotype. Progressive overload is the key. Targeting mitochondrial health.
The hard part is working on other goals at the same time.
Losing visceral fat (targeting metabolic issues).
Gut health (nutrient absorption, avoiding immune triggers and targeting gut and brain permeability).
Heart health—Blood flow (NO, BP, co2 tolerance, apoB).
4.Stress flexibility (tolerate high stress and be able to get into low stress states to have both high activation and quality sleep).
Etc.
But, this is just my attempt to create order from the chaos of the health and longevity advice floating around. I try to not be overly influenced by:
Studies of mice living in cages
Studies of improvements to the health of sedentary people (anything is better than nothing)
Studies that show the health improvements from being frail (vs having too much body fat)
