Efficient Combination of Longevity Strategies

#21

Some of these work through ROS and Oxygen exposure.

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#22

You can train fasted to force the maximum adaptations.
BTW you get even more AMPK activation when you train fasted at higher intensities.
Thatā€™s what I do. I even run marathons, trail runs and sprint sessions fasted.
Takes a few months for the body to adapt though.

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#23

@SilentWatcher I like your strategy, do you continue with the same approach?
I have a question, out of curiosity: wouldnā€™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?

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#24

@Sergi, thanks for engaging with my strategy. Youā€™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 bodyā€™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 bodyā€™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 bodyā€™s natural adaptive responses to exercise-induced stress with targeted support during recovery, based on my current understanding of oxidative stress and exercise physiology.

But happy to hear counter-arguments.

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#25

@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.

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#26

From my reading, the deficiency in glutathione comes primarily from low Glycine, but low Cysteine is also a major contributing factor.

Glycine will get you 10% of the way, but you need additional Glycine and Cysteine to get the other 90% of the way to optimal glutathione levels.

But, yes, always take in more Glycine than Cysteine.

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#28

I think cycling is definitely the way forward as itā€™s clear a lot of stuff thatā€™s beneficial work against each other too so youā€™re definitely on the right track here.

Couple of comments:

  1. Ashwaganda and Astaxanthin as AMPK activators (mTOR inhibitors). Possibly others on that list too.

  2. NAC has been shown to abolish the beneficial effects of increases in oxidative stress from AMPK activation in numerous studies. Itā€™s an extremely powerful anti-oxidant.

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#29

@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?

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#30

Remember AMPK activation causes mTOR deactivation. Thatā€™s precisely how rapamycin works too. So those supplements would work for both cardio and rest days IMO. I think youā€™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 youā€™d want to steer clear of mTOR inhibitors in that time. You also donā€™t want too many autophagy-focused days either. I personally wouldnā€™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 itā€™s a mTOR activator when present in plasma. So I think itā€™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 Iā€™m currently at.

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#31

Agreed. I tend to think of glycine as a ā€œcanā€™t go wrongā€ aid while ā€œNACā€ is the Uber strong chemical that is amazing when you need it but donā€™t do too much. Glycine every night and NAC when tired or feel something (illness) coming on or 1x/week otherwise to boost glutathione.

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#32

Following the path: alteration is a key :old_key: and incorporating valuable feedback from @Joseph_Lavelle, @murraci, @Ludovic, @cl-user, @Sergi, @DeStrider here is next iteration.

AMPK Days

(AMPK) Training Days with Aerobic Sessions (Running) :man_running: :running_woman: :running_man:

General:

  • Low protein intake: Facilitates the upregulation of AMPK, amplifying the effect of cardio exercise. Low protein leads to a reduction in Insulin-like Growth Factor 1 (IGF-1), a hormone associated with longevity.
  • No (Gly)NAC: NAC diminishes AMPK activation.

Morning:

Lunch:

After Run:

Pre-Sleep:

(AMPK) Resting Day Following Aerobic Sessions (Running)

General:

  • Low protein intake

Morning:

Lunch:

Pre-Sleep:

MTOR Days

(MTOR) Training Days with Anaerobic Sessions (Weight Lifting) :weight_lifting_man: :weight_lifting_woman: :man_lifting_weights:

General:

  • Elevated protein intake: This strategy is key for activating mechanistic target of rapamycin complex 2 (mTORC2), amplifying the effect of strength exercise, leading to an automatic increase in IGF-1, which is crucial for muscle building.
  • No (Gly)NAC: Controversial studies findings on mTOR activation.

Morning:

Lunch:

Evening / Pre-Sleep:

(MTOR) Resting Day Following Anaerobic Session

General:

  • Muscle synthesis remains elevated for 30+ hours after training: No NRF-2/AMPK activators.
  • High protein intake: Boost of mTOR.

Morning:

After Lunch:

  • (Gly)NAC

Evening / Pre-Sleep:

RAPA Days

Rest Days with mTORC1 Inhibition ā€“ Once Every 2-3 Weeks

  • Intermittent mTORC1 inhibition: Utilizing rapamycin in individually tailored dosages to intermittently inhibit mTORC1.
  • Training pause: Avoiding 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.
  • Lithium: The combination of lithium with rapamycin eliminated the undesirable effects on lipid metabolism.

Looking forward to critic :smiling_face_with_three_hearts:

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You are only as young as your oldest part...I now have all my stats pre starting Rapamycin
Bryan Johnson's Anti-aging Skincare Routine
#33

I think the general approach is good. Acetate/Vinegar is something where I think it is worth trying to minimise the acid intake. Acetate has a vasodilative effect.

That may be helpful in the short term, but I donā€™t think it has broader effects there. It does, however, have the potential to increase cytosolic acetate levels which then depending upon ACCS2 levels can increase cytosolic acetyl-CoA.

My normal route to acetate starts with ethanol, but I have tried triacetin. However, not had any obvious outcomes.

On the days you take Creatine it may be worth having some D-Ribose as well.

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#34

I like your in depth analysis and schedule. Iā€™ll be thinking about it and if I think of a way to improve it, Iā€™ll let you know!

Great job. :slight_smile:

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#35

@SilentWatcher i like it. The thought process is similar to my own. A few thoughts

  1. The lifting day is the 24 (or 30, as you say) hours after the lifting session. No need to preload protein. The key idea is to avoid over consuming protein when the body isnā€™t looking for extra protein to use for growth. Excessive protein is just extra calories at that point.
  2. I donā€™t try to activate autophagy or down regulate mTOR except 1x/week when I fast or dose rapamycin. My down cycles during the week are just recovery days when I try not to eat too many calories that will become fat that Iā€™ll have to lose with some difficulty.
  3. I use a 2 week cycle for rapamycin so my week after rapa is a lighter weight training week. I donā€™t push so hard. If if feel tired or sore I back off. I also take an extra day off of weight training. The second week after Rapa I am pushing hard. Going to failure. Aggressively using NIR light to heal. I go for maximum stimulus up to 24 hours before my next rapa dose. Repeat. Every 5th week is my rapa holiday, which also serves as my super anabolic week.
  4. Build muscle to have some to give back for injury, weight loss, life interruptionsā€¦so none of that is too stressful.
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#36

Thank you for your feedback! I appreciate your insights and the reference to the vasodilative effects of acetate.

I included apple cider vinegar because it:

  • Stimulates AMPK: Activates AMPK on AMPK-days, which is beneficial for longevity and metabolic health.
  • Decreases postprandial glucose peak: When taken before meals, apple cider vinegar can help reduce the spike in blood sugar levels after eating.
  • Increases bile production: Enhances digestion and nutrient absorption by stimulating bile production.
  • Acts as an adenosine reuptake inhibitor: When taken before bed, it might promote healthy sleep by increasing adenosine levels.

Could you please elaborate on your position regarding the reduction of acid intake from apple cider vinegar? Iā€™m interested in understanding your perspective in more detail.

Additionally, Iā€™ll study your suggestion about including D-Ribose on days I take Creatine. Thank you for that recommendation.

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#37

Perhaps consider Acarbose (and fasting) around rapa days to avoid/offset mTORC2 inhibition?

Perhaps also do breaks some weeks

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#38

Can you talk a bit more to this John?

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#39

How much does this mean that you exercise, roughly ever other day or more frequently?

#40

Thank you, @Joseph_Lavelle. You are totally right, and you already mentioned it before, protein loading makes sense only after a workout (24-36 hours). I will reflect this better in future iterations.

You also raise an interesting question with your weekly pattern: what is a meaningful cycle for mTOR/AMPK activation? I have not found any definitive recommendations for what can be recommended. Currently, I am trying to find a balance of 50/50% between 2-3 days of muscle building (mTOR) and 2-3 days of autophagy (AMPK), hoping that this maintains a balance. However, if it should be 30%/70% or 20%/80%, this is a really interesting question that warrants further exploration.

Integration of NIR is also very interesting optionā€¦ will try to study their effect on MTOR/AMPK and overall recovery.

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#41

Thank you for your comments (particularly explicit mentioning of Acarbose in MTORC2 - I was not aware of it)! and asking. I am doing ā€œhardā€ weight lifting followed by 1-2 rest days (mTOR days). Then I go into a cardio session with 1-2 rest days afterwards (AMPK days). Light walking of 2-5 km is part of my postprandial glucose handling every day (at least I am trying to maintain this shedule) - this was recommended by @Joseph_Lavelle before :slight_smile:

As I mentioned before, an interesting question for me is: what should the mTOR/AMPK days ratio be? Should it be 50/50%, 20/80%, or another balance? Any insights/thoughts on this would be highly valuable.

I am speculating about 50/50 balance for these subjective reasons:

  1. Metabolic Flexibility: Balancing mTOR and AMPK allows efficient switching between anabolic (building) and catabolic (breaking down) states, optimizing muscle growth and metabolic health.
  2. Longevity and Healthspan: Periodic mTOR activation supports muscle growth, while AMPK activation promotes autophagy and metabolic health. Chronic mTOR activation is linked to aging and diseases, but chronic AMPK activation can lead to muscle wasting, highlighting the need for balance.
  3. Insulin Sensitivity and Glucose Homeostasis: mTOR improves insulin sensitivity through muscle growth, while AMPK enhances glucose uptake and insulin sensitivity. Balancing both pathways reduces the risk of metabolic disorders.

Any opinion is welcome.

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