Efficient Combination of Longevity Strategies

[SilentWatcher]

Following the path: alteration is a key and incorporating valuable feedback from @约瑟夫_拉维尔, @murraci, @Ludovic, @cl-user, @Sergi, @DeStrider here is next iteration.

AMPK Days

(AMPK) Training Days with Aerobic Sessions (Running)

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:

• Berberine, Curcumin, Quercetin (Bromelain): Upregulate AMPK, inhibiting MTOR.
• Reishi: Inhibits mTORC1/2 by activating AMPK.

Lunch:

• Lithium: Activates and phosphorylates AMPKα to enhance autophagy.
• Selenium: Studies suggest that selenium can activate AMPK under certain conditions, such as oxidative stress. There is evidence suggesting that selenium can inhibit mTOR signaling, especially in cancer cells.
• Spermidine: Found to activate AMPK (still not fully validated).

After Run:

• Glucosamine: Induced the phosphorylation of AMPK and inhibited the phosphorylation of mTOR.

Pre-Sleep:

• Apigenin
• Vinegar: Activates AMPK by increasing AMP/ATP ratios.

(AMPK) Resting Day Following Aerobic Sessions (Running)

General:

• Low protein intake

Morning:

• Cold shower: Exposing your body to cold water, either through a shower, a cold swim, or cryotherapy has been shown to activate AMPK.
• Taurine: Stimulates AMP-Activated Protein Kinase.

Lunch:

• NRF-2/AMPK activators: Sulforaphane, Moringa, Astaxanthin, Lutein, Zeaxanthin, and Ashwagandha.
• Glucosamine: Induced the phosphorylation of AMPK and inhibited the phosphorylation of mTOR.
• Reishi: Inhibits mTORC1/2 by activating AMPK.
• Lithium: Activates and phosphorylates AMPKα to enhance autophagy.
• Extra virgin olive oil: By increasing AMPK, it has been shown to also stimulate autophagy.
• Selenium: Studies suggest that selenium can activate AMPK under certain conditions, such as oxidative stress. There is evidence suggesting that selenium can inhibit mTOR signaling, especially in cancer cells.
• Vinegar: Activates AMPK by increasing AMP/ATP ratios.
• Spermidine: Found to activate AMPK.

Pre-Sleep:

• Apigenin
• Vinegar: Activates AMPK by increasing AMP/ATP ratios.

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MTOR Days

(MTOR) Training Days with Anaerobic Sessions (Weight Lifting)

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:

• Creatine: Creatine Supplementation Upregulates mTORC1.

Lunch:

• Citrulline: Both leucine and citrulline stimulate muscle protein synthesis, in part through a common mechanism of action mediated by the mTOR signaling.

Evening / Pre-Sleep:

• Glycine: Regulates protein turnover by activating mTORC1.

(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:

• Creatine: Creatine Supplementation Upregulates mTORC1.
• Citrulline: Both leucine and citrulline stimulate muscle protein synthesis, in part through a common mechanism of action mediated by the mTOR signaling.

After Lunch:

• (Gly)NAC

Evening / Pre-Sleep:

• Glycine: Regulates protein turnover by activating mTORC1.

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RAPA Days

Rest Days with mTORC1 Inhibition – 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

[John_Hemming]

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.

Acetate relaxation of isolated vascular smooth muscle - PubMed

That may be helpful in the short term, but I don’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.

[DeStrider]

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

Great job.

[Joseph_Lavelle]

@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 isn’t looking for extra protein to use for growth. Excessive protein is just extra calories at that point.
2. I don’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 I’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 don’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 interruptions…so none of that is too stressful.

[SilentWatcher]

@John_Hemming

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.

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? I’m interested in understanding your perspective in more detail.

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

[Neo]

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

Evidence that mTORC2 inhibition is detrimental, by Dudley Lamming

Rapamycin, when taking at high doses on a continual basis, is known to eventually start to inhibit mTORC2. One of the results of ongoing mTORC2 inhibition is immune system suppression (while this is considered a feature, not a bug, in organ transplant patients, in anti-aging its definitely a “bug” (negative). Research also suggests that mTORC2 inhibition shortens healthspan and lifespan in animals. These are the reasons why, for rapamycin in anti-aging, we typically take rapamycin on a pulsed dosing schedule (e.g. once per week or once every two weeks). Here is a twitter thread where one of the leading researchers on rapamycin and mTOR outlines the evidence on mTORC2 inhibition:

Acarbose, An mTORC2 Promoter We Should All Take?

I have it in my cupboard and I keep it in my wallet for when I may be eating more starch and I have not taken an SGLT2 inhibitor, but generally don’t like, acarbose. Its gotten good results in terms of lifespan improvement from the NIA ITP studies, but the side effects of excessive gas, and sometimes diarrhea are so common as to make this medication less than desirable for me (your results may differ). But I saw these recent comments to renew my interest in acarbose. Perhaps it might be optimal to take lower doses of acarbose, even if you are already taking SGLT2 inhibitors… Research has shown that higher mTORC2 activation seems to increase lifespan and healthspan: Additionally, it was noted that Acarbose can increase mTORC2 activity: So, perhaps acarbose is something that should be added to our protocols even if we are already taking an SGLT2 inhibitor like canagliflozin or empagliflozin and blood sugar spikes are not an issue at all? Your thoughts?

UCLA study links fasting to mitochondrial splitting and mTORC2 Activation (UCLA)

Other studies have suggested that increasing mTORC2 can help improve lifespan… and this suggests perhaps why we don’t want to take high regular (daily) dosing of rapamycin, which eventually starts to suppress mTORC2. Perhaps this new research is also a rationale for periodic fasting for those taking rapamycin - it boosts mTORC2… UCLA researchers found that fasting increases the splitting of mitochondria, which may have implications for metabolic and aging-related diseases. In the study published in June, scientists examined the livers of mice that had been starved and identified the activated proteins, said Nuria Martinez-Lopez, the paper’s first author. They found that proteins in the mTORC2 cellular signaling pathway – known to be related to cell growth and metabolism – were activated by fasting, she added. These proteins increased the splitting of the mitochondria during fasting, which might allow cells to more efficiently burn fatty acids to cope with starvation, said Rajat S…

Perhaps also do breaks some weeks

Rapamycin Cycling (Time Off) - Who Is Right?

Breaks are recommended so that you don’t inhibit your MTORC2. This can happen if your Rapa levels are too high for too long. Hence the breaks.

[Neo]

@John_Hemming

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

Can you talk a bit more to this John?

[Neo]

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

[SilentWatcher]

@Joseph_Lavelle

my week after rapa is a lighter weight training week. I don’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.

Thank you, @约瑟夫_拉维尔. 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 option… will try to study their effect on MTOR/AMPK and overall recovery.

[SilentWatcher]

@Neo

How much does this mean that you exercise

Thank you for your comments (particularly explicit mentioning of Acarbose in MTORC2 - I was not aware of it)! and asking. I am doing “hard” 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 @约瑟夫_拉维尔 before

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.

[Joseph_Lavelle]

@SilentWatcher For me, longevity is a side effect of a good life program plus infrequent rapamycin to get an unnatural, temporary turn up of autophagy and turn down of mTOR. Still, I think of the process more broadly than just mTOR vs AMPK. I try to be a well rounded athlete. I try to keep my body composition near optimal to leave room for bad luck. I eat a healthy omnivorous diet with a few indulgences and a few fasts. I eat protein in support of my muscle building. I limit my added fats and sugars (and untimely protein) in support of my body comp efforts. I am working hard on my circadian rhythm and my sympathetic / parasympathetic balance. I try not to let myself fall into the trap of thinking supplements are critical (think icing vs cake).

[John_Hemming]

Creatine adds to ATP storage and D-Ribose makes it easier to create more ATP.

[John_Hemming]

Vinegar is acetic acid. In water it dissolves into a single positively charged cation of hydrogen and negatively charged anion of acetate. For its effects in the body you need to consider separately the effects of the proton H+ and the anion. The higher the concentration of protons in water the more acidic the water is. Personally i tend to want to minimise acid intake. Hence i would minimise drinking acid even a weak one such as acetic acid. I do like using a bit of vinegar, however.

[Joseph_Lavelle]

Balsamic vinegar and olive oil with good bread is one of the great pleasures in life. I miss it.

[John_Hemming]

Olive oil is supposed to be healthy. I have a small amount of balsamic with my salad most days.

[Joseph_Lavelle]

I also add a smidge onto my dinner (started after AGEs podcast). But in the good old days I’d eat a loaf of bread with a lot of olive oil and balsamic. That was when I’d go out for a ride and burn 5000-8000 kcals.

[John_Hemming]

The bread is the issue.

[RPS]

感谢@SilentWatcher and @约瑟夫_拉维尔 for prompting me to change my exercise regime from alternating daily between weights and zone2 aerobic so now I do 3 days of heavy weights followed by 2 days of zone 2 and then 2 days of rest.
Rapa is taken at the end of day5 for weeks 1 & 2. On week 3 Rapa is taken on days 5, 6 & 7 as a CR mimetic and complete washout with no Rapa on week 4 when I really push the heavy weights. (Have been experimenting with this Rapa regime for a couple of months with no ill effects).
High protein on days 1-4 and low protein on 5-7.
Taurine on days 4 - 7. (Not sure where to do the NAC and glycine - maybe only rest days in week 4?).

[SilentWatcher]

@RPS

(Not sure where to do the NAC and glycine - maybe only rest days in week 4?).

Good question. Glycine regulates protein turnover by activating mTORC1 - so I have allocated its use on weightlifting days AND rest days after weightlifting, because:

• glycine acts as a natural sleep aid in the evening, counteracting increased cortisol after weightlifting

• glycine counteracts the excess of methyl groups caused by creatine supplementation on those days.

• we are using activated mTOR on that day, in order to push collagen synthesis and support our skin.

• if high protein intake on these days comes with increased methionine intake - glycine help to counteract methionine toxicity.

With that, glycine impact is leveraged properly only on “MTOR”-days! → combination is a key.

NAC is an open topic for me. Considering that it is a strong antioxidant (as already mentioned by @murraci) - I am avoiding it on weightlifting days to prevent interfering with the body’s natural response to exercise. I am adding NAC to glycine on the rest days after weightlifting (MTOR days) and have a feeling, that it accelerates restoration on that days… But glad to see any alternative opinion.

[Curious]

I am curious, if you have an opinion about Taurine and its use?