MTOR Increases With Aging/Sarcopenia, (Partial) Inhibition Restores Muscle Mass

Limon9

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This was a nice experiment which upsets the naive axis of anabolism and catabolism commonly-associated with the mTOR (mammalian target of rapamycin). Its activation is not sufficient to maintain muscle mass, and partially inhibiting it can unexpectedly restore muscle. Common medical advice is for the elderly to "eat more protein", although this study seems to confirm Dr. Peat's contrary theory* that mTOR represents metabolic inertia, with its activation threshold decreasing over time, and that an aging person should instead go Okinawan, continually maintaining a balance between protein synthesis and catabolic "housekeeping" processes. The authors' focus on autophagy and AMPK should draw attention to lifestyles which reduce the production of endogenous debris. Everyone's favorite painkiller ought to play a beneficial role here, having additional uncoupling and anti-glucocorticoid effects. But most importantly, this explains why @Blossom's rapamycin-treated elderly chihuahua became playful and active, instead of becoming David Sinclair.

Key Points
- mTOR hyperactivated in sarcopenic (wasting) muscle of rats
- mTOR activity increased with aging
- Low-dose rapalog treatment partially restored muscle mass and innervation.

Partial Inhibition of mTORC1 in Aged Rats Counteracts the Decline in Muscle Mass and Reverses Molecular Signaling Associated with Sarcopenia
Mol Cell Biol. 2019 Sep 11;39(19):e00141-19. Joseph GA et al.

Highlights
"We found mTORC1 (mammalian target of rapamycin complex 1), a well-established positive modulator of muscle mass, to be surprisingly hyperactivated in sarcopenic muscle. Furthermore, partial inhibition of the mTORC1 pathway counteracted sarcopenia, as determined by observing an increase in muscle mass and fiber type cross-sectional area in select muscle groups, again surprising because mTORC1 signaling has been shown to be required for skeletal muscle mass gains in some models of hypertrophy. Additionally, several genes related to senescence were downregulated and gene expression indicators of neuromuscular junction denervation were diminished using a low dose of a “rapalog” (a pharmacological agent related to rapamycin)."
"This loss of muscle is called sarcopenia, and it is associated with a decrease in the ability to move, leading to morbidity and ultimately to mortality (2); indeed, a decrease in walking speed is one of the strongest predictors of mortality in humans, and this finding is associated with sarcopenia (3, 4)."
". . . there has always been concern about the potential effects of rapamycin and rapalogs on skeletal muscle. For example, inhibition of the mTORC1 pathway was shown to entirely block responses to compensatory hypertrophy in mice (18). This certainly gave the impression that activation of mTORC1 signaling was desirable for the maintenance of muscle mass. Most recently, it was shown that rapamcycin treatment inhibited muscle mass increase caused by myostatin loss (19). Thus, it seemed reasonable that inhibition of the pathway was not desirable in settings of muscle loss (1, 18, 20)."
"Both MuRF1 and MAFbx/atrogin-1 are specifically upregulated under atrophic conditions (33, 34) and target proteins that are critical for muscle structure and protein synthesis for degradation, thereby inducing muscle loss (35–37). mTORC1 itself can directly inhibit catabolic functions such as autophagy (38). Autophagy has been shown to promote muscle atrophy in response to fasting conditions in young animals (39). However, it was found that autophagy function is impaired in the aged and plays a role in age-related dysfunction in several different tissues (40, 41). Indeed, recent experimental evidence suggests that the restoration of autophagic flux in aged animals may prevent loss of muscle mass and function related to sarcopenia (42, 43)."
"In our study, male rats that were 6 months to 27 months of age were used. Protein lysates from gastrocnemius muscles were probed for the downstream effector of mTORC1, phosphorylated ribosomal protein S6 (rpS6), as a determinant of pathway activity. Basal (6-h-fasted) levels of phosphorylated rpS6 gradually increased as the rats aged, with a substantial increase of about 10-fold in the oldest animals (aged 27 months) compared with those aged 6 months (Fig. 1A and B). The age-related increase in mTORC1 signaling coincided with a decrease in muscle mass."
"Perturbation of mTORC1 pathway activity was assessed in tibialis anterior (TA), plantaris, and gastrocnemius muscles. Western blot analyses confirmed that the levels seen in the S6K1 arm of the mTORC1 signaling pathway were elevated in samples from multiple muscle groups of aged vehicle-treated animals relative to young adults (Fig. 2). Both LD RAD001 treatment and HD RAD001 treatment significantly reduced phosphorylation of S6K1, a direct downstream target of mTORC1, in the muscles of old rats relative to vehicle-treated animals of the same age (Fig. 2A and C). Phosphorylated S6K1 was undetectable in plantaris muscles from all treatment groups. However, phosphorylation of rpS6, a direct downstream target of S6K1, was also reduced in all muscles with both doses of RAD001 treatment compared to vehicle in old rats (Fig. 2). 4EBP1, another direct target of mTORC1, showed a partial reduction in its phosphorylation with LD RAD001, but the level was significantly reduced with the HD in TA and gastrocnemius muscles (Fig. 2A and C). Phosphorylation of 4EBP1 was significantly decreased at both doses of RAD001 in plantaris muscles (Fig. 2B). These data confirm that while HD RAD001 treatment can almost completely suppress the mTORC1 pathway, the relatively low dose of the rapalog used in the present study was also sufficient to inhibit mTORC1 signaling in aged skeletal muscle."
"Chronic activation of the mTORC1 pathway by muscle-specific deletion of Tsc1, a negative regulator of mTORC1, has been shown to cause late-onset myopathy with muscle atrophy in young adult mice (47). Inhibition of mTORC1 activity using rapamycin was able to reverse the observed pathological changes and normalize muscle mass in these animals (47)."
"Blood glucose levels were also comparable between all aged groups (Fig. 3B). Thus, our data provide strong evidence that, when administered to sarcopenic rats, rapalog treatment is not detrimental to muscle mass. Rather, especially when given at a clinically relevant low dose, it enables animals to maintain muscle."
". . . age-related gene expression changes that helped to demonstrate the molecular pathogenesis of sarcopenia (46). Those data revealed the transcriptional upregulation of several pathways, including pathways related to innate inflammation and senescence, cellular processes counterregulated by partial mTORC1 inhibition."
"Prior data suggest that autophagy induction via exercise or caloric restriction may provide protection from sarcopenia (56). Recent publications have identified the AMPactivated protein kinase (AMPK) energy-sensing pathway as a positive modulator of autophagy, acting via direct phosphorylation of Unc-51-like autophagy activating kinase 1 (ULK1) to initiate autophagy (38, 57). Muscle-specific knockout of AMPK in adult mice resulted in premature muscle deficiencies similar to those seen in sarcopenic mice (58). Of note, mTORC1 is a suppressor of autophagy; thus, we sought to determine whether RAD001 inhibition of mTORC1 would be sufficient to restore autophagy signaling in sarcopenic muscle."
"when we examined mTORC1 signaling in skeletal muscles in rats at ages where sarcopenia occurs (46), we were surprised to see that the level of signaling had increased rather than decreased—there was an age-related increase in the phosphorylation of S6K1 and rpS6, readouts of mTORC1 activity. Coincident with elevated mTORC1 signaling, there was a progressive decrease in skeletal muscle mass. These findings established at least that activation of mTORC1 was coincident with atrophy and therefore was not sufficient to prevent muscle loss under sarcopenic conditions."
"Following treatment, skeletal muscle mass was unchanged in the gastrocnemius muscles, but we were surprised to see that muscle mass increased rather than decreased in the TA muscles, with a moderate effect on the plantaris muscles, as a result of partial mTORC1 inhibition with a low dose of RAD001. This was not due to adverse events such as edema, and animals maintained body weight during treatment."
"Autophagy induction may also be required to promote muscle health. mTORC1 is a negative regulator of autophagy through its suppression of ULK1. Furthermore, muscle specific deletion of AMPK impairs autophagy in aged tissue, causing a premature pathological phenotype similar to that in sarcopenic muscle (58). Interestingly, in our study, only the muscle groups that showed an increase in mass with rapalog treatment had restored autophagy, possibly via activation of the AMPK pathway, as indicated by the presence of the autophagosomal marker LC3II. This effect was observed with partial mTORC1 inhibition only after low-dose RAD001 treatment, in comparison to the stronger inhibition induced by high doses of RAD001. It appears then that the amelioration of the sarcopenic phenotype requires a careful equilibrium between the inhibition of overactivated anabolic pathways such as the mTORC1 pathway and boosting the activity of catabolic pathways such as those governed by AMPK. Reestablishing a basal level of autophagy may serve to recycle macromolecules for the support of cell growth and clearance of dysfunctional organelles."
"In summary, mTORC1 signaling is hyperactivated in aged muscle, and this apparently contributes to sarcopenia. Partial rather than complete inhibition of mTORC1 signaling has beneficial effects in sarcopenic muscle since inhibition of this signaling can increase muscle mass, albeit not in all muscles. Reestablishment of autophagy via enhanced AMPK signaling is additionally required for the maintenance of muscle health. The inhibition of denervation and senescence markers and the subsequent decline in atrophy markers give a further therapeutic rationale for treating aged sarcopenic patients with an mTORC1 inhibitor."

*Ray Peat's Newsletter, Q1 2022, "Carcinogenic Metabolism"
"Hysteresis is a general phenomenon in which an effect lags behind its cause—for example, it takes less energy to maintain a flow of electricity than to start it; it describes the inertia of the system. Cancer demonstrates this property—a continuing stress gradually leads to an accumulation of functional and structural changes that sustain the stressed condition, such as changes in the extracellular environment as well as intracellular processes. For example, the presence of lactate modifies the extracellular matrix in ways that increase lactate formation (Sullivan, et al., 2018). An important factor in creating functional and metabolic inertia is a phosphate transfer enzyme that creates a general pattern of activation, the kinase called mTOR (mechanistic target of rapamycin).

A bacterial fungicidal antibiotic, rapamycin, originally used to treat candidiasis, was found to be immunosuppressive, and is used to prevent rejection of kidney transplants. The mTOR enzyme inhibited by rapamycin has been found to promote growth, inflammation, fibrosis, and cancer growth, and to accelerate aging. Lactate promotes the activation of mTOR, and mTOR activates aerobic glycolysis, the defining feature of cancer. Interrupting the vicious circles of cancerization is essential for the survival of the organism. There are many substances that can inhibit the inflammatory, degenerative processes acting at multiple levels, and these substances tend to be synergistic, so that a great number of substances can be safely used at the same time. This kind of supportive therapy has nothing in common with the ruling paradigm of cancer treatment—it is reinforcing the organism’s state of health, rather than attacking the disease of cancer.

Things that favor the production of CO2 rather than lactate include CO2, sodium bicarbonate and acetazolamide, flavonoids such as apigenin and fisetin (Constantin, et al., 2010; Shan, et al., 2017; Zhao, et al., 2021), thyroid hormone, progesterone, and lidocaine (Karniel and Beitner, 2000), Some of the things that inhibit mTOR include caffeine (Zhou, et al., 2010), aspirin (Din, et al.,2012), lidocaine (Zhang, et al., 2021), vitamin D (Al-Hendy, et al., 2016), and flavonoids. Things that increase intracellular calcium tend to increase mTOR (Amemiya, et al., 2021). Radiation (ultraviolet and ionizing radiation) increases mTOR, and this effect can be reduced by flavonoids (Bridgeman, et al., 2016). mTOR is one of the factors in the radiation bystander effect, which is responsible for prolonged damage of other unirradiated cells in the organism (Verma and Tiku, 2022)."
 
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Blossom

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Thank you so much for taking the time to share this information @Limon9.
 

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joaquin

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This correlates with my own experience while I was doing a couple of years of strict intermittent fasting. My muscles firmed up with no exercise. IF is said to down regulate mTor.
 

Blaine

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Great info, thank you.

I've been taking low doses of rapamycin for for just under a month now, as I detailed in the other thread, and my strength in the gym has been excellent as of late. Not that I think the rapa is necessarily causing an increase in strength, but it certainly doesn't seem to be hurting.
 

Normal Human

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@Limon9
Thanks for posting this nice study. I don't really get the David Sinclair reference here? Isn't he all about inhibiting mTOR, and doesn't the study confirm this to be beneficial at least in this narrow context? Am I missing something?
 

Motorneuron

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Other inhibitors through drugs and supplements?
 
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Limon9

Limon9

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@Limon9
Thanks for posting this nice study. I don't really get the David Sinclair reference here? Isn't he all about inhibiting mTOR, and doesn't the study confirm this to be beneficial at least in this narrow context? Am I missing something?
I just don't think a pet David Sinclair would be fun. He looks a bit ghostly.
 

joaquin

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Sinclairs speaks so softly. He may float away like an helium balloon.
 

Blossom

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I just don't think a pet David Sinclair would be fun. He looks a bit ghostly.
I don’t get the impression that there’s a lot of sun loving going on in longevity circles.
 

Blossom

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Limon9

Limon9

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This guys says his body temperature is down 3 degrees and he also avoids the sun. I’d certainly not enjoy his program!
Bryan takes rapamycin. Bryan also washes down iron and ascorbic acid together at 5AM for maximal bioavailability. Bryan is not smart. I think the sheer amount of medical stressors will cause premature death, with frequent injections and biopsies taking a severe toll on the organism. He has turned himself into a lab animal, with all the neglect and sterility.
 

Blossom

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Bryan takes rapamycin. Bryan also washes down iron and ascorbic acid together at 5AM for maximal bioavailability. Bryan is not smart. I think the sheer amount of medical stressors will cause premature death, with frequent injections and biopsies taking a severe toll on the organism. He has turned himself into a lab animal, with all the neglect and sterility.
Yes, I don’t think he will achieve what he’s set out to do but maybe rapa will help a little.
 
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