5 New Studies on Rapamycin / MTOR

#1

From @Charles_Richardson

Five new rapamycin studies, the last one showing a negative effect.

High fat diet-induced obesity leads to depressive and anxiety-like behaviors in mice via AMPK/mTOR-mediated autophagy

Takeaway: Mice fed a high-fat diet for 8 weeks developed a number of metabolic disorders, including obesity and hyperlipidemia. In addition, the mice exhibited depression and anxiety-like behaviors. “After treating with the mTOR inhibitor rapamycin, autophagy and BDNF levels were elevated. The number of activated microglia and astrocyte and pro-inflammation levels were reduced. Besides, rapamycin can also reduce the body weight and serum lipid level in high-fat feeding mice. Depressive and anxiety-like behaviors were also ameliorated to some extent after rapamycin treatment.”

Note: I’d like to know the composition of the high-fat diet. Was it just high-fat or also high carbohydrate? The full paper is behind a paywall.

Metabolic and immunomodulatory control of type 1 diabetes via orally delivered bile-acid-polymer nanocarriers of insulin or rapamycin

Takeaway: When they encapsulated insulin in nanoparticles it significantly improved the effectiveness in animals with established Type 1 diabetes. When they encapsulated rapamycin, it delayed the onset of diabetes by chemically-induced pancreatic inflammation.

Rapamycin attenuates depression and anxiety-like behaviors through modulation of the NLRP3 pathway in pentylenetetrazole-kindled male Wistar rats

Rapamycin delayed the development of kindling and the onset time of seizures. Rapamycin administration reduced immobility time in the FST, exerting antidepressant-like activity. In the EPM test, rapamycin produced an anxiolytic-like effect. In addition, rapamycin increased the catalase and superoxide dismutase levels in the serum and significantly decreased the gene expression of I11b and Nlrp3 compared to the PTZ group.

Conclusion: Our results showed that the inhibitory effect of mTOR inhibitor (rapamycin) on reactive oxygen species production during NLRP3 inflammasome activation could bring about behavioral alterations in anxiety and depression.

mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats

Rapamycin attenuated the increment in the expression of tumor necrosis factor-α and interleukin-1β, the inducible nitric oxide synthase, gp91phox, and p47phox in addition to nitrite levels elicited by LPS in tissues or sera. Concomitantly, rapamycin treatment reduced microglial activation, brain expression of caspase-3, and Bcl-2-associated X protein while it increased expression of B cell lymphoma 2 induced by LPS. Overall, this study supports the hypothesis that mTOR contributes to the detrimental effect of LPS-induced systemic inflammatory response associated with neuroinflammation via IκB-α/NF-κB/HIF-1α signaling pathway.

Here’s a study showing the negative effects of rapamycin on Alzheimer’s.

Astaxanthin Improved the Cognitive Deficits in APP/PS1 Transgenic Mice Via Selective Activation of mTOR

Abstract

Astaxanthin (Ast) is an effective neuroprotective and antioxidant compound used to treat Alzheimer’s disease (AD); however, the underlying in vivo molecular mechanisms remain unknown. In this study, we report that Ast can activate the mammalian target of rapamycin (mTOR) pathway in the 8-month-old APP/PS1 transgenic mouse model of AD. Our results suggest that Ast could ameliorate the cognitive defects in APP/PS1 mice by activating the mTOR pathway. Moreover, mTOR activation perturbed the mitochondrial dynamics, increased the synaptic plasticity after 21 days of treatment with Ast (10 mg/kg/day), and increased the expression of Aβ-degrading enzymes, mitochondrial fusion, and synapse-associated proteins and decreased the expression of mitochondrial fission proteins. Intraperitoneal injection of the mTOR inhibitor, rapamycin, abolished the effects of Ast. In conclusion, Ast activates the mTOR pathway, which is necessary for mitochondrial dynamics and synaptic plasticity, leading to improved learning and memory. Our results support the use of Ast for the treatment of cognitive deficits. Graphical abstract In summary, Ast ameliorates cognitive deficits via facilitating the mTOR-dependent mitochondrial dynamics and synaptic damage, and reducing Aβ accumulation. This model supports the use of Ast for the treatment of cognitive deficits.

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New interview with Rich Miller (ITP researcher)
#2

To me, that last study makes sense in the way that we know mTOR does some good things in muscle and brain (after all, exercise stimulates mTOR in muscle/brain and exercise has notable benefits in both, and we do need “building” phases to maintain the structures and tissues). It reinforces the need to cycle on/off such that we have periods of no mTOR inhibition from rapamycin (or at least minimal inhibition towards the end of a 1 week/2 week cycle, perhaps similar to a fast where we inhibit mTOR during the fast to maximally recycle cellular garbage, but then many of the benefits of the fast come after the fast upon refeeding (stem cell replenishment, etc). On the other hand, it seems like most research does continuous rapa dosing rather than periodic dosing, so maybe the “growth phase” is unnecessary and/or continues to happen via redundant pathways (as in muscle growth from resistance exercise while taking rapa).

Still, we’d have to compare this with other research, if it exists (and in the same strain of mice?). I don’t have time to do a pubmed search now, but what happens when you give the same strain of mice rapa alone? Matt Kaeberlein thinks there’s huge potential for rapa against Alzheimer’s disease, and I’m sure he didn’t get that opinion out of thin air.

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#3

I always look at mouse high-fat diet studies with dubiety since the mice usually become obese and highly inflamed. Many people on HFLC lose weight and decrease inflammation. Perhaps it is the specific mouse diet they feed (soybean oil? high carb also?).

I’m not surprised by the type 1 diabetes onset-delay that rapamycin causes. Inflammation of the pancreas, either caused by macrophages or as a cause of macrophagic invasion of the pancreas, is a key part of the disease onset. Rapamycin will reduce that inflammation.

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#4

preliminary evidence that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that contribute to depression relapse after ketamine administration

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#5

Agree about the high fat diet. A lot of times they never specify the fats, and they do not feel the need too. The general mouse diet is shit, basically the equivalent of the western diet.