Rapamycin

links: reference:

• For anyone worried about losing their gains on rapamycin: mTOR Inhibition Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt https://www.geneticlifehacks.com/rapamycin-mtor-and-your-genes/ 11-10-2021

Rapamycin (Sirolimus) #

Was originally discovered in the soil of Easter Island in 1975 from Streptomyces tsukubensis. Wtf. And that molecule: a macrolide.

• It inhibits Candida and other fungal infections, but it supresses the immune system by inhibiting activation of T Cells and B cells via reducing their sensitivity to IL-2.

  • Althoug, these things seem to have increased serum concentrations following treatment.

• Treatment with TOR-I results in a decrease in testosterone level, and an opposite increase in LH. Moreover, spermatogenesis seems to be disrupted by TOR-I and FSH levels are increased. R

• Independently increases PSD-95, NR2B expression, and glutamate recycling

• High levels in the periphery promote Beta Cell rest (somehow less sensitive to glucose)

• [Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system]

  • Many beneficial effects are via inhibiting mTORC1, and mTORC2 for the negative side effects.

• Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice

  • Decreases mTORC1, but not mTORC2.

• Chronic Rapamycin Treatment Causes Glucose Intolerance and Hyperlipidemia by Upregulating Hepatic Gluconeogenesis and Impairing Lipid Deposition in Adipose Tissue

• Fasting and rapamycin: diabetes versus benevolent glucose intolerance

  • This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes.

• Rapamycin: one drug, many effects

• Induces Erythropoietin resistanec in kidney transplant patients - levels increase.

• Intranasal produces 25x+ brain concentrations with 1% the systemic exposure.

• Effects of Rapamycin on Insulin Brain Endothelial Cell Binding and Blood-Brain Barrier Transport

  • Acute did not affect BBB binding but chronic insigifnificantly slowed BBB transport. It slightly raised serum concentration of insulin and:
  • 

• Rapamycin for longevity: opinion article this is pretty informal

  • It can be regarded not as an “immunosuppressant” so much as reducing hyperimmunity. That’s what it’s used for in organ transplants
  • Whether this is by insulin or nutrients, overactivation of (mTOR->)S6K inhibits insulin signaling,
    • [Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1]
      • Amino acids mediate mTOR activation via class 3 PI3K (aka hVps34), as opposed to class 1. Infusion of Amino Acids leads to S6K1 activation and inhibition of insulin-induced class 1, leading to insulin resistance.
      • IRS-1 downregulatory phosphorylation is always by means of JNK??
        • A central role for JNK in obesity and insulin resistance
          • Absence of JNK results in decreased adiposity, significanty improved insulin ressistance and recepto signalling capacity.

  • Balancing Akt with S6K implications for both metabolic diseases and tumorigenesis #

  • Ketogenic diets can cause symptoms of starvation psuedodiabetes (SPD)

• Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2

Disease #

• One thing to keep in mind about it potentiating Amyloid β in some pathologies is that the stuff may be protective!
• Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome
  • Preventing systemic alterations avoids imunosuppresant effects in ther periphery. But the brain?
• Rapamycin Activates Mitophagy and Alleviates Cognitive and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease Get access Arrow
  • Effectively alleviates defecits of plasticity in APP models, promoting lysosome-mitophagosome fusion. Impedes Cytochrome C-mediated apoptosis, etc.
• Restoration of aberrant mTOR signaling by intranasal rapamycin reduces oxidative damage: Focus on HNE-modified proteins in a mouse model of down syndrome
  • Oxidation of Arginase-1 and PP2A play a part in brain damage associated with synaptic transmission failure and NFTs.
  • InRapa reduced ARG-1 protein-bound HNE and rescues its activitiy.
• mTOR Attenuation with Rapamycin Reverses Neurovascular Uncoupling and Memory Deficits in Mice Modeling Alzheimer’s Disease
  • Restores eNOS-dependent cerebrovascular function funcions in AD models. (Since mTOR inhibits eNOS)
• Intranasal administration dring any point in the lifespan, besides late stage alzheimers, where it increases the toxicity of Amyloid β, will suppress its formation and disease progression and increase memory/cognition/mood.
• Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice
  • IGF-1 inhibition mitigates MPTP-induced neurological dysfunction.

Supplementation #

Stable as powder at room temp for 6 years. Its half life is basically a good 24 hours.

• 1mg every day or so. Intranasal in MCT oil (which has been done in studies - C8 is contentious) or just straight up. Dissolving it greatly increases efficacy according to Debonaire - makes sense.
• Apparently doses under 3mg have dramatically increased bioavailability
• Transcutol for cosmetic, topical application.
  • Balyhoo does 4oz of CeraVe cream, .5-1mL transcutol and 3-6mg rapamycin.