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Mammalian target of rapamycin (mTOR) and insulin-like growth factor-1 (IGF-1) are proteins that play critical roles in two major growth pathways in the human body. The intake of amino acids regulates these two pathways, which must remain in balance to facilitate muscle growth and repair. Overactivity of mTOR and IGF-1 has been implicated in contributing to aging and diseases associated with aging, such as cancer. In this clip, Dr. Peter Attia explains the interrelated mTOR and IGF-1 growth pathways and the delicate balance required to limit accelerated aging.
Rhonda: So just for people that don't know what mTOR is, can you explain why that's really important?
Peter: Yes. So there are probably, depending on who you talk with, I would say there are two or three major growth pathways in the body that are, kind of, responsible for growth both in the positive sense and in the pathologic sense. The two that I focus on the most are the IGF pathway and the mTOR pathway. Now, mTOR stands for mammalian target of rapamycin. I think for the sake of time I will not tell my favorite story, which is a story that is both the discovery of rapamycin and perhaps more interestingly the elucidation of how it worked. But suffice it to say the compound rapamycin was identified first long before a really amazing guy named David Sabatini as a PhD student at Hopkins in 1993, 1994 as a side project in a lab made the discovery that this thing, rapamycin, was actually working by inhibiting a protein complex of which TOR, target of rapamycin, as it became named was the central piece.
We now know today that it can form onto two complexes. One is called mTOR complex 1 or mTORC1 and the other is mTOR complex 2, mTORC2, and we also know that it exists in different tissues and it has different activities in different tissues. Like most things in the body, too much or too little is a bad thing. So if you have no mTORC1, for example, in your muscles, you'd wither away and that would be a debilitating condition. In fact, for people with muscular dystrophy one of the things you want to do is figure out how to alter that pathway. But similarly, we know that overactivity is predisposing us to aging and, of course, certain diseases of aging like cancer.
Rhonda: So for people that...you know when Peter mentioned that if you don't have any mTORC1 activity you might cause muscle wasting, well, that's because mTOR does a very important role in protein synthesis. And what's very interesting is that both the two pathways that you mentioned in being evolved in aging, mTOR and IGF-1, IGF-1 actually increases mTOR activity so you know they're in this...
Peter: Yeah. These aren't independent pathways, yeah.
Rhonda: Right. And what's also very interesting is that they're both regulated by amino acid intake, right?
Peter: Yes.
Rhonda: So IGF-1 is also a growth factor that you do need as well. So it's one of those things where you don't have any IGF-1, well you're going to be in trouble. I mean, there's a lot of positive things about IGF-1, muscle growth, muscle repair, neuronal growth. But too much IGF-1 also can allow damaged cells to continue growing.
The first enzyme in the electron transport chain. Complex I (also known as NADH Coenzyme Q oxidoreductase) is found in the mitochondria of eukaryotes and the plasma membranes of some bacteria. It couples the oxidation of NADH and the reduction of ubiquinone to provide the electrical gradient necessary to produce ATP. Complex I and its partner enzyme, complex III, are the primary sites of reactive oxygen species production in mitochondria. Mutations in complex I are associated with many disease conditions, including Parkinson's disease and Alzheimer's disease.
A naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and differentiation. Growth factors typically act as signaling molecules between cells. Examples include cytokines and hormones that bind to specific receptors on the surface of their target cells.
One of the most potent natural activators of the AKT signaling pathway. IGF-1 stimulates cell growth and proliferation, inhibits programmed cell death, mediates the effects of growth hormone, and may contribute to aging and enhancing the growth of cancer after it has been initiated. Similar in molecular structure to insulin, IGF-1 plays a role in growth during childhood and continues later in life to have anabolic, as well as neurotrophic effects. Protein intake increases IGF-1 levels in humans, independent of total caloric consumption.
An enzyme that participates in genetic pathways that sense amino acid concentrations and regulate cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. mTOR integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids. It plays key roles in mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain. It is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers. mTOR has two subunits, mTORC1 and mTORC2. Also referred to as “mammalian” target of rapamycin.
Rapamycin, the drug for which this pathway is named (and the anti-aging properties of which are the subject of many studies), was discovered in the 1970s and is used as an immunosuppressant in organ donor recipients.
A compound initially developed as an antifungal agent. This use was abandoned, however, when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit one of the complexes of mTOR (mTORC1). Rapamycin has since shown interesting lifespan extension properties in animals.
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