The Gut-Muscle-Immune Axis: How Mitophagy Rewires Your Body for Longevity

**Dr. Gabrielle Lyon** (0:00)
How can someone tell if their immune system is healthy?

**Dr. Anurag Singh** (0:04)
A lot of doctors, they only think about the immune system with one marker, C-reactive protein. That's all they do, and they say, oh, you're inflamed. Now, what happens with aging is that sort of your total leukocyte counts go down, and your total lymphocyte counts go down. Lymphocytes being sort of these sentinels, policemen or elite forces of the immune system. Inclusion body myositis happens classically in a 60, 65-year-old. The two key hallmarks in this disease, shot mitochondria, damaged mitochondria, and damaged immune cells. So I do believe that if we can tackle immune aging earlier, we can keep all the other organs healthier much longer. For many years, things like Alzheimer's were basically protein deposits in the brain. Now it turns out that all the immune cells, the microglial cells and all the immune cells that they can actually cross, they are in the super dysregulated state, they are in a super inflamed state, and now that whole field is turning out that actually Alzheimer's is an inflammatory disease.

**Dr. Gabrielle Lyon** (1:10)
Placebo affects 30%. So for example, if I say, take this pill, you're going to get better. Maybe there's a 30% chance that that works.

**Dr. Anurag Singh** (1:18)
That will work for muscle immune system you cannot deceive.

**Dr. Gabrielle Lyon** (1:21)
Wow. Dr. Anurag Singh, it's always a pleasure to see you.

**Dr. Anurag Singh** (1:33)
Lovely to be back.

**Dr. Gabrielle Lyon** (1:34)
Alzheimer's disease of skeletal muscle.

**Dr. Anurag Singh** (1:37)
It doesn't get a lot of, let's say, visibility, but one of the things that happens with aging in the skeletal muscle is sort of this muscle immune dysfunction, right? So people probably need to be aware that a lot of immune cells tend to hang around in the skeletal muscle as they do peripherally in most organs. They're kind of the sentinels watching out where the danger is. These immune cells, they kind of become dysregulated. With aging, muscle has become dysregulated. So you get this sequelae of like double whammy where your muscle is, mass is going down, your strength is going down, and you have this immune dysregulation. What that leads to is something called inclusion body myositis. So it's almost like you're seeing these protein deposits happen with aging in the skeletal muscle, just like in the brain.

**Dr. Gabrielle Lyon** (2:25)
It's crazy. You and I were chatting before because sarcopenia decreased muscle mass and function that we think about in an aging population. There's probably a phenotypic expression of youth, right? Especially now with the use of GLP-1s, potentially we're accelerating aging. Obviously, there might be some positives to that. But then this idea that, number one, that there's a lot of immune cells in the skeletal muscle, frankly, I hadn't thought much about it. Secondarily, this idea that skeletal muscle can become dysfunctional beyond decreased muscle mass strength, mitochondria. But what you were talking about is SIBM, which is this sporadic inclusion body myositis. People think that that's probably rare, but there's a lot of likely myopathies or diseases or inflammatory effects of skeletal muscle.

**Dr. Anurag Singh** (3:19)
Absolutely. As you said, over the human lifespan, there's a lot of myopathy. Some happen in kids, some happen in middle years of life. This is sporadic inclusion body myositis. Happens classically in a 60, 65 year old. They'll come to you in the clinic. They are mostly misdiagnosed for a long time because people tend to think, oh, it's sarcopenia or presarcopenia. It's just, you know, your your mass is melting away. Your strength is going down until the acceleration is so fast. And in probably a year from the first time somebody of the 65 year old says, oh, I can't get up properly from my chair. I can't walk. They do a biopsy and they found the two key hallmarks in this disease. Shot mitochondria, damaged mitochondria and damaged immune cells.

**Dr. Gabrielle Lyon** (4:06)
Oh, well, hopefully we're going to talk a lot about how do we keep those healthy? And perhaps again, I don't know if they know what the root cause of this sporadic inclusion body myositis is, right? They don't. They think it's an autoimmune dysregulation.

**Dr. Anurag Singh** (4:20)
It is. It's really an autoimmune condition of the muscle. And it's also an age related condition of the muscle. A lot of research has happened in the recent past. Still a rare disorder, but I believe it's misdiagnosed and underdiagnosed.

**Dr. Gabrielle Lyon** (4:34)
I hope you're wrong. I usually don't hope you're wrong, but I hope you're wrong on this. You know, one of the reasons I love having you on is you are actually involved in research and you're also a physician.