Inflammation and its role in Alzheimer's and Parkinson's | Tim Ferriss
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A growing body of scientific evidence suggests that there is a correlation between Alzheimer's disease, insulin resistance, and inflammation. Inflammation, a downstream consequence of insulin resistance, promotes the formation of reactive oxygen species and other damaging molecules, which can enter the brain via the lymphatic system. In this clip, Tim Ferriss describes his efforts to mitigate the risk of Alzheimer's disease by managing his insulin levels using the ketogenic diet.
- Rhonda: So you mentioned that you have Alzheimer's and Parkinson's on both sides of your family. So I'm curious. Has this changed your diet, your lifestyle?
- Tim: Oh, definitely.
- Rhonda: How so?
- Tim: Well, the Parkinson's maybe a bit less so. But on the Alzheimer's side, I have just looked at it like some scientists look at it, which is as brain diabetes. I think that's a helpful, simplified way of looking at it. You I'm sure know much more about this than I do. But there's the prevalent theory of why I say Alzheimer's has the effects it has on cognitive performance or, in this case, degradation or otherwise. For a long time, I was like, "It's the plaques, kind of like, plaques, it's this, it's that." And it turns out to be more complicated than that because you have people who have massive tangles of plaques but they seem asymptomatic. They're 100 and x years old but they still play the piano every day or whatever it may be. Great movie called "The Lady in Number Six" as a side note, 109 year old piano player. It doesn't get into Alzheimer's. But where it has led me is just to be more cognizant of insulin, things that are related to and/or affect insulin. To look at not only ketosis but fasting, to look at cyclical ketogenic diets and so on, targeted ketogenic diets where you're timing carbohydrate intake near workouts, which a lot of endurance athletes do so they can consume like 300 or 400 grams of carbohydrates in a day and still say in ketosis, pretty wild stuff.
- Rhonda: Wow.
- Tim: But what I start wondering, for instance in the case . . . because if I take supplemental MCTs or even beta-hydroxybutyrate, and there are tasty ways to do it now. I think it's Patrick Arnold and Prototype Nutrition. They have a . . . well, people say KetoCaNa, C-A-N-A, but it tastes like Gatorade, basically and it's beta-hydroxybutyrate. If I take that when I'm not, say, above 0.6 millimolars ketones, I don't feel much. But when my body has shifted into that fat-adapted state, I do feel it. Off hand, I don't know what my status is from the genetic standpoint. But what's been very interesting say for me when I'm thinking about it from the standpoint of brain diabetes is it's not just enough . . . and this comes back to how people, if they focus solely on the millimolar concentration, they can fool themselves because you can be in non-nutritional ketosis but consuming a lot of supplemental beta-hydroxybutyrate and be like, "Oh, I'm killing it. I'm at two millimolars concentration." Whereas I'm also taking my glucometer readings precisely because I don't want to be running at 120 glucose and dismiss that. If I wake up and I'm fasting 120 glucose each morning, something funny is going on that I need to pay attention to. Whereas if I drop into nutritional ketosis and let's just say I'm at 74, 80, even lower and I have high millimolar, my response to at that point supplemental beta-hydroxybutyrate is totally different.
- Rhonda: That's interesting.
- Tim: Anyway, I'm still kind of a novice in this space, but it's interesting stuff.
- Rhonda: So the cyclical ketogenic diet is something that you do now practicing. And that's, you think, as a consequence of thinking of Alzheimer's like type 2 diabetes. It's really interesting, that connection between insulin resistance and type 2 diabetes. I don't know if you measure any blood biomarkers or if you're aware of this, but there is a biomarker that is present in blood that's called insulin-like receptor 1, IRS1 and it's recently, very, very recently been shown to be a diagnostic for Alzheimer's 10 years in advance with 100% accuracy.
- Tim: [inaudible 00:19:13]
- Rhonda: So I don't think it's like something that . . . well, you can modulate. So 10 years in advance is a long to change.
- Tim: Just by the way, you are fucked.
- Rhonda: You're screwed.
- Tim: Good luck with that. Yeah.
- Rhonda: It's inactive.
- Tim: IRS1 using [inaudible 00:19:32]
- Rhonda: Yes. What's interesting to me is I typically think of the connection between type 2 diabetes and insulin resistance and Alzheimer's as the connection between inflammation and a nerve degenerative disease because inflammation, we've now recently found that the lymphatic system connects directly to the brain. The lymphatic system is what carries blood cells, cytokines, inflammatory molecules and inflammation is a major, major downstream consequence of being insulin resistance. Inflammation causes reactive oxygen species, things that damage all sorts of cells. But the inflammatory molecules get into the brain and they do start causing all sorts of immune type reactions and aggregation of more amyloid beta plaques and all that stuff starts to happen more quickly. So I think that the inflammation . . . because if you look at people, type 2 diabetics, being type 2 diabetic, you have a two-fold roughly increased chance of getting Alzheimer's. But if you look at people with Alzheimer's, a small percentage of them have type 2 diabetes. So I think that it's not just the insulin resistance. I think there are the consequences, the byproducts, the indirect things that are associated with . . .
- Tim: 100%
- Rhonda: . . . type 2 diabetes that lead to Alzheimer's.
- Tim: Yeah. It's rarely, if ever, just one thing. I think humans strive for simplicity and in sort of a sea of noise, especially if you're not a trained scientist, it's like, "God, thank goodness somebody gave me a definitive answer. Now I know A causes B." It's like, okay, maybe as a temporary holding bay, we can use that answer. But it's probably not right.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
A chemical produced in the liver via the breakdown of fatty acids. Beta-hydroxybutyrate is a type of ketone body. It can be used to produce energy inside the mitochondria and acts as a signaling molecule that alters gene expression by inhibiting a class of enzymes known as histone deacetylases.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
A broad category of small proteins (~5-20 kDa) that are important in cell signaling. Cytokines are short-lived proteins that are released by cells to regulate the function of other cells. Sources of cytokines include macrophages, B lymphocytes, mast cells, endothelial cells, fibroblasts, and various stromal cells. Types of cytokines include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
A type of signaling protein. IRS-1 is a key player in the insulin/PI3K/Akt and Erk/MAP kinase pathways. Mutations in the IRS-1 protein are associated with type 2 diabetes and susceptibility to insulin resistance.
A physiological condition in which cells fail to respond to the normal functions of the hormone insulin. During insulin resistance, the pancreas produces insulin, but the cells in the body become resistant to its actions and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level.
A diet that causes the body to oxidize fat to produce ketones for energy. A ketogenic diet is low in carbohydrates and high in proteins and fats. For many years, the ketogenic diet has been used in the clinical setting to reduce seizures in children. It is currently being investigated for the treatment of traumatic brain injury, Alzheimer's disease, weight loss, and cancer.
A class of saturated fats. Medium-chain triglycerides are composed of medium-length fatty acid chains (six to 12 carbons long) bound by a glycerol backbone. They occur naturally in coconut oil, palm oil, and butter, but they can also be synthesized in a laboratory or food processing setting. Evidence suggests that MCT therapy improves cognitive function in older adults with Alzheimer's disease.[1] Examples of MCTs include caprylic acid (C8), capric acid (C10), and lauric acid (C12).
- ^ Juby, Angela G.; Blackburn, Toni E.; Mager, Diana R. (2022). Use Of Medium Chain Triglyceride (MCT) Oil In Subjects With Alzheimer's Disease: A Randomized, Double‐Blind, Placebo‐Controlled, Crossover Study, With An Open‐Label Extension Alzheimer's & Dementia: Translational Research & Clinical Interventions 8, 1.
A neurodegenerative disorder that affects the central nervous system. Parkinson’s disease is caused by destruction of nerve cells in the part of the brain called the substantia nigra. It typically manifests later in life and is characterized by tremors and a shuffling gait.
Oxygen-containing chemically-reactive molecules generated by oxidative phosphorylation and immune activation. ROS can damage cellular components, including lipids, proteins, mitochondria, and DNA. Examples of ROS include: peroxides, superoxide, hydroxyl radical, and singlet oxygen.
A related byproduct, reactive nitrogen species, is also produced naturally by the immune system. Examples of RNS include nitric oxide, peroxynitrite, and nitrogen dioxide.
The two species are often collectively referred to as ROS/RNS. Preventing and efficiently repairing damage from ROS (oxidative stress) and RNS (nitrosative stress) are among the key challenges our cells face in their fight against diseases of aging, including cancer.
Abnormal aggregates of hyperphosphorylated tau, a protein found in the brain. Tau tangles are associated with traumatic brain injury and chronic traumatic encephalopathy and are one of the defining characteristics of Alzheimer’s disease. They inhibit normal brain function, and the degree of cognitive impairment in diseases such as Alzheimer’s is significantly correlated with their presence.
A metabolic disorder characterized by high blood sugar and insulin resistance. Type 2 diabetes is a progressive condition and is typically associated with overweight and low physical activity. Common symptoms include increased thirst, frequent urination, unexplained weight loss, increased hunger, fatigue, and impaired healing. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, diabetic retinopathy (and subsequent blindness), kidney failure, and diminished peripheral blood flow which may lead to amputations.
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