Neurodegenerative disease is the 5th leading cause of death in individuals over the age of 65. Prior to that though, the demand and desire for optimal cognitive performance requires consistent pursuit, and begs the question: what can I do to keep my brain functioning optimally across the lifespan? This newsletter will focus on two main kinks in the chain that can disrupt the optimal functioning of the nervous system, and then strategies that can be employed to correct or delay them.
Possibly the most important surrogate we have for the health of the brain comes from the cardiovascular system. If the heart, blood vessels, and control centers for activity are all uniform in their communication and efforts, then oxygen, nutrients, and feedback molecules will make their way into the brain and provide for its needs. I like to break down what ‘risk’ in the cardiovascular system looks like with three categories: lipoprotein profile, endothelial function, and inflammation. Any of you that have reviewed labs with me have heard this story, if not, ask me next time I see you!
The lipoprotein profile encompasses the classic understanding of cholesterol as a player in hardening arteries (atherosclerosis), as well as the deeper nuance of how cholesterol is transported in various kinds of vehicles. Cholesterol is not the enemy, or the causative agent in heart disease, but it is unquestionably necessary for plaque to build up in arteries. So, when evaluating risk through this lens, the weight I place on the lipoprotein profile greatly depends on the other two categories of inflammation and endothelial function, and seldomly does it need to be addressed in isolation. Still, as cholesterol levels the vehicle (particle) number increases, there is a concern based on the individual ability to clear them not only from circulation at large but also to metabolize them in the brain. Particle number is a better indicator of lipoprotein mediated risk due to receptor-complex dynamics that make smaller particles less likely to be cleared or metabolized, and because of that they stay in the blood for a longer relative time and that increases their chance of getting oxidized and finding their way into an artery wall or in brain cells. Uptake of too much cholesterol into a cell causes lipotoxicity and generally puts the brakes on normal cellular function, which isn’t something you want for optimal brain health.
Figure 1: Impact of LDL particle size and number at the same level of LDL cholesterol.
The endothelium is the innermost layer of cells in any given blood vessel, just one single-cell layer thick. On that layer there is another important layer of ‘hairs’ called the glycocalyx, which is made up of protein-carbohydrate chains (glycoproteins) that create a sort of jelly like surface. This jelly is where all of the magic happens – on this micro-stage, the balance of blood pressure, electrolytes, nutrient transport, immune system activation, and so many other functions are influenced by the health of the glycocalyx. So, what causes problems for the glycocalyx? Many of the same risk factors for dementia: smoking (due to inflammatory nature of inhaling combusted material, independent of product smoked), high blood pressure, high blood sugar, sedentary lifestyle, overweight, etc. all deteriorate the glycocalyx and disrupt the ability for the vessels to respond appropriately to changes in blood pressure. This ultimate reduction in vascular compliance is what leads to inflammatory changes, white blood cell infiltration, poor tissue oxygenation, and other problems that are permissive to a gradual development of atherosclerosis, as well as cognitive decline.
Figure 2: (a) Transmission electron microscopy visualizing the glycocalyx of a capillary. (b) Longitudinal view of a capillary that reveals the ‘exclusion zone’ between the endothelial wall and the red blood cells. [From Reitsma, S et al. (2007). The endothelial glycocalyx: composition, functions, and visualization. Pflugers Archiv : European journal of physiology, 454(3), 345–359. https://doi.org/10.1007/s00424-007-0212-8]
Inflammation gets a bad rap, but it isn’t all bad. It’s necessary for the initiation of tissue repair and resolution of tissue damage. However, chronic inflammation from health conditions like arthritis, autoimmunity, diabetes, overweight, fatty liver, and poor lifestyle habits surrounding sleep, nutrition, exercise, and stress management all contribute to the inability to finally resolve and close the inflammatory loop. The ability for inflammatory mediators to promote endothelial dysfunction and also permit cholesterol oxidation and deposition in to the vasculature is what makes it particularly worrisome, but it’s very difficult to parse out which one of these categories rears its head first. This is why we have to look at all of them in context.
Food and fluid intake provide our systems with the raw materials to keep us moving forward. For now, we will only venture into the final stages of the metabolic process. However, it’s important to acknowledge that by skipping everything from intake selection, timing, digestion, absorption, etc. that there are far more opportunities to improve metabolism as such before addressing it specifically. Mitochondria, which are the organelles within cells that are generally responsible for energy generation and signaling nutrient status, have been in the spotlight for a while now when it comes to their involvement in most chronic disease states. After all, if a cell can’t function due to an energy crisis, it will undergo a self-destructive process known as apoptosis (second ‘p’ is silent). If you extrapolate that across an organ like the brain, it’s no wonder that protecting these little factories as at the frontline of preventative neuroscience.
Figure 3: (A) General schematic and microanatomy of a mitochondrion. (B) The electron transport chain that is responsible for taking energy substrates derived from the metabolism of carbohydrates and/or fat and using them to shuttle energy into a usable, chemical intercessor - ATP (adenosine triphosphate).
Glucose and fatty acid-derived ketones are the main sources of energy for the mitochondria to break down and then redistribute for cellular functions. The brain as an organ uses around 20% of the body’s total energy requirements, an anatomically disproportionate amount as it only accounts for 2% of body mass. This speaks to the inordinate amount of work done by the brain in our day-to-day life. With age, head injury, chronic illness, obesity, and really any deviation from normality the ability for the individual cells in the brain to utilize fuel, glucose in particular, decreases. This is one of the reasons why a ketogenic diet, which essentially forces a shift in metabolism to use primarily ketones instead of glucose, has been put forward as a viable therapeutic option to mitigate or reverse cognitive decline, brain fog, and other cognitive challenges. It also has the additional benefit of dramatically lowering the hormone insulin, which is a major contributor to energy dysregulation as a result of overeating or just eating too much sugar/processed carbohydrates. As such, a significant strategy for mitigating mitochondrial dysfunction and the downfall of cognitive capacity is caloric restriction – the practice of reducing energy intake from food. This practice can take many different forms, from full-on water fasting to time-restricted eating. Normal diet can also just be manipulated to minimize carbohydrates or add ketone supplements. Various medications and supplements can also be used to facilitate better mitochondrial health and metabolism. But what else?
A critical point to remember is that energy is, at its core, just the movement of charges – and it is up to the system working with those charges to turn them into something useful. Ever wonder why we can’t just lay out and grow like a weed? Light is in fact a ubiquitous source of energy, but it is not just a source for plants! Indeed, it has been known since the 1960s that light has properties that can heal human tissue, and the mechanisms have since been elucidated. Certain wavelengths of light can actually be captured by the mitochondria and used just like calories from food. Obviously, there are barriers to how useful this can be – strength of the light source, the skin, dissipation of the energy as heat, and so on. That’s why the invention of the laser in the 60s precluded the discovery of light’s healing potential – because it provided adequate power to sufficiently ‘dose’ light in a particular wavelength/color. In the last twenty years there has been a substantial amount of research into the ways that light can influence biological processes, which has developed into the field of photobiomodulation. The fruit of this field is expansive and touches on many different health conditions and ailments, likely due to the target being mitochondrial function. The closer a healing modality hits a core dysfunctional node in a complex-system, the larger the impact. So, if poor bioenergetics is a component of cognitive decline, then light therapy is certainly in the toolkit to prevent and/or treat it.
The purpose of this blog was to discuss the contribution of blood flow and metabolism as broad categories to the development and mitigation of cognitive decline. While this is not an exhaustive treatise on the subjects, I hope it is at least a starting point to engage more conversation on the topic and encourage individual exploration and research.