November 28th, 2022

In a continuation from last week, we are going to dive deeper into this research. From The Journals of Gerontology: "Low skeletal muscle mass is associated with cognitive impairment and dementia in older adults. This review describes the possible underlying pathophysiological mechanisms: systemic inflammation, insulin metabolism, protein metabolism, and mitochondrial function. We hypothesize that the central tenet in this pathophysiology is the dysfunctional myokine

secretion consequent to minimal physical activity. Myokines, such as fibronectin type III domain containing 5/irisin and cathepsin B, are released by physically active muscle and cross the blood–brain barrier. These myokines upregulate local neurotrophin expression such as brain-derived neurotrophic factor (BDNF) in the brain microenvironment. BDNF exerts anti-inflammatory effects that may be responsible for neuroprotection. Altered myokine secretion due to physical inactivity exacerbates inflammation and impairs muscle glucose metabolism, potentially affecting the transport of insulin across the blood–brain barrier. Our working model also suggests other underlying mechanisms. A negative systemic protein balance, commonly observed in older adults, contributes to low skeletal muscle mass and may also reflect deficient protein metabolism in brain tissues. As a result of age-related loss in skeletal muscle mass, decrease in the abundance of mitochondria and detriments in their function lead to a decrease in tissue oxidative capacity. Dysfunctional mitochondria in skeletal muscle and brain result in the excessive production of reactive oxygen species, which drives tissue oxidative stress and further perpetuates the dysfunction in mitochondria. Both oxidative stress and accumulation of mitochondrial DNA mutations due to aging drive cellular senescence. A targeted approach in the pathophysiology of low muscle mass and cognition could be to restore myokine balance by physical activity." (Oudbier S. 2022)

In breaking this article down into digestible bites, we can follow the authors thought process.

The fundamentals are these: Age related changes that lead to neuronal loss and cognitive decline are related to loss or reduction of myokine release, systemic inflammation, insulin resistance, reactive oxygen induced mitochondrial stress, DNA mutations and poor protein intake.

First, exercise releases chemicals called myokines which are cell signaling molecules that have the job of telling other cells what to do via changes in gene expression, protein transcription and much more. The prototypical change is the increase of a substance called brain derived neurotrophic factor, BDNF, for short. BDNF is critical for brain cell mitochondrial biogenesis. BDNF promotes many developmental functions in the brain, including neuronal cell survival, differentiation, migration, dendritic arborization, and synaptic plasticity. Regular exercise promotes a progressive increase in BDNF protein for up to at least 3 mo. Coversely, BDNF mRNA in the brain is rapidly decreased by the cessation of exercise suggesting BDNF expression is tightly related to exercise volume. (Ruegsegger et. al. 2018) Again, BDNF increases mitochondria which are the powerhouses of our cells with the function of converting macronutrients like fatty acids, glucose and amino acids into ATP via the oxidative phosphorylation pathway within. This process consumes lots of oxygen and releases, ROS, reactive oxygen species as a waste product of the energy transformation reaction. Thus, exercise causes two effects via BDNF: 1) increase in ATP production in the brain via increased numbers of mitochondria, 2) increased ROS as a waste product. We will get into why this is important for damage later.

Second, as we age, muscle mass starts to decline every decade after we hit 30 years of age. There are many reasons for this. One is that we all develop mutations in our mitochondrial DNA leading to less functional energy centers that produce more ROS until the mitochondria/cells are taken out of circulation by autophagy. This is coupled to the lack of mitochondria in the first place in those individuals with less muscle mass = less mitochondria based on the first principle above. This results in a process whereby the brain, over time, has less ATP production per cell and more ROS per beneficial ATP produced per cell. This is a loop effect whereby mutations lead to more ROS which further damages the healthy mitochondria leading to more dysfunction and more ROS and on and on. This is a lose lose and is believed to be one of the pathways to dementia and age related cognitive decline.

Third, low muscle mass is associated with insulin resistance. Chronic poor lifestyle decisions leading excess weight gain pushes a person to be more sedentary for many reasons that we will only gloss over here including fatigue, muscle insulin resistance and hormonal shifts. Essentially, a person is weight heavy but lean mass light. This leads to metabolic and immune changes with age due to pro-inflammatory signaling from chronic hyperglycemia, hyperinsulinemia and hyperlipidemia that will inadvertently lead to mitochondrial damage system wide including the brain compounding the sedentary induced changes. And, oh by the way, these same diet choices also tend to be associated with less plant based antioxidants that could be reducing the ROS damage. Alas, it is another problem instead. It appears all to be tightly connected. The elevated glucose levels in the blood from the insulin resistance/diet dyad leads to poor glucose utilization in the brain damaging energy production unless adequate free fatty acids are available to metabolism. The primary problem here is that the hyperinsulinemic state that comes with the hyperglycemia down regulates the number of insulin receptors in the blood brain barrier leading to poor insulin action and metabolism damage in the brain.

Fourth, if we do not consume enough protein, we will not have enough circulating amino acids like leucine to promote the activation of protein biosynthesis by mTOR. mTOR is a master metabolic switch in humans that senses nutrient volume and pulses on and off when there is adequate leucine, insulin and resistance muscle activity. mTOR then triggers protein synthesis, regulates cell proliferation and growth. It also matters what type of protein as animal protein is more bioavailable than plant protein which becomes more important with age as we need to hit a 30 gram protein threshold per meal. Eating plant based proteins with 60-70% bioavailability means that you will need to get 40+grams to have the same effect.

Fifth, total body systemic inflammation, from various causes some of which are in number 3 above, leads to immune activity that induces brain localized inflammation which shifts the ability of local immune cells to fight viral pathogens well leading to further local intra cerebral inflammation and cellular damage. Peripherally, systemic inflammation also leads to the release of immune cytokines that effect muscle insulin sensitivity furthering the muscle centric myokine release dysfunction. Thus, we have the double whammy of inactive muscle and excess adipose tissue driving interleukin 6 and NFKb mediated inflammation signaling that has the downstream effect of cognitive dysfunction. Neuro-inflammation will follow over a chronic period of muscle centric pathophysiology. Systemic inflammation promoting cytokines in the place of the non produced beneficial myokines will travel via the blood stream to the brain crossing the blood brain barrier where they will activate the local microglial immune brain resident cells. These microglial cells will begin a process that is too difficult to simply describe here, but causes local neuronal damage leading to cellular dysfunction and the end result is cognitive decline and the final common pathway of dementia.

Overall, as we age, the number and volume of mitochondria will decrease in the low protein poorly exercised state leading to poor brain function. Thus, the key remains simple, exercise daily with resistance activity and eat adequate volumes of protein to trigger protein synthesis via mTOR.

Does this issue matter in children? Let us first look at disorders of mitochondria in children as the canary in the preverbal coal mine. From Mark Tarnopolsky: "Patients with mitochondrial cytopathies often experience exercise intolerance and may have fixed muscle weakness, leading to impaired functional capacity and lower quality of life. Endurance exercise training increases Vo2max, respiratory chain enzyme activity, and improves quality of life. Resistance exercise training increases muscle strength and may lower mutational burden in patients with mitochondrial DNA deletions. Both modes of exercise appear to be well tolerated. Patients with mitochondrial cytopathy should consider alternating both types of exercise to derive the benefits from each (endurance = greater aerobic fitness; resistance = greater strength)." (Tarnopolsky et. al. 2014) If we use these children as surrogates for the benefit of exercise on mitochondrial fitness and biogenesis, then the answer is a resounding yes that exercise matters for children. It is too much for this piece, but children have a major advantage whereby protein muscle synthesis is driven by hormones primarily and less so by mTOR. Thus, while protein is still necessary to be fit optimally, it is not as important as it is in adults.

This research is critical to our long term health. Activity is so important on so many levels, but in this case we are able to generate more BDNF and other enhanced metabolic properties of life for reduced inflammation and increased longevity in a healthful state. Everything is tied together in our neuroimmunometabolic pathways. To be sedentary, poorly nourished and toxic is to die younger with less functional ability of every system in the body. The take home point here is to get your children moving often and with vigor. That has a long term feed forward effect on keeping the brain clean and energetic in positive ways. Couple this data to the sleep data on glymphatics and sleep induced cleaning and you see a variable picture of preserving brain health. See below for a diagram of this reality.


Dr. M

Tarnopolsky Sage Journals
Boisseau Sports Medicine
Ruegsegger Cold Spring Harbor Pers Med