Human metabolism is a dizzingly complicated process. Every time we eat, our food must be first broken into smaller components by digestive enzymes, then absorbed across the gut into circulation, then shunted into various chemical pathways so that eventually it can be burned for energy, incorporated into our tissue structure, or excreted as waste. In a system with so many moving parts, there are an almost incomprehensible number of ways in which it can go wrong. Thousands of genes are involved in encoding the machinery involved in this process. One little mistake in any of them and the whole thing can unravel, typically with disastrous consequences. The fact that this happens so rarely is remarkable.
But, there are exceptions, classified as disorders of metabolism. These are genetic disorders, usually the result of a mistake in the DNA sequence for an enzyme that catalyzes a particular step in the metabolic process. Defects in the synthesis and breakdown of glycogen are known as the “glycogenoses,” defects in lipid metabolism the “lipodoses,” and so forth. One of the primary consequences of a missing enzyme is that it creates a bottleneck – a specific reaction in the metabolic dance can’t proceed, leading to pathological build-up of the reactants in various bodily tissues (which can be seen microscopically).
Many times this toxic sludge of metabolites builds up in the nervous system. When it does, it leads to progressive degeneration of nervous tissue and resultant loss of function – dementia, movement disorders, seizures, muscle weakness and so forth — until death occurs from the complications of this devastated state. In Globoid Cell Leukodystrophy, just to choose a random example, the absence of the lysosomal galactocerebrosidase enzyme (due to a recessively inherited mutation in the GALC gene) results in the inability to cleave galactose from ceramide derivatives inside the lysosomes. This leads to defects in myelin production, clumps of multinucleated “globoid cells” swollen with galactocerebroside, and brain cell death. Clinically, it is causes progressive loss of cognitive and motor skills, muscle rigidity, seizures, deafness, blindness, and eventually death.
To recap, in all of these neurodegenerative disorders of metabolism, the fundamental problem is a flaw in the metabolic apparatus itself. A particular metabolite can’t be cleared, and its excess becomes toxic. The trash is being taken to the street, but the trucks aren’t coming to pick it up. Eventually, the trash piles up in brain tissue, and the brain stops working as it should.
But what if the problem is that there’s just too much trash to begin with? What if, week after week, we’re bringing more than the trucks can carry?
We don’t typically think of the neurodegenerative diseases of adults as disorders of metabolism, as they’re commonly viewed as fundamentally distinct from the metabolic disorders of childhood that affect the brain. As such, little research has focused on the role of metabolism in adult-onset neurodegeneration, even though the scarcity of dementia amongst the elders in modern day hunter gatherer populations should’ve long ago steered us in that direction. Yet, as discussed in my last post, we now know that at least one metabolic disorder — diabetes — contributes directly to the risk of Alzheimer’s disease, likely via the accelerated formation of advanced glycation end products (AGEs) in the brain. Defective insulin secretion and insulin resistance in the tissues means too much glucose in the blood and in the brain. That this abundance of glucose leads to Alzheimer’s disease is yet another observation beckoning us to reconceptualize Alzheimer’s as a disorder of metabolism.
But that’s not all. AGEs, along with other signs of oxidative damage, have been found lurking inside the pathology of many other adult-onset neurodegenerative disorders, including Pick’s disease, Parkinson’s, Progressive Supranuclear Palsy, Lewy Body Dementia, and ALS. Each of these involves a progressive decline in neurological function with deficits that may include dementia, movement disorders, seizures, muscle weakness and so forth. And each is associated with pathological buildup of gunk that can be seen microscopically in nervous tissue.
I don’t think these similarities are coincidental, nor should they be surprising. As stated, pathological accumulation of metabolites can arise either from the inability to break them down (i.e. – trash trucks stop coming) or from consumption of particular dietary components in excess of what their obligate metabolic pathway can handle (i.e. – too much trash). Our hunter gatherer metabolic machinery can’t cope with 150 pounds of sugar or 50 pounds of industrial vegetable oil a year (in fact, likely only a small fraction of this). And, just as in the metabolic disorders of childhood, that excess becomes toxic, with results that are just as devastating.
If it walks like a duck…