This is a work-in-progress, and therefore not finished. Right now it mostly just looks like a curated list of research papers, but I wanted to get the ball rolling and post something so that maybe I won’t forget to finish it.

Summary

I’m going to make a case for why I think the amino acid L-serine (and/or glycine) would benefit brain and retinal health, especially as we get older. Cells that must sustain high rates of glucose consumption to function should be the first ones to deteriorate when insulin resistance or other age-related problems reduce the rate at which they can process glucose, maybe because housekeeping functions of the cell need some of the carbons from the incoming stream of glucose in order to synthesize important molecules that deal with the mess created by the cell’s high metabolism. For some of those important molecules, like glycine and glutathione, the first step is to divert some of that glucose toward serine synthesis. In the brain and the retina, it’s really a network of inter-dependent cells that becomes dysfunctional, but they still rely on a steady stream of glucose, and providing an alternative (dietary) source of serine and glycine may help alleviate some of the stress and prevent damage to the cells.

Introduction

Despite being considered a “non-essential” amino acid, your body considers serine to be so essential that it can’t rely on your diet to provide enough to cover what it needs: your cells have the ability to synthesize it from scratch (well, from glucose). There are many different kinds of cells in your body, and some of them have a particularly high demand for glucose; they are the Formula 1 race cars of the cellular world. Two kinds of cells that fall into that category are astrocytes and retinal cells. Some glucose is refined into ATP and used as an energy source for the cell, and some is used to build other important molecules for cellular growth and operational needs. Serine is one of those important molecules, and unlike many of the others, it can be obtained from your diet, which takes that burden off of your cells and allows the glucose to be used for other critical things. For most cells, diverting some glucose into serine synthesis is not a big deal; but for the Formula 1 race cars of the cellular world, it might be the difference between winning the race and crashing-and-burning.

[I’m trying to imagine what it looks like when your astrocytes can’t metabolize glucose as fast as they did when you were younger. I suspect that your cells start out with the ability to metabolize glucose faster than they really need to, and then that ability deteriorates (with age or other reasons) until it becomes the rate limiting step for glycolytic flux. After that, is it like underclocking a CPU, does your brain just slow down? It’s probably not quite that simple, but I suspect that is one of the effects (see Decreased Alpha Peak Frequency Is Linked to Episodic Memory Impairment in Pathological Aging).]

Motivation

I enjoy biochemistry and neuroscience, and I first got interested in this topic when I was reading about Alzheimer’s and glycolysis. But my mom has macular degeneration, and is going through treatments for that, and there seems to be a lot of overlap between some of the metabolic features of Alzheimer’s and macular degeneration, even if they don’t necessarily happen to the same people.

Research Papers

L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential

L-Serine, an Endogenous Amino Acid, Is a Potential Neuroprotective Agent for Neurological Disease and Injury

Glycine and aging: Evidence and mechanisms

Macular Degeneration and Retinal Health

A Metabolic Landscape for Maintaining Retina Integrity and Function. Viegas and Neuhauss, 2021

• This is a great overview of the retina from a metabolic perspective, and the figures are fantastic! It barely discusses serine, but Figure 1 helps illustrate the opportunity cost (in cells where glycolysis is a choke point) of using glucose to synthesize serine instead of pyruvate.

Serine biosynthesis defect due to haploinsufficiency of PHGDH causes retinal disease (Eade et al., 2021)

• A genetic inability to synthesize sufficient serine will cause a kind degeneration of the macula called macular telangiectasia type 2 (MacTel) that is different from the more typical presentation of “macular degeneration”

Serine and glycine physiology reversibly modulate retinal and peripheral nerve function (Lim et al., 2024)

• Highlights the potential importance of serine supplementation for treating MacTel
• The best excerpt, from the Discussion: We demonstrate that circulating serine is the primary supplier of serine to the eye, highlighting the importance of systemic sources (e.g., liver, kidney, and diet). De novo synthesis from glucose by PHGDH and, to a lesser extent, glycine via the glycine cleavage system and one-carbon metabolism also contribute. Unlike most tissues, the eye appears to have activity of all available pathways to obtain serine. The liver and kidney primarily rely on glycine transport and one-carbon metabolism, rather than producing serine from glucose, to ensure stable circulating levels of these amino acids. By contrast, the brain heavily depends on de novo serine biosynthesis in astrocytes. The retina, by heavily relying on circulating serine, appears to be highly susceptible to the function of peripheral tissues that impact serine levels (e.g., SGOC metabolism in the kidney and liver). This feature also offers an avenue by which supplying serine systemically can treat the retina. The uniquely diverse mechanisms by which the retina obtains serine likely reflect the importance of serine for retinal function and may explain why a systemic reduction of serine (as observed in MacTel) manifests in the retina.

Human macular Müller cells rely more on serine biosynthesis to combat oxidative stress than those from the periphery (Zhang et al., 2019)

• The macular (central) retinal cells (specifically Müller glia cells) synthesize significantly more serine than cells of the peripheral retina. Of course, their metabolism is higher across the board (glycolytic flux, mitochondrial respiration, ATP production), but the authors also state that glucose is preferentially shifted toward de novo serine synthesis instead of glycolysis/TCA cycle, suggesting that serine may be especially important in the macula.

The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration (Sinha et al., 2020)

• This paper reviews the ways in which retinal cells rely on serine
• “perhaps the most vital part of serine metabolism is free radical scavenging in the entire retina via serine-derived scavengers like glycine and glutathione. It is hard to imagine that a single tissue could have such a broad and extensive dependency on serine homeostasis. Any dysregulation in serine mechanisms can result in a wide spectrum of retinopathies.”

Alzheimer’s Disease

Impairment of Glycolysis-Derived L-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer’s Disease (Le Douce et al., 2020)

• “Here, we show that the astrocytic L-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients.”
• “Supplementation with L-serine in the diet prevents both synaptic and behavioral deficits in AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral L-serine as a ready-to-use therapy for AD.”
• But see also PHGDH expression increases with progression of Alzheimer’s disease pathology and symptoms and then Glycolysis-derived L-serine levels versus PHGDH expression in Alzheimer’s disease for some followup discussion on the above study.

Glycolytic Metabolism, Brain Resilience, and Alzheimer’s Disease (Zhang et al., 2021)

• Reviews research on the relationship between glycolysis and Alzheimer’s disease, and makes it clear that glycolysis is central to the problems associated with Alzheimer’s
• “Accumulation of neurotoxic Aβ plaques and hyperphosphorylation of tau have long been considered the pathological hallmarks that contribute to synaptic disruption and neuronal loss in the brains of AD patients. It is reported that Aβ distributes variably among brain regions, with more deposition found in areas of high dependence on glycolysis… the regions with increased glycolysis in the resting state of healthy young adults closely mirror the later regional pattern where Aβ accumulates in the brains of AD patients”

GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer’s disease

• Studied the effect of liraglutide (diabetes medication) on mouse cognition and astrocyte metabolism
• GLP-1 mediated a shift from oxidative phosphorylation to glycolysis in the Alzheimer’s animal and cellular models, and improved the astrocyte cells’ ability to support neurons as shown by increased cellular viability and robust dendrite and axon growth.