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THE AXES OF AGING For the last two years I've been working to develop a framework of aging which distills its complex mechanisms into a set of pathways which can be activated or inhibited by diet, lifestyle, and pharmacology This is still a work in progress which I plan to refine and clarify over time, including finding more practical applications
Today I'll simply be introducing each axis and briefly summarizing some of the key factors that modulate it While these are broadly independent they do overlap, interact, and promote each other, and similarly many factors will target multiple axes at once The Axes of Aging are: - Excitation - Deposition - Hypoxia - Inflammation - Permeability - Aggregation
Axis 1: Excitation This axis primarily refers to excess excitatory glutamate and deficiency in inhibitory GABA tone. Glutamate is active in every tissue in the body especially the brain, and its dysregulation contributes to mental illness, heart disease, cancer, diabetes, liver/kidney disease, and more. At a more primordial level this axis is governed by calcium influx into cells and mitochondria as part of the "universal stress response." Calcium influx regulates changes in metabolism, cell division, inflammation and more. In excess it causes cell death. While glutamate is a dominant regulator of calcium influx via the NMDA receptors, other factors promote excitation as well. Catabolic hormones like adrenaline, noradrenaline, and cortisol have higher-level impacts on this system via the stress response. Other factors like ammonia and homocysteine contribute to excitation and calcium influx as well. Axis activators: glutamate, cortisol, adrenaline, histamine, stress, sleep deprivation, blue light, EMF, heavy metals, homocysteine, ammonia Axis inhibitors: GABA, magnesium, l-theanine, taurine, glycine, adenosine, melatonin, neurosteroids, NMDA antagonists, sedative herbs, beta-carbolines
Axis 2: Deposition This axis primarily refers to the formation of insoluble deposits of calcium and phosphate crystals, as well as hydrophobic arterial plaque and visceral fat. The two are most clearly linked in heart disease, where arterial plaque can become calcified. Outside of this calcification occurs in various organ systems and plays a role in the aggregation axis as well. Visceral fat is often a prerequisite for arterial calcification. In some of my threads I have made the suggestion that "phosphication" would be a more appropriate term than calcification, as phosphate is one of the primary drivers of this axis. The liver and kidneys interact heavily with this axis. The kidneys produce factors that inhibit and regulate calcification including Klotho and calcitriol. The liver is affected by dietary components to produce more LDL and visceral fat. Axis activators: phosphate, parathyroid hormone, hypercaloric foods, palmitic acid, ApoB/LDL, oxidized PUFA, homocysteine, free iron, circadian dysregulation Axis inhibitors: calcium, magnesium, vitamin D, vitamin K2, inositol, IP6, choline, Klotho, FGF23, short-chain fats, soluble fiber, omega-3
Axis 3: Hypoxia This axis consists of two processes, hypoxia and reductive stress. Hypoxia is the inability of a cell or mitochondria to use or access oxygen. Reductive stress is the build up of excess electrons within redox cofactors that impairs metabolism. This can be observed using the NADH/NAD+ ratio or markers of tissue oxygenation. A variety of factors are created under hypoxic conditions which contribute to pathology, such as lactate and VEGF. While I will list these under activators they are protective in context (similar to other activators) but harmful when left unchecked. Blood flow, oxygen availability, CO2 availability, and electron transport chain bottlenecks are the primary factors in this axis. Infrared light is highly protective here, and in my view of health it is an "electromagnetic nutrient." Axis activators: hypoxia, nitric oxide, carbon monoxide, cyanide, HIF-1a, VEGF, lactate, blue light Axis inhibitors: oxygen, CO2, infrared light, thiamine, riboflavin, niacin, quinones, melatonin
Axis 4: Inflammation In some ways this is the axis that connects the others together. Many axis activators promote inflammation as part of their acute stress responses, and when elevated chronically cause damage as a result. The most broadly deactivating compounds also tend to have anti-inflammatory effects. The most specific case where this axis is isolated is in allergic and autoimmune responses. While hypoxia derives reductive stress, inflammation derives oxidative stress. Axis activators: histamine, serotonin, acetylcholine, endotoxin, TLR4, haptens, free iron, heavy metals, nitric oxide, blue light, homocysteine, cytokines Axis inhibitors: magnesium, l-theanine, flavonoids, quinones, polyphenols, probiotics, soluble fiber, antioxidants, infrared light
Axis 5: Permeability This axis extends across three main levels, the gut barrier, lining of blood vessels, and blood brain barrier (BBB). Gut barrier permeability is activated by infection and dietary components like gluten. It is primarily regulated by zonulin. Blood vessel permeability is driven by oxidative stress and damage to connective tissue proteins, particularly by activators of the inflammation axis. It is a primary factor in heart disease and edema. Blood brain barrier permeability overlaps heavily with the other two factors. Inflammatory and oxidative insults cause damaging compounds to enter the brain more easily. Axis activators: gluten, lectins, zonulin, endotoxin, histamine, serotonin, MMPs, homocysteine, free iron, hypertension, sleep deprivation, EMF Axis inhibitors: magnesium, l-theanine, polyphenols, probiotics, soluble fiber, mucin, quinones, fat-soluble vitamins
Axis 6: Aggregation This axis encompasses three primary levels, fibrosis, protein aggregation, and phase separation. Fibrosis refers to both collagen cross-linking, which increases in aging, and excessive collagen synthesis in scarring and organ damage. It goes hand in hand with inflammation and deposition. Protein aggregation and phase separation are the intracellular equivalents of this process. Protein aggregates include amyloid, tau, and lipofuscin. These proteins are created and are unable to be broken down by cells. They eventually accumulate extracellularly as cells break down in aging. Phase separation is a prerequisite for protein aggregation. It refers to liquid-liquid phase separation, where more viscous regions of water form around protein clusters. Phase separation plays a role in a huge variety of biological processes, but it is especially important in infection, cancer, and neurodegeneration. Hydrotropes like melatonin and ATP inhibit phase separation. The scaling of this axis generally follows: phase separation -> cross-linking -> fibrosis Axis activators: cytokines, TGF-b, serotonin, infection, calcification, free iron, homocysteine, heavy metals Axis inhibitors: magnesium, melatonin, l-theanine, inositol, IP6, infrared light, quinones, polyphenols
To briefly summarize each axis: Excitation: Calcium influx activated by glutamate and other factors which is responsible for stimulation and the stress response in cells. When it is chronically activated ATP levels fall, free radicals rise, and cell death results. Deposition: Inappropriate placement of insoluble material like mineral or fat deposits in tissue. It goes hand in hand with aggregation and leads to inappropriate cell injury response. Hypoxia: Restriction of circulation or direct inhibition of the electron transport chain. Triggers changes that contribute to protective adaptations in the short term but produce disease and aging when activated chronically. Inflammation: Immune response to infection, injury, or autoimmune activation. Most often a result of another axis being activated, but can occur in isolation. Permeability: Loss of barrier integrity in digestion or circulation. Causes water and larger molecules to be displaced into the extracellular space. Aggregation: Cross-linking of protein, lipids, and other molecules to produce complex molecules like lipofuscin which accumulate over time. These aggregates contain metal ions like iron which catalyze free radical formation in the presence of oxygen and blue light.
In general endogenous "activators" create protective responses which when chronically stimulated play a role in aging I visualize every axis as intersecting together to produce aging, though the ratio of which are activated to a greater extent plays a role in distinct diseases occurring In many cases lack of axis inhibitors like magnesium, B-vitamins, or infrared light plays a significant role