Age Pigment (Lipofuscin)

Age pigment (lipofuscin) is a brown, waxy material that accumulates in aging tissues and is largely derived from oxidized polyunsaturated fatty acids complexed with iron. 2 Peat identified it as a terminal toxin whose formation is accelerated by dietary polyunsaturated fats (PUFA), estrogen excess, iron overload, radiation, and oxygen deprivation. 3 Unlike the protective antioxidant melanin, lipofuscin promotes further oxidative injury by acting as a NADH-oxidase, an enzyme-like function that directly wastes oxygen and cellular energy while producing free radicals and hydrogen peroxide. 3 This oxygen-wasting property creates a self-sustaining respiratory defect, as the pigment consumes oxygen faster than the unoxidized unsaturated fats from which it formed. 2

The formation of lipofuscin involves a convergence of stressors. Under conditions of low energy or hypoxia, reduced iron is released from storage and attacks the unsaturated fats present in the cell, polymerizing them into the insoluble pigment granules. 2 Estrogen intensifies this process by causing cells to take up water immediately, altering the structure of cellular water to a more bulk-phase state, and by activating oxidative enzyme systems such as peroxidase. 2 The pigment itself contains trapped heme molecules that catalyze the conversion of oxygen to water without producing usable energy, making it a constant drain on fuel and oxygen that induces a chronic reductive, oxygen-deficient stress. 3 This contributes to vicious circles by activating hypoxia-inducible factor (HIF), which in turn promotes iron absorption, activates heme oxygenase to release free iron, and increases aromatase activity to raise estrogen further. 3

Once accumulated, lipofuscin acts as a systemic metabolic burden. It is found as the main material in cataracts, in the atheroma of hardening blood vessels, in the aging heart, and in the Alzheimer's brain. 2 Peat argued that after a certain threshold of accumulation, even removing dietary PUFA is insufficient to restore thyroid function and oxidative metabolism because the pigment itself will waste any oxygen the cells receive. 8 The presence of the pigment intensifies the effect of estrogen, and in the depleted, low-energy state that results, chromosome damage occurs and is not repaired as it would be in a youthful, high-energy state. 2 This creates a condition where trivial challenges become increasingly harmful, accelerating further lipofuscin production. 4

The accumulation is modifiable rather than genetically programmed. Calorie restriction slows the rate of aging precisely as it slows the rate of lipofuscin formation, contradicting doctrines of a fixed cellular division limit. 4 Pro-oxidant metals, especially iron, aluminum, and silicon, accelerate its formation, while vitamin E and selenium deficiency relative to PUFA consumption are major contributing factors. 3 Peat observed that topical progesterone and the cessation of estrogen could reverse visible age spots, and he speculated that phagocytes might be able to ingest and destroy lipofuscin, potentially relieving symptoms of oxygen deficiency in aging. 10 The pigment overlaps in composition and causative factors with other age-related inclusion bodies, including amyloid, with excess estrogen, PUFA, and oxidative metals being major factors in the development of both. 11