# Age Pigment (Lipofuscin)

Category: Metabolism

Also known as: age pigment, Age Pigment, lipofuscin, Lipofuscin

Age pigment is the brown material that forms spots on aging skin, and that accumulates in the lens of the eye forming cataracts, and in blood vessels causing hardening of the arteries, and in the heart and brain and other organs, causing their functions to deteriorate with age…

11 passages · 1 author · 1996–2021 · Most-cited: [Ray Peat](https://bioenergeticoracle.com/md/voices/ray-peat/index.md)

Canonical page: https://bioenergeticoracle.com/concepts/age-pigment-lipofuscin

## Synthesis

**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. [Source 1, 9] Peat identified it as a *terminal toxin* whose formation is accelerated by dietary polyunsaturated fats (PUFA), estrogen excess, iron overload, radiation, and oxygen deprivation. [Source 2, 4, 5] 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. [Source 2, 5, 7] 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. [Source 2, 6]

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. [Source 8, 10] 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. [Source 4, 7] 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. [Source 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. [Source 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. [Source 1, 8] 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. [Source 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. [Source 4, 9] This creates a condition where trivial challenges become increasingly harmful, accelerating further lipofuscin production. [Source 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. [Source 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. [Source 4, 7, 10] 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. [Source 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. [Source 11]

## People also ask

### How does lipofuscin waste oxygen in cells?

Peat described lipofuscin as acting like a NADH-oxidase enzyme that consumes oxygen to produce free radicals and hydrogen peroxide without generating usable energy, creating a self-sustaining respiratory defect.

### Why does estrogen accelerate age pigment formation?

The corpus states that estrogen intensifies lipofuscin formation by causing cells to take up water, altering cellular water structure, and activating oxidative enzyme systems like peroxidase.

### Can accumulated lipofuscin be removed from the body?

Peat speculated that phagocytes might be able to ingest and destroy lipofuscin, and he observed that topical progesterone with cessation of estrogen could reverse visible age spots.

## Related concepts

- [Amyloid](https://bioenergeticoracle.com/md/concepts/amyloid/index.md)
- [PUFA (polyunsaturated fatty acids)](https://bioenergeticoracle.com/md/concepts/pufa-polyunsaturated-fatty-acids/index.md)
- [Saccharide](https://bioenergeticoracle.com/md/concepts/saccharide/index.md)
- [Adrenaline](https://bioenergeticoracle.com/md/concepts/adrenaline/index.md)
- [Albumin](https://bioenergeticoracle.com/md/concepts/albumin/index.md)
- [Aldosterone](https://bioenergeticoracle.com/md/concepts/aldosterone/index.md)

## Cited passages

Passage numbers match the `[Source N]` markers in the synthesis above.

### Source 1 — Glossary

Ray Peat · Glossary

> Age Pigment (Lipofuscin)
>
> Age pigment is the brown material that forms spots on aging skin, and that accumulates in the lens of the eye forming cataracts, and in blood vessels causing hardening of the arteries, and in the heart and brain and other organs, causing their functions to deteriorate with age. It is made up of oxidized unsaturated oils with iron.

### Source 2 — The Science Behind The Dangers of Polyunsaturated Fats - East West Healing and Performance Interview (hosted by Josh and Jeanne Rubin)

Ray Peat · Interview · 2011 · https://www.youtube.com/watch?v=_AK-uiCWZPk

> **Josh Rubin:** Hey Ray, glad you're on the show. Today we're going to talk about Polyunsaturated fatty acids and of course, as you know, you've done way more researching on this subject than most people. It's quite a controvertial topic, because a lot of people are promoting that you need oils, or eating seeds. So I wanted on our show get your approach because we've studied you for years; it's definitely grey i think for a lot of people. We have a lot of questions and we want to get in as much as we can, but I want a brief introduction to kinda who you are and why you do what you do.
>
> **Ray Peat:** Ok. I was starting to study brain physiology in 1968, when I went to the University of Oregon, and I've found that the best scientists were working in reproductive physiology. So, even though the brain was my center of interest, I did my PhD work on reproductive physiology, in particularly, female aging. And, studying the effects of estrogen and the changes with aging, I saw that the old and animals actually had more estrogen stimulation in their tissues than younger animals.And it was working basically like contraceptive pills, to prevent fertility after middle age. And I noticed that the uteruses under the influence of aging and estrogen, typically were darkened and contained the brown pigment. And that got me interested in how that pigment develops through aging, estrogen excess, or radiation (that's another thing that can cause it), or deprivation of oxygen. So I started studying this pigment which is called lipofuscin, or age pigment, and saw that it had been studied quite a lot. In the 1930s and 40s they found that they were killing their animals by feeding them too much of the seeds, that were rich in the polyunsaturated Fats, or fish. In some cases such as mink, they were being killed by an excess of fish in the diet. But even horse meat was killing animals like mink, which were carnivorous (if the horses had eaten flax or linseed, their fat was toxic to the carnivorous animals). And in animals that ate too much of the unsaturated fats, they developed yellow-fat disease (in mink, it developed paralysis fairly quickly at the hind quarters, and then it would kill them). And it turned out that their fat tissue was inflammed and waterlogged, and eventually it would turn yellow or brown. And that's the same pigment that appears in the uterus that has been over-exposed to estrogen or in the skin of an old person that has been exposed to sunlight, and the brain.

### Source 3 — Estrogen, iron, degenerative aging, and progesterone

Ray Peat · Newsletter · 2021

> Some of the products of lipid peroxidation, interacting with iron and other cell materials, become the very complexly structured age pigment, lipofuscin. Among the substances in these dark granules are some heme molecules, protected against elimination, which can catalyze the conversion of oxygen to water, without producing usable energy; the pigment becomes a drain on fuel and oxygen, creating a constant reductive, oxygen deficient, stress. This tendency to reduce oxygen contributes to the formation of vicious circles, inducing hypoxia inducible factor, HIF, which is a crucial factor in promoting iron absorption, and which activates many potentially dangerous enzymes, including heme oxygenase, HO, which turns heme groups into free iron, carbon monoxide, and bilirubin. HIF also activates aromatase, increasing estrogen (Samarajeewa, et al., 2013). About 60% of newborn babies are jaundiced for a few days, showing that the stress of being born has activated their HO, turning heme into its toxic components. The presence of free bilirubin is known to be associated with lipid peroxidation and DNA damage (Basu, et al. 2014). Better prenatal conditions would probably reduce the incidence of neonatal jaundice and stress, and this might involve avoidance of highly unsaturated fats and large iron supplements, and avoiding stressful medical procedures. Stresses that increase exposure to excess iron and PUFA can shorten the life span of red blood cells, adding to the burden of heme and lipid peroxides. The well known association of the autoimmune diseases with excessive estrogen probably involves the increases of hypoxia, HIF, HO, iron, and PUFA under the influence of estrogen. Aldehydes produced by the breakdown of fats react with cell proteins, making them antigenic, while episodes of hypoxia and hypoglycemia make the immune system more reactive.
>
> All microorganisms require iron to grow, so limiting the availability of iron will limit their ability to be infective. Our respiratory and digestive membranes secrete two proteins, lactoferrin and transferrin, which have a very high affinity for iron atoms, as well as other germicidal properties, and provide a first defense against infection.

### Source 4 — Age Pigment: Cause and Effect of Aging and Stress

Ray Peat · Article · Dec 2013

> In the depleted, low energy state that develops when a large amount of lipofuscin has accumulated, chromosome damage will occur, and will not be repaired as it is in the youthful high energy state. Mutations in themselves don't cause aging (Curtis, 1963 ; Kohn, 1971,* see quotation at end), but aging creates a disposition for mutations to accumulate. (It was found that men who exercised before breakfast produced large numbers of chromosome breaks. The energy provided by breakfast made a visible difference in the amount of chromosome damage produced by exercise. The chronic low energy state that results from being full of rancid fat must amplify the damage done by ordinary stress.)
>
> Minimizing radiation, of course, is important, and if we aren't primarily worried about radiation as a direct mutagen, the comforting thought of a "threshold of safety" disappears. The same principle applies to the avoidance of environmental toxins (so many of which are estrogenic), since the factors that promote age pigment all seem to be additive. The age pigment is a final common pathway in which many types of damage converge, in the way many different factors converge in the drying of paint. By depleting the cell's energy, lipofuscin accumulation causes trivial challenges to become increasingly harmful, in a vicious circle that tends to accelerate the production of lipofuscin.
>
> Some of the factors that significantly accelerate the formation of lipofuscin--dietary polyunsaturated fats, deficiency of vitamin E and selenium, and excess iron--are things that can be manipulated without great effort. Some of the proven factors that retard its formation, such as a low calorie diet, are not so easy to sustain, and require some study.
>
> If a "program in the genes" controlled the rate of aging, dietary modification should make no difference at all, but calorie restriction slows the rate of aging, as it slows the rate of lipofuscin formation. (C. M. McCay's experiments in the 1930s, 1952 ; W. A. L. Moore, et al., 1995.)
>
> The doctrine of "programmed aging," and the Hayflick doctrine, maintain that cells have an innate capacity to undergo about 50 divisions, and that "aging" consists of having used up their limited capacity for division. It is clear that the medium in which the cells are cultured affects their ability to multiply, and that serum from old animals slows their growth.

### Source 5 — Age Pigment: Cause and Effect of Aging and Stress

Ray Peat · Article · Dec 2013

> In 1954, I asked my biology professor (who was in his sixties) what he thought the cause of aging was, and he said some people believed that it was the result of the accumulation in cells of insoluble metabolic by-products, called "metaplasm." His remark was in my mind later when I watched an amoeba dividing under the microscope ; it seemed to have become sludgy, viscous, and lethargic, and then as it divided, the new cells appeared to be moister and more elastic, as if they had diluted some kind of ballast that produced internal friction.
>
> In 1954 there was a report of a girl whose skin turned black from using an ointment containing estrogen. Later, in the 1960s, I noticed that many women using birth control pills developed patchy brown spots on their faces. As I read more about pigmentation, I saw that estrogen, like a variety of irritants, promoted the development of ordinary dark pigment, melanin, in the skin, and that this was different from the liver spots or age pigment that often begin to appear in middle age, and that become so noticeable on the hands, arms, and faces of most old people. As it turns out, both types of pigment are produced by oxidation of smaller molecules which causes them to coalesce into complex masses, but at that point the difference becomes total. Melanin protects against further oxidative injury, but lipofuscin tends to promote further injury. Later, I learned that estrogen was implicated in the production of age pigment, at least in the uterus. (Atkinson, et al., 1949; Kaunitz, et al., 1948.)
>
> Another kind of pigmentation, that is sometimes seen in the skin around the eyes, has been found to contain substances derived from hemoglobin. The heme/porphyrin pigments are interesting in relation to aging, not just because estrogen is known to be involved in the overproduction of the porphyrins, but because lipofuscin has been reported (Bjorkerud, 1963, 1964) to contain the heme group, and because the metabolites of heme (the bile pigments, With, 1968 ; pyrroles, Figge, 1945) have been associated with cancer.

### Source 6 — Sugar Myths 1 – Sugar and the Link Between Cholesterol.

Ray Peat · Transcript · 2011

> **Ray Peat:** I started in graduate school, I’d been reading on my own, but I decided to study in the physiology and biology department in the University of Oregon 1968. Since then I’ve been working pretty much full time in physiology related things, reproductive endocrinology was what I did my dissertation on: how oxidative metabolism interacts with ageing estrogen and so on to regulate fertility and sterility. The part of that thesis work involved the ageing of metabolism and how oxygen came to be wasted more and more with ageing, or under the influence of stress or high estrogen. The age pigment, lipofuscin was one of the things that I found was involved in high estrogen and ageing or radioactive damage. Lipofuscin is a breakdown product of polyunsaturated fatty acids largely, with other things bound into little brown lumps in the cells and it consumes oxygen and wastes energy and eventually can kill the cells, but it’s main function seems to be to waste oxygen and energy.
>
> **Andrew Murray:** And those are those little brown spots people call age spots or liver spots on their skin?

### Source 7 — Age Pigment: Cause and Effect of Aging and Stress

Ray Peat · Article · Dec 2013

> (Regarding glucose metabolism, Barnard, et al., 1995 ; many more references are given in my article on diabetes, scleroderma, and oils.)
>
> It is interesting that the first publication identifying dietary fat as an essential cause of cancer (1927) appeared almost at the same time as the demonstration (Pinkerton, 1928, cited by E. A. Porta, et al., 1987) that a substance resembling lipofuscin could be produced by bubbling oxygen through unsaturated fat (fish oil). Various types of unsaturated fish or seed oils have since then been used to produce lipofuscin in vivo and in vitro.
>
> Hartroft and Porta (1967) demonstrated that the pro-oxidant metals, especially iron, accelerate the formation of age pigment, and recent experiments confirm those observations. (Zs.-Nagy, et al., 1995.) Aluminum and silicon, which have a role in brain and blood vessel aging, also have a role in the formation of age pigment. (Tokutake and Oyanagi, 1995.)
>
> My observations of extracts of aged tissue, soaked in ether or pyridine, showed an absorption spectrum in the ultraviolet frequencies that indicated the pigment was a complex mixture with unsaturated fats, but with the specific absorption indicating the presence of heme or related material.
>
> When artificial lipofuscin, made by ultraviolet irradiation of mitochondrial preparations, is added to cell cultures, the cells act as if they had aged suddenly, and then die. (von Zglinicki, et al., 1995.)
>
> Similarly, when mitochondria are extracted from old cells, and injected into young cells, the young cells behave as if they had aged.
>
> One of the remarkable things about the NADH-oxidase described by Bjorkerud is that it is cold-inactivated. I have argued (Peat and Soderwall, 1971, 1972) that estrogen activates enzymes of this type, but a mere excess of water could have a similar function, and if these granules produce their own water, they will tend to support the condition which activates themselves, while also tending to decrease the metabolic activity of mitochondria. Where the water is being produced, there is a lack of ATP, and where the ATP is being produced, there is a limiting lack of oxygen.

### Source 8 — The Thyroid 1996 Gary Null Radio Show

Ray Peat · Interview · 1996 · http://l-i-g-h-t.com/files/gary-null-thyroid.mp4

> **Ray Peat:** But momentarily, if you, for example, take 1/2 an ounce of coconut oil, you get a burst of thyroid-like activity, and your cells respire more intensely for about an hour until that fat is burned up. But after about 2 years of a changed diet, you've burned up roughly half of your stored, inhibiting unsaturated fats, and your metabolism stabilizes at a much higher level. So to correct the age-associated decline of thyroid function and respiratory energy production, you could take a thyroid supplement, or you could simply change your diet away from the inhibitors -- the fatty acids are one type of metabolic inhibitor, there are a few others -- for example the age pigment is something that is constructed inside our cells every time we're under stress and don't get enough oxygen. In effect, iron is released from storage, put into an activated state in which it can attack the unsaturated fats that happen to be in the cell at the time, and the combination of the unsaturated fat and the iron and the stress turns these unsaturated fats into age pigment or lipofuscin, which accumulates in all of the tissues. It's found as the main material in cataracts in the lens of the eye, in the atheroma in the wall of blood vessels that are deteriorating from age and stress, in the heart that is aging and susceptible to all kinds of malfunction, in the Alzheimer's brain and so on -- the age pigment accumulates, and it in itself gets an enzyme function which bypasses the good energy producing system. So after a certain point, even changing your diet away from the toxic, inhibiting fats won't do the job of restoring your thyroid function if you have accumulated so much of this age pigment, because it is going to waste any oxygen that your cells can receive.

### Source 9 — Leakiness, aging, and cancer

Ray Peat · Article · 2006 · https://raypeat.com/articles/articles/leakiness.shtml

> Some experimenters have noticed that newborn animals sometimes have the postural reflex (lordosis) that indicates an estrogenic state, and that suffocation can produce the same reflex. Irradiating animals with x-rays will also produce the whole range of estrogenic effects.
>
> One of the features of the aged uterus that I studied was the age pigment, lipofuscin, a brown waxy material that accumulates in old or stressed tissues. Prolonged dosage with estrogen accelerates the formation of this pigment, which is largely derived from oxidized polyunsaturated fatty acids. Increased amounts of those fats in the diet, or a deficiency of vitamin E, or exposure to ionizing radiation, or oxygen deprivation, can also accelerate the formation of the age pigment. The presence of the pigment intensifies the effect of estrogen, since the pigment wastes oxygen by functioning as an oxidase enzyme.
>
> Other tests that I did on aged, or estrogenized, uterine tissue indicated that several oxidative systems were activated; for example, the tissues showed an extremely high activity of the enzyme peroxidase, and a very intense reduction of a chemical dye (tetrazolium/formazan) that indicates the presence of reductive and oxidative activity, of the sorts caused by radiation and oxygen deprivation. These reductive and oxidative processes include the production of some free radicals that are capable of reacting randomly with polyunsaturated fatty acids.
>
> The interactions between estrogen and the polyunsaturated fats are now coming to be more widely recognized as important factors in the inflammatory/hyperpermeable conditions that contribute to the development of heart and blood vessel disease, hypertension, cancer, autoimmune diseases, dementia, and other less common degenerative conditions.
>
> Estrogen increases lipid peroxidation, and maintains a chronically high circulating level of free fatty acids, mainly PUFA, activates the phospholipases that release arachidonic acid from cells leading to formation of prostaglandins and isoprostanes, and increases the enzymes that form the inflammation-promoting platelet activating factor (PAF) while suppressing the enzymes that destroy it, and increases a broad range of other inflammatory mediators, interleukins, and NF-kappa B.
>
> The leakage of enzymes out of cells and into the blood stream is recognized medically as evidence of damage to the organ that is losing them. Different combinations of enzymes are commonly considered to be evidence of a heart attack, or skeletal muscle damage, or liver disease, pancreatitis, prostate cancer, etc.

### Source 10 — Moles, DHEA, etc.

Ray Peat · Newsletter · 2015

> In this case, the concentric rings of brown pigment suggested that pigment cells might be returning to their normal locations, after having lived for ten years in an island on my temple. This might suggest that this particular skin area is the last to lose its ability to produce DHEA, and that well-nourished cells can remember where they belong.
>
> ## Lipofuscin Produced in Oxygen Deprivation
>
> Age pigment, lipofuscin, is produced in oxygen deprivation, apparently from reduced iron which attacks unsaturated fats. It has its own respiratory activity, acting as an NADH-oxidase. Melanin is produced by polymerization of amino acids, with copper as the catalyst. With aging, iron tends to replace copper. Melanin is an antioxidant. Thus, there is a sort of reciprocal relationship between the two types of pigment. A vitamin E deficiency relative to consumption of polyunsaturated fats, and an estrogen excess, accelerate the formation of lipofuscin.
>
> A 47 year-old woman who had only a few liver spots on the backs of her hands began taking large amounts of estrogen, and within a few months the brown spots had darkened and spread until most of her skin was covered with spots. When she stopped using estrogen, and applied progesterone topically, the spots disappeared.
>
> Since both keratinocytes (keratinophages) and melanophages can phagocytize melanin granules, the occasional rapid disappearance of age pigment makes me wonder whether pigment-loving cells can't ingest and destroy lipofuscin. To the extent that lipofuscin wastes oxygen, the phagocytes might be able to relieve some of the symptoms of oxygen deficiency in aging.
>
> (My recent experience with an 82 year-old man with emphysema who regained a normal pink color a few days after beginning to use DHEA and pregnenolone led me to wonder whether the improvement was mainly in the lungs, or in the other tissues.)
>
> If leukocytes can direct organized attacks on moles, with reconstruction of healthier tissue at the same location, the healing of an infection, or a wound, should be seen in the context of growth, construction, and creation, instead of simply attack upon a foreign body.

### Source 11 — BSE - mad cow - scrapie, etc.: Stimulated amyloid degeneration and the toxic fats

Ray Peat · Article · 2007 · https://raypeat.com/articles/aging/madcow.shtml

> In reading Prusiner’s autobiographical statements, I was even more surprised to see that he claimed to have been puzzled to find out, around 1983, that the infectious agent was a protein. I had thought that my professors were lethargic authoritarians when they refused to look at the evidence in 1970-72, but Prusiner’s expression of puzzlement so many years later over the absence of nucleic acid in the infectious agent is hard to account for.
>
> In my own research in 1971, I was interested in another kind of age-related “inclusion body,” which was variously called lipofuscin, age pigment, and ceroid pigment. This brown (yellow autofluorescent) pigment contained proteins and metals, as well as polyunsaturated lipids, and overlapped in many ways with the amyloid bodies. All of these inclusion bodies were known to be associated with radiation injury, aging, and hormonal-nutritional imbalances. Excess of estrogen, polyunsaturated fatty acids, and oxidative metals were major factors in the development of lipofuscin, and estrogen was also known to cause other types of “inclusion bodies” to develop in cells.
>
> Although very little was known about the composition of the inclusion bodies (they were usually thought to be organelles damaged by free radical activity, or antibodies resulting from autoimmunity), their involvement in aging and degenerative disease was clear, and it was widely known that ionizing radiation accelerated their formation. But it was just at this time that the national research priorities of the U.S. were redirected toward genetic explanations for all major diseases, with for example the “war on cancer” centering on the concepts of the “oncogene” and the cancer virus. Since the “slow virus” of cancer, or the viral oncogene, requires activation by something in the environment, its function is to distract the public’s attention from those environmental causes of disease, viz., radiation and chemical pollution.
>
> The U.S. Public Health Service has historically been one of the branches of the military, and currently has 6000 commissioned officers. It has been intimately involved in all aspects of chemical, biological, and nuclear warfare, and it has participated in many covert projects, including experimentation on people without their knowledge. For decades, information on radiation injury to the public was hidden, classified, altered, or destroyed by the PHS.

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