Lipofuscin is the name given to fine yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. [1] [2] It is considered to be one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, retina, adrenals, nerve cells, and ganglion cells. [3]
Lipofuscin appears to be the product of the oxidation of unsaturated fatty acids and may be symptomatic of membrane damage, or damage to mitochondria and lysosomes. Aside from a large lipid content, lipofuscin is known to contain sugars and metals, including mercury, aluminium, iron, copper and zinc. [4] Lipofuscin is also accepted as consisting of oxidized proteins (30–70%) as well as lipids (20–50%). [5] It is a type of lipochrome [6] and is specifically arranged around the nucleus.
The accumulation of lipofuscin-like material may be the result of an imbalance between formation and disposal mechanisms. Such accumulation can be induced in rats by administering a protease inhibitor (leupeptin); after a period of three months, the levels of the lipofuscin-like material return to normal, indicating the action of a significant disposal mechanism. [7] However, this result is controversial, as it is questionable if the leupeptin-induced material is true lipofuscin. [8] [9] There exists evidence that "true lipofuscin" is not degradable in vitro; [10] [11] [12] whether this holds in vivo over longer time periods is not clear.
The ABCR -/- knockout mouse has delayed dark adaptation but normal final rod threshold relative to controls. [13] Bleaching the retina with strong light leads to formation of toxic cationic bis-pyridinium salt, N-retinylidene-N-retinyl-ethanolamine (A2E), which causes dry and wet age-related macular degeneration. [14] From this experiment, it was concluded that ABCR has a significant role in preventing formation of A2E in extracellular photoreceptor surfaces during bleach recovery.[ citation needed ]
Lipofuscin accumulation in the eye, is a major risk factor implicated in macular degeneration, a degenerative disease, [15] and Stargardt disease, an inherited juvenile form of macular degeneration.
In the peripheral nervous system, abnormal accumulation of lipofuscin known as lipofuscinosis [1] is associated with a family of neurodegenerative disorders – neuronal ceroid lipofuscinoses, the most common of these is Batten disease.
Also, pathological accumulation of lipofuscin is implicated in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, certain lysosomal diseases, acromegaly, denervation atrophy, lipid myopathy, chronic obstructive pulmonary disease, [16] and centronuclear myopathy. Accumulation of lipofuscin in the colon is the cause of the condition melanosis coli.
On the other hand, myocardial lipofuscin accumulation more directly reflects chronological ageing rather than human cardiac pathology. [17]
Calorie restriction, [4] vitamin E, [4] and increased glutathione appear to reduce or halt the production of lipofuscin.
The nootropic drug piracetam appears to significantly reduce accumulation of lipofuscin in the brain tissue of rats. [18]
Other possible treatments:
Wet macular degeneration can be treated using selective photothermolysis where a pulsed unfocused laser predominantly heats and kills lipofuscin-rich cells, leaving untouched healthy cells to multiply and fill in the gaps.[ citation needed ] The technique is also used as a skin treatment to remove tattoos, liverspots, and in general make skin appear younger. This ability to selectively target lipofuscin has opened up research opportunities in the field of anti-aging medicine.[ citation needed ]
Soraprazan (remofuscin) has been found to remove lipofuscin from retinal pigment epithelial cells in animals. [24] This opens up a new therapy option for the treatment of dry age-related macular degeneration and Stargardt disease, for which there is currently no treatment. The drug has now been granted orphan drug designation for the treatment of Stargardt disease by the European Medicines Agency. [25]
Lipofuscin quantification is used for age determination in various crustaceans such as lobsters and spiny lobsters. [26] [27] Since these animals lack bony parts, they cannot be aged in the same way as bony fish, in which annual increments in the ear-bones or otoliths are commonly used. Age determination of fish and shellfish is a fundamental step in generating basic biological data such as growth curves, and is needed for many stock assessment methods. Several studies have indicated that quantifying the amount of lipofuscin present in the eye-stalks of various crustaceans can give an index of their age. This method has not yet been widely applied in fisheries management mainly due to problems in relating lipofuscin levels in wild-caught animals with accumulation curves derived from aquarium-reared animals.[ citation needed ]
Macular degeneration, also known as age-related macular degeneration, is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.
Batten disease is a fatal disease of the nervous system that typically begins in childhood. Onset of symptoms is usually between 5 and 10 years of age. Often, it is autosomal recessive. It is the common name for a group of disorders called the neuronal ceroid lipofuscinoses (NCLs).
Neuronal ceroid lipofuscinosis is a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins. Their name comes from the word stem "lipo-", which is a variation on lipid, and from the term "pigment", used because the substances take on a greenish-yellow color when viewed under an ultraviolet light microscope. These lipofuscin materials build up in neuronal cells and many organs, including the liver, spleen, myocardium, and kidneys.
A cone dystrophy is an inherited ocular disorder characterized by the loss of cone cells, the photoreceptors responsible for both central and color vision.
Choroideremia is a rare, X-linked recessive form of hereditary retinal degeneration that affects roughly 1 in 50,000 males. The disease causes a gradual loss of vision, starting with childhood night blindness, followed by peripheral vision loss and progressing to loss of central vision later in life. Progression continues throughout the individual's life, but both the rate of change and the degree of visual loss are variable among those affected, even within the same family.
Drusen, from the German word for node or geode, are tiny yellow or white accumulations of extracellular material that build up between Bruch's membrane and the retinal pigment epithelium of the eye. The presence of a few small ("hard") drusen is normal with advancing age, and most people over 40 have some hard drusen. However, the presence of larger and more numerous drusen in the macula is a common early sign of age-related macular degeneration (AMD).
Vitelliform macular dystrophy is an irregular autosomal dominant eye disorder which can cause progressive vision loss. This disorder affects the retina, specifically cells in a small area near the center of the retina called the macula. The macula is responsible for sharp central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. The condition is characterized by yellow, slightly elevated, round structures similar to the yolk of an egg.
Stargardt disease is the most common inherited single-gene retinal disease. In terms of the first description of the disease, it follows an autosomal recessive inheritance pattern, which has been later linked to bi-allelic ABCA4 gene variants (STGD1). However, there are Stargardt-like diseases with mimicking phenotypes that are referred to as STGD3 and STGD4, and have a autosomal dominant inheritance due to defects with ELOVL4 or PROM1 genes, respectively. It is characterized by macular degeneration that begins in childhood, adolescence or adulthood, resulting in progressive loss of vision.
Retinol binding protein 4, also known as RBP4, is a transporter protein for retinol. RBP4 has a molecular weight of approximately 21 kDa and is encoded by the RBP4 gene in humans. It is mainly, though not exclusively, synthesized in the liver and circulates in the bloodstream as a hepatokine bound to retinol in a complex with transthyretin. RBP4 has been a drug target for ophthalmology research due to its role in vision. RBP4 may also be involved in metabolic diseases as suggested by recent studies.
Astellas Institute for Regenerative Medicine is a subsidiary of Astellas Pharma located in Marlborough, Massachusetts, US, developing stem cell therapies with a focus on diseases that cause blindness. It was formed in 1994 as a company named Advanced Cell Technology, Incorporated (ACT), which was renamed to Ocata Therapeutics in November 2014. In February 2016 Ocata was acquired by Astellas for $379 million USD.
ATP-binding cassette, sub-family A (ABC1), member 4, also known as ABCA4 or ABCR, is a protein which in humans is encoded by the ABCA4 gene.
Granulin is a protein that in humans is encoded by the GRN gene. Each granulin protein is cleaved from the precursor progranulin, a 593 amino-acid-long and 68.5 kDa protein. While the function of progranulin and granulin have yet to be determined, both forms of the protein have been implicated in development, inflammation, cell proliferation and protein homeostasis. The 2006 discovery of the GRN mutation in a population of patients with frontotemporal dementia has spurred much research in uncovering the function and involvement in disease of progranulin in the body. While there is a growing body of research on progranulin's role in the body, studies on specific granulin residues are still limited.
Tripeptidyl-peptidase 1, also known as Lysosomal pepstatin-insensitive protease, is an enzyme that in humans is encoded by the TPP1 gene, also known as CLN2. TPP1 should not be confused with the TPP1 shelterin protein which protects telomeres and is encoded by the ACD gene. Mutations in the TPP1 gene leads to late-infantile neuronal ceroid lipofuscinosis.
Bestrophin-1 (Best1) is a protein that, in humans, is encoded by the BEST1 gene.
Macular telangiectasia is a condition of the retina, the light-sensing tissue at the back of the eye that causes gradual deterioration of central vision, interfering with tasks such as reading and driving.
Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.
Emixustat is a small molecule notable for its establishment of a new class of compounds known as visual cycle modulators (VCMs). Formulated as the hydrochloride salt, emixustat hydrochloride, it is the first synthetic medicinal compound shown to affect retinal disease processes when taken by mouth. Emixustat was invented by the British-American chemist, Ian L. Scott, and is currently in Phase 3 trials for dry, age-related macular degeneration (AMD).
Geographic atrophy (GA), also known as atrophic age-related macular degeneration (AMD) or advanced dry AMD, is an advanced form of age-related macular degeneration that can result in the progressive and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, choriocapillaris) which can lead to a loss of visual function over time. It is estimated that GA affects over 5 million people worldwide and approximately 1 million patients in the US, which is similar to the prevalence of neovascular (wet) AMD, the other advanced form of the disease.
Occult macular dystrophy (OMD) is a rare inherited degradation of the retina, characterized by progressive loss of function in the most sensitive part of the central retina (macula), the location of the highest concentration of light-sensitive cells (photoreceptors) but presenting no visible abnormality. "Occult" refers to the degradation in the fundus being difficult to discern. The disorder is called "dystrophy" instead of "degradation" to distinguish its genetic origin from other causes, such as age. OMD was first reported by Y. Miyake et al. in 1989.
Stem cell therapy for macular degeneration is an emerging treatment approach aimed at restoring vision in individuals suffering from various forms of macular degeneration, particularly age-related macular degeneration (AMD). This therapy involves the transplantation of stem cells into the retina to replace damaged or lost retinal pigment epithelium (RPE) and photoreceptor cells, which are critical for central vision. Clinical trials have shown promise in stabilizing or improving visual function, but are nevertheless inefficient.
{{cite journal}}: CS1 maint: multiple names: authors list (link)20. Young B, Lowe JS, Stevens A, Heath JW. Wheater's Functional Histology: A Text and Atlas. 6th ed. Elsevier