Lipofuscin: mechanisms of age-related accumulation and influence on cell function12 1Guest Editor: Rajindar S. Sohal 2This article is part of a series of reviews on “Oxidative Stress and Aging.” The full list of papers may be found on the homepage of the journal.
Abstract
The accumulation of lipofuscin within postmitotic cells is a recognized hallmark of aging occurring with a rate inversely related to longevity. Lipofuscin is an intralysosomal, polymeric substance, primarily composed of cross-linked protein residues, formed due to iron-catalyzed oxidative processes. Because it is undegradable and cannot be removed via exocytosis, lipofuscin accumulation in postmitotic cells is inevitable, whereas proliferative cells efficiently dilute it during division. The rate of lipofuscin formation can be experimentally manipulated. In cell culture models, oxidative stress (e.g., exposure to 40% ambient oxygen or low molecular weight iron) promotes lipofuscin accumulation, whereas growth at 8% oxygen and treatment with antioxidants or iron-chelators diminish it. Lipofuscin is a fluorochrome and may sensitize lysosomes to visible light, a process potentially important for the pathogenesis of age-related macular degeneration. Lipofuscin-associated iron sensitizes lysosomes to oxidative stress, jeopardizing lysosomal stability and causing apoptosis due to release of lysosomal contents. Lipofuscin accumulation may also diminish autophagocytotic capacity by acting as a sink for newly produced lysosomal enzymes and, therefore, interfere with recycling of cellular components. Lipofuscin, thus, may be much more directly related to cellular degeneration at old age than was hitherto believed.
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Cross-linked products that reach the lysosome through sporadic fusion with double membrane vesicles exert a potent inhibitory effect on lysosomal proteolysis by inducing posttranslational modifications in the enzymatic machinery and changing the intralysosomal milieu.
“cross-linked products that reach the lysosome through their sporadic fusion with the double membrane vesicles, exert a potent inhibitory effect on lysosomal proteolysis by directly inducing undesired posttranslational modifications in the enzymatic machinery and also by changing the properties of the intralysosomal milieu, normally optimal for functioning of these enzymes (Brunk and Terman, 2002;”
From Protein Homeostasis and Aging: the importance of exquisite quality control (2011) · cites this paper as Brunk and Terman, 2002
LF accumulation in aged post-mitotic tissues occurs most probably in the context of post-mitotic cellular senescence (PoMiCS), which is suspected to play a significant role in driving tissue aging, but LF can be present in non-senescent post-mitotic tissues and thus is not strictly senescence-specific.
“Of note, LF accumulation in aged post-mitotic tissues occurs most probably in the context of post-mitotic cellular senescence (PoMiCS), which is suspected to play a significant role in driving tissue aging29,30, but can be present in non-senescent post-mitotic tissues and thus is not strictly senescence-specific31.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [31]
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- Authors
- Brunk, U. T., & Terman, A.
- Affiliations
- Linköping University (SE)
- Corresponding author
- Brunk, Ulf T
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2002-09
- Volume
- 33
- Issue
- 5
- Pages
- 611-619
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W1538904872
- Cited by
- 919
- References
- 76
- Citations by year
- 2026: 36 · 2025: 49 · 2024: 36 · 2023: 49 · 2022: 31 · 2021: 36 · 2020: 44 · 2019: 42 · 2018: 42 · 2017: 48 · 2016: 41 · 2015: 46 · 2014: 35 · 2013: 34 · 2012: 46
- FWCI
- 20.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vetenskapsrådet
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- lipofuscin, aging, oxidative stress, iron-catalyzed oxidation, lysosomes, postmitotic cells, age-related macular degeneration, lysosomal stability, apoptosis, autophagy, antioxidants, iron chelators, cell degeneration, longevity
- MeSH terms
- Age Factors, Aging, Animals, Free Radicals, Humans, Iron, Lipofuscin, Lysosomes, Microscopy, Fluorescence, Models, Biological, Oxygen, Phagocytosis, Oxidative Stress
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