Lipofuscin - Revision history

Dmitry Dzhagarov: /* Remofuscin */

2024-08-01T11:35:57Z

Remofuscin

← Older revision		Revision as of 11:35, 1 August 2024
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	Aging biomarkers were improved in remofuscin-treated ''Caenorhabditis elegans'' worms, resulting in '''a significant (p <0.05) increase in their lifespan'''.<ref name="elegans"/> The expression levels of genes related to lysosomes, a nuclear hormone receptor, fatty acid beta-oxidation, and xenobiotic detoxification were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. ''elegans'' with loss-of-function mutations of genes related to lysosomes and xenobiotic detoxification, suggesting that these genes are associated with lifespan extension in remofuscin-treated C. ''elegans''.<ref name="elegans"/>		Aging biomarkers were improved in remofuscin-treated ''Caenorhabditis elegans'' worms, resulting in '''a significant (p <0.05) increase in their lifespan'''.<ref name="elegans"/> The expression levels of genes related to lysosomes, a nuclear hormone receptor, fatty acid beta-oxidation, and xenobiotic detoxification were increased in remofuscin-treated worms. Moreover, remofuscin failed to extend the lives of C. ''elegans'' with loss-of-function mutations of genes related to lysosomes and xenobiotic detoxification, suggesting that these genes are associated with lifespan extension in remofuscin-treated C. ''elegans''.<ref name="elegans"/>

			=== Curcumin ===
			Intestinal lipofuscin levels were reduced by 39.5% and 47.5%, respectively, in curcumin-treated adult ''C. elegans'' day-4 and -8 days of adulthood nematodes, compared to untreated controls.<ref>Liao, V. H. C., Yu, C. W., Chu, Y. J., Li, W. H., Hsieh, Y. C., & Wang, T. T. (2011). Curcumin-mediated lifespan extension in Caenorhabditis elegans. Mechanisms of ageing and development, 132(10), 480-487. PMID: 21855561 DOI: 10.1016/j.mad.2011.07.008</ref> This ability of curcumin is apparently not related to its action as a [[senolytics]], since the potent senolytic fisetin, although it removed old cells, did not affect lipofuscin levels.<ref>Kampkötter, A., Gombitang Nkwonkam, C., Zurawski, R. F., Timpel, C., Chovolou, Y., Wätjen, W., & Kahl, R. (2007). Effects of the flavonoids kaempferol and fisetin on thermotolerance, oxidative stress and FoxO transcription factor DAF-16 in the model organism Caenorhabditis elegans. Archives of toxicology, 81, 849-858. PMID: 17551714 </ref>

	=== NMDA receptor antagonists ===		=== NMDA receptor antagonists ===

Dmitry Dzhagarov at 10:42, 1 August 2024

2024-08-01T10:42:15Z

← Older revision		Revision as of 10:42, 1 August 2024
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	'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref>		'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref> In motor neurons of centenarians, up to 75% of cell volume can be occupied by lipofuscin.<ref>Yin, D. (1996). Biochemical basis of lipofuscin, ceroid, and age pigment-like fluorophores. Free Radical Biology and Medicine, 21(6), 871-888. PMID: 8902532 DOI: 10.1016/0891-5849(96)00175-x</ref>
	[[File:Lipofuscin.jpg\|thumb\|Lipofuscin spots on the upper surface of the hands.]]		[[File:Lipofuscin.jpg\|thumb\|Lipofuscin spots on the upper surface of the hands.]]
	Lipofuscin is proposed as a [[Cellular senescence\|senescent]] marker in long-lived, non-dividing cells of different tissues across species. However, it is not 100% specific to senescent cells, as it can accumulate in conditions such as age-related macular degeneration (AMD).<ref>Georgakopoulou EA, Tsimaratou K, Evangelou K, Fernandez Marcos PJ, Zoumpourlis V, Trougakos IP, Kletsas D, Bartek J, Serrano M, Gorgoulis VG. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013 Jan;5(1):37-50. doi: 10.18632/aging.100527.</ref> Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy\|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>		Lipofuscin is proposed as a [[Cellular senescence\|senescent]] marker in long-lived, non-dividing cells of different tissues across species. However, it is not 100% specific to senescent cells, as it can accumulate in conditions such as age-related macular degeneration (AMD).<ref>Georgakopoulou EA, Tsimaratou K, Evangelou K, Fernandez Marcos PJ, Zoumpourlis V, Trougakos IP, Kletsas D, Bartek J, Serrano M, Gorgoulis VG. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013 Jan;5(1):37-50. doi: 10.18632/aging.100527.</ref> Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy\|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>

Dmitry Dzhagarov: /* See also */

2024-07-30T16:02:29Z

Dmitry Dzhagarov: /* NMDA receptor antagonists */

2024-04-10T11:16:14Z

NMDA receptor antagonists

← Older revision		Revision as of 11:16, 10 April 2024
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	=== NMDA receptor antagonists ===		=== NMDA receptor antagonists ===
	N-methyl-D-aspartate (NMDA) signaling is a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. NMDA receptor antagonists, such as '''Ro 25-6981''', '''CP-101,606''' and '''AZD6765''', degrade lipofuscin via [[autophagy]] in human RPE cells.<ref>Lee, J. R., & Jeong, K. W. (2022). NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells. Medicina, 58(8), 1129. PMID: 36013596 ~~PMCID~~: PMC9415004 DOI: 10.3390/medicina58081129</ref>		N-methyl-D-aspartate (NMDA) receptors signaling is a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. NMDA receptor antagonists, such as '''Ro 25-6981''', '''CP-101,606''' and '''AZD6765''', degrade lipofuscin via [[autophagy]] in human RPE cells.<ref>Lee, J. R., & Jeong, K. W. (2022). NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells. Medicina, 58(8), 1129. PMID: 36013596 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9415004 PMC9415004] DOI: 10.3390/medicina58081129</ref> Ro 25-6981 has not yet been approved for clinical use. Among the clinically approved NMDA antagonists, '''memantine''' and '''ifenprodil''' have been proposed as drug repositioning to remove N-retinylidene-N-retinylethanolamine (A2E), an intracellular lipofuscin component.<ref>Lee, J. R., & Jeong, K. W. (2023). N-retinylidene-N-retinylethanolamine degradation in human retinal pigment epithelial cells via memantine-and ifenprodil-mediated autophagy. The Korean Journal of Physiology & Pharmacology: Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology, 27(5), 449. PMID: 37641807 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10466070 PMC10466070] DOI: 10.4196/kjpp.2023.27.5.449</ref>

			=== ATM inhibition ===
			The increase in lipid peroxidation during oxidative stress increases the content of intra-lysosomal lipofuscins in fibroblasts during senescence.<ref>McHugh, D., & Gil, J. (2018). Senescence and aging: Causes, consequences, and therapeutic avenues. Journal of Cell Biology, 217(1), 65-77.</ref> Senescence amelioration in normal aging cells is mediated by the recovered mitochondrial function upon inhibition of a key mediator of DNA damage signaling and repair - Ataxia telangiectasia mutated (ATM).<ref>Khanna, K. K., Lavin, M. F., Jackson, S. P., & Mulhern, T. D. (2001). ATM, a central controller of cellular responses to DNA damage. Cell Death & Differentiation, 8(11), 1052-1065.</ref><ref>Kang, H. T., Park, J. T., Choi, K., Kim, Y., Choi, H. J. C., Jung, C. W., ... & Park, S. C. (2017). Chemical screening identifies ATM as a target for alleviating senescence. Nature chemical biology, 13(6), 616-623. PMID: 28346404 DOI: 10.1038/nchembio.2342</ref><ref>Song, S. B., & Hwang, E. S. (2020). High levels of ROS impair lysosomal acidity and autophagy flux in glucose-deprived fibroblasts by activating ATM and Erk pathways. Biomolecules, 10(5), 761. PMID: 32414146 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277562/ PMC7277562] DOI: 10.3390/biom10050761</ref>

			ATM inhibitors '''KU-60019''', '''CP-466722''' or antioxidant '''N-acetyl-cysteine (NAC)''' significantly reduced lipofuscin accumulation.<ref>Song, S. B., Shim, W., & Hwang, E. S. (2023). Lipofuscin granule accumulation requires autophagy activation. Molecules and Cells, 46(8), 486-495. PMID: 37438887 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440269 PMC10440269] DOI: 10.14348/molcells.2023.0019</ref>

	== See also ==		== See also ==

Dmitry Dzhagarov: /* Relation to aging diseases */

2024-03-30T14:56:50Z

Relation to aging diseases

← Older revision		Revision as of 14:56, 30 March 2024
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	== Relation to aging diseases ==		== Relation to aging diseases ==
	Because lipofuscin is a covalently cross-linked aggregate, it cannot be removed from the cytosol by the ubiquitin-proteasome system.<ref>Brunk, U. T., & Terman, A. (2002). Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radical Biology and Medicine, 33(5), 611-619. DOI: 10.1016/s0891-5849(02)00959-0</ref><ref>Höhn, A., & Grune, T. (2013). Lipofuscin: formation, effects and role of macroautophagy. Redox biology, 1(1), 140-144. PMID: 24024146 PMCID: PMC3757681 DOI: 10.1016/j.redox.2013.01.006</ref> Furthermore, lipofuscin could belong to [[~~advanced~~ glycation end ~~product~~ (~~AGE~~)]] deposits.<ref>Nozynski, J., Zakliczynski, M., Konecka-Mrowka, D., Zakliczynska, H., Pijet, M., Zembala-Nozynska, E., ... & Zembala, M. (2013). Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart. Experimental Gerontology, 48(2), 223-228. PMID: 22982091 DOI: 10.1016/j.exger.2012.09.002</ref>		Because lipofuscin is a covalently cross-linked aggregate, it cannot be removed from the cytosol by the ubiquitin-proteasome system.<ref>Brunk, U. T., & Terman, A. (2002). Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radical Biology and Medicine, 33(5), 611-619. DOI: 10.1016/s0891-5849(02)00959-0</ref><ref>Höhn, A., & Grune, T. (2013). Lipofuscin: formation, effects and role of macroautophagy. Redox biology, 1(1), 140-144. PMID: 24024146 PMCID: PMC3757681 DOI: 10.1016/j.redox.2013.01.006</ref> Furthermore, lipofuscin could belong to [[Advanced glycation end products (AGEs)]] deposits.<ref>Nozynski, J., Zakliczynski, M., Konecka-Mrowka, D., Zakliczynska, H., Pijet, M., Zembala-Nozynska, E., ... & Zembala, M. (2013). Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart. Experimental Gerontology, 48(2), 223-228. PMID: 22982091 DOI: 10.1016/j.exger.2012.09.002</ref>

	Isolated lipofuscin aggregates, as shown in vitro, were readily incorporated by fibroblasts and caused cell death at low concentrations (LC50 = 5.0 µg/mL) via a pyroptosis-like pathway. Lipofuscin boosted mitochondrial ROS production and caused lysosomal dysfunction by lysosomal membrane permeabilization leading to reduced lysosome quantity and impaired cathepsin D activity.<ref>Baldensperger T., Jung T., Heinze T., Schwerdtle T., Höhn A., Grune T. (2024). Age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death. bioRxiv .03.25.586520; doi: https://doi.org/10.1101/2024.03.25.586520</ref>		Isolated lipofuscin aggregates, as shown in vitro, were readily incorporated by fibroblasts and caused cell death at low concentrations (LC50 = 5.0 µg/mL) via a pyroptosis-like pathway. Lipofuscin boosted mitochondrial ROS production and caused lysosomal dysfunction by lysosomal membrane permeabilization leading to reduced lysosome quantity and impaired cathepsin D activity.<ref>Baldensperger T., Jung T., Heinze T., Schwerdtle T., Höhn A., Grune T. (2024). Age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death. bioRxiv .03.25.586520; doi: https://doi.org/10.1101/2024.03.25.586520</ref>

Dmitry Dzhagarov: /* Relation to aging diseases */

2024-03-30T14:54:43Z

Relation to aging diseases

← Older revision		Revision as of 14:54, 30 March 2024
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	== Relation to aging diseases ==		== Relation to aging diseases ==
	Because lipofuscin is a covalently cross-linked aggregate, it cannot be removed from the cytosol by the ubiquitin-proteasome system.<ref>Brunk, U. T., & Terman, A. (2002). Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radical Biology and Medicine, 33(5), 611-619. DOI: 10.1016/s0891-5849(02)00959-0</ref><ref>Höhn, A., & Grune, T. (2013). Lipofuscin: formation, effects and role of macroautophagy. Redox biology, 1(1), 140-144. PMID: 24024146 PMCID: PMC3757681 DOI: 10.1016/j.redox.2013.01.006</ref> Furthermore, lipofuscin could belong to [[advanced glycation end product (AGE)]] deposits.<ref>Nozynski, J., Zakliczynski, M., Konecka-Mrowka, D., Zakliczynska, H., Pijet, M., Zembala-Nozynska, E., ... & Zembala, M. (2013). Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart. Experimental Gerontology, 48(2), 223-228. PMID: 22982091 DOI: 10.1016/j.exger.2012.09.002</ref>		Because lipofuscin is a covalently cross-linked aggregate, it cannot be removed from the cytosol by the ubiquitin-proteasome system.<ref>Brunk, U. T., & Terman, A. (2002). Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radical Biology and Medicine, 33(5), 611-619. DOI: 10.1016/s0891-5849(02)00959-0</ref><ref>Höhn, A., & Grune, T. (2013). Lipofuscin: formation, effects and role of macroautophagy. Redox biology, 1(1), 140-144. PMID: 24024146 PMCID: PMC3757681 DOI: 10.1016/j.redox.2013.01.006</ref> Furthermore, lipofuscin could belong to [[advanced glycation end product (AGE)]] deposits.<ref>Nozynski, J., Zakliczynski, M., Konecka-Mrowka, D., Zakliczynska, H., Pijet, M., Zembala-Nozynska, E., ... & Zembala, M. (2013). Advanced glycation end products and lipofuscin deposits share the same location in cardiocytes of the failing heart. Experimental Gerontology, 48(2), 223-228. PMID: 22982091 DOI: 10.1016/j.exger.2012.09.002</ref>

			Isolated lipofuscin aggregates, as shown in vitro, were readily incorporated by fibroblasts and caused cell death at low concentrations (LC50 = 5.0 µg/mL) via a pyroptosis-like pathway. Lipofuscin boosted mitochondrial ROS production and caused lysosomal dysfunction by lysosomal membrane permeabilization leading to reduced lysosome quantity and impaired cathepsin D activity.<ref>Baldensperger T., Jung T., Heinze T., Schwerdtle T., Höhn A., Grune T. (2024). Age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death. bioRxiv .03.25.586520; doi: https://doi.org/10.1101/2024.03.25.586520</ref>

	Lipofuscin granules accumulation can lead to pathology and accelerate the aging process.<ref>Feldman, T. B., Dontsov, A. E., Yakovleva, M. A., & Ostrovsky, M. A. (2022). Photobiology of lipofuscin granules in the retinal pigment epithelium cells of the eye: norm, pathology, age. Biophysical Reviews, 1-15. PMID: 36124271 PMCID: PMC9481861 (available on 2023-08-08) DOI: 10.1007/s12551-022-00989-9</ref> The rate of lipofuscin formation has been shown to be negatively correlated with the life expectancy of postmitotic cells, i.e., the higher the rate, the shorter the lifespan of the cell due to decrease of cellular adaptability.<ref>Jung, T., Bader, N., & Grune, T. (2007). Lipofuscin: formation, distribution, and metabolic consequences. Annals of the New York Academy of Sciences, 1119(1), 97-111. PMID: 18056959 DOI: 10.1196/annals.1404.008</ref> Therefore, progressive deposition of lipofuscin might promote the development of age-related pathologies, including macular degeneration, heart failure, and neuro-degenerative diseases.		Lipofuscin granules accumulation can lead to pathology and accelerate the aging process.<ref>Feldman, T. B., Dontsov, A. E., Yakovleva, M. A., & Ostrovsky, M. A. (2022). Photobiology of lipofuscin granules in the retinal pigment epithelium cells of the eye: norm, pathology, age. Biophysical Reviews, 1-15. PMID: 36124271 PMCID: PMC9481861 (available on 2023-08-08) DOI: 10.1007/s12551-022-00989-9</ref> The rate of lipofuscin formation has been shown to be negatively correlated with the life expectancy of postmitotic cells, i.e., the higher the rate, the shorter the lifespan of the cell due to decrease of cellular adaptability.<ref>Jung, T., Bader, N., & Grune, T. (2007). Lipofuscin: formation, distribution, and metabolic consequences. Annals of the New York Academy of Sciences, 1119(1), 97-111. PMID: 18056959 DOI: 10.1196/annals.1404.008</ref> Therefore, progressive deposition of lipofuscin might promote the development of age-related pathologies, including macular degeneration, heart failure, and neuro-degenerative diseases.

Dmitry Dzhagarov at 07:25, 24 August 2023

2023-08-24T07:25:52Z

← Older revision		Revision as of 07:25, 24 August 2023
Line 1:		Line 1:
	'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref>		'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref>
			[[File:Lipofuscin.jpg\|thumb\|Lipofuscin spots on the upper surface of the hands.]]
	Lipofuscin is proposed as a [[Cellular senescence\|senescent]] marker in long-lived, non-dividing cells of different tissues across species. However, it is not 100% specific to senescent cells, as it can accumulate in conditions such as age-related macular degeneration (AMD).<ref>Georgakopoulou EA, Tsimaratou K, Evangelou K, Fernandez Marcos PJ, Zoumpourlis V, Trougakos IP, Kletsas D, Bartek J, Serrano M, Gorgoulis VG. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013 Jan;5(1):37-50. doi: 10.18632/aging.100527.</ref> Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy\|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>		Lipofuscin is proposed as a [[Cellular senescence\|senescent]] marker in long-lived, non-dividing cells of different tissues across species. However, it is not 100% specific to senescent cells, as it can accumulate in conditions such as age-related macular degeneration (AMD).<ref>Georgakopoulou EA, Tsimaratou K, Evangelou K, Fernandez Marcos PJ, Zoumpourlis V, Trougakos IP, Kletsas D, Bartek J, Serrano M, Gorgoulis VG. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013 Jan;5(1):37-50. doi: 10.18632/aging.100527.</ref> Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy\|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>

Andrea at 00:07, 21 July 2023

2023-07-21T00:07:57Z

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Andrea: /* */

2023-02-15T19:02:30Z

← Older revision		Revision as of 19:02, 15 February 2023
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	One of the diseases associated with the accumulation of lipofuscin is dry [[Aging and eye disease\|age-related macular degeneration]] (dry AMD) – a disease often diagnosed in people over 70 years of age and a leading cause of rapid vision loss. Dry AMD is a slow-progressing disease in which yellow drusen containing lipofuscin are deposited between the retinal pigment epithelial (RPE) cell layer and Bruch’s membrane.<ref>Jhingan, M., Singh, S. R., Samanta, A., Arora, S., Tucci, D., Amarasekera, S., ... & Chhablani, J. (2021). Drusen ooze: predictor for progression of dry age-related macular degeneration. Graefe's Archive for Clinical and Experimental Ophthalmology, 259(9), 2687-2694. DOI:[https://doi.org/10.1007/s00417-021-05147-7 10.1007/s00417-021-05147-7]</ref> A phototoxic components of lipofuscin such as A2E (Bis-retinoid N-retinyl-N-retinylidene ethanolamine) that induces inflammation and apoptosis in RPE cells,<ref>Sparrow, J. R., & Boulton, M. (2005). RPE lipofuscin and its role in retinal pathobiology. Experimental eye research, 80(5), 595-606.</ref> are accumulated with age and mediate damage under blue light exposure.<ref>Brandstetter, C., Mohr, L. K., Latz, E., Holz, F. G., & Krohne, T. U. (2015). Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. Journal of Molecular Medicine, 93(8), 905-916. PMID: 25783493 PMC4510924 DOI: 10.1007/s00109-015-1275-1</ref><ref name="Light">Jin, H. L., & Jeong, K. W. (2022). Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells. Biomolecules & therapeutics, 30(3), 291. PMID: 35074938 PMCID: PMC9047491 DOI: 10.4062/biomolther.2021.155</ref> It has been reported that iron levels increase in RPE during ageing and this intracellular iron can interact with bisretinoid lipofuscin in RPE to promote cell damage.<ref>Zhao, T., Guo, X., & Sun, Y. (2021). Iron accumulation and lipid peroxidation in the aging retina: implication of ferroptosis in age-related macular degeneration. Aging and disease, 12(2), 529. PMID: 33815881 PMCID: PMC7990372 DOI: 10.14336/AD.2020.0912</ref> Therefore, to alleviate the deteriorating effects of lipofuscin on age-related macular degeneration, iron chelation, either independently or in combination with bisretinoid inhibitors could potentially serve as AMD treatments.<ref>Ueda, K., Kim, H. J., Zhao, J., Song, Y., Dunaief, J. L., & Sparrow, J. R. (2018). Iron promotes oxidative cell death caused by bisretinoids of retina. Proceedings of the National Academy of Sciences, 115(19), 4963-4968. PMID: 29686088 PMCID: PMC5948992 DOI: 10.1073/pnas.1722601115</ref> To protect human RPE cells from oxidative damage, caused by reactive oxygen species generated by the photo-excited lipofuscin, also is able L‐Citrulline, a naturally occurring amino acid with known antioxidant properties<ref>Hassel, C., Couchet, M., Jacquemot, N., Blavignac, C., Loï, C., Moinard, C., & Cia, D. (2022). Citrulline protects human retinal pigment epithelium from hydrogen peroxide and iron/ascorbate induced damages. Journal of Cellular and Molecular Medicine, 26(10), 2808-2818. PMID: 35460170 PMCID: PMC9097847 DOI: 10.1111/jcmm.17294</ref> and the main active component of ''Spirulina maxima'' P-phycocyanin - pigment with anti-inflammatory and antioxidant activities.<ref>Cho, H. M., Jo, Y. D., & Choung, S. Y. (2022). Protective Effects of Spirulina maxima against Blue Light-Induced Retinal Damages in A2E-Laden ARPE-19 Cells and Balb/c Mice. Nutrients, 14(3), 401. PMID: 35276761 PMCID: PMC8840079 DOI: 10.3390/nu14030401</ref>		One of the diseases associated with the accumulation of lipofuscin is dry [[Aging and eye disease\|age-related macular degeneration]] (dry AMD) – a disease often diagnosed in people over 70 years of age and a leading cause of rapid vision loss. Dry AMD is a slow-progressing disease in which yellow drusen containing lipofuscin are deposited between the retinal pigment epithelial (RPE) cell layer and Bruch’s membrane.<ref>Jhingan, M., Singh, S. R., Samanta, A., Arora, S., Tucci, D., Amarasekera, S., ... & Chhablani, J. (2021). Drusen ooze: predictor for progression of dry age-related macular degeneration. Graefe's Archive for Clinical and Experimental Ophthalmology, 259(9), 2687-2694. DOI:[https://doi.org/10.1007/s00417-021-05147-7 10.1007/s00417-021-05147-7]</ref> A phototoxic components of lipofuscin such as A2E (Bis-retinoid N-retinyl-N-retinylidene ethanolamine) that induces inflammation and apoptosis in RPE cells,<ref>Sparrow, J. R., & Boulton, M. (2005). RPE lipofuscin and its role in retinal pathobiology. Experimental eye research, 80(5), 595-606.</ref> are accumulated with age and mediate damage under blue light exposure.<ref>Brandstetter, C., Mohr, L. K., Latz, E., Holz, F. G., & Krohne, T. U. (2015). Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage. Journal of Molecular Medicine, 93(8), 905-916. PMID: 25783493 PMC4510924 DOI: 10.1007/s00109-015-1275-1</ref><ref name="Light">Jin, H. L., & Jeong, K. W. (2022). Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells. Biomolecules & therapeutics, 30(3), 291. PMID: 35074938 PMCID: PMC9047491 DOI: 10.4062/biomolther.2021.155</ref> It has been reported that iron levels increase in RPE during ageing and this intracellular iron can interact with bisretinoid lipofuscin in RPE to promote cell damage.<ref>Zhao, T., Guo, X., & Sun, Y. (2021). Iron accumulation and lipid peroxidation in the aging retina: implication of ferroptosis in age-related macular degeneration. Aging and disease, 12(2), 529. PMID: 33815881 PMCID: PMC7990372 DOI: 10.14336/AD.2020.0912</ref> Therefore, to alleviate the deteriorating effects of lipofuscin on age-related macular degeneration, iron chelation, either independently or in combination with bisretinoid inhibitors could potentially serve as AMD treatments.<ref>Ueda, K., Kim, H. J., Zhao, J., Song, Y., Dunaief, J. L., & Sparrow, J. R. (2018). Iron promotes oxidative cell death caused by bisretinoids of retina. Proceedings of the National Academy of Sciences, 115(19), 4963-4968. PMID: 29686088 PMCID: PMC5948992 DOI: 10.1073/pnas.1722601115</ref> To protect human RPE cells from oxidative damage, caused by reactive oxygen species generated by the photo-excited lipofuscin, also is able L‐Citrulline, a naturally occurring amino acid with known antioxidant properties<ref>Hassel, C., Couchet, M., Jacquemot, N., Blavignac, C., Loï, C., Moinard, C., & Cia, D. (2022). Citrulline protects human retinal pigment epithelium from hydrogen peroxide and iron/ascorbate induced damages. Journal of Cellular and Molecular Medicine, 26(10), 2808-2818. PMID: 35460170 PMCID: PMC9097847 DOI: 10.1111/jcmm.17294</ref> and the main active component of ''Spirulina maxima'' P-phycocyanin - pigment with anti-inflammatory and antioxidant activities.<ref>Cho, H. M., Jo, Y. D., & Choung, S. Y. (2022). Protective Effects of Spirulina maxima against Blue Light-Induced Retinal Damages in A2E-Laden ARPE-19 Cells and Balb/c Mice. Nutrients, 14(3), 401. PMID: 35276761 PMCID: PMC8840079 DOI: 10.3390/nu14030401</ref>

	The drug Lysoclear is an enzyme developed to enter RPE cells and break down lipofuscin deposits in the lysosomes, a therapeutic approach that proposes to reverse dry age-related macular degeneration and Stargardt's macular degeneration.<ref>www.ichortherapeutics.com</ref>		The drug Lysoclear is an enzyme developed to enter RPE cells and break down lipofuscin deposits in the lysosomes, a therapeutic approach that proposes to reverse dry age-related macular degeneration and Stargardt's macular degeneration.<ref>www.ichortherapeutics.com</ref> Phase 1 clinical trials started in 2018.

	==== Zinc deficiency ====		==== Zinc deficiency ====

Andrea: /* Added clarification and relevant reference */

2023-02-15T18:59:50Z

Added clarification and relevant reference

← Older revision		Revision as of 18:59, 15 February 2023
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	'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref>		'''Lipofuscin''' is a yellow-brown autofluorescent pigment also known as "aging pigment" due to its age-related progressive accumulation. It is a waste product consisting of insoluble granules made of lipids and proteins that accumulate in the '''lysosomes''' of cells. Over time, the lysosome becomes clogged and is not able to continue working properly.<ref>Strehler, B. L., Mark, D. D., Mildvan, A. S., & Gee, M. V. (1959). Rate and magnitude of age pigment accumulation in the human myocardium. Journal of gerontology, 14(4), 430-439. DOI: 10.1093/geronj/14.4.430</ref><ref>Reichel, W. (1968). Lipofuscin pigment accumulation and distribution in five rat organs as a function of age. Journal of gerontology, 23(2), 145-153. DOI: 10.1093/geronj/23.2.145</ref><ref>Mann, D. M. A., Yates, P. O., & Stamp, J. E. (1978). The relationship between lipofuscin pigment and ageing in the human nervous system. Journal of the Neurological Sciences, 37(1-2), 83-93. DOI: 10.1016/0022-510x(78)90229-0</ref>

	Lipofuscin is proposed as a ~~robust~~ [[Cellular senescence\|senescent]] marker in long-lived non-dividing cells of different tissues across species. Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy\|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>		Lipofuscin is proposed as a [[Cellular senescence\|senescent]] marker in long-lived, non-dividing cells of different tissues across species. However, it is not 100% specific to senescent cells, as it can accumulate in conditions such as AMD.<ref>Georgakopoulou EA, Tsimaratou K, Evangelou K, Fernandez Marcos PJ, Zoumpourlis V, Trougakos IP, Kletsas D, Bartek J, Serrano M, Gorgoulis VG. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging (Albany NY). 2013 Jan;5(1):37-50. doi: 10.18632/aging.100527.</ref> Lipofuscin accumulation in the lysosomes cause dysregulation and reduction of its [[Autophagy\|autophagic]] capacity, generating ROS (reactive oxygen species), elevating lysosomal pH and leading to lysosome leakage.<ref>Dutta, R. K., Lee, J. N., Maharjan, Y., Park, C., Choe, S. K., Ho, Y. S., ... & Park, R. (2022). Catalase-deficient mice induce aging faster through lysosomal dysfunction. Cell Communication and Signaling, 20(1), 1-22. PMID:36474295 PMC9724376 DOI: 10.1186/s12964-022-00969-2</ref> Lipofuscin consists of a non-degradable intralysosomal substance, which forms mainly due to iron-catalyzed oxidation/polymerization of misfolded proteins (~30–70%) and lipid (~20–50%) residues together with metals such as iron, copper, zinc, manganese, and calcium, in a concentration up to 2%.<ref>Höhn, A., Jung, T., Grimm, S., & Grune, T. (2010). Lipofuscin-bound iron is a major intracellular source of oxidants: role in senescent cells. Free Radical Biology and Medicine, 48(8), 1100-1108. PMID: 20116426 DOI: 10.1016/j.freeradbiomed.2010.01.030</ref><ref>Double, K. L., Dedov, V. N., Fedorow, H., Kettle, E., Halliday, G. M., Garner, B., & Brunk, U. T. (2008). The comparative biology of neuromelanin and lipofuscin in the human brain. Cellular and Molecular Life Sciences, 65(11), 1669-1682. PMID: 18278576 Doi:[https://doi.org/10.1007/s00018-008-7581-9 10.1007/s00018-008-7581-9]</ref><ref name="Terman">Terman, A., & Brunk, U. T. (1998). Lipofuscin: mechanisms of formation and increase with age. Apmis, 106(1‐6), 265-276. Doi:[https://doi.org/10.1111/j.1699-0463.1998.tb01346.x 10.1111/j.1699-0463.1998.tb01346.x]</ref><ref name="iron">Marzabadi, M. R., & Løvaas, E. (1996). Spermine prevent iron accumulation and depress lipofuscin accumulation in cultured myocardial cells. Free Radical Biology and Medicine, 21(3), 375-381. DOI:[https://doi.org/10.1016/0891-5849(96)00038-X 10.1016/0891-5849(96)00038-x]</ref><ref>Terman, A., & Brunk, U. T. (2004). Lipofuscin. The international journal of biochemistry & cell biology, 36(8), 1400-1404. Doi:[https://doi.org/10.1016/j.biocel.2003.08.009 10.1016/j.biocel.2003.08.009]</ref>

	Accumulation of lipofuscin or "aging pigment" is part of normal aging, and should be distinguished from accumulation of '''ceroid''' - autofluorescent storage material associated with disease and usually produced under various pathological conditions not necessarily related to aging.<ref>Seehafer, S. S., & Pearce, D. A. (2006). You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiology of aging, 27(4), 576-588. PMID: 16455164 DOI: 10.1016/j.neurobiolaging.2005.12.006</ref> Ceroid has been suggested to jeopardize cell performance and viability by inducing membrane fragility, mitochondrial dysfunction, DNA damage, and oxidative stress-induced apoptosis.<ref>		Accumulation of lipofuscin or "aging pigment" is part of normal aging, and should be distinguished from accumulation of '''ceroid''' - autofluorescent storage material associated with disease and usually produced under various pathological conditions not necessarily related to aging.<ref>Seehafer, S. S., & Pearce, D. A. (2006). You say lipofuscin, we say ceroid: defining autofluorescent storage material. Neurobiology of aging, 27(4), 576-588. PMID: 16455164 DOI: 10.1016/j.neurobiolaging.2005.12.006</ref> Ceroid has been suggested to jeopardize cell performance and viability by inducing membrane fragility, mitochondrial dysfunction, DNA damage, and oxidative stress-induced apoptosis.<ref>

← Older revision		Revision as of 16:02, 30 July 2024
Line 59:		Line 59:

	== See also ==		== See also ==
			* Renteln, M. (2024). Toward systemic lipofuscin removal. Rejuvenation Research, (ja). https://doi.org/10.1089/rej.2024.0034
	* Ilie, O. D., Ciobica, A., Riga, S., Dhunna, N., McKenna, J., Mavroudis, I., ... & Riga, D. (2020). Mini-review on lipofuscin and aging: focusing on the molecular interface, the biological recycling mechanism, oxidative stress, and the gut-brain axis functionality. Medicina, 56(11), 626. PMID: 33228124 PMCID: PMC7699382 DOI: 10.3390/medicina56110626		* Ilie, O. D., Ciobica, A., Riga, S., Dhunna, N., McKenna, J., Mavroudis, I., ... & Riga, D. (2020). Mini-review on lipofuscin and aging: focusing on the molecular interface, the biological recycling mechanism, oxidative stress, and the gut-brain axis functionality. Medicina, 56(11), 626. PMID: 33228124 PMCID: PMC7699382 DOI: 10.3390/medicina56110626
	* Nasiri, L., Vaez-Mahdavi, M. R., Hassanpour, H., Ghazanfari, T., Ardestani, S. K., Askari, N., ... & Rahimlou, B. (2023). Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence. International Immunopharmacology, 114, 109549. https://doi.org/10.1016/j.intimp.2022.109549 <small>Chronic oxidative stress and continuous inflammatory stimulation in veterans, due to mustard gas poisoning once in 1987, led to cells senescence with increased lipofuscin, and telomere shortening.</small>		* Nasiri, L., Vaez-Mahdavi, M. R., Hassanpour, H., Ghazanfari, T., Ardestani, S. K., Askari, N., ... & Rahimlou, B. (2023). Increased serum lipofuscin associated with leukocyte telomere shortening in veterans: a possible role for sulfur mustard exposure in delayed-onset accelerated cellular senescence. International Immunopharmacology, 114, 109549. https://doi.org/10.1016/j.intimp.2022.109549 <small>Chronic oxidative stress and continuous inflammatory stimulation in veterans, due to mustard gas poisoning once in 1987, led to cells senescence with increased lipofuscin, and telomere shortening.</small>