Extensive accumulation of misfolded protein aggregates during natural aging and senescence
Open accessAbstract
Accumulation of misfolded protein aggregates is a hallmark event in many age-related protein misfolding disorders, including some of the most prevalent and insidious neurodegenerative diseases. Misfolded protein aggregates produce progressive cell damage, organ dysfunction, and clinical changes, which are common also in natural aging. Thus, we hypothesized that aging is associated to the widespread and progressive misfolding and aggregation of many proteins in various tissues. In this study, we analyzed whether proteins misfold, aggregate, and accumulate during normal aging in three different biological systems, namely senescent cells, Caenorhabditis elegans , and mouse tissues collected at different times from youth to old age. Our results show a significant accumulation of misfolded protein aggregates in aged samples as compared to young materials. Indeed, aged samples have between 1.3 and 2.5-fold (depending on the biological system) higher amount of insoluble proteins than young samples. These insoluble proteins exhibit the typical characteristics of disease-associated aggregates, including insolubility in detergents, protease resistance, and staining with amyloid-binding dye as well as accumulation in aggresomes. We identified the main proteins accumulating in the aging brain using proteomic studies. These results show that the aged brain contain large amounts of misfolded and likely non-functional species of many proteins, whose soluble versions participate in cellular pathways that play fundamental roles in preserving basic functions, such as protein quality control, synapsis, and metabolism. Our findings reveal a putative role for protein misfolding and aggregation in aging.
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Defective myelination is a feature of many LSDs, as well as neurodegeneration.
“Thus, defective myelination is a feature of many LSDs, as well as neurodegeneration,39”
From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [39]
The Introduction and Discussion discuss protein misfolding, aging, and neurodegeneration, but do not link defective myelination to neurodegeneration or lysosomal storage diseases. Searches for myelin, myelination, oligodendrocytes, and lysosomal storage diseases found no passage addressing the claim; page numbers were not available in our copy. (LLM, conf=0.76)
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- Authors
- Cuanalo-Contreras, K., Schulz, J., Mukherjee, A., Park, K.-W., Armijo, E., & Soto, C.
- Affiliations
- The University of Texas Health Science Center at Houston (US)
- Universidad de Los Andes, Chile (CL)
- Corresponding author
- Soto, Claudio
- Venue
- Frontiers in Aging Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2023-01-26
- Volume
- 14
- Pages
- 1090109-1090109
- ISSN
- 1663-4365 (ISSN-L)
- PMC
- PMC9909609
- OpenAlex
- W4318067741
- Cited by
- 92
- References
- 91
- Citations by year
- 2026: 23 · 2025: 33 · 2024: 30 · 2023: 6
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Aging Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- normal aging, cellular senescence, neurodegenerative diseases, aggresomes, protease resistance, amyloid-like aggregates, brain aging, protein quality control, Caenorhabditis elegans, mouse tissues
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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