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Cited by 149Autophagy in Disease and TherapyLysosomal Storage Disorders ResearchGenetics, Aging, and Longevity in Model Organisms

The aging lysosome: An essential catalyst for late-onset neurodegenerative diseases

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Nixon, Ralph A.·2020·Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
DOI 10.1016/j.bbapap.2020.140443PMC PMC7388076
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Abstract

Lysosomes figure prominently in theories of aging as the proteolytic system most responsible for eliminating growing burdens of damaged proteins and organelles in aging neurons and other long lived cells. Newer evidence shows that diverse experimental measures known to extend lifespan in invertebrate aging models share the property of boosting lysosomal clearance of substrates through the autophagy pathway. Maintaining an optimal level of lysosome acidification is particularly crucial for these anti-aging effects. The exceptional dependence of neurons on fully functional lysosomes is reflected by the neurological phenotypes that develop in congenital lysosomal storage disorders, which commonly present as severe neurodevelopmental or neurodegenerative conditions even though the lysosomal deficit maybe systemic. Similar connections are now being appreciated between primary lysosomal deficit and the risk for late age-onset neurodegenerative disorders. In diseases such as Alzheimer's and Parkinson's, as in aging alone, primary lysosome dysfunction due to acidification impairment is emerging as a frequent theme, supported by the growing list of familial neurodegenerative disorders that involve primary vATPase dysfunction. The additional cellular roles played by intraluminal pH in sensing nutrient and stress and modulating cellular signaling have further expanded the possible ways that lysosomal pH dysregulation in aging and disease can disrupt neuronal function. Here, we consider the impact of cellular aging on lysosomes and how the changes during aging may create the tipping point for disease emergence in major late-age onset neurodegenerative disorders.

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  • NCL-associated genes typically encode proteins involved in proteolysis, lipid catabolism, or have unidentified lysosomal roles.

    “The genes associated with NCLs are typically in proteins involved in proteolysis (such as the cathepsin proteases), lipid catabolism, or have unidentified roles in the lysosome (e.g., MSFD8).118”

    From The lysosome and proteostatic stress at the intersection of pediatric neurological disorders and adult neurodegenerative diseases (2025) · cites this paper as [118]

    The Introduction (“Aging lysosomes – a critical precondition for late-age onset neurodegenerative diseases”; page unavailable) links progranulin mutations to childhood NCL, but does not classify NCL-associated genes by protein function. Searches for MFSD8, proteolysis, lipid catabolism, and NCL-associated genes found no passage in our copy stating the claimed categories. (LLM, conf=0.73)

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Authors
Nixon, R. A.
Affiliations
Nathan Kline Institute for Psychiatric Research (US)
Corresponding author
Nixon, Ralph A.
ORCID
Nixon, Ralph A.
Venue
Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Publisher
Elsevier BV
Published
2020-09
Volume
1868
Issue
9
Pages
140443
ISSN
1570-9639 (ISSN-L)
DOI
10.1016/j.bbapap.2020.140443
PMC
PMC7388076
OpenAlex
W3024127790
Cited by
149
References
139
Citations by year
2026: 31 · 2025: 24 · 2024: 30 · 2023: 21 · 2022: 20 · 2021: 18 · 2020: 4 · 2019: 1
FWCI
2.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
lysosomes, cellular aging, lysosomal acidification, autophagy, lysosomal storage disease, Alzheimer's disease, Parkinson's disease, lysosomal pH, lifespan extension, neuronal function, protein clearance
MeSH terms
Aging, Alzheimer Disease, Animals, Autophagy, Humans, Hydrogen-Ion Concentration, Hydrolases, Lysosomes, Parkinson Disease, Oxidative Stress, Neurodegenerative Diseases, Proteolysis

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