Abstract
Globally, 50 million people live with dementia, with Alzheimer disease (AD) being responsible for two-thirds of the total cases. As ageing is the main risk factor for dementia-related neurodegeneration, changes in the timing or nature of the cellular hallmarks of normal ageing might be key to understanding the events that convert normal ageing into neurodegeneration. Cellular senescence is a candidate mechanism that might be important for this conversion. Under persistent stress, as occurs in ageing, both postmitotic cells — including neurons — and proliferative cells — such as astrocytes and microglia, among others — can engender a state of chronic cellular senescence that is characterized by the secretion of pro-inflammatory molecules that promote the functional decline of tissues and organs. Ablation of senescent cells has been postulated as a promising therapeutic venue to target the ageing phenotype and, thus, prevent or mitigate ageing-related diseases. However, owing to a lack of evidence, it is not possible to label cellular senescence as a cause or a consequence of neurodegeneration. This Review examines cellular senescence in the context of ageing and AD, and discusses which of the processes — cellular senescence or AD — might come first.
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Change history
13 August 2020
A Correction to this paper has been published: https://doi.org/10.1038/s41583-020-0366-3
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This work was supported in part by the Intramural Research Program of the NIH, National Institute on Ageing.
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Glossary
- INK4–ARF locus
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A locus containing two genes, CDKN2A and CDKN2B. CDKN2A encodes two proteins, p16INK4a and ARF (known as p14ARF in humans and p19ARF in mice). Both proteins are cell cycle regulators that act as tumour suppressors and play an essential role in the induction and maintenance of senescence. CDKN2B encodes p15INK4b, a cyclin-dependent kinase inhibitor.
- Sterile inflammation
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A pathogen-free inflammatory process that can be triggered by an acute stimulus, such as ischaemia reperfusion injury, trauma or toxin exposure, or a chronic stimulus, as occurs in chronic diseases and ageing. Damaged cells produce and release damage-associated molecular patterns that activate innate immune cells, which release cytokines and chemokines, further activating an adaptive immune response. Unresolved and prolonged sterile inflammation is detrimental and contributes to ageing.
- Inflammaging
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Chronic and low-grade inflammation that is associated with ageing and contributes to the pathology of age-related disease. Three main stimuli sustain inflammaging: cell debris accumulation, microbial products from human microbiota and cellular senescence.
- Senolytic
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A small molecule that selectively eliminates senescent cells. The majority of senolytic compounds aim to target the anti-apoptotic members of the B cell lymphoma 2 (BCL-2) protein family, as they have been shown to be upregulated in senescent cells. Other senolytic strategies have explored impeding p53 activation, by blocking either the interaction of the E3 ubiquitin ligase MDM2 with p53 or the interaction of p53 with forkhead box protein O4 (FOXO4). More recently, drugs have been designed that get converted into cytotoxic compounds in senescent cells, inducing apoptosis, through cleavage by lysosomal β-galactosidase.
- Mitochondrial dysfunction-associated senescence
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A particular type of senescence observed in vitro and in vivo that is triggered by mitochondrial DNA damage. It involves activation of AMPK and subsequent activation of p53. Senescent cells induced by mitochondrial dysfunction-associated senescence exhibit a senescence-associated secretory phenotype, although it lacks IL-1-dependent factors.
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Saez-Atienzar, S., Masliah, E. Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat Rev Neurosci 21, 433–444 (2020). https://doi.org/10.1038/s41583-020-0325-z
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DOI: https://doi.org/10.1038/s41583-020-0325-z
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