You are hereDecember 16, 2018 | Aging
Eliminating Senescent Cells as a New Approach to Neurodegenerative Disease Treatment
Review of “Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline” from Nature by Stuart P. Atkinson
Recent studies have established that the specific elimination of senescent tissue-resident cells can reverse many aging-related comorbidities, including deterioration of the cardiovascular system , the loss of insulin sensitivity , the loss of bone mass , and increased overall frailty . While reports have linked senescence to the development of aging-related neurodegenerative diseases in human patients , many questions, such as whether so-called “senolytic” drugs that target and eliminate senescent cells may improve symptoms, remain unanswered.
In a new Nature article, researchers led by Darren J. Baker (Mayo Clinic, Rochester, MN, USA) now describe a causal link between the accumulation of senescent glia and cognition-associated neuronal loss . Additionally, their analyses employing a mouse model of tau-dependent neurodegenerative disease  demonstrate that the pharmacological elimination of senescent glia represents a potentially effective therapeutic approach for the treatment of such pathologies.
Bussian et al. first analyzed the brains of mice specifically overexpressing human mutant tau in their neurons, discovering the accumulation of senescent glial cells before the deposition of neurofibrillary tangles (NFTs), neurodegeneration, and loss of cognitive function. The authors further engineered their mouse model to permit the inducible elimination of p16Ink4a-expressing senescent glia, which led to a reduction in the levels of hyperphosphorylated tau protein (both the soluble and insoluble fractions), NFTs in the dentate gyrus (a brain area associated with memory formation and cognition), and overall neurodegeneration and cognition loss. The authors then assessed the potential for pharmacological elimination of senescent cells with senescent-cell targeting “senolytic” drugs, reporting that treatment inhibited senescence-associated gene expression and attenuated tau phosphorylation.
The reduced degree of tau-dependent neurodegenerative disease after the selective elimination of senescent cells argues that disease progression depends on extracellular signaling from p16Ink4a-expressing senescent microglia, although the authors do note that other models of neurodegenerative disease may exhibit senescence-associated alterations in distinct cell types. The team now aims to propel their research forward in the hope that senolytic strategies can transit from the bench to the bedside and halt or even revert aging-related neurodegenerative disease in human patients.
For more on the role of senescent cells in human disease and the future of senolytic strategies as a new treatment approach to aging-related neurodegenerative disease, stay tuned to the Stem Cells Portal.
- Roos CM, Zhang B, Palmer AK, et al., Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 2016;15:973-7.
- Xu M, Palmer AK, Ding H, et al., Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 2015;4:e12997.
- Farr JN, Xu M, Weivoda MM, et al., Targeting cellular senescence prevents age-related bone loss in mice. Nature Medicine 2017;23:1072-1079.
- Xu M, Tchkonia T, Ding H, et al., JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proceedings of the National Academy of Sciences 2015;112: E6301-10.
- Tan FC, Hutchison ER, Eitan E, et al., Are there roles for brain cell senescence in aging and neurodegenerative disorders? Biogerontology 2014;15:643-60.
- Bussian TJ, Aziz A, Meyer CF, et al., Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 2018;562:578-582.
- Yoshiyama Y, Higuchi M, Zhang B, et al., Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007;53:337-51.