Scientists at the Mayo Clinic have implicated senescent cells in yet another age-related pathology—namely, Alzheimer’s disease. Led by Dr. Darren Baker, the Mayo Clinic team discovered that clearing senescent microglia and astrocytes in murine brains leads to a much better prognosis for neurodegenerative disease .
Cellular senescence, which is characterized by an irreversible cell-cycle arrest accompanied by a distinctive secretory phenotype, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16INK4A have been found to actively drive naturally occurring age-related tissue deterioration and contribute to several diseases associated with ageing, including atherosclerosis and osteoarthritis. Various markers of senescence have been observed in patients with neurodegenerative diseases; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPTP301SPS19 mouse model of tau-dependent neurodegenerative disease accumulates p16INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INKATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.
Cellular senescence explained
Cellular senescence, one of the most currently active fields of biogerontological research, is a state of arrested growth in which cells stop dividing yet linger around. This state is associated with the expression of certain characteristic proteins, which can be used as markers to detect senescent cells, and the secretion of the senescence-associated secretory phenotype (SASP), which is a pro-inflammatory chemical cocktail that acts as a driving factor for a number of age-related pathologies.
Accumulation of senescent cells has been observed in a range of age-related diseases, such as osteoarthritis, and based on data from animal studies, it is thought that their selective elimination may contribute to the slowdown, prevention, and possibly reversal of a vast array of age-related ailments. Multiple senolytics, which are drugs that selectively purge senescent cells without harming the surrounding tissues, are currently under development by several rejuvenation-focused biotech companies.
Accumulation of senescent cells was previously observed even in the context of neurodegenerative pathologies, such as Alzheimer’s and Parkinson’s disease, but until now, a causal link between cellular senescence and neurodegeneration had never been established; this study, as Dr. Baker explained, shows exactly that.
A stage of Alzheimer’s disease is the production of so-called neurofibrillary tangles—webs built out of sticky tau proteins that impair neuronal activity. The Mayo Clinic team made use of an engineered mouse model of this pathology, which also had a sort of “backdoor”—a genetic modification that allows easy elimination of senescent cells.
Prior to cognitive loss, the model animals exhibit accumulation of senescent cells in the brain—specifically, microglia and astrocytes, crucial cell types that contribute to the maintenance of neurons and signaling between them. Unlike their untreated counterparts, mice in which these senescent cells were removed did not go on to develop neurofibrillary tangles and didn’t show the inflammation markers typical of their pathology, and their ability to form memories was preserved, as was normal brain mass.
This study cannot translate directly into clinical practice, as it involves genetically engineered mice; however, it does show how senescent cells are part of the complex picture of neurodegenerative disease and that pharmacologically clearing senescent cells might help ameliorate it—potentially in humans as well. It also provides further evidence that the pathologies of aging result from a convoluted interaction between several factors, of which senescence is only one and all of which need addressing if we are to comprehensively eliminate age-related diseases.
As the first specifically developed senolytic drug is being tested in a human clinical trial for its effects on osteoarthritis, we can be hopeful that first-generation human senolytics will be proven to work and clinically available in the relatively near future.
 Bussian, T. J., Aziz, A., Meyer, C. F., Swenson, B. L., van Deursen, J. M., & Baker, D. J. (2018). Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature.