Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance

Abstract

Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.

Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures

“…However, a limitation of our study is that we did not quantify differences in microglia population dynamics, either in microglia number or turnover, resulting from miR-155 loss in the APP/PS1 brain. Since senescence and inflammatory expression profiles are increase with age and are brain region- and sex-specific [ 53 ], the effect of miR-155 modulation in the aged APP/PS1 brain requires further study. Future studies should focus not only on the changes in inflammatory gene expression in microglia in vivo as a result of miR-155 loss, but also on the impact of miR-155 loss in microglia population dynamics and other compensatory mechanisms potentially mediated by astrocytes.…”

An aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease

“…Indeed, shortened telomere lengths and increased immunosenescence are found in patients with LOAD 18 , 19 . Multiple mouse models displaying cognitive impairment and tissue dysfunction demonstrated senescent cells in the brain, where removing p16 INK4A -upregulated, likely-senescent cells was able to reduce inflammation and increased performance in spatial memory tasks 15 , 17 , 39 , 56 . The aged vs younger mouse brain has higher levels of senescent cell markers 15 , 17 .…”

“…Senescence is considered to play physiological roles, yet with aging it becomes implicated with accelerated mortality 7 . Senolytic drugs selectively removing senescent cells increase lifespan and quality of life in mice 15 – 17 . Although senescence involvement in LOAD has been explored 5 , 6 , 18 – 20 , how senescence relates to LOAD and Braak staging is not well defined.…”

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…The impaired surveillance of pre-malignant senescent cells resulted in the development of murine hepatocellular carcinoma (HCC) [ 109 ]. Senescent cells were reported to secrete various inflammatory cytokines, such as IL-1β, IL-6, IL-8, TGF-β, granulocyte-macrophage colony-stimulating factor (GM-CSF), and MCP-1, to induce senescence surveillance in p16-positive myeloid cells [ 110 ]. During Ras-induced senescence, Cyclooxygenase-2 (COX-2) promoted senescence surveillance and tumor suppression by regulating multiple components of the SASP, such as prostaglandin E2 (PGE2) and IL-6 [ 81 ].…”

“…Ras promotes cisplatin resistance through HDAC4, which activates transcription factor CREB3 regulatory factor (CREBZF) to increase ATG3 expression [ 110 ]. This suggests the positive regulatory role of HDAC4 in autophagy and anticancer drug resistance.…”