Microdose lithium reduces cellular senescence in human astrocytes - a potential pharmacotherapy for COVID-19?

Abstract

Cell senescence is a process that causes growth arrest and the release of a senescence associated secretory phenotype (SASP), characterized by secretion of chemokines, cytokines, cell growth factors and metalloproteases, leading to a tissue condition that may precipitate cancers and neurodegenerative processes. With the recent pandemic of coronavirus, senolytic drugs are being considered as possible therapeutic tools to reduce the virulence of SARS-CoV-2. In the last few years, our research group showed that lithium carbonate at microdose levels was able to stabilize memory and change neuropathological characteristics of Alzheimer's disease (AD). In the present work, we present evidence that low-dose lithium can reduce the SASP of human iPSCs-derived astrocytes following acute treatment, suggesting that microdose lithium could protect cells from senescence and development of aging-related conditions. With the present findings, a perspective of the potential use of low-dose lithium in old patients from the "high risk group" for COVID-19 (with hypertension, diabetes and chronic obstructive pulmonary disease) is presented.

Keywords: COVID-19; cell senescence; chronic inflammation; lithium; senolytics.

Figure 1

Effects of increasing lithium concentrations on cell viability and induction of senescence and the SASP in human iPSC-derived astrocytes. (A, B) cell viability measured by the MTT assay. Data are expressed as individual points, mean and SEM; performed in triplicate. (C, D) Relative levels of secreted IL-6 and IL-8. Conditioned media was collected 24h following induction of senescence with 1% FBS and data was normalized to cell number. (E–G) RNA isolated from human iPSCs-derived astrocytes was analyzed for IL-1α, p16^INK4a and p21 mRNA levels by qPCR. Transcripts were normalized to actin and are shown as fold change over control levels. (H) GSK-3β activation measured as the proportion of phosphorylated and total GSK-3β. Data are expressed as individual points, mean and SEM. (I) SA β-gal in iPSC-derived astrocytes in the absence and presence of Aβ with increasing concentrations of lithium. Values show relative amounts of SA β-gal positive cells in three independent experiments. (J) Representative panels of SA-β gal staining under various treatment conditions.*p<0.05; **: p<0.01; ***:p < 0.001. For (C–H), data are expressed as individual points, mean and SEM of 4-5 independent experiments.