Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice

Abstract

Cellular senescence, a persistent state of cell cycle arrest, accumulates in aged organisms, contributes to tissue dysfunction, and drives age-related phenotypes. The clearance of senescent cells is expected to decrease chronic, low-grade inflammation and improve tissue repair capacity, thus attenuating the decline of physical function in aged organisms. However, selective and effective clearance of senescent cells of different cell types has proven challenging. Herein, we developed a prodrug strategy to design a new compound based on the increased activity of lysosomal β-galactosidase (β-gal), a primary characteristic of senescent cells. Our prodrug SSK1 is specifically activated by β-gal and eliminates mouse and human senescent cells independently of senescence inducers and cell types. In aged mice, our compound effectively cleared senescent cells in different tissues, decreased the senescence-and age-associated gene signatures, attenuated low-grade local and systemic inflammation, and restored physical function. Our results demonstrate that lysosomal β-gal can be effectively leveraged to selectively eliminate senescent cells, providing a novel strategy to develop anti-aging interventions.Cell Research (2020) 0:1-16; https://doi.

Effective treatment of SARS-CoV-2-infected rhesus macaques by attenuating inflammation

“…This safety profile was further supported by comparison to SSK1 effector gemcitabine, an approved clinical drug. 9 Therefore, the in-vivo safety of SSK1 demonstrated in this and our recent studies provides a foundation for the potential of clinical applications in treating COVID-19 patients.…”

“…8 We found that SSK1 treatment efficiently decreased macrophage numbers and their infiltration in lung injured mouse model, which accompanied with significant attenuation of inflammation. 9 Basing on these results, we reasoned that SSK1 is a promising new drug that can be applied to target macrophages and treat excessive inflammation in COVID-19 patients. In this study, we investigated the therapeutic effects of SSK1 in SARS-CoV-2-infected nonhuman primate model.…”

“…S2a, b), which is consistent with our previous findings that SSK1 reduced macrophages in the ALI mouse model. 9 To investigate the serum levels of various inflammatory cytokines that have been thought to play a key role in the progression of severe COVID-19 pneumonia, we compared the concentrations of 23 cytokines/chemokines in blood samples before (21 dpi) and after (28 dpi) SSK1 treatment. For the SSK1treated old monkeys, inflammatory cytokines including IFN-γ, IL-1RA, IL-6, IL-8, IL-10, IL-15, TGF-α and MCP-1, were reduced at 28 dpi compared with 21 dpi, especially for those in the high-dosage group (2.0 mg/kg), suggesting attenuation of inflammation.…”

Identification of a Proteomic Signature of Senescence in Primary Human Mammary Epithelial Cells

“…Senolytics have emerged as an exciting area with great therapeutic promise in aging (Xu et al 2018;Zhu et al 2015), cancer (Dörr et al 2013;Guerrero et al 2019), and other diseases. In mice, clearance of senescent cells restores tissue homeostasis and delays age-related dysfunction (Baar et al 2017;Baker et al 2011;Cai et al 2020;Baker et al 2016). Furthermore, clinical trials of the senolytic combination dasatinib and quercetin have shown encouraging results (Hickson et al 2019).…”

Advantages and Disadvantages of His-Tagged Beta-Galactosidase

“…3 β-D-galactosidase [EC 3.2.1.23] (β-Gal) is a glycoside hydrolase enzyme that catalyzes the hydrolysis of glycosidic bonds, producing monosaccharides from β-galactosides 1 . β-Gal has been extensively studied because of its nutritional, biotechnological and therapeutic impact 2,3 . In our laboratory, we are interested in describing how the recombinant production of proteins, particularly β-Gal, and the purification strategies could modulate their structure/function relationship.…”