Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis
Tesfahun Dessale Admasu,
Kristie Kim,
Michael Rae,
Roberto Avelar,
Ryan L. Gonciarz,
Abdelhadi Rebbaa,
João Pedro de Magalhães,
Adam R. Renslo,
Alexandra Stolzing,
Amit Sharma
Affiliations
Tesfahun Dessale Admasu
SENS Research Foundation, Mountain View, CA 94041, USA; Corresponding author
Kristie Kim
SENS Research Foundation, Mountain View, CA 94041, USA
Michael Rae
SENS Research Foundation, Mountain View, CA 94041, USA
Roberto Avelar
Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
Ryan L. Gonciarz
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
Abdelhadi Rebbaa
SENS Research Foundation, Mountain View, CA 94041, USA
João Pedro de Magalhães
Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
Adam R. Renslo
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA
Alexandra Stolzing
Loughborough University, Centre for Biological Engineering, School of Mechanical, Electrical and Manufacturing Engineering, Epinal Way, Loughborough LE113TU, UK
Amit Sharma
SENS Research Foundation, Mountain View, CA 94041, USA; Corresponding author
Summary: Senescent cells can spread the senescent phenotype to other cells by secreting senescence-associated secretory phenotype factors. The resulting paracrine senescent cells make a significant contribution to the burden of senescent cell accumulation with age. Previous efforts made to characterize paracrine senescence are unreliable due to analyses being based on mixed populations of senescent and non-senescent cells. Here, we use dipeptidyl peptidase-4 (DPP4) as a surface maker to isolate senescent cells from mixed populations. Using this technique, we enrich the percentage of paracrine senescence from 40% to 85%. We then use this enriched culture to characterize DPP4+ primary and paracrine senescent cells. We observe ferroptosis dysregulation and ferrous iron accumulation as a common phenomenon in both primary and paracrine senescent cells. Finally, we identify ferroptosis induction and ferrous iron-activatable prodrug as a broad-spectrum senolytic approach to ablate multiple types of primary and paracrine senescent cells.
