Matthew J. Yousefzadeh a,1, Yi Zhu b,1, Sara J. McGowan a,1, Luise Angelini a,1, Heike Fuhrmann-Stroissnigg a,
Ming Xu b, Yuan Yuan Ling a, Kendra I. Melos a, Tamar Pirtskhalava b, Christina L. Inman b, Collin McGuckian a,
Erin A. Wade a, Jonathon I. Kato a, Diego Grassi a, Mark Wentworth c, Christin E. Burd d, Edgar A. Arriaga e,
Warren L. Ladiges f, Tamara Tchkonia b, James L. Kirkland b, Paul D. Robbins a,⁎, Laura J. Niedernhofer a,⁎

a Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States
b Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, United States
c Office of Research Regulatory Support, Mayo Clinic, Rochester, MN 55905, United States
d Department of Molecular Genetics and Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, United States
e Department of Chemistry, University of Minnesota, Minneapolis, MN 55455-0431, United States
f Department of Comparative Medicine, University of Washington, Seattle, WA 98195, United States

a r t i c l e  i n f o

Article history:
Received 11 July 2018
Received in revised form 30 August 2018
Accepted 10 September 2018
Available online 29 September 2018

a b s t r a c t

Background: Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of
damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related dis-
eases using genetic and pharmacologic approaches. We previously demonstrated that the combination of
dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including
frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more po-
tent senolytic activity.
Methods: A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and
human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid
was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type
mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers,
health span and lifespan. Human adipose tissue explants were used to determine if results translated.
Findings: Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of
progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-
run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue,
demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeo-
stasis, reduced age-related pathology, and extended median and maximum lifespan.
Interpretation: The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life in-
tervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to transla-
tion to human clinical studies.
Fund: NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37
AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/American
Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and
Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Part-
nership Grant (AMAY-UMN#99)-P004610401–1 (JLK, EAA).