Cellular Senescence & Senolytics (Fisetin, Quercetin, Dasatinib) — References

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• Parent Topic: Cellular Senescence & Senolytics (Fisetin, Quercetin, Dasatinib)
• Reference Hub: 04 - Longevity & Environment References MOC

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Primary Literature Dossier

1. Yousefzadeh et al. (2018) — Fisetin Is a Senotherapeutic That Extends Health and Lifespan

• Citation: Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018 Oct;36:18-28.
• Identifiers: PMID: 30279143 (PubMed · Europe PMC) | DOI: 10.1016/j.ebiom.2018.09.015 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Preclinical screening of 10 polyphenols in progeroid (${\text{Ercc1}}^{-/\Delta }$) and aged wild-type C57BL/6 mice (treated at 85 weeks of age) + ex vivo human adipose tissue explants.
• Key Quantitative Outcomes:
  • Out of 10 flavonoids (including resveratrol, curcumin, EGCG, luteolin, and quercetin), fisetin was the most potent senolytic at $5\text{–}10\mu \text{M}$, selectively inducing apoptosis in senescent without harming proliferating cells.
  • Intermittent oral fisetin reduced ${\text{p16}}^{\text{INK4a}}$ and ${\text{p21}}^{\text{CIP1}}$ mRNA and $\text{SA-}\beta {\text{-gal}}^{+}$ cells by 25–50% across adipose, liver, kidney, and splenic T/NK cell compartments.
  • Late-life fisetin administration extended median lifespan by ~10–15% and maximum lifespan in wild-type mice while reducing age-related pathology scores and SASP cytokines ($\text{IL-6},\text{TNF-}\alpha ,\text{MCP-1}$) in human adipose explants.

2. Hickson et al. (2019) — Senolytics Decrease Senescent Cells in Humans (First-in-Human Adipose Biopsy Proof)

• Citation: Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456.
• Identifiers: PMID: 31542390 (PubMed · Europe PMC) | DOI: 10.1016/j.ebiom.2019.08.069 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Open-label Phase 1 clinical trial ($n=9$ human subjects aged 50–80 years with diabetic kidney disease; paired abdominal subcutaneous adipose biopsies and blood draws taken at baseline and 11 days after a single 3-day oral course of Dasatinib $100\text{ mg/day}$ + Quercetin $1,000\text{ mg/day}$).
• Key Quantitative Outcomes:
  • Eleven days after completing the 3-day “hit-and-run” pulse (long after drug clearance), human adipose tissue ${\text{p16}}^{\text{INK4a}+}$ cells decreased by 35% ($p=0.001$), ${\text{p21}}^{\text{CIP1}+}$ cells decreased by 17% ($p=0.009$), and $\text{SA-}\beta {\text{-gal}}^{+}$ cells fell by 62% ($p=0.005$).
  • Adipose crown-like structures and ${\text{CD68}}^{+}$ macrophages decreased by 28% ($p=0.006$).
  • Plasma SASP factors including $\text{IL-1}\alpha$, $\text{IL-6}$, and $\text{MMP-9/-12}$ were significantly reduced.

3. Justice et al. (2019) — Senolytics in Human Idiopathic Pulmonary Fibrosis (First-in-Human Functional Trial)

• Citation: Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019 Feb;40:554-563.
• Identifiers: PMID: 30728124 (PubMed · Europe PMC) | DOI: 10.1016/j.ebiom.2018.12.052 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Open-label pilot clinical study ($n=14$ older adults with idiopathic pulmonary fibrosis; intermittent Dasatinib $100\text{ mg/day}$ + Quercetin $1,250\text{ mg/day}$ for 3 consecutive days per week over 3 weeks; total 9 dose days).
• Key Quantitative Outcomes:
  • Physical function improved significantly 1 week after treatment completion: 6-minute walk distance (6MWD) increased by $+21.5\text{ meters}$ ($p<0.05$), 4-meter gait speed increased by $+0.12\text{ m/s}$ ($p<0.05$), and 5-repetition chair-stand time improved by $-2.2\text{ seconds}$ ($p<0.01$).
  • Gains in physical function correlated directly with reductions in circulating SASP matrix-remodeling proteins and microRNAs.

4. Zhu et al. (2015) — Discovery of the First Senolytics Targeting SCAP Networks

• Citation: Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M, O’Hara SP, LaRusso NF, Miller JD, Roos CM, Verzosa GC, LeBrasseur NK, Wren JD, Farr JN, Khosla S, Stout MB, McGowan SJ, Fuhrmann-Stroissnigg H, Gurkar AU, Zhao J, Colangelo D, Dorronsoro A, Ling YY, Barghouthy AS, Navarro DC, Sano T, Robbins PD, Niedernhofer LJ, Kirkland JL. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015 Aug;14(4):644-658.
• Identifiers: PMID: 25754370 (PubMed · Europe PMC) | DOI: 10.1111/acel.12344 (DOI · SciDB · Scholar)
• Study Design & Sample Size: Transcriptomic RNAi screen of senescent vs. non-senescent human preadipocytes and HUVECs, followed by validation in aged (24-month-old) mice.
• Key Quantitative Outcomes:
  • Mapped the core Senescent Cell Anti-Apoptotic Pathways (SCAPs) ($\text{Ephrin/Src}$, $\text{PI3K/AKT}$, $\text{p53/p21/Serpine}$, $\text{BCL-2/BCL-xL}$) and proved that a single dose of D+Q in 24-month-old mice increased cardiac left ventricular ejection fraction (LVEF) and vascular nitric oxide relaxation to levels comparable to young mice within 5 days.