Background: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.
Method: In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (n = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg⁄m2; eGFR:27·0 ± 2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed.
Results: D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and −12.
Interpretation: “Hit-and-run” treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, statistically-significantly decreases senescent cell burden in humans.
Funding: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.
[Keywords: senolytics, cellular senescence, dasatinib, quercetin, diabetic kidney disease, senescence-associated secretory phenotype (SASP)]
Evidence before this study: Senescent cells accumulate in tissues with ageing and at etiological sites in multiple chronic diseases, including adipose tissue in diabetes. Senescent cells can release products that cause inflammation and death of non-senescent cells, the senescence-associated secretory phenotype (SASP). Intermittent administration of the senolytic drug combination, Dasatinib plus Quercetin (D + Q), which transiently disables the pro-survival pathways that defend senescent cells against their own apoptotic environment, selectively eliminates senescent cells from mouse and human cell cultures, ageing mice, mice with insulin resistance and many other chronic disorders, and freshly-isolated adipose tissue explants from obese, diabetic human subjects. In the first clinical trial of senolytics, D + Q alleviated physical dysfunction in patients with idiopathic pulmonary fibrosis (IPF), a progressive, fatal, cellular senescence-associated disease. In another clinical trial, prolonged D administration to patients with systemic sclerosis appeared to reduce the SASP and other senescence markers in skin biopsies. To date, no peer-reviewed clinical trial report has directly demonstrated that administering senolytics decreases senescent cells.
Added value of this study: Here, in an open-label Phase 1 pilot study, we show for the first time that senolytic drugs decrease senescent cell abundance in humans. A 3-day oral course of D + Q in subjects with diabetic kidney disease (DKD) reduced adipose tissue senescent cell burden 11 days later, as indicated by decreases in cells with markers of senescence: p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated β-galactosidase (SAβgal) activity, and adipocyte progenitors with limited replicative potential. Consistent with decreased overall senescent cell burden in humans treated with senolytics, skin epidermal p16INK4A-expressing and p21CIP1-expressing cells were also reduced, as were key SASP factors, including interleukin (IL)-1α, IL-6, and MMPs 9 & 12, in blood. Thus, “hit-and-run” treatment with senolytic agents, which in the case of D + Q have elimination half-lives of <11 h, is sufficient to decrease senescent cell burden in humans. Thereafter, senescent cell burden remains low for days to weeks, consistent with the >2 weeks it takes for new senescent cells to develop (at least in cell culture).
Implications of all the available evidence: Interventions targeting fundamental ageing processes such as cellular senescence could delay, prevent, or alleviate multiple age-related diseases and disorders as a group, instead of one-at-a-time, as per the Geroscience Hypothesis.
Increasingly in mice, this hypothesis appears to be true. Combined with the first clinical trial of senolytic agents showing that D + Q improves physical function in patients with IPF published earlier this year in this journal, our current article showing that D + Q actually decreases senescent cell burden in humans is consistent with the possibility that the Geroscience Hypothesis may also hold true for humans.
If clinical trials over the next few years support and extend our findings to show that these agents can alleviate additional age-related and cellular-senescence-related disorders and diseases (beyond IPF) and reduce senescent cell burden (beyond adipose tissue and skin and as reflected by decreased SASP factors in blood), senolytics might become an entirely new path for alleviating currently untreatable chronic diseases and enhancing human healthspan.