TY - JOUR
T1 - Strategies for late phase preclinical and early clinical trials of senolytics
AU - Wissler Gerdes, Erin O.
AU - Misra, Avanish
AU - Netto, Jair Machado Espindola
AU - Tchkonia, Tamar
AU - Kirkland, James L.
N1 - Publisher Copyright:
© 2021 The Author(s)
PY - 2021/12
Y1 - 2021/12
N2 - Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.
AB - Cellular senescence and the hallmarks of aging contribute to age-related disease and dysfunction. The Unitary Theory of Fundamental Aging Mechanisms highlights the interdependence among the hallmarks of aging and suggests that by intervening in one fundamental aging process, most or all of the other processes could be impacted. Accumulation of senescent cells is associated with frailty, cardiovascular disease, obesity, diabetes, cognitive decline, and other age- and/or chronic disease-related disorders, suggesting that senescent cells are a target for intervention. Early preclinical data using senolytics, agents that target senescent cells, show promising results in several aging and disease models. The first in-human trials using the senolytic combination of Dasatinib and Quercetin indicated reduced senescent cell burden in adipose tissue of diabetic kidney disease patients and improved physical function in patients with idiopathic pulmonary fibrosis. Clinical trials with other senolytics, including the flavonoid Fisetin and BCL-xL inhibitors, are underway. These results from preclinical and early clinical trials illustrate the potential of senolytics to alleviate age-related dysfunction and diseases. However, multiple clinical trials across different aging and disease models are desperately needed. Parallel trials across institutions through the Translational Geroscience Network are facilitating testing to determine whether senolytics can be translated into clinical application.
KW - Dasatinib
KW - Fisetin
KW - Quercetin
KW - Senolytics
KW - Translational Geroscience Network
KW - Unitary Theory of Fundamental Aging Processes
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U2 - 10.1016/j.mad.2021.111591
DO - 10.1016/j.mad.2021.111591
M3 - Article
C2 - 34699859
AN - SCOPUS:85117747774
SN - 0047-6374
VL - 200
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
M1 - 111591
ER -