Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans

Cellular senescence and senolytics: the path to the clinic

“…The non-feminizing estrogen, 17α-estradiol, declines with aging in females and males and 17α-estradiol treatment extends healthspan and alleviates age-related metabolic dysfunction and inflammation in mice 142 . As considered above, senolytics can increase α-Klotho, which is geroprotective, neuroprotective and linked to healthspan in mice 19 . Interestingly, α-Klotho overexpression in mice increases healthspan and lifespan by up to 30% (ref.…”

“…Results suggested that senolytics improved physical function in these frail patients. Furthermore, post hoc analysis of a study involving 20 patients with IPF showed that urine levels of the 'geroprotective' factor α-Klotho were higher after oral D + Q than before treatment 19 . In an open-label phase 1 pilot study in 9 patients with diabetic kidney disease, a 3-d course of oral D + Q was sufficient to decrease adipose tissue senescent cell burden, inflammation, fibrosis and circulating SASP factors for at least 11 d after the last dose of senolytics, indicating target engagement and suggesting that an intermittent dosing regimen may be effective in humans 48 .…”

“…Identification and monitoring of senescent cell burden in situ, especially during clinical trials to assess safety and efficacy, can be challenging if solely based on analysis of tissue biopsies given the contextual and complex regulation of the senescent cell fate. However, SASP factors, senescence markers and markers of other fundamental aging processes (for example, α-Klotho) can be assayed in body fluids such as urine, saliva, blood or cerebrospinal fluid 7,19,48,59,61,64,132,133 . Additionally, ongoing efforts are underway to identify and define biomarkers of senescent cell accumulation (senescence biomarkers) and destruction of senescent cells during senolytic treatment (senolysis biomarkers) that meet requirements of regulatory authorities.…”

“…fundamental aging mechanisms leading to reduced inflammation, attenuated exhaustion of progenitors, decreased fibrosis, alleviated mitochondrial dysfunction and a partially restored microbiome in experimental animal models of aging and chronic diseases 6,7,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] .…”

The 6th international cell senescence association conference

“…The transplantation of senescent cells themselves or tissues in which senescent cells have accumulated into young mice induces cellular senescence in the surrounding cells via SASPs, causing a functional decline of the tissue (Iske et al, 2020; Xu et al, 2018), suggesting that senescent cells have a negative impact on the homeostasis of the organism during the aging process. Ongoing clinical trials have reported that administration of D (dasatinib) + Q (quercetin), the first senolytic drug found by them, suppresses SASP factors in the blood of diabetic patients (Hickson et al, 2019), improves idiopathic pulmonary fibrosis by removing senescent cells (Justice et al, 2019; Zhu et al, 2022), suggesting that senolytic drugs currently under development may improve tissue hypofunction and tissue fibrosis.…”