The Achilles' heel of senescent cells: from transcriptome to senolytic drugs methods
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Treadmill endurance
As a measure of physical function, exercise capacity was determined on a motorized treadmill (LeBrasseur et al., ). Running time was recorded, and running distance (a function of time and speed on the treadmill) and work were calculated.
Senolytic siRNAs
Interfering with expression of EFNB1 or 3, PI3KCD, p21, BCL-xL, or PAI-2 significantly reduced the viability (ATPLite intensity; Fig. D) and survival (crystal violet; Fig. F and ) of senescent but not proliferating human abdominal subcutaneous preadipocytes. Reducing EFNB2 or 4 or PI3K isoforms other than PI3KCD had less or no effect (; ). siRNA transfection efficiencies and extent of mRNA knockdown were similar in senescent and proliferating preadipocytes ( ). Results were confirmed using second, distinct siRNAs or by Western immunoanalysis ( ). While proliferating human umbilical vein cells (HUVECs) tended to be generally susceptible to siRNAs under the conditions used, senescent HUVECs were more susceptible to EFNB1 and BCL-xL siRNAs than nonsenescent cells (Fig. E,G). EFNB1 or 3 and PI3KCD siRNAs also interfered with the viability of preadipocytes made senescent by serial subcult...
Dasatinib and quercetin reduce senescent cells in vivo
In anticipation of testing D+Q in a preclinical model, the drugs were tested for the efficacy in reducing the viability of senescent murine cells. The combination of D+Q led to a significant reduction in the number of senescent, C 12 FDG-positive, primary mouse embryonic fibroblasts (MEFs) compared to either drug alone (Fig. A). Likewise, Q alone or D+Q caused a significant reduction in the number of senescent bone marrow-derived murine mesenchymal stem cells (Fig. B). These data and those in Fig. demonstrate that both D and Q are able to selectively kill senescent cells in two species, albeit with distinct cell-type specificity. We tested whether D+Q administered by oral gavage was senolytic in vivo. We initially tested D+Q in old mice (> 24 months-old), as senescent cell burden increases in fat tissue with aging and both preadipocytes and endothelial cells contribute...
Dasatinib and quercetin reduce senescent cells in vivo
Dasatinib and quercetin reduce senescent cell abundance in mice. (A) Effect of D (250 n m ), Q (50 µ m ), or D+Q on levels of senescent Ercc1 -deficient murine embryonic fibroblasts (MEFs). Cells were exposed to drugs for 48 h prior to analysis of SA-βGal + cells using C 12 FDG. The data shown are means ± SEM of three replicates, *** P < 0.005; t -test. (B) Effect of D (500 nM), Q (100 µ m ), and D+Q on senescent bone marrow-derived mesenchymal stem cells (BM-MSCs) from progeroid Ercc1 -/Δ mice. The senescent MSCs were exposed to the drugs for 48 h prior to analysis of SA-βGal activity. The data shown are means ± SEM of three replicates. ** P < 0.001; anova. (C-D) The senescence markers, SA-βGal and p16, are reduced in inguinal fat of 24-month-old mice trea...
Effects of senolytic agents on cardiovascular function in old mice
Cellular senescence is associated with cardiovascular dysfunction in humans (Tchkonia et al.,; Kirkland & Tchkonia, ), a major cause of morbidity and mortality in the elderly. While only mild cardiac dysfunction has been reported in old mice (Dai et al.,; Roos et al., ), substantial impairment in vascular reactivity is observed in aged mice (Roos et al., ). We tested whether treating 24-month-old mice with D+Q would improve cardiac ejection fraction (the fraction of heart volume pumped during each heart contraction) and vascular responses to acetylcholine, nitroprusside, or U46619 [endothelium-dependent relaxation, smooth muscle vascular reactivity to nitric oxide, and smooth muscle contractile function, respectively (Roos et al., )]. To allow time for senescent cells to apoptose and exclude potential 'off-target' effects of the drugs on non...
Effects of senolytic agents on cardiovascular function in old mice
Despite the fact that mice are relatively resistant to the development of age-related systolic dysfunction, treatment of 24-month-old mice with a single dose of D+Q significantly improved left ventricular ejection fraction (Fig. A) and fractional shortening ( ), effects that were mediated by reductions in end-systolic cardiac dimensions (Fig. C) but not cardiac preload (Fig. B) or alterations in cardiac mass ( ). Consistent with previous reports from our group and others (Roos et al.,; Gioscia-Ryan et al., ), carotid arteries from aged mice displayed markedly impaired vascular relaxation in response to endothelium-dependent and -independent vasodilators compared to young mice. While D+Q elicited somewhat variable but statistically significant improvements in vascular endothelial function (Fig. D), a complex amalgam of nitric oxide, endothelium-derived hyperpolarizing fact...
Effects on treadmill exercise capacity in mice after single leg radiation exposure
To test further the hypothesis that D+Q functions through elimination of senescent cells, we tested the effect of a single treatment in a mouse leg irradiation model. One leg of 4-month-old male mice was irradiated at 10 Gy with the rest of the body shielded. Controls were sham-irradiated. By 12 weeks, hair on the irradiated leg turned gray (Fig. A) and the animals exhibited reduced treadmill exercise capacity (Fig. B). Five days after a single dose of D+Q, exercise time, distance, and total work performed to exhaustion on the treadmill was greater in the mice treated with D+Q compared to vehicle (Fig. C). Senescent markers were reduced in muscle and inguinal fat 5 days after treatment (Fig. G-I). At 7 months after the single treatment, exercise capacity was significantly better in the mice that had been irradiated and received the single dose of D+Q than in vehicle-tre...
Effects on treadmill exercise capacity in mice after single leg radiation exposure
Senolytic administration alleviates radiation-induced impairment in treadmill exercise endurance. (A-B) One leg of 4-month-old mice was radiated at 10 Gy. Three months later, hair on the irradiated leg had turned gray (A) and treadmill exercise capacity (B) was lower in irradiated ( N = 13) than sham-irradiated mice ( N = 14). ** P < 0.002; t -test. (C) Five days after a single dose of D+Q, treadmill endurance was better than in vehicle-treated controls. D+Q had no effect in sham-irradiated controls. ( N = 6-9 animals per group). Bars represent means ± SEM; * P < 0.05; ** P < 0.001; anova; Tukey-Kramer test. (D) 7 months after a single dose of D+Q, treadmill endurance was again assayed. All groups ran on the treadmill on four occasions, each 1 week apart. Bars represent means ±SEM of...
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As a measure of physical function, exercise capacity was determined on a motorized treadmill (LeBrasseur et al., ). Running time was recorded, and running distance (a function of time and speed on the treadmill) and work were calculated.
Interfering with expression of EFNB1 or 3, PI3KCD, p21, BCL-xL, or PAI-2 significantly reduced the viability (ATPLite intensity; Fig. D) and survival (crystal violet; Fig. F and ) of senescent but not proliferating human abdominal subcutaneous preadipocytes. Reducing EFNB2 or 4 or PI3K isoforms other than PI3KCD had less or no effect (; ). siRNA transfection efficiencies and extent of mRNA knockdown were similar in senescent and proliferating preadipocytes ( ). Results were confirmed using second, distinct siRNAs or by Western immunoanalysis ( ). While proliferating human umbilical vein cells (HUVECs) tended to be generally susceptible to siRNAs under the conditions used, senescent HUVECs were more susceptible to EFNB1 and BCL-xL siRNAs than nonsenescent cells (Fig. E,G). EFNB1 or 3 and PI3KCD siRNAs also interfered with the viability of preadipocytes made senescent by serial subculturing compared to nonsenescent cells ( ) and did not interfere with the viability of quiescent, differentiated preadipocytes ( ). Results were confirmed using crystal violet to measure cell survival (Fig. G; ).
In anticipation of testing D+Q in a preclinical model, the drugs were tested for the efficacy in reducing the viability of senescent murine cells. The combination of D+Q led to a significant reduction in the number of senescent, C 12 FDG-positive, primary mouse embryonic fibroblasts (MEFs) compared to either drug alone (Fig. A). Likewise, Q alone or D+Q caused a significant reduction in the number of senescent bone marrow-derived murine mesenchymal stem cells (Fig. B). These data and those in Fig. demonstrate that both D and Q are able to selectively kill senescent cells in two species, albeit with distinct cell-type specificity. We tested whether D+Q administered by oral gavage was senolytic in vivo. We initially tested D+Q in old mice (> 24 months-old), as senescent cell burden increases in fat tissue with aging and both preadipocytes and endothelial cells contribute to senescent cell burden with aging in fat (Tchkonia et al., ). A single dose of D+Q (D: 5 mg kg -1 body weight and Q: 50 mg kg -1 by oral gavage here and in the following studies), a drug ratio that was most effective in senescent MEFs (data not shown), reduce...
Dasatinib and quercetin reduce senescent cell abundance in mice. (A) Effect of D (250 n m ), Q (50 µ m ), or D+Q on levels of senescent Ercc1 -deficient murine embryonic fibroblasts (MEFs). Cells were exposed to drugs for 48 h prior to analysis of SA-βGal + cells using C 12 FDG. The data shown are means ± SEM of three replicates, *** P < 0.005; t -test. (B) Effect of D (500 nM), Q (100 µ m ), and D+Q on senescent bone marrow-derived mesenchymal stem cells (BM-MSCs) from progeroid Ercc1 -/Δ mice. The senescent MSCs were exposed to the drugs for 48 h prior to analysis of SA-βGal activity. The data shown are means ± SEM of three replicates. ** P < 0.001; anova. (C-D) The senescence markers, SA-βGal and p16, are reduced in inguinal fat of 24-month-old mice treated with a single dose of senolytics (D+Q) compared to vehicle only (V). Cellular SA-βGal activity assays and p16 expression by RT-PCR were carried out 5 days after treatment. N = 14; means ± SEM. ** P < 0.002 for SA-βGal, * P <...
Cellular senescence is associated with cardiovascular dysfunction in humans (Tchkonia et al.,; Kirkland & Tchkonia, ), a major cause of morbidity and mortality in the elderly. While only mild cardiac dysfunction has been reported in old mice (Dai et al.,; Roos et al., ), substantial impairment in vascular reactivity is observed in aged mice (Roos et al., ). We tested whether treating 24-month-old mice with D+Q would improve cardiac ejection fraction (the fraction of heart volume pumped during each heart contraction) and vascular responses to acetylcholine, nitroprusside, or U46619 [endothelium-dependent relaxation, smooth muscle vascular reactivity to nitric oxide, and smooth muscle contractile function, respectively (Roos et al., )]. To allow time for senescent cells to apoptose and exclude potential 'off-target' effects of the drugs on nonsenescent cell types, which require continued presence of the drugs, for example, through direct vasoactive/antioxidant effects or through changing NAD + (Chen & Pace-Asciak,; Ajay et al., ), we gave a single dose of the drugs and waited 5 days before assaying cardiac function. D and Q a...
Despite the fact that mice are relatively resistant to the development of age-related systolic dysfunction, treatment of 24-month-old mice with a single dose of D+Q significantly improved left ventricular ejection fraction (Fig. A) and fractional shortening ( ), effects that were mediated by reductions in end-systolic cardiac dimensions (Fig. C) but not cardiac preload (Fig. B) or alterations in cardiac mass ( ). Consistent with previous reports from our group and others (Roos et al.,; Gioscia-Ryan et al., ), carotid arteries from aged mice displayed markedly impaired vascular relaxation in response to endothelium-dependent and -independent vasodilators compared to young mice. While D+Q elicited somewhat variable but statistically significant improvements in vascular endothelial function (Fig. D), a complex amalgam of nitric oxide, endothelium-derived hyperpolarizing factors, and other vasoactive substances (Feletou & Vanhoutte, ), D+Q, yielded physiologically important and consistent improvements in vascular smooth muscle sensitivity to nitroprusside (Fig. E). Interestingly, senescent cell clearance did not alter smooth muscle contractile function (Fig. F). Collect...
To test further the hypothesis that D+Q functions through elimination of senescent cells, we tested the effect of a single treatment in a mouse leg irradiation model. One leg of 4-month-old male mice was irradiated at 10 Gy with the rest of the body shielded. Controls were sham-irradiated. By 12 weeks, hair on the irradiated leg turned gray (Fig. A) and the animals exhibited reduced treadmill exercise capacity (Fig. B). Five days after a single dose of D+Q, exercise time, distance, and total work performed to exhaustion on the treadmill was greater in the mice treated with D+Q compared to vehicle (Fig. C). Senescent markers were reduced in muscle and inguinal fat 5 days after treatment (Fig. G-I). At 7 months after the single treatment, exercise capacity was significantly better in the mice that had been irradiated and received the single dose of D+Q than in vehicle-treated controls (Fig. D). D+Q-treated animals had endurance essentially identical to that of sham-irradiated controls. The single dose of D+Q had no effect on endurance 7 months later in sham-irradiated controls vs. vehicle. Thus, a single dose of D+Q 7 months previously led to sustained imp...
Senolytic administration alleviates radiation-induced impairment in treadmill exercise endurance. (A-B) One leg of 4-month-old mice was radiated at 10 Gy. Three months later, hair on the irradiated leg had turned gray (A) and treadmill exercise capacity (B) was lower in irradiated ( N = 13) than sham-irradiated mice ( N = 14). ** P < 0.002; t -test. (C) Five days after a single dose of D+Q, treadmill endurance was better than in vehicle-treated controls. D+Q had no effect in sham-irradiated controls. ( N = 6-9 animals per group). Bars represent means ± SEM; * P < 0.05; ** P < 0.001; anova; Tukey-Kramer test. (D) 7 months after a single dose of D+Q, treadmill endurance was again assayed. All groups ran on the treadmill on four occasions, each 1 week apart. Bars represent means ±SEM of the average performance of each group on each of the four occasions they ran. Endurance is shown as a function of the overall performance of all four groups on each occasion when mice ran (expressed as %: mean Joules per group/total Joules per all groups that day). * Different from the other groups...
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