Fig. 4: Oral administration of SLC-D011 suppresses premature aging features.
A Gross morphology of SLC-D011-treated (D011) mice at 8 weeks old. Body size of treated mouse was apparently larger than that of the untreated control (Con) mouse. B Oral administration of SLC-D011 increases body weights of LmnaG609G/G609G mice. Compared with untreated control group, body weight of treated mouse was increased by ~35%, *p < 0.05. C Oral administration of SLC-D011 extends the life span of LmnaG609G/G609G mouse. SLC-D011 in monoolein-based solution was treated by oral gavage (50 mg/kg, daily) from 5 weeks old. Compared with untreated control group (ave = 16.8 weeks and max = 18 weeks), treated group showed extended life span (ave = 25.2 weeks and max = 26 weeks), **p < 0.001. D Reduction of progerin expression and increase of H3K9me3 expression in tissues of LmnaG609G/+ mice after treatment with SLC-D011 by oral gavage (50 mg/kg, daily) for 8 weeks (n = 3 independent experiments; two-tailed Student’s t test). E Grip test of LmnaG609G/+ mice at 41-week-old was performed after administration of SLC-D011 for 6 weeks. The test was repeated 10 times for each mouse (n > 4), **p < 0.001. Data are presented as mean ± SD. F Electrocardiographic analysis of LmnaG609G/+ mice (untreated: n = 4; SLC-D011: n = 4) and Lmna+/+ mice (n = 3) after treatment with SLC-D011 for 6 weeks (unpaired t test). Heart rate is shown as beats per minute (bpm). G Dental abnormalities in LmnaG609G/+ mice (untreated: n = 4; SLC-D011: n = 5) and Lmna+/+ mice (n = 4). X-ray lateral projection of the skull of untreated LmnaG609G/+ mouse (untreated: n = 4; SLC-D011: n = 5) at 41 weeks of age compared to Lmna+/+ mouse (n = 4) at same age shows abnormalities of incisors (unpaired t test). Lower incisors of LmnaG609G transgenic mice grow toward the palate because of malocclusion. Oral administration of SLC-D011 for 6 weeks alleviates dental abnormalities. H Anti-aging effects of single treatment of SLC-D011 or lonafarnib were measured in HGPS patients-derived cells (AG11513, AG03199, AG11498, and AG03198, Coriell Cell Repositories). Single treatment of SLC-D011, compared to lonafarnib, reduced the expression of progerin but induced the expression of H3K9me3 and cyclin B1 in HGPS cells more effectively. HGPS patients-derived cells were treated with SLC-D011 (500 nM) or lonafarnib (500 nM) for 3 days. I Scheme of interaction between lamin A and progerin. SLC-D011 interrupts the interaction between lamin A and progerin through direct binding to the C-terminal region of progerin. “Con” and “untreated” mean vehicle (monoolein-based solution)-treated mouse group or vehicle (DMSO)-treated cells.
