Lisinopril Preserves Physical Resilience and Extends Life Span in a Genotype-Specific Manner in Drosophila melanogaster

Abstract

Physical resiliency declines with age and comorbid conditions. In humans, angiotensin-converting enzyme (ACE) has been associated with attenuation of the decline in physical performance with age. ACE-inhibitor compounds, commonly prescribed for hypertension, often have beneficial effects on physical performance however the generality of these effects are unclear. Here, we tested the effects of the ACE-inhibitor Lisinopril on life span, and age-specific speed, endurance, and strength using three genotypes of the Drosophila melanogaster Genetic Reference Panel. We show that age-related decline in physical performance and survivorship varies with genetic background. Lisinopril treatment increased mean life span in all Drosophila Genetic Reference Panel lines, but its effects on life span, speed, endurance, and strength depended on genotype. We show that genotypes with increased physical performance on Lisinopril treatment experienced reduced age-related protein aggregation in muscle. Knockdown of skeletal muscle-specific Ance, the Drosophila ortholog of ACE, abolished the effects of Lisinopril on life span, implying a role for skeletal muscle Ance in survivorship. Using transcriptome profiling, we identified genes involved in stress response that showed expression changes associated with genotype and age-dependent responsiveness to Lisinopril. Our results demonstrate that Ance is involved in physical decline and demonstrate genetic variation in phenotypic responses to an ACE inhibitor.

Keywords: Aging; Angiotensin; Genetic variation; Locomotion; Muscle.

Figure 1.

Ace inhibition improves speed, endurance, and strength in an age- and genotype-specific manner. (A) DGRP_229 (n = 540). (B) DGRP_73 (n = 540). (C) DGRP_304 (n = 540). Data are means ± SEM. *p < .05; **p < .01. The measure of strength is the inverse of the amount of time in seconds it took for flies to escape.

Figure 2.

Effects of Lisinopril on life span. (A) DGRP_73 (p < .01; n = 520). (B) DGRP_229 (p < .01; n = 520). (C) DGRP_304 (p < .001; n = 520). Solid black lines depict control and dashed lines depict Lisinopril-treated flies.

Figure 3.

Effect of Lisinopril on life span depends on Ance expression in skeletal muscle. Lisinopril treatment extended the life span of mCherry control flies, and reduced life span of attP2 flies. There is no significant difference in life span between untreated and treated dj667-Gal4 × RNAi-Ance males.

Figure 4.

Lisinopril reduces protein aggregation with age and line. Immunostaining of indirect flight muscles from control and treated (A and B) DGRP_229, (D and E) DGRP_73, and (G and H) DGRP_304 flies at 5 weeks of age. Poly-Ubiquitin (Cy3, red) immunoreactivity reveals deposition of aggregates (arrows), phalloidin staining (green) labels F-actin, and DAPI (blue) marks nuclei. (C) Mean intensity of protein aggregates increases with age in DGRP_229 and DGRP_73. Light gray bar is 1 week of age, dark gray is 5 weeks of age (F) At old age, treatment reduces mean intensity of protein aggregates in DGRP_229 and nearly reduces mean intensity in DGRP_73. Dark gray bar is control, striped gray is Lisinopril-treated; data are means and SEM bars (n = 8 to 12 flies). Scale bar, 100 µm. *p < .05; **p < .01 unpaired t test. Note that the 5-week control data are used for the comparisons shown in panels C and D, so the p values shown are not adjusted for use of the data in two comparisons.