Angelica keiskei Impacts the Lifespan and Healthspan of Drosophila melanogaster in a Sex and Strain-Dependent Manner

Abstract

Angelica keiskei is a perennial plant, belonging to the Apiaceae family and originating from Japan. This plant has been reported to act as a diuretic, analeptic, antidiabetic, hypertensive, tumor, galactagogue, and laxative. The mechanism of action of A. keiskei is not known, but previous studies have suggested that it may act as an antioxidant. In this work, we used Drosophila melanogaster to evaluate the impact of A. keiskei on lifespan and healthspan and its potential anti-aging mechanism by conducting multiple assays on three fly strains: w¹¹¹⁸, chico, and JIV. We observed that the extract extended lifespan and improved healthspan in a sex- and strain-dependent manner. A. keiskei extended lifespan and improved reproductive fitness in female flies and either had no effect or decreased survival and physical performance in males. The extract protected against the superoxide generator paraquat in both sexes. These sex-specific effects suggest that A. keiskei may act through age-specific pathways such as the insulin and insulin-like growth factor signaling (IIS) pathways. Upon examination, we found that the increased survival of A. keiskei-fed females was dependent on the presence of the insulin receptor substrate chico, supporting the role of IIS in the action of A. keiskei.

Keywords: Angelica keiskei; Apiaceae; Drosophila melanogaster; healthspan; insulin/IGF-1 pathway; lifespan.

Figure 1

The impact of Angelica keiskei on lifespan of Drosophila melanogaster (A) w¹¹¹⁸ males, (B) w¹¹¹⁸ females, (C) JIV males, and (D) JIV females. Angelica keiskei was found to be detrimental to w¹¹¹⁸ male flies, as evidenced by a shortened lifespan (A), while it had no effect on the lifespan of JIV male flies (C). Both female w¹¹¹⁸ and JIV strains were found to have an increased lifespan with 0.4 mg/mL of A. keiskei supplementation (B,D). p-values were calculated using the Mantel–Cox log-rank test (n = 190–210 for w¹¹¹⁸ flies and 120 for JIV flies). Survival curves with symbols filled with color denote statistical significance of the dose compared to control (males, p < 0.05; females p < 0.001); clear symbols denote lack of statistical significance compared to control.

Figure 2

The impact of Angelica keiskei on locomotion. (A) By week 3, A. keiskei-fed male flies showed a significant decrease in locomotion compared to controls (* p < 0.05, Mann–Whitney test). (B) Control or A. keiskei-fed female flies showed no significant difference in locomotion throughout 5 weeks of treatment (Mann–Whitney test). For both males and females, n = 9 groups of 20 flies.

Figure 3

The impact of Angelica keiskei on fecundity. (A) w¹¹¹⁸ females fed A. keiskei showed a significant improvement in fecundity (*p < 0.0001) compared to controls. (B) JIV females, irrespective of treatment, showed no difference in average progeny number per female. Statistical significance was calculated using 2-Way ANOVA for each time point, n = 20 individually housed females for each group.

Figure 4

The protective effect of Angelica keiskei against oxidative and environmental stress in JIV flies. (A) Both male and female flies pretreated with A. keiskei showed protection against paraquat toxicity; neither male nor female flies showed protection against oxidative stress induced by (B) iron, (C) heat, (D) starvation and (E) desiccation. Statistically significant differences were calculated using the Mantel–Cox log-rank test with n = 100–220 flies per group.

Figure 5

Angelica keiskei requires the insulin receptor substrate (chico) to extend the lifespan of female flies. (A) Male and (B) female homozygous mutant chico flies showed no significant effect on longevity, when fed A. keiskei. Mantel–Cox log-rank test with n = 100 flies per group.