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• Research Paper Volume 7, Issue 8 pp 535-552

  Endurance exercise and selective breeding for longevity extend Drosophila healthspan by overlapping mechanisms

  Relevance score: 13.735642

  Alyson Sujkowski, Brian Bazzell, Kylie Carpenter, Robert Arking, Robert J Wessells

  Keywords: endurance training, selective breeding, healthspan, cardiac performance, mobility

  Published in Aging on August 8, 2015

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  Endurance exercise has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. In addition, long-term exercise reduces the incidence of age-related diseases in humans and in model organisms. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood. Here, we compare gene expression changes during endurance training in Drosophila melanogaster to gene expression changes during selective breeding for longevity. Microarrays indicate that 65% of gene expression changes found in flies selectively bred for longevity are also found in flies subjected to three weeks of exercise training. We find that both selective breeding and endurance training increase endurance, cardiac performance, running speed, flying height, and levels of autophagy in adipose tissue. Both interventions generally upregulate stress defense, folate metabolism, and lipase activity, while downregulating carbohydrate metabolism and odorant receptor expression. Several members of the methuselah-like (mthl) gene family are downregulated by both interventions. Knockdown of mthl-3 was sufficient to provide extension of negative geotaxis behavior, endurance and cardiac stress resistance. These results provide support for endurance exercise as a broadly acting anti-aging intervention and confirm that exercise training acts in part by targeting longevity assurance pathways.

  

  (A) Female La flies live longer than the control Ra females after three weeks of exposure to the Power Tower training machine (logrank; p <.0001). Training has little effect on longevity of either line. (B) La females have a delayed increase in mortality with age that is independent of exercise. Mortality during the training period is similar for all groups. (C) Male La flies live longer than control Ra males after three weeks of exposure to the training machine (logrank; p <.0001). Training does not increase longevity, and slightly decreases longevity in La males. (D) Mortality of La males is similar to Ra males during training, but is consistently lower than control Ra males after day 20. Exercised La males had somewhat increased mortality between days 40 and 65 compared to unexercised La males. n ≥ 250 for all survival and mortality experiments. Mortality and survival data are from same cohorts.

  
  
  

  

  (A) Exercised Ra males are protected against declining negative geotaxis speed with age compared to unexercised controls (two‐way ANOVA, p <.0001, n ≥ 100). La males have higher negative geotaxis speed than Ra males across ages and receive no further benefit from exercise. (B) Female control flies were unaffected by training in negative geotaxis speed across five weeks of age, while female La flies showed a slight trend toward increased speed. (C) Ra males improved endurance significantly following training (log‐rank; p <.0001, n ≥ 160). La males showed higher endurance than Ra (log‐rank; p <.0001), but received no further benefit from exercise. (D) Neither Ra nor La females receives a benefit to endurance following training, although La showed a trend toward an increase (log‐rank; p = .2290, n ≥ 160). (E) Ra males improved flight ability following training. La males display higher landing height than both untrained and trained Ra flies. (ANOVA, p <.0001, n ≥ 160). (F) Unexercised La males had significantly less cardiac failure in response to electrical pacing stress than did unexercised Ra (error bars indicate ±SD, t‐test; p = .0289, n ≥ 100). Following training, Ra males had statistically similar failure rates to exercised or unexercised La. (G) Unexercised La males showed significantly higher Lysotracker staining in dissected abdominal adipose tissue than unexercised Ra (error bars indicate ±SD, t‐test; p =.0428, n ≥ 10). Following training, Ra flies showed statistically similar Lysotracker staining to exercised or unexercised La.

  
  
  

  

  (A) Venn diagram showing transcripts altered by breeding from Ra to La (beige), transcripts altered by exercise training Ra males (blue), and the transcripts commonly altered by both interventions (overlap). (B) Plot of variance in gene expression explained by each treatment, when each is treated as the principal component (PCA). Training creates an expression pattern in Ra that is substantially similar to La. Ra (green), exercise trained Ra (blue) and selectively bred La (red). (C) Heat map of genes contained in KEGG pathways that are significantly altered by both interventions.

  
  
  

  

  (A) Endurance of both gr64a and or83b mutants is significantly higher than a w¹¹¹⁸ background control (log-rank; p <.0001 for each, n ≥ 100). (B) Exercised w¹¹¹⁸ background control males had significantly less cardiac failure in response to electrical pacing stress than did unexercised cohorts (ANOVA with Tukey post-hoc comparison, p <.0001). Both Gr64a and Or83b flies had significantly less cardiac failure than unexercised w¹¹¹⁸ controls whether exercised or not (ANOVA with Tukey post-hoc comparison, p <.0001). Exercised Or83b flies displayed a higher failure rate than exercised background controls (t-test, p=.0009) while maintaining a failure rate significantly lower than unexercised w¹¹¹⁸ flies (t-test, p <.0001). (C) Unexercised gr64a males have a slower decline in negative geotaxis speed than control males (two-way ANOVA, p <.0001). Nevertheless, gr64a males still display significant improvement in negative geotaxis following training (two-way ANOVA, p <.0001, n ≥ 100). Exercised controls have higher climbing index across ages compared to unexercised controls (two-way ANOVA, p <.0001, n ≥ 100). (D) Unexercised or83b males have a slower decline in negative geotaxis speed than control males (two-way ANOVA, p <.0001, n ≥ 100). Nevertheless, or83b males still display significant improvement in negative geotaxis following training (two-way ANOVA, p <.0001, n ≥ 100). Exercised controls have higher climbing index across ages compared to unexercised controls (two-way ANOVA, p <.0001, n ≥ 100).

  
  
  

  

  (A) Ubiquitous expression of RNAi against mthl3 using an RU-inducible driver increases the endurance of both males (log-rank; p = .0452) and females (log-rank; p <.0001) compared to RU- controls. n ≥ 160 for all endurance assays. (B) mthl3 knockdown reduces cardiac failure in response to pacing stress compared to RU- controls (t-test; p <.0001, n ≥ 100). (C) mthl3 knockdown increases negative geotaxis in males compared to RU- controls (2-way ANOVA; p <.0001, n ≥ 100). (D) Ubiquitous overexpression of mthl3 reduces the endurance of males compared to RU- controls (log-rank; p =.0005, n ≥ 160). (E) Ubiquitous overexpression of mthl3 increases cardiac failure in response to pacing (error bars indicate ±SD, t-test; p <.0001, n ≥ 100). (F) Ubiquitous overexpression of mthl3 decreases negative geotaxis in males compared to RU- controls (2-way ANOVA; p <.0001, n ≥ 100).

  
  
  

  

  (A) Ubiquitous knockdown of mthl3 does not extend lifespan, and in fact reduces longevity of both males and females (log-rank; p <.0001 for each, n ≥ 260). (B) Ubiquitous knockdown of mthl3 improves flight ability of females compared to RU- control (t-test, p = .0001, n ≥ 160), but not males.