Research Article: Stress resistance and lifespan enhanced by downregulation of antimicrobial peptide genes in the Imd pathway

Date Published: April 19, 2018

Publisher: Impact Journals

Author(s): Yuh-Ru Lin, Hardik Parikh, Yongkyu Park.


Biological behaviors and longevity of ectothermic animals are remarkably influenced by ambient temperature. Development at 18°C significantly enhances the stress resistance of adult flies with more accumulation of nutrients (especially fat) in the body than development at 25°C. Gene expression analysis between the flies developed at 18°C and 25°C revealed that the Immune deficiency (Imd) pathway, including the downstream antimicrobial peptides (AMPs), is downregulated in the flies developed at 18°C. When hypomorphic imd mutant flies with reduced AMP expressions were developed at 25°C, they showed induced stress resistance with higher fat content in the body similar to the wild-type flies developed at 18°C. However, severe hypomorphic imd mutants could not enhance stress resistance due to the downregulation of another downstream JNK pathway that expresses stress tolerance genes. Interestingly, the downregulation of AMP genes, itself, extended lifespan with increased stress resistance. Especially, fat body-specific downregulation of Imd AMP genes exhibited a longer lifespan with higher heat resistance. The fat body is known to function in metabolic homeostasis, stress tolerance, growth, and longevity in Drosophila. Here, we provide the first evidence that mild downregulation of the Imd pathway with AMP genes increases fat content, stress resistance, and lifespan in adult flies.

Partial Text

Fruit flies, which are ectothermic animals, can live more than twice as long at 18°C than at 25°C [1]. Even though it has been thought that this enhanced longevity at a lower temperature (18°C) is caused by a change of metabolic rate [2], the mechanisms that regulate longevity by ambient temperature are poorly understood. Previously, we found that development at 18°C (from embryo to newborn adult) significantly enhances stress resistance of adult flies with more accumulation of nutrients (especially fat) in the body than development at 25°C [3]. This enhanced resistance to stress was similarly observed in both sexes and sustained up to 30 days (middle age) after hatching of the adult flies [3], indicating that development at a lower temperature, 18°C, significantly enhances the mechanism(s) of stress resistance. Higher stress resistance and/or fat accumulation are frequently found in long-lived flies [4-6] such as mutants of the IGF (insulin/insulin-like growth factor) signaling pathway [7,8]. From the RT-PCR tests of representative stress-related genes, we showed that the development at a lower temperature (18°C) downregulates antimicrobial peptide genes, AttA and DptB, of the Immune deficiency (Imd) pathway [3]. The Imd pathway is known to regulate innate immune responses in Drosophila [9], and the Imd protein activates two downstream branches, JNK/basket and NF-kB/Relish, which are subsequently responsible for the upregulation of stress tolerance and antimicrobial peptide genes, respectively [10,11].

The antimicrobial peptide (AMP) genes in the Imd pathway were specifically downregulated in the wild-type flies developed at a lower temperature 18°C (Fig. 1D), which exhibited the stronger resistance to all three applied stressors (starvation, oxidation, and heat) (Fig. 1A) [3]. We found that the flies developed at 25°C also can enhance stress resistances (Fig. 2B-C) when the imd and downstream AMP genes are downregulated (Fig. 2A). However, these additional stress resistances by the imdP mutation in development at 25°C were not observed when the imdP flies were developed at 18°C (Fig. S2), indicating that the stress resistances are already induced by the downregulation of Imd AMP genes in wild-type flies developed at 18°C (Fig. 1). Instead, a heat resistance was significantly reduced in the imdP flies developed at 18°C (Fig. S2B) as shown in the severe hypomorphic imd1 flies (Table 1). It implies that intense downregulation of the Imd pathway has a negative effect on the heat resistance with additional downregulation of another downstream JNK/basket pathway (Fig. 3B) that is required to activate the stress response genes [10,11]. Overall, our data support that a mild downregulation of the Imd pathway enhances stress resistance. However, the increased levels of stress resistance by imdP flies developed at 25°C (Fig. 2B-C) were not enough to reach the levels that the 18°C development of wild-type flies induces (Fig. 1A), suggesting that the downregulation of Imd AMP genes alone cannot fully explain the higher stress resistances in flies developed at 18°C (Fig. 1A).




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