Alterations in brain glycogen levels influence life-history traits and reduce the lifespan in female Drosophila melanogaster

One of the long-standing questions in biology is the factors determining the lifespan of a species in a population (Medawar, 1952). Variations in longevity between different species and between members of the same species remain inexplicable (Weisman, 1891). In this respect, sexual dimorphism in lifespan, where females outlive males across species, including humans, is an established concept now, yet the underlying mechanisms are not fully understood (Austad, 2006, 2011; Austad and Bartke, 2015). Several theories have been proposed to elucidate the variations in lifespan between the two sexes. One is the ‘unguarded X hypothesis’, where the heterogametic sex (XY males/ZW females) is expected to have a shorter lifespan as they express deleterious alleles located on the X chromosome. The homogametic sex (XX females), in contrast, might live longer since the effect of the deleterious alleles gets diluted because of the two copies of the X chromosome (Tower and Arbeitman, 2009; Maklakov and Lummaa, 2013). Another hypothesis that explains the gender-specific difference in the lifespan is ‘maternal inheritance’, wherein maternally derived mitochondria are thought to function sub-optimally in males, thus adding to the survival advantage in females (Tower and Arbeitman, 2009; Maklakov and Lummaa, 2013). A difference in the hormone signaling pathways and metabolic circuits has also been suggested to account for the difference in the lifespan of the two sexes (Tower, 2017). Few examples include the reduction in the female lifespan post-mating by the male-specific hormone ‘sex peptide’ (Tower et al., 2017) and the shortening of male survival upon activation of the neuropeptide signaling by a female-specific pheromone (Gendron et al., 2014). Sex differences in lifespan are also linked with stress-related traits and biochemical factors (Niveditha et al., 2017). According to the ‘free radical theory of aging’ (Harman, 1992), reactive oxygen species (ROS) are one of the critical determinants of lifespan trade-offs, and a negative correlation exists between lifespan and ROS abundance in particular sex (Sohal and Orr, 2012). Studies have indicated that effective mitochondrial function and higher levels of antioxidant enzymes in females compensate for increased ROS levels (Austad and Bartke, 2015), thus earning a survival benefit over males. Other factors contributing to lifespan variations between males and females are social interaction, sex-specific genetic architecture, aging mechanisms, and fitness parameters (Tower and Arbeitman, 2009; Tower et al., 2020).

At the molecular level, studies on sex-specific lifespan have mostly looked at the difference in the expression levels of essential genes, genes coding for the hormonal and immune response, and genes involved in healthy aging (Tower et al., 2020; Tian et al., 2017). For example, a genetic perturbation in the insulin-signaling pathway increases the survival rate of Drosophila melanogaster females as compared to males (Clancy et al., 2001). Similarly, chronic treatment of Drosophila with lithium, which acts on the mechanistic target of rapamycin (mTOR) and glycogen synthase kinase-3β (GSK3β), abolishes the female advantage in lifespan with no significant changes in male survival (Zhu et al., 2015). Dietary restriction, which dramatically enhances lifespan across species, also has a pronounced effect on the female lifespan compared to the males (Magwere et al., 2004). In this context, glycogen has recently been identified as a potential regulator for the aging process (Duran et al., 2012; Sinadinos et al., 2014). Glycogen, the branched polymer of glucose, acts as an energy reservoir in animals wherein the abundance of glucose in the body activates glycogen synthase (GS), the key enzyme for glycogen synthesis (Roach et al., 2012). Interestingly, glycogen in the brain is mostly stored in astrocytes (Pellerin and Magistretti, 1994), and the glycogen content in the neurons is negligible (Saez et al., 2014). This suggests a neuron-specific adaptive response, as abnormal glycogen has been associated with Lafora disease (Parihar et al., 2018) and aberrant levels diminish the overall lifespan in the GS-overexpressing fly lines and mice models (Duran et al., 2012). In addition, neuronal GS knockdown promoted healthy aging in Drosophila (Sinadinos et al., 2014). Moreover, glycogen-mediated accelerated aging is seen in Caenorhabditis elegans, where a high sugar diet as a precursor for glycogen results in a shortened lifespan of the worms (Seo et al., 2018). The metabolic shift of glycogen synthesis from the astrocytes to the neurons in the aging hippocampus (Drulis-Fajdasz et al., 2018) and the presence of glycogen deposits in the form of corpora amylacea in the aging brain (Duran et al., 2019), further establish glycogen as a modifier of the aging process. We, therefore, evaluated the role of brain-specific glycogen changes as a possible factor that can influence the sex-specific lifespan in Drosophila. We demonstrate that Drosophila females with an imbalance in the level of brain glycogen display a shortened lifespan, increased resistance to starvation, elevated glycogen reserves, and higher oxidative stress than male flies. A shortening in the lifespan of females in the current study is attributed to the altered brain glycogen levels that correspond to the increased oxidative stress in the female flies.

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