Biological aging of two innate behaviors of Drosophila melanogaster: Escape climbing versus courtship learning and memory.

Motor and cognitive aging can severely affect life quality of elderly people and burden health care systems. In search for diagnostic behavioral biomarkers, it has been suggested that walking speed can predict forms of cognitive decline, but in humans, it remains challenging to separate the effects of biological aging and lifestyle. We examined a possible association of motor and cognitive decline in Drosophila, a genetic model organism of healthy aging. Long term courtship memory is present in young male flies but absent already during mid life (4-8 weeks). By contrast, courtship learning index and short term memory (STM) are surprisingly robust and remain stable through mid (4-8 weeks) and healthy late life (>8 weeks), until courtship performance collapses suddenly at ~4.5 days prior to death. By contrast, climbing speed declines gradually during late life (>8 weeks). The collapse of courtship performance and short term memory close to the end of life occur later and progress with a different time course than the gradual late life decline in climbing speed. Thus, during healthy aging in male Drosophila, climbing and courtship motor behaviors decline differentially. Moreover, cognitive and motor performances decline at different time courses. Differential behavioral decline during aging may indicate different underlying causes, or alternatively, a common cause but different thresholds for defects in different behaviors.

Longitudinal assessment of health-span and pre-death morbidity in wild type Drosophila.

The increase in human life expectancy is accompanied by age-related cognitive and motor disability, thus raising the demand for strategies toward healthy aging. This requires understanding the biology of normal aging and late-life functional phenotypes. Genetic model organisms, such as Drosophila melanogaster, can help identifying evolutionary conserved mechanisms underlying aging. Longitudinal assessment of motor performance of more than 1000 individual flies revealed age-related motor performance decline and specific late-life motor disabilities. This allows defining heath- and ill-span and scoring late-life quality of individual flies. As in mammals, including humans, onset, duration, severity, and progression dynamics of decline are heterogenic and characterized by both, progressive worsening and sudden late-life events. Flies either become increasingly incapacitated by accumulating disability over multiple days prior to death, or they escape disability until few hours prior to death. Both late-life trajectories converge into a terminal stage characterized by stereotypical signs of functional collapse and death within 3 hours. Drosophila can now be used to evaluate life prolonging manipulations in the context of late-life quality. High sugar diet increases lifespan and late-life quality, whereas lifespan prolonging antioxidant supplementation has either no, or negative effects on late-life quality, depending on base diet and gender.

Differential Electrophysiological Responses to Odorant Isotopologues in Drosophilid Antennae.

Olfaction presents the ultimate challenge to molecular recognition as thousands of molecules have to be recognized by far fewer olfactory receptors. We have presented evidence that Drosophila readily distinguish odorants based on their molecular vibrations using a battery of behavioral assays suggesting engagement of a molecular vibration-sensing component. Here we interrogate electrophysiologically the antennae of four Drosophilids and demonstrate conserved differential response amplitudes to aldehydes, alcohols, ketones, nitriles, and their deuterated isotopologues. Certain deuterated odorants evoked larger electroantennogram (EAG) amplitudes, while the response to the normal odorant was elevated in others. Significantly, benzonitrile isotopologues were not distinguishable as predicted. This suggests that isotopologue-specific EAG amplitudes result from differential activation of specific olfactory receptors. In support of this, odorants with as few as two deuteria evoke distinct EAG amplitudes from their normal isotopologues, and this is independent of the size of the deuterated molecule. Importantly, we find no evidence that these isotopologue-specific amplitudes depend on perireceptor mechanisms or other pertinent physical property of the deuterated odorants. Rather, our results strongly suggest that Drosophilid olfactory receptors are activated by molecular vibrations differentiating similarly sized and shaped odorants in vivo, yielding sufficient differential information to drive behavioral choices.

A muscle-specific p38 MAPK/Mef2/MnSOD pathway regulates stress, motor function, and life span in Drosophila.

Molecular mechanisms that concordantly regulate stress, life span, and aging remain incompletely understood. Here, we demonstrate that in Drosophila, a p38 MAP kinase (p38K)/Mef2/MnSOD pathway is a coregulator of stress and life span. Hence, overexpression of p38K extends life span in a MnSOD-dependent manner, whereas inhibition of p38K causes early lethality and precipitates age-related motor dysfunction and stress sensitivity, that is rescued through muscle-restricted (but not neuronal) add-back of p38K. Additionally, mutations in p38K are associated with increased protein carbonylation and Nrf2-dependent transcription, while adversely affecting metabolic response to hypoxia. Mechanistically, p38K modulates expression of the mitochondrial MnSOD enzyme through the transcription factor Mef2, and predictably, perturbations in MnSOD modify p38K-dependent phenotypes. Thus, our results uncover a muscle-restricted p38K-Mef2-MnSOD signaling module that influences life span and stress, distinct from the insulin/JNK/FOXO pathway. We propose that potentiating p38K might be instrumental in restoring the mitochondrial detoxification machinery and combating stress-induced aging.