Cognitive decline is a significant health concern in our aging society. Here, we used the model organism C. elegans to investigate the impact of the IIS/FOXO pathway on age-related cognitive decline. The daf-2 Insulin/IGF-1 receptor mutant exhibits a significant extension of learning and memory span with age compared to wild-type worms, an effect that is dependent on the DAF-16 transcription factor. To identify possible mechanisms by which aging daf-2 mutants maintain learning and memory with age while wild-type worms lose neuronal function, we carried out neuron-specific transcriptomic analysis in aged animals. We observed downregulation of neuronal genes and upregulation of transcriptional regulation genes in aging wild-type neurons. By contrast, IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including upregulation of stress response genes and downregulation of specific insulin signaling genes. We tested the roles of significantly transcriptionally-changed genes in regulating cognitive functions, identifying novel regulators of learning and memory. In addition to other mechanistic insights, a comparison of the aged vs young daf-2 neuronal transcriptome revealed that a new set of potentially neuroprotective genes is upregulated; instead of simply mimicking a young state, daf-2 may enhance neuronal resilience to accumulation of harm and take a more active approach to combat aging. These findings suggest a potential mechanism for regulating cognitive function with age and offer insights into novel therapeutic targets for age-related cognitive decline.

[This corrects the article DOI: 10.3389/fnagi.2022.893444.].

Reduced Insulin/IGF-like signaling (IIS) plays an evolutionarily conserved role in improving longevity and some measures of health-span in model organisms. Recent studies, however, have found a disconnection between lifespan extension and behavioral health-span. We have previously shown that reduction of IIS in Drosophila neurons extends female lifespan but does not improve negative geotaxis senescence and has a detrimental effect on exploratory walking senescence in both sexes. We hypothesize that individual neuronal subtypes respond differently to IIS changes, thus the behavioral outcomes of pan-neuronal IIS reduction are the balance of positive, negative and neutral functional effects. In order to further understand how reduced IIS in neurons independently modulates lifespan and locomotor behavioral senescence we expressed a dominant negative Insulin receptor transgene selectively in individual neuronal subtypes and measured the effects on lifespan and two measures of locomotor senescence, negative geotaxis and exploratory walking. IIS reduction in cholinergic, GABAergic, dopaminergic, glutamatergic, and octopaminergic neurons was found to have either no affect or a detrimental effect on lifespan and locomotor senescence. However, reduction of IIS selectively in serotonergic neurons resulted in extension of lifespan in females with no effect on locomotor senescence. These data indicate that individual neuronal subtypes respond differently to IIS changes in the modulation of lifespan and locomotor senescence, and identify a specific role for the insulin receptor in serotonergic neurons in the modulation of lifespan.

With increasing release of nanoparticles (NPs) into the environment, soil organisms likely suffer from high dose and long duration of NPs contamination, while the effect of NPs across multiple generations in soil is rarely studied. Herein, we investigated how multigenerational exposure to different crystal forms (anatase, rutile, and their mixture) of TiO2 NPs (nTiO2) affected the survival, behavior, physiological and biochemical traits, and lifespan of nematodes (C. elegans) in a paddy soil. The soil property changed very slightly after being spiked with nTiO2, and the toxicities of three nTiO2 forms were largely comparable. The nTiO2 exposure adversely influenced the survival and locomotion of nematodes, and increased intracellular reactive oxygen species (ROS) generation. Interestingly, the toxic effect gradually attenuated and the lifespan of survived nematodes increased from the P0 to F3 generation, which was ascribed to the survivor selection and stimulatory effect. The lethal effect and the increased oxidative stress may continuously screen out offspring possessing stronger anti-stress capabilities. Moreover, key genes (daf-2, age-1, and skn-1) in the insulin/IGF-like signaling (IIS) pathway actively responded to the nTiO2 exposure, which further optimized the selective expression of downstream genes, increased the antioxidant enzyme activities and antioxidant contents, and thereby increased the stress resistance and longevity of survived nematodes across successive generations. Our findings highlight the crucial role of bio-responses in the progressively decreased toxicity of nTiO2, and add new knowledge on the long-term impact of soil nTiO2 contamination.