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The zebrafish is a popular model organism that has been widely used in developmental biology. Due to its integrated nervous system with homologous structures to those of mammals and displays of similar age-related behavioral and neurobiological changes, it is invaluable for understanding the neuroscience of aging. Besides the advantages that stem from the nature of the zebrafish, several genetic and nongenetic gerontological and disease models are available for understanding the progression of age-related changes. These genetic models provide grounds to study accelerated/decelerated aging phenotypes and neurodegenerative diseases throughout the life span or within a specific time frame of development. Moreover, nongenetic interventions such as dietary restriction, drug applications, and environmental enrichment have been used with both wild-type or mutant strains as possible means of reversing age-related changes. This chapter focuses on the age-related alterations in cognitive, behavioral, and molecular domains in zebrafish, as well as existing models and antiaging interventions.

Intermittent fasting (IF) and its mimetic, rapamycin extend lifespan and healthspan through mechanisms that are not fully understood. We investigated different short-term durations of IF and rapamycin on cellular and molecular changes in the brains of young (6-10 months) and old (26-31 months) zebrafish. Interestingly, our results showed that IF significantly lowered glucose levels while increasing DCAMKL1 in both young and old animals. This proliferative effect of IF was supported by the upregulation of foxm1 transcript in old animals. Rapamycin did not change glucose levels in young and old animals but had differential effects depending on age. In young zebrafish, proliferating cell nuclear antigen and the LC3-II/LC3-I ratio was decreased, whereas glial fibrillary acidic protein and gephyrin were decreased in old animals. The changes in proliferative markers and a marker of autophagic flux suggest an age-dependent interplay between autophagy and cell proliferation. Additionally, changes in glia and inhibitory tone suggest a suppressive effect on neuroinflammation but may push the brain toward a more excitable state. Mammalian target of rapamycin (mTOR) activity in the brain following the IF and rapamycin treatment was differentially regulated by age. Interestingly, rapamycin inhibited mTOR more potently in young animals than IF. Principal component analysis supported our conclusion that the regulatory effects of IF and rapamycin were age-specific, since we observed different patterns in the expression levels and clustering of young and old animals. Taken together, our results suggest that even a short-term duration of IF and rapamycin have significant effects in the brain at young and old ages, and that these are age and treatment dependent.

Chapter 1 Across the world, the aging population is expanding due to an increasing average life expectancy. The percentage of elderly over the age of 65 is expected to be more than 15% of the total world population by 2025. As the lifespan increases, there will be a need for maintaining a healthy state for these individuals. Our current knowledge on types and durations of potential anti-aging therapies is quite limited. Recently the zebrafish has emerged as a promising model for understanding the cognitive and neurobiological changes during aging, as well as its use with potential anti-aging interventions. Like humans this model organism ages gradually, displays similar behavioral properties and social characteristics, and in addition, there is a wealth of molecular and genetic tools to uncover the cellular mechanism that contribute to age-related cognitive declines. Drug effect and toxicity can be easily tested in the zebrafish. Therefore, this animal model can provide information about potential therapies that could be translated directly into human populations or provide a more focused treatment direction for testing in other mammalian animal models. The zebrafish will be a powerful tool for uncovering the mysteries of the aging brain.

Chapter 11 Normal aging is accompanied by cognitive impairment with subtle cellular and molecular changes in the brain, whereas, pathological brain aging manifests as severe behavioral impairments with cellular pathology. Understanding the factors that contribute to both states is undoubtedly important for determining appropriate interventions that alter their progression. Mammalian target of rapamycin (mTOR) signaling has been implicated in affecting lifespan and age-related diseases such as cancer. The relationship of mTOR signaling with pathological brain aging has been more extensively studied, whereas the association with normal brain aging is not well understood. In this chapter we present information about normal and pathological brain aging, the relationship with mTOR signaling and use information from other age-related diseases to suggest that mTOR may have a role in promoting the cellular and molecular changes that underlie age-related cognitive changes. Future work should be directed towards understanding the precise role of mTOR signaling in brain aging. © 2016 Elsevier Inc. All rights reserved.