Principles of brain aging: Status and challenges of modeling human molecular changes in mice

Due to the extension of human life expectancy, the prevalence of cognitive impairment is rising in the older portion of society. Developing new strategies to delay or attenuate cognitive decline is vital. For this purpose, it is imperative to understand the cellular and molecular events at the basis of brain aging. While several organs are directly accessible to molecular analysis through biopsies, the brain constitutes a notable exception. Most of the molecular studies are performed on postmortem tissues, where cell death and tissue damage have already occurred. Hence, the study of the molecular aspects of cognitive decline largely relies on animal models and in particular on small mammals such as mice. What have we learned from these models? Do these animals recapitulate the changes observed in humans? What should we expect from future mouse studies? In this review we answer these questions by summarizing the state of the research that has addressed cognitive decline in mice from several perspectives, including genetic manipulation and omics strategies. We conclude that, while extremely valuable, mouse models have limitations that can be addressed by the optimal design of future studies and by ensuring that results are cross-validated in the human context.