Aging is associated with gradual deterioration of physiological and biochemical functions, including cognitive decline. Transcriptome profiling of brain samples from individuals of varying ages has identified the whole-transcriptome changes that underlie age-associated cognitive declines. In this review, we discuss transcriptome-based research on human brain aging performed by using microarray and RNA sequencing analyses. Overall, decreased synaptic function and increased immune function are prevalent in most regions of the aged brain. Age-associated gene expression changes are also cell dependent and region dependent and are affected by genotype. In addition, the transcriptome changes that occur during brain aging include different splicing events, intersample heterogeneity, and altered levels of various types of noncoding RNAs. Establishing transcriptome-based hallmarks of human brain aging will improve the understanding of cognitive aging and neurodegenerative diseases and eventually lead to interventions that delay or prevent brain aging. Brain aging: RNA profiling to elucidate cognitive decline Extensive exploration of RNA changes in the human brain over time should provide hallmarks for cognitive decline and neurodegenerative diseases. Changes in the messenger RNA profile, the 'transcriptome', of individual cells play a key role in brain aging, and could influence the progression of neurodegenerative diseases. Seung-Jae V. Lee and Seokjin Ham at the Korea Advanced Institute of Science and Technology, Daejeon, South Korea, reviewed current understanding of brain aging gained via transcriptomic profiling. Most aging brain regions display decreased synaptic function and plasticity, together with increased expression of immune response genes. Individual genotypes influence specific regional and cellular transcriptomic changes. The role of RNA-binding proteins and changes in expression of non-coding RNAs are of particular interest. The researchers call for widespread research in all ethnic groups, as most studies involve mainly Caucasian participants.