Gene Expression in the Aging Brain

Many studies have assessed the anatomical, physiological, and cognitive changes that occur in the brain as we age.1 For instance, brain regions such as the prefrontal cortex (PFC), undergo significant age-related volume decreases, and neuroimaging studies reveal age-related activity changes in the PFC associated with memory performance tasks.2-4 Although cognitive changes are certainly variable between individuals, aging is generally accompanied by slower processing speeds and a decrease in the ability to convert experiences into episodic memory.1 In contrast, autobiographical and implicit memory remains relatively unaffected by normal aging.1 Despite all that is known regarding age-dependent changes in brain architecture and cognitive function, much is yet to be learned regarding the mechanisms that underlie these processes.

To further our understanding, a recent study by Lu et al. has used DNA microarray technology to assess the expression patterns of more than 11,000 genes from the frontal cortex of neuropathologically normal individuals ranging in age from 26 to 106 years.5 The study reveals that the expression levels of about 4% of these genes underwent significant changes (≥1.5 fold) when comparing individuals ≤42 and ≥73 years of age. The authors show that expression patterns are relatively stable until approximately age 40 when significant variability begins to appear among individuals. By age 70, this variability has declined and defined clusters of genes associated with specific cellular functions show distinct alterations in expression levels (Table 1). For instance, genes involved in synapse structure exhibit significant declines in older individuals. In addition, elements thought to be associated with synaptic plasticity and/or learning and memory, including glutamate receptor subunits and signaling factors such as Calmodulin and CAM kinases, also undergo significant decreases. Other important signaling-associated genes exhibiting expression declines were members of the Ras/MAP Kinase, PKC, and PI 3-kinase families. In contrast, clusters of genes associated with DNA damage and repair, the stress response, inflammation, and protection against damaging oxidizing agents, were upregulated in the aged brain. The authors went on to use this information to look for putative mechanisms responsible for the observed changes. They showed that the promotor regions of several genes that exhibited age-related declines were damaged in the aged cortex, and in vitro these promotors were especially susceptible to oxidative stress and resistant to DNA repair.

Although this study does not directly link changes in gene expression with cognitive ability, it does provide clues regarding what factors are involved in cognitive declines associated with normal aging and potentially age-related neurodegenerative diseases. It may also help to genetically characterize when the aging process begins in the brain, and help define why some individuals are more susceptible to age-related decreases in cognitive function.

Declining Expression in Aging Brain   Increasing Expression in Aging Brain
Gene Fold Δ   Gene Fold ?
Synapse Function/Structure     DNA Repair  
GluR1 -2.2 to -2.4   8-oxo-d 1.6
NMDA Receptor 2A -2.2 to -2.4   Uracil DNA N-Glycolase 1.7
GABA A Receptor ß3 -3.2   Topoisomerase I Binding Protein 1.6
Serotonin Receptor 2A -2.0      
Neurexin-1 -1.6   Stress Response  
Synaptobrevin -3.4   Heat Shock 70-kDa Protein 2 1.9 to 2.2
Synapsin II beta -3.4   HIF-1 alpha 2.0
alpha SNAP -1.6   Transglutaminase 2 2.8
? SNAP -2.2   p53-binding Protein 2 1.7
      Crystallin aB 1.6 to 2.0
Signaling     RAP140 1.8
Calmodulin 1 -2.2      
Calmodulin 3 -1.6   Inflammation  
CaM Kinase IIa -1.7   TNF-alpha/TNFSF1A 2.7
CaM Kinase IV -2.0   CD31/PECAM-1 2.2
Calcineurin B -2.8   C-type Lectin 2.7
PKC beta 1 -1.9 to -2.9   Interferon Regulatory Factor 7 1.9
PKC? -1.8   Integrin alpha 1 1.7
PKC? -1.7   Integrin alpha 5 1.8
ERK2 -1.9      
JNK2 -1.7   Antioxidants  
MAPKK4 -3.1   Paraoxonase 2 1.6
PAK -2.7   Selenoprotein P 1.7
Ras-GNRF -2.4 to -4.7   Nonselenium Glutathione Peroxidase 1.7
PI 3-Kinase p110ß -1.7   Cystathionine beta Synthase 1.6
Table 1. A representative selection of genes either upregulated or downregulated in the aged frontal cortex. [Note: table adapted from Lu, T. et al. (2004) Nature 429:883.]


  1. Hedden, T. & J.D.E. Gabrieli (2004) Nat. Rev. Neurosci. 5:87.
  2. Resnick, S.M. et al. (2003) J. Neurosci. 23:3295.
  3. Raz, N. et al. (2004) Neurobiol. Aging 25:377.
  4. Langley, L.K. & D.J. Madden (2000) Microsc. Res. Tech. 51:75.
  5. Lu, T. et al. (2004) Nature 429:883.