Despite its ubiquity and importance, aging remains a poorly understood process. This lack of understanding is due in part to the complexity of aging, which is characterized by the gradual and progressive decline of numerous physiological processes and homeostasis, eventually leading to death [1–6]. However, recent progress in aging research has made it clear that aging processes are amenable to biochemical and genetic dissection, in both humans and model organisms [3–6].
Both environmental and genetic alterations in model organisms have been found to have profound effects on aging and lifespan. In particular, dietary restriction has been found to dramatically increase the lifespan of organisms including yeast, flies, nematodes, and mammals [4,5]; the mechanism by which this intervention reduces mortality rates is still under investigation. Additionally, inactivating myriad single genes has been found to be able to significantly increase the average lifespan of model organisms [4,5], and the identification of the pathways to which these genes belong is beginning to shed light on their possible modes of action. For example, many genes implicated in regulating lifespan in the nematode Caenorhabditis elegans belong to the insulin/IGF (insulin-like growth factor) signaling pathway, indicating possible connections to metabolism and a state of arrested development known as “dauer” [4,5]. Another class of genes found to be involved in the aging process is related to the production and scavenging of molecules known as reactive oxygen species (ROS), thus providing genetic evidence in support of a mechanistic theory of aging known as the free radical theory [2,3].
The free radical theory of aging was first introduced by Harman almost half a century ago [2]. This theory, as well as the related “rate of living” theory proposed earlier by Pearl [1], holds that aging is at least in part due to deleterious side effects of aerobic respiration. Specifically, mitochondrial activity leads to the production of ROS that can damage many cellular components, including DNA, lipids, and proteins [3]. These ROS, such as the hydroxyl radical (OH•) and hydrogen peroxide (H2O2), are produced in large part by the mitochondrial electron transport chain. The free radical theory has garnered widespread support in recent years; in addition to the genetic evidence mentioned above, studies from a number of model organisms showing that decreasing ROS levels leads to an increase in lifespan indicate that ROS can strongly modulate the aging process [3–5].
Exactly how macromolecules damaged by ROS may lead to aging has been studied in detail in recent years, and the human brain has been intensively examined in this regard because of its overall importance in human senescence. For example, up to one-third of the proteins in the brains of elderly individuals may be oxidatively damaged, and these damaged proteins have been shown to sometimes have diminished catalytic function [3,6]. One recent study of aging in the human brain demonstrated that oxidative damage to DNA can be caused by mitochondrial dysfunction, and tends to accumulate preferentially in some areas of the genome that include promoters, resulting in lower levels of transcription [7] (possibly due to loss of transcription factor or other protein binding [8–10]). In this same study, genome-wide patterns of aging-associated gene expression change in one region of the human brain cortex (the frontal pole; Figure 1) were measured using DNA microarrays, and genes that had decreased transcription with age were shown to be the ones that are most susceptible to oxidative damage [7]. Since different regions of the human brain have been shown to accumulate DNA damage at different rates [11,12], it is reasonable to suppose that these different regions may show different gene expression changes with age as a result.
Complementing studies of aging differences in various tissues within a single species, research into the evolution of aging has begun to shed light on the similarities and differences between species, although the expectation for how well conserved the effects of aging will be on a gene-by-gene basis is still unclear. One the one hand, if aging is largely caused by the deleterious effects of many alleles late in life—as is often the interpretation of two widely held models for the evolution of aging, known as “antagonistic pleiotropy” and “mutation accumulation” [
4,
5,
13]—then rapid evolutionary change of the aging process, at least at a mechanistic level, should be impossible. This reasoning is supported by empirical observations that many aging-related factors (such as ROS-induced damage) and pathways (such as insulin/IGF signaling) appear to be highly conserved [
4,
5,
13]. However, even if the mechanistic underpinnings of aging are indeed relatively constant, the phenotypic effects may be subject to dramatic change. This is best demonstrated by the observation that artificial selection on model organisms in the lab can lead to dramatic changes in lifespan in a very small number of generations [
5,
13], implying that the consequences of aging could be subject to rapid evolutionary change in the wild as well. Clearly, this issue cannot be resolved solely by laboratory evolution experiments or theoretical work.
One promising approach to answering this question of evolutionary conservation lies at the level of gene expression: Do orthologous genes tend to undergo the same patterns of expression changes with age in diverse species, or can a common factor such as ROS lead to different gene expression patterns in different organisms? Using DNA microarrays, this question can now be addressed in a systematic, genome-wide manner. One such study found that a small but significant portion of aging-related gene expression changes are shared by the very distantly related nematode and fruit fly [14]; another study comparing aging patterns in muscle cells of two more closely related species, mouse and human, also found a great deal of divergence in aging patterns [15]. Although both of these studies are informative, neither addresses the questions of how quickly age-related gene expression patterns can evolve over short periods of time, and if humans in particular show unique patterns of aging not shared by closely related primates.
The human brain is of particular interest for studying the divergence in phenotypes that have changed rapidly during evolution (such as aging). Brain-specific genes have undergone accelerated evolution in the lineage leading to human since the split with chimpanzee at the levels of both protein sequence and gene expression [16,17], pointing to the numerous functional differences that have accumulated between these two species since their divergence only 5 to 7 million years ago. Aging in the human brain is also of interest because ROS-induced damage and age are both major risk factors in many neurodegenerative diseases (such as Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis [18]). In this study we addressed two questions about the relationship between gene expression and aging. First, using published data, we asked whether the pattern of gene expression change with age previously observed in the frontal pole [7] is representative of other regions of the human brain. Then, using data generated for this project, we asked how similar the aging-associated changes in gene expression observed in human brain [7] are to those observed in our closest living relative, the chimpanzee.
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