Although there is much debate about the processes driving human aging, there is little doubt that genetic influences play a significant role (1). Humans clearly live very much longer than the currently favored laboratory models of aging, and such interspecies differences in reproductively ‘fit’ life span must have an inherited genetic foundation. Within human populations, environmental and behavioral exposures are important but at least a quarter of life expectancy variation in twin or family studies is attributable to inherited genetic or epigenetic factors (2). Age-related conditions such as type 2 diabetes, myocardial infarction, common cancers, and Alzheimer’s disease (AD) typically have onsets after the fourth decade of life; “successful” agers delay these onsets until relatively late in life (3). Many aging traits and diseases show moderate heritability, including cardiovascular disease (CVD) (4) and impaired physical functioning (5), independent of known environmental risk factors. Inherited genetic variations in DNA sequences come in several forms, including single-nucleotide polymorphisms (SNPs), insertions/deletions, and copy-number variations. Of the 54 million variants documented in the database of genetic variation (db SNP) (6), more than 88% are single base pair substitutions or “SNPs” (7). SNPs located close to one another are more likely to be inherited together (called linkage disequilibrium) (8), and this tendency coupled with new array technology allows the assaying of millions of SNPs per sample, capturing most common variation. The effect a variant has on a given phenotype depends on its position in the genome. Within each gene, only a small proportion of the DNA sequence is used as a template for assembling amino acids into specific proteins (9) (Figure 1); these DNA sections are termed exons. Exon sequences are “transcribed” (in part or in full) from DNA into messenger RNA (mRNA), which undergoes “processing” before forming the template for protein production. If the DNA sequence within an exon is changed, this could have profound consequences to the final structure of the protein synthesized from the gene. However, the protein-coding regions of genes are highly conserved, even between species (10). This highlights an intriguing question; if highly similar genes are used in the growth and development of different organs, tissues, and cell types, how can so much phenotypic variation occur? The answer lies in the complex machinery that regulates gene transcription and protein production in different cells types and in response to specific stimuli. Figure 1. The central dogma—extensive regulation provides specificity. Gene expression in higher organisms requires regulation that is often specific to cell type and is responsive to the cells environment. Here, we show an example of a gene being transcribed, ... Transcription can vary in amount (ie, particular mRNAs can be up or down regulated) but can also produce specific versions or “isoforms” of proteins, in a fine-tuning system that contributes to specialization of cell types and tissues. This involves the removal, or “splicing,” of introns—sequences of DNA that separate the exons from one another—allowing many protein products to be derived from a single gene. Transcription and RNA processing require extensive regulation by transcription factors binding to sites in proximity to the gene, which can be many thousands of base pairs away. DNA variants located within these regulatory binding sites can alter when, where, and for how long a gene is expressed by altering the affinity of the various transcription factors to that particular regulatory sequence (Figure 1). Differential regulation of genes—both in location and timing—between species likely contributes to the divergence and isolation of different species (11). Human studies are lacking, but work in mice has shown regulatory differences between subspecies (12). Affordable genomic array technologies that measure the expression of thousands of genes are now being used in human population studies. Progress in this field is likely to receive a boost in the coming years as studies use large sample collections to investigate the differential regulation of gene expression in humans, and how these differences influence disease and longevity (13). Epigenetic changes, such as DNA methylation and histone modifications, are also heritable and affect mRNA expression (14). These changes to the structure of DNA do not affect the sequence and can change with advancing age (15). It appears that genetic and epigenetic variations exert their effects by altering either the amount of RNA transcribed from a gene or the relative proportion of alternatively expressed isoforms produced by the alternative splicing mechanisms. These ultimately affect other downstream elements of the pathway, such as binding partners or inhibitors, resulting in a change in phenotype. It will therefore be necessary for future research programs to integrate genetic variation, epigenetics, and associated gene expression profiles to understand the origins of heritable traits and diseases. Such mechanistic understanding may contribute to the discovery of new therapeutic targets for aging pathologies (16).