Academic journal article Annual Review of Gerontology & Geriatrics

Gene Expression Biomarkers and Longevity

Academic journal article Annual Review of Gerontology & Geriatrics

Gene Expression Biomarkers and Longevity

Article excerpt

ABSTRACT

Every human cell contains the same set of genes, yet only a small proportion of these are active at any one time in particular cell types. Array technology is allowing measures of upregulation or downregulation or aberrant forms of expression of many genes simultaneously, and these changes can be related to diseases and traits. For several cancers, gene-expression signatures have led to new understanding of the disease and are being used clinically to target treatment. Recent studies of circulating white cell gene expression changes in the Invecchiare in Chianti (InCHIANTI) cohort suggest that deregulation with age is relatively limited, with a small minority of expressed genes showing strongly age-related changes in expression. Changes in the format of expressed transcripts (so-called splicing changes) were also identified: these suggest that white cells are losing fine tuning of gene expression. Expression changes with muscle strength and cognition have highlighted the role of macrophage-mediated clean up and regeneration processes and have confirmed mouse models. Challenges for the future include access to other tissues, and studying gene expression changes over time.

INTRODUCTION

Chronological age, a count of how many orbits of the sun an individual has made as a passenger of planet Earth, is a useful but limited proxy of aging processes. Some individuals die of age-related diseases in their 60s, whereas others live to double that age. As a result, a great deal of effort has been put into identifying biomarkers that reflect the underlying biological changes involved in aging. These markers would provide insights into what processes were involved, provide measures of how much biological aging had occurred, and provide an outcome measure for monitoring the effects of interventions to slow ageing processes.

Our DNA sequence is the fixed reference template from which all our proteins are produced. With the sequencing of the human genome, we now have an accurate reference library of gene sequences. The recent development of a new generation of high-throughput array technology makes it relatively inexpensive to simultaneously measure a large number of base sequences in DNA (or RNA, the molecule of gene expression). In the last decade, array technologies have supported great progress in identifying common DNA sequence differences (SNPs) that confer risks for age-related diseases, and similar approaches are being used to identify variants associated with exceptional longevity (Pilling et al., 2012). A striking feature of the findings is that most common disease-associated variants are located not in the protein coding sequences of genes but in regions of the genome that do not produce proteins. This indicates that they may be involved in the regulation of nearby genes or in the processing of their messages.

Although DNA holds the static reference sequences for life, an elaborate regulatory system influences whether and in what abundance gene transcripts and proteins are produced. The relative abundance of each transcript is a good guide to the demand for each protein product in cells (see "Introducing Gene Expression" section). Thus, by examining gene expression patterns or signatures associated with aging or age-related traits, we can peer into the underlying production processes at a fundamental level. This approach has already proved successful in clinical applications, for example, using gene signatures to classify cancer subtypes (Harris & McCormick, 2010). In aging research, recent work conducted in the Invecchiare in Chianti (InCHIANTI) cohort has identified geneexpression signatures in peripheral leukocytes linked to several aging phenotypes, including low muscle strength, cognitive impairment, and chronological age itself. In the sections that follow, we provide a brief introduction to the underlying processes involved in gene expression and summarize key work in laboratory models of aging. …

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