Voltage-gated sodium (Na(V)) channel inhibitors are an important class of drugs that are used to treat a number of CNS indications including pain, local anaesthesia, epilepsy and bipolar disorder. These drugs all have their origins in traditional "empirical" pharmacology, and it was only some time after discovery that they were found to inhibit Na(V) channels. The basis for therapeutic selectivity of these drugs within different disease indications is currently unknown. However, the subsequent discovery of a multi-gene family of Na(V) channels suggests a possible mechanism and has opened the way for more targeted approaches to finding improved therapeutic inhibitors. This article describes some ongoing approaches to systematically clone, express and characterise the entire family of Na(V) subtypes in order to better understand their properties and define their individual physiological and pathophysiological roles. As well as providing specific disease validation for individual subtypes, this also provides a panel of reagents for comprehensively exploring the efficacy, selectivity and potency relationships of existing Na(V)-blocking drugs. In this way, a gene family-based approach to Na(V) channels has enabled a "drug-to-target" approach, reversing the more usual "gene-to-target-to-drug" paradigm. Together with recent advances in assay technology, gene family-based approaches are increasing the tractability of these targets and are re-invigorating Na(V) drug discovery within the pharmaceutical industry.
The sequencing of a growing number of genomes, and of the human genome in particular, has paved the way for remarkable technological innovations that are revolutionizing research across the life sciences. Large-scale sequencing and emerging techniques and approaches, like microarrays and systems biology, are changing the way researchers study life and its intrinsic complexity. Cells and the molecules that compose them, in particular proteins programmed from the genome to give rise to complex interactions and functions, can now be studied in a high-throughput fashion. Genomics and its derivative technologies promise to transform biomedical research and be the preeminent area of scientific discovery during the 21st century. New technologies are particularly useful in scientific fields that have already been the subject of considerable research, and thus for which substantial observations exist, but that remain largely unsolved (de Magalhães and Toussaint, 2004a). Biogerontology is one of such fields and the post-genome era promises to be a time of unprecedented breakthroughs in our understanding of ageing. The goal of this chapter is to review some of the key technological and methodological advances made possible by the recent sequencing of genomes and summarize their relevance to the study of complex traits like longevity, ageing and age-related diseases.
The senescent decline that leads inevitably to death in most animal species is accompanied by a massive increase in molecular damage. Yet, the chain of events that initially causes this process, and the determinants of the rate at which it happens, remain poorly understood. For many years, much research on this topic has been guided by an interrelated set of theories that view oxidative damage as a potential primary cause of aging. These theories have framed the construction and interpretation of many studies in the nematode Caenorhabditis elegans. In this chapter, we critically survey these studies. Overall, these investigations have either disproved or, at least, failed to find clear evidence for many of the oxidative damage theories. In particular, they have failed to demonstrate any role of metabolic rate or mitochondrial superoxide (O2 •−) in aging. However, they have revealed a powerful influence of mitochondria on the rate of aging in C. elegans. This may or may not have something to do with mitochondrial O2 •− production.
