Brian J. Morris

Since the discovery of renin 80 years ago, there have been remarkable advances in our understanding of the renin-angiotensin system. The system as it is known today is summarized in Figure 1. Angiotensin III, the active component of the system, has several important physiological actions. The first of these to be identified was its pressor action, and for many years it was felt that the sole function of the renin-angiotensin system was regula­ tion of blood pressure. A new dimension was added in 1960 with the discovery that angiotensin II stimulates the secretion of aldosterone and is therefore in a position to exert important effects on salt and water balance. Several additional actions of angiotensin II were then discovered. It was found that the peptide can increase the secretion of catecholamines from the adrenal and facilitate adrenergic transmission. It also acts directly on the brain to increase blood pressure via sympathetic and parasympathetic path­ ways, to produce thirst, and to stimulate the secretion of vasopressin and ACTH. Through these actions, the renin-angiotensin system plays an im­ portant role in the regulation of blood pressure and of the volume and composition of the extracellular fluid. Major advances have also been made in our understanding of other aspects of the renin-angiotensin system. It has become clear that the hep­ tapeptide metabolite of angiotensin II, [des-Aspl] angiotensin II (angio-

BACKGROUND: The gene FOXO3, encoding the transcription factor forkhead box O-3 (FoxO3), is one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations. OBJECTIVE: Here, we review the multitude of actions of FoxO3 that are relevant to health, and thus healthy ageing and longevity. METHODS: The study involved a literature search for articles retrieved from PubMed using FoxO3 as keyword. RESULTS: We review the molecular genetics of FOXO3 in longevity, then current knowledge of FoxO3 function relevant to ageing and lifespan. We describe how FoxOs are involved in energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance. The single FoxO in Hydra confers immortality to this fresh water polyp, but as more complex organisms evolved, this role has been usurped by the need for FoxO to control a broader range of specialized pathways across a wide spectrum of tissues assisted by the advent of as many as 4 FoxO subtypes in mammals. The major themes of FoxO3 are similar, but not identical, to other FoxOs and include regulation of cellular homeostasis, particularly of stem cells, and of inflammation, which is a common theme of age-related diseases. Other functions concern metabolism, cell cycle arrest, apoptosis, destruction of potentially damaging reactive oxygen species and proteostasis. CONCLUSIONS: The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. The prospect of optimizing FoxO3 activity in humans to increase lifespan and reduce age-related diseases represents an exciting avenue of clinical investigation. Research strategies directed at developing therapeutic agents that target FoxO3, its gene and proteins in the pathway(s) FoxO3 regulates should be encouraged and supported.

The pseudoautosomal regions (PAR1 and PAR2) of the human X and Y chromosomes pair and recombine during meiosis. Thus genes in this region are not inherited in a strictly sex-linked fashion. PAR1 is located at the terminal region of the short arms and PAR2 at the tips of the long arms of these chromosomes. To date, 24 genes have been assigned to the PAR1 region. Half of these have a known function. In contrast, so far only 4 genes have been discovered in the PAR2 region. Deletion of the PAR1 region results in failure of pairing and male sterility. The gene SHOX (short stature homeobox-containing) resides in PAR1. SHOX haploinsufficiency contributes to certain features in Turner syndrome as well as the characteristics of Leri-Weill dyschondrosteosis. Only two of the human PAR1 genes have mouse homologues. These do not, however, reside in the mouse PAR1 region but are autosomal. The PAR regions seem to be relics of differential additions, losses, rearrangements and degradation of the X and Y chromosome in different mammalian lineages. Marsupials have three homologues of human PAR1 genes in their autosomes, although, in contrast to mouse, do not have a PAR region at all. The disappearance of PAR from other species seems likely and this region will only be rescued by the addition of genes to both X and Y, as has occurred already in lemmings. The present review summarizes the current understanding of the evolution of PAR and provides up-to-date information about individual genes residing in this region.

To isolate a human glandular kallikrein gene, a human genomic library was screened with a probe made from a mouse kallikrein cDNA (pMK-1). Overlapping clones were obtained and nucleotide sequence determination showed that they together contained a human glandular preprokallikrein gene, hGK-1, of 5.2 kb. The gene encoded a unique preproprotein of 261 amino acids. The sequence of the mature 237-amino-acid protein had 66% homology with the sequence predicted for human kallikrein synthesized in the pancreas, kidney, and salivary gland. Moreover, it had even stronger homology (78%) with human prostate-specific antigen. The latter lacks an aspartic acid residue essential for kallikrein-specific cleavage, whereas the sequence of this new protein had all of the attributes needed to confer kallikrein-like specificity. Southern blotting indicated that the number of glandular kallikrein genes in man could be limited to three, a situation very different from mouse and rat, which each have a large multigene family. Furthermore, unlike kallikrein genes in the mouse, hGK-1 was not closely linked to other human kallikrein genes. In other respects the structure of the human kallikrein gene resembled that in mouse: coding sequences in the five exons were organized similarly, homology was higher with other members of the kallikrein gene family in the same species, and the three key amino acid residues required by serine proteases for their catalytic activity, together with the residue that confers kallikrein-specific cleavage, were conserved and located on different exons. Thus, if hGK-1 is expressed, its product represents a new, and possibly the only other enzyme with true kallikrein-like specificity in man.