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.

The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1 , NR4A2 , NR4A3 , PER1 , and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3′ untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1 , AMBP , APOE , CD36 , EFNB1 , NDUFAF1 , PRDX5 , REN , RENBP , SLC13A1 , STX4 , and TNNT2 mRNAs and for miRNAs hsa-miR-21, hsa-miR-126, hsa-miR-181a, hsa-miR-196a, hsa-miR-451, hsa-miR-638, and hsa-miR-663. Functional experiments in HEK293 cells demonstrated that hsa-miR-663 can bind to the REN and APOE 3′ untranslated regions and can regulate REN and APOE mRNA levels, whereas hsa-miR-181a regulated REN and AIFM1 mRNA. Our data demonstrated for the first time that miRNAs can regulate renin expression. The observed downregulation of 2 miRNAs in hypertension could explain the elevation in intrarenal renin mRNA. Renin, CD36, and other mRNAs, as well as miRNAs and associated pathways identified in the present study, provide novel insights into hypertension etiology.

Male circumcision (MC) status and genital infection risk are interlinked and MC is now part of HIV prevention programs worldwide. Current MC prevalence is not known for all countries globally. Our aim was to provide estimates for country-specific and global MC prevalence. MC prevalence data were obtained by searches in PubMed, Demographic and Health Surveys, AIDS Indicator Surveys, and Behavioural Surveillance Surveys. Male age was ≥15 years in most surveys. Where no data were available, the population proportion whose religious faith or culture requires MC was used. The total number of circumcised males in each country and territory was calculated using figures for total males from (i) 2015 US Central Intelligence Agency (CIA) data for sex ratio and total population in all 237 countries and territories globally and (ii) 2015 United Nations (UN) figures for males aged 15–64 years. The estimated percentage of circumcised males in each country and territory varies considerably. Based on (i) and (ii) above, global MC prevalence was 38.7 % (95 % confidence interval [CI]: 33.4, 43.9) and 36.7 % (95 % CI: 31.4, 42.0). Approximately half of circumcisions were for religious and cultural reasons. For countries lacking data we assumed 99.9 % of Muslims and Jews were circumcised. If actual prevalence in religious groups was lower, then MC prevalence in those countries would be lower. On the other hand, we assumed a minimum prevalence of 0.1 % related to MC for medical reasons. This may be too low, thereby underestimating MC prevalence in some countries. The present study provides the most accurate estimate to date of MC prevalence in each country and territory in the world. We estimate that 37–39 % of men globally are circumcised. Considering the health benefits of MC, these data may help guide efforts aimed at the use of voluntary, safe medical MC in disease prevention programs in various countries.