Cytokine dysregulation is believed to play a key role in the remodeling of the immune system at older age, with evidence pointing to an inability to fine-control systemic inflammation, which seems to be a marker of unsuccessful aging. This reshaping of cytokine expression pattern, with a progressive tendency toward a pro-inflammatory phenotype has been called “inflamm-aging.” Despite research there is no clear understanding about the causes of “inflamm-aging” that underpin most major age-related diseases, including atherosclerosis, diabetes, Alzheimer’s disease, rheumatoid arthritis, cancer, and aging itself. While inflammation is part of the normal repair response for healing, and essential in keeping us safe from bacterial and viral infections and noxious environmental agents, not all inflammation is good. When inflammation becomes prolonged and persists, it can become damaging and destructive. Several common molecular pathways have been identified that are associated with both aging and low-grade inflammation. The age-related change in redox balance, the increase in age-related senescent cells, the senescence-associated secretory phenotype (SASP) and the decline in effective autophagy that can trigger the inflammasome, suggest that it may be possible to delay age-related diseases and aging itself by suppressing pro-inflammatory molecular mechanisms or improving the timely resolution of inflammation. Conversely there may be learning from molecular or genetic pathways from long-lived cohorts who exemplify good quality aging. Here, we will discuss some of the current ideas and highlight molecular pathways that appear to contribute to the immune imbalance and the cytokine dysregulation, which is associated with “inflammageing” or parainflammation. Evidence of these findings will be drawn from research in cardiovascular disease, cancer, neurological inflammation and rheumatoid arthritis.

De novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.

Background-Particulate air pollution has been associated with excess deaths from, and increases in hospital admissions for, cardiovascular disease among older people. A study was undertaken to determine whether this may be a consequence of alterations in the blood, secondary to pulmonary inflammation caused by the action of fine particles on alveolar cells, by repeatedly measuring haematological factors in older people and relating them to measurements of exposure to airborne particles. Methods-One hundred and twelve individuals aged 60+ years in two UK cities provided repeated blood samples over 18 months, 108 providing the maximum of 12 samples. Estimates of individual exposure to particles of less than 10 µm diameter (PM 10 ), derived from a mathematical model based on activity diaries and comparative measurements of PM 10 at multiple sites and during a variety of activities, were made for each three day period prior to blood sampling. The relationships between blood values and estimates of both personal exposure and city centre measurements of PM 10 were investigated by analysis of covariance, adjusting for city, season, temperature, and repeated individual measurements. Results-Estimated personal exposure to PM 10 over the previous three days showed negative correlations with haemoglobin concentration, packed cell volume (PCV), and red blood cell count (p<0.001), and with platelets and factor VII levels (p<0.05). The changes in red cell indices persisted after adjustment for plasma albumin in a sample of 60 of the subjects. City centre PM 10 measurements over three days also showed negative correlations with haemoglobin and red cell count (p<0.001) and with PCV and fibrinogen (p<0.05), the relationship with haemoglobin persisting after adjustment for albumin. C reactive protein levels showed a positive association with city centre measurements of PM 10 (p<0.01). Based on a linear relationship, the estimated change in haemoglobin associated with an alteration in particle concentration of 100 µg/m 3 is estimated to have been 0.44 g/ dl (95% CI 0.62 to 0.26) for personal PM 10 and 0.73 g/dl (95% CI 1.11 to 0.36) for city centre PM 10 measurements. Conclusions-This investigation is the first to estimate personal exposures to PM 10 and to demonstrate associations between haematological indices and air pollution. The changes in haemoglobin adjusted for albumin suggest that inhalation of some component of PM 10 may cause sequestration of red cells in the circulation. We propose that an action of such particles either on lung endothelial cells or on erythrocytes themselves may be responsible for changing red cell adhesiveness. Peripheral sequestration of red cells oVers an explanation for the observed cardiovascular eVects of particulate air pollution.