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Unravelling environmental exposures
in the core axis of ageing

Final Report Summary - ENVIRONAGE (Unravelling environmental exposures in the core axis of ageing)

Although universal and unavoidable, ageing does not occur in a uniform way. AGEing is a complex phenotype, responsive to a plethora of ENVIRONmental inputs (ENVIRONAGE). Age related conditions in adults (cardiovascular, neurological ageing) often find their origin in risk factors operative in early life. The molecular mechanisms behind these phenomena remain largely unknown. The ENVIRONAGE study focused on three main aspects telomere length at early life, placental omics and new exposomics markers to quantify the internal exposure to particulate air pollution.

1. Determinants and importance of telomere length in early life
Telomere attrition is considered a primary hallmark of aging and extensive research on the determinants of telomere length in adults has been performed. Telomere length shortens with each cell division and accumulating DNA damaging effects caused by oxidative stress and inflammation during life contributes to a more rapid decline in telomere length. This may explain differences in aging rates. Telomere length may be a predictor of lifespan and the susceptibility for developing age-related diseases and is considered as a marker of biological aging. For the first time, we showed the importance of telomere length at birth for setting telomere length in adult life. To this end, we tracked telomere length of 200 newborns from birth till adulthood and found strong correlations between telomere length at birth and at young adulthood. Further, at birth, telomere length is highly variable and this may be largely determined by both genetics and environmental exposures during embryonic and fetal development. It has been hypothesized that the origins of health and disease later in life may be determined early in life or even during the prenatal life. Therefore the programming of telomere biology at birth and during early life may be an important biological pathway in the developmental origins of later life health and disease. Knowledge on factors that determines telomere length at birth is scarce. The ENVIRONAGE study studied potential factors operative during the in utero life that may relate to the early biological aging process, by studying their relationship with newborn telomere length.
In summary we found that newborn telomere length is shorter in association with higher pre-pregnancy BMI, low socio-economic status, and higher prenatal exposure to particulate matter and ambient temperature. Comparing our observed results from both cord blood with placental telomere length were mostly consistent. Our results shows that maintaining a healthy weight during the reproductive life may increase overall molecular longevity of the offspring. Besides we show that, even though in an affluent country such as Belgium, socio-economic differences still relates to differences in potential lifespans from birth onwards, as reflected by telomere length at birth. Additionally, we showed that air pollution exposures under the European Union accepted limit clearly impacts the molecular aging process. Besides we showed for the first time that ambient temperature exposures are associated with the aging process, reflected by telomere length, and this may be severely impacted in the future by the global climate change. These results aim for simple but adequate human interventions and governmental actions to reduce global air pollution levels and arrest the further global warming process. These interventions greatly may impact global human health across the different phases of life, and as shown by our results, this may start from life in the womb.

2. Placenta as important target in developmental origin of health an disease
Individual differences in utero may affect developmental processes later in life by changing normal trajectory. A wide variety of biologically unfavourable environmental factors are believed to play some role in the etiology of these differences by inducing inflammatory, oxidative and nitrosative stress responses, mitochondrial dysfunction, apoptosis, and epigenetic dysregulation. At delivery, the placenta represents a precious source of the morphological, functional, and molecular information accumulated during the gestational period. These biological signatures enshrined in the placenta as a result of various external exposures make the placenta a suitable, non-invasive matrix for research pertaining to the pregnancy period. Moreover, there is growing awareness that prenatal epigenetic dysregulation due to adverse in utero environments not only affect fetal brain development, but also predispose an individual to neurodevelopmental, behavioral and cognitive deficits later in life. We found that prenatal exposure to ambient air pollution (PM2.5) exposure was associated with nitorosative stress, placental changes in DNA methylation or gene expression of factors involved with (neuro)development (BDNF), circadian rhythm and DNA repair genes. In addition, prenatal exposure to PM2.5 and black carbon, but not NO2, was associated with an increased placental mutation rate. We have to stress the public health significance of our findings as it has been shown before that lifetime cancer risk increases when exposure to carcinogens occurs early in life. Although recent studies strongly suggest that particle translocation in biological systems is biologically plausible, they do not prove that ambient fossil fuel-derived carbonaceous nanoparticles enter the human systemic circulation in real-life conditions. We demonstrated the presence of these black carbon particles in urine and placenta and its relation with the external environmental air pollution. This pioneering study is of innovative value, as it paved the way for a non-invasive assessment of long-term individual exposure to one of the most toxic air pollutants, black carbon, and will be useful in future epidemiological investigations, biomonitoring studies as well as in occupational settings.

Overall conclusion
The ENVIRONAGE project forms a basis in the understanding of lifestyle and environmental factors that associates with early human molecular aging and the potential fetal programming of diseases in newborns. We were able to identify and explore important factors of newborn telomere length and established to our knowledge the largest birth cohort with data on newborn telomere length. Further technological innovations in the framework of exposure sciences were established by introducing internal markers of black carbon into the field of environmental epidemiology. Our results gain new insights on telomere dynamics that are present very early in life. These results may have important later life consequences as early life telomere length first of all may predict lifespan, secondly sets later life telomere length, and thirdly therefore may predict later life disease susceptibility. Whether our identified factors act in a direct or indirect (through parental telomere mediation) way remains unclear, but nevertheless our results clearly indicates what important effects of unhealthy lifestyle and environmental exposures during pregnancy may have on the next generation and more precise on the level of newborn telomere length.