Moderation: G. Fuellen, Rostock; M. Gogol, Heidelberg; A. Simm, Halle (Saale)
Despite the importance of precision medicine, the topic of precision prevention still receives little attention. Precise biomarker-based interventions should enable each individual to live a long, healthy life with a high quality of life and independence. For example, recent results on the prevention of cognitive disorders using lifestyle intervention, treatment of risk factors and medication management (FINGER study, PreDIVA study, MAPT study) show low effect sizes in the totality of all study participants. However, analyses in specific subgroups with characteristic risk patterns show clear effects. There is every indication that preventive measures must be adapted to the individual risk profile in order to increase their effectiveness. In view of the demographic challenge, precision prevention is thus key to reducing high age-related disease rates (dementia, heart, diabetes, and cancer) and long-term care. In this session, research towards the implementation of precision prevention will be presented.
There is an enormous diversity in health span ranging from unhealthy 60- to vital 90-year-olds. Medical interventions are tested rarely amongst the heterogeneous population of elderly over 70 years. Preventive interventions often also reveal to be effective especially for subgroups. To generate markers on the basis of which this diversity, especially at higher ages, can be classified is a challenge. Biomarker research is vital to classify those in need of prevention, those at risk of progressive ageing, adversity during treatment, for monitoring the response to treatment and provide surrogate endpoints. The last twenty years of ageing research in animal models and humans has revealed that mechanisms involved in energy metabolism and immunity can be considered as drivers of health in ageing and longevity. Biomarker research has been based on this knowledge on one end and on deviation from calendar age on the other. Traditionally metabolic health is measured by serum insulin and lipids, blood pressure and BMI, but among the fastest growing population of elderly the predictive power of these parameters declines. The omics field is making progress in recording age-related changes in metabolite composition, glycosylation, transcriptome and epigenetic regulation of the nuclear and mitochondrial genome, gut microbiome composition and somatic DNA sequence changes with ageing. Many biomarkers show associations with interesting biological or clinical endpoints, but how useful are they in practice? Coordinated efforts are necessary to test biomarkers in longitudinal, clinical and intervention studies. In a BBMRI consortium in The Netherlands we have explored the use of metabolomics marker profiles in this framework by jointly investigating over 20 cohorts, intervention and clinical studies.
The protein homeostasis network is a complex regulatory system that controls protein synthesis, folding, posttranslational modifications, and degradation. Failure of protein quality control is an early event in aging, and many animal models of longevity display improved protein folding and turnover capacity.
In a number of independent screening approaches, we found that the metabolic hexosamine pathway is a novel regulator of protein homeostasis. In fact, we identified two independent regulators of the hexosamine pathway (HP) that are highly conserved: mutagenesis screens in Caenorhabditis elegans revealed gain-of-function (gof) mutations in glutamine-fructose-6-phosphate aminotransferase (gfat-1), the key enzyme of the HP. These result in elevated levels of the HP product UDP-N-acetylglucosamine (UDP-GlcNAc). C. elegans mutants carrying gfat-1 gof alleles display increased ER-associated degradation and autophagy, resulting in significant protection from various toxic misfolding-prone proteins and lifespan extension. Furthermore, in genetic screens using mouse haploid embryonic stem cells, we identified AMDHD2 as a new HP enzyme that regulates metabolite flux in the pathway.
Finally, to test if HP activation improves mammalian protein quality control, we expressed poly-glutamine Huntingtin in Neuro2a cells. Supplementation with the HP precursor GlcNAc resulted in decreased Huntingtin aggregation. This suggests that the HP might be a viable pharmacological target to prevent age-associated diseases such as neurodegeneration. Given the high conservation of the HP, we expect that its activation will likewise promote healthspan in humans. Furthermore, we know that cellular UDP-GlcNAc concentrations decrease with age in the nematode. It will be of particular interest to examine whether this metabolite might serve as a biomarker for cellular fitness in aging.
The clinical manifestation of sporadic Alzheimer's disease in a given individual is driven among others by molecular factors such as cortical amyloid accumulation, degeneration of allocortical and neocortical projecting neurons, cholinergic dysfunction, and cerebrovascular and other neurodegenerative comorbidities. Imaging markers allow stratification of individuals according to risk factors, such as amyloid load, cortical hypometabolism and cholinergic dysfunction. The application of such risk stratification for individual decision on treatment or prevention in AD is still wanting, but methods are available that will make such approach possible in the future. Here, we present an in vivo staging scheme for cortical amyloid accumulation based on amyloid-PET in preclinical and prodromal AD cases; we demonstrate the advantage of such staging over the current gold standard of binary reading of amyloid PET and show the perspective of an extension by staging of tau pathology, cholinergic dysfunction and hypometabolism. We also point to the concept of a theranostic marker as a predictor of treatment response in clinical trials; this concept represents an important step towards a precision medicine approach to AD treatment and prevention, where a theranostic marker serves to select the appropriate case to a given treatment study. On this basis, future studies will then be able to select the appropriate combination of treatments for a given individual.
Knowing the molecular basis of health can help towards undoing its deterioration, and this should help to focus approaches towards undoing aging on the truly important goal: fostering well-being. However, a precise operational definition of health and healthspan is not straightforward, and its molecular basis is largely unknown.
Building upon previous work, we define health as the lack of major chronic diseases and dysfunctions. Based on an extensive review of the literature, we aggregate a list of features of health and healthspan, and of the genes and genetic variants associated with them. Clusters of these genes based on molecular interaction and biological process annotation data give rise to maps of healthspan pathways.
We identify healthspan pathways for human, featuring transcription initiation, proliferation and cholesterol/lipid processing, and for C. elegans, featuring biosynthetic response, macro-autophagy and mitochondria. By mapping healthspan-related gene expression data, describing effects of caloric restriction associated with improvements in health, onto the healthspan pathway maps, we confirm, for example, the downregulation of the cell-cycle in C. elegans and of Notch signalling in human. The latter reflects the inflammatory role of Notch.
Defining health accurately, and investigating its molecular determinants on a large scale, is still a major challenge. Our literature-based data corpus, including visualization, is being made available as a reference for future investigations.
Development of age-associated diseases like atherosclerosis depends not only on genetic disposition but also on environmental influences. The Aryl Hydrocarbon Receptor (AhR) is a ubiquitously expressed transcription factor activated by ligands like 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo[a]pyrene. Epidemiological studies on populations heavily exposed to dioxin like 1976 in Seveso indicate increasing development of cardiovascular diseases in these populations. Furthermore, dioxin-exposed workers display higher incidence in atherosclerotic plaques and increased intima-media wall thickness, a risk factor and predictor for stroke and myocardial infarction. However, a direct role for AhR in cardiovascular and organismal aging has never been demonstrated across species from invertebrates to humans. To investigate the role of the AhR with respect to aging and age-related vascular processes, we analyzed vessel stiffness in AhR-deficient mice, functional parameters in primary human endothelial cells and AhR expression in blood cells of healthy human volunteers. Old (17-20 months) wt mice showed increased pulse wave velocity (PWV), which is indicative of impaired vessel function. Interestingly, in AhR-deficient mice, we observed reduced PWV in both old and young (3-6 months) mice, suggesting reduced vessel stiffness. Analysis of eNOS phosphorylation by Western Blot showed increased eNOS activity in thoracic aortas of AhR-deficient mice and a concomitant increase in NO production. In line with this finding, AhR activation and/or overexpression reduced the migratory capacity of primary human endothelial cells without affecting proliferation and apoptosis, impaired eNOS activation and reduced the S-NO content, which are all signs of endothelial dysfunction. Furthermore, AhR expression in blood cells of healthy human volunteers positively correlated with vessel stiffness, suggesting that AhR expression levels could serve as an additional new predictor of vessel aging. Detailed characterization of AhR-functions in aging and age-related disease might help to uncover the ancient functions of this protein and to develop strategies for healthier aging in the future.