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Validating C. elegans healthspan model for better understanding factors causing health and disease, to develop evidence based prevention, diagnostic, therapeutic and other strategies.

Periodic Reporting for period 4 - Ageing with elegans (Validating C. elegans healthspan model for better understanding factors causing health and disease, to develop evidence based prevention, diagnostic, therapeutic and other strategies.)

Reporting period: 2019-11-01 to 2020-10-31

Over the past decades, lifespan has increased all over Europe and in many other countries, but these additional years are often not spent in good health. As societies age, the increasing fraction of elderly and the care they need threatens to place a growing burden on society, unless the elderly can age in a more healthy way.
Healthspan (the life period when one is generally healthy and free from serious disease) depends on nature (genetic make-up) and nurture (environmental influences, from the earliest stages of development throughout life). Genetic studies increasingly reveal mutations and polymorphisms that may affect healthspan. Similarly, claims abound about lifestyle modifications or treatments improving healthspan. In both cases, rigorous testing is hampered by the long lifespan of model organisms like mice (let alone humans) and the difficulty of introducing genetic changes to examine the phenotype of the altered genome.
We will develop C. elegans as a healthspan model. Already validated extensively as an ageing model, this organism can be readily modified genetically, and effects of environmental manipulations on healthspan can be measured in days or weeks. Once validated as a healthspan model, it can be used for an initial assessment of preventive and therapeutic measures for humans, as well as for risk identification and the initial evaluation of potential biomarkers. It will also prove useful to study interactions between genetic and various environmental factors.
The following work was performed:
1. A project website was set up (with a publicly accessible and a private section only accessible to project participants) and a position paper was published to bring the project to the attention of the scientific community.
2. Genome-wide association studies based on SNP-arrays have been carried out on in groups of over 70-year old individuals in good health, compared to a control group with similar characteristics but suffering from health problems. The individual were recruited from existing cohorts in Finland, Estonia and Sweden.
3. A new automated instrument (WormCAMP) for screening healthspan in C. elegans was developed, as a successor to the initial WorMotel, as well as improved measures for healthspan (maximum velocity after stimulation with a blue light flash).
4. RNAi screening for healthspan was validated on the WormCAMP, and over 3700 genes have been tested so far by RNAi knock-down. A number of these have a differential effect on lifespan versus healthspan.
5. A reporter panel, consisting a set of genetic C. elegans strains expressing GFP-reporters to monitor the activation of 8 cytoprotective signalling pathways, was created.
6. AnalytiCon Discovery has provided pure natural products, fractions from edible plants and 11 organic - as well as aqueous extracts from 11 carefully selected TCM plants with reported anti-ageing effects. Moreover, fractions were generated from the active organic extracts of the TCM plants by separation on silica gel columns. So far, 427 samples have been analysed for healthspan effects in C. elegans, and from one TCM plant with clear activity, bioassay-guided purification has led to active compounds.
7. Adult human skin fibroblasts PCP1 and hTERT-MSC stem cell cultures were used to study long-term (> 375 days) effects of rapamycin on the survival, lifespan, stress tolerance, telomere length and global DNA methylation. Three pure compounds were provided by AnalytiCon Discovery and tested on PCS cells for short-term effects (up to 10 days) with a wide range of concentrations (between 1 nM to 200 mM). Biphasic hormetic dose responses were observed for cell toxicity, growth, proliferation, stress tolerance.
8. Two pure compounds were tested for short-term (2-3 month) and longer-term effects on ageing in male and female 24-month-old C57 mice.
9. Based on bioinformatics an data mining analyses, a healthspan pathway map was inferred.
10. Abiomics prepared several data analysis models.
11. Agilent Technologies developed algorithms to analyse large cohorts of NGS and CNV data.
1. Several candidate healthspan genes have been identified, and are being followed up by replication in other populations and by RNAi-testing of the orthologues in C. elegans. If confirmed, they could become drug targets or lead to diagnostics.
2. An automated image-based screen has been developed for C. elegans. It can be used for any phenotype that can be deduced from the video images.
3. A novel measure of healthspan was developed in C. elegans, which will permit a clearer distinction between lifespan and healthspan effects.
4. Over a dozen new candidate healthspan genes have been identified in C. elegans. If confirmed, they will form the basis of the discovery of novel healthspan pathways.
5. A novel set of C. elegans reporter strains will permit rapid mechanism-based sorting of novel RNAi or compounds affecting healthspan into groups with similar mechanism of action.
6. Healthspan effects have been demonstrated for three TCM plants. This could form the starting point of further preclinical or even clinical development of a healthspan treatment.
7. Clear behavioural effects were demonstrated for one of the tested compounds, with differences between males and females. If confirmed in longer-term testing, this could become a candidate drug.
8. Agilent Technologies has expanded its software suite to include GWAS studies and the analysis of cohorts.