Along with the expanding application of engineered nanomaterials (ENMs), there is a growing concern over their adverse toxicological effects on human health and the environment upon release and exposure. ENMs are increasingly used in consumer products, as food additives and in drug delivery. To keep up with the fast pace of ENM development, medium to high throughput methodology is required to understand the bioavailability and long-term effects related to ENMs. For the analysis of ENM-long-term effects, we use the invertebrate Caenorhabditis elegans which lives for only 3-4 weeks and is a realistic target organism of ENMs in the environment as well as a top animal model in the laboratory. We exposed adult worms with environmentally relevant ENMs such as silver, silica, ZnO, CeO2 and polystyrene (nano plastics) in liquid media with bacteria in 96-well microtiter plates. The microhabitat in 96-well microtiter plates apparently excluded cultivation stress and thus, enabled analyses of ENM-bio-interactions over the entire life span. Age-resolved analysis identified especially middle-aged worms as vulnerable target group to certain ENMs. In vulnerable groups, the distribution of ENMs throughout the cytoplasm and the cell nucleus in single intestinal and vulval cells as well as in the pharyngeal tissue was correlated with functional alterations. Nano silica induces nuclear amyloid and perturbs the peptide metabolism in intestinal cells. Global protein is reduced which promotes a ‘petite’ phenotype. Consistently, mass spectrometry analysis identifies a silica NP-induced aggregome network that contains predominantly the gene ontology (GO) groups of proteostasis, metabolic processes, rRNA processing and translation. Among the molecular ENM-effects, nano silica-exposed worms show an early onset of age-associated stigmata including widespread protein aggregation and premature neurodegeneration of serotonergic and dopaminergic neurons. Impaired neurosignaling is related with reproductive and locomotion defects. All age-related defects result in reduced fitness and health span which normally occur in old worms but are prematurely induced by certain ENMs like nano silica. System biology-based analyses have the potential to identify common pathways of nanoparticle-bio-interactions across species from worm via other taxa to human and thus, to evaluate the risk of nano silica to human health. A Scharf, A Piechulek, A von Mikecz, ACS Nano 7, 12 (2013) A Scharf, KH Gührs, A von Mikecz, Nanotoxicology 10, 4 (2016) A Piechulek, A von Mikecz, Environ Pollut 233 (2018) A von Mikecz, Environ Sci: Nano 5 (2018)