To find drivers of healthy ageing, a genome-wide association study (GWAS) was performed in healthy and unhealthy older individuals. Healthy individuals were defined as free from cardiovascular disease, stroke, heart failure, major adverse cardiovascular event, diabetes, dementia, cancer, chronic obstructive pulmonary disease (COPD), asthma, rheumatism, Crohn’s disease, malabsorption or kidney disease. Six single nucleotide polymorphisms (SNPs) with unknown function associated with ten human genes were identified as candidate healthspan markers. Thirteen homologous or closely related genes were selected in the model organism C. elegans for evaluating healthspan after targeted RNAi-mediated knockdown using pathogen resistance, muscle integrity, chemotaxis index and the activity of known longevity and stress response pathways as healthspan reporters. In addition, lifespan was monitored in the RNAi-treated nematodes. RNAi knockdown of yap-1, wwp-1, paxt-1 and several acdh genes resulted in heterogeneous phenotypes regarding muscle integrity, pathogen resistance, chemotactic behaviour, and lifespan. Based on these observations, we hypothesize that their human homologues WWC2, CDKN2AIP and ACADS may play a role in health maintenance in the elderly.

Sarcopenia encompasses a progressive decline in muscle quantity and quality. Given its close association with ageing, it may represent a valuable healthspan marker. The commonalities with human muscle structure and facile visualization possibilities make Caenorhabditis elegans an attractive model for studying the relationship between sarcopenia and healthspan. However, classical visual assessment of muscle architecture is subjective and has low throughput. To resolve this, we have developed an image analysis pipeline for the quantification of muscle integrity in confocal microscopy images from a cohort of ageing myosin::GFP reporter worms. We extracted a variety of morphological descriptors and found a subset to scale linearly with age. This allowed establishing a linear model that predicts biological age from a morphological muscle signature. To validate the model, we evaluated muscle architecture in long-lived worms that are known to experience delayed sarcopenia by targeted knockdown of the daf-2 gene. We conclude that quantitative microscopy allows for staging sarcopenia in C. elegans and may foster the development of image-based screens in this model organism to identify modulators that mitigate age-related muscle frailty and thus improve healthspan.

Sarcopenia encompasses a progressive decline in allover muscle quantity and quality. Given its close association with aging, it may represent a valuable healthspan marker. Given the strong commonalities with human muscle structure and the facile visualization possibilities, C. elegans represents an attractive model for studying the relationship between sarcopenia and healthspan. However, classical assessment relies on visual scoring of muscle architecture, which is subjective and inaccurate. To resolve this, we have developed an automated image analysis pipeline for the detailed quantification and classification of muscle integrity in confocal microscopy images from a cohort of aging myosin::GFP reporter strains. We then extracted a variety of morphological descriptors and found a subset to scale linearly with age. This allowed us to establish a general linear model that predicts biological age from a morphological muscle signature. To validate the model, we evaluated muscle architecture in long-lived worms that are known to experience delayed sarcopenia by targeted RNAi-mediated knockdown of the daf-2 gene. We conclude that quantitative microscopy allows for staging sarcopenia in C. elegans and will be of use for systematic screening for pharmacological or genetic modulators that mitigate age-related muscle frailty and thus improve healthspan in C. elegans.