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Seinstra, R. I.

Publications and source records attributed to Seinstra, R. I..

2 recordsLinked to original sources

Deep behavioural phenotyping reveals divergent trajectories of ageing and quantifies health state in C. elegans

Neurodegenerative diseases may be the cause or the consequence of an acceleration of physiological ageing. Evidence for this concept is lacking due to practical limitations of human studies. Here, we compared the processes of physiological and pathological ageing of individual C. elegans over their lifespan. Using multi-parametric phenotyping, trajectories of ageing can be defined within a phenotypic landscape made of a large set of phenotypical features. Rather than an acceleration of ageing, a model for synucleinopathy showed a divergent trajectory of ageing. The pathological progression in individual animals can be predicted from early phenotypes with high accuracy. Despite of similar lifespans, disease-model worms display an early onset of decline in their phenotypic range of ability. This loss of flexibility provides an index of health valid for physiological and pathological contexts. Finally, we demonstrate the power of multi-parametric dataset to describe ageing, to quantify health and to predict specific health risks.

systems biology

Transcriptomics-based screening identifies pharmacological inhibition of Hsp90 as a means to defer aging

Aging is a major risk factor for human morbidity and mortality. Thus, the identification of compounds that defer aging, also known as geroprotectors, could greatly improve our health and promote a longer life. Here we screened for geroprotectors, employing the power of human transcriptomics to predict biological age. We used age-stratified human tissue transcriptomes to generate machine-learning-based classifiers capable of distinguishing transcriptomes from young versus old individuals. Then we applied these classifiers to transcriptomes induced by 1300 different compounds in human cell lines and ranked these compounds by their ability to induce a youthful transcriptional state. Besides known geroprotectors, several new candidate compounds emerged from this ranking. Testing these in the model organism C. elegans, we identified two Hsp90 inhibitors, Monorden and Tanespimycin, which substantially extended the animals lifespan and improved their health. Hsp90 inhibition specifically induces the expression of heat shock proteins, known to improve protein homeostasis. Consistently, Monorden treatment improved the survival of C. elegans under proteotoxic stress, and its lifespan benefits were fully dependent on the master regulator of the cytosolic unfolded protein response, the transcription factor HSF-1. Taken together, we present an innovative transcriptomics-based screening approach to discover aging-preventive compounds and highlight Hsp90 inhibitors as powerful geroprotectors that could be of great value, to target the aging process in humans.

cell biology