A CellAgeClock for expedited discovery of anti-ageing compounds

Abstract

27 28We aim to improve anti-ageing drug discovery, currently achieved through laborious and 29 lengthy longevity analysis. Recent studies demonstrated that the most accurate molecular 30 method to measure human age is based on CpG methylation profiles, as exemplified by 31 several epigenetics clocks that can accurately predict an individual's age. Here, we 32 developed CellAge, a new epigenetic clock that measures subtle ageing changes in primary 33 human cells in vitro. As such, it provides a unique tool to measure the effects of relatively 34 short pharmacological treatments on ageing. We validated our CellAge clock against known 35 longevity drugs such as rapamycin and trametinib. Moreover, we uncovered novel anti-36 ageing drugs, torin2 and Dactolisib (BEZ-235), demonstrating the value of our approach as a 37 screening and discovery platform for anti-ageing strategies. CellAge outperforms other 38 epigenetic clocks in measuring subtle ageing changes in primary human cells in culture. The 39 tested drug treatments reduced senescence and other ageing markers, further consolidating 40 our approach as a screening platform. Finally, we showed that the novel anti-ageing drugs 41 we uncovered in vitro, indeed increased longevity in vivo. Our method expands the scope of 42 CpG methylation profiling from measuring human chronological and biological age from 43 human samples in years, to accurately and rapidly detecting anti-ageing potential of drugs 44 using human cells in vitro, providing a novel accelerated discovery platform to test sought 45 after geroprotectors.One of the remarkable achievements of developed countries is a continuous increase in life 47 expectancy at birth, leading to greater longevity. However, a higher proportion of elderly in modern 48 societies is accompanied by a steep increase in people suffering from age-related diseases. For 49 example, cancer incidence rates, currently at 17 million worldwide, are expected to increase to 26 50 million in 2040 1 , and a similar rise is expected for Alzheimer's and Parkinson's disease 2 . 51Compression of late-life morbidity is, therefore, a priority to alleviate suffering in the elderly 3 and to 52 reduce a growing economic burden to society 4 . 53Critically, seminal discoveries in the biology of ageing showed that ageing is a malleable process 54 and that down-regulation of major cellular nutrient signalling pathways, either glucose-sensing insulin 55 signalling or amino acid-sensing target-of-rapamycin signalling, results in longevity and health 56 improvement in all model organisms tested from yeast to mammals 5 . For instance, the long-lived 57 mutants in C. elegans are protected from tumorous cell proliferation 6 and have reduced toxic protein 58 aggregation 7 , while Drosophila show less deterioration in their hearts 8 . Long-lived mouse mutants 59 are protected from osteoporosis, cataracts and skin pathology, as well as decline in glucose 60 homeostasis, immune and motor function 9 . The effect of these mutations is conserved from yeast to 61 mamma...

IF1 Protein Controls Aging Rate

“…of my US patent application [16], can slow the ticking of the epigenetic clock of human cells in vitro . In the assay used in [120–121].…”

Directly Reprogrammed Human Neurons to Understand Age‐Related Energy Metabolism Impairment and Mitochondrial Dysfunction in Healthy Aging and Neurodegeneration

“…It has been reported that the genome becomes globally hypomethylated, except for certain hypermethylated regions [ 94 , 95 ]. In particular, DNA methylation analysis of 353-specific CpG loci, commonly referred to as the epigenetic clock [ 94 ], allows to estimate DNA methylation (DNAm) or epigenetic age and is currently considered the most reliable biomarker correlating biological and chronological aging [ 96 , 97 ].…”

Phenotypic Screening in C. elegans as a Tool for the Discovery of New Geroprotective Drugs

“…Hence, the screen resulted in the identification of one prime candidate, the chalcone Gr-4D, for follow-up studies [79]. Finally, most recently, a methylation-based clock was developed and used to screen for geroprotective compounds in vitro [80].…”