Many groups are working on ways to lower the cost and improve the outcomes of screening for small molecules that slow the pace of aging. Sadly, unbiased screening is great way to produce calorie restriction mimetics and other interventions with a low probability of producing sizable effects on aging in long-lived mammals. The calorie restriction response is so sweeping, so entwined with fundamental cellular biochemistry, that there are many, many ways to induce some fraction of its benefits by altering expression of specific genes or interactions of specific proteins. Nonetheless, screening is the way in which much of the biotech research and development community does its work. The future of the longevity industry will likely involve a great many drug candidates that modestly slow aging, less effective than the actual practice of calorie restriction, at least until more researchers and companies find success in developing repair therapies that actually reverse aspects of aging.
Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan and healthspan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we present a novel screening readout for the expedited discovery of compounds that restrain ageing of cell populations in vitro and enable extension of in vivo lifespan. We monitored DNA methylation changes accompanying long-term passaging of adult primary human cells in culture. This enabled us to develop, test, and validate the CellPopAge Clock, an epigenetic clock with underlying algorithm, unique among existing epigenetic clocks for its design to detect anti-ageing compounds in vitro. Additionally, we measured markers of senescence and performed longevity experiments in vivo in Drosophila, to further validate our approach to discover novel anti-ageing compounds. We find that the CellPopAge Clock can detect decelerated passage-based ageing of human primary cells treated with rapamycin or trametinib, well-established longevity drugs. We then utilise the CellPopAge Clock as a screening tool for the identification of compounds which decelerate ageing of cell populations, uncovering novel anti-ageing drugs, torin2 and dactolisib (BEZ-235). We demonstrate that delayed epigenetic ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophila. We show that the novel anti-ageing drugs, torin2 and dactolisib (BEZ-235), increase longevity in vivo.
Link: https://doi.org/10.1186/s13073-024-01349-w
