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The quest to slow ageing through drug discovery

Abstract

Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD+ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.

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Fig. 1: Age composition of the global population and incidence of major age-related diseases.
Fig. 2: Agents and their influence on different hallmarks of ageing.
Fig. 3: Effects of rapamycin and inhibition of mTORC1.
Fig. 4: Some of the modes of action for senolytics.

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Acknowledgements

L.P. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 741989), and from the Wellcome Trust (UK). M.F. has received funding from the Comisión Nacional de Investigación Científica y Tecnológica-Government of Chile (CONICYT scholarship).

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L.P. and B.K.K. discussed content and wrote the article, L.P. and M.F. revised the manuscript before submission, and M.F. developed Figure 1.

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Correspondence to Linda Partridge or Brian K. Kennedy.

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Competing interests

B.K.K. is board chair of Torcept Therapeutics, a board member and scientific adviser for PDL Pharma, a scientific adviser for AFFIRMATIVhealth, and a board member of L-Nutra. B.K.K. is named on patents held by PDL Pharma related to ageing interventions and performs corporate-sponsored research for Gero LLC. L.P. and M.F. declare no competing interests.

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Related links

Global Burden of Disease Study 2017: http://ghdx.healthdata.org/gbd-2017

UN World Population Prospects 2019: https://population.un.org/wpp/DataQuery

Glossary terms

Healthspan

The time in a person’s life when they are in general good health.

Immunosenescence

Decline in function of the immune system with age.

Senostatics

Chemicals that prevent senescent cells from producing the senescence-associated secretory phenotype, which can damage surrounding tissue and cause systemic inflammation.

Dietary restriction

(DR). Reduced food intake from its voluntary level while avoiding malnutrition.

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Partridge, L., Fuentealba, M. & Kennedy, B.K. The quest to slow ageing through drug discovery. Nat Rev Drug Discov 19, 513–532 (2020). https://doi.org/10.1038/s41573-020-0067-7

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