Therapeutic Manipulation of Ageing: Repurposing Old Dogs and Discovering New Tricks

Abstract

Ageing is a leading risk factor for many debilitating diseases. While age-related diseases have been the subject of over a century of intense investigation, until recently, physiological ageing was considered unavoidable. Pharmacological and genetic studies have since shown that ageing is a malleable process and that its abrogation can prevent its associated diseases. This review summarises a sample of the most promising efforts to deliver the products of ageing research to the clinic. Current efforts include the use of clinically approved drugs that have since been repurposed, as well as the development of novel therapeutics, to target ageing. Furthermore, ongoing research has sought reliable biomarkers of ageing that will accelerate the development of such therapeutics. Development of these technologies will improve quality of late-life and help relieve the enormous stress placed on state healthcare systems by a rapidly ageing global population. Thus, for both medical and socioeconomic reasons, it is imperative that ageing is made to yield to intervention.

Keywords: Ageing; Biomarkers; Clinical trials; Drug repurposing.

Graphical abstract

Fig. 1

Mechanisms of human ageing. Ageing affects several systems acting at several hierarchical levels from molecular events such as mitochondrial dysfunction and genomic lesions, through to cellular events such as senescence or over-proliferation. Dysfunctional cells lead to tissue dysfunction, culminating in organ failure and death. Interactions between levels serve to exacerbate pathology at all levels. Black lightening symbolises damage or failure; SASP refers to the senescence-associated secretory phenotype.

Fig. 2

Mechanisms of promising repurposed anti-ageing drugs. Metformin and rapamycin are thought to act synergistically to improve protein and energy homeostasis. Inhibitors of IL-6 and NF-κB could act to reverse systemic inflammation and TFGβ inhibitors have been shown to reverse aberrant signalling caused by an aged stem cell niche (of which extracellular matrix is a major component). Green arrows indicate stimulation of the indicated process. Red, flat arrows indicate inhibition. Indirect interactions are indicated by dashed arrows. Processes that have effects at the tissue or organ level are surrounded by blue circles.

Fig. 3

Promising novel drugs designed to target ageing. (A) NAD⁺ supplementation seeks to improve nuclear-mitochondrial communication in old cells and avoid accumulation of orphaned, hydrophobic electron transport chain subunits, thus aiding protein and organelle homeostasis. (B) Senolytic drugs act to remove senescent cells from tissues and thus ablate SASP (senescence-associated secretory phenotype) mediated tissue remodelling and restore regenerative capacity by removing SASP-induced restrictions of stem cell mobility and proliferation.