WG3 - Testing novel interventions to promote healthy ageing: a roadmap for the translation of geroprotectors
Leader José Luis Trejo
Despite evidence that both lifestyle and pharmaceuticals interventions promote healthy ageing and delay the onset of multiple age-related diseases, progress to translate these interventions for patient benefit are limited. Lifestyle interventions have low compliance and pharmaceutical interventions lack the appropriate regulatory framework which allows translation from bench to bedside. In addition studies are limited by financial, organizational resources, infrastructure and specialised personnel required to conduct robust studies.
The objectives of this work package are to:
- Identify and agree among researchers in the biology of ageing, geriatricians, industrial partners and regulatory affairs experts a roadmap detailing the steps required for preclinical testing of interventions to facilitate the rapid translation of geroprotectors to the clinic.
- Work with WG1 and WG2 to reach consensus on endpoint measurements, standardized methodologies which reflect the clinical endpoints, as well as to examine the effects of variables such as environment, diet and mouse strain on the selected endpoints.
- Select and coordinate existing European infrastructures for preclinical testing so that testing is performed in an integrated way. Identify partners, a pipeline and funding to progress the testing of at least two new interventions.
Progress to date:
- We have established a group with multiple expertise.
- Frailty (see WG1) and multimorbidity were identified as two major targets for treatment with geroprotectors, due to the high frequency in the over 65s leading to poor quality of life, the difficulty in treating these conditions and the associated high healthcare costs.
- We support the model of development of age-related diseases as a progressive multi-hit process which starts with dysregulation of mechanisms of ageing and progressively accumulates deficits.
- We support the concept that geroprotectors should be given in the initial phase of tissue dysregulation to boost resilience and delay onset of multiple age-related diseases.
- We believe that due to the possibility to prevent more than one disease at the same time geroprotectors have the potential to be superior to any other treatment to-date.
Through thorough literature search we have gathered evidence that common mechanisms of ageing (i.e. inflammation, oxidative stress and senescence and autophagy) drive multiple age-related disorders. We have also reviewed the most common geroprotectors and identified those which target those mechanisms. We will give precedence to those molecules for testing.(http://dx.doi.org/10.1016/j.mad.2016.09.009).
We have identified a pipeline of tests for longitudinal study of the effects of geroprotectors in mice and we are in the process of standardising these protocols across the MouseAGE network and with major institutions in the USA (Mayo Clinic, Buck Institute for Research on Ageing, National Institute on Ageing - Translational Gerontology Branch).
We have also reviewed potential models of physical resilience, focusing on those where there is some evidence that the administration of acute stressors requires integrative responses involving multiple tissues and where aged mice showed a delayed recovery or a worse outcome then young mice in response to the stressor. These models include sepsis, trauma, drug- and radiation exposure, kidney and brain ischemia, exposure to noise, heat and cold shock (https://www.ncbi.nlm.nih.gov/pubmed/30290161).
- An online survey was launched to understand the need of the community in terms of infrastructure required to test interventions in ageing models. See useful downloads below for report of the survey results,