In vivo medical imaging for assessing geroprotective interventions in humans

Abstract

There is a growing interest in developing drugs with a general geroprotective effect, aimed at slowing down aging. Several compounds have been shown to increase the lifespan and reduce the incidence of age-related diseases in model organisms. Translating these results is challenging, due to the long lifespan of humans. To address this, we propose using a battery of medical imaging protocols that allow for assessments of age-related processes known to precede disease onset. These protocols, based on magnetic resonance imaging, positron emission-, computed-, and optical coherence tomography, are already in use in drug development and are available at most modern hospitals. Here, we outline how an informed use of these techniques allows for detecting changes in the accumulation of age-related pathologies in a diverse set of physiological systems. This in vivo imaging battery enables efficient screening of candidate geroprotective compounds in early phase clinical trials, within reasonable trial durations.

Keywords: Age-related disease; Biomarker; CT; Drug development; Geroprotection; Imaging; MRI; OCT; PET.

Fig. 1

Schematic over-included tissues and organs where age-related pathological processes are known to cause to morbidity and mortality. Image-based assessments of these processes are listed in Table 2

Fig. 2

(A) An example design of a randomized controlled clinical trial with imaging outcomes. The number of imaging occasions can be varied to increase power (here, in vivo imaging is done at baseline, year 1, year 2 and at trial conclusion). (B) An example of a diverse imaging battery designed for detecting an effect of a geroprotective intervention. (C) Schematic of potential results from the trial. Here the presence of an effect in several age-related tissue pathologies would be interpreted as support that the treatment holds a general geroprotective effect. The largest effect is observed for the prostate gland, showing a decrease in volume (i.e., a reversal of pathology). This data could be used to consider benign prostatic hyperplasia as a suitable indication for regulatory approval

Fig. 3

Example images from our ongoing clinical trial “Evaluating the effect of rapamycin treatment in Alzheimer’s disease and aging using in vivo imaging” [119] that includes a subset of protocols from Table 2. (A) Bone mineral density using computed tomography, axial image over the second lumbar vertebrae with the CT phantom used for absolute quantification visible in the lower part of the image. (B) Heart MRI for calculation of myocardial volume, diastolic function, and strain. (C) Brain MR with an overlaid [¹⁸F]FDG PET image for quantification of gray matter volume and cerebral glucose metabolism, respectively. (D) MR image of the knee for assessment of joint cartilage volume. (E) Optical coherence tomography, for measurement of retinal nerve fiber layer thickness and drusen accumulation, (F) CT image of tooth bearing bone status