Pathology assessment is necessary to validate translational endpoints in preclinical aging studies

Abstract

The Geropathology Research Network has established a plan to identify and use pathology-based surrogate endpoints for aging intervention in preclinical drug studies to provide a predictable and short-term anti-aging drug response in line with clinical trials. The plan involves pathological assessment of tissues and organs from strains of old mice, by independent pathology groups in a concurrent manner in order to characterize the changes in lesion incidence and severity in response to anti-aging drugs at specific time points. This approach allows for connection with translational endpoints of aging, such as serum factors and physiological parameters, between mice and humans. Preclinical drug testing is a critical component of the plan, designed to shorten testing times from lengthy lifespan studies by comparing lesion grades and composite scores in treated and placebo cohorts at cross-sectional time points. In conclusion, a geropathology-based preclinical testing program is a step toward assuring maximum utilization of translational resources and increasing predictability of efficacy of new or repurposed drugs for clinical aging intervention studies.

Keywords: anti-aging drugs; geropathology; translational research.

Fig. 1

Hematoxylin- and eosin-stained heart tissue shows striking histological changes in 32-month-old CB6F1 male mice (a) compared with strain and gender-matched 8-month-old mice (b). The heart section from the old mouse shows an increased cellular infiltrate indicative of localized reactive sites, and extensive areas of fibrosis. These lesions help explain the cardiac dysfunction and increased heart weight observed in the older-aged mice.

Fig. 2

The occurrence of multiple histological lesions increases with increasing age as shown by a dramatic shift of the curve to the right in 32-month-old CB6F1 male mice compared with the respective 8-month-old mice.