A New Preclinical Paradigm for Testing Anti-Aging Therapeutics

Abstract

Testing drugs for anti-aging effects has historically been conducted in mouse life-span studies, but are costly and time consuming, and more importantly, difficult to recapitulate in humans. In addition, life-span studies in mice are not well suited to testing drug combinations that target multiple factors involved in aging. Additional paradigms for testing therapeutics aimed at slowing aging are needed. A new paradigm, designated as the Geropathology Grading Platform (GGP), is based on a standardized set of guidelines developed to detect the presence or absence of low-impact histopathological lesions and to determine the level of severity of high-impact lesions in organs from aged mice. The GGP generates a numerical score for each age-related lesion in an organ, summed for total lesions, and averaged over multiple mice to obtain a composite lesion score (CLS). Preliminary studies show that the platform generates CLSs that increase with the age of mice in an organ-dependent manner. The CLSs are sensitive enough to detect changes elicited by interventions that extend mouse life span, and thus help validate the GGP as a novel tool to measure biological aging. While currently optimized for mice, the GGP could be adapted to any preclinical animal model.

Keywords: Aging; Aging lesions in mice; Anti-aging therapeutics; Geropathology Grading Platform; Preclinical drug testing.

Figure 1.

Composite lesion scores generated by the Geropathology Grading Platform in mice change in an age- and drug-dependent manner. (A) Composite lesion scores in four age groups of C57BL/6N male mice increase with increasing age and in an organ-dependent manner, N = 12/cohort. (B) Composite lesion scores in four age groups of CB6F1 male mice increase with increasing age and in an organ-dependent manner, N = 12/cohort. (C) Composite lesion scores are suppressed in 24-month-old C57BL/6 mice after 2 months of oral rapamycin, 42 ppm, N = 6–7/cohort, p ≤ .05. (D) Composite lesion scores in the heart increase in alignment with left ventricular mass index (LVMI) and organ weight as measures of the progression of cardiac decline with increasing age in C57BL/6N mice, N = 12/cohort.