The Vital Role of Pathology in Improving Reproducibility and Translational Relevance of Aging Studies in Rodents

Abstract

Pathology is a discipline of medicine that adds great benefit to aging studies of mice by integrating in vivo, biochemical, and molecular data. It is not possible to diagnose systemic illness, co-morbidities, and proximate causes of death in aging studies without the morphologic context provided by histopathology. To date, many rodent aging studies do not utilize endpoints supported by systematic histopathology, which leaves studies incomplete, contradictory, and difficult to interpret. Similar to traditional toxicity studies, if the effect of a drug, dietary treatment, or altered gene expression on aging is to be studied, systematic pathology analysis must be included to determine the causes of age-related illness, moribundity, and death. In this Commentary we discuss the factors which should be considered in the design of aging studies in mice, with the inclusion of robust pathology practices modified after those developed by toxicologic and discovery research pathologists. Investigators in the field of aging must consider the use of histopathology in their rodent aging studies in this era of integrative and preclinical geriatric science (geroscience).

How age, sex and genotype shape the stress response

“…The lack of standardization across studies brings limitations to the analysis of stress effects in aging. For instance, the use of different endpoints across studies, combined with the lack of a necropsy report, can render an aging study incomplete ( Santulli et al., 2015 , Treuting et al., 2016 ). Similarly, the use of different paradigms of chronic stress render inter-study consistency even more difficult to achieve ( Allard and Duan, 2011 ).…”

Reproducibility of histopathological findings in experimental pathology of the mouse: a sorry tail

“…Enrollment of an experienced pathologist onto a study early in its inception and planning stages and then its subsequent analysis is clearly highly desirable, as many of the problems we discuss above are unlikely to arise under the guidance of appropriately trained personnel. The issue of finding experienced mouse pathologists has been discussed at length elsewhere 2, 24, 34 , though the authors feel that the mouse pathology community is sufficiently interactive that good advice can easily be sought out by motivated investigators.…”

“…Reproducibility of histopathological endpoints therefore depends on the implementation of a common standardized vocabulary, competent work-up, and an in-depth knowledge of the mouse strains under investigation so that, for example, background lesions are not mistaken for those that are experimentally induced. Such knowledge is critical in the design of experiments, as well as in understanding the impact of husbandry, the microbiome, and diet on the interpretation of results 2, 5 .…”

Fundamental Concepts for Semiquantitative Tissue Scoring in Translational Research

“…33,34 Specifically, statistical and pathological analyses are common components in translational studies, but trained statisticians and board-certified pathologists are often omitted from these multidisciplinary teams, leading to data interpretations that are more prone to errors. 22,23,35 For tissue scoring, a designated "observer" must thoroughly examine samples and ascribe scores. Various biomedical personnel (including principal investigators, postdocs, and even students) have been assigned the role of observer to score tissues.…”