Principles of Animal Use for Gerontological Research

Richard A. Miller

Animals, and in particular rats and mice, have long been a mainstay of experimental work in biological gerontology. This chapter presents ten key principles that should be considered in designing and interpreting reports that use laboratory rodents to learn about aging. In a nutshell, experimenters are implored (1) to use mice that are neither too old nor (2) too young; (3) to use more than two age groups; (4) to use rodents that are demonstrably specific pathogen-free; (5) to consider the use of genetically heterogeneous rodent populations; (6) to obtain necropsy data as a source of important covariates; (7) not to pool across individuals; (8) to reduce cost by judicious distribution ofmoney across age classes; (9) to favor designs that use young mice destined to age at differing rates; and (10) to abandon— or at least subjugate—rodent-oriented research in favor of comparative biology.

Introduction

As of this writing, a PubMed search for ''aging AND (mouse OR mice OR rat Or rats)'' yields 46964 citations, of which 9256 appeared in the current millennium, and 1813 appeared in 2004, a rate of 5 papers per day. (For reference: substitute ''fly OR flies OR Drosophila'' and you obtain 117 papers in 2004; the analogous search produces 90 papers on aging worms.) Worms and flies, for all their obvious virtues, are organized along alien design principles, and seem sufficiently dissimilar to people, physiologically and developmentally, to make extrapolation of all but the most fundamental findings feel unsafe. Experimental studies of the aging process in humans are stymied by ethical constraints on most interventions of biological interest, inaccessibility of internal tissues, catch-as-catch-can genetics, and discouragingly long life spans. Mice and rats occupy the sweet spot: organized like humans in most ways that count, relatively shortlived, and willing to eat what we give them and to breed with whom we suggest. Rodent-oriented gerontologists are, in addition, blessed by a pre-existing and quickly expanding infrastructure that makes interesting mice and has developed powerful methods for assessing their genetic and physiological characteristics; ''mice AND

(transgenic or knockout)'' gets you 9466 papers in 2004 alone.

This chapter aims to provide a broad overview, not of the nitty gritty of animal care and manipulation, but of the strategic planning that might help a researcher select a rodent model to answer questions of interest in the biology of aging. Emerging from the ''Dear Abby'' and Emily Post tradition of ex cathedra advice givers, it will employ the imperative voice more often than is typical for an academic review. It will also use the term ''mice'' to mean ''mice and rats'' except in those rare cases where the distinction is critical. The chapter will range over Ten Basic Principles for studies of aging rodents. Principles 1-4 and 6-8 are more-or-less conventional wisdom, or minor twists thereon. Principles #5, #9, and #10 are more radical proposals (though not entirely without adherents): these are the ones least likely to be taken seriously, but the ones most worthy of contemplation.

Principle #1: Do not Use Mice that are too Old

Newcomers to rodent gerontology show a strong preference for the oldest available mice or rats they can get their hands on, on the grounds that the older the animals are, the more they will differ from the young control group, the sooner the work will be finished, and the more striking the effects to be documented. There are three good reasons to avoid very old mice: they are expensive, sick, and unrepresentative.

Expensive: the Gompertz equation, though originally devised in another context, provides a good guide to the estimation of relative mouse costs, too; because the risk of mortality increases exponentially with age, so does the cost of producing a live mouse. Because the mortality rate doubling time for lab mice is about 4 months (Finch, 1990), the cost of producing a 30-month-old mouse is not 25% higher than the cost of a 24-month-old specimen, but roughly 400% higher, given reasonable estimates of the Gompertz parameters for laboratory mice. Table 3.1 presents a sample calculation illustrating the cost for producing mice at various ages, and provides a strong rationale for designs in which the ''old'' mice are as young

Handbook of Models for Human Aging

Copyright © 2006 by Academic Press All rights of reproduction in any form reserved.

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