Program for testing biological interventions to promote healthy aging

Abstract

The National Institute on Aging (NIA) sponsored a workshop on September, 1999 to discuss the feasibility of establishing a program to evaluate potential intervention strategies to decelerate the rate of aging in mammals. The ultimate goal is to identify promising interventions in animals that might lead to clinical trials in humans. The participants discussed various animal models, biological endpoints and possible structure of such a program. The ability to implement such a program will require a decision by NIA staff about whether the anticipated benefits to be derived from identification of effective interventions under well controlled conditions in an animal model, in this case the mouse, would justify the anticipated cost of the testing program.

Introduction

The National Institute on Aging (NIA) sponsored a workshop on September 14–16, 1999 to discuss the possibility of establishing a program to evaluate treatment strategies thought likely to decelerate the pace of aging in mammals. Similarly delaying adverse age-dependent changes in multiple cells and tissues in humans could be expected to diminish the burden of disease in old age, and subsequently increase the length of healthy life span. The specific aims of the workshop were to discuss: (1) whether there is a real need for such a program, and if so, (2) what animal model(s) should be used, (3) what endpoints should be followed in evaluating the efficacy of the intervention being tested, and (4) what strategies should be employed to optimize the program. The workshop was organized by NIA staff and was attended by staff from the NIA and FDA, as well as non-federal experts with experience in aging research. Currently, caloric restriction (CR) is the only intervention which is generally accepted to extend the maximum life span of mammalian animal models. Robust results have been consistently obtained using rats and mice, but CR also extends the life span of a wide variety of invertebrate animal models (Weindruch and Walford, 1988). More importantly, CR delays the onset of age-related pathology in rats and mice, and it is even effective when started in mature animals. It is not known whether it will work in non-human primates, but several studies in rhesus monkeys are already underway, and results so far appear to be somewhat promising (Kemnitz et al., 1994, Lane et al., 1995, Cefalu et al., 1997). However, it is unlikely that a significant portion of the human population would routinely submit to a comparable regimen, even if it were known for sure that doing so would provide 20–30 years of additional healthy life. Nevertheless, the CR phenomenon provides a paradigm for testing other interventions in animals which might be useful in human clinical trials. Considerable progress has been made identifying genes in invertebrate species which affect the rate of aging of members of these species, but less information is available about mammals. Mutations in the dw and df genes have been shown to attenuate the rate of aging in mice (Brown-Borg et al., 1996, Miller, 1999), and mice lacking the p66^shc protein also may have an extended life span (Migliaccio et al., 1999). The testing program described below would be useful for understanding genetic alterations which extend life span in such mammalian models, although genetic intervention in humans is not the main goal of the testing program discussed here.

Papers identifying life span and health span-extending interventions appear sporadically in the gerontological literature. A few recent examples of these include interventions to: not only reduce oxidative stress (Carney et al., 1991), but also extend life span with N-t-butyl-α-phenylnitrone (Edamatsu et al., 1995); restore biochemical and physical function with acetyl-l-carnitine (Hagen et al., 1998); prevent cardiovascular and renal pathology with aminoguanidine (Li et al., 1996); and extend life span with melatonin (Pierpaoli and Regelson, 1994). A different approach has been to transgenically extend life span by overexpression of Cu/Zn superoxide dismutase (Parkes et al., 1998, Sun and Tower, 1998).

However, many of these reports are compromised by one or more design flaws, e.g. too few animals per cohort, failure to control for possible CR, use of wrong animal model, poor housing conditions, etc. Furthermore, many research laboratories do not have either the resources or the expertise to design and conduct a scientifically robust study. For example, few of these studies have been accompanied by pathology or other biomarker assessment, which would help assess the impact of the intervention on health span. Because most of the informative endpoints in such a study may require invasive procedures, adequate testing cannot usually be done directly in humans. However, the identification of effective substances or treatments in mice could serve as a powerful spur and guide for the design of intervention studies in humans or non-human primates.

A successful program would not only achieve the above goal, but it would also provide new theories and hypotheses about basic mechanisms of aging for further research. Finally, negative results could prevent continued investment of research funds into unpromising areas of research.

A program of this kind would most likely be successful if it can bring together a group of experienced investigators and NIA staff members to design an optimized protocol for intervention evaluation that reflects substantial consensus within the research community, and can at the same time build in standardization and replicability.