should be noted, however, that genetics alone has little hope of unraveling molecular mechanisms and that the strongest analysis results from the combined use of biochemistry, cell biology, and genetics.
I will first review the concept of genetic determination of life span and life expectancy and the concept of longevity-determining genes that we call ''gerontogenes." Next, we will review relevant literature and experiments done in an effort to identify such gerontogenes. This review will focus mostly on invertebrates because few experiments in vertebrates, notably the mouse, have tried to identify gerontogenes. We will speculate as to how these gerontogenes might be identified in other species, paying careful attention to the mapping of quantitative trait loci (QTLs). This discussion will focus on identifying gerontogenes in nematodes and mice; much of the material has been selected from ongoing experiments in our own laboratory. Their subsequent extension to humans and/or the identification of gerontogenes directly in humans is the subject of another author. Finally, we will review work from our laboratory on the genetic determination of mortality rates. Many recent reviews are available on the genetics of aging (Johnson et al., 1996; Fleming and Rose, 1996; Jazwinski, 1996; Lithgow, 1996; Martin et al., 1996; Nooden and Guiamét, 1996).
The gene is the basic unit of inheritance; typically a gene makes a protein. A gerontogene, then, makes a protein involved in aging and, more precisely, a protein involved in determining life span. Gerontogenes are defined functionally: they can be altered by mutation such that animals carrying them have a longer-than-normal life span. Vijg and Papaconstantinou (1990) suggested that gerontogenes might be separated into four distinct categories based upon their effects on life span and their evolutionary origin. "Deleterious" and "pleiotropic" genes are predicted by the evolutionary theory of aging (Charlesworth, 1980; Rose, 1991) and have evolved as a result of mutation accumulation or pleiotropic gene action, respectively. "Aging" genes that actively kill the organism are thought not to operate in organism senescence by evolutionary criteria; "longevity" genes promote survival, and presumably most genes that are fixed in an organism are of this type. "Longevity assurance gene," a term used by Sacher (1978) and by D'mello et al. (1994), means essentially the same as the term gerontogene.
Five methods have been used to identify genes involved in aging, with variable success. These approaches mirror the approaches used to identify genes involved in other biological processes. These approaches are: (1) gene association, (2) selective breeding, (3) quantitative trait locus (QTL) mapping, (4) induc-