Vol. 47 No. 2/2000 269–279 QUARTERLY Review Aging and longevity genes. S. Michal Jazwinski½ Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112 U.S.A. Received: 13 March, 2000 Key words: aging, longevity genes The genetics of aging has made substantial strides in the past decade. This progress has been confined primarily to model organisms, such as filamentous fungi, yeast, nematodes, fruit flies, and mice, in which some thirty-five genes that determine life span have been cloned. These genes encode a wide array of cellular functions, indicat- ing that there must be multiple mechanisms of aging. Nevertheless, some generaliza- tions are already beginning to emerge. It is now clear that there are at least four broad physiological processes that play a role in aging: metabolic control, resistance to stress, gene dysregulation, and genetic stability. The first two of these at least are common themes that connect aging in yeast, nematodes, and fruit flies, and this con- vergence extends to caloric restriction, which postpones senescence and increases life span in rodents. Many of the human homologs of the longevity genes found in model organisms have been identified. This will lead to their use as candidate human longev- ity genes in population genetic studies. The urgency for such studies is great: The pop- ulation is graying, and this research holds the promise of improvement in the quality of the later years of life. Why do we age? This question has fascinated sight into the aging process. It shifts the focus and troubled the human race for generations. from a process that has evolved to serve a pur- However, this may not be the best way to pose to one that has escaped the force of natu- phrase our concern about longevity and aging. ral selection [1]. It also argues forcefully In fact, I will argue that the relevant query is: against a program of aging, especially a ge- Why do we live as long as we do? This subtle netic program in which each step is dependent change in emphasis conceals a powerful in- on completion of the previous one in the se- .Research in my laboratory was supported by grants from the National Institute on Aging of the National Institutes of Health (U.S.P.H.S.). ½Send correspondence to: Dr. S. Michal Jazwinski, Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1901 Perdido Street, Box P7-2, New Orleans, Louisi- ana 70112, U.S.A.; Phone/Fax 504 568 4725; e-mail [email protected] 270 S. M. Jazwinski 2000 quence. This argument against a genetic pro- WHAT IS AGING? gram of organismal aging is not inconsistent with programmed cell death or apoptosis, be- Before we turn to a discussion of longevity cause cell death can be adaptive for the genes, we must define the matter of the sub- metazoan organism. After all, the organism is ject with which we are dealing. This is not a the object of natural selection, whose force is trivial task. Aging is not easy to define even filtered, as it were, before impinging on the though we know it when we see it. We are cells that constitute it. The foregoing does not faced with a sliding scale of phenotypic char- in any way suggest that genes are not impor- acteristics encompassing profound decline tant in the biological aging process, in the and “successful aging”. Successful aging is sense that it is the genetic constitution that characterized by the avoidance of disease, the determines life span. Thus, the focal point maintenance of high cognitive and physical moves from genes of aging to longevity assur- function, and an engagement with life [5]. ance genes, which help determine the charac- This characterization brings us closer to a def- teristic life span of the organism. inition of the biological aging process; how- There have been many approaches to the ever, it is evident that successful aging goes study of aging. Through much of the past fifty beyond biology per se. Indeed, it has been years, much effort has been devoted to the de- found that, in addition to physical exercise, so- scription of biological aging as it takes place in cial activity and productive pursuits contrib- mammals, particularly rodents and man. This ute to what can be termed successful aging description includes all levels of biological or- [6]. Clearly, the latter two enter the realm of ganization, from the molecular to the organis- the psychosocial. A useful definition of aging mal, and it even reaches the supraorganismal holds that it is a progressive decline in the in demography. This cataloging endeavor has ability to withstand stress, damage, and dis- spawned many theories of biological aging, ease, and that it is characterized by an in- encompassing virtually every level of descrip- crease in the incidence of degenerative and tion [2]. However, the past ten years have neoplastic disorders. seen the rise of genetic analyses of aging, and, A distinction is often made between the in- with it, the beginnings of an understanding of trinsic aging process and age-related disease. molecular mechanisms, pathways, and physi- (One extreme view has it that there is no in- ological processes important for longevity [3]. trinsic aging process, but only disease). This The emphasis of this article on genetics is distinction has some important conse- not intended to belittle the importance of the quences; therefore, it is worth pursuing. To environment in aging. Indeed, any phenotype, bring the difference between aging and dis- including aging, plays itself out through an in- ease into closer focus, it is worth considering teraction of genes, or more correctly the geno- the following scenario. An elderly man does type, with the environment. There is also a not see a rock in his path, stumbles over it, probabilistic component to aging. This is evi- loses his balance, and falls. His eyesight isn’t dent from the fact that even under constant what it used to be. More importantly, skeletal conditions members of a genetically homoge- muscle atrophy has weakened his legs pre- neous group of individuals do not die all in venting easy recovery from the faulty footing. tandem. Thus, there exists an epigenetic strat- The fall results in a hip fracture; perhaps, ification of such an aging population, the there was an underlying osteoporotic process. source of which has been modeled mathemati- In any case, he ends up a hip-replacement pa- cally as random change [4]. This, however, tient in the hospital. Healing slowly, his resi- lies beyond the scope of this presentation. dence there is extended. His immunity not be- Vol. 47 Aging and longevity genes 271 ing what it used to be, he contracts pneumo- periment. For these reasons, we have turned nia and dies. The attending physician lists the to model organisms to study aging. Conserva- cause of death as pneumonia. In reality, it tion of basic biological processes throughout could easily be argued that its ultimate cause phylogeny makes this approach rational. Fur- was skeletal muscle atrophy. The disease was thermore, about one-fifth of human disease pneumonia, but the aging process included genes that have been positionally cloned pos- skeletal muscle atrophy and other functional sess yeast homologs, reflecting a remarkable decline. degree of genetic conservation [7]. Many of Aging is not a disease, from the foregoing these genes are interchangeable between the discussion. However, aging can predispose to two species. The comparison between yeast disease. This is not surprising if we consider and human is, of course, the most extreme ex- the functional decline that is the essence of ample; we would expect even more similarity the intrinsic aging process. Indeed, aging pre- between humans and invertebrates. disposes to a variety of diseases. Turning this The major genetic model systems used in ag- around, we come to the conclusion that allevi- ing research are the filamentous fungus ation of some of the functional deficits of ag- Podospora anserina, bakers’ yeast (Saccharo- ing should reduce the incidence of many dis- myces cerevisiae), the roundworm (Caenor- eases and disorders. Thus, we can make major habditis elegans), the fruit fly (Drosophila inroads in many age-related diseases and dis- melanogaster), and the mouse (Mus musculus). orders by amelioration of aging, rather than There are several genetic methodologies that taking the piecemeal approach of curing them have been applied to the study of aging in one by one. This has obvious practical signifi- these organisms, although not necessarily all cance. in each of them (Table 1). Mutagenesis in- volves the generation of mutants by physical or chemical treatment, followed by screening GENETIC MODEL SYSTEMS for individuals that possess the sought pheno- types. Molecular genetic strategies are similar Human genetics is the archival analysis of except that they target known genetic loci that chance encounters. This designation contains are considered candidates for genes involved the gist of one of the two problems in studying in determining the phenotype of interest. Table 1. Genetic model systems for the study of aging Organism Genetic methodology used Podospora anserina Mutagenesis Saccharomyces cerevisiae Mutagenesis, molecular genetics Caenorhabditis elegans Mutagenesis, molecular genetics, QTL* analysis Drosophila melanogaster Mutagenesis, molecular genetics, QTL analysis, selective breeding Mutagenesis, molecular genetics, QTL analysis, selective breeding, Mus musculus associative genetics *quantitative trait loci human aging. Genetically, humans are not Quantitative trait loci (QTL) analysis encom- very malleable both for practical and for ethi- passes a family of techniques that are used to cal reasons. In addition, their life expectancy zero in on the location of genes responsible makes humans less attractive as the subject of for the variation in a particular phenotype.