Vol. 47 No. 2/2000

269–279

QUARTERLY

Review

Aging and .

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 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, 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 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 Mutagenesis, molecular genetics Mutagenesis, molecular genetics, QTL* analysis 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 zero in on the location of genes responsible makes humans less attractive as the subject of for the variation in a particular phenotype. Se- aging research; it takes a lifetime to do an ex- lective breeding is used to progressively comb 272 S. M. Jazwinski 2000 together the genetic variants in a population highlight. I have used the term longevity that are responsible for a particular trait by genes in tabulating the progress of the genet- choosing for breeding in each generation indi- ics of aging in the model organisms. This em- viduals with the most extreme phenotypic ex- phasizes the fact that life span has been the pression. Associative genetics tests for differ- phenotype analyzed in each case. The difficul- ences in the frequency in a population of ap- ties encountered with the definition of human pearance of genetic variants in individuals aging are more acute when aging in these or- displaying extreme values of the chosen phe- ganisms is considered. This is because little notype. has been done to describe the pathology of the These genetic methodologies have now iden- aging organism. However, in some ways, this tified some 35 cloned genes that determine may be a blessing in disguise. The metric of longevity in the model organisms listed (Ta- life span keeps us on a firm footing, because ble 2). These genes encode a wide variety of the best predictor of mortality is life span it-

Table 2. Cloned longevity genes from model systems

Podospora Saccharomyces Caenorhabditis Drosophila Mus grisea LAG1 daf-2 sod1 Prop-1 LAC1 age-1/daf-23 cat1 p66shc RAS1 daf-18 mth RAS2 akt-1/akt-2 PHB1 daf-16 PHB2 daf-12 CDC7 ctl-1 BUD1 old-1 RTG2 spe-26 RPD3 clk-1 HDA1 mev-1 SIR2 SIR4-42 UTH4 YGL023 SGS1 RAD52 FOB1

with a diversity of functions, suggest- self. Thus, longevity becomes the tool, while ing the existence of many different mecha- health span is the target of investigation. nisms of aging. At this point, little direct overlap between Yeast the functions identified in the different mod- els is evident. However, as will be seen, there The individual yeast cell buds a limited num- is considerable convergence of the physiologi- ber of times, producing a daughter cell each cal mechanisms of aging that these genes time. The daughter has, in principle, the ca- Vol. 47 Aging and longevity genes 273 pacity for a full replicative life span [8, 9]. absence of RAS2 [13]. This gene appears to be Thus, the yeast population is immortal, even important in the downregulation of the re- though the individual is mortal. The measure sponse to heat once this stress is removed. of the yeast life span is thus the number of di- Thus, it is as important for the cell to visions of the mother cell before it dies, and downregulate the stress response efficiently not chronological time. The genetic analysis as it is for it to mount a robust response. of aging in yeast points to four broad physio- Overexpression of RAS2 can completely abol- logical processes important for longevity. ish the deleterious effect on life span of They are metabolic control, resistance to chronic, sublethal heat stress. It acts through stress, gene dysregulation, and genetic stabil- the adenylate cyclase signaling pathway in ex- ity. In addition, two molecular mechanisms of erting this salutary effect. The importance of aging have been elucidated in this model sys- stress resistance for longevity is evidenced by tem, on the basis of the genetic studies. the fact that the induction of thermotolerance Finally, the RAS2 gene has emerged as a early in life leads to a persistent, though not homeostatic device in yeast longevity. permanent, reduction in mortality rate result- An intracellular signaling pathway from the ing in extension of life span [14]. For this ef- to the nucleus, called the retro- fect, both RAS1 and RAS2 are essential, as is grade response, has been shown to determine HSP104. yeast life span [10]. This pathway of One of the manifestations of aging is the loss interorganelle communication signals the of transcriptional silencing of genes located in functional status of the mitochondrion, lead- the heterochromatic regions of the yeast ge- ing to changes in the expression of nuclear nome near and at the silent mating genes that encode proteins that localize to the type loci [15, 16]. This gene dysregulation was cytoplasm, the mitochondrion, and the suggested to be a possible cause of aging in peroxisome. The enzymatic changes that the yeast, and some evidence for its involvement retrograde response elicits represent a shift to in aging was forthcoming [3, 17]. The pro- the glyoxylate cycle to provide Krebs cycle in- posal that gene dysregulation plays a role in termediates, an induction of gluconeogenesis, aging is now on a firm foundation. It has been and a change from the utilization of glucose to shown that the yeast deacetylase acetate. The latter translates into a shift to a genes RPD3 and HDA1 determine yeast lon- carbon source of lower caloric content. These gevity [18]. These genes not only affect the si- metabolic and enzymatic changes resemble lencing status of the heterochromatic regions those found in C. elegans mutants that display mentioned above, but they also modulate the extended longevity. They are reminiscent of silencing at the heterochromatic ribosomal the metabolic changes found in fruit flies se- DNA in yeast. In fact, their effects on lected for extended life span, and they bear re- longevity are associated with enhanced silenc- semblance to some of the features of caloric ing of ribosomal DNA. The picture that is be- restriction in rodents which results in the ex- ginning to emerge is that aging results in tension of life span. RAS2 modulates the ret- dysregulation of the ribosomal DNA locus re- rograde response and the it pro- sulting in the excessive production of ribo- vides. somal RNA that is not balanced by the synthe- Resistance to ultraviolet radiation is associ- sis of ribosomal proteins. This would lead to ated with life span in yeast [11]. Similarly, re- the assembly of defective ribosomes. In fact, sistance to is important for there is an increase in ribosomal RNA with longevity [12]. Yeasts exposed to chronic age, coupled to a reduction in the efficiency of bouts of sublethal heat stress show a curtail- synthesis [19]. ment of life span, which is more severe in the 274 S. M. Jazwinski 2000

Another mechanism of aging involving the this is the disposable soma theory of aging re- ribosomal DNA has been described. The tan- duced to the molecular level. The homeostat dem ribosomal DNA repeats lend themselves in both cases cannot afford to put all the eggs nicely to recombinational events that result in in one basket. In the case of the disposable the excision of monomers which are known to soma, the balance is struck between somatic generate circular species. These have been maintenance and reproduction. shown to accumulate with age, and their ex- cessive accumulation can cause cell death C. elegans [20]. It is not clear how this demise is actually brought about. This simple and attractive A signal transduction pathway that deter- mechanism does not appear to play a domi- mines the life span of the worm has been elab- nant role in yeast aging. The retrograde re- orated [22]. At its head is the recep- sponse, whose induction extends life span, re- tor-like gene daf-2, whose ligand is not known sults in a massive increase in the ribosomal at present. The signal this receptor receives is DNA circles. Thus, the circles are not suffi- transduced to the phosphatidylinositol-3-hy- cient to cause aging. They are also not neces- droxyl kinase gene age-1/daf-23, which in turn sary, because deletion of SIR2 which abro- transmits the signal to akt-1/akt-2 (protein gates ribosomal DNA silencing and might be kinase B) [23]. This signal is modulated by expected to result in circle production, short- daf-18, a phosphatidylinositol phosphatase ens life span but does not generate circles gene [24]. The downstream effector of this [18]. This points to the role of SIR2 in silenc- pathway is a forkhead en- ing of ribosomal DNA in determining life coded by daf-16. Interestingly, HNF-3 a span. forkhead transcription factor involved in elic- I have alluded to RAS2 as a homeostatic de- iting the metabolic effects of insulin is vice in yeast longevity [21]. The source of this downregulated by the insulin pathway [25], characterization is two-fold. First, there ap- much like DAF-16 is downregulated by the pears to be an optimal level of RAS2 expres- DAF-2 pathway. The elimination of the DAF-2 sion associated with maximum longevity. This signal extends life span. It also results in pro- may be dependent on the genetic background, found metabolic changes, including the accu- on environmental conditions, and on mulation of lipid and glycogen. The enzymatic epigenetic exigencies. It should be noted that changes that occur resemble those found in in the absence of overt stress it is an adenylate the retrograde response, including a shift to cyclase-independent pathway through which the glyoxylate cycle [26]. RAS2 acts to determine life span. Second, One other daf gene impinges on the pathway RAS2 modulates several processes that ap- described above. This gene, daf-12, encodes a pear to play a role in yeast longevity. They in- member of the steroid receptor superfamily. clude growth or metabolism, stress resis- Mutants in this gene act synergistically with tance, cell cycling, chromatin-dependent daf-2 mutants in extending life span [27]. transcriptional silencing, and cellular spatial DAF-12 also appears to be involved in the organization. I hypothesize that this gene also transmisson of signals from germ cells to contributes to genetic stability. In this way, DAF-16 [28]. DAF-2 is the recipient of signals RAS2 allocates cellular resources (energy and from the somatic gonad [28]. All of this makes nutrients) to the competing demands made on for a rather intricate network of signaling that them by these cellular processes. The only determines life span of the adult worm. known signal to which it responds is nutri- The downstream targets of this DAF path- tional status. It must maintain a balance in way for determining life span are not known, the face of shifting requirements. In a sense, except for one. This appears to be a cytoplas- Vol. 47 Aging and longevity genes 275 mic catalase encoded by ctl-1 [29]. It is there- dismutase in motorneurons alone was suffi- fore not surprising that this pathway not only cient to increase life span, pointing to the im- plays a role in determining life span, but that portance of this tissue for fly longevity [38]. it also is important in stress resistance. In- The mutagenesis approach has been success- deed, the pathway specifies resistance to a ful in Drosophila more recently. A gene encod- multiplicity of stressors, including heat, ultra- ing a G-protein coupled transmembrane re- violet radiation, and oxidative stress [30]. ceptor called methuselah was identified in a Another set of genes also affects nematode screen for mutants showing increased longev- aging. This set of genes is typified by clk-1 ity [39]. Coincident with the increased longev- [31]. There is some controversy whether or ity was an enhanced resistance to heat, starva- not this gene falls into the same category as tion, and oxidative stress. It has not been de- the daf genes in having daf-16 as a down- termined whether the mutant alters metabolic stream effector and in specifying stress resis- capacity. tance. CLK-1 protein is homologous to the yeast Coq7 protein, which is involved in Mouse ubiquinone biosynthesis. This may not be the only function of CLK-1 in the nematode; it The oldest method for extending rodent life may not even be the essential function. span is the reduction of caloric intake [40]. Al- Clearly, there are changes in metabolism, in- though this is not a genetic approach, it has re- cluding a slowing of its rate, in clk-1 mutants. cently been subjected to gene expression pro- It has been suggested that in this mutant a sig- filing [41]. Two aspects of the global patterns nal is sent from the mitochondrion to the nu- of gene expression deserve some comment. cleus that impacts longevity [32]. This is remi- First, they confirm earlier studies indicating niscent of the retrograde response. the altered metabolism of the calorie re- stricted animals. Second, the altered gene ex- pression portends the kind of metabolic D. melanogaster changes that occur in yeasts in which the ret- Until recently, the major impact of genetics rograde response has been induced. Calorie in aging research in Drosophila has been the restricted rodents are resistant to stress, selection of lines displaying extended longev- show a postponement of many of the func- ity [33, 34]. Fruit flies thus selected show a tional deficits associated with aging, exhibit a greater metabolic capacity. They are also re- delayed appearance of various age-related pa- sistant to heat, desiccation, and ethanol va- thologies, such as cancer, and have an in- pors, and they have higher activities of several creased lifetime metabolic capacity [40]. (In- antioxidative enzymes. They are more effi- duction of the retrograde response renders cient in their utilization of nutrients, and they yeast more resistant to stress, as well). It has have enhanced storage of lipid and glycogen. been proposed that calorie restricted animals Many of these features bear similarity to ones display these features because of a change in found in yeast and worms that have an ex- the way that glucose is metabolized, in es- tended life span [35]. sence more effectively [40]. Direct evidence for the significance of oxida- Two genetic interventions have been shown tive stress in fly aging has been obtained to extend the life span of the mouse. The Ames through the generation of transgenic animals dwarf mouse (Prop-1) has a deficit in the de- expressing either copper/zinc superoxide velopment of the pituitary that results in a dismutase, catalase, or both. The transgenic marked reduction in growth hormone produc- flies lived longer while suffering less oxidative tion. This mouse is small, as the name indi- damage [36, 37]. In fact, expression of the cates, but it has an enhanced longevity [42]. 276 S. M. Jazwinski 2000

There must be metabolic consequences to this serve [3]. This is not a physical entity, but , but the analysis has not yet been re- rather an abstract concept. This life mainte- ported. More recently, a mutation in the gene nance reserve establishes our functional ca- encoding p66shc, which is involved in signal pacity that allows us to withstand the assaults transduction involving c-H-ras1, has been of the environment and epigenetic change to found to increase life span in the mouse [43]. retain homeostasis. This capacity is not un- The consequences are a marked reduction in limited, and the probability that it will be over- apoptosis and resistance to oxidative stress. whelmed increases with time, especially be- No other phenotypic changes have been de- cause it does not remain intact but is con- scribed; there is apparently no change in size stantly changing. The life maintenance re- of the animal. serve determines why we live as long as we do. Evidence for epigenetic changes during ag- It is not the derivative of an aging program ing, similar to those discussed in yeast, has that is specified by aging genes. been found in the mouse. This involves the stable somatic inactivation on translocation Towards human longevity genes to the X of autosomal genes that determine coat color. The epigenetic control With the identification, cloning, and charac- of the inactivation decreased with age, but the terization of longevity genes from model or- gene expression was random in time and loca- ganisms, the next step in the hunt for human tion [44]. This sort of random change with age longevity genes can be contemplated. Human has been discussed here earlier. It is the kind homologs of the genes from the model organ- of change that could give rise to epigenetic isms must be cloned. This step has already stratification of individuals in a population, been taken in several instances. One example resulting in the variance of life spans about is the human homolog of yeast LAG1 [46]. The the mean in an inbred population maintained human gene is located at 19p12. It can replace under constant conditions. One might imag- the yeast gene where it performs longevity ine that the frequency, though not the proba- gene function. The human LAG1 and other bilistic , of such epigenetic changes human homologs of the longevity genes from might be under genetic control. This is in fact model organisms can be considered candi- the case. A putative genetic locus has been dates for human longevity genes. This iden- identified in the mouse. This locus affects the tity must, however, be verified by demonstrat- variance of life spans of an aging cohort about ing that the candidate gene indeed performs the mean [45]. This locus was demonstrated this function in humans. This task can be ap- in recombinant inbred lines; it affects the vari- proached genetically. ance but not the mean life span. Linkage analysis has been used to map hu- man genes associated with a particular trait. Usually, disease genes that result from muta- RAMIFICATIONS FOR HUMAN AGING tions at a single locus have been hunted down in this manner, followed by positional cloning. This is a methodology that is nearly impossi- Life maintenance reserve ble to employ in the case of a complex trait Why do we live as long as we do? It’s the lon- such as aging. Aging is particularly difficult to gevity genes that are responsible. They help to address in this manner because it is not very specify the metabolic capacity and the stress likely that one would identify parents of indi- responses that interplay with epigenetic fac- viduals who are very long-lived. Longevity, af- tors, such as the environment during develop- ter all, would again be the most direct pheno- ment, to establish the life maintenance re- type to consider. Vol. 47 Aging and longevity genes 277

Fortunately, there are other approaches that REFERENCES can be utilized. They include allele sharing, us- ing affected siblings, and associative genetics, 1. Rose, M.R. (1991) Evolutionary Biology of a population based approach [47]. The latter Aging. Oxford University Press, New York. methodology has been useful in the identifica- 2. Warner, H.R., Butler, R.N., Sprott, R.L. & tion of risk factors in complex genetic disor- Schneider, E.L. (1987) Modern Biological The- ders. It has already been employed in aging studies. The most universal finding in this do- ories of Aging. Raven Press, New York. main is that the APOE gene is associated with 3. Jazwinski, S.M. (1996) Longevity, genes, and human longevity [48]. We have begun the aging. Science 273, 54–59. Louisiana Centenarian Study to test the can- didate genes developed in the yeast system for 4. Jazwinski, S.M., Kim, S., Lai, C.-Y. & Ben- longevity function in humans, using first an guria, A. (1998) Epigenetic stratification: The associative genetic approach. There may be role of individual change in the biological ag- something special about extreme old age. ing process. Exp. Gerontol. 33, 571–580. There is a hint that mortality rate plateaus at 5. Rowe, J.W. & Kahn, R.L. (1998) Successful older ages in humans [49]. There is no doubt Aging. Pantheon Books, New York. that this happens for older yeasts [4]. It is ob- vious that it would be worthwhile to deter- 6. Glass, T.A., de Leon, C.M., Marottoli, R.A. & mine the nature of the factors that lead to Berkman, L.F. (1999) Population based study such a plateau, because this could provide a of social and productive activities as predic- means to improve human function in old age. tors of survival among elderly Americans. Brit. Med. J. 319, 478–483.

Demographics 7. Bassett, D.E., Boguski, M.S., Spencer, F., Reeves, R., Kim, S-h., Weaver, T. & Hieter, P. The elderly population is growing rapidly in (1997) Genome cross-referencing and relative numbers in the developed world. In- XREFdb: Implications for the identification deed, those 85 and older are increasing at a and analysis of genes mutated in human dis- rate 6-times faster than the general popula- ease. Nature Genet. 15, 339–344. tion, while for those 100 and older the rate is 10-times faster than the population at large. 8. Mortimer, R.K. & Johnston, J.R. (1959) Life This has led many to project that the social se- span of individual yeast cells. Nature 183, curity and medicare systems will be bank- 1751–1752. rupted early in this century. At least one way 9. Muller, I., Zimmermann, M., Becker, D. & for preventing such an occurrence is to im- Flomer, M. (1980) Calendar life span versus prove the quality of life in old age by helping budding life span of Saccharomyces cerevisiae. people to remain functionally independent. Mech. Dev. 12, 47–52. This would reduce the strain on our social fab- ric, and help us enjoy the later years of life. 10. Kirchman, P.A., Kim, S., Lai, C.-Y. & Jaz- The goal of aging research then is for people winski, S.M. (1999) Interorganelle signaling is ‘to die young at an old age’. a determinant of longevity in Saccharomyces cerevisiae. Genetics 152, 179–190. 11. Kale, S.P. & Jazwinski, S.M. (1996) Differen- I would like to thank the organizers of the tial response to UV stress and DNA damage symposium for inviting me to make these during the yeast replicative life span. Dev. opening comments. Genet. 18, 154–160. 278 S. M. Jazwinski 2000

12.Wawryn, J., Krzepilko, A., Myszka, A. & gevity and reproduction in Caenorhabditis Bilinski, T. (1999) Deficiency in superoxide elegans. Genetics 148, 703–717. dismutases shortens life span of yeast cells. 23.Paradis, S. & Ruvkun, G. (1998) Caenor- Acta Biochim. Polon. 46, 249–253. habditis elegans Akt/PKB transduces insu- 13. Shama, S., Kirchman, P.A., Jiang, J.C. & lin-like receptor signals from AGE-1 PI3 Jazwinski, S.M. (1998) Role of RAS2 in recov- kinase to the DAF-16 transcription factor. ery from chronic stress: Effect on yeast life Genes Dev. 12, 2488–2498. span. Exp. Cell Res. 245, 368–378. 24.Ogg, S. & Ruvkun, G. (1998) The C. elegans 14. Shama, S., Lai, C.-Y., Antoniazzi, J.M., Jiang, PTEN homolog, DAF-18, acts in the insulin re- J.C. & Jazwinski, S.M. (1998) Heat stress-in- ceptor-like metabolic signaling pathway. Mol. duced life span extension in yeast. Exp. Cell Cell 2, 887–893. Res. 245, 379–388. 25.O’Brien, R.M., Noisin, E.L., Suwanichkul, A., 15. Kim, S., Villeponteau, B. & Jazwinski, S.M. Yamasaki, T., Lucas, P.C., Wang, J.C., Powell, (1996) Effect of replicative age on trans- D.R. & Granner, D.K. (1995) Hepatic nuclear criptional silencing near telomeres in factor-3 and hormone-regulated expression of Saccharomyces cerevisiae. Biochem. Biophys. the phosphoenolpyruvate carboxykinase and Res. Commun. 219, 370–376. insulin-like growth factor-binding protein 1 genes. Mol. Cell. Biol. 15, 1747–1758. 16. Smeal, T., Claus, J., Kennedy, B., Cole, F. & Guarente, L. (1996) Loss of transcriptional si- 26.Vanfleteren, J.R. & De Vreese, A. (1995) The lencing causes sterility in old mother cells of S. gerontogenes age-1 and daf-2 determine meta- cerevisiae. Cell 84, 633–642. bolic rate potential in aging Caenorhabditis elegans. FASEB J. 9, 1355–1361. 17. Jazwinski, S.M. (1990) Aging and senescence of the budding yeast Saccharomyces cerevisiae. 27. Larsen, P.L., Albert, P.S. & Riddle, D.L. Mol. Microbiol. 4, 337–343. (1995) Genes that regulate both development and longevity in Caenorhabditis elegans. Genet- 18. Kim, S., Benguria, A., Lai, C.-Y. & Jazwinski, ics 139, 1567–1583. S.M. (1999) Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae. 28.Hsin, H. & Kenyon, C. (1999) Signals from the Mol. Biol. Cell 10, 3125–3136. reproductive system regulate the lifespan of C. elegans. Nature 399, 362–366. 19. Motizuki, M. & Tsurugi, K. (1992) The effect of aging on protein synthesis in the yeast 29.Taub, J., Lau, J.K., Ma, C., Hahn, J.H., Hoque, Saccharomyces cerevisiae. Mech. Ageing Dev. R., Rothblatt, J. & Chalfie, M. (1999) A 64, 235–245. cytosolic catalase is needed to extend adult lifespan in C. elegans daf-C and clk-1 mutants. 20.Sinclair, D.A. & Guarente, L. (1997) Extra- Nature 399, 162–166. chromosomal rDNA circles — A cause of aging in yeast. Cell 91, 1033–1042. 30.Murakami, S. & Johnson, T.E. (1996) A ge- netic pathway conferring life extension and re- 21. Jazwinski, S.M. (1999) The RAS genes: A sistance to UV stress in Caenorhabditis homeostatic device in Saccharomyces elegans. Genetics 143, 1207–1218. cerevisiae longevity. Neurobiol. Aging 20, 471– 478. 31. Ewbank, J.J., Bames, T.M., Lakowski, B., Lussier, M., Bussey, H. & Hekimi, S. (1997) 22.Tissenbaum, H.A. & Ruvkun, G. (1998) An in- Structural and functional conservation of the sulin-like signaling pathway affects both lon- Vol. 47 Aging and longevity genes 279

Caenorhabditis elegans timing gene clk-1. Sci- 41. Lee, C.-K., Klopp, R.G., Weindruch, R. & ence 275, 980–983. Prolla, T.A. (1999) Gene expression profile of aging and its retardation by caloric restric- 32.Felkai, S., Ewbank, J.J., Lemieux, J., Labbe, tion. Science 285, 1390–1393. J.-C., Brown, G.G. & Hekimi, S. (1999) CLK-1 controls respiration, behavior and aging in the 42.Brown-Borg, H., Borg, K.E., Meliska, C.J. & nematode Caenorhabditis elegans. EMBO J. Bartke, A. (1996) Dwarf mice and the ageing 18, 1783–1792. process. Nature 384, 33. 33.Luckinbill, L.S., Arking, R., Clare, M.J., 43.Migliaccio, E., Giorgio, M., Mele, S., Pelicci, Cirocco, W.C. & Buck, S.A. (1984) Selection G., Reboldi, P., Pandolfi, P.P., Lanfrancone, L. for delayed senescence in Drosophila melano- & Pelicci, P.G. (1999) The p66shc adaptor pro- gaster. Evolution 38, 996–1003. tein controls oxidative stress response and life span in mammals. Nature 402, 309–313. 34.Rose, M.R. (1984) Laboratory evolution of postponed senescence in Drosophila melano- 44.Cattanach, B.L. (1974) Position effect variega- gaster. Evolution 38, 1004–1010. tion in the mouse. Genet. Res. 23, 291–306. 35.Jazwinski, S.M. (2000) Coordination of meta- 45.de Haan, G., Gelman, R., Watson, A., Yunis, bolic activity and stress resistance in yeast lon- E. & Van Zant, G. (1998) A putative gene gevity; in The Molecular Genetics of Aging causes variability in lifespan among geno- (Hekimi, S., ed.) pp. 21–44, Springer- Verlag, typically identical mice. Nature Genet. 19, Berlin. 114–116. 36.Orr, W.C. & Sohal, R.S. (1994) Extension of 46.Jiang, J.C., Kirchman, P.A., Zagulski, M., life-span by overexpression of superoxide Hunt, J. & Jazwinski, S.M. (1998) Homologs dismutase and catalase in Drosophila mela- of the yeast longevity gene LAG1 in nogaster. Science 263, 1128–1130. Caenorhabditis elegans and human. Genome Res. 8, 1259–1272. 37. Sun, J. & Tower, J. (1999) FLP recombinase- mediated induction of Cu/Zn-superoxide dis- 47. Lander, E.S. & Schork, N.J. (1994) Genetic mutase transgene expression can extend the dissection of complex traits. Science 265, life span of adult Drosophila melanogaster 2037–2048. flies. Mol. Cell. Biol. 19, 216–228. 48.Schachter, F., Faure-Delanef, L., Guenot, F., 38.Parkes, T.L., Elia, A.J., Dickinson, D., Rouger, H., Froguel, P. Lesueur-Ginot, L. & Hilliker, A.J., Phillips, J.P. & Boulianne, G.L. Cohen, D. (1994) Genetic associations with hu- (1998) Extension of Drosophila lifespan by man longevity at the APOE and ACE loci. overexpression of human SOD1 in moto- Nature Genet. 6, 29–32. rneurons. Nature Genet. 19, 171–174. 49.Vaupel, J.W., Carey, J.R., Christensen, K., 39.Lin, Y.-J., Seroude, L. & Benzer, S. (1998) Ex- Johnson, T.E., Yashin, A.I., Holm, N.V., tended life-span and stress resistance in the Iachine, I.A., Kannisto, V., Khazaeli, A.A., Drosophila mutant methuselah. Science 282, Liedo, P., Longo, V.D., Zeng, Y., Manton, K.G. 943–946. & Curtsinger, J.W. (1998) Biodemographic trajectories of longevity. Science 280, 855– 40.Masoro, E. (1995) Dietary restriction. Exp. 860. Gerontol. 30, 291–298.