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The genetics of aging in optimal and stressful environments
0531-5565/78/1 O01-0357502.00/0
Exp. Geront.Vol. 13, pp. 357-363.
~) Pergamon Press Ltd., 1978. Printed in Great Britain.
THE GENETICS OF A G I N G IN OPTIMAL A N D STRESSFUL ENVIRONMENTS P. A. PARSONS Department of Genetics and Human Variation, La Trobe University, Bundoora, Victoria 3083, Australia
(Received 9 November 1977; receivedfor publication 3 April 1978)
INTRODUCTION MANY aging studies in man are based upon people living under optimal conditions. The life expectancy of U.S. males in 1970 was 67.40 yr and females 74.80 yr, compared with figures over 20 yr lower for countries such an India. While genetic differences cannot be excluded, environmental factors such as nutrition, disease, and hygiene are critically important in explaining the differences. In addition, the behavioural effects of population density could be important in crowded cities of less affluent countries, although difficult to prove (Ehrman and Parsons, 1976). Is there necessarily a direct association between longevity under optimal and stressful environments? In other words, would those surviving longest under an optimal environment do so under a stressful environment, defining the environment to include both biological and sociological factors? In addition, what do we know of the genetic basis of aging in man and again is this the same under all environments? There is remarkably little on these points in the literature (Stern, 1973). A reasonable initial approach is to look at experimental animals where these questions can be asked and one hopes answered. Much relevant data are from Drosophila--an organism with a life span sufficiently short for detailed aging studies. The approach of first reviewing experimental animals then considering man frequently helps to put many of the controversial issues on heredity vs environment in man into proper perspective (see Ehrman and Parsons, 1976, on the heredity-l.Q, issue, for example). GENETICS OF LONGEVITY IN DROSOPHILA In Drosophila as in man, there are genes with major morphological, physiological, and behavioral effects having associated effects on life span. In this discussion, however, longevity is treated as a metrical trait based on strains without obvious major abnormalities. For unstressed environments, a number of studies on inbred strains in D. melanogaster and D. subobscura reveal differences in longevity under partial genetic control (Malick and Kidwell, 1966; Parsons, 1966; Clarke and Maynard Smith, 1955). Environmental factors such as mating status are relevant and sex differences occur favoring one or other of the sexes in different strains. Heterosis is normal in crosses among inbred strains and is usually greater in females than males (Parsons, 1966; Westerman and Parsons, 1973) and additive and non-additive genetic effects controlling longevity are not usually large. Such results are reasonable since longevity cannot be regarded as being directly related to fitness as are traits like viability or hatchability (Matb_er, 1966 for discussion). However, there is presumably some selection in nature for increased longevity insofar as this would increase fecundity. The argument is not particularly direct since the inbred strains do not form coadapted complexes as found in nature although hybrids would be somewhat closer to coadapted complexes because of their high level of heterozygosity. 357
358
P . A . PARSONS
Genetic bases of quantitiative traits in natural populations can be assayed using diallel crosses among isofemale strains collected from nature (Parsons, 1977a). For example, McKenzie and Parsons (1974) analyzed desiccation resistance as assessed by longevity in natural populations of the sibling species D. melanogaster and D. sh,ulans in this way. This trait can be rapidly assayed (a maximum of 16 hours under 0H relative humidity at 25'~C), whereas longevity estimates in unstressed environments require up to 3 months so the rarity of such studies is not unexpected. However, Parsons (1978) studied the longevity of 20 isofemale strains in D. melanogaster at 20 and 25°C based on data expressed as 50'~,;, survival times. Differences among strains were found at both temperatures with a high correlation across temperatures. This implies that longevity in natural populations is under genetic control but no comments can be made about its genetic basis without carrying out diallet cross experiments as for the desiccation experiments. E X T R E M E ENVIRONMENTS--6°Co-7 I R R A D I A T I O N TEMPERATURE
AND
HIGH
A stress of great interest for aging studies is exposure to 6°Co-7 irradiation since longevity falls as dose increases. The linear regressions of mean mortality on dose for 4 inbred strains of D. melanogaster from 0 to 130 krad (Fig. 1) are all highly significant. The regression lines of 3 of the 4 strains are similar, but the 4th (OR) differs in that the line is steeper. This explains why OR strains live longest at 0 krad and shortest at very high doses and shows that the most resistant strain to 7 irradiation is not necessarily that which lives longest in an unstressed environment (Westerman and Parsons, 1972). In agreement MacBean (1970) found no association between radiosensitivity and longevity of untreated flies for 6 isofemale strains in D. melanogaster. Apparently there must be differing genes or
30
~, 20 -o
N4
Y4
~E = 10 =E
50
Dose
100
130
(krads)
FIG. 1. Linear regressions of mean mortalities in days on dose in 10 krad steps from 0 to 130 krad for four inbred strains of D. melanogaster (after Westerman and Parsons, 1972).
359
THE GENETICS OF AGING IN OPTIMAL AND STRESSFUL ENVIRONMENTS
gene complexes determining longevity alone, compared with longevity under y irradiation especially at extreme doses. Westerman and Parsons (1973) investigated the genetics of resistance to y irradiation based upon diallel crosses between the 4 inbred strains in Fig. 1. As expected the OR strain had the steepest slope as did all hybrids with it. The relative importance of additive genetic variation and non-additive (presumably dominance) variation are summarized by levels of significance in Table 1. At the extreme stress of 120 krad additive genetic control is highly significant and the non-additive genetic component, while still significant at p < 0-001, is minor by comparison. At all other doses the non-additive effect is more important than the additive, the latter being insignificant except for 100 krad where it is marginally significant. The control data are discussed above. The genetic basis of longevity clearly varies according to the level of environmental stress, in this case 6°Co-y irradiation. TABLE 1. LEVELS OF SIGNIFICANCE IN D. melanogaster OF GENERAL COMBINING ABILITIES MEASURING ADDITIVE GENETIC EFFECTS, AND SPECIFIC COMBINING ABILITIES MEASURING NONADDITIVE (DOMINANCE) EFFECTS AT EXPOSURES TO 6OCo-y IRRADIATION BETWEEN 0 AND 120 krad (BASED ON DATA OF WESTERMAN AND PARSONS,
1973) Dose (krad) 0 General combiningability <0-01 Specific combiningability <0.05
40 <0.001
60 <0.01
80 <0.001
100 <0'05 <0.001
120 <0.001 <0.001
Limited evidence indicates an association between mortalities after acute temperature shock and high doses of 6°Co-y irradiation in isofemale strains (Parsons, 1969) and strains selected for heat resistance (Ogaki and Nakashima-Tanaka, 1966). Parsons (1966) examined the longevity of adults in a 4 x 4 diallel cross at 25°C, an optimal temperature for D. melanogaster, and at 29.5°C which is relatively extreme. The mean longevity at 29.5°C was intermediate between the mean longevity at 60-80 krad and its genetic basis almost entirely non-additive (p < 0.001), which corresponds to the mode of inheritance found in the 40-80 krad range. Therefore, for both stresses assessed in this way there are correspondences in their genetic control. For other very extreme stresses where mean longevities are measured in hours rather than less acute stresses where longevities are measured in days, additive genetic control predominates, usually with some degree of dominance for resistance to the stress. This conclusion applies to desiccation, exposure to CO2 and anoxia, and more specific chemical stresses such as ether, chloroform, phenylthiourea and various insecticides (Parsons, 1973). These are therefore stresses for which gene localization studies can be most readily carried out, using methods pioneered by Thoday (1961) and his colleagues. Except for DDTresistance most of the above stresses have not been analyzed to the gene level. However, variability has been localized in particular segments of chromosomes in some cases, especially extreme 6°Co-y irradiation. For this latter stress, major additive effects associated with chromosomes II and III, and a minor effect associated with the X-chromosome have been found (MacBean, 1970). Dominance effects were associated with chromosomes II and III as expected and were small. Since the largest effect was for chromosome II, intrachromosomal activity for radioresistance was investigated; major genetic activity for radiosensitivity in the centromeric region and radioresistance in the extreme of the left arm of the chromosome was found. Since flies cannot be scored individually for this trait, estimating whether genes or gene complexes are involved would be a formidable task. In summation, the genetic basis of longevity can be readily analyzed under conditions of
360
P.A. PARSONS
extreme environmental stress, but not under optimal environmental conditions or less acute stresses. Given the low apparent heritability of longevity under more optimal conditions it is not surprising that our knowledge of its genetic basis is rudimentary, since it is clearly highly dependent upon environment. This last conclusion is well supported by studies on the longevities (Parsons, 1977b) of 20 recently collected isofemale strains of D. simulans at 20 and 25°C. Strains were reared and kept at 20°C before testing--a temperature which is far more favorable for D. simulans development than 25°C since it is difficult to culture the species at this temperature (Parsons, 1975). At both temperatures there was genetic heterogeneity among strains indicating polymorphism for longevity in natural populations. However, there was a large and significant strains x temperature interaction. Arguing from differing genetic architectures according to environment for a given set of strains as above, it is important to ask whether there is a correspondence between the longevities of strains across temperatures. The correlation coefficient for strain means across temperatures was effectively zero so that the above interaction is clearly due to a lack of correspondence of strain longevities across temperatures. The conclusion is that studies on the genetics of aging are on/)" relevant to the environment selected. This contrasts with D. melanogaster where there is a correspondence for Iongevities at 20 and 25°C which are temperatures permissive of easy laboratory culture and hence species continuity in contrast with D. shnulans. This suggests that if the environment is insufficiently extreme to prevent species continuity, there may be some correspondences across environments. It is not therefore surprising that studies on the genetic basis of aging in natural populations have not proceeded far, especially as the temperatures 20 and 25°C are more meaningful for natural populations being frequently encountered in nature (although not of course continuously). EXTREME ENVIRONMENTS--MAN The data discussed show that if a population is exposed to an acute environmental stress, longevity differences between genotypes wilt be magnified compared with optimal conditions. Such general conclusions are not expected to be restricted to Drosophila and should apply to other organisms including rodents and man. Man is a special case since environments cannot be controlled as for experimental animals. However, devastating effects of some environmental changes are well known, especially disease caused by bacteria and viruses when introduced to previously unexposed populations (see Curr, 1886; Darlington, 1970). Eventually adaptation is expected as genetically resistant individuals survive at the expense of susceptibles. A classic animal example is myxomatosis, a virus introduced to Australian wild rabbits in 1950. Rabbit populations were initially decimated but now are stabilized at lower population sizes resulting from a combination of the evolution of higher resistance on the part of the rabbits and reduced virulence on the part of the virus (Fenner and Ratcliffe, 1965). Modern medicine can be regarded as a way of minimizing the effects of extreme environments. In any society where preventive or curative medicine plays a significant role a greater proportion of zygotes survive to reproduction than previously with an associated longevity increase. Genotypes normally eliminated by natural selection continue to survive and reproduce, for example insulin enables diabetics to survive, and the I.Q. of phenylketonurics can be improved by a special diet. In this way such genes will spread, so that in considering the future evolution of man the effect of medicine on the gene pool must be
THE GENETICS OF AGING IN OPTIMAL AND STRE~l:~tJL ENVIRONlVlENTS
361
considered. Under optimal environmental conditions differences between genotypes are likely to be small as for longevity in Drosophila. If, however, the environment in the future deteriorates then the effects of natural selection will become more apparent and longevity differences between genotypes will increase. By environment we mean the physical, biological and social environments and the rate of change of each. The possible effect of a deterioration of the social environment is shown by behavioral and genetic changes in experiments in the vole, Microtus pennsylmnicus, on the effects of overcrowding (Krebs et al., 1973), coupled with evidence in mice (Vale et al., 1971) indicating the possibility of socially tolerant and socially intolerant animals as suggested by Chitty (1967). With increasing crowding there would be selection of certain behavioral patterns (and hence genotypes) at the expense of others. If the human gene pool acquires many deleterious genes due to modern medicine, any future environmental deterioration, however it is manifested, may have severe effects when the full magnitude of the effects of deleterious genes is likely to be expressed. THE FEATURES OF OPTIMAL GENOTYPES In experimental animals (and plants) fitness differences between heterozygotes and heterokaryotypes on the one hand, and homozygotes and homokaryotypes on the other, are frequently maximal in extreme environments favoring heterozygotes and heterokaryotypes (Parsons, 1971). The extreme-environments so far studied mainly involve extremes of high and low temperature. It has therefore been argued that extreme-environment heterosis may be associated with temperature sensitive and correlated enzymes (although recent work indicates that the situation is undoubtedly more complex--Hedrick et al., 1976). The alternative interpretation relates to the general poorer fitness of homozygotes compared with corresponding heterozygotes due to the breakdown of coadaptation in heterozygotes in forming homozygotes; it is argued that this is magnified in extreme environments. For longevity in Drosophila crossing inbred strains in several species often leads to heterosis (Comfort, 1964) which is magnified under extreme temperatures (Parsons, 1966). The same situation pertains for longevity after exposure to e°Co-y irradiation (Westerman and Parsons, 1973); here levels of hybrid superiority tend to increase with irradiation dose especially for the comparison between the control and 120 krad data. Considering an outbred species in nature it can therefore be argued that individuals with high levels of heterozygosity would be fitter than those with lower levels, although we must not ignore the possibility of associations between environmental and genetic heterogeneity in general. Longevity is difficult to examine from these points of view, but it is instructive to look at studies where genetically controlled enzyme and protein polymorphisms have been assessed for overall heterozygosity levels in relation to traits directly or indirectly contributing to fitness. Garten (1976) investigated the relationships between aggressive behavior and genie heterozygosity in the Oldtield mouse, Peromyscus polionotus, and found a positive correlation between mean heterozygosity and measures of aggressiveness, social dominance abilities, and the ability to compete successfully for limited food. Body weight was positively correlated with measures of social dominance, food control and aggressive grooming (and hence heterozygosity levels). Garten asks, "If heterosis for aggressive behavior is a general phenomenon in small mammals, what might be the consequences for small mammal populations?" He concludes that in peak and declining populations, competition for space
362
~,. A. ~ARSOrqS
and resources will put nonaggressive phenotypes at a disadvantage. In competitive environments aggressive heterozygous mice are better equipped to survive, such that the decreased fitness of homozygous genotypes in peak populations may precipitate a decline in numbers with mostly aggressive, heterozygous mice surviving the population crash. Garten argues that fluctuating uncompetitive and competitive environments may give rise to densitydependent selection for heterozygosity, and that population heterozygosity will affect the behavior and demographic attributes (including longevity) of rodent populations. In conclusion, there often is an association between heterozygosity and fitness lbr direct physical stresses imposed on organisms such as temperature extremes, and behavioral stresses. Extreme-environment heterosis as proposed by Parsons (I 971) for physical stresses can almost certainly be extended to behavioral stresses. This is of particular significance for man, an organism for which the physical environment may in theory be controlled (or regulated) more than for other organisms on earth. This cannot be assumed so readily lbr his social environment where overcrowding is a likely causal factor of behavioral stresses. The advantage of heterozygosity is apparently a feature of not only the density-independent features of the environment such as temperature, but also of density-dependent features occurring from population size variations. DISCUSSION The mechanism of aging or the biological basis of senescence is not being considered here. That is the subject of innumerable articles and books (Comfort, 1964). The interest here is in the genetic basis of aging on which there is remarkably little information in man except for specific disorders (Stern, 1973). The discussion on experimental animals confirms this difficulty by stressing the environmental lability of longevity, especially the D. stimulans data at 20 and 25°C. Genetic studies of longevity under acute environmental stresses are, however, feasible and have been done. The stresses are too extreme to be of relevance to man. On the other hand, there is good evidence for heterozygote advantage in experimental animals under conditions of physical and behavioral stresses suggesting that a way of surviving a long time is to be very heterozygous. In man considering carriers of variants at the hemoglobin locus under the stress of malaria, H b A Hbs heterozygotes have a selective advantage such that H b A Hb~ H b A H b A > bibs Hbs, while in non-malarial (more optimal) environments relative fitnesses become H b A H b A > H b A Hb~ > Hb ~ Hb~. Indeed malaria is involved in a number of human polymorphisms leading to increased heterozygosity levels under its influence, namely abnormal hemoglobins C and E and thalassemia, and glucose-6-phosphate dehydrogenase deficiency (Livingstone, 1971). This is significant for the theme of this paper since malaria is a severe stress of human populations having probably killed more human beings than any other single disease. As a leading cause of human morbidity and mortality, malaria has been a major agent of natural selection and consequently a determinant of the evolution of the human gene pool. SUMMARY The genetic basis of aging in Drosophila varies according to environment, as shown by variations in temperatures and levels of 6°Co-7 irradiation. Under conditions of extreme stress large additive differences occur not found under less acute stresses. In addition. longevities of strains are not necessarily correlated across levels of 6°Co-¥ irradiation or temperatures, so that studies on the genetics of aging are only relevant to the enviroment
THEGENETICSOF AGINGIN OPTIMALAND STRESSFULENVIRONMEN'IS
363
selected. Given these results on experimental animals, it appears impossible to separate clearly genetic and environmental factors determining longevity in man--a conclusion that it any case appears likely from human studies. In experimental organisms such as Drosophila, differences between genotypes for longevity are magnified under stress compared with optimal environments. Hybrid and heterozygote superiority frequently occur for density-independent physical stresses of the environment as well as density-dependent behavioral stresses due to crowding levels. It is argued that these conclusions apply to man, so that for maximum longevity genotypes are likely to be highly heterozygous. Acknowledgements--Dr. Lee Ehrman kindly reviewed the manuscript. Financial support was received from the Australian Institute of Nuclear Science and Engineering and the Australian Research Grants Committee.
REFERENCES CHITTV, D. (1967) Proc. ecol. Soc. Aust. 2, 51. CLARKE,J. M. and MAYNARDSMITH,J. (1955) J. Genet. 53, 172. COMFORT,A. (1964) Ageing, the Biology of Senescence. Routledge & Kegan Paul, London. CURR, E. M. (1886) The Australian Race, Vol. 1. Government Printer, Melbourne. DARLINGTON,C. D. (1970) The Evolution of Man and Society. Allen & Unwin, London. ErIRMAN,L. and PARSONS,P. A. (1976) The Genetics of Behavior. Sinauer Associates, Massachusetts. FENNER,F. and RATCLIFF,F. N. (1965) Myxomatosis. Cambridge University Press, London. GARTeN,C. J. (1976) Evolution 30, 59. HEDRICK,P. W., GINEVAN,M. E. and EWING,E. P. (1976) Ann. Rev. Ecol. Syst. 7, 1. KR~aS, C. J., GAINES,M. S., KELLER,B. L., MYERS,J. H. and TAMARIN,R. H. (1973) Science 179, 35. LIVINGSTONE,F. B. (1971) Adv. Genet. 5, 33. MAC'BEAN,I. T. (1970) Ph.D. Thesis, La Trobe University. MCKENZIE,J. A. and PARSONS,P. A. (1974) Aust. J. biol. Sci. 27, 441. MALICK,L. E. and KIDWELL,J. F. (1966) Genetics 54, 203. MAr'HER, K. 0966) Proc. R. Soc. London (B) 164, 328. OGAKI,M. and NAKASHIMA-TANAKA,E. (1966) Mutat. Res. 3, 458. PARSONS,P. A. (1966) Aust. J. biol. Sci. 19, 587. PARSONS,P. A. (1969) Experientia 25, 1000. PARSONS,P. A. (1971) Heredity 26, 579. PARSONS,P. A. (1973) Ann. Rev. Genet. 5, 17. PARSONS,P. A. (1975) Q. Rev. Biol. 50, 151. PARSONS,P. A. (1977a) Am. Naturalist 111, 613. PARSONS,P. A. (1977b) Exp. Geront. 12, 241. PARSONS,P. A. (1978) Exp. Geront. 13, 167. STERN, C. (1973) Principles of Human Genetics. 3rd Edn. Freeman, San Francisco. THODAY,J. M. 0961) Nature, Lond. 191, 368. VALE,J. R., VALE,C. A. and HARLEY,J. P. (1971) Commun. Behav. Biol. 6, 209. WESTeRt~AN,J. M. and PARSONS,P. A. (1972) Int. J. radiat. Biol. 21, 145. WESTeRMAN,J. M. and PARSONS,P. A. (1973) Can. J. Genet. Cytol. 15, 289.
Exp. Geront.Vol. 13, pp. 357-363.
~) Pergamon Press Ltd., 1978. Printed in Great Britain.
THE GENETICS OF A G I N G IN OPTIMAL A N D STRESSFUL ENVIRONMENTS P. A. PARSONS Department of Genetics and Human Variation, La Trobe University, Bundoora, Victoria 3083, Australia
(Received 9 November 1977; receivedfor publication 3 April 1978)
INTRODUCTION MANY aging studies in man are based upon people living under optimal conditions. The life expectancy of U.S. males in 1970 was 67.40 yr and females 74.80 yr, compared with figures over 20 yr lower for countries such an India. While genetic differences cannot be excluded, environmental factors such as nutrition, disease, and hygiene are critically important in explaining the differences. In addition, the behavioural effects of population density could be important in crowded cities of less affluent countries, although difficult to prove (Ehrman and Parsons, 1976). Is there necessarily a direct association between longevity under optimal and stressful environments? In other words, would those surviving longest under an optimal environment do so under a stressful environment, defining the environment to include both biological and sociological factors? In addition, what do we know of the genetic basis of aging in man and again is this the same under all environments? There is remarkably little on these points in the literature (Stern, 1973). A reasonable initial approach is to look at experimental animals where these questions can be asked and one hopes answered. Much relevant data are from Drosophila--an organism with a life span sufficiently short for detailed aging studies. The approach of first reviewing experimental animals then considering man frequently helps to put many of the controversial issues on heredity vs environment in man into proper perspective (see Ehrman and Parsons, 1976, on the heredity-l.Q, issue, for example). GENETICS OF LONGEVITY IN DROSOPHILA In Drosophila as in man, there are genes with major morphological, physiological, and behavioral effects having associated effects on life span. In this discussion, however, longevity is treated as a metrical trait based on strains without obvious major abnormalities. For unstressed environments, a number of studies on inbred strains in D. melanogaster and D. subobscura reveal differences in longevity under partial genetic control (Malick and Kidwell, 1966; Parsons, 1966; Clarke and Maynard Smith, 1955). Environmental factors such as mating status are relevant and sex differences occur favoring one or other of the sexes in different strains. Heterosis is normal in crosses among inbred strains and is usually greater in females than males (Parsons, 1966; Westerman and Parsons, 1973) and additive and non-additive genetic effects controlling longevity are not usually large. Such results are reasonable since longevity cannot be regarded as being directly related to fitness as are traits like viability or hatchability (Matb_er, 1966 for discussion). However, there is presumably some selection in nature for increased longevity insofar as this would increase fecundity. The argument is not particularly direct since the inbred strains do not form coadapted complexes as found in nature although hybrids would be somewhat closer to coadapted complexes because of their high level of heterozygosity. 357
358
P . A . PARSONS
Genetic bases of quantitiative traits in natural populations can be assayed using diallel crosses among isofemale strains collected from nature (Parsons, 1977a). For example, McKenzie and Parsons (1974) analyzed desiccation resistance as assessed by longevity in natural populations of the sibling species D. melanogaster and D. sh,ulans in this way. This trait can be rapidly assayed (a maximum of 16 hours under 0H relative humidity at 25'~C), whereas longevity estimates in unstressed environments require up to 3 months so the rarity of such studies is not unexpected. However, Parsons (1978) studied the longevity of 20 isofemale strains in D. melanogaster at 20 and 25°C based on data expressed as 50'~,;, survival times. Differences among strains were found at both temperatures with a high correlation across temperatures. This implies that longevity in natural populations is under genetic control but no comments can be made about its genetic basis without carrying out diallet cross experiments as for the desiccation experiments. E X T R E M E ENVIRONMENTS--6°Co-7 I R R A D I A T I O N TEMPERATURE
AND
HIGH
A stress of great interest for aging studies is exposure to 6°Co-7 irradiation since longevity falls as dose increases. The linear regressions of mean mortality on dose for 4 inbred strains of D. melanogaster from 0 to 130 krad (Fig. 1) are all highly significant. The regression lines of 3 of the 4 strains are similar, but the 4th (OR) differs in that the line is steeper. This explains why OR strains live longest at 0 krad and shortest at very high doses and shows that the most resistant strain to 7 irradiation is not necessarily that which lives longest in an unstressed environment (Westerman and Parsons, 1972). In agreement MacBean (1970) found no association between radiosensitivity and longevity of untreated flies for 6 isofemale strains in D. melanogaster. Apparently there must be differing genes or
30
~, 20 -o
N4
Y4
~E = 10 =E
50
Dose
100
130
(krads)
FIG. 1. Linear regressions of mean mortalities in days on dose in 10 krad steps from 0 to 130 krad for four inbred strains of D. melanogaster (after Westerman and Parsons, 1972).
359
THE GENETICS OF AGING IN OPTIMAL AND STRESSFUL ENVIRONMENTS
gene complexes determining longevity alone, compared with longevity under y irradiation especially at extreme doses. Westerman and Parsons (1973) investigated the genetics of resistance to y irradiation based upon diallel crosses between the 4 inbred strains in Fig. 1. As expected the OR strain had the steepest slope as did all hybrids with it. The relative importance of additive genetic variation and non-additive (presumably dominance) variation are summarized by levels of significance in Table 1. At the extreme stress of 120 krad additive genetic control is highly significant and the non-additive genetic component, while still significant at p < 0-001, is minor by comparison. At all other doses the non-additive effect is more important than the additive, the latter being insignificant except for 100 krad where it is marginally significant. The control data are discussed above. The genetic basis of longevity clearly varies according to the level of environmental stress, in this case 6°Co-y irradiation. TABLE 1. LEVELS OF SIGNIFICANCE IN D. melanogaster OF GENERAL COMBINING ABILITIES MEASURING ADDITIVE GENETIC EFFECTS, AND SPECIFIC COMBINING ABILITIES MEASURING NONADDITIVE (DOMINANCE) EFFECTS AT EXPOSURES TO 6OCo-y IRRADIATION BETWEEN 0 AND 120 krad (BASED ON DATA OF WESTERMAN AND PARSONS,
1973) Dose (krad) 0 General combiningability <0-01 Specific combiningability <0.05
40 <0.001
60 <0.01
80 <0.001
100 <0'05 <0.001
120 <0.001 <0.001
Limited evidence indicates an association between mortalities after acute temperature shock and high doses of 6°Co-y irradiation in isofemale strains (Parsons, 1969) and strains selected for heat resistance (Ogaki and Nakashima-Tanaka, 1966). Parsons (1966) examined the longevity of adults in a 4 x 4 diallel cross at 25°C, an optimal temperature for D. melanogaster, and at 29.5°C which is relatively extreme. The mean longevity at 29.5°C was intermediate between the mean longevity at 60-80 krad and its genetic basis almost entirely non-additive (p < 0.001), which corresponds to the mode of inheritance found in the 40-80 krad range. Therefore, for both stresses assessed in this way there are correspondences in their genetic control. For other very extreme stresses where mean longevities are measured in hours rather than less acute stresses where longevities are measured in days, additive genetic control predominates, usually with some degree of dominance for resistance to the stress. This conclusion applies to desiccation, exposure to CO2 and anoxia, and more specific chemical stresses such as ether, chloroform, phenylthiourea and various insecticides (Parsons, 1973). These are therefore stresses for which gene localization studies can be most readily carried out, using methods pioneered by Thoday (1961) and his colleagues. Except for DDTresistance most of the above stresses have not been analyzed to the gene level. However, variability has been localized in particular segments of chromosomes in some cases, especially extreme 6°Co-y irradiation. For this latter stress, major additive effects associated with chromosomes II and III, and a minor effect associated with the X-chromosome have been found (MacBean, 1970). Dominance effects were associated with chromosomes II and III as expected and were small. Since the largest effect was for chromosome II, intrachromosomal activity for radioresistance was investigated; major genetic activity for radiosensitivity in the centromeric region and radioresistance in the extreme of the left arm of the chromosome was found. Since flies cannot be scored individually for this trait, estimating whether genes or gene complexes are involved would be a formidable task. In summation, the genetic basis of longevity can be readily analyzed under conditions of
360
P.A. PARSONS
extreme environmental stress, but not under optimal environmental conditions or less acute stresses. Given the low apparent heritability of longevity under more optimal conditions it is not surprising that our knowledge of its genetic basis is rudimentary, since it is clearly highly dependent upon environment. This last conclusion is well supported by studies on the longevities (Parsons, 1977b) of 20 recently collected isofemale strains of D. simulans at 20 and 25°C. Strains were reared and kept at 20°C before testing--a temperature which is far more favorable for D. simulans development than 25°C since it is difficult to culture the species at this temperature (Parsons, 1975). At both temperatures there was genetic heterogeneity among strains indicating polymorphism for longevity in natural populations. However, there was a large and significant strains x temperature interaction. Arguing from differing genetic architectures according to environment for a given set of strains as above, it is important to ask whether there is a correspondence between the longevities of strains across temperatures. The correlation coefficient for strain means across temperatures was effectively zero so that the above interaction is clearly due to a lack of correspondence of strain longevities across temperatures. The conclusion is that studies on the genetics of aging are on/)" relevant to the environment selected. This contrasts with D. melanogaster where there is a correspondence for Iongevities at 20 and 25°C which are temperatures permissive of easy laboratory culture and hence species continuity in contrast with D. shnulans. This suggests that if the environment is insufficiently extreme to prevent species continuity, there may be some correspondences across environments. It is not therefore surprising that studies on the genetic basis of aging in natural populations have not proceeded far, especially as the temperatures 20 and 25°C are more meaningful for natural populations being frequently encountered in nature (although not of course continuously). EXTREME ENVIRONMENTS--MAN The data discussed show that if a population is exposed to an acute environmental stress, longevity differences between genotypes wilt be magnified compared with optimal conditions. Such general conclusions are not expected to be restricted to Drosophila and should apply to other organisms including rodents and man. Man is a special case since environments cannot be controlled as for experimental animals. However, devastating effects of some environmental changes are well known, especially disease caused by bacteria and viruses when introduced to previously unexposed populations (see Curr, 1886; Darlington, 1970). Eventually adaptation is expected as genetically resistant individuals survive at the expense of susceptibles. A classic animal example is myxomatosis, a virus introduced to Australian wild rabbits in 1950. Rabbit populations were initially decimated but now are stabilized at lower population sizes resulting from a combination of the evolution of higher resistance on the part of the rabbits and reduced virulence on the part of the virus (Fenner and Ratcliffe, 1965). Modern medicine can be regarded as a way of minimizing the effects of extreme environments. In any society where preventive or curative medicine plays a significant role a greater proportion of zygotes survive to reproduction than previously with an associated longevity increase. Genotypes normally eliminated by natural selection continue to survive and reproduce, for example insulin enables diabetics to survive, and the I.Q. of phenylketonurics can be improved by a special diet. In this way such genes will spread, so that in considering the future evolution of man the effect of medicine on the gene pool must be
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considered. Under optimal environmental conditions differences between genotypes are likely to be small as for longevity in Drosophila. If, however, the environment in the future deteriorates then the effects of natural selection will become more apparent and longevity differences between genotypes will increase. By environment we mean the physical, biological and social environments and the rate of change of each. The possible effect of a deterioration of the social environment is shown by behavioral and genetic changes in experiments in the vole, Microtus pennsylmnicus, on the effects of overcrowding (Krebs et al., 1973), coupled with evidence in mice (Vale et al., 1971) indicating the possibility of socially tolerant and socially intolerant animals as suggested by Chitty (1967). With increasing crowding there would be selection of certain behavioral patterns (and hence genotypes) at the expense of others. If the human gene pool acquires many deleterious genes due to modern medicine, any future environmental deterioration, however it is manifested, may have severe effects when the full magnitude of the effects of deleterious genes is likely to be expressed. THE FEATURES OF OPTIMAL GENOTYPES In experimental animals (and plants) fitness differences between heterozygotes and heterokaryotypes on the one hand, and homozygotes and homokaryotypes on the other, are frequently maximal in extreme environments favoring heterozygotes and heterokaryotypes (Parsons, 1971). The extreme-environments so far studied mainly involve extremes of high and low temperature. It has therefore been argued that extreme-environment heterosis may be associated with temperature sensitive and correlated enzymes (although recent work indicates that the situation is undoubtedly more complex--Hedrick et al., 1976). The alternative interpretation relates to the general poorer fitness of homozygotes compared with corresponding heterozygotes due to the breakdown of coadaptation in heterozygotes in forming homozygotes; it is argued that this is magnified in extreme environments. For longevity in Drosophila crossing inbred strains in several species often leads to heterosis (Comfort, 1964) which is magnified under extreme temperatures (Parsons, 1966). The same situation pertains for longevity after exposure to e°Co-y irradiation (Westerman and Parsons, 1973); here levels of hybrid superiority tend to increase with irradiation dose especially for the comparison between the control and 120 krad data. Considering an outbred species in nature it can therefore be argued that individuals with high levels of heterozygosity would be fitter than those with lower levels, although we must not ignore the possibility of associations between environmental and genetic heterogeneity in general. Longevity is difficult to examine from these points of view, but it is instructive to look at studies where genetically controlled enzyme and protein polymorphisms have been assessed for overall heterozygosity levels in relation to traits directly or indirectly contributing to fitness. Garten (1976) investigated the relationships between aggressive behavior and genie heterozygosity in the Oldtield mouse, Peromyscus polionotus, and found a positive correlation between mean heterozygosity and measures of aggressiveness, social dominance abilities, and the ability to compete successfully for limited food. Body weight was positively correlated with measures of social dominance, food control and aggressive grooming (and hence heterozygosity levels). Garten asks, "If heterosis for aggressive behavior is a general phenomenon in small mammals, what might be the consequences for small mammal populations?" He concludes that in peak and declining populations, competition for space
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and resources will put nonaggressive phenotypes at a disadvantage. In competitive environments aggressive heterozygous mice are better equipped to survive, such that the decreased fitness of homozygous genotypes in peak populations may precipitate a decline in numbers with mostly aggressive, heterozygous mice surviving the population crash. Garten argues that fluctuating uncompetitive and competitive environments may give rise to densitydependent selection for heterozygosity, and that population heterozygosity will affect the behavior and demographic attributes (including longevity) of rodent populations. In conclusion, there often is an association between heterozygosity and fitness lbr direct physical stresses imposed on organisms such as temperature extremes, and behavioral stresses. Extreme-environment heterosis as proposed by Parsons (I 971) for physical stresses can almost certainly be extended to behavioral stresses. This is of particular significance for man, an organism for which the physical environment may in theory be controlled (or regulated) more than for other organisms on earth. This cannot be assumed so readily lbr his social environment where overcrowding is a likely causal factor of behavioral stresses. The advantage of heterozygosity is apparently a feature of not only the density-independent features of the environment such as temperature, but also of density-dependent features occurring from population size variations. DISCUSSION The mechanism of aging or the biological basis of senescence is not being considered here. That is the subject of innumerable articles and books (Comfort, 1964). The interest here is in the genetic basis of aging on which there is remarkably little information in man except for specific disorders (Stern, 1973). The discussion on experimental animals confirms this difficulty by stressing the environmental lability of longevity, especially the D. stimulans data at 20 and 25°C. Genetic studies of longevity under acute environmental stresses are, however, feasible and have been done. The stresses are too extreme to be of relevance to man. On the other hand, there is good evidence for heterozygote advantage in experimental animals under conditions of physical and behavioral stresses suggesting that a way of surviving a long time is to be very heterozygous. In man considering carriers of variants at the hemoglobin locus under the stress of malaria, H b A Hbs heterozygotes have a selective advantage such that H b A Hb~ H b A H b A > bibs Hbs, while in non-malarial (more optimal) environments relative fitnesses become H b A H b A > H b A Hb~ > Hb ~ Hb~. Indeed malaria is involved in a number of human polymorphisms leading to increased heterozygosity levels under its influence, namely abnormal hemoglobins C and E and thalassemia, and glucose-6-phosphate dehydrogenase deficiency (Livingstone, 1971). This is significant for the theme of this paper since malaria is a severe stress of human populations having probably killed more human beings than any other single disease. As a leading cause of human morbidity and mortality, malaria has been a major agent of natural selection and consequently a determinant of the evolution of the human gene pool. SUMMARY The genetic basis of aging in Drosophila varies according to environment, as shown by variations in temperatures and levels of 6°Co-7 irradiation. Under conditions of extreme stress large additive differences occur not found under less acute stresses. In addition. longevities of strains are not necessarily correlated across levels of 6°Co-¥ irradiation or temperatures, so that studies on the genetics of aging are only relevant to the enviroment
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selected. Given these results on experimental animals, it appears impossible to separate clearly genetic and environmental factors determining longevity in man--a conclusion that it any case appears likely from human studies. In experimental organisms such as Drosophila, differences between genotypes for longevity are magnified under stress compared with optimal environments. Hybrid and heterozygote superiority frequently occur for density-independent physical stresses of the environment as well as density-dependent behavioral stresses due to crowding levels. It is argued that these conclusions apply to man, so that for maximum longevity genotypes are likely to be highly heterozygous. Acknowledgements--Dr. Lee Ehrman kindly reviewed the manuscript. Financial support was received from the Australian Institute of Nuclear Science and Engineering and the Australian Research Grants Committee.
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