The limit to human longevity: an approach through a stress theory of ageing

ilB.XhhS OfitJl!illJ

and development Mechanisms

ELSEVIER

of Ageing

and Development

87 (1996) ‘ll~~‘l8

The limit to human longevity: an approach stress theory of ageing Peter

Received

10 October

1995: revised

through a

A. Parsons*

16 January

1996: accepted

I6 February

1996

Abstract Survival to oId age is enhanced by high vitality and resilience associated with substantial physiological and morphological homeostasis. This is underlain by genes for stress resistance, which confer high metabolic efficiency and hence adaptation to the energy costs of the stresses to which free-living populations are exposed. Under the stress theory of ageing. selection for genes for stress resistance is primary. and achieved life-span is secondary. In some human populations of the modern era, selection for stress resistance is less intense than in earlier times, because of adequate nutrition and reduced exposure to environmental stresses. Such relaxed selection should permit the accumulation of deleterious mutants that are likely to be stress sensitive. Accordingly, increased maximum life-span in future human populations would appear difficult to achieve.

KCJJWOIY~S: Ageing; resistance

Homeostasis;

Life-span:

Metabolic

efficiency;

Oxidative

stress:

Stress

1. Introduction From Greek and Roman times to this day, some individuals have achieved extremely old ages [I]. This suggests survival to the stage when various age-dependent causes of frailty overcome the individual [2]. However, interventions aimed at extending the maximum life-span have generally been unsuccessful. In the modern era, the proportion of people approaching this limit has been increasing, i.e. the median life-span has been shifting upwards with little effect on the maximum life-span [3].

* Present

address:

0047-6374:96!‘509.50

P.O. Box 906. Unley.

SA 5061. Australia

0 1996 Elsevier Science

P/I SOO47-6374(96)01710-I

Ireland

Ltd. All rights

reserved

In free-living animal populations and in most past human populations, maximum reproductive and survival rates are unlikely to be achieved. This is because exposure to various physical (abiotic) stresses and their interactions with biotic variables such as competitors, predators and parasites is the normal scenario. Organisms in free-living populations, therefore. struggle to survive in an environment that is inadequate from the nutritional and energy perspectives [4]. [5]. This converges with earlier discussions of ageing [6], where an organism is regarded as being composed of a number of subsystems which are continually subject to displacement by internal and external factors, or stresses, and these stresses have energy costs in terms of re-establishing the original steady condition. In parallel, a predominantly theoretical analysis incorporates an upper limit for the maximum life-span in terms of energy costs [7]. As a first approximation, habitats of organisms can be expressed as an interaction between stress intensity, magnitude of environmental fluctuations and energy from resources [S]. Since exposure to stress has energy costs, preferred habitats should occur where minimum energy is expended. These tend to be the thermoneutral zones between the boundary conditions for survival, where energy costs for adaptation should be lowest. Therefore, energy available for behavior, growth and reproduction should be maximal in these environments [9]. Commonly, longevity and specific metabolic rate are inversely correlated [lo]. Assuming this rate-of-living theory of ageing, longevity should, hence, be maximal in organisms living around the thermoneutral zone, where the energy costs of stress should be low. On energy grounds, this provides for a maximum life-span, provided that nutrition is adequate. However, the maximum is under continuous threat from the energy costs of the diverse range of internal and external stresses to which organisms are normally exposed, especially when in environments diverging from those where they have evolved [l 11, [ 121. Such considerations have led to a stress theory of ageing [I 31. A common genetic adaptation to stress, imposed over several generations. is a reduction in metabolic rate [4]. Assuming that the primary target of selection of stress is at the level of energy carriers. tradeoffs under the rate-of-living theory of ageing predict increased longevity from selection for stress resistance. In other words, changes in longevity can be regarded as mainly secondary to primary or direct selection for stress resistance [13]. In the remainder of this paper. the author examines limits to human longevity in the context of this stress theory of ageing.

2. Vitality

and stress resistance

In experimental organisms such as nematodes, Drosophilrr and mice. heritability estimates indicate relatively low degrees of genetic determination for longevity, often with substantial genotype x environment interactions [14]. Extensive studies on humans give similar conclusions [15]. Therefore, it is not surprising that experiments directly selecting for longevity tend to be lengthy and laborious, although responses to selection are common. For instance. in D. nzrlmogc~~tc~,

substantial responses for increased longevity were obtained after 21 generations. with significant responses after nine generations [16]. The stress theory of ageing suggests that a more direct procedure for increasing longevity is to select for stress resistance as the primary trait. For desiccation resistance. which is an ecologically important trait in natural populations, large increases in resistance occurred in D. t~wlmopster in four generations of selection. underlain by a realized heritability around 0.65 [ 171. Longevity increased substantially and metabolic rate fell in accordance with the stress theory. Furthermore. the selected strains were resistant to other generalized stresses including starvation. high temperature, irradiation, anoxia and toxic concentrations of ethanol and acetic acid [4]. [17]. In addition. other recent experiments [IS] have shown increased longevity following selection for both resistance to starvation and desiccation. In conclusion. individuals with the potential for a long life should carry genes for generalized stress resistance. Emphasizing humans [19], vitality or vigor declines with chronological age, and ultimately falls below some critical threshold value so that individuals succumb. Indeed, vitality can be regarded as the energy reserve for counteracting challenges to organisms in order to restore proper function [13]. More broadly. vitality can also be viewed as resilience, which involves notions of an ability to recover from ‘insults’ such as accidents, infection or psychological trauma [19]. Somewhat analogously [20], taking account of the hazards to which humans are subjected throughout their life-span. children appear to inherit frailty from their parents more directly than longevity. Therefore. whether considering vitality, vigor, resilience or frailty, there is an implied emphasis on an ability to withstand the energy cost due IO the stresses of living [6], [1 11, [12]. Carriers of stress resistant genes would be at an advantage in this regard. Furthermore, there is evidence that susceptibility to disease and to death is inherited more directly than life-span [15], and that high genetic control of frailty can be associated with a small heritability for longevity [‘O]. As ageing proceeds, the homeostatic mechanisms that ameliorate the erects of abiotic stress progressively deteriorate. For instance. body temperature oscillates between wider limits than at younger ages in humans. so that heat stroke increases dramatically in the elderly [21]. [22]. Deterioration occurs for a wide variety of functions. including the ability of cells to express heat shock proteins [22]. Therefore, the efficiency of homeostatic regulation declines in old age. resulting in a reduced capacity to react to internal and external stresses and to adapt to new environments [23]. This implies that another component of stress resistance is high physiological homeostasis. Fluctuating morphological asymmetry, FA. is a measure of the extent to which an individual can control development under given environmental conditions [34]. A low FA, indicating high morphological homeostasis, tends to occur in insects that live longest [25], [26]. Since one manifestation of the energy dissipation caused by stress is a high FA, symmetric individuals would appear most capable of resisting the ravages of stress. because of their metabolic efficiency in the face of stress [27]. and consequently they should be stress resistant.

In summary, survival to an old age is enhanced by a tendency to manifest high morphological and physiological homeostasis and high vitality (and low frailty). This is underlain by metabolically efficient genes for high stress resistance, which enable maximum tolerance of the rigors of the stresses of free-living populations [28]. In this way, various age-dependent causes of increasing frailty that are destined ultimately to overcome an individual may be delayed as long as possible. deferring the crossing of the critical threshold value where individuals succumb.

3. Oxidative

stress and optimum nutrition

A common physiological response to diverse stresses, including the above, is increased metabolic rate. This translates into oxidative stress causing damage from free radicals. which makes a major contribution to the rate of ageing [29]. In the nematode, Caenorhabditis rkg-am, and in D. ~nel~~nog~~s~a, there are mutants with an extended life-span that show a high resistance to oxidative stress [30], [31], 1321, as would be expected from the discussion of other stresses so far. Of the various metabolic pathways involved in the detoxification of free radicals, the most effective are those involving catalase and superoxide dismutase (SOD) conjointly. Indeed, in transgenic D. nwlunogaster with overexpression of SOD and catalase, life-span was substantially increased [33]. Therefore, individuals with the potential to approach the maximum life-span have metabolic pathways that have evolved to minimize the effects of oxidative stress. The rate-of-living theory of ageing can be expressed as the free radical theory, based upon the free radicals that arise as a normal product of metabolism [29], [34]. Therefore, excess food should be deleterious and reduce life-span, since metabolic rate and free-radical production are increased. Anti-ageing effects of calorically restricted diets have been observed in rodents, invertebrates and Protozoa [7], [35]. Some dietary restriction can exert a positive anti-ageing effect at the cellular level by preserving some physicochemical properties of the lipids of cell membranes in a more fluid state than under an unrestricted dietary regime [36]. Turning to free-living populations, nutritional stress is the norm [5] so that excess food should be disadvantageous, since animals should evolve the metabolic capacity appropriate to their habitats [37]. For instance, humans can be regarded as being adapted to Stone Age conditions. so that in this context the modern diet is often stressful in various ways [38], including excessive nutrition in some populations. Therefore. on evolutionary grounds, some dietary restriction should confer greater fitness than when food is unlimited. Similarly, feeding anti-oxidants to reduce free radical damage should increase life-span. In rats, this procedure extends the median but not the maximum life-span [39]. Consequently, while environmental improvements can be devised to increase longevity, it appears difficult to extend life expectancy beyond the limit at which homeostatic mechanisms enabling organisms to cope with the energy consequences of diverse inevitable environmental stresses ultimately fail. Accordingly, life expectancy at birth appears unlikely to exceed an age of around 85 years. but increasing

proportions of populations may approach this limit ]2]. Even so, in recent decades in the US. the tendency to approach this limit is becoming stabilized [40]. which is in accord with finite energy reserves to counter stresses from the external environment [12].

4. Metabolic

costs and deleterious mutants

The above analysis indicates three conditions whereby the proportion of individuals approaching the limit of maximum achievable age can, in principle, be increased: (1) to have an adequate but not excessive diet; (2) to exist in habitats around the thermoneutral zone so minimizing metabolic costs; and (3) to possess genotypes for stress resistance that underlie vitality and resilience to survive to an old age. Conditions (1) and (2) are being increasingly met in advanced human societies. Achieving (3) depends, in the longer term, on being normally exposed to the stressful environments of free-living populations. However, conditions (1) and (7) can only be achieved when the intensity of selection is reduced from these stress levels. In other words, in some modern human populations [3], an environmental increase in longevity is occurring from improved nutrition. protection from exposure to environmental extremes (including diseases), and improved medicine generally, but as a consequence, the intensity of selection for stress resistance is falling. The likely consequence is increased survival of relatively stress-sensitive and. hence, relatively unfit individuals, that in the environment of hunter-gatherers would be ill-equipped for survival. The ecological analogy consists of captive populations which tend to be managed under relatively optimum conditions of nutrition. crowding levels are avoided [41] and exposure to extreme physical stresses is unlikely. In fact, rapid evolutionary changes can occur in captivity. In particular. a tendency towards sensitivity to temperature extremes has been found in some captive animal populations [42]. IJnder a mutationaccumulation mechanism of ageing, deleterious mutants accumulate at later ages [43], which should not survive for long under strong selection from stress in free-living populations [13]. In contrast, under more benign environments, especially if continued over several generations, such mutants would have greater potential to accumulate. There are many examples of mutants which do not totally inactivate enzymes but are sensitive to abiotic stress [44]. [45]. These mutants could survive under benign circumstances, but should be vulnerable in more stressful environments. For instance, lines of D. ndunogastu in which mutants survived in benign laboratory conditions for up to 62 generations were found to have very low fitness when exposed to nutritional and crowding stress [46]. In particular, this emphasizes that mutants may be close to neutral under benign

conditions. but can become very inferior under stressful circumstances. This suggests that many mutants are sensitive to both nutritional inadequacy and temperature extremes, but under benign conditions they can rapidly accumulate. Under energetically demanding conditions of stress, they should become immediately deleterious. Amelioration of the normal stressful scenario of free-living populations under conditions (I) and (2). therefore, reduces the intensity of selection for stress resistance and allows stress-sensitive mutants to accumulate. Ultimately, the vitality and homeostasis needed to survive to an old age could be reduced by this process. In these terms, extending the boundary conditions for longevity could be an unattainable dream in modern human populations.

5. Conclusion Limits to longevity are considered assuming a world in which substantial stress is the norm. where the habitats of organisms are determined from an energy balance between the costs of stress and energy from resources. Validity of this model is suggested by the rarity of creatures that commonly die from homeostatic collapse in old age, perhaps only certain humans in recent times. Consequently, selection for stress resistance should be primary and that achieved life-span would be a secondary consequence of such selection. While various stresses have been considered, the immediate consequence of diverse stresses is an increase in metabolic rate, and hence oxidative stress. This implies an integrated approach to the effects of stresses to which all organisms are exposed. In the modern era, these stresses have been ameliorated compared with past populations. Consequently. the proportion of individuals carrying metabolically efficient stress-resistant genes should slowly fall, which could ultimately reduce the age at death. Extensions of maximum life-span may consequently become progressively more difficult to achieve in any population exposed to benign circumstances for increasing numbers of generations. Indeed, on evolutionary grounds the reverse appears more likely, especially if at some future stage in human history. a general deterioration in the abiotic environment occurs.

References [I] R.G. Cutler. Antioxidants. aging and longevity. In W.A. Pryor (cd.). Ftw Rtrdiccr/.s itt Biche,.. Vol. V. Academic Press. Orlando. 1984. pp. 371 428. [2] S.J. Olshansky, B.A. Carnes and C. Cassel. In search of Methuselah: estimating the upper limits to human longevity. S&we. -750 ( 1990) 634-640. [3] L. HayRick. Hatt. uw I+‘/~Fwr il,qe. Ballantine Books. Nev. York. lY94. p, 377. [4] AA. Hoffmann and P.A. Parsons, E~.~/uti~~~u~~~ Grnctw.~ corrl Grriwnrwnttrl S~w.s~. Oxford IJniversity Press. Oxford. 1991. p. 184. [5] T.C.R. White. The Itdeq~rc~t~ Etrrirottttwttt: jYirrogot wd rhe .~hrrtttlutwc~ of .4ttittdr, Springer-Vcrlag. Berlin, 1993. p. 425.

[6] B.L. Strehler

and A.S. Mildvan.

General

theory

of mortality

and aging.

Science.

132

( 1960) 14-21.

[7] M. Witten, A return to some possible roles for [8] P.A. Parsons, Habitats. [9] R.B. Huey. Physiological [IO] J.P. Phillips and A.J.

[ 1I] [I?]

[ 131 [I31

[ 151

[ 161 1171

[IQ

cells, systems. and aging: III Gompertrian models of biological aging and critical elements. hlr,ch. .d,q:ring Dcr.. i-7 ( 1985)I41 177. stress and evolutionary rates. J. Ecol. Biol.. 7 (1994) 387 3Y7. consequences of habitat selection. .jnl. :Vtr/.. li7 (1991) S91 Sl 15. Hilliker, Genetic analysis of oxygen defence mechanisms in Drovoph~l~r wdunognstrr. Adr. Gmrr., .?S ( 1990) 43 7 I. B.L. Strehlcr. Time. C&J um/ rfgirtg. 2nd edn.. Academic Press. New York, 1977. p. 356. R. Lestienne. On the thermodynamical and biological interpretation of the Gompertzian mortalit) rate distribution. Aleec,/~.,-!geing Drr.. 42 (1988) 197 214. P.A. Parsons. Inherited stress resistance and longevity: a strcsh theol-y of ageing. ffodit~~. S5 ( 1995) 216 121. P.A. Parsons, The importance and consequences of stress in Irving and fossil populations: firom life-history variation to evolutionary change. .-lr~l. .Yut.. 142(1993) S5-S20. A.I. Yashin and I. lachinr. How long can humans live? Lower bound for biological limit of human longevity calculated from Danish twin data using correlated frailty method. .~~cc,/I. .Jaeir~~ DCL ._ SO (1995) lJ7m 16’). L.S. Luckinbill and M.J. Glare, Selection for lift \pan in D~-o.r~~p/ri/~~ ,n~krrzoptr.trrr. Hvwdirl~. 55 ( 1985) 9-l s. Selection for adult desiccation resistance in D~-o.q~/t~k~ A.A. Hoirmann and P.A. Parsons. ,,le/~zn~,gcrst‘,r: fitness components. larval reslstancc and strc>s correlations. Bid. J. Liur~. Scu ._ -A? (1993) 43-54. M.R. Rose. L.N. Vu, S.U. Park and J.L. Graves Jr.. SelectIon on stress rchlstancr Increases longevity in Dmwphi/cr mrltrwgast~~r. M&learn, The many genetics

of aging.

Ewlutkm

.1

[19] G.E.

of’ Lorlgccit>~

BI .drzimnk:

E.\~J. Ger.ontcJ/..

27 ( 1092) 241

In A.D.

Couqxrvcrtic~c

250.

Woodhead and .-lpp~wc~h. Plenum.

K.H. Thompson (eds.). Ncu \r’ork. 1987. pp.

l35m 144. [10] J.W. Vaupel, Inherited frailty and longevity. Drnwpq~h~. 25 ( 1988) 277-187. [:I] D.E. Crews, Biological anthropology and human aging: some current directions in aging research. ..l/11211.Rc,t’. .Arlt/mpn/.. 2.2 ( 1993) 395-~423. [Z] A.R. Heydari. R. Takahashi, A. Gutsmann. S. \rou and .A RIchardson. Hsp 70 and aging. E\,/z,/ irniict. 3-O ( 1994) I092 1098. [Zi] K.J. Collins and A.M. Exton-Smith. Effects of ageing on human homeostasis. In A..H. Bittles and K.J. Collins (eds.). The Bicdqq of HWWII .-lgrirrg. Cambridge University Press. Cambridge. 1986. pp. 131 145. [24] P.A. Parsons, Fluctuating asymmetry: an epigenetic medsurc of stress. Biol. Rpr.. 6i (1’390) I31 145. [25] R. Thornhill. Fluctuatmg asymmetry and the mating system of the Japanese scorpionfly. Ptnlor/~r jc//mkr. Arriru. Brlra~.. 4J ( 1991) 867-879. [26] C.T. Naugler and S.M. Leech, Fluctuating asymmetry and survival ability in the forest tent caterpillar moth IZ/NI~~.O,\~~~~I(I dissrritr: implications for pest management. Et~tor~~ol. E.lp .-II~/I/.. 70 (19943 205m 298. [27] J.B. Mitton. Enzyme heterozygosity, metabolism. and developmental variability. Gc,rrc,ric,rr. 91) ( 1993) 47 63. [1X] R.K. Koehn and B.L. Bayne. Towards response. Bid. J. Limi. So< ., 37 (1989)

a physiological l57- 171.

and gcnetlcal

understanding

of the %tre)s

[19] R.S. Sohal. The rate of livmg theory: a contemporary interpretation. In K.G. Collatz and R.S. Sohal (eds.). blsecr &itlg. Springer-Verlag. Berlin. 1986. pp. 23 44. [30] R. .4rking. S. Buck. A. Berrios. S. Dwyer and G.T. Baker 111. Elrcated paraquat resistance can bc used as a bioassay for longevity in a genetically based long-lived strain of Drosopllila. D(,I-. Go~et.. 1-7 (1991, 362~~370. [i I] P.L. Larsen. SC,;. (‘S.-l.

Aging and resistance 90 (1993) 8905 -s909.

to oxidaticr

damage

in C’~r~~~r~~~/~~r/~~/iti,~ &~uK~.

PIW.

.\;c/r/. J~o~/.

[32] J.R. Vanfleteren, Oxidative stress and ageing in Caenorhabdiris r1qun.s. Biodwm. J.. .?Y+?(1993) 605-608. [33] W.C. Orr and R.S. Sohal, Extension of life-span by overexpression of superoxide dismutase and cat&se in Drosophih rdarrogustc/-. Sciencr, -763 ( 1994) I 128-l 130. [34] B..N. Ames, M.K. Shigenaga and T.M. Hagen. Oxidants, antioxidants. and the degenerative diseases of aging. Prw. Nat/. ,Icatl. Sci. USA, 90 (1993) 7915-7972. [35] C;.S. Roth. D.K. Ingram and M.A. Lane. Slowing ageing by caloric restriction. ,V&. .%I&., I (1995) 414-415. F. Moroni and F. Marcheaelli. Diet restriction: a tool to [76] C. Pieri. M. Falasca. R. Recchioni. prolong lifespan of experimental animals. Models and current hypotheses of action. C’o171p. BiO(.hL’I?I.P/IjXO/., 10311 (1992) 55 I -554. [37] J.M. Diamond and K.A. Hammond. Intestinal determinants of muscle performance. .4&. BioSc~i. 8-I (1992) 363-170. [%I G.C. Williams and R.M. Nessr. The dawn of Darwinian medicine. @tort. Rer. Bid.. 66 (1991) 391 D. Harman. The aging process. Proc,. Nail. .4&. Si. USA. 78 ( 198I ) 7124&71X. 401 T. Eakin and M. Witten, How square is the survival curve of a given species’? E.x~. Gerotz~ol.. 30 (1995) 33 64. 411 R. Frankham and D.A. Loebel. Modeling problems in conservation genetics using captive Dn>.sr#iiirt populations: rapid genetic adaptation to captivity. Z(X) Bioi.. Ii ( 1992) 333 342. 421 M.J. Kohane and P.A. Parsons, Domestication: evolutionary change under stress. Ewl. Bid.. -73 (1988) 31-48. 431 M.R. Rose, Ewhr~ionur~~ Biologic II/ Aging. Oxford University Press. Neu York, 1991. p. 221. [44] J. Langridge, Thermal responses of mutant enzymes and temperature limits to growth. :ZIo/. G<,!r. Grriet.. 103 (1968) 116~136. [45] T. Homyk, J. Szidonya and D.T. Suzuki, Behavioral mutants of Dmwphila rwlmopurer. III. isolation and mapping of mutations by direct visual observation of behavioral phenotypes. Alo/. G<,n. Gerrrt.. 177 (1980) 553 565. [46] A.S. Kondrashov and D. Houle. Genotype-environment interactions and the estimation of the genomic mutation rate in Drmuplrik~ rnelar~opster. Prw. R. SIJ~. LOIIL~N. Ser. B.. 258 ( 1994) 221 227.