Biogerontology1: 273–278, 2000.© 2000Kluwer Academic Publishers. Printed in the Netherlands.

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Opinion

Longevity and the immune response

Richard AspinallDepartment of Immunology, Imperial College of Science Technology and Medicine at Chelsea and WestminsterHospital, 369 Fulham Road, London SW10 9NH, UK (e-mail: r.aspinall@ic.ac.uk; fax: +44-208-746-5997)

Received 15 February 2000; accepted 22 February 2000

Key words:ageing, thymic atrophy, male, female, longevity

Abstract

The domino hypothesis of the onset of age associated immune insufficiency suggests that it is the consequence ofa cascade of events beginning with involution of the thymus. Involution is associated with a reduced thymic outputleading to fewer naïve T cells contributing to the peripheral T-cell pool. Homeostatic mechanisms, which maintainthe number of T cells in the peripheral pool within precise limits, induce the proliferation and prolong the survivalof resident T cells to fill the niches left vacant by the absent naïve T cells. In this hypothesis, falling thymicoutput would be matched by resident T-cell proliferation and with age these proliferating cells will reach theirreplicative limit. Their prolonged survival will lead to the accumulation of cells unable to replicate, producing adecline in immune function and a susceptibility to infection, or certain cancers. Comparison of gender differencesin life-span and rates of death in each age group due to infectious or parasitic disease suggests that the immunesystem in females works more efficiently and effectively for longer than the immune system in males. This leadsto the suggestion that involution of the thymus, and hence thymic output, occurs more rapidly in males than infemales.

The life history of the immune system

T cells which are the more recent products of thethymus enter the pool of T cells present in the bodyand circulate through the secondary lymphoid organsto improve their chances of meeting an antigen whichmatches their specific receptor. Activation of thesecells usually occurs once the antigen is met andrequires a number of steps including recognition of thespecific peptide antigen presented in the appropriateMHC molecule in conjunction with the necessaryco-stimulatory molecules. In a successful response,activation of these cells, termed antigen naïve T cellsleads to their clonal expansion and the generationof effector cells and the subsequent reduction in theamount and source of the antigen. This is then fol-lowed by a period of cell death since from this point onthe immune system no longer requires large numbersof T cells bearing that specific receptor. However somecells with this antigenic specificity remain to become

memory T cells and subsequently enter the memoryT cell pool. Repeated exposure of the immune sys-tem to the potential pathogen will be met by thesememory T cells and will lead to a response that ismore rapid and of greater magnitude than the responsefollowing the initial exposure. This immunologicalmemory provides the rational basis for protection byvaccination.

Since there are few completely sterile environ-ments, each of us is confronted on a daily basiswith different organisms, some of which could bepathogenic if we were not protected by our immunesystem. Change in environment will also bring changein the local organisms and so with time the numberof potential pathogens the immune system meets mustincrease. Provided these do not result in the death ofthe individual the responses should broaden the indi-viduals immunological memory and so increase thenumber of memory cells. Analysis of both mouse andman show this to be the case so that ageing is indeed

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Table 1. Deaths due to influenza or pneumonia in the years 1993–1995.

Cause of death Year Age range 25–45 Age range 65–85

Influenza 1993 9/439 (2%) 193/439 (44%)

1994 0/72 (0%) 31/72 (43%)

1995 7/227 (3%) 110/227 (48%)

Pneumonia 1993 488/54265 (1%) 24143/54265 (44%)

1994 506/48917 (1%) 21579/48917 (44%)

1995 544/54538 (1%) 23762/54538 (44%)

associated with an increase in the number of memoryT cells.

Observations on disease susceptibility with age

Extrapolating from the concept of immune memoryoutlined above, one could anticipate that the immuneresponse in aged individuals should be more efficientthan that found in younger individuals. This is not thecase. The elderly are more at risk from certain infec-tions than younger individuals. Examples for a viralinfection (influenza) and a bacterial infection (pneu-monia) are given in Table 1. The number of deathswithin a single year from either of these causes in a20 year age span from 25–45 is less than 3% of thetotal deaths for that year. If we look at another 20year age span, 40 years later, we find that more than40% of the deaths are contained within this population(age range 65–85). One of the implications from thisdata is that age related changes in the immune systemmay be a contributory factor to this increase in diseasesusceptibility. Further evidence for the immune sys-tem becoming less efficient in its function can be seenfrom the higher incidence of specific tumours with age(Office of National Statistics 1997).

Possible causes of the onset of immuneinsufficiency

The thymus is responsible for producing the majorityof T lymphocytes of the peripheral pool, at birth andas it atrophies its output drops considerably (Mackallet al. 1995; Scollay et al. 1980). This change in con-tribution to the T-cell pool is not matched by changesin the numbers of T cells in the body. T-cell numbersremain relatively stable, on the evidence from theirnumbers in the blood (Hulstaert et al. 1994; Hannet et

al. 1992) and constitute between 1–2% of the T cellsin the body. Such stability in total numbers could bemaintained by having very little turnover in the T-cellpool, but even in the normal healthy individual theperipheral T-cell pool is in a constant state of flux withexpansions and contractions of clonal populations. Ina competent immune system the kinetics in the peri-pheral tissue of cell production and loss are high, andso the maintenance of total number of T cells withintight boundaries in the absence of thymic input mustbe achieved either by preventing cell loss or by per-mitting the survival of cells which have responded toother antigens. This in effect is the maintenance ofT-cell numbers by the proliferation of antigen exper-ienced (memory) T cells to ‘fill the space’ left bythe reduced numbers of antigen inexperienced (naïve)T cells coming from the thymus. The consequence ofthis proliferation is that ageing of an individual wouldbe associated with the accumulation of memory cellsat or close to their replicative limit which are unable toreplicate enough to produce an effective clone size forefficient activation of the effector arm of the immunesystem. This premise is supported by studies fromseveral laboratories which show that there is an accu-mulation of T cells which respond less well, withinthe peripheral T-cell pool in mouse and man with age(Jackola et al. 1994; Witkowski et al. 1994; Muraskoet al. 1987; Aggrawal et al. 1997).

Longevity and the immune response

Susceptibility to infection from pathogens, which anormal immune system would cope with, dependsupon the presence of cells capable of making aresponse. There are several reports of where absenceof these cells (lymphopaenia) leads to overwhelminginfection (Margolick and Donnenberg 1997). Stud-

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ies have also been carried out on allophenic mice,produced from the aggregation of genotypically dis-tinct embryos from strains of different lifespan. Theallophenic mice with the longest life spans were theones which had the greatest percentage of lympho-cytes from the parental strain with the longer life-span (Warner et al. 1985). Studies analysing changesin T-cell subsets in peripheral blood showed that ingenetically heterogeneous mice the strongest immun-ological predictor of life span was the proportion ofCD4 memory cells measured at 18 months of agewith high levels of CD4 memory cell correlating toa shorter life-span (Miller et al. 1997). These studiesemphasise the need for an effective immune responsewith a prolonged life span.

An example of a sector of the population who haveaged successfully are those individuals who are 100years of age or greater. Analysis of the blood T cells ofcentenarians shows that there appears to be a declinein the absolute number of T cells within the peripheralT-cell pool, but this does not appear to be matched bya loss in any of the Vβ families which all appear to bepresent. Furthermore there appears to be no loss in theproliferative vigour of the T cells from these excep-tional individuals compared with younger individuals.This finding is unlike the results seen in other stud-ies using T cells from less elderly individuals (usuallyunder 85 years of age) where it is apparent that T cellsfrom these individuals do not reach the same peakof proliferation as T cells from young individuals. Itappears that the T cells of centenarians are fully cap-able of proliferating with the only difference betweenthese cells and those from younger individuals being ashort delay in reaching peak responsiveness (Sansoniet al. 1997; Franceschi et al. 1995).

An hypothesis for longevity and thymic function

The clonal exhaustion hypothesis of immunosenes-cence proposes that the age-related onset of immuneinsufficiency is related to the accumulation of cellswith the properties of senescent cells, being incap-able of further proliferation to an appropriate stimulus(Effros and Pawelec 1997; Pawelec et al. 1997).

It is not clear whether the immune insufficiencyis directly related to the inability of cells with thecorrect receptor specificity to proliferate or indirectlydue to some inhibitory effect generated by unrespon-sive T cells acting upon other T cells and preventingtheir normal proliferation (Dozmorov et al. 1995).

Whichever mechanism produces the immune insuffi-ciency, a key feature is the accumulation of T cellswhich are relatively unresponsive to normal stimuliwithin the peripheral T-cell pool. If this state of unre-sponsiveness is a property of a T-cell close to theend of its replicative life-span, and is reached becauseresidents in the peripheral T-cell pool are driven toproliferate by the homeostatic forces which maintainT-cell numbers, then thymic output is a crucial factorin the timing of onset of the state of immune insuffi-ciency. For example if there is rapid thymic atrophyearly in life due to nutritional deficiencies then theremay be a subsequent shortening of life-span (Mooreet al. 1997). Alternatively if thymic output is main-tained for longer this could provide a continued supplyof naïve T cells for the peripheral T-cell pool for alonger period, reducing the homeostatic driven rep-lication of memory T cells in the pool and delayingthe onset of accumulation of unresponsive T cells.Delayed accumulation of these cells should main-tain immune function for longer, which in turn couldprolong life-span.

From this one could hypothesise a direct correla-tion between thymic output and life-span; so slowerthymic atrophy, which would maintain thymic out-put higher for longer would in turn lead to a longerlife-span.

Males versus females

Analysis of life expectancy at birth from several coun-tries (Japan, USA, UK, Germany, Italy, Sweden,France) for individuals born during the 1990s revealsthat life-expectancy for females is greater than formales (Statistics and Information Department 1999)This gender related increase in life span is not restric-ted only to humans but also exists in anthropoid apes(Schwab et al. 1997). Because this gender relatedimprovement in life span does not appear to be relatedto beneficial local environmental factors or dietaryfactors it must be due to an intrinsic factor. The reasonoften cited for this difference is risk-taking behaviour.The usual explanation is that males involve themselvesin more risky behaviour than females and this accountsfor their earlier deaths. This is a well-trodden pathwith many anecdotal accounts. Risky behaviour is afavourite explanation because of its very pliability,being able to account for everything from gender dif-ferences in car deaths to gender differences in bowelcancer. Although differences in risk taking behaviourmay account for some of the differences in mortality

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Figure 1. Death rates in age defined groups from infectious andparasitic diseases (ICD 9 code 001–999) from the mortality statisticsprovided by the Office for National Statistics for England and Walesfor the years 1995–1997. The figures are for both males and females.

rates, risk avoidance by females cannot be the onlyreason for the additional longevity.

If we analyse the death rates from infectious andparasitic diseases (ICD 9 code 001–999) from the mor-tality statistics provided by the Office for NationalStatistics for England and Wales the years 1995–1997(Figure 1) we can see two peaks in the graphs. Thefirst peak occurs at the age group 35–44 and the secondpeak in the age group 75–84. Separation on the basisof gender (Figure 2) reveals that although both sexesmake almost equivalent contributions to the peak at

Figure 2. Death rates in age defined groups from infectious andparasitic diseases (ICD 9 code 001–999) from mortality statisticsprovided by the Office for National Statistics for England and Walesthe years 1995–1997. Deaths of males are represented by opensquares and for females by open triangles.

75–84 years of age, the overwhelming contribution tothe peak at 35–44 is made up of deaths in the malepopulation. Attempts to resolve this by considering itdue to deaths from diseases affecting more males thanfemales (e.g. AIDS during this period) fail to providea conclusive answer. Since these are deaths due toinfectious or parasitic disease a more likely possibilityis that the increased deaths in males may be related

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to a reduced efficiency of functioning of the immunesystem in males.

Results from studies on the rate of thymic invol-ution according to gender has always proved con-troversial. Analysis of thymic atrophy in the mouseand man reveals that the rate of loss of active thymictissue is greatest towards the mid-life period (by 12months of age in C57BL/10 mice and 30–40 years ofage in humans) after which the rate of decline is lessapparent (Aspinall 1997; Bertho et al. 1997). In thehuman study quoted the analysis was done on tissuefrom both sexes but the murine study only used malemice. Differences in the rate of human thymic involu-tion between males and females has been describedpreviously based on an approach using histologicalanalysis (Smith and Ossa Gomez 1981; Simpson et al.1975) although these descriptions have been contested(Steinmann 1986) they have recently been supportedby a study in mice (Aspinall and Andrew 2000). Thislatter study suggested that in C57BL/10 animals thethymus appeared to atrophy faster in males than infemales and that the rate of atrophy was not due todifferences in the number of early T-cell precursors.The results suggested that the difference was foundat the level of the CD4+CD8+ immature thymocytewith more of these found in females than in males.The suggestion from these studies was that since thiswas the stage at which the TCRα chain was chosento join with the TCRβ chain then not only would theoutput of the female thymus be greater but also thatthe breadth of the repertoire would also be larger infemales than males. These studies, which are currentlybeing carried out in humans where the preliminarydata supports the results seen in mice (Pido and Aspin-all, manuscript in preparation), provide some evidencethat gender related difference in thymic output maybe a contributory cause to the gender differences seenwith longevity.

Interventionist therapy

If the hypothesis is correct then any therapy whichcould improve the functioning of the immune systemcould in the first instance prolong life (by reducingdeaths due to specific infections or cancers) for someindividuals. In addition to increasing life-span (aneffect more likely to show up in males rather thanfemales) there should also be an improvement in thequality of life (as a result of a reduced incidence ofinfection). One of the major questions for an approach

to an interventionist therapy would be where to directthis therapy. Clearly if immune insufficiency arisesfrom an accumulation of cells at or close to theirreplicative limit then the targets have to be to either(i) replace these almost unresponsive cells with cells atan earlier stage of their life-span (i.e. new naïve T cellsfrom the thymus) or (ii) to extend the replicative limitof those cells already in the peripheral T-cell pool.Potential agents which can extend replicative life-spanwithout inducing immortality or tumourgenic proper-ties in the target cell are rare and at early stages ofdevelopment. A more likely interventionist approachwould be to reverse the age-associated thymic invol-ution and induce renewed thymopoeisis to providenew T cells for the peripheral T-cell pool through-out life at an unvarying rate. Experimental evidencehas already provided some support for this concept(Hirokawa and Utsuyama 1984). However a feasibletherapeutic strategy require the determination of whatis the cause of age-associated thymic atrophy. One cur-rent hypothesis is that this atrophy is due a deficiencyin available Interleukin 7 (Aspinall 1997; Aspinall andAndrew 2000) and that the provision of Interleukin 7can reverse this atrophy (Aspinall and Andrew 1999).The identification of a therapy which could reverse theatrophy seen in the thymus and renew thymopoiesiscould prevent the onset of immune insufficiency seenin the elderly population and in also may be of benefitto those individuals rendered T-cell lymphopaenic byeither disease or as a product of another therapeuticregimen.

Acknowledgements

The author would like to thank Professor FrancesGotch and Dr Nesrina Imami for fruitful discussionsand reading this manuscript. Work by the author issupported by a grant from the Wellcome Trust (GrantNumber 051541).

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