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Measuring the human ageing rate
Mechanisms of Ageing and Development Elsevier Sequoia S.A., Lausanne - Printed in The Netherlands
MEASURING THE HUMAN AGEING RATE
ALEX COMFORT Director of Research, Gerontology, University College, London (Great Britain) (Received February 24th, 1972)
" T h e concept of measuring ageing biologically rather than chronologically is of enormous general interest, of importance in industry, and indeed in all areas of human endeavour, but has received relatively little attention from medical scientists." (Hollingsworth et al.1). It was, in fact, an early and highly unfruitful concern of savants calculs such as du Nouy. But for a proper account of ageing it has so far been necessary to insist on the force of mortality as the sole generally applicable criterion, in the absence of any definite information about the nature and identity of the "clock". A new attempt to work out battery tests of human physiological age is now overdue. It is justified by experimental necessity. Agents are known which seem to prolong the life-span of rats and m i c e - - o n e (dietary restriction) has been known for over 30 years. It is highly probable that some of these would affect human life-span if they could be tested briefly and ethically. That we can now think in terms of human experiment is due to the large recent increase in information from longitudinal and cross-sectional sample studies on time-dependent variables in man, the availability of computers and of automated clinical chemistry, and the application (e.g. by Gitman 2) to routine screening tests. Experimental gerontology may well prove the medical growth stock of the next decade, and its philosophy requires brief restatement. Ageing is the process, or group of processes, which cause the eventual breakdown of mammalian homoeostasis with the passage of time. The timing of these processes, although it shows some genetic scatter, is uncommonly stable. It is the universal experience of man that while we may die sooner from single causes, between 70 and 90 years of age homoeostasis declines "across the board", causes of sickness accumulate, and causes of death become multiple. Between 65 and 70, the average number of unrelated lesions per individual at necropsy is 5.71 ; by 80-85 years it has risen to 8.42 (Howell3). We require a battery of tests by which rates of ageing could be examined in treated and untreated humans in a study of feasible size. For this purpose the variables chosen must: (1) Be sufficiently diverse and unrelated to any single assumed process for it Mech. Age. Dev., 1 (1972) 101-110
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to be highly likely that a manoeuvre which is found to stabilize all of them will aIso affect the rate of actuarial ageing; (2) Correlate closely with chronological age, either directly or in a simple transformation; (3) Change sufficiently, and sufficiently regularly, with age for us to expect significant differences over a 3-5 year run at the selected age of test; and (4) Be measurable in volunteers without unacceptable hazard, discomfort, labour, or expense. Age-dependent variables in man show three main patterns of change. In one large group, change is greatest between infancy and adulthood and negligible thereafter. It was this group which prompted repeated statements by 20th-century biophilosophers that "the rate of ageing is highest in infancy". This saying indicates the limits of their usefulness as alternative indices to mortality. Others exhibit peaking (blood cholesterol) or are suspect by reason of covert selection (blood pressure). Of the serviceable variables, we select from those which are arithlinear with age, regardless of sign, and those which are Gompertzian or log-linear with age, paralleling the force of mortality. Mortality itself is lowest at around 12 years, but by reason of the large dispersion at low ages when the function is inverted to read off chronological age from the other variables, rather than vice versa, useful curves are best taken from an arbitrary origin about 40 years (i.e. from the end of the plateau of adult vigour rather than from the low point of the Gompertz curve). Other indices which are more consistently linear (e.g. collagen contractility) are therefore best adapted to the same arbitrary origin, and the test-period set between 40 and 70 years. The ideal battery accordingly measures what happens at the point of maximal change, and after the end of the period of adult vigour. The function(s) fit better with Teissier's convention 4 than with the conventional Gompertz-Makeham function giving / z x = e a(x b ) ; x > b rather than #x =/-toe at -~- A b representing the duration of the "plateau" as seen in small population samples. The samples will in any case be small by actuarial standards. In fact, however, the postulated origin at about 40 years corresponds roughly with the origin of the linear part of the Gompertz curve allowing for the irregularity seen in real human mortality curves at earlier ages. The study should in any case be set for choice at age 50-55 or age 60-65 where mortality will be significant and the rate of change in log mensurables large. The battery is based on that described by Hollingsworth et al. 1 which was designed to measure rate of ageing in Hiroshima survivors, from studies of about 450 Japanese. Here nine functions selected from seventeen functions examined gave a correlation with age of nearly 0.90. Compared with other attempts (e.g. Ciuca and Jucovski 5) which lean heavily on clinical impressions, this study appears the best available starting-point. It can, however, be expanded considerably in both number and variety of indices. (Davis and Hargen6; ConradT; Beier et al.S; Parot et alP; 102
Mech. Age. Dev., 1 (1972) 101-110
Bourli~rel°; Ciuca and Jucovskin; Bocher and Heemskerk12). For our objective, viz. leap-frogging dog or primate studies and testing non-hazardous procedures directly on man, the most numerous and available primate, as well as the beneficiary in view, we require a test-procedure of realistic size and duration, comparable, for example, to dietary studies or clinical trials on a single lesion. This means, in effect, a procedure giving reasonable expectation of significance for between 100 and 500 subjects including controls, with the probability of having to settle for the smaller number. The same battery could be used both for gerontological work and for environmental or radiation studies (which are now, in man, both contradictory and necessarily retrospective). Experience gained here, even if the tested agent proves inactive and both series are pooled as controls, will be invaluable in the next 10-20 years if repbrted influences on human longevity multiply. TEST BATTERY For initial use, the test age should be 50 years and the sample should be confined to males to avoid further statistical breakdown and complications associated with differences in age of menopause, which affects some variables. Available test-procedures fall into three groups: straightforward (anthropometry, clinical and chemical examination, sensory tests, psychometric tests), those requiring, for example, biopsy, and those depending on the fact that deaths will occur in the test samples. The "straightforward" groups might be modelled on the procedure used for clinical screening by Gitman 2, based on a flow-type centre using lay staff; the psychometric test should be automated, probably by means of the machine devised by Gedye and WedgwoodlL The inclusion or exclusion of biopsy procedures would be a matter for a policy decision. The draft (see Table I) includes four possible tests requiring live tissue-fibroblast clone duration, culture latency period, thigh-skin melanocyte count, and wound healing. Collagen testing is barely feasible in man except at necropsy, and is covered in part by other measurements (skin elasticity, vascular state, blood elastase). Lymphocyte R N A : D N A ratio (Sakai et al. 14) and leucocyte chromosome count are in theory derivable from a blood sample, though there is evidence that, for the second of these, sternal puncture would be preferable (Chlebovsky et al.15). On grounds of labour most of these more elaborate, though theoretically important, tests would probably have to be limited to 1/5 or 1/10 of the sample. Mortality would be expected in a 50-year-old sample. For U.S. or U.K. White males we would expect thirty deaths between 50 and 55, and about fifty between 60 and 65 for a sample, n, of 500 lives (i.e. too few for significance if the sample were any smaller, but enough to give some necropsies). A full legal-consent and pathological programme should be written in, however, to secure these. Necropsybased measurements would include cause of death, number of lesions present, lipofuscin, collagen, cell counts, presence of amyloid and atheroma, and organ weight. In Hollingsworth's series of seventeen tests, the highest age-correlations were for characters (hair graying, skin elasticity) which contribute most to the "clinical Mech. Age. Dev., 1 (1972) 101-110
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TABLE I D R A F T TEST BATTERY FOR PHYSIOLOGICAL AGE IN MAN a, selected for Hollingsworth battery; b, included in Gitman inventory; c, biopsy dependent; d, necropsy dependent; r, coefficient of correlation. Test
Hair-graying score Skin elasticity
a,b
Systolic blood pressure
b b b a,b
Diastolic blood pressure Heart size Thorax size Total vital capacity
b b
Tidal volume One-second expiratory volume
a a a a,b b
Hand-grip strength Light extinction test Vibrometer Visual acuity Audiometry, 200 cps
a,b
Audiometry, 4000 cps
a,b
Serum cholesterol
b
Total serum albumin
b
Albumin: globulin ratio
b b
b b b
c
Plasma water Mean venous pressure Protein-bound iodine Enzyme induction rate Serum copper Serum elastase Serum ribonuclease Nail Ca content Stature Seated stature Trunk height Biacromial diameter Metacarpal osteoporotic index Lean body mass Lymphocyte R N A : D N A ratio Explant latency
Serum growth promotion
104
References
r
Hollingsworth e t al. 1 Hollingsworth e t al. 1 Robertson e t al. 4° Anderson 41 Grahame and Holt '~2 Hollingsworth e t al. 1 Pflanz and Torok 43 Hollingsworth e t al. 1 Hollingsworth e t al. 1 Hollingsworth e t al. 1 Hollingsworth e t al. 1 Rosenzweig e t al. 44 Hollingsworth e t al. 1 Hollingsworth e t al. 1 Rosenzweig e t al. 44 Hollingsworth e t al),'~5 Hollingsworth e t a 1 2 Hollingsworth e t al. ~ Hollingsworth e t al. 1 Hollingsworth e t al. 1 Jalavisto 46 Hollingsworth e t al. 1 Jalavisto 46 Hollingsworth e t al. ~ Libow z5 Keys3~ Hollingsworth e t al. I Wagner 47 Burger 2z Wagner 47 Hall4S Burger 21 Libow 35 Adelman49,5o Barman 22 Hall51 Sved e t al. ~2 Mattei e t al. zo ParotZS; Dequeker e t al. 53 Parot 25 Parot 2~ Parot z5 Dequeker e t al. 53 Forbes and Reina ~4 Sakai e t al. 14 Medawar55; Soukupov~, e t a/.56,sv; Waters and Walford 5s; Heine and Parchwitz59 Carrel and Ebeling6°; Baker and Carrel 61 Mech.
Age. Dev.,
0.717 0.604
0.519 0.409 0.294 --0.124 --0.402
--0.126 --0.323 0.488 0.537 --0.432 0.445 0.596 0,234
--0.267
0.33
--0.532 --0.53 --0.34 --0.40 --0.786
1 (1972) 101-110
TABLE I (continued) Test
References
c
Biopsy healing and contraction
c
Clonal further viability
Howes and Harvey62; Billingham and Russel6a; Landag164 Hayflick65; Hay and Strehler~6; Hay et a/.67; Martin et al. 68 Jacobs et al.69; Goodman et al. 7° Hildemann and Walford28; Makinodan and Peterson ~4 Snell and Bischitz17; Fitzpatrick et a1.18; Walsh 19 Gedye and Wedgwoodla; Jarvik and Falek26; LibowaS; Jalavisto 46
Leucocyte aneuploidy Autoantibody titres c
Skin melanocyte count W.A.I.S.* tests (automated set) similarities digit span vocabulary digit symbol block design digit copying tapping test Reaction time, ruler test Reaction time, light Flicker-fusion frequency Taste sensitivity Total 5-year mortality Organ weights Disease specific mortality Tumour incidence, living Tumour incidence, necropsy Arterial pathology Amyloidosis, stain Cartilage H20 content Lipofuscin amount Aortic calcium Collagen contractility Collagen, fluorescence
Jalavisto 4~ Jalavisto 4~ Jalavisto 46 Hughes 71 -Tauchi7~ -----Bihari-Varga and Bir673 Strehler et al. 74 Lansing et a/.75; Burger 21 -LaBella and Paul 76
r
--0.44 0.48 0.35 --0.48 ---
----
-
---
* Wechsler adult intelligence scale. impression" o f age, a n d eleven out o f seventeen overlap G i t m a n ' s test battery. Hair graying was excluded from the final H i r o s h i m a series because o f difficulty in q u a n t i fication. Various ways o f estimating it have b e e n suggested (Hollingsworth et al.16): percentage gray hairs per axilla and, if skin biopsy were done, skin, melanocyte conc e n t r a t i o n might prove a n alternative (Snell a n d Bischitz17; Fitzpatrick et al.18; Walsh19). Besides the H o l l i n g s w o r t h - G i t m a n series, a n u m b e r o f additional tests are suggested in Table I either because they are easy, even if poorly correlated with age ( a n t h r o p o m e t r y ) , or because they are evidence of things n o t seen (nail calcium accum u l a t i o n , which parallels aortic calcification in time (Mattei et al.2°; Burger21)) or because, t h o u g h speculative, they are theoretically i m p o r t a n t (blood copper c o n t e n t (Harman22), b l o o d elastase, a u t o a n t i b o d i e s ( H i l d e m a n n a n d Walford2a; M a k i n o d a n a n d Peterson24)). These are chosen o n the basis of the most accessible measure, e.g. Mech. Age. Dev., 1 (1972) 101-110
]05
skin elasticity rather than skin collagen properties, nail calcium rather than aortic calcium. Anthropometric age measures are worth confirming, and give little trouble. The most promising seem to be seated stature, trunk height, and biacromial diameter (Parot 25) though the change is greatest in females and is less than one standard deviation over the interval 50-85 years. Psychometric tests are highly important; several (vocabulary, digit symbol, similarity, block designs, digits forward and backward, and tapping tests) correlate with five-year survival (Jarvik and Falek 26) as well as with chromosome error accumulation (Jarvik et a1.27). Others (serial choice task performance) seem to correlate with cardiovascular status (Szafran2S; Spieth 20) though at a low level of significance. Psychometric changes may reflect both normal ageing and subclinical disease (Davies30). It would be valuable to extend our knowledge of these correlations. Automation of the Wechsler adult intelligence scale test battery should be feasible (Gedye and Wedgwood13; Schonfield and Robertson31). Sensory tests (audiometry, flicker-fusion frequency, optometry), though time-consuming, are also essential. It should in theory be possible to measure homoeostatic failure directly by measuring variance (Storer3~), but this has pitfalls arising from the ageing organism's capacity for improvisation, as well as from the selection exercised at high ages by mortality itself(ComfortZa), though it may shortly be possible to measure, for example, the proportion of misspecified enzyme in certain systems (Gershon and Gershon34), and new measures of this kind may well multiply over the next 5-10 years. The Gitman battery has a statistical advantage in that it can show not only whether the observed values are in the normal range, but also the trend of readings in the individual at reexamination. It was designed as a clinical screen, not as a measure of ageing, but includes a great many indices which have been independently standardized against age, albeit in a small sample only (n -- 47) (LibowZ5). Serum-cholesterol is an unsuitable direct measure of ageing since it commonly rises until the age of 50 and falls thereafter (Keys36), and the results in different studies have been discrepant (Libow35; Nowlin et al.37). Of the other age-related variables in Libow's paper (Libow a5; Nowlin et al. 37) serum albumin (r = --0.267) declines, and protein-bound iodine (r z --0.33), maximal breathing capacity (r -- --0.43) and vital capacity (r = --0.50) correlate with age at levels approaching those selected by Hollingsworth et al. 1. PROCEDURE The battery is designed, essentially, to test any non-hazardous agent or manoeuvre which might be offered as being likely to affect the ageing clock. The feasible size of an ageing study depends on the number of.available volunteers, and on the procedure (diet, injections, or additives) required in the treated group. Recruitment of volunteers would normally be from a large employer, a closed group (monks, prisoners, pensioners), or from a profession (physicians, academics, Government employees). Administration and supervision of treatments cannot be discussed in vacuo. The most likely agents for trial within the next 5-10 years would appear to be diets, antioxidants, and possibly anticaloric or anti-crosslinking drugs. 106
Mech. Age. Dev., 1 (1972) 101-110
All these create problems of supervision and continuity, and English society provides few healthy closed communities from which volunteers could be recruited; some of the major difficulties of long-term diet experiments were well illustrated by a recent Veterans Administration trial on cholesterol and atheroma (Dayton et al.SS). This type of experiment does, however, provide a practical and ethical model. Had these investigators, moreover, had access to the kind of test battery I am suggesting, important information about potential free-radical effects in accelerating certain age indices might conceivably have been obtained as a by-product of the main study (Harman39). Antioxidant trials seem feasible, although the dose levels would be heroic by comparison with current permitted use in foodstuffs (a full and frequent review of haematology and side-effects would in this case be needed, multiplying the number of attendances and involving a complete health-check battery in addition to the running measurements). Substances which we already ingest have their attractions for trial purposes, but the known safety of, for example, tert.-butylhydroxytoluene as a food additive could be more than offset by the risk of sensitization to most process foods, for which the volunteer would not thank us. It might in this case be wiser to use a low-toxicity antioxidant not already widespread in groceries. Naturally occurring antioxidants might well be tested in this way (tocopherols, ubiquinones, - S H donors). Physicians are a potential source of volunteers: they might in theory be self-policing, and they would certainly be capable of giving themselves a parenteral agent, if one such were available for trial. Choice of a 50- or 60-year baseline makes the problem of a controlled population of willing volunteers more complex by excluding students or soldiers, for example, but it must be part of the philosophy of attempts at age control that we should aim, initially at least, at the possibility of a late-acting agent, so as to reduce the total span of treatment required. This may, of course, prove impossible. Nor may it be possible (or desirable) to run even a superficially harmless procedure, such as the use of low-calorie foods, without a separate and frequent "toxicity" assessment; it might, indeed, have been wise and profitable to include one in the dietary cholesterol studies already cited (Dayton et al.3S). Viewed purely as an ageing test the model requires annual or twiceyearly attendance, depending on numbers, at a clinical centre, which will also provide records storage, a secretariat, and a manned telephone to give appointments. A small sample (n : 100) could be dealt with surgery fashion, by hand. It seems preferable, however, to aim at a Gitman-type flow system set up, for example, in an empty ward, with patients admitted in batches of 4, and with all tests requiring more than 5 minutes (e.g. audiometry and ECG) duplicated. While it may be necessary to limit the tests strictly to those required by the study, there is a case for giving the full Gitman screening battery so as to provide a periodic check-up as a direct incentive to volunteers, with a physician present to answer questions and deal with anxieties. The clinically relevant parts of the print-out should be sent to the volunteer's physician. PAY-OFF Testing of specific agents apart, the creation of an "ageing assessment unit"
Mech. Age. Dev., I (1972) 101-110
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in G r e a t Britain, t h o u g h n o t cheap, is likely to be a r e w a r d i n g investment. It will a l m o s t certainly be needed some t i m e before 1980 if clinical trials o f possible a p p r o a ches to the slowing o f the ageing clock a r e n o t to be confined to rats o r to patients in o t h e r countries. Tests o f this kind a r e a l r e a d y in p r e p a r a t i o n in the U.S. I f the a g e n t o r p r o c e d u r e first chosen for test proves wholly inactive, the results will still be o f p r i m e i m p o r t a n c e as a test-run o f the p a r a m e t e r s chosen, the a d m i n istrative structure, a n d the c o o p e r a t i o n o f physicians and volunteers. W e need to find out how to d o this kind o f e x p e r i m e n t , and the " k n o w - h o w " o b t a i n e d could well be a p r i m e tool in the e x p e r i m e n t a l medicine o f the 1980's, as well as in the assessment o f diets, e n v i r o n m e n t a l h a z a r d s and r a d i a t i o n effects. It is an interesting t h o u g h t t h a t acceleration (or delay) in the process o f ageing, which would affect the age o f onset o f all diseases, n o t the frequency o f one, is a perfectly possible side-effect o f drugs o r e n v i r o n m e n t a l factors now current. It would also be, at present, undetectable unless gross e n o u g h to influence the life table for the whole p o p u l a t i o n , a n d then only inferentially a n d in retrospect. A n ageing b a t t e r y w o u l d bring this kind o f effect within the scope o f i m m e d i a t e detection. T h e G i t m a n - t y p e clinical screening centre is a possible tool for future g r o u p practice a n d health service use. W h e t h e r clinical screening is economically effective as a means o f early diagnosis is still questionable; b u t if it is, we require experience with it. This would be o b t a i n a b l e w i t h o u t a d d i t i o n a l cost as a b y - p r o d u c t o f the kind o f ageing study here p r o p o s e d , a n d might r e n d e r the investment a c c e p t a b l e while the i m p o r t a n c e o f rate-modification in the preventive medicine o f the future is being realised by the scientific c o m m u n i t y . REFERENCES 1 J. W. Hollingsworth, A. Hashizume and S. Hablon, Correlations between tests of aging in Hiroshima subjects: An attempt to define "physiologic age", Yale J. Biol. Med., 38 (1965) 11-26. 2 L. Gitman, Multiphasic Health Screening Center Manual, Brookdale Hospital Center, N.Y., 1969. 3 T. Howell, Multiple pathology in a septuagenarian, J. Am. Geriatr. Soc., 16 (1968) 760-762. 4 G. Teissier, Recherches sur le vieillissement et sur les lois de la mortalit6, Ann. Physiol. Phys.Chim. Biol., I0 (1934) 260-284. 5 A. Ciuca and V. Jukovski, Recherches concernant la d6termination de "L'fige biologique moyen", Riv. Esp. Gerontol., 4 (1969) 97-116. 6 R. L. Davis and S. M. Hargen, Biomedical studies of different aging populations, Gerontologbt, 10 (1970) 31-33. 7 R. A. Conrad, An attempt to quantify some clinical criteria of aging, J. Gerontol., 15 (1960) 358-365. 8 W. Beier, K. H. Brehmer and D. Wiegel, Eine M6glichkeit zur Ermittelung des wahrscheinlichen biologischen Alters, Z. Alternsforsch., 24 (1971) 77-78. 9 S. Parot, E. Jacquemin and J. Poitrenaud, La capacit6 des sujets fig6s et tr6s-fig6s, J. Physiol. (Paris), 61 (1969) 265-276. 10 F. Bourli6re, Les m6thodes de mesure de l'fige biologique de l'homme, Cah. Santd Publ. 37, Geneva, W.H.O., 1969. 11 A. Ciuca and V. Jucovski, Studium fiber Alterswandel der somatophysiometrischen Indikatoren, Z. Gerontol., 3 (1970) 133-230. 12 W. Bocher and J. J. Heemskerk, Zur Problematik des funktionalen Alters, Z. Gerontol., 2 (1969) 339-349. 13 J.L. Gedye and J. Wedgwood, The use of an interactive computer terminal for assessing the mental state of geriatric patients, Abstr. Proc. 8th Int. Congr. Gerontol. (Washington), 1969. 108
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14 H. Sakai, E. Kato, S. Matsuki and S. Asano, Age and lymphocyte nucleic acids, Lancet, i (1968) 818-819. 15 O. Chlebovsky, M. Praslica and J. Horak, Chromosome aberrations - - increased incidence in bone marrow of continuously irradiated rats, Science, 153 (1966) 195-196. 16 J. W. Hollingsworth, G. Ishi and R. A. Conrad, Skin aging and hair graying in Hiroshima, Geriatrics, 16 (1961) 27-36. 17 R. S. Snell and P. G. Bischitz, The melanocytes and melanin in human abdominal wall skin, J. Anat., 97 (1963) 361-376. 18 T. B. Fitzpatrick, G. Szabo and R. E. Mitchell, Age changes in the human melanocyte system, Adv. Biol. Skin, 6 (1964) 35-50. 19 R. J. Walsh, Variations in the melanin content of the skin of New Guinea natives at different ages, J. Invest. Dermatol., 42 (1964) 261-265. 20 C. Mattei, P. A. Cognasso and M. Torazzo-Gazzera, Sul contenuto in calcio delle unghie nelle varies eta dell'uomo, Giorn. Gerontol., 3 (1955) 511-517. 21 M. Burger, Altern und Krankheit, Georg Thieme Verlag, Leipzig, 1954. 22 D. Harman, The free radical theory of aging: Effects of age on serum copper levels, J. Gerontol., 20 (1965) 151-154. 23 W. H. Hildemann and R. L. Walford, Autoimmunity in relation to aging as measured by the agar plaque technique, Proc. Soc. Exp. Biol. Med., 123 (1966) 417-421. 24 T. Makinodan and W. J. Peterson, Secondary antibody forming potential of mice in relation to age, Dev. Biol., 14 (1966) 96-111. 25 S. Parot, Recherches sur la biomrtrie du vieillissement humain, Bull. Soc. Anthropol., 2 (1959) 299-341. 26 L. J. Jarvik and A. Falek, Intellectual stability and survival in the aged, J. Gerontol., 18 (1963) 173-176. 27 L. J. Jarvik, J. E. Blum and T. Kato, Chromosomal changes and psychometric scores, Abstr. Proc. 8th Int. Congr. Gerontol. (Washington), 1969. 28 J. Szafian, Age differences in sequential decisions and cardiovascular status among pilots, Aerospace Med., 36 (1965) 303-310. 29 W. E. Spieth, in A. T. Welford and J. F. Birren (Eds.), Behavior, Aging and the Nervous System, C. C. Thomas, Springfield, Ill., 1965, p. 366. 30 A. D. M. Davies, in S. S. Chown and K. F. Rieyel (Eds.), Interdisciplinary Topics in Gerontology, Vol. 1, Karger, Basle, 1968, p. 78. 31 D. Schonfield and E. A. Robertson, The coding and sorting of digits by an elderly sample, J. Gerontol., 23 (1968) 318-323. 32 J. B. Storer, in A. M. Brues and G. A. Sacher (Eds.), Aging andLevels of Biological Organization, Chicago, 1965, p. 192. 33 A. Comfort, Test battery to measure ageing rate in Man, Lancet, ii (1969) 1411-1415. 34 H. Gershon and D. Gershon, Detection of inactive enzyme molecules in aging of the organism, Nature (Lond.), 227 (1970) 1214-1217. 35 L. S. Libow, in J. E. Birren, R. N. Butler, S. W. Greenhouse, L. Sokoloff and M. R. Yarrow (Eds.), Human Aging, a Behavioral and Biological Study, Bethesda, 1963, p. 37. 36 A. Keys, The age trend of serum concentration of cholesterol and of Sf 10-20 ( " G " ) substances in rats, J. Gerontol., 7 (1952) 201-206. 37 J. B. Nowtin, C. Eisdorfer and E. Bates, A longitudinal appraisal of serum cholesterol in a geriatric population, Abstr. Proc. 8th Int. Congr. Gerontol. (Washington), 1969. 38 S. Dayton, M. L. Pearce, S. Hashimoto, W.J. Dixon and U. Tomiyasu, Am. Heart Assoc. Monogr., 25 (1969). 39 D. Harman, Free-radical theory of aging: Effect of amount and degree of unsaturation of dietary fat on mortality rate, J. Gerontol., 26 (1971) 451-456. 40 E. G. Robertson, H. E. Lewis, W. Z. Billewicz and I. N. Foggett, Two devices for quantifying the rate of deformation of skin and subcutaneous tissue, J. Lab. Clin. Med., 73 (1969) 594-602. 41 R. E. Anderson, Aging in Hiroshima atomic bomb survivors, Arch. Pathol., 79 (1965) 1-6. 42 R. Grahame and P. J. L. Holt, The influence of aging on the in vivo elasticity of human skin, Gerontologia, 15 (1969) 121-139. 43 M. Pflanz and M. Torok, Steigt der Blutdruck mit dem Alter an?, Z. Gerontol., 2 (1969) 156-167. 44 D. Y. Rosenzweig, J. A. Arkins and L. G. Schrock, Ventilation studies on a normal population after a 7-year interval, Am. Rev. Resp. Dis., 94 (1966) 74-78.
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45 D. R. Hollingsworth, J. W. Hollingsworth, S. Bogitch and R. J. Keelin, Neuromuscular tests of aging in Hiroshima survivors, J. Gerontol., 24 (1969) 276-283. 46 E. Jalavisto, in A. T. Welford and J. F. Birren (Eds.), Behavior, Aging and the Nervous System, C. C. Thomas, Springfield, I11., 1965, p. 353. 47 E. Wagner, Die physiologischen klinischen Laboratoriumswerte in Alter, Actuelle Gerontol., 9 (1971) 531-538. 48 D. A. Hall, Age changes in the water content of human plasma, Gerontol. Clin., 10 (1968) 193-200. 49 R. C. Adelman, A biochemical parameter of aging, Gerontologist, 10 (1970) 24. 50 R. C. Adelman, Reappraisal of biological aging, Nature (Lond.), 228 (1970) 1095. 51 D. A. Hall, Elastase and the aging subject, Abstr. Proc. 7th Int. Congr. Gerontol. (Vienna), 1966. 52 S. Sved, V. A. Kral, H. E. Enesco, L. Solyom, B. T. Wigdor and S. M. Mauer, Memory and serum ribonuclease activity in the aged, J. Am. Geriatr. Soc., 15 (1967) 629-639. 53 J. V. Dequecker, J. P. Baeyens and J. V. Claessens, The significance of stature as a clinical measurement of aging, J. Am. Geriatr. Sot., 17 (1969) 169-179. 54 G. B. Forbes and J. C, Reina, Adult lean body mass declines with age: Some longitudinal observations, Metabolism, 19 (1970) 653-663. 55 P. B. Medawar, The growth, growth-energy and ageing of the chicken's heart, Proc. Roy. Soc. B, 129 (1940) 332-340. 56 M. Soukupovfi. and E. Hole6kovfi, The latent period of explanted organs of newborn adult and senile rats, Exp. Cell Res., 33 (1964) 361-367. 57 M. Soukupovfi, E. Hole6kovfi and O. Cinnerovfi, Behaviour ofexplanted kidney cells from young, adult and old rats, Gerontologia, 11 (1965) 141-152. 58 H. Waters and R. L. Walford, Latent period for outgrowth of human skin explants as a function of age, J. Gerontol., 25 (1970) 381-383. 59 U. I. Heine and E. Parchwitz, Explantationsversuche am Herzen und an den Haut vershieden alter M/iuse, Arch. Geschwulstforsch., 11 (1957) 111-114. 60 A. Carrel and A. H. Ebeling, Antagonistic growth principles of serum and their relation to old age, J. Exp. Med., 38 (1921) 419~425. 61 L. Baker and A. Carrel, Au sujet du pouvoir inhibiteur du s6rum pendant la vieillesse, C. R. Soc. Biol., 95 (1926) 958. 62 E. L. Howes and S. C. Harvey, The age factor in the velocity of the growth of fibroblasts in the healing wound, J. Exp. Med., 55 (1932) 577-590. 63 R. E. Billingham and P. S. Russel, Studies on wound healing with special reference to the phenomenon of contracture in experimental wounds in rabbits' skin, Ann. Surg., 144 (1956) 961-981. 64 H. D. Landahl, in J. E. Birren (Ed.), Handbook of Aging and the Individual, Chicago, 1959, p. 81. 65 L. Hayflick, The limited in vitro lifetime of human diploid strains, E~xp. Cell Res., 37 (1965) 614-636. 66 R. J. Hay and B. L. Strehler, Cell and tissue culture in aging research, Adv. Gerontol. Res., 2 (1967) 121-158. 67 R. J. Hay, R. A. Menzies, H. P. Morgan and B. L. Strehler, The division potential of cells in continuous growth, Exp. Gerontol., 3 (1968) 35-44. 68 G. M. Martin, C. A. Sprague and C. J. Epstein, Replicative lifespan of human cultured cells, Lab. Invest., 22 (1970) 86-91. 69 P. A. Jacobs, M. Brunton, W. M. Court Brown, R. Doll and J. Goldstein, Change of human chromosome counts with age: Evidence of a sex difference, Nature (Lond.), 197 (1963) 1080-1081. 70 R. M. Goodman, N. S. Fechheimer, F. Miller, R. Miller and D. Zartman, Chromosomal alterations in three age groups of human females, Am. J. Med. Sci., 258 (1969) 26-34. 71 G. Hughes, Changes in taste sensitivity with advancing age, Gerontol. Clin., I 1 (1969) 224-230. 72 H. Tauchi, On the fundamental morphology of the senile changes, Nagoya J. Med. Sci., 8 (1961) 1-22. 73 M. Bihari-Varga and T. Bir6, Thermoanalytical investigations on the age-related changes in articular cartilage, meniscus and tendon, Gerontologia, 17 (1971) 2 15. 74 B. L. Strehler, D. D. Mark, A. S. Mildvan and V. Gee, Rate and magnitude of pigment accumulation in the human myocardium, J. Gerontol., 14 (1959) 430-439. 75 A. I. Lansing, T. B. Rosenthal and M. Alex, Significance of medial age changes in the human pulmonary artery, J. Gerontol., 5 (1950) 211-215. 76 F. S. LaBella and G. Paul, Structule of collagen from human tendon as influenced by age and sex, J. Gerontol., 20 (1965) 54-59.
110
Mech. Age. Dev., 1 (1972) 101-110
MEASURING THE HUMAN AGEING RATE
ALEX COMFORT Director of Research, Gerontology, University College, London (Great Britain) (Received February 24th, 1972)
" T h e concept of measuring ageing biologically rather than chronologically is of enormous general interest, of importance in industry, and indeed in all areas of human endeavour, but has received relatively little attention from medical scientists." (Hollingsworth et al.1). It was, in fact, an early and highly unfruitful concern of savants calculs such as du Nouy. But for a proper account of ageing it has so far been necessary to insist on the force of mortality as the sole generally applicable criterion, in the absence of any definite information about the nature and identity of the "clock". A new attempt to work out battery tests of human physiological age is now overdue. It is justified by experimental necessity. Agents are known which seem to prolong the life-span of rats and m i c e - - o n e (dietary restriction) has been known for over 30 years. It is highly probable that some of these would affect human life-span if they could be tested briefly and ethically. That we can now think in terms of human experiment is due to the large recent increase in information from longitudinal and cross-sectional sample studies on time-dependent variables in man, the availability of computers and of automated clinical chemistry, and the application (e.g. by Gitman 2) to routine screening tests. Experimental gerontology may well prove the medical growth stock of the next decade, and its philosophy requires brief restatement. Ageing is the process, or group of processes, which cause the eventual breakdown of mammalian homoeostasis with the passage of time. The timing of these processes, although it shows some genetic scatter, is uncommonly stable. It is the universal experience of man that while we may die sooner from single causes, between 70 and 90 years of age homoeostasis declines "across the board", causes of sickness accumulate, and causes of death become multiple. Between 65 and 70, the average number of unrelated lesions per individual at necropsy is 5.71 ; by 80-85 years it has risen to 8.42 (Howell3). We require a battery of tests by which rates of ageing could be examined in treated and untreated humans in a study of feasible size. For this purpose the variables chosen must: (1) Be sufficiently diverse and unrelated to any single assumed process for it Mech. Age. Dev., 1 (1972) 101-110
101
to be highly likely that a manoeuvre which is found to stabilize all of them will aIso affect the rate of actuarial ageing; (2) Correlate closely with chronological age, either directly or in a simple transformation; (3) Change sufficiently, and sufficiently regularly, with age for us to expect significant differences over a 3-5 year run at the selected age of test; and (4) Be measurable in volunteers without unacceptable hazard, discomfort, labour, or expense. Age-dependent variables in man show three main patterns of change. In one large group, change is greatest between infancy and adulthood and negligible thereafter. It was this group which prompted repeated statements by 20th-century biophilosophers that "the rate of ageing is highest in infancy". This saying indicates the limits of their usefulness as alternative indices to mortality. Others exhibit peaking (blood cholesterol) or are suspect by reason of covert selection (blood pressure). Of the serviceable variables, we select from those which are arithlinear with age, regardless of sign, and those which are Gompertzian or log-linear with age, paralleling the force of mortality. Mortality itself is lowest at around 12 years, but by reason of the large dispersion at low ages when the function is inverted to read off chronological age from the other variables, rather than vice versa, useful curves are best taken from an arbitrary origin about 40 years (i.e. from the end of the plateau of adult vigour rather than from the low point of the Gompertz curve). Other indices which are more consistently linear (e.g. collagen contractility) are therefore best adapted to the same arbitrary origin, and the test-period set between 40 and 70 years. The ideal battery accordingly measures what happens at the point of maximal change, and after the end of the period of adult vigour. The function(s) fit better with Teissier's convention 4 than with the conventional Gompertz-Makeham function giving / z x = e a(x b ) ; x > b rather than #x =/-toe at -~- A b representing the duration of the "plateau" as seen in small population samples. The samples will in any case be small by actuarial standards. In fact, however, the postulated origin at about 40 years corresponds roughly with the origin of the linear part of the Gompertz curve allowing for the irregularity seen in real human mortality curves at earlier ages. The study should in any case be set for choice at age 50-55 or age 60-65 where mortality will be significant and the rate of change in log mensurables large. The battery is based on that described by Hollingsworth et al. 1 which was designed to measure rate of ageing in Hiroshima survivors, from studies of about 450 Japanese. Here nine functions selected from seventeen functions examined gave a correlation with age of nearly 0.90. Compared with other attempts (e.g. Ciuca and Jucovski 5) which lean heavily on clinical impressions, this study appears the best available starting-point. It can, however, be expanded considerably in both number and variety of indices. (Davis and Hargen6; ConradT; Beier et al.S; Parot et alP; 102
Mech. Age. Dev., 1 (1972) 101-110
Bourli~rel°; Ciuca and Jucovskin; Bocher and Heemskerk12). For our objective, viz. leap-frogging dog or primate studies and testing non-hazardous procedures directly on man, the most numerous and available primate, as well as the beneficiary in view, we require a test-procedure of realistic size and duration, comparable, for example, to dietary studies or clinical trials on a single lesion. This means, in effect, a procedure giving reasonable expectation of significance for between 100 and 500 subjects including controls, with the probability of having to settle for the smaller number. The same battery could be used both for gerontological work and for environmental or radiation studies (which are now, in man, both contradictory and necessarily retrospective). Experience gained here, even if the tested agent proves inactive and both series are pooled as controls, will be invaluable in the next 10-20 years if repbrted influences on human longevity multiply. TEST BATTERY For initial use, the test age should be 50 years and the sample should be confined to males to avoid further statistical breakdown and complications associated with differences in age of menopause, which affects some variables. Available test-procedures fall into three groups: straightforward (anthropometry, clinical and chemical examination, sensory tests, psychometric tests), those requiring, for example, biopsy, and those depending on the fact that deaths will occur in the test samples. The "straightforward" groups might be modelled on the procedure used for clinical screening by Gitman 2, based on a flow-type centre using lay staff; the psychometric test should be automated, probably by means of the machine devised by Gedye and WedgwoodlL The inclusion or exclusion of biopsy procedures would be a matter for a policy decision. The draft (see Table I) includes four possible tests requiring live tissue-fibroblast clone duration, culture latency period, thigh-skin melanocyte count, and wound healing. Collagen testing is barely feasible in man except at necropsy, and is covered in part by other measurements (skin elasticity, vascular state, blood elastase). Lymphocyte R N A : D N A ratio (Sakai et al. 14) and leucocyte chromosome count are in theory derivable from a blood sample, though there is evidence that, for the second of these, sternal puncture would be preferable (Chlebovsky et al.15). On grounds of labour most of these more elaborate, though theoretically important, tests would probably have to be limited to 1/5 or 1/10 of the sample. Mortality would be expected in a 50-year-old sample. For U.S. or U.K. White males we would expect thirty deaths between 50 and 55, and about fifty between 60 and 65 for a sample, n, of 500 lives (i.e. too few for significance if the sample were any smaller, but enough to give some necropsies). A full legal-consent and pathological programme should be written in, however, to secure these. Necropsybased measurements would include cause of death, number of lesions present, lipofuscin, collagen, cell counts, presence of amyloid and atheroma, and organ weight. In Hollingsworth's series of seventeen tests, the highest age-correlations were for characters (hair graying, skin elasticity) which contribute most to the "clinical Mech. Age. Dev., 1 (1972) 101-110
103
TABLE I D R A F T TEST BATTERY FOR PHYSIOLOGICAL AGE IN MAN a, selected for Hollingsworth battery; b, included in Gitman inventory; c, biopsy dependent; d, necropsy dependent; r, coefficient of correlation. Test
Hair-graying score Skin elasticity
a,b
Systolic blood pressure
b b b a,b
Diastolic blood pressure Heart size Thorax size Total vital capacity
b b
Tidal volume One-second expiratory volume
a a a a,b b
Hand-grip strength Light extinction test Vibrometer Visual acuity Audiometry, 200 cps
a,b
Audiometry, 4000 cps
a,b
Serum cholesterol
b
Total serum albumin
b
Albumin: globulin ratio
b b
b b b
c
Plasma water Mean venous pressure Protein-bound iodine Enzyme induction rate Serum copper Serum elastase Serum ribonuclease Nail Ca content Stature Seated stature Trunk height Biacromial diameter Metacarpal osteoporotic index Lean body mass Lymphocyte R N A : D N A ratio Explant latency
Serum growth promotion
104
References
r
Hollingsworth e t al. 1 Hollingsworth e t al. 1 Robertson e t al. 4° Anderson 41 Grahame and Holt '~2 Hollingsworth e t al. 1 Pflanz and Torok 43 Hollingsworth e t al. 1 Hollingsworth e t al. 1 Hollingsworth e t al. 1 Hollingsworth e t al. 1 Rosenzweig e t al. 44 Hollingsworth e t al. 1 Hollingsworth e t al. 1 Rosenzweig e t al. 44 Hollingsworth e t al),'~5 Hollingsworth e t a 1 2 Hollingsworth e t al. ~ Hollingsworth e t al. 1 Hollingsworth e t al. 1 Jalavisto 46 Hollingsworth e t al. 1 Jalavisto 46 Hollingsworth e t al. ~ Libow z5 Keys3~ Hollingsworth e t al. I Wagner 47 Burger 2z Wagner 47 Hall4S Burger 21 Libow 35 Adelman49,5o Barman 22 Hall51 Sved e t al. ~2 Mattei e t al. zo ParotZS; Dequeker e t al. 53 Parot 25 Parot 2~ Parot z5 Dequeker e t al. 53 Forbes and Reina ~4 Sakai e t al. 14 Medawar55; Soukupov~, e t a/.56,sv; Waters and Walford 5s; Heine and Parchwitz59 Carrel and Ebeling6°; Baker and Carrel 61 Mech.
Age. Dev.,
0.717 0.604
0.519 0.409 0.294 --0.124 --0.402
--0.126 --0.323 0.488 0.537 --0.432 0.445 0.596 0,234
--0.267
0.33
--0.532 --0.53 --0.34 --0.40 --0.786
1 (1972) 101-110
TABLE I (continued) Test
References
c
Biopsy healing and contraction
c
Clonal further viability
Howes and Harvey62; Billingham and Russel6a; Landag164 Hayflick65; Hay and Strehler~6; Hay et a/.67; Martin et al. 68 Jacobs et al.69; Goodman et al. 7° Hildemann and Walford28; Makinodan and Peterson ~4 Snell and Bischitz17; Fitzpatrick et a1.18; Walsh 19 Gedye and Wedgwoodla; Jarvik and Falek26; LibowaS; Jalavisto 46
Leucocyte aneuploidy Autoantibody titres c
Skin melanocyte count W.A.I.S.* tests (automated set) similarities digit span vocabulary digit symbol block design digit copying tapping test Reaction time, ruler test Reaction time, light Flicker-fusion frequency Taste sensitivity Total 5-year mortality Organ weights Disease specific mortality Tumour incidence, living Tumour incidence, necropsy Arterial pathology Amyloidosis, stain Cartilage H20 content Lipofuscin amount Aortic calcium Collagen contractility Collagen, fluorescence
Jalavisto 4~ Jalavisto 4~ Jalavisto 46 Hughes 71 -Tauchi7~ -----Bihari-Varga and Bir673 Strehler et al. 74 Lansing et a/.75; Burger 21 -LaBella and Paul 76
r
--0.44 0.48 0.35 --0.48 ---
----
-
---
* Wechsler adult intelligence scale. impression" o f age, a n d eleven out o f seventeen overlap G i t m a n ' s test battery. Hair graying was excluded from the final H i r o s h i m a series because o f difficulty in q u a n t i fication. Various ways o f estimating it have b e e n suggested (Hollingsworth et al.16): percentage gray hairs per axilla and, if skin biopsy were done, skin, melanocyte conc e n t r a t i o n might prove a n alternative (Snell a n d Bischitz17; Fitzpatrick et al.18; Walsh19). Besides the H o l l i n g s w o r t h - G i t m a n series, a n u m b e r o f additional tests are suggested in Table I either because they are easy, even if poorly correlated with age ( a n t h r o p o m e t r y ) , or because they are evidence of things n o t seen (nail calcium accum u l a t i o n , which parallels aortic calcification in time (Mattei et al.2°; Burger21)) or because, t h o u g h speculative, they are theoretically i m p o r t a n t (blood copper c o n t e n t (Harman22), b l o o d elastase, a u t o a n t i b o d i e s ( H i l d e m a n n a n d Walford2a; M a k i n o d a n a n d Peterson24)). These are chosen o n the basis of the most accessible measure, e.g. Mech. Age. Dev., 1 (1972) 101-110
]05
skin elasticity rather than skin collagen properties, nail calcium rather than aortic calcium. Anthropometric age measures are worth confirming, and give little trouble. The most promising seem to be seated stature, trunk height, and biacromial diameter (Parot 25) though the change is greatest in females and is less than one standard deviation over the interval 50-85 years. Psychometric tests are highly important; several (vocabulary, digit symbol, similarity, block designs, digits forward and backward, and tapping tests) correlate with five-year survival (Jarvik and Falek 26) as well as with chromosome error accumulation (Jarvik et a1.27). Others (serial choice task performance) seem to correlate with cardiovascular status (Szafran2S; Spieth 20) though at a low level of significance. Psychometric changes may reflect both normal ageing and subclinical disease (Davies30). It would be valuable to extend our knowledge of these correlations. Automation of the Wechsler adult intelligence scale test battery should be feasible (Gedye and Wedgwood13; Schonfield and Robertson31). Sensory tests (audiometry, flicker-fusion frequency, optometry), though time-consuming, are also essential. It should in theory be possible to measure homoeostatic failure directly by measuring variance (Storer3~), but this has pitfalls arising from the ageing organism's capacity for improvisation, as well as from the selection exercised at high ages by mortality itself(ComfortZa), though it may shortly be possible to measure, for example, the proportion of misspecified enzyme in certain systems (Gershon and Gershon34), and new measures of this kind may well multiply over the next 5-10 years. The Gitman battery has a statistical advantage in that it can show not only whether the observed values are in the normal range, but also the trend of readings in the individual at reexamination. It was designed as a clinical screen, not as a measure of ageing, but includes a great many indices which have been independently standardized against age, albeit in a small sample only (n -- 47) (LibowZ5). Serum-cholesterol is an unsuitable direct measure of ageing since it commonly rises until the age of 50 and falls thereafter (Keys36), and the results in different studies have been discrepant (Libow35; Nowlin et al.37). Of the other age-related variables in Libow's paper (Libow a5; Nowlin et al. 37) serum albumin (r = --0.267) declines, and protein-bound iodine (r z --0.33), maximal breathing capacity (r -- --0.43) and vital capacity (r = --0.50) correlate with age at levels approaching those selected by Hollingsworth et al. 1. PROCEDURE The battery is designed, essentially, to test any non-hazardous agent or manoeuvre which might be offered as being likely to affect the ageing clock. The feasible size of an ageing study depends on the number of.available volunteers, and on the procedure (diet, injections, or additives) required in the treated group. Recruitment of volunteers would normally be from a large employer, a closed group (monks, prisoners, pensioners), or from a profession (physicians, academics, Government employees). Administration and supervision of treatments cannot be discussed in vacuo. The most likely agents for trial within the next 5-10 years would appear to be diets, antioxidants, and possibly anticaloric or anti-crosslinking drugs. 106
Mech. Age. Dev., 1 (1972) 101-110
All these create problems of supervision and continuity, and English society provides few healthy closed communities from which volunteers could be recruited; some of the major difficulties of long-term diet experiments were well illustrated by a recent Veterans Administration trial on cholesterol and atheroma (Dayton et al.SS). This type of experiment does, however, provide a practical and ethical model. Had these investigators, moreover, had access to the kind of test battery I am suggesting, important information about potential free-radical effects in accelerating certain age indices might conceivably have been obtained as a by-product of the main study (Harman39). Antioxidant trials seem feasible, although the dose levels would be heroic by comparison with current permitted use in foodstuffs (a full and frequent review of haematology and side-effects would in this case be needed, multiplying the number of attendances and involving a complete health-check battery in addition to the running measurements). Substances which we already ingest have their attractions for trial purposes, but the known safety of, for example, tert.-butylhydroxytoluene as a food additive could be more than offset by the risk of sensitization to most process foods, for which the volunteer would not thank us. It might in this case be wiser to use a low-toxicity antioxidant not already widespread in groceries. Naturally occurring antioxidants might well be tested in this way (tocopherols, ubiquinones, - S H donors). Physicians are a potential source of volunteers: they might in theory be self-policing, and they would certainly be capable of giving themselves a parenteral agent, if one such were available for trial. Choice of a 50- or 60-year baseline makes the problem of a controlled population of willing volunteers more complex by excluding students or soldiers, for example, but it must be part of the philosophy of attempts at age control that we should aim, initially at least, at the possibility of a late-acting agent, so as to reduce the total span of treatment required. This may, of course, prove impossible. Nor may it be possible (or desirable) to run even a superficially harmless procedure, such as the use of low-calorie foods, without a separate and frequent "toxicity" assessment; it might, indeed, have been wise and profitable to include one in the dietary cholesterol studies already cited (Dayton et al.3S). Viewed purely as an ageing test the model requires annual or twiceyearly attendance, depending on numbers, at a clinical centre, which will also provide records storage, a secretariat, and a manned telephone to give appointments. A small sample (n : 100) could be dealt with surgery fashion, by hand. It seems preferable, however, to aim at a Gitman-type flow system set up, for example, in an empty ward, with patients admitted in batches of 4, and with all tests requiring more than 5 minutes (e.g. audiometry and ECG) duplicated. While it may be necessary to limit the tests strictly to those required by the study, there is a case for giving the full Gitman screening battery so as to provide a periodic check-up as a direct incentive to volunteers, with a physician present to answer questions and deal with anxieties. The clinically relevant parts of the print-out should be sent to the volunteer's physician. PAY-OFF Testing of specific agents apart, the creation of an "ageing assessment unit"
Mech. Age. Dev., I (1972) 101-110
107
in G r e a t Britain, t h o u g h n o t cheap, is likely to be a r e w a r d i n g investment. It will a l m o s t certainly be needed some t i m e before 1980 if clinical trials o f possible a p p r o a ches to the slowing o f the ageing clock a r e n o t to be confined to rats o r to patients in o t h e r countries. Tests o f this kind a r e a l r e a d y in p r e p a r a t i o n in the U.S. I f the a g e n t o r p r o c e d u r e first chosen for test proves wholly inactive, the results will still be o f p r i m e i m p o r t a n c e as a test-run o f the p a r a m e t e r s chosen, the a d m i n istrative structure, a n d the c o o p e r a t i o n o f physicians and volunteers. W e need to find out how to d o this kind o f e x p e r i m e n t , and the " k n o w - h o w " o b t a i n e d could well be a p r i m e tool in the e x p e r i m e n t a l medicine o f the 1980's, as well as in the assessment o f diets, e n v i r o n m e n t a l h a z a r d s and r a d i a t i o n effects. It is an interesting t h o u g h t t h a t acceleration (or delay) in the process o f ageing, which would affect the age o f onset o f all diseases, n o t the frequency o f one, is a perfectly possible side-effect o f drugs o r e n v i r o n m e n t a l factors now current. It would also be, at present, undetectable unless gross e n o u g h to influence the life table for the whole p o p u l a t i o n , a n d then only inferentially a n d in retrospect. A n ageing b a t t e r y w o u l d bring this kind o f effect within the scope o f i m m e d i a t e detection. T h e G i t m a n - t y p e clinical screening centre is a possible tool for future g r o u p practice a n d health service use. W h e t h e r clinical screening is economically effective as a means o f early diagnosis is still questionable; b u t if it is, we require experience with it. This would be o b t a i n a b l e w i t h o u t a d d i t i o n a l cost as a b y - p r o d u c t o f the kind o f ageing study here p r o p o s e d , a n d might r e n d e r the investment a c c e p t a b l e while the i m p o r t a n c e o f rate-modification in the preventive medicine o f the future is being realised by the scientific c o m m u n i t y . REFERENCES 1 J. W. Hollingsworth, A. Hashizume and S. Hablon, Correlations between tests of aging in Hiroshima subjects: An attempt to define "physiologic age", Yale J. Biol. Med., 38 (1965) 11-26. 2 L. Gitman, Multiphasic Health Screening Center Manual, Brookdale Hospital Center, N.Y., 1969. 3 T. Howell, Multiple pathology in a septuagenarian, J. Am. Geriatr. Soc., 16 (1968) 760-762. 4 G. Teissier, Recherches sur le vieillissement et sur les lois de la mortalit6, Ann. Physiol. Phys.Chim. Biol., I0 (1934) 260-284. 5 A. Ciuca and V. Jukovski, Recherches concernant la d6termination de "L'fige biologique moyen", Riv. Esp. Gerontol., 4 (1969) 97-116. 6 R. L. Davis and S. M. Hargen, Biomedical studies of different aging populations, Gerontologbt, 10 (1970) 31-33. 7 R. A. Conrad, An attempt to quantify some clinical criteria of aging, J. Gerontol., 15 (1960) 358-365. 8 W. Beier, K. H. Brehmer and D. Wiegel, Eine M6glichkeit zur Ermittelung des wahrscheinlichen biologischen Alters, Z. Alternsforsch., 24 (1971) 77-78. 9 S. Parot, E. Jacquemin and J. Poitrenaud, La capacit6 des sujets fig6s et tr6s-fig6s, J. Physiol. (Paris), 61 (1969) 265-276. 10 F. Bourli6re, Les m6thodes de mesure de l'fige biologique de l'homme, Cah. Santd Publ. 37, Geneva, W.H.O., 1969. 11 A. Ciuca and V. Jucovski, Studium fiber Alterswandel der somatophysiometrischen Indikatoren, Z. Gerontol., 3 (1970) 133-230. 12 W. Bocher and J. J. Heemskerk, Zur Problematik des funktionalen Alters, Z. Gerontol., 2 (1969) 339-349. 13 J.L. Gedye and J. Wedgwood, The use of an interactive computer terminal for assessing the mental state of geriatric patients, Abstr. Proc. 8th Int. Congr. Gerontol. (Washington), 1969. 108
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