Normal Values in Extreme Old Age V. MARIGLIANO,“ C. BAUCO,“ F. CAMPANA,” M. CACCIAFESTA,b E. BAGAGLINI,‘ C. FRITZ,“ AND E. ETTORRE“ “Cattedra Geriatria e Gerontologia ”Istituto di I Clinica Medica Universita di Roma “La Sapienza” 00161 Rome, Italy “lstituto Geriatric0 “Villa d e l e Querce” Nemi (Rome), Italy Aging is one of the great paradoxes of nature. As the distinguished evolutionary biologist George Williams has pointed out: “It is indeed remarkable that after a seemingly miraculous feat of morphogenesis a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed.”’ Gerontologists generally agree that aging occurs in all animal species that reach a large size and that each species has a characteristic life span. The mus musculus (field mouse) has a longevity of 3 years, the common swift lives a maximum of 21 years. Man lives 14 times longer than the shortest-living of the primate species. Man appears to be the longest living of all mammalian species, and probably of all mammalian species that ever lived.* Aging in its most profound expression of longevity certainly occurs in those animals that are protected by environment. Thus, maximum potential life span appears to be related to the innate ability of the animal to maintain its general mental and physical health. Before the research of Hayflick, and even afterwards, aging was considered as an unavoidable, irreversible deteriorating process, as a more-or-less rapid physical, mental, and social decline. Age is looked upon as something useless in our society, in which autonomy and independence in all functions are absolutely necessary. Some gerontologists believe that after 85 years of age there is a rapid decline in the organism as an unavoidable consequence of biological deterioration that increases with increasing age. In this regard we are more optimistic. To our knowledge those who “survived” everything to near the limit of biological potential age, at least over 100 years old, are in good health and without specific pathologies. In trying to discover the determining factor of longevity our attention has been concentrated on centenarian^,^-' that small, selected group of individuals in whom the genetic potential has been able to express itself at its best. Our research tried to evaluate the physical and psychic conditions of centenarians and to determine normal values in extreme old age, as well as markers predictive of longevity. Research regarding centenarians’ life style should permit one to discover which factors determined or at least positively influence l o n g e ~ i t y . It ~ , is ~ also of great importance to discover how it is possible to maintain a good functional level, adapted to the changed needs of the organism, up to the end of the potential life span. Methodology has to be evaluated with utmost care, for it has to be capable of allowing multidimensional evaluation” and obtaining data comparable with 23
ANNALS NEW YORK ACADEMY OF SCIENCES
24
international studies.” It is very important to have instruments capable of comparing the results obtained from studies on people living in the same or different environmental conditions. This requires the use of standardized tests to quantify single variables. We considered biological (diet, pathological agents, etc.) and nonbiological factors (climate, height, pollution, etc.) as well as social factors. We examined a group of centenarians, of mean age 102.58 + I - 2.28, selected by birth registers. Interviews were performed taking into consideration education level, work habits, social-economic conditions, family life, physiopathologic conditions, and level of independence. Furthermore, medical examination was performed, and hematochemical data were collected. One-quarter of the centenarians studied were illiterate; 59% attended primary school, 16% high school; 87.5% of them lived with their family, only one individual lived in an institution, and two still lived on their own. For all the centenarians their working years represented 41s of their lifetime; 50% were farm workers, 21% performed nonmanual work, and 8% were craftsmen. Long-lasting work seems to go together with a high degree of independence. Most interesting in this regard seems to be the correlation between the degree of independence (evaluated by the ADL [Activities of Daily Living] index of Katz) and mental activity (evaluated by M.M.S.E. [Mini Mental State Examination]): 22% of the centanarians are completely self-sufficient (ADL level A), with a mean M.M.S.E. score of 26.3 2.9 (reference scores: 0-20 pathological, 21-26 borderline, 27-30 normal). Levels A, B, and C in ADL (people who need help in taking a bath and are dependent in only one more function) comprise 54.2% of observations on the whole, with an M.M.S.E. score of 24.4 4.8. This suggests that a high degree of self-sufficiency is correlated to good mental activity. Twothirds of the centenarians were requested to repeat the cognitive test after 18 months in order to quantify cognitive impairment. No noteworthy changes were found. Preliminary results of the follow-up of our centenarians show that the individuals who obtained a low score in M.M.S.E. were those who died first. Data suggest that it is possible to reach 100 years and even more with good mental activity in spite of eventual pathologies due to age. If there are no remarkable metabolic or vascular diseases, there is no particular decline or cerebral functions in longevity. Centenarians who maintain good mental activity are not exceptions but are the result of a complex interaction between genetic heritage and favorable environment. Even though genetic factors (species-specificlife span, limited number of replications of the cell, aging genes, etc.) determine longevity, a number of exogenous elements have to be considered. Obviously potential life span will not be changed by exogenous factors, but mean survival depends on surrounding conditions, which, for human beings, are not only ecological but psychological and social as well. The remarkable growth of longevity in recent years-more rapid and more consistent in the group of people over 85 years of age-has introduced what has been called the “revolution of longevity.”” The development of medical science and medical aid, as much with regard to prevention as to cure, together with the general improvement of social and economic conditions, has made it possible for a greater number of individuals to reach an age that nobody would have dared to dream of at the beginning of our century. We have to distinguish between ‘‘normal’’ and “pathological” aging. Very often degenerative diseases, such as arteriosclerosis and osteoporosis, are studied apart from the physiological aging of tissues and organs. This is not the way to proceed. It is not always easy to distinguish between physiological aging and
*
*
MARIGLIANO et al.: NORMAL VALUES IN EXTREME OLD AGE
25
pathological proce~ses,’~-thatis, to determine at what time a pathological mechanism is taking over. Mostly it is a matter of quantitative differences over the background of a great interindividual variability. The DNA responsible for the genetic program14.” determines not only speciesspecific life span but interindividual differences as well. At one extreme we find cases of progeria, which are caused by a certain number of regulating genes; at the other extreme we find longevity, which in the same way is due to genetic factors but certainly in interaction with exogenous factors. We could compare longevity to a tissue, a good solid tissue woven on a solid frame, carrying the design to completion in all the little details and ornaments, bleached and worn out at the end, probably with a few holes and rips, but still perfect-an individual masterpiece. Aging is characterized by the decrease of activity of several enzyme syst e m ~ . ’ ~At* the ’ ~ level of the cell membrane, it is known that the activity of many ionic transport systems is strictly related to the changes of membrane lipid content; the level of active transport of K + in various mammalian erythrocytes is inversely related to the SPM : PC (sphingosylphosphorylcholine: phosphatidylcholine) ratio.’*,20It has also been shown that physiological aging is accompanied by an increase of membrane lipid peroxidation, triggered by increases of serum free radicals?’ and of the cholesterollphospholipidratio, following reduced microsomal synthesis of phosphatidylethanolamine and phosphatidylcholine.22 Many authors, indeed, report decreased activity of the Na-K ATPase-dependent pump in old age.’3-26 As to our knowledge, there has been no study of changes occurring in old age on other cell sodium transport mechanisms. It is now well known that cell sodium efflux, which can be observed after ouabain inhibition of the ATPase-dependent pump, is not only the expression of passive permeability: the Na-K pump, in other words, is not the only mechanism controlling the sodium efflux from the Today it is known that there are several transport mechanisms that can couple the movement of cations to that of chloride ions and that for that reason are called cotransport: the Na+/K+/CI-, Na+/CI-, and K+/CI- cotransport systems have been shown to be present in different cell types. These systems have the function of maintaining the transmembrane chloride gradient. The most important of these systems, the Na+/K+/CI- cotransport system, effects the translocation in the same direction of an Na+ ion, a K’ ion, and two CI ions (thus not having any effect on membrane polarization), using the concentration gradient of potassium without using ATP. At physiological conditions of N a + , K + , and C1- in human red blood cells, this system performs a net Na+ and K + efflux, while in endothelial cells (characterized by low intracellular chloride concentration) the flux seems instead to be directed inwards. As regards sodium, the efflux is considerably less compared to that controlled by the ATPase-dependent pump (in human red blood cells, the percentage of active sodium extrusion due to cotransport has been evaluated at about 10%); but it is important in the regulation of cellular volume. Studies carried out on human red blood cells and on mouse macrophages appear to indicate that cotransport can work as a kind of auxiliary system that can help the ATPase-dependent pump in extruding any excess of cell Na+ content; and that this process is almost nonexistent under physiological conditions: that is, the Na+ / K+/CI- cotransport system behaves as a silent “second pump.” unmasked by any increase in cell Na+ content. In our study of a group of old people (mean age 79) the internal Na concentration peak, measured by NMR spectroscopy, was 6 1 mM/1 cells, similar to what we observed in a control group of younger people. Sodium furosemide-sensitive efflux
*
26
ANNALS NEW YORK ACADEMY OF SCIENCES
(cotransport) has been evaluated in the presence of ouabain. Mean values of ouabain-resistant Na+ efflux was 0.30 f 0.03 mM/I cells/h. The difference between this value and that observed in younger people (0.46 0.20) was statistically significant ( p < 0.01). The sample we studied followed a strictly normosodic diet; had no concomitant ascertainable pathologies,28-32no pharmacological therapy under way, and no positive family history of essential arterial hypertension: and presented normal values of cholesterolemia, tryglicerydemia, insulin plasma levels and, renal function index. The group of young subjects, considered as control, was selected with the same criteria and, therefore, with similar clinical and laboratory characteristics. Membrane properties are strictly dependent upon their composition, which can undergo changes with increasing age. It has been noted that age-dependent changes of phospholipid metabolism, phospholipid content, and other membrane constituents-namely, protein, cholesterol, etc.-may result in modification of such membrane properties as fluidity,j3 activity of membrane-bound enzyme^,^^.^^ receptor m ~ b i l i t y , ~ excitability, ~.~’ and transduction of biological According to the considerations expounded above, the changes in cotransport activity may justly be considered a primitive involution of this transport system, related to changes in membrane lipid content occurring in old age, and not related to changes in metabolism (like hypercholesterolemia, hypertrygliceridemia, hyperinsulinemia, etc.) linked to aging. Centenarians generally present a low concentration of insulin, with a mean insulin level of 7.1 f 4.0 (normal values [n.v.] 3-35 IU/ml); and a normal lipidic equilibrium, with a cholesterol value of 182.3 f 34.9 mg/dl (n.v. 120-200) and tryglyceride level of 99.8 k 33.7 mg/dl (n.v. 30-190) and intermediate values of HDL 46.7 5 11.8. We can conclude that, even if it is difficult to define “normal” values in aging because of interindividual variability in the alteration of physiological functions of organs and tissues, it is possible to find very old people, in particular centenarians, whose values are not different from those of younger adults. Most important is to identify and treat the weakest apparatus, in order to preserve a level of functioning suitable to the modified needs of old age.
*
REFERENCES
I . WILLIAMS, G . C. 1957. Pleiotropy, natural selection, and the evolution of senescence. Evolution (11): 398-41 I . 2. COMFORT,A. 1929. I n The Biology of Senescence. Elsevier North Holland. New York, NY. 3. MARIGLIANO, v.,c. BAIJCO,E.BAGAGLINI. D. BRIOLI, M. CACCIAFESTA,A. ARABIA, A. L. TAssl & M. G . GALLI. 1990. I Centenan nel Lazio: II diritto alla longevith. Rass. Geriatrica %(I): 5-1 I . 4. MARIGLIANO, v.,c. BAIJCO,M. CACCIAFESTA, c. BIJCCA,E. BAGAGLINI, D. BRlOLl & F. CAMPANA. 1991. Health and living conditions of centenarians in Italy. Proceedings of the Conference “Mechanisms of Aging and Longevity,” Tblisi, C.I.S.: 244-246. v., c. BAIJCO,M. CACCIAFESTA, c. BUCCA,E. BAGAGLINI, D. BRIOLI 5 . MARIGLIANO & F. CAMPANA. 1991. Mental activity in centenarians. Proceedings of the Conference “Mechanisms of Aging and Longevity,” Tblisi, C.I.S.: 246-248. 6. MARlGLlANOV., c. BAUCO,F. CAMPANA, M.CACCIAFESTA,E. ETTORRE&E. BAGAGLiN i. 1991. Arnbiente e stile di vita dei centenari nel nostro paese. Proceedings of the International Medical Congress of Mountain Climatology, Roccaraso, Italy. G. C. Di Lollo, Ed. Casa Editrice L’Antologia. Naples. In press. 7. MARlGLlANOV., c. BAUCO.M.CACCIAFESTA, c.,BIJCCA,E. BAGAGLINI & D. BRIOLI.
MARIGLIANO era/.: NORMAL VALUES IN EXTREME OLD AGE
8.
9. 10.
II. 12. 13. 14. 15.
16. 17. 18.
19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
27
1991. A proposito di longevita estrema: I centenari del Lazio. G. Gerontol. 3 9 17 1- 175. BEREGI.E. & A. KLINGER.1989. Health and living conditions of centenarians in Hungary. Int. Psychogeriatrics l(2): 195-200. LEHR,U . M. 1982. Social-psychological correlates of longevity. I n Annual Review of Gerontology and Geriatrics, Vol. 3. C. Eisdorfer. Ed.: 101-147. Springer. New York, NY. RUBENSTEIN. L. Z., A. L. SIU& D. WIELAND. 1989. Comprehensive geriatric assessment: Toward understanding its efficacy. Aging 1: 87-98. G. D. WIELAND & R. KANE. 1984. Systematic RUBENSTEIN. L. Z., C. SCHAIRER, biases in functional status assessment of elderly adults: Effects of different data sources. J. of Gerontol. 39(6): 686-691. GOLINI.A. 1991. LongevitA e durata della vita: Un approccio statistico-demografico. Proceedings of “Regional Congress on Longevity,” Rome, October 18, 1990. G. Gerontol. In press. HAYFLICK. L. 1988. Why do we live so long? Geriatrics 43(10): 77-87. L. 1985. Theories of biological aging. Exp. Gerontol. 20: 145-159. HAYFLICK. HAYFLICK, L. 1985. The cell biology of aging. Clin. Geriatric Med. l(1):15-27. F. PALMA,M. DACHA& G . FORNAINI. 1983. M A G N A NMI ,. , E. PIATTI,M. SERAFINI, The age-dependent metabolic decline of the red blood cell. Mech. Ageing Dev. 22(3-4): 295-308. T U R N E RB., M., R. A. KOHER& H. HARRIS.1974. The age-related loss of activity of four enzymes in the human erythrocyte. Clin. Chim. Acta 5 0 85-95. SCHROEDER. F. 1984. Role of membrane lipid asymmetry in aging. Neurobiol. of Aging 5: 323-333. BARENHOLZ, Y. & s. GATT. 1982. Sphingomyelin: Metabolism, chemical synthesis, chemical and physical properties, Vol. 4. I n Phospholipids. J. N. Hawthorne & G. B. Ansell, Eds. 129-177. Elsevier. New York, NY. C A L D E R I NG.. I , A. C. BONETTI,A. BATTISTELLA, F. T. CREWS& G. TOFFANO. 1983. Biochemical changes of rat brain membranes with aging. Neurochem. Res. 8: 483-492. HARMAN D., 1968. Free radical theory of aging: Effect offree radical reaction inhibitors on the mortality rate of male LAF mice. J. Gerontol. 2Jk 476-482. BARTOSZ,G. 1991. Erythrocyte aging: Physical and chemical membrane changes. Gerontology 37: 33-65. NAYLOR, G. J., D. A. T. DICK,E. P. WORRAL,E. G. DICK& L. BOARDMAN. 1977. Change5 in erythrocyte sodium pump with age. Gerontology 23: 256-261. 1981. Potassium changes with age. Gerontology 27: C o x , J . R. & W. A. SHALABY. 340. S. R. & B. H. DUTHIE,JR. 1983. Effect of age on red cell membrane NaGAMBERT, K dependent adenosine triphosphatase (Na+-K’ ATPase) activity in healthy men. J . Gerontol. 38(1): 23-25. WITKOWSKY, M.. A. MYSLIWSKY & J. MYSLIWSKY. 1985. Decrease of lymphocyte (Na’-K’) ATPase activity in aged people. Mech. Ageing Dev. 33(1): 11-17. & P. MEYER.1980. GARAY.R. P., G . DAGHER,M. G . PERNOLLET, M. A. DEVYNCK Inherited defect in a N a + , K + cotransport system in erythrocytes from essential hypertensive patients. Nature 284: 281-283. P. HANNAERT & M. PRICE.1983. Abnormal N a + , K + GARAY.R. P., C. NAZARET, cotransport function in a group of patients with essential hypertension. Eur. J. Clin. Invest. 13: 311-320. GARAY,R. P. 1987. Kinetic aspects of red blood cell sodium transport systems in essential hypertension. Hypertension lO(Supp1. 1). 5: 11-14. JACKSON, P. A. & D. B. MORGAN.1982. The relation between membrane cholesterol and phospholipid and sodium efflux in erythrocytes from healthy subjects and patients with chronic cholestasis. Clin. Science 62: 101-107. HAJEM.S . . T . MOREAU, P. HANNAERT, J. LELLOUCH, G. ORSSAUD, G. HUEL,J. R. CLAUD& R. P. GARAY.1990. Erythrocyte cation transport system and plasma lipids in a general male population. J. Hypertens. 8: 891-896. J. B. SMITH & K. 0. ASH. 1986. Association of HUNT,S. C., R. R. WILLIAMS.
28
33. 34.
35. 36.
37. 38.
ANNALS NEW YORK ACADEMY OF SCIENCES three erythrocyte cation transport systems with plasma lipids in Utah subjects. Hypertension 8: 30. 1979. The decreased membrane SHICA,T., N. MAEDA,T. SUDA,K. KON& M. SEKIYA. fluidity of in vivo aged, human erythrocytes. A spin label study. Biochem. Biophys. Acta 55% 84-95. COLEMAN, R. 1973. Membrane-bound enzymes and membrane ultra structure. Biochim. Biophys. Acta 300: 1-30. KAMBER, E., A. POYIAGI& G. DELICONSTANTINOS. 1984. Modifications in the activity of membrane-bound enzymes during in vivo ageing of human and rabbit erythrocytes. Comp. Biochem. Physiol. 77b: 95-99. LOH,H. H. & P. Y. LAW. 1980. The role of membrane lipids in receptor mechanisms. Annu. Rev. Pharmacol. Toxicol. 2 0 201-234. ALOJ, S. M. 1982. Membrane lipids and modulation of hormone receptor expression. I n Hormone Receptors. L. D. Kohn, Ed.: 83-100. Wiley. New York, NY. HIRATA,F. & J. AXELROD. 1980. Phospholipid methylation and biological signal transmission. Science 209: 1082-1090.
ANNALS NEW YORK ACADEMY OF SCIENCES
24
international studies.” It is very important to have instruments capable of comparing the results obtained from studies on people living in the same or different environmental conditions. This requires the use of standardized tests to quantify single variables. We considered biological (diet, pathological agents, etc.) and nonbiological factors (climate, height, pollution, etc.) as well as social factors. We examined a group of centenarians, of mean age 102.58 + I - 2.28, selected by birth registers. Interviews were performed taking into consideration education level, work habits, social-economic conditions, family life, physiopathologic conditions, and level of independence. Furthermore, medical examination was performed, and hematochemical data were collected. One-quarter of the centenarians studied were illiterate; 59% attended primary school, 16% high school; 87.5% of them lived with their family, only one individual lived in an institution, and two still lived on their own. For all the centenarians their working years represented 41s of their lifetime; 50% were farm workers, 21% performed nonmanual work, and 8% were craftsmen. Long-lasting work seems to go together with a high degree of independence. Most interesting in this regard seems to be the correlation between the degree of independence (evaluated by the ADL [Activities of Daily Living] index of Katz) and mental activity (evaluated by M.M.S.E. [Mini Mental State Examination]): 22% of the centanarians are completely self-sufficient (ADL level A), with a mean M.M.S.E. score of 26.3 2.9 (reference scores: 0-20 pathological, 21-26 borderline, 27-30 normal). Levels A, B, and C in ADL (people who need help in taking a bath and are dependent in only one more function) comprise 54.2% of observations on the whole, with an M.M.S.E. score of 24.4 4.8. This suggests that a high degree of self-sufficiency is correlated to good mental activity. Twothirds of the centenarians were requested to repeat the cognitive test after 18 months in order to quantify cognitive impairment. No noteworthy changes were found. Preliminary results of the follow-up of our centenarians show that the individuals who obtained a low score in M.M.S.E. were those who died first. Data suggest that it is possible to reach 100 years and even more with good mental activity in spite of eventual pathologies due to age. If there are no remarkable metabolic or vascular diseases, there is no particular decline or cerebral functions in longevity. Centenarians who maintain good mental activity are not exceptions but are the result of a complex interaction between genetic heritage and favorable environment. Even though genetic factors (species-specificlife span, limited number of replications of the cell, aging genes, etc.) determine longevity, a number of exogenous elements have to be considered. Obviously potential life span will not be changed by exogenous factors, but mean survival depends on surrounding conditions, which, for human beings, are not only ecological but psychological and social as well. The remarkable growth of longevity in recent years-more rapid and more consistent in the group of people over 85 years of age-has introduced what has been called the “revolution of longevity.”” The development of medical science and medical aid, as much with regard to prevention as to cure, together with the general improvement of social and economic conditions, has made it possible for a greater number of individuals to reach an age that nobody would have dared to dream of at the beginning of our century. We have to distinguish between ‘‘normal’’ and “pathological” aging. Very often degenerative diseases, such as arteriosclerosis and osteoporosis, are studied apart from the physiological aging of tissues and organs. This is not the way to proceed. It is not always easy to distinguish between physiological aging and
*
*
MARIGLIANO et al.: NORMAL VALUES IN EXTREME OLD AGE
25
pathological proce~ses,’~-thatis, to determine at what time a pathological mechanism is taking over. Mostly it is a matter of quantitative differences over the background of a great interindividual variability. The DNA responsible for the genetic program14.” determines not only speciesspecific life span but interindividual differences as well. At one extreme we find cases of progeria, which are caused by a certain number of regulating genes; at the other extreme we find longevity, which in the same way is due to genetic factors but certainly in interaction with exogenous factors. We could compare longevity to a tissue, a good solid tissue woven on a solid frame, carrying the design to completion in all the little details and ornaments, bleached and worn out at the end, probably with a few holes and rips, but still perfect-an individual masterpiece. Aging is characterized by the decrease of activity of several enzyme syst e m ~ . ’ ~At* the ’ ~ level of the cell membrane, it is known that the activity of many ionic transport systems is strictly related to the changes of membrane lipid content; the level of active transport of K + in various mammalian erythrocytes is inversely related to the SPM : PC (sphingosylphosphorylcholine: phosphatidylcholine) ratio.’*,20It has also been shown that physiological aging is accompanied by an increase of membrane lipid peroxidation, triggered by increases of serum free radicals?’ and of the cholesterollphospholipidratio, following reduced microsomal synthesis of phosphatidylethanolamine and phosphatidylcholine.22 Many authors, indeed, report decreased activity of the Na-K ATPase-dependent pump in old age.’3-26 As to our knowledge, there has been no study of changes occurring in old age on other cell sodium transport mechanisms. It is now well known that cell sodium efflux, which can be observed after ouabain inhibition of the ATPase-dependent pump, is not only the expression of passive permeability: the Na-K pump, in other words, is not the only mechanism controlling the sodium efflux from the Today it is known that there are several transport mechanisms that can couple the movement of cations to that of chloride ions and that for that reason are called cotransport: the Na+/K+/CI-, Na+/CI-, and K+/CI- cotransport systems have been shown to be present in different cell types. These systems have the function of maintaining the transmembrane chloride gradient. The most important of these systems, the Na+/K+/CI- cotransport system, effects the translocation in the same direction of an Na+ ion, a K’ ion, and two CI ions (thus not having any effect on membrane polarization), using the concentration gradient of potassium without using ATP. At physiological conditions of N a + , K + , and C1- in human red blood cells, this system performs a net Na+ and K + efflux, while in endothelial cells (characterized by low intracellular chloride concentration) the flux seems instead to be directed inwards. As regards sodium, the efflux is considerably less compared to that controlled by the ATPase-dependent pump (in human red blood cells, the percentage of active sodium extrusion due to cotransport has been evaluated at about 10%); but it is important in the regulation of cellular volume. Studies carried out on human red blood cells and on mouse macrophages appear to indicate that cotransport can work as a kind of auxiliary system that can help the ATPase-dependent pump in extruding any excess of cell Na+ content; and that this process is almost nonexistent under physiological conditions: that is, the Na+ / K+/CI- cotransport system behaves as a silent “second pump.” unmasked by any increase in cell Na+ content. In our study of a group of old people (mean age 79) the internal Na concentration peak, measured by NMR spectroscopy, was 6 1 mM/1 cells, similar to what we observed in a control group of younger people. Sodium furosemide-sensitive efflux
*
26
ANNALS NEW YORK ACADEMY OF SCIENCES
(cotransport) has been evaluated in the presence of ouabain. Mean values of ouabain-resistant Na+ efflux was 0.30 f 0.03 mM/I cells/h. The difference between this value and that observed in younger people (0.46 0.20) was statistically significant ( p < 0.01). The sample we studied followed a strictly normosodic diet; had no concomitant ascertainable pathologies,28-32no pharmacological therapy under way, and no positive family history of essential arterial hypertension: and presented normal values of cholesterolemia, tryglicerydemia, insulin plasma levels and, renal function index. The group of young subjects, considered as control, was selected with the same criteria and, therefore, with similar clinical and laboratory characteristics. Membrane properties are strictly dependent upon their composition, which can undergo changes with increasing age. It has been noted that age-dependent changes of phospholipid metabolism, phospholipid content, and other membrane constituents-namely, protein, cholesterol, etc.-may result in modification of such membrane properties as fluidity,j3 activity of membrane-bound enzyme^,^^.^^ receptor m ~ b i l i t y , ~ excitability, ~.~’ and transduction of biological According to the considerations expounded above, the changes in cotransport activity may justly be considered a primitive involution of this transport system, related to changes in membrane lipid content occurring in old age, and not related to changes in metabolism (like hypercholesterolemia, hypertrygliceridemia, hyperinsulinemia, etc.) linked to aging. Centenarians generally present a low concentration of insulin, with a mean insulin level of 7.1 f 4.0 (normal values [n.v.] 3-35 IU/ml); and a normal lipidic equilibrium, with a cholesterol value of 182.3 f 34.9 mg/dl (n.v. 120-200) and tryglyceride level of 99.8 k 33.7 mg/dl (n.v. 30-190) and intermediate values of HDL 46.7 5 11.8. We can conclude that, even if it is difficult to define “normal” values in aging because of interindividual variability in the alteration of physiological functions of organs and tissues, it is possible to find very old people, in particular centenarians, whose values are not different from those of younger adults. Most important is to identify and treat the weakest apparatus, in order to preserve a level of functioning suitable to the modified needs of old age.
*
REFERENCES
I . WILLIAMS, G . C. 1957. Pleiotropy, natural selection, and the evolution of senescence. Evolution (11): 398-41 I . 2. COMFORT,A. 1929. I n The Biology of Senescence. Elsevier North Holland. New York, NY. 3. MARIGLIANO, v.,c. BAIJCO,E.BAGAGLINI. D. BRIOLI, M. CACCIAFESTA,A. ARABIA, A. L. TAssl & M. G . GALLI. 1990. I Centenan nel Lazio: II diritto alla longevith. Rass. Geriatrica %(I): 5-1 I . 4. MARIGLIANO, v.,c. BAIJCO,M. CACCIAFESTA, c. BIJCCA,E. BAGAGLINI, D. BRlOLl & F. CAMPANA. 1991. Health and living conditions of centenarians in Italy. Proceedings of the Conference “Mechanisms of Aging and Longevity,” Tblisi, C.I.S.: 244-246. v., c. BAIJCO,M. CACCIAFESTA, c. BUCCA,E. BAGAGLINI, D. BRIOLI 5 . MARIGLIANO & F. CAMPANA. 1991. Mental activity in centenarians. Proceedings of the Conference “Mechanisms of Aging and Longevity,” Tblisi, C.I.S.: 246-248. 6. MARlGLlANOV., c. BAUCO,F. CAMPANA, M.CACCIAFESTA,E. ETTORRE&E. BAGAGLiN i. 1991. Arnbiente e stile di vita dei centenari nel nostro paese. Proceedings of the International Medical Congress of Mountain Climatology, Roccaraso, Italy. G. C. Di Lollo, Ed. Casa Editrice L’Antologia. Naples. In press. 7. MARlGLlANOV., c. BAUCO.M.CACCIAFESTA, c.,BIJCCA,E. BAGAGLINI & D. BRIOLI.
MARIGLIANO era/.: NORMAL VALUES IN EXTREME OLD AGE
8.
9. 10.
II. 12. 13. 14. 15.
16. 17. 18.
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