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Clin Exp Immunol. Oct 2004; 138(1): 158–163.
PMCID: PMC1809173

High prevalence of autoantibodies among Danish centenarians

Abstract

The aim of this study was to investigate the prevalence of organ and nonorgan specific autoantibodies in relation to disability and comorbidity in an unselected population of centenarians. A population-based survey of all persons living in Denmark who celebrated their 100th birthday during the period 1 April 1995 to 31 May 1996, a total of 276 persons, was undertaken. Participants underwent an interview, a physical examination and blood sampling. Organ specific autoantibodies (Tg-ab, TPO-ab, PCA-ab) and nonorgan specific autoantibodies (ANA, IgM RF, IgA RF, MPO-ab, c-ANCA, p-ANCA, oxLDL-ab, IgM ACA, IgG ACA, PR3-ANCA, histone-ab, SSA-ab, SSB-ab, Mit-ab) were measured, and comorbidity and disability (Katz Index of ADL) were registered. In all, 207 (75·0%) of 276 eligible subjects participated, and 148 agreed to blood tests. A large majority (79·3%) had at least one autoantibody detected. Organ specific autoantibodies were present in 32·1% of the centenarians. The high level of autoantibodies did not reflect an equally high level of overt autoimmune disease. While nonorgan specific autoantibodies were equally represented in less-disabled/disabled subjects as well as in subjects with low/high comorbidity, significantly fewer subjects with organ specific autoantibodies were found among less-disabled subjects or subjects with low comorbidity. Autoantibodies (both nonorgan and organ specific) are common in an unselected population of centenarians of today, but do not reflect an equally high level of overt autoimmune disease. Non-organ specific autoantibodies are evenly distributed irrespective of the level of disability or comorbidity, suggesting underlying, undiagnosed pathological processes which may be part of the processes involved in frailty.

Keywords: autoimmunity, immunosenescence, centenarians, autoantibodies, comorbidity

INTRODUCTION

It is well-established that, in general, immune functions deteriorate with advancing age [1,2], and the prevalence of autoantibodies increases progressively with ageing [36]. However, it has been hypothesized that extreme survivors, such as centenarians, must be benefiting from a well-preserved immune function [7]. Indeed, based on their research on ‘healthy’ centenarians, i.e. subjects in good mental and physical condition, Franceschi et al. [7,8] have found evidence of a continuous remodelling of the immune system, rather than a general deterioration. In agreement with this Mariotti et al. [5] found lower prevalences of organ-specific antibodies to thyroglobulin (Tg-ab) and to thyroid peroxidase (TPO-ab) in 34 ‘healthy’ centenarians, compared to elderly controls aged 70–85, thus pointing to an unusually efficient immune system, as a possible explanation for these subjects’ extreme longevity. The same pattern is described in two other Italian studies, the first showing lower levels of thyroid autoantibodies in centenarians compared to younger old people [9], and the second finding higher prevalences of thyroid autoantibodies in disabled, compared to free-living healthy and fully independent octo- and nonagenarians [10]. In the latter study it is suggested that thyroid autoimmune phenomena in the elderly may be an expression of age-associated disease rather than related to the ageing process per se.

In a recent nation-wide study, The Danish Longitudinal Centenarian Study (DLCS) [11], initially launched to study the health and morbidity of an unselected population of extremely old people, some of the major findings was that healthy centenarians do not exist, and that centenarians of today suffer from a wide range of diseases and chronic conditions. Hence, following the thesis of Mariotti et al. [10], we should expect a high prevalence of autoantibodies among Danish centenarians, especially in those with high comorbidity and disability. The aim of our study was to investigate the prevalence of organ and nonorgan specific autoantibodies in an unselected population-based cohort of subjects aged 100, stratified for comorbidity and disability.

MATERIALS AND METHODS

Material

The DLCS is a nation-wide clinical epidemiological survey of all subjects living in Denmark who celebrated their 100th birthday during the period 1 April 1995 to 31 May 1996, a total of 276 subjects. Two hundred and seven subjects (162 women and 45 men, participation rate 75·0%) participated in the survey. The study has been described in detail in Andersen-Ranberg et al. [11].

Interview and clinical assessment

Approximately two weeks after their 100th anniversary all centenarians received a letter explaining the study. After informed consent the centenarians were visited in their domiciles by a geriatrician (K.A-R) and a geriatric nurse in order to do an interview and to make an extensive clinical assessment [11]. Further health information was retrieved from the general practitioner's medical records, The National Discharge Registry (valid from 1977), and from The Danish Cancer Registry (valid from 1943). Only medically confirmed diagnoses are used in the present work, not self-reported ones. After consent, blood was drawn by venipuncture from 148 (71·5%) of 207 centenarians participating. The DLCS has been approved by the Scientific-ethical Committee of the Counties of Funen and Vejle, Odense, Denmark. Trial numbers: 95/93 and 95/93MC.

The following present and medically confirmed diseases and chronic conditions, potentially threatening to health and well-being, were noted: Iron deficiency anaemia, vitamin B12 and folic acid deficiency anaemia, hyperthyroidism, hypothyroidism, diabetes mellitus, dementia (details in [12]), schizophrenia or chronic psychotic symptoms, bipolar affective disorder, Parkinson's disease, epilepsy, hypertension (actual treatment and/or blood pressure (≥160/≥100)), ischaemic heart disease including myocardial infarction, atrial fibrillation and flutter, chronic heart failure, stroke, chronic obstructive lung disease, emphysema, asthma, fibrosis, esophagitis or gastritis, gastric ulcer, diseases of gallbladder and liver, rheumatoid arthritis, gout, polyarteritis nodosa, polymyalgia rheumatica, lupus erythematosus disseminatus, osteoarthritis in major joints, recurring urinary bladder infections, prostatic hypertrophy, and pacemaker (a sign of existing failure of the cardiac conduction system). Included is also poor vision in spite of spectacles, hearing difficulties in spite of hearing aids, and urinary incontinence. Every single diagnosis or chronic condition was counted as one.

The autoimmune diseases identified in medical documents obtained from all participants were: pernicious anaemia, Graves’ disease, chronic autoimmune thyroiditis, rheumatoid arthritis (RA), polymyalgia rheumatica, and polyarteritis nodosa. One subject originally classified as having RA by his GP was, based on clinical features (butterfly shaped facial exanthema, asymmetric distribution of arthritis in the joints), re-classified as having lupus erythematosus disseminatus.

Comorbidity was dichotomized into 0–3 diseases (low comorbidity) and four or more diseases (high comorbidity). Disability was evaluated by activities of daily living using Katz's Index of ADL [13], and dichotomized into a group of less disabled or ‘relatively independent centenarians’ (Katz groups A, B and C), and a group of disabled or ‘relatively or very dependent’ (Katz groups D, E, F and G).

Antibody analysis

All antibodies were determined in EDTA plasma, which had been frozen for a maximum of 18 months at −70°C. Serum anti-thyroid peroxidase antibodies (TPO-ab) (N = 148) (normal range, <60 U/ml) were determined by the RIA DYNO test anti-TPOn (Brahms Diagnostica, Berlin, Germany). Serum thyroglobulin antibodies (Tg-ab) (N = 148) (normal range, <60 U/ml) were determined by the RIA DYNO test anti-Tg (Brahms Diagnostica, Berlin, Germany). Anti-dsDNA antibodies (dsDNA-ab) (normal range < 40 IU/ml) were determined by the SynELISA anti-dsDNA kit (Pharmacia, Copenhagen). Anti-SSA/SSB antibodies (SSAab, SSBab) (normal ranges < 2 U/ml) were determined using DIASTAT anti-Ro (SSA) and DIASTAT anti-La (SSB) kits (SHIELD Diagnostics, Scotland), anti-histone antibodies (normal range < 5 U/ml) by the DIASTAT anti-histone kit (SHIELD Diagnostics), anti-parietal cell antibodies (PCA-ab) of the IgG class reacting selectively with purified H+K+ATP-ase (normal range < 5 Uml) were determined by the Varelisa Parietal Cell Antibodies kit (Pharmacia), but PCA-ab were also studied by indirect immunofluorescense (IIF) on monkey stomach cryostat sections at serum dilution 1 : 10.

Anti-nuclear antibodies of the IgG class (ANA) were looked for by IIF using commercial HEp-2 ANA slides (ImmunoConcepts, Sacramento, CA, USA). The plasma was screened at a dilution of 1 : 160, and FITC-labelled anti-human IgG (Dako, Copenhagen) was used as conjugate. The reactivity was described as positive reactions with titres from 160 to = 1280.

IgM rheumatoid factors (IgM RF) were demonstrated by an ELISA technique as previously described using a cut-off for positivity of 8 IU/ml [14]. IgA RF was detected using similar reagents but peroxidase-labelled F(ab)2 fragments of rabbit anti-human IgA were used as conjugate, and the results were expressed in units related to a local standard (normal range < 25 U/ml).

Anti-neutrophil cytoplasmic antibodies (ANCA) of the IgG class were determined by IIF using smears of human leucocytes as antigen and a serum dilution of 1 : 20 as described [15]. The positive results were recorded as P-ANCA or C-ANCA dependent on the staining pattern and graduated as strong, intermediate or weak positive [16].

Proteinase 3-ANCA of the IgG class (PR3-ANCA) were determined by ELISA using purified PR3 as antigen [16], and the positive results were expressed in units related to a local standard (normal range < 10 U/ml).

Myeloperoxidase-ANCA of the IgG class (MPO-ANCA) was determined by the same method using purified MPO as antigen (normal range < 10 U/ml). Anti-cardiolipin antibodies of the IgG and IgM classes (ACA) were determined by ELISA as described by Mouritsen et al. [17] (normal range for IgG ACA < 30 U/ml and < 35 for IgM ACA). Anti-β2 glycoprotein-1 of the IgG and IgM classes (β2GP1-ab) was determined by ELISA using purified human β2GP1 as antigen [18,19] (normal range for IgG and IgM < 10 U/ml). Anti-mitochondrial antibodies of the IgG class (mit-ab) were determined by ELISA using submitochondrial particles as antigen substrate [20] (normal range < 6 U/ml).

Anti-extractable nuclear antigen antibodies (ENA-ab comprising U1RNP-ab and Sm-ab) were determined by passive microhaemagglutination technique as described [21] (normal range titre < 200 for both U1RNP and Sm antibodies). Anti-oxidated low density lipoprotein (IgG) (antiox-LDL) test was determined by in house ELISA using purified low density lipoprotein as antigen (normal range < 50 U/ml).

Statistical methods

Statistical calculations were performed using the SPSS for Windows (version 9·0 and 10·0) statistical software (SPSS Inc.). Simple proportions and their confidence intervals were calculated. Differences between autoantibody-positive and autoantibody-negative individuals were studied by χ2 test. Analysis of variance (F-test) and t-test for equality of means were used to compare the mean number of diseases in relation to being autoantibody positive or negative.

RESULTS

Overall, there were no significant differences between participants and nonparticipants in the principal study regarding either gender or type of housing [11]. In total, blood specimens were obtained in 148 participants, but in the present analyses plasma was only available in 140 (67·6%) of 207 participants. Again, no significant differences were seen between those who had and those who had not had a blood sample taken either for gender, type of housing or level of physical functioning [22].

Nearly all centenarians (95%) received medicine prescribed by a doctor on a regular basis. The median number (not including ‘prn’ medication) was 3. Consumption of alcohol was rather common, as 86% of all 207 participants enjoyed a drink on a daily basis or now and then. None were known to be addicted to alcohol.

Prevalence of autoantibodies

The prevalences of autoantibodies are given in Table 1. The most common autoantibody was the nonorgan specific IgM-RF found in 37 (26·6%) subjects (Confidence Interval (CI): (20, 34). The most common organ-specific autoantibody was a-PCA, present in 26 subjects (18·6%, CI: 13; 26) when using the IIF-test, but dropping to 15 (10·7%) subjects (CI: 6; 16) when using the specific anti-H+K+ATPase-test (data not shown). All ELISA-positive a-PCA were IIF positive as well. SSB-ab, Sm-ab, U1RNP-ab, IgG and IgM antibodies to β2 GP1 were not detected.

Table 1
Prevalence of organ and nonorgan specific autoantibodies among Danish centenarians

There were no significant gender specific differences in the distribution of autoantibodies with the exception of Histone-ab and ANCA (c & p), being present in only 2 male subjects and in 24 female and 1 male subject, respectively. The ANCA positive man was both p-ANCA and c-ANCA positive.

In total, 79·3% (n = 111) of the 140 centenarians had at least one autoantibody (Table 2). The proportion of individuals having organ specific autoantibodies (Tg-ab, TPO-ab or PCA-ab) either alone or in combination with nonorgan specific antibodies was 32·1% (n = 45; data not shown).

Table 2
Distribution of autoantibodies among Danish centenarians (n = 140)

Based on medical records 30 of the 140 centenarians were found to suffer from one autoimmune disease, while five suffered from two concomitant autoimmune diseases (Table 3).

Table 3
Relationship between medically confirmed autoimmune diseases and autoantibodies among Danish centenarians

Autoantibodies in relation to disability and comorbidity

While nonorgan specific autoantibodies were evenly distributed irrespective of level of disability or comorbidity, a significantly lower proportion of individuals positive for organ specific autoantibodies was identified in the group of subjects being less disabled compared to disabled subjects, 22·0% and 39·5%, respectively, P = 0·029 (Table 4). The association becomes stronger when looking at comorbidity, where only 12 of 63 subjects (19·0%) with low comorbidity were positive for organ-specific autoantibodies, compared to 33 of 77 subjects (42·9%) with high comorbidity (P = 0·003). Accordingly, the mean number of diseases was significantly lower among subjects with no organ specific autoantibodies compared to subjects with organ specific autoantibodies, being 4·1 (SD 1·7) and 5·1 (SD 1·6), respectively (P = 0·002, a mean difference of 0·99 (95%CI: 0·38; 1·60)). Subjects with no autoantibodies at all had a little lower (but not significantly lower) mean number of diseases compared to subjects who had both organ and nonorgan specific autoantibodies, mean number of diseases being 4·0 (SD 1·5) and 4·5 (SD 1·8), respectively (P = 0·143, a mean difference of 0·54 (95%CI: – 0·18; 1·26)). The tendency of increasing occurrence of organ-specific autoantibodies with increasing comorbidity is depicted in Fig. 1.

Fig. 1
Presence (An external file that holds a picture, illustration, etc.
Object name is cei0138-0158-mu1.jpg) or absence (□) of organ-specific autoantibodies in relation to comorbidity among Danish centenarians.
Table 4
Presence of organ and non-organ specific autoantibodies in relation to disability and comorbidity among danish centenarians.

DISCUSSION

This nationwide epidemiological study shows that, in a population of unselected extremely old subjects aged 100, autoantibodies are present in the majority (79·3%) of the population. Moreover, all three organ specific autoantibodies under study were present in a substantial part of centenarians (32·1%). However, while nonorgan specific autoantibodies were found to be evenly distributed among centenarians irrespective of both disability and comorbidity, organ specific autoantibodies (Tg-ab, TPO-ab, and PCA-ab) were significantly less represented in centenarians with low comorbidity or low disability.

These findings support the possibility that organ specific autoimmune phenomena in the elderly and oldest-old may be an expression of age-associated disease rather than related to the ageing process itself [10]. The low prevalence of organ-specific autoantibodies in centenarians who are less disabled or have low comorbidity may also indicate that those subjects benefit from a successful immunosenescence as proposed by Franceschi et al. [8]. However, these subjects comprise a minority of today's centenarians.

Our findings of high prevalences of autoantibodies in general among centenarians is in accordance with the present knowledge of increasing prevalences of autoantibodies with advancing age [2325], probably mirroring the increasing comorbidity and disability with advancing age. Yet, the high prevalence of autoantibodies did not reflect an equally high number of diagnosed antibody-associated diseases. As an example we found a high prevalence of both IgA and IgM RF in this study, but only a fraction of these sera came from patients with known RF-associated connective tissue diseases.

Interestingly, we found a high prevalence of IgM ACA and a low prevalence of IgG ACA, which is in contrast to both a Greek study of people aged 81 [26] and an Italian centenarian study [27], which both showed a very high prevalence of IgG ACA (58% in both cases). As ACA has been associated with thromboembolic episodes a low prevalence could be expected in centenarians due to differential mortality.

IgG-ANA was demonstrated in 14·3%, when using the most recently recommended cut-off titre 1 : 160 [28], but when applying the formerly used cut-off titre 1 : 40 IgG-ANA was the most prevalent autoantibody, demonstrated in 37·1% of Danish centenarians.

ANCA in centenarians have thus far only been studied by our group. The prevalence of 18% as shown by IIF (and slightly higher as shown by specific ELISAs) is higher than what is seen in healthy subjects less than 60 years of age in our laboratory (4–5%). ANCA produced in chronic inflammatory diseases, e.g. rheumatoid arthritis and ulcerative colitis are regarded as an immune response to constantly dying neutrophils at a site of chronic inflammation [29,30]. The increased prevalence of ANCA in centenarians may reflect an active neutrophil engagement in compensation for an inefficient anti-infectious immune capacity in older people, named ‘decreased protective immunity’ [31].

In this study organ-specific antibodies to parietal cells (PCA-ab) were identified in 18·6% by IIF (10·7% by ELISA) with the H+K+ATPase antigen as target, both being clearly more frequent than among Italian centenarians [27]. But other studies on old people find the same small, but substantial prevalence as we did [3234]. In the latter study, it was assumed to be related to the likely presence of atrophic gastritis in many centenarians [34], i.e. a disease-related phenomenon. In contrast, Mariotti et al. [5] did not find any PCA-ab in 34 so-called healthy centenarians.

Autoantibodies to the thyroid antigens TPO and Tg were as common in the present study as in younger healthy controls each being found in around 10%. Positive sera showed levels of TPO-ab and Tg-ab similar to those found in young blood donors (range 366–5629 and 62- > 2000 U/ml, respectively. This is in agreement with our previous conclusion that thyroid dysfunction is not more frequent in centenarians than in younger elderly people [22].

To be able to understand the development of autoantibodies with ageing per se they should preferably be examined in healthy subjects with no overt diseases. We tried to apply the SENIEUR criteria [35] upon our centenarians but we could only identify 9 subjects, a number much too small to allow statistical calculations. However, the small number also shows how rare healthy subjects – in the sense of being free from diseases and chronic conditions – are in an unselected population of extremely old people like centenarians.

To our knowledge no other study has investigated the presence of a large number of autoantibodies in an unselected population of centenarians. We found no differences in housing, gender, or functional capacity when comparing those who gave their consent to have a blood sample taken with those who did not. Yet, a weakness in this study lies in the fact that we were not able to retrieve all medical information from all the centenarians, and not all subjects agreed upon going through a complete medical examination. However, the diagnoses we have are not self-reported, but confirmed either by medical documents or by the clinical examination performed by an experienced specialist in geriatrics. Therefore the disease prevalences should be regarded as ‘best case scenarios’ [11].

To summarize, organ specific autoantibodies were more frequent among centenarians than previously reported, but significantly fewer were identified among a minor proportion of centenarians with low comorbidity or little disability. Hence, successful immunosenescence seems only to affect a small proportion of today's centenarians. It may have been more pronounced in earlier decades, when fewer and more selected subjects got the chance to become centenarians. However, as a probable result of improved health care and nursing facilities, most developed countries are experiencing an ongoing, increasing proportion of centenarians in recent decades which has made it possible for the oldest-old to survive in spite of a high comorbidity and disability [11,36]. Even in such more frail centenarians a better immune function in younger years compared to their fellow birth cohort members may have contributed to their ability to reach the last decades of human life span.

The high prevalence of autoantibodies was mainly due to nonorgan specific autoantibodies, which was unaffected by the level of comorbidity and disability. The lack of an equally high level of overt autoimmune disease to the high level of autoantibodies may be explained by a less well-controlled humoral antiself response, most probably stimulated by autoantigens released from cells undergoing increased apoptosis as part of the ageing processes. Maybe these processes are correlated to other underlying, undiagnosed pathological processes, which are not exclusively associated with disability or comorbidity, like the processes involved in frailty [37,38].

Acknowledgments

This study was supported by a grant from The Danish Interdisciplinary Research Council.

REFERENCES

1. Wick G, Grubeck-Loebenstein B. Primary and secondary alterations of immune reactivity in the elderly: Impact of dietary factors and disease. Immunol Rev. 1997;160:171–84. [PubMed]
2. Makinodan T, Kay MMB. Age influence on the immune system. Adv Immunol. 1980;29:287–330. [PubMed]
3. Tomer Y, Shoenfeld Y. Ageing and autoantibodies. Autoimmunity. 1988;1:141–9. [PubMed]
4. Hijmans W, Radl J, Bottazzo GF, et al. Autoantibodies in highly aged humans. Mech Ageing Dev. 1984;26:83–9. [PubMed]
5. Mariotti S, Sansoni P, Barbesino G, et al. Thyroid and other organ-specific autoantibodies in healthy centenarians. Lancet. 1992;339:1506–8. [PubMed]
6. Mariotti S, Chiovato L, Franceschi C, et al. Thyroid autoimmunity and aging. Exp Gerontol. 1998;33:535–41. [PubMed]
7. Franceschi C, Monti D, Sansoni P, et al. The immunology of exceptional individuals: the lesson of centenarians. Immunol Today. 1995;16:12–6. [PubMed]
8. Francesci C, Monti D, Barbieri D, et al. Successful immunosenescence and the remodelling of immune responses with ageing. Nephrol Dial Transplant. 1996;11:18–25. [PubMed]
9. Magri F, Muzzoni B, Cravello L, et al. Thyroid function in physiological aging and in centenarians: possible relationships with some nutritional markers. Metabolism. 2002;51:105–9. [PubMed]
10. Mariotti S, Barbesino G, Chiovato L, et al. Circulating thyroid autoantibodies in a sample of Italian octo-nonagenarians: Relationship to age, sex, disability, and lipid profile. Ageing (Milano) 1999;11:362–6. [PubMed]
11. Andersen-Ranberg K, Schroll M, Jeune B. Healthy centenarians do not exist, – but autonomous centenarians do: a population-based study of morbidity among Danish centenarians. J Am Geriatr Soc. 2001;49:900–8. [PubMed]
12. Andersen-Ranberg K, Vasegaard L, Jeune B. Dementia in centenarians. J Gerontol Psy Sci. 2001;56B:P152–P159.
13. Katz S, Ford AB, Moskowitz RW, et al. Studies of illness in the aged. The Katz Index of ADL. a standardized measure of biological and psychosocial function. J Am Med Assoc. 1963;185:914–9. [PubMed]
14. Høier-Madsen M, Nielsen LP, Møller S. Determination of IgM rheumatoid factors by enzyme-linked immunosorbent assay (ELISA) Ugeskr Laeger. 1986;148:2018–21. (In Danish). [PubMed]
15. Wiik A. Delineation of a standard procedure for indirect immunofluorescence detection of ANCA. APMIS. 1989;97(Suppl. 6):12–3. [PubMed]
16. Wiik A. Antineutrophil cytoplasmic antibodies (ANCA’s) and ANCA testing. In: Rose NR, Hamilton RG, Detrick B, editors. Manual of Clinical Laboratory Immunology. 6. Washington DC: ASM Press; 2002. pp. 981–6.
17. Mouritsen S, Høier-Madsen M, Wiik A, et al. The specificity of anti-cardiolipin antibodies from syphilis patients and from patients with systemic lupus erythematosus. Clin Exp Immunol. 1989;76:178–83. [PMC free article] [PubMed]
18. Erickson EN, Najmey SS, Keil LB, et al. Reference calibrators for investigators. Clin Chem. 1996;42:1116–7. [PubMed]
19. Voss A, Jacobsen S, Heegaard NH. Association of β2–glycoprotein I IgG and IgM antibodies with thrombosis and thrombocytopenia. Lupus. 2001;10:533–8. [PubMed]
20. Mouritsen S, Høier-Madsen M, Demant EJF, et al. Enzyme-linked immunosorbent assay for determination of anti-mitochondrial antibodies. APMIS Section C. 1985;93:205–10. [PubMed]
21. Høier-Madsen M, Andersen M. Microhaemagglutination test for detection of antibodies to ‘extractable nuclear antigen’ (ENA). Comparative investigations in different groups of patients for ANA, DNA- and ENA-antibodies. Ugeskr Laeger. 1980;142:2627–30. (In Danish). [PubMed]
22. Andersen-Ranberg K, Jeune B, Høier-Madsen M, et al. Thyroid function, morphology and prevalence of thyroid disease in a population-based study of Danish centenarians. J Am Geriatr Soc. 1999;47:1238–43. [PubMed]
23. Svee KH, Veit BC. Age-related antinuclear factor. immunologic characteristics and associated clinical aspects. Arthritis Rheum. 1967;10:509–16. [PubMed]
24. Willkens RF, Whitaker RR, Andersen RV, et al. Significance of antinuclear factors in older persons. Ann Rheum Dis. 1967;26:306–10. [PMC free article] [PubMed]
25. Wiik A, Jensen E, Friis J. Granulocyte-specific antinuclear factors in synovial fluids and sera from patients with rheumatoid arthritis. Ann Rheum Dis. 1974;33:515–22. [PMC free article] [PubMed]
26. Manousakis MN, Tzioufas AG, Silis MP, et al. High prevalence of anticardiolipin and other autoantibodies in a healthy elderly population. Clin Exp Immunol. 1987;69:557–65. [PMC free article] [PubMed]
27. Candore G, Di Lorenzo G, Mansueto P, et al. Prevalence of organs-specific and non organ-specific autoantibodies in healthy centenarians. Mech Ageing Dev. 1997;94:183–90. [PubMed]
28. Tan EM, Feltkamp TEW, Smolen JS, et al. Range of antinuclear antibodies in ‘healthy’ individuals. Arthrtis Rheum. 1997;40:1602–11. [PubMed]
29. Brimnes J, Halberg P, Wiik A, et al. Specificities of antineutrophil autoantibodies in patients with rheumatoid arthritis. Clin Exp Immunol. 1997;110:250–6. [PMC free article] [PubMed]
30. Brimnes J, Nielsen OH, Wiik A, et al. Molecular targets of autoantibodies in patients with ulcerative colitis. Dig Dis Sci. 1999;44:415–23. [PubMed]
31. Talor E, Rose NR. Hypothesis. the aging paradox and autoimmune disease. Autoimmunity. 1991;8:245–9. [PubMed]
32. Roberts-Thompson IC, Whittingham S, Young-Chayud V, et al. Ageing, immune response and mortality. Lancet. 1974;2:368–70. [PubMed]
33. Potocka-Plazak K, Pituch-Noworolska A, Kocembra J. Prevalence of autoantibodies in the very elderly: association with symptoms of ischemic heart disease. Ageing (Milano) 1995;7:218–20. [PubMed]
34. Reinberg-Laiko L, Louhija J, Rautelin H, et al. Helicobacter antibodies in Finnish centenarians. J Gerontol Med Sci. 1999;54A:M400–M403. [PubMed]
35. Lighthart GJ, Corberand JX, Fournier C, et al. Admission criteria for immuno-gerontological studies in man: The SENIEUR protocol. Mech Ageing Dev. 1984;28:47–55. [PubMed]
36. Jeune B. Living longer – but better? Aging Clin Exp Res. 2002;14:72–93. [PubMed]
37. Fried L, Tangen C, Walston J, et al. Frailty in older adults: Evidence for a phenotype. J Gerontol Med Sci. 2001;56A:M146–M156. [PubMed]
38. Morley JE, Perry HM, III, Miller DK. Something about frailty (Editorial) J Gerontol Med Sci. 2002;57A:M698–M704. [PubMed]

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