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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58:M367-M371 (2003)
© 2003 The Gerontological Society of America

More Favorable Midlife Cardiovascular Risk Factor Levels in Male Twins and Mortality After 25 Years of Follow-Up Is Related to Longevity of Their Parents

Terry Reed1, Dorit Carmelli2, Tiffany S. Robinson1, Shannon A. Rinehart1 and Christopher J. Williams3

1 Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis.
2 Center for Health Sciences, SRI International, Menlo Park, California.
3 Division of Statistics, University of Idaho, Moscow.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. Genetic studies of life span in humans have used broad survival measures, most commonly longevity, which is moderately correlated between parents and offspring. We examined whether genetic cardiovascular disease risk factors in male twin offspring are related to longevity of their parents in the National Heart, Lung, and Blood Institute twin study.

Methods. Cholesterol levels, body mass index, blood pressures, and pulmonary function measured over the first three examinations (average subject age 48, 58, and 63 years, respectively) were compared with the twins' paternal, maternal, and parental mean longevity divided into upper versus lower quintiles. The presence of an apolipoprotein E {epsilon}4 allele typed from DNA collected at Exam 3 and mortality in the twin cohort through 1997 were also examined in relation to parental longevity quintiles.

Results. Twins, particularly whose fathers died at younger ages, had significantly higher total cholesterol (p <.05), ratio of total cholesterol to high-density lipoprotein (p <.01), and blood pressures (p <.01) in middle age. This relationship decreased at the subsequent two examinations, but consistently, twins with longer-lived parents tended to have better risk factor profiles. A twin death (mean age 65) was significantly more common in families with mothers (p <.001) and, to a lesser extent, fathers who died early. An apolipoprotein {epsilon}4 allele was more common in families with parents' age at death in the lowest quintile (p <.05).

Conclusions. Systolic blood pressures, cholesterol levels, and the presence of the apolipoprotein E {epsilon}4 allele likely contribute to the observed familial correlations in longevity that have been reported in the literature.

LONGEVITY is correlated between parents and offspring (1–4), but the correlations are small and compounded by environmental differences across generations. Twin studies have generally found greater concordances in longevity, smaller intrapair differences, and overall higher similarity in age at death for identical (monozygotic, MZ) twins (5–8). Estimates of heritability using more recent genetic modeling methods have been in the range of 0.20–0.30 (6–8). Another approach has been to use twins to estimate the heritability of susceptibility to death, termed frailty. Such loci are related to aging through several different fatal or disabling diseases (9). Heritability estimates of frailty have consistently been near 0.5 (10,11). The higher estimates of frailty have been suggested to indicate that some genes effect longevity by altering the risk of death at different ages rather than directly determining age at death (7).

Families may be found with clustering of segregation of old age (12–14). Siblings of persons living to the age of 100 (centenarians) have an approximate fourfold risk to live into their nineties than do siblings of persons dying in their seventies (15). Such centenarians have a compression of morbidity and mortality into their later years, suggesting that the older an individual gets, the healthier he or she has been (16). No environmental trait has been significantly related to the ability to survive to extreme old age (14). Likewise, no environmental trait has been shown to be consistently associated with studies of longevity (17).

We hypothesized that some cardiovascular disease risk factors measured in the National Heart, Lung, and Blood Institute (NHLBI) twin study might be related to familial effects on parental longevity. More specifically, we asked the following question: Do subjects with long-lived parents differ on these traits compared with subjects whose parents had the shortest life spans? Furthermore, if twins are divided on the basis of their parental life spans, do they have differences in deaths after 25 years of follow-up? Apolipoprotein E (apoE) typing was performed on DNA samples collected at the third examination of the NHLBI twins. At the apoE locus, the frequency of the {epsilon}4 allele has been found to be less in older versus younger cohorts of the same population (18,19). We hypothesized that the presence of the apoE {epsilon}4 allele might also be related to parental longevity because of its association with Alzheimer's and cardiovascular diseases.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study Population
The NHLBI twins were ascertained from the National Academy of Sciences–National Research Council (NAS–NRC) twin registry (20). Details of recruitment into the NHLBI twin panel from the NAS–NRC registry, participation rate, determination of zygosity, and initial examination protocol are published in the literature (21). There have been a total of five examinations over a roughly 30-year period. Between 1969 and 1973, 514 twin-pairs volunteered for the first exam. Mean age of the cohort at entry was 48 years. The second examination took place in 1981–1982, and 792 twin subjects (363 complete pairs) were examined at a mean age of 58. The third examination took place in 1986–1987, and 622 twin subjects (268 pairs and 86 singletons) participated at the age of 63. Between July 1995 and April 1997, the fourth examination of the NHLBI twins took place. Five hundred and two subjects were examined, including 203 complete pairs, at a mean age of 72 years. The final full examination of this twin cohort took place in 1999–2000, with 337 subjects examined.

Family History
At entry, family history information (including birth year or current age, and cause and age at death, if deceased) was collected on each individual twin's parents by a physician during a physical examination. At Exam 2, a physician updated the family history and inconsistencies provided by the two twins separately at the first examination were resolved. At Exams 3 and 4, a genetic assistant updated the family history; family history at Exam 5 was further updated only at the Indiana center.

With the use of the most recent information for each twin-pair, age at death of both parents was determined. Parents whose deaths were accidental, or were due to communicable diseases before age 40, and maternal deaths during childbirth were excluded. After excluded parents and those without any known information were removed, deaths were recorded for 462 of 491 (93.3%) fathers and for 433 of 493 (87.8%) mothers. For the 60 mothers and 29 fathers known to be alive at the last examination of the twin's participation, projected ages of death using life tables were made. Mean ages at death were 74.9 for fathers, 78.5 for mothers, and 76.9 for the combined parental ages. From the distribution of deaths and projected age of death, quintiles were determined. In this study, we compared the lowest quintile with the highest quintile. Cutoffs for the low and high quintiles were as follows: fathers, low of <=65 and high of >=86; mothers, low of <=68 and high of >=89; and parents, low of <=69 and high of >=85.

Statistical Methods
Variables measured at the first three examinations included lipids, that is, total cholesterol, high-density lipoprotein (HDL) cholesterol, and the total cholesterol–HDL ratio, body mass index (weight in kilograms divided by height in meters squared), and systolic and diastolic blood pressures. Blood pressures were the mean of seated measures taken twice at the initial examination and three times at Exams 2 and 3. Forced vital capacity (FVC) was examined only from Exams 2 and 3 when the methods from center to center were standardized. A greater proportion of subjects who did not return for later exams did so because of illness or mortality associated with some of these risk factors, and treatment for chronic disease (e.g., hypertension medication) progressively increased in subsequent examinations.

Systolic blood pressures and FVC were adjusted for age by means of linear regression. Variables not normally distributed were log transformed to reduce skewness, and the analyses were repeated, including removal of any outliers after transformation. The means presented in Table 1 are those using nontransformed or age-adjusted raw data with p values presented for comparisons in which variables were transformed.


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  		Table 1. Comparison of Means of Quintile 5 Versus Quintile 1 at Exam 1.

 
High and Low Group Comparisons
Subjects whose parents were in the highest longevity quintile were compared with subjects whose parents were in the lowest longevity quintile. Separate analyses were done for paternal, maternal, and the mean parental age quintiles. As a way to test for differences between the extreme quintiles, F tests were calculated by use of the Proc MIXED program in SAS (SAS Institute, Cary, NC). This procedure allowed a test to be conducted between the quintiles while also accounting for the correlation between twin-pairs within a family. It further allowed the twin correlation to differ between zygosity groups. This approach allowed measured values of both twins to be used in complete pairs.

A 2 x 2 chi-square square analysis between extreme quintile groups was compared for mortality outcome data as of Exam 5 when the mean age of participating twins was in the midseventies. If a death occurred in one or both of the twins in a pair, the family was scored as having a death. If both cotwins were still living, then the family was scored as having no death. If a twin's death was accidental, the family was scored as not having a death. A similar statistical analysis was used for the presence of the apoE {epsilon}4 allele. Families in which one or both cotwins had an {epsilon}4 allele were compared with families in which both cotwins did not have this allele. Only six families with a twin with the 4-4 genotype were in the two extreme quintiles (three each).


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Table 1 displays the results for comparisons of twins with paternal, maternal, and mean parental deaths in quintile 5 (most long-lived) versus quintile 1 (least long-lived) for the entry examination. None of the comparisons at Exams 2 or 3 displayed any significant difference for paternal, maternal, or parental longevity quintiles. The means of nearly all variables, even if not significantly different, at Exams 1–3 were in the direction of expectation of better profile in the twins whose parents were long-lived (lower systolic blood pressures, higher HDL cholesterol, lower total cholesterol–HDL ratios, lower total cholesterol, and higher FVC). There was no trend for body mass index related to parental quintile of longevity.

Significant differences were more common in men based on the longevity of their fathers at the initial examination for both blood pressure measures, total cholesterol, and the total cholesterol–HDL ratio (Table 1). There were few significant differences in twins divided on the longevity of the mother or the longevity of their parents in the first three examinations. Systolic blood pressure at the first examination was significant for comparisons based on maternal longevity and at the.05 probability level for overall parental longevity. Table 2 shows that the apoE {epsilon}4 allele was significantly associated with twins whose father's had the shortest life spans and also the average parental quintile of death.


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  		Table 2. Relationship of Children of Quintile 5 Versus Quintile 1 and the Presence of the ApoE {epsilon}4 Allele.

 
Multivariate analyses (data not shown) indicated that systolic blood pressure and the total cholesterol–HDL ratio were independent of each other. For systolic blood pressure (by means of paternal and maternal quintiles) and the total cholesterol–HDL ratio by paternal quintile, we further compared the means in quintiles 1 and 5 with each of the other middle quintiles. If familial factors related to longevity were more predominant, then quintile 5 might differ from some of the other quintiles. Conversely, if familial factors related to a shortened life span because of early cardiovascular disease predominate, then quintile 1 might differ from other than quintile 5. For all three variables, there was no significant difference between quintile 1 (shortest parental longevity) and any of the middle quintiles. Table 3 shows that quintile 5 (longest-lived parents) had a significantly lower blood pressure and total cholesterol–HDL ratio than one or more of the middle quintile groups.


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  		Table 3. Comparison of Middle Quintiles Means Versus Quintiles 5 and 1 for Systolic BP and Total Cholesterol–HDL Ratio.

 
Outcome Comparisons
At the time of the fifth examination, there were 268 known deaths in the NHLBI twins. Of these, 11 deceased twins had parents for which no family history information was available, including adoption; 14 other deaths were accidental, suicides, or of unknown cause on the death certificate. Table 4 shows the breakdown of the remaining deaths by longevity quintile of the parents. Early death of the father or mother or early mean parental age at death led to a twofold to threefold increase of death by Exam 5 in the NHLBI twins. The strongest association was with the mother's age at death (odds ratio of 2.93). The association with the father's quintile of death was just beyond statistical significance (.06).


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  		Table 4. Comparison of Twin Participant Death by Parental Longevity Quintile.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
At the entry examination, when the NHLBI male twins were at a mean age of 48, blood pressures and serum lipids were significantly associated with the quintile of survival of their fathers. Men whose fathers lived to be 86 or older had significantly lower blood pressures and significantly lower total cholesterol levels and total cholesterol–HDL ratios than did men whose fathers lived no longer than to the age of 65. The relationship steadily declined in the two subsequent examinations, when the mean ages of the twins were 58 and 63 years, respectively. Similar trends were also noted for systolic blood pressure based on maternal quintile of death. The relationship at Exam 1 between cholesterol level with the father's longevity, and blood pressures with both the mother's and father's longevity in our study, may be composed of two not necessarily mutual exclusive explanations. There could be earlier morbidity and mortality in quintile 1 with early parental deaths or later morbidity and mortality in those with later parental deaths (quintile 5). Fabsitz and colleagues (22) showed that nonparticipants at Exam 2 had greater overall mortality, higher frequencies of hypertension, diabetes, and pulmonary disease at the entry examination than did subsequent participants at the second examination. In Framingham offspring, familial similarities for age at death may be mediated through coronary heart disease risk factors, including systolic blood pressures, serum cholesterol, and maternal age at death (23). In our comparisons among all quintile groups for significant variables between quintiles 5 and 1 (Table 3), quintile 1 did not have significantly higher systolic blood pressure levels or total cholesterol–HDL ratios than any of the middle three quintiles. These risk factors did show lower values for those in quintile 5 compared with some of the other middle quintiles. We also found similar results for Exams 1–3, if we restricted the quintile 1 versus 5 comparisons to only those individual twins who participated in all three examinations. The results are more consistent with familial effects related to later morbidity in those with the most long-lived parents.

Previously, we showed that the highest risk group for mortality by the third and fourth examinations in this twin cohort were those with higher systolic blood pressure and lower HDL cholesterol at the entry examination (24,25). Our results also show that the risk of death by 1997 was strongest if the twin-pair had a mother who died early in comparison with those whose mothers were most long-lived (Table 4). This result is more consistent with other studies that found living to older age tends to be more strongly associated with maternal than paternal longevity (1,2,23).

Total serum cholesterol is known to decline in importance as a risk factor for cardiovascular disease with age (26). We previously reported that total cholesterol at the entry examination of the NHLBI twins was related to a family history score for heart disease based on the age and sex of other family members (27). This relationship declined with cholesterol levels at subsequent examinations. Parental longevity and cholesterol levels in this study show the same pattern. Our results suggest a similar relationship with blood pressure.

One limitation of our study is that none of the stated parental causes of death or ages were verified by medical record. However, the twins independently gave family histories at the first two exams and these were later compared and any differences resolved. All individuals with parents who died before the age of 40 from infectious disease (5 mothers, 2 fathers), childbirth (5), or unknown causes (4 mothers, 6 fathers) were omitted, as were all accidental causes of death (7 mothers, 15 fathers), regardless of the age of the parent. Over 90% of fathers and nearly 90% of mothers had died by the last examination of the twins' participation. The remainder of parents had a projected age of death calculated on the basis of life tables. In the lowest quintile, none of the twins had a parent who was not already deceased. In quintile 5, 19 of 29 mothers with a projected age at death were already in quintile 5 (at least age 89), and the other 10 had a mean age of 85 (range 81–88 years). Similarly, 8 of 15 living fathers had reached age 86 (quintile 5) and the remaining 7 were at a mean age of 81.

Swan and associates (28) have suggested that risk factors associated with mortality may have different profiles depending on when they were assessed over the life span. In centenarian families, siblings (15) and parents live longer (12,29). In centenarians, the frequency of the apoE {epsilon}4 allele is decreased (19,30–32), and there are decreased arterial pressures (33) and more favorable lipid profiles (34,35). Barzilai and colleagues (36) have shown that children of centenarians have better lipid profiles than their spouses. An abstract was published that suggests children of centenarians take fewer blood pressure medications (37). We found a decreased frequency of the {epsilon}4 allele at the apoE locus in those subjects whose parents were long-lived from DNA collected at the third examination (Table 2). In the smaller sample of our twins surviving to participate at Exam 4 at an average age of 72, we observed that systolic blood pressure levels again become significantly related to quintile of death for mothers, fathers, and the parental average age at death (Table 5). It is possible that, had we done blood lipid studies at Exam 4, some of the lipid measures would also have become related to parental longevity, as this panel aged and disease pathology became more common.


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  		Table 5. Comparison of BP Means of Quintile 5 Versus Quintile 1 at Exam 4.

 
An assumption in our study was that the tendency of long-lived parents to have longer-lived offspring was due to familial factors. Most of the cardiovascular risk factors we analyzed are genetically complex and have significant environmental components. Gerdes and associates have suggested that apoE is a frailty locus (38). A frailty locus is one that is related to aging through different fatal or disabling diseases, not a locus that is responsible for longevity per se. Recently, a locus on chromosome 4 in humans was linked with longevity in families that have centenarians (13). The DNA stored on the NHLBI twins when the men were an average age of 63 may be worthwhile for typing other aging-related loci in the future. Our results suggest that systolic blood pressure, cholesterol, and the presence of the apoE {epsilon}4 allele likely contribute to the observed familial correlation of longevity in the literature.


   Acknowledgments
 
This work was supported by Grant HL51429 from the NHLBI and by Grants MO1RR00750 and AG18736 from the National Institute on Aging.

Address correspondence to Dr. Terry Reed, Department of Medical & Molecular Genetics, IB 130, 975 West Walnut Street, Indianapolis, IN 46202-5251. E-mail: treed{at}iupui.edu

Received June 12, 2002

Accepted September 25, 2002


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

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