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Increased longevity in the siblings of late fertile women

Ken R. Smith1, 2

Geri Mineau2, 3

Richard A. Kerber2, 3

Elizabeth O’Brien2

Richard M. Cawthon4

1Department of Family and Consumer Studies

2Huntsman Cancer institute

3Department of Oncological Sciences

4Department of Human Genetics

University of Utah

Salt Lake City, Utah 84112-5330

USA.

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Summary

Evolutionary theory predicts genetically determined inter-individual differences in rates of aging

in humans should exist that contribute to inter-individual variation in both the duration of

reproductive life and the age at death. Here we show that among persons with a long-lived

opposite sex sibling (a sister age 98 or older or a brother age 96 or older), those with a late fertile

sister (childbirth at age 46.4 or older) enjoyed a higher median life expectancy (+ 3.9 years for

men, + 6.5 years for women) and probability of surviving to the 95th percentile for age at death

(3.5-fold higher for men, 6.6-fold higher for women) than those whose sisters all completed their

childbearing before age 43.9. These results support the hypothesis that some genetic variants in

human populations simultaneously slow aging, maintain female fertility later in life, and

contribute to longevity in both sexes.

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Introduction

Senescence, the deterioration in functioning that is associated with advancing adult age

and increasing adult mortality rates(Finch 1990), is subject to genetic regulation (Jazwinski

1998; Vaupel, Carey et al. 1998). Delayed senescence and increased mean and maximum life

spans in both sexes of the fruit fly Drosophila melanogaster have been achieved by selective

breeding of late-reproducing females from genetically heterogeneous stocks (Rose and

Charlesworth 1981; Luckinbill and Clare 1987; Rose, Nusbaum et al. 1992; Partridge, Prowse et

al. 1999). Recent work has shown that selection for late reproduction in female mice also yields

longer-lived strains (Nagai, Lin et al. 1995). Furthermore, field studies of reproductive histories

and mortality patterns in opossums (Austad 1993), and in baboons and lions (Packer, Tatar et al.

1998), suggest that the timing of reproductive cessation in female mammals is determined

primarily by the rate of senescence.

If there were evidence for genetic co-determination of late fertility in women and

longevity in both sexes, then researchers would then be able to select for study the long-lived

individuals most likely to carry genes for slower aging, i.e., those from families containing late

fertile women. Furthermore, late fertility, along with other putative biomarkers of slower aging

that can be measured in middle-aged women and their family members, may constitute a trait or

trait cluster sufficiently specific for slow aging to allow the identification of the relevant genes

even when long-lived research subjects are not available.

Early age at natural, but not surgical, menopause is associated with higher rates of all-

cause mortality (Snowdon, Kane et al. 1989; Cooper and Sandler 1998). Childbearing after age

40 was four times more frequent in centenarian women than in control women who died in their

early seventies (Perls, Alpert et al. 1997). During a period of natural fertility, late female

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fertility was associated with excess longevity after adjusting for the effects of parity (Smith,

Mineau et al. 2002). These studies support the hypothesis that late menopause and late fertility

are markers for slower rates of aging in women. Family and twin studies of age at natural

menopause per se (Torgerson, Thomas et al. 1997; Snieder, MacGregor et al. 1998) and

longevity per s e (Bocquet-Appel 1990; McGue, Vaupel et al. 1993; Perls, Bubrick et al. 1998;

Kerber, O'Brien et al. 2001) indicate that each has a significant genetic component. However,

this body of work has not determined whether longevity is more frequent in the relatives of late

fertile (or late menopausal) women, as would be predicted if genes that slow aging promote both

late fertility in women and longevity in both sexes. Here we compare survival to extreme ages in

sibships containing at least one late fertile woman to survival in sibships in which no woman was

late fertile. To evaluate possible social and environmental explanations of increased sibling

longevity associated with late fertility, we also examine survival among the spouses of the

siblings of late fertile women.

Dataset and Approach

Complete data on human fertility and mortality among all siblings are rare. Most sources

of data on entire human sibships lack death dates, usually because the birth dates are relatively

recent. A unique and very useful resource to investigate our hypothesis is the Utah Population

Database (UPDB). This database includes genealogical data on over one million individuals.

Approximately 70% of the records in the UPDB are for individuals affiliated with the Church of

Jesus Christ of Latter-day Saints (LDS) or Mormons. These records include basic demographic

data (dates and places of birth, marriage, death) and religious data on parents and their children

spanning the years 1800 to 1997. The analysis presented here is for sibships in which all siblings

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were born between 1850 and 1900. We further restricted the sample to those siblings who

survived to age 60, in an attempt to remove some of the variability in survival unrelated to

variation in the rate of aging that would have been present otherwise. Requiring that individuals

survive to age 60 also ensured that female fertility was complete.

The hypothesis is that long life in some families is in part attributable to genetic variants

that slow the rate of aging in both sexes via a mechanism that also facilitates late fertility in

women. Long life in other families, however, while associated with a relative lack of risk factors

for early death, does not involve slower rates of aging and therefore is less likely to be associated

with late fertility. The hypothesis predicts better survival of both sexes in sibships containing

late fertile women than in sibships containing women who were not fertile late. However, the

difference in survival between these groups is expected to be small at younger adult ages when

the majority of deaths are attributable to causes unrelated to aging and larger at older ages when

the primary factor determining the timing of death is the rate of aging itself. According to this

model, as sibships are selected for increasingly long-lived probands, the risk of death from

causes unrelated to rates of aging should decrease, the longevity observed in the remaining

siblings should increase, and (of greatest importance here) the benefit to survival to extreme ages

associated with having a late fertile sister versus not having one should also increase.

To test the above prediction, we examined survival of same-sex siblings from sibships

classified according to the longevity of the longest-lived opposite-sex sibling (the maximum age

at death, or MaxAAD, among opposite-sex siblings), and the age at last birth of the latest fertile

sister (the maximum age at last birth, or MaxALB, among sisters). The control sibships were

those below the 75th percentiles of the distributions for both MaxAAD and MaxALB. Survival

was assessed only in individuals who were married only once and lived to at least age 60, from

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

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sibships containing at least three sisters and three brothers who all met these requirements. The

absence of extreme longevity and/or late fertility in control sibships in spite of the presence of

multiple siblings in which these traits could appear increased the probability that the sibships

truly did not carry factors that contributed to these traits. Sibship categories, numbers of sibships

in the UPDB, and numbers of individuals contributing to the analysis of brothers’ survival are

given in Table 1; similar data for the sisters’ analysis are in Table 2.

Methods

Inclusion and Exclusion Criteria

Only individuals with known birth and death dates, or with a known birth date and confirmation

from the federal Health Care Financing Administration that the individual was alive in early

1997, were included in this study. Sibships with a MaxALB less than age 32 (the fifth percentile

of the full distribution of MaxALB) were excluded from the study, on the assumption that early

cessation of fertility of the latest fertile sister was likely the result of disease or adverse

environmental circumstances and less likely the consequence of factors related to rates of aging

per se. To reduce the level of environmental risk factors for early death in men unrelated to rates

of aging, we restricted the brothers’ survival analysis to men affiliated with the LDS church (for

both the selected and control sibships); church affiliation has previously been shown to be

associated with increased life expectancy in men (but not in women).

Logistic Regression

Logistic regressions were used to derive Relative Risks (RRs) of extreme longevity

associated with MaxAAD and MaxALB, because the outcome measures are binary variables

(coded 1 or 0) that indicate that an individual, who must have reached his or her 60th birthday,

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

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either lived beyond selected extreme ages or died at a younger age. The threshold for extreme

longevity varied across analyses: living to the 85th, 90th, and 95th sex-specific percentile for age

at death. The definition of non-extreme longevity was always the same: not living to the 75th

sex-specific percentile for age at death. The primary covariates are dummy variables (again

coded 1 or 0) that measured whether an individual was in one of several categories of sibships

defined by various combinations of MaxAAD and MaxALB (Hosmer and Lemeshow 1999).

In a model that predicts, for example, the probability of living to the 95th percentile,

denoted as Y>95, versus the probability of not living past the 75th percentile, denoted as Y<75, a

logistic regression was estimated with the following form:

loge(Y>95/ Y<75) = α + {β1 x (MaxAAD+ and MaxALB+)} +

{β2 x (MaxAAD+ and MaxALB-)} +

{β3 x (MaxAAD- and MaxALB+)}.

The terms MaxAAD and MaxALB were flagged with ‘+’ or ‘-’ to denote whether or not an

individual had a long-lived opposite-sex sibling and whether or not they had a late fertile sister.

Three dummy variables were constructed for each of three pairs of MaxAAD and MaxALB

conditions (i.e., {++}, {+-}, {-+}) such that persons received a score of one if they satisfied both

MaxAAD and MaxALB conditions and a score of zero if they did not. The longevity of persons

comprising the three combinations of MaxAAD and MaxALB shown in this equation were

compared to the longevity of persons in a reference group of {MaxAAD- and MaxALB-}. The

terms α and βi (i=1,2,3) are the intercept and regression coefficients, respectively. The RR for

living to the 95th percentile for those in the {MaxAAD+ and MaxALB+} group, relative to the

reference group, was calculated by RR = exp(β1). Similarly, the RRs for the other two

comparisons were exp(β2) and exp(β3). For simplicity, the equation above does not show terms

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for covariates measuring birth year, affiliation with the LDS church, and sibship size although

these covariates were included in the estimated models.

Given that our analysis relies on a sample containing sets of brothers and sets of sisters,

extreme longevity among siblings will be correlated. This lack of independence of responses can

occur when unobservable genetic and/or environmental factors that are the same within sibships

are thought to create significant variability in longevity between sibships not accounted for by

observable factors (e.g., MaxALB, MaxAAD). To take into account unmeasured heterogeneity

between sibships, logistic regression models with unobservable normally-distributed random

effects were estimated (Davidian and Giltinian 1995). Our approach maximised an

approximation to the likelihood function integrated over the random effects; the integral was

based on an adaptive Gaussian quadrature approximation (Diggle, Liang et al. 1994). Results

based on models that incorporate random effects were quite similar (data not shown) to those

reported in Figures 2 and 3.

Sibship Size Effects

It was expected that individuals with many siblings would be more likely to live long than those

with fewer siblings, because of the significant social support that siblings may provide one

another. Social support provided by siblings may have been especially important at times when

government social programs were absent or not widely available (pre-1950s). The LDS church

also has not been a provider of extensive economic support, given its emphasis on personal

economic independence and self-sufficiency (Mangum and Blumell 1993).

Given this potential benefit of larger sibship sizes to sibling survival, and given that

selection for the maximum values of traits (in our case, MaxALB and/or MaxAAD) across

sibships tends by chance alone to select for larger sibships, one might expect to observe some

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

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association between late fertility in women and sibling longevity simply due to sibship size

effects. Therefore, we examined the effects that adjustments for sibship size might have on the

association between late fertility in women and survival of siblings to extreme ages.

Our requirement that each sibship have at least three once-married brothers and three

once-married sisters live to age 60 greatly limited the variation in sibship size in our sample.

Within this sample, we tested for associations between sibling survival and sibship size in

several configurations, differing in the way in which sibship size was determined, including

number of siblings ever born (all siblings, sisters only, or brothers only) and number who lived to

age 60 (all siblings, sisters only, or brothers only). We included sibship size as a covariate in our

logistic regression models in order to control statistically for its possible effects (either linear or

non-linear) on longevity. We also partitioned the sample into strata defined by sibship size and

tested whether the longevity benefits associated with the various longevity and fertility selections

changed when all sibships being compared had identical numbers of siblings. Sibship size was

never found to have a significant effect on extreme longevity.

Survival of siblings after age 60

Survival probabilities and mortality relative risks (RR) were estimated using Cox

proportional hazards regression. All RRs were adjusted for the potential confounding effects of

an individual’s year of birth, affiliation with the LDS church, and number of siblings, because

these variables are either known or suspected to be related to an individual’s own longevity, to

female fertility, and/or to overall longevity within a sibship. Figure 1a compares the survival of

men from four sibship categories. In sibships containing no sister who was fertile late, survival

after age 60 was significantly better for men who had a long-lived sister (green curve) than for

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men who had no long-lived sister (black curve). In sibships containing a long-lived sister,

survival after age 60 was significantly better for men who had a late fertile sister (red curve) than

for men who had no sister who was fertile late (green curve). The median male life expectancy

after 60 associated with having both a long-lived and a late fertile sister was 5.9 years higher

than that associated with having neither a long-lived nor a late fertile sister, and 3.9 years higher

than that associated with having a long-lived sister but no sister who was fertile late.

Figure 1b compares the survival of women from four sibship categories. In sibships

containing no sister who was fertile late, survival after age 60 was significantly better for women

who had a long-lived brother (green curve) than for women who had no long-lived brother (black

curve). In sibships containing a long-lived brother, survival after age 60 was significantly better

for women who had a late fertile sister (red curve) than for women who had no sister who was

fertile late (green curve). The median female life expectancy after 60 associated with having

both a long-lived brother and a late fertile sister was 9.8 years higher than that associated with

having neither a long-lived brother nor a late fertile sister, and 6.5 years higher than that

associated with having a long-lived brother but no sister who was fertile late.

Relative risks of siblings surviving to extreme ages

Estimates of relative risk (RR) of survival to various extreme ages were based on multivariate

maximum likelihood logistic regression techniques (see Methods). Adjustments for the same

confounders as those used in the survival analyses were also made here.

It is possible that some benefits to survival associated with having a long-lived opposite-

sex sibling and/or a late fertile sister arise by a social or environmental mechanism other than

those adjusted for above (birth year, church affiliation, sibship size). If this is correct, and if

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marriage partners tend to share environments, then spouses of siblings of long-lived and/or late

fertile individuals would be expected to live longer than spouses of individuals from sibships

without a long-lived or a late fertile individual. To test this, the same longevity thresholds and

covariates used in the logistic regression analysis to examine brothers’ and sisters’ longevity

were used to study spouses’ longevity. The spouse analysis was restricted to once-married

couples in which both spouses survived to age 60.

Figure 2 compares brothers’ survival in three categories of sibships: those containing a

long-lived sister and a late fertile sister (Category 1 in Table 1), those containing a long-lived

sister but no late fertile sister (Category 2 in Table 1), and those containing neither a long-lived

nor a late fertile sister (Category 4 in Table 1, the control group). Figure 2a shows that in

sibships containing no late fertile sister, the relative risks (z axis) of brothers surviving to various

ages (y axis) improved as the age at death of the longest-lived sister (x axis) increased (Category

2 vs. Category 4 sibships). Figure 2b shows that this association of brothers’ survival with the

longevity of the longest-lived sister was stronger in sibships containing a late fertile sister

(Category 1 vs. Category 4 sibships). Here, the RR for men attaining the 95th percentile of

survival reached 6.94. Figure 2c shows the significant benefit to men’s survival of having a late

fertile sister when all sibships in the analysis contain a long-lived sister (Category 1 vs. Category

2 sibships; p < 0.05 at the white filled triangles in 2c). Furthermore, survival risks generally

improved as the age at last birth of the latest fertile sister increased from the 85th to the 95th

percentile (data not shown).

Figure 3 compares sisters’ survival in three categories of sibships: those containing a

long-lived brother and a late fertile sister (Category 1 in Table 2), those containing a long-lived

brother but no late fertile sister (Category 2 in Table 2), and those containing neither a long-lived

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

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brother nor a late fertile sister (Category 4 in Table 2, the control group). Figure 3a shows that in

sibships containing no late fertile sister, the relative risks (z axis) of sisters surviving to various

ages (y axis) improved as the age at death of the longest-lived brother (x axis) increased

(Category 2 vs. Category 4 sibships). Figure 3b shows that this association of sisters’ survival

with the longevity of the longest-lived brother was stronger in sibships containing a late fertile

sister (Category 1 vs. Category 4 sibships). Here, the RR for women attaining the 95th percentile

of survival reached 21.9. Figure 3c shows the significant benefit to women’s survival of having

a late fertile sister when all sibships in the analysis contain a long-lived brother (Category 1 vs.

Category 2 sibships; p < 0.05 at the white filled triangle, and 0.05 < p < 0.1 at the white filled

circle in 3c). Furthermore, survival risks generally improved as the age at last birth of the latest

fertile sister increased from the 85th to the 95th percentile (data not shown).

In contrast, no significant differences in the survival of wives were associated with their

husbands having (or not having) a long-lived sister and/or a late fertile sister, and no significant

differences in the survival of husbands were associated with their wives having (or not having) a

long-lived brother and/or a late fertile sister (data not shown). Furthermore, while the sibling

survival benefits associated with longevity and late fertility that are presented here have been

adjusted for the effects of birth year, affiliation with the LDS church, and sibship size, these

benefits were not substantively different even in the absence of these adjustments.

A frequently discussed evolutionary theory argues that there should be a trade-off

between reproductive success and longevity (e.g., ref. 19): slower rates of aging should be

associated with lower fertility and longer life. Indeed, a recent study found that lower parity

(bearing fewer children) was associated with significantly longer life in women (Westendorp and

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Kirkwood 1998). Therefore, we tested whether the already elevated relative risks of long life

associated with having a long-lived opposite-sex sibling and a late fertile sister (MaxALB in the

top 15% of the distribution of MaxALB) could be further increased by removing the 25% of

sibships in which the MaxALB sisters’ parities were the highest (12 or more children born per

sister). No significant changes in survival risks were observed (data not shown). These results

do not mean that there is no trade-off between reproductive success and longevity in humans;

further investigation of this question is needed. However, these results do suggest that sibships

selected for longevity, late fertility, and low parity are no more likely to carry genes that slow

aging than sibships selected simply for longevity and late fertility.

Discussion

The observation that late fertile sisters are associated with increased risks of sibling survival to

extremely old ages supports the hypothesis that there are genetic variants in the population that

slow aging by a mechanism that facilitates late fertility in women and contributes to longevity in

both sexes. The results also suggest that among sibships with equally long-lived individuals, the

sibships with late fertile sisters are more likely to carry genes that slow aging. Furthermore,

because longevity associated with late fertility is a more specific phenotype than longevity per

se, the genetic heterogeneity underlying this dual phenotype is likely to be less. Therefore,

genetic linkage analyses of longevity may be more powerful in families with late fertile women

than in families with no late fertile women. It may also be useful to substitute or supplement

phenotyping for late fertility with phenotyping for late menopause, if it can be established that

late menopause is associated with increased sibling survival to extreme ages.

There was only a small increase in sibling survival associated with selection on late

fertility in the absence of a long-lived opposite-sex sibling (Figure 1, blue survival curves). This

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may suggest that only some late fertility involves slower aging. However, such modest survival

benefits may be expected even in the presence of slower rates of aging, since selection only for

late female fertility in sibships does little to reduce the frequency of major risk factors (some

genetic, some non-genetic) for common diseases (e.g. heart disease, cancer, stroke) that can

threaten life in late middle and early old age. To begin to assess what proportion of late fertile

women are truly aging slowly, in women exceeding various thresholds for lateness of fertility,

additional indicators of slow aging other than longevity will need to be measured.

It may be feasible, therefore, to map genes that slow aging even without long-lived

research subjects, if heritable quantitative traits that are as good or better indicators of slow rates

of aging can be measured in middle-aged individuals. Late fertility, late menopause, and

continuing menstruation at an age that guarantees a late menopause are reasonable candidate

traits. Among middle-aged menstruating women approaching the average age at natural

menopause (50-51 years), those maintaining relatively high fertility may be distinguishable by

serum Follicle- Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels that are lower

than expected for the women’s ages (Ahmed Ebbiary, Lenton et al. 1994). Even among young

fertile women it may be possible to identify those destined for a late menopause (and possibly

late fertility) as those with menstrual cycle lengths at the high end of the normal range (Whelan,

Sandler et al. 1990). Furthermore, any largely heritable trait that predicts lower age-specific

mortality rates from multiple causes in longitudinal studies may be a marker for genetically-

determined slow aging. Examples are low peripheral blood leukocyte count (Grimm, Neaton et

al. 1985; Whitfield and Martin 1985; de_Labry, Campion et al. 1990; Weiss, Segal et al. 1995;

Weijenberg, Feskens et al. 1996), low resting heart rate (Dyer, Persky et al. 1980; Hanson, Tuna

et al. 1989; Wannamethee, Shaper et al. 1993; Mensink and Hoffmeister 1997; Greenland,

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Daviglus et al. 1999), and high percent-predicted forced expiratory volume in one second (Bang,

Gergen et al. 1993; McClearn, Svartengren et al. 1994; Rodriguez, Masaki et al. 1994; Weiss,

Segal et al. 1995; Hole, Watt et al. 1996; Emery, Pedersen et al. 1998). Low resting body

temperature may be another such trait (Lane, Baer et al. 1996). In middle-aged sibships initially

identified based on a late birth, one or more of the above traits could be measured in the proband

and her siblings; the families in which these phenotypes are clustering at higher than chance rates

may be those most suitable for genetic linkage efforts to identify genes that slow aging.

Social factors as well as the hypothesised genetic factors may play a role in explaining

the association between longevity and late fertility. It is possible, for example, that an individual

whose sister has children late in life will have a lower risk of death at extreme ages because of

social benefits conferred by the presence of younger adult kin. An individual who has long-lived

siblings may also expect to have above average longevity because of the support such siblings

might provide late in life. Our analysis of spouse longevity suggests that social variables

contribute less than genetic factors to the familial patterns of longevity we have observed.

However, it is clear that biological relatives sometimes share social factors more than non-

biological relatives, and it is not possible to definitively distinguish social and genetic

transmission of longevity in these data. Nevertheless, the results presented here should

encourage researchers to proceed with genetic analyses of slower aging and longevity in humans.

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Acknowledgements

We thank Drs. Sandra Hasstedt and Mark Leppert for helpful discussions. We thank the

Huntsman Cancer Institute for Utah Population Database support. This work was funded by the

AlliedSignal Award for Research on Aging (to R.M.C.), by National Institutes of Health /

National Institute on Aging grants (to K.R.S. and R.M.C.), and by a National Institutes of Health

National Cancer Institute grant (to R.A.K.).

Correspondence and requests for materials should be addressed to ken.smith@fcs.utah.edu

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

20

By definition, the longest-lived sister in a sibship was “long-lived” if her age at death (AAD) was in the top

15% of the distribution of AAD for longest-lived sisters (MaxAAD), and not long-lived if her AAD was

below the 75th percentile of MaxAAD. The latest fertile sister in a sibship was “late fertile” if her age at

last birth (ALB) was in the top 15% of the distribution of ALB for latest fertile sisters (MaxALB) and not

late fertile if her ALB was below the 75th percentile of MaxALB. These definitions placed all sibships

examined into one of four categories based on the presence or absence of a long-lived and/or a late fertile

sister (Column 1). Additional subsets of sibships (Columns 2 and 3) were identified, also based on the

MaxAAD and MaxALB among the sisters in each sibship. Column 5 gives the number of married-once

brothers who survived to at least 60, and Column 6 gives the number who were affiliated with the LDS

church, upon whom the survival analysis was based. Actual numbers of brothers surviving to various ages

are provided in Columns 7-10, but to derive the relative risks of survival presented in Figure 2, adjustments

were made for the effects on survival of birth year, church affiliation, and sibship size.

_______________________________________________________________________________________________________

Table 1 Sibships and individuals contributing to the analysis of brothers’ survival

Number of Brothers Surviving to the followingPercentiles of the Age at Death Distribution:

Sibship Categories

Longest-Lived Sister’s AAD as

Percentile of the MaxAAD Distribution

Latest Fertile Sister’s ALB as

Percentile of the MaxALB Distribution

Numberof

Sibships

Number of

Brothers

Number of LDSBrothers

<75th percentile

(83 yr)

≥ 85th percentile

(87 yr)

≥ 90th percentile

(89 yr)

≥ 95th percentile

(93 yr) 1. (+) Long-lived Sister (+)Late Fertile Sister

a. ≥ 85th (95 yr) ≥ 95th (46.4 yr) 39 131 89 59 30 27 11 b. ≥ 90th (96 yr) ≥ 95th (46.4 yr) 32 105 71 46 25 23 9 c. ≥ 95th (98 yr) ≥ 95th (46.4 yr) 18 58 40 24 16 16 7

2. (+) Long-lived Sister (-)Late Fertile Sister

a. ≥ 85th (95 yr) < 75th (43.9 yr) 386 1243 790 549 241 185 75 b. ≥ 90th (96 yr) < 75th (43.9 yr) 282 913 590 409 181 140 56 c. ≥ 95th (98 yr) < 75th (43.9 yr) 150 486 317 220 97 75 30

3. (-) Long-lived Sister (+)Late Fertile Sister

a. < 75th (93 yr) ≥ 85th (44.9 yr) 294 978 623 491 132 85 30 b. < 75th (93 yr) ≥ 90th (45.5 yr) 193 637 403 309 94 62 26 c. < 75th (93 yr) ≥ 95th (46.4 yr) 101 323 188 145 43 28 12

4. (-) Long-lived Sister (-)Late Fertile Sister < 75th (93 yr) < 75th (43.9 yr) 1633 5340 3248 2613 635 449 175

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

21

_______________________________________________________________________________________________________

Table 2 Sibships and individuals contributing to the analysis of sisters’ survival

Number of Sisters Surviving to the followingPercentiles of the Age at Death Distribution:

Sibship Categories

Longest-Lived Brother’s AAD as Percentile of the MaxAAD Distribution

Latest FertileSister’s ALB

as Percentile ofthe MaxALB Distribution

Numberof

Sibships

Number of

Sisters

Number ofSisters

below 75th

Percentileof ALB

<75th percentile

(87 yr)

≥ 85th percentile

(90 yr)

≥ 90th percentile

(92 yr)

≥ 95th percentile

(95 yr) 1. (+)Long-lived Brother (+)Late Fertile Sister

a. ≥ 85th (92 yr) ≥ 95th (46.4 yr) 42 132 41 27 14 10 6 b. ≥ 90th (94 yr) ≥ 95th (46.4 yr) 26 78 25 16 9 6 5 c. ≥ 95th (96 yr) ≥ 95th (46.4 yr) 11 35 10 6 4 4 3

2. (+)Long-lived Brother (-)Late Fertile Sister

a. ≥ 85th (92 yr) < 75th (43.9 yr) 399 1296 623 455 168 113 60 b. ≥ 90th (94 yr) < 75th (43.9 yr) 236 759 360 260 100 75 41 c. ≥ 95th (96 yr) < 75th (43.9 yr) 117 374 177 122 55 44 24

3. (-) Long-lived Brother (+)Late Fertile Sister

a. < 75th (90 yr) ≥ 85th (44.9 yr) 288 1046 321 264 57 39 18 b. < 75th (90 yr) ≥ 90th (45.5 yr) 186 678 207 173 34 25 11 c. < 75th (90 yr) ≥ 95th (46.4 yr) 99 366 112 97 15 12 4

4. (-) Long-lived Brother (-)Late Fertile Sister < 75th (90 yr) < 75th (43.9 yr) 1585 5300 2474 2056 418 247 118

By definition, the longest-lived brother in a sibship was “long-lived” if his age at death (AAD) was in the top

15% of the distribution of AAD for longest-lived brothers (MaxAAD), and not long-lived if his AAD was

below the 75th percentile of MaxAAD. “Late fertile” and not late fertile sisters were defined as in Table 1.

These definitions placed all sibships examined in one of four categories based on the presence or absence of a

long-lived brother and/or a late fertile sister (Column 1). Additional subsets of sibships (Columns 2 and 3)

were identified, also based on the MaxAAD among brothers and the MaxALB among sisters. Column 5 gives

the total number of married-once sisters who survived to at least 60. Column 6 gives the numbers for the

subset of sisters whose own ALBs were below the 75th percentile of the ALB distribution (41.9 years);

survival outcomes were evaluated only in these women to ensure that any increased risk of longevity observed

in them could not be due to the personal experience of a late birth and/or its consequences. The purpose of this

table is primarily to show sample sizes; actual numbers of sisters surviving to various ages are provided in

Columns 7-10, but to derive the relative risks of survival presented in Figure 3, adjustments were made for the

effects on survival of birth year, church affiliation, and sibship size.

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

22

Figure 1 Survival in sibships selected for longevity and late fertility. (a) For the brothers’

survival analysis, selection was based on the maximum age at death (MaxAAD) and the

maximum age at last birth (MaxALB) among the sisters of each sibship. The survival curves

presented here and the Table 1 categories to which they correspond are as follows: red curve,

Category 1c; green curve, Category 2c; blue curve, Category 3c; and black curve, Category 4.

Category 4, the control group, contained 66.4% of all the men in the study. The inset table

shows the relative risk of dying for men in each selected group, compared to this control group.

(b) For the sisters’ survival analysis, selection was based on the MaxAAD among the brothers

and the MaxALB among the sisters of each sibship. Survival was examined only in sisters

whose own ALBs were below the 75th percentile of the ALB distribution (41.9 years) to ensure

that the longevity observed would not be influenced by the personal experience of a late birth

and/or its consequences. The survival curves presented here and the Table 2 categories to which

they correspond are as follows: red curve, Category 1c; green curve, Category 2c; blue curve,

Category 3c; and black curve, Category 4. Category 4, the control group, contained 69.9% of all

the women in the study. The inset table shows the relative risk of dying for women in each

selected group, compared to this control group.

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

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Figure 2 Relative risks of survival in men associated with the highest age at death and age at

last birth among their sisters. (a) The risks (z axis) of surviving to various ages (y axis) for

brothers whose longest-lived sister died at an age (x axis) in the top 15% of the MaxAAD

distribution, relative to the survival risks for control brothers whose longest-lived sister died at

an age below the 75th percentile of the MaxAAD distribution; in all sibships the latest fertile

sister’s age at last birth was below the 75th percentile of the MaxALB distribution. (b)

Equivalent to panel a except that all brothers with a long-lived sister also had a sister who gave

birth at an age in the top 5% of the MaxALB distribution. Control brothers were identical to

those in panel a. (c) Survival of the brothers who had both a long-lived sister (MaxAAD ≥ 95th

percentile) and a late fertile sister (MaxALB ≥ 95th) is compared to the survival of the brothers

who had a long-lived sister (MaxAAD ≥ 95th percentile) but no sister who was fertile late (i.e.

the MaxALB sister’s last birth was below the 75th percentile for MaxALB). Two scales are

provided for both the x and y axes, one to show percentile of survival and the other to show

actual ages. In each panel the 9 datapoints upon which the contour plot is based are indicated by

the positions of symbols within and along the borders of the plot. RR values are shown at the

boundaries between contour bands. In panels a and b the same level of grey occurring in both

panels signifies approximately the same level of RR. The RRs in the top right corners of panels

a, b, and c were 1.97, 6.94, and 3.53, respectively. The level of statistical significance at each

datapoint is indicated by the symbols used: (p ≤ 0.01 = white filled diamond; p ≤ 0.05 = white

filled triangle; and p > 0.1 = black filled circle). These p values are based on a two-tailed test.

Late Fertility and Longevity Smith, Mineau, Kerber, O’Brien, Cawthon

24

Figure 3 Relative risk of survival in women associated with the highest age at death among

their brothers and highest age at last birth among their sisters. (a) The risks (z axis) of surviving

to various ages (y axis) for sisters whose longest-lived brother lived to an age (x axis) in the top

15% of the MaxAAD distribution, relative to the survival risks for control sisters whose longest-

lived brother died at an age below the 75th percentile of the MaxAAD distribution; in all sibships

the latest fertile sister’s age at last birth was below the 75th percentile of the MaxALB

distribution. Survival outcomes were evaluated only in sisters whose own age at last birth was

below the 75th percentile of the ALB distribution; this restriction was imposed to ensure that

longevity observed in these sisters was not influenced by the personal experience of a late birth

and/or its consequences. (b) Equivalent to panel a except that in panel b all sisters with a long-

lived brother also had a sister whose age at last birth was in the top 5% of the MaxALB

distribution. Control sibships were identical to those in panel a. (c) Survival of the sisters who

had both a long-lived brother (MaxAAD ≥ 95th percentile) and a late fertile sister (MaxALB ≥

95th) is compared to the survival of the sisters who had a long-lived brother (MaxAAD ≥ 95th

percentile) but no sister who was fertile late (i.e. the MaxALB sister’s last birth was below the

75th percentile for MaxALB). Other aspects of the contour plots are handled in the same way as

in Figure 2 (see above). The RRs in the top right corners of panels a, b, and c were 3.29, 21.9,

and 6.64 respectively. One symbol not present in Figure 1 appears here, the white filled circle.

This symbol signifies that the p value was between 0.05 and 0.1.

a

b

Frac

tion

aliv

eFr

actio

n al

ive

HighMaxAAD

HighMaxALB

Mortality RR(95% CI)

+ + 0.53 (0.34, 0.83)+ - 0.79 (0.71, 0.88)- + 0.90 (0.79, 1.03)- - 1.00 (reference)

HighMaxAAD

HighMaxALB

Mortality RR(95% CI)

+ + 0.35 (0.19, 0.65)+ - 0.69 (0.60, 0.80)- + 0.95 (0.79, 1.15)- - 1.00 (reference)

Men

Women

Age

85 90 9585

90

Perc

entil

e of

Sur

viva

l of B

roth

ers

Age

at D

eath

of B

roth

ers

9593

87

89

85 90 95Percentile of Survival of Longest-lived Sister

85

90

Perc

entil

e of

Sur

viva

l of B

roth

ers

Age

at D

eath

of B

roth

ers

95

Age at Death of Longest- lived Sister

95 96 98

93

87

89

b

c

Percentile of Survival of Longest-lived Sister

Percentile of Survival of Longest-lived Sister

a

85 90 9585

90

Perc

entil

e of

Sur

viva

l of B

roth

ers

Age

at D

eath

of B

roth

ers

9593

87

89

b

c

Percentile of Survival of Longest-lived Brother

Percentile of Survival of Longest-lived Brother

Percentile of Survival of Longest-lived Brother85 90 95

85

90

95

Age at Death of Longest-lived Brother

969492

Perc

entil

e of

Sur

viva

l of S

iste

rs

90

92

95

Age

at D

eath

of S

iste

rs

85 90 95

85

90

95

Perc

entil

e of

Sur

viva

l of S

iste

rs

90

92

95

Age

at D

eath

of S

iste

rs

a

85 90 9585

90

Perc

entil

e of

Sur

viva

l of S

iste

rs

90

92

95

Age

at D

eath

of S

iste

rs

95