An unprecedented number of women will experience menopause in the next decade. Although the timing of menopause affects long-term disease risk, little is known about factors that affect this timing. In the present 1995--1997 cross-sectional study, the Study of Women's Health Across the Nation, the relation of demographic and lifestyle factors to age at natural menopause was examined in seven US centers and five racial/ethnic groups. All characteristics were self-reported by women aged 40--55 years (n = 14,620). Cox proportional hazards models were used to estimate the probability of menopause by age. Overall, median age at natural menopause was 51.4 years, after adjustment for smoking, education, marital status, history of heart disease, parity, race/ethnicity, employment, and prior use of oral contraceptives. Current smoking, lower educational attainment, being separated/widowed/divorced, nonemployment, and history of heart disease were all independently associated with earlier natural menopause, while parity, prior use of oral contraceptives, and Japanese race/ethnicity were associated with later age at natural menopause. This sample is one of the largest and most diverse ever studied, and comprehensive statistical methods were used to assess factors associated with age at natural menopause. Thus, this study provides important insights into this determinant of long-term disease risk in women.

In this protocol we describe a method to obtain telomere length parameters using Southern blots of terminal restriction fragments (TRFs). We use this approach primarily for epidemiological studies that examine leukocyte telomere length. However, the method can be adapted for telomere length measurements in other cells whose telomere lengths are within its detection boundaries. After extraction, DNA is inspected for integrity, digested, resolved by gel electrophoresis, transferred to a membrane, hybridized with labeled probes and exposed to X-ray film using chemiluminescence. Although precise and highly accurate, the method requires a considerable amount of DNA (3 μg per sample) and it measures both the canonical and noncanonical components of telomeres. The method also provides parameters of telomere length distribution in each DNA sample, which are useful in answering questions beyond those focusing on the mean length of telomeres in a given sample. A skilled technician can measure TRF length in ∼130 samples per week.

Some individuals remain uninfected with human immunodeficiency virus type-1 (HIV-1) despite multiple high-risk sexual exposures. We studied a cohort of 25 subjects with histories of multiple high-risk sexual exposures to HIV-1 and found that their CD8+ lymphocytes had greater anti-HIV-1 activity than did CD8+ lymphocytes from nonexposed controls. Further studies indicated that their purified CD4+ lymphocytes were less susceptible to infection with multiple primary isolates of HIV-1 than were CD4+ lymphocytes from the nonexposed controls. This relative resistance to HIV-1 infection did not extend to T-cell line-adapted strains, was restricted by the envelope glycoprotein, was not explained by the cell surface density of CD4 molecules, but was associated with the activity of the C-C chemokines RANTES, MIP-1alpha, and MIP-1beta. This relative resistance of CD4+ lymphocytes may contribute to protection from HIV-1 in multiply exposed persons.

Telomere length is similar in different organs of the human fetus but variable among fetuses. During extrauterine life telomere length is highly variable among individuals and longer in women than men. In the present work we addressed the following questions: 1) Are there sex-related differences in telomere length at birth? 2) Is there synchrony (i.e. correlation in length) of telomeres in tissues within the newborn? 3) Is the variability in telomere length among newborns as large as that in adults? We studied normal male and female newborns who donated DNA samples from three sources: white blood cells, umbilical artery, and foreskin. Telomere length was measured by the mean length of the terminal restriction fragments (TRF). TRF length was not different between male and female newborns. It was highly synchronized among the DNA samples from white blood cells, umbilical artery and skin within individual donors but exhibited a high variability among donors. We conclude that there is no evidence for the effect of sex on telomere length at birth, suggesting that longer telomeres in women than men arise from a slower rate of telomeric attrition in women. The variability in telomere length among newborns and synchrony in telomere length within organs of the newborn are consistent with the concept that variations in telomere length among adults are in large part attributed to determinants (genetic and environmental) that start exerting their effect in utero. The loss of telomere repeats associated with replication of human somatic cells in culture is central to the concept that in these cells telomeres serve as a "mitotic clock" (1). In human beings, telomere length of replicating somatic cells is inversely related to donor age (2-4), highly variable among donors of the same age (2-4), highly heritable (3, 5), and longer in women than in men (5, 6). These observations suggest that in human somatic cells telomere length is a biomarker of replicative history not only in vitro but also in vivo and that it is modified by genetic factors and sex.In contrast to the considerable information available about telomere length in humans during extrauterine life, little is known about telomere length during intrauterine life. Limited information indicates that in utero, the length of human telomeres is highly synchronized in that it is similar among tissues of the same fetus, but variable among fetuses (7). The present research was undertaken to answer the following key questions about telomere length: 1) Do male and female newborns differ in the length of their telomeres? 2) At birth, is there synchrony of telomere length in cells derived from three tissues (blood, umbilical artery and foreskin)? 3) Is the variability of telomere length among newborns the same as that observed in adults? METHODS Subjects.We studied normal newborns born at two hospitals, i.e. The University Hospital of the University of Medicine and Dentistry of NJ (UMDNJ) in Newark, NJ, and the affiliated Hackensack University Medical Center in Hackensack, NJ. Gen...

Abstract-There is evidence that telomeres, the ends of chromosomes, serve as clocks that pace cellular aging in vitro and in vivo. In industrialized nations, pulse pressure rises with age, and it might serve as a phenotype of biological aging of the vasculature. We therefore conducted a twin study to investigate the relation between telomere length in white blood cells and pulse pressure while simultaneously assessing the role of genetic factors in determining telomere length. We measured by Southern blot analysis the mean length of the terminal restriction fragments (TRF) in white blood cells of 49 twin pairs from the Danish Twin Register and assessed the relations of blood pressure parameters with TRF. TRF length showed an inverse relation with pulse pressure. Both TRF length and pulse pressure were highly familial. We conclude that telomere length, which is under genetic control, might play a role in mechanisms that regulate pulse pressure, including vascular aging. This process also occurs in vivo because an inverse relation exists between telomere length in replicating somatic cells and the age of human beings who have donated these cells (References 5 through 9; reviewed in References 1 through 4). Thus, the replicative history of somatic cells is a major determinant of telomere length. Another determinant of telomere length is heredity, since the high variability in this parameter among human beings is to a large extent genetically determined. 5 Recent experimental data support the concept that telomeres might serve as "biological clocks," pacing not only life span at the cellular level but also aging at the systemic level. These data show that (1) the prevention of telomere attrition by the forced expression in cultured somatic cells of the catalytic component of telomerase, the reverse transcriptase that adds telomere repeats onto the ends of chromosomes, postpones replicative senescence 10,11 and (2) the "knockout" of telomerase in the mouse amplifies some characteristics associated with systemic aging in later generations of mice that exhibit substantially shortened telomere length. 12 At least 2 fundamental questions therefore arise with respect to the clinical implications of telomere biology. First, can the length of telomeres serve as an in vivo indicator of biological aging of replicating somatic cells in different organ systems of humans? A related question is: Is the aging of tissues from persons who are genetically endowed with long telomeres likely to occur later in life or at a slower pace than of tissues from persons who inherit short telomeres? Second, which biological parameters can serve as indicators of aging in human beings, since for obvious reasons chronological age (which is determined by calendar time) is a poor criterion for biological aging?In light of these considerations, this work had 2 goals. The first goal was driven by the following concept. Since in industrialized nations pulse pressure increases with age, 13 pulse pressure might serve as a phenotype of cardiovascular agin...