Research ArticleHEALTH AND MEDICINE

A null mutation in SERPINE1 protects against biological aging in humans

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Science Advances  15 Nov 2017:
Vol. 3, no. 11, eaao1617
DOI: 10.1126/sciadv.aao1617
  • Fig. 1 Association of SERPINE1 genotype status and leukocyte telomere length as a function of age in the Berne Amish kindred.

    (A and B) LTL in SERPINE1 null allele carriers and noncarriers in the Berne Amish kindred as quantified by (A) polymerase chain reaction (PCR) and (B) Southern Blot. Relative LTL is shown in (A), and mean terminal restriction fragment (TRF) length is shown in (B) as a function of age stratified by SERPINE1 mutation status. P value represents difference in mean LTL and TRF by SERPINE1 mutation status (carriers versus noncarriers) after adjustment for age, sex, and family structure in Sequential Oligogenic Linkage Analysis Routines (SOLAR) (P = 0.007 and P = 0.039, respectively). Every 1-year increase in age of study participant was associated with a 0.0087 lower relative LTL (P < 0.0001) and a 30–base pair lower mean TRF (P < 0.0001).

  • Fig. 2 Age at death in the extended Berne Amish kindred by genotype status for SERPINE1.

    On the basis of ancestral data obtained from the extended pedigree and extensive fieldwork, we identified 221 individuals with known dates of birth and death. Genotype status for SERPINE1 was ascertained by direct genotyping or obligate ascertainment in 56 family members. The mean ± SD age at death was delayed by 7 years in SERPINE1 null carriers compared with unaffected individuals (82 ± 10 versus 75 ± 12; P = 0.037 by Wilcoxon rank sum test).

  • Fig. 3 Association of SERPINE1 genotype status and cardiovascular measures of aging as a function of age in the Berne Amish kindred.

    (A to C) Components of the aging composite scores, including brachial pulse pressure (A), e′ velocity (B), and carotid IMT (C) as a function age in Amish participants by genotype status for SERPINE1 null allele. (D to F) Composite scores of cardiovascular, cardiometabolic, and comprehensive biological aging in SERPINE1 null allele carriers and noncarriers in the Berne Amish kindred. Several cardiovascular measures that correlated strongly with chronological age with absolute correlation coefficients (|R|) greater than 0.60 (P < 0.0001) were identified. Pulse pressure [PP = 34.7 + 0.39 (age in years)] and carotid IMT [0.32 + 0.01 (age in years)] increased with age. e′ velocity [e′ = 20.3 − 0.2 (age in years)] decreased with age, as expected. These measures of vascular structure and stiffness and myocardial health were then standardized to have mean = 0 and SD = 1 (z scores) and were integrated into composite score 1 (cardiovascular age composed of brachial pulse pressure, e′ velocity, and carotid IMT), composite score 2 (cardiometabolic age composed of score 1 plus fasting insulin), and composite score 3 (comprehensive biological age composed of score 2 and LTL). Z scores were coded so that higher values corresponded to older levels of the measures of biological aging; that is, The z scores for LTL and e′ velocity, which decline with age, were reverse-coded so that higher z scores corresponded to lower levels [**P value represents difference in components and composite scores of aging by SERPINE1 mutation status (carriers versus noncarriers) after adjustment for age, sex, and family structure in SOLAR].

  • Table 1 Clinical characteristics of the Berne Amish kindred by SERPINE1 genotype status.

    Continuous values are listed as mean ± SD unless otherwise specified. HDL, high-density lipoprotein; LDL, low-density lipoprotein.

    SERPINE1+/+
    (n = 127)
    SERPINE1+/−
    (n = 43)
    P*
    Age (years)46 ± 2044 ± 170.97
    Female, n (%)70 (55)28 (65)0.43
    Hypertension, n (%)41 (33)14 (33)0.85
    Systolic blood pressure (mmHg)130 ±18128 ± 200.69
    Diastolic blood pressure (mmHg)77 ± 1078 ± 120.60
    Obesity, n (%)38 (30)12 (28)0.60
    Body mass index (kg/m2)27.7 ± 5.926.9 ± 6.30.29
    Diabetes, n (%)8 (7)0 (0)<0.01
    Fasting insulin (uIU/ml)4.9 (3.3–6.7)4.0 (2.9–5.1)0.04
    Total cholesterol (mg/dl)188 ± 40188 ± 550.92
    HDL cholesterol (mg/dl)60 ± 1563 ± 120.25
    Triglyceride (mg/dl)81 (57–113)76 (51–110)0.54
    LDL cholesterol (mg/dl)109 ± 32107 ± 440.67
    Serum creatinine (mg/dl)0.80 ± 0.160.75 ± 0.150.13
    Ever smoked, n (%)48 (38)12 (28)0.11

    *Polygenic model adjusted for carrier status and family structure in SOLAR.

    †Non-normally distributed, reported as median (25th to 75th percentile).

    • Table 2 Comparison of clinical characteristics of the Berne Amish kindred SERPINE1+/+ and CARDIA.
      SERPINE1+/+
      (n = 127)
      CARDIA
      (n = 2793)
      P
      Age (years)46 ± 2050 ± 40.03
      Female, n (%)70 (55)1605 (57)0.60
      Hypertension, n (%)41 (33)1023 (37)0.42
      Systolic blood pressure (mmHg)130 ± 18119 ± 16<0.01
      Diastolic blood pressure (mmHg)77 ± 1075 ± 110.02
      Obesity, n (%)38 (30)1181 (42)<0.01
      Body mass index (kg/m2)28 ± 630 ± 7<0.01
      Diabetes, n (%)8 (7)296 (11)0.17
      Fasting glucose (mg/dl)*88 (82–98)94 (87–102)<0.01
      Total cholesterol (mg/dl)188 ± 40192 ± 360.23
      HDL cholesterol (mg/dl)60 ± 1558 ± 180.18
      Triglyceride (mg/dl)*81 (57–113)91 (68–132)<0.01
      LDL cholesterol (mg/dl)109 ± 32112 ± 320.28
      Serum creatinine (mg/dl)0.80 ± 0.160.88 ± 0.44<0.01
      Ever smoked, n (%)48 (38)1007 (37)0.77

      *Non-normally distributed, reported as median (25th to 75th percentile).

      Supplementary Materials

      • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/11/eaao1617/DC1

        Supplementary Materials and Methods

        table S1. Clinical characteristics of homozygous participants for the null SERPINE1 mutation.

        table S2. Association of null SERPINE1 mutant allele status with PAI-1, telomere length, and fasting insulin: secondary analyses.

        table S3. Association of cardiometabolic aging composite scores with 5-year CVD morbidity and mortality in the CARDIA cohort (n = 2793).

        table S4. Association of biological aging composite scores including telomere length with 5-year CVD morbidity and mortality in the CARDIA cohort (n = 872).

        fig. S1. Abbreviated pedigree of the Berne Amish kindred.

      • Supplementary Materials

        This PDF file includes:

        • Supplementary Materials and Methods
        • table S1. Clinical characteristics of homozygous participants for the null SERPINE1 mutation.
        • table S2. Association of null SERPINE1 mutant allele status with PAI-1, telomere length, and fasting insulin: secondary analyses.
        • table S3. Association of cardiometabolic aging composite scores with 5-year CVD morbidity and mortality in the CARDIA cohort (n = 2793).
        • table S4. Association of biological aging composite scores including telomere length with 5-year CVD morbidity and mortality in the CARDIA cohort (n = 872).
        • fig. S1. Abbreviated pedigree of the Berne Amish kindred.

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