The Health Outcome
Human longevity is the epitome of a complex multifactorial condition resulting from a combination of environmental and genetic characteristics. Individuals who achieve exceptionally long life encompass traits (most likely both lifestyle and genetic) that protect them from the common age related conditions, such as cardiovascular disease, diabetes, Alzheimer disease, and cancer. However, certain individuals undergo premature aging and suffer from many age-related conditions such as diabetes mellitus, arteriosclerosis, cataracts, wrinkles and gray hair. Premature aging syndromes, such as Werner’s, increase the sensitivity of cells to environmental factors such as DNA damage (1). Because premature aging can be attributed to genetic aberrations, there may also be genetic predispositions that act to increase life span by decreasing individual susceptibility to environmental insults. Twin studies suggest that the genetic contribution to longevity is 20-30% (2). Additionally, a study of the siblings of centenarians showed that their likelihood of reaching 100 was increased 17-fold (males) and 8-fold (females) compared with a control cohort of persons born in 1900 ascertained from US Social Security Administration records (3).
The Finding
This study suggests that lipoprotein (HDL and LDL) particle size is heritable and contributes to healthy aging. Persons with increased lipoprotein particle size had increased homozygosity for the I405V variant of cholesteryl ester transfer protein (CETP) as well as lower prevalence of cardiovascular disease, hypertension, and the metabolic syndrome.
This was a case control study of 213 Ashkenazi Jewish probands with exceptional longevity (mean age of 98.3 years, SD 5.3 years). Enrollment criteria included living independently at age 95 as an indicator of good health, and having offspring willing to participate in the study. The authors designed this study to look for factors that contribute to healthy aging by studying lipoprotein phenotypes in the offspring of the long-lived probands (n=216, mean age 68.3 years, SD 6.7 years). Offspring, who may have inherited the longevity phenotype, were compared with both their parents and two different age-matched control groups. One of the control groups consisted of age-matched individuals (n=183, mean age 71.3 years, SD 9.1 years) of Ashkenazi Jewish descent enrolled in an unrelated study; this group also included the Ashkenazi Jewish spouses of some of the offspring of the probands (n=75, mean age 70.2 years, SD 10.5 years). The second control group consisted of white participants enrolled in the Framingham study (n=589, mean age 67.8 years SD 3.5 years).
Although many parameters were compared, the probands, their offspring, and the control groups had similar blood chemistries and lipoprotein levels. However, the lipoprotein particle size, as determined by nuclear magnetic resonance (NMR), was increased in both the probands and their offspring compared with both control groups. Interestingly, 46% of female and 42 % of male offspring had HDL particle sizes that were a standard deviation above the mean, suggesting that some offspring inherited this characteristic and others did not. Although the bimodal inheritance pattern mentioned by the authors is not readily apparent from the data in Figure 1, the HDL protein particle size distribution in the offspring was more similar to that in the probands than to that in Ashkenazi controls. On average, women in the study had particle sizes larger than those in men, which may help explain the over representation of women in the ranks of those who reach their 100 th birthday. Females represent 80% of this population (4).
The body mass index (BMI) and ages of the offspring and controls were similar; however, the offspring had significantly reduced rates of metabolic syndrome (26% vs. 39%). Metabolic syndrome is defined as the presence 3 of these 5 risk factors: increased waist girth, increased blood pressure, increased fasting glucose, low HDL levels and high fasting triglycerides. Metabolic syndrome is associated with increased risk of death from many causes (5). In this study, persons with the largest HDL particle sizes were the least likely to have metabolic syndrome, even when cholesterol levels were excluded from the criteria for defining metabolic syndrome. Cardiovascular disease was also less common in individuals with large HDL particle sizes. These data suggest that the large particle sizes correlate not only with longevity but with better health.
Interestingly, this physiological phenotype was associated with a genotypic variation in CETP. In mice, CETP functions indirectly to prevent the formation of large HDL molecules (6). Many previously reported CETP polymorphisms were distributed randomly in the populations in this study; however, one variant in CETP, an isoleucine to valine change in exon 14 (I405V) was overrepresented in the probands and their offspring. Of the probands, 26% were homozygous for I450V compared with only 8.6% of the Ashkenazi controls (P<0.001); 20.7% of the offspring were homozygous (P=0.004). The I405V variant of CETP reduces CETP enzymatic activity in the homozygote to 17% of that in other genotypes. These data suggest that the I405V variant in the homozygous state reduces CETP activity and increases lipoprotein particle size, which may be associated with long healthy life. Unfortunately, the Framingham study controls were not genotyped. The prevalence of this genotype in populations outside of the Ashkenazi community is critical to determining how much it might contribute to extreme longevity in other populations.
The authors estimated that the population attributable “risk” (fraction) for longevity of homozygosity for CETP I450V was 18.1 percent. This can be estimated from a case-control study because extreme longevity is rare. The equation published in the article is incorrect. One common formula for estimating population attributable fraction (by Levin) is:
AF= P(OR-1)/1+P(OR-1)
Using this equation and data provided in the article (OR for longevity = 3.56, prevalence of the homozygous genotype = 0.086 among Ashkenazi controls), the attributable fraction is approximately 18.0 percent, similar to the 18.1 percent reported by the authors.
Public Health Implications
This research offers an interesting clue to one possible mechanism for common age-related illnesses such as cardiovascular disease and diabetes. Additional studies are required to examine this association in other populations. Only 26% of the probands were homozygous for the CETP I450V genotype; other factors associated with large lipoprotein formation in the remaining probands are unknown. Data from all study participants (probands, offspring, and controls) were combined in Table 3, which summarizes the relationship of CETP genotype with lipoprotein characteristics; notably, 8.6% of controls also had the favorable CETP genotype. Modifications of lipoproteins and their pathways are biologically plausible mediators of longevity; probands and their offspring had markedly reduced incidence of cardiovascular disease compared with controls.
Genetic testing for CETP I450V is not called for at this time. However, lipid profiles, including measures of lipoprotein particle size, are already used clinically for assessing and managing cardiovascular disease risk, both with lifestyle changes and targeted pharmaceutical intervention. This study demonstrates the importance of genetic factors in determining lipid profiles and the value of studying exceptionally healthy persons for clues to common diseases.
References
- Kamath-Loeb AS, Loeb LA, Johansson E, et al . 2001 Interactions between the Werner syndrome helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence. J Biol Chem 2001 May 11;276(19):16439-46.
- Ljungquist B, Berg S, Lanke J, et al. The effect of genetic factors for longevity: a comparison of identical and fraternal twins in the Swedish Twin Registry. J Gerontol A Biol Sci Med Sci 1998 Nov;53(6):M441-6.
- Perls TT, Wilmoth J, Levenson R et al. ,Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A 2002 Jun 11;99(12):8442-7.
- Perls T., Levenson R., Regan M., et al. What does it take to live to 100? Mech Ageing Dev 2002;123:231-242
- Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002 Dec 4;288(21):2709-16.
- Jiang XC, Beyer TP, Li Z, et. al. Enlargement of high density lipoprotein in mice via LXR activation requires apolipoprotein E and is abolished by cholesteryl ester transfer protein expression. J Biol Chem 2003 Aug 28 [Epub ahead of print].
