This web page was produced as an assignment for an undergraduate course at Davidson College.
Will You Live to be 100 or Older?
Cholesterol Gene Linked to Longevity
A comparison of popular press and scientific writing
Photo of reportedly the world's oldest person ever, Jeanne Calment, who died at 122 years of age
Cholesteryl Ester Transfer Protein (CETP), also known as Lipid Transfer Protein I, is found on the human genome map locus at 16q21 and consists of 493 amino acids (click here to view the sequence). CETP plays a crucial role in the transport of lipoproteins, particularly insoluble cholesteryl esters. CETP affects not only the amount of cholesterol particles in the blood, but also the sizes of those particles. Research implicates that larger particles lead to a reduced risk of cardiovascular disease. One CETP inhibitor, called JTT-705 was reported to increase "good" HDL cholesterol levels, decrease "bad" non-HDL cholesterol, and inhibit the progression of atherosclerosis in rabbits. CETP is important to cholesterol homeostasis and might play a vital role in inheritance of cardiovascular diseases. The three-dimensional structure of CETP in humans has not yet been fully resolved.
Popular Press: Gene Mutation Causes People to Live Longer Lives: Researchers find it in centenarians and their children (See article in www.seniorjournal.com, 2003 Oct 15)
This popular press article begins by claiming, "[r]esearchers... have discovered that a gene mutation helps people live exceptionally long lives and apparently can be passed from one generation to the next." This eye-catching statement is certain to grab the attention of many of its presumably elderly readers. In the study, centenarians were three times as likely to have the CETP mutation as compared to the general population, and their offspring were twice as likely to have it. After reading such statements, one is likely to wonder if he or she possesses this "magic" gene for long life.
Next, the article addresses the increasing amount of evidence demonstrating that people with small LDL (low-density lipoprotein, or "bad" cholesterol) particles are more likely to develop cardiovascular disease. The research model assumes that small particles are more likely to penetrate and/or adhere to artery walls, leading to the development of atherosclerosis, which in turn can contribute to heart disease and stroke. (See Figure 1 below.)
Fig.1: Small LDL particles penetrate or stick to artery walls, whereas larger LDL particles can flow freely in the blood.
The popular press article explains the scientific study of the Ashkenazi (Eastern European) Jewish population as beneficial because the group has a known "founder effect," which implicates a lack of genetic diversity. This means that generations subsequent to the original "founders" of the population should not have much more diversity than initially existed. In the case of the Ashkenazi Jewish people, the founder effect was a result of inbreeding and many years of social isolation. The article identifies that 213 individuals from ages 95 to 107, and 216 of their children were studied. Additionally, they examined 258 spouses and neighbors of the offspring as a control group. For key information, the article directly quotes Dr. Barzilai, "'These results are significant because they mean that the mutation of the CETP gene is clearly associated with longevity... Furthermore, finding this mutation in both centenarians and their offspring suggests that the mutation may be inherited.'" In addition, Dr. Barzilai comments on the lack of research about longevity and the absence of disease in part of the geriatric population. He states, "...our findings bring us a step closer to understanding the role that genes play in longevity."
The second portion of the article called "Notes by Dr. Nir Barzilai on the research: Searching for longevity genes in humans" includes more detailed information about his research method. He explains the division of groups: 1) the probands, who were the Ashkenazi Jewish centenarians, 2) their offspring, and 3) the control group, comprised of spouses and neighbors of the offspring. The scientists studied the "genetic and metabolic profiles" of these subjects. They found high levels of "good" high-density lipoprotein (HDL) and low levels of "bad" low-density lipoprotein (LDL) in the Ashkenazi populations. Such cholesterol readings relate to a lower prevalence of diseases like hypertension and cardiovascular disease. In the study, they "...used novel genetic screens such as analysis of SNP sites and genechip mapping techniques to identify mutations in new, uncharacterized genes that may be liked to diseases of aging such as cardiovascular disease and cancers."
Scientific Article: Unique Lipoprotein Phenotype and Genotype Associated With Exceptional Longevity (see abstract of article by N. Barzilai in JAMA, 2003 Oct 15; 290(15):2030-40)
The introduction in the scientific literature emphasizes the lack of age-related diseases, such as cardiovascular disease, diabetes mellitus, Alzheimer disease, and cancer, in very elderly persons. Studies have shown that siblings of centenarians have an 8- to 17-fold higher probability of living past the age of 100 years. Only 1 out of 10,000 individuals in the general population lives to be such an age. One study linked a locus on chromosome 4 to exceptional longevity. In addition, genes which may play a role in longevity have been shown in other species, but their orthologs are debatable in humans. The paper introduces CETP as being involved in the regulation of reverse cholesterol transport and high-density lipoprotein levels.
Exactly 213 Ashkenazi Jewish probands with exceptional longevity (157 women, 56 men; mean age 98.2 +/- 5.3 years; range 95-107 years) participated in the study, which took place from 1998 to 2002. Their ages were verified with birth certificates, and it was required that they lived independently at age 95 as a measure of health. Their offspring had to be willing to participate in the study as well.
For evaluation, each participant gave a blood sample to be screened for total plasma cholesterol, triglycerides, HDL, LDL, very LDL, and apolipoprotein A-I and B concentrations. LDL and HDL subclass levels and mean particle sizes were determined by nuclear magnetic resonance. In addition, medical histories, heights and weights were recorded, and physical exams were performed.
The article states that lipoprotein sizes are largely determined by hepatic lipase and CETP. As such, they sequenced the promoter region of hepatic lipase in 100 centenarians and found no differences as compared to controls in known and unknown polymorphic markers. Next, they examined known CETP polymorphic markers in the promoter and in exons 14 and 15.
Ultimately, the researchers discovered many significant differences between their three groups. The probands had a significantly lower body mass index (BMI, or weight to height ratio). Although not statistically significant, the male and female probands had lower total cholesterol and lower LDL levels than the offspring or the controls. Most importantly, the HDL and LDL particle sizes were markedly higher in the probands than their offspring or the controls (P=.001 in women and men). The offspring had significantly larger particle sizes than the controls (P=<.001 for men and women). In the CETP sequence analysis, the researchers found allele frequencies of the I405V allele to be 0.46 in probands, 0.43 in offspring, and 0.29 in controls. The frequency of homozygosity of this mutation was 24.8% in female and male probands compared to 20.7% in the offspring, and to 8.6% in the control group (P<.001 for men and women).
The study suggests that families with exceptional longevity have markedly larger particle sizes of HDL and LDL, which likely relates to a decreased risk for hypertension and cardiovascular disease. The marked increase in the I405V mutation in the probands and offspring strongly implicates a genetic component. In the discussion, the author states “…additional genes that modulate LDL size or environmental factors are likely to be involved in the regulation of LDL particle sizes and may be necessary to enhance the probability of exceptional longevity.” Furthermore, he concludes by saying, “The important findings of this work suggest pleiotropic vascular effects of lipoproteins with large particle sizes that are health promoting,” (emphasis added).
The popular press article entitled “Gene mutation causes people to live longer lives” immediately leads readers to believe that one gene mutation could be the key to longevity. One might wonder if he or she possesses the gene. And if he or she does not have it, could there be a way to change his/her seemingly predetermined, “premature” fate? The article alludes to some possible drug treatments which would “focus on preventing or delaying the onset of age-related diseases,” but the reader is left wondering about how realistic this possibility is, and how soon such life-extending drugs might be available to the public.
On the whole, however, the popular press article does an excellent job of portraying complicated scientific information to a general audience. Kua (2004) states, "The role of the science reporter is to explain research clearly so that the reader can understand the science and the issues involved and act accordingly." This article does almost exactly that. The wording is clear, and the vocabulary is reasonable. Ideas are presented simplistically, but they are not so diluted that the scientists would scoff at the article. The article also does a nice job of fully explaining the experimental design to a public audience. A few important details are missing, though. For instance, the actual mechanism of the gene and the mutation are not described fully, and the clinical procedure of the study is not explained in detail, either. The reader is left wondering how and what they tested on the subjects to obtain such obviously astonishing results. Nevertheless, the results are presented clearly and appropriately (with the exception of a few eye-catching embellishments to initially interest the reader). This article was by far the most impressive presentation that I encountered concerning the “longevity” gene.
"Gene mutation causes people to live longer lives" was particularly interesting in this case, because www.seniorjournal.com most likely writes to an elderly audience. We can assume that the possibility of discovering a "longevity" gene or "life-extending" medication is particularly interesting to these readers. Nevertheless, the author sensationalizes the science with attention-grabbing questions like, "Why do some people live much longer than the others? What allows these individuals to escape age-associated diseases that contribute to mortality in the elderly? Is this a result of favorable genes or a healthy life style? If there is a role for genes, what are the mechanisms?" This "hype" is not seen as clearly in the straightforward article "Cholesterol gene offers 'exceptional' longevity" found at www.betterhumans.com. On the other hand, the popular press article entitled "For some, long life is in the genes" found at a government web site www.healthfinder.gov, exaggerates the most in order to grab the reader's attention. It states boldly that "...a genetic mutation that may let people live into their 90s and even past 100." It is clear that the three different authors use distinctive wording choices to cater to their particular audience, while also conveying the same basic idea. All of the popular press papers, however, tend to portray CETP as the "key" to longevity, instead of as one of the variables in the intricate equation of long life.
Although the popular press article hilighted above does an excellent job of portraying the scientific information to the public, it does not stress the importance of the combination of factors that control longevity. Often the press and the public wish to find the “magic bullet” or simple cure, for today’s health problems. The scientific article, however, makes it clear that a combination of many factors—both environmental and genetic—determine the length of one’s life.
Reporters are restricted by space limitations and must capture the interest of an audience to be successful writers. They must also convey complicated scientific information to a general audience with presumably little or no background in the sciences. Kua (2004) states that in some instances, "...there is, in fact, a significant difference in what is said rather than in how it is said." I believe that the writer of the featured popular press article "Gene mutation causes people to live longer lives" does a nice job of balancing the two responsibilities. He seizes the reader's attention without straying too far from the facts, and he also communicates clearly the scientific side of the matter. Certainly, he could better express the details of the experimental procedure or could further emphasize the importance of the many factors that contribute to longevity, but on the whole, the article is very well written.
Even after reading the scientific article and knowing that longevity is a multi-faceted phenomenon, the popular press articles still tempt me to wonder if I might have a mutation in my CETP gene that would allow me to have exceptionally large cholesterol particles. Then maybe I will have a reduced risk for cardiovascular disease. But is it so simple? Already I have learned in Genomics that Mendel’s maxim “one gene, one protein, one phenotype” is not always as straightforward as it sounds. First, the definition of a gene is a controversial topic. One "gene" can make many proteins and many phenotypes, while genes and proteins interact with each other in very complicated ways. The presentation of the CETP "longevity" mutation in the popular press is a perfect example of the overgeneralization of complicated science.
Still, it might be nice to know if you had the gene that implicates longevity… or would it?
Here's good way to remember the difference between the two types of cholesterol molecules mentioned above:
Ideally, we want a High amount of HDL (high density lipoprotein, or "good" cholesterol) and we want a Low amount of LDL (low-density lipoprotein, or "bad" cholesterol).
[SJ] Senior Journal. 2003 Oct 15. Gene mutation causes people to live longer lives: Researchers find it in centenarians and their children. <www.seniorjournal.com/NEWS/SeniorStats/3-10-15livelonger.htm>. Accessed 2004 Aug 30.
Cholesterol gene confers "exceptional" longevity. 2003 Oct 15. <www.betterhumans.com/News/news.aspx?articleID=2003-10-15-4>. Accessed 2004 Aug 30.
Gardner A. 2003 Oct 14. For some, long life is in the genes. <www.healthfinder.gov/news/newsstory.asp?docID=515507>. Accessed 2004 Aug 30.
Dreifus C. It's not the yogurt: Looking for longevity genes. A conversation with Nir Barzilai. New York Times, 2004 Feb 24, sec F, col 1, Health & Fitness, pg 5. View summary: <http://search.epnet.com/direct.asp?AuthType=cookie,ip,url,uid&db=nfh&an=12624333>.
Barzilai N, et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. J Amer Med Assoc 2003 Oct 15; 290(15): 2030-40. See abstract: <http://jama.ama-assn.org/cgi/content/abstract/290/15/2030?maxtoshow=&eaf>.
[OMIM] Online Mendelian Inheritance in Man. 2004. Cholesterly Ester Transfer Protein, Plasma; CETP. <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=118470>. Accessed 2004 Aug 30.
Kua E, et al. Science in the news: a study of reporting genomics. Public Understand. Sci. 13 (2004) 309-322.
For more information, please refer to the Genomics Home Page or to the Davidson College Home Page.
Questions or comments? E-mail me: "jehoekstra" at "davidson.edu".
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Page last updated 2004 Sept 11 by J. Hoekstra.