Genes, Lifestyle, Attitude Influence Longevity, Cognitive Health

Researchers dedicated to discovering risk factors for Alzheimer disease and other dementias are broadening their focus to identify genes and lifestyle factors involved in the protection and enhancement of longevity and cognitive health in older adults. Three of these scientists— George Zubenko, MD, PhD, Gary Small, MD, and Dilip V. Jeste, MD— reported on their research at a recent meeting of the American College of Neuropsychopharmacology (ACNP).

At the University of Pittsburgh School of Medicine, Zubenko, who is a professor of psychiatry, and his colleagues have been conducting a systematic genome survey to identify the locations of particular genes that affect the likelihood of reaching age 90 with preserved cognitive abilities.

"I would say, and I think most people would agree, that reaching age 90 with intact mental processes is a reasonable definition of successful aging. We are looking for biologic and lifestyle pathways that would lead us there," he told Psychiatric Times.

The study, funded by the NIH, is among the first to identify genetic links to cognitive longevity. Each step in reaching that goal has necessitated overcoming substantive hurdles, according to Zubenko.

"The recruitment of men and women who reach 90 years of age with preserved cognition is a major undertaking because few people reach that age [0.5% of the population], and for those who do, cognitive impairment is common. The effort on the ‘front end,' including the establishment of libraries of cell lines and DNA samples, and an electronic database to store the resulting clinical and laboratory information, was a monumental task," said Zubenko, who is also an adjunct professor of biologic sciences at Carnegie Mellon University.

The research team recruited and characterized 100 older adults (94 nonagenarians and 6 centenarians) who were cognitively normal, as reflected by clinical evaluations and psychometric assessments such as the Mini-Mental State Examination and the Dementia Rating Scale. They were matched to 100 cognitively normal young adults (ages 18 to 25 years) with regard to sex (50 men and 50 women in each group), race (white), ethnicity, and geographic location (southwestern Pennsylvania).

The genome survey was conducted at 10 cM resolution for simple sequence tandem repeat polymorphisms (SSTRPs) that identify genes for successful aging by virtue of linkage disequilibrium. Equal amounts of genomic DNA from the 100 older adults and 100 younger adults were combined to create 2 individual "pools" of DNA representing each group. The frequency distribution of alleles at each SSTRP of interest was determined for the 2 groups by typing the 2 pools and comparing the relative abundance of each allele-specific band. This approach, according to Zubenko and his colleagues,¹ is considerably more efficient than typing 200 people individually for each of nearly 400 marker loci.

Some preliminary results of the study, which involved validation of the experimental method and results for the Y chromosome, were reported by Zubenko and coworkers¹ in 2002.

"That paper set the stage for our subsequent genome survey, which is now complete. The results are interesting," Zubenko told Psychiatric Times.

Both the preliminary and additional results from the completed survey were reported at the ACNP meeting.² The genome survey method detected the expected elevation of the apolipoprotein-E gene (APOE) "ε2 allele frequency and reciprocal reduction in the ε4 frequency in the older adults as compared with the young adults. This pattern has been associated with exceptional longevity among American, European, and Asian populations. Conversely, elevation of the frequency of the APOE ε4 allele and the reciprocal reduction in the frequency of the ε2 allele has been widely linked to Alzheimer disease.¹

The genome study also detected significant differences in the Y-linked SSTRPs, DYS389, and DYS390. The distributions of alleles at both DYS389 and DYS390 differed significantly between the older and younger men.

Evidence for additional genetic loci that selectively influence the development of successful aging in men or women was also observed, according to Zubenko, and will be reported in an upcoming journal article.

"Historically, women have lived longer than men on average," Zubenko said in a news release.³ "The prevalence of numerous serious diseases differs in men and women, and there are important differences in age-related physiological changes that occur between the sexes over the lifespan. It would not be surprising if the collection of genes that influences the capacity to reach old age with normal mental capacity differs somewhat for men and women."

In the same genome study, Zubenko and colleagues evaluated disease and lifestyle factors such as smoking and alcohol consumption, with the goal of eventually exploring the interactive effects of genes and lifestyle on successful aging.

The older adults suffered from an average of 8.5 medical conditions, most frequently heart problems, hypertension, vision and hearing problems, and diseases of the digestive system. Only 1 older adult had no identified medical conditions, while 27 young adults reported no medical conditions. Despite the number of medical problems among the older adults, assessments of activities of daily living revealed only modest functional impairment on average.

None of the older adults had a history of mental disorders in early or middle adulthood. The prevalence of mental disorders in older adults was 4%, and all of the mental disorders in this group had developed when the patients were 81 years or older. Major depressive disorder was the most common mental disorder identified in both groups. While about 40% of individuals in both age groups had a history of cigarette smoking, only 1 of the older adults was currently smoking, compared with 34 young adults. Similarly, the older adults drank alcoholic beverages much less frequently than the younger adults. Eighty percent of the older adults consumed alcohol less than once a month, compared with 15% of the young adults. These findings, according to Zubenko, support previous reports of the negative consequences of mental disorders, cigarette smoking, and excessive alcohol consumption on successful aging.

In summing up the impact of the study, Zubenko³ said in the news release, "The finding that genetics, lifestyle decision making, and their interactions may influence the ability to reach old age with preserved cognition is exciting. Identifying such genetic and behavioral factors may hold promise for better understanding the aging process and perhaps one day enriching or extending the lives of other individuals."