Genes, Lifestyle, Attitude Influence Longevity, Cognitive Health

May 1, 2006

The search in identifying risk factors affecting cognitive health and longevity, including Alzheimer disease and other dementias, has broadened to include genes and lifestyle factors.

Researchers dedicated to discoveringrisk factors for Alzheimerdisease and other dementiasare broadening their focus to identifygenes and lifestyle factors involved inthe protection and enhancement oflongevity and cognitive health in olderadults. Three of these scientists--George Zubenko, MD, PhD, GarySmall, MD, and Dilip V. Jeste, MD--reported on their research at a recentmeeting of the American College ofNeuropsychopharmacology (ACNP).

Genetic links to cognitive longevity

At the University of Pittsburgh Schoolof Medicine, Zubenko, who is a professorof psychiatry, and his colleagueshave been conducting a systematicgenome survey to identify the locationsof particular genes that affect the likelihoodof reaching age 90 with preservedcognitive abilities.

"I would say, and I think mostpeople would agree, that reaching age90 with intact mental processes is areasonable definition of successfulaging. We are looking for biologic andlifestyle pathways that would lead usthere," he told Psychiatric Times.

The study, funded by the NIH, isamong the first to identify genetic linksto cognitive longevity. Each step inreaching that goal has necessitatedovercoming substantive hurdles, accordingto Zubenko.

"The recruitment of men and womenwho reach 90 years of age with preservedcognition is a major undertaking becausefew people reach that age [0.5% of thepopulation], and for those who do, cognitiveimpairment is common. The efforton the 'front end,' including the establishment of libraries of cell lines and DNAsamples, and an electronic database tostore the resulting clinical and laboratoryinformation, was a monumentaltask," said Zubenko, who is also anadjunct professor of biologic sciences atCarnegie Mellon University.

The research team recruited andcharacterized 100 older adults (94 nonagenariansand 6 centenarians) who werecognitively normal, as reflected by clinicalevaluations and psychometricassessments such as the Mini-MentalState Examination and the DementiaRating Scale. They were matched to100 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 geographiclocation (southwestern Pennsylvania).

The genome survey was conductedat 10 cM resolution for simple sequencetandem repeat polymorphisms (SSTRPs)that identify genes for successful agingby virtue of linkage disequilibrium.Equal amounts of genomic DNA fromthe 100 older adults and 100 youngeradults were combined to create 2 individual"pools" of DNA representingeach group. The frequency distributionof alleles at each SSTRP of interest wasdetermined for the 2 groups by typingthe 2 pools and comparing the relativeabundance of each allele-specific band.This approach, according to Zubenkoand his colleagues,1 is considerablymore efficient than typing 200 peopleindividually for each of nearly 400marker loci.

Some preliminary results of thestudy, which involved validation of theexperimental method and results for theY chromosome, were reported byZubenko and coworkers1 in 2002.

"That paper set the stage for oursubsequent genome survey, which isnow complete. The results are interesting,"Zubenko told Psychiatric Times.

Both the preliminary and additionalresults from the completed survey werereported at the ACNP meeting.2 Thegenome survey method detected theexpected elevation of the apolipoprotein-E gene (APOE) "ε2 allele frequencyand reciprocal reduction in the ε4frequency in the older adults ascompared with the young adults. Thispattern has been associated with exceptionallongevity among American,European, and Asian populations.Conversely, elevation of the frequencyof the APOE ε4 allele and the reciprocalreduction in the frequency of theε2 allele has been widely linked toAlzheimer disease.1

The genome study also detectedsignificant differences in the Y-linkedSSTRPs, DYS389, and DYS390. Thedistributions of alleles at both DYS389and DYS390 differed significantlybetween the older and younger men.

Evidence for additional genetic locithat selectively influence the developmentof successful aging in men orwomen was also observed, accordingto Zubenko, and will be reported in anupcoming journal article.

"Historically, women have livedlonger than men on average," Zubenkosaid in a news release.3 "The prevalenceof numerous serious diseases differs inmen and women, and there are importantdifferences in age-related physiologicalchanges that occur between thesexes over the lifespan. It would not besurprising if the collection of genes thatinfluences the capacity to reach old agewith normal mental capacity differssomewhat for men and women."

Disease and lifestyle factors

In the same genome study, Zubenkoand colleagues evaluated disease andlifestyle factors such as smoking andalcohol consumption, with the goal ofeventually exploring the interactiveeffects of genes and lifestyle on successfulaging.

The older adults suffered from anaverage of 8.5 medical conditions, mostfrequently heart problems, hypertension,vision and hearing problems, anddiseases of the digestive system. Only1 older adult had no identified medicalconditions, while 27 young adultsreported no medical conditions. Despitethe number of medical problems amongthe older adults, assessments of activitiesof daily living revealed only modestfunctional impairment on average.

None of the older adults had a historyof mental disorders in early or middleadulthood. The prevalence of mentaldisorders in older adults was 4%, andall of the mental disorders in this grouphad developed when the patients were 81 years or older. Major depressivedisorder was the most common mentaldisorder identified in both groups.While about 40% of individuals in bothage groups had a history of cigarettesmoking, only 1 of the older adults wascurrently smoking, compared with 34young adults. Similarly, the older adultsdrank alcoholic beverages much lessfrequently than the younger adults.Eighty percent of the older adultsconsumed alcohol less than once amonth, compared with 15% of theyoung adults. These findings, accordingto Zubenko, support previousreports of the negative consequencesof mental disorders, cigarette smoking,and excessive alcohol consumption onsuccessful aging.

In summing up the impact of thestudy, Zubenko3 said in the news release,"The finding that genetics, lifestyle decisionmaking, and their interactions mayinfluence the ability to reach old agewith preserved cognition is exciting.Identifying such genetic and behavioralfactors may hold promise for betterunderstanding the aging process andperhaps one day enriching or extendingthe lives of other individuals."

Lifestyle changes to improve memory

A team led by Dr Gary Small, directorof the University of California, LosAngeles (UCLA), Memory and AgingResearch Center and assistant professorof psychiatry and biobehavioralsciences at UCLA's David GeffenSchool of Medicine, found that adultscould improve their memory by makingsimple lifestyle changes.4,5

In the 14-day study, 17 personsbetween 35 and 70 years of age (meanage, 53) with normal baseline memoryperformance scores were randomlyassigned to an intervention group (n =8) or a control group (n = 9).

"We put them [intervention group]on a healthy lifestyle program that had4 components: memory training, physicalconditioning, healthy diet, and stressreduction," Small told

Psychiatric Times


Memory training involved the dailyuse of brainteasers, crossword puzzles,and memory techniques emphasizingverbal skills; the healthy diet involvedeating 5 meals per day that were richin omega-3 fats, low-glycemic indexcarbohydrates, and antioxidant foods;and the physical conditioning involvedbrisk daily walks and stretching exercises.Breathing and relaxation techniqueswere added to reduce stress,since stress causes the body to releasecortisol, and chronically high levels ofcortisol can impair memory and shrinkmemory centers in the brain, Small saidin a news release.4

Participants in the intervention groupagreed to follow the memory improvementplan and were minimally monitored,said Small.

The participants were given a prepublicationcopy of Chapter 3 of Small'sThe Memory Prescription,6 whichcontains specific daily recommendationson what to do and when and howto do it. Small explained, "For example,Monday morning instructs thevolunteer to do a stretching exercisebefore a suggested healthy breakfast.Later in the morning, a memory techniqueis described. The exercises andmeal menus are detailed each day ofthe week for 14 days." A research nursereviewed the 14-day plan with the interventiongroup participants and answeredtheir questions.

"We called them midway to makesure they were doing the program. Wehad them keep notes to make surethey understood and followed theprogram. . . . Our monitoring suggeststhat they made a reasonable effort,"Small added.

Immediately before and after the 2-week program, brain function wasassessed, using flurodeoxyglucosepositron emission tomography (PET)scanning during mental rest, whichmeasures regional rates of corticalglucose metabolism. Statistical parametricmapping analysis was used todetermine the differences between the2 groups.5

The short-term healthy lifestyleintervention program "had significanteffects on brain function as measuredby PET scans," Small told PsychiatricTimes. Compared with controls, individualsin the intervention groupexperienced a "5% change in brainmetabolism, not randomly throughoutthe brain, but in the left dorsolateralprefrontal cortex, which is an areaof the brain that controls everydayworking memory." The region ofchange involved a stretch of cortex inBrodmann areas 8, 9, and 10. Incontrast, the control group showed nochange in brain metabolism.

Small explained that the reducedglucose metabolic rates in the leftdorsolateral prefrontal cortex suggestgreater cognitive efficiency in thatregion of the brain and that the significantchange observed in the left hemisphereis consistent with the verbalemphasis in the program's memorytraining exercises.

He added that the dorsolateralprefrontal cortex has been linked toanxiety symptoms, so stress reductiontechniques might show some effect inthat same brain region.

Future studies will involve determiningspecific effects of individualcomponents of the program and testingthe intervention program in differentsettings.

In the pilot study, Small said, "Wethrew in the kitchen sink, to see if wecould see any kind of an effect. Wedon't know what part of that recipechanged the brain."

Future direction

For the next study, Small said the investigatorsplan to focus on stress reductionand memory training. There wouldbe a control group and 2 interventiongroups--one in which participantsreceive memory training alone andanother in which they receive bothmemory training and tai chi instruction.Why tai chi? Small explained thatpsychiatrist Michael Irwin, affiliatedwith UCLA's Norman Cousins Centerfor Psychoneuroimmunology, hasconducted some studies on tai chi andfound that it improves measures ofimmune function and is enjoyablefor many older adults. Small addedthat the study will include a longerfollow-up period to explore whether theeffects, as measured by brain scans, aresustained.

The pilot study was funded by theFran and Ray Stark Foundation Fundfor Alzheimer's Disease Research, theJudith Olenick Elgart Fund for Researchon Brain Aging, and the Parlow-Solomon Professorship on Aging;Small said he intends to seek governmentgrants for the next study.

Existing programs

Small is also chief scientific andmedical advisor for the Memory FitnessInstitute, a for-profit company thathelps people of all ages optimize theirmemory function and brain health,using state-of-the-art diagnostic, intervention,and prevention strategies. Heexplained that the Memory FitnessInstitute has adapted the 14-day lifestyleintervention program for use in assistedliving facilities and retirement communitiesand is testing the model in a realworldenvironment, a retirementcommunity facility in Maryland.

"It will be a 6-week program, 2 daysa week, taught by trainers there," Smallsaid.

The program will screen participantsin advance to ensure that they canperform the physical conditioningportion (walking) without hurting themselves;provide some education abouta healthy diet; and introduce them tomemory training exercises and stressreduction techniques.

Although brain scanning will not bepart of the study, Small said, measureswill be taken to systematically assesschanges.

The Memory Fitness Institute hasbeen developing some memory trainingprograms based on Small's books,The Memory Prescription6 and TheMemory Bible.7

"They have done some educationalmeetings, and they are testing out someof these programs at different sites tosee what works and what doesn't," heexplained.

On the nonprofit front, UCLA'sCenter on Aging, which Small directs,has just received a grant from theArchstone Foundation to supportmemory training. The Center hascreated a 5-week memory trainingprogram based on The Memory Bible.Volunteers teach the program, and sofar about 1500 people have taken thecourse, Small said. It also has beenlicensed to the University of Texas andto a senior center in Chicago. Smallalso uses several memory and lifestyleapproaches to help his own patients whocomplain of memory problems.

"I ask what their diet is like. . . . Arethey exercising every day? What kindof stress are they under? I try to individualizea memory and brain healthprogram for each of them," Small said."These are things that will not only helptheir brain health but also their generalhealth and their heart health."He also tries to live the lifestylehimself.

"I write these books with my wife,who is a professional writer, and we checkthings out in advance, so we try the recipesourselves. We just finished a new bookcalled the Longevity Bible, which willbe out in June, that includes the four areas[diet, physical exercise, memory training,and stress reduction], but others aswell, including relationships, positiveoutlook, the environment, medications,and supplements. So we try to live ahealthy lifestyle as best we can."

In a related area, Small discussedhis UCLA research team's use of a PETscan approach, in which "we can seethe physical evidence of Alzheimerdisease in a living patient." It uses achemical marker injected into the veinto determine the localization and loadof neurofibrillary tangles and -amyloidsenile plaques in the brains of livingpatients.

"We can see a pattern of plaque andtangle deposition that is very consistentwith what you see in autopsy studies.Our latest data are very promisingthat plaque and tangle PET scanningwill be a useful approach to diagnosisand treatment monitoring. We publisheda study8 a few years ago with 16subjects [9 with Alzheimer's disease],and now we have 60 subjects in followup,so we can be much more confidentin the findings."

Eventually, Small hopes to placeindividuals whose PET scans showevidence of abnormal protein buildupon a healthy lifestyle regimen and toinvestigate how the intervention mightmodify the disease process.

Attitudes and aging

While researchers define successfulaging in various ways, few investigatorshave explored older adults' selfperceptionsof successful aging. At theStein Institute for Research on Agingat the University of California, SanDiego, researchers led by Dilip V. Jeste,MD, professor of psychiatry and neurosciencesand Estelle and Edgar LeviChair in Aging, found that perceptionsof the aging process depend not ondisease or physical disability but ratheron attitude and coping style.9

The researchers conducted a studyinvolving self-rating of successful agingin more than 1200 community-dwellingresidents between the ages of 60 and99 years. The participants completeda detailed survey questionnaire on theirmedical history, health behaviors, qualityof life, resilience, and cognitiveperformance, and rated themselves onsuccessful aging. Nearly three fourthsof the respondents felt they were agingwell, often despite their having physicalillnesses and some disability.10

"What is most interesting aboutthis study is that people who think theyare aging well are not necessarily themost healthy individuals," Jeste notedin a news release.9 "In fact, optimismand effective coping styles were foundto be more important to aging successfullythan traditional measures ofhealth and wellness. These findingssuggest that physical health is not thebest indicator of successful aging—attitude is."

Another strong indicator of successfulaging was the level of social andcommunity involvement. Participantswho spent time each day on hobbies,such as reading and writing, or socializingwith other members of thecommunity consistently gave themselveshigh scores, as did participantswho had a paid job outside of the home.




Zubenko GS, Stiffler JS, Hughes HB 3rd, et al.Genome survey for loci that influence successfulaging: sample characterization, method validation,and initial results for the Y chromosome.

Am J GeriatrPsychiatry

. 2002;10:619-630.


Zubenko GS. Successful aging: a neuropsychiatricentity. Paper presented at: 44th Annual Meeting ofthe American College of Neuropsychopharmacology;December 11-15, 2005; Waikoloa, Hawaii.


American College of Neuropsychopharmacology.New research examines genetics of successful aging.News release, December 12, 2005.


American College of Neuropsychopharmacology.New study finds that older Americans may improvememory by exercising their brains and bodies. Newsrelease, December 12, 2005.


Small G. Effects of a 14-day healthy aging lifestyleprogram on brain function. Paper presented at: 44thAnnual Meeting of the American College ofNeuropsychopharmacology; December 11-15, 2005;Waikoloa, Hawaii.


Small G. The Memory Prescription: Dr. Gary Small's14-Day Plan to Keep Your Brain and Body Young.New York: Hyperion; 2004.


Small G. The Memory Bible: An Innovative Strategyfor Keeping Your Brain Young. New York: Hyperion;2002.


Shoghi-Jadid K, Small GW, Agdeppa ED, et al.Localization of neurofibrillary tangles and betaamyloidplaques in the brains of living patients withAlzheimer disease.

Am J Geriatr Psychiatry



American College of Neuropsychopharmacology.New study shows successful aging a question of "mindover matter." News release, December 12, 2005.


Jeste D. A psycho-bio-social study of successfulaging among community-dwelling seniors. Paperpresented at: 44th Annual Meeting of the AmericanCollege of Neuropsychopharmacology; December 11-15, 2005; Waikoloa, Hawaii.