Qimei He

Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.

Long-term caloric restriction (CR) is a robust means of reducing age-related diseases and extending life span in multiple species, but the effects in humans are unknown. The low caloric intake, long life expectancy, and the high prevalence of centenarians in Okinawa have been used as an argument to support the CR hypothesis in humans. However, no long-term, epidemiologic analysis has been conducted on traditional dietary patterns, energy balance, and potential CR phenotypes for the specific cohort of Okinawans who are purported to have had a calorically restricted diet. Nor has this cohort's subsequent mortality experience been rigorously studied. Therefore, we investigated six decades of archived population data on the elderly cohort of Okinawans (aged 65-plus) for evidence of CR. Analyses included traditional diet composition, energy intake, energy expenditure, anthropometry, plasma DHEA, mortality from age-related diseases, and current survival patterns. Findings include low caloric intake and negative energy balance at younger ages, little weight gain with age, life-long low BMI, relatively high plasma DHEA levels at older ages, low risk for mortality from age-related diseases, and survival patterns consistent with extended mean and maximum life span. This study lends epidemiologic support for phenotypic benefits of CR in humans and is consistent with the well-known literature on animals with regard to CR phenotypes and healthy aging.

Article AbstractObjective: To demonstrate the noninferiority of a telemedicine modality, videoteleconferencing, compared to traditional in-person service delivery of a group psychotherapy intervention for rural combat veterans with posttraumatic stress disorder (PTSD).Method: A randomized controlled noninferiority trial of 125 male veterans with PTSD (according to DSM criteria on the Clinician-Administered PTSD Scale) and anger difficulties was conducted at 3 Veterans Affairs outpatient clinics. Participants were randomly assigned to receive anger management therapy delivered in a group setting with the therapist either in-person (n†‰=†‰64) or via videoteleconferencing (n†‰=†‰61). Participants were assessed at baseline, midtreatment (3 weeks), posttreatment (6 weeks), and 3 and 6 months posttreatment. The primary clinical outcome was reduction of anger difficulties, as measured by the anger expression and trait anger subscales of the State-Trait Anger Expression Inventory-2 (STAXI-2) and by the Novaco Anger Scale total score (NAS-T). Data were collected from August 2005 to October 2008.Results: Participants in both groups showed significant and clinically meaningful reductions in anger symptoms, with posttreatment and 3 and 6 months posttreatment effect sizes ranging from .12 to .63. Using a noninferiority margin of 2 points for STAXI-2 subscales anger expression and trait anger and 4 points for NAS-T outcomes, participants in the videoteleconferencing condition demonstrated a reduction in anger symptoms similar ("non-inferior") to symptom reductions in the in-person groups. Additionally, no significant between-group differences were found on process variables, including attrition, adherence, satisfaction, and treatment expectancy. Participants in the in-person condition reported significantly higher group therapy alliance.Conclusions: Clinical and process outcomes indicate delivering cognitive-behavioral group treatment for PTSD-related anger problems via videoteleconferencing is an effective and feasible way to increase access to evidence-based care for veterans residing in rural or remote locations.Trial Registration: clinicaltrials.gov Identifier: NCT00122109J Clin Psychiatry 2010;71(7):855-863Submitted: August 11, 2009; accepted September 28, 2009.Online ahead of print: January 26, 2010 (doi:10.4088/JCP.09m05604blu).Corresponding author: Leslie A. Morland, PsyD, National Center for PTSD-Pacific Islands Division, Department of Veterans Affairs Pacific Islands Healthcare System, 3375 Koapaka St, Suite I-560, Honolulu, HI 96819 (Leslie.Morland@va.gov).

CONTEXT: Healthy survival has no clear phenotypic definition, and little is known about its attributes, particularly in men. OBJECTIVE: To test whether midlife biological, lifestyle, and sociodemographic risk factors are associated with overall survival and exceptional survival (free of a set of major diseases and impairments). DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study within the Honolulu Heart Program/Honolulu Asia Aging Study. A total of 5820 Japanese American middle-aged men (mean age, 54 [range, 45-68] years) free of morbidity and functional impairments were followed for up to 40 years (1965-2005) to assess overall and exceptional survival. Exceptional survival was defined as survival to a specified age (75, 80, 85, or 90 years) without incidence of 6 major chronic diseases and without physical and cognitive impairment. MAIN OUTCOME MEASURE: Overall survival and exceptional survival. RESULTS: Of 5820 original participants, 2451 participants (42%) survived to age 85 years and 655 participants (11%) met the criteria for exceptional survival to age 85 years. High grip strength and avoidance of overweight, hyperglycemia, hypertension, smoking, and excessive alcohol consumption were associated with both overall and exceptional survival. In addition, high education and avoidance of hypertriglyceridemia were associated with exceptional survival, and lack of a marital partner was associated with mortality before age 85 years. Risk factor models based on cumulative risk factors (survival risk score) suggest that the probability of survival to oldest age is as high as 69% with no risk factors and as low as 22% with 6 or more risk factors. The probability of exceptional survival to age 85 years was 55% with no risk factors but decreased to 9% with 6 or more risk factors. CONCLUSION: These data suggest that avoidance of certain risk factors in midlife is associated with the probability of a long and healthy life among men.

Okinawa, an isolated island prefecture of Japan, has among the highest prevalence of exceptionally long-lived individuals in the world; therefore, we hypothesized that, within this population, genes that confer a familial survival advantage might have clustered. We analyzed the pedigrees of 348 centenarian families with 1142 siblings and compared sibling survival with that of the 1890 Okinawan general population cohort. Both male and female centenarian siblings experienced approximately half the mortality of their birth cohort-matched counterparts. This mortality advantage was sustained and did not diminish with age in contrast to many environmentally based mortality gradients, such as education and income. Cumulative survival advantages for this centenarian sibling cohort increased over the life span such that female centenarian siblings had a 2.58-fold likelihood, and male siblings a 5.43-fold likelihood, versus their birth cohorts, of reaching the age of 90 years. These data support a significant familial component to exceptional human longevity.