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1.  Prenatal and childhood growth and physical performance in old age—findings from the Helsinki Birth Cohort Study 1934–1944 
Age  2015;37(6):108.
Health in adulthood is in part a consequence of development and growth taking place during sensitive periods in early life. It has not been explored previously whether early growth is associated with physical performance in old age from a life course perspective taking into account health-related behavior, biological risk factors, and early life experiences. At a mean age of 71 years, physical performance was assessed using the Senior Fitness Test (SFT) in 1078 individuals belonging to the Helsinki Birth Cohort Study. We used multiple linear regression analysis to assess the association between the SFT physical fitness scores and individual life course measurements. Several adult characteristics were associated with physical performance including socioeconomic status, lifestyle factors, and adult anthropometry. Higher birth weight and length were associated with better physical performance, even after adjusting for potential confounders (all p values <0.05). The strongest individual association between life course measurements and physical performance in old age was found for adult body fat percentage. However, prenatal growth was independently associated with physical performance seven decades later. These findings suggest that physical performance in old age is at least partly programmed in early life.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-015-9846-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-015-9846-1
PMCID: PMC5005845  PMID: 26499818
Physical performance; Senior Fitness Test; Prenatal growth; Birth weight; Aging; Physical fitness
2.  Infant motor development and cognitive performance in early old age: the Helsinki Birth Cohort Study 
Age  2015;37(3):44.
Motor development and cognitive development in childhood have been found to be fundamentally interrelated, but less is known about the association extending over the life course. The aim of this study was to examine the association between early motor development and cognitive performance in early old age. From men and women belonging to the Helsinki Birth Cohort Study, who were born between 1934 and 1944 and resided in Finland in 1971, 1279 participated in cognitive performance tests (CogState®, version 3.0.5) between 2001 and 2006 at an average age of 64.2 years (SD 3.0). Of these, age at first walking extracted from child welfare clinic records was available for 398 participants. Longer reaction times in cognitive tasks measuring simple reaction time (SRT), choice reaction time (CRT), working memory (WM), divided attention (DA), and associated learning (AL) indicated poorer cognitive performance. Adjustment was made for sex, age at testing, father’s occupational status and own highest attained education, and occupation in adulthood. Average age of learning to walk was 12.2 months (SD 2.1). After adjusting for covariates, earlier attainment of learning to walk was associated with shorter reaction times in cognitive performance tasks (SRT 10.32 % per month, 95 % CI 0.48–21.12, p = 0.039; CRT 14.17 % per month, 95 % CI 3.75–25.63, p = 0.007; WM 15.14 % per month, 95 % CI 4.95–26.32, p = 0.003). People who learned to walk earlier had better cognitive performance in early old age. The earlier attainment of motor skills may track over to early old age and possibly reflect greater cognitive reserve in older age.
doi:10.1007/s11357-015-9785-x
PMCID: PMC4416091  PMID: 25929653
Infant motor development; Age at first walking; Cognitive performance; Cognitive reserve; Older age
3.  Mobility Modification Alleviates Environmental Influence on Incident Mobility Difficulty among Community-Dwelling Older People: A Two-Year Follow-Up Study 
PLoS ONE  2016;11(4):e0154396.
Background
Environmental barriers increase risk for mobility difficulties in old age. Mobility difficulty is preceded by a phase where people try to postpone a difficulty through mobility modification. We studied whether perceived environmental mobility barriers outdoors correlate with mobility modification and mobility difficulty, predict development of mobility difficulty over a two-year follow-up, and whether mobility modification alleviates the risk for difficulty.
Methods
At baseline, 848 people aged 75–90 were interviewed face-to-face. Telephone follow-up interviews were conducted one (n = 816) and two years (n = 761) later. Environmental barriers to mobility were self-reported using a15-item structured questionnaire at baseline, summed and divided into tertiles (0, 1 and 2 or more barriers). Mobility difficulty was assessed as self-reported ability to walk 2 km at all assessment points and categorized into ‘no difficulty’, ‘no difficulty but mobility modifications’ (reducing frequency, stopping walking, using an aid, slowing down or resting during the performance) and ‘difficulty’.
Results
At baseline, 212 participants reported mobility modifications and 356 mobility difficulties. Those reporting one or multiple environmental barriers had twice the odds for mobility modifications and up to five times the odds for mobility difficulty compared to those reporting no environmental barriers. After multiple adjustments for health and functioning, reporting multiple environmental barriers outdoors continued to predict the development of incident mobility difficulty over the two-year follow-up. Mobility modifications attenuated the association.
Conclusion
For older people who successfully modify their performance, environmental influence on incident mobility difficulty can be diminished. Older people use mobility modification to alleviate environmental press on mobility.
doi:10.1371/journal.pone.0154396
PMCID: PMC4841513  PMID: 27104750
4.  Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error 
Fan, Qiao | Verhoeven, Virginie J. M. | Wojciechowski, Robert | Barathi, Veluchamy A. | Hysi, Pirro G. | Guggenheim, Jeremy A. | Höhn, René | Vitart, Veronique | Khawaja, Anthony P. | Yamashiro, Kenji | Hosseini, S Mohsen | Lehtimäki, Terho | Lu, Yi | Haller, Toomas | Xie, Jing | Delcourt, Cécile | Pirastu, Mario | Wedenoja, Juho | Gharahkhani, Puya | Venturini, Cristina | Miyake, Masahiro | Hewitt, Alex W. | Guo, Xiaobo | Mazur, Johanna | Huffman, Jenifer E. | Williams, Katie M. | Polasek, Ozren | Campbell, Harry | Rudan, Igor | Vatavuk, Zoran | Wilson, James F. | Joshi, Peter K. | McMahon, George | St Pourcain, Beate | Evans, David M. | Simpson, Claire L. | Schwantes-An, Tae-Hwi | Igo, Robert P. | Mirshahi, Alireza | Cougnard-Gregoire, Audrey | Bellenguez, Céline | Blettner, Maria | Raitakari, Olli | Kähönen, Mika | Seppala, Ilkka | Zeller, Tanja | Meitinger, Thomas | Ried, Janina S. | Gieger, Christian | Portas, Laura | van Leeuwen, Elisabeth M. | Amin, Najaf | Uitterlinden, André G. | Rivadeneira, Fernando | Hofman, Albert | Vingerling, Johannes R. | Wang, Ya Xing | Wang, Xu | Tai-Hui Boh, Eileen | Ikram, M. Kamran | Sabanayagam, Charumathi | Gupta, Preeti | Tan, Vincent | Zhou, Lei | Ho, Candice E. H. | Lim, Wan'e | Beuerman, Roger W. | Siantar, Rosalynn | Tai, E-Shyong | Vithana, Eranga | Mihailov, Evelin | Khor, Chiea-Chuen | Hayward, Caroline | Luben, Robert N. | Foster, Paul J. | Klein, Barbara E. K. | Klein, Ronald | Wong, Hoi-Suen | Mitchell, Paul | Metspalu, Andres | Aung, Tin | Young, Terri L. | He, Mingguang | Pärssinen, Olavi | van Duijn, Cornelia M. | Jin Wang, Jie | Williams, Cathy | Jonas, Jost B. | Teo, Yik-Ying | Mackey, David A. | Oexle, Konrad | Yoshimura, Nagahisa | Paterson, Andrew D. | Pfeiffer, Norbert | Wong, Tien-Yin | Baird, Paul N. | Stambolian, Dwight | Wilson, Joan E. Bailey | Cheng, Ching-Yu | Hammond, Christopher J. | Klaver, Caroline C. W. | Saw, Seang-Mei | Rahi, Jugnoo S. | Korobelnik, Jean-François | Kemp, John P. | Timpson, Nicholas J. | Smith, George Davey | Craig, Jamie E. | Burdon, Kathryn P. | Fogarty, Rhys D. | Iyengar, Sudha K. | Chew, Emily | Janmahasatian, Sarayut | Martin, Nicholas G. | MacGregor, Stuart | Xu, Liang | Schache, Maria | Nangia, Vinay | Panda-Jonas, Songhomitra | Wright, Alan F. | Fondran, Jeremy R. | Lass, Jonathan H. | Feng, Sheng | Zhao, Jing Hua | Khaw, Kay-Tee | Wareham, Nick J. | Rantanen, Taina | Kaprio, Jaakko | Pang, Chi Pui | Chen, Li Jia | Tam, Pancy O. | Jhanji, Vishal | Young, Alvin L. | Döring, Angela | Raffel, Leslie J. | Cotch, Mary-Frances | Li, Xiaohui | Yip, Shea Ping | Yap, Maurice K.H. | Biino, Ginevra | Vaccargiu, Simona | Fossarello, Maurizio | Fleck, Brian | Yazar, Seyhan | Tideman, Jan Willem L. | Tedja, Milly | Deangelis, Margaret M. | Morrison, Margaux | Farrer, Lindsay | Zhou, Xiangtian | Chen, Wei | Mizuki, Nobuhisa | Meguro, Akira | Mäkelä, Kari Matti
Nature Communications  2016;7:11008.
Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
This report by the Consortium for Refractive Error and Myopia uses gene-environment-wide interaction study (GEWIS) to identify genetic loci that affect environmental influence in myopia development, and identifies ethnic specific genetic loci that attribute to eye refractive errors.
doi:10.1038/ncomms11008
PMCID: PMC4820539  PMID: 27020472
5.  Midlife work ability and mobility limitation in old age among non-disability and disability retirees - a prospective study 
BMC Public Health  2016;16:154.
Background
Little is known about the wellbeing and mobility limitation of older disability retirees. Personal and environmental factors, such as time spent in working life, may either exacerbate or mitigate the onset of mobility limitation in general population.
We aimed to study perceived midlife work ability as a determinant of self-reported mobility limitation in old age among municipal employees who transitioned into non-disability and disability retirement.
Methods
4329 participants of the Finnish Longitudinal Study of Municipal Employees (FLAME) had retired during January 1985 and July 2000. They had data on retirement, perceived work ability in 1985, and self-reported mobility limitation (non-disability retirement n = 2870, men 39 %; and diagnose-specific disability retirement n = 1459, men 48 %). Self-reported mobility was measured in 1985, 1992, 1997 and 2009. The latest score available was used to assess the number of mobility limitation. Work ability was measured by asking the respondents to evaluate their current work ability against their lifetime best in 1985. Incidence rate ratios (IRRs) and 95 % confidence intervals (CIs) for work ability predicting mobility limitation in non-disability and diagnose-specific disability retirement groups were calculated using Poisson regression models.
Results
The prevalence of mobility limitation for those who transitioned into non-disability retirement (Incidence Rate, IR = 0.45, 95 % CI = 0.44–0.46) was lower compared to those who retired due to disability (IR = 0.65, CI = 0.63–0.66). A one-point increase in the work ability score decreased the risk for having one more mobility limitation among non-disability and all diagnose-specific retirement groups (musculoskeletal disease, cardiovascular disease, mental disorder, and other diseases).
Conclusions
Better midlife work ability may protect from old age mobility limitation among those who retire due to non-disability and disability. Promoting work ability in midlife may lead to more independent, active aging, regardless of type of retirement.
doi:10.1186/s12889-016-2846-y
PMCID: PMC4754857  PMID: 26880684
Work ability; Disability retirement; Mobility limitation; Aging; Municipal employees
6.  G×E Interaction Influences Trajectories of Hand Grip Strength 
Behavior genetics  2015;46(1):20-30.
Age-related decline in grip strength predicts later life disability, frailty, lower well-being and cognitive change. While grip strength is heritable, genetic influence on change in grip strength has been relatively ignored, with non-shared environmental influence identified as the primary contributor in a single longitudinal study. The extent to which gene-environment interplay, particularly gene-environment interactions, contributes to grip trajectories has yet to be examined. We considered longitudinal grip strength measurements in seven twin studies of aging in the Interplay of Genes and Environment across Multiple Studies consortium. Growth curve parameters were estimated for same-sex pairs, aged 34–99 (N = 10,681). Fisher's test for mixture distribution of within-monozy-gotic twin-pair differences (N = 1724) was performed on growth curve parameters. We observed significant gene-environment interaction on grip strength trajectories. Finally, we compared the variability of within-pair differences of growth curve parameters by APOE haplotypes. Though not statistically significant, the results suggested that APOE ε2ε2/ε2ε3 haplotypes might buffer environmental influences on grip strength trajectories.
doi:10.1007/s10519-015-9736-4
PMCID: PMC4720577  PMID: 26318288
Grip strength; Gene-environment interaction; Twins; APOE
7.  Work-related stress in midlife is associated with higher number of mobility limitation in older age—results from the FLAME study 
Age  2014;36(6):9722.
The aim of this study is to investigate whether work-related stress symptoms in midlife are associated with a number of mobility limitations during three decades from midlife to late life. Data for the study come from the Finnish Longitudinal Study of Municipal Employees (FLAME). The study includes a total of 5429 public sector employees aged 44–58 years at baseline who had information available on work-related stress symptoms in 1981 and 1985 and mobility limitation score during the subsequent 28-year follow-up. Four midlife work-related stress profiles were identified: negative reactions to work and depressiveness, perceived decrease in cognition, sleep disturbances, and somatic symptoms. People with a high number of stress symptoms in 1981 and 1985 were categorized as having constant stress. The number of self-reported mobility limitations was computed based on an eight-item list of mobility tasks presented to the participants in 1992, 1997, and 2009. Data were analyzed using joint Poisson regression models. The study showed that depending on the stress profile, persons suffering from constant stress in midlife had a higher risk of 30–70 % for having one more mobility limitation during the following 28 years compared to persons without stress after adjusting for mortality, several lifestyle factors, and chronic conditions. A less pronounced risk increase (20–40 %) was observed for persons with occasional symptoms. The study suggests that effective interventions aiming to reduce work-related stress should focus on both primary and secondary prevention.
doi:10.1007/s11357-014-9722-4
PMCID: PMC4223109  PMID: 25378119
Aging; ICF; Mobility; Mortality; Prospective study; Stress
8.  Frailty and depression in older adults: A high-risk clinical population 
Objectives
To identify salient characteristics of frailty that increase risk of death in depressed elders.
Design
Data from the Nordic Research on Ageing Study.
Setting
Research sites in Denmark, Sweden, and Finland.
Participants
Sample included 1027 75-year-old adults, 436 men and 591 women.
Main Outcome Measure
Time of death was obtained, providing a maximum survival time of 11.08 years (initial evaluation took place between 1988-1991).
Results
Depressed elders showed greater baseline impairments in each frailty characteristic (gait speed, grip strength, physical activity levels, and fatigue). Simultaneous models including all four frailty characteristics showed slow gait speed (HR, 1.84; 95% CI, 1.05-3.21) and fatigue (HR, 1.94; 95% CI, 1.11-3.40) associated with faster progression to death in depressed women; none of the frailty characteristics in the simultaneous model were associated with death in depressed men. In women, the effect of impaired gait speed on mortality rates nearly doubled when depression was present (mortality rates, nondepressed women: no gait impairment =26%; slow gait =40%; depressed women: no gait impairment=32%; slow gait =58%). A similar pattern was observed for fatigue.
Conclusions
The confluence of specific characteristics of frailty (fatigue and slow gait speed) and depressive illness is associated with an increased risk of death in older adults; this association is particularly strong in older depressed women. Future research should investigate whether multimodal interventions targeting depressive illness, mobility deficits, and fatigue can decrease mortality and improve quality of life in older depressed individuals with characteristics of the syndrome of frailty.
doi:10.1016/j.jagp.2013.04.010
PMCID: PMC3930630  PMID: 23973252
9.  Self-reported hearing difficulties and changes in life-space mobility among community-dwelling older adults: a Two-year follow-Up study 
BMC Geriatrics  2015;15:121.
Background
Life-space mobility reflects individuals’ actual mobility and engagement with society. Difficulty in hearing is common among older adults and can complicate participation in everyday activities, thus restricting life-space mobility. The aim of this study was to examine whether self-reported hearing predicts changes in life-space mobility among older adults.
Methods
We conducted a prospective cohort study of community-dwelling older adults aged 75–90 years (n = 848). At-home face-to-face interviews at baseline and telephone follow-up were used. Participants responded to standardized questions on perceived hearing at baseline. Life-space mobility (the University of Alabama at Birmingham Life-Space Assessment, LSA, range 0–120) was assessed at baseline and one and two years thereafter. Generalized estimating equations were used to analyze the effect of hearing difficulties on changes in LSA scores.
Results
At baseline, participants with major hearing difficulties had a significantly lower life-space mobility score than those without hearing difficulties (mean 54, 95 % CI 50–58 vs. 57, 95 % CI 53–61, p = .040). Over the 2-year follow-up, the life-space mobility score declined in all hearing categories in a similar rate (main effect of time p < .001, group x time p = .164). Participants with mild or major hearing difficulties at baseline had significantly higher odds for restricted life-space (LSA score < 60) at two years (OR 1.8, 95 % CI 1.0–3.2 and 2.0, 95 % CI 1.0–3.9, respectively) compared to those without hearing difficulties. The analyses were adjusted for chronic conditions, age, sex and cognitive functioning.
Conclusions
People with major hearing difficulties had lower life-space mobility scores at baseline but did not exhibit accelerated decline over the follow-up compared to those without hearing difficulties. Life-space mobility describes older people’s possibilities for participating in out-of-home activities and access to community amenities, which are important building blocks of quality of life in old age. Early recognition of hearing difficulties may help prevent life-space restriction.
doi:10.1186/s12877-015-0119-8
PMCID: PMC4603343  PMID: 26459630
Hearing; Life-space; Aging; Cohort; Longitudinal study
10.  Moving through Life-Space Areas and Objectively Measured Physical Activity of Older People 
PLoS ONE  2015;10(8):e0135308.
Objectives
Physical activity–an important determinant of health and function in old age–may vary according to the life-space area reached. Our aim was to study how moving through greater life-space areas is associated with greater physical activity of community-dwelling older people. The association between objectively measured physical activity and life-space area reached on different days by the same individual was studied using one-week longitudinal data, to provide insight in causal relationships.
Methods
One-week surveillance of objectively assessed physical activity of community-dwelling 70–90-year-old people in central Finland from the “Life-space mobility in old age” cohort substudy (N = 174). In spring 2012, participants wore an accelerometer for 7 days and completed a daily diary including the largest life-space area reached (inside home, outside home, neighborhood, town, and beyond town). The daily step count, and the time in moderate (incl. walking) and low activity and sedentary behavior were assessed. Differences in physical activity between days on which different life-space areas were reached were tested using Generalized Estimation Equation models (within-group comparison).
Results
Participants’ mean age was 80.4±4.2 years and 63.5% were female. Participants had higher average step counts (p < .001) and greater moderate and low activity time (p < .001) on days when greater life-space areas were reached, from the home to the town area. Only low activity time continued to increase when moving beyond the town.
Conclusion
Community-dwelling older people were more physically active on days when they moved through greater life-space areas. While it is unknown whether physical activity was a motivator to leave the home, intervention studies are needed to determine whether facilitation of daily outdoor mobility, regardless of the purpose, may be beneficial in terms of promoting physical activity.
doi:10.1371/journal.pone.0135308
PMCID: PMC4529301  PMID: 26252537
11.  Genome-wide association analysis on normal hearing function identifies PCDH20 and SLC28A3 as candidates for hearing function and loss 
Human Molecular Genetics  2015;24(19):5655-5664.
Hearing loss and individual differences in normal hearing both have a substantial genetic basis. Although many new genes contributing to deafness have been identified, very little is known about genes/variants modulating the normal range of hearing ability. To fill this gap, we performed a two-stage meta-analysis on hearing thresholds (tested at 0.25, 0.5, 1, 2, 4, 8 kHz) and on pure-tone averages (low-, medium- and high-frequency thresholds grouped) in several isolated populations from Italy and Central Asia (total N = 2636). Here, we detected two genome-wide significant loci close to PCDH20 and SLC28A3 (top hits: rs78043697, P = 4.71E−10 and rs7032430, P = 2.39E−09, respectively). For both loci, we sought replication in two independent cohorts: B58C from the UK (N = 5892) and FITSA from Finland (N = 270). Both loci were successfully replicated at a nominal level of significance (P < 0.05). In order to confirm our quantitative findings, we carried out RT-PCR and reported RNA-Seq data, which showed that both genes are expressed in mouse inner ear, especially in hair cells, further suggesting them as good candidates for modulatory genes in the auditory system. Sequencing data revealed no functional variants in the coding region of PCDH20 or SLC28A3, suggesting that variation in regulatory sequences may affect expression. Overall, these results contribute to a better understanding of the complex mechanisms underlying human hearing function.
doi:10.1093/hmg/ddv279
PMCID: PMC4572074  PMID: 26188009
12.  Pre-Stroke Weight Loss is Associated with Post-Stroke Mortality among Men in the Honolulu-Asia Aging Study 
Objective
To examine baseline pre-stroke weight loss and post-stroke mortality among men.
Design
Longitudinal study of late-life pre-stroke body mass index (BMI), weight loss and BMI change (midlife to late-life), with up to 8-year incident stroke and mortality follow-up.
Setting
Honolulu Heart Program/Honolulu-Asia Aging Study.
Participants
3,581 Japanese-American men aged 71–93 years and stroke-free at baseline.
Main Outcome Measure
Post-stroke Mortality: 30-day post-stroke, analyzed with stepwise multivariable logistic regression and long-term post-stroke (up to 8-year), analyzed with stepwise multivariable Cox regression.
Results
Weight loss (10-pound decrements) was associated with increased 30-day post-stroke mortality (aOR=1.48, 95%CI 1.14–1.92), long-term mortality after incident stroke (all types n=225, aHR=1.25, 95%CI=1.09–1.44) and long-term mortality after incident thromboembolic stroke (n=153, aHR 1.19, 95%CI-1.01–1.40). Men with overweight/obese late-life BMI (≥25kg/m2, compared to normal/underweight BMI) had increased long-term mortality after incident hemorrhagic stroke (n=54, aHR=2.27, 95%CI=1.07–4.82). Neither desirable nor excessive BMI reductions (vs. no change/increased BMI) were associated with post-stroke mortality. In the overall sample (n=3,581), nutrition factors associated with increased long-term mortality included 1) weight loss (10-pound decrements, aHR=1.15, 1.09–1.21); 2) underweight BMI (vs. normal BMI, aHR=1.76, 1.40–2.20); and 3) both desirable and excessive BMI reductions (vs. no change or gain, separate model from weight loss and BMI, aHRs=1.36–1.97, p<0.001).
Conclusions
Although obesity is a risk factor for stroke incidence, pre-stroke weight loss was associated with increased post-stroke (all types and thromboembolic) mortality. Overweight/obese late-life BMI was associated with increased post-hemorrhagic stroke mortality. Desirable and excessive BMI reductions were not associated with post-stroke mortality. Weight loss, underweight late-life BMI and any BMI reduction were all associated with increased long-term mortality in the overall sample.
doi:10.1016/j.apmr.2013.09.019
PMCID: PMC3943854  PMID: 24113337
older men; stroke; weight loss; BMI; mortality; aged; longitudinal
13.  A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol 
Genome-wide association analysis on monozygotic twin pairs offers a route to discovery of gene–environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high density lipoprotein (HDL) cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (p = 3.98 × 10−8). We followed up the association in further genotyped monozygotic twins (N = 1 261) which showed a moderate association for the variant (p = .002, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (p = 4.03 × 10−8).
doi:10.1017/thg.2012.63
PMCID: PMC4333218  PMID: 23031429
twins; association; lipids; apolipoproteins; interaction
14.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
15.  Coronary artery calcium and physical performance as determinants of mortality in older age: the AGES-Reykjavik Study 
International journal of cardiology  2013;168(3):2094-2099.
Background
Coronary artery calcium (CAC) and physical performance have been shown to be associated with mortality, but it is not clear whether one of them modifies the association. We investigated the association between the extent of CAC and physical performance among older individuals and explored these individual and combined effects on cardiovascular disease (CVD) and non-CVD mortality.
Methods
We studied 4074 participants of the AGES-Reykjavik Study who were free from coronary heart disease, had a CAC score calculated from computed tomography scans and had data on mobility limitations and gait speed at baseline in 2002-2006 at a mean age of 76 years. Register-based mortality was available until 2009.
Results
Odds for mobility limitation and slow gait increased according to the extent of CAC. Altogether 645 persons died during the follow-up. High CAC, mobility limitation and slow gait were independent predictors of CVD and non-CVD mortality. The joint effect of CAC and gait speed on non-CVD mortality was synergistic, i.e. compared to those with low CAC and normal gait, the joint effect of high CAC and slow gait exceeded the additive effect of these individual exposures on non-CVD mortality. For CVD mortality, the effect was additive i.e. the joint effect of high CAC and slow gait did not exceed the sum of the individual exposures.
Conclusions
The extent of CAC and decreased physical performance were independent predictors of mortality and the joint presence of these risk factors increased the risk of non-CVD mortality above and beyond the individual effects.
doi:10.1016/j.ijcard.2013.01.067
PMCID: PMC3674198  PMID: 23414742
atherosclerosis; coronary artery calcification; cardiovascular disease risk factors; aging; mortality; epidemiology
16.  Persistence of the effect of birth size on dysglycaemia and type 2 diabetes in old age: AGES-Reykjavik Study 
Age  2012;35(4):1401-1409.
We studied the effect of birth size on glucose and insulin metabolism among old non-diabetic individuals. We also explored the combined effect of birth size and midlife body mass index (BMI) on type 2 diabetes in old age. Our study comprised 1,682 Icelanders whose birth records included anthropometrical data. The same individuals had participated in the prospective population-based Reykjavik Study, where BMI was assessed at a mean age of 47 years, and in the AGES-Reykjavik Study during 2002 to 2006, where fasting glucose, insulin and HbA1c were measured and homeostasis model assessment for the degree of insulin resistance (HOMA-IR) calculated at a mean age of 75.5 years. Type 2 diabetes was determined as having a history of diabetes, using glucose-modifying medication or fasting glucose of >7.0 mmol/l. Of the participants, 249 had prevalent type 2 diabetes in old age. Lower birth weight and body length were associated with higher fasting glucose, insulin, HOMA-IR and HbA1c among old non-diabetic individuals. Higher birth weight and ponderal index at birth decreased the risk for type 2 diabetes in old age, odds ratio (OR), 0.61 [95 % confidence interval (CI), 0.48–0.79] and 0.96 (95 % CI, 0.92–1.00), respectively. Compared with those with high birth weight and low BMI in midlife, the odds of diabetes was almost five-fold for individuals with low birth weight and high BMI (OR, 4.93; 95 % CI, 2.14–11.37). Excessive weight gain in adulthood might be particularly detrimental to the health of old individuals with low birth weight.
doi:10.1007/s11357-012-9427-5
PMCID: PMC3705119  PMID: 22588637
Aging; Birth size; Type 2 diabetes; Dysglycaemia; Birth weight; AGES-Reykjavik Study
17.  Improving a Measure of Mobility-Related Fatigue (The Mobility-Tiredness Scale) by Establishing Item Intensity 
OBJECTIVES
To improve the construct validity of self-reported fatigue by establishing a formal hierarchy of scale items and to determine whether such a hierarchy could be maintained across time (aged 75–80), sex, and nationality.
DESIGN
Cohort study.
SETTING
Two Nordic urban locations: Jyväskylä, Finland, and Glostrup, Denmark.
PARTICIPANTS
Baseline (1989/90) consisted of a random sample of citizens of Finland or Denmark born in 1914 (n = 837). At 5-year follow-up, excluding those lost to follow-up and with baseline disability resulted in a sample of n = 690.
MEASUREMENTS
The Mobility-Tiredness (Mob-T) Scale is a six-item scale that requires subjects to self-report on whether they become tired performing mobility-related tasks. Employing item response theory, an attempt was made to enhance construct validity by confirming a hierarchy of mobility-related fatigue.
RESULTS
A formal hierarchy of fatigue tasks, maintained across time, was established using the revised Mob- T Scale. At age 75, the scalability statistics were a homogeneity coefficient (H) of 0.80, HaT of 3.9% and an HT value of 0.66. The corresponding figures at age 80 were 0.75, 6.9% and 0.59. The property of invariant item ordering was maintained across subgroups based on sex and nationality.
CONCLUSION: Establishing a formal hierarchy at age 75 allowed which tasks were most debilitating to be identified more clearly and the individual’s “distance” from these tasks to be gauged. Because it was possible to confirm that the item hierarchy was maintained across time (aged 75–80), researchers or clinicians can be more confident that performance over time is the result of real change and has less to do with measurement error.
doi:10.1111/jgs.12122
PMCID: PMC4047030  PMID: 23452001
mobility-related fatigue; task intensity; scale validation
18.  Life-space mobility assessment in older people in Finland; measurement properties in winter and spring 
BMC Research Notes  2014;7:323.
Background
Life-space mobility refers to the spatial area an individual moves through, the frequency and need for assistance. Based on the assumption that measurement scale properties are context-specific, we tested the scale distribution, responsiveness, and reproducibility of the 15-item University of Alabama at Birmingham Study of Aging Life-Space Assessment in older people in Finland, specifically accounting for season.
Methods
Community-dwelling older men and women in central Finland aged 75-90 years were interviewed to determine life-space mobility (score range 0-120). Baseline (January-June 2012) and one-year follow-up data (January-June 2013; n = 806) from the cohort study “Life-space mobility in old age” were used to investigate the scale distribution and responsiveness over a period of one year. In addition, with a sub-sample in conjunction with the one-year follow-up, we collected data to study the two-week test-retest reproducibility (n = 18 winter and n = 21 spring 2013).
Results
The median life-space mobility score at baseline was 64. The median change in score over the one-year follow-up was zero. However, participants reporting a decline in health (repeated measures ANOVA p = .016) or mobility (p = .002) status demonstrated a significantly larger decrease in life-space mobility score than those reporting no or positive changes over the year. The two-week intra-class correlation (ICC) coefficient was .72. Lower ICC was found in the winter than in the spring sample and for items that represent higher life-space levels.
Conclusions
The test-retest reproducibility of the Life-Space Assessment was fair but somewhat compromised in the winter. Mobility of older people at the life-space levels of “town” and “beyond town” may be more variable. Life-space mobility was responsive to change, regardless of season. Further study is warranted to obtain insight in the factors contributing to seasonal effects.
doi:10.1186/1756-0500-7-323
PMCID: PMC4055210  PMID: 24886670
Reliability; Scale; Methods; Psychometrics; Mobility; Life-space; Aging; Season
19.  Walking Recovery after a Hip Fracture: A Prospective Follow-Up Study among Community-Dwelling over 60-Year Old Men and Women 
BioMed Research International  2014;2014:289549.
Purpose. Recovery of walking outdoors after hip fracture is important for equal participation in the community. The causes of poor recovery are not fully understood. This study investigates recovery of walking outdoors and associated determinants after hip fracture. Methods. A prospective follow-up study, among clinical sample of 81 community-dwelling hip fracture patients over 60 years. Perceived difficulty in walking outdoors and 500 meters was assessed before fracture, at discharge to home (3.2 ± 2.2 weeks after surgery), and on average 6.0 ± 3.3 weeks after discharge. Potential determinants for walking recovery were assessed. Linear latent trajectory model was used to analyse changes during follow-up. Association between walking trajectories and potential determinants was analysed with a logistic regression model. Results. Two trajectories, No-to-minor-difficulty and Catastrophic, were found. Thirty-eight percent of the participants ended up in the Catastrophic trajectory for walking outdoors and 67% for 500 meters. Multivariate logistic regression analysis revealed that use of walking aid and indoor falls before fracture and prolonged pain were independently associated with catastrophic decline in both primary outcomes: difficulty in walking outdoors and 500 meters. Conclusions. A large proportion of community-dwelling older people recovering from hip fracture experienced catastrophic decline in outdoor walking. Acknowledging recovery prognoses at early stage enables individualized rehabilitation.
doi:10.1155/2014/289549
PMCID: PMC3912885  PMID: 24511530
20.  Job strain in the public sector and hospital in-patient care use in old age: a 28-year prospective follow-up 
Age and Ageing  2013;43(3):393-399.
Background: high job strain increases the risk of health decline, but little is known about the specific consequences and long-term effects of job strain on old age health.
Objectives: purpose was to investigate whether physical and mental job strain in midlife was associated with hospital care use in old age.
Methods: study population included 5,625 Finnish public sector employees aged 44–58 years who worked in blue- and white-collar professions in 1981. The number of in-patient hospital care days was collected from the Finnish Hospital Discharge Register for the 28-year follow-up period.
Results: rates of hospital care days per 1,000 person-years for men were 7.78 (95% confidence interval [CI] 7.71–7.84) for low, 9.68 (95% CI 9.50–9.74) for intermediate and 12.56 (95% CI 12.47–12.66) for high physical job strain in midlife. The corresponding rates for women were 6.63 (95% CI 6.57–6.68), 7.91 (95% CI 7.87–7.95) and 10.35 (95% CI 10.25–10.42), respectively. Rates were parallel but lower for mental job strain. Reporting high physical job strain in midlife increased the risk of hospital care in old age compared with those who reported low job strain, fully adjusted incidence rate ratio 1.17 (95% CI 1.00–1.38) for men and 1.42 (95% CI 1.25–1.61) for women. These associations were robust in analyses confined to hospital care that took place after the employees had turned 65 years.
Conclusion: exposure to high mental and, particularly, high physical job strain in midlife may set employees on a higher healthcare use trajectory which persists into old age.
doi:10.1093/ageing/aft192
PMCID: PMC4001173  PMID: 24321842
ageing; job strain; hospital care; epidemiology; cohort study; older people
21.  Environmental mobility barriers and walking for errands among older people who live alone vs. with others 
BMC Public Health  2013;13:1054.
Background
Walking is the most popular form of physical activity among older people and for community-dwelling older people walking for errands is especially important. The aim of this study is to examine the association between self-reported environmental mobility barriers and amount of walking for errands among older people who live alone compared to those who live with others.
Methods
This observational study is based on cross-sectional data on 657 people aged 75–81 living in Jyväskylä, Central Finland. Self-reports of environmental mobility barriers were collected under four categories: Traffic, Terrain, Distances and Entrance. Persons who reported walking for errands ≤ 1.5 km/week or at most once a week were categorized as having low amount of walking for errands (LOWER). High walking for errands (HIGWER) was defined as the highest quartile of kilometers walked per week (cut-off 8.5 km, referent). The rest were defined as having moderate amount of walking for errands (MODWER). Multinominal regression analysis was used to compare the odds for LOWER vs. HIGWER and MODWER vs. HIGWER, which were formed for each environmental mobility barrier separately.
Results
Participants walked on average 6.5 km (SD 5.2) and 4.0 times (SD 2.2) per week and 14% reported LOWER. Persons living alone (57% of the participants) reported environmental mobility barriers more often than those living with others. LOWER was more common among those living with others. Among those living with others, all the environmental mobility barriers increased the odds for LOWER. In turn, among those living alone, only Distance- and Entrance- related environmental mobility barriers increased the odds for LOWER. People living alone typically run errands by themselves and become better aware of the barriers to environmental mobility, while those living with others have less exposure to environmental mobility barriers, as their walking for errands is more likely to be low.
Conclusions
These findings emphasize the need to take living arrangements into account when analyzing the association between environmental mobility barriers and walking for errands. Future longitudinal studies are warranted to better understand the temporal order of events and to find ways to enhance walking for errands among older people.
doi:10.1186/1471-2458-13-1054
PMCID: PMC4226209  PMID: 24207063
Aging; Mobility; Environmental barriers; Living arrangements
22.  Environmental barriers, person-environment fit and mortality among community-dwelling very old people 
BMC Public Health  2013;13:783.
Background
Environmental barriers are associated with disability-related outcomes in older people but little is known of the effect of environmental barriers on mortality. The aim of this study was to examine whether objectively measured barriers in the outdoor, entrance and indoor environments are associated with mortality among community-dwelling 80- to 89-year-old single-living people.
Methods
This longitudinal study is based on a sample of 397 people who were single-living in ordinary housing in Sweden. Participants were interviewed during 2002–2003, and 393 were followed up for mortality until May 15, 2012.
Environmental barriers and functional limitations were assessed with the Housing Enabler instrument, which is intended for objective assessments of Person-Environment (P-E) fit problems in housing and the immediate outdoor environment. Mortality data were gathered from the public national register. Cox regression models were used for the analyses.
Results
A total of 264 (67%) participants died during follow-up. Functional limitations increased mortality risk. Among the specific environmental barriers that generate the most P-E fit problems, lack of handrails in stairs at entrances was associated with the highest mortality risk (adjusted RR 1.55, 95% CI 1.14-2.10), whereas the total number of environmental barriers at entrances and outdoors was not associated with mortality. A higher number of environmental barriers indoors showed a slight protective effect against mortality even after adjustment for functional limitations (RR 0.98, 95% CI 0.96-1.00).
Conclusion
Specific environmental problems may increase mortality risk among very-old single-living people. However, the association may be confounded by individuals’ health status which is difficult to fully control for. Further studies are called for.
doi:10.1186/1471-2458-13-783
PMCID: PMC3765774  PMID: 23981906
ENABLE AGE-project; Environment; Mortality; Older people; Housing Enabler
23.  Effects of a Rehabilitation Program on Perceived Environmental Barriers in Older Patients Recovering from Hip Fracture: A Randomized Controlled Trial 
BioMed Research International  2013;2013:769645.
Objectives. To study effects of a one-year multicomponent intervention on perceived environmental barriers in hip fracture patients. Design. Randomized controlled trial of a 12-month home-based rehabilitation aiming to improve mobility and function (ISRCTN53680197); secondary analyses. Subjects. Community-dwelling hip fracture patients on average 70 days after trauma (n = 81). Methods. Assessments at baseline, 3, 6, and 12 months later included perceived entrance-related barriers (e.g., indoor/outdoor stairs, lighting, floor surfaces, and storage for mobility devices) and perceived barriers in the outdoor environment (poor street condition, hilly terrain, long-distances, and lack of resting places). Sum scores for entrance-related and outdoor barriers were analyzed using general estimating equation models. Results. At baseline, 48% and 37% of the patients perceived at least one entrance-related barrier, and 62% and 60% perceived at least one outdoor barrier in the intervention and control group, respectively. Over time, (P = 0.003) the number of entrance-related barriers decreased in both groups (group P = 0.395; interaction P = 0.571). For outdoor barriers, time (P = 0.199), group (P = 0.911), and interaction effect (P = 0.430) were not significant. Conclusion. Our intervention had no additional benefit over standard care in hip fracture patients. Further study is warranted to determine whether perceived environmental barriers can be reduced by interventions targeted at the older individual. This trial is registered with ISRCTN53680197.
doi:10.1155/2013/769645
PMCID: PMC3748419  PMID: 23986910
24.  Promoting Mobility in Older People 
Out-of-home mobility is necessary for accessing commodities, making use of neighborhood facilities, and participation in meaningful social, cultural, and physical activities. Mobility also promotes healthy aging as it relates to the basic human need of physical movement. Mobility is typically assessed either with standardized performance-based tests or with self-reports of perceived difficulty in carrying out specific mobility tasks. Mobility declines with increasing age, and the most complex and demanding tasks are affected first. Sometimes people cope with declining functional capacity by making changes in their way or frequency of doing these tasks, thus avoiding facing manifest difficulties. From the physiological point of view, walking is an integrated result of the functioning of the musculoskeletal, cardio-respiratory, sensory and neural systems. Studies have shown that interventions aiming to increase muscle strength will also improve mobility. Physical activity counseling, an educational intervention aiming to increase physical activity, may also prevent mobility decline among older people. Sensory deficits, such as poor vision and hearing may increase the risk of mobility decline. Consequently, rehabilitation of sensory functions may prevent falls and decline in mobility. To promote mobility, it is not enough to target only individuals because environmental barriers to mobility may also accelerate mobility decline among older people. Communities need to promote the accessibility of physical environments while also trying to minimize negative or stereotypic attitudes toward the physical activity of older people.
doi:10.3961/jpmph.2013.46.S.S50
PMCID: PMC3567319  PMID: 23413006
Aging; Walking; Motor activity; Muscle strength; Environmental barriers; Health promotion
25.  Individual and environmental factors underlying life space of older people – study protocol and design of a cohort study on life-space mobility in old age (LISPE) 
BMC Public Health  2012;12:1018.
Background
A crucial issue for the sustainability of societies is how to maintain health and functioning in older people. With increasing age, losses in vision, hearing, balance, mobility and cognitive capacity render older people particularly exposed to environmental barriers. A central building block of human functioning is walking. Walking difficulties may start to develop in midlife and become increasingly prevalent with age. Life-space mobility reflects actual mobility performance by taking into account the balance between older adults internal physiologic capacity and the external challenges they encounter in daily life. The aim of the Life-Space Mobility in Old Age (LISPE) project is to examine how home and neighborhood characteristics influence people’s health, functioning, disability, quality of life and life-space mobility in the context of aging. In addition, examine whether a person’s health and function influence life-space mobility.
Design
This paper describes the study protocol of the LISPE project, which is a 2-year prospective cohort study of community-dwelling older people aged 75 to 90 (n = 848). The data consists of a baseline survey including face-to-face interviews, objective observation of the home environment and a physical performance test in the participant’s home. All the baseline participants will be interviewed over the phone one and two years after baseline to collect data on life-space mobility, disability and participation restriction. Additional home interviews and environmental evaluations will be conducted for those who relocate during the study period. Data on mortality and health service use will be collected from national registers. In a substudy on walking activity and life space, 358 participants kept a 7-day diary and, in addition, 176 participants also wore an accelerometer.
Discussion
Our study, which includes extensive data collection with a large sample, provides a unique opportunity to study topics of importance for aging societies. A novel approach is employed which enables us to study the interactions of environmental features and individual characteristics underlying the life-space of older people. Potentially, the results of this study will contribute to improvements in strategies to postpone or prevent progression to disability and loss of independence.
doi:10.1186/1471-2458-12-1018
PMCID: PMC3534010  PMID: 23170987
Life-space; Mobility; Quality of life; Environment; Participation; Physical activity; Walking; Aging; Cohort studies

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