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BACKGROUND AND AIMS: Genes associated with longevity have been identified using both single gene and genome-wide approaches in a variety of species. The aim of this study was to identify quantitative trait loci (QTLs) that influence longevity in male and female mice from twenty-three C57BL/6J by DBA/2J (BXD) recombinant inbred (RI) strains. METHODS: Approximately 12 animals of each sex for each RI strain were maintained under standard conditions until natural death or moribundity criteria were met. RESULTS: A number of life span-relevant loci previously reported on chromosomes (Chrs) 7, 8, 10 and 11 were confirmed. In addition, 5 previously unreported QTLs for mouse life span on Chrs 1, 2, 6, 11, and X were identified as significant and 3 QTLs on Chrs 5, 8, and 16 were suggestive. CONCLUSIONS: Several QTLs were coincident in males and females although the modest correlation between male and female median lifespans and the identification of sex specific QTLs provide evidence that the genetic architecture underlying longevity in the sexes may differ substantially. The identification of multiple QTLs for longevity will provide valuable resources for both reductionist and integrationist research into mechanisms of life span determination. [ABSTRACT FROM AUTHOR]

AIMS AND METHODS: The primary purpose was to characterize mean and individual-level patterns of change in physical functional performance over eight years (2 year intervals) in a community dwelling sample of Swedish twins (579 men and women aged 79-96 years at baseline). RESULTS: Mixed linear models revealed linear rates of decline for handgrip strength (grip) and time to complete five chair stands, and accelerating decline for peak expiratory flow rate (PEFR) for both sexes. Significant random effects were found for intercept and time for grip and PEFR tests, indicating differences between participants initially and over time. Individual differences in chairstand performance were significant for initial status only. Age at baseline was predictive of initial status in grip, PEFR and chair performance (women only), but not rate of change. Measures of body size at baseline were predictive of individual variation in initial grip (height), PEFR (weight in men, height in women), and chair performance (height), but had less consistent associations with changes in test performance over time. In the deceased sub-sample (85% of participants), having been further from death was related to less steep declines in grip, but not PEFR or chair performance. Twins from the same pair were related in initial status (twin level variance 30-70%), but they were not generally related in rate of change. CONCLUSIONS: These results indicate that changes in physical functional performance in an elderly, communitydwelling population vary across individuals in a testand sex-dependent manner. Constitutional variables (age, sex, body size) are predictive of baseline performance, but explain little variance in change over time. Initial status and rate of change in grip strength had the strongest association with proximity from death, indicating that while PEFR and repeated chair stand time are useful tests to assess function, grip strength appears to be a particularly useful biomarker in the oldest- old. [ABSTRACT FROM AUTHOR]

BACKGROUND: The present study aimed to investigate the relative importance of genetic and environmental influences on depressive symptoms in the elderly. METHOD: Depressive symptoms were assessed through the Center for Epidemiological Studies-Depression (CES-D) scale. The CES-D scale was administered to 959 twin pairs (123 female MZs, 90 male MZs, 207 same-sex female DZs, 109 same-sex male DZs and 430 opposite-sex DZs) aged 50 years or older (mean age 72 years). A dichotomous depressed state variable was constructed based on CES-D cut-offs and self-reported use of antidepressant medication. Structural equation models were fitted to the data to dissect genetic and environmental variance components. RESULTS: The sex-specific heritability estimates for depressive symptoms were 14% for males and 29% for females and 23% when constrained to be equal for men and women. The prevalence of clinically significant depressive symptoms was 16% for men and 24% for women. Heritability estimates for the dichotomous depressed state measure were 7% for males and 49% for females in the full model and 33% when constrained to be equal. CONCLUSION: Our results suggest that depressive symptoms in the elderly are moderately heritable, with a higher heritability for women than men, although differences in heritability estimates were not statistically significant. [ABSTRACT FROM AUTHOR]

We investigated sex differences in genetic and environmental effects on cognitive abilities among older adult twins. We drew participants from the Swedish Twin Registry; our sample included 647 twin pairs. Our cognitive measures included Synonyms, Block Design, Digit Span, Thurstone's Picture Memory, Symbol Digit, and general cognitive ability tests. Higher age was related to lower performance in all cognitive measures, except synonyms. For digit span forward, symbol digit, and general cognitive ability tasks, there was a Sex x Age interaction, with greater deficits in the performance of women compared with those of men at higher ages. We found no sex-specific genetic influences. In other words, the same genetic effects were operating for men and women. Furthermore, the magnitude of genetic effect was similar for men and women. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The primary goal of this study was to assess gender differences in various measures of health conditions, symptoms, and self-rated health among older persons by comparing brothers and sisters in a sample of unlike-sex twins. METHODS: All living pairs of unlike-sex twins born between 1906 and 1925 were identified through the Swedish Twin Registry and sent surveys assessing health and other factors. This population-based sample consisted of 605 twin pairs. Paired sample t tests were used to analyze gender differences in health-related measures, including a three-level measure of health problems based on physicians' ratings. RESULTS: Women had more total health conditions, not life-threatening health conditions, somewhat life-threatening cardiovascular conditions, and physical and psychological symptoms. Men had more very life-threatening health conditions and cardiovascular conditions. No gender differences were found in somewhat life-threatening health conditions, total cardiovascular conditions, or self-rated health. DISCUSSION: Important gender differences and similarities in health were found using an unlike-sex twin design that reduced variability due to background characteristics. This design also minimized problems caused by gender differences in survival. Research on gender and health in older persons requires more detailed approaches to address the complexity of this topic. [ABSTRACT FROM AUTHOR]

Previous studies have found cognitive deficits in patients with impaired pulmonary function, and recent data from healthy older adults suggest an association of pulmonary function with cognitive function. This 6-year longitudinal study evaluated genetic and environmental sources of covariation in the association of pulmonary function and cognitive performance. The sample included 222 Swedish twin pairs (60% women) with a mean age of 62.3 (+/- 7.7) years (age range: 40-84). Hierarchical multiple regression analyses, controlling for the effects of age, gender, and height, were employed to predict performance on cognitive tests of fluid intelligence (Digit Symbol, Block Design, Digit Span-Backward) and crystallized intelligence (Information) from forced expiratory volume in one second (FEV1). Bivariate cross-twin correlations were used to evaluate the contribution of genetic and environmental factors in the association of pulmonary function and cognitive performance. Results indicated that FEV1 predicted performance on tests of fluid intelligence but not crystallized intelligence at the initial assessment and at the 6-year follow-up. Cross-twin correlational analyses indicated that genetic effects accounted for a greater share of the association of pulmonary function and cognitive performance than environmental effects, but environment also accounted for a substantial share of the covariance. [ABSTRACT FROM AUTHOR]

Research has attempted to identify biomarkers of aging that are predictive of longevity and specific age-related changes during animal life span. Tail tendon break time (TTBT), one presumed biomarker, measures collagen cross-linking, known to increase with age. Significant differences in the rate of increase of TTBT with age have been reported between mouse strains and animal species. We measured both TTBT and longevity in C57BL/6J, DBA/2J, and 23 recombinant inbred (RI) strains (B×D RIs), with TTBT measured at 200, 500, and 800 days of age. Longevity demonstrated considerable variability among these strains (116-951 days). TTBT, also highly variable, increased significantly with age in both sexes and all genotypes. Neither TTBT nor its rate of change correlated significantly with life span. There were suggestive trends for rate of TTBT change to correlate with male longevity and strain longevity to correlate with female TTBT. We conclude that for the range of genetic variation found among these mouse genotypes, TTBT cannot be considered a robust biomarker of longevity.

Tail tendon break time (TTBT), a measure of collagen cross-linking, shown to increase with age differs significantly among inbred strains of mice, indicating underlying genetic influences. This study was aimed to identify quantitative trait loci (QTLs) associated with tail tendon break time at three ages (200, 500, and 800 days of age) for 23 BxD recombinant inbred strains of mice and B6D2F(2) mice derived from C57BL/6J and DBA/2J strains. Heritability estimates were calculated, and QTL analyses were conducted using interval-mapping methods. Mean tail tendon break time values were higher in males and increased nonlinearly with age. Eight total QTLs were nominated in the B6D2F(2) mice at the three measured ages, with the QTL at 800 days confirmed in the recombinant inbred strains. Allelic effect modeling for the identified QTLs suggests differences in gene action between sexes. Candidate genes in the QTL regions include collagen genes and an advanced glycation end-product receptor. The QTLs identified demonstrate influence at some but not all ages.

There are advantages and limitations to using genetically heterogeneous stocks and selective breeding procedures in gerontological and health span research. Animal models that address complex systems of aging involve constraint or manipulation of genetic diversity. They derive from levels of genetic analysis ranging from molecular to quantitative and are relevant to levels of causal hierarchy from base sequences to complex multivariate phenotypes. For some research purposes control of the genotypic source of phenotypic variability by fixation is desirable; others involve establishing genetic diversity or deliberately manipulating identified genes or anonymous gene complexes to specification. Genetic heterogeneity is essential or advantageous for multivariate description of complex phenomena, the examination of associations among variables, or manipulation of polygenic systems. This review concentrates on these latter quantitative requirements. Space limitations preclude a comprehensive review, but relevant sample references and some hints of historical perspectives are provided, with apologies to the many relevant authors not cited.

The precise locations of attachment points of muscle to bone-the origin and insertion sites-are crucial anatomical and functional characteristics that influence locomotor performance. Mechanisms that control the development of these interactions between muscle, tendon, and bone are currently not well understood. In a subset of BXD recombinant inbred (RI) strains derived from the C57BL/6J and DBA/2J strains, we observed a soleus femoral attachment anomaly (SFAA) that was rare in both parental strains (Lionikas, Glover et al. 2006). The aim of the present study was to assess suitability of SFAA as a model to study the genetic mechanisms underlying variation in musculoskeletal anatomy. We scored the incidence of SFAA in 55 BXD strains (n = 9 to 136, median = 26, phenotyped animals per strain, for a total number of 2367). Seven strains (BXD1, 12, 38, 43, 48, 54, and 56) exhibited a high incidence of unilateral SFAA (47-89%), whereas 23 strains scored 0%. Exploration of the mechanisms underlying SFAA in 2 high incidence strains, BXD1 and BXD38, indicated that SFAA-relevant genes are to be found in both C57BL/6J and DBA/2J regions of the BXD1 genome. However, not all alleles relevant for the expression of the phenotype were shared between the 2 high-incidence BXD strains. In conclusion, the anatomical origin of the soleus muscle in mouse is controlled by a polygenic system. A panel of BXD RI strains is a useful tool in exploring the genetic mechanisms underlying SFAA and improving our understanding of musculoskeletal development.

Using data from the first four waves of the OCTO-Twin study (twins 80 + years), the present study investigated the stability and change of genetic and environmental contributions to pulmonary function. Using a genetic simplex model, variance in peak expiratory flow (PEF) at each wave was decomposed into additive genetic and nonshared (specific) environmental factors. Additionally, this analysis distinguished the source of these influences, either from previous waves (transmissions) or from novel influences at each wave (innovations). At each time point (except wave 1), the genetic variance was due to genetic transmissions from prior time points. Conversely, the specific environmental variance in PEF at each time point was mainly due to environmental innovations. These results imply that genetic factors contribute to the stability of pulmonary function over time whereas environmental factors contribute to its change.

A quantitative trait locus (QTL) analysis of behaviors across the life span was conducted in F(2) mice from a C57BL/6J x DBA/2J cross and 22 BXD recombinant inbred (RI) strains. Mice of three age groups were tested in a hole-board apparatus for 3 min on three occasions approximately 1 month apart (average age at test 150, 450 and 750 days, approximately 400 mice per group, divided equally by sex). Quantitative trait loci with small effect size were found on 11 chromosomes for hole-board activity (Hbact) and hole-board rearing (Hbrear). Analysis of 22 RI strains tested at 150 and 450 days of age found only suggestive linkage, with four QTL for Hbact overlapping with those from the F(2) analysis. There was a significant phenotypic correlation between Hbact and Hbrear (approximately 0.55-0.69) and substantial commonality among QTL for the two behaviors. QTL analyses of head-pokes (HP) and fecal boli (FB) only identified QTL at the suggestive level of significance. Age accounted for approximately 15% of the phenotypic variance (sex approximately 3%), and there were genotype by age interactions at approximately 25% of the Hbact and Hbrear QTL. Quantitative trait loci for Hbrear were relatively stable across the three measurement occasions (those for Hbact somewhat less so), although mean levels of each index declined markedly comparing the first to subsequent trials. Considered as a whole, the polygenic system influencing exploratory behaviors accounts for approximately the same amount of phenotypic variance as age (within the range studied), is stable across substantial periods of time, and acts, for the most part, independently of age and sex.

Correlations among bone strength, muscle mass, and physical activity suggest that these traits may be modulated by each other and/or by common genetic and/or environmental mechanisms. This study used structural equation modeling (SEM) to explore the extent to which select genetic loci manifest their pleiotropic effects through functional adaptations commonly referred to as Wolff's law. Quantitative trait locus (QTL) analysis was used to identify regions of chromosomes that simultaneously influenced skeletal mechanics, muscle mass, and/or activity-related behaviors in young and aged B6xD2 second-generation (F(2)) mice of both sexes. SEM was used to further study relationships among select QTLs, bone mechanics, muscle mass, and measures of activity. The SEM approach provided the means to numerically decouple the musculoskeletal effects of mechanical loading from the effects of other physiological processes involved in locomotion and physical activity. It was found that muscle mass was a better predictor of bone mechanics in young females, whereas mechanical loading was a better predictor of bone mechanics in older females. An activity-induced loading factor positively predicted the mechanical behavior of hindlimb bones in older males; contrarily, load-free locomotion (i.e., the remaining effects after removing the effects of loading) negatively predicted bone performance. QTLs on chromosomes 4, 7, and 9 seem to exert some of their influence on bone through actions consistent with Wolff's Law. Further exploration of these and other mechanisms through which genes function will aid in development of individualized interventions able to exploit the numerous complex pathways contributing to skeletal health.

Objectives: The study investigates whether markers of life satisfaction identified in a cross-sectional study-quality of social network, self-rated health, depressive symptoms, locus of control and widowhood, in addition to financial satisfaction and the personality traits of extraversion and neuroticism-predict change in life satisfaction (LSI-Z) across four measurement occasions during a 6-year period in individuals aged 80+., Method: Data were drawn from the Swedish OCTO-Twin-study of individuals aged 80 and older., Results: Growth curve analysis showed a relatively consistent significant linear decline in life satisfaction, but certain markers predicted change in life satisfaction. The loss of spouse, in particular in men, and higher levels of depressive symptoms were related to lower levels of life satisfaction over time., Conclusion: The results from the study question the notion of a life-long stability of life satisfaction.

A quantitative trait locus (QTL) approach was used to define the genetic architecture underlying variation in systolic blood pressure (SBP) and heart rate (HR), measured indirectly on seven occasions by the tail cuff procedure. The tests were conducted in 395 F(2) adult mice (197 males, 198 females) derived from a cross of the C57BL/6J (B6) and DBA/2J (D2) strains and in 22 BXD recombinant-inbred (RI) strains. Interval mapping of F(2) data for the first 5 days of measurement nominated one statistically significant and one suggestive QTL for SBP on chromosomes (Chr) 4 and 14, respectively, and two statistically significant QTL for HR on Chr 1 (which was specific to female mice) and Chr 5. New suggestive QTL emerged for SBP on Chr 3 (female-specific) and 8 and for HR on Chr 11 for measurements recorded several weeks after mice had undergone stressful blood sampling procedures. The two statistically significant HR QTL were confirmed by analyses of BXD RI strain means. Male and female F(2) mice did not differ in SBP or HR but RI strain analyses showed pronounced strain-by-sex interactions and a negative genetic correlation between the two measures in both sexes. Evidence for a role for mitochondrial DNA was found for both HR and SBP. QTL for HR and SBP may differ in males and females and may be sensitive to different environmental contexts.

Background: The 2-bottle preference test is a popular protocol for characterizing a rodent's selection of a variety of solutions. Little attention has been paid, however, to the role of learning in this procedure., Methods: We explored the role of learning in 2-bottle alcohol preference (AP) in mice by recording changes between days and periods (every 3 days the alcohol and water tubes were interchanged) throughout a 15-day standard exposure protocol in use in our laboratory., Results: Male and female ethanol-naive mice of 2 BALB strains (cJ and cByJ), both characterized by low AP scores in the 2-bottle test, exhibited decreases in AP among days but the magnitude of the change depended on test period: relatively large reductions in AP between Day 1 and the subsequent 2 days of the first 3-day test period, smaller decreases between days during Period 2, while there were no significant differences between days during Periods 3 and 4. Thus, the ability of the mice to adapt to changes in tube position improved with increasing experience with the test until asymptote was reached. Study of mice from a C57BL/6JXBALB/cCrgl intercross with a wide range of AP scores showed that learning in the 2-bottle test was not restricted to inbred animals. In this genetically heterogeneous group, learning was shown to be flexible according to an animal's idiosyncratic pattern of alcohol intake: mice characterized by low AP scores on the basis of their 15-day mean AP index exhibited decreases across Days and Periods similar to those shown by the BALB mice (who also had low alcohol consumption) but F(2) mice characterized by high overall AP scores exhibited increases in AP across Periods., Conclusions: Two-bottle AP scores are known to be affected by genetic influences and environmental variation before test administration. The present data provide evidence of learning within the 2-bottle test situation and this phenomenon may help understand the biobehavioral mechanisms underlying preference behavior.

Telomeres prevent the loss of coding genetic material during chromosomal replication. Previous research suggests that shorter telomere length may be associated with lower survival. Because genetic factors are important for individual differences in both telomere length and mortality, this association could reflect genetic or environmental pleiotropy rather than a direct biological effect of telomeres. We demonstrate through within-pair analyses of Swedish twins that telomere length at advanced age is a biomarker that predicts survival beyond the impact of early familial environment and genetic factors in common with telomere length and mortality. Twins with the shortest telomeres had a three times greater risk of death during the follow-up period than their co-twins with the longest telomere measurements [hazard ratio (RR) = 2.8, 95% confidence interval 1.1-7.3, P = 0.03].

Unlabelled: A sample of 693 mice was used to identify regions of the mouse genome associated with trabecular bone architecture as measured using microCT. QTLs for bone in the proximal tibial metaphysis were identified on several chromosomes indicating regions containing genes that regulate properties of trabecular bone., Introduction: Age-related osteoporosis is a condition of major concern because of the morbidity and mortality associated with osteoporotic fractures in humans. Osteoporosis is characterized by reduced bone density, strength, and altered trabecular architecture, all of which are quantitative traits resulting from the actions of many genes working in concert with each other and the environment over the lifespan. microCT gives accurate measures of trabecular bone architecture providing phenotypic data related to bone volume and trabecular morphology. The primary objective of this research was to identify chromosomal regions called quantitative trait loci (QTLs) that contain genes influencing trabecular architecture as measured by microCT., Materials and Methods: The study used crosses between C57BL/6J (B6) and DBA/2J (D2) as progenitor strains of a second filial (F2) generation (n = 141 males and 148 females) and 23 BXD recombinant inbred (RI) strains (n approximately 9 of each sex per strain). The proximal tibial metaphyses of the 200-day-old mice were analyzed by microCT to assess phenotypic traits characterizing trabecular bone, including bone volume fraction, trabecular connectivity, and quantitative measures of trabecular orientation and anisotropy. Heritabilities were calculated and QTLs were identified using composite interval mapping., Results: A number of phenotypes were found to be highly heritable. Heritability values for measured phenotypes using RI strains ranged from 0.15 for degree of anisotropy in females to 0.51 for connectivity density in females and total volume in males. Significant and confirmed QTLs, with LOD scores 4.3 in the F2 cohort and 1.5 in the corresponding RI cohort were found on chromosomes 1 (43 cM), 5 (44 cM), 6 (20 cM), and 8 (49 cM). Other QTLs with LOD scores ranging from 2.8 to 6.9 in the F2 analyses were found on chromosomes 1, 5, 6, 8, 9, and 12. QTLs were identified using data sets comprised of both male and female quantitative traits, suggesting similar genetic action in both sexes, whereas others seemed to be associated exclusively with one sex or the other, suggesting the possibility of sex-dependent effects., Conclusions: Identification of the genes underlying these QTLs may lead to improvements in recognizing individuals most at risk for developing osteoporosis and in the design of new therapeutic interventions.

Complex phenotypes result from multiple inputs from genetic and environmental sources, with intricate subsystems mediating the influence of both sources on the phenotype. Experiments that attempt to describe the influence of a particular gene involve partial isolation of the sub-system in which that gene is an element from other components of the total system influencing the phenotype. Any interactions that exist between the controlled variables and the processes downstream of the gene in the normally operating total system become undetectable; therefore, the results of the experiment can be restricted to the particular configuration of the controlled variables. The inescapable price of the precision of knowledge generated by experiment is a reduction in the generalizability of the results beyond the constrained circumstances of the particular experimental situation. Integrative research, permitting the influence of related subsystems, is required to provide a comprehensive assessment of the influence of a gene.

Baseline serum hematocrit varies substantially in the population. While additive genetic factors account for a large part of this variability, little is known about the genetic architecture underlying the trait. Because hematocrit levels vary with age, it is plausible that quantitative trait loci (QTL) that influence the phenotype also show an age-specific profile. To investigate this possibility, hematocrit was measured in three different age cohorts of mice (150, 450, and 750 days) of the C57BL/6J (B6) and the DBA2/J (D2) lineage. QTL were searched in the B6D2F(2) intercross and the BXD recombinant inbred (RI) strains. The effects of these QTL were explored across the different age groups. On the phenotypic level, baseline serum hematocrit declines with age in a sex-specific manner. In the B6D2F(2) intercross, suggestive QTL that influence the phenotype were located on Chromosomes (Chr) 1, 2, 7, 11, 13, and 16. With the exception of the QTL on Chr 2, all of these QTL exerted their largest effect at 750 days. The QTL on Chr 1, 2, 7, 11 and 16 were confirmed in the BXD RIs in a sex- and age-specific manner. Linkage analysis in the BXD RIs revealed an additional significant QTL on Chr 19. Baseline serum hematocrit is influenced by several QTL that appear to vary with the age and sex of the animal. These QTL primarily overlap with QTL that have been shown to regulate hematopoietic stem cell phenotypes.

Recent studies have shown that 'return to home cage' can serve as a reward for maze learning in adult male mice. The present study examined whether the same reward is an effective motivator of learning in young and old mice and included females in the study design. We tested 25- and 65-d-old HS mice and 85- and 800-d-old B6D2F2 mice in a Lashley III maze. Return to home cage motivated maze acquisition in all groups. Compared with 65-d-old HS mice, 25-d-olds acquired the maze more slowly, took longer to achieve the test criterion, and showed increased latency to reach the goal box. There was no difference between 85- and 800-d-old B6D2F2 mice in rate of acquisition. This reward procedure may reduce the potentially confounding effects of deprivation or aversive stimuli on maze performance and may be suitable as a motivational procedure for a wide range of subject groups.

The main goal of the study was to explore the genetic architecture underlying muscle weight in old mice. Weight of soleus, tibialis anterior (TA), extensor digitorum longus (EDL), and gastrocnemius muscles was measured in the C57BL/6J (B6) and DBA/2J (D2) strains and derivative generations: a panel of the BXD recombinant inbred (RI) strains and a B6D2 F(2) intercross at the age of 800 days. The between-strain difference in muscle weight (B6 > D2) ranged between 16% and 38%. Linkage analysis identified suggestive quantitative trait loci (QTL) on Chromosomes (Chr) 2, 6, 7, 8, 19, and X that influenced muscle weight in the 800-day-old group. Comparison of weights at 200, 500, and 800 days revealed a variable effect of age among the four muscles. Linkage analysis in the B6D2 F(2) population combined across the three different age groups identified muscle-, sex-, and age-specific QTL on Chr 1, 2, 3, 5, 6, 8, 9, 11, 13, 17, X, and Y. Genetic factors that influence the rate of weight change (within-strain weight difference at two ages) over the lifespan of BXD RIs were mapped to the markers D2Mit369 and D3Mit130 at the genome-wide p < 0.05 for TA muscle in males (between 200 and 800 days) and females (between 500 and 800 days), respectively. Analysis of all age groups supported previous findings that the genetic effects may be muscle-, age-, and sex-specific.

The purpose of this study was to examine factors associated with life satisfaction in the oldest-old within a spectrum of psychosocial and health related variables. Scores on the life satisfaction index (LSI-Z) were related to scales and questions regarding, demographics, depression, locus of control, cognitive function, functional capacity (instrumental and personal activities of daily living), self-rated overall health and medically based health, and social network. The sample consisted of 315 participants, aged 80-98 years; (M = 83 years, 66% women). Regression analyses indicated that social network quality, self-rated overall health, sense of being in control of one's life, and depressive symptoms were significantly associated with life satisfaction. There was no gender difference in overall life satisfaction. However, there were different patterns of variables associated with life satisfaction in men and women. Self-rated overall health and depressive symptoms were related to life satisfaction in women, whereas widowhood was significantly associated with lower life satisfaction among men. The results emphasize the need to analyse associates of life satisfaction within a broader context of psychosocial variables and separately for men and women.

In the laboratory mouse, the soleus muscle arises at the head of the fibula and inserts via the Achilles tendon on the tuber calcanei together with the gastrocnemius muscle. During routine dissection of mice from the BXD recombinant inbred (RI) strains, we found that the soleus often originated from the lateral epicondyle of the femur instead of the head of the fibula. This soleus femoral attachment anomaly (SFAA) changes the soleus from being a single-joint to a two-joint muscle. The incidence of SFAA was 45% in the BXD38 RI strain. Bilateral inspection indicated that SFAA may be present unilaterally or bilaterally within an individual mouse. We explored the effect of SFAA on muscle weight in mice with unilateral expression. The weight of SFAA soleii was significantly less (P < 0.01) than that of the soleii with normal attachment by 6% (females) and 14% (males). Similar anatomical anomalies of the soleus muscle have been noted in humans. The mouse model will provide the means to explore the physiological consequences and genetic basis for such anomalies.

Quantitative trait locus (QTL) analyses were conducted to identify chromosomal regions that contribute to variability in serum alkaline phosphatase (AP) enzyme activity in mice derived from the C57BL/6J (B6) and DBA/2J (D2) inbred strains. Serum AP was measured in 400 B6D2 F2 mice at 5 mo and 400 B6D2 F2 mice at 15 mo of age that were genotyped at 96 microsatellite markers, and in 19 BXD recombinant inbred (RI) strains at 5 mo of age. A QTL on the distal end of chromosome 4 was present in all sex- and age-specific analyses with a peak logarithm of odds (LOD) score of 20.36 at 58.51 cM. The Akp2 gene, which encodes the major serum AP isozyme, falls within this QTL region at 70.2 cM where the LOD score reached 13.2 (LOD significance level set at 4.3). Serum AP activity was directly related to the number of D2 alleles of a single nucleotide polymorphism in the 5'-flanking region of the Akp2 gene, although no strain-related differences in hepatic expression of Akp2 RNA were found. A variety of sequence polymorphisms in this chromosomal region could be responsible for the differences in serum AP activity; the Akp2 gene, however, with several known amino acid substitutions between protein sequences of the B6 and D2 strains, is a leading candidate.

Unlabelled: The aim of this study was to compare three methods of adjusting skeletal data for body size and examine their use in QTL analyses. It was found that dividing skeletal phenotypes by body mass index induced erroneous QTL results. The preferred method of body size adjustment was multiple regression., Introduction: Many skeletal studies have reported strong correlations between phenotypes for muscle, bone, and body size, and these correlations add to the difficulty in identifying genetic influence on skeletal traits that are not mediated through overall body size. Quantitative trait loci (QTL) identified for skeletal phenotypes often map to the same chromosome regions as QTLs for body size. The actions of a QTL identified as influencing BMD could therefore be mediated through the generalized actions of growth on body size or muscle mass., Materials and Methods: Three methods of adjusting skeletal phenotypes to body size were performed on morphologic, structural, and compositional measurements of the femur and tibia in 200-day-old C57BL/6J x DBA/2 (BXD) second generation (F(2)) mice (n = 400). A common method of removing the size effect has been through the use of ratios. This technique and two alternative techniques using simple and multiple regression were performed on muscle and skeletal data before QTL analyses, and the differences in QTL results were examined., Results and Conclusions: The use of ratios to remove the size effect was shown to increase the size effect by inducing spurious correlations, thereby leading to inaccurate QTL results. Adjustments for body size using multiple regression eliminated these problems. Multiple regression should be used to remove the variance of co-factors related to skeletal phenotypes to allow for the study of genetic influence independent of correlated phenotypes. However, to better understand the genetic influence, adjusted and unadjusted skeletal QTL results should be compared. Additional insight can be gained by observing the difference in LOD score between the adjusted and nonadjusted phenotypes. Identifying QTLs that exert their effects on skeletal phenotypes through body size-related pathways as well as those having a more direct and independent influence on bone are equally important in deciphering the complex physiologic pathways responsible for the maintenance of bone health.

C57BL/6J (B6) and DBA/2J (D2) strains and two derivative populations, BXD recombinant inbred strains (BXD RIs) and B6D2F2, were used to explore genetic basis for variation in muscle weight at 500 days of age. In parallel with findings in 200-day-old mice (Lionikas A, Blizard DA, Vandenbergh DJ, Glover MG, Stout JT, Vogler GP, McClearn GE, and Larsson L. Physiol Genomics 16: 141-152, 2003), weight of slow-twitch soleus, mixed gastrocnemius, and fast-twitch tibialis anterior (TA) and extensor digitorum longus (EDL) muscles was 13-22% greater (P < 0.001) in B6 than in D2. Distribution of BXD RI strain means indicated that genetic influence on muscle weight (strain effect P < 0.001, all muscles) was of polygenic origin, and effect of genetic factors differed between males and females (strain-by-sex interaction: P < 0.01 for soleus, EDL; P < 0.05 for TA, gastrocnemius). Linkage analyses in B6D2F2 population identified QTL affecting muscle weight on Chr 1, 2, 6, and 9. Pleiotropic influences were observed for QTL on Chr 1 (soleus, TA), 2 (TA, EDL, gastrocnemius), and 9 (soleus, TA, EDL) and were not related to muscle type (fast/slow-twitch) or function (flexor/extensor). Effect of QTL on Chr 9 on soleus muscle was male specific. QTL on Chr 2 and 6 were previously observed at 200 days of age, whereas QTL on Chr 1 and 9 are novel muscle weight QTL. In summary, muscle weight in B6/D2 lineage is affected by a polygenic system that has variable influences at different ages, between males and females, and across muscles in a manner independent of muscle type.

Unlabelled: QTL analyses identified several chromosomal regions influencing skeletal phenotypes of the femur and tibia in BXD F2 and BXD RI populations of mice. QTLs for skeletal traits co-located with each other and with correlated traits such as body weight and length, adipose mass, and serum alkaline phosphatase., Introduction: Past research has shown substantial genetic influence on bone quality, and the impact of reduced bone mass on our aging population has heightened the interest in skeletal genetic research., Materials and Methods: Quantitative trait loci (QTL) analyses were performed on morphologic measures and structural and material properties of the femur and tibia in 200-day-old C57BL/6J x DBA/2 (BXD) F2 (second filial generation; n = 400) and BXD recombinant inbred (RI; n = 23 strains) populations of mice. Body weight, body length, adipose mass, and serum alkaline phosphatase were correlated phenotypes included in the analyses., Results: Skeletal QTLs for morphologic bone measures such as length, width, cortical thickness, and cross-sectional area mapped to nearly every chromosome. QTLs for both structural properties (ultimate load, yield load, or stiffness) and material properties (stress and straincharacteristics and elastic modulus) mapped to chromosomes 4, 6, 9, 12, 13, 15, and 18. QTLs that were specific to structural properties were identified on chromosomes 1, 2, 3, 7, 8, and 17, and QTLs that were specific to skeletal material properties were identified on chromosomes 5, 11, 16, and 19. QTLs for body size (body weight, body length, and adipose mass) often mapped to the same chromosomal regions as those identified for skeletal traits, suggesting that several QTLs identified as influencing bone could be mediated through body size., Conclusion: New QTLs, not previously reported in the literature, were identified for structural and material properties and morphological measures of the mouse femur and tibia. Body weight and length, adipose mass, and serum alkaline phosphatase were correlated phenotypes that mapped in close proximity of skeletal chromosomal loci. The more specific measures of bone quality included in this investigation enhance our understanding of the functional significance of previously identified QTLs.

Ethanol exposure during adolescence is a rite of passage in many societies, but only a subset of individuals exposed to ethanol becomes dependent on alcohol. To explore individual differences in response to ethanol exposure, we compared the effects of periadolescent ethanol exposure on alcohol drinking in an animal model. Male and female mice of two BALB substrains were exposed to ethanol in one of three forms--choice [water vs. 10% (volume/volume) ethanol], forced (10% ethanol in a single bottle), or gradual (single bottle exposure, starting with 0.5% ethanol and increasing at 2-day intervals to 10% ethanol)--from the 6th through the 12th week of age and administered two-bottle alcohol preference tests (10% ethanol vs. water) for 15 days immediately thereafter. All three forms of ethanol exposure increased alcohol preference in male and female BALB/cByJ mice, relative to findings for ethanol-naive control animals. Only gradual ethanol exposure produced an increase in alcohol preference in BALB/cJ mice. During extended alcohol preference testing (for a total of 39 days) of mice in the gradual ethanol exposure group, the higher alcohol preference of the gradual ethanol-exposed BALB/cByJ male mice persisted, but alcohol preference of control group female mice in this strain--formerly ethanol naive, but at this point having received 10% ethanol in the two-bottle paradigm for 15 days--rose to the level of alcohol preference of female mice in the gradual ethanol exposure group. This finding demonstrated that both adolescent and adult ethanol exposure stimulated alcohol preference in female mice of this strain. Across days of testing in adulthood, alcohol preference of the gradual ethanol-exposed BALB/cJ mice decreased, resulting in a lack of effect of gradual exposure to ethanol on alcohol preference in both male and female mice of this strain during the period of extended testing. These strain differences support a genetic basis for the effects of ethanol exposure on alcohol preference and fit within a body of literature, showing substantial individual differences in the effects of ethanol exposure among genetically undefined rats and differences in response to ethanol exposure among inbred rat strains. Exploration of the mechanisms underlying this gene by environment interaction in a mouse model may help elucidate individual differences in the effects of ethanol exposure in human beings and contribute to the understanding of the causes of alcoholism.

Change in cognitive abilities was assessed over a 6-year period in a sample of monozygotic and same-sex dizygotic twin pairs (N = 507 individuals), aged 80 and older (mean age = 83.3 years: SD = 3.1). who remained nondemented over the course of the study. Latent growth models (LGMs) show that chronological age and time to death are consistent predictors of decline in measures of memory, reasoning, speed, and verbal abilities. Multivariate LGM analysis resulted in weak and often negative correlations among rates of change between individuals within twin pairs, indicating greater differential change within twin pairs than occurs on average across twin pairs. These findings highlight several challenges for estimating genetic sources of variance in the context of compromised health and mortality-related change.

The sophistry of the "Nature versus Nurture" formulation is becoming ever more apparent as a consequence of the rapid advances in understanding of the basic mechanisms of heredity and in the application of this knowledge to a wide spectrum of issues of human health and welfare. It is clear that a more accurate formulation would emphasize the interaction and coaction of genetic and environmental factors in their influence on complex phenotypes. Furthermore, the potential dependence of the influence of a particular gene on other genes in the system is increasingly realized. This paper documents these perspectives by examples of gene-environment interaction and gene-gene interaction both from animal model and from human research that reveal both the potential power and subtlety of these interactive effects., (Copyright 2004 Wiley-Liss, Inc.)

The aim of the study was to explore the genetic architecture influencing weight of fast- and slow-twitch skeletal muscles. The weights of the slow-twitch soleus, the mixed gastrocnemius, the fast-twitch tibialis anterior (TA), and extensor digitorum longus (EDL) muscles were 11-34% greater (P < 0.001) in 200-day-old C57BL/6J (B6) than in DBA/2J (D2) mice. Male muscles were 13-28% larger than female (P < 1 x 10(-5), no strain by sex interaction). The sex-related difference in muscle weight, however, varied significantly among the 23 derivative BXD recombinant inbred (RI) strains (strain by sex interaction for soleus, P < 0.01; TA, P < 1 x 10(-4); EDL, not significant; and gastrocnemius, P < 0.001). Quantitative trait loci (QTL) affecting muscle weight were mapped in an F2 intercross of B6 and D2 mice (B6D2F2) and BXD RIs. A total of 10 autosomal, muscle-specific, but not muscle-type-specific, QTL, explaining a total of 5.4, 7.7, 22.9, and 8.6% of phenotypic variance for soleus, TA, EDL, and gastrocnemius muscles, respectively, were found across chromosomes 1 (Chr 1), 2, 3 (female-specific), 5 (two), 6, 7, 8, and 9 in B6D2F2 mice. The QTL on Chr 8 for EDL and the female-specific QTL on Chr 3 for gastrocnemius muscles were statistically significant, but the remaining QTL were at the suggestive level of statistical significance. Ten QTL on Chr 1, 2, 4, 5, 7, 8, 14, 17 (two), and 19 were identified in BXD RIs. Half of the QTL in BXD RIs had pleiotropic effects and were at the suggestive level of significance (except for the significant QTL for gastrocnemius muscle on Chr 17). The B6D2F2 nominated QTL on Chr 8 for EDL weight was validated in BXD RIs (P < 0.03). Support intervals for the QTL on Chr 1 and 5 overlapped between B6D2F2 and BXD RIs. An epistatic interaction between markers on Chr 1 and 17 affected gastrocnemius weight in BXD RIs. The interaction was not, however, validated in the B6D2F2 population. Our results indicate that the differences in muscle weight in the B6 and D2 segregating populations were the outcome of a polygenic system, with each factor contributing a small amount to the phenotypic variance and the genetic architecture affecting muscle weight was muscle specific, but not muscle-type specific, and in some instances sex specific.

The aim of this study was to investigate any possible association between depressed mood in the elderly and two candidate SNPs in the serotonin system: one in the 5-HTR2A gene promotor (-1438 G/A) and one in the 5-HT transporter gene (-925 C/A). DNA from a population-based Swedish twin sample (N = 1,592; mean age = 73) was genotyped using Pryosequencing trade mark. An association was found between the 5-HTR2A gene promotor polymorphism and depressed mood (OR: 1.5, CI: 1.1-2.1) for the A/A genotype in the total sample. When the sample was analyzed by gender, a significant association (OR: 2.4, CI: 1.4-4.4) was found for males and the A/A genotype, but not for females. The 5-HT transporter gene was not associated with depressed mood in this elderly population. These results suggest that there might be different genetic mechanisms for males and females contributing to the development of depressed mood in the elderly., (Copyright 2003 Wiley-Liss, Inc.)

In female mice, anogenital distance (AGD), measured at weaning, provides an estimate of uterine exposure to testosterone from flanking male mouse littermates. A variant of the anogenital distance index (AGDI) that uses the residual value of AGD after accounting for the effect of weight by regression (AGDWTRES) was measured at weaning in F(2) female mice from a C57BL/6J x DBA2/J cross. AGDWTRES was used to examine the relationship between intrauterine environment and blood chemistry variables and activity-related behaviors when the females were 450 days old. Longer AGDWTRES values correlated with lower levels of calcium, cholesterol, phosphorus, iron, and protein, which is opposite to the expected direction, based on underlying sex differences for blood chemistry. A positive correlation was found between AGDWTRES and two activity-related measures (the number of rears in a test of exploration, and the number of sectors of a rod that are entered by the mouse). These findings suggest that in utero proximity to males, as indexed by AGDWTRES, may have effects on fundamental aspects of blood chemistry and behavior that extend well into mouse middle age, and could play an important role in health.

Objective: The purpose of the present study was to identify sources of variability for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) in a sample of adult African-American twins., Design: The classic twin design was employed to examine genetic and environmental sources of variance in the outcome measures of interest., Participants: Participants were 143 (71 MZ and 72 DZ) same-sex, intact twin pairs (mean age = 49.87 years; SD 13.62), who took part in the Carolina African-American Twin Study of Aging (CAATSA)., Main Outcome Measures: Outcome measures of interest included SBP and DBP, and PP., Results: For older twins, heritabilities were .52 for SBP, .36 for DBP, and .14 for PP. However, for younger twins, heritabilities were .44 for SBP, .27 for DBP, but no genetic influence on PP was observed., Conclusion: The results indicate that genetic factors are a significant source of variance in hemodynamic indices, and also suggest that, with advancing age, genetic factors play an increasing role in determining blood pressure and PP in this population.

With the advent of high-density DNA marker data sets for the mouse and other model systems, 100 or more genotype are routinely generated from large groups of mice. Issues of the accuracy and reliability of the genotyping are extremely important but often not addressed until genetic analysis is conducted. Simple tests that rely on the robust predictions arising from Mendelian genetics can be made quickly in the molecular laboratory as the data are generated, and require only a spreadsheet program. In this report, genotype data from 392 mice tested at 96 marker sites were analyzed for errors that are typical when handling large volumes of data generated in a repetitive process. The testing consisted of: (1) repeating the genotyping of approximately 1% of the samples; (2) examining the deviation from the expected segregation ratio ( 1:2:1 ) on a marker-by-marker basis; and (3) testing the correlation of the genotype at one marker with that at neighboring genetic markers on a chromosome. These three steps allowed analysis at the level of the microtiter plate, where errors are most likely to occur. A set of 96 dinucleotide repeat markers that are polymorphic between the C57BL/6J and DBA/2J mouse strains and can be multiplexed is reported for use in other genotyping projects.

Tests of cognition in mice frequently employ deprivations or aversive stimuli to motivate learning. Such manipulations may confound interpretation of differences in performance. Concerns arising from the potential confounding are accentuated when the object of the experiment is to compare cognitive function of young and old animals because aging alters many processes that affect maze performance. To assuage some of these concerns, we tested the potential of a novel reward procedure to motivate maze learning. Food-and water-satiated mice of two genetically heterogeneous groups that gained access to their home cage after reaching the goal box of a Lashley III maze attained the acquisition criterion as quickly as did mice motivated by hunger and given food reward. We suggest that "return to home cage" is a useful reinforcer in tests of cognition. This reward procedure is unusual in that it offers an important animal-friendly alternative to the usual ways of motivating cognitive performance, is economical of experimenter time, and may avoid the potentially confounding effects of physiological deprivations and aversive stimuli on maze performance of aged mice.

Animal models have played an important role in elucidating the nature of aging processes in general, and of behavioral aging specifically. Both aging and the behavioral processes of interest in this context are manifestly complex. Recent scholarship focusing on the nature of systems has provided new and varied conceptual schemata for addressing such intricacy. In this report, animal model systems are viewed in relation to some elementary systems notions. Limitations of the prototypical animal model are discussed, with particular emphasis on the implications of gene-gene and gene-environment interactions. These same interactions also provide opportunities. The traditional methods of genetic manipulation and control, combined with the powerful new tools of molecular genetics, and informed by systems considerations, offer broadened research horizons.

Background and Aims: Reports of diseases and health problems vary as a function of the information source. In the present study we compared the capture of information on morbidity using medical records, self-reports, and drug registrations., Methods: A concurrent review of medical records, self-reports, and registration of marker drugs was conducted to determine diagnosis for 44 common diseases. Diagnoses from the various sources were uniformly classified according to ICD-10. The study included a sample of 702 individuals, aged 80 and older, enrolled in population-based longitudinal studies., Results: The morbidity rates differed considerably across the used sources. Although medical records captured most of the morbidity, self-reports offered supplemental information especially for less objective health problems. Marker drugs typically confirmed information in the records, but only for a limited number of diseases., Discussion: In studies of aging and health, a thorough review of medical records and a concurrent evaluation of self-reports and marker drugs represent a valuable strategy for portraying morbidity. This strategy goes beyond the use of a single source like self-reports, and provides better estimates of health conditions in the elderly.

The factor structure of health locus of control (Form A; K. A. Wallston, B. S. Wallston, & R. DeVellis, 1978) was examined in 420 octogenarians (M age = 83.2 years), and the contributions of genetic and environmental factors to health-control beliefs in 141 octogenarian twin pairs (71 identical, 70 same-sex fraternal) were estimated. Factor analyses reproduced previously proposed factors (Internal, Chance, and Powerful Others). Associations between health-control beliefs and life satisfaction, depression, and other health-related measures (e.g., self-rated health, outpatient contacts, and hospitalization), were modest. Quantitative genetic analyses revealed significant shared environmental influence on the Chance subscale, and significant familiality (attributable to a combination of genetic and shared environmental influences) on the Powerful Others subscale; there was no evidence of familiality on the Internal subscale.

Alcohol consumption is a complex trait, responding to the influence of various genes and environmental influences acting in a quantitative fashion. Various studies in alcohol consumption processes have identified quantitative trait locus (QTL) regions across the mouse genome that appear to contribute to this phenotype. The purpose of this study was to examine the influence of interactions between alleles at different loci, a phenomenon known as epistasis, on previously identified QTLs for alcohol consumption in mice. A multiple regression model was developed and applied to test for the significance of the interaction between two QTLs and to quantify this interaction. Our results indicate the presence of epistasis between loci on mouse chromosomes 2 and 3 accounting for 7-8% of the variation in alcohol preference, respectively.

Background: A substantial body of literature indicates that intakes of "sweet" solutions and ethanol are positively correlated across inbred strains of rats and mice but there has been speculation that the correlation is fortuitous and there is no agreement on the underlying mechanism., Methods and Results: We assessed the correlation between intake of sucrose and ethanol in congenic mice created by backcrossing alleles favoring sucrose intake from the BXD RI-5 strain into DBA/2J. In addition, to probe more specifically the interrelationship between intake of the two solutions, we examined aversion generalization from sucrose to ethanol in C57BL/6J mice. Among the congenic mice, a statistically significant product-moment correlation of r = 0.36 (p < 0.02) was found between 6-hr intake of sucrose corrected for differences in baseline water intake and preference for 10% ethanol presented in a 96-hr 2-bottle test. Furthermore, C57BL/6J male mice conditioned to avoid a 0.2 M sucrose solution generalized their aversion to a 10% ethanol solution presented in the same 2-bottle test, drinking 42.1 +/- 9.38% (mean +/- SE) of their total fluid intake from the ethanol tube, compared with the control group mean of 69.86 +/- 8.84%., Conclusions: The positive association between intake of sucrose and ethanol in congenic mice provides strong evidence that the previously demonstrated genetic correlation between intake of these solutions is not the result of fortuitous fixation of unrelated alleles and provides suggestive evidence that, at least in the B6/D2 lineage, the genetic association between intakes of the two solutions reflects close linkage or the pleiotropic effects of the same genes. The demonstration that a conditioned taste aversion to sucrose generalized to ethanol in the C57BL/6J inbred mouse strain is an extension of similar observations in outbred rats and specifically demonstrates that intake of the two solutions is controlled by some of the same physiologic or neurological processes and thus is consistent with the pleiotropic interpretation of the genetic correlation.

During the past half century, researchers have identified and examined sex differences in alcohol-related phenotypes, focusing more recently on understanding of the mechanisms underlying these differences. In general, the genetic contributions influencing these differences are not consistent with an interpretation of sex linkage and must, therefore, reflect some form of sex limitation in which allelic differences at particular autosomal loci have different consequences in males and females. Significant sex differences in measures of alcohol consumption in mice have been demonstrated in previous work in our laboratory. To investigate these differences further, we explore the limiting case of sex-exclusive effects using data from (BXD) recombinant inbred (RI) strains of mice and from an intercross derived from the same progenitors, C57BL/6J (B) and DBA/2J (D). By the use of two statistical approaches (examination of residual scores as a sex-exclusive phenotypic value for the RI strains and multivariate regression on sex and genotype in the F(2)) we have identified and confirmed female-exclusive markers for alcohol acceptance on chromosomes 9 and 12 and one marker for alcohol preference on chromosome 2. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:647-652, 1999., (Copyright 1999 Wiley-Liss, Inc.)

We recently conducted a dose-response study of the effects of cocaine on several activity measures in the panel of BxD/Ty recombinant inbred mice. Animals were tested in an automated activity chamber over 2 days with i.p. saline on day 1 and i.p. cocaine on day 2, at one of four doses, 5, 15, 30 or 45 mg kg(-1). The monitor recorded total distance traveled, nosepokes in a holeboard, repeated movements and time spent by an individual in proximity to the centre of the apparatus. Dose-response curves for locomotor activation, i.e. the difference between cocaine and saline scores, showed that for all strains tested, scores increased 5-30 mg kg(-1). With few exceptions, locomotor activity at 45 mg kg(-1) was not significantly higher than that at 30 mg kg(-1). Repeated movement scores showed patterns similar to locomotor activity and nosepokes tended to be progressively inhibited by increasing doses of cocaine. Recombinant inbred strain mean distributions for all behaviours and at all doses exhibited continuous, rather than discrete variation, thus providing evidence of multiple-gene effects on cocaine-related behaviours. Quantitative trait loci (QTL) analysis pointed to several chromosomal locations associated with variations in cocaine-related behaviours and some are either identical or close to QTL reported by others. In separate groups of animals, densities of dopamine D1, and D2 receptors and dopamine uptake transporters were measured in the medial prefrontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. In all areas, all measures showed distributions consistent with polygenic influence and were associated with QTL. Of particular interest was our finding of a large segment on chromosome 15, which is related to dopamine receptor densities and cocaine-related behaviours.

The identification of differential patterns of change across the lifespan in quantitative traits is of abiding interest in the biological and gerontological research communities. These differential phenotypic patterns in complex systems illuminate developmental processes and form the foundation for the identification of putative biomarkers of aging. The goal of the present study was to explore changes in locomotor activity through the lifespan of Drosophila melanogaster. A replicated serial cross-sectional sampling design was used to test activity in five genetically independent inbred strains at 7, 14, 21, 28, 35, and 42 days of age. Differences were observed in activity level across ages and strains, suggesting that patterns of activity throughout the lifespan of D. melanogaster are influenced by genetic factors. Observed sex differences in change in activity level indicate that the aging processes may proceed differently in males and females.

The relative importance of genetic and environmental influences on episodic memory in very late life was studied using a quantitative genetic approach. Identical (n = 125) and same-sex fraternal (n = 157) twin pairs, aged 80 and older (mean age = 83.3; SD = 3.1) and without a diagnosis of dementia were tested with seven memory measures: (1-2) Digit Span Forward and Backwards, (3) Prose Recall, (4) Thurstone's picture memory test, and the Memory in Reality (MIR) test, including the subtasks of (5) free recall, (6) recognition, and (7) relocation. Heritabilities, estimated by structural equation modeling, ranged from .04 to .49. The digit span backward test showed the highest heritability (h2 = .49), while heritabilities were typically lower for the long-term memory measures. The results demonstrate genetic influences on memory in the oldest-old, but suggest that the magnitude of these effects differs across memory measures.