The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10−8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10−36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

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Summary Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in fifteen study centers of eleven European countries as part of the Genetics of Healthy Ageing (GEHA) project. In the joint linkage analyses we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD=3.47), chromosome 17q12-q22 (LOD=2.95), chromosome 19p13.3-p13.11 (LOD=3.76) and chromosome 19q13.11-q13.32 (LOD=3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1,228 unrelated nonagenarian and 1,907 geographically matched controls. Using a fixed effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (p-value=9.6 × 10−8). By combined modeling of linkage and association we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with p-value=0.02 and p-value=1.0 × 10−5, respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22 and 19p13.3-p13.11. Since the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

BackgroundIt is unclear whether physical activity in later life is beneficial for maintenance of cognitive function. We performed a systematic review examining the effects of exercise on cognitive function in older individuals, and present possible mechanisms whereby physical activity may improve cognition.MethodsSources consisted of PubMed, Medline, CINAHL, the Cochrane Controlled Trials Register, and the University of Washington, School of Medicine Library Database, with a search conducted on August 15, 2012 for publications limited to the English language starting January 1, 2000. Randomized controlled trials including at least 30 participants and lasting at least 6 months, and all observational studies including a minimum of 100 participants for one year, were evaluated. All subjects included were at least 60 years of age.ResultsTwenty-seven studies met the inclusion criteria. Twenty-six studies reported a positive correlation between physical activity and maintenance or enhancement of cognitive function. Five studies reported a dose-response relationship between physical activity and cognition. One study showed a nonsignificant correlation.ConclusionThe preponderance of evidence suggests that physical activity is beneficial for cognitive function in the elderly. However, the majority of the evidence is of medium quality with a moderate risk of bias. Larger randomized controlled trials are needed to clarify the association between exercise and cognitive function and to determine which types of exercise have the greatest benefit on specific cognitive domains. Despite these caveats, the current evidence suggests that physical activity may help to improve cognitive function and, consequently, delay the progression of cognitive impairment in the elderly.

In this unrandomized trial, oral miltefosine was at least as effective as heroic doses of parenteral amphotericin B. The cure rate for miltefosine was approximately equivalent to historical cure rates using parenteral pentavalent antimony for mild and extensive disease in neighboring Peru. Although gastrointestinal side reactions do occur with miltefosine, its toxicity profile is superior to that of antimony and far superior to that of amphotericin B--in part because of the inherent attractiveness of oral versus parenteral agents. Our results suggest that miltefosine should be the treatment of choice for mucosal disease in North and South America.