Effect of interleukin-6 polymorphisms on human longevity: A systematic review and meta-analysis

Several studies have assessed changes in frequency of -174 interleukin (IL)-6 single nucleotide polymorphism (SNP) with age. If IL-6 tracks with disability and age-related diseases, then there should be reduction, in the oldest old, of the frequency of homozgyous GG subjects, who produce higher IL-6 levels. However, discordant results have been obtained. To explore the relationship between this polymorphism and longevity, we analyzed individual data on long-living subjects and controls from eight case-control studies conducted in Europeans, using meta-analysis. There was no significant difference in the IL-6 genotype between the oldest old and controls (Odds Ratio [OR]=0.96; 95% C.I.: 0.77-1.20; p=0.71), but there was significant between-study heterogeneity (I(2)=55.5%). In a subgroup analyses when male centenarians from the three Italian studies were included, the frequency of the IL-6 -174 GG genotype was significantly lower than the other genotypes (OR=0.49; 95% C.I.: 0.31-0.80; p=0.004), with no evidence of heterogeneity (I(2)=0%). Our data supports a negative association between the GG genotype of IL-6 SNP and longevity in Italian centenarians, with males who carry the genotype being two times less likely to reach extreme old age compared with subjects carrying CC or CG genotypes. These findings were not replicated in other European groups suggesting a possible interaction between genetics, sex and environment in reaching longevity.

No or only population-specific effect of PON1 on human longevity: A comprehensive meta-analysis

Paraoxonase 1 (PON1) has been suggested as a plausible candidate gene for human longevity due to its modulation of cardiovascular disease risk, by preventing oxidation of atherogenic low-density lipoprotein. The role of the PON1 192 Q/R polymorphism has been analyzed for association with survival at old age in several populations, albeit with controversial results. To reconcile the conflicting evidence, we performed a large association study with two samples of 2357 Germans and 1025 French, respectively. We combined our results with those from seven previous studies in the largest and most comprehensive meta-analysis on PON1 192 Q/R and longevity to-date, to include a total of 9580 individuals. No significant association of PON1 192 Q/R with longevity was observed, for either R allele or carriership. This finding relied on very large sample sizes, is supported by different analysis methods and is therefore considered very robust. Moreover, we have investigated a potential interaction of PON1 192 Q/R with APOE epsilon4 using data from four populations. Whereas a significant result was found in the German sample, this could not be confirmed in the other examined groups. Our large-scale meta-analysis provided no evidence that the PON1 192 Q/R polymorphism is associated with longevity, but this does not exclude the possibility of population-specific effects due to the influence of, and interaction between, different genetic and/or environmental factors (e.g. diet).

First record of minimum Irish hare (Lepus timidus hibernicus Bell 1837) longevity in the wild.

Average longevity of the mountain hare (Lepus timidus L., 1758) has been estimated at nine years in the wild (Macdonald D. and Barrett, P. 1993 Mammals of Britain and Europe. Harper Collins Publishers, London) with a maximum recorded age of 18 years for one marked animal (Angerbjörn, A. and Flux, J. E. C. 1995 Lepus timidus. Mammalian Species 495: 1–11). However, the longevity of the Irish hare (L. t. hibernicus Bell 1837) is entirely unknown. A total of 14 Irish hares was trapped and tagged at Belfast International Airport, Co. Antrim from February to April 2005. The sex, age (juvenile or adult) and weight of each animal were recorded. Adults were taken as those individuals >8-10 months old defined by the fusing of the notch between the apophysis and diaphysis of the tibia and humerus (Flux, J. E. C. 1970 Journal of Zoology 161: 75-123). Individual identification was made by a system of colourcoded ear tags (Roxan iD Ltd. Selkirk, Scotland) being inserted in the centre of the pinna of each ear. Each ear tag (6 × 34 mm) and puncture site was disinfected with 70 per cent ethanol prior to insertion. An adult male, #001/002 ‘Blue/Blue’, was tagged on 3 March 2005 weighing 3.8 kg and was sighted during a return site visit on 4 April 2007. An adult female, #026/003 ‘Green/Yellow’, was tagged on 15 April 2005 weighing 4.0 kg and was sighted during return visits on 25 March 2010 and 19 October 2010. The latest possible date of birth for both individuals was spring/summer 2004. Consequently, they were at least 3 years and 6.5 years old, respectively. This is the first record of minimum Irish hare longevity in the wild. These observations suggest that ear tagging does not compromise animal welfare and is an effective means of long-term monitoring. Future research may utilize capture-mark-recapture methods.

Genome-wide linkage analysis for human longevity: Genetics of healthy aging study

Clear evidence exists for heritability of humanlongevity, 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 2118nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (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 1228 unrelated nonagenarian and 1907 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). By combined modeling of linkage and association, we showed that association of longevity with APOEe4 and APOEe2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10, 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. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.

Is the phenotypic combination A1B8Cw7DR3 a marker for male longevity?

To study whether individual Human Leucocyte Antigens (HLA) at the HLA 1 or 11 loci or the phenotypic combination A1B8Cw7DR3 were associated with longevity.

Dietary Restriction Induced Longevity is Mediated by Nuclear Receptor NHR-62 in Caenorhabditis elegans

Dietary restriction (DR) extends lifespan in a wide variety of species, yet the underlying mechanisms are not well understood. Here we show that the C. elegans HNF4a- related nuclear hormone receptor NHR-62 is required for metabolic and physiologic responses associated with DR-induced longevity. nhr-62 mediates the longevity of eat- 2 mutants, a genetic mimetic of dietary restriction, and blunts the longevity response of DR induced by bacterial food dilution at low nutrient levels. Metabolic changes associated with DR, including decreased Oil Red O staining, increased autophagy, and changes in fatty acid composition are partly reversed by mutation of nhr-62. Expression profiles reveal that several hundred genes induced by DR depend on the activity of NHR-62, including a putative lipase required for the DR response. This study provides critical evidence that nuclear hormone receptors regulate the DR response, suggesting hormonal and metabolic control of life span.

Effect of interleukin-6 polymorphisms on human longevity:a systematic review and meta-analysis

Several studies have assessed changes in frequency of -174 interleukin (IL)-6 single nucleotide polymorphism (SNP) with age. If IL-6 tracks with disability and age-related diseases, then there should be reduction, in the oldest old, of the frequency of homozygous GG subjects, who produce higher IL-6 levels. However, discordant results have been obtained. To explore the relationship between this polymorphism and longevity, we analyzed individual data on long-living subjects and controls from eight case-control studies conducted in Europeans, using meta-analysis. There was no significant difference in the IL-6 genotype between the oldest old and controls (Odds Ratio [OR]=0.96; 95% C.I.: 0.77-1.20; p=0.71), but there was significant between-study heterogeneity (I2=55.5%). In a subgroup analyses when male centenarians from the three Italian studies were included, the frequency of the IL-6 -174 GG genotype was significantly lower than the other genotypes (OR=0.49; 95% C.I.: 0.31-0.80; p=0.004), with no evidence of heterogeneity (I2=0%). Our data supports a negative association between the GG genotype of IL-6 SNP and longevity in Italian centenarians, with males who carry the genotype being two times less likely to reach extreme old age compared with subjects carrying CC or CG genotypes. These findings were not replicated in other European groups suggesting a possible interaction between genetics, sex and environment in reaching longevity.

The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific.

To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes

How to classify the Oldest Old according to Health Status: A study of 1160 subjects belonging to 552 90+ Italian sibships characterised by familial longevity recruited within the GeHA EU project

The health status of the oldest old, the fastest increasing population segment worldwide, progressively becomes more heterogeneous, and this peculiarity represents a major obstacle to their classification. We compared the effectiveness of four previously proposed criteria (Franceschi et al., 2000; Evert et al., 2003; Gondo et al., 2006; Andersen-Ranberg et al., 2001) in 1160 phenotypically fully characterized Italian siblings of 90 years of age and older (90+, mean age: 93 years; age range: 90–106 years) belonging to 552 sib-ships, recruited in Northern, Central and Southern Italy within the EU-funded project GEHA, followed for a six-year-survival. Main findings were: (i) ‘‘healthy’’ subjects varied within a large range, i.e. 5.2% (Gondo), 8.7% (Evert), 17.7% (Franceschi), and 28.5% (Andersen-Ranberg); (ii) Central Italy subjects showed better health than those from Northern and Southern Italy; (iii) mortality risk was correlated with health status independently of geographical areas; and (iv) 90+ males, although fewer in number, were healthier than females, but with no survival advantage. In conclusion, we identified a modified version of Andersen-Ranberg criteria, based on the concomitant assessment of two basic domains (cognitive, SMMSE; physical, ADL), called ‘‘Simple Model of Functional Status’’ (SMFS), as the most effective proxy to distinguish healthy from not-healthy subjects. This model showed that health status was correlated within sib-ships, suggesting a familial/genetic component.