Browsing by Author "Franceschi, Claudio"

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Open Access
Demographic characteristics of Sardinian centenarian genealogies: Preliminary results of the AKeA2 study
(Demographic Research, 2015-05) Lipsi, Rosa Maria; Caselli, Graziella; Pozzi, Lucia; Baggio, Giovannella; Carru, Ciriaco; Franceschi, Claudio; Vaupel, James W; Deiana, Luca
Open Access
Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.
(Aging Cell, 2013-04) Beekman, Marian; Blanché, Hélène; Perola, Markus; Hervonen, Anti; Bezrukov, Vladyslav; Sikora, Ewa; Flachsbart, Friederike; Christiansen, Lene; De Craen, Anton JM; Kirkwood, Tom BL; Rea, Irene Maeve; Poulain, Michel; Robine, Jean-Marie; Valensin, Silvana; Stazi, Maria Antonietta; Passarino, Giuseppe; Deiana, Luca; Gonos, Efstathios S; Paternoster, Lavinia; Sørensen, Thorkild IA; Tan, Qihua; Helmer, Quinta; van den Akker, Erik B; Deelen, Joris; Martella, Francesca; Cordell, Heather J; Ayers, Kristin L; Vaupel, James W; Törnwall, Outi; Johnson, Thomas E; Schreiber, Stefan; Lathrop, Mark; Skytthe, Axel; Westendorp, Rudi GJ; Christensen, Kaare; Gampe, Jutta; Nebel, Almut; Houwing-Duistermaat, Jeanine J; Slagboom, Pieternella Eline; Franceschi, Claudio; GEHA consortium
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 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(-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. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.
Open Access
Low tobacco-related cancer incidence in offspring of long-lived siblings: a comparison with Danish national cancer registry data.
(Ann Epidemiol, 2015-08) Pedersen, Jacob K; Skytthe, Axel; McGue, Matt; Honig, Lawrence S; Franceschi, Claudio; Kirkwood, Thomas BL; Passarino, Giuseppe; Slagboom, P Eline; Vaupel, James W; Christensen, Kaare
PURPOSE: Familial clustering of longevity is well documented and includes both genetic and other familial factors, but the specific underlying mechanisms are largely unknown. We examined whether low incidence of specific cancers is a mechanism for familial clustering of longevity. METHODS: The study population of individuals from longevity-enriched families consisted of 3267 offspring from 610 Danish long-lived families defined by two siblings attaining an age of 90 years or more. The offspring of the long-lived siblings were followed from 1968 to 2009. Using high-quality registry data, observed numbers of cancers were compared with expected numbers based on gender-, calendar period-, and age-specific incidence rates in the general population. RESULTS: During the 41-year-follow-up period, a total of 423 cancers occurred in 397 individuals. The standardized incidence ratios (95% confidence interval) for offspring of long-lived individuals were 0.78 (0.70-0.86) for overall cancer; 0.66 (0.56-0.77) for tobacco-related cancer; 0.34 (0.22-0.51) for lung cancer; 0.88 (0.71-1.10) for breast cancer; 0.91 (0.62-1.34) for colon cancer. CONCLUSIONS: The low incidence of tobacco-related cancers in long-lived families compared with non-tobacco-related cancers suggests that health behavior plays a central role in lower early cancer incidence in offspring of long-lived siblings in Denmark.
Open Access
Novel loci and pathways significantly associated with longevity.
(Sci Rep, 2016-02-25) Zeng, Yi; Nie, Chao; Min, Junxia; Liu, Xiaomin; Li, Mengmeng; Chen, Huashuai; Xu, Hanshi; Wang, Mingbang; Ni, Ting; Li, Yang; Yan, Han; Zhang, Jin-Pei; Song, Chun; Chi, Li-Qing; Wang, Han-Ming; Dong, Jie; Zheng, Gu-Yan; Lin, Li; Qian, Feng; Qi, Yanwei; Liu, Xiao; Cao, Hongzhi; Wang, Yinghao; Zhang, Lijuan; Li, Zhaochun; Zhou, Yufeng; Wang, Yan; Lu, Jiehua; Li, Jianxin; Qi, Ming; Bolund, Lars; Yashin, Anatoliy; Land, Kenneth C; Gregory, Simon; Yang, Ze; Gottschalk, William; Tao, Wei; Wang, Jian; Wang, Jun; Xu, Xun; Bae, Harold; Nygaard, Marianne; Christiansen, Lene; Christensen, Kaare; Franceschi, Claudio; Lutz, Michael W; Gu, Jun; Tan, Qihua; Perls, Thomas; Sebastiani, Paola; Deelen, Joris; Slagboom, Eline; Hauser, Elizabeth; Xu, Huji; Tian, Xiao-Li; Yang, Huanming; Vaupel, James W
Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10(-5)). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.
Open Access
The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific.
(Aging Cell, 2014-06) Raule, Nicola; Sevini, Federica; Li, Shengting; Barbieri, Annalaura; Tallaro, Federica; Lomartire, Laura; Vianello, Dario; Montesanto, Alberto; Moilanen, Jukka S; Bezrukov, Vladyslav; Blanché, Hélène; Hervonen, Antti; Christensen, Kaare; Deiana, Luca; Gonos, Efstathios S; Kirkwood, Tom BL; Kristensen, Peter; Kristensen, Peter; Leon, Alberta; Pelicci, Pier Giuseppe; Poulain, Michel; Rea, Irene M; Remacle, Josè; Robine, Jean Marie; Schreiber, Stefan; Sikora, Ewa; Eline Slagboom, Peternella; Spazzafumo, Liana; Antonietta Stazi, Maria; Toussaint, Olivier; Vaupel, James W; Rose, Giuseppina; Majamaa, Kari; Perola, Markus; Johnson, Thomas E; Bolund, Lars; Yang, Huanming; Passarino, Giuseppe; Franceschi, Claudio
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.
Open Access
The second international conference "genetics of aging and longevity".
(Aging (Albany NY), 2012-05) Anisimov, Vladimir N; Bartke, Andrzej; Barzilai, Nir; Batin, Mikhail A; Blagosklonny, Mikhail V; Brown-Borg, Holly; Budovskaya, Yelena; Campisi, Judith; Friguet, Bertrand; Fraifeld, Vadim; Franceschi, Claudio; Gems, David; Gladyshev, Vadim; Gorbunova, Vera; Gudkov, Andrei V; Kennedy, Brian; Konovalenko, Maria; Kraemer, Brian; Moskalev, Alexey; Petropoulos, Isabelle; Pasyukova, Elena; Rattan, Suresh; Rogina, Blanka; Seluanov, Andrei; Shaposhnikov, Mikhail; Shmookler Reis, Robert; Tavernarakis, Nektarios; Vijg, Jan; Yashin, Anatoli; Zimniak, Piotr