No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Human Longevity and Variation in GH/IGF-1/Insulin Signaling, DNA Damage Signaling and Repair and Pro/antioxidant Pathway Genes: Cross Sectional and Longitudinal Studies
... The frequency distribution of the NFE2L2, KEAP1, MPO, PRNP, PTGR1, HSPA1A, TXNRD2, GSR, SIRT2, and PTGS1 polymorphisms and their association with COPD hadn't been investigated yet in populations of Russia. Association studies of polymorphic markers in such candidate genes affecting development and progression of cancers, type 2 diabetes mellitus, cardiovascular diseases, and ageing were published (Figarska et al., 2014;Wei et al., 2014;Wang et al., 2017;Cao et al., 2014;Dulin et al., 2012;He et al., 2009;Edvardsen et al., 2013;Kariž et al., 2015;Kopp et al., 2017;Hartikainen et al., 2015;Smid et al., 2013;Soerensen et al., 2012;Liu et al., 2018). To avoid possible problems arising from population stratification, in our study, we analyzed the association of SNP markers with COPD in ethnically homogenous group -ethnic Tatars, historically dispersed over the territory of the Volga-Ural region of Russia. ...
... Our study revealed an association of GSR polymorphism (c.-386C > A, rs1002149) and COPD in the general population sample (Table 4); this association was also confirmed in the subgroup of nonsmokers (Table 8). The rs1002149 polymorphism is located in the GSR promoter region and may affect the level of the gene expression (Soerensen et al., 2012). Glutathione-disulfide reductase (GSR), the enzyme encoded by GSR, reduces oxidized glutathione (Han et al., 2017). ...
... Most biological functions of glutathione rely on the transformation of its reduced form (GSH) into the oxidized form (GSSG) by glutathione peroxidase and its subsequent reversal to GSH mediated by NADPH-dependent glutathione reductase. The GSH/GSSG ratio is determined by the activity of these two enzymes and specifies the oxidative status of the cell; thus, GSR is a key enzyme of antioxidant defense (Soerensen et al., 2012;Han et al., 2017). It was found that GSR may play a key role in the regulation of drug resistance in tumor cells (Zhu et al., 2018). ...
Background and objective: Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system affecting primarily distal respiratory pathways and lung parenchyma. This work was designed as a case-control study aimed at investigating the association of the NRF2/KEAP1 signaling system, and antioxidant defense gene polymorphisms with COPD in population from Russia. Methods: Ten SNPs: NFE2L2 (rs35652124), KEAP1 (rs1048290), MPO (rs2333227), PRNP (rs1799990), PTGR1 (rs2273788), HSPA1A (rs1008438), TXNRD2 (rs1139793), GSR (rs1002149), SIRT2 (rs10410544), and PTGS1 (rs1330344) were genotyped by the real-time polymerase chain reaction (TaqMan assays) in a case-control study (425 COPD patients and 457 controls, from the same region of Russia, representatives of Tatar population). Logistic regression was used to detect the association of SNPs in different models. Linear regression analyses were performed to estimate the relationship between SNPs and lung function parameters and smoking pack-years. The results: In our population, a significant associations of KEAP1 (rs1048290) (P = 0.0015, OR = 0.72 in additive model), HSPA1A (rs1008438) (P = 0.006, OR = 2.26 in recessive model), GSR (rs1002149) (P = 0.037, OR = 1.31 in additive model) with COPD were revealed. NFE2L2 (rs35652124), PRNP (rs1799990), and HSPA1A (rs1008438) were significantly associated with COPD only in smokers. In nonsmokers, significant association was established for GSR (rs1002149). KEAP1 (rs1048290) was associated with COPD in both groups. The relationship between KEAP1 (rs1048290), NFE2L2 (rs35652124), and HSPA1A (rs1008438) and smoking pack-years was found (P = 0.005, P = 0.0028, P = 0.015). A significant genotype-dependent variation of forced vital capacity and forced expiratory volume in 1 s was observed for SIRT2 (rs10410544) (P = 0.04), NFE2L2 (rs35652124) (P = 0.028), and PRNP (rs1799990) (P = 0.044).
... Several SNPs in genes belonging to distinct pathways have been associated with the longevity phenotype (Soerensen et al., 2012;Dato et al., 2013 and references therein, Rose et al., 2015;Crocco, Montesanto, Passarino & Rose, 2016;De Luca, Crocco, De Rango, Passarino & Rose, 2016). GWAS of human longevity in worldwide samples (North America, Europe and very recently China) generally failed to give new insights into genetic determinants of human longevity: only the TOMM40/APOE/APOC1 locus, associated with longevity, was replicated in different populations (Deelen et al., 2014;Lin et al., 2016;Newman et al., 2010;Sebastiani et al., 2012), while rs2149954 on 5q33.3 (Deelen et al., 2014;Zeng et al., 2016) and the FOXO3A locus (Broer et al., 2015 and references therein) are the other signals showing population-specific associations. ...
... Here, we wanted to explore synergies inside a large SNP data set, by applying statistical methodologies allowing us to test the interaction both inside and among SNP variants belonging to three main candidate pathways of human longevity such as IIS, DNA damage signalling and repair, and pro/antioxidant response. To this aim, we analysed 1,058 SNPs from 140 genes in 1,825 subjects (1,089 cases aged 92-93, 736 controls aged 46-55) of Danish origin, previously analysed for single-SNP associations with longevity (Soerensen et al., 2012). ...
... White cells indicate no subjects with those genotype combinations that were observed in the data set ERCC2-DNA repair pathway). Furthermore, while the interaction analysis confirmed the association of rs572169 of GHSR reported in a previous study using single-SNP-analysis (Soerensen et al., 2012), single variants in TP53, TXNRD1 or ERCC2 here identified were not previously found. In particular, a central role of TP53 might not seem surprising as TP53 is a very well-known tumour suppressor in DNA damage response which balances tumour surveillance and maintenance of stem cell pools, finally resulting in beneficial effects both for cancer protection and longevity (Reinhardt & Schumacher, 2012). ...
In human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with small effects, yet not easily replicable in different populations. New insights may come from the combined analysis of different SNPs, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNPs belonging to three candidate pathways, the insulin/insulin‐like growth factor signalling (IIS), DNA repair and pro/antioxidant. We analysed data from 1,058 tagging SNPs in 140 genes, collected in 1825 subjects (1,089 unrelated nonagenarians from the Danish 1905 Birth Cohort Study and 736 Danish controls aged 46–55 years) for evaluating synergic interactions by SNPsyn. Synergies were further tested by the multidimensional reduction (MDR) approach, both intra‐ and interpathways. The best combinations (FDR<0.0001) resulted those encompassing IGF1R‐rs12437963 and PTPN1‐rs6067484, TP53‐rs2078486 and ERCC2‐rs50871, TXNRD1‐rs17202060 and TP53‐rs2078486, the latter two supporting a central role of TP53 in mediating the concerted activation of the DNA repair and pro‐antioxidant pathways in human longevity. Results were consistently replicated with both approaches, as well as a significant effect on longevity was found for the GHSR gene, which also interacts with partners belonging to both IIS and DNA repair pathways (PAPPA, PTPN1, PARK7, MRE11A). The combination GHSR‐MREA11, positively associated with longevity by MDR, was further found influencing longitudinal survival in nonagenarian females (p = .026). Results here presented highlight the validity of SNP‐SNP interactions analyses for investigating the genetics of human longevity, confirming previously identified markers but also pointing to novel genes as central nodes of additional networks involved in human longevity.
... Rs9456497 is a common variant in the intron 6 of IGF-2R, with an A > G substitution at nt. 58298. Very recently, this polymorphism had been linked to longevity in Danes in a cross-sectional study (Soerensen et al., 2012). Nevertheless, no validation study in other ethnic cohorts or functional research data on this variant was published thereafter. ...
... To the best of our knowledge, we are the first to report the polymorphic data of IGF-2R rs9456497 in other Chinese population, Zhuang ethnic group, the biggest minority in China who mainly resides Guangxi province, since the 1000 Genomes Project released that of Beijing Chinese Hans (CHB). The MAF of rs9456497 in the combined population studied herein is 48.9%, being slightly lower than that of CHB (56.8%) but extremely higher than that of Danish Caucasian (19.1%) (Soerensen et al., 2012). We observed a marginally prevalent AG/GG genotype in males versus females in the average population (P = 0.033), resembling the trend seen in the oldest-old Danes (Soerensen et al., 2012). ...
... The MAF of rs9456497 in the combined population studied herein is 48.9%, being slightly lower than that of CHB (56.8%) but extremely higher than that of Danish Caucasian (19.1%) (Soerensen et al., 2012). We observed a marginally prevalent AG/GG genotype in males versus females in the average population (P = 0.033), resembling the trend seen in the oldest-old Danes (Soerensen et al., 2012). However, we did not note other significantly different genotypic frequency distribution of this SNP among the oldest old, their offspring and other subgroups of local controls, implying its indirect involvement in longevity, if any. ...
Objectives:
To look at the possible effect of IGF2R rs9456497 on cardiovascular risks in a long-lived population.
Methods:
IGF-2R rs9456497 was genotyped by iMLDR for 496 long-lived Zhuang Chinese (90-107 y/o) and their offspring (n = 723, 60-75 y/o) and healthy controls (n = 611, 60-75 y/o). Association analyses were then conducted among genotypes and cardiovascular risks.
Results:
The G genotype (GA/GG) was found to represent more frequently in males of general population. No significantly difference was detected among genotypes in each group except that G genotype tended to reduce the systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels in longevity group. However, after sex stratification, total cholesterol (TC) of each genotype in offspring males was elevated versus relevant genotype in longevity and control group; the triglyceride (TG), fasting plasma glucose (FPG) and BMI of each genotype in longevity group were lower while SBP and DBP were higher than that of the relevant genotype in offspring and controls. After stratified by lipid status, the frequency of G allele was markedly increased in the dyslipidemic subgroup in the combined population and controls. Linear regressive analyses showed that HDL was positively correlated to rs9456497 GA genotype while BMI was negatively correlated to AA genotype in offspring group, whereas TC and TG were reversely while BMI was positively associated with AA genotype in CG.
Conclusions:
IGF-2R rs9456497 G genotype correlates to detrimental cardiovascular risks in ordinary population which might partially interpret their less preservation of health as compared to long-lived cohort.
... 9). Genetic variabilities of TXNRD1 correlate with functional activities at very old age [10][11][12][13] . A lower expression of TXNRD1 is associated with frailty 14 , a geriatric syndrome characterized by a diminished functional reserve and increased vulnerability to low-power stressors 15 . ...
... Pathway analysis with DAVID (Database for Annotation, Visualization and Integrated Discovery) revealed enrichment of 15 domains (false discovery rate (FDR) < 10%, at least twofold enrichment, at least ten proteins), with 2 domains being related to TXN ( Fig. 1a and Extended Data Fig. 1e). Given the implication of TXNRD1 in tissue aging [10][11][12][13][14] and its critical role in the TXN pathway 9 , we chose TXNRD1 for validation. We observed that TXNRD1 was present in purified CCFs and was localized to CCFs ( Fig. 1b-d). ...
Sterile inflammation, also known as ‘inflammaging’, is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1’s role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments and interacts with cGAS in a senescence-status-dependent manner, which is necessary for the SASP. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not with an inhibitor of its enzymatic activity alone, downregulated markers of inflammaging in several tissues. In summary, our results show that TXNRD1 promotes the SASP through the innate immune response, with implications for inflammaging. This suggests that the TXNRD1–cGAS interaction is a relevant target for selectively suppressing inflammaging.
... While it is not possible to genetically manipulate the expression levels of thioredoxin system genes in humans, multiple studies have identified genetic variants that are associated with extended longevity. In a study comparing oldest-old individuals (age 92-93) with middle-aged Danes, an allele of the cytoplasmic thioredoxin reductase gene TXNRD1 was found to be associated with longevity [104]. A subsequent study found that genetic variation in TXNRD1 is associated with physical and cognitive performance in very old individuals [105]. ...
... A subsequent study found that genetic variation in TXNRD1 is associated with physical and cognitive performance in very old individuals [105]. The association of TXNRD1 with physical performance in old age was confirmed in a cohort from Southern Italy [106], while the association of TXNRD1 with longevity was supported by results from a Dutch cohort, which showed the same relationship but failed to reach significance [104]. Taken together, these results suggest that the thioredoxin system may also contribute to longevity in humans. ...
Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. A number of studies have examined the role of thioredoxin and thioredoxin reductase in determining longevity. Disruption of either thioredoxin or thioredoxin reductase is sufficient to shorten lifespan in model organisms including yeast, worms, flies and mice, thereby indicating conservation across species. Similarly, increasing the expression of thioredoxin or thioredoxin reductase can extend longevity in multiple model organisms. In humans, there is an association between a specific genetic variant of thioredoxin reductase and lifespan. Overall, the cytoplasmic and mitochondrial thioredoxin systems are both important for longevity.
... 9). Genetic variabilities of TXNRD1 correlate with functional activities at very old age [10][11][12][13] . A lower expression of TXNRD1 is associated with frailty 14 , a geriatric syndrome characterized by a diminished functional reserve and increased vulnerability to low-power stressors 15 . ...
... Pathway analysis with DAVID (Database for Annotation, Visualization and Integrated Discovery) revealed enrichment of 15 domains (false discovery rate (FDR) < 10%, at least twofold enrichment, at least ten proteins), with 2 domains being related to TXN ( Fig. 1a and Extended Data Fig. 1e). Given the implication of TXNRD1 in tissue aging [10][11][12][13][14] and its critical role in the TXN pathway 9 , we chose TXNRD1 for validation. We observed that TXNRD1 was present in purified CCFs and was localized to CCFs ( Fig. 1b-d). ...
Cellular senescence regulates cancer and tissue aging in part through the secretion of proinflammatory factors known as the senescence-associated secretory phenotype (SASP). For example, sterile inflammation or ‘inflammaging’ is a hallmark of tissue aging. Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and is often upregulated in human cancers. TXNRD1’s role in regulating tissue aging and cancer has been attributed to its enzymatic role in regulating cellular redox. Here we show that TXNRD1 drives the SASP and inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments (CCF) and interacts with cGAS in a senescence status dependent manner, which is required for the SASP. Biochemically, TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune-surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse tumor models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not an inhibitor of its enzymatic activity alone, downregulated inflammaging in several tissues. In summary, our results report TXNRD1 promotes inflammation via activating the innate immune response in a manner depending on its interaction with cGAS but not its enzymatic activity. Our findings have important implications for both tissue aging and cancer.
Citation Format: Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Hsin Yao Tang, Aaron Havas, Andrew V. Kossenkov, Shelley Berger, Peter D. Adams, David W. Speicher, Rugang Zhang. TXNRD1 drives innate immune response in senescent cells to promote tumor immune surveillance and age-associated inflammation [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR011.
... Telomere length is a complex phenotypic trait (Aviv, 2012;Hansen et al., 2016) expected to be polygenic, that is, affected by small effects of many genes Hill, 2010). Accordingly, numerous genome-wide association studies (GWAS), which tests correlative associations of single-nucleotide polymorphisms (SNPs) with specific traits, have identified several loci correlated with TL in humans that map to genes involved in telomere and telomerase maintenance, DNA damage repair, cancer biology, and several nucleotide metabolism pathways (e.g., Andrew et al., 2006;Codd et al., 2010Codd et al., , 2013Coutts et al., 2019;Deelen et al., 2013;Delgado et al., 2018;Jones et al., 2012;Levy et al., 2010;Li et al., 2020;Liu et al., 2014;Mangino et al., 2012Mangino et al., , 2015Mirabello et al., 2010;Nersisyan et al., 2019;Ojha et al., 2016;Soerensen et al., 2012;Vasa-Nicotera et al., 2005;Zeiger et al., 2018). None of the GWA studies in humans specifically tested the marker associations of early-life TL, which pose a challenge to the interpretation of the results, as TL shortens through life in humans (Blackburn et al., 2015) and genes may have different impacts at various life stages (Weng et al., 2016). ...
... The AQP1 protein is abundant in erythrocytes (where TL is measured) and important in regulating body water transport and balance (Nielsen et al., 2002), but also in a range of other physiological functions including cell migration, wound healing, fat metabolism and oxidative stress (Saadoun et al., 2005;Verkman et al., 2014). The same SNP is located 39 kb from the growth hormone-releasing hormone receptor (GHRHR), which controls body growth (Mullis, 2005), and has been associated with telomerase activity (Banks et al., 2010), lifespan (Soerensen et al., 2012) and the progression of several types of cancer (Chu et al., 2016;Schally et al., 2018;Villanova et al., 2019). ...
Early-life telomere length (TL) is associated with fitness in a range of organisms. Little is known about the genetic basis of variation in TL in wild animal populations, but to understand the evolutionary and ecological significance of TL it is important to quantify the relative importance of genetic and environmental variation in TL. In this study, we measured TL in 2746 house sparrow nestlings sampled across 20 years and used an animal model to show that there is a small heritable component of early-life TL (h²=0.04). Variation in TL among individuals was mainly driven by environmental (annual) variance, but also brood and parental effects. Parent-offspring regressions showed a large maternal inheritance component in TL (h²maternal=0.44), but no paternal inheritance. We did not find evidence for a negative genetic correlation underlying the observed negative phenotypic correlation between TL and structural body size. Thus, TL may evolve independently of body size and the negative phenotypic correlation is likely to be caused by non-genetic environmental effects. We further used genome-wide association analysis to identify genomic regions associated with TL variation. We identified several putative genes underlying TL variation; these have been inferred to be involved in oxidative stress, cellular growth, skeletal development, cell differentiation and tumorigenesis in other species. Together, our results show that TL has a low heritability and is a polygenic trait strongly affected by environmental conditions in a free-living bird.
... gene variability could modify the antioxidants associated with aging (Soerensen et al. 2012;Dato et al. 2014;Dato et al. 2015). We found that the principal genetic risk factor for osteoporotic fracture is being a carrier of the variant genotype of the rs4077561 polymorphism, which is a genetic variant located in the promoter region of the TXNRD1 gene. ...
... have been associated with cardiovascular disease, heart failure, stroke, Alzheimer disease, arthritis, cancer and other diseases associated with aging (Soerensen et al. 2012;Dato et al. 2014;Dato et al. 2015), but this is the first time they have been associated with the risk of bone fracture. Thioredoxin 2 (Txn2) is another redox protein of the Txn pathway that is essential for the control of ROS homeostasis, apoptosis and cell viability (Cunningham et al. 2015;Pérez et al. 2008;Holzerova et al. 2016). ...
The most widely accepted etiopathogenesis hypothesis of the origin of osteoporosis and its complications is that they are a consequence of bone aging and other environmental factors, together with a genetic predisposition. Evidence suggests that oxidative stress is crucial in bone pathologies associated with aging. The aim of this study was to determine whether genetic variants in oxidative stress-related genes modified the risk of osteoporotic fracture. We analysed 221 patients and 354 controls from the HORTEGA sample after 12-14 years of follow up. We studied the genotypic and allelic distribution of 53 SNPs in 24 genes involved in oxidative stress. The results showed that being a carrier of the variant allele of the SNP rs4077561 within TXNRD1 was the principal genetic risk factor associated with osteoporotic fracture and that variant allele of the rs1805754 M6PR, rs4964779 TXNRD1, rs406113 GPX6, rs2281082 TXN2 and rs974334 GPX6 polymorphisms are important genetic risk factors for fracture. This study provides information on the genetic factors associated with oxidative stress which are involved in the risk of osteoporotic fracture and reinforces the hypothesis that genetic factors are crucial in the etiopathogenesis of osteoporosis and its complications.
... Furthermore, functional variants in IGF1R were shown to be enriched in centenarians . Polymorphisms in other genes of the IIS pathway were also linked to longevity in GWAS, although not without contradictions (Soerensen et al., 2012a). In fact, some studies reported a decrease in GH and IGF1 plasma levels during normal aging (Breese et al., 1991;Sonntag et al., 1997). ...
... The SMAD family member 2 (SMAD2) gene, which functions in the transforming growth factor beta (TGF-β) pathway ( Figure 6C) (Vellai, 2009), was associated with body size (Rimbault et al., 2013) and was previously found to be in linkage with mortality of dog breeds (Jones et al., 2008). The growth hormone receptor (GHR) and growth hormone (GH) genes, which also modulate dogs' body size, were shown to affect longevity in humans (Soerensen et al., 2012a;van der Spoel et al., 2016), and in mice Flurkey et al., 2001;Kinney et al., 2001;Amador-Noguez et al., 2004). ...
Aging research has experienced a burst of scientific efforts in the last decades as the growing ratio of elderly people has begun to pose an increased burden on the healthcare and pension systems of developed countries. Although many breakthroughs have been reported in understanding the cellular mechanisms of aging, the intrinsic and extrinsic factors that contribute to senescence on higher biological levels are still barely understood. The dog, Canis familiaris, has already served as a valuable model of human physiology and disease. The possible role the dog could play in aging research is still an open question, although utilization of dogs may hold great promises as they naturally develop age-related cognitive decline, with behavioral and histological characteristics very similar to those of humans. In this regard, family dogs may possess unmatched potentials as models for investigations on the complex interactions between environmental, behavioral, and genetic factors that determine the course of aging. In this review, we summarize the known genetic pathways in aging and their relevance in dogs, putting emphasis on the yet barely described nature of certain aging pathways in canines. Reasons for highlighting the dog as a future aging and gerontology model are also discussed, ranging from its unique evolutionary path shared with humans, its social skills, and the fact that family dogs live together with their owners, and are being exposed to the same environmental effects.
... On the other hand, centenarians are more sensitive to insulin than other people, and often show lower IGF-1 plasma levels [174]. SNP studies have found an association of particular alleles or haplotypes for INS (insulin) [175], INSR (insulin receptor) [176], IGF1 (insulin growth factor 1) [177], IGF1R (insulin growth factor 1 receptor); in fact, a specific haplotype of the IGF-I receptor and the kinase PI3KCB is frequently found in individuals living longer together with low plasma levels of IGF-1 [178], IGF2 (insulin growth factor 2) [179], IGF2R (insulin growth factor 2 receptor) [180], IRS1 (insulin receptor substrate 1) [177], GH1 (growth hormone 1) [177], GHSR (growth hormone secretagogue receptor type 1) [175], FOXO1A (forkhead box protein O1 A), and FOXO3A (forkhead box protein O3 A) transcription factor, which contains alleles that are associated with longevity in multiple Asian and European populations [181][182][183][184][185]. ...
... On the other hand, centenarians are more sensitive to insulin than other people, and often show lower IGF-1 plasma levels [174]. SNP studies have found an association of particular alleles or haplotypes for INS (insulin) [175], INSR (insulin receptor) [176], IGF1 (insulin growth factor 1) [177], IGF1R (insulin growth factor 1 receptor); in fact, a specific haplotype of the IGF-I receptor and the kinase PI3KCB is frequently found in individuals living longer together with low plasma levels of IGF-1 [178], IGF2 (insulin growth factor 2) [179], IGF2R (insulin growth factor 2 receptor) [180], IRS1 (insulin receptor substrate 1) [177], GH1 (growth hormone 1) [177], GHSR (growth hormone secretagogue receptor type 1) [175], FOXO1A (forkhead box protein O1 A), and FOXO3A (forkhead box protein O3 A) transcription factor, which contains alleles that are associated with longevity in multiple Asian and European populations [181][182][183][184][185]. ...
Research on longevity and healthy aging promises to increase our lifespan and decrease the burden of degenerative diseases with important social and economic effects. Many aging theories have been proposed, and important aging pathways have been discovered. Model organisms have had a crucial role in this process because of their short lifespan, cheap maintenance, and manipulation possibilities. Yeasts, worms, fruit flies, or mammalian models such as mice, monkeys, and recently, dogs, have helped shed light on aging processes. Genes and molecular mechanisms that were found to be critical in simple eukaryotic cells and species have been confirmed in humans mainly by the functional analysis of mammalian orthologues. Here, we review conserved aging mechanisms discovered in different model systems that are implicated in human longevity as well and that could be the target of anti-aging interventions in human.
... The variants associated with longevity in the hTERC gene are also intronic (IVS-99 C > G, and IVS + 12 A > G), and might also affect gene expression (Atzmon et al. 2010). The variants associated with longevity found in the Werner helicase gene are rs13251813 (an intronic variant found in the Danish population), and the L787L synonymous variant (found in American families) (Sebastiani et al. 2012;Soerensen et al. 2012). It is intriguing that rare variants in those genes can cause premature aging syndromes, such as the TBDs (in the case of rare missense/nonsense variants), while some intronic and synonymous variants are enriched in centenarians. ...
Telomere Biology Disorders (TBDs) are a group of rare diseases characterized by the presence of short and/or dysfunctional telomeres. They comprise a group of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and liver disease, among other diseases. Genetic alterations (variants) in the genes responsible for telomere homeostasis have been linked to TBDs. Despite the number of variants already identified as pathogenic, an even more significant number must be better understood. The study of TBDs is challenging since identifying these variants is difficult due to their rareness, it is hard to predict their impact on the disease onset, and there are not enough samples to study. Most of our knowledge about pathogenic variants comes from assessing telomerase activity from patients and their relatives affected by a TBD. However, we still lack a cell-based model to identify new variants and to study the long-term impact of such variants on the genes involved in TBDs. Herein, we present a cell-based model using CRISPR base editing to mutagenize the endogenous alleles of 21 genes involved in telomere biology. We identified key residues in the genes encoding 17 different proteins impacting cell growth. We provide functional evidence for variants of uncertain significance in patients with TBDs. We also identified variants resistant to telomerase inhibition that, similar to cells expressing wild-type telomerase, exhibited increased tumorigenic potential using an in vitro tumour growth assay. We believe that such cell-based approaches will significantly advance our understanding of the biology of TBDs and may contribute to the development of new therapies for this group of diseases.
... Other hypotheses that may explain the abnormal GH response in obesity include increased fatty acids and leptin [5]. Changes in growth hormone -GH secretion and plasma GH concentrations decrease with age, both basally and in response to provocative stimuli, and there is a parallel decrease in serum IGF-1 concentrations [7,8]. ...
Obesity is a complex, multifactorial metabolic pathology, within the path of modification of the endocrine system plays a significant role. Changes in growth hormone (GH) and in-sulin growth factor (IGF) have been associated with obesity in various ways, mainly through changes in GH-binding proteins, insulin and ghrelin levels. The balneal treat-ment with Techirghiol Romanian sapropelic mud has an important impact on the endo-crine system, primarily through the action on the hypothalamic-pituitary-adrenal axis. We investigated the secretory changes of the IGF-1 hormone that appeared after the balne-al treatment. It was a total number of 52 patients, divided into two groups: 1 group who performed the treatment with Techirghiol sapropelic mud at thermoneutrality tempera-tures - warm mud baths, and the second group who followed treatment with the balneal therapeutic factor in a thermal contrast regime - cold mud baths. We studied whether there are correlations between the body mass index (BMI) and the secretion of this hor-mone. We also determined the serum levels of blood glucose at admission and discharge. In the cold mud baths- thermal contrast therapy, can be observed a statistically significant increase in IGF-1 values during the balneal treatment (p = 0.044 < α = 0.05). Comparative-ly, in the warm mud baths, the increase in serum IGF-1 reached values close to statistical significance at the end of the treatment (p = 0.067 > α = 0.05). There were no statistically significant correlations between BMI and IGF-1 hormone secretion at admission and at discharge. The results showed a statistically significant decrease in blood glucose values determined at admission and discharge in the group that performed warm mud baths. The balneal treatment with sapropelic mud of Techirghiol lake, from Romania, through the impact on the endocrine system, on the hypothalamic-pituitary-adrenal axis, can be registered as a treatment with a natural therapeutic factor with an impact on obesity, ther-apy carried out within the parameters of metabolic safety, and the conduct of future re-search in this direction it will help develop new concepts and approaches to obesity.
... The decrease of GH/IGF-1 signaling has proven to extend longevity in many model organisms, including yeast, worms, fruit flies, and mice [53]. The minor allele A in the intronic rs2267723 of the GHRHR gene was significant for longevity in the Danish population [54]. It was also among the top-ranked interactions in a study that explored the combined effect of SNPs from candidate pathways on longevity [55]. ...
Longevity is a hallmark of successful ageing and a complex trait with a significant genetic component. In this study, 43 single nucleotide polymorphisms (SNPs) were chosen from the literature and genotyped in a Croatian oldest-old sample (85+ years, sample size (N) = 314), in order to determine whether any of these SNPs have a significant effect on reaching the age thresholds for longevity (90+ years, N = 212) and extreme longevity (95+ years, N = 84). The best models were selected for both survival ages using multivariate logistic regression. In the model for reaching age 90, nine SNPs explained 20% of variance for survival to that age, while the 95-year model included five SNPs accounting for 9.3% of variance. The two SNPs that showed the most significant association (p ≤ 0.01) with longevity were TERC rs16847897 and GHRHR rs2267723. Unweighted and weighted Genetic Longevity Scores (uGLS and wGLS) were calculated and their predictive power was tested. All four scores showed significant correlation with age at death (p ≤ 0.01). They also passed the ROC curve test with at least 50% predictive ability, but wGLS90 stood out as the most accurate score, with a 69% chance of accurately predicting survival to the age of 90.
... Originally discovered in forward genetic screens in nematode worms (51,52), the role of glucose and energy metabolism in aging continues to be refined (53) and retains relevance across vertebrates, including mammals (54), and humans (55)(56)(57)(58)(59)(60)(61). Recent analysis of rare coding variants in centenarians converge on ILS pathways (62). ...
Longevity is a defining, heritable trait that varies dramatically between species. To resolve the genetic regulation of this trait, we have mined genomic variation in rockfishes, which range in longevity from 11 to over 205 years. Multiple shifts in rockfish longevity have occurred independently and in a short evolutionary time frame, thus empowering convergence analyses. Our analyses reveal a common network of genes under convergent evolution, encompassing established aging regulators such as insulin signaling, yet also identify flavonoid (aryl-hydrocarbon) metabolism as a pathway modulating longevity. The selective pressures on these pathways indicate the ancestral state of rockfishes was long lived and that the changes in short-lived lineages are adaptive. These pathways were also used to explore genome-wide association studies of human longevity, identifying the aryl-hydrocarbon metabolism pathway to be significantly associated with human survival to the 99th percentile. This evolutionary intersection defines and cross-validates a previously unappreciated genetic architecture that associates with the evolution of longevity across vertebrates.
... POLB is a DNA polymerase that is involves in base excision and repair. Polymorphisms in POLB are known to be associated with longevity [35,36]. The top ranked chemical compounds that are predicted to upregulate LGI3 include vorinostat, panobinostat, SB-939, and belinostat which are all HDAC inhibitors. ...
The L1000 technology, a cost-effective high-throughput transcriptomics technology, has been applied to profile a collection of human cell lines for their gene expression response to > 30,000 chemical and genetic perturbations. In total, there are currently over 3 million available L1000 profiles. Such a dataset is invaluable for the discovery of drug and target candidates and for inferring mechanisms of action for small molecules. The L1000 assay only measures the mRNA expression of 978 landmark genes while 11,350 additional genes are computationally reliably inferred. The lack of full genome coverage limits knowledge discovery for half of the human protein coding genes, and the potential for integration with other transcriptomics profiling data. Here we present a Deep Learning two-step model that transforms L1000 profiles to RNA-seq-like profiles. The input to the model are the measured 978 landmark genes while the output is a vector of 23,614 RNA-seq-like gene expression profiles. The model first transforms the landmark genes into RNA-seq-like 978 gene profiles using a modified CycleGAN model applied to unpaired data. The transformed 978 RNA-seq-like landmark genes are then extrapolated into the full genome space with a fully connected neural network model. The two-step model achieves 0.914 Pearson’s correlation coefficients and 1.167 root mean square errors when tested on a published paired L1000/RNA-seq dataset produced by the LINCS and GTEx programs. The processed RNA-seq-like profiles are made available for download, signature search, and gene centric reverse search with unique case studies.
... However, in this study, the expression of hsp-16.2 was not changed, suggesting that manganese did not cause protein stress to C. elegans. The upregulation of antioxidantrelated genes helps to scavenge free radicals and improves the antioxidant defense of nematodes [62]. We found that Se-PCS increased SOD and CAT enzymes in nematodes, and the high level of ROS induced by manganese was also effectively eliminated, confirming that, after treatment with Se-PCS, a large number of free radicals were indeed scavenged. ...
Manganese (Mn) is now known to have a variety of toxicities, particularly when exposed to it in the workplace. However, there are still ineffective methods for reducing Mn’s hazardous effects. In this study, a new selenium polysaccharide (Se-PCS) was developed from the shell of Camellia oleifera to reduce Mn toxicity in vitro and in vivo. The results revealed that Se-PCS may boost cell survival in Hep G2 cells exposed to Mn and activate antioxidant enzyme activity, lowering ROS and cell apoptosis. Furthermore, after being treated with Se-PCS, Caenorhabditis elegans survived longer under Mn stress. daf-16, a tolerant critical gene, was turned on. Moreover, the antioxidant system was enhanced as the increase in strong antioxidant enzyme activity and high expression of the sod-3, ctl-2, and gst-1 genes. A variety of mutations were also used to confirm that Se-PCS downregulated the insulin signaling pathway. These findings showed that Se-PCS protected Hep G2 cells and C. elegans via the insulin/IGF-1 signaling pathway and that it could be developed into a promising medication to treat Mn toxicity.
... The genome of Aldabrachelys gigantea (Aldabra giant tortoise), one of the identified species in the current study, has previously been sequenced and was shown to contain IGF2R (Insulin Like Growth Factor 2 Receptor) variants (Quesada et al. 2019). These genomic variants which were reported to be associated with longevity in humans may also explain extreme longevity in these animals (Soerensen et al. 2012). Similarly, sequencing of the genomes of other species with exceptional lifespans in the future will provide data on other genomic variants which contribute to long lifespans of these animals, and may be valuable for aging research in humans. ...
Animals have a considerable variation in their longevity. This fundamental life-history trait is shaped by both intrinsic and extrinsic mortality pressures, influenced by multiple parameters including ecological variables and mode-of-life traits. Here, we examined the distribution of maximum age at multiple taxonomic ranks (class, order and family) in Chordata, and identified species with exceptional longevity within various taxa. We used a curated dataset of maximum longevity of animals from AnAge database, containing a total of 2542 chordates following our filtering criteria. We determined shapes of maximum age distributions at class, order and family taxonomic ranks, and calculated skewness values for each distribution, in R programming environment. We identified species with exceptional longevity compared to other species belonging to the same taxa, based on our definition of outliers. We collected data on ecological variables and mode-of-life traits which might possibly contribute, at least in part, to the exceptional lifespans of certain chordates. We found that 23, 12 and 4 species have exceptional longevity when we grouped chordates by their class, order and family, respectively. Almost all distributions of maximum age among taxa were positively skewed (towards increased longevity), possibly showing the emergence of longer lifespans in contrast to shorter lifespans, through the course of evolution. However, potential biases in the collection of data should be taken into account. Most of the identified species in the current study have not been previously studied in the context of animal longevity. Our analyses point that certain chordates may have evolved to have longer lifespans compared to other species belonging to the same taxa, and that among taxa, outliers in terms of maximum age have always longer lifespans, not shorter. Future research is required to understand how and why increased longevity have arose in certain species.
... A more successful pathway-based gene set approach evaluated the joint effect of SNPs in genes from relevant aging pathways on longevity in humans, and yielded significant results supporting the role of genetic variation in the IGF-1 signaling in human longevity (Deelen, Uh et al. 2013). Another study that focused on 148 candidate genes from the aging-related pathways found promising associations with human longevity of common SNPs in genes from IGF-1 signaling (e.g., IGF2R, INS) and DNA damage repair (e.g., RAD52, NTLH1, WRN) pathways (Soerensen, Dato et al. 2012). The RAD52 variants were also found in familial cases of exceptional longevity (Cash, Pita et al. 2014), which supports the role of the inherent quality of DNA repair (which characterizes cell resilience to DNA damage) in maximum longevity. ...
Decline in biological resilience (ability to recover) is a key manifestation of aging that contributes to increase in vulnerability to death with age eventually limiting longevity even in people without major chronic diseases. Understanding the mechanisms of this decline is essential for developing efficient anti-aging and pro-longevity interventions. In this paper we discuss: a) mechanisms of the decline in resilience with age, and aging components that contribute to this decline, including depletion of body reserves, imperfect repair mechanisms, and slowdown of physiological processes and responses with age; b) anti-aging interventions that may improve resilience or attenuate its decline; c) biomarkers of resilience available in human and experimental studies; and d) genetic factors that could influence resilience. There are open questions about optimal anti-aging interventions that would oppose the decline in resilience along with extending longevity limits. However, the area develops quickly, and prospects are exciting.
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
Comparative studies of different antigens such as AFP, IGF-I, IGF-II or VEGF, and EGF presence in neoplastic cells have demonstrated that IGF-I constitutes an essential target for genetic testing and therapy purpose. The arrest of IGF-I expression has diminished or stopped neoplastic development due to the apoptosis and anti-tumor immune response (MHC-I) produced by this arrest. These two phenomena, which play an important role in the mechanism of IGF-I, are barely present if not nonexistent in other oncoprotein and growth factor mechanisms such as EGF, VEGF or TGF-beta.
In terms of growth factors involved in both ontogenesis and carcinogenesis, IGF-I may be a highly promising therapeutic and diagnostic target (400 publications/year). Indeed, IGF-I, similarly to AFP, is involved in tissue development and differentiation, especially in the development of the nervous system as a mediator of Growth Hormone, ISH, and glucose metabolism; acting locally with autocrine/paracrine, with a predominant role compared to other growth factors.
... ; https://doi.org/10.1101/240606 doi: bioRxiv preprint genes/pathways 57,58 . Specifically, an ATM SNP that could enhance the transcription of ATM is associated with longevity in both Chinese and Italian populations 59,60 . ...
DNA damage accumulates with age ¹ . However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that activation of ataxia-telangiectasia mutated (ATM) via low dose of chloroquine (CQ) promotes DNA damage clearance, rescues age-related metabolic shift, and extends lifespan in nematodes and mice. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 in Atm -/- mice extend lifespan, accompanied with restored metabolic homeostasis. In a progeria mouse model with low ATM protein level and DNA repair capacity, the treatment with CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.
... This is reflected in significant associations of NTHL1 with human longevity, discovered in two independent studies. In a case controlled 11-year longitudinal study in the Danish population, a rare allelic variant of NTHL1, rs3211994, was discovered to be significantly associated with longer lifespan, especially males [24]. In another study on genotyped participants of Framingham Heart Study cohort, out of 550,000 SNPs, a rare SNP in the intronic sequence of NTHL1 (rs2516739) emerged among the top 40 candidates significantly associated with longevity [25]. ...
A R T I C L E I N F O keywords: DNA repair DNA glycosylase Base excision repair A B S T R A C T Efficient DNA repair is essential to maintain genomic integrity. An average of 30,000 base lesions per cell are removed daily by the DNA glycosylases of the base excision repair machinery. With the advent of whole genome sequencing, many germline mutations in these DNA glycosylases have been identified and associated with various diseases, including cancer. In this graphical review, we discuss the function of the NTHL1 DNA glyco-sylase and how genomic mutations and altered function of this protein contributes to cancer and aging. We highlight its role in a rare tumor syndrome, NTHL1-associated polyposis (NAP), and summarize various other polymorphisms in NTHL1 that can induce early hallmarks of cancer, including genomic instability and cellular transformation.
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
After demonstrating the convergence between ontogenesis and oncogenesis using alpha-fetoprotein as a new biomarker of neoplastic development[1,2], the phenomenon was confirmed using another cancer biomarker—IGF-I[3,4], followed by the development of genetic testing of IGF-I[5,6], and the establishment of cancer gene therapy, applying the anti-gene IGF-I approach[7]. Through the example of the IGF-I biomarker, which plays an important role in cancerology[7], the presented review article describes the common ethical problems triggered by genetic testing. Biomarkers or molecular markers are defined by the National Cancer Institute (NCI) as "biological molecules found in blood, other body fluids, or tissues, including RNA and microRNA that are a sign of a normal or abnormal process, or of a condition or disease". Biomarkers, especially those associated with genetic mutations or epigenetic alterations, help to identify early stages of cancer, its prognostic, treatment choice, and therapy response[8-14].
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
After demonstrating the convergence between ontogenesis and oncogenesis using alpha-fetoprotein as a new biomarker of neoplastic development[1,2], the phenomenon was confirmed using another cancer biomarker—IGF-I[3,4], followed by the development of genetic testing of IGF-I[5,6], and the establishment of cancer gene therapy, applying the anti-gene IGF-I approach[7]. Through the example of the IGF-I biomarker, which plays an important role in cancerology[7], the presented review article describes the common ethical problems triggered by genetic testing. Biomarkers or molecular markers are defined by the National Cancer Institute (NCI) as "biological molecules found in blood, other body fluids, or tissues, including RNA and microRNA that are a sign of a normal or abnormal process, or of a condition or disease". Biomarkers, especially those associated with genetic mutations or epigenetic alterations, help to identify early stages of cancer, its prognostic, treatment choice, and therapy response[8-14].
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
After demonstrating the convergence between ontogenesis and oncogenesis using alpha-fetoprotein as a new biomarker of neoplastic development[1,2], the phenomenon was confirmed using another cancer biomarker—IGF-I[3,4], followed by the development of genetic testing of IGF-I[5,6], and the establishment of cancer gene therapy, applying the anti-gene IGF-I approach[7]. Through the example of the IGF-I biomarker, which plays an important role in cancerology[7], the presented review article describes the common ethical problems triggered by genetic testing. Biomarkers or molecular markers are defined by the National Cancer Institute (NCI) as "biological molecules found in blood, other body fluids, or tissues, including RNA and microRNA that are a sign of a normal or abnormal process, or of a condition or disease". Biomarkers, especially those associated with genetic mutations or epigenetic alterations, help to identify early stages of cancer, its prognostic, treatment choice, and therapy response
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
After demonstrating the convergence between ontogenesis and oncogenesis using alpha-fetoprotein as a new biomarker of neoplastic development[1,2], the phenomenon was confirmed using another cancer biomarker—IGF-I[3,4], followed by the development of genetic testing of IGF-I[5,6], and the establishment of cancer gene therapy, applying the anti-gene IGF-I approach[7]. Through the example of the IGF-I biomarker, which plays an important role in cancerology[7], the presented review article describes the common ethical problems triggered by genetic testing. Biomarkers or molecular markers are defined by the National Cancer Institute (NCI) as "biological molecules found in blood, other body fluids, or tissues, including RNA and microRNA that are a sign of a normal or abnormal process, or of a condition or disease". Biomarkers, especially those associated with genetic mutations or epigenetic alterations, help to identify early stages of cancer, its prognostic, treatment choice, and therapy response[8-14].
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
... In recent studies regarding prostate cancer survival-IGF-I pathway genetic polymorphisms, in parallel to the circulating level of IGF-1 and IGFBP3-has demonstrated that primarily IGF2-AS and SSTR2 genes were associated with pancreatic cancer mortality. Therefore, the genetic testing of these two genes may be important in the survival of pancreas cancer patients [125] . Also, genetic variation in the IGF-1, IGFBP3, and SSTR2 genes (single nucleotide polymorphisms, SNPs was genotyped) seems to influence the circulating levels of IGF-I and IGFBP3, in prostate and breast cancer [126] . ...
Introduction
After demonstrating the convergence between ontogenesis and oncogenesis using alpha-fetoprotein as a new biomarker of neoplastic development[1,2], the phenomenon was confirmed using another cancer biomarker—IGF-I[3,4], followed by the development of genetic testing of IGF-I[5,6], and the establishment of cancer gene therapy, applying the anti-gene IGF-I approach[7]. Through the example of the IGF-I biomarker, which plays an important role in cancerology[7], the presented review article describes the common ethical problems triggered by genetic testing. Biomarkers or molecular markers are defined by the National Cancer Institute (NCI) as "biological molecules found in blood, other body fluids, or tissues, including RNA and microRNA that are a sign of a normal or abnormal process, or of a condition or disease". Biomarkers, especially those associated with genetic mutations or epigenetic alterations, help to identify early stages of cancer, its prognostic, treatment choice, and therapy response[8-14].
New "array" technologies such as Comparative Genomic Hybridization arrays (CGH), Single Nucleotide Polymorphisms arrays (SNP), protein arrays, among others, are powerful sources of data when identifying biomarkers. In fact, studies in cancer using this kind of technology, have been able to identify genes involved with initiation, promotion, progression, and treatment response, as well as understandingthe biological characteristics of cancer cells. Finally, changes in micro RNA (miRNAs) expression can also be a biomarker i.e. the increase of miR-206 and -221 gene expression or down expression of miR-125b and let-7 genes[13,14]. As far as biomarkers are considered, related genetic testing constitutes an important domain of clinical laboratory diagnostic. In this context, possible patents related to genetic testing should be discussed. The idea of patenting genes may seem absurd, yet it is a reality – as the "invention" is prior to the inventor. Just 15 years ago, the United States counted at least 48 private companies with three patents class 435/6 minimum (molecular biology involving nucleic acids)[15]. Genes of plants, animals, and humans are being patented[16,17]. If the human genome is, in a symbolic sense, heritage of humanity (UNESCO, 1997)[18]. In addition, there is great concern that gene sequence patents may hinder future biotechnological innovations in the medical field[19].
... In fact, the human ortholog of the CG5316 gene identified via the Integrative Ortholog Prediction Tool available at https://www.flyrnai.org/cgi-bin/DRSC_orthologs.pl, the APTX gene, which encodes the DNA strand-break repair protein aprataxin was found to have a broader role in DNA single-strand break repair in neurodegenerative disease (reviewed in [41]) that shortens lifespan. In a longitudinal study with 11 years of follow-up on survival in the oldest-old Danes, Soerensen et al. [42] have shown that rs705649 SNP in DNA repair protein XRCC5, which is the human ortholog of the ku80 gene, is associated with mortality in late life. ...
Despite a growing number of studies on longevity in Drosophila, genetic factors influencing lifespan are still poorly understood. In this paper we propose a conceptually new approach for the identification of novel longevity-associated genes and potential target genes for SNPs in non-coding regions by utilizing the knowledge of co-location of various loci, governed by the three-dimensional architecture of the Drosophila genome. Firstly, we created networks between genes/genomic regions harboring SNPs deemed to be significant in two longevity GWAS summary statistics datasets using intra- and inter-chromosomal interaction frequencies (Hi-C data) as a measure of co-location. These networks were further extended to include regions strongly interacting with previously selected regions. Using various network measures, literature search and additional bioinformatics resources, we investigated the plausibility of genes found to have genuine association with longevity. Several of the newly identified genes were common between the two GWAS datasets and these possessed human orthologs. We also found that the proportion of non-coding SNPs in borders between topologically associated domains is significantly higher than expected by chance. Assuming co-location, we investigated potential target genes for non-coding SNPs. This approach therefore offers a stepping stone to identification of novel genes and SNP targets linked to human longevity.
... Another gene that is associated to human longevity in various population is the forkhead box O3A (FOXO3A) gene, which play an important role in the insulin/insulin growth factor 1 (IGF-1) signaling pathway. Some studies have shown that polymorphisms in the insulin growth factor-1 (IGF-1) signaling pathway genes may influence human aging and longevity (Albani et al. 2011;Soerensen et al. 2012). Similarly, the presence of SNPs in FOXO3A gene has been strongly associated to longevity and resulted also correlated with several phenotypes of healthy aging (Willcox et al. 2008;Anselmi et al. 2009;Flachsbart et al. 2009). ...
Longevity is mainly conditioned by genetic, epigenetic and environmental factors. Different genetic modifications seem to be positively associated to longevity, including SNPs in SIRT1, APOE, FOXO3A, ACE, ATM, NOS1 and NOS2 gene. Epigenetic changes as DNA hyper- and hypo-methylation influence significantly human longevity by activating/deactivating different genes involved in physiological mechanisms. Several studies have confirmed that centenarians have a lower DNA methylation content compared to young subjects, which showed more homogeneously methylated DNA region. Also the up-regulation of miR-21 seems to be more associated with longevity in different populations of long-lived subjects, suggesting its role as potential epigenetic biomarkers. A non-pharmacological treatment that seems to contrast age-related diseases and promote longevity is represented by dietary intervention. It has been evaluated the effects of dietary restriction of both single nutrients or total calories to extend lifespan. However, in daily practice it is very difficult to guarantee adherence/compliance of the subjects to dietary restriction and at the same time avoid dangerous nutritional deficiencies. As consequence, the attention has focused on a variety of substances both drugs and natural compounds able to mime the beneficial effects of caloric restriction, including resveratrol, quercetin, rapamycin, metformin and 2-deoxy-d-glucose.
... The SNP rs9315202 has not previously been described in the literature, but is in complete or high LD with other SNPs (which are not included on this genotyping chip) which have been identified in prior longevity-related studies. The literature suggests that rs1207362, which is in high LD with our peak SNP (r 2 = 0.93, D' = 1.0) was associated with longevity in a highly aged sample (Soerensen et al., 2012). Few studies have comprehensively studied the landscape of KL variants in association with multiple age-related phenotypes or in interaction with environmental stressors and our results highlight the importance of doing so. ...
Background. Longevity gene klotho (KL) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined KL and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging.
Methods. The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (n = 252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; n = 185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips.
Results. In gene by environment analyses, two KL variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected p = .044) and sleep disturbance (peak corrected p = .034) to predict advanced epigenetic age. KL variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected p = .048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (p = .046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (p = .049), and white matter microstructural integrity in two tracts (corrected ps = .005 - .035). This SNP evidenced a main effect with an index of metabolic syndrome severity (p = .015). Effects were generally accentuated in older subjects.
Conclusions. Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. KL genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.
... Interestingly, we also found in tortoises a short deletion in the coding region of IGF2R that results in the loss of two amino acids. The fact that IGF2R variants have been associated with human longevity 53 opens the possibility that the variant found in tortoises could also contribute to increasing the lifespan of these long-lived animals. ...
Giant tortoises are among the longest-lived vertebrate animals and, as such, provide an excellent model to study traits like longevity and age-related diseases. However, genomic and molecular evolutionary information on giant tortoises is scarce. Here, we describe a global analysis of the genomes of Lonesome George—the iconic last member of Chelonoidis abingdonii—and the Aldabra giant tortoise (Aldabrachelys gigantea). Comparison of these genomes with those of related species, using both unsupervised and supervised analyses, led us to detect lineage-specific variants affecting DNA repair genes, inflammatory mediators and genes related to cancer development. Our study also hints at specific evolutionary strategies linked to increased lifespan, and expands our understanding of the genomic determinants of ageing. These new genome sequences also provide important resources to help the efforts for restoration of giant tortoise populations.
... Furthermore, joint roles of genetic variants and phenotypes in longevity have been suggested to improve our understanding on aging and longevity [48]. Pathway-based candidate gene studies have been performed to encompass their molecular and biological networks in longevity [118][119][120][121]. However, their roles in longevity remain controversial. ...
Aged population is increasing worldwide due to the aging process that is inevitable. Accordingly, longevity and healthy aging have been spotlighted to promote social contribution of aged population. Many studies in the past few decades have reported the process of aging and longevity, emphasizing the importance of maintaining genomic stability in exceptionally long-lived population. Underlying reason of longevity remains unclear due to its complexity involving multiple factors. With advances in sequencing technology and human genome-associated approaches, studies based on population-based genomic studies are increasing. In this review, we summarize recent longevity and healthy aging studies of human population focusing on DNA repair as a major factor in maintaining genome integrity. To keep pace with recent growth in genomic research, aging- and longevity-associated genomic databases are also briefly introduced. To suggest novel approaches to investigate longevity-associated genetic variants related to DNA repair using genomic databases, gene set analysis was conducted, focusing on DNA repair- and longevity-associated genes. Their biological networks were additionally analyzed to grasp major factors containing genetic variants of human longevity and healthy aging in DNA repair mechanisms. In summary, this review emphasizes DNA repair activity in human longevity and suggests approach to conduct DNA repair-associated genomic study on human healthy aging.
... 6 El componente genético que está en la base de la mayor concordancia del fenotipo longevo entre hermanos que entre cónyuges ha sido ampliamente estudiado, pero en los estudios de genes candidatos, basados en estudios de asociación; hasta el presente, la mayoría de los datos apuntan a vías específicas, no solamente a nuevos loci puntuales de longevidad, si bien existen dificultades para replicar los hallazgos de los estudios de asociación, con independencia de la población estudiada, y persisten dificultades para identificar polimorfismos de longevidad universales. 7 El gen AKT1 ha sido considerado como un posible candidato funcional, además de APOE y FOX3, y se ha encontrado asociación en varios estudios, aunque una evaluación en nonagenarios y centenarios daneses y alemanes no confirmaron esta asociación; por ello, no puede decirse que sea un gen universal asociado a la longevidad. Se planteó la existencia de clúster de genes para la longevidad, se rastrearon las regiones cromosómicas de 6p y 11 p, en busca de genes candidatos para la longevidad, y se encontraron tres genes (TNFalpha, TNFbeta, HSP70.1) ...
Introducción: la longevidad humana es un fenotipo de determinación compleja donde están implicados factores genéticos y ambientales, no completamente comprendidos.Objetivos: determinar la heredabilidad de la longevidad en un grupo de familias de excepcional larga vida.Métodos: con el objetivo de estudiar la epidemiología genética de la longevidad, se confeccionó el árbol genealógico a 340 longevos procedentes de familias de excepcional larga vida de Villa Clara; se analizó la concordancia del fenotipo en hermanos y cónyuges, la correlación del fenotipo mediante coeficiente de correlación de Pearson en 2 125 parejas de hermanos, evaluadas según sexo, y en 302 parejas longevo-cónyuge. La heredabilidad fue determinada en sentido estrecho, sobre la base de la correlación intraclase entre hermanos y de la correlación entre cónyuges.Resultados: el fenotipo tuvo elevada concordancia entre hermanos del probando, superior a la encontrada entre los cónyuges; la heredabilidad, en un diseño que considera parejas que incluyen el probando, fue de 0,35. En el diseño que utilizó a todas las parejas independientes de hermanos, donde se excluyó el probando, la heredabilidad fue de 0,39 para familias con probando masculino y de 0,58 para familias de probandos femeninos.Conclusiones: la heredabilidad moderada muestra el incremento de años vividos, como un genotipo de determinación continua. La concordancia elevada para la longevidad entre los esposos, sin que existiera parentesco entre ellos, indica que el componente ambiental del fenotipo no es insignificante.
... Moreover, genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar disorder patients (via haplotype association and a gene test with wide significance of permutation testing for all markers genotyped IGF-1) implicate IGF-1 as a candidate gene that causes genetic susceptibility to this psychiatric disease [112] . The study of IGF-I genetic variation in GH/IGF-1/insulin signaling pathway has demonstrated a potentially new human longevity loci [127] . We need to underline that there is a strong relation between genetics, signal transduction pathway, and metabolism. ...
Certain specific antigens, which behave as oncoproteins, are present in normal fetal/neonatal developing brain. It was demonstrated that a convergence exists between ontogenesis and onco-genesis. The most malignant example of central nervous system neoplasia is glioblastoma multiforme. The biomarker – oncoprotein - characteristic of glial fetal and tumoral cells, but not neuronal cells, is IGF-I. For this reason, for therapy purpose, the arrest of IGF-I synthesis in cancer glial cells of glioblastoma was performed using in vitro anti – gene anti IGF-I strategy (IGF-I antisense /triple helix, AS/TH). The created AS/TH cells, became immunogenic and expressed MHC-I, B71 antigens. The AS/TH cells while injected in glioblastoma patients, induced the antitumor immune response and stopped the progression of tumor development. The survival of treated glioblastoma patients reached 2 years, and in some cases, up to 3-4 years. The established Anti - Gene IGF-I cancer immunotherapy was introduced in USA, Europe, China and Latin America.
... Moreover, genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar disorder patients (via haplotype association and a gene test with wide significance of permutation testing for all markers genotyped IGF-1) implicate IGF-1 as a candidate gene that causes genetic susceptibility to this psychiatric disease [112] . The study of IGF-I genetic variation in GH/IGF-1/insulin signaling pathway has demonstrated a potentially new human longevity loci [127] . We need to underline that there is a strong relation between genetics, signal transduction pathway, and metabolism. ...
Certain specific antigens, which behave as oncoproteins, are present in normal fetal/neonatal developing brain. It was demonstrated that a convergence exists between ontogenesis and onco-genesis. The most malignant example of central nervous system neoplasia is glioblastoma multiforme. The biomarker – oncoprotein - characteristic of glial fetal and tumoral cells, but not neuronal cells, is IGF-I. For this reason, for therapy purpose, the arrest of IGF-I synthesis in cancer glial cells of glioblastoma was performed using in vitro anti – gene anti IGF-I strategy (IGF-I antisense /triple helix, AS/TH). The created AS/TH cells, became immunogenic and expressed MHC-I, B71 antigens. The AS/TH cells while injected in glioblastoma patients, induced the antitumor immune response and stopped the progression of tumor development. The survival of treated glioblastoma patients reached 2 years, and in some cases, up to 3-4 years. The established Anti - Gene IGF-I cancer immunotherapy was introduced in USA, Europe, China and Latin America.
... Moreover, genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar disorder patients (via haplotype association and a gene test with wide significance of permutation testing for all markers genotyped IGF-1) implicate IGF-1 as a candidate gene that causes genetic susceptibility to this psychiatric disease [112] . The study of IGF-I genetic variation in GH/IGF-1/insulin signaling pathway has demonstrated a potentially new human longevity loci [127] . We need to underline that there is a strong relation between genetics, signal transduction pathway, and metabolism. ...
Certain specific antigens, which behave as oncoproteins, are present in normal fetal/neonatal developing brain. It was demonstrated that a convergence exists between ontogenesis and onco-genesis. The most malignant example of central nervous system neoplasia is glioblastoma multiforme. The biomarker – oncoprotein - characteristic of glial fetal and tumoral cells, but not neuronal cells, is IGF-I. For this reason, for therapy purpose, the arrest of IGF-I synthesis in cancer glial cells of glioblastoma was performed using in vitro anti – gene anti IGF-I strategy (IGF-I antisense /triple helix, AS/TH). The created AS/TH cells, became immunogenic and expressed MHC-I, B71 antigens. The AS/TH cells while injected in glioblastoma patients, induced the antitumor immune response and stopped the progression of tumor development. The survival of treated glioblastoma patients reached 2 years, and in some cases, up to 3-4 years. The established Anti - Gene IGF-I cancer immunotherapy was introduced in USA, Europe, China and Latin America.
... To date, different analytic approaches were proposed, from PLINK set-based test, to Global test, GRASS, SNP ratio test and competitive gene-set enrichment analysis (GSEA), all suitable for studying gene-gene interactions in complex traits Deelen et al, 2013;Debrabant et al, 2014). Their application confirms the relevance of conserved mechanisms along the evolutionary scale, previously indicated also by univariate analysis, such as DNA repair (Debrabant et al, 2014), telomere maintenance (Atzmon et al, 2010;Soerensen et al, 2012a;Crocco et al, 2015), stress response (Altomare et al, 2003;Ross et al, 2003;Rose et al, 2011), nutrient-sensing signaling, and regulation of gene transcription mechanisms, like IGF-1/insulin axis (Soerensen et al, 2012b), TOR (target of rapamycin) pathway , MAPK (Mitogen-Activated Protein Kinase) and calcium signalling pathways; in addition, the analysis of sub-processes allows to discriminate pathways with epistatic effects, responsible for the association with longevity, (like INS/IGF-1 signalling, found in Deelen et al, 2013) from others where one master gene can concentrate the effect (as POT1 in the telomere maintenance pathway) . Particularly interesting is the observation that many of these pathways, like immunity, stress response or xenobiotic metabolism, have homeostatic functions and answer to different kind of environmental stimuli (Zeng et al, 2016). ...
Approximately one-quarter of the variation in lifespan in developed countries can be attributed to genetic factors. However, even large population based studies investigating genetic influence on human lifespan have been disappointing, identifying only a few genes accounting for genetic susceptibility to longevity. Some environmental and lifestyle determinants associated with longevity have been identified, which interplay with genetic factors in an intricate way. The study of gene-environment and gene-gene interactions can significantly improve our chance to disentangle this complex scenario. In this review, we first describe the most recent approaches for genetic studies of longevity, from those enriched with health parameters and frailty measures to pathway-based and SNP-SNP interaction analyses. Then, we go deeper into the concept of "environmental influences" in human aging and longevity, focusing on the contribution of life style changes, social and cultural influences, as important determinants of survival differences among individuals in a population. Finally, we discuss the contribution of the microbiome in human longevity, as an example of complex interaction between organism and environment. In conclusion, evidences collected from the latest studies on human longevity provide a support for the collection of life-long genetic and environmental/lifestyle variables with beneficial or detrimental effects on health, to improve our understanding of the determinants of human lifespan.
... Moreover, genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar disorder patients (via haplotype association and a gene test with wide significance of permutation testing for all markers genotyped IGF-1) implicate IGF-1 as a candidate gene that causes genetic susceptibility to this psychiatric disease [112] . The study of IGF-I genetic variation in GH/IGF-1/insulin signaling pathway has demonstrated a potentially new human longevity loci [127] . We need to underline that there is a strong relation between genetics, signal transduction pathway, and metabolism. ...
p>As we have come to know, there is a connection between cancer biomarkers and genes, along with their susceptibility to a particular disease, all of which have an obvious impact on the clinical practice and development of genetic testing. In any cancer disease, the diagnosis and treatment should be related to the investigation of specific biomarkers (generally antigens and proteins) and their corresponding genes. The study of different antigens such as alpha-fetoprotein, insulin-like growth factor I (IGF-I), insulin-like growth factor II, vascular endothelial growth factor, and epidermal growth factor, as well as their presence in neoplastic cells have demonstrated that IGF-I is an essential target for gene testing and therapeutic purpose. An over-expression of the IGF-I gene in mature tissues is a sign of neoplastic processes , e.g. brain or breast malignancy. A lot of questions have arisen regarding the ethics of gene testing, particularly concerns on the selection of patients for specific growth hormone/insulin-like growth factor I (GHIIGF-I) testing. Evidently, our current society is involved in a process of geneticization – the redefinition of individuals in terms of genetic codes. As such, we should take extreme care when making ethical judgments based on “scientific evidence” derived from genetic testing (typically those involving different biomarkers such as DNA, RNA, chromosomes, and proteins) in relation to genetic abnormalities that could predict current or future diseases. In this situation, the understanding of bioethics is of utmost importance.</p
... In addition to variations of mitochondrial and nuclear DNA, also the composition of gut microbiome has been suggested to play an important role for longevity [3]. Variations of nuclear DNA that have been postulated to be associated with aging phenotypes include polymorphisms of genes encoding proteins of the immune system [4], the DNA repair system, particularly variations affecting telomere length [5,6], metabolism [7,8], and variations associated with the onset of age-related diseases such as atherosclerosis resulting in cardiovascular diseases (CVD), diabetes mellitus, Alzheimer Disease, and cancer [9]. ...
Background
The cholesteryl ester transfer protein (CETP) polymorphism I405V has been suggested to be involved in longevity and susceptibility to cardiovascular diseases. An enhanced reverse cholesterol transport due to enhanced HDL levels has been hypothesized to be the underlying mechanism. However, clinical trials with HDL-enhancing drugs failed to show beneficial effects. Consequently, it has been postulated that genetic variations enhancing HDL levels are cardioprotective only if they also decrease LDL levels.
Methods
A cross-sectional study was conducted to genotype 1028 healthy blood donors and 1517 clinically well characterized elderly for CETP I405V.
Results
We could not find any association of this polymorphism with age for both, males or females, in any of these cohorts (P = 0.71 and P = 0.57, respectively, for males and P = 0.55 and P = 0.88, respectively, for females). In addition, no association with cardiovascular diseases could be observed in the elderly cohort (males OR = 1.12 and females OR = 0.88). In the same cohort, the CETP V405V genotype was associated with significantly enhanced HDL levels (P = 0.03), mostly owing to the female sex (P = 0.46 for males, P = 0.02 for females), whereas LDL and triglyceride levels were unchanged (P = 0.62 and P = 0.18, respectively).
Conclusion
Our data support the recent hypothesis that variations enhancing HDL levels without affecting LDL levels are not associated with the risk for cardiovascular diseases.
... The diversity in life history across species indicates that it has a strong genetic basis. Several genetic pathways have been found in animals that regulate survival and fertility, including the signalling cascade of growth hormone (GH), insulinlike growth factor 1 (IGF1), and insulin, signalling by target of rapamycin (TOR), DNA repair mechanisms, immune regulation, and telomere maintenance [3,4]. These pathways have been discovered mostly in studies on mutant animal models, but likely contribute to variation in survival and fertility in wild-type animals as well [5,6]. ...
Human survival probability and fertility decline strongly with age. These life history traits have been shaped by evolution. However, research has failed to uncover a consistent genetic determination of variation in survival and fertility. As an explanation, such genetic determinants have been selected in adverse environments, in which humans have lived during most of their history, but are almost exclusively studied in populations in modern affluent environments. Here, we present a large-scale candidate gene association study in a rural African population living in an adverse environment. In 4387 individuals, we studied 4052 SNPs in 148 genes that have previously been identified as possible determinants of survival or fertility in animals or humans. We studied their associations with survival comparing newborns, middle-age adults, and old individuals. In women, we assessed their associations with reported and observed numbers of children. We found no statistically significant associations of these SNPs with survival between the three age groups nor with women's reported and observed fertility. Population stratification was unlikely to explain these results. Apart from a lack of power, we hypothesise that genetic heterogeneity of complex phenotypes and gene-environment interactions prevent the identification of genetic variants explaining variation in survival and fertility in humans.
... The underlying mechanism in many artificial selection experiments on complex traits such as life span, growth rate, and body size is changes in allele frequencies of IIS network components. For example, genetic variation in the IIS network explains considerable variation in the body size among dog breeds, cattle musculature, and has been associated with human longevity (Pereira et al. 2005;Soerensen et al. 2012;Rimbault et al. 2013). Among chicken breeds, genetic variation in IGF1 and IGF2 genes has been associated with body weight, body composition, and egg production (Wang et al. 2005;Yan et al. 2015). ...
The insulin and insulin-like signaling (IIS) molecular network regulates cellular growth and division, and influences organismal
metabolism, growth and development, reproduction, and lifespan. As a group, reptiles have incredible diversity in the complex
life history traits that have been associated with the IIS network, yet the research on the IIS network in ectothermic reptiles
is sparse. Here, we review the IIS network and synthesize what is known about the function and evolution of the IIS network
in ectothermic reptiles. The primary hormones of this network—the insulin-like growth factors 1 and 2 (IGFs) likely function
in reproduction in ectothermic reptiles, but the precise mechanisms are unclear, and likely range from influencing mating
and ovulation to maternal investment in embryonic development. In general, plasma levels of IGF1 increase with food intake
in ectothermic reptiles, but the magnitude of the response to food varies across species or populations and the ages of animals.
Long-term temperature treatments as well as thermal stress can alter expression of genes within the IIS network. Although
relatively little work has been done on IGF2 in ectothermic reptiles, IGF2 is consistently expressed at higher levels than IGF1 in juvenile ectothermic reptiles. Furthermore, in contrast to mammals that have genetic imprinting that silences the maternal
IGF2 allele, in reptiles IGF2 is bi-allelically expressed (based on findings in chickens, a snake, and a lizard). Evolutionary analyses indicate some members
of the IIS network are rapidly evolving across reptile species, including IGF1, insulin (INS), and their receptors. In particular,
IGF1 displays extensive nucleotide variation across lizards and snakes, which suggests that its functional role may vary across
this group. In addition, genetic variation across families and populations in the response of the IIS network to environmental
conditions illustrates that components of this network may be evolving in natural populations. The diversity in reproductive
physiology, metabolic plasticity, and lifespan among reptiles makes the study of the IIS network in this group a potentially
rich avenue for insight into the evolution and function of this network. The field would benefit from future studies that
discern the respective functions of IGF1 and IGF2 and how these functions vary across taxa, perfecting additional assays for
measuring IIS components, and determining the role of IIS in different tissues.
Metabolic intermediates serve as precursors for bioactive molecule synthesis, the energy source for life activities, and signals for environmental adaptation. Ketone bodies are important metabolic intermediates produced in the liver by the degradation of fatty acids, acting as an alternative energy source for extrahepatic tissues when glucose is short in supply (especially during starvation). β-hydroxybutyric acid, with its conjugate base β-hydroxybutyrate, constitutes approximately 70% of ketone bodies. A growing number of studies have demonstrated the beneficial effects of β-hydroxybutyrate, especially in delaying aging, intervening in aging-related disease, and promoting longevity. This review systematically reviews the role of β-hydroxybutyrate in aging hallmarks, shedding light on the possible molecular mechanism by which β-hydroxybutyrate supports healthy aging. Higher circulating β-hydroxybutyrate can be achieved by lifestyle modification (ketogenic diet or caloric restriction) or exogenous β-hydroxybutyrate (or β-hydroxybutyrate precursors, derivates and agonists) supplementation. We will also discuss the pros and cons of different ways to upregulate β-hydroxybutyrate, emphasizing the promising future clinical use of poly-β-hydroxybutyrate, the polymers of β-hydroxybutyrate, which can be easily produced via a microbial platform and synthetic biology.
Immune system function changes during aging, but the molecular mechanisms of this phenomenon are not fully understood. The present study identified pathways that are associated with age-associated changes in human B lymphocytes. Initial in silico analysis of 1355 genes involved in aging revealed the strongest association (p = 4.36E-21) with the gonadotropin-releasing hormone receptor (GnRHR) pathway. Extended analysis of 2736 aging-related genes using updated databases confirmed such association (p = 2.41E-16). Genes involved in both aging and the GnRHR pathway were significantly involved in lymphocyte B and T activation and aging-related phenotypes, including hyperinsulinemia and diabetes, arthritis, cerebrovascular disease, and cancers. We, therefore, examined non-tumorigenic Epstein-Barr virus (EBV)-transformed B-lymphocyte cell lines that originated from 12 young subjects (20–31 years old) and 10 centenarians (100–102 years old). Gonadotropin-releasing hormone I (GnRH-I) and GnRHR levels did not depend on the age of the cell donors. Inhibition of the GnRHR pathway age-independently decreased cell proliferation (p < 0.001) and increased apoptosis (p < 0.001). However, the decrease in immunoglobulin G synthesis (p < 0.01) was twice as high in centenarian cells than in young cells.
In conclusion, the GnRHR pathway regulated essential properties of B lymphocytes. However, upon EBV transformation, memory class-switched B cells became the dominant cell subpopulation. Therefore, the observed effects of GnRHR inhibition were attributable to this subpopulation.
Early-life telomere length (TL) is associated with fitness in a range of organisms. Little is known about the genetic basis of variation in TL in wild animal populations, but to understand the evolutionary and ecological significance of TL it is important to quantify the relative importance of genetic and environmental variation in TL. In this study, we measured TL in 2746 house sparrow nestlings sampled across 20 years and used an animal model to show that there is a small heritable component of early-life TL (h2=0.04), but with a strong component of maternal inheritance. Variation in TL among individuals was mainly driven by environmental (year) variance, but also brood and parental effects. We did not find evidence for a negative genetic correlation underlying the observed negative phenotypic correlation between TL and structural body size. Thus, TL may evolve independently of body size and the negative phenotypic correlation is likely to be caused by non-genetic environmental effects. We further used genome‐wide association analysis to identify genomic regions associated with TL variation. We identified several putative genes underlying TL variation; these have been inferred to be involved in oxidative stress, cellular growth, skeletal development, cell differentiation and tumorigenesis in other species. Together, our results show that TL is a lowly heritable, polygenic trait which is strongly affected by environmental conditions in a free-living bird.
The study of the underpinnings of ageing provides insight not only into the kinds of genetic factors that influence the ageing process, but also into the physiological mechanisms influencing ageing and longevity. Notions that ageing was necessary to create living space for future generations, or to facilitate turnover of the population, are generally unsound. Instead, ageing is thought to have its evolutionary origins in how the force of natural selection declines with age, the later portions of the lifespan being under indirect evolutionary control. The most widely supported explanation of why organisms age is the disposable soma theory. This posits that, under pressure of selection to make the best use of available resources, genomes evolved to put only enough effort into cellular maintenance to keep the individual in sound condition through the period that it might normally have been expected to survive and reproduce in ancestral, wild environments.
We present a list of basic functions to ensure viability of living systems and highlight the roles that telomerase plays. Telomere length is an intrinsic determinant of cellular and perhaps organismal lifespan. The limitation of DNA polymerases in replicating the end of linear replication is partly taken care of by addition of hexanucleotide repeats at the end of the template strands by telomerase reverse transcriptase. Interaction of telomerase with other cellular molecules enables it to perform several extra-curricular functions. It is essential for dividing cells such as those of developing embryo, activated immune cells, activated stem cells, and cancerous cells, to have active telomerase in them. Telomere length is a qualifying feature to monitor cellular health and let it proceed along cell cycle, and hence telomerase takes the center stage and communicates with diverse cellular phenomena involving key regulators like transforming growth factor B, translationally controlled tumor protein, survivin, and p53. It is an anti-apoptotic factor and promotes cell survival. It also influences redox homoeostasis of cells. Genetic and environmental factors influencing telomerase expression can influence the aging process. We also comment on the relevance of telomerase as a therapeutic target in cancers that necessarily depend on maintenance of telomere length.
Ageing can be defined as the age-progressive decline in intrinsic physiological function, leading to an increase in age-specific mortality rate. To date, the mechanisms responsible for natural variation in lifespan and the evolution of longevity are poorly understood, especially in vertebrates. A major limitation is given by the lack of suitable experimental models for ageing studies in terms of limited survival and genetic manageability. Nothobranchius furzeri is an African annual fish known to be actually the shortest-lived vertebrate raised in laboratory and validated in the last decade as new promising model for ageing research: its lifespan can be modulated by environmental, pharmacological and dietary manipulations, and it shows most of the major ageing markers described in mammals (SA-beta galactosidase, lipofuscin, brain gliosis, etc.); the genome, the transcriptome and the proteome of this species are actually available, and RNA-seq analysis has shown a strong evolutionary conservation of many age-related gene pathways and patterns of transcripts regulation. Moreover, it is amenable to genetic manipulation and in the last years the CRISPR/Cas9 technology has been developed in this organism. In addition, its short lifespan allows to perform longitudinal studies in a manageable time frame, giving the opportunity to investigate the relationship between non-genetic lifespan variation and individual ageing. For all these reasons, this animal model represents an ideal platform to rapidly assess the impact of genetic manipulations on vertebrate ageing and age-associated pathologies. Nothobranchius furzeri is also a model for evolutionary genetics of ageing: indeed, it has been observed that geographic differences in habitat duration led to the evolution of a different rate of senescence and expression of ageing markers in Nothobranchius species from humid versus arid habitats, and finally a clear example of parallel evolution has been demonstrated for different populations belonging to two evolutionary independent Nothobranchius lineages. Finally, Nothobranchius furzeri strains show genetic differences in captive lifespan and a quantitative trait loci (QTL) approach was applied to map loci responsible for lifespan differences. This approach clearly showed that the basis for interstrain differences in lifespan is polygenic and also suggests that heritability of lifespan is low (as observed in humans). Therefore, this fish can be used to investigate the quantitative genetics of ageing.
ELife digest
As cells live and divide, their genetic material gets damaged. The DNA damage response is a network of proteins that monitor, recognize and fix the damage, which is also called DNA lesions. For example, an enzyme called ATM senses when DNA is broken and then begins a process that will get it repaired, while another enzyme known as SIRT6 participates in the actual mending process.
When organisms get older, the repair machinery becomes less efficient, and the number of DNA lesions and errors increases. The accumulation of DNA damage may cause the ‘symptoms’ of old age – from cancer, to wrinkles and the slowing down of the body’s chemical processes. In fact, individuals with defective ATMs (who thus struggle to repair their DNA) age abnormally fast; conversely, SIRT6 promotes longevity. If declining repair mechanisms cause aging, would boosting the DNA damage response slow down this process?
Chloroquine is a drug used to combat malaria, but it can also enhance the activity of ATM without damaging DNA. Qian, Liu et al. show that chloroquine helps cells remove broken DNA and keep dividing for longer. In animals, the drug increases the lifespan of worms and prolongs the lives of mice who have mutations that make them age quicker.
Qian, Liu et al. also demonstrate that ATM works by chemically altering the pro-longevity enzyme SIRT6. These changes make SIRT6 more stable, and keep it safe from cellular processes that destroy it. In addition, mice that are genetically engineered to lack ATM can survive for longer if they also produce extra SIRT6. These experiments show that enhancing the DNA damage response can slow down aging, thus linking the DNA repair machinery to longevity.
Progeria is a group of rare genetic conditions with inefficient DNA repair; people with progeria age fast and die young. The results by Qian, Liu et al., if confirmed in humans, could provide a new way of treating these diseases.
Studies in invertebrates have led to the identification of a number of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signalling pathways. Examples include the related tyrosine kinase receptors InR (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To investigate whether IGF-1R also controls longevity in mammals, we inactivated the IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null mutants are not viable, we report that Igf1r(+/-) mice live on average 26% longer than their wild-type littermates (P < 0.02). Female Igf1r(+/-) mice live 33% longer than wild-type females (P < 0.001), whereas the equivalent male mice show an increase in lifespan of 16%, which is not statistically significant. Long-lived Igf1r(+/-) mice do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility and reproduction are unaffected. The Igf1r(+/-) mice display greater resistance to oxidative stress, a known determinant of ageing. These results indicate that the IGF-1 receptor may be a central regulator of mammalian lifespan.
The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses – the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferroni-type procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.
In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9340-3) contains supplementary material, which is available to authorized users.
Many epidemiological studies have shown that parents, siblings and offspring of long-lived subjects have a significant survival advantage when compared with the general population. However, how much of this reported advantage is due to common genetic factors or to a shared environment remains to be resolved.We reconstructed 202 families of nonagenarians from a population of southern Italy. To estimate the familiarity of human longevity, we compared survival data of parents and siblings of long-lived subjects to that of appropriate Italian birth cohorts. Then, to estimate the genetic component of longevity while minimizing the variability due to environment factors, we compared the survival functions of nonagenarians' siblings with those of their spouses (intrafamily control group).We found that both parents and siblings of the probands had a significant survival advantage over their Italian birth cohort counterparts. On the other hand, although a substantial survival advantage was observed in male siblings of probands with respect to the male intrafamily control group, female siblings did not show a similar advantage. In addition, we observed that the presence of a male nonagenarians in a family significantly decreased the instant mortality rate throughout lifetime for all the siblings; in the case of a female nonagenarians such an advantage persisted only for her male siblings.The methodological approach used here allowed us to distinguish the effects of environmental and genetic factors on human longevity. Our results suggest that genetic factors in males have a higher impact than in females on attaining longevity.
A set of currently known alleles increasing the risk for coronary artery disease, cancer, and type 2 diabetes as identified by genome-wide association studies was tested for compatibility with human longevity. Here, we show that nonagenarian siblings from long-lived families and singletons older than 85 y of age from the general population carry the same number of disease risk alleles as young controls. Longevity in this study population is not compromised by the cumulative effect of this set of risk alleles for common disease.
Studies of Nordic twins suggest an increased genetic influence on mortality with age. Contrary to this, the heterogeneity hypothesis predicts that the mortality of individuals carrying a 'frail' or 'risky' genotype in a population will approach that of noncarriers with age because of selection pressure. The ApoE ε4 allele is associated with an increased mortality risk, and its effect has been suggested to decrease with age. Here, we investigated the effect of ApoE ε4 allele on survival in a sample of the healthiest and long-lived Danes. The study population comprised Danes born in 1905 and a replicate sample of the 1895 cohort. For the 1905 cohort, a total of 350 carriers and 1256 noncarriers of the ApoE ε4 allele were followed from 1998 until death or end of follow-up. Cox regression models were used for the analysis. Of the 1606 persons with known ApoE ε4 status in 1998, 1546 had died at the end of the 10-year follow-up. Carriers of the ApoE ε4 allele had an increased mortality compared to noncarriers, and the influence of ApoE status on mortality increased in the age interval 92-103. For the covariates sex and independency status, the difference in relative risk of death between groups decreased with advancing age. Our findings of increasing influence of ApoE ε4 allele on mortality with age do not support previous findings of decreased influence ApoE ε4 allele on mortality with age, and alternative models such as the multifactorial threshold models should be considered for understanding the genetic effects on mortality at advanced age.
The results of genome-wide association studies of complex traits, such as life span or age at onset of chronic disease, suggest that such traits are typically affected by a large number of small-effect alleles. Individually such alleles have little predictive values, therefore they were usually excluded from further analyses. The results of our study strongly suggest that the alleles with small individual effects on longevity may jointly influence life span so that the resulting influence can be both substantial and significant. We show that this joint influence can be described by a relatively simple "genetic dose - phenotypic response" relationship.
One of the many debated topics in ageing research is whether progeroid syndromes are really accelerated forms of human ageing. The answer requires a better understanding of the normal ageing process and the molecular pathology underlying these rare diseases. Exciting recent findings regarding a severe human progeria, Hutchinson-Gilford progeria syndrome, have implicated molecular changes that are also linked to normal ageing, such as genome instability, telomere attrition, premature senescence and defective stem cell homeostasis in disease development. These observations, coupled with genetic studies of longevity, lead to a hypothesis whereby progeria syndromes accelerate a subset of the pathological changes that together drive the normal ageing process.
We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study.
The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study.
Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.
Ghrelin is involved in several metabolic and cardiovascular processes. Recent evidence suggests its involvement in blood pressure regulation and hypertension. The aim of the study was to determine associations of single-nucleotide polymorphisms (SNPs) and haplotypes of the ghrelin gene (GHRL) with hypertension and atherosclerotic disease. Six GHRL SNPs (rs27647, rs26802, rs34911341, rs696217, rs4684677 and a -473G/A (with no assigned rsID)) were investigated in a sample of 1143 hypertensive subjects and 1489 controls of Caucasian origin. Both single-locus and haplotype association analyses were performed. In single-locus analyses, only the non-synonymous rs34911341 was associated with hypertension (odds ratio (OR)=1.95 (95% confidence interval (CI): 1.26-3.02), P=0.003). Six common haplotypes with frequency >1% were inferred from the studied GHRL SNPs, and their frequency distribution was significantly different between hypertensive subjects and controls (chi(2)=12.96 with 5 d.f. (degree of freedom), P=0.024). The effect of rs26802 was found to be significantly (P=0.017) modulated by other GHRL SNPs, as its C allele conferred either an increased risk (OR=1.30 (1.08-1.57), P=0.005) or a decreased risk (OR=0.50 (0.23-1.06), P=0.07) of hypertension according to the two different haplotypes on which it can be found. No association of GHRL SNPs or haplotypes with atherosclerotic disease was observed. In conclusion, we observed statistical evidence for association between GHRL SNPs and risk of hypertension.
Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs). To study the role of PON1 in vivo, we created PON1-knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1-knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1-null mice were more susceptible to atherosclerosis than their wild-type littermates.
FOXO1A and FOXO3A are two members of the FoxO family. FOXO3A has recently been linked to human longevity in Japanese, German and Italian populations. Here we tested the genetic contribution
of FOXO1A and FOXO3A to the longevity phenotype in Han Chinese population. Six tagging SNPs from FOXO1A and FOXO3A were selected and genotyped in 1817 centenarians and younger individuals. Two SNPs of FOXO1A were found to be associated with longevity in women (P = 0.01–0.005), whereas all three SNPs of FOXO3A were associated with longevity in both genders (P = 0.005–0.001). One SNP from FOXO1A was found not to be associated with longevity. In haplotype association tests, the OR (95% CI) for haplotypes TTG and CCG
of FOXO1A in association with female longevity were 0.72 (0.58–0.90) and 1.38 (1.08–1.76), P = 0.0033 and 0.0063, respectively. The haplotypes of FOXO3A were associated with longevity in men [GTC: OR (95% CI) = 0.67 (0.51–0.86), P = 0.0014; CGT: OR (95% CI) = 1.48 (1.12–1.94), P = 0.0035] and in women [GTC: OR (95% CI) = 0.75 (0.60–0.94), P = 0.0094; CGT: OR (95% CI) = 1.47 (1.16–1.86), P = 0.0009]. The haplotype association tests were validated by permutation analysis. The association of FOXO1A with female longevity was replicated in 700 centenarians and younger individuals that were sampled geographically different
from the original population. Thus, we demonstrate that, unlike FOXO3A, FOXO1A is more closely associated with human female longevity, suggesting that the genetic contribution to longevity trait may be
affected by genders.
A number of potential candidate genes in a variety of biological pathways have been associated with longevity in model organisms. Many of these genes have human homologs and thus have the potential to provide insights into human longevity. Recently, several studies suggested that FOXO3A functions as a key bridge for various signaling pathways that influence aging and longevity. Interestingly, Willcox and colleagues identified several variants that displayed significant genotype-gender interaction in male human longevity. In particular, a nested case-control study was performed in an ethnic Japanese population in Hawaii, and five candidate longevity genes were chosen based on links to the insulin-insulin-like growth factor-1 (IGF-1) signaling pathway. In the Willcox study, the investigated genetic variations (rs2802292, rs2764264, and rs13217795) within the FOXO3A gene were significantly associated with longevity in male centenarians. We validated the association of FOXO3A polymorphisms with extreme longevity in males from the Southern Italian Centenarian Study. Particularly, rs2802288, a proxy of rs2802292, showed the best allelic association--minor allele frequency (MAF) = 0.49; p = 0.003; odds ratio (OR) = 1.51; 95% confidence interval (CI), 1.15-1.98). Furthermore, we undertook a meta-analysis to explore the significance of rs2802292 association with longevity by combining the association results of the current study and the findings coming from the Willcox et al. investigation. Our data point to a key role of FOXO3A in human longevity and confirm the feasibility of the identification of such genes with centenarian-controls studies. Moreover, we hypothesize the susceptibility to the longevity phenotype may well be the result of complex interactions involving genes and environmental factors but also gender.
In this case-control study with 387 White esophageal patients and 462 White controls matched to cases by age and sex, we evaluated the associations between 13 potential functional polymorphisms in eight major nucleotide excision repair (NER) genes and esophageal cancer risk. In individual single nucleotide polymorphism analysis, after adjustment for multiple comparisons, the heterozygous GT genotype of the ERCC1 3' untranslated region (UTR) was associated with an increased risk, whereas the homozygous variant genotype TT was associated with 60% reduction in risk with an odds ratio (OR) of 0.40 (95% confidence interval [CI] = 0.19-0.86). The heterozygous AG genotype of XPA 5' UTR was at 2.11-fold increased risk (95% CI = 1.33-3.35) and the risk reached 3.10-fold (95% CI = 1.94-4.95) for the homozygous variant GG genotype. These associations were also significant when restricted the analyses in patients with esophageal adenocarcinoma. Further, the CT genotype of the RAD23B Ala249Val was associated with increased esophageal cancer risk (OR = 1.44; 95% CI = 1.05-1.97), whereas the poly-AT-/+ genotype of the XPC intron 9 conferred a decreased risk (OR = 0.71, 95% CI = 0.51-0.97). In joint analysis, individuals carrying 1 (OR = 2.64, 95% CI = 1.57-4.52) and > or = 2 (OR = 2.74, 95% CI = 1.58-4.75) unfavorable genotypes exhibited significantly increased risk for esophageal cancer risk with significant dose-response trend (P for trend = 0.006). The pathway-based risk was more evident in ever smokers, overweight/obese individuals, men and ever drinkers. Our results support the hypothesis that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of esophageal cancer. These findings warrant further replications in different populations.
The human forkhead box O3A gene (FOXO3A) encodes an evolutionarily conserved key regulator of the insulin-IGF1 signaling pathway that is known to influence metabolism and lifespan in model organisms. A recent study described 3 SNPs in the FOXO3A gene that were statistically significantly associated with longevity in a discovery sample of long-lived men of Japanese ancestry [Willcox et al. (2008) Proc Natl Acad Sci USA 105:13987-13992]. However, this finding required replication in an independent population. Here, we have investigated 16 known FOXO3A SNPs in an extensive collection of 1,762 German centenarians/nonagenarians and younger controls and provide evidence that polymorphisms in this gene were indeed associated with the ability to attain exceptional old age. The FOXO3A association was considerably stronger in centenarians than in nonagenarians, highlighting the importance of centenarians for genetic longevity research. Our study extended the initial finding observed in Japanese men to women and indicates that both genders were likely to be equally affected by variation in FOXO3A. Replication in a French centenarian sample generated a trend that supported the previous results. Our findings confirmed the initial discovery in the Japanese sample and indicate FOXO3A as a susceptibility gene for prolonged survival in humans.
We have engaged in an international program designated the Bank On A Cure, which has established DNA banks from multiple cooperative and institutional clinical trials, and a platform for examining the association of genetic variations with disease risk and outcomes in multiple myeloma. We describe the development and content of a novel custom SNP panel that contains 3404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease severity at diagnosis, toxicity, progression or other treatment outcomes. A systematic search of national databases was used to identify non-synonymous coding SNPs and SNPs within transcriptional regulatory regions. To explore SNP associations with PFS we compared SNP profiles of short term (less than 1 year, n = 70) versus long term progression-free survivors (greater than 3 years, n = 73) in two phase III clinical trials.
Quality controls were established, demonstrating an accurate and robust screening panel for genetic variations, and some initial racial comparisons of allelic variation were done. A variety of analytical approaches, including machine learning tools for data mining and recursive partitioning analyses, demonstrated predictive value of the SNP panel in survival. While the entire SNP panel showed genotype predictive association with PFS, some SNP subsets were identified within drug response, cellular signaling and cell cycle genes.
A targeted gene approach was undertaken to develop an SNP panel that can test for associations with clinical outcomes in myeloma. The initial analysis provided some predictive power, demonstrating that genetic variations in the myeloma patient population may influence PFS.
Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.
• gene
• insulin
• healthy aging
• disease
• disability
The aim of this study was to explore, in a large and non-censored twin cohort, the nature (i.e., additive versus non-additive) and magnitude (i.e., heritability) of genetic influences on inter-individual differences in human longevity. The sample comprised all identified and traced non-emigrant like-sex twin pairs born in Denmark during the period 1870-1900 with a zygosity diagnosis and both members of the pairs surviving the age of 15 years. A total of 2872 pairs were included. Age at death was obtained from the Danish Central Person Register, the Danish Cause-of-Death Register and various other registers. The sample was almost non-censored on the date of the last follow-up (May 1, 1994), all but 0.6% had died, leaving a total of 2872 pairs for analysis. Proportions of variance attributable to genetic and environmental factors were assessed from variance-covariance matrices using the structural equation model approach. The most parsimonious explanation of the data was provided by a model that included genetic dominance (non-additive genetic effects caused by interaction within gene loci) and non-shared environmental factors (environmental factors that are individual-specific and not shared in a family). The heritability of longevity was estimated to be 0.26 for males and 0.23 for females. The small sex-difference was caused by a greater impact of non-shared environmental factors in the females. Heritability was found to be constant over the three 10-year birth cohorts included. Thus, longevity seems to be only moderately heritable. The nature of genetic influences on longevity is probably non-additive and environmental influences non-shared. There is no evidence for an impact of shared (family) environment.
A new gene, termed klotho, has been identified that is involved in the suppression of several ageing phenotypes. A defect in klotho gene expression in the mouse results in a syndrome that resembles human ageing, including a short lifespan, infertility, arteriosclerosis, skin atrophy, osteoporosis and emphysema. The gene encodes a membrane protein that shares sequence similarity with the beta-glucosidase enzymes. The klotho gene product may function as part of a signalling pathway that regulates ageing in vivo and morbidity in age-related diseases.
A cause of aging in
Saccharomyces cerevisiae
is the accumulation of extrachromosomal ribosomal DNA circles (ERCs). Introduction of an ERC into young mother cells shortens life span and accelerates the onset of age-associated sterility. It is important to understand the process by which ERCs are generated. Here, we demonstrate that homologous recombination is necessary for ERC formation.
rad52
mutant cells, defective in DNA repair through homologous recombination, do not accumulate ERCs with age, and mutations in other genes of the
RAD52
class have varying effects on ERC formation.
rad52
mutation leads to a progressive delocalization of Sir3p from telomeres to other nuclear sites with age and, surprisingly, shortens life span. We speculate that spontaneous DNA damage, perhaps double-strand breaks, causes lethality in mutants of the
RAD52
class and may be an initial step of aging in wild-type cells.
The purpose of this study was to test the hypothesis that overexpression of glutathione reductase in transgenic Drosophila melanogaster increases resistance to oxidative stress and retards the aging process. Transgenic flies were generated by microinjection and subsequent mobilization of a P element construct containing the genomic glutathione reductase gene of Drosophila, with 4 kb upstream and 1.5 kb downstream of the coding region. Transgenic animals stably overexpressed glutathione reductase by up to 100% throughout adult life and under continuous exposure to 100% oxygen or air. Under hyperoxic conditions, overexpressors had increased longevity, decreased accrual of protein carbonyls, and dramatically increased survival rates after recovery from a semi-lethal dose of 100% oxygen. Under normoxic conditions, overexpression of glutathione reductase had no effect on longevity, protein carbonyl content, reduced glutathione, or glutathione disulfide content, although the total consumption of oxygen was slightly decreased. Glutathione reductase activity does not appear to be a rate-limiting factor in anti-aging defenses under normoxic conditions, but it may become a limiting factor when the level of oxidative stress is elevated.
In population studies of aging, the data on genetic markers are often collected for individuals from different age groups.
The idea of such studies is to identify “longevity” or “frailty” genes by comparing the frequencies of genotypes in the oldest
and in the younger groups of individuals. In this paper we discuss a new approach to the analysis of such data. This approach,
based on the maximum likelihood method, combines data on genetic markers with survival information obtained from standard
demographic life tables. This method allows us to evaluate survival characteristics for individuals carrying respective candidate
genes. It can also be used in the estimation of the effects of allele–area and allele–allele interaction, either in the presence
or absence of hidden heterogeneity. We apply this method to the analysis of Italian data on genetic markers for five autosomal
loci and mitochondrial genomes. Then we discuss basic assumptions used in this analysis and directions of further research.
Gender accounts for important differences in the incidence and prevalence of a variety of age-related diseases. Considering people of far advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In the present investigation, we report data from a nationwide study on Italian centenarians (a total of 1162 subjects), and from two studies on centenarians living in two distinct zones of Italy, i.e., the island of Sardinia (a total of 222 subjects) and the Mantova province (Northern Italy) (a total of 43 subjects). The female/male ratio was about 2:1 in Sardinia, 4:1 in the whole of Italy, and about 7:1 in the Mantova province. Thus, a complex interaction of environmental, historical and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. Gender differences in the health status of centenarians are also reported, and an innovative score method to classify long-lived people in different health categories, according to clinical and functional parameters, is proposed. Our data indicate that not only is this selected group of people, as a whole, highly heterogeneous, but also that a marked gender difference exists, since male centenarians are less heterogeneous and more healthy than female centenarians. Immunological factors regarding the age-related increase in pro-inflammatory status, and the frequency of HLA ancestral haplotypes also show gender differences that likely contribute to the different strategies that men and women seem to follow to achieve longevity. Concerning the different impact of genetic factors on the probability of reaching the extreme limits of the human life-span, emerging evidence (regarding mtDNA haplogroups, Thyrosine Hydroxilase, and IL-6 genes) suggests that female longevity is less dependent on genetics than male longevity, and that female centenarians likely exploited a healthier life-style and more favorable environmental conditions, owing to gender-specific cultural and anthropological characteristics of the Italian society in the last 100 years.
Unlabelled:
We have developed an integrated laboratory information system that allows the flexible handling of pedigree, phenotype and genotype information. Specifically, it includes client applications for an integrated data import from TaqMan typing files, Mendel checking, data export, handling of pedigree and phenotype information and analysis features.
Availability:
The SQL source code, sources and binaries of the client applications (NT and Windows95/98 platforms) and additional documentation are available at http://www.mucosa.de/.
The authors studied nonagenarians, a rapidly growing age group whose cognitive and physical abilities have yet to be investigated systematically.
All Danes born in 1905 were invited to participate in a home-based 2-hour multidimensional interview, including cognitive and physical performance tests and collection of DNA, carried out by lay interviewers. Population-based registers were used to evaluate representativeness.
There were 2,262 participants. A total of 1,632 (72%) gave a DNA sample. Participants and nonparticipants were highly comparable with regard to marital status, institutionalization, and hospitalization patterns, but men and rural area residents were more likely to participate. Six months after the survey began, 7.2% of the participants and 11.8% of the nonparticipants had died.
Despite the known difficulties of conducting surveys among the extremely old, it was possible to conduct a nationwide survey, including collection of DNA, among more than 2,000 fairly nonselected nonagenarians using lay interviewers.
The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.
The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.
Current literature indicates that abrogation of the IGF-I response pathway affects longevity in Caenorhabditis elegans, and that the down-regulation of IGF-I gene expression is associated with an extension of the life span in mice. In this paper we tested the hypothesis that polymorphic variants of IGF-I response pathway genes, namely IGF-IR (IGF-I receptor; G/A, codon 1013), PI3KCB (phosphoinositol 3-kinase; T/C, -359 bp; A/G, -303 bp), IRS-1 (insulin receptor substrate-1; G/A, codon 972), and FOXO1A (T/C, +97347 bp), play a role in systemic IGF-I regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF-IR have low levels of free plasma IGF-I and are more represented among long-lived people. Moreover, genotype combinations at IGF-IR and PI3KCB genes affect free IGF-I plasma levels and longevity. These findings represent the first indication that free IGF-I plasma levels and human longevity are coregulated by an overlapping set of genes, contributing to the hypothesis that the impact of the IGF-I/insulin pathway on longevity is a property that has been evolutionarily conserved throughout the animal kingdom.
Reduced activity of the insulin/insulin-like growth factor signaling (IIS) pathway increases life-span in diverse organisms. We investigated the timing of the effect of reduced IIS on life-span and the role of a potential target tissue, the fat body. We overexpressed dFOXO, a downstream effector of IIS, in the adult Drosophila fat body, which increased life-span and reduced fecundity of females but had no effect on male life-span. The role of FOXO transcription factors and the adipose tissue are therefore evolutionarily conserved in the regulation of aging, and reduction of IIS in the adult is sufficient to mediate its effects on life-span and fecundity.
The antioxidant enzyme paraoxonase 1 (PON1) has previously been suggested to confer protection against coronary heart disease (CHD), one of the main causes of death in the Western world. Two coding polymorphisms, 55M/L and 192Q/R, and a promoter variant, -107C/T, has been extensively studied with respect to susceptibility to CHD. In this study, we have investigated the impact of these three polymorphisms on mortality using a sample of 1932 Danish individuals aged 47-93 years, previously used in gene-longevity studies. A cross-sectional study comparing the genotype distribution of the three polymorphisms separately as well as the haplotype distribution in different age groups did not reveal any difference. However, a longitudinal follow-up study on survival in the same sample indicated that 192RR homozygotes have a poorer survival compared to QQ homozygotes (hazard rate: 1.38, P = 0.04). We hereafter used an independent sample of 541 Danish individuals from the oldest cohort and confirmed the initial findings (hazard rate: 1.38, P = 0.09). In both samples, the effect was most pronounced in women. Using self-reported data on ischemic heart disease to evaluate the impact of the PON 192Q/R polymorphism on susceptibility to CHD, we found only a nonsignificant trend of 192RR homozygosity in women being a risk factor. Our results thus indicates that PON1 192RR homozygosity is associated with increased mortality in women in the second half of life and that this increased mortality is possibly related to CHD severity and survival after CHD rather than susceptibility to development of CHD.
The common approach to the multiplicity problem calls for controlling the familywise error rate (FWER). This approach, though, has faults, and we point out a few. A different approach to problems of multiple significance testing is presented. It calls for controlling the expected proportion of falsely rejected hypotheses — the false discovery rate. This error rate is equivalent to the FWER when all hypotheses are true but is smaller otherwise. Therefore, in problems where the control of the false discovery rate rather than that of the FWER is desired, there is potential for a gain in power. A simple sequential Bonferronitype procedure is proved to control the false discovery rate for independent test statistics, and a simulation study shows that the gain in power is substantial. The use of the new procedure and the appropriateness of the criterion are illustrated with examples.
Nature 464, 504–512 (2010) In this review, the first line of the Figure 2 legend inadvertently states that the arrows depict changes in gene expression. The correct statement is that the arrows depict changes in gene-product activity. In the section entitled ‘Inhibition of respiration’, the second sentence inadvertently states that perhaps increasing respiration extends lifespan for one reason and inhibits it for another.
Werner syndrome (WS) is a progeroid syndrome caused by autosomal recessive null mutations at the WRN locus. The WRN gene encodes a nuclear protein of 180 kD that contains both exonuclease and helicase domains. WS patients develop various forms of arteriosclerosis, particularly atherosclerosis, and medial calcinosis. The most common cause of death in Caucasian subjects with WS is myocardial infarction. Previous studies have identified specific polymorphisms within WRN that may modulate the risk of atherosclerosis. Population studies of the 1074Leu/Phe and 1367Cys/Arg polymorphisms were undertaken to evaluate the role of WRN in atherogenesis. Frequencies of the 1074Leu/Phe polymorphisms in Finnish and Mexican populations revealed an age-dependent decline of 1074Phe/Phe genotype. In Mexican newborns, but not in Finnish newborns, the 1074Leu/Phe and 1367Cys/Arg polymorphisms were in linkage disequilibrium. Among coronary artery disease subjects, there was a tendency for the 1074Phe allele to be associated with coronary stenosis in a gene dose-dependent manner. Furthermore, the 1367Arg/Arg genotype predicted a lower degree of coronary artery occlusion, as measured by NV50, when compared to the 1367Cys/Cys or 1367Cys/Arg genotypes. However, these tendencies did not achieve statistical significance. Samples from Mexican patients with ischemic stroke showed a trend of haplotype frequencies different from that in a control group of Mexican adults. These data support the hypothesis that WRN may mediate not only WS, but may also modulate more common age-related disorders and, perhaps, a basic aging process. Am. J. Med. Genet. 95:374–380, 2000. © 2000 Wiley-Liss, Inc.
The insulin/IGF1 signaling pathways affect lifespan in several model organisms, including worms, flies and mice. To investigate whether common genetic variation in this pathway influences lifespan in humans, we genotyped 291 common variants in 30 genes encoding proteins in the insulin/IGF1 signaling pathway in a cohort of elderly Caucasian women selected from the Study of Osteoporotic Fractures (SOF). The cohort included 293 long-lived cases (lifespan ≥ 92 years (y), mean ± standard deviation (SD) = 95.3 ± 2.2y) and 603 average-lifespan controls (lifespan ≤ 79y, mean = 75.7 ± 2.6y). Variants were selected for genotyping using a haplotype-tagging approach. We found a modest excess of variants nominally associated with longevity. Nominally significant variants were then replicated in two additional Caucasian cohorts including both males and females: the Cardiovascular Health Study and Ashkenazi Jewish Centenarians. An intronic single nucleotide polymorphism in AKT1, rs3803304, was significantly associated with lifespan in a meta-analysis across the three cohorts (OR = 0.78 95%CI = 0.68–0.89, adjusted P = 0.043); two intronic single nucleotide polymorphisms in FOXO3A demonstrated a significant lifespan association among women only (rs1935949, OR = 1.35, 95%CI = 1.15–1.57, adjusted P = 0.0093). These results demonstrate that common variants in several genes in the insulin/IGF1 pathway are associated with human lifespan.
The free radical theory of aging postulates that free radical reactions are responsible for the progressive accumulation of
changes with time associated with or responsible for the ever-increasing likelihood of disease and death that accompanies
advancing age.
Modulation of the normal distribution of deleterious free radical reaction-induced changes throughout the body by genetic
and environmental differences between individuals results in patterns of change, in some sufficiently different from the normal
aging pattern to be recognized as disease. These “free radical” diseases can be classified into three groups in which a given
disorder is mainly due to: 1) genetics, 2) a combination of genetic and environmental factors, and 3) largely to environmental
influences.
The growing number of “free radical” diseases includes the two major causes of death, cancer and atherosclerosis. To illustrate
the role of free radicals in disease a discussion is presented, of cancer, atherosclerosis, essential hypertension, senile
dementia of the Alzheimer’s type, amyloidosis, and the immune deficiency of age.
Dietary intervention in the “free radical” diseases can reasonably be expected to decrease the period of senescence and to
increase by 5 or more years the span of healthy productive life.
Genetic variation in FOXO3A has previously been associated with human longevity. Studies published so far have been case-control studies and hence vulnerable to bias introduced by cohort effects. In this study we extended the previous findings in the cohorts of oldest old Danes (the Danish 1905 cohort, N=1089) and middle-aged Danes (N=736), applying a longitudinal study design as well as the case-control study design. Fifteen SNPs were chosen in order to cover the known common variation in FOXO3A. Comparing SNP frequencies in the oldest old with middle-aged individuals, we found association (after correction for multiple testing) of eight SNPs; 4 (rs13217795, rs2764264, rs479744, and rs9400239) previously reported to be associated with longevity and four novel SNPs (rs12206094, rs13220810, rs7762395, and rs9486902 (corrected P-values 0.001-0.044). Moreover, we found association of the haplotypes TAC and CAC of rs9486902, rs10499051, and rs12206094 (corrected P-values: 0.01-0.03) with longevity. Finally, we here present data applying a longitudinal study design; when using follow-up survival data on the oldest old in a longitudinal analysis, we found no SNPs to remain significant after the correction for multiple testing (Bonferroni correction). Hence, our results support and extent the proposed role of FOXO3A as a candidate longevity gene for survival from younger ages to old age, yet not during old age.
Twin studies have shown that longevity in humans is moderately heritable with a genetic component of 25-32%. Experimental model organisms point to the existence of core survival and anti-ageing pathways that have been conserved throughout evolution. It has been shown that mutations in single genes involved in these pathways can either delay or accelerate the ageing process and that many of these genes and pathways are also present in humans. Here, we performed a targeted investigation of selected genes (i) involved in longevity pathways (insulin receptor/insulin-like growth factor-I signaling and energy metabolism, intracellular signaling, apoptosis and stress response) and (ii) in which mutations lead to genetic perturbations in animal models or human diseases. Altogether, we tested 500 nonsynonymous single nucleotide polymorphisms (SNPs) in 343 candidate genes for association with the longevity phenotype in a German sample comprising about 400 centenarians and an equal number of younger control subjects. Thus, this study presents one of the largest candidate studies in human genetic longevity research conducted to-date. The three top-ranking markers, which are located in the genes DUSP6, NALP1 and PERP, revealed p-values≤0.01 in the allelic case-control comparisons. Although the association signals in Germans were not replicated in an independent French sample, the large number of analysis results is deemed a valuable reference point for further genetic studies.
The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions.
Human longevity is heritable with a genetic component of 25-32%. Variation in genes regulating the levels of somatic maintenance and DNA repair functions is thought to modulate the aging process and to contribute to survival at advanced age. We tested 92 non-synonymous SNPs in 49 DNA repair genes for a possible association with longevity in a sample of 395 German centenarians and 411 controls. The obtained association signal in exonuclease 1 (EXO1) was further investigated by fine mapping and mutation detection, leading to the identification of the functionally relevant SNP rs1776180. Our detailed analyses revealed that the C allele of this promoter SNP is significantly enriched in female centenarians. This finding replicated in 455 female French centenarians and 109 controls. The C allele leads to the loss of a binding site for the basic helix-loop-helix transcription factor E47, resulting in higher EXO1 expression. Thus, we have detected a hitherto undescribed role for E47 as a negative regulator of EXO1 transcription and a genetic variant in the EXO1 promoter that counteracts the E47-mediated repression of the gene. Given the survival advantage that is associated with the C allele of rs1776180, EXO1 can be considered a candidate for a novel longevity-enabling gene.
CDKN2A is a major susceptibility gene for cutaneous malignant melanoma (CMM), but the variable penetrance and clinical manifestations among mutation carriers suggest the existence of modifier factors. The goal of this study was to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations. We genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A+, 9 CDKN2A-) for 1,536 SNPs in 152 genes involved in DNA repair, apoptosis and immune response pathways. We used conditional logistic regression to account for family ascertainment and differences in disease prevalence among families. Pathway- and gene-based permutation analyses were used to assess the risk of CMM associated with genes in the 5 pathways (DNA repair, apoptosis, TNF/NFkappaB, TH1:TH2 and other immune regulation). Our analyses identified some candidate genes such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9 and JAK3 that were associated with CMM risk (p<0.01, gene-based test). After correction for multiple comparisons, IL9 remained significant (Bonferroni p<0.05). The effects of some genes were stronger in CDKN2A-positive families (BCL7A and IL9), while some were stronger in CDKN2A-negative families (BCL2L1). Our findings support the hypothesis that common genetic polymorphisms in DNA repair, apoptosis and immune response pathways may modify the risk of CMM in CMM-prone families with or without CDKN2A mutations.
Avoiding age-related disease until late in life is key to 'successful' ageing. Over 300 genome-wide association study papers have been published. Over 50 variants have already been identified as associated with four key age-related diseases, namely cardiovascular disease, type 2 diabetes, osteoporosis and prostate cancer. We review these findings with reference to pathways linked to ageing, including cell cycle control or cell senescence, oxidative stress, insulin, IGF1 and other endocrine signalling, and inflammation. Many variants are disease specific or of unknown function. Of the remainder, those with functions likely to be relevant to ageing are predominantly in cell cycle control and therefore tissue repair. Three loci associated with two or more age-related diseases have been identified, two apparently related to cell cycle control. The third shared locus (near TERT), may be involved in telomerase activity and is associated with several environmentally caused age-related cancers. These findings challenge current ideas, suggesting large numbers of cell type specific effects, often driven by regulatory rather than coding changes. They also confirm the central role of cell cycle and re-growth as a key pathway underlying the human variation in successful ageing.
Ghrelin exerts a stimulatory effect on appetite and regulates energy homeostasis. Ghrelin gene variants have been shown to be associated with metabolic traits, although there is evidence suggesting linkage and association with obesity and the ghrelin receptor (GHSR). We hypothesized that these genes are good candidates for susceptibility to obesity. Direct sequencing identified 12 ghrelin single-nucleotide polymorphisms (SNPs) and 8 GHSR SNPs. The 10 common SNPs were genotyped in 1,275 obese subjects and in 1,059 subjects from a general population cohort of European origin. In the obesity case-control study, the GHSR SNP rs572169 was found to be associated with obesity (P = 0.007 in additive model, P = 0.001 in dominant model, odds ratio (OR) 1.73, 95% confidence interval (1.23-2.44)). The ghrelin variant, g.A265T (rs4684677), showed an association with obesity (P = 0.009, BMI adjusted for age and sex) in obese families. The ghrelin variant, g.A-604G (rs27647), showed an association with insulin levels at 2-h post-oral glucose tolerance test (OGTT) (P = 0.009) in obese families. We found an association between the eating behavior "overeating" and the GHSR SNP rs2232169 (P = 0.02) in obese subjects. However, none of these associations remained significant when corrected for multiple comparisons. Replication of the nominal associations with obesity could not be confirmed in a German genome-wide association (GWA) study for rs4684677 and rs572169 polymorphisms. Our data suggest that common polymorphisms in ghrelin and its receptor genes are not major contributors to the development of polygenic obesity, although common variants may alter body weight and eating behavior and contribute to insulin resistance, in particular in the context of early-onset obesity.
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.
A mouse model for the nucleotide excision repair disorder Cockayne syndrome (CS) was generated by mimicking a truncation in the CSB(ERCC6) gene of a CS-B patient. CSB-deficient mice exhibit all of the CS repair characteristics: ultraviolet (UV) sensitivity, inactivation of transcription-coupled repair, unaffected global genome repair, and inability to resume RNA synthesis after UV exposure. Other CS features thought to involve the functioning of basal transcription/repair factor TFIIH, such as growth failure and neurologic dysfunction, are present in mild form. In contrast to the human syndrome, CSB-deficient mice show increased susceptibility to skin cancer. Our results demonstrate that transcription-coupled repair of UV-induced cyclobutane pyrimidine dimers contributes to the prevention of carcinogenesis in mice. Further, they suggest that the lack of cancer predisposition in CS patients is attributable to a global genome repair process that in humans is more effective than in rodents.
Diapause, aging, and fat accumulation in Caenorhabditis elegans are regulated by DAF-2, a homolog of mammalian insulin/insulin-like growth factor-I (IGF-I) receptors. We have cloned and characterized a C. elegans gene encoding a new insulin/IGF-like peptide. The gene containing three exons encodes a precursor protein 95 residue long. Although the putative precursor contains a signal peptide, B chain, C peptide, and A chain like the preproinsulin, the mature peptide consists of one polypeptide-like IGF. The predicted tertiary structure seems similar to crystal structure of insulin. Therefore, the peptide may be a hybrid molecule of insulin and IGF. The peptide expression was detected at the embryonic and several larval stages. Disruption of the peptide production led to an extended life span like the daf-2 mutation, suggesting that the peptide should be one of the ligands of the DAF-2. This is the first description of the peptide that mediates animal longevity.
Single-gene mutations that extend lifespan provide valuable tools for the exploration of the molecular basis for age-related changes in cell and tissue function and for the pathophysiology of age-dependent diseases. We show here that mice homozygous for loss-of-function mutations at the Pit1 (Snell dwarf) locus show a >40% increase in mean and maximal longevity on the relatively long-lived (C3H/HeJ x DW/J)F(1) background. Mutant dw(J)/dw animals show delays in age-dependent collagen cross-linking and in six age-sensitive indices of immune system status. These findings thus demonstrate that a single gene can control maximum lifespan and the timing of both cellular and extracellular senescence in a mammal. Pituitary transplantation into dwarf mice does not reverse the lifespan effect, suggesting that the effect is not due to lowered prolactin levels. In contrast, homozygosity for the Ghrhr(lit) mutation, which like the Pit1(dw) mutation lowers plasma growth hormone levels, does lead to a significant increase in longevity. Male Snell dwarf mice, unlike calorically restricted mice, become obese and exhibit proportionately high leptin levels in old age, showing that their exceptional longevity is not simply due to alterations in adiposity per se. Further studies of the Pit1(dw) mutant, and the closely related, long-lived Prop-1(df) (Ames dwarf) mutant, should provide new insights into the hormonal regulation of senescence, longevity, and late life disease.
We tested the hypothesis that an additional effort to increase the response rate would diminish selection bias in a community-based cohort study. In the Leiden 85-plus Study, all subjects of the town of Leiden who had reached their 85th birthday were informed of the study by mail and then asked to participate by telephone. In an additional recruitment stage, those subjects who did not participate directly were visited and personally asked to participate. When these subjects refused, some nonresponse questions were asked. In this way we collected data on the whole source population. Of 691 eligible elderly subjects, 511 subjects (74%) participated directly. Of those who did not participate directly, 88 subjects participated after the additional effort. The response rate increased from 74% to 87%. Compared to the 511 subjects who directly participated, the 88 subjects who entered the study after the additional effort had poorer health and lower survival. The subjects who refused were more healthy and had poorer mood. The direct sample did not differ from the source population with respect to socio-demographics, health, and mortality. In conclusion, we showed that given a moderately high direct response the additional effort was effective in increasing the response rate, but was also selective and was not necessary to prevent selection bias.
T cells accumulate genetic damage over time but nai;ve cells display higher genomic stability and longer lifespan as compared to memory cells. We found in nai;ve and memory T cells from young and elderly subjects that DNA damage in unirradiated cells is higher in memory than in nai;ve T cells, and is increased by radiation in both cell types. Repair of the radiation-induced DNA damage was much higher in nai;ve than in memory T cells from young subjects but null in both cell types from elderly subjects. Molecular mechanisms involved in DNA damage recognition and repair were analyzed in both cell subsets from young subjects. The intracellular distribution and amount of the DNA-dependent protein kinase (DNA-PK) complex components (ku 70, ku 80, DNA-PKcs), which are involved in the recognition and repair of DNA breaks caused by ionizing radiations, V(D)J recombination and isotype switching, was assessed in nai;ve and memory T cells from young subjects. While the expression of ku 70 and ku 80 was at comparable levels in both T cell subsets, DNA-PKcs, phosphorylated ku 80, and DNA-binding of ku 70/80 were mostly evident in nai;ve but negligible or absent in memory T cells. These findings may account for the higher genomic stability and longer lifespan of nai;ve as compared to memory human T cells from young subjects.