Editorial

4 pages, 169 KiB

Open AccessEditorial

Untangling the Genetics of Human Longevity—A Challenging Quest

by Serena Dato, Mette Soerensen and Giuseppina Rose

Genes 2019, 10(8), 585; https://doi.org/10.3390/genes10080585 - 31 Jul 2019

Cited by 4 | Viewed by 3205

Human average life expectancy in developed countries has increased dramatically in the last century, a phenomenon which is potentially accompanied by a significant rise in multi-morbidity and frailty among older individuals [...] Full article

(This article belongs to the Special Issue Genetic Determinants of Human Longevity)

Research

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11 pages, 724 KiB

Open AccessArticle

Inter-Individual Variability in Xenobiotic-Metabolizing Enzymes: Implications for Human Aging and Longevity

by Paolina Crocco, Alberto Montesanto, Serena Dato, Silvana Geracitano, Francesca Iannone, Giuseppe Passarino and Giuseppina Rose

Genes 2019, 10(5), 403; https://doi.org/10.3390/genes10050403 - 27 May 2019

Cited by 16 | Viewed by 3338

Abstract

Xenobiotic-metabolizing enzymes (XME) mediate the body’s response to potentially harmful compounds of exogenous/endogenous origin to which individuals are exposed during their lifetime. Aging adversely affects such responses, making the elderly more susceptible to toxics. Of note, XME genetic variability was found to impact [...] Read more.

Xenobiotic-metabolizing enzymes (XME) mediate the body’s response to potentially harmful compounds of exogenous/endogenous origin to which individuals are exposed during their lifetime. Aging adversely affects such responses, making the elderly more susceptible to toxics. Of note, XME genetic variability was found to impact the ability to cope with xenobiotics and, consequently, disease predisposition. We hypothesized that the variability of these genes influencing the interaction with the exposome could affect the individual chance of becoming long-lived. We tested this hypothesis by screening a cohort of 1112 individuals aged 20–108 years for 35 variants in 23 XME genes. Four variants in different genes (CYP2B6/rs3745274-G/T, CYP3A5/rs776746-G/A, COMT/rs4680-G/A and ABCC2/rs2273697-G/A) differently impacted the longevity phenotype. In particular, the highest impact was observed in the age group 65–89 years, known to have the highest incidence of age-related diseases. In fact, genetic variability of these genes we found to account for 7.7% of the chance to survive beyond the age of 89 years. Results presented herein confirm that XME genes, by mediating the dynamic and the complex gene–environment interactions, can affect the possibility to reach advanced ages, pointing to them as novel genes for future studies on genetic determinants for age-related traits. Full article

(This article belongs to the Special Issue Genetic Determinants of Human Longevity)

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12 pages, 1223 KiB

Open AccessArticle

Exceptional Longevity and Polygenic Risk for Cardiovascular Health

by Mary Revelas, Anbupalam Thalamuthu, Christopher Oldmeadow, Tiffany-Jane Evans, Nicola J. Armstrong, Carlos Riveros, John B. Kwok, Peter R. Schofield, Henry Brodaty, Rodney J. Scott, John R. Attia, Perminder S. Sachdev and Karen A. Mather

Genes 2019, 10(3), 227; https://doi.org/10.3390/genes10030227 - 18 Mar 2019

Cited by 7 | Viewed by 4935

Abstract

Studies investigating exceptionally long-lived (ELL) individuals, including genetic studies, have linked cardiovascular-related pathways, particularly lipid and cholesterol homeostasis, with longevity. This study explored the genetic profiles of ELL individuals (cases: n = 294, 95–106 years; controls: n = 1105, 55–65 years) by assessing [...] Read more.

Studies investigating exceptionally long-lived (ELL) individuals, including genetic studies, have linked cardiovascular-related pathways, particularly lipid and cholesterol homeostasis, with longevity. This study explored the genetic profiles of ELL individuals (cases: n = 294, 95–106 years; controls: n = 1105, 55–65 years) by assessing their polygenic risk scores (PRS) based on a genome wide association study (GWAS) threshold of p < 5 × 10⁻⁵. PRS were constructed using GWAS summary data from two exceptional longevity (EL) analyses and eight cardiovascular-related risk factors (lipids) and disease (myocardial infarction, coronary artery disease, stroke) analyses. A higher genetic risk for exceptional longevity (EL) was significantly associated with longevity in our sample (odds ratio (OR) = 1.19–1.20, p = 0.00804 and 0.00758, respectively). Two cardiovascular health PRS were nominally significant with longevity (HDL cholesterol, triglycerides), with higher PRS associated with EL, but these relationships did not survive correction for multiple testing. In conclusion, ELL individuals did not have significantly lower polygenic risk for the majority of the investigated cardiovascular health traits. Future work in larger cohorts is required to further explore the role of cardiovascular-related genetic variants in EL. Full article

(This article belongs to the Special Issue Genetic Determinants of Human Longevity)

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10 pages, 388 KiB

Open AccessArticle

Lifespans of Twins: Does Zygosity Matter?

by Jacob Hjelmborg, Pia Larsen, Jaakko Kaprio, Matt McGue, Thomas Scheike, Philip Hougaard and Kaare Christensen

Genes 2019, 10(2), 166; https://doi.org/10.3390/genes10020166 - 20 Feb 2019

Cited by 8 | Viewed by 3716

Abstract

Studies with twins provide fundamental insights to lifespans of humans. We aim to clarify if monozygotic and dizygotic twin individuals differ in lifespan, that is, if zygosity matters. We investigate whether a possible difference in mortality after infancy between zygosities is stable in [...] Read more.

Studies with twins provide fundamental insights to lifespans of humans. We aim to clarify if monozygotic and dizygotic twin individuals differ in lifespan, that is, if zygosity matters. We investigate whether a possible difference in mortality after infancy between zygosities is stable in different age cohorts, and whether the difference remains when twins with unknown zygosity are taken into account. Further, we compare the distribution of long-livers, that is, the upper-tail of the lifespan distribution, between monozygotic and same-sex dizygotic twin individuals. The Danish Twin Registry provides a nationwide cohort of 109,303 twins born during 1870 to 1990 with valid vital status. Standard survival analysis is used to compare mortality in monozygotic and dizygotic twin individuals and twin individuals with unknown zygosity. The mortality of monozygotic and dizygotic twin individuals differs slightly after taking into consideration effects of birth- and age-cohorts, gender differences, and that twins are paired. However, no substantial nor systematic differences remain when taking twins with unknown zygosity into account. Further, the distribution of long-livers is very similar by zygosity, suggesting the same mortality process. The population-based and oldest twin cohort ever studied suggests that monozygotic and dizygotic twins have similar lifespans. Full article

(This article belongs to the Special Issue Genetic Determinants of Human Longevity)

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12 pages, 530 KiB

Open AccessArticle

Inositol Polyphosphate Multikinase (IPMK), a Gene Coding for a Potential Moonlighting Protein, Contributes to Human Female Longevity

by Francesco De Rango, Paolina Crocco, Francesca Iannone, Adolfo Saiardi, Giuseppe Passarino, Serena Dato and Giuseppina Rose

Genes 2019, 10(2), 125; https://doi.org/10.3390/genes10020125 - 08 Feb 2019

Cited by 6 | Viewed by 3363

Abstract

Biogerontological research highlighted a complex and dynamic connection between aging, health and longevity, partially determined by genetic factors. Multifunctional proteins with moonlighting features, by integrating different cellular activities in the space and time, may explain part of this complexity. Inositol Polyphosphate Multikinase (IPMK) [...] Read more.

Biogerontological research highlighted a complex and dynamic connection between aging, health and longevity, partially determined by genetic factors. Multifunctional proteins with moonlighting features, by integrating different cellular activities in the space and time, may explain part of this complexity. Inositol Polyphosphate Multikinase (IPMK) is a potential moonlighting protein performing multiple unrelated functions. Initially identified as a key enzyme for inositol phosphates synthesis, small messengers regulating many aspects of cell physiology, IPMK is now implicated in a number of metabolic pathways affecting the aging process. IPMK regulates basic transcription, telomere homeostasis, nutrient-sensing, metabolism and oxidative stress. Here, we tested the hypothesis that the genetic variability of IPMK may affect human longevity. Single-SNP (single nuclear polymorphism), haplotype-based association tests as well as survival analysis pointed to the relevance of six out of fourteen genotyped SNPs for female longevity. In particular, haplotype analysis refined the association highlighting two SNPs, rs2790234 and rs6481383, as major contributing variants for longevity in women. Our work, the first to investigate the association between variants of IPMK and longevity, supports IPMK as a novel gender-specific genetic determinant of human longevity, playing a role in the complex network of genetic factors involved in human survival. Full article

(This article belongs to the Special Issue Genetic Determinants of Human Longevity)

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11 pages, 419 KiB

Open AccessArticle

Analysis of the Association Between TERC and TERT Genetic Variation and Leukocyte Telomere Length and Human Lifespan—A Follow-Up Study

by Daniela Scarabino, Martina Peconi, Franca Pelliccia and Rosa Maria Corbo

Genes 2019, 10(2), 82; https://doi.org/10.3390/genes10020082 - 25 Jan 2019

Cited by 15 | Viewed by 3192

Abstract

We investigated the possible influence of TERC and TERT genetic variation and leukocyte telomere length (LTL) on human lifespan. Four polymorphisms of TERT and three polymorphisms of TERC were examined in a sample of elderly subjects (70–100 years). After nine years of follow-up, [...] Read more.

We investigated the possible influence of TERC and TERT genetic variation and leukocyte telomere length (LTL) on human lifespan. Four polymorphisms of TERT and three polymorphisms of TERC were examined in a sample of elderly subjects (70–100 years). After nine years of follow-up, mortality data were collected, and sub-samples of long-lived/not long-lived were defined. TERT VNTR MNS16A L/L genotype and TERT rs2853691 A/G or G/G genotypes were found to be associated with a significantly higher risk to die before the age of 90 years, and with a significantly lower age at death. The association between lifespan and LTL at baseline was analyzed in a subsample of 163 subjects. Age at baseline was inversely associated with LTL (p < 0.0001). Mean LTL was greater in the subjects still living than in those no longer living at follow-up (0.79 T/S ± 0.09 vs. 0.63 T/S ± 0.08, p < 0.0001). Comparison of age classes showed that, among the 70–79-year-olds, the difference in mean LTL between those still living and those no longer living at follow-up was greater than among the 80–90-year-olds. Our data provide evidence that shorter LTL at baseline may predict a shorter lifespan, but the reliability of LTL as a lifespan biomarker seems to be limited to a specific age (70–79 years). Full article

(This article belongs to the Special Issue Genetic Determinants of Human Longevity)

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Review

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20 pages, 654 KiB

Open AccessReview

Longevity: Lesson from Model Organisms

by Giusi Taormina, Federica Ferrante, Salvatore Vieni, Nello Grassi, Antonio Russo and Mario G. Mirisola

Genes 2019, 10(7), 518; https://doi.org/10.3390/genes10070518 - 09 Jul 2019

Cited by 62 | Viewed by 12178

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Genetic Determinants of Human Longevity)

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28 pages, 1538 KiB

Open AccessReview

The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity

by Paolo Abondio, Marco Sazzini, Paolo Garagnani, Alessio Boattini, Daniela Monti, Claudio Franceschi, Donata Luiselli and Cristina Giuliani

Genes 2019, 10(3), 222; https://doi.org/10.3390/genes10030222 - 15 Mar 2019

Cited by 90 | Viewed by 14805

Abstract

Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of [...] Read more.

Human longevity is a complex phenotype resulting from the combinations of context-dependent gene-environment interactions that require analysis as a dynamic process in a cohesive ecological and evolutionary framework. Genome-wide association (GWAS) and whole-genome sequencing (WGS) studies on centenarians pointed toward the inclusion of the apolipoprotein E (APOE) polymorphisms ε2 and ε4, as implicated in the attainment of extreme longevity, which refers to their effect in age-related Alzheimer’s disease (AD) and cardiovascular disease (CVD). In this case, the available literature on APOE and its involvement in longevity is described according to an anthropological and population genetics perspective. This aims to highlight the evolutionary history of this gene, how its participation in several biological pathways relates to human longevity, and which evolutionary dynamics may have shaped the distribution of APOE haplotypes across the globe. Its potential adaptive role will be described along with implications for the study of longevity in different human groups. This review also presents an updated overview of the worldwide distribution of APOE alleles based on modern day data from public databases and ancient DNA samples retrieved from literature in the attempt to understand the spatial and temporal frame in which present-day patterns of APOE variation evolved. Full article

(This article belongs to the Special Issue Genetic Determinants of Human Longevity)

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