Editorial

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2 pages, 158 KiB

Open AccessEditorial

Genetic and Environmental Factors in Ageing and Age-Related Disease

by Karen A. Mather

Genes 2022, 13(3), 396; https://0-doi-org.brum.beds.ac.uk/10.3390/genes13030396 - 23 Feb 2022

Cited by 2 | Viewed by 1176

Abstract

Globally, the population is growing older [...] Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

Research

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14 pages, 2150 KiB

Open AccessArticle

ALDH2 p.E504K Variation and Sex Are Major Factors Associated with Current and Quitting Alcohol Drinking in Japanese Oldest Old

by Takashi Sasaki, Yoshinori Nishimoto, Takumi Hirata, Yukiko Abe, Toru Takebayashi and Yasumichi Arai

Genes 2021, 12(6), 799; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060799 - 24 May 2021

Cited by 4 | Viewed by 5737

Abstract

This study identified the factors associated with current and quitting alcohol drinking in the Oldest Old to better understand the associated factors and mechanisms underlying drinking behaviors in this age group. Results of a questionnaire for drinking behavior in 1015 Japanese Oldest Old [...] Read more.

This study identified the factors associated with current and quitting alcohol drinking in the Oldest Old to better understand the associated factors and mechanisms underlying drinking behaviors in this age group. Results of a questionnaire for drinking behavior in 1015 Japanese Oldest Old citizens aged 85 to 89 years revealed that 56.0% of men and 24.0% of women were current drinkers. A genome-wide association study revealed that the rs671 G > A variation, which corresponds to the aldehyde dehydrogenase 2 (ALDH2) p.E504K missense variant, was significantly associated with current drinking (odds ratio: 3.8, p = 3.33 × 10⁻³¹). Variable selection with 41 factors and multivariate regression logistic analysis for current drinking indicated that the rs671 genotype and sex were the most significant factors in the Oldest Old. Further analysis revealed that the rs671 genotype, alcohol-associated biomarkers, a history of heart or kidney disease, and frailty score are factors associated with quitting drinking in the Oldest Old men, whereas smoking history, walking time, and depression score were factors associated with quitting drinking in the Oldest Old women. These results indicate that the ALDH2 p.E504K variation is a major factor associated with current and quitting drinking in the Japanese Oldest Old. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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13 pages, 1152 KiB

Open AccessArticle

Investigating Olfactory Gene Variation and Odour Identification in Older Adults

by Siddharth Raj, Anbupalam Thalamuthu, Nicola J Armstrong, Margaret J Wright, John B Kwok, Julian N Trollor, David Ames, Peter R Schofield, Henry Brodaty, Perminder S Sachdev and Karen A Mather

Genes 2021, 12(5), 669; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050669 - 29 Apr 2021

Cited by 4 | Viewed by 3360

Abstract

Ageing is associated with a decrease in odour identification. Additionally, deficits in olfaction have been linked to age-related disease and mortality. Heritability studies suggest genetic variation contributes to olfactory identification. The olfactory receptor (OR) gene family is the largest in the human genome [...] Read more.

Ageing is associated with a decrease in odour identification. Additionally, deficits in olfaction have been linked to age-related disease and mortality. Heritability studies suggest genetic variation contributes to olfactory identification. The olfactory receptor (OR) gene family is the largest in the human genome and responsible for overall odour identification. In this study, we sought to find olfactory gene family variants associated with individual and overall odour identification and to examine the relationships between polygenic risk scores (PRS) for olfactory-related phenotypes and olfaction. Participants were Caucasian older adults from the Sydney Memory and Ageing Study and the Older Australian Twins Study with genome-wide genotyping data (n = 1395, mean age = 75.52 ± 6.45). The Brief-Smell Identification Test (BSIT) was administered in both cohorts. PRS were calculated from independent GWAS summary statistics for Alzheimer’s disease (AD), white matter hyperintensities (WMH), Parkinson’s disease (PD), hippocampal volume and smoking. Associations with olfactory receptor genes (n = 967), previously identified candidate olfaction-related SNPs (n = 36) and different PRS with BSIT scores (total and individual smells) were examined. All of the relationships were analysed using generalised linear mixed models (GLMM), adjusted for age and sex. Genes with suggestive evidence for odour identification were found for 8 of the 12 BSIT items. Thirteen out of 36 candidate SNPs previously identified from the literature were suggestively associated with several individual BSIT items but not total score. PRS for smoking, WMH and PD were negatively associated with chocolate identification. This is the first study to conduct genetic analyses with individual odorant identification, which found suggestive olfactory-related genes and genetic variants for multiple individual BSIT odours. Replication in independent and larger cohorts is needed. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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13 pages, 1594 KiB

Open AccessArticle

APOE Variants in an Iberian Alzheimer Cohort Detected through an Optimized Sanger Sequencing Protocol

by Ricardo D. González, Iva Gomes, Catarina Gomes, Rita Rocha, Luís Durães, Patrícia Sousa, Manuel Figueruelo, Maria Rodríguez, Carmen Pita, Roberto Hornero, Carlos Gómez, Alexandra M. Lopes, Nádia Pinto and Sandra Martins

Genes 2021, 12(1), 4; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010004 - 22 Dec 2020

Cited by 4 | Viewed by 2569

Abstract

The primary genetic risk factor for late onset Alzheimer’s disease (LOAD) is the APOE4 allele of Apolipoprotein E (APOE) gene. The three most common variants of APOE are determined by single nucleotide polymorphisms (SNPs) rs429358 and rs7412. Our aim was to [...] Read more.

The primary genetic risk factor for late onset Alzheimer’s disease (LOAD) is the APOE4 allele of Apolipoprotein E (APOE) gene. The three most common variants of APOE are determined by single nucleotide polymorphisms (SNPs) rs429358 and rs7412. Our aim was to estimate allele and genotype frequencies of APOE variants in an Iberian cohort, thus helping to understand differences in APOE-related LOAD risk observed across populations. We analyzed saliva or buccal swab samples from 229 LOAD patients and 89 healthy elderly controls (≥68 years old) from Northern Portugal and Castile and León region, Spain. The genotyping was performed by Sanger sequencing, optimized to overcome GC content drawbacks. Results obtained in our Iberian LOAD and control cohorts are in line with previous large meta-analyses on APOE frequencies in Caucasian populations; however, we found differences in allele frequencies between our Portuguese and Spanish subgroups of AD patients. Moreover, when comparing studies from Iberian and other Caucasian cohorts, differences in APOE2 and APOE4 frequencies and subsequent different APOE-related LOAD risks must be clarified. These results show the importance of studying genetic variation at the APOE gene in different populations (including analyses at a regional level) to increase our knowledge about its clinical significance. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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12 pages, 1061 KiB

Open AccessArticle

The Reversion of cg05575921 Methylation in Smoking Cessation: A Potential Tool for Incentivizing Healthy Aging

by Robert Philibert, James A. Mills, Jeffrey D. Long, Sue Ellen Salisbury, Alejandro Comellas, Alicia Gerke, Kelsey Dawes, Mark Vander Weg and Eric A. Hoffman

Genes 2020, 11(12), 1415; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121415 - 27 Nov 2020

Cited by 13 | Viewed by 2928

Abstract

Smoking is the largest preventable cause of mortality and the largest environmental driver of epigenetic aging. Contingency management-based strategies can be used to treat smoking but require objective methods of verifying quitting status. Prior studies have suggested that cg05575921 methylation reverts as a [...] Read more.

Smoking is the largest preventable cause of mortality and the largest environmental driver of epigenetic aging. Contingency management-based strategies can be used to treat smoking but require objective methods of verifying quitting status. Prior studies have suggested that cg05575921 methylation reverts as a function of smoking cessation, but that it can be used to verify the success of smoking cessation has not been unequivocally demonstrated. To test whether methylation can be used to verify cessation, we determined monthly cg05575921 levels in a group of 67 self-reported smokers undergoing biochemically monitored contingency management-based smoking cessation therapy, as part of a lung imaging protocol. A total of 20 subjects in this protocol completed three months of cotinine verified smoking cessation. In these 20 quitters, the reversion of cg05575921 methylation was dependent on their initial smoking intensity, with methylation levels in the heaviest smokers reverting to an average of 0.12% per day over the 3-month treatment period. In addition, we found suggestive evidence that some individuals may have embellished their smoking history to gain entry to the study. Given the prominent effect of smoking on longevity, we conclude that DNA methylation may be a useful tool for guiding and incentivizing contingency management-based approaches for smoking cessation. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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Review

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14 pages, 1026 KiB

Open AccessReview

Formaldehyde and De/Methylation in Age-Related Cognitive Impairment

by Ting Li, Yan Wei, Meihua Qu, Lixian Mou, Junye Miao, Mengqi Xi, Ying Liu and Rongqiao He

Genes 2021, 12(6), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060913 - 13 Jun 2021

Cited by 19 | Viewed by 3296

Abstract

Formaldehyde (FA) is a highly reactive substance that is ubiquitous in the environment and is usually considered as a pollutant. In the human body, FA is a product of various metabolic pathways and participates in one-carbon cycle, which provides carbon for the synthesis [...] Read more.

Formaldehyde (FA) is a highly reactive substance that is ubiquitous in the environment and is usually considered as a pollutant. In the human body, FA is a product of various metabolic pathways and participates in one-carbon cycle, which provides carbon for the synthesis and modification of bio-compounds, such as DNA, RNA, and amino acids. Endogenous FA plays a role in epigenetic regulation, especially in the methylation and demethylation of DNA, histones, and RNA. Recently, epigenetic alterations associated with FA dysmetabolism have been considered as one of the important features in age-related cognitive impairment (ARCI), suggesting the potential of using FA as a diagnostic biomarker of ARCI. Notably, FA plays multifaceted roles, and, at certain concentrations, it promotes cell proliferation, enhances memory formation, and elongates life span, effects that could also be involved in the aetiology of ARCI. Further investigation of and the regulation of the epigenetics landscape may provide new insights about the aetiology of ARCI and provide novel therapeutic targets. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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26 pages, 842 KiB

Open AccessReview

Influence of Age on Skeletal Muscle Hypertrophy and Atrophy Signaling: Established Paradigms and Unexpected Links

by Eun-Joo Lee and Ronald L. Neppl

Genes 2021, 12(5), 688; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050688 - 03 May 2021

Cited by 6 | Viewed by 3905

Abstract

Skeletal muscle atrophy in an inevitable occurrence with advancing age, and a consequence of disease including cancer. Muscle atrophy in the elderly is managed by a regimen of resistance exercise and increased protein intake. Understanding the signaling that regulates muscle mass may identify [...] Read more.

Skeletal muscle atrophy in an inevitable occurrence with advancing age, and a consequence of disease including cancer. Muscle atrophy in the elderly is managed by a regimen of resistance exercise and increased protein intake. Understanding the signaling that regulates muscle mass may identify potential therapeutic targets for the prevention and reversal of muscle atrophy in metabolic and neuromuscular diseases. This review covers the major anabolic and catabolic pathways that regulate skeletal muscle mass, with a focus on recent progress and potential new players. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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22 pages, 1426 KiB

Open AccessReview

No Time to Age: Uncoupling Aging from Chronological Time

by Dana Larocca, Jieun Lee, Michael D. West, Ivan Labat and Hal Sternberg

Genes 2021, 12(5), 611; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050611 - 21 Apr 2021

Cited by 10 | Viewed by 12886

Abstract

Multicellular life evolved from simple unicellular organisms that could replicate indefinitely, being essentially ageless. At this point, life split into two fundamentally different cell types: the immortal germline representing an unbroken lineage of cell division with no intrinsic endpoint and the mortal soma, [...] Read more.

Multicellular life evolved from simple unicellular organisms that could replicate indefinitely, being essentially ageless. At this point, life split into two fundamentally different cell types: the immortal germline representing an unbroken lineage of cell division with no intrinsic endpoint and the mortal soma, which ages and dies. In this review, we describe the germline as clock-free and the soma as clock-bound and discuss aging with respect to three DNA-based cellular clocks (telomeric, DNA methylation, and transposable element). The ticking of these clocks corresponds to the stepwise progressive limitation of growth and regeneration of somatic cells that we term somatic restriction. Somatic restriction acts in opposition to strategies that ensure continued germline replication and regeneration. We thus consider the plasticity of aging as a process not fixed to the pace of chronological time but one that can speed up or slow down depending on the rate of intrinsic cellular clocks. We further describe how germline factor reprogramming might be used to slow the rate of aging and potentially reverse it by causing the clocks to tick backward. Therefore, reprogramming may eventually lead to therapeutic strategies to treat degenerative diseases by altering aging itself, the one condition common to us all. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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12 pages, 673 KiB

Open AccessReview

A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing

by Bhabesh Kumar Tripathy, Kavita Pal, Snehal Shabrish and Indraneel Mittra

Genes 2021, 12(2), 163; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020163 - 26 Jan 2021

Cited by 5 | Viewed by 2820

Abstract

It is estimated that 10–50 DNA double-strand breaks (DSBs) occur in a nucleated human cell per cell cycle. We reviewed the present state of knowledge and hypothesized that the currently accepted mechanisms cannot explain such high frequency of DSBs occurring daily under normal [...] Read more.

It is estimated that 10–50 DNA double-strand breaks (DSBs) occur in a nucleated human cell per cell cycle. We reviewed the present state of knowledge and hypothesized that the currently accepted mechanisms cannot explain such high frequency of DSBs occurring daily under normal physiological conditions. We propose an alternative model that implicates illegitimate genomic integration into healthy cells of cell-free chromatin (cfCh) particles released from the billions of cells that die in the body every day. Repeated genomic integration of cfCh may have catastrophic consequences for the cell, such as DSBs, their faulty repair by nonhomologous end joining (NHEJ) followed by apoptosis with release of more cfCh which would integrate into genomes of surrounding cells. This can creates a vicious cycle of cfCh integration, DSBs, NHEJ, and more apoptosis, thereby providing a potential explanation as to why so many billions of cells die in the body on a daily basis. We also recount the recent observation that cfCh integration and the resulting DSBs activate inflammatory cytokines. This leads us to propose that concurrent DSBs and induction of inflammation occurring throughout life may be the underlying cause of ageing, degenerative disorders, and cancer. Finally, we discuss the prospect that agents that can inactivate/degrade cfCh may hold the key to making healthy ageing a realizable goal. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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Other

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7 pages, 770 KiB

Open AccessBrief Report

Prolonged Glucocorticoid Exposure Does Not Accelerate Telomere Shortening in Cultured Human Fibroblasts

by Anthony S. Zannas, Oksana Kosyk and Calvin S. Leung

Genes 2020, 11(12), 1425; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121425 - 27 Nov 2020

Cited by 9 | Viewed by 2317

Abstract

Psychosocial stress, especially when chronic or excessive, can increase disease risk and accelerate biological aging. Although the underlying mechanisms are unclear, in vivo studies have associated exposure to stress and glucocorticoid stress hormones with shorter telomere length. However, the extent to which prolonged [...] Read more.

Psychosocial stress, especially when chronic or excessive, can increase disease risk and accelerate biological aging. Although the underlying mechanisms are unclear, in vivo studies have associated exposure to stress and glucocorticoid stress hormones with shorter telomere length. However, the extent to which prolonged glucocorticoid exposure can shorten telomeres in controlled experimental settings remains unknown. Using a well-characterized cell line of human fibroblasts that undergo gradual telomere shortening during serial passaging in culture, we show that prolonged exposure (up to 51 days) to either naturalistic levels of the human endogenous glucocorticoid cortisol or the more potent synthetic glucocorticoid dexamethasone is not sufficient to accelerate telomere shortening. While our findings await extension in other cell types and biological contexts, they indicate that the in vivo association of psychosocial stress with telomere shortening is unlikely to be mediated by a direct and universal glucocorticoid effect on telomere length. Full article

(This article belongs to the Special Issue Genetic and Environmental Factors in Ageing and Age-Related Disease)

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