Special Issue "Genetic and Environmental Factors in Ageing and Age-Related Disease"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (25 March 2021).

Special Issue Editor

Dr. Karen Mather
E-Mail Website
Guest Editor
Centre for Healthy Brain Ageing, University of New South Wales, 2170 Sydney, Australia
Interests: human ageing and longevity; genetics; epigenetics; genetic epidemiology; human lifespan; dementia; age-related disease; telomeres

Special Issue Information

Dear Colleagues,

Our population is ageing. Indeed, 2020–2030 has been designated the Decade of Healthy Ageing by the World Health Organization, with the aim of improving the quality of life of older adults. Deepening our understanding of the biological and pathological processes as well as the pathways underlying ageing and age-related disease is imperative to finding strategies to promote healthy ageing. However, our knowledge of the specific genetic, epigenetic and environmental factors and their relative contributions to ageing is still in its infancy. Moreover, interactions between genetic and environmental factors and the role epigenetics plays in ageing have rarely been considered in the literature. The relatively recent advances in genomic and epigenomic assays and the reduction in costs has led to an unprecedented amount of data available to the research community. In addition, the sharing of data between collaborators, the ease of open access repositories and the development of large international biobanks has facilitated a rapid expansion of genetic/epigenetic studies. This Special Issue of Genes aims to provide an overview of the latest research on genetic, epigenetic and environmental factors in human ageing, longevity and ageing-related phenotypes and disease, and to suggest directions for future research. We therefore invite submissions of reviews, research articles and short communications reporting on genetic, epigenetic and environmental factors, particularly those looking at the effects of gene–environment interactions on human and mammalian ageing, longevity, age-related phenotypes and age-related disease.

Dr. Karen Mather
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • genetics
  • environmental factors
  • human ageing
  • age-related disease
  • longevity
  • gene by environment interaction
  • epigenetics

Published Papers (9 papers)

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Research

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Article
ALDH2 p.E504K Variation and Sex Are Major Factors Associated with Current and Quitting Alcohol Drinking in Japanese Oldest Old
Genes 2021, 12(6), 799; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060799 - 24 May 2021
Viewed by 726
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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Article
Investigating Olfactory Gene Variation and Odour Identification in Older Adults
Genes 2021, 12(5), 669; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050669 - 29 Apr 2021
Viewed by 920
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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Article
APOE Variants in an Iberian Alzheimer Cohort Detected through an Optimized Sanger Sequencing Protocol
Genes 2021, 12(1), 4; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12010004 - 22 Dec 2020
Viewed by 807
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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Article
The Reversion of cg05575921 Methylation in Smoking Cessation: A Potential Tool for Incentivizing Healthy Aging
Genes 2020, 11(12), 1415; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121415 - 27 Nov 2020
Cited by 3 | Viewed by 955
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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Review
Formaldehyde and De/Methylation in Age-Related Cognitive Impairment
Genes 2021, 12(6), 913; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060913 - 13 Jun 2021
Cited by 2 | Viewed by 769
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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Review
Influence of Age on Skeletal Muscle Hypertrophy and Atrophy Signaling: Established Paradigms and Unexpected Links
Genes 2021, 12(5), 688; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050688 - 03 May 2021
Cited by 1 | Viewed by 829
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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Review
No Time to Age: Uncoupling Aging from Chronological Time
Genes 2021, 12(5), 611; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050611 - 21 Apr 2021
Cited by 1 | Viewed by 4561
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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Review
A New Perspective on the Origin of DNA Double-Strand Breaks and Its Implications for Ageing
Genes 2021, 12(2), 163; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020163 - 26 Jan 2021
Cited by 1 | Viewed by 944
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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Brief Report
Prolonged Glucocorticoid Exposure Does Not Accelerate Telomere Shortening in Cultured Human Fibroblasts
Genes 2020, 11(12), 1425; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11121425 - 27 Nov 2020
Cited by 2 | Viewed by 778
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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