Review
Collagens and elastin genetic variations and their potential role in aging-related diseases and longevity in humans

https://doi.org/10.1016/j.exger.2019.110781Get rights and content

Highlights

  • Genetic mutations in collagens and elastin lead to lethal congenital diseases.

  • Mutations can also cause disease and disability that accelerates the aging process.

  • There is some evidence for genetic variations being associated with healthy aging.

  • Research on aging genomics requires a health determinants and lifecourse approach.

  • Gerontology can help with methodologies that operationalize biological aging.

Abstract

Collagens and elastin are ‘building blocks’ of tissues and extracellular matrix. Mutations in these proteins cause severe congenital syndromes. Adverse genetic variations may accelerate the aging process in adults contributing to premature morbidity, disability and/or mortality. Favorable variants may contribute to longevity and/or healthy aging, but this is much less studied. We reviewed the association between variation in the genes of collagens and elastin and premature aging, accelerated aging, age-related diseases and/or frailty; and the association between genetic variation in those and longevity and/or healthy aging in humans. A systematic search was conducted in MEDLINE and other online databases (OMIM, Genetics Home Reference, Orphanet, ClinVar). Results suggest that genetic variants lead to aging phenotypes of known congenital disease, but also to association with common age-related diseases in adults without known congenital disease. This may be due to the variable penetrance and expressivity of many variants. Some collagen variants have been associated with longevity or healthy aging. A limitation is that most studies had <1000 participants and their criterion for statistical significance was p < 0.05. Results highlight the importance of adopting a lifecourse approach to the study of the genomics of aging. Gerontology can help with new methodologies that operationalize biological aging.

Introduction

Collagens are the most common proteins in humans; they support the structure of tissues and are widely distributed in the extracellular matrix, where they play active biological roles (Benias et al., 2018). The biosynthesis and molecular structure of collagens has been well described (Gelse et al., 2003). Collagens are the major constituent of skin, bones, tendons, cartilages, blood vessels and teeth (Ricard-Blum, 2011). The collagens family encompasses 46 genes.1 Elastin is another abundant protein in humans and is responsible for the elastic properties of tissues such as the aorta, nuchal ligament, lungs or skin. Elastin also plays biologically active roles in the extracellular matrix (Debelle and Tamburro, 1999). ELN is the gene encoding elastin.2

Mutations in collagens and elastin cause a constellation of diseases in humans. As regards collagens, these diseases have been described elsewhere under the umbrella term of collagenopathies (Arseni et al., 2018; Jobling et al., 2014). Genetic diseases driven by elastin have also been well described (Duque Lasio and Kozel, 2018).

Collagens and elastin mutations causing significant pediatric mortality are in the spectrum of rare diseases, but many mutations have variable penetrance and expressivity. Low penetrance is evident when the parents of an individual with dominantly inherited disease are asymptomatic or minimally symptomatic; variable expressivity is evident when affected individuals with the identical genotype show different expression of the disease phenotype. Milder phenotypes of disease related to collagen mutations that present in adulthood are increasingly recognized (Jobling et al., 2014); hence, carriers of pathogenic mutations may achieve chronologically older ages with signs of ‘premature’ or ‘accelerated’ aging (Franceschi et al., 2018; Puzianowska-Kuznicka and Kuznicki, 2005). For example, these patients may present with a higher burden of multimorbidity and disability compared to their same age peers, with a ‘biological age’ that seems higher than their chronological one. These patients can also be described as ‘frail’ (Kim and Jazwinski, 2015; Mitnitski et al., 2002).

As well as giving rise to aging phenotypes of known congenital disease, unfavorable genetic variants may lead to accelerated aging phenotypes in people who grow old without knowledge of having a congenital disease. Conversely, clinicians often identify patients who are chronologically very old (e.g. in their late eighties, nineties and even hundreds) but appear to be ‘younger than their age’. Typically, these patients have accumulated few physiological deficits compared to peers of the same chronological age. Clinicians often comment that these ‘fitter-than-their-peers’ patients have a ‘youthful look’ to their skin. As collagens and elastin are building blocks of many tissues as well as the skin, it is plausible that favorable genetic polymorphisms could have whole-system consequences in terms of resilience and ability to age successfully. Little is known on the latter.

Our objectives were two-fold: first, to review the association between variation in the genes of collagens and elastin and premature aging, accelerated aging, age-related diseases and/or frailty; second, to review the association between genetic variations in those genes and healthy aging and/or longevity in humans. We did not consider genes of other components of the extracellular matrix, even if they are implicated in collagen or elastin turnover or metabolism. In addition, we excluded mutations of collagen or elastin genes that are seen in cancer cells or tissues.

We performed a systematic literature search on MEDLINE Ovid® using all terms under the headings of ‘collagen’ and ‘elastin’. Those were combined with all terms under the following headings: ‘premature aging’, ‘skin aging’, ‘aging’, ‘healthy aging’, ‘cognitive aging’, ‘frail elderly’, ‘frailty’, ‘frail’, “aged 80 and over’, and ‘longevity’. The search was limited to humans and conducted up to the 31st of December 2018. The search strategy can be seen in Appendix A. In addition, the following online databases were searched: OMIM (https://www.omim.org), Genetics Home Reference (https://ghr.nlm.nih.gov), Orphanet (https://www.orpha.net/) and ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/).

Results were presented by gene and according to the above-described lifecourse approach, in the form of a single table summarizing the literature findings. In the table, details for each study included: genetic variant (rs number where possible), study type, population, sample size, and level of statistical significance. Meta-analyses were preferentially reported. Case-control studies were reported when the sample size (of cases and controls combined) was at least 100.

Section snippets

A lifecourse-focused review of genetic variation in collagens and elastin

This section summarizes the results of the literature review. Table 1 shows further study details.

Discussion

This review addressed genetic variation in collagens and elastin and their associations with disease and health in humans, from a lifecourse perspective. Results suggest that mutations or polymorphisms in those genes may be associated with a full range of aging phenotypes, from catastrophic congenital scenarios that cause death in early childhood, through premature aging phenotypes in chronologically young people, to accelerated aging phenotypes in adulthood and older age that lead to high

Conclusions and directions for further research

Mutations and genetic variations in collagen and elastin genes are associated with a wide range of aging phenotypes but their relationship with longevity and healthy aging phenotypes remains poorly understood and under-researched. The determinants of longevity and healthy aging in populations are not only genetic; indeed, epigenetic, socioeconomic, environmental, lifestyle, and healthcare-related factors must also be taken into account (Fuellen et al., 2016).

The relative contributions of, and

Funding sources

This research was supported by a “Building Engagements in Health Research” bursary granted in 2018 to Roman Romero-Ortuno and Ross McManus by the Trinity Translational Medicine Institute, Trinity College Dublin: https://www.tcd.ie/news_events/articles/trinity-symposium-shows-breadth-of-translational-cancer-research/

Declaration of competing interest

None.

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