Ageing Research Reviews 66 (2021) 101255

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Ageing Research Reviews

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Review

Elastic fibers during aging and disease

Andrea Heinz *
Department of Pharmacy, LEO Foundation Center for Cutaneous Drug Delivery, University of Copenhagen, Copenhagen, Denmark

A R T I C L E I N F O A B S T R A C T

Keywords: Elastic fibers are essential constituents of the extracellular matrix of higher vertebrates and endow several tissues
Calcification and organs including lungs, skin and blood vessels with elasticity and resilience. During the human lifespan,
Elastokines elastic fibers are exposed to a variety of enzymatic, chemical and biophysical influences, and accumulate damage
Fibrillin
due to their low turnover. Aging of elastin and elastic fibers involves enzymatic degradation, oxidative damage,
Fibrillinopathies
Glycation
glycation, calcification, aspartic acid racemization, binding of lipids and lipid peroxidation products, carbamy­
Microfibrils lation and mechanical fatigue. These processes can trigger an impairment or loss of elastic fiber function and are
associated with severe pathologies. There are different inherited or acquired pathological conditions, which
influence the structure and function of elastic fibers and microfibrils predominantly in the cardiorespiratory
system and skin. Inherited elastic-fiber pathologies have a direct or indirect impact on elastic-fiber formation due
to mutations in the fibrillin genes (fibrillinopathies), in the elastin gene (elastinopathies) or in genes encoding
proteins that are associated with microfibrils or elastic fibers. Acquired elastic-fiber pathologies appear age-
related or as a result of multiple factors impairing tissue homeostasis. This review gives an overview on the
fate of elastic fibers over the human lifespan in health and disease.

1. Introduction unglycosylated protein in different isoforms by fibroblasts, endothelial

Elastic fibers are extremely durable macromolecular components of
the extracellular matrix (ECM) of higher vertebrates, whose primary
function is to confer elasticity and recoil to organs and tissues such as
skin, lungs, blood vessels, ligaments and tendon. Elastic fibers comprise
an insoluble inner core of elastin, which represents ~90 % of the mature
fibers, and a peripheral mantle of fibrillin-rich microfibrils (Fig. 1) (Shin
and Yanagisawa, 2019).
Elastin is composed of units of its monomeric precursor tropoelastin
(TE), which is cross-linked at lysine residues, forming an extremely
durable and insoluble biopolymer. The human elastin gene is located on
chromosome 7q11.23 (Fazio et al., 1991), and TE is produced as an
cells, smooth muscle cells, chondrocytes, and keratinocytes (Vindin
et al., 2019). The structure of TE is characterized by the presence of large
amounts of the four hydrophobic amino acids glycine, alanine, valine,
and proline, and TE consists of alternating highly hydrophobic and more
hydrophilic lysine-containing domains (termed KA and KP domains).
While the more hydrophobic regions are responsible for self-aggregation
and tensile properties of elastin, the more hydrophilic regions are
involved in cross-linking. Cross-linking is initiated by lysyl oxidase
(LOX) and LOX-like proteins, which induce the formation of allysine
(α-aminoadipic acid-δ-semialdehyde) through oxidative deamination of
an ε-amino group of a lysine residue. A variety of intra- and
inter-molecular cross-links are subsequently formed by non-enzymatic

Abbreviations: AAA, abdominal aortic aneurysm; AAT, thoracic aortic aneurysm; AD, acromicric dysplasia; ADAMTS, a disintegrin and metalloproteinase with
thrombospondin motifs; ADCL, autosomal dominant cutis laxa; AGE, advanced glycation endproduct; ARCL, autosomal recessive cutis laxa; ARMD, age-related
macular degeneration; ATAA, ascending thoracic aortic aneurysm; ATP, adenosine triphosphate; BOS, Buschke-Ollendorff syndrome; COPD, chronic obstructive
pulmonary disease; DES, desmosine; EBP, elastin-binding protein; ECM, extracellular matrix; ECTOL, ectopia lentis; EGF, epidermal growth factor; EMILIN, elastin
microfibril interfacer; GD, geleophysic dysplasia; HLE, human leukocyte elastase; HS, heparan sulfate; IDES, isodesmosine; ISOXO, isooxodesmosine; LOX, lysyl
oxidase; LTBP, latent TGFβ-binding proteins; MAGP, microfibril-associated glycoprotein; MD, Menkes disease; MFS, Marfan syndrome; MGP, matrix gla protein;
MMP, matrix metalloproteinase; OHS, occipital horn syndrome; OXO, oxodesmosine; PACE, paired basic amino acid cleaving enzyme; PXE, pseudoxanthoma
elasticum; ROS, reactive oxygen species; SSKS, stiff skin syndrome; SVAS, supravalvular aortic stenosis; TE, tropoelastin; TGFβ, transforming growth factor beta; UV,
ultraviolet; WBS, Williams-Beuren syndrome; WMS, Weill-Marchesani syndrome.
* Correspondence to: University of Copenhagen, Department of Pharmacy, LEO Foundation Center for Cutaneous Drug Delivery, Universitetsparken 2, 2100,
Copenhagen, Denmark.
E-mail address: andrea.heinz@sund.ku.dk.

https://doi.org/10.1016/j.arr.2021.101255
Received 30 September 2020; Received in revised form 29 November 2020; Accepted 30 December 2020
Available online 9 January 2021
1568-1637/© 2021 The Author. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
A. Heinz
condensation, producing allysine aldol or dehydrolysinonorleucine,
which further condense to form the stable and non-reducible cross-links
desmosine (DES) and isodesmosine (IDES), unique to elastin (Eyre et al.,
1984; Akagawa and Suyama, 2000; Schmelzer et al., 2019). Due to its
high hydrophobicity and cross-linked structure, elastin is insoluble and
highly resistant to proteolytic degradation. It shows virtually no turn­
over in healthy tissues and exhibits a half-life greater than 70 years, as
determined analyzing aspartic acid racemization and 14C levels post
mortem in human lung parenchyma (Shapiro et al., 1991) and aspartic
acid racemization in human aorta (Powell et al., 1992).
Fibrillins are large (300 kDa – 315 kDa) extracellular glycoproteins
and vital components of the ECM. They play a pivotal role in tissue
development, homeostasis, and repair through their interaction with
other ECM components. They further provide mechanical support and
limited elasticity to connective tissues in the form of larger assemblies
referred to as microfibrils, alone or as part of elastin-containing elastic
fibers. Fibrillins occurred over 600 million years ago and remained
virtually unaltered until present day, showing a wide distribution from
cnidarians to mammals (Piha-Gossack et al., 2012). One example that
underlines the importance of fibrillins concerns fibers in jellyfish - an
organism that does not contain elastin - whose elasticity can be attrib­
uted solely to fibrillin-rich microfibrils (Megill et al., 2005). In higher
vertebrates, microfibrils occur not only associated with elastin, but also
in elastin-free bundles in kidneys, tendon, the eye (ciliary zonules) or the
skin (oxytalan fibers in the papillary dermis) (Sakai et al., 1986).
Fibrillins are highly homologous, with modular structures composed of
repeating calcium-binding epidermal growth factor (EGF)-like domains
interspersed between 8-cysteine domains similar to those found in the
latent transforming growth factor β (TGFβ)-binding protein family. The
Fig. 1. Formation of microfibrils and elastic fibers. Microfibril formation (upper part of Fig. 1) comprises multimerization of fibrillin molecules and subsequent
formation of a microfibrillar network by deposition on fibronectin and cross-linking by transglutaminase. Elastogenesis (lower part of Fig. 1) involves the deposition
of coacervated tropoelastin onto a scaffold of fibrillin-rich microfibrils, where tropoelastin molecules are aligned and eventually cross-linked through the help of
various matrix molecules, forming mature elastic fibers.
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fibrillin superfamily comprises three fibrillin isoforms (fibrillin-1, -2, -3)
and latent transforming growth factor β-binding proteins (LTBPs) 1–4
(Godwin et al., 2019; van Loon et al., 2020). While fibrillin-1 is
expressed throughout life, fibrillin-2 and -3 expression mainly occurs in
developing fetal tissues (Sabatier et al., 2011). Fibrillin-1 is the main
component of the microfibrils, which provide the scaffold for elastin
deposition during elastic fiber formation, and fibrillin-2 also plays an
essential role in elastic fiber formation, forming the structural core of
microfibrils that are surrounded by an outer layer of fibrillin-1 (van
Loon et al., 2020). Although it is able to form microfibrils (Corson et al.,
2004), the specific function of fibrillin-3 in developing tissues is still
unclear. However, it shows high expression in the brain parenchyma in
contrast to the other two fibrillins (Corson et al., 2004). In addition to
TE, fibrillin microfibrils interact with various other matrix molecules,
generating supramolecular protein assemblies with essential functions
including the mediation of cell signaling and modulation of growth
factors. Those matrix molecules comprise fibronectin,
microfibril-associated glycoproteins (MAGPs), decorin, versican, perle­
can, elastin microfibril interfacers (EMILINs), fibulins, bone morpho­
genetic proteins, LTBPs (and hence indirectly TGFβ), a disintegrin and
metalloproteinase with thrombospondin motifs (ADAMTS) and
ADAMTS-like proteins (Penner et al., 2002; Hanssen et al., 2004;
Sabatier et al., 2009, 2014; Sengle and Sakai, 2015; Hubmacher et al.,
2017; Thomson et al., 2019).
Microfibril assembly is a complex multistep process involving mul­
timerization of fibrillin molecules and subsequent formation of a
microfibrillar network by deposition on fibronectin and cross-linking by
transglutaminase (Qian and Glanville, 1997) (Fig. 1). Before or upon
secretion into the ECM, profibrillins are processed by N- and C-terminal
A. Heinz Ageing Research Reviews 66 (2021) 101255

cleavage by furin/PACE-type proprotein convertases, facilitating ter­
minal interactions between mature fibrillin molecules (Raghunath et al.,
1999). After this processing, multimerization of the C-termini of multi­
ple fibrillin molecules into disulfide-bonded, multimeric, bead-like
structures with peripheral arms and a dense core occurs (Hubmacher
et al., 2008). Subsequent interactions between the N- and C-termini of
multimerized fibrillin molecules lead to the formation of microfibrils of
10 nm – 12 nm diameter with ~56 nm periodicity in a bead-on-a-string
fashion at the cell surface (Keene et al., 1991). Deposition of the mi­
crofibrils on a fibronectin network stabilizes the microfibrils and

Fig. 2. Intrinsic and extrinsic aging processes of elastic fibers and their consequences. Elastic fibers are exposed to various extrinsic and intrinsic factors during the
human lifespan. As a consequence, for instance cardiopulmonary aging occurs and is characterized by a complex interplay of the negative effects of elastokines
released from the damaged elastic fibers, the development and progression of severe pathological conditions and/or a loss of function of elastic fibers.

3
A. Heinz
enhances interactions with other microfibril proteins (Sabatier et al.,
2009). A few years ago, it has been shown that multimerization of all
three fibrillins increased interactions with heparin/heparan sulfate
(HS). Since heparin/HS strongly inhibits homo- and heterotypic
N-to-C-terminal fibrillin interactions, the authors concluded that hep­
arin/HS controls the formation of microfibrils at the bead interaction
stage (Sabatier et al., 2014).
The complex process of elastic fiber assembly (Fig. 1) is termed
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elastogenesis and involves many ECM components, such as fibulins-4
and -5, LTBP4, transglutaminase-2 and LOX in addition to fibrillin mi­
crofibrils and TE (Kozel and Mecham, 2019; Thomson et al., 2019; Shin
and Yanagisawa, 2019; Godwin et al., 2019; Lockhart-Cairns et al.,
2020). According to the current model of elastogenesis, TE is hydrox­
ylated at prolyl residues by prolyl 4-hydroxylase after its production on
the surface of the rough endoplasmic reticulum. It is then transported
through the Golgi apparatus to the cell surface and binds with its
Fig. 3. Elastin in aging and disease. Scanning electron micro­
graphs of aortic elastin obtained from a 67-year-old healthy
individual (A and B), aortic elastin derived from a 6-year-old
WBS patient (C and D), skin elastin obtained from a 40-year-
old healthy individual (E and F), skin elastin from a 19-year-
old WBS patient (G and H), and skin elastin from a 90-year-
old healthy individual (I and J). The white bars represent
either 30 μm (A, C, E, G, and I) or 10 μm (B, D, F, H, and J).
Reprinted from (Heinz et al., 2016) with permission from
Wiley.
A. Heinz
chaperon, the elastin-binding protein (EBP), after which the EBP-TE
complex is secreted (Hinek and Rabinovitch, 1994; Davis and
Mecham, 1998). TE is released from EBP in the extracellular space and
self-assembles in an endothermic, entropically driven liquid–liquid
phase separation termed coacervation (Muiznieks et al., 2018). Coac­
ervated TE is then deposited onto a scaffold of fibrillin-rich microfibrils,
where TE molecules are aligned and cross-linked to eventually form
mature elastic fibers (Muiznieks and Keeley, 2013). Cross-linking is
promoted by fibulin-4, which mediates the association between TE and
LOX (Nakamura, 2018). LTBP4 does not directly interact with TE but
with a fibulin-5-fibulin-4-TE complex and seems to be required for the
proper linear deposition on the microfibril network (Bultmann-Mellin
et al., 2015). Recent research suggests two other pathways, one of which
describes partial cross-linking of TE on the cell surface or outside the cell
and subsequent interaction with the microfibrils, while the other reports
trafficking of TE and LOX (and potentially fibulin-4) in an
endosomal-like compartment in the cell, before partially cross-linked TE
is secreted from membrane-bound vesicles and binds to the microfibrils
(Kozel and Mecham, 2019). Disruptions in microfibril and elastic-fiber
assembly or homeostasis as a consequence of aging-related processes
or local inflammation and may lead to a variety of pathological condi­
tions, ranging from mild alterations in connective tissue architecture to
severe life-threatening implications (Hill et al., 2020). This review gives
an overview on aging processes and inherited and acquired pathologies
that affect the structure and function of microfibrils and elastic fibers.
2. Aging of elastic fibers
Aging is a gradual and progressive deterioration of the integrity of
multiple organs and tissues and is induced by various intrinsic and
extrinsic factors. Intrinsic or innate aging is a naturally occurring pro­
cess, which is genetically determined and a result of slow tissue
degeneration, while extrinsic aging, whose effects are superimposed on
those of innate aging, is induced and accelerated by environmental in­
fluences, primarily ultraviolet (UV) radiation, but also smoking and air
pollution (Naylor et al., 2011; Vierkötter and Krutmann, 2012; Fer­
nandez-Flores and Saeb-Lima, 2019; Langton et al., 2020a, 2020b)
(Fig. 2). Elastic fibers are exposed to a variety of enzymatic, chemical
and biophysical influences over the lifespan of an organism and accu­
mulate damage due to their low turnover. Histologically, aging pro­
cesses in elastic fibers are characterized by fragmentation and thinning
of elastin structures (Fig. 3) and may result in an impaired elastic fiber
function, a reduced tissue elasticity or even a loss of function of organs
and tissues such as the cardiopulmonary system, which considerably
increases morbidity and mortality (Green et al., 2014). On the molecular
level, aging of elastin and elastic fibers involves enzymatic degradation
(Antonicelli et al., 2007; Heinz, 2020), oxidative damage (Watanabe
et al., 1996), formation of advanced glycation endproducts (AGEs) (Paul
and Bailey, 1996), calcification (Urry, 1971), aspartic acid racemization
(Powell et al., 1992; Sivan et al., 2012), lipid binding (Jacob et al., 1983;
Robert et al., 2008), carbamylation (Gorisse et al., 2016) and mechan­
ical fatigue (O’Rourke, 2007) (Fig. 2). With respect to the contribution
of the different mechanisms to elastic-fiber aging, it has been shown that
a combination of the processes of calcification, lipid binding and enzy­
matic degradation, which promote and enhance each other, have a
strong impact on elastic fibers and affect primarily tissues rich in elastin
such as the cardiorespiratory system and the eye, leading to mechanical
fatigue and severe pathologies (Robert et al., 2008). Interestingly,
research has shown that even a healthy lifestyle cannot fully prevent
intrinsic aging processes associated with lipid accumulation, calcifica­
tion and enzymatic degradation of elastin as lipids, calcium and carbo­
hydrates are important part of the human diet and elastin accumulates
more and more damage with increasing age of the individual. Therefore,
even with a healthy lifestyle and the postponement of an onset of
age-related disorders, human life expectancy cannot be increased
endlessly, and there is an upper limit for the elastic properties of the
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Ageing Research Reviews 66 (2021) 101255
cardiorespiratory system of about 100 years – 120 years (Robert et al.,
2008).
2.1. Intrinsic aging
2.1.1. Enzymatic degradation
Upon aging of an individual, enzymatic degradation of elastin occurs
during constitutive expression of proteases in healthy tissues and as a
result of up-regulation of elastase expression during inflammatory
conditions. Proteases involved in elastin degradation in human tissues
are serine proteases (cathepsin G, proteinase 3, human leukocyte elas­
tase and chymotrypsin-like elastase 1) (Heinz et al., 2012; Joshi et al.,
2018), matrix metalloproteinases (MMP-2, -7, -9, 12, -14 and neprilysin)
(Mecham et al., 1997; Heinz et al., 2010; Mora Huertas et al., 2018), as
well as cysteine proteases, namely cathepsins B, F, K, L, S and V (Yasuda
et al., 2004; Panwar et al., 2020). Elastin degradation may go along with
impairment or even loss of function of elastic fibers and also leads to the
liberation of bioactive elastin peptides, so-called elastokines, which play
an active role in various physiological processes, including cell adhe­
sion, chemotaxis, migration, proliferation, protease activation, and
apoptosis (Heinz, 2020) (Fig. 2). Proteolytic damage of elastic fibers
upon aberrant expression of elastases, together with further biological
processes triggered by elastokines, contribute to the development and
progression of severe pathological conditions including a variety of in­
flammatory conditions, lung emphysema, atherosclerosis, chronic
obstructive pulmonary disease (COPD), aortic aneurysm and
UV-induced photoaging (Fisher et al., 1996; Antonicelli et al., 2007;
Baud et al., 2013; Duca et al., 2016; Wahart et al., 2019). More detailed
summaries on elastin degradation by elastases as well as the effects of
elastokines can be found elsewhere (Duca et al., 2016; Wahart et al.,
2019; Heinz, 2020).
The susceptibility of elastin towards enzymatic cleavage depends on
the age and, hence, the intactness of the substrate (Schmelzer et al.,
2012). For instance, a greater susceptibility for cleavage by human
leukocyte elastase, pancreatic elastase and neprilysin was observed in
elastin from old individuals (Schmelzer et al., 2012; Mora Huertas et al.,
2016, 2018), which is related to extrinsic and intrinsic aging processes
that cause damage to elastin, impair elastin’s structure and make it more
susceptible towards enzymatic attack (Braverman and Fonferko, 1982).
In addition to enhancement of enzymatic cleavage through age-related
pre-damage, some proteases act synergistically with each other, as
described for instance for cathepsin G and human leukocyte elastase,
where pre-digestion of elastin by cathepsin G significantly enhanced
cleavage by human leukocyte elastase (Boudier et al., 1981). It is worth
mentioning that UV-induced extrinsic skin aging has been shown to lead
to a higher susceptibility of elastin and fibrillin-1 towards enzymatic
degradation (Mora Huertas et al., 2016; Eckersley et al., 2020). A few
years ago, it has been demonstrated that skin aging is associated with
elastin breakdown, and proteolytic susceptibility was found to be most
pronounced skin samples of old individuals and of sun-exposed skin
regions as described under 2.1. (Mora Huertas et al., 2016). It has further
been established that there is a connection between elastin degradation
and the processes of glycation of calcification, which will be described in
the following two Sections 2.1.2 and 2.1.3 (Winlove et al., 1996; Basa­
lyga et al., 2004; Bouvet et al., 2008).
2.1.2. Glycation
Mature elastin is prone to non-enzymatic glycation due to its low
turnover in human organs and tissues (Paul and Bailey, 1996). Glycation
involves the binding of sugar carbonyl groups to amino groups of pro­
teins, leading to the formation of Schiff’s bases, which rearrange to
ketoamines (Amadori’s product). Amadori’s products and their degra­
dation products such as glyoxal or 3-deoxy-glucosone undergo chemical
re-arrangements and eventually form irreversible AGEs through further
oxidative processes (glycoxidation). AGEs, such as
N-ε-carboxy-methyl-lysine, N-ε-carboxy-ethyl-lysine and pentosidine,
A. Heinz
may then generate reactive oxygen species (ROS) or interact with spe­
cific cell surface structures (Basta et al., 2004). Only few glycation sites
(free ε-amino groups) are available in elastin as lysine residues are
mainly involved in cross-linking and only few arginine residues are
present. More than two decades ago, glycation of aortic elastin was
found to be associated with conformational changes in the protein,
involving the loss of basic groups, shifts in pK of the acidic groups and
alterations in interionic interactions (Winlove et al., 1996). Incubation
with the sugars for two months resulted in the formation of low amounts
of AGEs such as pentosidine (Winlove et al., 1996). It has further been
shown that the amount of AGEs increased in human and rat aorta with
age (Brüel and Oxlund, 1996; Konova et al., 2004), and pentosidine
amounts increased in elastin from intervertebral disc with age (Sivan
et al., 2012). With respect to the implications of elastin glycation, in vitro
glucose and ribose binding by elastin were demonstrated to exert an
influence on its the mechanical properties. While two studies report that
glycation makes elastin stiffer (Winlove et al., 1996; Silverstein et al.,
2015), which may contribute to an overall increase in the stiffness of the
of vessel walls with aging (Brüel and Oxlund, 1996), another study de­
scribes a decrease in stiffness of elastin with increased glycation (Ste­
phen et al., 2014). Interestingly, calcification has been found to be
enhanced both in elastin glycated through reaction with glucose/ribose
and in elastin from diabetic rats (Tomizawa et al., 1993; Winlove et al.,
1996). Moreover, an increase in the susceptibility towards enzymatic
degradation is associated with glycation of elastin and structural alter­
ations in the protein, leading to an overall reduction of tissue elastin
amounts (Winlove et al., 1996). It has further been reported that an
increased LOX activity reduced elastin AGEs in the aorta, most likely due
to enhanced cross-linking and reduced availability of lysine residues for
the formation of AGEs (Coquand-Gandit et al., 2017). With regards to
potential systemic consequences of AGE formation, it has been discussed
that AGEs lead to mechanical dysfunction due to the formation of cross
bridges between matrix molecules and may, further, contribute to the
progression of atherosclerosis through stimulating the adhesion of
circulating blood cells to the vessel walls (Basta et al., 2004). Moreover,
Yoshinaga et al. demonstrated in an in vitro study that
Nε-(carboxymethyl)lysine accumulates in elastin in photoaged skin,
which in turn impairs elastin degradation by neutrophil elastase. The
authors concluded that this may contribute to the accumulation of
elastotic material in the skin, a hallmark of photoaging (see Section
2.2.1) (Yoshinaga et al., 2012).
2.1.3. Calcification
Calcification leads to the deposition of calcium phosphate minerals
on ECM molecules such as collagen and elastin, and plays a crucial role
in the formation and progression of atherosclerosis. The process of
calcification of elastin has already been described in the 1970s (Urry,
1971; Molinari et al., 1971; Starcher and Urry, 1973; Rucker, 1974).
There are two hypotheses regarding Ca2+ binding to elastin. As it has
been found to increase with increasing pH, it has been suggested that
Ca2+ binding may involve the interaction of Ca2+ with ionized carboxyl
groups (Molinari et al., 1971). Another study suggested that Ca2+ binds
to uncharged sites exhibiting specific local conformations such as
β-turns, which are present in elastin due to its high content in glycine
(Urry, 1971). Ca2+ then interacts with acyl oxygens from the elastin
backbone. With Ca2+ binding, local areas in elastin become positively
charged, which attracts counterions such as phosphate and carbonate
and initiates the crystallization process (Urry, 1971). A recent study has
shown in an in vivo mouse model for arterial calcification that mineral
deposition on elastin is a multistep process, involving adsorption of
Ca2+, formation of amorphous calcium phosphate and octacalcium
phosphate and thereafter transformation to hydroxyl apatite and
carbonated hydroxyl apatite (Gourgas et al., 2018). In an in vitro calci­
fication study on membranes of cross-linked elastin-like polypeptides, it
was confirmed that mineralization of elastin is a multistep process.
Moreover, it was demonstrated that fibers and filaments mineralize first,
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Ageing Research Reviews 66 (2021) 101255
suggesting that the fiber-like ultrastructure of elastin makes it suscep­
tible to calcification (Gourgas et al., 2019). In a follow-up in vitro study,
the same membranes of elastin-like polypeptides as well as ELN-­
transfected cells and osteoblasts were exposed to matrix gla protein
(MGP)-derived peptides, respectively. MGP has been described as an
inhibitor of ECM mineralization earlier (Murshed et al., 2004). A sig­
nificant reduction and a complete inhibition of mineral deposition by an
MGP-derived peptide carrying phosphorylated serine residues were
found in the case of the membranes and the ELN-transfected cells,
respectively. Interestingly, mineralization in the osteoblast culture
exhibiting a collagen-rich matrix could not be prevented by the
MGP-derived peptide. The study showed that phosphorylation of MGP’s
conserved serine residues may have a critical role in maturation of
mineral phases on elastin (Parashar et al., 2020).
With respect to the implications of elastin calcification, it has been
found to be associated with lipid and lipoprotein accumulation (Hor­
nebeck and Partridge, 1975; Proudfoot and Shanahan, 2001). Calcifi­
cation further seems to be connected to an increase in cholesterol
binding, which has been attributed to conformational changes in elastin
that expose hydrophobic sites cholesterol can interact with (Hornebeck
and Partridge, 1975). This is likely to have a pathophysiological rele­
vance in the development and progression of atherosclerosis. Experi­
ments on soluble elastin peptides revealed that elastin peptides exhibit a
higher affinity for cholesterol in the presence of Ca2+ as compared to
insoluble elastin, which indicates that cholesterol and Ca2+ binding may
be increased with proceeding elastin degradation in vivo, contributing to
the progression of several pathological conditions (Jacob et al., 1983).
Research of the last two decades indeed points to a direct correlation
between calcification and elastin degradation by MMPs (Basalyga et al.,
2004; Lee et al., 2006; Bouvet et al., 2008). It was found in rat models
that perivascular administration of low concentrations of CaCl2 induces
both calcification and elastin degradation by MMP-2 and MMP-9
(Basalyga et al., 2004). Both processes have a strong relevance in the
development and progression of cardiovascular diseases. Bouvet et al.
further demonstrated in an in vivo rat study that MMP-9 activation was
followed by an increase of TGFβ signaling as well as an increase in both
vascular elastocalcinosis and stiffness (Bouvet et al., 2008). Since it has
earlier been shown that elastokines induce osteogenic responses in
vascular smooth muscle cells (Simionescu et al., 2005), it is possible that
the release of elastokines by elastin degradation contributes to calcifi­
cation of elastin and, hence, the progression of cardiovascular diseases.
A recent study revealed that not only MMPs, but also the cysteine pro­
teases cathepsin K, S and V promote calcification of elastin. The disor­
ganization of the elastic fibers as a result of enzymatic degradation by
the cysteine proteases enhances their calcification, and soluble elastin
peptides released during digestion of elastin have a stimulatory effect on
the calcification of vascular smooth muscle cells (Andrault et al., 2019).
Another recent study focused on the calcification of isolated bovine
elastin in vitro and revealed that even small damages at the surface of
elastin fibrillar structures are able to enhance the calcification process.
Mineral deposition was found to be favored on hydrolyzed fibrillar
structures due to the availability of multiple charged sites, leading to the
adsorption of Ca2+ and counterions such as phosphate to the point of
supersaturation at which hydroxyapatite formed. It has further been
concluded that the degree of elastin mineralization at physiological pH
is influenced not only by pre-damage to elastin, but also by the
complexity of the surrounding medium in terms of ion species, such as
sodium, potassium and magnesium in addition to calcium and phos­
phorus (Boraldi et al., 2020).
2.1.4. Oxidative damage
Damage to elastin and other ECM components as a result of oxidative
stress is associated with alterations in the structure and function of these
molecules and the progression of various cardiovascular diseases.
Sources of extracellular oxidants include metal ions, membrane-bound
oxidase complexes, extracellular peroxidases, radical precursors, nitric
A. Heinz
oxide synthases and exogenous agents such as UV radiation or atmo­
spheric pollutants (sulfur and nitrogen oxide, ozone, smoke, airborne
particles) (Rees et al., 2008). Studies that investigated structural
changes in collagen as a result of oxidative damage are reviewed else­
where (Rees et al., 2008); however, not much work has focused on the
direct effects of oxidative stress to elastin. In an in vitro study, it has been
shown that oxidation of the tetrafunctional cross-links DES and IDES to
oxodesmosine (OXO) and isooxodesmosine (ISOXO) occurs in the
presence of hydrogen peroxide (Umeda et al., 2001). It is known that
hydrogen peroxide is produced under normal physiological conditions
and that its production increases upon aging (Sohal and Orr, 1992).
Another study has shown that the content of OXO and ISOXO varied in
adults, which indicates that the formation of these oxidation products is
not only age-related, but also associated with pathophysiological con­
ditions (Watanabe et al., 1996). An increase of the ratio (OXO +
IDOXO)/(DES + IDES) with increasing age points to an increase of
oxidative damage to elastin upon aging. With respect to the connection
of oxidative damage to elastin and pathological conditions, it has
recently been demonstrated that LOX up-regulation is associated with
enhanced oxidative stress through the formation of H2O2 and ROS,
which in turn contributes to vascular stiffness and elastin remodeling
during progression of hypertension (Martinez-Revelles et al., 2017).
2.1.5. Aspartic acid racemization
Aging processes in elastin are associated with accumulation of D-
aspartate, which is formed through age-dependent racemization from L-
aspartate at a rate of approximately 0.1 % per year (Powell et al., 1992;
Ritz-Timme et al., 2003; Sivan et al., 2012). The racemization of L- to
D-aspartate can only be determined in long-lived proteins with very little
turnover as racemization occurs very slowly. It was found that the
D-aspartate content in elastin from various tissues increases to different
extent. Elastin from skin and yellow ligament showed the highest
accumulation rates (36 × 10− 4 year− 1 and 41 × 10− 4 year− 1, respec­
tively) (Aswad, 1984), while lung elastin (17.6 × 10− 4 year− 1) (Shapiro
et al., 1991), intervertebral disc (11.7 × 10− 4 year− 1 – 16.2 × 10− 4
year− 1) (Sivan et al., 2012) and aorta (around 11 × 10− 4 year− 1) (Powell
et al., 1992) showed lower rates. D-aspartate in infrarenal aortic elastin
increased linearly with age from 4 % of the total aspartate in individuals
of 18 years to 13 % in individuals of 85 years (Powell et al., 1992). It has
been hypothesized that accumulation of D-aspartate and its methylation
by carboxymethyltransferases may induce conformational changes
inducing further cross-linking (e.g. formation of pentosidine) (Helfman
et al., 1977) and higher susceptibility towards enzymatic degradation
(Geiger and Clarke, 1987; Powell et al., 1992). In another study, it has
been shown that there is connection between oxidative stress and the
formation of D-aspartate in heat-treated solution of elastin peptides,
suggesting that the racemization of L-aspartate in aging tissues may be
influenced by oxidative stress (Kuge et al., 2010).
2.1.6. Carbamylation
Carbamylation is a non-enzymatic post-translation modification
formed upon binding of isocyanate derived from urea dissociation or
myeloperoxidase-mediated catabolism of thiocyanate to free ε-NH2
groups of Lys residues under formation of homocitrulline. It has been
described that the risk for cardiovascular events such as atherosclerosis
or type 2 diabetes is enhanced with increasing amounts of carbamylated
plasma proteins. Strong carbamylation of elastin may have an impact on
the functional and structural properties of elastin and, for instance,
contribute to skin aging by reducing skin elasticity. It was found pre­
viously that the homocitrulline concentration in elastin increased with
increasing age of the subject (Gorisse et al., 2016).
2.1.7. Binding of lipids and lipid peroxidation products
Already in the 1970s and 1980s, it has been shown that there is
connection between calcification and cholesterol binding by elastin as
described in Section 2.1.3 (Hornebeck and Partridge, 1975; Jacob et al.,
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1983). Jacob et al. showed that insoluble elastin and elastin peptides
bind cholesterol, and that cholesterol binding is increased when Ca2+ is
present. The authors proposed that binding of Ca2+ induces conforma­
tional changes to elastin and elastin peptides, leading to an increase in
the affinity for cholesterol. Interestingly, elastin peptides exhibited a
higher affinity for cholesterol as compared to insoluble elastin, sug­
gesting the possibility of increased cholesterol and Ca2+ binding in vivo
in response to proteolytic elastin degradation (Jacob et al., 1983).
Cholesterol binding, calcification and elastin degradation may, there­
fore, play a role during development of cardiovascular diseases such as
atherosclerosis. Lipid peroxidation leads to the formation of undesirable
aldehydes, which in turn react with various proteins and enhance the
progression of pathological conditions including atherosclerosis,
ischemic heart disease and cancer. It has been demonstrated that alde­
hydes generated from peroxidation of polyunsaturated fatty acids,
particularly 4-hydroxynonenal and acrolein, bind to elastin and appear
in the context of photoaging in elastotic material in the skin (see Section
2.2.1) (Tanaka et al., 2001). A more recent study on mice confirmed the
previous observations. It was found that UVA radiation triggers the
formation of 4-hydroxynonenal adducts with elastin, and the mice
showed typical signs of actinic elastosis, including the presence of deep
wrinkles. In an in vitro part of the same work, the authors demonstrated
that elastin modified with 4-hydroxynonenal becomes resistant to
cleavage by neutrophil elastase, which may contribute to its accumu­
lation as elastotic material during photoaging (Larroque-Cardoso et al.,
2015). In another study, it has been found that the AGE pentosidine and
lipid peroxidation product malondialdehyde occur bound to elastin in
the atherosclerotic arterial intima of patients with end-stage renal dis­
ease, indicating a close connection between glycation and lipid peroxi­
dation in the development of vascular diseases (Yamamoto et al., 2002).
2.1.8. Mechanical fatigue
Even though elastin shows a high durability and chemical stability, it
is still prone to mechanical failure during its long half-life. The human
arterial system, for instance, undergoes about 30 million repetitive
pulsations per year, and aging causes fatigue and fracture of elastic
lamellae. This in turn results in stiffening and dilation of central arteries,
which favors the development and progression of cardiovascular dis­
eases. Clinical manifestations that may occur as a result of these pro­
cesses include angina pectoris, heart failure and small vessel
degeneration in brain and kidney leading to intellectual deterioration
and renal failure (Virmani et al., 1991; O’Rourke, 2007). A study on the
mechanical aspects of elastin fatigue in the aorta revealed that a loss of
viscous content in the arterial wall upon aging goes along with higher
shear stresses within the vessel walls, resulting in a higher loading on
elastin and eventually elastin fatigue. Elastin’s load-bearing function is
subsequently taken over by collagen, which is less elastic and more rigid,
thereby further enhancing vascular aging (Hodis and Zamir, 2009).
2.2. Extrinsic aging
2.2.1. UV-induced
UV-induced extrinsic aging (photoaging) leads to coarse wrinkling
and loss of elasticity alongside an apparent thickening of the skin. At the
histological level, it is characterized by the presence of elastotic mate­
rial, a homogeneous basophilic deposit, in the papillary and reticular
dermis. The deposition of elastotic material is also referred to as solar
elastosis or actinic damage, and elastotic material exhibits non-
functional, disorganized, thickened fibrous structures (Chen et al.,
1986) composed of abnormally cross-linked elastin, fibrillin, versican
and hyaluronic acid (Uitto and Bernstein, 1998). There has been some
controversy as to whether de novo synthesis of non-functional ECM
components or enzymatic degradation of previously functional ECM
components contributes most to the pathology of solar elastosis. Both an
activation of the elastin promoter (Bernstein et al., 1995) and an
increased activity of elastolytic and collagenolytic MMPs around
A. Heinz
elastotic material (Saarialho-Kere et al., 1999) have been observed.
Therefore, it has been concluded that both de novo synthesis of elastotic
material and fragmentation of functional elastic and collagen fibers,
play a role in solar elastosis, with one or the other process dominating at
different stages of the pathological condition (Sellheyer, 2003; Fernan­
dez-Flores and Saeb-Lima, 2019). In addition, as mentioned in Sections
2.1.2 and 2.1.7, some studies point to a small contribution of the pro­
cesses of glycation and lipid peroxidation of elastin to the symptoms
photoaging, which make elastin less susceptible to enzymatic degrada­
tion, adding to the accumulation of damaged elastin as part of the
elastotic material (Yoshinaga et al., 2012; Larroque-Cardoso et al.,
2015). Recently, an increase in the cytoplasmic LOX activity in the
epidermis and the dermis has been described as a result of chronic
exposure to UV radiation; however, it is still unclear, which implications
this increase has. It may contribute to an additional cross-linking in
elastin both in elastotic material and in functional elastic fibers, which in
turn increases tissue stiffness (Langton et al., 2017).
Photoaging is further characterized by truncation and depletion of
fibrillin microfibrils in the papillary dermis (Watson et al., 1999). It has
recently been shown that there is a direct causal link between the
exposure to UV radiation, ROS and structural damage to fibrillin mi­
crofibrils and fibronectin (Hibbert et al., 2019). Structurally, the expo­
sure of isolated microfibrils to broadband UV radiation (270 nm – 380
nm) is associated with an increase in fibrillin microfibril periodicity and
central bead height as well as changes in bead morphology (Eckersley
et al., 2020). The exposure to UV radiation further increases the pro­
teolytic susceptibility of fibrillin microfibrils as compared to
non-irradiated microfibrils, which are relatively resistant to enzymatic
cleavage by MMP-1, -3, -7, -9 (Hibbert et al., 2019; Eckersley et al.,
2020). This suggest that the packing of fibrillin in microfibrils may mask
MMP cleavage sites, which get exposed after exposure to UV radiation
and ROS. It is, hence, likely that the degradation of the microfibrils
during photoaging is due to both molecular damage as a result of UV
exposure and increased susceptibility towards enzymatic degradation
(Hibbert et al., 2019). With respect to photoaging of elastin, it has been
shown that it is also associated with degradation of elastin. Changes in
the ultrastructure of elastin were found to be more pronounced in
sun-exposed skin samples as compared to non-exposed regions of the
body, with elastin fibers being rougher or more fragmented and broken
in the case of skin samples from sun-exposed regions (Fig. 3). On the
molecular level, intrinsic aging is associated to cleavages all throughout
TE with preference on the large hydrophobic domains in the central and
C-terminal parts of TE, while sun exposure of the skin is accompanied by
enhanced destruction of the N-terminal and central parts of TE and a
higher susceptibility towards enzymatic cleavage (Mora Huertas et al.,
2016).
Overall, it has been hypothesized that proteins rich in UV chromo­
phores (cysteine, tryptophan, tyrosine) such as fibronectin dimers and
fibrillin microfibrils play a role as sacrificial sunscreens that degrade
upon exposure to UV radiation to reduce further tissue damage. This
hypothesis is supported by the fact that the mentioned proteins and
other UV-absorbing proteins including the late cornified envelope pro­
teins, keratin-associated proteins and elastic fiber-associated compo­
nents are localized in skin regions of high exposure to UV radiation
(Sherratt et al., 2010; Hibbert et al., 2015). It is further worth noting
extrinsic and intrinsic aging processes show partially contrasting
symptoms in the skin (intrinsic aging: slowed down metabolic processes,
strongly associated with degree of pigmentation, no inflammatory
response, dilated vessels; extrinsic aging: increased metabolic processes,
only slightly associated with degree of pigmentation, pronounced
inflammation, microvessels decrease), and extrinsic aging should,
hence, not be understood merely as an accelerated intrinsic aging pro­
cess. In fact, as described above, extrinsic aging can cause more drastic
changes in the skin as compared to intrinsic aging (Farage et al., 2008).
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2.2.2. Smoking-induced
Tobacco smoke contains a variety of components, which induce
toxicological, carcinogenic and mutagenic effects and biological dam­
age, including tar as well as toxic volatile compounds with free radicals
and ROS (Valavanidis et al., 2009; Talhout et al., 2011). Smoking has
been described as one factor that leads to premature skin aging,
involving both facial wrinkle formation and a loss of skin elasticity
(Daniell, 1971; Kadunce et al., 1991; Koh et al., 2002; Morita, 2007). It
has been shown that the biosynthesis of new collagen is decreased
significantly, while a significant increase in TE mRNA as well as an in­
duction of ECM-degrading MMP-1 and MMP-3 mRNA occurs in cultured
skin fibroblasts after exposure to water-soluble tobacco smoke extracts
(Yin et al., 2000). It has further been reported that the effects of pho­
toaging and solar elastosis were enhanced in the skin of smokers as
compared to non-smokers (Boyd et al., 1999). Just et al. showed that the
mean relative area and the total number of elastic fibers per mm2 were
significantly increased in heavy smokers compared to non-smokers.
Both effects were due to fragmentation of elastic fibers, which made
them more numerous and shorter (Just et al., 2007). Recently, Langton
et al. demonstrated that a significant remodeling of the elastic fiber
network (both elastin and fibrillin-rich microfibrils) occurred in pho­
toprotected skin of chronic smokers as compared to the skin of age- and
sex-matched non-smokers. This remodeling was found to be associated
with a loss of the elastic fiber architecture and an increased deposition of
elastin and fibrillin microfibrils in the photoprotected skin of smokers,
with fibrillin microfibrils being shorter and showing a higher inter-bead
periodicity in the skin of smokers as compared to non-smokers. It was
further found that the stiffness of both dermis and epidermis was
increased in skin of smokers (Langton et al., 2020b). Langton et al. have
previously shown that the activity of LOX is increased in the skin of
smokers (Langton et al., 2017) and have suggested that the increase in
the stiffness of the epidermis of smokers could at least partially be due to
an increase of the LOX function (Langton et al., 2020b). With respect to
systemic effects of smoking, it has recently been shown in an in vivo
mouse study that smoking may contribute to the pathogenesis of
age-related macular degeneration (ARMD) as it enhances degenerative
changes in the Bruch’s membrane of the retinal pigment epithelium
(Annamalai et al., 2020). It has further been shown that the develop­
ment and progression of emphysema is influenced by an interplay be­
tween the effects of cigarette smoke and the action of human leukocyte
elastase (Shapiro et al., 2003). Both ARMD and emphysema are further
discussed in Sections 3.1.1 and 3.2.3, respectively.
3. Pathologies that affect the elastic-fiber system
The formation, structure, distribution and abundance of elastic fibers
and microfibrils is influenced by a variety of inherited or acquired
pathological conditions, leading to severe symptoms in the cardiovas­
cular, pulmonary and skeletal connective tissue. Due to the complexity
of elastogenesis and the important functions of elastic fibers and mi­
crofibrils, a wide range of pathologies occur.
3.1. Acquired pathologies
Acquired elastic-fiber disorders occur as a result of an aging- or
inflammation-related impairment of the structure and function of elastic
fibers (Table 1). They often show complex pathologies, are caused
multiple environmental factors and may or may not have a genetic
component. In fact, some of these pathologies occur as a symptom of
inherited elastic-fiber and microfibril pathologies (see Section 3.2).
3.1.1. Aging- and inflammation-related pathologies
Aging-related damage to elastin in blood vessels may lead to
atherosclerosis, ascending thoracic aortic aneurysm (ATAA), abdominal
aortic aneurysm (AAA), heart insufficiency or heart arrest, while aging
processes in the lungs may cause pulmonary emphysema and COPD
A. Heinz
Table 1
Acquired pathologies that affect the elastic-fiber system.
Acquired pathologies Cause
affecting elastic fibers
Atherosclerosis Inflammation in large and medium-size arteries
Abdominal aortic Exposure to cigarette smoke, high blood pressure,
aneurysm (AAA) inflammation in the arterial wall, overproduction
of proteolytic enzymes, genetic predisposition
Ascending thoracic Inflammatory conditions, atherosclerosis, genetic
aortic aneurysm predisposition (multiple genes can be affected)
(ATAA)
Chronic obstructive Chronic inflammation in the lungs due to
pulmonary disease exposure to noxious particles and gases such as
(COPD) tobacco smoke or air pollution, genetic
predisposition
Acquired cutis laxa Postinflammatory phenomenon, e.g. after
urticariae
Solar/actinic elastosis UV-induced extrinsic skin aging (photoaging)
Acquired Unclear cause
pseudoxanthoma
elasticum
Cancer progression Multifactorial, genetic predisposition
(Table 1) (Antonicelli et al., 2007; Robert et al., 2008; Labat-Robert and
Robert, 2014). AAA and ATAA are associated with progressive structural
deterioration, gradual enlargement, dilatation and eventual rupture of
the aorta (Choudhury et al., 2009; Loftus and Thompson, 2002). AAA is
triggered by several factors including exposure to cigarette smoke,
inflammation in the arterial wall, accumulation of inflammatory cells
and overproduction of proteolytic enzymes such as MMPs, leading to
accelerated ECM turnover (Plana et al., 2020). In the aneurysmal aorta,
the loss of elastin and glycosaminoglycans is a striking histological
feature, while the collagen content increases most likely as compensa­
tory mechanism (Tsamis et al., 2013). Overexpression or involvement of
MMPs such as MMP-1, -2, -3, -8, -9, -12, -13 and -14 and partly a
decrease of their inhibitors have been reported (Loftus and Thompson,
2002; Rabkin, 2017). ATAA has also been described to be characterized
by reduced elastin content and unchanged collagen content in the
arterial wall (Sokolis et al., 2012). Involvement of MMP-1, -2, -3, -8, -9,
-14, and -19 in TAA has been identified, resulting in degradation of
components maintaining arterial structure such as collagen, elastin,
laminin, proteoglycans and fibronectin (Rabkin, 2017).
Atherosclerosis is a progressive inflammatory disease characterized
by arterial wall thickening as a result of the formation of atherosclerotic
plaques and involves continuous ECM degradation and remodeling. The
growth of the plaques and subsequent narrowing of the arterial lumen
are induced by the secretion of cytokines and growth factors and further
deposition and degradation of ECM components. Studies have shown
that after plaques are formed, several MMPs including MMP-1, -2, -3, -7,
-9, -12, -13 and -14 are involved in the degradation of the fibrous cap
and plaque through their elastinolytic and collagenolytic activity, which
may lead to plaque rupture, cap ulceration and ischemic events (Katsuda
and Kaji, 2003; Loftus and Thompson, 2002). Elastin peptides have also
been shown to accelerate the progression of the disease by enhancing
lipid oxidation and calcification of the vascular wall (Maurice et al.,
Ageing Research Reviews 66 (2021) 101255
Clinical symptoms Elastic fiber abnormalities
Arterial wall thickening, presence of atherosclerotic plaques Fragmentation of elastic fibers (
characterized by ECM degradation and remodeling, Loftus and Thompson, 2002)
ultimately leading to thrombus formation upon plaque
rupture (Maurice et al., 2013)
Structural deterioration, gradual enlargement and dilatation Fragmentation and loss of elastic
and eventual rupture of the aorta, loss of elastin and fibers (Rabkin et al., 2017)
glycosaminoglycans, collagen content increases as a
compensatory mechanism (Plana et al., 2010; Loftus and
Thompson, 2002; Rabkin 2017)
Structural deterioration, gradual enlargement and dilatation Fragmentation and loss of elastic
and eventual rupture of the aorta, reduced elastin content in fibers (Rabkin et al., 2017)
the arterial wall, shortness of breath, cough (Sokolis et al.,
2012, Rabkin, 2017)
Breathing problems, shortness of breath, cough with sputum Fragmentation of elastic fibers (
production, pulmonary emphysema, i.e. permanent Elkington and Friedland, 2006)
enlargement of the peripheral airspaces of lung bronchioles
as a result of the destruction of alveolar wall matrix
structures, involvement of proteases such as MMPs and
other matrix-degrading enzymes (Houghton et al., 2015;
Pandey et al., 2017)
Emphysema, intestinal diverticula and hernias, skin laxity, Systemic elastolysis results in aortic
appearance of erythematous papules or plaques (Hu et al., rupture (Hu et al., 2006)
2006)
Coarse wrinkling, furrowing and loss of elasticity along with Accumulation of elastotic material
an apparent thickening of the skin (Naylor et al., 2011) in the papillary and reticular
dermis (Uitto and Bernstein, 1998)
Papular eruption, cutaneous mineralization, lax and Fragmentation of elastic fibers (
redundant skin, limited to the skin and not associated with Lewis et al., 2004)
systemic involvement (Lewis et al., 2004)
ECM degradation and remodeling, LOX upregulation, MMP Degradation of elastic fibers (
upregulation, elastin degradation releases elastin peptides Scandolera et al., 2016)
which increase cancer progression (Scandolera et al., 2016;
Chitty et al., 2019)
2013); Wahart et al., 2019).
COPD is an obstructive lung disease, which occurs as a result of the
exposure to noxious particles and gases such as tobacco smoke or air
pollution (Perng and Chen, 2017). It involves chronic inflammation,
parenchymal destruction and respiratory symptoms such as shortness of
breath and airflow limitations. The primary symptom of COPD is
emphysema, a permanent enlargement of the peripheral airspaces of
lung bronchioles due to the destruction of alveolar wall matrix struc­
tures (Houghton, 2015). It is caused by relative excess of proteases such
as MMPs and other matrix-degrading enzymes including neutrophil
elastase and caspase-3, -8 and -9 (Pandey et al., 2017). The
up-regulation of MMP-1, -2, -8, -9, -12, -13 and -14 has been associated
mainly with the degradation of collagens and elastin during COPD
(Elkington and Friedland, 2006; Lagente et al., 2009). Elastinolytic
cysteine proteases such as cathepsin K, L and S have also been hypoth­
esized to be important contributors to COPD (Tetley, 2002). Further,
COPD has been described to be associated with systemic consequences
such as cardiovascular disease, and it has been postulated that the
degradation of elastin in the lungs and arterial wall represents the link
between pulmonary and systemic vascular manifestations of COPD
(Maclay et al., 2012).
Solar elastosis is a consequence of UV-induced extrinsic skin aging
(photoaging) and is characterized by wrinkling, loss of skin elasticity
and accumulation of elastotic material in the dermis (Uitto et al., 1989;
Naylor et al., 2011) as described in Section 2.2.1. Acquired pseudox­
anthoma elasticum (PXE) is a non-systemic disease, which only occurs in
the skin and is characterized by a papular eruption, cutaneous miner­
alization and fragmentation of elastic fibers leading to a lax, redundant
skin (Lewis et al., 2004), while acquired cutis laxa is associated with an
inflammatory phase that precedes skin laxity and leads to the appear­
ance of erythematous papules or plaques. The disease causes systemic
elastolysis, which results in aortic rupture, emphysema, and hernias (Hu
9
A. Heinz
et al., 2006).
3.1.2. Tumor progression
Cancer is the second leading cause of death worldwide after car­
diovascular diseases. The development of tumors involves ECM degra­
dation and remodeling, during which healthy ECM limiting tumor
expansion and migration is replaced by tumor-derived ECM, which is
stiffer due to increased cross-linking and deposition of collagens. The
latter processes occur in response to elevated expression and activity
LOX (Lu et al., 2011; Cox and Erler, 2011; Chitty et al., 2019), while
ECM degradation is mainly induced by MMPs and allows for cancer-cell
invasion and metastasis (Kessenbrock et al., 2010). Elastin has also been
described to be involved in tumor progression in several ways, for
instance through binding of insoluble elastin to tumor cells via EBP,
which is expressed by cancer cells (Lapis and Timar, 2002). Moreover,
elastin degradation releases elastokines, which have an impact on cell
proliferation, invasion, apoptosis, stimulation of cytokines, angiogenesis
and the production of matrix-degrading proteases (Brassart et al., 1998),
which favors tumor invasion, growth and metastasis (Lapis and Timar,
2002; Maquart et al., 2005; Pocza et al., 2008; Coquerel et al., 2009).
Toupance et al. have shown that elastokines and κ-elastin, a mixture of
elastin peptides derived from treatment of elastin with potassium hy­
droxide, increased the invasive capacity of lung tumor cells in cell cul­
ture by increasing the pro-MMP-2 and urokinase plasminogen activator
expression, which in turn increased the MMP-2 levels in the invasive
cells (Toupance et al., 2012). κ-elastin and (VGVAPG)3 have also been
demonstrated to increase the invasiveness of glioma brain tumor cells
through enhanced MMP-2 secretion and MMP-12 synthesis (Coquerel
et al., 2009). Moreover, κ-elastin and VGVAPG have been described to
stimulate heat-shock protein 90 up-regulation as well as MMP-2 and
urokinase plasminogen activator accumulation, thereby strongly
potentiating fibrosarcoma cell migration and matrix invasion capacities
(Donet et al., 2014). Elastinolytic MMPs that contribute to tumor pro­
gression include MMP-7 (Ii et al., 2006), MMP-9 (Masson et al., 2005)
and MMP-12 (Kerkelä et al., 2000). The contribution of elastin degra­
dation on cancer progression is reviewed in more detail elsewhere
(Scandolera et al., 2016).
3.2. Inherited pathologies
Inherited elastic-fiber and microfibril pathologies are mainly related
to mutations in the genes encoding elastin (elastinopathies), fibrillins
(fibrillinopathies), and proteins directly or indirectly involved in
microfibril and elastic fiber assembly (Table 2).
3.2.1. Mutations in the elastin gene (elastinopathies)
Genetic diseases that are directly associated with mutations in elastin
gene (ELN) include isolated supravalvular aortic stenosis (SVAS), auto­
somal dominant cutis laxa (ADCL) and Williams-Beuren syndrome
(WBS) (Table 2) (Milewicz et al., 2000; Baldwin et al., 2013; Duque
Lasio and Kozel, 2018). Isolated SVAS is caused by different mutations
such as translocations, gen deletions and point mutations within ELN
(Urbán et al., 2001). The disease leads to morphological and functional
changes in the cardiovascular system, especially to a narrowing and
obstruction of the ascending aorta resulting from thickening of the aortic
media. With respect to elastic fibers, a deposition of smaller amounts of
insoluble elastin in the arterial walls has been described (Urbán et al.,
2002). ADCL is related to frameshift mutations at the 3′ -end of ELN,
which are predicted to result in a mutant TE with an extended
carboxy-terminal missense peptide sequence (Callewaert et al., 2011).
ADCL is characterized by an aged facial appearance of the patients and
the presence of loose redundant skin folds as well as pulmonary
emphysema and aortic root dilatation (Davidson and Giro, 2002).
Moreover, elastin secretion and deposition are reduced, leading to
smaller elastic lamellae in the aorta, while vascular smooth muscle cells
proliferate to greater extent (Hadj-Rabia et al., 2013). With respect to
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the skin, fragmentation and severe disorganization of elastic fibers have
been reported (Davidson and Giro, 2002). WBS is a congenital devel­
opmental disorder that occurs as a consequence of a hemizygous dele­
tion of 1.55–1.84 Mb on the long arm of chromosome 7 (Martens et al.,
2008), involving multiple genes including ELN (Pober, 2010). WBS af­
fects about 1 in 7500 people at birth (Strømme et al., 2002). Charac­
teristic features include connective tissue and central nervous system
abnormalities as well as cardiovascular, craniofacial and behavioral
changes as compared to healthy individuals (Gosch and Pankau, 1994).
For the skin, premature skin aging as well as a reduced deposition of
elastin in dermal elastic fibers, a lower diameter and a less continuous
appearance of these fibers have been described for WBS patients (Dridi
et al., 1999; Urbán et al., 2000). The lack of one elastin gene further
results in severe cardiovascular pathologies including congenital heart
disease, pulmonary stenosis, and SVAS (Lacolley et al., 2002). Moreover,
mild macrocytosis without anemia effects affects a moderate number of
individuals with WBS (Yu et al., 2020), and actionable hypercalcemia
occurs in 6.1 % of WBS patients (Sindhar et al., 2016). Recently, Parrish
et al. used whole exome sequencing followed by disease modeling in
mice to identify novel pathways that may modify the stenosis risk in
WBS patients, including immune pathway genes, but also genes involved
with the ECM, an increase elastic fiber deposition, G protein-coupled
receptor signaling and lipid metabolism (Parrish et al., 2020). A few
years ago, a study on elastin isolated from skin samples of WBS patients
revealed broken fibers, rough fiber surfaces and disintegrated fiber
bundles (Fig. 3) as well as a higher susceptibility towards enzymatic
degradation as compared to elastin from healthy individuals. With
respect to elastin’s molecular-level structure, it was found that the
proline hydroxylation degree differed, while no differences in the con­
tent of the cross-links DES and IDES were found between WBS and
healthy elastin (Heinz et al., 2016).
3.2.2. Mutations in the fibrillin genes (fibrillinopathies)
Genetic diseases that are directly associated with mutations in the
fibrillin genes include Marfan syndrome (MFS), autosomal dominant
Weill-Marchesani syndrome 2 (WMS2), geleophysic dysplasia 2 (GD2),
acromicric dysplasia (AD), stiff skin syndrome (SSKS), isolated ectopia
lentis 1 (ECTOL1), MASS syndrome and congenital contractural arach­
nodactyly (CCA) (Table 2) (Halper, 2014). MFS is an autosomal domi­
nant heritable disorder caused by mutations in the fibrillin-1 gene
(FBN1) with a prevalence of 2–3 in 10.000 individuals, leading to
skeletal, ocular, adipose tissue and cardiovascular abnormalities,
including myopia, ectopia lentis, arachnodactyly, joint laxity, aortic root
dilatation, aortic aneurysms as well as loose skin and fragmented elastic
fibers (Dietz et al., 1991; Collod-Béroud and Boileau, 2002). More than
1.800 different mutations in FBN1 have been reported to cause MFS.
Mutations in FBN1 have an impact on the formation and function of
microfibrils and, hence, on the formation of elastic fibers, which are
deposited onto a microfibrillar scaffold. Mechanisms that impair elas­
togenesis in MFS include the incorporation of mutated fibrillin-1 into
microfibrils or the presence of reduced amounts of fibrillin-1 (Muthu
and Reinhardt, 2020). It is worth noting that a recent study compared
micro computed tomography scans of ascending aortae of middle-aged
wild type and MFS mice. The results revealed that tissue remodeling
in the aortae of MFS mice resembled an accelerated normal cardiovas­
cular aging process (Lopez-Guimet et al., 2018).
In contrast to patients of MFS, who are characterized by a tall stature,
arachnodactyly, hypermobile joints and a thin hypomuscular build,
patients of WMS2 (Faivre et al., 2003), GD2 and AD (Le Goff et al., 2011)
exhibit a short statue, brachydactyly, stiff joints and a hypermuscular
build (Schrenk et al., 2018). All three disorders display a low number of
microfibrils (Wirtz et al., 1996), microfibrillar network disorganization
(Le Goff et al., 2011), post-assembly changes in microfibrils (Jensen
et al., 2015) as well as reduced fibrillin-1 binding to HS (Cain et al.,
2012). SSKS, also termed congenital scleroderma, is caused by muta­
tions in the arginine-glycine-aspartic acid (RGD) sequence-encoding
A. Heinz Ageing Research Reviews 66 (2021) 101255

Table 2
Inherited elastic-fiber and microfibril pathologies.
Inherited elastic-fiber Mutated gene OMIM Clinical symptoms Elastic fiber and microfibril abnormalities
and microfibril number
pathologies

Supravalvular aortic ELN 185500 Narrowing and obstruction of the ascending aorta Reduced elastin mRNA levels, deposition of low amounts
stenosis (SVAS) resulting from thickening of the aortic media (Urbán et al., of insoluble elastin in the arterial walls (Urbán et al.,
2001) 2001, 2002)
ADCL1: aged facial appearance, presence of loose
ADCL1: redundant skin fold, pulmonary emphysema, aortic root
ADCL1: ELN
123700 dilatation, (Callewaert et al., 2011; Davidson and Giro,
2002) Smaller elastic lamellae in the aorta, fragmentation and
Autosomal dominant
ADCL2: ADCL2: ADCL2: loose skin, mitral valve regurgitation (Markova severe disorganization of dermal elastic fibers (
cutis laxa (ADCL)
FBLN5 614434 et al., 2003) Hadj-Rabia et al., 2013; Davidson and Giro, 2002)
ADCL3: thin, lax skin with wrinkles, joint hyperlaxity,
ADCL3: ADCL3:
cataract or corneal clouding, clenched fingers, pre- and
ALDH18A1 616603
postnatal growth retardation (Fischer-Zirnsak et al., 2015)
Premature skin aging, congenital heart disease, pulmonary
Williams-Beuren stenosis, SVAS, dental anomalies, elfin face, mental Reduced deposition of elastin in dermal elastic fibers (
ELN 194050
syndrome (WBS) retardation (Dridi et al., 1999; Urbán et al., 2000; Lacolley Urbán et al., 2002)
et al., 2002)
Aortic aneurysms and dissections, ectopia lentis, increased Impaired elastogenesis, incorporation of mutated
Marfan syndrome height, disproportionally long limbs and digits, joint laxity fibrillin-1 into microfibrils, presence of reduced amounts
FBN1 154700
(MFS) and loose skin (Collod-Béroud and Boileau, 2002; Loeys of fibrillin-1 (Muthu and Reinhard, 2020), fragmented
et al., 2010a) elastic fibers (Collod-Béroud and Boileau, 2002)
Weill-Marchesani WMS1: WMS1: WMS2: short stature, thickened skin, brachydactyly, joint
syndrome (WMS) ADAMTS10 277600 stiffness, lens abnormalities (Faivre et al., 2003) Decrease of microfibrils in the skin together with an
WMS2: apparent increase in elastic fibers in WMS2 (Wirtz et al.,
WMS2: FBN1 WMS1, WMS3 and WMS4: Short stature, pseudomuscular
608328 1996), reduced or abolished fibrillin-1 binding to
build, brachydactyly, stiff joints, thickened skin, lens
WMS3: WMS3: heparan sulphate in WMS2 (Cain et al., 2012), post
dislocations and heart valve abnormalities (Dagoneau
LTBP2 614819 assembly changes in microfibril interactions in WMS2
et al., 2004; Haji-Seyed-Javadi et al., 2012; Morales et al.
WMS4: WMS4: (Jensen et al., 2015),
2009)
ADAMTS17 613195
GD1: GD1: GD1 and GD3: short stature, short hands and feet, joint
ADAMTSL2 231050 limitations, thick skin, eye abnormalities as found in WMS
are missing, “happy” face (geleos = happy, physis =
GD1: Dysregulation of fibrillin-1/ADAMTSL2/TGFβ
nature) with full cheeks and shortened nose,
GD3: relationships (Le Goff and Cormier-Daire, 2012)
GD3: LTBP3 hypertelorism, thin upper lip, progressive cardiac valvular
617809
thickening often leading to an early death, tracheal
Geleophysic dysplasia stenosis (Le Goff et al., 2008; McInerney-Leo et al., 2016)
(GD) GD2: reduced number of microfibrils and microfibril
network disorganization (Le Goff et al., 2011) post
assembly changes in microfibril interactions, TGFβ
GD2: GD2: abovementioned symptoms without cardiac
GD2: FBN1 dysregulation, fibrosis and dermal accumulation of
614185 involvement or early death (Le Goff et al., 2011)
microfibril aggregates (Jensen et al., 2015), reduced or
abolished fibrillin-1 binding to heparan sulphate (Cain
et al., 2012)
Reduced number of microfibrils and microfibril network
disorganization (Le Goff et al., 2011), post assembly
changes in microfibril interactions (Jensen et al., 2015),
Acromicric dysplasia Short stature, brachydacytly, stiff joints, pseudomuscular
FBN1 102370 reduced or abolished fibrillin-1 binding to heparan
(AD) build, thick skin (Le Goff et al., 2011)
sulphate (Cain et al., 2012), TGFβ dysregulation, fibrosis
and dermal accumulation of microfibril aggregates (
Jensen et al., 2015)
Microfibril accumulation and impaired elastogenesis (
Loeys et al., 2010b), presumably intracellular retention
Stiff skin syndrome Excessive skin fibrosis, increased TGFβ concentrations (
FBN1 184900 of fibrillin-1 to some extent, altered cell
(SSKS) Loeys et al., 2010b)
matrix-interactions due to mutation in RGD motif of
fibrillin-1 (Jensen et al., 2015)
ECTOL1: Lens dislocation and acute or chronic visual
ECTOL1: ECTOL1: impairment, skeletal features typical for MFS, absence of
Isolated ectopia lentis FBN1 129600 cardiovascular symptoms such as aortic root dilatation ( Disruption of the zonular fiber composed of elastin and
(ECTOL) Loeys et al., 2010a) fibrillin (Ahram et al., 2009)
ECTOL2: ECTOL2: ECTOL2: Lens dislocation and visual impairment (Ahram
ADAMTSL4 225100 et al., 2009)
Myopia, mitral valve prolapse, borderline aortic root
Impairment of microfibril formation with milder
MASS syndrome FBN1 604308 enlargement, skin and skeletal findings, lack of ectopia
phenotype as compared to MFS (Dietz et al., 1993)
lentis (Loeys et al., 2010a; Rippe et al., 2016)
Skeletal problems, joint contractures, abnormally shaped Altered fibrillin-2 secretion in early development,
Congenital contractural ears, in some cases cardiovascular symptoms such as however, functional microfibrils and elastic fibers in skin
FBN2 121050
arachnodactyly (CCA) mitral valve prolapse or interrupted aortic arches (Hecht and lung present due to presence of fibrillin-1 (Chaudry
and Beals, 1972; Wang et al., 1996) et al., 2001)
Age-related macular
Alterations of elastogenesis in the Bruch’s membrane of
degeneration 3 FBLN5 608895 Progressive loss of vision (Lotery et al., 2006)
the macula (Lotery et al., 2006)
(ARMD3)
Familial thoracic aortic Aortic root aneurysms or fusiform aneurysms involving Disorganized ultrastructural properties of the aortic wall
LOX 617168
aneurysm (AAT10) both the aortic root and ascending aorta (Guo et al., 2016) with fragmented elastic lamellae (Lee et al., 2016)
(continued on next page)

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Table 2 (continued )
Inherited elastic-fiber Mutated gene OMIM Clinical symptoms Elastic fiber and microfibril abnormalities
and microfibril number
pathologies

ARCL1A: SVAS, pulmonary artery stenosis, tortuosity of

ARCL1A: ARCL1A: ARCL1A: Disorganized elastic fibers with granular
the arteries, emphysematous changes in the lung (Loeys
FBLN5 219100 appearance (Loeys et al., 2002)
et al., 2002)
ARCL1B: Collagen bundles reduced in size, vascular
Autosomal recessive ARCL1B: ARCL1B: tortuosity, aortic aneurysm, hypertension, developmental ARCL1B: Underdeveloped elastic fibers (Hucthagowder
cutis laxa 1 (ARCL1) FBLN4 614437 emphysema, skin and joint laxity, arachnodactyly ( et al., 2006)
Hucthagowder et al., 2006)
ARCL1C: developmental emphysema, tortuosity, ARCL1C: Dermal elastic fibers fragmented, elastin less
ARCL1C: ARCL1C:
gastrointestinal malformations such as diverticulosis ( present in microfibril bundles, but located external to the
LTBP4 613177
Urbán et al., 2009) bundles in large globular aggregates (Urbán et al., 2009)
ARCL2A: ARCL2A:
Impaired secretion and increased intracellular retention
Autosomal recessive ATP6VOA2 219200 Developmental delay, facial dysmorphia and inelastic skin
of tropoelastin, significantly reduced extracellular
cutis laxa 2 (ARCL2) ARCL2B: ARCL2B: (Hucthagowder et al., 2009)
deposition of mature elastin (Hucthagowder et al., 2009)
PYCR1 612940
ARCL3A: Cutis laxa, a progeroid appearance, thin and
ARCL3A: ARCL3A: translucent skin, skeletal and ophthalmologic ARCL3A: Elastic fibers are often small, sparse and
Autosomal recessive ALDH18A1 219150 abnormalities as well as intellectual retardation (Fischer fragmented (Fischer et al., 2014)
cutis laxa 3 (ARCL3) et al., 2014)
ARCL3B: ARCL3B: ARCL3B: Cutis laxa, aged appearance, sparse hair, ARCL3B: Reduction in the number and diameter of elastic
PYCR1 614438 ophthalmologic abnormalities (Kivuva et al., 2008) fibers (Kivuva et al., 2008)
Fibrous skin papules, skin lesions showing collagen
Buschke-Ollendorff Elastin abnormalities, thick, slightly granular and
LEMD3 166700 abnormalities (dermatofibrosis lenticularis disseminata) (
syndrome (BOS) tortuous elastic fibers (elastoma) (Hellemans et al., 2004)
Hellemans et al., 2004)
Abnormalities in the skin, retina and cardiovascular
Pseudoxanthoma system, mild ultrastructural changes in collagen fibrils and Progressive elastic fiber mineralization and
ABCC6 264800
elasticum (PXE) glycosaminoglycans, progressive mineralization of blood fragmentation (elastorrhexia) (Chassaing et al., 2005)
vessels (Chassaing et al., 2005)
Collagen abnormalities including small collagen fibers ( Elastic-fiber abnormalities: small, sparse and fragmented
Menkes disease ATP7A 309400
Pasquali-Ronchetti et al., 1994) elastic fibers (Pasquali-Ronchetti et al., 1994)
Laxity of skin and joints and connective tissue disorders Formation of smaller, sparse and fragmented elastic
Occipital horn syndrome
ATP7A 304150 such as occipital exostosis (occipital horns) (Kodama et al., fibers, symptoms less severe than in Menkes disease (
(OHS)
1999) Beyens et al., 2019)
Loose skin, cardiomyopathy, predisposition to tumors ( Impaired elastogenesis, decrease in TE expression, thin
Costello syndrome HRAS 218040
Aoki et al., 2005) and fragmented elastic fibers (Tatano et al., 2006)
Dwarfism, mental retardation, high deposition of collagen Impaired elastogenesis leads to poorly developed elastic
Hurler disease IDUA 607014
(Hinek and Wilson, 2000) fibers (Hinek and Wilson, 2000)
type I:
230500
type II: Neurodegeneration and skeletal abnormalities (Hinek Impaired secretion of tropoelastin and elastic fiber
GM1-gangliosidosis GLB1
230600 et al., 2000b) assembly (Hinek et al., 2000b)
type III:
230650
Corneal clouding, connective tissue and skeletal Impaired secretion of tropoelastin and elastic fiber
Morquio disease type B GLB1 253010
abnormalities (Hinek et al., 2000b) assembly (Hinek et al., 2000b)
Elongated and tortuous arteries, skin and joint laxity, cutis
Arterial tortuosity Fragmented elastic fibers, inhibited elastogenesis (
SLC2A10 208050 laxa, arachnodactyly (Callewaert et al., 2008; Ciurica
syndrome Callewaert et al., 2008)
et al., 2019)

domain of fibrillin-1 that mediates integrin binding, and is characterized
by excessive skin fibrosis, increased TGFβ concentrations, microfibril
accumulation and impaired elastogenesis (Loeys et al., 2010b). Patients
with autosomal dominant isolated ECTOL1 show an abnormal stretching
of the zonular fibers, resulting in lens dislocation and in acute or chronic
visual impairment. The condition is associated with systemic symptoms
including skeletal features of MFS, and Loeys et al. therefore proposed
the designation ectopia lentis syndrome to emphasize the systemic na­
ture of the condition (Loeys et al., 2010a). The MASS syndrome is
characterized by MFS-like symptoms including mitral valve prolapse,
skeletal features and skin striae. However, in contrast to MFS, MASS
syndrome patients lack ectopia lentis and show only mild aortic dila­
tation (Rippe et al., 2016) and mild impairment of microfibril formation
(Dietz et al., 1993). Mutations in the fibrillin-2 gene (FBN2) lead to CCA
(Beals-Hecht syndrome), a disorder characterized by congenital con­
tractures, dolichostenomelia, arachnodactyly, and abnormally shaped
ears (Hecht and Beals, 1972; Wang et al., 1996). An altered fibrillin-2
secretion, but also the presence of functional microfibrils and elastic
fibers has been described to occur, presumably due to the presence of
functional fibrillin-1 (Chaudhry et al., 2001).
3.2.3. Mutations in genes encoding microfibril- and elastic fiber-associated
proteins
Inherited pathologies with mutations in genes encoding microfibril-
or elastic fiber-associated proteins include autosomal dominant cutis
laxa 2 (ADCL2), autosomal recessive cutis laxa (ARCL) 1, autosomal
recessive WMS, GD1 and 3, isolated ectopia lentis 2 (ECTOL2) and
ARMD3 (Table 2). ADCL2 (OMIM 614434) has been described to man­
ifest as extensive folding of redundant skin on the abdomen and arms as
well as mitral valve regurgitation (Markova et al., 2003). There are
different types of ARCL, of which type 1 is caused by mutations in the
genes encoding fibulin-5 (subtype A), fibulin-4 (subtype B) or LTBP4
(subtype C or Urban-Rifkin-Davis syndrome). Loss of function mutations
in the fibulin-5 gene (FBLN5) in ARCL1A lead to severe manifestations
such as SVAS, pulmonary artery stenosis, tortuosity of the arteries and
emphysematous changes in the lung. Folding and secretion of fibulin5
are affected in ARCL1A, which hinders proper interaction of elastin with
the microfibril scaffold during elastogenesis. This results in the forma­
tion of disorganized elastic fibers with granular appearance (Loeys et al.,
2002). The exact role of fibulin-5 during elastogenesis is still unclear,
but it has been shown that the protein binds LOX, fibrillin-1, TE, LTBP2
and LTBP4 and facilitates elastic fiber formation through increasing

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coacervation and cross-linking of TE (Nakamura, 2018). Systemic
symptoms of ARCL1B include vascular tortuosity, aortic aneurysm,
developmental emphysema and skin and joint laxity. It has been shown
that collagen bundles were reduced in size and that elastic fibers were
underdeveloped in the skin of ARCL1B patients (Hucthagowder et al.,
2006). ARCL1C is characterized by developmental emphysema, tortu­
osity and gastrointestinal malformations (Urbán et al., 2009). Dermal
elastic fibers were found to be fragmented and elastin to be less present
in microfibril bundles, but located external to the bundles in large
globular aggregates instead. This is most likely due to an impairment of
the LTBP4 function, which binds fibulin-5 (Noda et al., 2013), fibulin-4
(Bultmann-Mellin et al., 2015) and fibrillin-1 (Isogai et al., 2003),
thereby influencing elastin deposition onto the microfibrillar scaffold
during elastogenesis.
The different forms of autosomal recessive WMS are all associated
with mutations in genes encoding for proteins, which interact with
fibrillin-1 or fibrillin-1-containing microfibrils, hence, affecting micro­
fibril and elastic fiber formation. WMS1 is caused by mutations in the
ADAMTS10 gene (ADAMTS10) (Dagoneau et al., 2004), while WMS3
(Haji-Seyed-Javadi et al., 2012) and WMS4 (Morales et al., 2009)
develop as a result of mutations in the LTBP2 and ADAMTS17 genes,
respectively. All three disorders affect the musculoskeletal system, the
eyes and the heart, and WMS patients are of short stature and pseudo­
muscular build, and exhibit brachydactyly, stiff joints, thickened skin,
lens dislocations and heart valve abnormalities (Karoulias et al., 2020b).
ADAMTS10 cleaves fibrillin1 (Kutz et al., 2011) and fibrillin-2 (Wang
et al., 2019) and has been shown to bind to fibrillin-1 and fibrillin mi­
crofibrils, accelerating microfibril assembly (Kutz et al., 2011), which is
why mutations in ADAMTS10 in WMS1 impact microfibril deposition.
LTBP2 associates with fibrillin-1, and mutations in the LTBP2 gene in
WMS3 patients, therefore, result in elastic fiber anomalies such frag­
mented elastic fibers (Haji-Seyed-Javadi et al., 2012). ADAMTS17 is a
secreted protease, whose exact biological function is still unclear. Recent
work by Karoulias et al. suggests a potential role of ADAMTS17 as a
chaperone for the secretion of fibrillin-1 and collagen type I or in their
early assembly in the pericellular matrix or the ECM. Due to the
impaired secretion of fibrillin-1, elastic fiber abnormalities were also
observed in a WMS4 patient, whose elastic fibers were sparse, small and
displayed disorganized microfibrillar structures, with fragmented
elastin aggregates present on the microfibrillar scaffold (Karoulias et al.,
2020a).
GD1 (Le Goff et al., 2008) and GD3 (McInerney-Leo et al., 2016) are
caused by mutations in the ADAMTSL2 and LTBP3 genes, respectively,
with GD1 being associated with a dysregulation in the
fibrillin-1/ADAMTSL2/TGFβ interplay (Le Goff and Cormier-Daire,
2012). Both, ADAMTSL2 (Hubmacher and Apte, 2015) and LTBP3
(Robertson et al., 2015) have been found to interact with fibrillin-1.
Clinical symptoms of GD1 and GD3 include short stature, short hands
and feet, joint limitations and thick skin in the patients; however, eye
abnormalities as found in WMS are missing (Sakai and Keene, 2019). It
has further been suggested that ADAMTSL2 may be involved in TGFβ
signaling as fibroblasts isolated from patients with GD1 secreted more
latent and active TGFβ (Hubmacher and Apte, 2015). Autosomal
recessive ECTOL2 is associated with mutations in the ADAMTSL4 gene
and leads to an abnormal stretching and disruption of the zonular fibers
(which contain elastin and fibrillin), lens dislocation and visual
impairment (Ahram et al., 2009). ADAMTSL4 has been shown to bind
fibrillin-1 and enhance its assembly in tissue culture. It has further been
suggested that ADAMTSL4 promotes fibrillin-1 assembly in the zonular
apparatus of the eye under healthy conditions (Gabriel et al., 2012).
ARMD, the most common disease that leads to irreversible visual loss
in the Western world, shows a complex pathogenesis. There is a great
genetic heterogeneity in ARMD and there are 15 types caused by mul­
tiple mutations and polymorphisms of genes. ARMD3, for instance, is
caused by FBLN5 mutations, altering elastogenesis in the Bruch’s
membrane of the macula (Auer-Grumbach et al., 2011; Lotery et al.,
13
Ageing Research Reviews 66 (2021) 101255
2006; Stone et al., 2004). Thoracic aortic aneurysms (AAT) and dissec­
tions are a large group of heterogeneous conditions, which in some cases
are caused by missense mutations in the LOX gene (AAT10). This leads
to an insufficient cross-linking of elastin and collagen in the aortic wall
and consequently to a disorganized aortic wall with fragmented elastic
lamellae (Lee et al., 2016). Patients have been described to display
either aortic root aneurysms or fusiform aneurysms that involved both
the aortic root and ascending aorta, with some dying of ascending aortic
dissections (Guo et al., 2016). Recently, it has been shown that the
accumulation of the large proteoglycan versican and aggrecan contrib­
utes to ascending aortic dissection and/or rupture (Cikach et al., 2018).
3.2.4. Mutations in genes encoding proteins indirectly involved in
microfibril- or elastic fiber assembly
Pathologies including Buschke-Ollendorff syndrome (BOS), PXE,
Menkes disease, occipital horn syndrome (OHS), ARCL2 and 3, ADCL3,
Costello syndrome, Hurler diseases, GM1-gangliosidosis, Morquio dis­
ease type B and arterial tortuosity syndrome indirectly interfere with
elastic-fiber formation (Table 2). BOS is a rare autosomal dominant
disease that occurs at a frequency of about 1 in 20,000 live births (Giro
et al., 1992). It is characterized by the occurrence of fibrous skin papules
as well as skin lesions showing collagen (dermatofibrosis lenticularis
disseminata) and elastin (elastoma) abnormalities. The disease is caused
by mutations in the LEMD3 gene, which encodes a protein associated
with connective tissue and bone morphogenesis (Hellemans et al.,
2004). PXE is an autosomal recessive systemic disorder with a proposed
incidence of 1–25,000–70,000 caused by mutations in the ABCC6 gene,
a member of the large adenosine triphosphate (ATP)-dependent trans­
membrane transporter family. The exact pathology is unclear; however,
the mutations lead to a lack or accumulation of molecules affecting the
synthesis, turnover, and/or maintenance of the ECM, which results in
abnormalities in the skin, retina and cardiovascular system (Chassaing
et al., 2005; Uitto et al., 2010). Symptoms include progressive elastic
fiber mineralization and fragmentation (elastorrhexia) as well as milder
ultrastructural changes in collagen fibrils and glycosaminoglycans
(Chassaing et al., 2005). Skin manifestations are related to the appear­
ance of yellow papules containing calciumphosphate complexes and
aberrant, clumped and fragmented elastic fibers that eventually coalesce
into larger, inelastic plaques. With respect to the cardiovascular system,
progressive mineralization of blood vessels may lead to hypertension,
angina pectoris and myocardial infarction (Chassaing et al., 2005).
Menkes disease is a lethal multisystemic disorder inherited as an X-
linked recessive trait, thus affecting mainly male individuals, who die in
their early childhood (Tümer and Moller, 2010). The disease has a
prevalence of 1 in 100,000–250,000 live births and is caused by a va­
riety of mutations in the copper-transporting ATPase gene ATP7A
(Kodama et al., 1999). Different copper-dependent enzymes such as LOX
are affected. As a result of the deficient function of LOX, collagen- and
elastic-fiber abnormalities including smaller collagen fibers and smaller,
sparse and fragmented elastic fibers are observed (Pasquali-Ronchetti
et al., 1994). Similar to Menkes disease, OHS is caused by mutation in
the ATP7A gene (Kodama et al., 1999). The disease is also known as
X-linked cutis laxa or Ehlers-Danlos syndrome type IX and is charac­
terized by skin and joint laxity and connective tissue disorders such as
occipital exostosis (occipital horns). Connective tissue abnormalities are
partly attributable to a LOX deficiency (Kaler, 2011) and sparse and
fragmented elastic fibers have been reported (Beyens et al., 2019).
Loss of function mutations in the ATP6VOA2 gene lead to ARCL2A
and ARCL2B (Urbán and Davis, 2014). ARCL3A, also known as De Barsy
syndrome type A, is caused by homozygous mutations in the ALDH18A1
gene (Fischer et al., 2014), while ARCL3B, De Barsy syndrome type B, is
a result of mutations in the PYCR1 gene (Lin et al., 2011). ARCL2 pa­
tients show a variety of symptoms including developmental delay, facial
dysmorphia and inelastic skin. The mutation of the proton pump enco­
ded by the ATP6VOA2 gene indirectly leads to defective intracellular
trafficking of TE vesicles, which disrupts TE secretion and results in
A. Heinz
accumulation of TE in the Golgi apparatus and decreased deposition of
mature elastin (Hucthagowder et al., 2009). Only small amounts of
fibrillar elastin are observed, while higher amounts of globular TE de­
posits are present in the cells. ARCL3A is characterized by cutis laxa, a
progeroid appearance, thin and translucent skin, skeletal and ophthal­
mologic abnormalities as well as intellectual retardation. Elastic fibers
are often small, sparse and fragmented (Fischer et al., 2014). ARCL3B
patients show various symptoms including aged appearance, sparse hair,
ophthalmologic abnormalities, marked reduction in the number and
diameter of elastic fibers and cutis laxa (Kivuva et al., 2008). ADCL3 is
also caused by mutations in the ALDH18A1 gene, and clinical features
include cataract or corneal clouding, thin skin with visible veins and
wrinkles, joint laxity, clenched fingers, and pre- and postnatal growth
retardation (Fischer-Zirnsak et al., 2015).
Costello syndrome occurs as a result of heterozygous mutations in
the HRAS gene that encodes a guanosin triphosphate-binding protein
and causes loose skin, cardiomyopathy and predisposition to tumors
(Aoki et al., 2005). With respect to elastic fibers, Costello syndrome
patients show an impaired elastogenesis due to a functional deficiency of
the EBP (Hinek et al., 2000a; Tatano et al., 2006). Hurler disease
(mucopolysaccharidosis type I) is caused by homozygous or
compound-heterozygous mutation in the gene encoding α-L-iduronidase
(IDUA), which leads to an accumulation of HS and dermatan sulfate
glycosaminoglycans and subsequent disruption of EBP function. In
addition to dwarfism and mental retardation, patients with Hurler dis­
ease show poorly developed elastic fibers (Hinek and Wilson, 2000).
Mutations in the β-galactosidase gene (GLB1) are responsible for the
occurrence of GM1-gangliosidosis type I-III and Morquio disease type B
(mucopolysaccharidosis type IVB) (Morrone et al., 2000). Patients of
GM1-gangliosidosis type I and Morquio disease display characteristic
connective tissue and skeletal abnormalities. It was shown that both
diseases lead to deficient TE secretion and elastogenesis due to peri­
cellular accumulation of galactosugar-bearing moieties, which bind to
EBP and induce its shedding from the cell surface and early release of TE
(Hinek et al., 2000b). Arterial tortuosity syndrome is due to
loss-of-function mutations in the SLC2A10 gene that encodes the glucose
transporter GLUT10. This results in diminished glucose-responsive
transcription of decorin, an inhibitor of the TGFβ signaling pathway,
indirectly inhibiting normal ECM formation, in particular elastogenesis.
Connective tissue manifestations include skin and joint laxity, arach­
nodactyly, fragmented elastic fibers, as well as elongated and tortuous
arteries, along with cutis laxa (Callewaert et al., 2008; Ciurica et al.,
2019).
4. Conclusions
Elastic fibers are long-lived molecular assemblies of the ECM of
higher vertebrates, which are essential for the function of several tissues
and organs including lung, skin and blood vessels during the entire
human lifespan. Under healthy conditions, elastic fibers are very resis­
tant towards extrinsic and intrinsic influences; however, due to their
very low turnover, they are prone to accumulate damage as a result of
exposure to ultraviolet radiation, cigarette smoke, enzymatic degrada­
tion, oxidative damage, formation of advanced glycation endproducts,
calcification, aspartic acid racemization, binding of lipids and lipid
peroxidation products, carbamylation and mechanical fatigue. All these
effects may contribute – alone and in combination – to the development
and progression of severe pathologies involving the skin, lungs and
cardiovascular system. Research has shown that the processes of elastin
calcification, glycation and cholesterol binding as well as enzymatic
elastin degradation and release of elastokines complement and poten­
tially enhance each other. Even with a healthy lifestyle, elastin is prone
to the accumulation of damage, and intrinsic aging processes cannot
fully be stopped but only slowed down, as lipids, carbohydrates and
calcium are important parts of the human diet. Hence, such processes
contribute over shorter or longer term, for example, to the pathology of
14
Ageing Research Reviews 66 (2021) 101255
atherosclerosis through stimulating the formation of atherosclerotic
plaques, destroying elastin and making the vascular walls stiffer. The
disease progression is multifactorial, complex and still insufficiently
understood. Current research is, therefore, focusing on the contribution
of specific proteases to elastin degradation and the functional loss of
elastic fibers on the one hand, and the release of elastokines and their
effects on vascular aging and cardiovascular diseases on the other hand.
A better understanding of the complex connection between functional
impairment of elastin and stimulation of disease-enhancing biological
processes by elastokines may aid in the development of directed treat­
ment against cardiovascular pathologies. Further current research aims
at shedding light on the contribution of specific ECM components such
as fibulins, LTBPs, ADAMTS and LOX on microfibril or elastic fiber as­
sembly in health and disease, as the exact biological roles of some of
these molecules are still unknown. This concerns, for instance, providing
a better understanding of how ADAMTS and ADAMTSL proteins influ­
ence microfibril deposition. Moreover, it is still not fully understood how
cross-linking by LOX and transglutaminase occurs and affects elastic
fiber assembly. Gaining a deeper understanding of the biological roles
and interplay of matrix molecules will help understanding the clinical
symptoms of congenital diseases and will provide molecular targets for
medicines that avert elastic fiber destruction and, hence, the progression
of inherited and acquired elastic-fiber pathologies.
Declaration of Competing Interest
The author declares no competing financial interests.
Acknowledgement
The work was supported by the LEO Foundation grant LF17063.
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