52
related to genomic instability. The accumulation of DNA damage over time is the
result of environmental factors (e.g., chemicals, UV/IR radiation) as well as endogenous agents (e.g., DNA replication errors, reactive oxygen species). DNA damage
accumulates when intrinsic mechanisms cannot eliminate these dysfunctional cells,
and thus tissue and organism homeostasis become compromised [67]. However,
more than being genetically predetermined, organismal lifespan is also epigenetically modified. Exposure to environmental stresses (e.g., smoking, pollution, sedentary lifestyles) during an individual’s lifetime may induce epigenetic alterations that
can compromise normal gene expression without altering the underlying DNA
sequence [71]. These exogenous factors are major players in premature defects in
mitochondrial functionality, insulin signaling, endothelial homeostasis, and redox
balance, promoting early senescent features [27]. To overcome intracellular damage
that accumulates with age, a quality control network, which maintains correctly
folded proteins and degrades unfolded or misfolded proteins, is fundamental. This
maintenance system, known as proteostasis, is supported by the heat shock family
of proteins (namely, chaperones) and by the proteolytic systems ubiquitinproteasome and lysosome-autophagy, which determine cell fate [56]. However, protein homeostasis declines with age, promoting proteotoxicity that further leads to
the development of age-related proteinopathies [101]. Another trigger of normal
aging is cell senescence. Cellular senescence acts as an anticancer mechanism
through the activation of tumor-suppressor mechanisms in response to oncogenic
stimuli, including the p53/p21 and p16
INK4a
/pRB pathways [22]. However, it was
recently demonstrated that eliminating senescent cells from a mice model not only
increased longevity but also improved overall health, thus suggesting that senescent
cells are major drivers of aging [5, 6].
This chapter reviews the physiological and pathological aging process of vessels
in Hutchinson-Gilford progeria syndrome, a disease characterized by premature
aging in children (focusing on the biophysical and cellular changes that occur in the
vessels during aging). Many aspects observed in physiological aging are shared by
pathological aging. Therefore, the use of accelerated aging models may facilitate
the study of vascular aging. Finally, we review the latest efforts to create suitable
in vitro models to study the process of aging in the vascular system.
3.2 Vascular Aging: General Insights
Several molecular mechanisms are implicated in vascular aging including sirtuins,
telomere shortening and telomerase, progerin, klotho gene, and JunD, among others
[59]. Vascular aging is characterized by collagen deposition, vascular remodeling,
interstitial fibrosis, and inflammation which further leads to wall thickening, arterial
stiffening, and vessel dilatation [27].
Vascular aging is evaluated in multiple ways. Vascular stiffness increases with
aging and is easily monitored by pulse wave velocity [60]. High levels of C-reactive
protein, an inflammatory marker, and low levels of adiponectin, an anti-atherogenic
P. R. Pitrez et al.
related to genomic instability. The accumulation of DNA damage over time is the
result of environmental factors (e.g., chemicals, UV/IR radiation) as well as endogenous agents (e.g., DNA replication errors, reactive oxygen species). DNA damage
accumulates when intrinsic mechanisms cannot eliminate these dysfunctional cells,
and thus tissue and organism homeostasis become compromised [67]. However,
more than being genetically predetermined, organismal lifespan is also epigenetically modified. Exposure to environmental stresses (e.g., smoking, pollution, sedentary lifestyles) during an individual’s lifetime may induce epigenetic alterations that
can compromise normal gene expression without altering the underlying DNA
sequence [71]. These exogenous factors are major players in premature defects in
mitochondrial functionality, insulin signaling, endothelial homeostasis, and redox
balance, promoting early senescent features [27]. To overcome intracellular damage
that accumulates with age, a quality control network, which maintains correctly
folded proteins and degrades unfolded or misfolded proteins, is fundamental. This
maintenance system, known as proteostasis, is supported by the heat shock family
of proteins (namely, chaperones) and by the proteolytic systems ubiquitinproteasome and lysosome-autophagy, which determine cell fate [56]. However, protein homeostasis declines with age, promoting proteotoxicity that further leads to
the development of age-related proteinopathies [101]. Another trigger of normal
aging is cell senescence. Cellular senescence acts as an anticancer mechanism
through the activation of tumor-suppressor mechanisms in response to oncogenic
stimuli, including the p53/p21 and p16
INK4a
/pRB pathways [22]. However, it was
recently demonstrated that eliminating senescent cells from a mice model not only
increased longevity but also improved overall health, thus suggesting that senescent
cells are major drivers of aging [5, 6].
This chapter reviews the physiological and pathological aging process of vessels
in Hutchinson-Gilford progeria syndrome, a disease characterized by premature
aging in children (focusing on the biophysical and cellular changes that occur in the
vessels during aging). Many aspects observed in physiological aging are shared by
pathological aging. Therefore, the use of accelerated aging models may facilitate
the study of vascular aging. Finally, we review the latest efforts to create suitable
in vitro models to study the process of aging in the vascular system.
3.2 Vascular Aging: General Insights
Several molecular mechanisms are implicated in vascular aging including sirtuins,
telomere shortening and telomerase, progerin, klotho gene, and JunD, among others
[59]. Vascular aging is characterized by collagen deposition, vascular remodeling,
interstitial fibrosis, and inflammation which further leads to wall thickening, arterial
stiffening, and vessel dilatation [27].
Vascular aging is evaluated in multiple ways. Vascular stiffness increases with
aging and is easily monitored by pulse wave velocity [60]. High levels of C-reactive
protein, an inflammatory marker, and low levels of adiponectin, an anti-atherogenic
P. R. Pitrez et al.