https://onlinelibrary.wiley.com/doi/abs/10.1111/acel.12773
Kirsty Foote, Johannes Reinhold, Emma P. K. Yu, Nichola L. Figg, Alison Finigan, Michael P. Murphy, Martin R. Bennett.
INTRODUCTION
Ageing
of the large conduit arteries is a major cause of morbidity and
mortality, contributing to hypertension. Arterial
ageing is associated with multiple structural and functional changes,
including vessel dilatation and wall thickening, loss of elastin and
deposition of collagen.
Several
invasive and noninvasive parameters of vascular stiffness can
reliably predict cardiovascular events. However, furthering research
in mouse models is not easy. Improved animal welfare means that laboratory mice can now live more than 2 years. This complicates ageing research, since such aged animals might be too frail for functional analyses, and makes ageing studies very long and expensive to perform. Furthermore, it is unclear what the earliest time
points that constitute vascular ageing in laboratory mice are, which
physiological measures of large artery stiffness correspond most
closely to humans.
It is
unclear whether decreased mitochondrial function promotes vascular
ageing directly or is just a consequence of ageing.
The
authors examine multiple parameters of vascular function,
histological markers, and markers of mitochondrial damage and
function during normal vascular ageing, and the effects of reducing or
augmenting mitochondrial function on the onset and progression of
vascular ageing.
RESULTS
The authors show that:
Vascular
ageing in mice can be demonstrated by changes in a variety of
physiological parameters, with multiple robust reproducible markers
appearing as early as 44 wk (earlier than previously thought,
allowing for shorter vascular ageing protocols).
Mouse
vascular ageing is associated with characteristic structural changes
over the same time, confirming that these changes in physiological
parameters represent structural changes associated with ageing.
Mitochondrial copy number (mtCN),
the proteins that regulate it, and mitochondrial respiration are
all reduced at the same age that changes in functional and structural
parameters were observed.
Finally,
using gain- and loss-of-mitochondrial-function mouse models, we
identify that mtCN and mtDNA integrity directly regulate the onset
and progression of vascular ageing in mice. In
other words, manipulations
that result in increased or decreased respiration delay or
accelerate changes associated with ageing, respectively.
The mouse models used were mice overexpressing the helicase Twinkle, to increase mtCN and mitochondrial respiration, and the PolG mutator mice, to compromise mtDNA integrity. These mice do not show change of ROS (at least in early life for the PolG mice, which is when these mice were examined). This suggests that the role of mitochondria in vascular ageing goes beyond ROS.
