Free radicals and vascular ageing; move your muscles, move your mind!
Submitting InstitutionUniversity of South Wales
Unit of AssessmentSport and Exercise Sciences, Leisure and Tourism
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Neurosciences
Summary of the impact
The Vascular Health Group led by Bailey has achieved
international impact by transforming our understanding of the source,
mechanisms and consequences of free radical formation in the ageing human.
The development of novel biomarkers of health and well-being has
challenged conventional wisdom, informed public policy and debate and
raised public awareness to the vascular benefits of physical activity.
These advances have improved health and welfare outcomes of the elderly
including those suffering from advanced atheroslcerotic disease. Applied
research focused on the pro-oxidant stimulus hypoxia, has led to
improvements in the management of high-altitude illness amongst both
mountaineers and native communities.
Free radicals have long been implicated in the ageing process though
human evidence is lacking due to a traditional reliance on indirect
non-specific biomarkers confined to the peripheral circulation. By
employing novel analytical techniques including electron paramagnetic
resonance spectroscopic spin-trapping with regional arterio-venous blood
sampling, Bailey has provided unique insight into the source,
mechanisms and consequences of free radical formation in the ageing human
with a clinical focus on the vascular endothelium.
Initial studies with the University of California San Diego (Richardson)
were the first to identify that exercising human skeletal muscle directly
generates free radicals. These works were subsequently extended to
demonstrate that resting and exercise-induced free radical formation was
more pronounced in old compared to young skeletal muscle (i), providing
the first human evidence in support of the Free Radical Theory of
Ageing postulated more than half a century ago. Follow-up studies provided
a mechanistic basis to explain why vascular endothelial function becomes
impaired with ageing which was attributed to a free radical-mediated
reduction in the vascular bioavailability of the vasodilator molecule
nitric oxide. These studies also highlighted the vascular benefits of
antioxidant prophylaxis which has implications for slowing down the ageing
process. The observation that exercise-induced free radical formation was
associated with a reduction in mitochondrial oxygenation led to a focus on
hypoxia involving collaborations with the Universities of Heidelberg
(Bärtsch) and Copenhagen (Pedersen, Saltin, Möller and Secher) with
funding from the Danish Research Council to support a post-doctoral
researcher (Evans). The research provided the first human
evidence that free radical formation increased during hypoxia,
contrary to traditional opinion. The brain and lungs were later
indentified as "regional generators" allowing the team to calculate for
the first time, local rates of free radical turnover (ii, iii). The
findings also provided unique insight into the pathophysiology of
high-altitude illness, notably the neurological and pulmonary syndromes of
acute mountain sickness, high-altitude cerebral and pulmonary oedema.
Contrary to prevailing dogma, it was later suggested that in
physiologically controlled albeit undefined amounts, free radical
formation in hypoxia may prove an adaptive phenomenon that can accelerate
acclimatisation and boost exercise performance, akin to human
"oxygen-sensing". (iv). A series of follow-up studies in native
highlanders, individuals born and bred at high-altitude, introduced the novel
concept of a "physiological free radical threshold" beyond which
diseases characterised by premature vascular ageing such as chronic
mountain sickness may occur (v).
The past five years has seen the team focus on the ageing brain
concentrating efforts towards the development and implementation of novel
haemodynamic measures of cerebrovascular function in collaboration with Ainslie.
Recent findings have identified physical activity maintained over the
human lifespan can reduce the brain's "functional age" by over a decade
providing a mechanistic basis to explain why exercise reduces the risk of
stroke and dementia (vi). These techniques have also been applied in the
sporting context, providing improved sensitivity for the detection of
subtle brain injury following concussion, a unique sports-based model of
accelerated brain ageing that increases susceptibility to dementia.
References to the research
i. Bailey, D.M., McEneny, J., Mathieu-Costello, O., Henry,
R.R., James, P.E., McCord, J.M., Pietri, S., Young, I.S. and Richardson,
R.S. (2010). Sedentary aging increases resting and exercise-induced
intramuscular free radical formation Journal of Applied Physiology
ii. Bailey, D.M., Taudorf, S., Berg, R.M.G., Lundby, C.,
McEneny, J., Young, I.S., Evans, K.A., James, P.E., Shore, A., Hullin,
D.A., McCord, J.M., Pedersen, B.K. and Møller, K. (2009). Increased
cerebral output of free radicals during hypoxia: implications for acute
American Journal of Physiology (Regulatory, Integrative and
Comparative Physiology) 297: R1283-R1292.
iii. Bailey, D.M., Dehnert, C., Luks, A., Menold, E.,
Castell, C., Schendler, G., Faoro, V., Gutowski, M., Evans, K., Taudorf,
S., James, P., McEneny, J., Young, I.S., Swenson, E., Mairbäurl, H.,
Bärtsch, P. and Berger, M.M. (2011). High-altitude pulmonary hypertension
is associated with a free radical-mediated reduction in pulmonary nitric
Journal of Physiology 588: 4837-4847
iv. Bailey, D.M., Taudorf, S., Berg, R.M., Lundby, C.,
Pedersen, B.K., Rasmussen, P. and Møller, K. (2011). Cerebral formation of
free radicals during hypoxia does not cause structural damage and is
associated with a reduction in mitochondrial PO2; evidence of O2-sensing
Journal of Cerebral Blood Flow and Metabolism
v. Bailey, D.M., Rimoldi, S.F., Rexhaj, E., Pratali, L.,
Salmòn, C.S., Vilena, M., McEneny, J., Young, I.S., Nicod, P., Allemann,
Y., Scherrer, U. and Sartori, C. (2013). Oxidative-nitrosative stress and
systemic vascular function in highlanders with and without exaggerated
hypoxemia. Chest 143: 444-451.
vi. Bailey, D.M., Marley, C.J., Brugniaux, J.V., Hodson,
D., New, K.J., Ogoh, S. and Ainslie, P.N. (2013). Elevated aerobic fitness
sustained throughout the adult lifespan is associated with improved
Stroke 44: 3235-3238.
Details of the impact
Health and welfare impacts
Having identified increased free radical formation and impaired vascular
structure/function subsequent to a selective depletion of the antioxidant
vitamin C in patients with abdominal aortic aneurysms (AAA), the Vascular
Health Group in collaboration with Prof MH Lewis (Visiting Professor,
Consultant Vascular Surgeon and Bailey's PhD student), are
involved in the Wales AAA Screening Programme (http://www.aaascreening.wales.nhs.uk/home).
The Group have widened the protocol to include novel free radical and
vascular biomarkers including cardiopulmonary exercise testing to reduce
the vascular complications and untimely deaths associated with AAA rupture
and direct surgery. By improving screening sensitivity, these activities
have had a beneficial impact on the patients' quality of life, their
families and society in general. We anticipate that this will improve on
the current 53% risk reduction in AAA-related deaths and mean cost
effectiveness of £28k per patient per life-year gained.
Similar approaches have been applied to stroke patients scheduled for
elective carotid endarterectomy, a surgical procedure that corrects
carotid stenosis improving perfusion to the brain. Bailey's Group
have shown that the speed of surgical repair (ie. reducing the time
that clamps are applied to the diseased artery) dictates the extent of
free radical formation and corresponding neurocognitive decline that
persists during the post-operative recovery phase, highlighting why
"surgical speed" is so critical for patient outcome. Furthermore, it was
generally accepted that this procedure improves cognitive function, due in
part to increased cerebral perfusion. This was "misinformed" given that
prior investigators consistently failed to take into account learning
effects. As a consequence, patients are now being advised cognitive
function will be impaired during the recovery period thereby reducing
Given that arterial hypoxaemia is a common feature of vascular disease
with the capacity to stimulate free radical formation, the group have also
focused on chronic mountain sickness (CMS), a novel model of accelerated
vascular ageing and decreased longevity. Recognised by the World Health
Organisation, CMS affects 5-10% of an estimated 140 million natives living
at altitude with treatment largely ineffective. They identified that CMS
was associated with impaired systemic vascular structure/function due to a
free radical-mediated reduction in the vascular bioavailability of nitric
oxide. Similar to the surgical patients previously outlined, this was
attributed to a selective depletion in the antioxidant vitamin C,
providing clear justification for antioxidant prophylaxis as a viable
clinical intervention. In collaboration with the Bolivian High Altitude
Biology Institute (IBBA), pharmacological (iv ascorbate infusion)
and dietary (fresh fruit and vegetables) approaches have since been
deployed to increase the concentration of circulating antioxidants,
interventions that are already having a positive impact on patient health
and well-being (personal communication, Dr M Villena, IBBA).
Extending this work from the systemic to the cerebral circulation, novel
cerebrovascular function tests have been deployed within the sporting
context, notably in mountaineers to screen for "subtle" imperfections in
brain blood flow regulation that can be detected even at sea-level and
inform the risk of developing altitude-related illnesses during ascent to
high-altitude. These tests have been communicated to commercial companies
(eg. Altitude Centre, Icicle Expeditions) given that they have the
potential to improve management of environmental risk with implications
for indemnity and insurance. Similar tests have been applied for the
detection of subtle brain injury following concussion, a novel model of
accelerated brain ageing that increases susceptibility to dementia. A
recent publication in professional boxers highlighted that the majority of
brain injury occurs due to the mechanical trauma incurred by repetitive,
sub-concussive head impacts associated with sparring "training" and not as
traditionally believed, due to a single knockout blow during
"competition". This message has been communicated globally through the USA
warning combat specialists to limit their sparring. Similar warnings have
been communicated to rugby union players (including the Welsh Rugby Union)
and help inform "return-to-play" guidelines that currently lack any
clinical or scientific gravitas with an arbitrary 3 week suspension.
Creativity and practitioner impacts
The analytical advances outlined have led to research findings that have
challenged conventional wisdom/established norms and changed the modes of
thought and practice of research groups that have traditionally relied on
indirect, non-specific biomarkers of free radical activity to inform the
disease process. Internationally-renowned groups in the USA and Europe
have adopted the direct technique of EPR spectroscopy with specialist
input from Bailey.
Science communication impacts
Concerted attempts have been made to engage with the public to
disseminate research findings that have clear practical implications for
improving lifelong health and well-being in both the clinical and sporting
context. The reach has been considerable raising awareness both locally
Sources to corroborate the impact
i. Citation by broadcaster/public debate in the media/parliamentary
debate/improved welfare/satisfaction measures for beneficiaries
Patient testimonial(s) broadcast by the BBC attesting to the life-saving
benefits of vascular screening involving members of the Vascular Health
Group (May 2010).
ii. "End-user" engagement
Older People & Ageing Research & Develoment Network (OPAN)
Translational Research Seminar/Workshop -, Novotel, Cardiff (May 2012)
The OPAN Stroke Research Group held a research development event on Monday
9th May in Cardiff with the theme of Translational Research. The aim of
the day was to bring together stroke and ageing researchers and clinicians
and service users from across Wales to link "bench" to "bedside", to
identify priorities for clinical research with input from stroke patients
and develop potential collaborations.
iii. Committee positions helping inform public policy and debate
Cardiovascular Physiology Lead (2010-present) to the Cardiovascular
Research Group Cymru (CVRG-C),a Registered Research Group funded by the
National Institute for Social Care and Health Research. The aim of the
CVRG-C is to improve NHS healthcare by facilitating and supporting high
quality cardiovascular research in both the commercial and academic
sectors, encouraging collaborations between academics, cardiovascular
clinicians, cardiovascular service users and research funders.
iv-vi. Dissemination activities
Reaching out to local government:
Science and the Assembly: Sports and Science conference (May 2012).
Reaching out to the lay public:
Cheltenham Science Festival (June 2013).
Reaching out to school children:
I'm a Scientist Get Me Out of Here! Human Limits Zone (c/o The
Physiological Society, August 2013).
vii. Practitioner debate
Formal invitation (October 2012) from the lead clinician and founder of FightMedicine.net
to contribute monthly columns to an American website reaching out to an
international audience of combat specialists. Based on an original article
published by Bailey [Bailey, D.M., et al. (2013).
Impaired cerebral hemodynamic function in professional boxers. Clinical
Science 124: 177-189], the forum provides educational material
and practical advice highlighting the long-term health implications of
sports concussion focusing on chronic traumatic brain injury.
viii-x. Broadcast citations
Wales Online (April 2012).
"Researchers to play high-altitude rugby matches to test male vs
female brain theory. A group of researchers will play a high-altitude
game of rugby sevens at the culmination of a unique project to
discover whether the female brain is better than the male".
and April 2010.
"Fifteen former Wales captains and coach Warren Gatland will attempt
to reach the summit of Kilimanjaro in September to raise money for
lung cancer research. Health Editor Madeleine Brindley, who will be
part of the Brains SA Captains Climb, examines the impact the
high-altitude trek will have on the team".
BBC News (July 2009).
"Medical students from Glamorgan University prepare for a trek to
test the levels of human endurance at high altitude".