Remote tissue conditioning — An emerging approach for inducing body-wide protection against diseases of ageing

doi:10.1016/j.arr.2017.05.005

Ageing Research Reviews

Volume 37, August 2017, Pages 69-78

https://doi.org/10.1016/j.arr.2017.05.005 Get rights and content

Highlights

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Mild stress to a tissue elicits an endogenous response that enhances its resilience.
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Two examples are brief ischemia and photobiomodulation with low-intensity light.
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For both stresses, protection appears to spread beyond the site of application.
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This phenomenon of indirect protection is termed “remote tissue conditioning” (RIC).
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RIC holds promise for prevention or treatment of chronic age-related diseases.

Abstract

We have long accepted that exercise is ‘good for us’; that – put more rigorously – moderate exercise is associated with not just aerobic fitness but also reduced morbidity and reduced mortality from cardiovascular disease and even malignancies. Caloric restriction (moderate hunger) and our exposure to dietary phytochemicals are also emerging as stresses which are ‘good for us’ in the same sense. This review focuses on an important extension of this concept: that stress localized within the body (e.g. in a limb) can induce resilience in tissues throughout the body. We describe evidence for the efficacy of two ‘remote’ protective interventions – remote ischemic conditioning and remote photobiomodulation – and discuss the mechanisms underlying their protective actions. While the biological phenomenon of remote tissue conditioning is only partially understood, it holds promise for protecting critical-to-life tissues while mitigating risks and practical barriers to direct conditioning of these tissues.

Introduction

One major health challenge facing modern society is the extension of lifespan beyond the good health of the individual, resulting in prolonged end-of-life morbidity. The rising incidence of chronic diseases in an ageing population, and the related economic and social burden of ageing, provide great impetus to the development of ways to delay or prevent chronic disease, compressing the period of end-of-life morbidity.

Biological ageing can be considered to be a loss of physiological reserve (Rowe and Kahn, 1997) and of tissue resilience in the face of the stresses of ageing. Tissue ageing and chronic end-of-life disease might then be delayed by enhancing the body’s capacity to endure and adapt to physiological stressors and pathological threats. Because ageing affects many body tissues, interventions to counter its effects must have systemic actions, inducing protective mechanisms in a broad range of tissues and organs.

This broad range has been demonstrated for dietary restriction and exercise, which both up-regulate body-wide endogenous stress response mechanisms (Gems and Partridge, 2008, Mattson, 2008). However, emerging evidence suggests that body-wide protective effects may also arise from localized insults or stresses – a phenomenon which has therapeutic promise as well as fundamental scientific implications.

This review will discuss some of the pre-clinical and clinical evidence that two stresses that can be localized in the body – ischemia and photobiomodulation – can induce a significant self-protective response in remote parts of the body, in a reaction termed remote tissue conditioning, and provide an overview of what is known of the pathways involved. Remote tissue conditioning is already being used or evaluated in conditions (e.g. ischemic heart disease, cerebrovascular disease, neurodegenerative disease, renal injury) that predominantly affect the older population. The ability to protect critical organs by directing treatment to less critical tissues, such as a limb or the torso, could offer safe, convenient and minimally-invasive interventions for age-related chronic diseases.

Section snippets

Low-level stress enhances tissue resilience

In the late 19th Century, toxicologists reported that some known toxins had trophic effects at low doses; the phenomenon was first termed the Arndt-Schulz law, and later hormesis, as reviewed elsewhere (Calabrese et al., 2007). With hindsight, the observation that many substances are toxic at some high dose seems less interesting; it is a re-statement of Paracelsus’ principle or generalisation, which is often identified as a foundation of toxicology. Paracelsus wrote Sola dosis facit venenum

Localized low-level stress induces body-wide resilience

Many of the stressful stimuli that induce tissue resilience at low doses affect much or all of the body; examples include dietary restriction, exercise and phytochemical consumption (Mattson, 2014). In a few forms, the stimulus can be applied locally and it is possible to test whether the response is confined to the target region, or spreads more widely. The best-studied forms of localized stresses are ischemia, which often affects or can be experimentally confined to only part of the body, and

Remote ischemic conditioning

Perhaps the best characterised example of a localized stress acting distally is remote ischemic conditioning (RIC), in which the application of brief ischemia to one tissue, usually a limb, induces a self-protective response in a distant tissue, usually a critical organ such as heart, brain or kidney (Crowley and McIntyre, 2013, Hess et al., 2015, Lim and Hausenloy, 2012).

Remote photobiomodulation

Photobiomodulation (PBM) involves the irradiation of tissue with low-intensity red to near-infrared light (600–1100 nm). Like ischemic conditioning, PBM elicits a self-protective response at low doses (<10 J/cm² daily) in the directly targeted tissue, and the response diminishes with increasing daily doses (Huang et al., 2011). Current clinical applications of PBM include tissue and wound healing in the setting of oral mucositis (Fekrazad and Chiniforush, 2014), diabetic foot ulcers (

Conclusions

The availability of non-pharmaceutical interventions that enhance the resilience of cells, tissues and organisms against acute stresses such as ischemia and toxins and against the chronic stresses of age-related decline is steadily earning acceptance in the scientific mainstream. Many interventions have been advocated in recent years – dietary restriction, exercise, phytochemicals – raising questions as to (i) which is safest, (ii) which is most effective and (iii) which is least burdensome for

Acknowledgements

DMJ is supported by an Early Career Fellowship from the National Health & Medical Research Council (NHMRC) of Australia. JS is supported by the Sir Zelman Cowen Universities Fund.

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ReviewRemote tissue conditioning — An emerging approach for inducing body-wide protection against diseases of ageing

Highlights

Abstract

Introduction

Section snippets

Low-level stress enhances tissue resilience

Localized low-level stress induces body-wide resilience

Remote ischemic conditioning

Remote photobiomodulation

Conclusions

Acknowledgements

Cell Stem Cell

Lancet

Toxicol. Appl. Pharmacol.

Pharmacol. Res.

Pharmacol. Res.

J. Am. Coll. Cardiol.

Clin. Neurol. Neurosurg.

JACC Cardiovasc. Interv.

Cell

J. Mol. Cell. Cardiol.

Cell Metab.

Exp. Neurol.

J. Photochem. Photobiol. B

Eur. J. Pharmacol.

Brain Res.

Neuroscience

Cell Stem Cell

J. Photochem. Photobiol. B

Nat. Med.

J. Inflamm. (Lond).

Brain Res.

J. Mol. Cell. Cardiol.

Brain Res.

Ageing Res. Rev.

Neurotherapeutics

Cell Metab.

Pharmacol. Ther.

Role of 830 nm low reactive level laser on the growth of an implanted glioma in mice

Keio J. Med.

Photobiomodulation protects the retina from light-induced photoreceptor degeneration

Invest. Ophthalmol. Vis. Sci.

Renal protection by brief liver ischemia in rats

Transplantation

Remote ischaemic pre- and delayed postconditioning – similar degree of cardioprotection but distinct mechanisms

Exp. Physiol.

Effects of remote ischemic preconditioning on perioperative period in elective aortic valve replacement

Anesteziol. Reanimatol.

Near-infrared light increases ATP, extends lifespan and improves mobility in aged Drosophila melanogaster

Biol. Lett.

Cardioprotection by remote ischemic preconditioning is blocked in the aged rat heart in vivo

J. Cardiothorac. Vasc. Anesth.

Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit

Circulation

Low-level laser therapy in acute pain: a systematic review of possible mechanisms of action and clinical effects in randomized placebo-controlled trials

Photomed. Laser Surg.

Low-Level laser therapy to the bone marrow reduces scarring and improves heart function post-Acute myocardial infarction in the pig

Photomed. Laser Surg.

Loss of cardioprotection with ageing

Cardiovasc. Res.

Remote limb ischemic preconditioning: a neuroprotective technique in rodents

J. Vis. Exp.

Effect of helium-neon and infrared laser irradiation on wound healing in rabbits

Lasers Surg. Med.

Cardiac parasympathetic regulation: respective associations with cardiorespiratory fitness and training load

Am. J. Physiol. Heart Circ. Physiol.

Light promotes regeneration and functional recovery and alters the immune response after spinal cord injury

Lasers Surg. Med.

Remote ischemic preconditioning confers late protection against myocardial ischemia-reperfusion injury in mice by upregulating interleukin-10

Basic Res. Cardiol.

Hormesis: a revolution in toxicology, risk assessment and medicine

EMBO Rep.

Effect of remote ischaemic preconditioning on clinical outcomes in patients undergoing cardiac bypass surgery: a randomised controlled clinical trial

Heart

Mesenchymal stem cells as trophic mediators

J. Cell. Biochem.

The role of NMDA receptors in the development of brain resistance through pre- and postconditioning

Aging Dis.

Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts

PLoS One

Review
Remote tissue conditioning — An emerging approach for inducing body-wide protection against diseases of ageing