Staff Profile:Dr Alistair VW Nunn

Areas of Interest:

Dr Alistair Nunn joined the University of Reading as the GW Pharmaceuticals Associate Professor in Hormesis and Metabolic Adaptation in October 2013, prior to this he had been a visiting scientist in the department from Imperial College. This post is based in the School of Pharmacy. His main interests are lifestyle-induced disease, the ageing process, and the mode of action of cannabis as a medicine; the common link in understanding these maybe the concept of "hormesis" - a biological epiphenomena where a non-lethal dose of a stressor induces adaptation to resist it and is characterised by the biphasic stimulation/inhibition curve.

His focus is the interaction between metabolic stressors and how they affect the ageing process, in particular, the adaptive response to agents that threaten energy and redox homeostasis. This phenomenon has been observed for 100s, if not 1000s of years in the guise of "what doesn't kill you makes you stronger". This concept can be derived from evolution by natural selection because organisms evolved in a generally energy poor environment where individual survival in times of hardship became a priority when reproduction became less likely; by redirecting energy towards somatic maintenance the individual can survive to breed again another day, so passing on its genes. In contrast, with plenty of energy, there is no particular selective pressure for an individual to survive because offspring can be produced. However, it is now becoming clear that this could also be supported by something even more basic: mathematical proof in relation to an emerging idea that biological systems are basically dynamically unstable, but appear to develop self-organising emergent properties in response to external conditions.

The above idea would explain the long known observations that calorie restriction, exercise and eating plant compounds can have beneficial effects on health and thus, longevity. In contrast, it has been equally obvious that over-eating, especially of diets heavy in animal products and low in vegetable matter, coupled with a sedentary lifestyle, had the opposite effect. The ancient Greeks knew it, as did the Romans. Paracelsus noted in the 16th century that the dose makes the poison, while Schultz, amongst others in the 19th Century, observed that many compounds that inhibited bacteria and yeast growth at higher concentrations actually stimulated growth at lower concentrations. It wasn't until the 20th Century that this biphasic effect was given a name "hormesis", which comes from the Greek "hormeain", to urge on. In effect, it has been known for 1000s of years that a low dose of something that might be potentially harmful at a higher dose, actually improved health.

Unfortunately, despite much contradictory evidence, this threshold biphasic adaptive effect was essentially overlooked by large sections of the scientific community when the linear dose no threshold (linear no threshold, LNT) model took hold in the 1940 and 1950s in relation to ionizing radiation-induced mutation - a concept largely driven by HJ Muller in his race to demonstrate inducible inheritable changes. In effect, he wanted to prove that background radiation could drive mutation and explain evolution, and thus, even at low doses, the effects of radiation were linear. Although it became clear that the background radiation was too low to explain this, the physics based "mutation hit theory" of the time took hold in relation to cancer. The LNT idea was subsequently applied by many regulatory authorities in the world of pharmacology/toxicology and the biphasic concept was not examined in any great depth. Indeed, it almost gained pariah status because of its unfounded links with homeopathy; the world of science shied away from low dose effects that appeared to be below classic toxic levels. One of the reasons for the LNT being so popular is that in regulatory terms, it is much easier to understand and apply, for instance, in relation to radiation or carcinogens. Alas, nature is not that simple.

This is unfortunate, because it is becoming clear that life is highly adaptive to mild stressors and the resulting phenotype is often tougher and longer lived, and usually smarter (in its broadest definition, intelligence is the ability to learn and adapt - an important survival trick). Life is in fact dynamically unstable, and illusions of stability arise because of robustness faced with a constantly changing environment. Understanding hormesis, and the molecular mechanisms involved, can provide real insight to many modern diseases - this can range from classical lifestyle-induced ones, like the metabolic syndrome and diabetes, to conditions where mutations can lead to metabolic dysfunction and chronic inflammation, such as epilepsy, multiple sclerosis and possibly, even muscular dystrophy. The common factor appears to be a failure to resolve a dysfunctional homeostatic system, such as inflammation; it may well be that a degree of hormesis is important in inducing resolution, perhaps by limiting energy. Using this concept it may be possible to explain why many bioactive plant compounds have benefits; they mildly inhibit cell function and thus instigate a reparative response that is very similar to that encompassed by the term "hormesis". In particular, data support the involvement of the mitochondrion as a key organelle in this process, and indicate a delicate yin-yang balance between oxidative phosphorylation, inflammation and glycolysis. In fact, the pathways involved in hormesis, ageing and the xenobiotic response share many common factors. But perhaps the most fundamental point of all is that modern multicellular life, in particular, relies on the ability to protect a proton gradient, and thus, the ability to generate energy and store information; this has it echoes from the very beginning of life. Anything that challenges this will induce adaptation, otherwise we wouldn't be here. Life would never have even started, or evolved, in a stable environment. The take home message is simple; we all require a degree of metabolic stress to optimise our fitness, smartness and thus, longevity.

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This list was generated on Thu Mar 26 23:36:17 2015 GMT.

Visiting scientist in the Molecular Imaging Group, Imperial College, Hammersmith Campus, London.

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