Age old question

We’re all getting older but what can we do to halt its wicked ways?

Old age. It’s something we all have in common. We either are old or, with a certain amount of fortune, we will experience it at some stage in the future. But with old age, comes trepidation.

At first the shadow of being old is too far away to see or even to imagine. But with each passing year the shadow creeps ever closer.

While still distant in adolescence, young adulthood and even later adulthood, the shadow looms larger in middle age and beyond until one day, organically and subtly, without fanfare, it merges with the person, who has now become a shadow of his or her former self.

The once rosy-cheeked face in the mirror, previously aglow with the vigour of youth, and now covered in stress lines and wrinkles, has become faded and unrecognisable along with thinning grey hair, tremoring hands, hunched posture and unsteady gait.

But what if it were possible to catch old age and to arrest its progress? If this sounds like science fiction, consider that the inhabitants of five geographical regions around the world, called Blue Zones, with a high prevalence of centenarians have appeared to do just that.

These five less populous, geographic regions of extreme longevity are Okinawa Prefecture, Japan; Nuoro Province, Sardinia, Italy; the Nicoya Peninsula, Costa Rica; Icaria, Greece; and Loma Linda, California, USA.

If the Blue Zones possess a common denominator, it is the promotion of oxidative and inflammatory eustress through lifestyle and environmental factors that include outdoor physical activity, calorie restriction, the prevalent consumption of phytochemical-rich foods and beverages, cognitive stimulation and minimal exposure to chemical contaminants.

Eustress, a term that refers to ‘good stress’, is distinguished from distress or ‘bad stress’.

Oxidative and inflammatory eustress involves minimisation of free radical and inflammatory damage to DNA, proteins and mitochondria, and the prevention or delayed onset of diseases like cancer, neurodegeneration, organ failure, diabetes, autoimmunity, atherosclerosis, hypertension and obesity as a result.

The purpose of this brief review is to present environmental, lifestyle and pharmaceutical interventions that may contribute to healthy longevity.

What exercise, calorie restriction and the regular consumption of berries, fruits, nuts, dark chocolate, spices, vegetables, olive oil, coffee and tea have in common is that being pro-oxidant and pro-inflammatory in nature they stimulate adaptive antioxidant and anti-inflammatory defence mechanisms.

This may sound paradoxical, but in fact, many of the foods and beverages like fruits, vegetables, coffee and tea with supposed antioxidant activity are actually low-dose toxins with pro-oxidant activity that protect plants against predation from insects, fungi and animals.

These plant-derived toxins include ascorbic acid in citrus fruits, quercetin in blueberries, beta-carotene and lycopene in carrots, α-lipoic acid in olive oil, sulforaphane in broccoli, turmeric in curry, epigallocatechin-3-gallate in green tea, catechins in coffee and resveratrol in red wine.

At the sub-lethal doses consumed by humans and other animals as part of their diet, these pro-oxidant toxins activate mild stress responses that benefit health and longevity.

The same is true of exercise, exposure to intermittent heat and cold, cognitive stimulation, intermittent fasting and calorie restriction.

These are stressors (eustressors) that, so long as they remain brief and not too intense or strenuous, stimulate repair mechanisms and resistance to similar or larger stressors (distressors) that would, perhaps in another context, represent detrimental situations.

In the long term, regularly intermittent exposure to these several stressors protects against age-associated diseases and extends longevity at least in animal models and possibly in Blue Zones as well.

Key cell-protective molecules are nuclear factor erythroid-2 (Nrf2), superoxide dismutase (SOD), insulin-like growth factor-1 (IGF-1), AMP-activated protein kinase (AMPK) and sirtuins.

Potential anti-ageing medications that stimulate key repair and protective molecules are statins like simvastatin and atorvastatin, aspirin, metformin and angiotensin-converting-enzyme inhibitors.

They also include angiotensin II receptor blockers (ARBs) like lisinopril and losartan, and inhibitors of mTOR, including clinically available therapies such as rapamycin (Sirolimus) and Everolimus, and beta blockers like propranolol.

Furthermore, a polypill that contains aspirin, an ACE inhibitor and a statin has been approved across more than 30 countries.

Ancient man was a hunter-gatherer whose very survival depended on prolonged physical activity and the traversal of large geographical distances over potentially complicated surfaces like mountains.

This involved foraging fruits, roots, nuts, seeds, leaves, stalks and eggs, hunt wild animals, find water and shelter, and to escape large predators.

In addition, these early Homo sapiens primarily survived on a very high-fibre diet of vegetables, fruits and nuts with only occasional consumption of meat and fish, when available, and likely practised intermittent fasting to conserve food resources.

By contrast many modern western societies have minimised or eliminated environmental threats and stresses that early humans regularly faced and adapted to, including food and water scarcity, predation, infections, extremes of temperature and regular physical activity.

Moreover, the limitless 24/7 availability of processed foods high in calories, saturated fats, salt and refined sugars, and low in nutrients dominate the modern western diet.

The result of this sedentary obesogenic environment is a state of chronic low-grade inflammation and oxidation.

Chronic inflammation and oxidation appear to underlie most, if not all, chronic diseases like heart failure, depression, type 2 diabetes, osteoarthritis, Alzheimer’s disease and cancer that accelerate ageing and ageing, in a vicious circle, accelerates the development of these chronic diseases.

Besides abstention from cigarette smoking and avoidance of sunburn, perhaps the best advice to increase healthspan and lifespan is to stress more, not less.

Intermittent exposure to eustressors, which harks back to a distant evolutionary past, may immunise against the ills of modern life.

These eustressors include physical activity with a target of > or = to 10,000 steps, calorie restriction/fasting, cognitive/sensory stimulation, dietary phytochemicals, intermittent cold (e.g., ice baths, cold showers), occasional heat (e.g., sauna, hot tub) and certain medications described above.

All of these elicit adaptive stress responses that increase resilience and forestall ageing, while lack of stress increases vulnerability to chronic diseases and accelerated ageing.

To purposefully misquote the philosopher, George Santayana, those who cannot remember the distant evolutionary past are doomed to not repeat it.

Bryan Oronsky is Chief Medical Officer at EpicentRx. Go to epicentrx.com