Age of posterity

Anti-inflammaging – a very modern dichotomy

A common command that adults use with hyperactive children is “act your age!”. For hypoactive middle-aged and older adults, the best advice is “don’t act your age”.

Many of these older adults, beset by chronic conditions that are rare in childhood, would do well to sit less and move more.

Ageing and inactivity contribute to ‘inflammaging’, a hybrid term of inflammation and ageing. This term describes a state of chronic, low-grade inflammation, which progresses with age and contributes to deterioration of the mind and body.

Inflammation is a tradeoff between acutely beneficial and chronically harmful. Acute or short-term inflammation is helpful and necessary to eliminate invading microorganisms. When inflammation persists and turns chronic, however, it is more harmful than helpful.

These harmful effects are related to the ‘scorched earth’ tactics of inflamed immune cells, which release a toxic mix of chemicals.

The longer that inflammation goes on, the greater the collateral damage, which drives a vicious circle of more inflammation and more damage that eventually leads to irreversible organ dysfunction and disease.

Besides infection, other so-called ‘sterile’ or non-infectious triggers or signals that activate an inflammatory response include cholesterol, uric acid and obesity. Exposure to these triggers tends to accumulate with age, which leads to inflammaging.

The onset and continuation of inflammation depends on a series of proteins called the inflammasome, which assemble in response to the above triggers.

The main outputs of inflammasome activation are secretion of the inflammatory cytokines, IL-1β and IL-18, and the initiation of a form of cell death called pyroptosis.
It is common to attribute ill health to ‘bad genes’, and while genetic predisposition certainly plays a role, lifestyle and dietary factors may play an even more important one.

In so-called ‘blue zones’ around the world, where longer-lived individuals reside, commonalties include a high level of physical activity, family solidarity, social interaction, and plant-based diets or caloric restriction.

The emphasis of this article is on anti-inflammaging interventions with the proven (or hypothesised) potential to increase not only lifespan, but perhaps, more importantly healthspan – that is, the duration of health and independence before chronic disease and disability set in.

These interventions include diet, exercise, metformin, statins and angiotensin receptor blockers, rapamycin, indirect antioxidants, and senolytic drugs.

Indirect antioxidants: Antioxidants neutralise free radicals, which randomly oxidise and damage cells. The main source of free radicals are the mitochondria, the ‘tesla-like’ battery packs that take up residence in every cell and give them energy.

A common misconception is that antioxidant supplements decrease inflammation and extend healthspan. In fact, the opposite is true. In several clinical trials high doses of antioxidant supplements, like vitamin E, beta carotene or vitamin A and vitamin C that directly scavenge free radicals, increase mortality and decrease exercise performance.

This unexpected result is most likely related to interference with Nrf2 activation. Nrf2 is a gene, which turns on many antioxidant and detoxifying enzymes. By contrast, indirect oxidants mostly found in vegetables and fruits activate Nrf2.

Direct antioxidants decrease reactive oxygen species and a protective antioxidant response. Indirect antioxidants activate antioxidant defences such as Nrf2.

Diet: The intrinsic appeal of plant-based diets is that they are rich in indirect antioxidants, which activate Nrf2. A prototypical example is the Mediterranean diet, which consists mainly of vegetables, fruit, whole grain, legumes and nuts.

Other Nrf2-activating patterns of eating include the ketogenic diet, calorie restriction and intermittent fasting. Also, a Western diet is associated with gut inflammation and ageing. Meanwhile, diets rich in non-digestible fiber or prebiotics may reduce the risk of inflammaging.

Metformin: The most prescribed treatment for type 2 diabetes, metformin, blocks activation of the NLRP3 inflammasome. Metformin also turns on other beneficial proteins. Metformin is also associated with anti-ageing effects in C. elegans and mice, however whether this benefit extends to humans is unknown. Anti-ageing studies in humans are ongoing.

Exercise: Longer life expectancy correlates with exercise, in general, the more the better. Mechanisms include activation of Nrf2, and inhibition of the inflammasome.
Direct inflammasome inhibitors: The most clinically advanced of the direct inflammasome inhibitors is RRx-001, in a Phase 3 trial for the treatment of cancer. Its anti-inflammatory properties make it potentially well suited for the treatment of age-related conditions like Parkinson’s Disease and ALS/MND, where it is under evaluation.

Heat stress: In response to heat exposure, as in a sauna, increased production of heat shock proteins (HSPs) occurs. These stress proteins may contribute to anti-ageing effects through removal of misfolded proteins, which accumulate during ageing, and that are toxic.

Statins and angiotensin receptor blockers (ARBs): These are drugs used to treat high cholesterol and high blood pressure respectively. In a study of 130 middle-aged males, treatment with a low dose of the statin, fluvastatin and/or the ARB, valsartan, either separately or in combination substantially increased the expression of several longevity genes.

Senolytic drugs: Senescent cells also known as zombie cells accumulate during ageing and disease, where they activate the inflammasome. Senolytics are drugs, which selectively kill or eliminate senescent cells.

They are associated with anti-ageing effects in experimental animals. Examples of potential senolytics include rapamycin and dasatinib, which are already FDA approved for other diseases.

The quest to live forever is as old as recorded history – and as urgently pursued as ever.
As a common denominator, all the anti-inflammaging interventions discussed in this article activate mild-to-moderate stress responses.

‘Adapt or die’ is a basic principle of evolution. To survive and thrive it was – and still is – primordially necessary to acclimate to multiple stressful conditions from which life on Earth emerged. These include oxidation, frigid temperatures, radiation, starvation, pollution, heavy metal exposure, infection and trauma.

In modern life the absence of these ‘old’ known stresses, to which human physiology adapted, is a ‘new’ stress, which contributes to inflammaging.

In summary, deliberate exposure to moderate and intermittent levels of stress dials up adaptive protective responses. With age, however, resilience to stress decreases.

The more that these protective responses are activated the better equipped an individual, especially an older individual, is to mount a defence against inflammaging and stave off age-related diseases either now or in the future.

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