Hunger games

Hara hachi bu is a Confucian adage that dates back 2500 years and instructs people to eat until they are 80% full. The Okinawans from Japan use this mantra before every meal, enabling them to be mindful of their food consumption. Elderly Okinawans have among the lowest mortality rates in the world from a multitude of chronic diseases of aging and as a result enjoy not only what may be the world’s longest life expectancy, but also the world’s longest health expectancy. Their longevity can be attributed to multiple environmental factors such as the quality of dietary intake, energy output, genetics, and their social structures. However, I want to emphasize the caloric restriction that is implied in the above mantra. It has been shown in numerous organisms ranging from yeast to mammals that calorie restriction without malnutrition by 30-40% typically delays diseases of aging and extends lifespan. We have known about the benefits of caloric restrictions for decades and even centuries (check out Luigi Cornaro from the 1400s and Clive McCay more recently). This might seem counterintuitive at first glance, but if viewed through an evolutionary prism, it makes perfect sense. As hunter gatherers, we were always at risk for enduring long and lean winters, and consequently have regulatory pathways that are primed for these environments. Exposure to stressors such as a cold environment or low energy states trigger a set of conserved pathways that optimize energy utilization and cellular survival.

The sirtuin class of genes is one such candidate, which acts as the master metabolic regulatory switch. These genes are conserved evolutionarily, and therefore are present in organisms ranging from yeast to human. Consequently, they must play an essential role for organism survival as key evolutionary mechanisms are often conserved and replicated. Sirtuins have been shown to regulate important biological processes ranging from critical aspects of glucose homeostasis including insulin sensitivity, and gluconeogenesis to neuronal survival and anti-inflammatory processes. Thus, overexpression of these genes can lead to beneficial life extending effects. Stressors such as calorie restriction and exposure to cool environments both trigger expression of these pathways. Interestingly, increased polyphenol concentration in a diet can also stimulate sirtuin gene expression. It has been hypothesized that increasing concentrations of polyphenol (plant based diet) signaled an impending decrease in high density energy sources (meat) and therefore, activated a favorable stress response mediated via these genes. Therefore, it might not be macronutrient (carbohydrate vs fat) constitution nor the purported antioxidant properties of a plant based diet that confers its advantage but the micronutrient concentration  that influence sirtuin gene expression.

In summary, disease and aging, largely comes down to a matter of energetics. We now live in a world filled with excesses – warmth, calories – and these excesses are most likely the root cause of our chronic disease burden. A recent article in Journal of the American Medical Association study showed “US baby boomers have higher rates of chronic disease, more disability, and lower self-rated health than members of the previous generation at the same age.” By some estimates, overall US life expectancy might actually drop over the next two decades. Until we can utilize the advances in bioinformatics to engineer more precise hacks to target selective gene expression we will have to design culturally accepted societal systems that exogenously decrease this energy imbalance. Ideas such as calorie restriction via programs of intermittent fasting, non-shivering thermogenesis (by turning down the thermostat in public places), a societal focus on consuming diversely sourced plants versus calorically dense meats via campaigns such as “meatless Monday,” and building activity into our daily life will all go a long way in staving off the effects of chronic diseases.