How Much of the Benefit of a Healthier Diet is Due to Natural Calorie Restriction Mimetics?

How much of the benefit of a healthier diet arises from the effects of natural calorie restriction mimetic compounds? That question is an interesting one from a scientific perspective, but the answers are probably not all that valuable in a practical sense. We have a fairly good idea as to the size of the benefits to long-term health obtained via a better diet, and separately by eating less of that diet, the practice of calorie restriction while still obtaining sufficient micronutrients. Calorie restriction mimetic compounds trigger some of the same beneficial cellular stress response mechanisms as does a low calorie diet, though in lesser and more piecemeal ways. Knowing more about how and why a better diet is a better diet isn't the path to large improvements in human longevity, but it is a fascinating subject, nonetheless.

In addition to genetic, environmental and lifestyle factors, nutrition plays a vital role in shaping health throughout human aging. Recently, health was defined as the sum of several hallmarks, including, the ability to react to environmental and cellular stress, integrity of barriers and maintenance of cellular and organismal homeostasis, of which many cross-talk with dietary factors. While a moderate consensus has been reached on what defines an unhealthy diet, the constitution of a healthy diet remains debated and subject to different beliefs. In principle, healthy diets should have positive effects on diverse health parameters, while not evoking negative effects. Different concepts of healthy dietary plans have been developed. These indices estimate and rate the intake of 8-12 components (for instance whole grain, nuts, legumes, fruit, vegetable, alcohol, etc.) and good scores are linked to lower cardiovascular disease (CVD) incidence and cancer mortality.

Accumulating evidence suggests that caloric restriction (CR) and various forms of fasting (intermittent fasting, time restricted eating, periodic fasting), avoiding malnutrition and including an adequate intake of macro- and micronutrients, present yet additional possibilities to promote the health status by reducing CVDs and cancer, among other beneficial effects. Recently, the concept of caloric restriction mimetics (CRMs) was developed to describe pharmacologically active substances that mimic some of CR's myriads of effects. At the core of the CRM definition, we and others argue that potential CR-mimicking compounds should in principle increase life- and/or healthspan and ameliorate age-associated diseases in model organisms, thus often the simultaneous use of the term "anti-aging substances." Additionally, CRMs should be capable of inducing autophagy, a homeostasis-regulating cellular recycling mechanisms that degrades obsolete, damaged or otherwise unneeded proteins, cellular structures or organelles.

Natural CRM candidates are widely present in foods and, in most cases, inevitably consumed by humans. Given their prominent occurrence in plant-based foods (especially polyphenols and polyamines), it is conceivable that these compounds contribute to the beneficial effects of healthy diets. Nevertheless, to date, specific dietary recommendations must be read with caution as too many uncertainties remain regarding bioavailability, concentration in food, stability and optimal intake levels. Furthermore, estimations of CRM levels in healthy diet plans are largely elusive and should be evaluated in future studies, as they could add to or be responsible for some of the beneficial effects of these diets.

Overall, the promising and emerging field of dietary CRM candidates needs to be considered with scientific rigor, as large parts of evidence on their effects in humans come from epidemiological and/or small-scale studies, often conducted with plant-based extracts that contain numerous bioactive substances. Problems may also arise when translating pre-clinical and epidemiological evidence of dietary and body-endogenous substances to clinical studies. For many of the herein discussed substances important data yet need to be collected: oral bioavailability, stability throughout the intestinal tract, metabolization, cellular uptake, distribution throughout the body, organ-specific effects, interaction with body-endogenous biosynthesis pathways and bioactive levels, just to name a few. More importantly, epidemiological data on dietary components can only be as good as the underlying food databases. Unfortunately, regionally varying food compositions, quality, the influence of meal preparation techniques and storage conditions are sometimes insufficiently studied or documented.