Evaluating the beneficial effects of dietary restrictions: A framework for precision nutrigeroscience

Abstract

Dietary restriction (DR) has long been viewed as the most robust nongenetic means to extend lifespan and healthspan. Many aging-associated mechanisms are nutrient responsive, but despite the ubiquitous functions of these pathways, the benefits of DR often vary among individuals and even among tissues within an individual, challenging the aging research field. Furthermore, it is often assumed that lifespan interventions like DR will also extend healthspan, which is thus often ignored in aging studies. In this review, we provide an overview of DR as an intervention and discuss the mechanisms by which it affects lifespan and various healthspan measures. We also review studies that demonstrate exceptions to the standing paradigm of DR being beneficial, thus raising new questions that future studies must address. We detail critical factors for the proposed field of precision nutrigeroscience, which would utilize individualized treatments and predict outcomes using biomarkers based on genotype, sex, tissue, and age.

Keywords: aging; biomarkers; caloric restriction; dietary restriction; healthspan; lifespan; precision medicine; precision nutrigeroscience; senescence.

Figure 1.. Biochemical mechanisms of dietary restriction

Nutrient signals (purple) are received by sensors at the cell membrane. These sensors (yellow) activate regulators (red) of diet-responsive mechanisms, which in turn regulate the effectors (blue) of stress response, cell growth, and metabolism.

Figure 2.. Possible gene-specific lifespan responses to dietary interventions

Loss of a gene can lead to one of four general responses: (A) Lifespan extension on a nutrient-rich diet, but no effect under DR. (B) Negation of typical DR-mediated lifespan extension, but no effect on a nutrient-rich diet. (C) Lifespan shortening under nutrient-rich conditions, but no effect under DR. (D) DR-specific lifespan extension, but no effect under nutrient-rich conditions.

Figure 3.. Reported effects of DR on human tissues in disease and normal aging

(A) Reported benefits and detriments of DR under different disease states in the brain, intestine, bone, muscle, heart, fat stores, and kidneys. (B) Benefits and detriments of DR under normal tissue aging. Benefits are shown in blue, detriments in red. See text for details.

Figure 4.. A framework for precision nutrigeroscience based on optimizing diet/pharmacology-based interventions to optimize health and longevity to accommodate factors that lead to individual variation

We propose the concept of precision nutrigeroscience, the study of which will aim to utilize nutrient interventions and compounds that influence nutrient-signaling pathways to optimize lifespan, healthspan, and tissue-specific decline. However, these interventions need to be optimized based on factors such as sex, genetics, epigenetics, and age to optimize the desired outcomes. Furthermore, the use of biomarkers like circulating factors in the blood from transcriptomic, proteomic, or metabolomic changes associated with health outcomes could be used to appropriately change the nutrient and pharmacological interventions to optimize health outcomes. Together, the combination of these approaches could help achieve the goals of precision nutrigeroscience.