The ups and downs of caloric restriction and fasting: from molecular effects to clinical application

Abstract

Age-associated diseases are rising to pandemic proportions, exposing the need for efficient and low-cost methods to tackle these maladies at symptomatic, behavioral, metabolic, and physiological levels. While nutrition and health are closely intertwined, our limited understanding of how diet precisely influences disease often precludes the medical use of specific dietary interventions. Caloric restriction (CR) has approached clinical application as a powerful, yet simple, dietary modulation that extends both life- and healthspan in model organisms and ameliorates various diseases. However, due to psychological and social-behavioral limitations, CR may be challenging to implement into real life. Thus, CR-mimicking interventions have been developed, including intermittent fasting, time-restricted eating, and macronutrient modulation. Nonetheless, possible side effects of CR and alternatives thereof must be carefully considered. We summarize key concepts and differences in these dietary interventions in humans, discuss their molecular effects, and shed light on advantages and disadvantages.

Keywords: caloric restriction; fasting; healthspan; intermittent fasting; lifespan; time-restricted eating.

Figure 1. Theoretical concepts underlying dietary healthy aging intervention

Different courses of aging, and how dietary approaches might influence the curves. Y‐axis shows survival proportions of a population and theoretical, individual healthiness. X‐axis shows the relative lifespan.

Figure 2. Different concepts of caloric restriction and fasting applications that have transitioned to clinical trials

Blue = non‐restricted calorie intake, magenta = fasting or restricted calorie intake, CI = calorie intake, CRM = CR mimetic.

Figure 3. Key molecular events during CR and fasting at the cellular and metabolic levels

CR and fasting act on multiple levels, eliciting an increase in cellular and organismal multi‐stress resistance, which leads to systemic health benefits. AKT = protein kinase B/PKB, AMPK = AMP‐activated protein kinase, AMP/ATP = ratio of adenosine monophosphate to adenosine triphosphate, BCAA = branched‐chain amino acid, FFA = free fatty acid, FGF21 = fibroblast growth factor 21, FOXO = forkhead box O, IGF‐1 = insulin‐like growth factor, (V)LDL = (very) low‐density lipoprotein, mTOR = mechanistic target of rapamycin, NAD⁺/NADH = ratio of oxidized to reduced nicotinamide adenine dinucleotide, NRF2 = nuclear factor erythroid 2‐related factor 2, PARP1 = Poly [ADP‐ribose] polymerase 1, PGC‐1α = peroxisome proliferation‐activated receptor gamma co‐activator 1α, TG = triglycerides.

Figure 4. Human organs affected by CR and fasting and selected health benefits

Evidence from amounting clinical trials point towards systemic health benefits of CR and IF in humans. A selection of key observations and important metabolic events is presented.