Calorie Restriction as a Means to Improve Surgical Outcomes

The long-term response to calorie restriction has long been of interest to the aging research community, and particularly in the past few decades as the tools of biotechnology allowed for a more detailed analysis of the metabolic changes that accompany a reduced calorie intake. A restricted diet extends healthy life spans in near all species tested to date, though to a much greater extent in short-lived species than in long-lived species such as our own. Considerable effort is presently devoted to the development of drugs that can replicate some fraction of calorie restriction - more effort than is merited in my opinion, given that the optimal result for extension of human life span achieved via calorie restriction mimetics will be both hard to achieve safely and very limited in comparison to the gains possible through rejuvenation therapies after the SENS model. Repairing damage within the existing system should be expected to outdo attempts to change the system in order to slow the accumulation of damage, in both efficiency and size of result.

Not everyone is interested in the long term, however. The short term health benefits of calorie restriction appear quickly and are surprisingly similar in mice and humans, given that calorie restriction in mice results in significantly extended life and calorie restriction in humans does not. The beneficial adjustments to metabolism and organ function are for the most part larger and more reliable than similar gains presently achievable through forms of medicine. That is more a case of medical science having a long way to go yet than calorie restriction being wondrous, however. Still, the short term benefits are coming to the attention to wider audience within the research and medical community. For example, calorie restriction and fasting are proving to be useful adjuvant treatments that improve outcomes for cancer patients: you might recall an interview with one of the researchers involved, as well as a paper from a few years back showing that periodic fasting improves recovery of the immune system from the damage caused by chemotherapy. In addition there is good evidence for calorie restriction and fasting to improve the outcomes following surgery, priming the body for the stress of that experience. Researchers have made some inroads in tracing the important mechanisms in this effect, as outlined in the following open access review paper:

Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes

Dietary restriction (DR), or reduced food intake without malnutrition, was found in 1935 to extend lifespan of laboratory rats. Since that time, longevity extension by DR has been demonstrated in numerous experimental organisms from yeast to non-human primates. Fortunately, DR confers other important benefits that do not require long periods of food restriction, including increased resistance to multiple forms of acute stress. One of the biggest planned stressors many people will face in their life is that of major elective surgery, which carries inherent risks of complications. A novel concept in surgical risk mitigation emerging from basic research on DR and aging is dietary preconditioning, or short-term DR lasting one week or less prior to surgery. In rodent models of surgical stress ranging from ischemia reperfusion injury (IRI) to vascular restenosis (intimal hyperplasia), short-term DR or fasting before surgery, followed by a return to normal food intake after surgery, leads to improved outcomes.

Because of the plethora of physiological and molecular changes that occur even upon short-term restriction of a single essential amino acid from the diet, identification of critical downstream mechanisms of DR-mediated protection against surgical stress is challenging. Elucidation of upstream nutrient-sensing pathways such as GCN2 and mTORC1, for which genetic full-body or tissue-specific knockout models are available, has proven a critical step forward. Using experimental designs in which dietary interventions are combined with genetic models lacking upstream nutrient sensors that fail to gain protection upon DR, two major downstream mechanisms involving increased prosurvival insulin signaling and endogenous H2S production have recently been elucidated.

How does the DR-mediated improvement in hepatic insulin sensitivity contribute to protection from hepatic IRI? In addition to regulating energy metabolism, insulin can act as a prosurvival factor via negative regulation of apoptosis. Consistent with this mechanism of action, circulating insulin levels and antiapoptotic signaling are both increased in the hours after liver reperfusion in wild-type mice preconditioned on DR, while this effect is absent in mice with constitutive insulin resistance. Taken together, these data suggest that a major mechanism of DR action is via increased insulin sensitivity prior to an injury, which then facilitates increased prosurvival signaling and reduced hepatocyte apoptosis after injury.

Although toxic at high levels, endogenously produced H2S by one of three evolutionarily conserved enzymes is now recognized to have pleiotropic cytoprotective, anti-inflammatory and vasodilatory effects resulting in cardioprotection and resistance to ischemic injury. H2S also has direct antioxidant properties, and can participate in mitochondrial energy production by donating electrons to the mitochondrial electron transport chain protein SQR, with a potential role in protection from ischemia. Since pharmacological delivery of H2S also protects in models of surgical stress, as well as more broadly in preclinical models of cardiovascular disease, it remains to be seen if supplementation with exogenous sources of H2S, or increased endogenous H2S production through dietary or other means, will ultimately turn out to be more beneficial in the context of surgical stress resistance.

The findings that short-term fasting or restriction of food intake - on the order of days to a week - leads to robust functional benefits in rodents has profound implications for the mechanism of DR action in mammals. Rather than previous notions of DR as an intervention whose benefits accumulate over long periods of time due to reduced calorie intake, DR is now viewed as a rapid adaptation to the mild stress of calorie and/or nutrient deprivation with the potential to protect against many other forms of stress. This new understanding has important practical implications for attempts to leverage DR against clinically relevant endpoints, including planned surgery. If future clinical trials identify brief DR regimens or pharmacological DR mimetics that are safe and effective against the stress and potential complications of surgery, how would this change current preoperative nutritional standards? With few exceptions, there is currently no consensus on what should or should not be eaten up to 1 day prior to surgery, so long as the patient is not suffering from malnutrition.

Currently, the duration of preoperative fasting used as an "anesthetic precaution" in humans is likely too short to tap into DR benefits, while the progressive clinical application of existing nutritional guidelines promotes an alternate although not mutually exclusive concept of increased nutrition immediately prior to surgery. Future clinical trials are required to test the safety, feasibility, and potential efficacy of short-term DR, including extended periods of fasting, to reduce risk of surgical complications and improve outcomes. If successful, this approach has the potential to change the paradigm for preoperative nutritional care based on concepts derived from research into the basic biology of aging.