1 REVIEW Open Access 2 Time-restricted feeding and the realignment of 3 biological rhythms: translational opportunities 4 and challenges 5 Jag Sunderram 1 , Stavroula Sofou 2,3 , Kubra Kamisoglu 3 , Vassiliki Karantza 4 and Ioannis P Androulakis 2,3* 6 7 8 9 10 Abstract 11 It has been argued that circadian dysregulation is not only a critical inducer and promoter of adverse health effects, 12 exacerbating symptom burden, but also hampers recovery. Therefore understanding the health-promoting roles of 13 regulating (i.e., restoring) circadian rhythms, thus suppressing harmful effects of circadian dysregulation, would likely 14 improve treatment. At a critical care setting it has been argued that studies are warranted to determine whether 15 there is any use in restoring circadian rhythms in critically ill patients, what therapeutic goals should be targeted, 16 and how these could be achieved. Particularly interesting are interventional approaches aiming at optimizing the 17 time of feeding in relation to individualized day–night cycles for patients receiving enteral nutrition, in an attempt 18 to re-establish circadian patterns of molecular expression. In this short review we wish to explore the idea of transiently 19 imposing (appropriate, but yet to be determined) circadian rhythmicity via regulation of food intake as a means of 20 exploring rhythm-setting properties of metabolic cues in the context of improving immune response. We highlight some 21 of the key elements associated with his complex question particularly as they relate to: a) stress and rhythmic variability; 22 and b) metabolic entrainment of peripheral tissues as a possible intervention strategy through time-restricted feeding. 23 Finally, we discuss the challenges and opportunities for translating these ideas to the bedside. 24 Introduction 25 Biological rhythms are major determinants of behavioural 26 outcome [1,2] and are controlled by a tightly regulated 27 network of genes and proteins entrained by external 28 signals (light and food). The suprachiasmatic nucleus 29 (SCN) is the fundamental, central, regulator of circadian 30 rhythmicity (biological rhythms of, roughly, 24 h period) 31 and is considered the master clock designed to align, and 32 coordinate the independent, self-sustained, peripheral 33 oscillators (a.k.a. peripheral clocks) found in every cell, 34 tissue and organ [3-6]. In that respect, understanding 35 the mechanisms by which the various pacemakers interact 36 to coordinate functions becomes a critical question [7]. 37 Despite the fact that all peripheral clocks effectively utilize 38 the same time-keeping machinery [8-11] (Figure F1 1) each 39 peripheral entity is impacted by unique stimuli capable of 40 setting clock rhythmicity locally, directly or indirectly. As 41 such, core physiological functions are strongly impacted 42 by the appropriate alignment of peripheral clocks to cen- 43 tral (SCN) rhythms [12,13] likely mediated via circulating 44 hormones [14,15]. While biological rhythms convey antici- 45 patory signals priming the host for periods of food intake, 46 increased activity and rest [16-18] (Figure F2 2) the loss of 47 these rhythms has deleterious effects on overall health 48 [19]. The interplay between a host’ s well-being and its 49 biological rhythms is critical and bi-directional: disrupted 50 rhythms impact the response to stress whereas stress 51 alters the characteristics of biological rhythms [20-22]. 52 Emerging evidence suggesting that rhythmic signals play 53 a major role in immune [25-27] and metabolic [28] func- 54 tions naturally leads to the possibility of exploring biological 55 rhythms as targets of intervention strategies, and in par- 56 ticular in the context of intensive care units (ICU) where 57 non-natural light schedules and time-invariant nutritional 58 and/or pharmaceutical interventions may deprive patients 59 of the rhythmic cues necessary to maintain appropriate 60 biological rhythmicity during the recovery phase [29,30] * Correspondence: yannis@rci.rutgers.edu 2 Biomedical Engineering Department, Rutgers University, Piscataway, NJ 08854, USA 3 Chemical & Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854, USA Full list of author information is available at the end of the article © 2014 Sunderram et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sunderram et al. Journal of Translational Medicine 2014, 12:79 http://www.translational-medicine.com/content/12/1/79