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Time-restricted feeding and the realignment of biological rhythms: Translational opportunities and challenges

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It has been argued that circadian dysregulation is not only a critical inducer and promoter of adverse health effects, exacerbating symptom burden, but also hampers recovery. Therefore understanding the health-promoting roles of regulating (i.e., restoring) circadian rhythms, thus suppressing harmful effects of circadian dysregulation, would likely improve treatment. At a critical care setting it has been argued that studies are warranted to determine whether there is any use in restoring circadian rhythms in critically ill patients, what therapeutic goals should be targeted, and how these could be achieved. Particularly interesting are interventional approaches aiming at optimizing the time of feeding in relation to individualized day-night cycles for patients receiving enteral nutrition, in an attempt to re-establish circadian patterns of molecular expression. In this short review we wish to explore the idea of transiently imposing (appropriate, but yet to be determined) circadian rhythmicity via regulation of food intake as a means of exploring rhythm-setting properties of metabolic cues in the context of improving immune response. We highlight some of the key elements associated with his complex question particularly as they relate to: a) stress and rhythmic variability; and b) metabolic entrainment of peripheral tissues as a possible intervention strategy through time-restricted feeding. Finally, we discuss the challenges and opportunities for translating these ideas to the bedside.
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1R E V I E W 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*
6789
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 daynight 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] (FigureF1 1) each
39 peripheral entity is impacted by unique stimuli capable of
40setting clock rhythmicity locally, directly or indirectly. As
41such, core physiological functions are strongly impacted
42by the appropriate alignment of peripheral clocks to cen-
43tral (SCN) rhythms [12,13] likely mediated via circulating
44hormones [14,15]. While biological rhythms convey antici-
45patory signals priming the host for periods of food intake,
46increased activity and rest [16-18] (Figure F22) the loss of
47these rhythms has deleterious effects on overall health
48[19]. The interplay between a hosts well-being and its
49biological rhythms is critical and bi-directional: disrupted
50rhythms impact the response to stress whereas stress
51alters the characteristics of biological rhythms [20-22].
52Emerging evidence suggesting that rhythmic signals play
53a major role in immune [25-27] and metabolic [28] func-
54tions naturally leads to the possibility of exploring biological
55rhythms as targets of intervention strategies, and in par-
56ticular in the context of intensive care units (ICU) where
57non-natural light schedules and time-invariant nutritional
58and/or pharmaceutical interventions may deprive patients
59of the rhythmic cues necessary to maintain appropriate
60biological 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
61 and loss of entraining inputs may significantly impact
62 recovery [10,31-34]. In fact circadian abnormalities correl-
63 ate with severity of illness and outcome [35]. Due to the
64 strong role rhythmicity plays in recovering from trauma
65 [36,37], its regulation and realignment are emerging as
66 potentially critical controllers influencing patient outcome
67 by regulating entraining signals in a non-invasive manner.
68 Circadian cues that control rest cycles and metabolism are
69primarily driven by light and food [38,39]. These play a
70fundamental role in that they maintain proper synchrony
71between the peripheral clocks (Figure F33). The importance
72of maintaining good coordination between the peripheral
73oscillators is so critical that physicians have speculated
74that []healthy organs behave as biological oscillators,
75which couple to one another during human development,
76and that this orderly coupling is maintained through a
Figure 1 The periodic expression of clock genes is driven by Per and Cry inhibiting the activity of the CLOCK/BMAL1 dimer (negative
feedback) and stimulating Bmal1 gene transcription (positive feedback). Through a negative feedback loop, the heterocomplex CLOCK/
BMAL1 activates the transcription of period (Per) and cryptochrome (Cry) genes upon binding to the E-box promoter region. After the expression
of PER/CRY proteins in the cytoplasm, they translocate to the nucleus where they inhibit their own transcription by shutting off the transcriptional
activity of the CLOCK/BMAL1 heterocomplex . Through the positive feedback loop the nuclear compartment of PER/CRY protein (y3) activates
indirectly Bmal1 mRNA (y4) transcription, which after its translation to BMAL1 protein and its translocation to the nucleus, increases the expression
of CLOCK/BMAL1 heterodimer. However, the peripheral clocks are entrainedby external signals cortisol (F) in this case. The role of the entertainer is
to synchronize the responses across a collection of cells. Figure adapted from [23].
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77 communications network, including neural, humoral,
78 and cytokine components. [We] suggest that the systemic
79 inflammatory response syndrome initiates disruption of
80 communication and uncoupling, and further suggest that
81 progression into the multiple organ dysfunction syndrome
82 reflects progressive uncoupling that can become irreversible.
83 Resolution of the inflammatory response and reestablish-
84 ment of the communications network are necessary but
85 may not be, by itself, sufficient to allow organs to appro-
86 priately recouple[40].
87Exploring these cycles in order to realign patientsbio-
88logical rhythms during the recovery phase may prove to
89be highly rewarding in terms of outcome [41]. Therefore,
90understanding the mechanisms that entrain the central and
91peripheral clocks, and the ways in which these rhythms
92influence the ability of the host organism to respond to,
93and recover from, external threats and challenges is critical
94to developing new models of patient care capable of
95engaging these rhythms in an attempt to, potentially,
96improve outcome. It must be noted that although it is
Figure 3 Systemic signals act as coordinators of peripheral oscillators maintaining synchrony of function and health.
Figure 2 Biological clocks enable the integration of behavioural cycles (sleep/wake feed/fast) and metabolic processes across
different organs. While each tissue maintains its own clock ad intrinsic rhythms, external signals (zeitgebers) coordinate functions inorder to
maintain appropriate balances. (Figure adapted from [24]).
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97 well established that ICU patients have abnormal circadian
98 patterns [35,42] the overall environment in the ICU,
99 including the patients condition, the lighting and noise
100 levels in ICU as well as and likely very importantly the
101 treatment the patient receives, induces significant circa-
102 dian alterations [43,44].
103 In this short review we focus on one particular approach
104 to resetting biological rhythmicity in the context of time-
105 restricted feeding (TRF; access to food is restricted for
106 specific time intervals during the day without calorie
107 restrictions) and explore the possibility of pursuing circa-
108 dian re-alignment via nutritionally-inspired interventions.
109 Although the focus of the review is on the implications
110 of restoring circadian rhythms we should point out that
111 appropriate sampling and analysis of biochemical and
112 physiological circadian data requires careful design and
113 execution and these have been the subject of numerous
114 excellent reviews [45].
115
116 Circadian reprogramming as an intervention
117 strategy: opportunities for time-restricted feeding
118 Stress-induced loss of circadian rhythmicity
119 Evidence establishing the strong links between biological
120 rhythms and stress response is overwhelming and, by now,
121 very well established and accepted [14,46]. However, the
122 translational implications, opportunities and challenges of
123 how to manipulate rhythms in an ICU environment are
124 only now beginning to emerge in the scientific discourse
125 [30]. A number of recent, and older, reviews have discussed
126 the connections between immune function and biological
127 rhythms [46] where the bi-directional relationship between
128 disrupted rhythms and immune dysfunction; and its impli-
129 cation on the bedside have been clearly identified [36,37].
130 What is even more interesting is the fact that we begin to
131 realize that circadian dysfunction following stress may have
132 long lasting ramifications [47] pointing to possible sources
133 of comorbidities. In fact, it has been argued that different
134 procedures impact post-operative circadian disruption in a
135 differential manner, thus affecting recovery, raising the
136 possibility of guiding operative procedures based on their
137 capacity to minimize impact on biological rhythms [48].
138 Clinical studies specifically emphasized that biological
139 night and day cycles (measured by urinary 6-sulfatoxyme-
140 latonin) were phase-delayed and normal features of sleep
141 were lacking (REM sleep was identified only in 2 patients
142 out of 21) in the critical care patients [49]. Studies on
143 patients undergoing elective maxillofacial surgery showed
144 that strengthening circadian rhythms in anticipation of
145 disruption following surgery can be efficacious for improv-
146 ing the recovery phase. Patients whose circadian rhythms
147 were adjusted pre-operatively by combined sleep/wake
148 cycle alteration and timed food and caffeine ingestion
149 had reduced disruption in their body temperature cycles
150throughout their recovery in comparison to the control
151group [50].
152One of the most active areas of research pointing dir-
153ectly to circadian disruption and biological rhythm-setting
154interventions relate to mood disorders [51-55]. A vast
155literature exists on enhancing circadian rhythms for treat-
156ing depression, bipolar disorder and other related mood
157disorders either via pharmacological (melatonin) [55,56]
158or non-pharmacological means (light) [57] aimed at boost-
159ing circadian rhythms.
160Circadian (re)alignment and time-restricted feeding
161Time restricted feeding (TRF) is essentially imposing
162rhythms on nutrient availability. Entrainment by TRF
163has generated significant interest due to the possibility
164of synchronizing peripheral clocks without clear influences
165on (or from) the central pacemaker (SCN) [28,58]. It
166has been speculated that restricted feeding (RF) entrains
167rhythms in peripheral tissues (liver and lung) [6] is likely
168independent of the SCN. These works challenge the basic
169hierarchical paradigm that light entrains the SCN which
170subsequently entrains the peripheral clocks and empha-
171sized the role of RF as an entraining signal. The hypothesis
172of independently entrained peripheral clocks has been
173further reinforced by the observation that even lesions
174in brain nuclei do not eliminate food anticipatory activity,
175thus pointing to likelihood of a distributed system main-
176taining and regulating food-anticipatory activities [59,60].
177One of the main justifications is that when food acces-
178sibility adopts specific rhythmic characteristics so will the
179physiology and behaviour to match nutritional resource
180availability [61]. It has been shown that feeding mice
181during the day completely reverses the phase of circadian
182oscillators (specifically, four clock components, Per1, Per2,
183Per3, Cry1; and the two circadian transcription factors
184DBP and Rev-erbα) in multiple peripheral cells (liver,
185kidney, heart and pancreas), but has little if any effect
186on the central oscillator in the SCN [62]. However, we
187must point out that RF entrains the rhythm of clock
188protein Per2 even in the SCN as was shown in studies
189that eliminated photic stimulation by keeping mice in
190constant darkness [63], or at constant light conditions
191[64], thus raising the possibility of peripheral oscillators
192resetting the central clock.
193In a carefully designed study of a murine obesity model
194[53] the authors convincingly show the intimate relation-
195ship between the signalling and transcriptional components
196of energy metabolism and the circadian system. The study
197hypothesized that TRF improves diurnal rhythms; drives
198lipid homeostasis while preventing weight gain, hepatostea-
199tosis and liver damage; improves adipose homeostasis
200and reduces inflammation. The study demonstrated that
201preserving natural feeding rhythms significantly dampens
202metabolic disruption induced by a high fat diet, including
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203 improving oscillations of the liver circadian clock compo-
204 nents. Therefore, while the total calorie intake and food
205 composition (high fat) remained constant, the study clearly
206 demonstrated that an apparent lifestyle, i.e.,non-pharma-
207 cological, intervention prevented obesity, and related co-
208 morbidities, possibly by resetting metabolic cycles. The role
209 of food-anticipatory activity has also been explored with a
210 focus on energy metabolism, defined by oxygen consump-
211 tion [65]. Animals were allowed access to food for only few
212 hours during either the light or the dark phases. Locomotor
213 activity, body temperature, clock gene expression in liver
214 and energy metabolism were recorded and their changes
215 assessed as the time window over which food became
216 available was changing. Continuous monitoring of energy
217 metabolism and core body temperature indicated expected,
218 robust diurnal rhythmic characteristics but also rapid
219 re-entrainment and adaptation to restricted food access.
220 A series of publications has focused on comparing
221 protein synthesis under a continuous and, a likely more
222 physiologically realistic, intermittent bolus feeding regimen,
223 delivered by orogastric tube, in neonatal pigs in the context
224 of regulating protein synthesis [66-68]. The analysis
225 demonstrated that intermittent feeding (delivered every
226 4 hrs as a bolus feed) enhances muscle protein synthe-
227 sis by imposing pulsatile patterns of amino-acid and
228 insulin-induced translation initiation. In this very inter-
229 esting series of papers it has been argued that bolus
230 feeding promotes a more physiological surge of intes-
231 tinal hormones. The studies effectively hypothesize that
232 []cyclic surge of amino acids and insulin is needed
233 to maximally stimulate protein synthesis in skeletal
234 muscleand that []bolus compared to continuous
235 feeding has been advocated to promote more normal
236 feed-fast hormonal profiles. It has been further demon-
237 strated that either advancing or delaying meal time in
238 young adult mice results in reversible alterations of
239 temperature and overall cage activities [69]. Longer
240 time restriction (one week) alters rhythms in glucose,
241 triglyceride and HDL levels. Food restriction results in
242 behavioral arousal in anticipation of food presentation
243 and induces a shift in the circadian phase of many
244 physiological variables, likely independent of the SCN. As
245 such, RF is expected to exert changes in organs handling
246 nutrients(such as liver). As previous work had suggested
247 RF could be associated with significant stress due to hy-
248 perphagia, In a study examining the effect of restricted
249 feeding on stress markers, no marked changes in body
250 weight, retroperitoneal decrease in lipid deposits and peak
251 in glucocorticoids accompanying expectation to food ac-
252 cess were identified [70]. Given the probable relationship
253 between stress and metabolic alterations (in this case
254 interest was in liver) the study explored whether an in-
255 crease in acute phase proteins (APR) or pro-inflammatory
256 state occurred after 2 weeks of 2hr food restriction. The
257positive controlfor APR consisting of a group injected
258with LPS showed a significant increase in systems APR
259while neither the ad libitum nor restricted feeding induced
260a marked increase in any of the inflammatory markers.
261Furthermore, a marked change in the diurnal patterns of
262circulating cytokines was observed as a consequence of RF.
263The authors advance an interesting hypothesis stating that
264RFmayestablishadistinctivestate(rheostatic response
265earlier introduced in [71]) likely enabling the system to
266adopt a transient functional state change in set-point,
267boosting the rhythms and the overall fitness of the host.
268Time-restricted feeding and disease progression
269Peripheral circadian de-synchrony may be an early indica-
270tor of metabolic disruption in shift workers due to sleep
271deprivation mediated disruption of circadian rhythms. By
272extension, strengthening the peripheral circadian rhythm, by
273imposing metabolic rhythms via limiting food intake during
274the night, may counteract comorbidities seen in human shift
275workers [72]. This study further implies that the manipula-
276tion of circadian rhythms need not be such that it aims
277at restoring the homeostatic nature of the internal clock.
278Rather it implies that, at least in the short term, strength-
279ening other rhythmic frequencies may be more beneficial.
280Particularly interesting is the work investigating the effect
281of resetting circadian clocks in peripheral tissues using
282non-photic signals on tumor growth rate in rats [73,74].
283Restricting the timing of meals to light time in contrast
284to restricted feeding during the night (active phase of
285rats) thereby, imposing a reversed metabolic rhythm,
286induced, what is referred to as, internal desynchronization
287(described as loss of phase relationship between central
288light entrained and peripheral clocks) resulted in pro-
289longed survival and slowed down tumor growth. The
290authors speculate that meal timing during the light period
291amplifies host rhythms and assigns their peak in a time
292window when the tumor is most susceptible to host-
293mediated control and that tumor growth is hampered
294when the internal (metabolic) clock adopts specific
295rhythmic characteristics, interestingly the opposite of
296what would have been otherwise considered natural.
297Therefore, the emerging hypothesis is that, a radically
298different metabolic rhythmicity appears to be most effect-
299ive at least in the short term.
300Restricted-time feeding vs. calorie restriction
301It is important to draw a distinction between time-
302restricted feeding and caloric restriction. The former
303entails the delivery of a certain amount of calories albeit
304at specific time intervals of specific duration. Therefore
305subjects still receive a standard nutritional intake. Calorie
306restriction entails an overall reduction in caloric intake,
307albeit without malnutrition. While evidence for the bene-
308fits of calorie restriction in animals has been promising,
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309 the issue as it relates to humans is still debated as con-
310 ducting long term studies assessing the implications of
311 prolonged calorie restriction in a controlled manner is
312 rather complicated [75]. Although studies have shown
313 calorie restriction improves post-trauma outcomes [76-78],
314 it is likely that the long term effects of calorie restriction
315 are related to alterations of biological mechanisms respon-
316 sible for maintenance of health [79]. Recent work has
317 indicated the possibility of caloric restriction impacting
318 circadian clocks as well [80]. However, it is argued that
319 this may be a secondary effect of calorie restriction
320 resulting in time restricted feeding imposing specific
321 rhythms on metabolic function and entraining periph-
322 eral clocks. Nevertheless, the focus of this discussion is
323 on TRF and not on calorie restriction.
324 Clinical studies comparing continuous vs. bolus feeding
325 A number of fairly comprehensive clinical studies have
326 considered the impact of temporal delivery of enteral feed-
327 ing in critical patients [81-88]. Although these studies have
328 to be acknowledged in the context of our discussion, one
329 should be aware of the fact that clinical studies comparing
330 continuous vs. bolus feeding were motivated mostly by
331 the need to address some of the key practical limitations
332 associated with delivering nutritional support, such as in-
333 terruptions of continuous feeding leading to an inability to
334 achieve nutritional goals, gastrointestinal complications,
335 modulation of aspiration pneumonia, stool frequency etc.,
336 rather than as an attempt to capitalize on potentially advan-
337 tageous physiological and/or biochemical routes linking
338 metabolic rhythms and immune response. Earlier stud-
339 ies examined various parameters influenced by delivering
340enteral nutrition in the form of either continuous or bolus
341(intermittent) delivery and the conclusions are still de-
342bated in the clinical community [84]. Studies comparing
343continuous to intermittent tube feeding in adult burn
344patients concluded that patients continuously fed had
345reduced stool frequency and time required to achieve
346nutritional goals. More recent studies, however, despite
347minor differences in specific goals and targets, in general
348do not provide evidence of significant difference in terms
349of patient outcome. Results show that patients intermit-
350tently fed have a higher total intake volume, are extubated
351earlier, and have a lower risk of aspiration pneumonia.
352Postoperatively, feeding at night only is more energy effi-
353cient than is feeding continuously for 24 h, but is associ-
354ated with poorer nitrogen balance [82]. In one of the very
355few studies which complemented intermittent feeding
356in a clinical setting with monitoring of biomarkers, the
357observed decrease in urinary catecholamine secretion
358indicated a possible role of sympatho-adrenal mechanisms.
359This study provides a link between feeding patterns and
360putatively modulated pathways. However, no studies have
361been performed where time restricted feeding has been
362compared to either bolus or continuous feeding in the ICU.
363Concluding remarks
364Time restricted delivery of metabolites imposes rhythmic
365availability of nutrients which resets peripheral clocks
366in a way that potentially exerts a positive impact on the
367immune response. Recent clinical evidence indicates that
368restoring circadian rhythms in critically ill patients is
369important. We hypothesize that providing circadian cues
370in the ICU could be explored as a mechanism to improve
Figure 4 Robust circadian entrainment characterizes homeostasis, whereas disruptions (amplitude and phase) characterize stressful
critical conditions. Whereas in homeostasis circadian rhythms are properly aligned with clearly identifiable phase locking, circadian disruption
shifts peripheral clock rhythms. Restoration of peripheral rhythms, including nutritionally-driven metabolic rhythms through time-restricted feeding
will re-entrain the system and provide appropriate systemic cues.
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371 ICU outcome by reinforcing appropriate rhythms of
372 hormonal release [30,34] (FigureF4 4). As it is becoming
373 increasingly more evident that exploring alternatives
374 measures to re-establish circadian patters of molecular
375 expression via non-pharmacological means could hold
376 significant potential, feeding entrainment through the
377 possibility of optimizing the time of feeding in relation to
378 the light/dark cycle for patients receiving enteral nutrition
379 appears to beg for more investigation [29].
380 In this brief review we elaborated on the idea that
381 establishing abolished rhythms would have a beneficial
382 effect on the host response to stress. We highlighted some
383 of the key elements associated with this complex question
384 particularly as they relate to: a) stress and rhythmic vari-
385 ability; and b) metabolic entrainment of peripheral tissues
386 as a possible intervention strategy through time-restricted
387 feeding. Positive effects have been shown in the context
388 of psychological stress, mood disorders etc., using either
389 pharmacologic agents, aiming at restoring circadian sig-
390 nals, or using photic signals to activate the central pace
391 maker. The question, however, remains whether imposing
392 appropriate metabolic rhythms, likely not maintaining
393 homeostatic phase relations with the central clock, through
394 time-restricted feeding would lead to beneficial entrainment
395 of peripheral clocks resulting in improved health outcomes
396 with a host under stress.
397 Competing interests
398 The authors declare that they have no competing interests.
399 Authorscontributions
400 JS, SS, KK, VK edited the manuscript; IPA conceived the idea, prepared and
401 edited the manuscript. All authors read and approved the final manuscript.
402 Author details
403
1
Department of Medicine, Division of Pulmonary and Critical Care Medicine,
404 Rutgers - Robert Wood Johnson Medical School, New Brunswick, NJ 08901,
405 USA.
2
Biomedical Engineering Department, Rutgers University, Piscataway, NJ
406 08854, USA.
3
Chemical & Biochemical Engineering Department, Rutgers
407 University, Piscataway, NJ 08854, USA.
4
Rutgers Cancer Institute of New
408 Jersey, Rutgers University, New Brunswick 08901, USA.
409 Received: 21 December 2013 Accepted: 10 March 2014
410 Published: 28 March 2014
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652 doi:10.1186/1479-5876-12-79
653 Cite this article as: Sunderram et al.:Time-restricted feeding and the
654 realignment of biological rhythms: translational opportunities and
655 challenges. Journal of Translational Medicine 2014 12:79.
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