schedule shifts, cancer and longevity: good, bad or indifferent?

7/28/2019 Schedule shifts, cancer and longevity: good, bad or indifferent?

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Schedule shifts, cancer and longevity:

good, bad or indifferent?

Germaine Cornlissen, PhD1, Julia Halberg, MD, MS, MPH1, Franz Halberg, MD1, Salvador

Sanchez de la Pena, MD, PhD2, Walter Nelson, PhD1, Othild Schwartzkopff, MD1,Alexander

Stoynev, MD3, and Erhard Haus, MD, PhD4

1Halberg Chronobiology Center, University of Minnesota, 420 Delaware St. SE, Minneapolis, MN 55455,

USA. Tel.: +1 612 624 6976; e-mail: [email protected] and/or [email protected]

2Cronomic Research Center, Escuela Nacional de Medicina y Homeopata-IPN, Mexico City, Mexico

3Department of Pathophysiology, Medical University, Sofia, Bulgaria

4Department of Pathology, Regions Hospital, 640 Jackson St., St. Paul, MN 55101, USA

AbstractPrompted by a recent report of the possible carcinogenic effect of shiftwork focusing on the disruptionof circadian rhythms, we review studies involving shifts in schedule implemented at varying intervalsin unicells, insects and mammals, including humans. Results indicate the desirability to account fora broader-than-circadian view. They also suggest the possibility of optimizing schedule shifts byselecting intervals between consecutive shifts associated with potential side-effects such as anincrease in cancer risk. Toward this goal, marker rhythmometry is most desirable. The monitoringof blood pressure and heart rate present the added benefit of assessing cardiovascular disease risksresulting not only from an elevated blood pressure but also from abnormal variability in bloodpressure and/or heart rate of normotensive as well as hypertensive subjects.

In a Policy Watch report published in the December 2007 issue of The Lancet Oncology, the

WHO International Agency for Research on Cancer Monograph Working Group concluded:Shiftwork that involves circadian disruption is probably carcinogenic (1). Human life is alsopotentially carcinogenic and involves disruptions of a much broader-than-circadian timestructure that can be optimized, although generalizations are best qualified. In our hands (2,3) and in those of Kort et al. (4), a temporal disorder can be carcinostatic, as also found byCarlebach and Ashkenazi (5), and can even prolong lifespans (3,6,7), thorough adverse reportson humans notwithstanding (8).

Effects of competing photic and nonphotic synchronizers of circadian rhythms were tested inlifetime studies on mice subjected to calorie restriction and/or to weekly shifts of the lightingregimen, repeatedly reviewed (6,7). A prolongation of tenth-decile survival time beyond thatachieved by calorie restriction alone was observed among mice subjected to shifts in lightingbut not in feeding, so that in alternate weeks, food was offered during the rest (light) span.

Murine mammary carcinogenesis, under controlled conditions, was reduced in this group (2=4.15, P


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Universidad de So Paulo, So Paulo, Brazil), the late Dr. Laurence K. Cutkomp (at theDepartment of Entomology, University of Minnesota, St. Paul, Minnesota, USA), Dr. Dora K.Hayes (10) (at the US Department of Agriculture, Beltsville, Maryland) and the late Dr. Hans-Georg Schweiger (11) (at his Max-Planck-Institute for Cell Biology in Ladenburg, nearHeidelberg, Germany), we found that shifts can be favorable, notably inAcetabularia, a unicellfrom which the nucleus can be removed, and thus intracellular mechanisms can be studied.

These investigations were summarized for face flies (10), Figure 3, springtails (9), Figure 4,and unicells,Acetabularia(11), Figure 5. At overall 50% mortality, the number of deaths washighest in face flies shifted every 2 or 9 days. Mortality also differed as a function of the shiftinterval in springtails. For unicells subjected to 14 different patterns of shifts differing by 1day between consecutive shifts of the lighting regimen (implemented either every 2, 3, , or15 days), growth rates differed in a seemingly about-weekly (circaseptan) pattern, rather thanoutcomes being better or worse, depending linearly on the length of the inter-shift interval,suggesting the desirability to account for circaseptans in studies of schedule shifts.

Circaseptan gating had been found earlier in the effect of manipulating environmentaltemperature on oviposition by springtails (12). In a unicell, a circaseptan pattern becomescircasemiseptan (about half-weekly) after its enucleation (11). This finding suggested theoperation of a built-in circasemiseptan cytoplasmic mechanism in its own right. It is frequency-

demultiplied by the nucleus to a circaseptan pattern. Longitudinal series analyzed by signalaveraging of several cells document the partly endogenous nature of the circaseptan componentby its free-run and that of the also-present circasemiseptan component, the about-weeklyrhythm being more prominent than the concurrently assessed free-running circadian rhythmcharacterizingAcetabularias electrical activity after release into continuous light (13).Extrapolating to mammals, are nuclear and cytoplasmic infradian mechanisms (in mammalspineal or hypothalamus) subtractively coupled in frequency while the circadians of thesuprachiasmatic nuclei are subtractively coupled in amplitude (14)?

Melatonin suppression by increased light exposure of night-shift workers is putativelyassociated with increased cancer risk (1). Ultradian-to-infradian components are in thisvitamin/hormones chronome (15,16) that is affected by exposure to magnetic fields (17).Magnetic storms (18) depress the circadian amplitude of melatonin in human saliva. The

amplitude and MESOR (midline estimating statistic of rhythm, a rhythm-adjusted mean) ofthe rats circadian rhythms of melatonin in the first 3 (disturbed) vs. the last 3 (quiet) days ofa 7-day experiment were higher in the hypothalamus and lower in the pineal (19). There is noconsensus regarding magnetic effects on cancer risk (20-22). At the wrong circadian stage,melatonin can enhance tumor growth, as found first in vitro by Bartsch and Bartsch (23),reducing lifespan (24-26).

Whether melatonin supplementation reduces any increased cancer risk among night-shiftworkers remains to be determined, abiding by First do no harm when the same dose ofmelatonin given at different circadian stages can either reduce or increase tumor growth andsurvival. Cancer itself can be associated with a desynchronized circadian system (27-29).Nonphotic infradian cycles coded in our genes coexist, compete and sometimes dominate overcentral and peripheral circannual systems, prompting a time structural approach including

focus upon (age and other) trends, (deterministic) chaos and a rhythm spectrum withfeedsideward interactions among these elements that underlie different effects in differentcycles stages (30,31).

Schedule shifts may be good (prolonging the life of an enucleated single cell) (32), neutralor bad. This applies to effects on growth, Figure 5, including carcinogenesis, Figure 1, andsurvival (3,9,10). Chronomics investigating multi-frequency interactions among time

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structures in and around us, societal and climatic, including space weather is indicated forshiftwork studies.

Subjects monitoring blood pressure around-the-clock for decades reveal differences incircadian vs. circaseptan phase-behavior, Figure 6. The circadian amplitude of blood pressurebut not of heart rate is reduced and the circadian acrophase is delayed in night-shift workers(33-35). Table 1 summarizes results of a 24-hour study (a severe limitation in length) and shows

a sensitivity of a chronobiologic approach more generally.With an ambulatory monitor from Colin Medical Instruments, 33 male air traffic controllersworking at one of 3 airports (Varna, Burgos or Sofia, Bulgaria) measured their BP and HRmostly at 30-minute intervals for 24 hours. Their age ranged between 25 and 56 years; theyhad been on the job for 2 to 26 years. At the time of monitoring, 10 worked morning shifts, 9afternoon shifts and 14 night shifts. Only one air traffic controller had a hyperbaric index greaterthan 50 mm Hg h during 24 h for systolic (S) BP. A statistically significant circadianpopulation rhythm was demonstrated for each variable in each shift group (P 0.20). The circadian amplitude is more sensitive than thestandard deviation since in the latter case a difference is found only for DBP (P =0.023), thenight shifters having the smallest variation. A later acrophase is also found in night shiftworkers (SBP: P =0.029; DBP: P =0.004; HR: P =0.002), which is likely brought about bydifferences in rest-activity schedule.

Different variables and different spectral components in the same variable of the same organismcan adjust at different rates, abruptly or gradually, even in opposite directions. A broader-than-circadian clock perspective on longer than 24-h records (34,35) thus seems warranted.

Discrepancies among diverse shiftwork studies could relate in part to intervals between shifts.These intervals should be invariably stated (for eventually comparing studies in epidemiology)

and should be optimized based on one or several proxy endpoints, such as those available byvascular monitoring, which, as a dividend, will detect any increase in the cardiovascular diseaserisk of shiftworkers (35). It will reveal the presence of any vascular variability disorders(VVDs) that carry a risk of morbid events greater than hypertension (36-42). Infradians areinvolved in shiftwork, as in transmeridian flights (43-46), Figure 6. Optimizing the intervalbetween shifts in mammals, including humans, remains a practical challenge, in order toattempt to allay any worry about carcinogenicity on the part of shiftworkers. The step fromunicellulars and insects to rodents can never replace now-feasible human ambulatoryphysiologic (including motor activity, core and surface temperature and vascular) andperformance monitoring on a larger scale in keeping with Popes the proper study ofMankind is Man (47), in keeping with Charrons la vraye science et le vray estude delhomme, cest lhomme (48).

Acknowledgements

Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH).



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Figure 1.Tumor incidence is here shown to be statistically significantly less among mice subjected toweekly shifts of the lighting but not of the feeding regimen by comparison with mice kept on

a fixed lighting and feeding regimen. No statistically significant difference in tumor incidencewas found between this reference group and a group of mice subjected to weekly shifts of boththe lighting and feeding schedules, yet numerically tumor incidence was reduced in this groupas well. Shifts can thus be beneficial, e.g., carcinostatic under certain circumstances, when theymay enhance the effect of calorie restriction; food consumption was strictly controlled (3). Halberg.



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Figure 2.Studies on BALB/c mice showed that schedule-shifts implemented twice weekly were

associated with longer survival than weekly shifts, suggesting the importance of a structured(nonlinear) role played by the interval between consecutive shifts, which finding then led to along series of systematic studies on insects with Dr. Dora K. Hayes of the US Department ofAgriculture in Beltsville, MD, USA, and with the entomology department of the University ofMinnesota, and on unicells with Dr. Sigrid Berger, Max-Planck-Institute on Cell Biology,Ladenburg bei Heidelberg, Germany (see Figures 3-5). Shifts every 3 or 4 days probablyinvolve about half-weekly (circasemiseptan) rhythms more directly than weekly shifts and may



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offer a slight advantage, also insofar as the adjustment of some circadian rhythms, notably thatof mitotic activity, is as yet in an early, slow stage. Halberg.



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Figure 3.With an experimental design shown on top, 29 experiments were carried out by Dr. Dora K.Hayes over 18 months on 7,835 adult face flies kept at 26 1C. When overall mortality reached

about 50% in each separate experiment, groups of face flies subjected throughout a lifespan toshifts of a photoperiod of 16 hours of light alternating with 8 hours of darkness (as a 6-hourprolongation of the dark span) at varying intervals (every 2, 3, , or 11 days) had differentoutcomes. Their summary is shown as means standard errors as a function of shift interval,to which a 7-day cosine curve is fitted by cosinor (bottom left). The extent of reproducibility(and the uncertainty) of the circaseptan response across the 29 experiments is illustrated by thestatistically significant population-mean cosinor summary of the individual results (bottom



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right). The amplitude and phase of the response pattern are shown by the length and angle ofa directed line (vector). Non-overlap of the center (pole) by the 95% confidence ellipse of thevector indicates that the zero-amplitude (no-rhythm) assumption is rejected, attesting to thestatistical significance of the model. These results on face flies and those on springtails (Figure4) and unicells (Figure 5) indicate that the role of the interval is structured by the stages ofmulti-frequency rhythms, rather than being better (or worse), depending linearly and solelyupon the length of the inter-shift interval as a function only of the speed and phase relations of

circadian rhythm-adjustments and hence on internal circadian phase relations, some of whichmay constitute circadian rhythm disruption (cf.1). Halberg.



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Figure 4.Mortality differs as a function of shift interval in the springtail (Folsomia candida). At different

intervals (every 2, 3, , or 11 days), a regimen of quasi-optimal and non-optimal ambienttemperatures (alternating at 12-hour intervals) was shifted. Lifespan was lengthened ratherthan shortened by comparison with unshifted controls in association with shifts every 3 or 10days, a desirable effect like that in Figure 1. Table demonstrates a desynchronized about-weekly (147-hour) but synchronized half-weekly (84-hour) pattern (9). Halberg.



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Figure 5.Acetabulariagrowth rate was assessed as the change in the length of cells measured on days

(10, 20 and) 30 as compared to their length at the start of the experiment, when they averagedabout 30 mm. The response pattern in the growth rate of intact (middle) or enucleated (bottom)cells differs in groups of these unicells shifted at varying intervals ranging from 2 to 14 days,plotted on the abscissa as differing by 1-day between consecutive shifts implemented eitherevery 2, 3, , or 15 days (top). A 7-day (middle) or 3.5-day (bottom) cosine curve is fitted togrowth rate, using the interval between shifts as the time scale (left, middle and bottom). Polarplot (right, middle and bottom) shows amplitude and phase as the length and angle,respectively, of a directed line (vector). Elliptical 95% confidence regions attest to the statistical



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significance of the fitted model by their non-overlap of the pole (center of circle) whereby thezero-amplitude or no-rhythm assumption is rejected (11). Halberg.



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Figure 6.Adjustments after human transmeridian flights constitute a confounded, yet available modelfor the study of shifts in about 7-day (circaseptan) as well as circadian rhythms. A singlecircaseptan acrophase jump (upper row) is seen for the diastolic blood pressure of a 69-year-old man (FH) following a trip of 5 days from Minneapolis, Minnesota, USA, to Nice, France(W-E; vertical dashed line 1), and back to Minnesota (E-W; vertical dashed line 2). This patternwas also seen in a woman (EH), again with a lack of return of the circaseptan acrophase to theoriginal phase position after round-trip transmeridian flights (not shown).

The circadian acrophase (lower display) shows a) a gradual change after the trip from W-Eand b) asymmetry with a slower phase advance (after W-E) and rapid adjustment(resynchronization) after the return flight from E-W. A similar finding was also made whenthe initial flight away from home was from east to west and further, in the case of a man (EH)with a home on both continents, so that any effect of from home to abroad vs. from abroadto home was controlled. Note the 1-week interval used for analysis that shows a spuriousanticipation of the rapid circadian adjustment after the return flight, an artifact due to the fact

that results are plotted at the midpoints of a 7-day interval progressively displaced throughoutthe time series, thereby including data before and after each shift into the 1-week intervalsoverlapping the days of flights.

The shift in routine also involves circannual and other rhythms (not shown). The humanimmune system, in many of its components, is organized in a multi-frequency time structure(circadian, circaseptan, circannual) (43) and other (44) rhythms. To be investigated further aredifferent adjustment rates and sometimes different directions of shifts (polarity) of various



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circadian rhythms and by gating or modulation by rhythms with lower-than-circadian(infradian) frequencies, about half-weekly (circasemiseptan), circaseptan, circannual and other(44,45). The literature on signatures in human psychophysiology and pathology of a widespectrum of transdisciplinarily novel spectral components is here illustrated by a representativesingle figure involving only two spectral components. Halberg.



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Table

1

EffectofShiftworkonBloodPressu

re(BP)andHeartRate(HR)inBulga

rianAirTrafficControllers*.

Endpoint

Sys

tolicBP

DiastolicBP

HR

F

P

F

P

F

P

Single18:00value

0.3

72

0.6

92

0.2

82

0.757

0.1

99

0.8

20

Standarddeviation

1.3

80

0.2

67

4.290

0.023

1

0.4

79

0.6

24

MESOR

0.1

58

0.8

54

0.0

68

0.934

2.1

41

0.1

35

24-houramplitude

4.700

0.017

1,2

7.521

0.002

1,2

0.3

56

0.7

04

24-houracrophase

3.975

0.029

3

6.663

0.004

3

7.914

0.002

3

*Shiftschedules

beingcompared:Afternoon,

Morning,orNight

1Reducedinnight-shiftworkers

2Largestinafternoon-s

hiftworkers

3Delayedinnigh

t-shiftworkers


schedule shifts, cancer and longevity: good, bad or indifferent?

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