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Near 10-Year and Longer Periods Modulate Circadians

Intersecting Anti-aging and Chronoastrobiological Research

^a Halberg Chronobiology Center, University of Minnesota, Minneapolis
^b Department of Medicine, Tokyo Women's Medical University, Japan
^c Departments of Physiology, Masaryk University, Brno, Czech Republic
^d Departments of Functional Pathology, Masaryk University, Brno, Czech Republic
^e Institute of Medical Health Information, Prague, Czech Republic
^f Obstetrics and Gynecology Clinic, University of Milan, Italy
^g Institute of Pediatrics, Russian Academy of Medical Science, Moscow, Russia

Franz Halberg^,*, Halberg Chronobiology Center, University of Minnesota, 715 Mayo, Mayo Mail Code 8609, 420 Delaware St. S.E., Minneapolis, MN 55455 E-mail: halbe001{at}tc.umn.edu.

Decision Editor: John E. Morley, MB, BCh

	Abstract

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
Biological cycles with relatively long and some unusual periods in the range of the half-week, the half-year, years, or decades are being discovered. Their prior neglect constituted a confounder in aging and much other research, which then "flew blind" concerning the uncertainties associated with these cycles when they are not assessed. The resolution of more about 10-year and other cycles, some reported herein, replaces the admission of complete unpredictability, implied by using the label "secularity." Heretofore unaccounted-for variability becomes predictable insofar as it proves to be rhythmic and is mapped systematically to serve as a battery of useful reference values. About 10-year cycles in urinary 17-ketosteroid excretion and in heart rate and its variability, among others, are aligned with cycles of similar length in mortality from myocardial infarction. Associations accumulate between cycles of natural physical time structures, chronomes such as the 10.5-year (circadecennian) Schwabe and the 21-year (circavigintunennian) Hale cycles of solar activity, and chronomes in biota. There are about 50-year (circasemicentennian) cycles in mortality from stroke in Minnesota and in the Czech Republic and also in human morphology at birth, the latter result reducing the likelihood that these cycles are purely human made. Associations among large populations warrant long-term systematic coordinated sampling of natural physical and biological variables of interest for the design of countermeasures against already documented elevated risks of stroke, myocardial infarction, and other catastrophic diseases, notably in elderly adults. New findings will be introduced against the background of the documented value of mapping rhythms in medicine and gerontology. In both these fields, rhythms promise the seeming paradox of better care for less.

	History of Chronobiologic Concerns About Disease Risk Elevation and the Environment

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
Aging and the development of disease risk states have in common, first, that they occur over years and decades ⁽¹⁾. Cycles along these time scales will be a powerful confounder, unless they are resolved as components in the spectral element of an even broader time structure (chronome) that characterizes every physical, environmental, or biological variable measured densely for a long time ( Fig. 1) ^{(1) (2) (3) (4) (5) (6) (7) (8) (9)}.

View larger version (28K): [in this window] [in a new window]   Figure 1. The chronome (derived from chronos, "time," and nomos, "rule") represents quantitatively the measurable time structure of any variable, biological or environmental. In biology, the ending "-ome" stands for "chromosome" to convey the (habitat- and broader cosmos-influenced) genetic aspect of multifrequency rhythms, which are the major elements of chronomes, chaos and trends in rhythms and chaos being the other two elements, all interacting as feedsidewards to yield transdisciplinary complexity.

Second, both aging and disease risk elevation ( Fig. 2) can be asymptomatic for a very long time, sometimes from birth on ⁽¹³⁾, not only to adolescence ⁽¹⁴⁾ but to old age ^{(3) (13) (15)}, without being associated with any frank abnormality of location indices such as averages of vital signs or laboratory values. The warnings of an elevated risk may lie solely within the range of physiological variability that is resolved by the science of chronobiology, i.e., of life's partly genetic makeup in time, documented for instance by the emergenic inheritance of the extent of circadian change in heart rate of human twins reared apart ( Fig. 3) ( ⁽¹⁵⁾; cf. 16–18).

View larger version (43K): [in this window] [in a new window]   Figure 2. Relative risk of ischemic events associated with an excessive circadian blood pressure amplitude. To test for any interaction of the risk from an excessive circadian blood pressure amplitude with that from other known risk factors (obesity, high cholesterol, male gender, smoking, alcohol consumption, familial antecedents, old age, and MESOR hypertension), the relative risk was computed in subpopulations not presenting with the tested risk factor other than the circadian blood pressure amplitude. In each case, an excessive circadian blood pressure amplitude represents a larger risk factor for ischemic events than the tested risk factor. The fact that the 95% confidence intervals almost invariably do not overlap the number 1 indicates that an excessive circadian blood pressure amplitude raises the risk of ischemic events in a statistically significant way, irrespective of the effect of the other risk factor tested. *BMI (Body Mass Index) correlates positively with BP MESOR; **Drinking is associated with increased BP-A. **Relative Risk (RR) is the risk of patients with a risk factor (e.g., smoking or excessive BP-A) present relative to the risk of patients with that risk factor absent (whose RR = 1), computed as a ratio of incidences.

View larger version (16K): [in this window] [in a new window]   Figure 3. Groups of around-the-clock ECG records on twin pairs reared apart document the emergenic heritability of the circadian amplitude of human heart rate. Heart rate was assessed by statistically significant intraclass correlation (rI) for monozygotic (MZ) but not for dizygotic (DZ) twin pairs reared apart.

Most prominent is variability along the 24-hour scale in the form of the nearly ubiquitous circadians ^{(31) (32) (33)}. As to the innate mechanisms of these rhythms, by 1950 it was clear that certain cells in mouse blood, the eosinophils (depressed in count, among others, by corticosteroids), vary drastically within a day and that they do so around different average values, with a different extent of change depending on the inbred strain examined ⁽³¹⁾ (Appendix, Note 1).

That a genetically determined daily rhythm relates to our preparation for everyday activity, rather than being a mere response to "stress," was suggested by the timing of the adrenocortical rhythm that involved an activation of steroid secretion starting during daily rest and sleep ⁽³²⁾. The survival value of rhythms emerged when a stimulus application, along the 24-hour or some other scale (corresponding to a rhythm), was tested by systematically varying its timing. In the case of noise, whole-body irradiation, or drugs, timing made the difference between death and survival ^{(34) (35) (36) (37)} or between the acceleration and retardation of a malignant growth ^{(38) (39)}. Some of the rhythms that account for such differences depended at least in part on genetics, as suggested first by inferential statistics on data from different strains of inbred mice ⁽³¹⁾ and later on human twins reared apart ( Fig. 3) ^{(15) (17) (18)}.

The amplitude is too often ignored by exclusive concern about timing, i.e., by overly restricted focus on the circadian period or phase. The very demonstration of a rhythm depends on a zero-amplitude test. The amplitude is a major endpoint in its own right. The circadian overswinging of blood pressure precedes an elevation in the midline-estimating statistic of rhythm (MESOR; rhythm-adjusted mean) of blood pressure, as shown first in stroke-prone MESOR-hypertensive Okamoto rats ⁽⁴⁰⁾ and then in humans ⁽⁴¹⁾. This elevation of the circadian amplitude of blood pressure, occurring first in the absence of an increase in MESOR, proved to indicate a high risk of eclampsia in pregnant women ⁽⁴²⁾. Eventually, such blood pressure overswinging was revealed as a very high risk of stroke, nephropathy ^{(4) (13)}, and myocardial infarctions ⁽⁹⁾. Blood pressure overswinging carried a risk higher than the risk of a 24-hour mean of blood pressure above 130/80 mm Hg (systolic blood pressure/diastolic blood pressure), limits accounting for the low nightly values during sleep. The risk of stroke associated with overswinging was higher than and separate from the disease risk of old age. Circadian blood pressure overswinging in fact turned out to be a disease risk syndrome in its own right, circadian hyper-amplitude tension (CHAT). There may be the separate added risk of too little heart rate variability, gauged as a circadian standard deviation deficiency of heart rate (CSDD-HR), which is additive to the risk of CHAT. Thus, in a study on 297 patients, the relative vascular disease risk of 20 patients with diastolic CHAT was only 4.4, that of 19 patients with CSDD was only 5.3, and that of 5 patients with both these conditions was 10.1 (Table 1 ) ⁽⁴³⁾.

A threshold must be exceeded for a circadian amplitude of blood pressure to be too large ( Fig. 4, left) or for a circadian variability of heart rate to be too small ( Fig. 4, right) before the risk of morbidity increases ⁽⁵⁾. The latter thresholds resemble the environmental temperature threshold at lift-off in relation to the risk of the O-rings becoming brittle that, when ignored, may have been what led to the Challenger disaster ( Fig. 4, middle). Here, the interests of the elderly and of those who wish to go into extraterrestrial space meet. A disease risk syndrome diagnosed when one, the other, or both thresholds are exceeded (Table 1 ) ⁽⁴³⁾ should be recognized so that catastrophic disease jeopardizes neither a mission into space nor the crippling and cost of elderly people on earth. At all ages, variability beyond a threshold should be sought routinely, as advocated by the mayor of a suburban city for his residents ⁽⁷⁾.

View larger version (20K): [in this window] [in a new window]   Figure 4. Contrary to the linear increase in vascular disease risk in association with an increasing mean blood pressure value (not shown herein), the circadian amplitude of blood pressure (left) or the 24-hour standard deviation of heart rate (right) has to exceed a threshold value for the risk to steeply increase. Such a nonlinear relation was also observed in relation to the incidence of failure of the O-rings (located between the booster and rocket) in relation to external temperature at lift-off, which led to the Challenger disaster, as suggested by the late physicist Richard Feynman. It is a challenge for preventive medicine to avoid disaster before the available gender- and age-specified thresholds are reached, in particular for people away from hospitals or in space and also for the high-risk population of elderly adults. The cost of developing the system with available, acceptable tools, along with the development of less obtrusive instrumentation, may well be shared by those responsible for the elderly and for space travel, among others. *M. Fossel commenting on Halberg and colleagues (13); CHAT = circadian hyper-amplitude-tension; CAHRV = chronome alteration of heart rate variability. **Computed from data collected at 15-min intervals for 48 hours by K. Otsuka and colleagues (118). Computed from data of R. Feynman (119). ***In booster-rocket field joints; = statistically significant change.

In the past half-century, concern about variability within the physiological range, an endeavor with a long history, has led to focus on the biological mechanisms of time measurement, biological clocks and calendars. Far beyond circadians and circannuals, however, the past 50 years have also led to a much broader-than-circadian and circannual spectrum of rhythms and, further, separately to studies of chaotic changes. Rhythms and chaos all undergo age trends and, in addition, in some persons, trends with disease risk syndromes. Furthermore, we have learned, as sketched on the right of Fig. 5, that the rhythms in us are influenced now, as they were in the past, by both photic and nonphotic effects from the sun and possibly from the broader cosmos ⁽⁶⁾. Gerontologists and chronoastrobiologists alike may recognize that natural physical environmental factors carry a risk of their own, to be assessed so that countermeasures can be developed. An elevated risk arises perhaps largely from within when two unrelated yet additive features of a disease risk syndrome, CHAT with CSDD-HR (risks 1 and 2), Table 1 ⁽⁴³⁾, occur at an advanced age (risk 3). The elderly person may also respond to a magnetic storm created by a coronal mass ejection from the sun ( ^{(6) (19) (20) (21) (22) (51) (52) (53) (54) (55) (56) (57) (58) (59) (60) (61)}; risk 4). Moreover, if a circadecennian susceptibility resistance cycle to vascular or cerebral events is also anchored in our genes, whether or not it is synchronized by the environment, the stage of that cycle should further be considered.

View larger version (52K): [in this window] [in a new window]   Figure 5. The chronome in us, which came about as a function of chronomes around us, to be eventually coded genetically, awaits further exploration in health care, notably for stroke prevention. **Which further comprise age and other trends, including adaptive, integrative, and cultural evolution toward a chronoosphere, topics of chronobiology broadly.

	A Fraction of a Single Series Illustrates a Spurious Age Effect

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

The result in Fig. 6a from fitting a regression line is compatible with a decrease of steroid output during the aging of the subject investigated. This interpretation is at variance with a statistically highly significant increase seen during another about 3-year span when the subject was older ( Fig. 6b). If the statistically significant initial decrease in 17-ketosteroid excretion and significant increase thereafter had been studied by two different investigators who may have reported their results perhaps in two different journals, controversy could have ensued.

	17-Ketosteroid Excretion Cycle With a Relatively Long Period

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
The hypothetical controversy is resolved when all data over a 15-year span are analyzed as a whole. A statistically highly significant pattern is found by the test of the zero about 10-year (circadecennian) amplitude assumption ⁽⁵¹⁾. This null hypothesis, equivalent to the "no-about 10-year-rhythm" assumption, is rejected, as displayed in Fig. 6c. The period then found by nonlinear least squares is of 9.3 years; its 95% confidence interval extends from 8.1 to 10.0 years, as indicated with the scatter of original data, also shown in Fig. 6c. This cycle is at least a numerical near match of the cyclicity of solar activity revealed by sunspot numbers (Wolf's numbers). Fig. 6d shows a spot check by mathematical models of the time relations of the 17-ketosteroid excretion and Wolf's numbers during the same span investigated and suggests a small lag of the 17-ketosteroid excretion circadecennian as compared with that in Wolf's numbers. Fig. 6e displays the relative amplitudes of the various spectral components found earlier in CH's urine ⁽⁶²⁾ and shows that the new about 10-year cycle is the second largest component, exceeded in amplitude only by the circadian. Such hormonal changes previously described as secular, before being designated as a reproducible rhythm, require replications over several cycles. For a multitude of hormones, this is clearly a governmental task in view of the cost involved. But it is also a most promising task. An earlier mapping, with governmental support involving over 50,000 radioimmunoassays, has already revealed a number of marker rhythms for detecting disease risks ⁽¹⁶⁾, ranging from those for breast cancer and emotional disease to vascular disease. For the latter conditions, noninvasive monitoring of blood pressure and heart rate may be simple to implement. The mapping of basic chronomes, as in Acetabularia (Table 2 ), when it reveals about 10-year population rhythms already documented by analyses of the work of a Max-Planck-Institute, is also in the long term a governmental task with applied benefits ( Fig. 7).

View larger version (48K): [in this window] [in a new window]   Figure 7. . The alignment of spectra in and around us has just begun and requires lifetime monitoring of critical variables that may provide the reference values required for preventive health and environmental care. Homeostasis recognizes that physiological processes remain largely within relatively narrow ranges in health and that departure from such normal ranges is associated with overt disease. Variability within the normal range, however, is then often dealt with as if it were random, the body striving for "constancy." Learning about the rules of rhythmic and chaotic variations that take place within the "usual value ranges" led to the postulation of a "biological clock" that would enable the body to keep track of time. The fact that single cells are genetically coded for a spectrum of rhythmic variation indicates that the concept of "clock" needs extension. When the giant alga Acetabularia, a prominent model of a "clock," is placed into continuous light, its spectrum reveals the largest amplitude for a component of about 1 week rather than of 24 hours. The concept of a broad chronome takes the view that changes occurring within the usual value range resolvable as chronomes, with a predictable multifrequency rhythmic element, allow us to measure the essence of the dynamics of everyday life itself and are essential to obtain warnings before the fait accompli of disease so that prophylactic measures can be instituted in a timely way. *Indicates the "Master Switch." **Indicates several switches, including helio-geomagnetics. Inferential statistical methods map chronomes as molecular biology maps genomes; biologic chronomes await resolution of their interactions in us and around us, e.g., with magnetic storms in the interplanetary magnetic field (IMF).

	Physical Historical Aside

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

	Biological Aside: Duration Requirements for Assessing Periods

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
With data covering only 1.5 cycles on a single case, it cannot be stated whether the cycle is part of a rhythm and, if so, whether it is built-in, at least not by the criterion of free-running proposed in the early 1950s by Earl E. Bakken, who used the analogy of a free-running oscillator ⁽⁶⁵⁾. In the circadian case, a period shorter than 24 hours (by about 30 minutes on the average) in the rectal temperature of blinded mice led to a drift of the rhythm's peak, obvious to the naked eye. This drift occurred as an advance of about half an hour each day; after 20 days, it led to an antiphase and the drift in phase continued to cover an entire circadian cycle, so that eventually the rhythms of sham-operated and blinded mice were again in phase ^{(65) (66)}. The shorter-than-24-hour period was validated by a periodogram already on data covering only a fraction of the total time span required for the phase to return to in-phaseness with the rhythm of the sham-operated mice. The result led to the coining of the term "circadian" to convey both the genetic built-in component and the variability of gene expression requiring objective inferential statistical rhythm assessment ^{(65) (66) (67) (68)}.

For an about 7-day (circaseptan) rhythm, the drift of a near-weekly rhythm in the excretion of 17-ketosteroids was seen again as an advance of the acrophase, and the shorter-than-7-day period was validated by a least squares spectral analysis ⁽⁶²⁾. These observations led one of us to coin not just "circadian" but also other circa-rhythms ^{(62) (65)}. Free-running could be assessed in each case as a phase drift. In certain (C-strain) mice, this drift of the circadian peak could be followed within a span of about 1.5 months ^{(65) (66) (67)}, even though the variability on hand prompted replications over a decade for several life spans of mice.

In the case of rhythms with a period of a week, the condition of the scan of a complete cycle was more difficult to meet ⁽⁶²⁾. All else being equal (which it never is), the longer the periods of rhythms in and around us and the smaller the deviation of a body rhythm from its environmental near match happens to be, the longer it takes to examine the putative genetic aspect of a rhythm by the criterion of free-running. Further, there is the possibility that an environmental near match that cannot fully synchronize a presumably endogenous rhythm may nonetheless at least transiently pull the rhythm for a while; if there are not sufficient replications over a full cycle, the transient "lock-in" may be misinterpreted as a strict synchronization. Time series analysis is not a substitute for experimentation, but it serves for looking at the periods in the rhythmic element of chronomes in us and around us ( Fig. 7) and at internal-external relations gauged by cross-spectral coherence.

The demonstration of a free-run, if it involves the difference between an unstable "period" of Wolf's numbers (which is 10.29 years for the span covered by the 17-ketosteroid determinations) and that of 17-ketosteroids (of 9.28 years), would take roughly 100 years for a complete scan by the 17-ketosteroid maximum in a shorter-than-10-year biological cycle, in relation to an average longer-than-10-year cycle of solar activity. This arithmetic is complicated by the very likely wobble of each of the cycles involved and the possibility of transiently interacting potential synchronizers. Indeed, the period of the solar cycle itself varies greatly. A check of a putative endogenicity by a free-running circadecennian rhythm would thus be a lengthy, costly, and complex task. Nonetheless, for the near 10-year cycle in 17-ketosteroid excretion shown in Fig. 6c, we emphasize the statistical uncertainty of the estimated (about 10-year) period, apart from the problem of whether this period is not simply impressed from without but also resonating due to a component built within the organism of a population of giant unicells ^{(69) (70)} or humans studied by anthropometry over 112 years ⁽⁷¹⁾. Criteria other than free-running have to serve to scrutinize the question whether circadecennians may in fact originate and persist, at least to an appreciable extent, from within. Nonoverlapping 95% confidence intervals of the nonlinearly determined periods are a step in that direction.

A nonoverlap of the 95% confidence intervals of the periods resolved by nonlinear least squares in Wolf's numbers and in 17-ketosteroids can be seen in Fig. 6e. The wobbly nature of the sunspot cycle notwithstanding, it is not only conceivable but reasonable to assume that after a long exposure of life on earth to nonphotic solar (wind) activity, some near matches of these changes have been built into living things, just as we endow the (presumably photic in origin) biological day and year with obvious survival value. The circadian and circannual rhythms representing signatures to light from the sun may then be aligned with the host of rhythms corresponding perhaps to a spectrum of helio- and of geomagnetism, corresponding to corpuscles from the sun and/or from the changes in the flux of galactic cosmic rays that magnetic storms triggered by the solar wind displace. Components in current life's time structure could have come about the same way as a circadian rhythm is now genetically coded in bacteria ^{(72) (73) (74)} and humans ( Fig. 3) ^{(15) (17) (18)}. As to how environmental cycles may have got into genomes, Gregor Mendel, the discoverer of genetics, wrote about "earthly and cosmic influences" in a letter to Carl Naegeli, one of the leading biologists of his time ⁽⁷⁵⁾ (not in one of Mendel's publications).

	Wobbly Near 10-Year Cycle Associated With Human Mortality From Myocardial Infarction

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
Whether (as seems likely) or not there is a genetic basis of circadecennians, it is a fact that about 10-year cycles are important for human pathology. There has been a decreasing trend in mortality from myocardial infarction in Minnesota for the past two decades ( Fig. 8a, left); the detrended data ( Fig. 8a, middle) (and also the original values) show a statistically significant circadecennian cycle. Accordingly, with an N of 129,205 cases, more deaths from myocardial infarction are seen during times of high-versus-low solar activity ( Fig. 8b) ^{(5) (6)}. Table 3 and Table 4 , however, show the variabilities involved and the necessity for replications over more than a single cycle ( ^{(76) (77)}; cf. 6,21,22,51–61).

	Infradian Differences and Similarities in Biological Chronomes

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

View larger version (34K): [in this window] [in a new window]   Figure 9. . Time plot of weekly averages of urine volume of clinically healthy man 44 to 59 years of age recorded over 15 years. An about 4.2-year component is detected in this data series, showing a time structure different from that of the concomitantly assessed urinary 17-ketosteroid excretion. **Model was validated nonlinearly with period of 4.18 years, with a 95% confidence interval (CI) extending from 3.49 to 4.88 years, overlapping the CI of nearest period of 4.27 years (CI: 4.01–4.57 years in geomagnetic disturbances (Kp).

	Toward a Circadecennian Map

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

	Times of Changing Resistance

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
For half a century it has been extensively documented that the stage of circadian rhythms can account for the difference between life and death in response to the same physical or behavioral stimulus ^{(34) (35) (36) (37)}. By 1980, the role of circaseptan (the phase of about-weekly rhythms), as well as circadian and circannual stages, as accounting for the difference between an acceleration and an inhibition of malignant growth, was clarified ^{(38) (39)}: the same total weekly dose of a drug, as a function of its daily administration pattern (namely, sinusoidally changing vs equal daily doses) in the Louvain rat inhibited or stimulated the growth of an immunocytoma. Such findings can be exploited primarily in the elderly population. With only a few laudable exceptions (e.g., ⁽⁹⁴⁾), timing was unspecified in most papers dealing with the adrenal at an international symposium addressed recently by one of us ⁽⁹⁵⁾, a marked regression, as compared to an earlier international symposium decades ago on the same topic of "stress" ⁽⁹⁶⁾. Nonetheless, if the difference between shortening and lengthening life is accounted for by rhythms (it is a function of circadian, circaseptan, and circannual timing) ⁽³⁸⁾, we benefit from realizing that time and dose are complementary. Thus, administering equal daily doses of an immunomodulator and thereby failing to optimize timing can be the equivalent of ignoring dose: we can hurt rather than help by enhancing malignant growth rather than inhibiting it ^{(38) (39)}. Moreover, a chronobiological approach can make quite a difference before treatment; it is important in the diagnosis of disease risk syndromes that could prompt measures for prevention, such as strokes, that reportedly claim 160,000 lives in the United States (online: Brain Attack Coalition: www.stroke-site.org).

	Chronome (Time Structure) Watch

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
Researchers of aging, among others, benefit if they consider and, if need be, assess any putative infradian changes, rather than allowing them to remain, as secularity, unidentified confounders of their data interpretation. This concern applies doubly for circadian changes that have been explicitly viewed as confounders ⁽⁹⁷⁾. Circadian amplitudes in any one 24-hour cycle can exceed by far the extent of change encountered over a decade of aging ⁽⁹⁸⁾. A search for ways to eliminate "confounding," e.g., by fixing a time of day of sampling, is futile when there is a documented chance of a change in period or phase ^{(33) (99)}. Alternatively, the chronomes' characteristics are best assessed as gauges of, among others, pathology, e.g., Alzheimer's disease ^{(100) (101) (102)} or novel disease risk syndromes ^{(4) (5) (13)}.

	More Resolvable "Controversy"

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
Another example of divergent results is observed in the circulation in different stages of the Wolf's number-gauged solar cycle. Fig. 11a documents that correlations with solar activity of the heart rate mean may be present in one but not in another stage of the solar cycle in a clinically healthy cardiologist's record covering, mostly at half-hour intervals (with just a few interruptions), well over a decade of automatically recorded data. These differences are viewed in the broader context of Fig. 11b, showing heart rate (left) and the standard deviation of heart rate (right). In one series covering more than 32 years (Table 5 ) and another covering 112 years ⁽⁷¹⁾, biological near matches of the bipolar about 21-year Hale cycle in solar activity have been sought and found, along with about 50-year cycles ^{(6) (71)}.

	Coherence and Other Approaches to the Biosphere and the Cosmos (BIOCOS)

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
By tests for cross-spectral coherence, relations among two variables limited to a given frequency are sought by an international project, BIOCOS ⁽⁸⁾. Superposed epochs controlled by blanks and extended stepwise for longer and longer event-bracketing spans and other subtract-and-add approaches provide still weightier evidence. Thereby, we seek the mechanisms that underlie solar effects other than only sunshine. The diversity of findings in Table 1 Table 2 Table 3 Table 4 Table 5 constitutes a critical mass of new evidence, suggesting that we are also driven by nonphotic solar and perhaps galactic drummers. Results derived from time series revealing about 21- or even about 50-year cycles in large populations, when ignored, can lead to controversy, notably in research on aging. Even a record of 112 years, on 25 to 150 individuals per year, covers only two 50-year cycles ⁽⁷¹⁾. There arises the long-term task of securing time-specified reference values over many more 50-year cycles. Once several such cycles are documented, they will be available as useful time-specified reference standards, summarized as chronodesms ⁽¹⁰³⁾.

	Chronoastrobiology and Chronoastronautics: Interactions With Research on Aging

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
The study of biological rhythms has developed over the documentation of biological clocks and calendars, specialized areas of research, into the topic of a discipline in its own right, chronobiology. Rhythm, chaos, and trend characteristics at different levels of organization provide scholars of aging with opportunities for both basics and progress in disease prevention, diagnosis, and treatment based on the combination of several newly emerged technologies. These are:

• the availability of portable, personal, long-term ambulatory monitors of biologic variables: blood pressure, the ECG and electroencephalogram (EEG), gastric acidity, and core temperature are cases in point. These and other variables undergo changes that recur spontaneously and as responses;
  
• the availability of database systems to acquire, edit, and archive volumes of data obtained from personal monitors;
  
• the availability of statistical procedures to analyze and model the biologic dynamics and from them to devise optimal dosage time patterns for specific individuals;
  
• the availability of portable, programmed devices to administer therapy, e.g., by physiologic rate-adjusted cardiac pacemakers, defibrillators, or drug pumps that respond in a closed loop to the diagnostic information analyzed as one goes; and
  
• a chronobiologic understanding of the health effect of time structures that quantify aging and health positively inside the range of usual variation. Rhythms, chronomes, and their broader discipline, chronobiology, constitute an objective, useful way of approaching any problem in biology broadly and, in particular, in aging.
  

The evidence reviewed justifies a systematic long-term investment of resources for the pursuit in chronoastrobiology of what physicists have done and learned for centuries, originally by the recording of Wolf's numbers with telescopes on earth. They followed up with recordings of planetary geomagnetic disturbance, galactic cosmic rays, and, eventually, in space-borne vehicles, with studies on the solar wind and on the interplanetary magnetic field, to mention just a few of the many areas of intensive, purely physical research. The evidence suggests that, as soon as possible, physical monitoring should be aligned with the monitoring of human and other physiology and pathology as well as morphology. Humans are very sensitive magnetometers and even broader radiation detectors and are thus of use for physics, as are many aspects of biota, including bacteria. The coordinated endeavor of a formalized BIOCOS, a project specifically endorsed by a National Academy of Medical Sciences ⁽⁸⁾, could continue to provide invaluable data for much research, removing secularity as a confounder and transforming it into another tool, e.g., for anti-aging research revealing morphological, physiological, and pathological effects including new syndromes ( Fig. 2) ⁽¹³⁾.

Worry about magnetic storms, to cite one more example, is justified, not only because they may disturb communications via satellites or because they cause power failures on earth ^{(104) (105)}. These same storms also contribute to human pathology, as is now documented by their effect on myocardial infarctions and strokes ⁽¹⁰⁶⁾ and, what is most challenging, to human physiology as well.

We need maps of about 10-year changes in blood pressure, heart rate, and hormonal and other variables in and around us, cyclic or other ^{(107) (108) (109) (110) (111)}, deemed pertinent to aging. The findings herein on about 10-year cycles in metabolites of the adrenal cortex, the 17-ketosteroids, reflect, as noted, a major mechanism of defense; they can be viewed in the light of the great susceptibility to infection of patients with a deficient adrenal cortex, best seen in the 20th century before the introduction of substitution treatment with deoxycorticosterone pellets first and glucocorticoids starting in the 1950s. Results on 17-ketosteroids, among others, are on single cases, but chronobiology also rests on the finding of an about 10-year cycle in a multitude of air bacteria and from the 129,205 deaths from myocardial infarction in Minnesota ⁽⁵⁾ and corresponding earlier results elsewhere, including a database of more than 6,300,000 diagnoses made in Moscow during three years of an active sun ⁽²⁰⁾. Recent reviews of a possible role of infection in atherosclerosis and vasculopathies ^{(112) (113) (114)} could extend the focus to the evidence on the role of the cosmos in diseases of the circulation by tangible "cosmic" effects upon the heart and its variability and upon the adrenal cortex as a mechanism of resistance and even upon the microorganisms themselves, all effects exerted within the otherwise neglected "normal range" of everyday physiology.

Within this range is also the risk syndrome of blood pressure overswinging, CHAT. The opportunity of systematically resolving rhythms can lead to a biology and health care that is cost effective because focus is placed on prevention, with a view of diseases of the elderly population, started during pregnancy and in adolescence ⁽¹⁴⁾. Information on disease risk syndromes is indispensable for preventing catastrophic disease on long journeys in space, for chronobioastronautics, and for getting humans to sites remote from medical centers.

The development of a system for long-term physiological monitoring coordinated with physical monitoring is concomitantly an anti-aging and a chronobioastrological task and hence generally a governmental mandate for centuries to come. The development of unobtrusive instrumentation for this coordinated monitoring will facilitate the recruitment of subjects for the aligned life-long physiological and physical environmental monitoring and the coding of archival data. Thereby, in the footsteps of William Gilberd, the physician to Queen Elizabeth I and later to King James I of England, who separated electricity and magnetism and, in the opinion of physicists ⁽¹¹⁵⁾, wrote the first scientific treatise ⁽¹¹⁶⁾, humans as well as bacteria may serve physics. The biologists' search has revealed the 1.7-hour and 8-hour periods in the standard deviation of geomagnetic pulsations. We now need to test for any coherence with the REM state and the about 8-hour frequency of epinephrine ⁽¹¹⁷⁾ or endothelin-1 ^{(25) (26) (27)} in human blood or in the population density of endotheliocytes, as well as for about half-weekly, about half-yearly, and about 10-year changes that match the cycles of physicists (See Appendix, Note 3). Focusing on preventive measures found to be needed by humans may serve, along with physics and bioscience, health care, notably of elderly adults ( Fig. 12), while it may also cost effectively prevent a biological equivalent of the Challenger disaster at all ages (See Appendix, Note 4).

View larger version (24K): [in this window] [in a new window]   Figure 12. . Cost and quality trade-offs (left) or utilization of chronobiologic concepts for preventive as well as curative medical devices (right).

View larger version (154K): [in this window] [in a new window]   Figure 6. A (see p. M309), weekly averages of urinary 17-ketosteroid excretion by a clinically healthy man 46 to 49 years of age. A clear decrease in the urinary excretion of 17-ketosteroids is observed, leading to a plausible inference of biochemically and statistically highly accelerated aging. This inference is justified only by the unawareness of an underlying cycle. Retrospectively, the decrease in steroidal breakdown products excreted by this subject in his forties is at variance with his seemingly good health until his late eighties. **t in years (from 21 Dec 1947). B (see p. M309), weekly averages of urinary 17-ketosteroid excretion by a clinically healthy man 52 to 54 years of age. During this 3-year span, an increase in the urinary excretion of 17-ketosteroids is observed, at variance with the decreasing trend shown in A. A controversy could arise if the data of this figure were collected on another subject and were (mis)interpreted as an increase with age in 17-ketosteroid excretion, in marked contrast to the interpretation of A. **t in years (from 21 Dec 1947). C (see p. M309), weekly averages of urinary 17-ketosteroid excretion by a clinically healthy man during a 15-year span, fitted with a cosine curve with a period of 9.28 years, determined by nonlinear least squares analysis. A biological near match, at least numerically, of the about 10-year (circadecennian) solar activity cycle resolves the controversy resulting from the interpretation of parts of the record shown separately in A and B. "Circadecennian" is derived from circa, "about"; decem, "ten"; and annus, "year"; with vowel weakening and adjectival ending; the term is also suggested for use as a noun.**Model was validated nonlinearly with period of 9.28 years, with a 95% confidence interval (CI) extending from 8.72 to 9.95 years, nonoverlapping the CIs of nearest periods in geomagnetic disturbance (Kp) or in solar activity (Wolf's number). D (see p. M309), alignment of best-fitted curves to urinary 17-ketosteroid (17-KS) excretion by a clinically healthy man 44 to 59 years of age (shown in C) with the about 11-year cycle in solar activity gauged by Wolf's numbers (WN). The data on Wolf's numbers were equally analyzed by nonlinear least squares, the period resolved being 10.29 years. Despite the slight difference in period length between the two series estimated with relatively large uncertainties during the 15-year span of available biological data, the timing of high values is relatively close between the two series. For comparison, all data are expressed as a percentage of their respective average. Note different scales for WN and 17-KS. **On original data, ref: 21 Dec 1947. E (see p. M310), spectrum of urinary 17-ketosteroid excretion by a clinically healthy man over a 15-year span. The major component is the circadian rhythm, with an amplitude of 1.10 ± 0.28 mg, determined from samples collected around the clock along an about 1-week span. The second largest component is the about 10-year component, with an amplitude of 0.57 ± 0.04 mg. Other peaks in the spectrum correspond to components with periods of about 1 year and 7, 21, and 30 days. *From least squares spectra on mostly daily data over >15 calendar years, in 4 separate data sections, except for the circadian and circadecennian components.

View larger version (53K): [in this window] [in a new window]   Figure 8. A, from 1968 to 1996, the daily incidence of mortality from myocardial infarction in Minnesota decreases steadily (left). After detrending, a low-frequency variation with a period of about 10.5 years is detected with statistical significance (middle). This 10.5-year periodicity in the incidence of mortality from myocardial infarction in Minnesota is compared with the contemporaneous about 10.5-year periodicity in solar activity gauged by Wolf's numbers (right). B, daily incidences of mortality from myocardial infarction in Minnesota are stacked over an idealized solar cycle, subdivided into four stages of maximal or minimal solar activity or descending or ascending stage. During years of maximal solar activity, there is an excess of 220 deaths per year from myocardial infarction as compared to mortality during years of minimal solar activity. This difference of about 5% is statistically significant (p = .023). Values are mean ± SE (N = 129,205 deaths from myocardial infarction).

View larger version (57K): [in this window] [in a new window]   Figure 10. A, lag (bold numbers in the middle of graph) from solar extrema of several data series, all revealing a statistically significant circadecennian cycle validated by the cosinor-tested rejection of the zero-amplitude (no-cycle) assumption. Blood pressure and heart rate automatically measured around the clock mostly at 15-minute intervals for 11 years or self-measured about 5 times a day during waking for 30 years were analyzed by cosinor, along with contemporaneous Wolf's numbers. Bacterial sectoring, an indication of probable genetic change, was assessed daily on most days from February 1970 to July 1982. Mortality statistics in Minnesota from myocardial infarction span 29 years; daily urinary 17-ketosteroid excretion spans 15 years. Each data series was analyzed by linear-nonlinear least squares to resolve the about 10.5-year component characteristic of the solar activity cycle. Phase relations between the biological data and Wolf's numbers are mapped in each case, relying on solar maxima when the relation between the two variables is positive or on solar minima when dealing with an inverse relation. *Depending on a positive (+) or negative (-) association of the given variable with WN. (S)BP = (systolic) blood pressure; HR = heart rate; HRV = HR variability; P = peak; T = trough. Numbers in ( ) are nonlinearly extimated periods, in years; horizontal lines indicate spans of data availability. B, delays from solar extrema in A are aligned, irrespective of the calendar date of study, for different subjects, locations, and/or variables to reveal an apparent bunching of biological extrema with respect to those of the solar cycle. Focus on maxima or minima depends on the documented positive or negative association of the given variable with Wolf's numbers gauging solar activity. The biological cycles may contribute to mortality from myocardial infarction. Only a very small lag of 0.08 or 0.28 year is observed between the physiologic extrema of blood pressure, heart rate, and/or heart rate variability versus Wolf's number. A slightly longer lag of 1.56 years is found for bacterial sectoring, followed by a lag of 1.72 years of mortality from myocardial infarction versus Wolf's numbers. This makes biological sense because a decreased heart rate variability is a known risk factor for myocardial infarction and because an association of infections with myocardial infarction has been noted. It is hence not surprising that the lag of myocardial infarction versus Wolf's numbers occurs after that of bacterial sectoring and after that of heart rate variability in the sequence of events along the scale of the solar cycle. Last comes a lag of 2.09 years of 17-ketosteroids versus Wolf's numbers, perhaps reflecting a mechanism of organismic defense coming into play last.

View larger version (77K): [in this window] [in a new window]   Figure 11. . A, a clinically healthy cardiologist (YW, M, 35 years of age at the start of the study; Aug 1987–Jul 1998) monitored his heart rate around the clock, mostly at 15-minute intervals, with an ambulatory blood pressure monitor. Monthly averages of these data are plotted as a function of solar activity during the ascending (left) or descending (right) stage of the solar cycle. A positive correlation of human heart rate with Wolf's (sunspot) number is statistically significant during the ascending but not during the descending stage of the sunspot cycle, in keeping with the impression of a different time-macroscopic behavior of the two variables, gained by the naked eye from B. B, Monthly averages (left) and standard deviation (right) of heart rate data collected with an ambulatory monitor, mostly at 15-minute intervals around the clock for 11 years, are plotted as a function of time, together with Wolf's numbers gauging solar activity. When solar activity is high, heart rate is also elevated (left). An opposite relation is found between solar activity and heart rate variability, gauged by the monthly standard deviation (right). These long-term variations have to be replicated several times. They are a hint for grantors that "roads need to be built" in the form of the collection of systematic reference values. **Ascending stage (Aug 87–Jul 89 and Aug 96–Jul 98; ): HR means: r = 0.535 ( p < .001); HR-SD: r = -.481 ( p < .001); Descending stage (Aug 91–Jul 96; ): HR mean: r = .078 ( p = .556); HR-SD: r = -.467 ( p < .001).

	Acknowledgments

 
This research was supported by the U.S. Public Health Service (GM-13981); National Heart, Lung, and Blood Institute, National Institutes of Health (HL-40650); University of Minnesota Supercomputer Institute, Dr. h.c. Dr. h.c. Earl Bakken Fund; and Mr. Lynn Peterson, United Business Machines, Fridley, MN. We thank Sigrid Berger and Lübbo von Linden for their data preparation and editing on Table 2 .

This research is dedicated to the memory of Dr. Christian Hamburger, former director of the Hormone Department, Statens Seruminstitut, Copenhagen, Denmark, whose unique 15-year data series is here meta-analyzed (cf. 1 for original analysis); and to Dr. Frank Ungar and Dr. Salvador Sánchez de la Peña, who cooperated in much original modeling of interactions among the pineal, the pituitary, and the adrenal in vitro. This work led to feedsideward interactions that probably underlie modulations of physiology by the solar wind and, perhaps, by galactic cosmic rays. These interactions, taking place currently, may also have shaped the development of life since its origins, and some of their cyclic behavior eventually may have been coded in our genes, once it had survival value by organismic integration as well as environmental adaptation.

	Footnotes

 
Website: http://revilla.mac.cie.uva.es/chrono

Received April 3, 2000

Accepted November 1, 2000

	Appendix ENDIX

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 
Notes
1. From these original elements of the chronome, a transdisciplinary complexity arises by multiple interactions among elements in the same or different variables in an organism or in the environment and in the interactions of weather and climate with biota. A major aspect of intermodulations among the rhythmic elements of chronomes are the feedsidewards, i.e., multiple interrelated, time-dependent, and hence time-qualified feedbacks and feedforwards. Opposite (and hence confusing if left time-unqualified) effects of feedsideward intermodulations become predictable by the rhythmicity of their recurrence. Feedsidewards are critical when they account for the difference between the stimulation and inhibition of malignant growth by the same total dose per week of the same agent, dependent largely if not solely upon the time pattern of its administration ⁽³⁾.

More and more components in the spectrum of physiological variation are found to have natural physical numerical counterparts and, vice versa, numerical counterparts in heliogeomagnetics have been found for some unusual physiological cycles, believed to be purely societal. The week and the half-year, and most recently about 8-hour and about 1.7-hour periods as well as periods of about 7, about 10, about 21, and about 50 years, stand out in both biology and cosmo-, helio-, and/or geomagnetics. These physical and biological spectral components can be aligned with seemingly irregular but in part deterministically chaotic variations and with trends in endpoints of rhythms, chaos and a thus resulting transdisciplinary complexity constituting the chronomes. The exploration of physical and biological chronomes proceeds as yet opportunistically in a project on the biosphere and the Cosmos (BIOCOS) ⁽⁸⁾, with a systematic Asian Chronome Ecologic Study of Heart Rate Variability (ACEHRV), now extended to an International project (ICEHRV) focusing on the human electrocardiogram. A database of reference values thus accumulates with a minimal target length of at least 7 days beat to beat for the electrocardiogram and again for at least 7 days at intervals from 15 to 60 minutes in the case of human blood pressure. Such mapping is critical for a quantification of the dynamics of health in the range of otherwise neglected physiological variation in blood pressure, heart rate, or any other variable. There is documented merit in combining approaches by endpoints from two elements of the time structure. Rhythm parameters in the correlation dimension of R-R intervals have separated groups of clinically healthy men from patients with coronary artery disease. Not only were the patients found to have a lower value than the healthy controls, the difference was demonstrable only during the night and not during the day ⁽⁹⁾. The chaotic endpoint of both groups was characterized by a circadian rhythm, with larger values by night than by day. The circadian pattern also differed between the two groups, a 12-hour harmonic contributing with statistical significance to the circadian waveform of the patients but not to that of the healthy controls ⁽⁹⁾.

On the basic side, the demonstration of chaotic behavior in dense time series of the EEG and respiratory movement revealed nonlinear chaotic coordination between brain and lungs. The fact that this association is seen most prominently during REM sleep may shed light on our understanding of cerebral diseases that involve disturbances of respiration during sleep. These findings and the demonstration of partly chaotic nonlinear behavior in geomagnetic pulsations recorded by a stand-alone magnetometer in the presumably magnetically unpolluted ice of the Antarctic ⁽¹⁰⁾ suggests that nature "talks" to us in both the deterministically chaotic and rhythmic modes, as communication also occurs within the organism ⁽¹¹⁾.

When relatively dense data are analyzed over short spans, it is tempting to suggest that health is characterized by a chaotic behavior of biological signals while rhythms are primarily seen in the presence of disease ⁽¹²⁾. The longer a time series, however, the more apparent it becomes that biological data in both health and disease are characterized by a broad time structure that can be resolved within the range of an otherwise neglected everyday physiology. Before the onset of disease, and the appearance of symptoms usually associated with gross deviations outside the normal range of pertinent marker variables, more subtle alterations can be detected within the physiological range that do not necessarily affect endpoints such as the mean value, but may characterize dynamic chaotic endpoints such as the correlation dimension and/or rhythmic endpoints such as the amplitude or phase of a periodic component, or both. "Transdisciplinary" complexity is resolvable as a time-specified interaction between two or more chronome endpoints in us, interacting with chronomes of natural physical environmental factors outside us, as feedsidewards ⁽³⁾. Chronome maps are the invaluable and indispensable reference values for the detection of disease risk syndromes and render meaningfully measurable in time what otherwise is not, disease risk syndromes ( Fig. 2) being a case in point.

2. The necessary instrumentation for research in practice is available with a 90% reduction in cost, with analyses in light of gender- and age-specified reference values, at the Halberg Chronobiology Center of the University of Minnesota (E-mail: ).

3. There are cases, at every age, when the dominance in the spectrum of the circadian component is replaced, at least transiently, by frequencies higher and/or lower than 1 cycle per day. This can be the case under certain dietary conditions for epinephrine ⁽¹¹⁷⁾, for another circulating powerful vasoconstrictor, endothelin-1 ^{(25) (26) (27)}, and for the population density of endotheliocytes ⁽²⁸⁾. In the oxygen consumption of the giant alga Acetabularia mediterranea, a prominent circadian rhythm in light and darkness alternating at 12-hour intervals may be largely overshadowed by infradians, notably circaseptans, when this alga is kept in continuous light. In the new millennium, the circadian systems of the 1950s are just one piece of the much larger puzzle to which many more important pieces remain to be added.

4. By gestational week 20, a chronobiologic report of systolic blood pressure overswinging in a pregnant woman was given to her obstetrician. Continued monitoring beyond 48 hours was recommended (along with prophylactic low-dose aspirin treatment), because the circadian amplitude of systolic blood pressure exceeded peer limits. This written recommendation, however, was ignored, understandably since the woman's average systolic/diastolic blood pressure was 115/67 mm Hg, as measured over a 48-hour span. In this case, eclampsia led to the delivery of a boy in the 27th gestational week. He was hospitalized on and off for 26 months; his care during the first 13 months was cost accounted at $615,000, and his total care was estimated around $1 million.

	References

Top Abstract History of Chronobiologic... A Fraction of a... 17-Ketosteroid Excretion Cycle... Physical Historical Aside Biological Aside: Duration... Wobbly Near 10-Year Cycle... Infradian Differences and... Toward a Circadecennian Map Times of Changing Resistance Chronome (Time Structure) Watch More Resolvable "Controversy" Coherence and Other Approaches... Chronoastrobiology and... Appendix ENDIX References

 

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