We identified 73 out of 425 (36.5%) disease phenotypes across the human phenome that are predicted by decreased wrist temperature amplitudes; 26 of which (13%) were highly significant under more stringent criteria. By eliminating potentially undiagnosed mild or subclinical disease conditions during the monitoring period we decreased the risk of reverse causation where existence of an underlying disease condition might have dampened the temperature rhythms. Among the best predicted diseases were NAFLD, diabetes mellitus, hypertension, asthma, chronic airway obstruction, lipid disorders, chronic liver disease, renal failure, and pneumonia disorders. Most of these belong to the group of chronic conditions responsible for 90% of the $4.1 trillion spent annually on health care in the US 44 .
The strength of our phenome-wide approach is the systematic, disease-specific quantification of circadian disruption which so far has relied on annotating disease phenotypes separately by domain experts45. These results motivate and inform follow-up studies on whether maintaining or re-establishing strong, high amplitude temperature rhythms confer protection against developing chronic diseases. Clinical studies could, for example, deploy high heat capacity mattresses46,47 as an intervention to test whether this strategy could strengthen robustness of temperature biorhythms, and to discern underlying changes in the molecular fingerprint. Novel wearable omics devices that confer low patient burden can complement this to generate mechanistic insight48. These are natural steps to disentangle causal relationship where circadian disruption raises disease susceptibility and severity while many diseases disrupt circadian rhythms26. These insights are expected to empower a more nuanced personalization of circadian health 49, balancing lifestyle risk factors and disease pathology.
Thermoregulation in humans enables body temperature to stay within a narrow, tightly controlled range where physiological processes run most efficiently. Core and peripheral body temperature are inversely coupled to regulate body temperature by balancing heat production and loss10,11. Deviation from this is controlled during a febrile response to fight pathogens, or uncontrolled in cases of prolonged extrinsically caused hyper- or hypothermia, often resulting in multi-organ failure. The circadian aspect of thermoregulation is achieved through diurnal oscillations of the temperature set point in the hypothalamic preoptic area and controlled by the ‘master’ clock in the suprachiasmatic nucleus (SCN). Thermogenic and heat-dissipative processes modulate the set point throughout the course of 24 hours typically resulting in peak core temperatures in the afternoon with the nadir reached at the end of the sleeping phase. These oscillatory temperature cues are likely picked up in the periphery to entrain, for example, sets of hepatic gene transcripts independent of peripheral liver clocks. This was suggested in a mouse model where local oscillators present in hepatocytes were silenced by means of a doxycycline-dependent REV-ERBa-mediated suppression of Bmal150. Compared to controls, a set of 31 transcripts, among them core clock genes (Per2), members of the heat shock protein family and cold-inducible RNA-binding protein (Cirbp), continued to oscillate, supporting the hypothesis that entrainment is mediated through the SCN-temperature axis rather than by peripheral oscillators. For Cirbp, this was mechanistically further substantiated ex vivo in mouse fibroblasts which, when exposed to simulated body temperature cycles, started to oscillate51. RNA interference of Cirbp in these experiments demonstrated its role to drive circadian gene expression at high amplitudes. This robustness is driven by increasing rhythmic abundance of circadian clock gene transcripts, Clock and likely Rora, Ncor1, Sirt1, and Per3, in the cytoplasm51 through enhanced splicing efficiency as the likely post-transcriptional process52. This is consistent with Ki et al.53 who argue that the most thermo-sensitive mechanism is afforded by conformational changes of the RNA secondary structure. The internal ribosome entry site (IRES) is thought to be particularly prone to these temperature-divergent structural changes. IRES is responsible for mounting the cellular stress response under conditions of apoptosis, hypoxia, mitosis and nutrient deprivation through a cap-independent translational process, an alternative mechanism for protein production. IRES elements are found in about 10% of human 5’UTRs54. Dysregulation of this IRES-mediated translation in distinct transcripts, such as insulin-like growth factor 1 (IGF-1) receptor, are implicated under certain conditions with the corresponding pathology, i.e., diabetes (as suggested in Marques et al.55), pointing towards the clinical relevance of this pathway. In a cell culture model, IRES-specific translation was instrumental for murine Per1 oscillations56, a core regulator of the clock’s transcriptional feedback loop. This raises the question of whether a hampered IRES-dependent cellular stress response weakens the clock.
Of course, other mechanisms are at play. Temperature-dependent polyadenylation through RBM3, a cold-inducible RNA-binding protein, has been suggested to contribute to cell reprogramming during a stress response53,57. An explanation for some of the strong associations observed in this study might be that small amplitude temperature rhythms diminish thermosensitive gene regulation, which in combination with disease-specific perturbations, like those observed for diabetic neuropathy,31,32 lead to the emergence of specific disease phenotypes. We suggest that comprehensive studies, such as the one piloted in the human chronobiome43, are necessary to untangle mechanistic relationships. Time-integrated transomic assessments seem to be necessary to tease out how thermoregulatory rhythms entrained, for example, by microbiota58 fit into the picture.
We found a strong association between dampened temperature rhythms and mortality. The mortality rate was increased by 14% in those who displayed a wrist temperature amplitude that was diminished by two standard deviations (1.8°C); and the literature supports this association. For example, lifespan was increased in transgenic mice by 12% in males and 20% in females with strengthened temperature amplitudes59. And overexpression of uncoupling protein 2 in hypocretin neurons (Hcrt-UCP2) of these animals reduced core body temperature by 0.3–0.5°C accompanied (though this was not measured) by a presumable increase in peripheral temperature through the coupling of core and periphery in the thermoregulatory sleep model10.
One limitation of this study is that the wrist temperature readings were collected from a sensor enclosed within the wrist-worn actigraphy device where the sensor is separated from direct skin contact by a few millimeters of plastic. Our results indicate that the temperature traces in the UKBB study capture biological signal compellingly and agree with field studies13,22,31. Further support comes from a study where the skin temperature measurements did not correlate with ambient temperature readings from a second device placed nearby on the participants’ external clothing, suggesting that a device worn on the wrist sufficiently captures the biological signal and is little contaminated by ambient temperature31. Nevertheless, ambient temperature fluctuations should be considered as a potential factor. Here, wearables with discrete temperature tracing60 offer complementary monitoring of thermoregulation in future efforts. A second limitation is that disease phenotypes are collected from in-patient hospital diagnostic codes. Therefore, some phenotypes may be recorded significantly later than actual disease onset and others may be missed from the dataset entirely. This was partially corrected for by excluding subjects according to prior diagnoses of any related disease, derived from including self-reported medical conditions at the initial assessment. Another limitation is that temperature rhythms are confounded by BMI as illustrated in Figure S2. Although we included BMI as a covariate in the models, its measurement preceded actigraphy by about five years, so it served as an incomplete control.
In conclusion, we established that decreased wrist temperature amplitudes predict future onset of diseases in participants of the UKBB, suggesting peripheral thermoregulation as a digital biomarker.