The kinase activity of both CK1δ and CK1ε is inhibited by autophosphorylation of an intrinsically disordered inhibitory tail that follows the kinase domain to set these isoforms apart from other members of the CK1 family. Because the full-length kinase autophosphorylates and slowly inactivates itself in vitro, most biochemical studies exploring the activity of CK1δ/ε on clock proteins utilize the truncated, constitutively active protein, although new studies are finally beginning to explore the consequences of autophosphorylation in more detail. However, not much is known yet about how the phosphorylated tail interacts with the kinase domain to inhibit its activity; several autophosphorylation sites were previously identified on CK1ε at S323, T325, T334, T337, S368, S405, S407 and S408 using limited proteolysis and phosphatase treatment or through Ser/Thr to Ala substitutions in vitro, although it is currently not known which of these sites are important for kinase regulation of the clock. One potential interface has been mapped between the kinase domain and autoinhibitory tail through cross linking and mass spectrometry to suggest that the tail might dock some phosphorylated Ser/Thr residues close to the anion binding sites near the active site. This study also provided evidence that the tail may be able to regulate substrate binding, and therefore control specificity of the kinase,vertical plant rack by comparing the activity of CK1α, a tailless kinase, with CK1ε on two substrates, PER2 and Disheveled. Understanding the role of tail autophosphorylation and its regulation of kinase activity is sure to shed light on control of circadian rhythms by CK1δ/ε. Some sites within the C-terminal tail of CK1δ and/or CK1ε are known to be phosphorylated by other kinases, such as AMPK, PKA, Chk1, PKCα, and cyclindependent kinases.
PKA phosphorylates S370 in CK1δ to reduce its kinase activity; consistent with this, mutation of S370 to alanine increases CK1-dependent ectopic dorsal axis formation in Xenopus laevis. Chk1 and PKCα also reduce CK1δ kinase activity through phosphorylation of overlapping sites at S328, T329, S331, S370, and T397 in the tail of rat CK1δ. Phosphorylation of CK1δ T347 influences its activity on PER2 in cells, and was found to be phosphorylated by proline-directed cyclin-dependent kinases rather than autophosphorylation. CDK2 was also found to reduce the activity of rat CK1δ in vitro through phosphorylation of additional sites at T329, S331, T344, S356, S361, and T397. Unlike the other kinases listed here, phosphorylation of S389 on CK1ε by AMPK increases the apparent kinase activity on the PER2 phosphodegron in cells; consequently, activation of AMPK with metformin increased the degradation of PER2. Therefore, the phosphorylation of CK1δ and/or CK1ε tails by these other kinases therefore has the potential to link its regulation of PER2 and the circadian clock to metabolism, DNA damage response, and the cell cycle. There is now strong evidence that the C-terminus of CK1δ plays a direct role in regulation of circadian period. Recently, tissue-specific methylation of CK1δ was shown to regulate alternative splicing of the kinase into two unique isoforms, δ1 and δ2, that differ only by the extreme C-terminal 15 residues. Remarkably, expression of the canonical δ1 isoform decreases PER2 half-life and circadian period, while the slightly shorter δ2 isoform increases PER2 half-life and circadian period.Further biochemical studies revealed that these two variants exhibit differential activity on the stabilizing priming site of the PER2 FASP region––the δ1 isoform has a lower activity than δ2, which also closely resembles the C-terminus of the ε isoform.
These data suggest that a very short region at the C-terminal end of the tail could play a major role in regulation of CK1δ and the PER2 phosphoswitch to control circadian period. This is bolstered by the discovery of a missense mutation in the same region of the CK1ε tail at S408N in humans that has been associated with protection from Delayed Sleep Phase Syndrome and Non-24-hr Sleep-Wake Syndrome. Further studies will help to reveal biochemical mechanisms behind regulation of kinase activity and substrate selectivity by the C-terminal tail of CK1δ and CK1ε to determine how they play into regulation of circadian rhythms. The central thesis of this article is very simple: Health professionals have significantly underestimated the importance of lifestyle for mental health. More specifically, mental health professionals have underestimated the importance of unhealthy lifestyle factors in contributing to multiple psychopathologies, as well as the importance of healthy lifestyles for treating multiple psychopathologies, for fostering psychological and social well-being, and for preserving and optimizing cognitive capacities and neural functions. Greater awareness of lifestyle factors offers major advantages, yet few health professionals are likely to master the multiple burgeoning literatures. This article therefore reviews research on the effects and effectiveness of eight major therapeutic lifestyle changes ; the principles, advantages, and challenges involved in implementing them; the factors hindering their use; and the many implications of contemporary lifestyles for both individuals and society. Lifestyle factors can be potent in determining both physical and mental health. In modern affluent societies, the diseases exacting the greatest mortality and morbidity— such as cardiovascular disorders, obesity, diabetes, and cancer—are now strongly determined by lifestyle. Differences in just four lifestyle factors—smoking, physical activity, alcohol intake, and diet— exert a major impact on mortality, and “even small differences in lifestyle can make a major difference in health status” .
TLCs can be potent. They can ameliorate prostate cancer, reverse coronary arteriosclerosis, and be as effective as psychotherapy or medication for treating some depressive disorders . Consequently, there is growing awareness that contemporary medicine needs to focus on lifestyle changes for primary prevention, for secondary intervention, and to empower patients’ self-management of their own health. Mental health professionals and their patients have much to gain from similar shifts. Yet TLCs are insufficiently appreciated, taught, or utilized. In fact, in some ways, mental health professionals have moved away from effective lifestyle interventions. Economic and institutional pressures are pushing therapists of all persuasions toward briefer, more stylized interventions. Psychiatrists in particular are being pressured to offer less psychotherapy, prescribe more drugs, and focus on 15-minute “med checks,” a pressure that psychologists who obtain prescription privileges will doubtless also face . As a result, patients suffer from inattention to complex psychodynamic and social factors, and therapists can suffer painful cognitive dissonance and role strain when they shortchange patients who need more than what is allowed by mandated brief treatments . A further cost of current therapeutic trends is the underestimation and underutilization of lifestyle treatments despite considerable evidence of their effectiveness. In fact, the need for lifestyle treatments is growing,growing vegetables in vertical pvc pipe because unhealthy behaviors such as overeating and lack of exercise are increasing to such an extent that the World Health Organization warned that “an escalating global epidemic of overweight and obesity— ‘globesity’—is taking over many parts of the world” and exacting enormous medical, psychological, social, and economic costs.Lifestyle changes can offer significant therapeutic advantages for patients, therapists, and societies. First, TLCs can be both effective and cost-effective, and some—such as exercise for depression and the use of fish oils to prevent psychosis in high-risk youth—may be as effective as pharmacotherapy or psychotherapy . TLCs can be used alone or adjunctively and are often accessible and affordable; many can be introduced quickly, sometimes even in the first session . TLCs have few negatives. Unlike both psychotherapy and pharmacotherapy, they are free of stigma and can even confer social benefits and social esteem . In addition, they have fewer side effects and complications than medications .
TLCs offer significant secondary benefits to patients, such as improvements in physical health, self-esteem, and quality of life . Furthermore, some TLCs—for example, exercise, diet, and meditation—may also be neuroprotective and reduce the risk of subsequent age-related cognitive losses and corresponding neural shrinkage . Many TLCs—such as meditation, relaxation, recreation, and time in nature—are enjoyable and may therefore become healthy self-sustaining habits . Many TLCs not only reduce psychopathology but can also enhance health and well-being. For example, meditation can be therapeutic for multiple psychological and psychosomatic disorders . Yet it can also enhance psychological well-being and maturity in normal populations and can be used to cultivate qualities that are of particular value to clinicians, such as calmness, empathy, and self-actualization . Knowledge of TLCs can benefit clinicians in several ways. It will be particularly interesting to see the extent to which clinicians exposed to information about TLCs adopt healthier lifestyles themselves and, if so, how adopting them affects their professional practice, because there is already evidence that therapists with healthy lifestyles are more likely to suggest lifestyle changes to their patients . There are also entrepreneurial opportunities. Clinics are needed that offer systematic lifestyle programs for mental health that are similar to current programs for reversing coronary artery disease . For societies, TLCs may offer significant community and economic advantages. Economic benefits can accrue from reducing the costs of lifestyle-related disorders such as obesity, which alone accounts for over $100 billion in costs in the United States each year . Community benefits can occur both directly through enhanced personal relationships and service and indirectly through social networks. Recent research demonstrates that healthy behaviors and happiness can spread extensively through social networks, even through three degrees of separation to, for example, the friends of one’s friends’ friends . Encouraging TLCs in patients may therefore inspire similar healthy behaviors and greater well-being in their families, friends, and co-workers and thereby have far-reaching multiplier effects . These effects offer novel evidence for the public health benefits of mental health interventions in general and of TLCs in particular. So what lifestyle changes warrant consideration? Considerable research and clinical evidence support the following eight TLCs: exercise, nutrition and diet, time in nature, relationships, recreation, relaxation and stress management, religious and spiritual involvement, and contribution and service to others.Exercise offers physical benefits that extend over multiple body systems. It reduces the risk of multiple disorders, including cancer, and is therapeutic for physical disorders ranging from cardiovascular diseases to diabetes to prostate cancer . Exercise is also, as the Harvard Mental Health Letterconcluded, “a healthful, inexpensive, and insufficiently used treatment for a variety of psychiatric disorders.” As with physical effects, exercise offers both preventive and therapeutic psychological benefits. In terms of prevention, both cross-sectional and prospective studies show that exercise can reduce the risk of depression as well as neurodegenerative disorders such as age-related cognitive decline, Alzheimer’s disease, and Parkinson’s disease . In terms of therapeutic benefits, responsive disorders include depression, anxiety, eating, addictive, and body dysmorphic disorders. Exercise also reduces chronic pain, age-related cognitive decline, the severity of Alzheimer’s disease, and some symptoms of schizophrenia . The most studied disorder in relation to exercise to date is mild to moderate depression. Cross-sectional, prospective, and meta-analytic studies suggest that exercise is both preventive and therapeutic, and in terms of therapeutic benefits it compares favorably with pharmacotherapy and psychotherapy . Both aerobic exercise and nonaerobic weight training are effective for both short-term interventions and long-term maintenance, and there appears to be a dose–response relationship, with higher intensity workouts being more effective. Exercise is a valuable adjunct to pharmacotherapy, and special populations such as postpartum mothers, the elderly, and perhaps children appear to benefit . Possible mediating factors that contribute to these antidepressant effects span physiological, psychological, and neural domains. Proposed physiological mediators include changes in serotonin metabolism, improved sleep, as well as endorphin release and consequent “runner’s high” . Psychological factors include enhanced self-efficacy and self esteem, interruption of negative thoughts and rumination , and perhaps the breakdown of muscular armor, the chronic psychosomatic muscle tension patterns that express emotional conflicts and are a focus of somatic therapies . Neural factors are especially intriguing. Exercise increases brain volume , vascularization, blood flow, and functional measures . Animal studies suggest that exercise-induced changes in the hippocampus include increased neuronogenesis, synaptogenesis, neuronal preservation, interneuronal connections, and BDNF . Given these neural effects, it is not surprising that exercise can also confer significant cognitive benefits . These range from enhancing academic performance in youth, to aiding stroke recovery, to reducing age-related memory loss and the risk of both Alzheimer’s and non-Alzheimer’s dementia in the elderly . Multiple studies show that exercise is a valuable therapy for Alzheimer’s patients that can improve intellectual capacities, social functions, emotional states, and caregiver distress .