Respect of Rhythms

➥ Pushing the day into the night: irrespectuous

➥ Being on the qui vive, in a state of heightened vigilance: irrespectuous

➥ Self-giving alibis and behavioural justifications: irrespectuous

➥ Finding the proper locale to dwell and live before the exit

➥ @64 ䷿ 未濟 Not Yet Fording, Walt Whitman wrote:

"Today I enter my 64th year. The paralysis that first affected me nearly ten years ago, has since remained, with the varying course — seems to have settled quietly down, and will probably continue. I easily tire, am very clumsy, and cannot walk far; but my spirits are first-rate. I go around in public almost every day — now and then take long trips, by railroad or boat, hundreds of miles — live largely in the open air — am sunburnt and stout, (weigh 190) — keep up my activity and interest in life, people, progress, and the questions of the day. About two-thirds of the time I am quite comfortable. What mentality I ever had remains entirely unaffected; though physically I am a half-paralytic, and likely to be so, long as I live. But the principal object of my life seems to have been accomplished — I have the most devoted and ardent of friends, and affectionate relatives — and of enemies, I really make no account."

Above all, however, Walt Whitman found vitality in the natural world — in what he so poetically called “the bracing and buoyant equilibrium of concrete outdoor Nature, the only permanent reliance for sanity of book or human life.” Looking back on what most helped him return to life after the stroke, Whitman echoes Seneca’s wisdom on calibrating our expectations for contentment and writes:

"The trick is, I find, to tone your wants and tastes low down enough, and make much of negatives, and of mere daylight and the skies.

[…]

After you have exhausted what there is in business, politics, conviviality, love, and so on — have found that none of these finally satisfy, or permanently wear — what remains? Nature remains; to bring out from their torpid recesses, the affinities of a man or woman with the open air, the trees, fields, and the changes of seasons — the sun by day and the stars of heaven by night."

The master clock coordinates biological clocks from the received light

Inflammation, Sickness, and Sleep

Inflammation is a physiological response of the immune system to infection and injury regulated by different immune cells and inflammatory factors. Inflammatory molecules (cytokines, prostaglandins, and complement factors) act locally but also at a distance. Locally, they take action on nearby immune cells to stimulate their recruitment/activation, and on the vascular system to induce vasodilation and vascular permeability. They also communicate over great distances to other organs, establishing a systemic inflammation that can involve brain inflammation, also known as neuroinflammation. During infections and injuries, peripheral cytokines can come into contact with the brain via the humoral and neural routes, working in parallel and synergistically to cause neuroinflammation. A strategy to adaptively recover from infections and injuries includes sickness, which induces an inflammatory response associated with physiological and behavioural changes involving disturbed sleep. Evidence point to a reciprocal interaction between sleep and immune function, where poor sleep alters immune function and immune activation varies sleep. Inflammatory mechanisms, involving the pro-inflammatory cytokines interleukin (IL) 1α, IL1β, IL6, interferon (IFN)α, IFNγ, tumour necrosis factor (TNF)-α, and TNF-β, are induced by pathogen and are able to modulate sleep organization and main sleep-wake behaviour. Although IL-1 is commonly associated with pathological states and plays critical roles in host defence, this cytokine is also implicated in regulating physiological sleep.

Schematic of possible mechanisms underlying age-related changes in circadian rhythms. Progressive yellowing and thickening of the lens may reduce sensitivity to light, the strongest zeitgeber. Reduction of AVP and VIP expression and fewer GABAergic synapses may decrease signalling within the SCN, leading to a decrease in the overall amplitude of its firing rhythm. A weaker SCN output signal may in turn reduce the strength of downstream oscillators in central and peripheral tissues, including the cortex, pineal gland, liver, kidney, thyroid, and spleen. Providing other zeitgebers such as scheduled meals (green arrows), which act on the circadian system via extra-SCN pathways, may help entrain an ageing circadian system. 

Immunosenescence, Sleep, and Frailty

With ageing, the circadian indicators of the sleep-wake organization, i.e., sleep onset, body core temperature, motor activity, and melatonin phase, have an earlier daytime emergence; the circadian phase advances in parallel and the amplitude of the rhythms is reduced while the period is shortened. Evidence from animal studies indicates that the activity of the suprachiasmatic nuclei orchestrating the circadian rhythms is decreased with ageing and the clock gene expression is impaired; the autonomic nervous system's cyclic organization also changes with age. In peripheral blood cells, the level of Bmal1 expression, a core clock gene and a regulator of innate immunity, was shown to correlate inversely with age in women. Animal results further support these age-associated changes in clock gene expression, but also suggest a causal role for these changes in the ageing process. For example, knockouts of the clock genes Bmal1 and Period result in accelerated ageing in Drosophila and mice, characterized by increased tissue decline, cognitive dysfunction, and shorter lifespan compared with age-matched wild-type controls. On the other hand, the increased susceptibility to respiratory viral diseases in winter may be associated with the seasonal variation of Bmal1 expression, whose low levels in winter correlate with enhanced viral disease.

One of the most consistent evidence of age-associated circadian disruption is the age-associated changes in sleep, with its quantity progressively reducing (sleep deprivation) and quality worsening from around 55 yrs. of age to become worst over 65 yrs. also in subjects without major sleep disorders. Major sleep disorders and especially sleep deprivation are associated with immune dysfunction and chronic inflammation and higher risks of infection and psychiatric, cerebral/cardiovascular, metabolic/hormonal co-morbidity and related mortality irrespective of age, according to surveys and population-based studies. Congruently, the disruption of circadian rhythms results in comparable outcomes and in the elderly adds and contributes to the cumulative decline in several (brain, endocrine, immune, muscle) physiological systems during a lifetime.

The circadian system and sleep have emerged as important intertwined regulators of immune defence. Trafficking of immune cells and proinflammatory cytokines are under circadian regulation and oscillate in accordance with the rest/activity cycle. Animal studies found that global, brain or peripheral knockout of clock genes alters this circadian fluctuation and leads to an exacerbated inflammatory response to infection or other pathogenic stimuli, oxidative stress, and age-related phenotypes, thus revealing a direct role for clock genes in suppressing chronic inflammation and ensuring its timely resolution.

Additionally, adequate sleep quantity and quality support immune function, reduce infectious risks and improve vaccination responses by regulating immunological memory and humoral immunity (24). On the contrary, sleep deprivation is associated with chronic inflammation, greater susceptibility to infection and worse clinical protection after vaccines, as well as with increased risk for inflammatory diseases and total mortality. Notably, both the sleep-wake cycle and circadian clock components contribute to maintaining blood-brain barrier function, important for the neuroimmune system. Furthermore, the circadian rhythmicity of gene expression related to immune function and stress response, among others, is disrupted after sleep deprivation, as experimentally demonstrated in humans, underscoring the interrelationship between sleep and the circadian system and their interface with health. Together, observational and experimental data point to immune dysfunction and chronic, low-grade activation of inflammation in connecting circadian disruption to negative health consequences in ageing.

FIGURE 1. Schematic organization of the bidirectional relationship between central and peripheral clock genes expression and their effects on circadian rhythms, i.e., sleep-wake cycle, and on immunity. The infectious agent can interfere with both the expression of clock genes and the activation of the immune system. Host susceptibility to an invading pathogen modifies during 24 h and with ageing.