Aging circadian rhythms and cannabinoids

Abstract

Numerous aspects of mammalian physiology exhibit cyclic daily patterns known as circadian rhythms. However, studies in aged humans and animals indicate that these physiological rhythms are not consistent throughout the life span. The simultaneous development of disrupted circadian rhythms and age-related impairments suggests a shared mechanism, which may be amenable to therapeutic intervention. Recently, the endocannabinoid system has emerged as a complex signaling network, which regulates numerous aspects of circadian physiology relevant to the neurobiology of aging. Agonists of cannabinoid receptor-1 (CB1) have consistently been shown to decrease neuronal activity, core body temperature, locomotion, and cognitive function. Paradoxically, several lines of evidence now suggest that very low doses of cannabinoids are beneficial in advanced age. One potential explanation for this phenomenon is that these drugs exhibit hormesis-a biphasic dose-response wherein low doses produce the opposite effects of higher doses. Therefore, it is important to determine the dose-, age-, and time-dependent effects of these substances on the regulation of circadian rhythms and other processes dysregulated in aging. This review highlights 3 fields-biological aging, circadian rhythms, and endocannabinoid signaling-to critically assess the therapeutic potential of endocannabinoid modulation in aged individuals. If the hormetic properties of exogenous cannabinoids are confirmed, we conclude that precise administration of these compounds may bidirectionally entrain central and peripheral circadian clocks and benefit multiple aspects of aging physiology.

Keywords: Advanced age; Cannabis; Chronobiotic; Chronopharmacology; Circadian rhythm; Cognition; Endocannabinoid; Hormesis.

Figure 1.. Environmental inputs and physiological outputs of mammalian circadian rhythms.

Routine daily exposure to light entrains the SCN to a 24-hour period via the retinohypothalamic tract. Neurons of the SCN rhythmically alter their rates of firing in response to changing environmental conditions and humoral signals. Outputs from SCN neurons drive central rhythms in hormone production, locomotor activity, feeding behavior, and body temperature. Peripherally, cellular rhythms are entrained by the daily oscillation of body temperature and food-intake. Since endocannabinoid activity is known to regulate SCN neurons, body temperature, and food-intake, evidence suggests that the endocannabinoid system is a key component of physiological circadian rhythms.

Figure 2:. Molecular components of cellular circadian rhythms.

The core circadian molecular loop consists of two proteins, Brain and muscle arnt-like 1 (BMAL1) and Circadian Locomotor Output Cycles Kaput (CLOCK), which interact to form a transcriptional activator complex that stimulates transcription of the Period and Cryptochrome genes (PER1, PER2, CRY1, and CRY2). The Per and Cry proteins accumulate in the cytoplasm throughout the day and ultimately bind to the BMAL1:CLOCK complex. Sufficient binding of the PER:CRY complex to the BMAL1:CLOCK complex prohibits transcription of PER and CRY mRNA. As protein levels of PER and CRY diminish, the BMAL1:CLOCK complex is allowed to stimulate transcription once more.

Figure 3:. Hormesis and the chronobiotic potential of THC in aged subjects.

A) Hormetic dose-response of THC on rectal temperature in rats. Data redrawn from: Sofia, R.D., 1972. A paradoxical effect for 1-tetrahydrocannabinol on rectal temperature in rats. Research communications in chemical pathology and pharmacology, 4(2), pp.281–288. B) Declining amplitude and increasing lability of central and peripheral rhythms with age may be amenable to therapeutics which simultaneously alter neuronal activity in the SCN and body temperature. Using the chronopharmacological properties and hormetic dose-response of THC, low-dose exposure may help to rescue dysfunctional clocks in aging systems.