The aging clock: circadian rhythms and later life

Abstract

Circadian rhythms play an influential role in nearly all aspects of physiology and behavior in the vast majority of species on Earth. The biological clockwork that regulates these rhythms is dynamic over the lifespan: rhythmic activities such as sleep/wake patterns change markedly as we age, and in many cases they become increasingly fragmented. Given that prolonged disruptions of normal rhythms are highly detrimental to health, deeper knowledge of how our biological clocks change with age may create valuable opportunities to improve health and longevity for an aging global population. In this Review, we synthesize key findings from the study of circadian rhythms in later life, identify patterns of change documented to date, and review potential physiological mechanisms that may underlie these changes.

Figure 1. The molecular circadian clock.

Heterodimers of the transcription factors BMAL1 and CLOCK upregulate the expression of many target genes. Of these, the protein products of the Period (Per) and Cryptochrome (Cry) genes provide a feedback mechanism to inhibit the transcriptional activity of CLOCK-BMAL1. The activity of PER-CRY dimers is regulated at a posttranscriptional level via phosphorylation by kinases, including casein kinase 1ε (CKI). Other gene targets of CLOCK-BMAL1 include the nuclear receptors retinoid-related orphan receptor α (RORα) and REV-ERBα, which, respectively, promote and inhibit the transcription of Bmal1. In addition to these core components of the genetic clock, CLOCK-BMAL1 regulates the expression of a number of downstream targets that are referred to as clock-controlled genes (CCGs) (13, 14) P, phosphorylation.

Figure 2. Examples of circadian rhythms in older adults relative to rhythms in younger adults.

In the 24-hour cycle, documented changes include rhythms of waking activity; core body temperature; SCN firing; release of hormones, such as melatonin and cortisol; and fasting plasma glucose levels. Relative to younger adults (blue lines), the amplitude of many rhythms dampens in older adults (red lines). In some cases, the peak of the rhythm also advances.

Figure 3. 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 signaling 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 aging circadian system.