Aging signaling pathways and circadian clock-dependent metabolic derangements

Abstract

The circadian clock machinery orchestrates organism metabolism to ensure that development, survival, and reproduction are attuned to diurnal environmental variations. For unknown reasons, there is a decline in circadian rhythms with age, concomitant with declines in the overall metabolic tissue homeostasis and changes in the feeding behavior of aged organisms. This disruption of the relationship between the clock and the nutrient-sensing networks might underlie age-related diseases; overall, greater knowledge of the molecular mediators of and variations in clock networks during lifespan may shed light on the aging process and how it may be delayed. In this review we address the complex links between the circadian clock, metabolic (dys)functions, and aging in different model organisms.

Figure 1. Nutrient sensing pathways crosstalk during lifespan

Several distinct pathways sense dietary input from nutrients in the environment. Amino acids are sensed by the complex TSC1/TSC2 of the TOR pathway. This signal is relayed by a series of mediators, including TOR kinase to the downstream effectors S6K1 and 4E-BP. S6K and 4E-BP enhance translation, and hence, anabolism. Glucose is transported into the cell and converted from ADP and AMP to ATP, which ratios are sensed by the AMPK pathway. AMPK interacts with TSC1/TSC2 to ensure cell homeostasis. Circulating insulin and IGF (IIS) are sensed by the Insulin Receptor (IR) and transmitted to the Insulin Receptor Substrate (IRS, chico in flies). The activated IRS relays the signal to PI3K, which activates AKT, which in turn leads to transcriptional activation of target genes. AKT links the IIS pathway to the glucose sensors and TOR signaling and promotes anabolic processes. Reciprocally, signals from the TOR pathway are relayed via S6K to the IRS in the IIS pathway. As an organism's energy requirements vary throughout lifespan, these signaling pathways operate to maintain energy homeostasis during periods of high demand, such as development and reproduction. Decay in the relays of signals and/or crosstalk leads to aging and age related diseases like insulin resistance, glucose intolerance, diabetes, obesity, metabolic syndrome and cancer.

Figure 2. The circadian clock network is conserved in flies and mammals

Nematodes appear to use non-conserved mechanism to generate circadian rhythms. Light inputs generate oscillations on gene expression and locomotion, among other variables, and PDF and melatonin might be mediators of enviromental cues. In higher species, the circadian clock is constituted by the CPN in flies and the SCN in mammals. In Drosophila there are four clock genes, which interact in a negative feedback loop: Clock (Clk), cycle (cyc, an ortholog of BMAL1 in mammals), timeless (tim), and period (per). CLK and CYC activate and regulate expression levels of per and tim This leads to periodic increase in the levels of PER and TIM proteins, which accumulate in cell nuclei, and repress CLK/ CYC activators, causing suppression of per and tim transcription. PDF is expressed in a subset of CPNs and affects circadian period. Increased nutrient sensing via dTOR signaling lengthens the circadian period through S6K and GSK3, which also affects TIM. In mammals, CLOCK and BMAL1 are transcriptional activators that bind the enhancer sequences of mPer (Per 1, Per 2 and Per 3) and mCry (Cryptochrome; Cry1 and Cry2). PER and CRY proteins accumulate in the cytoplasm and translocate to the nucleus to inhibit CLOCK:BMAL1. The CLOCK/BMAL1 complex also activates transcription of the nuclear receptors REV-ERBα/β and RORα/β/δ and γ. REV-ERB acts as negative regulators of ROR. ROR and REV-ERB proteins compete for binding sites in the promoter region of Bmal1 and regulate its transcription. SIRT1 interacts with CLOCK and deacetylates BMAL1 and PER. AMPK modulated levels of CRY1 and PER and regulates SIRT1. mTOR is also regulated in a circadian manner in the mouse SCN. VIP is expressed in a subset of neurons of SCN and affects the circadian period. These interactions ensure temporal homeostasis during development and reproduction.

Figure 3. The circadian clock network and nutrient sensing pathways cross-talk during lifespan

In mammals, the circadian coordinator center, the suprachiasmatic cell nuclei (SCN), integrates light/dark cycles and nutrient cues from the environment. The SCN then relays signals to peripheral clocks. Nutrient sensing pathways in the SCN cross-talk with peripheral clocks, in a yet undefined manner. The crosstalk between nutrient sensing pathways and clock network leads to the oscillation of metabolites, ROS and hormones. These oscillations constitute individual “body time” and lead to the overall physiological homeostasis of the organism during development and reproduction. Desynchronization, disruption or decay of the clock network is associated with aging and age-associated diseases.