Hypothalamic circuits and aging: keeping the circadian clock updated

Abstract

Over the past century, age-related diseases, such as cancer, type-2 diabetes, obesity, and mental illness, have shown a significant increase, negatively impacting overall quality of life. Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels, including transcriptional, translational, and post-translational processes, resulting from cellular stress and circadian derangements. The circadian clock emerges as a key regulator, sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes, such as stem-cell function, cellular stress responses, and inter-tissue communication, which become disrupted during aging. Given the crucial role of hypothalamic circuits in regulating organismal physiology, metabolic control, sleep homeostasis, and circadian rhythms, and their dependence on these processes, strategies aimed at enhancing hypothalamic and circadian function, including pharmacological and non-pharmacological approaches, offer systemic benefits for healthy aging. Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions, like the hypothalamus, while reducing side effects associated with systemic drug delivery, thereby presenting new therapeutic possibilities for diverse age-related conditions.

Figure 1

Hypothalamus as a therapeutic target to reduce age-related diseases. (A) Hypothalamic nuclei and their clocks receive external and humoral signals, inducing neuronal and astrocytic responses that modulate peripheral tissues and clocks via the autonomous nervous system (ANS) and hormones. Circadian functional coherence between the hypothalamus and peripheral tissues is necessary to maintain organismal homeostasis and promote healthy aging. Intranasal (IN) drug administration might improve hypothalamic function. (B) Astrocytes and neurons interact to maintain hypothalamic functions, including appropriate cellular stress responses. Caloric restriction (CR) and exercise modulate metabolic sensors such as AMPK, MTOR, and SIRT1, ultimately inducing unfolded protein response (UPR), autophagy, cell cycle arrest, and DNA repair processes. These mechanisms support functional cellular processes like neuronal stem cells, neurogenesis, sleep homeostasis, hypothalamic metabolic control, and circadian rhythms. (C) During aging, accumulating alterations create a progressive vicious cycle that disrupts gene expression regulatory mechanisms, induces inflammation, and interferes with protective cellular responses, circadian coordination, sleep homeostasis, metabolic control, and more. However, specific therapies and chronotherapies aimed at improving hypothalamic functions, such as NAD⁺ boosters, CR, time-restricted feeding (TRF), melatonin, etc., may slow down this vicious cycle and promote healthy aging. Peripheral tissue figures were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). AMPK: AMP-activated protein kinase; ARC: arcuate nucleus; ATGs: autophagy-related; BMAL1: brain and muscle ARNT-like 1; CCGs: clock-controlled genes; CLOCK: circadian locomotor output cycles kaput; CR: caloric restriction; DMH: dorsomedial hypothalamus; Enampt: extracellular nicotinamide phosphoribosyltransferase; FOXO3: forkhead box O3; KCNQ2/3: potassium voltage-gated channel subfamily Q member 2/3; LH: lateral hypothalamus; MTOR: mammalian target of rapamycin; NAD: nicotinamide adenine dinucleotide; NAMPT: nicotinamide phosphoribosyltransferase; NBS1: nijmegen breakage syndrome 1; NFKB: nuclear factor kappa B; NKX2.1: NK2 homebox 1; NOTCH: notch receptor; OX2R: orexin 2 receptor; PARP: poly(ADP-ribose) polymerase; PER2: period circadian regulator 2; PON: preoptic nucleus; PRDM13: PR domain-containing protein 13; PVN: paraventricular nucleus; SCN: suprachiasmatic nucleus; SIRTs: sirtuins; SON: supraoptic nucleus; SP1: specificity protein 1; UPR: unfolded protein response; VMH: ventromedial hypothalamus.