ABSTRACT
With the aging world population, the prevalence of aging‐related disorders is on the rise. Diseases such as Alzheimer’s, type 2 diabetes mellitus (T2DM), Parkinson’s, atherosclerosis, hypertension, and osteoarthritis are age‐related, and most of these diseases are comorbidities or risk factors for AD; however, our understandings of molecular events that regulate the occurrence of these diseases are still not fully understood. Brain and muscle Arnt‐like protein‐1 (Bmal1) is an irreplaceable clock gene that governs multiple important physiological processes. Continuous research of Bmal1 in AD and associated aging‐related diseases is ongoing, and this review picks relevant studies on a detailed account of its role and mechanisms in these diseases. Oxidative stress and inflammation turned out to be common mechanisms by which Bmal1 deficiency promotes AD and associated aging‐related diseases, and other Bmal1‐dependent mechanisms remain to be identified. Promising therapeutic strategies involved in the regulation of Bmal1 are provided, including melatonin, natural compounds, metformin, d‐Ser2‐oxyntomodulin, and other interventions, such as exercise, time‐restricted feeding, and adiponectin. The establishment of the signaling pathway network for Bmal1 in aging‐related diseases will lead to advances in the comprehension of the molecular and cellular mechanisms, shedding light on novel treatments for aging‐related diseases and promoting aging‐associated brain health.
INTRODUCTION
Aging, a complex biological process, is characterized by decreased physiological function with increased age; often aging is associated with increased susceptibility to diseases, including type 2 diabetes mellitus (T2DM), cardiovascular and musculoskeletal diseases, and neurological diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Zhuang et al., 2019). AD is the foremost cause of impaired cognition in the elderly and has become the fifth leading cause of death worldwide (Cortes‐Canteli & Iadecola, 2020). Studies have found that many aging‐related diseases such as PD (Cibulka et al., 2022), diabetes mellitus, atherosclerosis (AS) (Xie, Shi, et al., 2020), hypertension (Shih et al., 2018), osteoarthritis (OA) (Innes & Sambamoorthi, 2020), and age‐related macular degeneration (AMD) (Wen et al., 2021) are closely related to AD, which may be comorbidities or risk factors for AD. This important commonality is why AD and these diseases are explored in the present study. It is known that PD and AD are common neurologic diseases of old age (Fang et al., 2018). Diabetes mellitus, hypertension, and OA have been reported to be common comorbidities in AD (Kao et al., 2021; Wang, Wu, et al., 2018). AS (Xie, Shi, et al., 2020), and AMD (Wen et al., 2021) had an increased risk of their condition advancing to AD. According to the World Health Organization (WHO) estimates, by 2050, the proportion of the global population with age > 60 years will ascend to 22% (Mahjoob & Stochaj, 2021). Emerging evidence now suggests an increased trend of patients with AD and associated aging‐related diseases. For example, in the United States, the number of patients aged ≥65 years with AD and related dementias is growing and is projected to reach 13.9 million by 2060 (Matthews et al., 2019). The number of adults aged ≥65 and 65–99 years with diabetes mellitus is expected to increase to 0.253 and 1.42 billion, respectively, over the next 23 years globally (Bellary et al., 2021); nearly half of these adults are expected with T2DM. These epidemiological studies indicate a serious threat to global health with reduced quality of life of older adults amidst increased risk of AD and associated aging‐related diseases.
Brain and muscle Arnt‐like protein‐1 (Bmal1), one of the families of basic helix–loop–helix/Per‐ARNT‐SIM (bHLH‐PAS) domain‐containing transcription factors (Majumdar et al., 2017), is the core regulator of the circadian clock, driving rhythmic expression of circadian clock genes. Bmal1 is essential for regulating the circadian rhythms and maintaining the physiological functions of cells and organs. Evidence indicates that the deletion of Bmal1 can accelerate aging. For example, symptoms of premature aging were observed in Bmal1 deletion animal models, such as organ atrophy, sarcopenia, and cataract; these animals also had shorter lifespans (Kondratov et al., 2006). During natural aging, Bmal1 expression attenuation was noticed in animal models (Duncan et al., 2013). These studies show that the decreased expression of Bmal1 is closely associated with aging. Alterations of Bmal1 during aging, along with other systemic stimulators such as hormones and the changed microenvironment of tissues, may have differential impacts on the brain and peripheral tissues, promoting the progression of aging‐related diseases. The underlying mechanisms of the possible role of Bmal1 dysfunction in AD and associated aging‐related diseases remain unclear; increased understanding of effects of abnormal Bmal1 expression may give rise to the evolvement of new diagnostic and therapeutic approaches for better management of these diseases.
To provide an integrated picture of the role and mechanism of Bmal1 in AD and associated aging‐related diseases, we performed a comprehensive search in PubMed and Google Scholar for relevant studies. Based on existing evidence from the in vivo, in vitro, and clinical studies, we tried to summarize Bmal1‐dependent mechanisms in AD and associated aging‐related diseases and pay attention to therapeutic interventions involved in the regulation of Bmal1.
THE BIOLOGICAL FUNCTION OF BMAL1
Bmal1, also called MOP3, is a core driver of the circadian clock in mammals and is considered the only irreplaceable clock gene that regulates rhythmic behaviors (Bunger et al., 2000; Welz et al., 2019). The molecular mechanism, that drives nearly 24 h autonomous circadian oscillations, involves the transcriptional–translational feedback loop (TTFL). Here, Bmal1 and circadian locomotor output cycles kaput (CLOCK) heterodimers form the positive limb that binds to the E‐box motifs and drives the expression of the period (PER1/2/3), cryptochrome (CRY1/2), reverse erythroblastosis virus α (REV‐ERBα), and retinoid‐related orphan receptor‐α (RORα); subsequently, PER and CRY, these two proteins interact and form heterodimers in the cytoplasm, which then translocate to the nucleus to suppress the expression of the positive limb (Richards & Gumz, 2013). Further, REV‐ERBα and RORα, which form additional feedback loops, facilitate and restrain the expression of Bmal1, respectively (Peng et al., 2022). In mammals, the molecular clock based on circadian rhythmicity exists in nearly all fully differentiated cells (Reinke & Asher, 2019). The master clock, situated in the suprachiasmatic nucleus (SCN) of the hypothalamus, receives an immediate projection from the retina via light‐dark cues from the environment (Reinke & Asher, 2019). The SCN synchronizes peripheral clocks located in the non‐SCN brain areas and peripheral tissues such as muscle, liver, adipose tissue, pancreas, and gut through neural, endocrine, temperature, and behavioral signals (Stenvers et al., 2019). The circadian system regulates various physiological processes, including food‐intake behavior, rest‐activity cycle, sleep‐wake cycle, and glucose metabolism (Stenvers et al., 2019). Bmal1 is not only an important regulator of the circadian system but also involves in preserving redox homeostasis (Chhunchha et al., 2020; Xie, Tang, et al., 2020). Furthermore, Bmal1 plays a crucial role in regulating inflammatory responses (Liu et al., 2020), insulin sensitivity (Shi et al., 2013), and mitochondrial functions (E. Li, Li, et al., 2020). Bmal1 deletion abolishes 24 h activity patterns (Ray et al., 2020), leading to circadian rhythm disorders and aging‐related diseases, such as glycolipid metabolism disorders including T2DM (Marcheva et al., 2010), and neurodegenerative diseases (Musiek & Holtzman, 2016), as presented in Figure 1. Besides, Bmal1 alterations among patients with aging‐related diseases are summarized in Table 1.