Crosstalk among aging, circadian rhythms, and cancers

1.Background：

There exists a complex synergistic relationship among cancer, circadian rhythms, and aging: aging is a major risk factor for cancer, disruption of circadian rhythms promotes tumor initiation and progression, and aging itself exacerbates circadian dysregulation. These three interact through shared mechanisms such as genomic instability, cellular senescence, and chronic inflammation. Their intricate relationship provides new directions for the clinical management of cancer.

2.Circadian Rhythms and Tumors

Circadian rhythms form a 24-hour cycle through transcription-translation feedback loops, involving core clock genes such as BMAL1, CLOCK, PERs, and CRYs. These genes interact to maintain circadian rhythms. Disruption of core clock genes promotes tumor initiation and progression by regulating mechanisms such as the cell cycle, DNA repair, apoptosis, and cancer stem cell activity. Abnormal expression and single nucleotide polymorphisms of these genes are significantly associated with the risk and prognosis of various cancers. Core genes like CLOCK/BMAL1 influence proliferation by periodically regulating cell cycle-related genes such as c-MYC and cyclin D1, while also participating in the maintenance of genomic stability through the regulation of the p53-MDM2 pathway and DNA repair factors like XPA. The loss of genes such as PER2 can impair the DNA damage response. Additionally, circadian genes like BMAL1 and PER2 regulate the cell cycle progression of glioblastoma stem cells, the immunosuppressive microenvironment, and self-renewal capacity, thereby influencing tumor malignancy. Relevant single nucleotide polymorphisms have shown significant associations with susceptibility and treatment response in various cancers, including breast cancer and colon cancer, revealing the multi-level regulatory role of the circadian system in tumorigenesis and targeted therapy.

3.Circadian Rhythms and Aging

With aging, the rhythmic intensity of neurons in the suprachiasmatic nucleus weakens, leading to desynchronization between the central and peripheral clocks and dysregulation of core circadian gene expression. This results in altered sleep patterns, attenuated rhythms of melatonin and cortisol secretion, and weakened metabolic rhythms, thereby accelerating immune aging, metabolic disorders, and the risk of chronic inflammation. Simultaneously, aging exacerbates circadian disruption through mechanisms such as oxidative stress and mitochondrial dysfunction, creating a vicious cycle. Studies suggest that restoring the synchronization between central and peripheral clocks can delay muscle function decline and maintain tissue rhythms, indicating that modulating circadian rhythms may serve as a novel strategy to intervene in age-related functional decline.

4.Aging and Tumors

Aging significantly increases cancer risk through various mechanisms, including genomic instability, epigenetic alterations, cellular senescence, and chronic inflammation. During aging, reduced DNA repair capacity, mitochondrial dysfunction, decreased NAD+ levels, and metabolic disturbances are closely linked to cancer initiation and progression. Chronic inflammation and the senescence-associated secretory phenotype (SASP) provide a favorable microenvironment for tumor growth, while epigenetic changes and dysregulated chromatin remodeling lead to the silencing of tumor suppressor genes, promoting tumor development. Research shows that aging and cancer are intertwined at molecular, cellular, and systemic levels, jointly driving tumor progression. Interventions targeting aging-related mechanisms may aid in cancer prevention and treatment.

5.Common Hallmarks and Mechanisms Linking Aging, Circadian Rhythms, and Cancer

5.1Aging, Circadian Rhythms, and Tumorigenesis

Studies indicate that circadian disruption accelerates aging and increases cancer risk by affecting telomere length, antioxidant enzyme activity, genomic stability, and the expression of senescence-associated proteins. Specific mechanisms include: night shift work leading to telomere shortening and increased breast cancer risk; continuous light exposure reducing superoxide dismutase and catalase activity, exacerbating oxidative stress; and the loss or mutation of core circadian genes influencing tumor susceptibility by regulating cellular senescence, proliferative signaling, and DNA repair.

5.2Aging, Circadian Rhythms, and Tumor Proliferation and Apoptosis

Aging and circadian rhythms profoundly influence tumor initiation and progression by regulating cell proliferation, apoptosis, and senescence-related mechanisms. Aging may suppress tumor proliferation by inducing cell cycle arrest and secreting SASP factors, but it may also promote tumor growth by altering immune regulation and the tumor microenvironment. Circadian rhythms, on the other hand, affect tumor cell proliferation and apoptosis by regulating the cell cycle, hormone secretion, and the expression of core clock genes. Additionally, anticancer molecules such as MLN4924 and M47 inhibit tumor proliferation and induce apoptosis by stabilizing the RORα-BMAL1 axis and degrading CRY1, respectively, offering potential targets for cancer therapy.

5.3Aging, Circadian Rhythms, and Genomic Instability in Cancer

Aging and circadian rhythms influence cancer initiation and progression by regulating mechanisms of genomic instability, such as DNA damage, telomere dysfunction, and repair defects. Circadian disruption reduces DNA repair efficiency, exacerbating genomic instability and cancer risk. Core clock genes interact with DNA damage response pathways, modulating the activity of key proteins like ATM and ATR, while BHLHE40 and CCAR2 serve as critical hubs connecting aging, circadian rhythms, and genomic instability by regulating cellular senescence, DNA repair, and circadian gene expression, revealing their complex interplay in cancer.

5.4 Cellular Senescence, Circadian Rhythms, and Cancer

Cellular senescence, a permanent growth arrest state triggered by telomere dysfunction, oncogene activation, and persistent DNA damage, is accompanied by reduced metabolic and repair capacity and plays a significant role in biological aging. Senescent cells exhibit a pro-inflammatory phenotype, which may prevent malignant transformation but also promote cancer and other age-related diseases. Research shows that activating circadian repressors can selectively induce death in cancer cells and oncogene-induced senescent cells, inhibiting tumor growth, while circadian components influence cellular senescence and tumor drug resistance by regulating p53 degradation. Furthermore, chronic circadian disruption promotes NK cell senescence, weakens immune surveillance, and facilitates tumor initiation and metastasis, highlighting the complex links between cellular senescence, circadian rhythms, and tumorigenesis, drug resistance, and immune evasion.

5.5 Dysregulated Cellular Metabolism in Aging, Circadian Rhythms, and Cancer

Aging, circadian rhythms, and dysregulated cellular metabolism are closely interconnected in cancer. AMPK and Sirtuins, as key regulators of cellular energy status, maintain energy balance and influence circadian rhythms. mTOR, a nutrient sensor, exhibits increased activity in aging and cancer, promoting tumor growth and synchronously regulating protein synthesis and cell proliferation with circadian rhythms. The insulin/IGF-1 signaling axis affects cell survival and proliferation through the AKT/FOXO cascade, forming a complex network with mTOR and AMPK pathways to jointly regulate lifespan and cancer susceptibility. Oxidative stress activates the PI3K/AKT pathway by inhibiting PTEN, regulating BMAL1 in an mTOR-dependent manner, revealing the intricate interactions among oxidative stress, PI3K/AKT signaling, BMAL1, and mTOR in cellular stress responses and circadian rhythms. These findings provide critical insights into the intersecting mechanisms of aging, circadian rhythms, and cancer metabolism, offering potential targets for anti-aging and anticancer strategies.

6. Summary and Perspectives:

Circadian genes regulate the expression of thousands of genes, including those related to cellular senescence, through core transcription-translation feedback loops and associated transcription factor networks, exhibiting 24-hour expression cycles across different tissues and organs. In the context of cancer, circadian genes significantly influence tumor initiation and progression by regulating mechanisms such as the cell cycle, DNA repair, metabolic pathways, immune function, oxidative stress responses, and the tumor microenvironment. Dysregulation or abnormal expression of these genes may lead to uncontrolled cell proliferation, accumulation of DNA damage, metabolic imbalance, and weakened immune surveillance, thereby increasing cancer risk and promoting tumor growth. Additionally, circadian rhythms play a crucial bridging role between aging and tumorigenesis by modulating inflammatory factors and key hormones in the endocrine system. With aging, circadian disruption alters hormone secretion patterns, accelerates cellular senescence and functional decline, and may trigger chronic inflammation and immune system weakening, creating a favorable environment for tumor development. Future research aimed at elucidating these mechanisms holds promise for developing circadian rhythm-based intervention strategies, not only to delay aging but also to reduce cancer incidence, offering new approaches to health management.

This review summarizes the physiological basis of circadian rhythms and their impact on tumor initiation and progression, explores the underlying mechanisms and relationships between aging and circadian rhythms, and highlights shared hallmarks of cancer and aging, such as cellular senescence, chronic inflammation, epigenetic alterations, and genomic instability. It also delves into the common features and interactions among cancer, aging, and circadian rhythms, including carcinogenesis, apoptosis, tumor growth, genomic instability, cellular senescence, and cellular metabolism. Finally, it provides insights into translating current research findings into clinical practice, with a focus on chronotherapy and anti-aging therapies achieved through integrating immunotherapy, senescent cell detection, and advanced nanocarrier delivery systems.