Telomeres: Dysfunction, Maintenance, Aging and Cancer

Abstract

Aging has emerged at the forefront of scientific research due to the growing social and economic costs associated with the growing aging global population. The defining features of aging involve a variety of molecular processes and cellular systems, which are interconnected and collaboratively contribute to the aging process. Herein, we analyze how telomere dysfunction potentially amplifies or accelerates the molecular and biochemical mechanisms underpinning each feature of aging and contributes to the emergence of age-associated illnesses, including cancer and neurodegeneration, via the perspective of telomere biology. Furthermore, the recently identified novel mechanistic actions for telomere maintenance offer a fresh viewpoint and approach to the management of telomeres and associated disorders. Telomeres and the defining features of aging are intimately related, which has implications for therapeutic and preventive approaches to slow aging and reduce the prevalence of age-related disorders.

Figure 1.

Telomere damage, shortening, and implications. (A) A transitory DNA damage response (DDR), which is brought on by genomic DNA damage (DD), might not be enough to produce senescence. Conversely, delayed DDR, along with cellular senescence that is linked to SASP-induced inflammatory response and subsequent fibrosis, results from irreparable, hence permanent, DNA damage at telomeres. The stem cell characteristics are harmed, and differentiation is altered by these processes in a stem cell environment. Altogether, this accelerates the aging of organisms [20]. (B) Telomeres in tissues that are prone to proliferation are shortened during cell cycle divisions, and when they get dangerously short, they induce a DDR. Telomere dysfunction in post-mitotic, non-proliferating tissues may be caused by telomeres that have irreversible DNA damage. A senescent phenotype that is defined by halted proliferation and SASP stimulation is maintained in both situations by prolonged DDR activation.

Figure 2.

Summary of clinical features of telomere biology disorders (TBDs). Multiple existing reviews and cohort studies have provided detailed descriptions of the clinical characteristics of TBDs [258,258]. Succinctly, the traditional diagnostic criteria for dyskeratosis congenita include nail dystrophy, a triad of mucocutaneous oral leukoplakias, lacy, and coloration of the reticular skin, which most frequently manifest in the second decade of life. Due to gradual bone marrow loss, dyskeratosis congenita is typically identified before these characteristics appear because of improvements in telomere length assessment and genetic screening. An increased loss of hematopoietic stem along with accompanying progenitor cells, which impairs the formation of one or more blood cell lineages, underlies bone marrow failure. Acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), or other conditions that need hematopoietic stem cell transplant, might develop from bone marrow failure [36,279-281]. Dyskeratosis congenita patients are also at risk for interstitial lung illnesses and solid malignancies (such as carcinomas) [279,282-284]. Other potentially fatal signs include gastrointestinal (GI) hemorrhage, cirrhosis of the liver, and hepatopulmonary syndrome [279,285,286]. Additional characteristics that impact life quality might emerge in several ways (see the Figure for details). In fact, only a few organ systems are exempted, highlighting the significance of telomere biology in a variety of tissues. Three severe TBDs with early onset include Coats plus syndrome, Revesz syndrome, and Hyeraal-Hreidarsson syndrome. The most common symptoms of Hyeraal-Hreidarsson syndrome in patients include fetal growth restriction, acute bone marrow failure that manifests early, cerebellar hypoplasia, and microcephaly [113]. Due to severe infections, immunodeficiency-which is primarily typified by a substantial decrease in B cells and natural killer (NK) cells-is a prevalent cause of mortality during the first few years of life. It is noteworthy that some individuals lack substantial immunodeficiency but have significant neurodevelopmental abnormalities; this distinction is probably genotype-dependent. Bilateral exudative retinopathy (also referred to as Coats disease), postnatal growth failure, GI bleeding, intrauterine growth restriction, osteopenia, bone marrow failure, cerebral calcification and cysts, and scant hair are all characteristics shared by Revesz syndrome and Coats plus syndrome [287-289]. Clinical markers that can differentiate between Revesz syndrome and Coats plus syndrome include the leukodystrophy and more severe bone marrow failure associated with Revesz syndrome, the unique pattern of cerebral cysts and calcifications, extensive gastrointestinal bleeding without a previous history of hematopoietic cell transplantation, and susceptibility to orthopedic fractures in the Coats plus syndrome. They can also be distinguished based on genotypes and how they affect the overall length of telomeres. Last but not least, adult-onset lung disorders like emphysema and pulmonary fibrosis are the most common kind of TBD [282,290,291]. AML, MDS, solid malignancies, liver and renal disorders, GI problems, and bone marrow failure are additional clinical symptoms of adult-onset TBDs. NASH, nonalcoholic steatohepatitis; GU, genitourinary; COPD, chronic obstructive pulmonary disease; AVM, arteriovenous malformation.

Figure 3.

Controls of telomere maintenance. (A) Sheltertin and the telomerase complex. (B) The relationship between thymidine nucleotide metabolism and telomere length. (C) Telomere vesicle transfer.

Figure 4.

Relevance of telomere dysfunction to cellular aging hallmarks.

Figure 5.

Tissue inflammation is caused by dysfunctional telomeres. By activating the ATM/cABL/YAP1 axis and causing the release of mature IL18 to draw in and activate T cells and macrophages, dysfunctional telomeres cause tissue inflammatory reactions. IL 18, interleukin 18; YAP1, Yes-associated protein1; cABL, Abelson murine leukemia viral oncogene homolog 1; ATM, Ataxia telangiectasia mutated.

Figure 6.

Two different yet functionally interrelated innate immune sensing pathways must be activated concurrently to promote crisis-related cell death. The production of various ISGs is primed by cGAS, which also identifies nuclear DNA species delivered to the cytosol as byproducts of breakage-fusion-bridge (BFB) cycles. ZBP1 is activated, and by identifying TERRA molecules derived from unprotected telomeres, it additionally strengthens innate immunity. This causes ZBP1 to self-oligomerize into mitochondrial filaments that can activate MAVS. The removal of abnormal cells containing unstable telomeres is mediated by the continuous synthesis of type I IFNs as well as other inflammatory markers brought on by the stimulation of DNA- and RNA-sensing pathways. Abbreviations: MAVS: mitochondrial antiviral-signalling protein; IFNs: interferons; MN: micronuclei; ZBP1(S): short isoform.

Figure 7.

Telomeres and telomerase in malignancy, aging, prospective treatments, and health. By modifying the telomere/telomerase axis in embryonic cells, maternal lifestyle choices, medications, and environmental variables may influence the length of telomeres in neonates. When the p53 checkpoint is active, telomere reduction in length causes senescence, fibrosis, apoptosis, inflammatory responses, and depletion of stem cells. Aging and many inflammatory and degenerative disorders are caused by these mechanisms. These mechanisms, as well as aging and disorders associated with aging, can be inhibited by telomerase activators and senolytics. Telomere fusion, as well as break-fusion-bridge cycles, are also brought on by short telomeresThese occurrences result in carcinogenesis when a p53 checkpoint is absent. The advancement to invasion and metastatic spread is brought on by subsequent telomerase activation. Senolytics and telomerase antagonists block the development, invasion, and metastatic spread of tumors. Lastly, there is a connection between the eight markers of health and telomere erosion. SASP, senescence-associated secretory phenotype.