Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases

Abstract

Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Cellular senescence is causally related to the occurrence and development of age-related disease. The elderly is liable to suffer from disorders such as neurodegenerative diseases, cancer, and diabetes. Therefore, it is increasingly imperative to explore specific countermeasures for the treatment of age-related diseases. Numerous studies on humans and mice emphasize the significance of metabolic imbalance caused by short telomeres and mitochondrial damages in the onset of age-related diseases. Although the experimental data are relatively independent, more and more evidences have shown that there is mutual crosstalk between telomeres and mitochondrial metabolism in the process of cellular senescence. This review systematically discusses the relationship between telomere length, mitochondrial metabolic disorder, as well as their underlying mechanisms for cellular senescence and age-related diseases. Future studies on telomere and mitochondrial metabolism may shed light on potential therapeutic strategies for age-related diseases. Graphical Abstract The characteristics of cellular senescence mainly include mitochondrial dysfunction and telomere attrition. Mitochondrial dysfunction will cause mitochondrial metabolic disorders, including decreased ATP production, increased ROS production, as well as enhanced cellular apoptosis. While oxidative stress reaction to produce ROS, leads to DNA damage, and eventually influences telomere length. Under the stimulation of oxidative stress, telomerase catalytic subunit TERT mainly plays an inhibitory role on oxidative stress, reduces the production of ROS and protects telomere function. Concurrently, mitochondrial dysfunction and telomere attrition eventually induce a range of age-related diseases, such as T2DM, osteoporosis, AD, etc. :increase; :reduce;⟝:inhibition.

The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence

“…When the DNA damage response (DDR) is prolonged, it promotes senescence [4]. Further known mechanisms underlying senescence are: (1) persistent DDR activation at telomeres, the ends of chromosomes, which is sufficient to activate replicative cell senescence [8]; (2) oncogene activation partly via reactive oxygen species (ROS) production, determining hyperproliferation and altered DNA replication profiles [4,8]; (3) cell cycle arrest by upregulation of p21 and p16 [9]; (4) mitochondrial abnormalities with an increase in ROS synthesis and impairment in biogenesis and mitophagy [10]; (5) induction to resistance to apoptosis by upregulation of the antiapoptotic proteins [10]; (6) metabolic changes determined by senescence-associated-β-galactosidase (SA-β gal) accumulation along with the increase in cellular lysosomal content [10]; (7) large-scale chromatin reorganization occurring with the generation of senescence-associated heterochromatin foci, which suppress transcription of pro-proliferation genes [10]; (8) secretion of pro-inflammatory cytokines, chemokines, proteases, and growth factors that influence the neighbouring cells (SASP profile); (9) morphological alterations including cellular flattening and enlargement [10]; (10) post-transcriptional regulatory pathways taking place at different levels: through the action of mRNA-binding proteins (RBPs) and noncoding RNAs [11][12][13][14]; through a dysregulated splicing factor expression [12,15]; and through N6-methyladenosine (m6A) processes with specific m6A-binding proteins [14].…”

Telomere Shortening and Increased Oxidative Stress in Lumbar Disc Degeneration

“…However, telomere shortening occurs in each DNA replication. This is due to DNA polymerase’s inability to replicate the region where the primers are placed on the DNA template, leading to cellular senescence or apoptosis [ 4 ]. A previous study has demonstrated that chronic inflammation can exacerbate telomere dysfunction by increasing reactive oxygen species (ROS)-mediated DNA damage and thus accelerate the accumulation of senescent cells in mice [ 5 ].…”

Functional association between telomeres, oxidation and mitochondria

“…A recent study suggests that such association between telomeres and mitochondria may have been present but not yet fully recognized. According to this recent study, telomeres control overall metabolic performance by acting through p53 ( 96 ). Making such a connection appears to have brought the mitochondria and the nucleus closer together and help elucidating the fundamental reasons of aging.…”