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Review
. 2021 Jan 21;184(2):306-322.
doi: 10.1016/j.cell.2020.12.028. Epub 2021 Jan 14.

Telomeres: history, health, and hallmarks of aging

Deepavali Chakravarti  1 , Kyle A LaBella  1 , Ronald A DePinho  2
Affiliations
Review

Telomeres: history, health, and hallmarks of aging

Deepavali Chakravarti et al. Cell. .

Abstract

The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases.

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Conflict of interest statement

Declaration of interests R.A.D. is a co-founder, director, and advisor of Tvardi Therapeutics and co-founder and advisor of Asylia Therapeutics, Nirogy Therapeutics, and Stellanova Therapeutics.

Figures

Figure 1.
Figure 1.
Timeline of discoveries in the human telomere field.
Figure 2.
Figure 2.. The vertebrate telomere/telomerase complex
(A) Structure of the D-loop and T-loop at the telomeric end. (B) Structure of tetomerase. NOP10, nucleolar protein family A, member 3; NHP2, nucleolar protein family A, member 2; TIN2, TERF1-interacting nuclear factor 2; TPP1, telomere protection protein 1; TRF1, telomeric repeat binding factor 1; TRF2, telomeric repeat binding factor 2, POT1, protection of telomeres 1; RAP1, TERF2-interacting protein; TCAB1, telomerase Cajal body protein 1; GAR1, nucleolar protein family A. member 1.
Figure 3.
Figure 3.. Relevance of telomere dysfunction to cellular aging hallmarks
Telomere dysfunction can drive the hallmarks of cellular aging.
Figure 4.
Figure 4.. Telomere dysfunction drives mitochondrial defects.
Telomere dysfunction compromises mitochondrial function and oxidative defense, increasing ROS and creating a feed-forward loop involving p53/PGC-1α/β signaling.
Figure 5.
Figure 5.. Telomere dysfunction drives tissue inflammation.
Telomere dysfunction drives tissue inflammation through activation of the ATM/cABL/YAP1 axis and driving secretion of mature IL18 to recruit and potentiate T cells and macrophages. ATM, Ataxia telangiectasia mutated; cABL, Abelson murine leukemia viral oncogene homolog 1; YAP1, Yes-associated protein1; IL 18, interleukin 18.
Figure 6.
Figure 6.. Telomere/telomerase in aging, cancer and potential therapy.
Telomere shortening leads to senescence, fibrosis, inflammation and stem cell depletion in the presence of a functional p53 checkpoint. These processes lead to aging and other degenerative and inflammatory diseases. Telomerase activators and senolytics can inhibit these processes and inhibit aging and age related diseases. Shortened telomeres also lead to telomeric fusion and cycles of break-fusion-bridges. In the absence of a p53 checkpoint, these events lead to tumorigenesis. Further activation of telomerase leads to the progression to invasion and metastasis. Telomerase inhibitors and senolytics inhibit processes that can thwart tumor progression, invasion and metastasis.
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