Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2012 Apr 27;110(9):1226-37.
doi: 10.1161/CIRCRESAHA.111.246868.

Telomeres and mitochondria in the aging heart

Javid Moslehi  1 , Ronald A DePinho, Ergün Sahin
Affiliations
Review

Telomeres and mitochondria in the aging heart

Javid Moslehi et al. Circ Res. .

Abstract

Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and PGC-1β in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Pathways implicated in contributing to mitochondrial dysfunction in the heart with aging
Multiple signaling pathways have been implicated in driving mitochondrial decline with age. Besides reduced activity of the PGC/ERRα network (see text) Angiotensin II has been suggested to play a role as activation of the Angiotensin receptor type I (AT-1) impairs mitochondrial biogenesis and mitochondrial respiratory chain activity and deletion of the AT-1 in mice is associated with increased number of mitochondria, decreased ROS induced oxidative damage, and improved cardiac function. Elevated norepinephrine and activation of β-adrenergic receptors in the heart increases ROS, impairs mitochondrial function and deletion of AC5 (the predominant isoform of adenyl cyclase in the heart), and protects from oxidative stress through activation of the RAF/MEK/ERK signaling pathway. Similarly, β-receptor blockade with carvedilol reduces oxidative stress levels in the heart., The insulin/IGF-1 pathway has been suggested to play a protective role, based on findings in mice deficient for either the insulin (CIRKO), the insulin-like growth factor 1 (IGF-1), or both receptors (MI2RKO)., These mice have varying degrees of reduced oxidative phosphorylation with decreased ATP generation, increased ROS, reduced tricarboxylic acid cycle and fatty acid oxidation genes, and impaired cardiac function. Of the 7 mammalian sirtuins, Sirtuin 1 and Sirtuin 3 have been particularly implicated in delaying cardiac aging and protecting from oxidative stress. Illustration credit: Cosmocyte/Ben Smith.
Figure 2
Figure 2. Telomere structure and telomerase
Telomeres (shown in green by fluorescence in situ hybridization) are repetitive TTAGGG sequences at the ends of chromosomes. The 3′ end contains a G-rich, single-stranded overhang that loops and invades the double-stranded telomeric region to form a so-called t-loop (not depicted). Telomeres exist in association with many different proteins that contribute to the overall stability. Six telomere-binding proteins (POT1, TRF1, TRF2, TIN2, TPP1, and Rap13) are telomere-specific and form the shelterin complex. Three, POT1, TRF1, and TRF2 directly bind to telomeres, whereas TIN2, TPP1, and Rap13 connect them (A). Telomeres are maintained by the enzyme telomerase, which consists of a RNA subunit (AAUCCC) and the reverse transcriptase, TERT, which are illustrated. The catalytic component TERT uses the RNA component to synthesize new telomeres (B). Progressive telomere shortening leads to telomere shortening and activation of the DNA damage machinery (53BP1, Mre11, and (phosphorylated) p-H2AX, p-ATM, and others) and subsequent activation of p53 and induction of apoptosis, growth arrest, and senescence (C). Telomere length is measured traditionally by Terminal Restriction Fragment (TRF) length analysis by Southern blot. TRF assesses the average telomere length within a cell population with up to 1-kb resolution. Telomere length can be alternatively measured by fluorescence in situ hybridization (FISH) with greater sensitivity (resolution, 0.3 kb) on metaphase or interphase chromosomes using directly fluorescently labeled (CCCTAA)3 peptide nucleic acid (PNA) probes. This method can be combined with immunohistochemical staining to detect TIFs. A variant of FISH has been adopted for flow (Flow-FISH). Newer methods use PCR methods with greater sensitivity (Single Telomere Length Analysis or STELA, Q-PCR, and monochrome multiplex Q-PCR). Illustration credit: Cosmocyte/Ben Smith.
Figure 3
Figure 3. Model of how telomere dysfunction and other pathways cause cardiac aging through either cellular or metabolic compromise
Telomere dysfunction–induced p53 plays an pivotal role in inducing age-associated functional decline. The pathways engaged by p53 are mutually nonexclusive and involve repression of PGC and consequent mitochondrial dysfunction, as well as induction of classic cellular outcomes of apoptosis, senescence, and growth arrest., Mitochondrial dysfunction per se can lead to growth arrest, senescence, or apoptosis, depending on extent and duration as well as other cellular events. Telomere dysfunction activates other p53-independent pathways to mediate mitochondrial dysfunction and cellular phenotypes. Illustration credit: Cosmocyte/Ben Smith.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. [April 2, 2012];National Population Projections. http://www.census.gov/population/www/projections/natproj.html.
    1. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics: 2011 update: a report from the American Heart Association. Circulation. 2011;123:e18–e209. - PMC - PubMed
    1. [April 2, 2012];Heart Disease and Stroke Prevention. http://www.cdc.gov/chronicdisease/resources/publications/aag/pdf/2011/He....
    1. Sahin E, Depinho RA. Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature. 2010;464:520–528. - PMC - PubMed
    1. Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA. P53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97:527–538. - PubMed

Publication types

MeSH terms

Substances