Mitochondrial oxidative stress in aging and healthspan - PubMed (original) (raw)

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Mitochondrial oxidative stress in aging and healthspan

Dao-Fu Dai et al. Longev Healthspan. 2014.

Abstract

The free radical theory of aging proposes that reactive oxygen species (ROS)-induced accumulation of damage to cellular macromolecules is a primary driving force of aging and a major determinant of lifespan. Although this theory is one of the most popular explanations for the cause of aging, several experimental rodent models of antioxidant manipulation have failed to affect lifespan. Moreover, antioxidant supplementation clinical trials have been largely disappointing. The mitochondrial theory of aging specifies more particularly that mitochondria are both the primary sources of ROS and the primary targets of ROS damage. In addition to effects on lifespan and aging, mitochondrial ROS have been shown to play a central role in healthspan of many vital organ systems. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and dysfunction in aging and healthspan, including cardiac aging, age-dependent cardiovascular diseases, skeletal muscle aging, neurodegenerative diseases, insulin resistance and diabetes as well as age-related cancers. The crosstalk of mitochondrial ROS, redox, and other cellular signaling is briefly presented. Potential therapeutic strategies to improve mitochondrial function in aging and healthspan are reviewed, with a focus on mitochondrial protective drugs, such as the mitochondrial antioxidants MitoQ, SkQ1, and the mitochondrial protective peptide SS-31.

Keywords: Aging; Healthspan; Mitochondria; Oxidative stress.

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Figures

Figure 1

Figure 1

Illustration of the continuum of oxidative stress in health and pathology. The redox stress pathway emphasizes the signaling role of oxidative stress and focuses on reversible regulation and depends on the interaction between cellular components and the redox environment of the cell. In contrast, prolonged or high oxidative stress leads to structural changes in proteins, lipids, and DNA that are generally more irreversible. These represent two points along the continuum of how oxidative stress may contribute to aging phenotypes. Modified from Marcinek and Siegel [120].

Figure 2

Figure 2

Interdependences of mtROS, nicotinamide nucleotides, and SIRT3: ROS-Induced ROS Signaling. Modified from Dai et al. [93].

Figure 3

Figure 3

Echocardiography of cardiac aging in wild-type (WT) and mCAT mice (A-D) and Polg m/m mice in the presence or absence of mCAT (E-H). (A, E) Left ventricular mass index (LVMI), (B, F) % FS (fractional shortening), (C, G) Ea/Aa by tissue Doppler imaging (diastolic function), (D, H) the myocardial performance index (MPI). The increased linear trends across ages in WT mice were significant for all parameters (P <0.05 for all, left panels). The beneficial effect of mCAT versus WT was analyzed by the interaction between genotype and the linear age trend, and was significant in all cases (P <0.01 for all except fractional shortening, P = 0.03). *P <0.05 versus Polgm/m at age 4 to 6 months, #P <0.05 versus Polgm/m at age 13 to 14 months (right panels). LVMI, Left ventricular mass index; mCAT, catalase targeted to mitochondria. Modified from Dai et al. [25,43].

Figure 4

Figure 4

Mitochondrial oxidative damage and mtDNA deletions in cardiac aging. (A). Mitochondrial protein carbonyl (nmol/mg) significantly increased in old wild-type (OWT, >24 months) and even more in middle-aged Polg (13.5 months) mouse hearts when compared with young WT mouse hearts. mCAT significantly reduced the age-dependent mitochondrial protein carbonylation. (B) Mitochondrial DNA deletion frequency significantly increased in OWT (>24 months) and young Polg (4 months) when compared with young WT, and this is dramatically increased in middle-aged Polg (13.5 months). mCAT overexpression significantly reduced the deletion frequency for both. *P <0.05 compared with YWT. Modified from Dai et al. [25,43].

Figure 5

Figure 5

Mitochondrial targeted SS-31 improves skeletal muscle function.In vivo mitochondrial coupling ratio (P/O) (A) and maximum mitochondrial ATP production (B) in the hindlimb muscles of aged mice were both increased 1 h after treatment with SS-31. In situ fatigue resistance in the aged mice was also increased 1 h after SS-31 treatment (C). Eight days of daily treatment with SS-31 led to increased endurance capacity in the aged mice (D) as well. Means ± SEM. n = 5-7 per group. **P <0.01 relative to age-matched control. ##P <0.01 relative to young control. Young - 5 months old; Old - 27 months old. Modified from Siegel et al. [54].

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References

    1. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956;11:298–300. doi: 10.1093/geronj/11.3.298. - DOI - PubMed
    1. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24:981–990. doi: 10.1016/j.cellsig.2012.01.008. - DOI - PMC - PubMed
    1. Sohal RS, Orr WC. The redox stress hypothesis of aging. Free Radic Biol Med. 2012;52:539–555. doi: 10.1016/j.freeradbiomed.2011.10.445. - DOI - PMC - PubMed
    1. Labunskyy VM, Gladyshev VN. Role of reactive oxygen species-mediated signaling in aging. Antioxid Redox Signal. 2013;19:1362–1372. doi: 10.1089/ars.2012.4891. - DOI - PMC - PubMed
    1. Van Raamsdonk JM, Hekimi S. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet. 2009;5:e1000361. doi: 10.1371/journal.pgen.1000361. - DOI - PMC - PubMed

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