Mitochondrial Turnover and Aging of Long-Lived Postmitotic Cells: The Mitochondrial–Lysosomal Axis Theory of Aging

Department of Clinical Pathology and Cytology, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 09/2009; 12(4):503-35. DOI: 10.1089/ars.2009.2598
Source: PubMed


It is now generally accepted that aging and eventual death of multicellular organisms is to a large extent related to macromolecular damage by mitochondrially produced reactive oxygen species, mostly affecting long-lived postmitotic cells, such as neurons and cardiac myocytes. These cells are rarely or not at all replaced during life and can be as old as the whole organism. The inherent inability of autophagy and other cellular-degradation mechanisms to remove damaged structures completely results in the progressive accumulation of garbage, including cytosolic protein aggregates, defective mitochondria, and lipofuscin, an intralysosomal indigestible material. In this review, we stress the importance of crosstalk between mitochondria and lysosomes in aging. The slow accumulation of lipofuscin within lysosomes seems to depress autophagy, resulting in reduced turnover of effective mitochondria. The latter not only are functionally deficient but also produce increased amounts of reactive oxygen species, prompting lipofuscinogenesis. Moreover, defective and enlarged mitochondria are poorly autophagocytosed and constitute a growing population of badly functioning organelles that do not fuse and exchange their contents with normal mitochondria. The progress of these changes seems to result in enhanced oxidative stress, decreased ATP production, and collapse of the cellular catabolic machinery, which eventually is incompatible with survival.

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    • "Furthermore, activities of antioxidant enzymes in brains of adult and aged mice are higher than in young mice, which might result in a better protection of mitochondria from reactive species [16]. The mitochondrial–lysosomal axis theory of aging suggests that the number of defective mitochondria within long-lived postmitotic cells increases throughout the aging process and is accompanied by mitochondrial enlargement and decreased ATP production [23]. In accordance with this, we observed a trend toward higher basal ATP concentrations in the young animals fed control diets or 500 mg curcuminoids per kg diet compared to their respective old counterparts, and significantly higher ATP in the Y2000 compared to the O2000 group (P b 0.05, Fig. 3C). "
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    ABSTRACT: Curcuminoids (curcumin, demethoxycurcumin, bis-demethoxycurcumin) are lipophilic polyphenols thought to be effective in the prevention and treatment of neurodegenerative disorders, of which mitochondrial dysfunction is a prominent feature. In particular, older people may thus benefit from increasing their curcuminoid intake. However until now, it is not investigated if there exist age differences in the bioavailability of curcuminoids and therefore, it is unclear if curcumin doses have to be adjusted to age. Thus, we explored if the tissue concentrations and biological activities of curcuminoids are affected by age.
    06/2015; 1:3-8. DOI:10.1016/j.nfs.2015.03.002
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    • "Indeed, in older people, mitochondria in skeletal muscle appear enlarged, more rounded in shape, with matrix vacuolization and shorter cristae [73] by comparison with mitochondria found in young people. Moreover, a greater proportion of mitochondria in the elderly are depolarized or nonfunctional, which may be indicative of defects in mitochondrial turnover [74]. The density of mitochondria in skeletal muscle also drops considerably with aging [75], as shown, for example, by means of electron microscopy in the vastus lateralis muscle of people over 60 years of age when compared to their younger counterparts [60] [76]. "
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    ABSTRACT: Decline in human muscle mass and strength (sarcopenia) is one of the principal hallmarks of the aging process. Regular physical exercise and training programs are certain powerful stimuli to attenuate the physiological skeletal muscle alterations occurring during aging and contribute to promote health and well-being. Although the series of events that led to these muscle adaptations are poorly understood, the mechanisms that regulate these processes involve the “quality” of skeletal muscle mitochondria. Aerobic/endurance exercise helps to maintain and improve cardiovascular fitness and respiratory function, whereas strength/resistance-exercise programs increase muscle strength, power development, and function. Due to the different effect of both exercises in improving mitochondrial content and quality, in terms of biogenesis, dynamics, turnover, and genotype, combined physical activity programs should be individually prescribed to maximize the antiaging effects of exercise.
    Oxidative medicine and cellular longevity 05/2015; 2015:1-15. DOI:10.1155/2015/917085 · 3.36 Impact Factor
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    • "High levels of ROS induce dysfunction of mitochondria, which in turn produce ROS at higher rate. Lipofuscin accumulates in senescent cells and inhibits mitophagy (dysfunctional mitochondria turnover) further inducing ROS production and senescence [12] [13]. "
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    ABSTRACT: Age-associated cardiovascular diseases are at least partially ascribable to vascular cell senescence. Replicative Senescence (RS) and Stress-Induced Premature Senescence (SIPS) are provoked respectively by endogenous (telomere erosion) and exogenous (H2O2, UV) stimuli resulting in cell cycle arrest in G1 and G2 phases. In both scenarios, mitochondria-derived ROS are important players in senescence initiation. We aimed to define whether a mtDNA-transcribed long-non-coding-RNA (lncRNA), ASncmtRNA-2, has a role in vascular aging and senescence. Aortas of old mice, characterised by increased senescence, showed an increment in ASncmtRNA-2 expression. In vitro analysis of Endothelial Cells (EC) and Vascular Smooth Muscle Cells (VSMC) established that ASncmtRNA-2 is induced in EC, but not in VSMC, during RS. Surprisingly, ASncmtRNA-2 is not upregulated in two different EC SIPS scenarios, treated with H2O2 and UV. The p16 gene displayed similar ASncmtRNA-2 expression patterns, suggesting a possible co-regulation of the two genes. Interestingly, the expression of two miRNAs, hsa-miR-4485 and hsa-miR-1973, with perfect homology to the double strand region of ASncmtRNA-2 and originating at least in part from a mitochondrial transcript, was induced in RS, opening to the possibility that this lncRNA functions as a non-canonical precursor of these miRNAs. Cell cycle analysis of EC transiently over-expressing ASncmtRNA-2 revealed an accumulation of EC in the G2/M phase, but not in the G1 phase. We propose that ASncmtRNA-2 in EC might be involved in the RS establishment by participating in the cell cycle arrest in G2/M phase, possibly through the production of hsa-miR-4485 and hsa-miR-1973. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 01/2015; 81. DOI:10.1016/j.yjmcc.2015.01.012 · 4.66 Impact Factor
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