Regulation of SIRT1 in aging: Roles in mitochondrial function and biogenesis
Introduction
Aging is a degenerative process, manifested by the progressive decline in physiological functions in biological systems. The deleterious changes are believed to be associated with metabolic activities and are controlled by many factors including genetic traits, environmental stimuli and stochastic processes. A well-known theory of aging, presented by Denham Harman is the “free radical theory of aging”. Briefly, the theory is based on the idea that free radicals, in particular reactive oxygen species (ROS) produced from normal metabolism, may be the primary cause of aging and aging-related degenerative diseases. Few years later, professor Harman updated the theory with the “mitochondrial theory of aging” (Lee and Wei, 2012) (Bereiter-Hahn, 2014), claiming that as an organism grows, mitochondria accumulate oxidative damage caused by the toxicity of ROS. Reactive species are associated with detrimental effects on mitochondrial function, leading to abnormal amounts of ROS production, and so further damage.
As an essential intracellular organelle for aerobic metabolism, mitochondria are critically relevant to energy homeostasis, since approximately 90% of cellular ATP production is associated with oxidative phosphorylation in the respiratory chain (RC) complexes located in their inner membrane (Romano et al., 2014). The decline of mitochondrial function has been reported to be important during the process of aging with distinct mitochondrial morphological changes, e.g., abnormal rounded mitochondria (Lin et al., 2015), reduction of mitochondrial DNA but increase of mutation rate (Gaziev et al., 2014, LaRocca et al., 2014), reduction of RC activity (Sudheesh et al., 2009) as well as impaired mitochondrial biogenesis (8). A decrease in mitochondrial biogenesis may reduce the turnover of mitochondrial components resulting in the accumulation of oxidized lipids, proteins and DNA (Ungvari et al., 2010). Thus, it is believed that maintenance of mitochondrial biogenesis capacity during aging is a key factor in preventing the progression of aging-related diseases.
With homology to Saccharomyces cerevisiae silent information regulator 2 (Sir2), the sirtuin family is a highly conserved class of nicotinamide adenine dinucleotide (NAD+) dependent deacetylases and ADP-ribosyltransferase proteins. This family is composed by seven members in both prokaryotes and eukaryotes (Morris, 2013). SIRT1 is the most extensively studied sirtuin protein, probably because of its involvement in the regulations of diverse cellular physiological and pathological processes including gene silencing, stress resistance, apoptosis, inflammation and senescence, as well as its potential for therapeutic approaches (Chung et al., 2010, LaRocca et al., 2014, Revollo and Li, 2013). Interestingly, overexpression of SIRT1 in mice (Sirt1-overexpressing transgenic mice) results in significant life span extension and exhibits phenotypes associated with delayed aging, such as enhancement in physical activity, body temperature, oxygen consumption, and quality of sleep compared to age-matched control mice, whereas inhibition of SIRT1 in these mice abrogates the effect of life span extension (Satoh et al., 2013).
Recent studies demonstrated that SIRT1 promotes mitochondrial biogenesis by deacetylation of target proteins such as peroxisome proliferator activated receptor γ co-activator 1α (PGC-1α) (Wenz, 2013) and hypoxia-inducible factor 1α (HIF-1α) (Gomes et al., 2013). These findings suggested potential therapeutic benefits of SIRT1 activation for metabolic and other aging-related diseases. For the better understanding of its molecular and cellular mechanisms, we discussed the role of SIRT1 in aging focusing on the regulation of mitochondrial biogenesis in this review.
Section snippets
Mitochondrial biogenesis
Mitochondria are the most dynamically responsive sensing systems in eukaryotic cells, acting to satisfy metabolic energy demands, supply biosynthetic precursors, and consequently regulate diverse processes, including proliferation (Li et al., 2015a), immune responses (Kim et al., 2015), apoptosis (Kuo et al., 2015), and cell viability (Radogna et al., 2015). Cells can degrade damaged mitochondria (the process of mitophagy) and under appropriate conditions, stimulate functional mitochondria to
SIRT1 and aging
SIRT1 has the capability to extend life span, delay aging and prevent aging-related diseases, mainly by catalyzing the deacetylation of histones, and regulation of transcription factors, or coactivators, such as P53, forkhead box O (FOXO), nuclear factor-κB (NF-κB), PGC-1α, and Ku70 (Table 1) (Ramis et al., 2015, Yao and Rahman, 2012). Activity is augmented by a SIRT1 activator (e.g., SRT1720), leading to attenuation of stress-induced premature cellular senescence and protection against
Role of SIRT1 in mitochondrial biogenesis
Evidence has suggested that increased mitochondrial biogenesis mediated by SIRT1 plays a key role in improving life span and aging-related diseases (Menzies and Hood, 2012). Indeed, some studies have proven that pharmacological treatment targeting for stimulating SIRT1 such as Resveratrol (Sin et al., 2014), Metformin (Qin et al., 2014), and Tetramethylpyrazine (Xu et al., 2014), increase mitochondrial biogenesis, slowing senescence. In respect to the mechanisms involved, both PGC1α-dependent
Conclusion
SIRT1 acts in the complex coordination of nuclear, cytosolic and mitochondrial metabolic and cell stress responses. Beside its role in metabolism, stress resistance, apoptosis, autophagy and inflammation, SIRT1 regulates senescence through deacetylation of target proteins when the NAD+/NADH balance is disturbed by ROS and oxidative stress. Through AMPK, HIF-1α and PGC1α, SIRT1 activates mitochondrial biogenesis promoting an increase in expression of mitochondrial genes critical for
Acknowledgement
This work was supported by the National Natural Science Foundation of China: Grant number: 81370824.
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