Sirtuins, a promising target in slowing down the ageing process

Abstract

Ageing is a plastic process and can be successfully modulated by some biomedical approaches or pharmaceutics. In this manner it is possible to delay or even prevent some age-related pathologies. There are some defined interventions, which give promising results in animal models or even in human studies, resulting in lifespan elongation or healthspan improvement. One of the most promising targets for anti-ageing approaches are proteins belonging to the sirtuin family. Sirtuins were originally discovered as transcription repressors in yeast, however, nowadays they are known to occur in bacteria and eukaryotes (including mammals). In humans the family consists of seven members (SIRT1-7) that possess either mono-ADP ribosyltransferase or deacetylase activity. It is believed that sirtuins play key role during cell response to a variety of stresses, such as oxidative or genotoxic stress and are crucial for cell metabolism. Although some data put in question direct involvement of sirtuins in extending human lifespan, it was documented that proper lifestyle including physical activity and diet can influence healthspan via increasing the level of sirtuins. The search for an activator of sirtuins is one of the most extensive and robust topic of research. Some hopes are put on natural compounds, including curcumin. In this review we summarize the involvement and usefulness of sirtuins in anti-ageing interventions and discuss the potential role of curcumin in sirtuins regulation.

Keywords: Ageing; Curcumin; Senescence; Sirtuins.

Fig. 1

Role of SIRT1 and SIRT6 in chromatin condensation. SIRT1 and SIRT6 promote formation of heterochromatin in three ways. Firstly, both of the sirtuins deacetylate H3K9 enabling its trimethylation and subsequent binding of HP1α indispensable for heterochromatin formation. Secondly, SIRT1 decreases activity of p300 histone acetyltransferase. Lastly, SIRT1 activates Suv39h1 methyltransferase by deacetylating K266 in its catalytic domain. Moreover, SIRT1 inhibits polyubiquitination of Suv39h1 by MDM2 and prevents its degradation. Arrows indicate positive regulation. Lines with T-shaped ending indicate inhibition. Thick upward and downward arrows inside boxes indicate increase or decrease during aging, respectively. (Color figure online)

Fig. 2

Involvement of sirtuins in lifespan/healthspan elongation pathways. Sirtuins modulate multiple pathways involved in mediating positive effects of some anti-ageing interventions, such as calorie/diet restriction (CR/DR) or exercise. Such effect can also be mimicked by sirtuin activating compounds (STACs). Prolonged activation of IGF1 pathway, involving PI3K-AKT, leads to phosphorylation and inhibition of FOXO and to inhibition of SIRT1 activity resulting in increased level of acetylated p53. Acetylation stabilizes p53, increases its activity and leads to premature cell senescence. Sirtuins contribute to life extension in animals with overactivated insulin/IGF1 signaling by increasing FOXO activity. Furthermore, sirtuins activate LKB1/AMPK pathway by deacetylating LKB1. AMPK downregulates mTOR/S6K activity preventing onset of senescence in cell cycle arrested cells. Moreover, AMPK can increase NAMPT activity, the enzyme indispensable in a salvage pathway, leading to NAD+ upregulation, which promotes sirtuin activity. Arrows indicate positive regulation. Lines with T-shaped ending indicate inhibition. Targets of lifespan/healthspan strategies are in light color boxes. Light color boxes with frame—pathways to be inhibited, without frame—beneficial activities. (Color figure online)

Fig. 3

Mechanism of sirtuin activation by curcumin. We propose that curcumin increases sirtuins level and activity through upregulation and activation of AMPK. Such action can be a result of ATP reduction and initial increase in superoxide production (which is later neutralized by elevated expression of antioxidant enzymes). AMPK activation promotes NAD+ production via increase in NAMPT activity. Moreover, AMPK activates FOXO transcription factors which can induce sirtuin expression. Upregulation and activation of sirtuins promote LKB1/AMPK activity creating a positive feedback loop. Additionally, curcumin can contribute to postponing of ageing by inhibiting AKT/mTOR pathway. Thin arrows indicate positive regulation. Lines with T-shaped ending indicate inhibition. Thick arrows indicate decreasing or increasing level as described in Grabowska et al. (2016). The level/activity of proteins in dark color boxes increased upon curcumin supplementation, in light color boxes, decreased. (Color figure online)

Fig. 4

Dose-dependent activity of curcumin. Curcumin in high concentrations can be toxic while low concentrations may exert beneficial effects. In cytotoxic concentrations curcumin can be useful for eliminating cancer cells (a beneficial role), but may induce cell death in normal cells (a detrimental role). Cytostatic doses of curcumin induce senescence both in cancer and primary cells. In some situations this could be beneficial (senescence of cancer cells, protection from atherosclerosis), in others on the contrary (premature senescence of primary cells). Senescence upon curcumin treatment is associated with increased ROS production, upregulation of mitochondrial sirtuins (sirtuin 3 and 5), decrease in the level of sirtuins 1, 6 and 7 and upregulation of proteins involved in anti-oxidative defense. In turn, in low doses curcumin is able to upregulate the level of sirtuins. Animal studies show that supplementation of diet with curcumin can attenuate symptoms of some age-related diseases and improve exercise performance. Such effect is elicited via direct influence of curcumin on processes such as inflammation and/or indirectly via sirtuin upregulation and activation. Arrows indicate positive regulation. Lines with T-shaped ending indicate inhibition. Low, cytostatic and toxic refer to the range of curcumin concentrations