The interplay between sirtuins and age-related pathologies

A narrative review published today in Journal of Experimental & Clinical Cancer Research reports on the role of sirtuin’s as tumor suppressive and/or oncogenic and thus a new target for drug development. Here, two authors of the review Zhen Mei and Yongguuang Tao tell us more.

The sirtuin family comprises seven NAD+-dependent enzymes (SIRT1-7) recognized as class III histone deacetylases (HDACs). They have gradually achieved celebrity status since their homologs Sir2 were shown to have anti-ageing functions in yeast. But do the mammalian sirtuins occupy a prominent position in anti-ageing proteins or merely appear as another entourage?

Ageing is defined as a functional and physiological decline of cells partly associated with reduced DNA integrity and genomic stability. SIRT1, a proto-member of SIRT family, was first reported to maintain telomere length and modulate DNA damage repair. After that, it was unveiled that SIRT1 and other members have implicated in DNA damage response mainly by modifying the chromatin and regulating the activity of DNA‑repair factors through deacetylation. Short of their roles in DNA repair, they have recently been found in cellular processes of human ageing-related pathologies such as metabolic syndrome and tumorigenesis.

Sirtuins are involved in many aspects of glucose and lipid homeostasis.

Metabolic syndrome is characterized as a combination of obesity, inflammation, high blood pressure and dyslipidemia. The major culprit for this disorder is the excessive calorie intake. Calorie restriction (CR), therefore, lies at the opposite ends of the same spectrum. CR was first described as a reduction in food intake in laboratory rodents that would partly extend their lifespan. It now seems that the salutary effects of CR may improve the physiological parameters in metabolic syndrome and protect against many diseases in rodents including cardiovascular disease and diabetes.

Further, it is proposed that metabolic syndrome and CR are mediated through the same set of regulators and sirtuins may be essentially required in their induced effects. Indeed, sirtuins are involved in many aspects of glucose and lipid homeostasis. Most sirtuins are reported to promote gluconeogenesis in liver, fatty acid oxidation in muscle, fatty acid mobilization in adipose tissues and enhance insulin secretion in pancreas. It is reasonable to believe that the metabolic activities of sirtuins may mimic the CR state and ameliorate several metabolic diseases.

Besides metabolic disorders, tumorigenesis is also a time-dependent process associated with ageing. Genomic instability and metabolic reprogramming are two characteristic hallmarks in cancer. Considering their pivotal roles in DNA repair and cellular metabolism, sirtuins are characterized as context-dependent tumor suppressor and/or oncogene. Nuclear sirtuins (SIRT1, SIRT6) may protect host cells from tumorigenesis by positively triggering DNA repair. But when they enhance genome integrity in tumor cells such as SIRT7, their roles are considered to be oncogenic.

Nuclear sirtuins (SIRT1, SIRT6) may protect host cells from tumorigenesis by positively triggering DNA repair.

Elevated aerobic glycolysis and extensive glutaminolysis are commonly found in most cancer cells. After their inhibitory roles in aerobic glycolysis were reported, sirtuins’ implication in glutamine metabolism attracted considerable attention. Glutamine metabolism is proposed to drive tumor growth by providing a ready source of carbon and nitrogen to support biomass synthesis and cellular homeostasis. It is uncovered that SIRT4 (one of mitochondrial sirtuins) elicits the inhibition of glutamine metabolism and an attendant halt of cell proliferation that provides opportunity for DNA damage repair, which spurred the hypothesis that sirtuins may coordinate genomic instability and aberrant cellular metabolism in cancer cells.

Functioning as tumor suppressor and/or oncogene, development of specific activators or inhibitors of these sirtuins might offer therapeutic opportunities for various types of cancer. The inhibitors of SIRT1 and SIRT2 seem to be promising in current preclinical trials. For example, the inhibitor Sirtinol induces growth arrest and enhances sensitivity to chemotherapy drugs of human breast cancer cells, lung cancer cells and leukaemic cells. Cambinol has been shown to prevent the growth of Burkitt lymphoma.

Clearly, there is much more to be learned about sirtuins and ageing-related pathologies (metabolic syndrome and tumorigenesis), but it is likely that sirtuins will have important roles in future therapy of these diseases.

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