1 Introduction
Sirtuins are a family of proteins regarded as nicotinamide adenine dinucleotide
(NAD
+
)-dependent histone deacetylase enzymes (HDACs) [1–5]. Sirtuins are
found in a wide variety of organisms from eukaryotes to humans. In mammals,
a total of seven sirtuins have been identified. In addition to the deacetylation
activity, some of the sirtuins have also other enzymatic activities; SIRT6 and
SIRT4 act as adenosine diphosphate (ADP)-ribosyltransferases [6, 7], SIRT5 has
higher demalonylase and desuccinylase activities than deacetylase activity [8], and
SIRT6 deacylates long-chain fatty acyl groups [9]. Sirtuins bind to many proteins in
various subcellular localizations, and thus they exert regulatory effects on many
biological processes.
Sirtuins are regarded as potential therapeutic targets in cancer, metabolic disorders, and cardiovascular and neurodegenerative diseases [10–19]. In the case of
cancer, sirtuins have been linked to the initiation and the development of cancer, but
their exact role has remained somewhat unclear as sirtuins have both tumorpromoting and tumor-suppressing effects [16, 17]. Therefore, both sirtuin inhibitors
and activators have been intensively studied in the therapy of cancer. Multiple
factors, such as tissue type, species, age, and the cellular localization of the sirtuins,
may be regulating their role in the development of cancer and may lie behind the
contradictory observations, e.g., on the tumor-suppressing and tumor-promoting
roles [17, 19].
Due to their NAD
+ dependency, sirtuins are activated in the conditions of nutrient
depletion, starvation, and cellular stress, thus exerting an important role in many
metabolic pathways [20]. The activators of sirtuins could serve as novel treatment
strategies for type2 diabetes [10]. In particular, nuclear sirtuins have been linked to
inflammatory signaling pathways, and thus sirtuin activators could confer beneficial
effects via the downregulation of these pathways [21]. Some sirtuins have protective
roles in the development of cardiovascular diseases, e.g., cardiac hypertrophy and
atherosclerosis [18, 22]. All in all, sirtuin activators hold great promise in treating
cardiovascular and metabolic diseases.
The impact of sirtuins in the development of common neurodegenerative
diseases has been extensively studied (e.g., [23–25]); for example, the progression
of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have been shown to be
affected by the enzymatic activity of sirtuins [26]. The aging process may decrease
SIRT1 activity, and thus specific sirtuin activators could be used as potential
treatments for AD [11]. However, it has been postulated that certain isoforms of
sirtuins should be inhibited rather than activated in neurodegenerative diseases
[27]. In addition, sirtuins have been linked to the progress of Huntington’s disease
(HD), amyotrophic lateral sclerosis, and spinal and bulbar muscular atrophy [12, 28].
Sirtuin Inhibitors and Activators
57
Sirtuins are a family of proteins regarded as nicotinamide adenine dinucleotide
(NAD
+
)-dependent histone deacetylase enzymes (HDACs) [1–5]. Sirtuins are
found in a wide variety of organisms from eukaryotes to humans. In mammals,
a total of seven sirtuins have been identified. In addition to the deacetylation
activity, some of the sirtuins have also other enzymatic activities; SIRT6 and
SIRT4 act as adenosine diphosphate (ADP)-ribosyltransferases [6, 7], SIRT5 has
higher demalonylase and desuccinylase activities than deacetylase activity [8], and
SIRT6 deacylates long-chain fatty acyl groups [9]. Sirtuins bind to many proteins in
various subcellular localizations, and thus they exert regulatory effects on many
biological processes.
Sirtuins are regarded as potential therapeutic targets in cancer, metabolic disorders, and cardiovascular and neurodegenerative diseases [10–19]. In the case of
cancer, sirtuins have been linked to the initiation and the development of cancer, but
their exact role has remained somewhat unclear as sirtuins have both tumorpromoting and tumor-suppressing effects [16, 17]. Therefore, both sirtuin inhibitors
and activators have been intensively studied in the therapy of cancer. Multiple
factors, such as tissue type, species, age, and the cellular localization of the sirtuins,
may be regulating their role in the development of cancer and may lie behind the
contradictory observations, e.g., on the tumor-suppressing and tumor-promoting
roles [17, 19].
Due to their NAD
+ dependency, sirtuins are activated in the conditions of nutrient
depletion, starvation, and cellular stress, thus exerting an important role in many
metabolic pathways [20]. The activators of sirtuins could serve as novel treatment
strategies for type2 diabetes [10]. In particular, nuclear sirtuins have been linked to
inflammatory signaling pathways, and thus sirtuin activators could confer beneficial
effects via the downregulation of these pathways [21]. Some sirtuins have protective
roles in the development of cardiovascular diseases, e.g., cardiac hypertrophy and
atherosclerosis [18, 22]. All in all, sirtuin activators hold great promise in treating
cardiovascular and metabolic diseases.
The impact of sirtuins in the development of common neurodegenerative
diseases has been extensively studied (e.g., [23–25]); for example, the progression
of Alzheimer’s disease (AD) and Parkinson’s disease (PD) have been shown to be
affected by the enzymatic activity of sirtuins [26]. The aging process may decrease
SIRT1 activity, and thus specific sirtuin activators could be used as potential
treatments for AD [11]. However, it has been postulated that certain isoforms of
sirtuins should be inhibited rather than activated in neurodegenerative diseases
[27]. In addition, sirtuins have been linked to the progress of Huntington’s disease
(HD), amyotrophic lateral sclerosis, and spinal and bulbar muscular atrophy [12, 28].
Sirtuin Inhibitors and Activators
57