Sirtuins took their name from Sir2 (silent information regulator 2), NAD⁺ dependent histone deacetylase which has been shown to slow down replicative aging in yeast. Increased Sir2 activity extends yeast replicative life span (Sinclair and Guarente, 1997; Guarente, 2000). Sirtuins attracted some attention of researchers when they presumed that inducing sirtuin action may be responsible, or at least co-responsible, for lifespan-extending effects of caloric restriction (Guarente, 2000; Tissenbaum and Guarente, 2001; Rogina and Helfand, 2004; Bordone and Guarente, 2005). In mammals, there are seven orthologs of yeast Sir2, called sirtuins (SIRT1 – SIRT7). Even if not all of them are used to silence transcription, they all have a common molecular mechanism of substrate targeting, through deacetylation, deacylation, or O-ADP-ribosylation, using NAD⁺ as a co-substrate. Mammalian sirtuins can have a different subcellular location, chemical structure, or target proteins (Michan and Sinclair, 2007), yet they are activated mainly by caloric restriction, i.e., the same way as yeast Sir2.

Caloric restriction results in a decreased influx of glucose and free fatty acids (FFA) into the cells, slowing down the tricarboxylic acid cycle (TCA). Since many TCA reactions are coupled with transforming NAD⁺ to NADH, the mitochondrial NAD⁺/NADH ratio can be increased by caloric restriction and decreased by a high-calorie diet. Increased concentration of NAD⁺, as a co-substrate for sirtuins, can be sufficient to boost their activity (Xiao et al., 2018). Caloric restriction can decrease intracellular ATP concentration, at the same time increasing AMP concentration. A 20 to 30% increase of the AMP/ATP ratio can improve the efficiency of oxidative phosphorylation because, in such circumstances, oxidative phosphorylation does not undergo end-product inhibition by ATP, which could be possible if intracellular ATP level were already high. Increased AMP concentration may activate sirtuins indirectly through stimulating NAD⁺ biosynthesis through inducing AMPK. A high-calorie diet results in the opposite effects: accelerating the rate of TCA reactions, decreased NAD⁺/NADH ratio and increased ATP concentration, because of abundance of substrates that can be used for its production. When ATP concentration is already high, and TCA is accelerated at the same time, there is a fall of NAD⁺/NADH ratio in the mitochondria, accompanied by an excess of free electrons, delivered by NADH, in the oxidative phosphorylation cascade. When intracellular ATP concentration is high, the oxidative phosphorylation cascade may become deranged, so some free electrons provided by NADH do not find acceptors, resulting in their non-enzymatic transfer to oxygen atoms, resulting in the production of reactive oxygen species (ROS) (Yeong et al., 2008; Murphy, 2009; Mailloux, 2015).

The premises mentioned above account for at least two metabolic pathways regulating sirtuin activity: one initiated by a change in AMP/ATP ratio through AMPK; and another induced by a change in NAD⁺/NADH ratio. Improved availability of NAD⁺ can activate all sirtuins, while increased AMP concentration can activate all sirtuins except SIRT4 (Guarente, 2011).

The starting point for research studies on the role of sirtuins in the biology of aging was discovering the activating role of AMP in reference to AMPK and, at the same time, the activating role of AMPK concerning most sirtuins. At that stage of the research studies, sirtuins were believed to be the missing link between caloric restriction and life span extension (Haigis and Sinclair, 2010; Burnett et al., 2011). From today’s perspective, it can be stated that even if sirtuin activation is not the only mechanism by which caloric restriction can extend life span, it may certainly be one of the mechanisms responsible, including increased NAD⁺/NADH ratio in the mitochondria (initiated by reduced glucose influx to the cells) and decreased mTOR activity in lysosomes (also directly linked to moderate deficiency of energetic substrates within the cells) (Papadopoli et al., 2019).

Applying caloric restriction, through reducing food availability up to 60% of what would be ingested if food were available ad libitum, results in moderate cellular undernutrition, which in turn facilitates the following effects: reduced ATP/AMP ratio due to increased AMP concentration; activation of AMP-activated kinase (AMPK); inhibition of mTOR activity; enhanced autophagy; and induction of caloric restriction-related intracellular signaling pathways in the cell, in part due to activation of the mechanisms mentioned above (Yeong et al., 2008; Guarente, 2011; Xiao et al., 2018; Ki and Hae, 2019).

Induction of caloric restriction-induced intracellular signaling pathways in the context of some aspects of cell behavior – such as cell auto-conservation (improved fidelity of translation, DNA damage repair, and protein turnover), cell cycle arrest, and anabolism inhibition can be in part due to SIRT1-dependent deacetylation of some vital regulatory proteins (e.g., FoxO1, FoxO3a, and p53). These actions can, in turn, change the enzymatic profile of these proteins through post-translational regulatory modifications (PTRMs), altering their affinity to individual substrates. And thus – general direction of their action, which subsequently results in an altered cell reaction to metabolic and genotoxic stress – e.g., a preference to repair DNA damage instead of inducing apoptosis, or to perform reversible cell cycle arrest instead of inducing cell senescence phenotype (CSP – comprising an irreversible cell cycle arrest, loss of cytokinesis, thus excluding the cell from the processes of tissue regeneration and remodeling) (Brunet et al., 2004). For example, such alterations in cell phenotype result from FoxO3a deacetylation by SIRT1 and subsequent Gadd-45 activation by deacetylated FoxO3a (Erol, 2010; Hori et al., 2013; Salvador et al., 2013). In general, cells undergoing caloric restriction care much more about DNA damage repair, cell cycle control, translational fidelity, and proteostasis, which in turn makes them much more resistant to environmental insults. Furthermore, this shift in cell behavior results directly from improved NAD⁺/NADH ratio and resulting sirtuins activation, as well as sirtuin-dependent secondary effects within intracellular signaling (Weidinger et al., 2008; Erol, 2010; Hori et al., 2013).

SIRT1 exerts anti-inflammatory and anti-lipogenic actions through inhibitory deacetylation of NF-KB and inhibition of SREBP-1c (Imai and Guarente, 2010; Ponugoti et al., 2010; Yang et al., 2011). In addition, SIRT1 actions that promote cell auto-conservation and induce caloric restriction-related cell phenotype are exerted through FoxO1 and FoxO3a activation and co-activation of SIRT6, which can be generated through the joined action of SIRT1, FoxO3a, and NRF-1 transcription factor – also induced by caloric restriction (Gertler and Cohen, 2013).

While the coexistence of overnutrition or insulin-related intracellular signaling pathways with DNA damage will usually generate either apoptosis or CSP, DNA damage coexisting with moderate undernutrition will rather lead to gradual removal of the damaged biomolecules through autophagy. In such case, CSP will not be induced, but rather replaced with a reversible cell cycle arrest. Therefore, the cell can return to its normal metabolic functions after the damage has been completely repaired (Brunet et al., 2004; Weidinger et al., 2008; Erol, 2010; Hori et al., 2013; Salvador et al., 2013).

These same actions of sirtuins may be co-responsible for the lifespan-extending effects of caloric restriction (Erol, 2010; Gertler and Cohen, 2013; Hori et al., 2013; Salvador et al., 2013). General depiction of caloric restriction effects toward sirtuin actions is presented on Figure 1, while both general profile and general effects of sirtuin enzymatic activity within human cells are shown on Figure 2.

The most neuroprotective sirtuins comprise SIRT1 and SIRT3 (Min et al., 2010; Jiang et al., 2011; Donmez et al., 2012; Rangarajan et al., 2015). In case of SIRT1, its neuroprotective actions are associated chiefly with its effect on some transcription factors, while SIRT3 is associated with its antioxidative and mitochondria-protective actions (Rangarajan et al., 2015). SIRT1 induction in neurons results in mTOR inhibition, activation of ADAM-10 transcription factor, and increased biosynthesis of chaperone proteins. Furthermore, the inhibitory effect of SIRT1 on mTOR activity results in promoting neurite outgrowth. In contrast, the remaining effects of SIRT1 in neurons depend on decreased production and increased degradation of toxic protein aggregates, like beta-amyloid, directly responsible for neurodegeneration. Besides, SIRT1 is neuroprotective in reference to POMC-ergic neurons responsible for adjusting energy expenditure to body nutritional status (Ramadori et al., 2008, 2010; Clark et al., 2012). Therefore, SIRT1 KO mice are more susceptible to diet-induced obesity due to insufficient energy expenditure (Ramadori et al., 2010).

Furthermore, research studies on transgenic BRASTO mice suggest that even central nervous system-confined SIRT1 overexpression tends to increase their lifespan due to local inactivation of NF-κB, and thus desensitizing the hypothalamus to TNF-alpha dependent signaling (Satoh et al., 2013; Zhang G. et al., 2013). On the other hand, neuroprotective actions of SIRT3 have not been studied as thoroughly so far. Still, we know that SIRT3 KO in microglial cells results in elevated mitochondrial ROS production, accompanied by reduced MnSOD activity (Rangarajan et al., 2015). Thus, the neuroprotective actions of SIRT3 may be dependent on its antioxidative and mitochondria-protecting effects.

Chronic but ineffective inflammation (inflammaging) takes part in the pathogenesis of many age-related diseases. SIRT1, SIRT2, and SIRT6 inhibit inflammatory response through inactivation of NF-κB, with detailed means of inactivation discussed further (Vazquez et al., 2021). NF-κB is a transcription factor that stimulates pro-inflammatory phenotype-related genes during some types of the cellular stress response. NF-κB is composed of five subunits: p50, p52, p65 (RelA), RelB, and c-Rel. During NF-κB activation, p50/p65, p50/c-Rel, or p52/RelB dimers are relocated to the cell nucleus (Vazquez et al., 2021).

NF-κB activation may occur through the canonical or non-canonical pathway. Still, in standard conditions, the canonical path is blocked by default due to IkB proteins, which sequestrate NF-κB in the cytoplasm. However, pro-inflammatory stimuli may activate IkB kinase (IKK), which promotes IkB degradation through inhibitory phosphorylation, and thus relocation of NF-κB to the cell nucleus (Vazquez et al., 2021). Sirtuins may inhibit NF-κB both directly and indirectly. Firstly – SIRT1 and SIRT2 can deacetylate NF-κB’s p65 subunit at lysine 310, which directly inhibits NF-κB activity (Yeung et al., 2004; Rothgiesser et al., 2010). Furthermore, such acetylation impedes methylation of adjacent lysine residues (K314 and K315), promoting ubiquitination and degradation of p65 (Rothgiesser et al., 2010; Yang et al., 2010). Secondly – SIRT1 can inhibit NF-κB through inhibitory phosphorylation of its transcriptional activators, such as PARP-1 and p300 histone acetyltransferase (Bouras et al., 2005; Rajamohan et al., 2009). Thirdly – SIRT1 and SIRT6 may inhibit the expression of NF-κB target genes due to transcriptional silencing through H3K9 DAC (Bouras et al., 2005). SIRT6 can induce the production of IkB at the level of transcription, which exerts an anti-inflammatory effect because IkB blocks the canonical pathway of NF-κB activation by default (Kawahara et al., 2009). In addition, SIRT6 may both desensitize cells to TNF-alpha, an upstream inducer of NF-κB, and inhibit TNF-alpha secretion. SIRT1 and SIRT6 actions described above are primarily responsible for their anti-inflammatory effects.

In BRASTO mice, increased expression of SIRT1 in the central nervous system can augment their lifespan and desensitize the hypothalamus to TNF-alpha (Zhang G. et al., 2013). In this way, “anti-inflammatory” action at the level of the hypothalamus produces an anti-aging and lifespan-extending effect.

Both sirtuins and their co-substrate NAD⁺ can prevent pathomechanisms of type 2 diabetes mellitus (T2DM) (Yoshino et al., 2011). While SIRT1 enhances pancreatic beta cells response to hyperglycemia in insulin secretion (Bordone et al., 2005), SIRT4 may blunt this response (Ahuja et al., 2007). However, SIRT4 activity is inhibited by caloric restriction. Therefore, caloric restriction promotes the appropriate response of pancreatic beta cells to hyperglycemia by inhibiting SIRT4 and activating SIRT1. In this way, it may improve glycemic parameters in metabolic syndrome or T2DM and even prevent those diseases. In addition, by acting on white adipose tissue, SIRT1 promotes the production of adiponectin – a protein that can prevent insulin resistance (Banks et al., 2008).

A separate matter is an effect of sirtuins toward lipolysis and gluconeogenesis in hepatocytes, adipocytes, and skeletal muscle cells, through the PGC-1 alpha transcription factor (Heilbronn et al., 2007). By activating PGC-1 alpha, SIRT1 can prevent metabolic syndrome by inducing lipolysis and enhancing glucose uptake with GLUT4 transporter. These actions of PGC-1 alpha are associated with its role as a transcription factor activated in case of cell undernutrition. In addition, sirtuins improve peripheral tissues sensitivity to insulin by inactivating PTPT1B phosphatase (Sun et al., 2007), which could otherwise weaken insulin-dependent signaling through dephosphorylation of IRS-1 and IRS-2 tyrosine residues (Seely et al., 1996; Goldstein et al., 2000; Zhang, 2007).

Hematopoietic stem cells (HSCs) in the bone marrow can undergo differentiation to any mature blood cells. HSCs can be divided into long-term HSCs (LT-HSCs), short-term HSCs (ST-HSCs), and multipotential progenitor precursors (MPPs), which may undergo both differentiation and proliferation, to maintain their number at a steady level. While ST-HSCs and MPPs provide everyday hematopoietic function, LT-HSCs do not proliferate in standard conditions. Still, they may become activated in case of hematopoietic stress – i.e., increased demand for hematopoiesis (Vazquez et al., 2021). Sirtuins are particularly important for maintaining proliferative quiescence of LT-HSCs, and thus their availability in case of hematopoietic stress.

As to the role of individual sirtuins in the regulation of hematopoiesis, they can be divided into two groups. The first one, consisting of SIRT6 and SIRT7, is especially significant for appropriate hematopoiesis in adults. The second one, consisting of SIRT1 and SIRT2, is significant from the standpoint of fetal hematopoiesis. SIRT6 KO and SIRT7 KO HSCs show some phenotypic traits typical for aged cells, i.e., abnormally high proliferation rate due to incapability to maintain mitotic quiescence (Mohrin et al., 2015; Wang et al., 2016). In addition, SIRT6 KO and SIRT7 KO mice show a progeroid phenotype, consisting of abnormally high HSCs in their bone marrow, combined with leukopenia found in their peripheral blood (Ou et al., 2011; Matsui et al., 2012; Mohrin et al., 2015; Vazquez et al., 2016; Wang et al., 2016). Both SIRT1 and SIRT2 deacetylate H4 histone at lysine 16 and thus remove epigenetic mark added by MOF protein – also an essential regulator of hematopoiesis (Vaquero et al., 2006).

In case of increased demand for hematopoiesis, some LT-HSCs leave the G1 phase of their cell cycle, thus allowing increased hematopoiesis; simultaneously, some of those cells proliferate to provide auto-replenishment. SIRT1 protects HSCs from DNA damage through deacetylation of FoxO3a, thus providing more effective DNA damage repair and promoting differentiation of adequately large percentage of HSCs into lymphocytes (Matsui et al., 2012; Singh et al., 2013; Rimmele et al., 2014). SIRT2 protects HSCs from programmed cell death through inhibition of NRLP3 inflammasome that may be otherwise activated as a result of mitochondrial dysfunction with subsequent oxidative damage (Luo et al., 2019). SIRT3 promotes mitochondrial homeostasis and well-being within HSCs, through its widely known actions within the mitochondria, such as improving overall ETC efficacy, induction of MnSOD, and thus mitigating oxidative stress (Brown et al., 2013). SIRT6 takes part in the maintenance of LT-HSCs metabolic quiescence by inhibiting Wnt signaling through H3K56 DAC, and thus transcriptional silencing of its target genes (Wang et al., 2016). HSC-protecting role of SIRT7 consists in the inhibition of mitochondrial protein synthesis in response to mitochondrial protein folding stress. In this way, SIRT7 prevents mitochondrial damage from unfolded protein response (Mohrin et al., 2015; Sigurdsson and Miharada, 2018). In adults, deficiency of SIRT1, SIRT6, and SIRT7 impairs HSC stress response. In addition, SIRT1 KO cells are more prone to DNA damage induced by cytostatics or irradiation (Singh et al., 2013; Rimmele et al., 2014).

SIRT6 KO HSCs have impaired capability of blood repopulation, mainly due to LT-HSCs deficiency appearing in such cases (Wang et al., 2016). SIRT6 maintains HSC number and functions at steady levels through deacetylation of H3 histone at lysine 56, promoting DNA damage response and transcriptionally inhibiting Wnt signaling (Wang et al., 2016). After a bone marrow transplant from SIRT7 KO donors, mice are more prone to graft damage with 5-fluorouracil and have an impaired peripheral blood regenerative capability than mice that have received a bone marrow transplant from wild type healthy donors (Mohrin et al., 2015; Vazquez et al., 2016). Besides, mitotically quiescent HSCs synthesize few proteins and thus have a lower risk of synthesizing unfolded or misfolded proteins that could initiate unfolded protein response (UPR) (Sigurdsson and Miharada, 2018). This status quo is supported by SIRT7, which maintains overall protein synthesis at a low level, thus preventing the production of unfolded or misfolded proteins (Mohrin et al., 2015).

Age-related dysfunction of the hematopoietic system results from cell damage accumulation which may cause anemia, adaptive immunity impairment, and increased incidence of myeloproliferative diseases. In aged HSCs, this damage is associated with epigenetic alterations, loss of cell polarity, DNA damage accumulation, and increased ROS production. In addition, the phenotypic traits mentioned above impair self-replenishment, balanced differentiation, and proliferation control of HSCs (Brown et al., 2013; Mohrin et al., 2015; Vazquez et al., 2021).

SIRT1, SIRT2, SIRT3, and SIRT7 expression becomes decreased with age, which impairs HSC homeostasis (Brown et al., 2013; Rimmele et al., 2014; Mohrin et al., 2015; Luo et al., 2019). SIRT1 KO young HSCs resembled aged cells as to the pattern of transcription (Rimmele et al., 2014), while SIRT2 and SIRT3 seem necessary to maintain completely functional HSCs in old mice, but not for adaptation to hematopoietic stress in young mice (Brown et al., 2013; Roth et al., 2013). SIRT2 can prevent deterioration of HSC function with age through activation of NRLP3 inflammasome in response to mitochondrial damage (Luo et al., 2019), while SIRT3 expression in HSCs is pronounced but falls with age. SIRT3 depletion does not impair the blood repopulation capability in mice, but – in experiments with serial bone marrow transplants in mice – SIRT3 is necessary for bone marrow regeneration, from the third transplant on (Brown et al., 2013).

In addition, SIRT1 deficiency may result in a tendency of HSCs to differentiate more into granulocytes than into lymphocytes (Rimmele et al., 2014; Abraham et al., 2019). SIRT6 and SIRT7 deficiency may have a similar result. Deficiency of SIRT6 results in an abnormally high percentage of MPPs in the bone marrow and peripheral blood. In the case of SIRT7 deficiency, abnormally high percentage of MPPs is found only in peripheral blood (Mohrin et al., 2015; Lasiglie et al., 2016; Wang et al., 2016). SIRT2 KO mice show a similar abnormality, but only in old age (Luo et al., 2019). As expected, increased expression of SIRT2, SIRT3, and SIRT7 can neutralize this abnormality (Brown et al., 2013; Mohrin et al., 2015; Luo et al., 2019).

In B lymphocytes, sirtuins increase their vitality, inhibit apoptosis (SIRT1), and act as tumor suppressor proteins (SIRT3 and SIRT4). As to the effect of sirtuin activity on T cells, decreased activity of SIRT1 in Th and Tc cells results in a tendency to their hyperactivation, but the reduced activity of SIRT3 in Treg cells can impair their function. Probably this is why a high-calorie diet promotes autoinflammatory and autoimmune response, while caloric restriction may diminish the efficacy of adaptive immune response, thus being contraindicated in severe infections (Warren and MacIver, 2019).

SIRT1 induction promotes genomic stability (Herranz et al., 2010) because SIRT1 stimulates DNA damage repair and can co-activate another sirtuin – SIRT6, which in turn deacetylates the H3 histone at Lys 56, promoting DNA repair and conservation through silencing gene expression. In addition, both SIRT1 and SIRT6 can activate p53, despite inhibiting its proapoptotic activity. In general, nuclear sirtuins can promote DNA conservation through histone deacetylation/deacylation and transcriptional silencing (Guarente, 2000; Haigis and Sinclair, 2010). In contrast, mitochondrial sirtuins can prevent DNA damage through abrogating ROS production (SIRT3) (Huang et al., 2010; Haigis et al., 2012), or even supporting nucleotide synthesis, necessary for DNA repair, through glutamine anaplerosis (SIRT4) (Jeong et al., 2013). By deacetylating histones, SIRT1 and SIRT6 can promote genome stability, silence the “transcriptional noise” that is a threat to old cells, and minimize the risk of DNA damage, since DNA bound to deacetylated or deacylated histones is less accessible both for transcription factors and for mutagens (Michishita et al., 2009; Yang et al., 2009; Jiang et al., 2013).

By activating some DNA-repairing enzymes, such as WRN helicases, DNA-PKcs, CtIP, and PARP-1, SIRT6 promotes DNA damage repair, including repair of double-strand breaks (DSB) through homologous recombination (HR). Due to this function, SIRT6 can prevent both carcinogenesis and aging, because both of these phenomena depend primarily on the accumulation of unrepaired DNA damage (Huertas, 2010; Beneke, 2012).

SIRT6 KO cells have shown overexpression of subtelomeric genes, such as ISG-16, which can accelerate telomere attrition. Thus, active SIRT6 can protect cells also from replicative stress (Mao et al., 2011; Tennen et al., 2011).

SIRT6 inhibits HIF-1 alpha and HIF-1 alpha-dependent glucose transport to the cells, relying on glucose transporters GLUT1 and GLUT4 (Seagroves et al., 2001; Xiao et al., 2010). Whereas Otto Warburg has already described the harmful effects of HIF-1 alpha hyperactivation in neoplastic cells in 1956 (Warburg, 1956), SIRT6 prevents hyperactivation of HIF-1 alpha in normal cells, thus preventing lethal hypoglycemia due to glucose uptake by too many cells at the same time (Xiao et al., 2010).

SIRT6 actions toward other aspects of cell phenotype (including inhibition of c-Jun, and thus IIS, rescuing p53 function, and activation of CCNDBP-1) can prevent carcinogenesis. Therefore, SIRT6 can be regarded as a TSP because of being a caretaker itself and its ability to activate many other caretakers – like DNA-repairing enzymes and gatekeepers – like p53 (Michishita et al., 2008; Das et al., 2011; Sundaresan et al., 2012; Wątroba and Szukiewicz, 2021).

Sirtuins may counteract organismal aging by altering the pattern of cellular stress response to generate much less disruption of tissue homeostasis. The alteration of cellular stress response pattern by sirtuins comprises 1- inhibition of apoptosis, 2- promoting DNA damage repair instead of apoptosis or CSP induction, 3- antioxidative action through activation of MnSOD, 4- preventing carcinogenesis through acting as TSPs, 5- inhibition of unnecessary inflammatory response/inflammaging through inactivation of NF-kB, and 6- preventing CSP and senescence-associated secretory phenotype (SASP) through mitochondrial protection and promoting DNA damage repair.

All the effects listed above combined may prevent disruption of tissue homeostasis – directly responsible for organismal aging in vertebrates while being itself a distant derivative of a prolonged, inappropriate pattern of cellular response to accidental damage of the biostructure. The mechanisms discussed in this article describe how exactly sirtuin-dependent modifications of the cellular stress response can slow down aging at the tissue level. Thus, sirtuins, especially SIRT1, SIRT3 and SIRT6, can modify cellular stress response to promote maintenance of tissue homeostasis and thus slow down phenotypic aging at the organismal level.

MW has made a critical review of the literature and wrote the revised version of the manuscript. DS contributed to the overall conception of this review including design and content of the figures and wrote the first draft of the manuscript. Both authors contributed to manuscript revision, read and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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