Редактирование: SIRT2

NAD-dependent protein deacetylase sirtuin-2 (EC 2.3.1.286) (Regulatory protein SIR2 homolog 2) (SIR2-like protein 2) [SIR2L] [SIR2L2]

==Publications==

{{medline-entry
|title=NAD  Repletion Rescues Female Fertility during Reproductive Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32049001
|abstract=Reproductive aging in female mammals is an irreversible process associated with declining oocyte quality, which is the rate-limiting factor to fertility. Here, we show that this loss of oocyte quality with age accompanies declining levels of the prominent metabolic cofactor nicotinamide adenine dinucleotide (NAD ). Treatment with the NAD  metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality in aged animals, leading to restoration in fertility, and this can be recapitulated by transgenic overexpression of the NAD -dependent deacylase [[SIRT2]], though deletion of this enzyme does not impair oocyte quality. These benefits of NMN extend to the developing embryo, where supplementation reverses the adverse effect of maternal age on developmental milestones. These findings suggest that late-life restoration of NAD  levels represents an opportunity to rescue female reproductive function in mammals.

|keywords=* SIRT2
* aging
* embryo development
* female fertility
* in vitro fertilization
* infertility
* nicotinamide adenine dinucleotide (NAD )
* nicotinamide mononucleotide (NMN)
* oocyte
* reproductive aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063679
}}
{{medline-entry
|title=Melatonin ameliorates the advanced maternal age-associated meiotic defects in oocytes through the [[SIRT2]]-dependent H4K16 deacetylation pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31980591
|abstract=It has been widely reported that advanced maternal age impairs oocyte quality. To date, various molecules have been discovered to be involved in this process. However, prevention of fertility issues associated with maternal age is still a challenge. In the present study, we find that both [i]in vitro[/i] supplement and [i]in vivo[/i] administration of melatonin are capable of alleviating the meiotic phenotypes of aged oocytes, specifically the spindle/chromosome disorganization and aneuploidy generation. Furthermore, we identify [[SIRT2]] as a critical effector mediating the effects of melatonin on meiotic structure in old oocytes. Candidate screening shows that [[SIRT2]]-controlled deacetylation of histone H4K16 is essential for maintaining the meiotic apparatus in oocytes. Importantly, non-acetylatable-mimetic mutant H4K16R partially rescues the meiotic deficits in oocytes from reproductive aged mice. In contrast, overexpression of acetylation-mimetic mutant H4K16Q abolishes the beneficial effects of melatonin on the meiotic phenotypes in aged oocytes. To sum up, our data uncover that melatonin alleviates advanced maternal aged-associated meiotic defects in oocytes through the [[SIRT2]]-depenendet H4K16 deacetylation pathway.

|keywords=* aging
* histone acetylation
* meiosis
* melatonin
* oocyte quality
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053624
}}
{{medline-entry
|title=Context-Dependent Roles for [[SIRT2]] and [[SIRT3]] in Tumor Development Upon Calorie Restriction or High Fat Diet.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31970087
|abstract=Calorie restriction (CR) is considered one of the most robust ways to extend life span and reduce the risk of age-related diseases, including cancer, as shown in many different organisms, whereas opposite effects have been associated with high fat diets (HFDs). Despite the proven contribution of sirtuins in mediating the effects of CR in longevity, the involvement of these nutrient sensors, specifically, in the diet-induced effects on tumorigenesis has yet to be elucidated. Previous studies focusing on [[SIRT1]], do not support a critical role for this sirtuin family member in CR-mediated cancer prevention. However, the contribution of other family members which exhibit strong deacetylase activity is unexplored. To fill this gap, we aimed at investigating the role of [[SIRT2]] and [[SIRT3]] in mediating the anti and pro-tumorigenic effect of CR and HFD, respectively. Our results provide strong evidence supporting distinct, context-dependent roles played by these two family members. [[SIRT2]] is indispensable for the protective effect of CR against tumorigenesis. On the contrary, [[SIRT3]] exhibited oncogenic properties in the context of HFD-induced tumorigenesis, suggesting that [[SIRT3]] inhibition may mitigate the cancer-promoting effects of HFD. Given the different functions regulated by [[SIRT2]] and [[SIRT3]], unraveling downstream targets/pathways involved may provide opportunities to develop new strategies for cancer prevention.

|keywords=* SIRT2
* SIRT3
* aging
* calorie restriction
* cancer
* high fat diet
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960403
}}
{{medline-entry
|title=[[SIRT2]] functions in aging, autophagy, and apoptosis in post-maturation bovine oocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31295472
|abstract=Sirtuins have been implicated in the aging process, however, the functions of [[SIRT2]] in post-maturation aging of oocytes are not fully understood. The purpose of the present investigation was to assess the roles of [[SIRT2]] in aged oocytes and mechanisms involved. The fresh MII oocytes were aging in vitro, and treated with [[SIRT2]] inhibitor (SirReal2), autophagy activator (Rapamycin), and autophagy inhibitor (3-Ma) for 24 h, respectively. Oocyte activation, cytoplasmic fragmentation, and spindle defects, mitochondrial distribution, ROS levels, ATP production, mitochondrial membrane potential, and early apoptosis were investigated. Western blotting was performed to determine LC3-II accumulation, [[SQSTM1]] degradation, and caspase-3 activity. [[SIRT2]] expression gradually decreased in a time-dependent manner during oocyte aging. Treatment with SirReal2 significantly increased the rates of oocyte activation, cytoplasmic fragmentation, and spindle defects. In particular, the high ROS levels, abnormal mitochondrial distribution, low ATP production, and lost ΔΨm were observed in SirReal2-exposed oocytes. Further analysis revealed that LC3-II accumulation and [[SQSTM1]] degradation were induced by [[SIRT2]] inhibition. By performing early apoptosis analysis showed that oocyte aging was accompanied with cellular apoptosis, and [[SIRT2]] inhibition increased apoptosis rates of aged oocytes. Importantly, upregulating autophagy with Rapamycin could mimic the effects of [[SIRT2]] inhibition on apoptosis by increasing caspase-3 activation, whereas downregulating autophagy with 3-MA could abolish those effects by blocking caspase-3 activation. Our results suggest that [[SIRT2]] inactivation is a key mechanism underlying of cellular aging, and [[SIRT2]] inhibition contributes to autophagy-dependent cellular apoptosis in post-maturation oocytes.
|mesh-terms=* Acetamides
* Animals
* Apoptosis
* Autophagy
* Cattle
* Cellular Senescence
* Female
* Membrane Potential, Mitochondrial
* Mitochondria
* Oocytes
* Sirolimus
* Sirtuin 2
* Thiazoles
|keywords=* SIRT2
* aging
* apoptosis
* autophagy
* oocyte
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2019.116639
}}
{{medline-entry
|title=Lifelong Football Training: Effects on Autophagy and Healthy Longevity Promotion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30837897
|abstract=Aging is a physiological process characterized by a progressive decline of biological functions and an increase in destructive processes in cells and organs. Physical activity and exercise positively affects the expression of skeletal muscle markers involved in longevity pathways. Recently, a new mechanism, autophagy, was introduced to the adaptations induced by acute and chronic exercise as responsible of positive metabolic modification and health-longevity promotion. However, the molecular mechanisms regulating autophagy in response to physical activity and exercise are sparsely described. We investigated the long-term adaptations resulting from lifelong recreational football training on the expression of skeletal muscle markers involved in autophagy signaling. We demonstrated that lifelong football training increased the expression of messengers: [[RAD23A]], [[HSPB6]], [[RAB1B]], [[TRAP1]], [[SIRT2]], and HSBPB1, involved in the auto-lysosomal and proteasome-mediated protein degradation machinery; of RPL1, [[RPL4]], [[RPL36]], MRLP37, involved in cellular growth and differentiation processes; of the Bcl-2, HSP70, HSP90, [[PSMD13]], and of the [[ATG5]]-[[ATG12]] protein complex, involved in proteasome promotion and autophagy processes in muscle samples from lifelong trained subjects compared to age-matched untrained controls. In conclusion, our results indicated that lifelong football training positively influence exercise-induced autophagy processes and protein quality control in skeletal muscle, thus promoting healthy aging.

|keywords=* autophagy
* cardiovascular capacity
* football
* lifelong training
* longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390296
}}
{{medline-entry
|title=Mitochondrial Stress-Initiated Aberrant Activation of the [[NLRP3]] Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30673616
|abstract=Aging-associated defects in hematopoietic stem cells (HSCs) can manifest in their progeny, leading to aberrant activation of the [[NLRP3]] inflammasome in macrophages and affecting distant tissues and organismal health span. Whether the [[NLRP3]] inflammasome is aberrantly activated in HSCs during physiological aging is unknown. We show here that [[SIRT2]], a cytosolic NAD -dependent deacetylase, is required for HSC maintenance and regenerative capacity at an old age by repressing the activation of the [[NLRP3]] inflammasome in HSCs cell autonomously. With age, reduced [[SIRT2]] expression and increased mitochondrial stress lead to aberrant activation of the [[NLRP3]] inflammasome in HSCs. [[SIRT2]] overexpression, [[NLRP3]] inactivation, or caspase 1 inactivation improves the maintenance and regenerative capacity of aged HSCs. These results suggest that mitochondrial stress-initiated aberrant activation of the [[NLRP3]] inflammasome is a reversible driver of the functional decline of HSC aging and highlight the importance of inflammatory signaling in regulating HSC aging.
|mesh-terms=* Animals
* Cellular Senescence
* Hematopoietic Stem Cells
* Inflammasomes
* Mice
* Mice, Knockout
* Mitochondria
* NLR Family, Pyrin Domain-Containing 3 Protein
* Sirtuin 2
* Stress, Physiological
|keywords=* NLRP3
* SIRT2
* SIRT3
* SIRT7
* aging
* clonal hematopoiesis
* hematopoietic stem cell
* inflammasome
* mitochondrial UPR
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371804
}}
{{medline-entry
|title=Hsp90 Stabilizes [[SIRT1]] Orthologs in Mammalian Cells and [i]C. elegans[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30463299
|abstract=Sirtuin 1 ([[SIRT1]]) othologs are ubiquitous NAD⁺-dependent deacetylases that act as nutrient sensors and modulate metabolism and stress responses in diverse organisms. Both mammalian [[SIRT1]] and [i]Caenorhabditis elegans[/i] SIR-2.1 have been implicated in dietary restriction, longevity, and healthspan. Hsp90 is an evolutionarily conserved molecular chaperone that stabilizes a plethora of signaling 'client' proteins and regulates fundamental biological processes. Here we report that Hsp90 is required for conformational stabilization of [[SIRT1]] and SIR-2.1. We find that inhibition of Hsp90 by geldanamycin (GA) induces the depletion of mammalian [[SIRT1]] protein in a concentration and time dependent manner in COS-7 and HepG2 cells. In contrast to [[SIRT1]], [[SIRT2]] level remains unchanged by GA treatment, reflecting a specific Hsp90 [[SIRT1]] interaction. Hsp90 inhibition leads to the destabilization and proteasomal degradation of [[SIRT1]]. Moreover, we observe a GA-sensitive physical interaction between [[SIRT1]] and Hsp90 by immunoprecipitation. We also demonstrate that [i]hsp-90[/i] gene silencing also induces SIR-2.1 protein depletion and proteasomal degradation in [i]C. elegans[/i]. Our findings identify metazoan [[SIRT1]] orthologs as Hsp90 clients and reveal a novel crosstalk between the proteostasis and nutrient signaling networks, which may have implications in various age related diseases.
|mesh-terms=* Animals
* Benzoquinones
* COS Cells
* Caenorhabditis elegans
* Chlorocebus aethiops
* HSP90 Heat-Shock Proteins
* Hep G2 Cells
* Humans
* Lactams, Macrocyclic
* Mammals
* Models, Biological
* Proteasome Endopeptidase Complex
* Protein Binding
* Protein Stability
* Proteolysis
* Sirtuin 1
|keywords=* HDAC
* aging
* daf-21
* epigenetics
* metabolism
* proteostasis
* signaling
* sir-2.1
* stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274930
}}
{{medline-entry
|title=Tenovin-1 Induces Senescence and Decreases Wound-Healing Activity in Cultured Rat Primary Astrocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30092626
|abstract=Brain aging induces neuropsychological changes, such as decreased memory capacity, language ability, and attention; and is also associated with neurodegenerative diseases. However, most of the studies on brain aging are focused on neurons, while senescence in astrocytes has received less attention. Astrocytes constitute the majority of cell types in the brain and perform various functions in the brain such as supporting brain structures, regulating blood-brain barrier permeability, transmitter uptake and regulation, and immunity modulation. Recent studies have shown that [[SIRT1]] and [[SIRT2]] play certain roles in cellular senescence in peripheral systems. Both [[SIRT1]] and [[SIRT2]] inhibitors delay tumor growth [i]in vivo[/i] without significant general toxicity. In this study, we investigated the role of tenovin-1, an inhibitor of [[SIRT1]] and [[SIRT2]], on rat primary astrocytes where we observed senescence and other functional changes. Cellular senescence usually is characterized by irreversible cell cycle arrest and induces senescence- associated β-galactosidase (SA-β-gal) activity. Tenovin-1-treated astrocytes showed increased SA-β-gal-positive cell number, senescence-associated secretory phenotypes, including [i]IL-6[/i] and [i]IL-1β[/i], and cell cycle-related proteins like phospho-histone H3 and [[CDK2]]. Along with the molecular changes, tenovin-1 impaired the wound-healing activity of cultured primary astrocytes. These data suggest that tenovin-1 can induce cellular senescence in astrocytes possibly by inhibiting [[SIRT1]] and [[SIRT2]], which may play particular roles in brain aging and neurodegenerative conditions.

|keywords=* Astrocyte
* Cellular senescence
* Senescence-associated secretory phenotype
* Tenovin-1
* Wound healing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513186
}}
{{medline-entry
|title=High expression of CPT1b in skeletal muscle in metabolically healthy older subjects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29657112
|abstract=Ageing is often associated with metabolic abnormalities such as insulin resistance, although some people remain metabolically healthy throughout their lives. The aim of this study was to gain more insight into metabolic health with increasing age. Two groups of robust and of frail subjects, respectively, were identified based on a composite ageing indicator and recruited from the French SU.VI.MAX 2 cohort of older disease-free subjects. In all, 14 men and 12 women, aged 67±4 years, with similar anthropometric and metabolic characteristics at baseline (BMI: 24.5±2.9kg.m ) were included in the Compaliclamp study. Skeletal muscle biopsy was performed to assess expression of a set of metabolic and sirtuin (SIRT) genes. Also, whole-body substrate oxidation and insulin sensitivity were determined using the euglycaemic-hyperinsulinaemic clamp and indirect calorimetry techniques. Robust subjects were more insulin-sensitive, oxidized more lipid in a fasting state and stored more glucose during the euglycaemic - hyperinsulinaemic clamp than did frail subjects. At the gene-expression level in skeletal muscle, carnitine palmitoyltransferase 1b (CPT1b) messenger RNA (mRNA) levels were around four times higher in the robust compared with frail counterparts. Moreover, both [[SIRT2]] and [[SIRT6]] expression was lower in robust subjects and correlated with CPT1b expression. CPT1b overexpression could be helping to maintain metabolic health with increasing age. Thus, it is suggested that targeting CPT1b expression might be an interesting strategy to counteract frailty at an early stage. In addition, future studies should examine the role of sirtuin in CPT1b expression regulation.
|mesh-terms=* Aged
* Aging
* Body Composition
* Carnitine O-Palmitoyltransferase
* Case-Control Studies
* Cohort Studies
* Female
* Frail Elderly
* Frailty
* France
* Health
* Healthy Volunteers
* Humans
* Male
* Middle Aged
* Muscle, Skeletal
* Up-Regulation
|keywords=* Ageing
* Calorimetry
* Glucose clamp technique
* Insulin resistance
* Sirtuins
|full-text-url=https://sci-hub.do/10.1016/j.diabet.2018.01.018
}}
{{medline-entry
|title=Expression of Sirtuins in the Retinal Neurons of Mice, Rats, and Humans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29249955
|abstract=Sirtuins are a class of histone deacetylases (HDACs) that have been shown to regulate a range of pathophysiological processes such as cellular aging, inflammation, metabolism, and cell proliferation. There are seven mammalian Sirtuins ([[SIRT1]]-7) that play important roles in stress response, aging, and neurodegenerative diseases. However, the location and function of Sirtuins in neurons are not well defined. This study assessed the retinal expression of Sirtuins in mice, rats, and humans and measured the expression of Sirtuins in aged and injured retinas. Expression of all 7 Sirtuins was confirmed by Western blot and Real-Time PCR analysis in all three species. [[SIRT1]] is highly expressed in mouse, rat, and human retinas, whereas [[SIRT2]]-7 expression was relatively lower in human retinas. Immunofluorescence was also used to examine the expression and localization of Sirtuins in rat retinal neurons. Importantly, we demonstrate a marked reduction of [[SIRT1]] expression in aged retinal neurons as well as retinas injured by acute ischemia-reperfusion. On the other hand, none of the other Sirtuins exhibit any significant age-related changes in expression except for [[SIRT5]], which was significantly higher in the retinas of adults compared to both young and aged rats. Our work presents the first composite analysis of Sirtuins in the retinal neurons of mice, rats, and humans, and suggests that increasing the expression and activity of [[SIRT1]] may be beneficial for the treatment of glaucoma and other age-related eye dysfunction.

|keywords=* Sirtuins
* aging
* animal
* human
* retinal neuron
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715387
}}
{{medline-entry
|title=Loss of [[SIRT2]] leads to axonal degeneration and locomotor disability associated with redox and energy imbalance.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28984064
|abstract=Sirtuin 2 ([[SIRT2]]) is a member of a family of NAD  -dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. [[SIRT2]] is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of [[SIRT2]] in the nervous system specifically during aging. Here, we show that middle-aged, 13-month-old mice lacking [[SIRT2]] exhibit locomotor dysfunction due to axonal degeneration, which was not present in young [[SIRT2]] mice. In addition, these Sirt2  mice exhibit mitochondrial depletion resulting in energy failure, and redox dyshomeostasis. Our results provide a novel link between [[SIRT2]] and physiological aging impacting the axonal compartment of the central nervous system, while supporting a major role for [[SIRT2]] in orchestrating its metabolic regulation. This underscores the value of [[SIRT2]] as a therapeutic target in the most prevalent neurodegenerative diseases that undergo with axonal degeneration associated with redox and energetic dyshomeostasis.
|mesh-terms=* Aging
* Animals
* Axons
* Cognition
* DNA, Mitochondrial
* Energy Metabolism
* Locomotion
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Neurodegenerative Diseases
* Oxidation-Reduction
* Sirtuin 2
|keywords=* aging
* axonal degeneration
* mitochondria
* redox dyshomeostasis
* sirtuin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676070
}}
{{medline-entry
|title=[[SIRT2]] Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28947430
|abstract=Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of [[SIRT2]] in aging-related and angiotensin II (Ang II)-induced pathological cardiac hypertrophy. Male C57BL/6J wild-type and [i]Sirt2[/i] knockout mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/d for 4 weeks) in male C57BL/6J [i]Sirt2[/i] knockout mice, cardiac-specific [i][[SIRT2]][/i] transgenic ([i][[SIRT2]][/i]-Tg) mice, and their respective littermates (8 to ≈12 weeks old). Metformin (200 mg/kg/d) was used to treat wild-type and [i]Sirt2[/i] knockout mice infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. [[SIRT2]] protein expression levels were downregulated in hypertrophic hearts from mice. [i]Sirt2[/i] knockout markedly exaggerated cardiac hypertrophy and fibrosis and decreased cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II-infused mice. Conversely, cardiac-specific [i][[SIRT2]][/i] overexpression protected the hearts against Ang II-induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, [[SIRT2]] maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II-induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of [[SIRT2]]. [[SIRT2]] bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of [[SIRT2]] blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function. [[SIRT2]] promotes AMPK activation by deacetylating the kinase LKB1. Loss of [[SIRT2]] reduces AMPK activation, promotes aging-related and Ang II-induced cardiac hypertrophy, and blunts metformin-mediated cardioprotective effects. These findings indicate that [[SIRT2]] will be a potential target for therapeutic interventions in aging- and stress-induced cardiac hypertrophy.
|mesh-terms=* AMP-Activated Protein Kinases
* Acetylation
* Age Factors
* Aging
* Angiotensin II
* Animals
* Cardiomegaly
* Cells, Cultured
* Disease Models, Animal
* Fibrosis
* Genetic Predisposition to Disease
* Lysine
* Male
* Metformin
* Mice, Inbred C57BL
* Mice, Knockout
* Myocardial Contraction
* Myocardium
* Phenotype
* Protein Binding
* Protein-Serine-Threonine Kinases
* Rats
* Signal Transduction
* Sirtuin 2
* Stroke Volume
* Ventricular Remodeling
|keywords=* AMPK
* LKB1
* SIRT2
* aging
* angiotensin II
* cardiac hypertrophy
* deacetylation
* metformin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698109
}}
{{medline-entry
|title=Molecular evolutionary patterns of NAD /Sirtuin aging signaling pathway across taxa.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28767699
|abstract=A deeper understanding of the conserved molecular mechanisms in different taxa have been made possible only because of the evolutionary conservation of crucial signaling pathways. In the present study, we explored the molecular evolutionary pattern of selection signatures in 51 species for 10 genes which are important components of NAD /Sirtuin pathway and have already been directly linked to lifespan extension in worms and mice. Selection pressure analysis using PAML program revealed that [[MRPS5]] and [[PPARGC1A]] were under significant constraints because of their functional significance. FOXO3a also displayed strong purifying selection. All three sirtuins, which were [[SIRT1]], [[SIRT2]] and [[SIRT6]], displayed a great degree of conservation between taxa, which is consistent with the previous report. A significant evolutionary constraint is seen on the anti-oxidant gene, [[SOD3]]. As expected, [[TP53]] gene was under significant selection pressure in mammals, owing to its major role in tumor progression. Poly-ADP-ribose polymerase (PARP) genes displayed the most sites under positive selection. Further 3D structural analysis of [[PARP1]] and [[PARP2]] protein revealed that some of these positively selected sites caused a change in the electrostatic potential of the protein structure, which may allow a change in its interaction with other proteins and molecules ultimately leading to difference in the function. Although the functional significance of the positively selected sites could not be established in the variants databases, yet it will be interesting to see if these sites actually affect the function of [[PARP1]] and [[PARP2]].
|mesh-terms=* Aging
* Animals
* Evolution, Molecular
* Helminths
* Humans
* Mice
* NAD
* Poly (ADP-Ribose) Polymerase-1
* Poly(ADP-ribose) Polymerases
* Selection, Genetic
* Signal Transduction
* Sirtuins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540417
}}
{{medline-entry
|title=Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27882448
|abstract=Sirtuins ([[SIRT1]]-SIRT7) are unique histone deacetylases (HDACs) whose activity depends on NAD  levels and thus on the cellular metabolic status. SIRTs regulate energy metabolism and mitochondrial function. They orchestrate the stress response and damage repair. Through these functions sirtuins modulate the course of aging and affect neurodegenerative diseases. SIRTSs interact with multiple signaling proteins, transcription factors (TFs) and poly(ADP-ribose) polymerases (PARPs) another class of NAD -dependent post-translational protein modifiers. The cross-talk between SIRTs TFs and PARPs is a highly promising research target in a number of brain pathologies. This review describes updated results on sirtuins in brain aging/neurodegeneration. It focuses on [[SIRT1]] but also on the roles of mitochondrial SIRTs (SIRT3, 4, 5) and on [[SIRT6]] and [[SIRT2]] localized in the nucleus and in cytosol, respectively. The involvement of SIRTs in regulation of insulin-like growth factor signaling in the brain during aging and in Alzheimer's disease was also focused. Moreover, we analyze the mechanism(s) and potential significance of interactions between SIRTs and several TFs in the regulation of cell survival and death. A critical view is given on the application of SIRT activators/modulators in therapy of neurodegenerative diseases.
|mesh-terms=* Aging
* Animals
* Brain
* Cell Death
* Cell Nucleus
* Cell Survival
* Cytosol
* Energy Metabolism
* Humans
* Mitochondria
* Neurodegenerative Diseases
* Neuroprotection
* Neuroprotective Agents
* Signal Transduction
* Sirtuins
* Somatomedins
* Transcription Factors
|keywords=* Alzheimer’s disease
* Brain aging
* Neuroprotection
* Parkinson’s disease
* Sirtuins
* Transcription factors
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357501
}}
{{medline-entry
|title=Resistance training and redox homeostasis: Correlation with age-associated genomic changes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27687219
|abstract=Regular physical activity is effective as prevention and treatment for different chronic conditions related to the ageing processes. In fact, a sedentary lifestyle has been linked to a worsening of cellular ageing biomarkers such as telomere length (TL) and/or specific epigenetic changes (e.g. DNA methylation), with increase of the propensity to aging-related diseases and premature death. Extending our previous findings, we aimed to test the hypothesis that 12 weeks of low frequency, moderate intensity, explosive-type resistance training (EMRT) may attenuate age-associated genomic changes. To this aim, TL, global DNA methylation, TRF2, Ku80, [[SIRT1]], [[SIRT2]] and global protein acetylation, as well as other proteins involved in apoptotic pathway (Bcl-2, Bax and Caspase-3), antioxidant response (TrxR1 and MnSOD) and oxidative damage (myeloperoxidase) were evaluated before and after EMRT in whole blood or peripheral mononuclear cells (PBMCs) of elderly subjects. Our findings confirm the potential of EMRT to induce an adaptive change in the antioxidant protein systems at systemic level and suggest a putative role of resistance training in the reduction of global DNA methylation. Moreover, we observed that EMRT counteracts the telomeres' shortening in a manner that proved to be directly correlated with the amelioration of redox homeostasis and efficacy of training regime, evaluated as improvement of both muscle's power/strength and functional parameters.
|mesh-terms=* Acetylation
* Aged
* Aging
* Antioxidants
* DNA Methylation
* Epigenesis, Genetic
* Female
* Homeostasis
* Humans
* Male
* Oxidation-Reduction
* Random Allocation
* Resistance Training
* Telomere
|keywords=* DNA methylation
* MnSOD
* Myeloperoxidase
* Telomeres
* TrxR1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040637
}}
{{medline-entry
|title=Aging-related 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurochemial and behavioral deficits and redox dysfunction: improvement by AK-7.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27235848
|abstract=Aging is a prominent risk factor for the occurrence and progression of Parkinson disease (PD). Aging animals are more significant for PD research than young ones. It is promising to develop effective treatments for PD through modulation of aging-related molecules. Sirtuin 2 ([[SIRT2]]), a strong deacetylase highly expressed in the brain, has been implicated in the aging process. In our present study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 12mg/kg once daily) was observed to bring about significant behavioral deficits and striatal dopamine depletion in aging male and female mice, while it did not do so in young animals. MPTP did not cause significant reduction in striatal 5-hydroxytryptamine content in aging male and female mice. Furthermore, we observed that MPTP treatment resulted in significant reduction in GSH content and significant increase in MDA content and [[SIRT2]] expression in the substantia nigra (SN) of aging mice, while it did not do so in young animals. Importantly, we observed that AK-7 (a selective [[SIRT2]] inhibitor) significantly improved behavior abnormality and neurochemical deficits in aging male and female mice treated with MPTP. Significant increase in GSH content and significant decrease in MDA content were also observed in the SN of aging male and female mice co-treated with MPTP and AK-7 compared with the MPTP-treated animals. Our results indicated that MPTP induce aging-related neurochemical and behavioural deficits and dysfunction of redox network in male and female mice and AK-7 may be neuroprotective in PD through modulating redox network.
|mesh-terms=* 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
* Aging
* Animals
* Behavior Rating Scale
* Benzamides
* Corpus Striatum
* Disease Models, Animal
* Dopaminergic Neurons
* Female
* Glutathione
* Male
* Malondialdehyde
* Mice
* Mice, Inbred C57BL
* Neuroprotective Agents
* Oxidation-Reduction
* Parkinsonian Disorders
* Sirtuin 2
* Substantia Nigra
* Sulfonamides
|keywords=* AK-7
* Aging
* Behavior
* GSH
* MDA
* Neurotransmitter
|full-text-url=https://sci-hub.do/10.1016/j.exger.2016.05.011
}}
{{medline-entry
|title=Increased expression of [[SIRT2]] is a novel marker of cellular senescence and is dependent on wild type p53 status.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27229617
|abstract=Sirtuins (SIRT) belonging to the NAD  dependent histone deacetylase III class of enzymes have emerged as master regulators of metabolism and longevity. However, their role in prevention of organismal aging and cellular senescence still remains controversial. In the present study, we now report upregulation of [[SIRT2]] as a specific feature associated with stress induced premature senescence but not with either quiescence or cell death. Additionally, increase in [[SIRT2]] expression was noted in different types of senescent conditions such as replicative and oncogene induced senescence using multiple cell lines. Induction of [[SIRT2]] expression during senescence was dependent on p53 status as depletion of p53 by shRNA prevented its accumulation. Chromatin immunoprecipitation revealed the presence of p53 binding sites on the [[SIRT2]] promoter suggesting its regulation by p53, which was also corroborated by the SEAP reporter assay. Overexpression or knockdown of [[SIRT2]] had no effect on stress induced premature senescence, thereby indicating that [[SIRT2]] increase is not a cause of senescence; rather it is an effect linked to senescence-associated changes. Overall, our results suggest [[SIRT2]] as a promising marker of cellular senescence at least in cells with wild type p53 status.
|mesh-terms=* Acetylation
* Acetylcysteine
* Base Sequence
* Binding Sites
* Biomarkers
* Cell Cycle Checkpoints
* Cell Death
* Cell Line, Tumor
* Cellular Senescence
* DNA Damage
* Doxorubicin
* Gene Knockdown Techniques
* Humans
* Mitochondrial Proteins
* Oncogenes
* Promoter Regions, Genetic
* Sirtuin 2
* Sirtuins
* Stress, Physiological
* Substrate Specificity
* Tumor Suppressor Protein p53
|keywords=* SIRT2
* Sirtuins
* doxorubicin
* p53
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968900
}}
{{medline-entry
|title=Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27038700
|abstract=Sirtuins are proteins that connect energy metabolism, oxidative stress and aging. Expression of heat shock proteins (Hsps) is regulated by heat shock factors (HSFs) in response to various environmental and physiological stresses, such as oxidative stress. Oxidative stress accumulates during aging which makes cells more prone to DNA damage. Although many experimental animal models have been designed to study the effects of knockdown or overexpression of sirtuins, HSFs and Hsps, little is known about how aging per se affects their expression. Here we study the impact of intrinsic aerobic capacity, aging and voluntary exercise on the levels of sirtuins, HSFs and Hsps in skeletal muscle. We studied the protein levels of sirtuins (SIRT1, [[SIRT2]], [[SIRT3]], [[SIRT4]], [[SIRT5]], [[SIRT6]] and SIRT7), [[HSF1]], [[HSF2]], Hsp10, Hsp27 and Hsp70 before and after one-year of voluntary running intervention of rat strains selectively bred for intrinsic aerobic exercise capacity; high capacity runners (HCR) and low capacity runners (LCR) differ by more than 30% for median lifespan. This setup enabled us to discern the effects of inborn aerobic capacity, aging and exercise activity on the protein levels of sirtuins, HSFs and Hsps in skeletal muscle. Our results revealed that the longer lived HCR rats had higher [[SIRT3]], [[HSF1]] and [[HSF2]] contents in skeletal muscle (gastrocnemius, p < 0.05) than LCRs. Neither aging nor voluntary running had a significant effect on the studied sirtuin proteins. Aging significantly increased the protein levels of [[HSF1]], [[HSF2]] and Hsp27 (p < 0.05). Our finding of elevated [[SIRT3]] levels in HCR rats is in line with previous studies; [[SIRT3]] in general is linked to elevated fatty acid oxidation and oxidative phosphorylation, which previously have been associated with metabolic profile of HCRs. [[HSF1]], [[HSF2]] and Hsp27 levels increased with aging, showing that aged muscles responded to aging-related stress. Our study shows for the first time that [[SIRT3]] protein level is linked to high inborn aerobic capacity, and may be directly interconnected to longevity.
|mesh-terms=* Aging
* Animals
* Body Weight
* Citrate (si)-Synthase
* Energy Intake
* Female
* Heat-Shock Proteins
* Muscle, Skeletal
* Oxidative Stress
* Physical Conditioning, Animal
* Rats, Inbred Strains
* Running
* Sirtuins
|keywords=* aging
* oxidative stress
* physical activity
* sirtuin
* skeletal muscle
|full-text-url=https://sci-hub.do/10.1016/j.exger.2016.03.015
}}
{{medline-entry
|title=Sirtuins, Cell Senescence, and Vascular Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26948035
|abstract=The sirtuins (SIRTs) constitute a class of proteins with nicotinamide adenine dinucleotide-dependent deacetylase or adenosine diphosphate-ribosyltransferase activity. Seven SIRT family members have been identified in mammals, from [[SIRT1]], the best studied for its role in vascular aging, to [[SIRT7]]. [[SIRT1]] and [[SIRT2]] are localized in the nucleus and cytoplasm. [[SIRT3]], [[SIRT4]], and [[SIRT5]] are mitochondrial, and [[SIRT6]] and [[SIRT7]] are nuclear. Extensive studies have clearly revealed that SIRT proteins regulate diverse cell functions and responses to stressors. Vascular aging involves the aging process (senescence) of endothelial and vascular smooth muscle cells. Two types of cell senescence have been identified: (1) replicative senescence with telomere attrition; and (2) stress-induced premature senescence without telomere involvement. Both types of senescence induce vascular cell growth arrest and loss of vascular homeostasis, and contribute to the initiation and progression of cardiovascular diseases. Previous mechanistic studies have revealed in detail that [[SIRT1]], [[SIRT3]], and [[SIRT6]] show protective functions against vascular aging, and definite vascular function of other SIRTs is under investigation. Thus, direct SIRT modulation and nicotinamide adenine dinucleotide stimulation of SIRT are promising candidates for cardiovascular disease therapy. A small number of pilot studies have been conducted to assess SIRT modulation in humans. These clinical studies have not yet provided convincing evidence that SIRT proteins alleviate morbidity and mortality in patients with cardiovascular diseases. The outcomes of multiple ongoing clinical trials are awaited to define the efficacy of SIRT modulators and SIRT activators in cardiovascular diseases, along with the potential adverse effects of chronic SIRT modulation.
|mesh-terms=* Aging
* Cardiovascular Diseases
* Cell Survival
* Cellular Senescence
* Endothelium, Vascular
* Homeostasis
* Humans
* Myocytes, Smooth Muscle
* Sirtuins
* Telomere

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848124
}}
{{medline-entry
|title=The expression levels of the sirtuins in patients with BCC.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26631040
|abstract=Basal cell carcinoma (BCC) is the most common tumor in humans. Reduced expression of sirtuins interferes with DNA repair, which may cause mutations and genomic instability, and eventually leads to tumor development. In the present study, we investigate the expression levels of SIRT genes in non-tumoral and tumor tissues of patients with BCC. A total of 27 patients (16 males, 11 females) with BCC were included in the study; the mean age was 65.40 ± 10.74 years and mean follow-up was 2.5 ± 0.5 years. There were multiple synchronous lesions in six patients, and the remaining 21 patients had a single lesion. Tumor and non-tumoral tissue samples were collected from all patients, and mRNA expression levels of [[SIRT1]]-7 (Sirt1.1, Sirt1.2, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6, and Sirt7) were examined by real-time PCR. The results showed that expressions of [[SIRT1]].1, [[SIRT1]].2, [[SIRT4]], [[SIRT5]], [[SIRT6]], and [[SIRT7]] mRNAs were unchanged in tumor tissues of BCC patients compared with non-tumoral tissue samples. Importantly, the expressions of [[SIRT2]] and [[SIRT3]] mRNAs were significantly reduced in tumor tissue samples from BCC patients compared with non-tumoral tissues (P = 0.02 and P = 0.03, respectively). In light of the previous reports that have demonstrated a link between SIRT proteins and cancer, our findings suggest that [[SIRT2]] and [[SIRT3]] may plan important roles in BCC pathogenesis and could be candidate prognostic biomarkers for BCC. 
|mesh-terms=* Aged
* Biomarkers, Tumor
* Carcinoma, Basal Cell
* Female
* Follow-Up Studies
* Gene Expression
* Humans
* Male
* Middle Aged
* Multigene Family
* Prognosis
* RNA, Messenger
* Sirtuins
|keywords=* BCC
* Cancer
* Lifespan
* Longevity
* SIRT
* Sirtuin
|full-text-url=https://sci-hub.do/10.1007/s13277-015-4522-8
}}
{{medline-entry
|title=Effects of Aging and Cardiovascular Disease Risk Factors on the Expression of Sirtuins in the Human Corpus Cavernosum.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26556180
|abstract=Sirtuin (SIRT)1 was recently identified in human corpus cavernosum (CC). We hypothesized that other sirtuins could also be expressed in the CC. Expression of these enzymes in tissues is affected by aging, the main independent risk factor for erectile dysfunction besides other cardiovascular disease risk factors (CVDRF), such as diabetes or obesity. The aim of this study was to characterize the expression of [[SIRT1]]-3 and [[SIRT5]]-7 in human CC relatively to age and CVDRF. Samples of CC collected from patients submitted to programmed surgeries or organ donors were divided in three groups according to age and presence of CVDRF. Expression of [[SIRT1]]-3 and [[SIRT5]]-7 mRNAs was assessed by real-time polymerase chain reaction. Cellular localization and semi-quantification of sirtuins proteins were performed by immunofluorescence and Western blotting (WB), respectively. Nuclear factor kappa B (NFkB)-p65, inducible (iNOS) and endothelial nitric oxide synthase (eNOS) levels were also assayed by WB. The main outcome measure was to characterize the expression of [[SIRT1]]-3 and [[SIRT5]]-7 in human CC. [[SIRT1]]-3 and [[SIRT5]]-7 mRNAs were detected in all individuals, without statistical differences among groups, excepting [[SIRT7]] that decreased four times in aged groups relatively to young (P = 0.013). WB analysis demonstrated that aged individuals with CVDRF presented higher levels of [[SIRT7]] protein relatively to young (P = 0.0495) and lower levels of [[SIRT3]] protein relatively to healthy aged (P = 0.0077). Expression of NFkB-p65 and iNOS were higher in aged than in young individuals (P = 0.0185; P = 0.004, respectively). No differences in other sirtuins or total eNOS were seen among groups although phospho eNOS Ser(1177) levels decreased in groups of aged men relatively to young (P = 0.0043; P = 0.0099). Our results demonstrate for the first time expression of [[SIRT2]]-3 and [[SIRT5]]-7 in the human CC. Aged individuals with CVDRF presented an increase in [[SIRT7]] protein levels and a decrease in mitochondrial [[SIRT3]]. This finding suggests that CVDRF induces the loss of antioxidant defense mechanisms leading to endothelial injury.
|mesh-terms=* Adult
* Aged
* Aging
* Blotting, Western
* Cardiovascular Diseases
* Endothelium
* Erectile Dysfunction
* Humans
* Male
* Middle Aged
* Nitric Oxide Synthase Type III
* Penis
* RNA, Messenger
* Real-Time Polymerase Chain Reaction
* Risk Factors
* Sirtuin 1
* Sirtuins
* Up-Regulation
|keywords=* Aging
* Cardiovascular Disease Risk Factors
* Human Corpus Cavernosum
* SIRT1
* SIRT2
* SIRT3
* SIRT5
* SIRT6
* SIRT7
|full-text-url=https://sci-hub.do/10.1111/jsm.13035
}}
{{medline-entry
|title=Localization of sirtuins ([[SIRT1]]-7) in the aged mouse inner ear.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26472659
|abstract=The expression of sirtuin in vestibular end organs and cochlea responds differently to age-related changes. Down-regulation of [[SIRT1]], 3, and 5 in the cochlea may weaken the protective activity regarding degeneration of the organ of Corti as well as of spiral ganglion cells, resulting in the development of age-related hearing loss. An increase in SIRT 1, 4, or 5 in vestibular tissue could indicate an increased need of detoxification of reactive oxygen species and an increased anti-ageing potential. To analyse the expression of sirtuins ([[SIRT1]]-7) in the normal young and old mouse inner ears. Young (8 weeks) and old (22 months) CBA/J mice were used in this study. Localization of [[SIRT1]]-7 in the inner ear, i.e. cochlea, vestibular end organs, and vestibular ganglion, was investigated using real-time PCR and immunohistochemistry. In the vestibular end organs, the expression of [[SIRT1]], 2, 4, 5 (both mRNA and protein), [[SIRT6]], and 7 (only mRNA) was found to be increased, while a slightly decreased immunoreactivity was observed in [[SIRT3]]. In the cochlea, the expression of [[SIRT1]], 3, and 5 (both mRNA and protein) was decreased in the old mice, whereas no noticeable difference was observed regarding [[SIRT2]], 4, 6, or 7.
|mesh-terms=* Aging
* Animals
* Ear, Inner
* Gene Expression Regulation, Developmental
* Immunohistochemistry
* Mice
* Mice, Inbred CBA
* RNA, Messenger
* Real-Time Polymerase Chain Reaction
* Sirtuin 1
* Sirtuin 3
* Sirtuins
* Tomography, X-Ray Computed
|keywords=* Sirtuin
* ageing
* inner ear
* mouse
* presbycusis
|full-text-url=https://sci-hub.do/10.3109/00016489.2015.1093172
}}
{{medline-entry
|title=Aging-related rotenone-induced neurochemical and behavioral deficits: role of [[SIRT2]] and redox imbalance, and neuroprotection by AK-7.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26089639
|abstract=Aging is one of the strongest risk factors for Parkinson's disease (PD). [[SIRT2]] has been implicated in the aging process. It is pertinent to investigate the role of [[SIRT2]] in aging-related dopaminergic neurotoxicity and to develop effective therapeutic strategies for PD through the use of aging animals. In this study, we observed that rotenone induced significant behavior abnormality and striatal dopamine depletion in aging rats, while it did not do so in young rats. No significant change in striatal serotonin level was observed in the aging rats after rotenone administration. There was also aging-related rotenone-induced increase in substantia nigra (SN) [[SIRT2]] expression in the rats. In addition, there was aging-related rotenone-induced SN malondialdehyde (MDA) increase and glutathione (GSH) decrease in the rats. No significant changes in cerebellar [[SIRT2]], MDA, or GSH levels were observed in the aging rats after rotenone administration. Striatal dopamine content was significantly inversely correlated with SN [[SIRT2]] expression in the rats. AK-7 significantly diminished striatal dopamine depletion and improved behavior abnormality in the rotenone-treated aging rats. Furthermore, AK-7 significantly decreased MDA content and increased GSH content in the SN of rotenone-treated aging rats. Finally, the effect of AK-7 on dopaminergic neurons and redox imbalance was supported by the results from primary mesencephalic cultures. Our study helps to elucidate the mechanism for the participation of aging in PD and suggests that SN [[SIRT2]] may be involved in PD neurodegeneration, that AK-7 may be neuroprotective in PD, and that maintaining redox balance may be one of the mechanisms underlying neuroprotection by AK-7. 
|mesh-terms=* Aging
* Animals
* Benzamides
* Corpus Striatum
* Disease Models, Animal
* Dopamine
* Dopaminergic Neurons
* Male
* Neuroprotective Agents
* Oxidation-Reduction
* Parkinsonian Disorders
* Rats
* Rats, Sprague-Dawley
* Rotenone
* Sirtuin 2
* Substantia Nigra
* Sulfonamides
|keywords=* Parkinson’s disease
* dopamine
* environmental toxin
* oxidative stress
* sirtuin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466888
}}
{{medline-entry
|title=Differential expression of sirtuins in the aging rat brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26005404
|abstract=Although there are seven mammalian sirtuins ([[SIRT1]]-7), little is known about their expression in the aging brain. To characterize the change(s) in mRNA and protein expression of [[SIRT1]]-7 and their associated proteins in the brain of "physiologically" aged Wistar rats. We tested mRNA and protein expression levels of rat [[SIRT1]]-7, and the levels of associated proteins in the brain using RT-PCR and western blotting. Our data shows that [[SIRT1]] expression increases with age, concurrently with increased acetylated p53 levels in all brain regions investigated. [[SIRT2]] and FOXO3a protein levels increased only in the occipital lobe. [[SIRT3]]-5 expression declined significantly in the hippocampus and frontal lobe, associated with increases in superoxide and fatty acid oxidation levels, and acetylated CPS-1 protein expression, and a reduction in MnSOD level. While [[SIRT6]] expression declines significantly with age acetylated H3K9 protein expression is increased throughout the brain. [[SIRT7]] and Pol I protein expression increased in the frontal lobe. This study identifies previously unknown roles for sirtuins in regulating cellular homeostasis and healthy aging. 

|keywords=* aging
* brain
* longevity
* p53
* sirtuins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424846
}}
{{medline-entry
|title=Polymorphisms Falling Within Putative miRNA Target Sites in the 3'UTR Region of [[SIRT2]] and [[DRD2]] Genes Are Correlated With Human Longevity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25934993
|abstract=Many studies have suggested that individual differences in aging phenotypes may be associated to polymorphisms affecting gene regulation. As single-nucleotide polymorphisms (SNPs) in the 3'-untranslated regions (3'UTR) targeted by microRNAs (miRNAs) can alter the strength of miRNA binding (and, consequently, the regulation of target genes), we wondered whether these SNPs (known as miRSNPs) affect the individual chance to become long-lived. Thus, we estimated the effect of miRSNPs falling in the 3'-untranslated regions of 140 aging-related genes on the DNA/miRNA bond. The 24 miRSNPs with the highest difference of binding energy between the two alleles were then investigated for their association with longevity by case-control analysis. Two SNPs,[[SIRT2]]-rs45592833 G/T and [[DRD2]]-rs6276 A/G, provided a significant association with human longevity, also after correcting for multiple comparisons. For both SNPs, the minor allele was associated with a significantly decreased chance to became long-lived in an allele dose-dependent manner (p= 1.090 × 10(-6)and 1.964 × 10(-4)for[[SIRT2]] and [[DRD2]], respectively). The results indicate that the individual aging phenotype may be affected by the variability of specific miRNA targeted regions, as shown for [[SIRT2]] and [[DRD2]], and may suggest further studies to analyze the variability of gene expression regulation as a modulator of aging phenotypes.
|mesh-terms=* 3' Untranslated Regions
* Aged
* Aged, 80 and over
* Case-Control Studies
* Female
* Genotype
* Humans
* Logistic Models
* Longevity
* Male
* MicroRNAs
* Polymorphism, Single Nucleotide
* Receptors, Dopamine D2
* Sirtuin 2
|keywords=* DRD2
* Longevity
* SIRT2
* SNP
* miRNA
|full-text-url=https://sci-hub.do/10.1093/gerona/glv058
}}
{{medline-entry
|title=The role of melatonin, sirtuin2 and FoXO1 transcription factor in the aging process of colon in male rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/25430724
|abstract=The protein family of sirtuins and FoXO1 transcription factor have been shown to play significant roles in the aging process. In this study we aimed to investigate the changes in the levels of [[SIRT2]], NFκB and FoXO1 and oxidative parameters of colonic mucosa during aging, and the effects of exogenous melatonin (MLT). A total of twenty-four young (3-months-old) and aged (24 months old) male Wistar rats, divided into control [1% ethanol--phosphate-buffered saline (PBS), s.c. for 21 days] and melatonin (10 mg kg(-1) MLT 1% ethanol in PBS, s.c. for 21 days) were used in the study. The levels of malondialdehyde (MDA) as a parameter of lipid peroxidation, glutathione, NFkB pathway activation, [[SIRT2]] expression, and FoXO1 transcription factor of colonic mucosa were assayed. The MDA levels and [[SIRT2]] expression in the colonic mucosa were significantly increased in the aged group when compared to the younger group. However, the levels of FoXO1 transcription factor were significantly decreased in the aged group. Melatonin significantly decreased the MDA and [[SIRT2]] expression levels of the colonic mucosa in the aged rats. In conclusion, our findings suggest a suppressive role of melatonin in the aging process of colonic tissue via decreasing [[SIRT2]] expression.
|mesh-terms=* Aging
* Animals
* Colon
* Forkhead Transcription Factors
* Intestinal Mucosa
* Lipid Peroxidation
* Male
* Malondialdehyde
* Melatonin
* Models, Animal
* NF-kappa B
* Nerve Tissue Proteins
* Rats
* Rats, Wistar
* Sirtuin 2

|full-text-url=https://sci-hub.do/10.1007/s10522-014-9540-1
}}
{{medline-entry
|title=[[[SIRT2]], a multi-talented deacetylase].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24939540
|abstract=Sirtuin 2 ([[SIRT2]]) is an NAD( ) (nicotinamide adenine dinucleotide)-dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of [[SIRT2]] on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. We have recently shown the involvement of [[SIRT2]] in the antiproliferative effects of resveratrol on primary cultures of human glioblastoma stem cells. [[SIRT2]] could become a new therapeutic target. 
|mesh-terms=* Animals
* Glioblastoma
* Humans
* Longevity
* Neoplasms
* Sirtuin 2

|full-text-url=https://sci-hub.do/10.1051/medsci/20143005016
}}
{{medline-entry
|title=[[SIRT2]] induces the checkpoint kinase BubR1 to increase lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24825348
|abstract=Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1(H/H)) live shorter and show signs of accelerated aging. As wild-type mice age, BubR1 levels decline in many tissues, a process that is proposed to underlie normal aging and age-related diseases. Understanding why BubR1 declines with age and how to slow this process is therefore of considerable interest. The sirtuins (SIRT1-7) are a family of NAD( )-dependent deacetylases that can delay age-related diseases. Here, we show that the loss of BubR1 levels with age is due to a decline in NAD( ) and the ability of [[SIRT2]] to maintain lysine-668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP. Overexpression of [[SIRT2]] or treatment of mice with the NAD( ) precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo. Overexpression of [[SIRT2]] in BubR1(H/H) animals increases median lifespan, with a greater effect in male mice. Together, these data indicate that further exploration of the potential of [[SIRT2]] and NAD( ) to delay diseases of aging in mammals is warranted.
|mesh-terms=* Animals
* Cell Cycle Proteins
* Enzyme Induction
* HeLa Cells
* Humans
* Longevity
* Male
* Mice
* Mice, Knockout
* NAD
* Protein-Serine-Threonine Kinases
* Sirtuin 2
|keywords=* BubR1
* NAD
 
* acetylation
* aging
* sirtuin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194088
}}
{{medline-entry
|title=Forever young: [[SIRT3]] a shield against mitochondrial meltdown, aging, and neurodegeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24046746
|abstract=Caloric restriction (CR), fasting, and exercise have long been recognized for their neuroprotective and lifespan-extending properties; however, the underlying mechanisms of these phenomena remain elusive. Such extraordinary benefits might be linked to the activation of sirtuins. In mammals, the sirtuin family has seven members ([[SIRT1]]-7), which diverge in tissue distribution, subcellular localization, enzymatic activity, and targets. [[SIRT1]], [[SIRT2]], and [[SIRT3]] have deacetylase activity. Their dependence on NAD( ) directly links their activity to the metabolic status of the cell. High NAD( ) levels convey neuroprotective effects, possibly via activation of sirtuin family members. Mitochondrial sirtuin 3 ([[SIRT3]]) has received much attention for its role in metabolism and aging. Specific small nucleotide polymorphisms in Sirt3 are linked to increased human lifespan. [[SIRT3]] mediates the adaptation of increased energy demand during CR, fasting, and exercise to increased production of energy equivalents. [[SIRT3]] deacetylates and activates mitochondrial enzymes involved in fatty acid β-oxidation, amino acid metabolism, the electron transport chain, and antioxidant defenses. As a result, the mitochondrial energy metabolism increases. In addition, [[SIRT3]] prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. Mitochondrial deficits associated with aging and neurodegeneration might therefore be slowed or even prevented by [[SIRT3]] activation. In addition, upregulating [[SIRT3]] activity by dietary supplementation of sirtuin activating compounds might promote the beneficial effects of this enzyme. The goal of this review is to summarize emerging data supporting a neuroprotective action of [[SIRT3]] against Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. 

|keywords=* SIRT3
* aging
* antioxidants
* caloric restriction
* mitochondria
* neurodegeneration
* neuroprotection
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764375
}}
{{medline-entry
|title=Dietary restriction increases protein acetylation in the livers of aged rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24008504
|abstract=Dietary restriction (DR) is a well-established biological method for lifespan extension in various organisms by delaying the progression of age-related disorders. With regard to its molecular mechanisms, a family of NAD-dependent protein deacetylases, such as sirtuins, is considered to mediate DR-induced lifespan extension in some lower organisms. Furthermore, the effects of DR on sirtuins (e.g. [[SIRT1]], [[SIRT2]], [[SIRT3]], and SIRT5) have also been reported in mammals. However, the relationship between sirtuins and DR-associated longevity in mammals is still not clear. In addition, ageing and DR-associated changes in cellular protein acetylation have not been fully elucidated, especially in DR-aged animals. We aimed to elucidate the effect of ageing and DR on cellular protein acetylation in young and aged rats. Fischer 344 rats were subjected to DR for 7.5 or 25.5 months from 1.5 months of age. Protein acetylation status in tissues was analyzed by Western blotting, subcellular fractionation, and immuno-pull-down assay. We also analyzed the quantitative changes in some related deacetylases and an acetyltransferase. Acetylation of multiple proteins in the liver of young and aged rats decreased slightly with ageing and increased markedly under DR. The results of subcellular fractionation revealed that the DR-induced increase in protein acetylation was more prominent in extranuclear proteins than in nuclear proteins, indicating that acetylation is global, but protein-specific. This was further confirmed in the results of immune-pull-down assays for mitochondrial acetylated proteins. Cellular protein acetylation is regulated by multiple factors, including various deacetylases and acetyltransferases. With regard to the possible mechanisms of DR-induced increases in protein acetylation, we observed that DR increased [[SIRT3]] expression in the liver of young and aged rats. Expression of the mitochondrial protein acetyltransferase GCN5L1 significantly increased with ageing but did not respond to DR. The increased acetylation of extranuclear proteins may be involved in DR-induced anti-ageing effects including longevity. However, the mechanisms underlying the changes in protein acetylation might not result from quantitative changes in mitochondrial sirtuins and the mitochondrial protein acetyltransferase.
|mesh-terms=* Acetylation
* Acetyltransferases
* Aging
* Animals
* Caloric Restriction
* Liver
* Male
* Mitochondria, Liver
* Mitochondrial Proteins
* Protein Processing, Post-Translational
* Proteins
* Rats
* Rats, Inbred F344
* Sirtuins

|full-text-url=https://sci-hub.do/10.1159/000354087
}}
{{medline-entry
|title=Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23997094
|abstract=The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wild-type (MnSOD( / )) and manganese SOD heterozygous haploinsufficient (MnSOD( /-)) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of [[SIRT1]], [[SIRT2]], [[SIRT3]], [[SIRT4]], and [[SIRT6]] were significantly reduced in the aortic valve. Expression of p16(ink4a), a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD( / ) and MnSOD( /-) mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD( / ) and MnSOD( /-) mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD( / ) mice but significantly impaired endothelial function in MnSOD( /-) mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific.
|mesh-terms=* Age Factors
* Aging
* Animals
* Antioxidants
* Aorta, Thoracic
* Aortic Valve
* Calcium
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Dose-Response Relationship, Drug
* Enzyme Inhibitors
* Forkhead Transcription Factors
* Gene Expression Regulation
* Genotype
* Haploinsufficiency
* Heterozygote
* Inflammation Mediators
* Mice
* Mice, 129 Strain
* Mice, Inbred C57BL
* Mice, Knockout
* Mitochondria
* NADPH Oxidases
* Nitric Oxide Synthase
* Osteogenesis
* Oxidative Stress
* Phenotype
* Sirtuins
* Superoxide Dismutase
* Transcription, Genetic
* Vasodilation
* Vasodilator Agents
|keywords=* aging
* aorta
* aortic valve
* endothelial function
* mitochondrial oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840262
}}
{{medline-entry
|title=Growth hormone and melatonin prevent age-related alteration in apoptosis processes in the dentate gyrus of male rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23852044
|abstract=It has been suggested that the age-related decrease in the number of neurons in the hippocampus that leads to alterations in brain function, may be associated with an increase in apoptosis due to the reduced secretion of growth hormone (GH) and/or melatonin in old animals. In order to investigate this possibility, male Wistar rats of 22 months of age were divided into three groups. One group remained untreated and acted as the control group. The second was treated with growth hormone (hGH) for 10 weeks (2 mg/kg/d sc) and the third was subjected to melatonin treatment (1 mg/kg/d) in the drinking water for the same time. A group of 2-months-old male rats was used as young controls. All rats were killed by decapitation at more than 24 month of age and dentate gyri of the hippocampi were collected. Aging in the dentate gyrus was associated with an increase in apoptosis promoting markers (Bax, Bad and AIF) and with the reduction of some anti-apoptotic ones (XIAP, NIAP, Mcl-1). Expressions of sirtuin 1 and 2 ([[SIRT1]] and 2) as well as levels of HSP 70 were decreased in the dentate gyrus of old rats. GH treatment was able to reduce the pro/anti-apoptotic ratio to levels observed in young animals and also to increase [[SIRT2]]. Melatonin reduced also expression of pro-apoptotic genes and proteins (Bax, Bad and AIF), and increased levels of myeloid cell leukemia-1 proteins and [[SIRT1]]. Both treatments were able to reduce apoptosis and to enhance survival markers in this part of the hippocampus.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Base Sequence
* DNA Primers
* Dentate Gyrus
* Growth Hormone
* Male
* Melatonin
* Rats
* Rats, Wistar
* Real-Time Polymerase Chain Reaction

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739870
}}