However, in older people, there was a significant decrease in PON-1 level as compared with adults. This may be related with oxidative stress because there are numerous researches which demonstrate the role of PON-1 on the age- and oxidative stress-related diseases such as diabetes and heart diseases [ 71 , 74 , 75 ]. Interestingly, decrease in the PON-1 level was dramatic in older people carrying mutant allele G for both rs and rs compared with adults.
Also, increase in LDL cholesterol level was significant in older people carrying mutant genoype GG for rs These results are consistent with our OSI levels which older people carrying mutant allele G had a significantly higher OSI level than adults.
In addition, there is a significant negative correlation between SIRT1 level and PON-1 level in older people again suggesting oxidative-stress related increase in SIRT1 level to compensate the decrease in antioxidant enzymes in elderly.
In conclusion, we observed a significant increase in SIRT1 level in older people. Interestingly, in our study population, the oldest people Also, OSI levels were higher and PON-1 levels were lower in older people than adults and children which may explain high levels of SIRT1 protein as a compensatory mechanism for oxidative stress in older people.
Therefore, further studies are warranted the relation between genetic and epigenetic mechanisms for SIRT1 to increase the quality of late life by reducing the burden of age-related chronic diseases with changing life styles and eating habits. This study has a strength being the first to demonstrate the changes of SIRT1 level in different ages. However, this is an initial Turkish population based study that needs to be larger sample size to better interpret the results for the SIRT1 polymorphisms.
Another draw-back of the current study is imbalance between the numbers of each gender and the absence of determination of SIRT1 activity and its interaction with eNOS. Therefore, future studies with larger sample size with nearly equal number of each sex by measuring activities of studied proteins in addition to their expressions are needed to potentiate the validity of this study.
University Research Council, Bezmialem Vakif University had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript; however, Ulkan Kilic, PhD, PhD had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Center for Biotechnology Information , U. PLoS One. Published online Mar Stephen E Alway, Academic Editor.
Author information Article notes Copyright and License information Disclaimer. Competing Interests: The authors have declared that no competing interests exist. Received Aug 26; Accepted Jan 5. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. This article has been cited by other articles in PMC. Abstract Aging is defined as the accumulation of progressive organ dysfunction.
Table 1 Clinical characteristics of the study population. Open in a separate window. Fig 1. Fig 2. Fig 3. Fig 4. Receiver-operating characteristic ROC curves for protein expressions. Discussion Aging is defined as the accumulation of progressive organ dysfunction.
Study Limitations This study has a strength being the first to demonstrate the changes of SIRT1 level in different ages. Data Availability All relevant data are within the paper. References 1. Int J Mol Sci 14 : — Transl Res : — Guarente L, Franklin H Epstein lecture: sirtuins, aging, and medicine.
N Engl J Med : — Cell : — Genes Dev 13 : — Rogina B, Helfand SL Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Nature : — Circ Res 95 : — Circ Res : — Koubova J, Guarente L How does calorie restriction work? Genes Dev 17 : — Masoro EJ Caloric restriction and aging: an update. Exp Gerontol 35 : — Sinclair DA Paradigms and pitfalls of yeast longevity research.
S1b , and present detectably higher levels of Sirt1 protein Supplementary Fig. S2a—c , as well as an increase in hepatic Sirt1 activity measured by the lower levels of acetylated lysine of p65RelA Supplementary Fig.
S2c , a known target of Sirt1 deacetylase activity In agreement with their similar levels of Sirt1 upregulation, both transgenic lines displayed similar phenotypes regarding protection from HFD, such as, decreased adipose tissue inflammation Supplementary Fig.
S3a , improved glucose tolerance Supplementary Fig. S3b and ref. S3c and ref. S4 and ref. To determine the impact of Sirt1 upregulation on longevity, we followed up cohorts of the two lines, together with their corresponding wild-type WT controls.
The corresponding survival curves are represented by either separating the two lines or pooling them together. Moreover, no significant differences were found between Sirt1-tg mice and their corresponding WT controls when each line was analyzed separately Fig.
We conclude that systemic threefold upregulation of Sirt1 has no detectable impact, neither detrimental nor beneficial, on mouse longevity.
Detailed histopathological analyses of old moribund mice revealed a lower incidence of malignant tumours in Sirt1-tg mice, compared with WT mice of both lines Fig. Remarkably, the suppressive effect of Sirt1 on malignant tumours was restricted to carcinomas and sarcomas mostly osteosarcomas , whereas it had no effect on the incidence of lymphomas and histiocytic lymphomas the latter also known as histiocytic sarcomas Fig.
It is important to mention that most spontaneous carcinomas and sarcomas were in general of small size as was the case of liver or lung carcinomas or affected non-vital organs such as Harderian gland carcinomas in the eyes or osteosarcomas in the limbs.
Therefore, despite their malignancy, most carcinomas and sarcomas were at a stage of dissemination that is unlikely to be the primary cause of death. This is in contrast to spontaneous lymphomas, which had similar incidences in WT and tg mice, and were highly aggressive and the likely cause of death.
In summary, these results indicate that Sirt1 upregulation provides protection from spontaneous carcinomas and sarcomas, but not from spontaneous lymphomas. Conceivably, the lack of effect of Sirt1 on spontaneous lymphomas could mask a putative effect of Sirt1 on longevity. To examine the impact of Sirt1 on ageing, we began by examining a physiological parameter related to metabolic syndrome, namely, ageing-associated glucose intolerance Young 3 months old WT and Sirt1-tg mice under a standard diet showed similar performance in glucose-tolerance tests 15 , 16 see also Supplementary Fig.
Interestingly, at 1. These results indicate that Sirt1 confers protection against ageing-associated metabolic damage under standard diet and, together with previous data on mice under an HFD 15 , 16 , 17 , reinforce and extend the concept that Sirt1 is a general protector against metabolic damage. Curves are shown to the left. Integrated AUCs area under curve are shown to the right.
Data are relative to the levels in young WT mice. Additional indicators of fitness at old age were obtained by measuring skin regeneration wound-healing assay, Fig.
To evaluate ageing at a molecular level, we measured two well-established markers of ageing, namely, the levels of p16 Ink4a mRNA 27 and the accumulation of nuclear foci of DNA damage proteins 28 , Collectively, the analysis of ageing-associated pathologies glucose intolerance, osteoporosis, decreased wound healing, impaired neuromuscular coordination and molecular markers of ageing p16 Ink4a , DNA damage support the concept that Sirt1 possesses antiageing activity in mammals.
After analysing the effect of Sirt1 on health and cancer during ageing, we wanted to further extend the cancer studies to a model relevant for metabolic syndrome, a condition that affects up to one-quarter of the human population after middle age 19 , The array of diseases comprised by metabolic syndrome can be initiated by a high dietary intake and, in the case of liver, results in fatty liver, which can be followed by cirrhosis and finally cancer 18 , To model metabolic syndrome-associated cancer, we treated mice with a single injection of a hepatic-specific carcinogen, diethylnitrosamine DEN , followed by continued exposure to HFD.
Furthermore, it is relevant to note that DEN is a poor carcinogen on its own in mice of a C57BL6 genetic background Importantly, all WT mice treated with DEN and under HFD for 11 months developed multiple tumours on an average 10 tumours that were quantified and measured in live mice by microcomputed tomography microCT Fig.
Notably, the corresponding Sirt1-tg littermate mice presented a significantly lower incidence and burden of liver tumours Fig. On necropsy, the differences in tumour number and size between WT and Sirt1-tg livers were dramatic Fig. However, when we induced fibrosarcomas with 3-methyl-cholanthrene 3MC , no differences were observed between WT and Sirt1-tg mice Fig. This differential cancer protection between hepatocytes and fibroblasts correlates with the effect of Sirt1 on DNA damage in the same cell types see below.
We conclude that moderate upregulation of Sirt1 strongly suppresses metabolic syndrome-associated liver cancer. Tumours were measured by microCT. Tumour burden per mouse was obtained by adding the areas of the biggest transversal section of each tumour.
Haematoxylin and eosin staining. Mice of the indicated genotypes were injected intramuscularly with 3MC in one of the rear legs and the latency for the development of fibrosarcomas was scored.
Sirt1-tg mice present a lower accumulation of ageing-associated DNA damage in the liver see above Fig. Although the protection of Sirt1 from HFD-induced damage is well substantiated 15 , 16 , 17 see also Supplementary Fig. S3 , nothing is known about the impact of Sirt1 on DEN-induced liver damage. Treatment of mice with DEN under standard feeding conditions triggers a well-known cascade of events in the liver that include DNA damage and apoptosis of centrilobular hepatocytes, production of proinflammatory cytokines and compensatory proliferation Serum levels of alanine transaminase 48 h after DEN injection already indicated a significant protection from liver injury in Sirt1-tg mice in standard diet Fig.
Immunohistological examination of livers 48 h after DEN showed intense nuclear staining of Sirt1 restricted to the centrilobular regions of the liver around the central veins and absent in the periportal regions around the portal triad Fig. Treatment of in vitro- cultured cells with genotoxic agents recruits Sirt1 to the chromatin 6 , and we questioned whether this also happens in vivo on treating with DEN.
Indeed, we observed that DEN increased the amount of chromatin-bound Sirt1 in liver extracts, without detectably affecting the total amount of Sirt1 Fig. After observing that Sirt1 actively responds to DEN by concentrating in the nucleus and stably binding to chromatin, we examined the impact of Sirt1-tg on the liver on treatment with DEN under standard feeding conditions.
Livers from WT mice showed a strong DNA damage response in centrilobular regions, accompanied by high levels of apoptosis and compensatory proliferation Fig. Importantly, and in sharp contrast, DEN-treated Sirt1-tg livers showed significantly lower levels of damage, apoptosis and compensatory proliferation Fig. Our assays suggest a cell-type specificity in the effects of Sirt1 on DNA damage, being more protective in hepatocytes than in fibroblasts.
However, the assays and DNA damage agents used here preclude a direct comparison and this point remains to be clarified in future studies. Histone H3 and actin were used as loading controls. In this study, we provide direct genetic evidence for the antiageing activity of Sirt1 in mammals. We have found that moderate upregulation of Sirt1 expression threefold improves healthy ageing but not longevity. Importantly, old Sirt1-tg mice are partially protected from the development of pathologies typically associated with ageing, such as glucose intolerance, osteoporosis and poor wound healing.
This improved maintenance of physiological fitness at old ages is accompanied by a decreased expression of molecular markers of ageing in liver, particularly p16 Ink4a mRNA levels and nuclear foci of DNA damage proteins.
However, the overall impact on ageing under standard ad libitum feeding conditions was not sufficiently potent to extend longevity. Given the beneficial impact of Sirt1 on ageing, it is tempting to speculate that attaining levels of Sirt1 activity higher than those achieved by us, either genetically or through the use of pharmacological activators, could lead to an extension of the lifespan.
Moreover, considering that there are seven different sirtuins in mammalian organisms, it is also possible that several sirtuins must be targeted concurrently to produce lifespan extension.
An important observation derived from the analyses of old moribund Sirt1-tg mice is that they are partially protected against spontaneous carcinomas and sarcomas, but not from lymphomas.
Other investigators have reported that Sirt1 protects against lymphomas in pheterozygous mice 5 , 6. It is conceivable that Sirt1 has a stronger protective effect against lymphomas with a high degree of genetic instability, such as those developed in pheterozygous mice, whereas, spontaneous lymphomas develop less aggressively late in life and are presumably less dependent on protection from acute DNA damage. Together, these factors could explain, at least in part, the differential effect of Sirt1 on ageing-associated carcinomas and sarcomas, versus lymphomas.
Caloric restriction CR is a well-known manipulation with the ability to delay ageing and increase lifespan It has been proposed that the beneficial effects of CR in mice are mediated, at least in part, through Sirt1 37 , 38 , In this regard, it is interesting to note that our Sirt1-tg mice present an improved glucose tolerance at old age, which is a characteristic feature of CR-treated mice Further studies are necessary to address the similarities between Sirt1-tg mice under ad libitum conditions and CR-treated mice.
In this context, it is also worth to point out the similarities between the phenotypes of our Sirt-tg mice and the reported effects of the small natural compound resveratrol on mice, which upregulates Sirt1 activity, perhaps indirectly through effects mediated by AMPK 13 , Sirtuins play vital roles in sustaining genome integrity, by contributing in maintaining the normal chromatin condensation state, and responding to DNA damage and repair.
Similar to mammalian Sirtuins, Drosophila dSir2 is also involved in the epigenetic inheritance of silent chromatin states 30 , and the mutation of dSir2 was reported to suppress the heterochromatin-mediated silencing phenomenon known as position effect variegation SIRT1 and SIRT6 are known to regulate the expression of telomere reverse transcriptase required for telomere elongation 32 , and to deacetylate histone 3 lysine 9 H3K9 and H3K56 resulting in maintaining the telomeric integrity In addition to the suppression of senescence of mitotic cells, Sirtuin also modulates the senescence of stem cells, and is required for the maintenance of stem cell self-renewal The expression level of SIRT1 is reported to be higher in embryonic stem cells, but decreases in differentiated cells through the miRNA-mediated post-transcriptional regulations Reduction of SIRT1 resulted in increased DNA damage, and induced aging phenotypes in hematopoietic stem cells and endothelial progenitor cells 46 , 47 , whereas an overexpression of SIRT1 delayed the senescence of bone marrow-derived mesenchymal stem cells In addition to the roles in cellular senescence, it is well established that Sirtuin regulates the organismal lifespan in several animal models.
Increased expression levels of Sirtuin , especially yeast SIR2 and its homologues, extends the lifespan of budding yeast S. The prolongevity effect of SIR2 has been confirmed in higher organisms, while there are different mechanisms of exerting prolongevity effects in yeast, including changes in mitochondrial function and biogenesis, suppression of inflammation, and regulation of genomic stability A 7-fold overexpression of sir In addition, sir In Drosophila , overexpression of dSir2 using a P-element mediated insertion of the UAS sequence upstream of dSir2 extended the lifespan 10 , whereas dSir2 null mutants showed a shortened lifespan These results indicate that the prolongevity effect of Sirtuin is tissue-specific.
Sirtuins other than SIRT1 are also reported to exert a prolongevity effect. In Drosophila , the overexpression of dSirt4 which has a mitochondria-targeting sequence in the whole body or fat body, was reported to extend the lifespan and increase the resistance to starvation The expression of dSirt4 was induced by starvation in the fat body, and a deficiency of dSirt4 resulted in decreased fertility, locomotion activity, and lifespan The molecular targets of this longevity effect of Sirtuins have been actively investigated.
Loss of daf using mutants or RNAi treatment abolished the lifespan extension of sir Daf was reported to physically interact with Sir Considering that FOXO is a major component in the IIS cascade to promote lifespan extension and stress resistance, several evidences have reported the association of the IIS pathway with the prolongevity effect of Sirtuin.
In addition, deletion of daf-2 did not result in further extending the lifespan of worms overexpressing sir In mammals, the relationship of IIS and Sirtuin has also been well investigated.
AMPK signaling belongs to the protein kinase family and restores cellular energy levels. Increased AMPK activity is known to extend the lifespan of some model organisms. In addition, AMPK contributes to the prolongevity effect of IIS, suggesting that these longevity pathways intricately cross-talk with each other. Apart from these, several other molecules are also reported to mediate lifespan extension by Sirtuin overexpression, including , kat-1 , hcf-1 , and cts-1 in C.
The protein is a small acidic protein that alters the subcellular localization of its target. The mutation of par-5 and ftt-2 , encoding the two proteins of a conserved family in worms, abolished the lifespan extension by sir In addition, in vivo GST-pull down assay and immunoprecipitation assay revealed that Sir These results support the concept that the lifespan-extension effect of SIR2 is mediated by the protein. In addition, a study of mutant screening reported that loss-of-function mutations of ketoacyl thiolase kat-1 resulted in premature aging and fully suppressed the lifespan extension exerted by overexpression of sir Also, host cell factor-1 hcf-1 , a nuclear co-repressor of FOXO, was shown to act downstream of sir Furthermore, mitochondrial regulators such as cts-1 and fzo-1 , and the mitochondrial unfolded protein response UPR mt gene hsp-6 , were reported to increase by sir Although numerous evidences indicate that overexpression of Sirtuin delays the cellular senescence and extends the lifespan of organisms, several reports have challenged this theory 71 , The outcrossing abrogated the lifespan extension phenotype of geIn3 worm strains, used for overexpressing Sirtuin 10—30 fold, indicating that the longevity effect of this Sirtuin overexpressing strain is due to a lack of genetic background standardization In addition, geIn3 strain also has an unlinked dyf mutation which attributes to the longevity effect of the strain 73 , indicating that the lifespan extension of geIn3 is also due to incorrectly matched controls.
The report also showed that overexpression of dSir2 using outcrossed dSir2 EP and the two newly constructed lines containing inducible UAS-dSir2 under ubiquitously expressing Tubulin-Gal4 driver did not extend the lifespan compared to the flies expressing the Gal4 driver only Independently, a reduction in the expression of dSir2 using Sir2 RNAi in the fat body did not affect the lifespan of flies Later, this argument was also refuted.
Viswanathan and Guarente showed that geIn3 worms still have long lifespan after outcrossing compared to outcrossed control lines These contradictory results concerning the effect of Sirtuin overexpression on lifespan might be explained by the extent of overexpression of Sirtuin.
Whitaker et al. Thus, they asserted that dSir2 expression in previous reports might not be relevant each other, since the extent of overexpression varied depending on the controls that were used for comparison.
In the previous reports showing the lifespan extension by dSir2, the dSir2 was overexpressed 3—4-fold 10 , 56 , The dose-dependent effect of Sirtuin was also presented in a mice model. Alcendor et al. Although still controversial, it is believed that the beneficial effects of CR on lifespan extension and prevention of age-related diseases is mediated by the induction of Sirtuins 79 , Increased levels of SIRT1 by CR were observed in white adipose tissue, skeletal muscle, kidney, brain and intestine, 81 , 83 , Furthermore, the latter report also showed that knock-out of SIRT1 in liver is dispensable in this tissue SIRT3 are induced by CR in diverse tissues, including muscle, white adipose tissue, and liver 86 ; SIRT3 is suggested to be essential for cochlea neurons against oxidative damage These studies indicate that the expression of Sirtuin is regulated by CR with tissue-specificity, suggesting that a more elaborate investigation is required to understand Sirtuin regulation by CR.
Numerous researches have also reported the requirement of Sirtuins in the lifespan-extension effect of CR in various organisms. The strain of eat-2 such as ad, ad, ad that have defective pumping and are considered as the CR model of worms, lived longer than the wild-type N2 stain The sir In Drosophila , the lifespan extending effects of CR were partially mediated by dSir2 10 , 76 , and mammalian Sirtuins are well known to mediate the beneficial effect of CR The role of Sirtuins in lifespan extension by CR has long been challenged Several reports asserted that Sirtuins are not required for lifespan extension by CR in yeast, C.
In addition, SIR2 overexpression increases the replicative lifespan of yeast in low glucose Our findings indicate future clinical trials are needed to validate this hypothesis. If successful, this may be public health and clinical intervention through targeting mechanisms to protect against air pollution insult on the human body. The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun. Guarente L, Picard F. Calorie restriction--the SIR2 connection. Cell Metab. The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations.
Lancet Neurol. SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity. Am J Physiol Endocrinol Metab. SIRT1 polymorphism, long-term survival and glucose tolerance in the general population.
PLoS One. Chin J Med Genet. CAS Google Scholar. Int J Mol Epidemiol Genet. Ambient particulate air pollution and daily mortality in cities. N Engl J Med. A county-level estimate of PM2. Environ Int. Estimates and year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the global burden of diseases study Article Google Scholar.
High secondary aerosol contribution to particulate pollution during haze events in China. Health burden attributable to ambient PM2.
Environ Pollut. Candidate gene expression in response to low-level air pollution. Comparison of gene expression profiles induced by coarse, fine, and ultrafine particulate matter. J Toxicol Environ Health A. Cell Signal. Cardiovasc Res. Acetylation-deacetylation of the transcription factor Nrf2 nuclear factor erythroid 2-related factor 2 regulates its transcriptional activity and nucleocytoplasmic localization.
J Biol Chem. Crosstalk between oxidative stress and SIRT1: impact on the aging process. Int J Mol Sci. Can J Physiol Pharmacol. Aging Albany NY. Nrf2-related gene expression and exposure to traffic-related air pollution in elderly subjects with cardiovascular disease: an exploratory panel study.
J Expo Sci Environ Epidemiol. Curr Opin Psychiatry. Fueling the flame: bioenergy couples metabolism and inflammation. J Leukoc Biol. SIRT1 protects against urban particulate matter-induced airway inflammation.
Global estimates of fine particulate matter using a combined geophysical-statistical method with information from satellites, models, and monitors. Environ Sci Technol. All-cause mortality risk associated with long-term exposure to ambient PM2. Lancet Public Health.
Interaction between residential greenness and air pollution mortality: analysis of the Chinese longitudinal healthy longevity survey. Lancet Planet Health. Sex differences in genetic associations with longevity. SIRT1 gene, age-related diseases, and mortality: the Leiden plus study. GxE interactions between FOXO genotypes and drinking tea are significantly associated with prevention of cognitive decline in advanced age in China.
Effect of particulate matter air pollution on cardiovascular oxidative stress pathways. Antioxid Redox Signal. SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD.
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