Delays Cellular Senescence Research Articles

Combat Ageing by Sirtuins and Sirtfoods: Genetic and Dietary way of reducing senescence

Ageing is a conserved phenomenon across all species and imposes an ever-increasing risk of dysfunction and death in older organisms.Growing evidences have shown that sirtuins are essential factors those delay cellular senescence and extends the organismal lifespan through the regulation of diverse cellular processes, this needs food rich in antioxidants and polyphenols to activate sirtuin Aging is beautiful. Every wrinkle, crinkle and spot is hard-earned proof of a life well lived. But just because you’ve earned your stripes or the lines on your face, it doesn’t mean you don’t want to look your very best. The truth is, you can love your age and yourself and still want to know how to look younger and live disease free life, One of the most promising targets for anti-ageing approaches are proteins belonging to the sirtuin family.

YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner

Accumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis independent of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal a noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.

Discovery of Salidroside as a Novel Non-Coding RNA Modulator to Delay Cellular Senescence and Promote BK-Dependent Apoptosis in Cerebrovascular Smooth Muscle Cells of Simulated Microgravity Rats.

Cardiovascular aging has been reported to accelerate in spaceflights, which is a great potential risk to astronauts' health and performance. However, current exercise routines are not sufficient to reverse the adverse effects of microgravity exposure. Recently, salidroside (SAL), a valuable medicinal herb, has been demonstrated to display an important role for prevention and treatment in cardiovascular and other diseases. In the present work, Sprague-Dawley rats with four-week tail-suspension hindlimb-unloading were used to simulate microgravity effects on the cardiovascular system. We found that intragastrical administration of SAL not only significantly decreased the expressions of senescence biomarkers, such as P65 and P16, but also obviously increased the expressions of BK-dependent apoptotic genes, including the large-conductance calcium-activated K+ channel (BK), Bax, Bcl-2, and cleaved caspase-3, in vascular smooth muscle cells (VSMCs) in vivo and in vitro. In addition, relative non-coding RNAs were screened, and a luciferase assay identified that SAL increased apoptosis by activating LncRNA-FLORPAR, inhibiting miR-193, and then triggering the activity of the BK-α subunit. Our work indicated that SAL is a novel non-coding RNA modulator for regulating the LncRNA-FLORPAR sponging miR-193 pathway, which significantly promoted BK-dependent apoptosis and delayed cerebrovascular aging-like remodeling during simulated microgravity exposure. Our findings may provide a new approach to prevent cardiovascular aging in future spaceflights.

Ginsenoside F1-Mediated Telomere Preservation Delays Cellular Senescence.

Telomeres play pivotal roles in processes closely related to somatic senescence and aging, making them a compelling target for interventions aimed at combating aging and age-related pathologies. Ginsenoside, a natural compound, has emerged as a potential remedy for promoting healthy aging, yet how it protects telomeres remains incompletely understood. Here, we show that treatment of F1 can effectively restore the level of TRF2, thereby preserving telomere integrity. This restoration leads to inhibition of the DNA damage response and improvements in mitochondrial function and, ultimately, delays in cellular senescence. Conversely, depletion of TRF2 causes mitochondrial dysfunction, accompanied by increased oxidative stress, autophagy inhibition, insufficient energy metabolism, and the onset of cellular senescence. These observations underscore the critical role of TRF2 in maintaining telomere integrity and direct association with the initiation of cellular senescence. We conduct a further analysis, suggesting F1 could bind in proximity to the TRF2 heterodimer interface, potentially enhancing dimerization stability. These findings suggest that F1 may be a promising natural remedy for anti-aging, and restoring TRF2 could potentially prevent telomere-dependent diseases commonly associated with the aging process.

The role of vitamin D on redox regulation and cellular senescence.

Vitamin D is considered an essential micronutrient for human health that is metabolized into a multifunctional secosteroid hormone. We can synthesize it in the skin through ultraviolet B (UVB) rays or acquire it from the diet. Its deficiency is a major global health problem that affects all ages and ethnic groups. Furthermore, dysregulation of vitamin D homeostasis has been associated with premature aging, driven by various cellular processes, including oxidative stress and cellular senescence. Various studies have shown that vitamin D can attenuate oxidative stress and delay cellular senescence, mainly by inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Klotho and improving mitochondrial homeostasis, proposing this vitamin as an excellent candidate for delaying aging. However, the mechanisms around these processes are not yet fully explored. Therefore, in this review, the effects of vitamin D on redox regulation and cellular senescence are discussed to propose new lines of research and clinical applications of vitamin D in the context of age-related diseases.

Human Placental Extract Delays In Vitro Cellular Senescence through the Activation of NRF2-Mediated Antioxidant Pathway.

Senescent cells accumulate in the organs of aged animals and exacerbate organ dysfunction, resulting in age-related diseases. Oxidative stress accelerates cellular senescence. Placental extract, used in the alleviation of menopausal symptoms and promotion of wound healing and liver regeneration, reportedly protects against oxidative stress. In this study, we investigated the effects of human placental extract (HPE) on cellular senescence in normal human dermal fibroblasts (NHDFs) under oxidative stress conditions. We demonstrated that HPE delays the onset of cellular senescence. Next-generation sequencing analysis revealed that under oxidative stress conditions, HPE treatment enhanced the expression of the antioxidant genes CYGB, APOE, NQO1, and PTGS1. Further, HPE treatment under oxidative stress conditions increased the protein level of nuclear factor-erythroid factor 2-related factor 2 (NRF2)—a vital molecule in the antioxidant pathway—via post-transcriptional and/or post-translational regulations. These findings indicate that HPE treatment in NHDFs, under chronic oxidative stress, delays cellular senescence by mitigating oxidative stress via upregulation of the NRF2-mediated antioxidant pathway, and HPE treatment could potentially ameliorate skin-aging-associated damage, in vivo.

Tsc2 knockout counteracts ubiquitin-proteasome system insufficiency and delays photoreceptor loss in retinitis pigmentosa

SignificanceStudies in multiple experimental systems have demonstrated that an increase in proteolytic capacity of post-mitotic cells improves cellular resistance to a variety of stressors, delays cellular aging and senescence. Therefore, approaches to increase the ability of cells to degrade misfolded proteins could potentially be applied to the treatment of a broad spectrum of human disorders. An example would be retinal degenerations, which cause irreversible loss of vision and are linked to impaired protein degradation. This study suggests that chronic activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway in degenerating photoreceptor neurons could stimulate the degradation of ubiquitinated proteins and enhance proteasomal activity through phosphorylation.

Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence through TLR2 and TLR5 Signaling.

In order to provide a sufficient number of cells for clinical use, mesenchymal stem cells (MSCs) must be cultured for long-term expansion, which inevitably triggers cellular senescence. Although the small size of MSCs is known as a critical determinant of their fate, the main regulators of stem cell senescence and the underlying signaling have not been addressed. Umbilical cord blood-derived MSCs (UCB-MSCs) were obtained using size-isolation methods and then cultured with control or small cells to investigate the major factors that modulate MSC senescence. Cytokine array data suggested that the secretion of interukin-8 (IL-8) or growth-regulated oncogene-alpha (GROa) by senescent cells was markedly inhibited during incubation of small cells along with suppression of cognate receptor (C-X-C motif chemokine receptor2, CXCR2) via blockade of the autocrine/paracrine positive loop. Moreover, signaling via toll-like receptor 2 (TLR2) and TLR5, both pattern recognition receptors, drove cellular senescence of MSCs, but was inhibited in small cells. The activation of TLRs (2 and 5) through ligand treatment induced a senescent phenotype in small cells. Collectively, our data suggest that small cell from UCB-MSCs exhibit delayed cellular senescence by inhibiting the process of TLR signaling-mediated senescence-associated secretory phenotype (SASP) activation.

Culturing at Low Cell Density Delays Cellular Senescence of Human Bone Marrow-Derived Mesenchymal Stem Cells in Long-Term Cultures.

Background and ObjectivesMesenchymal stem cells (MSCs) have immense therapeutic potential for treating intractable and immune diseases. They also have applications in regenerative medicine in which distinct treatments do not exist. Thus, MSCs are gaining attention as important raw materials in the field of cell therapy. Importantly, the number of MSCs in the bone marrow is limited and they are present only in small quantities. Therefore, mass production of MSCs through long-term culture is necessary to use them in cell therapy. However, MSCs undergo cellular senescence through repeated passages during mass production. In this study, we explored methods to prolong the limited lifetime of MSCs by culturing them with different seeding densities.Methods and ResultsWe observed that in long-term cultures, low-density (LD, 50 cells/cm2) MSCs showed higher population doubling level, leading to greater fold increase, than high-density (HD, 4,000 cells/cm2) MSCs. LD-MSCs suppressed the expression of aging-related genes. We also showed that reactive oxygen species (ROS) were decreased in LD-MSCs compared to that in HD-MSCs. Further, proliferation potential increased when ROS were inhibited in HD-MSCs.ConclusionsThe results in this study suggest that MSC senescence can be delayed and that life span can be extended by controlling cell density in vitro. These results can be used as important data for the mass production of stem cell therapeutic products.

Small Molecule from Natural Phytochemical Mimics Dietary Restriction by Modulating FoxO3a and Metabolic Reprogramming.

Many studies utilizing animal models have revealed the genetic and pharmacogenetic modulators of the rate of organismal aging. However, finding routes for healthy aging during extended life remains one of the largest questions. With regards to an antiaging reagent, it has been shown that natural phytochemical syringaresinol (SYR) delays cellular senescence by activating sirtuin1 (SIRT1). Here, it is found that SYR treatment results in metabolic changes similar to those observed during dietary restriction (DR). The DR mimetic effects are mediated by FoxO3a-dependent SIRT1 activation and insulin/insuline growth factor-1 signaling modulation. The direct binding of SYR-FoxO3a is identified and this could partially explain the DR-like phenotype. The report gives a clue as to how the longevity gene involves the DR pathway and suggests that natural phytochemicals applied as a geroprotector mimics DR effects.

246 Narcissus tazetta bulb extract delays cellular senescence by reducing mTOR pathway activation

Somatic mammalian cells enter cellular senescence after a finite number of cell divisions. Senescent cells are characterized by their inability to proliferate and the secretion of promoters of inflammation and tissue deterioration. Telomere shortening is a main underlying mechanism of replicative senescence – the molecular clock counting down towards a programmed limit on cell replications, ending in senescence. This contributes to intrinsic tissue aging, leading to dryness, wrinkling, loss of elasticity, weakened barrier function, and hyperpigmentation.

Twist1 regulates cellular senescence in mesenchymal stem cells

Purpose: Mesenchymal stem cells (MSCs) are promising cells to treat skeletal related diseases such as osteoarthritis (OA). One of the limitations that reduces the therapeutic use of MSCs for OA cell-based treatments is cellular senescence. Cellular senescence is a state of the cell in which cells stop proliferating, while still be metabolically active. By acquiring a specific senescence-associated secretory phenotype (SASP), senescent MSCs can contribute to cartilage degeneration and chronic inflammation. The molecular mechanism behind cellular senescence in MSCs remains largely unknown. The transcription factor TWIST1 is suggested to play a role in cellular senescence, since its expression is reduced in slow proliferating MSCs and we previously demonstrated that high TWIST1-expressing MSCs have an enhanced expansion capacity. The aim of this research is therefore to determine the role of TWIST1 in regulating cellular senescence of MSCs. Methods: Human MSCs were obtained from bone chips from leftover iliac crest of patients undergoing cleft palate reconstructive surgery (N=4, 9-13 years). MSCs were expanded in alpha-MEM containing 10% serum and 1 ng/ml FGF2. To determine the effect of TWIST1 silencing on senescence, MSCs were treated with 15 nM TWIST1 siRNA and Lipofectamine RNAMAX Transfection Reagent (siTWIST1). Scramble siRNA and untreated cells were used as controls. To overexpress TWIST1, MSCs were transduced with a third generation TWIST1 overexpression lentiviral construct. Untreated MSCs and MSCs which overexpress GFP or an empty vector were used as control. The transduction efficiency, of GFP-positive MSCs, was determined using fluorescent microscopy. To determine cellular senescence, we determined senescence-associated beta-galactosidase (SA-β-gal) activity and quantified negative, low and high positive cells. In addition gene expression for IL8, IL6, IL1B, P21 and P16 were analyzed to assess cellular senescence in MSCs. Gene expression was normalized using the best housekeeper index of HPRT, RSP27a and GAPDH. The expansion capacity of the MSCs was determined by cell count. To analyze statistical significance, linear mixed model was applied, the different conditions were considered as fixed parameter and the donors as random parameter. Bonferroni post hoc test was performed to correct for multiple comparisons. Results: TWIST1 transduced MSCs had an average of 151-fold increase in TWIST1 expression detected by RT-PCR, a reduced percentage of SA-B-gal positive cells (71% reduction) and a reduced expression of the SASP related genes IL6 (1.8-fold reduction), IL8 (2.4-fold reduction) and IL1B (1.3-fold reduction) compared to transduction control (Figure 1). In addition, the expansion capacity of MSCs overexpressing TWIST1 was increased, resulting in a 1.5-fold increase in cell number after 4 days. These data indicate that TWIST1 delays cellular senescence in MSCs. Next, we determined the effect of TWIST1 silencing on cellular senescence associated markers. A high percentage of siTWIST1 MSCs were high positive for SA-B-gal (9.5-fold compared to controls, Figure 2A) and cells had a reduced expansion capacity compared to control conditions (20-fold reduction in cell number after 14 days). These data suggest that silencing TWIST1 in MSCs increases cellular senescence. Surprisingly, the expression of SASP related genes IL6 and IL8 was reduced in siTWIST cells compared to untreated control (IL6, 1.6-fold; IL8, 7.2-fold reduction, Figure 2B) and no induction of IL1B was observed in the siTWIST1 MSCs. Low IL6, IL8 and IL1B expression in senescent cells was recently described as mitochondrial dysfunction-associated senescence (MiDAS). We then further analyzed siTWIST1 MSCs for the expression of senescent markers not associated with a SASP phenotype and found that P16 and P21, associated to the cell cycle regulation, were increased after TWIST1 silencing (5.9-fold and 1.6-fold, respectively) in accordance with a senescent phenotype. Overall, these data indicate that TWIST1 silencing results in cellular senescence of MSCs with an uncommon SASP expression. Conclusions: Our Results indicate that TWIST1 plays a role in a special type of cellular senescence, previously described as MiDAS, with a unique SASP expression profile, lacking IL6, IL8 and IL1B upregulation. In addition these data show that different type of senescent cells can have a different SASP expression and therefore potentially have different effects on the microenvironment. Here, we show how TWIST1 may be a target to modulate cellular senescence to improve MSC-based OA therapies.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signalling.

Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and up-regulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating telomere length is the transforming growth factor beta (TGFβ) signalling pathway where inhibiting TGFβ signalling maintains telomere length. The relationship between Pim1 and TGFβ has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFβ signalling pathways in proliferating A549 cells and post-mitotic cardiomyocytes. Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGFβ signalling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGFβ signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFβ pathway genes. Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFβ pathway downstream effectors Smad2 and Smad3, which prevents repression of telomerase reverse transcriptase. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.

Salidroside Delays Cellular Senescence by Stimulating Mitochondrial Biogenesis Partly through a miR-22/SIRT-1 Pathway.

Calorie restriction (CR) is a nongenetic intervention with a robust effect on delaying aging in mammals and other organisms. A mild stimulation on mitochondrial biogenesis induced by CR seems to be an important action mode for its benefits. Here, we reported that a component isolated from Rhodiola rosea L., salidroside, delays replicative senescence in human fibroblasts, which is related to its stimulation on mitochondrial biogenesis by activating SIRT1 partly resulted from inhibition on miR-22. Salidroside increased the mitochondrial mass that accompanied an increment of the key regulators of mitochondrial biogenesis including PGC-1α, NRF-1, and TFAM and reversed the mitochondrial dysfunction in presenescent 50PD cells, showing a comparable effect to that of resveratrol. SIRT1 is involved in the inducement of mitochondrial biogenesis by salidroside. The declined expression of SIRT1 in 50PD cells compared with the young 30PD cells was prevented upon salidroside treatment. In addition, pretreatment of EX-527, a selective SIRT1 inhibitor, could block the increased mitochondrial mass and decreased ROS production induced by salidroside in 50PD cells, resulting in an accelerated cellular senescence. We further found that salidroside reversed the elevated miR-22 expression in presenescent cells according to a miRNA array analysis and a subsequent qPCR validation. Enforced miR-22 expression by using a Pre-miR-22 lentiviral construct induced the young fibroblasts (30PD) into a senescence state, accompanied with increased senescence-related molecules including p53, p21, p16, and decreased SIRT1 expression, a known target of miR-22. However, salidroside could partly impede the senescence progression induced by lenti-Pre-miR-22. Taken together, our data suggest that salidroside delays replicative senescence by stimulating mitochondrial biogenesis partly through a miR22/SIRT1 pathway, which enriches our current knowledge of a salidroside-mediated postpone senility effect and provides a new perspective on the antidecrepitude function of this naturally occurring compound in animals and humans.

LncRNA RP11-670E13.6, interacted with hnRNPH, delays cellular senescence by sponging microRNA-663a in UVB damaged dermal fibroblasts.

Ultraviolet (UV) irradiation from the sunlight is a major etiologic factor for premature skin aging. Long noncoding RNAs (lncRNAs) are involved in various biological processes, and their roles in UV irradiation-induced skin aging have recently been described. Previously, we found that the lncRNA RP11-670E13.6 was up-regulated and delayed cellular senescence in UVB-irradiated primary human dermal fibroblasts. Here, we performed further investigations of RP11-670E13.6 function. The results showed that this lncRNA directly bound to miR-663a and functioned as a sponge for miR-663a to modulate the derepression of Cdk4 and Cdk6, thereby delaying cellular senescence during UV irradiation-induced skin photoaging. Moreover, we found that RP11-670E13.6 may facilitate DNA damage repair by increasing ATM and γH2A.X levels. In addition, heterogeneous nuclear ribonucleoprotein H physically interacted with RP11-670E13.6 and blocked its expression. Collectively, our results suggested that the RP11-670E13.6/miR-663a/CDK4 and RP11-670E13.6/miR-663a/CDK6 axis, which may function as competitive endogenous RNA networks, played important roles in UVB-induced cellular senescence.

Energy and Cellular‐Defense Systems are Target for Anti‐Senescence Activity of Methylene Blue

Methylene blue (MB) delays cellular senescence, induces complex‐IV, and activates Keap1/Nrf2. The molecular link of these effects to MB and cellular senescence is unclear. We investigated the effect of MB on specific factors that affect cell senescence. Since MB is redox‐active agent, we started by assaying its effect on NAD/NADH ratio. MB caused a transient increase in NAD/NADH. This increase triggered an investigation into the energy metabolism regulator AMPK. MB induced AMPK phosphorylation in a transient pattern, which was followed by the induction of PGC1α and SURF1: both are inducers of mitochondrial and complex‐IV biogenesis. As expected from previous results, MB‐treated cells doubled complex‐IV activity. In addition, a significant decline in cellular oxidants was measured in MB treated cells. The telomeres erosion rate was also significantly lower in MB‐treated cells. A previous research suggested that the pattern of AMPK activation (i.e., chronic vs. transient) determines AMPK's effect on cell senescence. We found that the anti‐senescence activity of MB (transient activator of AMPK) was 8‐times higher than that of AICAR (chronic activator of AMPK). We investigated the effect of MB on cell cycle. We found that MB lacked an effect on cell cycle, indicating that an MB‐dependent change to cell cycle is unlikely to contribute to the anti‐senescence activity of MB. The current findings in conjunction with the activation of Keap1/Nrf2 suggest a synchronized activation of the energy and cellular defense cellular systems as a possible key factor in MB's potent anti‐senescence activity.Support or Funding InformationNIHAFARAmesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

S100A13 promotes senescence-associated secretory phenotype and cellular senescence via modulation of non-classical secretion of IL-1α.

Senescent cells display the senescence-associated secretory phenotype (SASP) which plays important roles in cancer, aging, etc. Cell surface-bound IL-1α is a crucial SASP factor and acts as an upstream regulator to induce NF-κB activity and subsequent SASP genes transcription. IL-1α exports to cell surface via S100A13 protein-dependent non-classical secretory pathway. However, the status of this secretory pathway during cellular senescence and its role in cellular senescence remain unknown. Here, we show that S100A13 is up-regulated in various types of cellular senescence. S100A13 overexpression increases cell surface-associated IL-1α level, NF-κB activity and subsequent multiple SASP genes induction, whereas S100A13 knockdown has an opposite role. We also exhibit that Cu2+ level is elevated during cellular senescence. Lowering Cu2+ level decreases cell surface-bound IL-1α level, NF-κB activity and SASP production. Moreover, S100A13 overexpression promotes oncogene Ras-induced cell senescence (Ras OIS), Doxorubicin-induced cancer cell senescence (TIS) and replicative senescence, while impairment of non-classical secretory pathway of IL-1α delays cellular senescence. In addition, intervention of S100A13 affects multiple SASP and cellular senescence mediators including p38, γ-H2AX, and mTORC1. Taken together, our findings unveil a critical role of the non-classical secretory pathway of IL-1α in cellular senescence and SASP regulation.

Adjudin delays cellular senescence through Sirt3‑mediated attenuation of ROS production.

Aging, marked by the physical and functional decline in numerous biological processes, is associated with multiple pathologies including cancer, neurodegenerative diseases and cardiocerebral vascular diseases. The accumulation of reactive oxygen species(ROS) production is considered one of the major causes of aging‑associated diseases and a major therapeutic target. Hydroxyurea has been widely used for cellular senescence model. The expression level of cell cycle-related protein, ROS production and senescence-associated β-galactosidase are considered to be markers of cellular senescence. Strategies to slow senescence may be beneficial for various aging‑associated diseases. The results of the current study indicated that adjudin, a multi‑functional small molecule compound, delayed hydroxyurea‑induced senescence in mouse embryo fibroblasts(MEFs). Adjudin reduced the proportion of senescence‑associated β‑galactosidase‑positive cells and decreased the expression levels of senescence‑associated markers, p16 and p21. Mechanistically, adjudin exerted its anti‑senescence effect by elevating the expression level of sirtuin3 (Sirt3), which attenuated ROS production through the regulation of forkhead boxO3a and manganese superoxide dismutase expression. Furthermore, by comparing wild‑type and Sirt3‑knockout MEFs, it was demonstrated that Sirt3 mediated the anti‑senescence effect of adjudin. Taken together, the findings indicated that adjudin has anti‑aging properties that may be exploited to treat aging‑associated diseases.

Delaying premature aging

Premature Aging Cells from patients with Hutchinson-Gilford progeria syndrome (HGPS) have defects in nuclear architecture that lead to premature cellular senescence. Larrieu et al. investigated the mechanisms by which a small molecule called remodelin improves the phenotype of HGPS cells (see the Focus by Wilson). Remodelin restored a nuclear import pathway mediated by Transportin-1 that was defective in HGPS cells, thereby delaying premature senescence. These results could also be applied to delay cellular senescence in cells derived from aged healthy individuals. Sci. Signal. 11 , eaar5401; see also eaat9448 (2018).

Nicotinamide phosphoribosyltransferase delays cellular senescence by upregulating SIRT1 activity and antioxidant gene expression in mouse cells.

Senescent cells accumulate in tissues of aged animals and deteriorate tissue functions. The elimination of senescent cells from aged mice not only attenuates progression of already established age-related disorders, but also extends median lifespan. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ salvage pathway, has shown a protective effect on cellular senescence of human primary cells. However, it still remains unclear how NAMPT has a protective impact on aging in vitro and in vivo. In this study, we found that primary mouse embryonic fibroblast (MEF) cells undergo progressive decline of NAMPT and NAD+ contents during serial passaging before becoming senescent. Furthermore, we showed that constitutive Nampt over-expression increases cellular NAD+ content and delays cellular senescence of MEF cells in vitro. We further found that constitutive Nampt over-expression increases SIRT1 activity, increases the expression of antioxidant genes, superoxide dismutase 2 and catalase and promotes resistance against oxidative stress. These findings suggest that Nampt over-expression in MEF cells delays cellular senescence by the mitigation of oxidative stress via the upregulation of superoxide dismutase 2 and catalase gene expressions by SIRT1 activation.