Senescence Abstracts 4

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Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock.
            (Ayub et al., 2015)  Download
Resveratrol has been shown to potentiate mitochondrial function and extend longevity; however, there is no evidence to support whether resveratrol can improve survival or prolong life following hemorrhagic shock. We sought to determine whether (a) resveratrol can improve survival following hemorrhage and resuscitation and (b) prolong life in the absence of resuscitation. Using a hemorrhagic injury (HI) model in the rat, we describe for the first time that the naturally occurring small molecule, resveratrol, may be an effective adjunct to resuscitation fluid. In a series of three sets of experiments we show that resveratrol administration during resuscitation improves survival following HI (p < 0.05), resveratrol and its synthetic mimic SRT1720 can significantly prolong life in the absence of resuscitation fluid (<30 min versus up to 4 h; p < 0.05), and resveratrol as well as SRT1720 restores left ventricular function following HI. We also found significant changes in the expression level of mitochondria-related transcription factors Ppar-α and Tfam, as well as Pgc-1α in the left ventricular tissues of rats subjected to HI and treated with resveratrol. The results indicate that resveratrol is a strong candidate adjunct to resuscitation following severe hemorrhage.

Rehmannia glutinosa exhibits anti-aging effect through maintaining the quiescence and decreasing the senescence of hematopoietic stem cells.
            (Bai et al., 2018) Download
Background: The time-related decline in regenerative capacity and organ homeostasis is a major feature of aging. Rehmannia glutinosa and Astragalus membranaceus have been used as traditional Chinese herbal medicines for enhanced immunity and prolonged life. However, the mechanism by which this herbal medicine slows aging is unknown. In this study, we investigated the mechanism of the herbal anti-aging effect. Methods: Mice were fed diets supplemented with R. glutinosa or A. membranaceus for 10 months; the control group was fed a standard diet. The phenotypes were evaluated using a grading score system and survival analysis. The percentages of the senescence phenotypes of hematopoietic stem cells (HSCs) were determined by fluorescence-activated cell sorting analysis. The function and the mechanism of HSCs were analyzed by clonogenic assay and the real-time polymerase chain reaction. Results: The anti-aging effect of R. glutinosa is due to the enhanced function of HSCs. Mice fed with R. glutinosa displayed characteristics of a slowed aging process, including decreased senescence and increased rate of survival. Flow cytometry analysis showed decreased numbers of Lin-Sca1+c-kit- (LSK) cells, long-term HSCs (LT-HSCs) and short-term HSCs (ST-HSCs) in the R. glutinosa group. In vitro, clonogenic assays showed increased self-renewal ability of LT-HSCs from the R. glutinosa group as well as maintaining LSK quiescence through upregulated p18 expression. The R. glutinosa group also showed decreased reactive oxygen species levels and the percentage of β-gal+ cells through downregulation of the cellular senescence-associated protein p53 and p16. Conclusion: Rehmannia glutinosa exerts anti-aging effects by maintaining the quiescence and decreasing the senescence of HSCs.

Polychlorinated biphenyl (PCBs)-induced oxidative stress plays a critical role on cerebellar dopaminergic receptor expression: ameliorative role of quercetin.
            (Bavithra et al., 2012)  Download
Polychlorinated biphenyls (PCBs) exposure produces profound damage to the developing as well as adult central nervous system. Locomotor activities which are closely linked to dopaminergic neurotransmission are often impaired in PCBs toxicity. Targeting PCBs-induced oxidative stress using natural antioxidants is an attractive approach. Quercetin, a flavonoid is a safe and potent neuroprotective antioxidant. In this study, we sought to examine the protective role of quercetin against PCBs-induced neurodegeneration and dysfunction of dopaminergic receptors in the cerebellar region of adult male rats. They were divided into four groups. Group I received only vehicle (corn oil) intraperitoneally (i.p); Group II received Aroclor 1254 at a dose of 2 mg/kg bwt/day (i.p); Group III received Aroclor 1254 (i.p) and simultaneously quercetin (50 mg/kg bwt/day) through gavage; Group IV received quercetin alone (gavage). After 30 days treatment, rats were euthanized. The cerebellum was dissected from each rat brain, the levels of hydrogen peroxide, lipid peroxidation, protein carbonyl content, and activities of creatine kinase, acetylcholine esterase, membrane-bound ATPases were evaluated. Expressions of dopaminergic receptors and tyrosine hydroxylase in cerebellum were studied by semi-quantitative RT-PCR and western blot analysis, respectively. The PCBs-induced neurodegeneration was assessed by histological studies. Results proclaim that PCBs disturb dopaminergic receptors and also causes neurodegeneration in cerebellum via production of ROS. Simultaneous quercetin treatment had scavenged the free radicals induced by PCBs and protected dopaminergic receptors dysfunction in rat cerebellum.


 

Voluntary exercise promotes beneficial anti-aging mechanisms in SAMP8 female brain.
            (Bayod et al., 2015)  Download
Regular physical exercise mediates health and longevity promotion involving Sirtuin 1 (SIRT1)-regulated pathways. The anti-aging activity of SIRT1 is achieved, at least in part, by means of fine-tuning the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway by preventing the transition of an originally pro-survival program into a pro-aging mechanism. Additionally, SIRT1 promotes mitochondrial function and reduces the production of reactive oxygen species (ROS) through regulating peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), the master controller of mitochondrial biogenesis. Here, by using senescence-accelerated mice prone 8 (SAMP8) as a model for aging, we determined the effect of wheel-running as a paradigm for long-term voluntary exercise on SIRT1-AMPK pathway and mitochondrial functionality measured by oxidative phosphorylation (OXPHOS) complex content in the hippocampus and cortex. We found differential activation of SIRT1 in both tissues and hippocampal-specific activation of AMPK. These findings correlated well with significant changes in OXPHOS in the hippocampal, but not in the cerebral cortex, area. Collectively, the results revealed greater benefits of the exercise in the wheel-running intervention in a murine model of senescence, which was directly related with mitochondrial function and which was mediated through the modulation of SIRT1 and AMPK pathways.

Aging and brain rejuvenation as systemic events.
            (Bouchard and Villeda, 2015)  Download
The effects of aging were traditionally thought to be immutable, particularly evident in the loss of plasticity and cognitive abilities occurring in the aged central nervous system (CNS). However, it is becoming increasingly apparent that extrinsic systemic manipulations such as exercise, caloric restriction, and changing blood composition by heterochronic parabiosis or young plasma administration can partially counteract this age-related loss of plasticity in the aged brain. In this review, we discuss the process of aging and rejuvenation as systemic events. We summarize genetic studies that demonstrate a surprising level of malleability in organismal lifespan, and highlight the potential for systemic manipulations to functionally reverse the effects of aging in the CNS. Based on mounting evidence, we propose that rejuvenating effects of systemic manipulations are mediated, in part, by blood-borne 'pro-youthful' factors. Thus, systemic manipulations promoting a younger blood composition provide effective strategies to rejuvenate the aged brain. As a consequence, we can now consider reactivating latent plasticity dormant in the aged CNS as a means to rejuvenate regenerative, synaptic, and cognitive functions late in life, with potential implications even for extending lifespan. We review evidence of brain rejuvenation focusing on several systemic manipulations - exercise, caloric restriction, heterochronic parabiosis, and young plasma administration - and their ability to restore regenerative capacity, synaptic plasticity, and cognitive function in the brain.

Ascorbic Acid Attenuates Senescence of Human Osteoarthritic Osteoblasts.
(Burger et al., 2017)  Download
The accumulation of senescent cells is implicated in the pathology of several age-related diseases. While the clearance of senescent cells has been suggested as a therapeutic target for patients with osteoarthritis (OA), cellular senescence of bone-resident osteoblasts (OB) remains poorly explored. Since oxidative stress is a well-known inducer of cellular senescence, we here investigated the effect of antioxidant supplementation on the isolation efficiency, expansion, differentiation potential, and transcriptomic profile of OB from osteoarthritic subchondral bone. Bone chips were harvested from sclerotic and non-sclerotic regions of the subchondral bone of human OA joints. The application of 0.1 mM ascorbic acid-2-phosphate (AA) significantly increased the number of outgrowing cells and their proliferation capacity. This enhanced proliferative capacity showed a negative correlation with the amount of senescent cells and was accompanied by decreased expression of reactive oxygen species (ROS) in cultured OB. Expanded cells continued to express differentiated OB markers independently of AA supplementation and demonstrated no changes in their capacity to osteogenically differentiate. Transcriptomic analyses revealed that apoptotic, cell cycle-proliferation, and catabolic pathways were the main pathways affected in the presence of AA during OB expansion. Supplementation with AA can thus help to expand subchondral bone OB in vitro while maintaining their special cellular characteristics. The clearance of such senescent OB could be envisioned as a potential therapeutic target for the treatment of OA.

Resveratrol and cancer: focus on in vivo evidence.
            (Carter et al., 2014)  Download
Resveratrol is a naturally occurring polyphenol that provides a number of anti-aging health benefits including improved metabolism, cardioprotection, and cancer prevention. Much of the work on resveratrol and cancer comes from in vitro studies looking at resveratrol actions on cancer cells and pathways. There are, however, comparatively fewer studies that have investigated resveratrol treatment and cancer outcomes in vivo, perhaps limited by its poor bioavailability when taken orally. Although research in cell culture has shown promising and positive effects of resveratrol, evidence from rodents and humans is inconsistent. This review highlights the in vivo effects of resveratrol treatment on breast, colorectal, liver, pancreatic, and prostate cancers. Resveratrol supplementation in animal models of cancer has shown positive, neutral as well as negative outcomes depending on resveratrol route of administration, dose, tumor model, species, and other factors. Within a specific cancer type, there is variability between studies with respect to strain, age, and sex of animal used, timing and method of resveratrol supplementation, and dose of resveratrol used to study cancer endpoints. Together, the data suggest that many factors need to be considered before resveratrol can be used for human cancer prevention or therapy.

DNA damage, cellular senescence and organismal ageing: causal or correlative
            (Chen et al., 2007)  Download
Cellular senescence has long been used as a cellular model for understanding mechanisms underlying the ageing process. Compelling evidence obtained in recent years demonstrate that DNA damage is a common mediator for both replicative senescence, which is triggered by telomere shortening, and premature cellular senescence induced by various stressors such as oncogenic stress and oxidative stress. Extensive observations suggest that DNA damage accumulates with age and that this may be due to an increase in production of reactive oxygen species (ROS) and a decline in DNA repair capacity with age. Mutation or disrupted expression of genes that increase DNA damage often result in premature ageing. In contrast, interventions that enhance resistance to oxidative stress and attenuate DNA damage contribute towards longevity. This evidence suggests that genomic instability plays a causative role in the ageing process. However, conflicting findings exist which indicate that ROS production and oxidative damage levels of macromolecules including DNA do not always correlate with lifespan in model animals. Here we review the recent advances in addressing the role of DNA damage in cellular senescence and organismal ageing.

Icariin Delays Brain Aging in Senescence-Accelerated Mouse Prone 8 (SAMP8) Model via Inhibiting Autophagy.
            (Chen et al., 2019) Download
Icariin (ICA), a major flavonoid extracted from the Chinese tonic herb Epimedium, exerts beneficial effects in a variety of age-dependent diseases, such as Alzheimer's disease (AD). However, the antiaging mechanisms remain unclear. The senescence-accelerated mouse-prone 8 (SAMP8) model has been used to study age-related neurodegenerative changes associated with aging and the pathogenesis of AD. Hence, the current study was designed to examine the effect of ICA on age-related cognitive decline in SAMP8 mice and explore the role of autophagy in the ICA-mediated neuroprotection. SAMP8 mice were administered with ICA starting at 5 months of age, and the treatment lasted for 3 consecutive months. Morris water maze was used to evaluate cognitive function. The senescence-associated β-galactosidase staining was used to determine the number of senescence cells. The neuronal morphologic changes were examined via Nissl staining. The hippocampal neuronal ultrastructure was examined by transmission electron microscopy. The expression of autophagy protein was examined by Western blot. ICA-treated SAMP8 mice exhibited a robust improvement in spatial learning and memory function. Meanwhile, ICA reduced the number of senescence cells in the brains of SAMP8 mice, inhibited neuronal loss, and reversed neuronal structural changes in the hippocampi of SAMP8 mice. Moreover, ICA treatment also decreased the formation of autophagosomes in the hippocampus of SAMP8 mice, and reduced the expression of autophagy-related proteins LC3-II and p62. These results demonstrate that ICA possesses the ability to delay brain aging in SAMP8 mice, and the mechanisms are possibly mediated through the regulation of autophagy.

Anti-ageing and rejuvenating effects of quercetin.
            (Chondrogianni et al., 2010)  Download
Homeostasis is a key feature of the cellular lifespan. Its maintenance influences the rate of ageing and it is determined by several factors, including efficient proteolysis. The proteasome is the major cellular proteolytic machinery responsible for the degradation of both normal and damaged proteins. Alterations of proteasome function have been recorded in various biological phenomena including ageing and replicative senescence. Proteasome activities and function are decreased upon replicative senescence, whereas proteasome activation confers enhanced survival against oxidative stress, lifespan extension and maintenance of the young morphology longer in human primary fibroblasts. Several natural compounds possess anti-ageing/anti-oxidant properties. In this study, we have identified quercetin (QUER) and its derivative, namely quercetin caprylate (QU-CAP) as a proteasome activator with anti-oxidant properties that consequently influence cellular lifespan, survival and viability of HFL-1 primary human fibroblasts. Moreover, when these compounds are supplemented to already senescent fibroblasts, a rejuvenating effect is observed. Finally, we show that these compounds promote physiological alterations when applied to cells (i.e. whitening effect). In summary, these data demonstrate the existence of naturally occurring anti-ageing products that can be effectively used through topical application.

A hyaluronic acid-based compound inhibits fibroblast senescence induced by oxidative stress in vitro and prevents oral mucositis in vivo.
            (Cirillo et al., 2015) Download
Virtually all patients receiving radio- and chemotherapy for cancer develop oral mucositis, a severe and highly debilitating condition. The onset of mucositis is thought to involve the production of reactive oxygen species (ROS) in the submucosa. Here we investigated a possible protective effect of a commercial formulation of hyaluronic acid (HA) enriched with amino acids (Mucosamin(®)) against the damage induced by oxidative stress both in vitro and in vivo. Transient exposure of normal human oral fibroblasts to hydrogen peroxide (H(2)O(2)) led to irreversible senescence, as demonstrated by sustained increase in the levels of p16(INK4A) and SA-βGal. Conditioned media from senescent fibroblasts induced detrimental effects on keratinocytes, as shown by reduced metabolic activity and migration capability. Pre-treatment with Mucosamin(®) prevented H(2)O(2) -induced, but not TGF-β-induced, fibroblast senescence with a concomitant reduction of fibroblast-induced loss of keratinocyte vitality and functional activity. Finally, data from a case-series of patients undergoing radio/chemotherapy strongly suggested that prophylactic use of the hyaluronic acid-based compound in the form of a spray may be effective in preventing the onset of oral mucositis.

Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity.
            (Conboy et al., 2013)  Download
Pairing two animals in parabiosis to test for systemic or circulatory factors from one animal affecting the other animal has been used in scientific studies for at least 150 years. These studies have led to advances in fields as diverse as endocrinology, immunology, and oncology. A variation on the technique, heterochronic parabiosis, whereby two animals of different ages are joined to test for systemic regulators of aspects of aging or age-related diseases also has almost a century-long scientific history. In this review, we focus on the history of heterochronic parabiosis, methodological considerations and caveats, and the major advances that have emerged from those studies, including recent advances in our understanding of stem cell aging.

Combined oral supplementation of fish oil and quercetin enhances neuroprotection in a chronic rotenone rat model: relevance to Parkinson's disease.
            (Denny Joseph and Muralidhara, 2015)  Download
While the neuromodulatory efficacy of n-3 polyunsaturated fatty acids present in fish and fish oil (FO) are well known, some evidence in animal models suggests that chronic consumption of FO supplements may predispose the brain to lipid peroxidation. In view of this, recent approaches envisage the use of dietary antioxidants as adjuncts with FO to obtain a better clinical outcome in neurological disorders. In furtherance of our previous work, in the present study, we examined whether enrichment of FO with quercetin (Q) would enhance the neuroprotective outcome employing a chronic rotenone (ROT) model of neurotoxicity in rats. Growing male rats supplemented either with FO (2 mL/kg bw) or Q (25 mg/kg bw) or FO + Q for 28 days were administered with ROT (0.5 mg/kg bw, 21 days). Monitoring the behavioral phenotype by a battery of tests, terminally, oxidative response in brain regions, mitochondrial dysfunctions and striatal dopamine levels were determined. While both FO and Q offered varying degree of protection, the FO + Q combination offered a higher degree of protection. FO + Q combination significantly attenuated behavioral impairments, restored the ROT-induced oxidative markers, depleted dopamine levels in striatum and reduced mitochondrial dysfunction. These salient findings besides corroborating with our previous data suggest that enrichment of FO with Q indeed offers a higher degree of neuroprotection under chronic exposure to a model neurotoxin such as ROT. Hence, we propose that a combination of FO with known antioxidants such as quercetin is more likely to provide a superior therapeutic advantage in the prevention/treatment of oxidative stress-mediated neurodegenerative conditions such as Parkinson's disease.

Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study.
            (Egert et al., 2009)  Download
Regular consumption of flavonoids may reduce the risk for CVD. However, the effects of individual flavonoids, for example, quercetin, remain unclear. The present study was undertaken to examine the effects of quercetin supplementation on blood pressure, lipid metabolism, markers of oxidative stress, inflammation, and body composition in an at-risk population of ninety-three overweight or obese subjects aged 25-65 years with metabolic syndrome traits. Subjects were randomised to receive 150 mg quercetin/d in a double-blinded, placebo-controlled cross-over trial with 6-week treatment periods separated by a 5-week washout period. Mean fasting plasma quercetin concentrations increased from 71 to 269 nmol/l (P < 0.001) during quercetin treatment. In contrast to placebo, quercetin decreased systolic blood pressure (SBP) by 2.6 mmHg (P < 0.01) in the entire study group, by 2.9 mmHg (P < 0.01) in the subgroup of hypertensive subjects and by 3.7 mmHg (P < 0.001) in the subgroup of younger adults aged 25-50 years. Quercetin decreased serum HDL-cholesterol concentrations (P < 0.001), while total cholesterol, TAG and the LDL:HDL-cholesterol and TAG:HDL-cholesterol ratios were unaltered. Quercetin significantly decreased plasma concentrations of atherogenic oxidised LDL, but did not affect TNF-alpha and C-reactive protein when compared with placebo. Quercetin supplementation had no effects on nutritional status. Blood parameters of liver and kidney function, haematology and serum electrolytes did not reveal any adverse effects of quercetin. In conclusion, quercetin reduced SBP and plasma oxidised LDL concentrations in overweight subjects with a high-CVD risk phenotype. Our findings provide further evidence that quercetin may provide protection against CVD.

A revival of parabiosis in biomedical research.
            (Eggel and Wyss-Coray, 2014)  Download
Modern medicine wields the power to treat large numbers of diseases and injuries most of us would have died from just a hundred years ago, yet many of the most devastating diseases of our time are still untreatable. Chronic conditions of age such as cardiovascular disease, diabetes, osteoarthritis or Alzheimer's disease turn out to be of a complexity that may require transformative ideas and paradigms to understand and treat them. Parabiosis, which is characterised by a shared blood supply between two surgically connected animals, may just provide such a transformative experimental paradigm. Although forgotten and shunned now in many countries, it has contributed to major breakthroughs in tumour biology, endocrinology and transplantation research in the past century. Interestingly, recent studies from the United States and Britain are reporting stunning advances in stem cell biology and tissue regeneration using parabiosis between young and old mice, indicating a possible revival of this paradigm. We review here briefly the history of parabiosis and discuss its utility to study physiological and pathophysiological processes. We argue that parabiosis is a technique that should enjoy wider acceptance and application, and that policies should be revisited to allow its use in biomedical research.

SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation.
            (Hayakawa et al., 2015)  Download
Senescent cells develop a pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). As many SASP components affect surrounding cells and alter their microenvironment, SASP may be a key phenomenon in linking cellular senesence with individual aging and age-related diseases. We herein demonstrated that the expression of Sirtuin1 (SIRT1) was decreased and the expression of SASP components was reciprocally increased during cellular senescence. The mRNAs and proteins of SASP components, such as IL-6 and IL-8, quickly accumulated in SIRT1-depleted cells, and the levels of these factors were also higher than those in control cells, indicating that SIRT1 negatively regulated the expression of SASP factors at the transcriptional level. SIRT1 bound to the promoter regions of IL-8 and IL-6, but dissociated from them during cellular senescence. The acetylation of Histone H3 (K9) and H4 (K16) of the IL-8 and IL-6 promoter regions gradually increased during cellular senescence. In SIRT1-depleted cells, the acetylation levels of these regions were already higher than those in control cells in the pre-senescent stage. Moreover, these acetylation levels in SIRT1-depleted cells were significantly higher than those in control cells during cellular senescence. These results suggest that SIRT1 repressed the expression of SASP factors through the deacetylation of histones in their promoter regions.


 

References

Ayub, A, N Poulose, and R Raju (2015), ‘Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock.’, Mol Med, 21 305-12. PubMed: 25879628
Bai, L, et al. (2018), ‘Rehmannia glutinosa exhibits anti-aging effect through maintaining the quiescence and decreasing the senescence of hematopoietic stem cells.’, Animal Model Exp Med, 1 (3), 194-202. PubMed: 30891565
Bavithra, S, et al. (2012), ‘Polychlorinated biphenyl (PCBs)-induced oxidative stress plays a critical role on cerebellar dopaminergic receptor expression: ameliorative role of quercetin.’, Neurotox Res, 21 (2), 149-59. PubMed: 21748531
Bayod, S, et al. (2015), ‘Voluntary exercise promotes beneficial anti-aging mechanisms in SAMP8 female brain.’, J Mol Neurosci, 55 (2), 525-32. PubMed: 25027560
Bouchard, J and SA Villeda (2015), ‘Aging and brain rejuvenation as systemic events.’, J Neurochem, 132 (1), 5-19. PubMed: 25327899
Burger, MG, et al. (2017), ‘Ascorbic Acid Attenuates Senescence of Human Osteoarthritic Osteoblasts.’, Int J Mol Sci, 18 (12), PubMed: 29186811
Carter, LG, JA D’Orazio, and KJ Pearson (2014), ‘Resveratrol and cancer: focus on in vivo evidence.’, Endocr Relat Cancer, 21 (3), R209-25. PubMed: 24500760
Chen, FJ, et al. (2019), ‘Icariin Delays Brain Aging in Senescence-Accelerated Mouse Prone 8 (SAMP8) Model via Inhibiting Autophagy.’, J Pharmacol Exp Ther, 369 (1), 121-28. PubMed: 30837279
Chen, JH, CN Hales, and SE Ozanne (2007), ‘DNA damage, cellular senescence and organismal ageing: causal or correlative’, Nucleic Acids Res, 35 (22), 7417-28. PubMed: 17913751
Chondrogianni, N, et al. (2010), ‘Anti-ageing and rejuvenating effects of quercetin.’, Exp Gerontol, 45 (10), 763-71. PubMed: 20619334
Cirillo, N, et al. (2015), ‘A hyaluronic acid-based compound inhibits fibroblast senescence induced by oxidative stress in vitro and prevents oral mucositis in vivo.’, J Cell Physiol, 230 (7), 1421-29. PubMed: 25536474
Conboy, MJ, IM Conboy, and TA Rando (2013), ‘Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity.’, Aging Cell, 12 (3), 525-30. PubMed: 23489470
Denny Joseph, KM and Muralidhara (2015), ‘Combined oral supplementation of fish oil and quercetin enhances neuroprotection in a chronic rotenone rat model: relevance to Parkinson’s disease.’, Neurochem Res, 40 (5), 894-905. PubMed: 25687767
Egert, S, et al. (2009), ‘Quercetin reduces systolic blood pressure and plasma oxidised low-density lipoprotein concentrations in overweight subjects with a high-cardiovascular disease risk phenotype: a double-blinded, placebo-controlled cross-over study.’, Br J Nutr, 102 (7), 1065-74. PubMed: 19402938
Eggel, A and T Wyss-Coray (2014), ‘A revival of parabiosis in biomedical research.’, Swiss Med Wkly, 144 w13914. PubMed: 24496774
Hayakawa, T, et al. (2015), ‘SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation.’, PLoS One, 10 (1), e0116480. PubMed: 25635860