The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism.

Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism.

Epigenetic clocks indicate that kidney transplantation and not dialysis mitigate the effects of renal ageing.

BACKGROUND: Chronic kidney disease (CKD) is an age-related disease that displays multiple features of accelerated ageing. It is currently unclear whether the two treatment options for end-stage kidney disease (dialysis and kidney transplantation [KT]) ameliorate the accelerated uremic ageing process. METHODS: Data on clinical variables and blood DNA methylation (DNAm) from CKD stage G3-G5 patients were used to estimate biological age based on blood biomarkers (phenotypic age [PA], n = 333), skin autofluorescence (SAF age, n = 199) and DNAm (Horvath, Hannum and PhenoAge clocks, n = 47). In the DNAm cohort, we also measured the change in biological age 1 year after the KT or initiation of dialysis. Healthy subjects recruited from the general population were included as controls. RESULTS: All three DNAm clocks indicated an increased biological age in CKD G5. However, PA and SAF age tended to produce implausibly large estimates of biological age in CKD G5. By contrast, DNAm age was 4.9 years (p = 0.005) higher in the transplantation group and 5.9 years (p = 0.001) higher in the dialysis group compared to controls. This age acceleration was significantly reduced 1 year after KT, but not after 1 year of dialysis. CONCLUSIONS: Kidney failure patients displayed an increased biological age as estimated by DNAm clocks compared to population-based controls. Our results suggest that KT, but not dialysis, partially reduces the age acceleration.

Child maltreatment and telomere length in middle and older age: retrospective cohort study of 141 748 UK Biobank participants.

BACKGROUND: There is evidence that child maltreatment is associated with shorter telomere length in early life. AIMS: This study aims to examine if child maltreatment is associated with telomere length in middle- and older-age adults. METHOD: This was a retrospective cohort study of 141 748 UK Biobank participants aged 37-73 years at recruitment. Leukocyte telomere length was measured with quantitative polymerase chain reaction, and log-transformed and scaled to have unit standard deviation. Child maltreatment was recalled by participants. Linear regression was used to analyse the association. RESULTS: After adjusting for sociodemographic characteristics, participants with three or more types of maltreatment presented with the shortest telomere lengths (ß = -0.05, 95% CI -0.07 to -0.03; P < 0.0001), followed by those with two types of maltreatment (ß = -0.02, 95% CI -0.04 to 0.00; P = 0.02), referent to those who had none. When adjusted for depression and post-traumatic stress disorder, the telomere lengths of participants with three or more types of maltreatment were still shorter (ß = -0.04, 95% CI -0.07 to -0.02; P = 0.0008). The telomere lengths of those with one type of maltreatment were not significantly different from those who had none. When mutually adjusted, physical abuse (ß = -0.05, 95% CI -0.07 to -0.03; P < 0.0001) and sexual abuse (ß = -0.02, 95% CI -0.04 to 0.00; P = 0.02) were independently associated with shorter telomere length. CONCLUSIONS: Our findings showed that child maltreatment is associated with shorter telomere length in middle- and older-aged adults, independent of sociodemographic and mental health factors.

A normative microbiome is not restored following kidney transplantation.

Dialysis and kidney transplantation (Ktx) mitigate some of the physiological deficits in chronic kidney disease (CKD), but it remains to be determined if these mitigate microbial dysbiosis and the production of inflammatory microbial metabolites, which contribute significantly to the uraemic phenotype. We have investigated bacterial DNA signatures present in the circulation of CKD patients and those receiving a KTx. Our data are consistent with increasing dysbiosis as CKD progresses, with an accompanying increase in trimethylamine (TMA) producing pathobionts Pseudomonas and Bacillus. Notably, KTx patients displayed a significantly different microbiota compared with CKD5 patients, which surprisingly included further increase in TMA producing Bacillus and loss of salutogenic Lactobacilli. Only two genera (Viellonella and Saccharimonidales) showed significant differences in abundance following KTx that may reflect a reciprocal relationship between TMA producers and utilisers, which supersedes restoration of a normative microbiome. Our metadata analysis confirmed that TMA N-oxide (TMAO) along with one carbon metabolism had significant impact upon both inflammatory burden and the composition of the microbiome. This indicates that these metabolites are key to shaping the uraemic microbiome and might be exploited in the development of dietary intervention strategies to both mitigate the physiological deficits in CKD and enable the restoration of a more salutogenic microbiome.

Planetary Health, Nutrition, and Chronic Kidney Disease: Connecting the Dots for a Sustainable Future.

The increasing consumption of ultra-processed food (UPF) and the global chain of food production have a negative impact on human health and planetary health. These foods have been replacing the consumption of nonprocessed healthy foods. This shift has not only worsened human health by increasing the risk of the development of noncommunicable diseases, but also resulted in environmental perturbations. This review aims to bring awareness of the problems caused by the industrialized food production chain, addressing the negative effects it has on the environment and human health, with special reference to chronic kidney disease (CKD). We discuss possible solutions focusing on the benefits of adopting plant-based diets with low UPF content to promote a sustainable and healthy food production and diet for patients with CKD. For a sustainable future we need to "connect the dots" of planetary health, food production, and nutrition in the context of CKD.

Lessons from evolution by natural selection: An unprecedented opportunity to use biomimetics to improve planetary health.

Planetary health embraces the concept that long-term human welfare depends on the well-being of its ecological systems. Current practices, however, have often ignored this concept and have led to an anthropocentric world, with the consequence of increased greenhouse gas emissions, heat stress, lack of clean water and pollution, that are threatening the environment as well as the health and life of Homo sapiens and many other species. One consequence of environmental stressors has been the stimulation of inflammatory and oxidative stress that may not only promote common lifestyle diseases, but the ageing process. Despite the harshness of the current reality, treatment opportunities may exist 'in our backyard'. Biomimicry is an emerging field of research that explores how nature is structured and aims to mimic ingenious solutions that have evolved in nature for different applications that benefit human life. As nature always counteracts excesses from within, biodiversity could be a source of solutions that have evolved through the natural selection of animal species that have survived polluted, warm, and arid environments - i.e. the same presumptive changes that now threaten human health. One example from the emerging science suggests that animals use the cytoprotective Nrf2 antioxidant pathway to combat environmental stress and this may be a case example that we can apply to better human health. Learning from nature may provide opportunities for environmental management and solutions to the most challenging issue that face the future of the planet.

Food for healthier aging: power on your plate.

Inflammageing is a persistent low-level inflammatory burden that accompanies age-related dysregulation of the immune system during normative aging and within the diseasome of aging. A healthy diet containing a balanced amount of macronutrients, vitamins and minerals, adequate in calories and rich in poly(phenols), has an essential role in mitigating the effects of inflammageing and extending healthspan through modulation of the activity of a range of factors. These include transcription factors, such as nuclear factor erythroid-derived 2 related factor 2 (Nrf2) and nuclear factor-κB (NF-kB), the inflammasome and the activities of the gut microbiota. The aim of this narrative review is to discuss the potential of food to ameliorate the effects of the diseasome of aging.

The magical smell and taste: Can coffee be good to patients with cardiometabolic disease?

Coffee is a beverage consumed globally. Although few studies have indicated adverse effects, it is typically a beneficial health-promoting agent in a range of diseases, including depression, diabetes, cardiovascular disease, and obesity. Coffee is rich in caffeine, antioxidants, and phenolic compounds, which can modulate the composition of the gut microbiota and mitigate both inflammation and oxidative stress, common features of the burden of lifestyle diseases. This review will discuss the possible benefits of coffee on complications present in patients with diabetes, cardiovascular disease and chronic kidney disease, outwith the social and emotional benefits attributed to caffeine consumption.

Manipulating the exposome to enable better ageing.

The sum total of life course exposures creates an exposome that has a significant impact on age-related health. Understanding the interplay between exposome factors and the (epi) genome, offers pertinent insights into the ageing process and its relationship with the accumulation of allostatic load. We propose to exploit this to develop a biomimetic approach that will provide insight into how evolution through natural selection in other species has solved many age related human health issues. In particular, we will emphasise the need to reconnect a more mechanistic approach to medical science with a broader natural sciences approach, using biomimetics to mitigate the global burden of age related ill health. In particular, we will discuss how such an approach indicates leverage of the activities of the Nrf 2 gene to enhance health span via reintroduction of the classical 'Food as Medicine' concept, including modulation of the microbiome and the creation of more salutogenic and biophilic environments. Additionally, we will discuss how this approach integrates with novel and developing senotherapies.

Archaea from the gut microbiota of humans: Could be linked to chronic diseases?

Archaea comprise a unique domain of organisms with distinct biochemical and genetic differences from bacteria. Methane-forming archaea, methanogens, constitute the predominant group of archaea in the human gut microbiota, with Methanobrevibacter smithii being the most prevalent. However, the effect of methanogenic archaea and their methane production on chronic disease remains controversial. As perturbation of the microbiota is a feature of chronic conditions, such as cardiovascular disease, neurodegenerative diseases and chronic kidney disease, assessing the influence of archaea could provide a new clue to mitigating adverse effects associated with dysbiosis. In this review, we will discuss the putative role of archaea in the gut microbiota in humans and the possible link to chronic diseases.

The oxygen cascade in patients treated with hemodialysis and native high-altitude dwellers: lessons from extreme physiology to benefit patients with end-stage renal disease.

Patients treated with hemodialysis (HD) repeatedly undergo intradialytic low arterial oxygen saturation and low central venous oxygen saturation, reflecting an imbalance between upper body systemic oxygen supply and demand, which are associated with increased mortality. Abnormalities along the entire oxygen cascade, with impaired diffusive and convective oxygen transport, contribute to the reduced tissue oxygen supply. HD treatment impairs pulmonary gas exchange and reduces ventilatory drive, whereas ultrafiltration can reduce tissue perfusion due to a decline in cardiac output. In addition to these factors, capillary rarefaction and reduced mitochondrial efficacy can further affect the balance between cellular oxygen supply and demand. Whereas it has been convincingly demonstrated that a reduced perfusion of heart and brain during HD contributes to organ damage, the significance of systemic hypoxia remains uncertain, although it may contribute to oxidative stress, systemic inflammation, and accelerated senescence. These abnormalities along the oxygen cascade of patients treated with HD appear to be diametrically opposite to the situation in Tibetan highlanders and Sherpa, whose physiology adapted to the inescapable hypobaric hypoxia of their living environment over many generations. Their adaptation includes pulmonary, vascular, and metabolic alterations with enhanced capillary density, nitric oxide production, and mitochondrial efficacy without oxidative stress. Improving the tissue oxygen supply in patients treated with HD depends primarily on preventing hemodynamic instability by increasing dialysis time/frequency or prescribing cool dialysis. Whether dietary or pharmacological interventions, such as the administration of L-arginine, fermented food, nitrate, nuclear factor erythroid 2-related factor 2 agonists, or prolyl hydroxylase 2 inhibitors, improve clinical outcome in patients treated with HD warrants future research.

A biomimetic natural sciences approach to understanding the mechanisms of ageing in burden of lifestyle diseases.

The worldwide landscape of an ageing population and age-related disease brings with it huge socio-economic and public healthcare concerns across nations. Correspondingly, monumental human and financial resources have been invested in biomedical research, with a mission to decode the mechanisms of ageing and how these contribute to age-related disease. Multiple hallmarks of ageing have been identified that are common across taxa, highlighting their fundamental importance. These include dysregulated mitochondrial metabolism and telomeres biology, epigenetic modifications, cell-matrix interactions, proteostasis, dysregulated nutrient sensing, stem cell exhaustion, inflammageing and immuno-senescence. While our understanding of the molecular basis of ageing is improving, it remains a complex and multifactorial process that remains to be fully understood. A key aspect of the shortfall in our understanding of the ageing process lies in translating data from standard animal models to humans. Consequently, we suggest that a 'biomimetic' and comparative approach, integrating knowledge from species in the wild, as opposed to inbred genetically homogenous laboratory animals, can provide powerful insights into human ageing processes. Here we discuss some particularities and comparative patterns among several species from the animal kingdom, endowed with longevity or short lifespans and unique metabolic profiles that could be potentially exploited to the understanding of ageing and age-related diseases. Based upon lessons from nature, we also highlight several avenues for renewed focus in the pathophysiology of ageing and age-related disease (i.e. diet-microbiome-health axis, oxidative protein damage, adaptive homoeostasis and planetary health). We propose that a biomimetic alliance with collaborative research from different disciplines can improve our understanding of ageing and age-related diseases with long-term sustainable utility.

Early vascular ageing in chronic kidney disease: impact of inflammation, vitamin K, senescence and genomic damage.

Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by cardiovascular disease, persistent uraemic inflammation, osteoporosis muscle wasting and frailty. The accelerated early vascular ageing (EVA) process mediated by medial vascular calcification (VC) is a hallmark of senescence as well as a strong predictor of cardiovascular morbidity and mortality in the CKD population. Current clinical therapeutic strategies and novel treatments for VC have not yet been proven to prevent or reverse VC progression in patients with CKD. Knowledge of the fundamental mechanism underlying EVA is urgently needed to identify and develop novel and efficient therapeutic targets for VC and EVA. An accumulating body of evidence indicates that deoxyribonucleic acid (DNA) damage-induced cellular senescence and 'inflammaging' may largely contribute to such pathological conditions characterized by accelerated EVA. Growing evidence shows that nuclear factor erythroid 2-related factor 2 (NRF2) signalling and vitamin K play a crucial role in counteracting oxidative stress, DNA damage, senescence and inflammaging, whereby NRF2 activation and vitamin K supplementation may provide a novel treatment target for EVA. In this review we discuss the link between senescence and EVA in the context of CKD, with a focus on the role of NRF2 and vitamin K in DNA damage signalling, senescence and inflammaging.

Understanding the role of the cytoprotective transcription factor nuclear factor erythroid 2-related factor 2-lessons from evolution, the animal kingdom and rare progeroid syndromes.

The cytoprotective transcriptor factor nuclear factor erythroid 2- related factor 2 (NRF2) is part of a complex regulatory network that responds to environmental cues. To better understand its role in a cluster of inflammatory and pro-oxidative burden of lifestyle diseases that accumulate with age, lessons can be learned from evolution, the animal kingdom and progeroid syndromes. When levels of oxygen increased in the atmosphere, mammals required ways to protect themselves from the metabolic toxicity that arose from the production of reactive oxygen species. The evolutionary origin of the NRF2-Kelch-like ECH-associated protein 1 (KEAP1) signalling pathway from primitive origins has been a prerequisite for a successful life on earth, with checkpoints in antioxidant gene expression, inflammation, detoxification and protein homoeostasis. Examples from the animal kingdom suggest that superior antioxidant defense mechanisms with enhanced NRF2 expression have been developed during evolution to protect animals during extreme environmental conditions, such as deep sea diving, hibernation and habitual hypoxia. The NRF2-KEAP1 signalling pathway is repressed in progeroid (accelerated ageing) syndromes and a cluster of burden of lifestyle disorders that accumulate with age. Compelling links exist between tissue hypoxia, senescence and a repressed NRF2 system. Effects of interventions that activate NRF2, including nutrients, and more potent (semi)synthetic NRF2 agonists on clinical outcomes are of major interest. Given the broad-ranging actions of NRF2, we need to better understand the mechanisms of activation, biological function and regulation of NRF2 and its inhibitor, KEAP1, in different clinical conditions to ensure that modulation of this thiol-based system will not result in major adverse effects. Lessons from evolution, the animal kingdom and conditions of accelerated ageing clarify a major role of a controlled NRF2-KEAP1 system in healthy ageing and well-being.

Adverse childhood experiences, epigenetics and telomere length variation in childhood and beyond: a systematic review of the literature.

A systematic review following PRISMA guidelines was conducted to answer the question: What epigenetic, telomeric and associated biological changes are associated with exposure to adverse childhood experiences (ACEs) in the under 12s? Using PRISMA guidelines, appropriate databases were searched. 190 papers were returned with 38 articles fully reviewed. Articles were each independently quality rated by two authors using the Crowe Critical Appraisal Tool and data were extracted. Of the 38 articles, 23 were rated as very high quality. Most study participants were adults (n = 7769) with n = 727 child participants. Only seven of the very/high-quality studies were prospective and involved children. Methylation was the most studied method of epigenetic modification. There is some evidence supporting epigenetic modification of certain markers in participants exposed to ACEs measured in adulthood. Research is lacking on non-coding aspects of the epigenome and on coding aspects other than DNA methylation. There is some evidence of a more powerful effect on telomere length if physical neglect was involved. Much further work is required to model biological and psychological effects of epigenetic changes during childhood using prospective study designs. The effect of ACEs on the cellular ageing process during childhood is inadequately investigated and relies solely on measure of telomere length. Future research suggestions are proposed.

The Neglectable Impact of Delayed Graft Function on Long-term Graft Survival in Kidneys Donated After Circulatory Death Associates With Superior Organ Resilience.

OBJECTIVE: To explore putative different impacts of delayed graft function (DGF) on long-term graft survival in kidneys donated after brain death (DBD) and circulatory death (DCD). BACKGROUND: Despite a 3-fold higher incidence of DGF in DCD grafts, large studies show equivalent long-term graft survival for DBD and DCD grafts. This observation implies a differential impact of DGF on DBD and DCD graft survival. The contrasting impact is remarkable and yet unexplained. METHODS: The impact of DGF on DBD and DCD graft survival was evaluated in 6635 kidney transplants performed in The Netherlands. DGF severity and functional recovery dynamics were assessed for 599 kidney transplants performed at the Leiden Transplant Center. Immunohistochemical staining, gene expression profiling, and Ingenuity Pathway Analysis were used to identify differentially activated pathways in DBD and DCD grafts. RESULTS: While DGF severely impacted 10-year graft survival in DBD grafts (HR 1.67; P < 0.001), DGF did not impact graft survival in DCD grafts (HR 1.08; P = 0.63). Shorter dialysis periods and superior posttransplant eGFRs in DBD grafts show that the differential impact was not caused by a more severe DGF phenotype in DBD grafts. Immunohistochemical evaluation indicates that pathways associated with tissue resilience are present in kidney grafts. Molecular evaluation showed selective activation of resilience-associated pathways in DCD grafts. CONCLUSIONS: This study shows an absent impact of DGF on long-term graft survival in DCD kidneys. Molecular evaluation suggests that the differential impact of DGF between DBD and DCD grafts relates to donor-type specific activation of resilience pathways in DCD grafts.

Long-lived animals with negligible senescence: clues for ageing research.

Among several theories to explain the complicated process of human ageing, the mitochondrial oxidative stress hypothesis has received recent attention. Considering that lifespan and ageing rates vary considerably across taxa, a better understanding of factors that lead to negligible or extremely rapid senescence in mammals may generate novel approaches to target human ageing. Several species, such as naked mole rats, ocean quahog, rockfish and Greenland shark, have been identified that exhibit negligible senescence and superior resistance to age-related diseases. Considering that the available literature suggests that their outstanding stress resistance is linked to maintenance of protein homeostasis and robust mitochondrial functions, treatments that target protein modification and upregulation of matrix antioxidants may have implications for extending human health span.

Allostatic load and ageing: linking the microbiome and nutrition with age-related health.

Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome.Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the 'diseasome' of ageing. Additionally, it can be influenced by the 'foodome', via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

Methyl Donor Nutrients in Chronic Kidney Disease: Impact on the Epigenetic Landscape.

Epigenetic alterations, such as those linked to DNA methylation, may potentially provide molecular explanations for complications associated with altered gene expression in illnesses, such as chronic kidney disease (CKD). Although both DNA hypo- and hypermethylation have been observed in the uremic milieu, this remains only a single aspect of the epigenetic landscape and, thus, of any biochemical dysregulation associated with CKD. Nevertheless, the role of uremia-promoting alterations on the epigenetic landscape regulating gene expression is still a novel and scarcely studied field. Although few studies have actually reported alterations of DNA methylation via methyl donor nutrient intake, emerging evidence indicates that nutritional modification of the microbiome can affect one-carbon metabolism and the capacity to methylate the genome in CKD. In this review, we discuss the nutritional modifications that may affect one-carbon metabolism and the possible impact of methyl donor nutrients on the microbiome, CKD, and its phenotype.