Sirtuins, bioageing, and cancer

The Sirtuins are a family of orthologues of yeast Sir2 found in a wide range of organisms from bacteria to man. They display a high degree of conservation between species, in both sequence and function, indicative of their key biochemical roles. Sirtuins are heavily implicated in cell cycle, cell division, transcription regulation, and metabolism, which places the various family members at critical junctures in cellular metabolism. Typically, Sirtuins have been implicated in the preservation of genomic stability and in the prolongation of lifespan though many of their target interactions remain unknown. Sirtuins play key roles in tumourigenesis, as some have tumour-suppressor functions and others influence tumours through their control of the metabolic state of the cell. Their links to ageing have also highlighted involvement in various age-related and degenerative diseases. Here, we discuss the current understanding of the role of Sirtuins in age-related diseases while taking a closer look at their roles and functions in maintaining genomic stability and their influence on telomerase and telomere function

Has the expansion in extended criteria deceased donors led to a different type of delayed graft function and poorer outcomes?

Objectives: There has been considerable change in the practice of deceased kidney transplantation in the past 15 years, with more extreme phenotypes implanted. The aim of this study was to determine whether increased use of expanded criteria donors (extended criteria donors and donors after circulatory death) affected clinical outcomes, including the incidence and pattern of delayed graft function. Methods and materials: A retrospective analysis of 1359 renal transplants was performed over 15 years. The first 10 years of data (group 1) were compared with the subsequent 5 years (group 2). Outcomes were analyzed at 6 months and 12 months in addition to serum creatinine and patterns of delayed graft function (posttransplant times: on hemodialysis, to peak creatinine, for creatinine to half, and for creatinine to fall within 10% of baseline). Results: There was a significant increase in the percentage of expanded criteria donor allografts used in group 2 with a significant increase in the incidence of delayed graft function. Despite this, serum creatinine and the incidence of biopsy-proven acute rejection had both improved in group 2. Group 2 expanded criteria donor kidneys had a significantly lower incidence of type 1 delayed graft function and a significantly higher incidence of types 3 and 4 delayed graft function. Time for creatinine to half in both groups was the best predictor of a serum creatinine <180 μmol/L at 1 year. Conclusion: The increased use of expanded criteria donor kidneys has led to a higher incidence of delayed graft function, but the pattern has shown that the requirement for hemodialysis has significantly reduced

Klotho, ageing and the failing kidney

Klotho has been recognised as a gene involved in the ageing process in mammals for over thirty years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α -Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian ageing and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of ageing; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of ageing

Innovations conceptuelles et technologieques a l'aube du trosième millenaire

No abstract available