Metformin alleviates stress-induced cellular senescence of aging human adipose stromal cells and the ensuing adipocyte dysfunction

Aging is associated with central fat redistribution and insulin resistance. To identify age-related adipose features, we evaluated the senescence and adipogenic potential of adipose-derived-stromal cells (ASCs) from abdominal subcutaneous fat obtained from healthy normal-weight young (<25y) or older women (>60y). Increased cell passages of young-donor ASCs (in vitro aging), resulted in senescence but not oxidative stress. ASC-derived adipocytes presented impaired adipogenesis but no early mitochondrial dysfunction. Conversely, aged-donor ASCs at early passages displayed oxidative stress and mild senescence. ASC-derived adipocytes exhibited oxidative stress, and early mitochondrial dysfunction but adipogenesis was preserved. In vitro aging of aged-donor ASCs resulted in further increased senescence, mitochondrial dysfunction, oxidative stress and severe adipocyte dysfunction. When in vitro aged young-donor ASCs were treated with metformin, no alteration was alleviated. Conversely, metformin treatment of aged-donor ASCs decreased oxidative stress and mitochondrial dysfunction resulting in decreased senescence. Metformin's prevention of oxidative stress and of the resulting senescence improved the cells' adipogenic capacity and insulin sensitivity. This effect was mediated by the activation of AMP-activated-protein-kinase as revealed by its specific inhibition and activation. Overall, aging ASC-derived adipocytes presented impaired adipogenesis and insulin sensitivity. Targeting stress-induced senescence of ASCs with metformin may improve age-related adipose tissue dysfunction.

Metformin alleviates aging-associated cellular senescence of human adipose stem cells and derived adipocytes

SUMMARYAging is associated with central fat redistribution, and insulin resistance. To identify age-related adipose features, we evaluated the senescence and adipogenic potential of adipose-derived-stemcells (ASCs) from abdominal subcutaneous fat obtained from healthy normal-weight young (<25y) or older women (>60y).Aged-donor ASCs showed more intense features of aging (senescence, mitochondrial dysfunction, and oxidative stress) than young-donor ASCs. Oxidative stress and mitochondrial dysfunction occurred earlier in adipocytes derived from aged-donor than from young-donor ASCs, leading to insulin resistance and impaired adipogenesis.When aged-donor ASCs were treated with metformin, senescence, oxidative stress and mitochondrial dysfunction returned to the levels observed in young-donor ASCs. Furthermore, metformin’s prevention of senescence and dysfunction during ASC proliferation restored the cells’ adipogenic capacity and insulin sensitivity. This effect was mediated by the activation of AMP-activated-protein-kinase.We show here that targeting senescent ASCs from aged women with metformin may alleviate age-related dysfunction, insulin resistance, and impaired adipogenesis.

P1716MULTI-NATIONAL SURVEY AMONG NEPHROLOGISTS & TRANSPLANT SURGEONS ABOUT THE SUITABILITY & ACCEPTANCE OF MARGINAL LIVE KIDNEY DONORS REGARDING AGE DISCREPANCY

Background and Aims Living donor kidney transplantation is the best option for patients on dialysis. There are no guidelines or generally accepted consensus about the acceptable kidney donor age and what is the acceptable donor-recipient age discrepancy. Method This is a cross sectional survey of nephrologists and transplant surgeons about acceptable age of living kidney donors. The survey was sent to participants in different countries and through AST and ERA/EDTA. Results 122 respondents from 22 countries answered 4 questions related to donor age. Most respondents (N=86, 70%) would allow an 18-years old man to donate to his older sibling. However, this percentage would fall to (N=69, 57%) if the donor was an 18-years old woman (P=0.02), reflecting the impact of childbearing period as a major criterion in considering kidney donation. On the opposite side, up to 20% of respondents will decline a very young donor regardless of the gender of the donor. The acceptance rate of a very young donor drops to only 37% if the recipient is 75-year-old (versus 70% in case of younger recipient, P = 0.004). In case of old donor( &gt; 65 years old) old to an 18 year old recipient with expected prolonged waiting time for deceased donor, ( N= 80, 65%) will advise to find an alternative donor but will allow the donation if no alternative donor is available. Conclusion The majority of the nephrologists and transplant surgeons will allow a very young donor to donate to a sibling especially if the donor is a male. However up to 20% will decline this donation regardless of the gender of the donor. The transplant community is divided about allowing a very young donor to donate to a very old recipient. However, the majority will accept &gt; 65 years old donor to donate to an 18 years old recipient with expected prolonged waiting time for deceased donor.

Myocardial bridging in the era of a drug epidemic: a case report addressing the need to revisit donor organ assessment

Background Myocardial bridging (MB), though typically a benign finding, may occasionally lead to syncope, myocardial infarction, arrhythmia, or sudden death. Surgical denervation of transplanted hearts complicates the management of such incidentally detected post-transplant coronary anomalies due to the lack of classic ischaemic symptoms. Case summary A middle-aged female underwent an uncomplicated cardiac transplantation from a healthy male donor in his early 20s who had suffered a cardiac arrest while using cocaine. Given the young donor age, a pre-transplant coronary angiogram (CAG) was deferred. However, 6-week post-transplant, routine CAG, and intravascular ultrasound revealed an extensive MB spanning a significant portion of the left anterior descending coronary artery with substantial myocardium at risk. A stress test with myocardial perfusion imaging performed to evaluate the functional significance of the bridge did not reveal any perfusion abnormalities in the myocardium at risk. Discussion In current practice, younger donors often do not undergo pre-transplantation CAG routinely performed in older donors given the lower prevalence of significant coronary disease. However, post-operatively this young donor was found to have passed on a potentially life-threatening MB to a denervated recipient, who cannot manifest typical anginal symptoms during ischaemia, thereby challenging providers to choose among strategies of watchful waiting, risk stratification, or pre-emptive intervention. In retrospect, the donor’s mode of death may have signalled an underlying structural abnormality that warranted further pre-transplant characterization. In order to ensure optimal quality of transplanted hearts, young donors may warrant pre-transplant CAG despite their age, particularly those with a history of drug use or suspicious mode of death.