Most organ transplantations involve supply from older donors to younger recipients. Aging cells can become senescent, a condition in which they stop multiplying and secrete chemicals that negatively affect neighboring cells. Senescent cells accumulate in older donor organs, and have the potential to compromise transplant outcomes.
A study led by researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, found that in preclinical models, transplanting older organs can trigger senescence in younger recipients. They observed that young and middle-aged mice that received heart transplants from older mice had impaired physical capacity, with reduced running times and grip strengths. Middle-aged mice who received older hearts also showed increased anxiety-related behavior, impaired memory and poorer learning performances.
The authors found that these accelerated aging-related effects in younger recipients were driven by the release of senescence-associated factors and mitochondrial DNA from older transplants. Treating older donor mice with senolytics, or senescence-inhibiting drugs, before organ extraction reduced symptoms of senescence in the recipient mice.
“Currently, due to insufficient supply in clinical organ transplantation, donor and recipient ages differ substantially,” said principal investigator Stefan G. Tullius, MD, PhD, of the Division of Transplant Surgery. “Our results suggest that senolytic treatments can be a potential therapeutic approach for improving the outcomes of older organs.”
Read more in American Journal of Transplantation.
 

Cell-Type-Specific Genetic Risk Contributes to Distinct Stages of Alzheimer’s Disease Progression

Hyun-Sik Yang

Developing treatments for Alzheimer’s disease (AD) is difficult because complex underlying mechanisms drive different types of cells that may contribute to the disorder. Microglia and astrocytes, resident immune and support cells in the central nervous system, are known to exclusively express several genes linked to risk of AD — particularly AD dementia. However, it was previously unclear exactly how and when these genetic risk factors contributed to other, distinct stages of AD progression, such as the accumulation of amyloid-β plaques and tau tangles.
Researchers led by a team at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, identified the impact of AD genetic risk specific to each major brain cell type on key disease processes. They implemented single nucleus RNA sequencing to calculate cell-type-specific AD polygenic risk scores from two large clinical research study datasets.
Using autopsy data spanning all stages of disease severity, along with independent neuroimaging data from asymptomatic, preclinical stages of AD, the investigators were able to characterize the contributions of cell-specific risk genes. Astrocyte-specific genetic risk contributed to earlier stages of disease progress, like amyloid-β accumulation, while microglia-specific risk played a part in later phases of plaque and tau tangle accumulation, and cognitive decline.
“Our results provide human evidence for how genetic risk in specific brain cells affects AD processes, some even before the onset of clinical symptoms.,” said Hyun-Sik Yang, MD, of the Department of Neurology. “Future studies could extend our technique to other aspects of AD or even other diseases, in order to help develop targeted treatments.”


This content is taken from Brigham and Women's Hospital

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"Older Organs Accelerate Aging in Transplant Recipients", MachPrinciple, December 08, 2023, https://machprinciple.com/post/Older-Organs-Accelerate-Aging-in-Transplant-Recipients