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Responses to Age-Slowing Interventions Differ by Organ and Gender


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Posted 27 September 2021 - 10:11 AM


Once one starts to investigate, tissue type by tissue type, the effects of interventions known to modestly slow aging, one finds differences. This could be a matter of differences in the biodistribution of a particular therapeutic agent, or it could be that various forms of age-related damage are more or less significant in different organs, or that the regulation of stress responses differs from tissue to tissue, such that some therapeutics target a regulatory pathway more relevant to a kidney than a lung, for example. All of this implies that great deal of work lies ahead, if every potential therapy must be mapped by its effects on every type of tissue in the body, and optimization proceeds tissue type by tissue type.

The ability to study and compare organ aging in the context of organismal aging has recently been documented using a geropathology approach. This concept consists of identifying and grading age-related histopathologic lesions so that a quantitative score is established for each organ allowing for comparison of lesion scores between all organs examined and between all animals in a specific cohort. Therefore, the contribution of each organ to aging can be assessed, in contrast to studying the effect of aging or age-related disease on each organ.

Geropathological interrogation of individual organs provides a powerful look at the morphologic changes associated with increasing age in an organ-dependent manner. For example, based on severity of age-related histopathologic lesion scores, it can be seen that different organs age at different rates with increasing age in C57BL/6 and CB6F1 mice. The heart ages earlier and more rapidly in CB6F1 mice from 8 months to 24 months compared to C57BL/6 mice. Surprisingly, there is no difference in aging of the lungs across this age span in the two strains. For the liver, age-related lesions are seen 8 months earlier in C57BL/6 mice and there is an increase in aging in C57BL/6 mice from 16 to 32 months. The pattern was similar for the kidney, with age-related lesions occurring earliest in C57BL/6 mice at 16 months and then progressing more rapidly.

The second example provides insight into how different organs respond to therapeutic drugs based on changes in severity of lesion scores. Studies with C57BL/6 mice treated for 3 months starting at 20 months of age have shown that organ response based on lesion scores is drug dependent in four major organs- heart, lungs, liver and kidney. For rapamycin, an mTOR inhibitor, kidney, heart and liver were most responsive in males but only kidney was responsive in females using a dose of 14 ppm in the feed. For acarbose, an antidiabetic drug, heart and kidney were most responsive in both genders at a dose of 1000 ppm in the feed. For phenyl butyric acid, an inhibitor of histone deacetylation, lungs and kidney were most responsive in both genders at a dose of 1000 ppm in the feed. In addition, published observations for fisetin, a natural product with senolytic activity, have shown lungs and kidney to be most responsive. It is worth noting that the kidney appears to be less drug dependent, suggesting it might serve as a sentinel organ in drug studies investigating effects on aging, at least in C57BL/6 mice of both genders. These types of observations will be invaluable for helping make decisions on selection of effective drug combinations for aging intervention studies.

Link: https://doi.org/10.15761/JTS.1000458


View the full article at FightAging




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