DIFFERENTIAL EFFECTS OF ITP LIFESPAN EXTENSION DRUGS ON ADIPOSE TISSUE INFLAMMATION IN AGING.

The National Institute on Aging-sponsored Interventions Testing Program (ITP) has identified a number of dietary drug interventions that significantly extend median lifespan, including mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition), acarbose, and 17-α estradiol. However, these drugs have diverse downstream targets, and their effects on age-associated organ-specific changes are unclear. Potential mechanisms by which these drugs may be extending life could be through their effect on inflammatory processes often noted in tissues of aging mice and humans. Our study focuses on the effects of three lifespan extension drugs in the ITP on inflammation in gonadal white adipose tissue (gWAT) of female and male UM-HET3 mice. gWAT was harvested to study the drugs’ impact on adipose tissue inflammation—including age-related fat mass gain, adipose tissue macrophage (ATM) M1/M2 polarization, markers of cellular senescence(definition) and endoplasmic reticulum stress. We observe that rapamycin led to a 56% increase of CD45+ leukocytes in gWAT, where the majority of these are macrophages. Specifically, rapamycin led to an 216% and 106% increase of M1 (CD45+CD64+CD206-) macrophages in females and males, respectively. We found that UM-HET3 mice exhibit a spectrum of age-associated changes in the gWAT, but acarbose and 17-α estradiol did not significantly alter these phenotypes. Our data suggest that rapamycin may achieve lifespan extension in part through adipose tissue inflammation. Our data also suggest that acarbose and 17-α estradiol may not influence lifespan through mechanisms involving adipose tissue inflammation.