Effect of Chronic Polypharmacy and the Drug Burden Index (Dbi) on Physical Function in Aged Mice

Abstract

predictors of performance on a proxy version of the Minicog, a screening tool for cognitive impairment, assessed at age 60. We additionally tested general cognitive ability assessed at age 50 as a potential mediator of associations between childhood personality and Mini-cog scores. These are some of the first data available to test associations between personality in childhood and cognitive outcomes decades later in adulthood. The sample was comprised of 330 participants (52% women) who completed half day clinic exams at average age 50 and again at age 60. Childhood personality traits were assessed at average age 10 using teacher ratings of personality. General cognitive ability was measured at average age 50 using the Woodcock-Johnson Brief Abilities Inventory (BIA). At age 60, participants completed a clock drawing task and the Hopkins Verbal Learning Task (HVLT-R). These were used to construct a proxy Mini-cog. Partial correlations controlling for age and gender showed that childhood Conscientiousness (r = -.13), Intellect/Openness (r = -.12), and Agreeableness (r = .12) were associated with Mini-cog scores. In path analyses testing age 50 cognitive ability as a mediator of these effects, both childhood Intellect/Openness and Conscientiousness showed indirect effects through age 50 cognitive ability on Mini-cog performance at age 60. Childhood Agreeableness maintained an independent association with Min-cog scores, not mediated by adult cognitive ability. We discuss possible mechanisms that may account for the observed associations. In mitotic cells, senescence and apoptosis occur in response to certain stressors (e.g., aging). However, in postmitotic cells, such as multinucleated skeletal muscle myofibers the extent to which cellular senescence and apoptosis occurs is largely unknown. Therefore, the purpose of this study was to explore the role of senescence and apoptosis as drivers of age-associated sarcopenia. We hypothesized that biomarkers of senescence and apoptosis would increase in aging skeletal myofibers and that these changes would be associated with sarcopenia. To identify biomarkers of senescence and apoptosis, the extensor digitorum longus (EDL) and tibialis anterior (TA) muscles were examined from adult (<12 months, N=11) and elderly (>28 months, N=11) male C57BL/6 mice. The EDL was used to assess ex vivo whole muscle physiology while the TA was used to determine protein content (p53, p21, p16, caspase 3, and IL-6) and presence of SA ß-gal and Tunnel via histological staining. Muscle wet weight and absolute force production were significantly reduced in the elderly mice. Aging significantly increased p21, IL-6, and caspase 3 content; however, did not appear to impact p53 nor p16 expression. Myofibers of elderly mice had an increase of apoptotic myonuclei, but only presented a small percentage of SA ß-gal. Taken together, biomarkers of cellular senescence and apoptosis are present in muscle of elderly mice. Because p21, IL-6, caspase 3, and apoptotic cells were increased in the elderly muscle it...