SEX DIMORPHISM IN AGING

Abstract In this symposium, the speakers will discuss how sex can influence aging trajectories using complementary perspectives and approaches across multiple biological scales and systems. Indeed, accumulating evidence across species has revealed that aging is a highly sex-dimorphic process. On the one hand, women outlive men consistently across populations, and most supercentanarians are women. On the other hand, especially after the onset of menopause, women are at increased risk for most age-related diseases (e.g. Alzheimer’s disease, osteoporosis, etc.). However, the molecular pathways underlying such sex-differences in aging and longevity are still largely unexplored and poorly understood. Dr. Austad will discuss how compatibility between the mitochondrial and nuclear genomes during aging is influenced as a function of sex. Dr. Dubal will discuss the impact of sex chromosome complement on cognition with aging in mouse models, and how sex chromosomes may underlie sex-differences in brain aging. Dr. Ucar will discuss work from her lab revealing that the genomic signatures of immune aging in humans are specific to sex. Finally, Dr. Benayoun will discuss how aging of innate immune cells (e.g. macrophages or neutrophils) is regulated by the female vs. male milieu, with sex-specific age-related trajectories remodeling the immune compartment in mice.

Motor vehicle crashes are a leading cause of injury and death for older adults in the United States. Braking reaction time (BRT), how quickly a driver responds to the situational demands of driving, is a known predictor of driver fitness and hypothesized as sensitive to difficulties with executive functioning. Unclear is how BRT may vary across different levels of executive functioning, including objective test performance and perceived executive dysfunction, and if awareness of executive dysfunction in the presence of objective difficulties jointly predicts BRT. Using data from a simulated driving study, 50 adults aged 65-94 years old (49.1% female) completed computerized EF tests (inhibition [Stroop], working memory [Automated Operation Span]), the Behavior Rating Inventory of Executive Function, the Big Five Inventory, and a simulated drive. Multilevel modeling analyses controlling for covariates of empirical and design relevance (simulated road segment, age, gender, and neuroticism) were performed. Our results show a significant interaction between perceived executive dysfunction and objective test performance on BRT. Specifically, associations with BRT were stronger for individuals who perceived more executive dysfunction in the presence of worse inhibition (b = 0.79, 95%CI = 0.27, 1.30) and worse working memory (b = 0.94, 95%CI = 0.26, 1.62). Findings provide further justification for the role of executive functioning in monitoring driver fitness in older age. Future directions and implications are discussed.

QUALITY OF LIFE IN ADULTS LIVING WITH COGNITIVE IMPAIRMENT: DEVELOPMENT OF A UNIVERSAL MEASURE
Keith Anderson 1 , Lisa Peters-Beumer 2 , Megan Westmore 3 , and Rebecca Logsdon 4 , 1. University of Mississippi,Oxford,Mississippi,United States,2. Concordia University Chicago,River Forest,Illinois,United States,3. University of Texas at Arlington,Arlington,Texas,United States,4. University of Washington,Seattle,Washington,United States Quality of life is one of the most important and holistic measures of perceived overall well-being across the lifespan. For older adults living with cognitive impairment, quality of life has been conceptualized as consisting of an array of intertwined domains, such as relationship quality, physical health and ability, and opportunities for roles and activities. A subset of measures have been developed to gauge quality of life in older adults living with cognitive impairment, yet no "gold standard" in measurement has emerged. Quality of Life -Alzheimer's Disease (QOL-AD) is one of the most commonly used and long-standing measures, yet it was developed in 2002 and has yet to be updated to reflect the evolution of our understanding of quality of life in adults living with cognitive impairment. Drawing from the literature on adults living with intellectual and developmental disabilities (IDD), the researchers identified several domains and items to update and expand the applicability of the QOL-AD measure. The proposed revised measure, Quality of Life -Alzheimer's Disease/Intellectual and Developmental Disabilities (QOL-AD/IDD), is intended for adults living with cognitive impairment regardless of age or cause of impairment (e.g., dementia, IDD). The QOL-AD/IDD retains the format of the original measure, most notably the useful prompts that accompany each item and the supplemental proxy measure for caregivers. In this presentation, the researchers will discuss the development of the QOL-AD/IDD and ongoing (e.g., Delphi review) and planned steps to evaluate the reliability and validity of this promising measure. Driver behavior will continue to play a critical role in driving safety for the foreseeable future. Utilizing behavior change theory appropriately presents opportunities to improve the effectiveness of risky driving countermeasures that have been under-utilized to date. Older drivers should not be excluded from consideration of risky behaviors. Fortysix drivers (33% age 65+) completed surveys, then drove for three weeks with data collection during all trips. The Theory of Planned Behavior guided a two-phased regression analysis approach: 1) behavioral intentions were predicted using attitudes about behaviors and demographics; 2) observed risky behavior was predicted using behavioral intentions, theory constructs, personality/psychosocial characteristics, demographics, and driving exposure. Results were synthesized and the emergent themes were used to formulate guidelines for developing theory-based education and communication risky driving countermeasures. Guidelines focused on four risky driving behaviors observed in a large proportion of participants (72% -96%): holding/ using a cellphone; eating/drinking; speeding; and tailgating. Twenty-six guidelines were developed across four categories: 1) relationships among risky behaviors; 2) characteristics or underlying dimensions of risky driving (e.g., time, location, emotion); 3) behavior change theory constructs; 4) audience and message factors. While older drivers self-reported low frequencies of risky behaviors, low intentions for future risky behaviors, and less favorable attitudes toward risky behaviors than younger drivers they were regularly observed engaging in risky behaviors: distracted behaviors in 79% of trips and 2.1 speeding events per trip. Risky driving countermeasures are appropriate for older drivers and the emergent guidelines will be presented with recommended variations for older drivers.

SEX DIMORPHISM IN AGING Chair: Bérénice Benayoun
In this symposium, the speakers will discuss how sex can influence aging trajectories using complementary perspectives and approaches across multiple biological scales and systems. Indeed, accumulating evidence across species has revealed that aging is a highly sex-dimorphic process. On the one hand, women outlive men consistently across populations, and most supercentanarians are women. On the other hand, especially after the onset of menopause, women are at increased risk for most age-related diseases (e.g. Alzheimer's disease, osteoporosis, etc.). However, the molecular pathways underlying such sex-differences in aging and longevity are still largely unexplored and poorly understood. Dr. Austad will discuss how compatibility between the mitochondrial and nuclear genomes during aging is influenced as a function of sex. Dr. Dubal will discuss the impact of sex chromosome complement on cognition with aging in mouse models, and how sex chromosomes may underlie sex-differences in brain aging. Dr. Ucar will discuss work from her lab revealing that the genomic signatures of immune aging in humans are specific to sex. Finally, Dr. Benayoun will discuss how aging of innate immune cells (e.g. macrophages or neutrophils) is regulated by the female vs. male milieu, with sex-specific age-related trajectories remodeling the immune compartment in mice.

SEX-DIMORPHIC REGULATION OF INNATE IMMUNITY DURING AGING Bérénice Benayoun, University of Southern California, Los Angeles, California, United States
Aging is accompanied by striking changes in chromatin and gene expression across cell types and species. Yet, how chromatin landscapes change with age and regulate transcription, and how epigenomic changes in turn influence aging in response to external or internal cues, is largely unknown. In addition, accumulating evidence indicates that sex hormones play a key role in driving aspects of cellular and molecular sex-dimorphism. In parallel to sex hormones, karyotypic sex (i.e. XX vs. XY) is also likely to have important impact outside of gonadal sex determination. A key compartment whose activity can be actively modulated by sex-dimorphic mechanisms throughout life is the immune system, whose function declines sharply with aging and may be actively modulated by sex. Indeed, aspects of the immune responses differ between sexes, with a more robust immune response in females and an increased susceptibility to infection in males. Thus, our main cell models of study are key components of the innate immune system and the inflammatory response: macrophages, which accomplish key tasks such as phagocytosis, antigen presentation and cytokine production, and neutrophils, the most abundant leukocyte type serving as a "first line of defense" against infection. Excitingly, we and others have observed strong sex-related differences in the transcriptional and functional phenotypes of these cells and have observed sex-dimorphic "omic" trajectories for these cells with aging. Based on our data and published literature, it is likely that mechanisms involving both gonadal hormones and sex chromosomes may fine-tune different aspects of immunity and, thus, overall health and lifespan.

THE ROLE OF MITOCHONDRIAL-NUCLEAR INTERACTIONS IN SEX DIFFERENCES IN AGING Steven Austad, University of Alabama at Birmingham, Birmingham, Alabama, United States
Sex differences in longevity and the aging phenotype are rampant if not ubiquitous. They are also highly variable and content dependent. That is, although there appears to be an overall female longevity bias in many species, that pattern has many exceptions. In virtually all of the best-studied species, with humans being a notable exception, longevity sex bias is context-dependent. To try to understand sex differences in aging, it is useful to consider the impact of mitochondria, which are exclusively inherited through the female lineage. Mitochondria are endosymbiotic bacteria that have given away most of their genes to the nucleus. Therefore, mitochondrial function depends on compatibility and coordination of the mitochondrial genome with the nuclear genome. The evolutionary success of mitochondrial genomes, specifically, will depend on how effectively they interact with female nuclear genomes, male nuclear genomes being evolutionary dead-ends for them. This talk will employ this logic to examine observations of sex differences in the aging phenotype.

X CHROMOSOME-DERIVED MECHANISMS OF SEX DIFFERENCES IN LIFESPAN AND BRAIN AGING Dena Dubal, University of California San Francisco, San Francisco, California, United States
Women live longer than men worldwide -and also show cognitive resilience in many aging populations. One major source of biologic difference between the sexes is that females have two X chromosomes and males have one. This difference in sex chromosome complement causes unique X-derived mechanisms that are sex-specific. In mammalian development, one X randomly inactivates in XX cells. One X-derived sex difference is that females are mosaics with the active X chromosome in each cell being either maternallyderived (Xm) or paternally-derived (Xp), whereas males harbor only a maternally-derived X (Xm) in all cells. Interestingly, some females show considerable or complete skew toward Xm or Xp. We utilized several genetic models of sex biology to understand mechanisms of sex difference in aging. We found that the X chromosome contributes to longevity and better cognition in male and female mice. In aging, a genetic manipulation in females to express only the maternally-derived X (Xm), like males, accelerated cognitive decline and epigenetic brain aging. This suggests that Xm is harmful and that female mosaicism (Xm+Xp) provides a buffer to deleterious processes in aging. To assess if Xm alters transcription, we used mice with nuclear localized genetic reporters and sorted Xm from Xp neurons from young and aging XX hippocampi. We found that Xm imprinted several genes within aging hippocampal neurons, suggesting silenced cognitive loci. Our data suggests that Xm -the maternal X -accelerates brain aging and causes cognitive deficits. Understanding how Xm impairs brain function could increase understanding of female heterogeneity and of sex differences in cognitive heath -and unlock new X-derived pathways against cognitive deficits and brain aging of males, females, or both.