MITOCHONDRIAL COMMUNICATION AND AGING

Abstract Mitochondria evidently originate from endosymbiotic bacteria that presumably provided several advantages for eukaryotic life. For the past 1–2 billion years, mitochondria co-evolved with the ancestral cell to coordinate various cellular functions. Coordination requires communication and mitochondrial signaling has been shown to be vital to cellular fitness and aging. In this symposium, the speakers will discuss the role of mitochondria as a signaling organelle and their impact on key cellular functions in the context of aging. Consistent with emerging evidence of the complexity and sophistication of mitochondrial communication mechanisms, some of the mitochondrial-to-nuclear communication modes, including nuclear transcriptional programs and cellular signaling networks, that regulate molecular and cellular processes to promote fitness will be discussed. Dr. Chen will discuss how a mitochondrial metabolic checkpoint can regulate stem cell quiescence and maintenance that is important to stem cell aging. Dr. Picard will discuss the impact of mitochondrial stress on increased energetic cost of living (i.e. hypermetabolism) and cellular lifespan. Finally, Dr. Lee will discuss how signaling peptides that are encoded withing the mitochondrial genome regulate cellular homeostasis, increase physiological resilience, and promote healthy aging.

with limited benefits. The Affordable Care Act Medicaid expansion increased health insurance access among low-income individuals but there are concerns that public insurance may disincentivize labor supply. In this study, we examine whether Medicaid expansion affected the labor supply of low-educated DCWs at both extensive and intensive margin overall, and by different healthcare settings. Using annual American Community Survey data from 2010 to 2019 retrieved via Integrated Public Use Microdata Series, we identify 100,676 adult DCWs (age: 19-64) with a high school or less degree from 50 states and DC. We examine the potentially causal effect of Medicaid expansion on labor supply of DCWs using difference-in-differences and event-study regressions We find that Medicaid expansion is associated with a 2.9 percentagepoint (p< 0.01) increase in full-time employment (>=35 hours) and a 1.9 percentage point (p< 0.05) decrease in part-time employment (20-34 hours). We also find that unemployment decreased by 0.8 percentage points (p< 0.1) among DCWs mainly driven by those working in the long-term care industry. Our study suggests that Medicaid expansion does not have a negative impact on labor supply among low-educated DCWs. States that have not expanded Medicaid can consider policies to increase insurance coverage for DCWs as a strategy to strengthen this workforce. Chenjuan Ma, New York University, New York, New York, United States Despite the rapid increase in the needs for home-and community-based services (HCBS), including home health care which is the most commonly used HCBS, workforce shortage has become a critical challenge to home health agencies in providing quality care to meet the needs of millions of homebound Americans. This study aimed to examine the availability of home health care workforce and its variations by neighborhood characteristics. We linked several national datasets from 2019 and included information from 11,005 HHC agencies in 1,849 counties. The unit for analysis is county. We found that on average county had fulltime equivalent (FTE) 83 (SD=351) home health care nurses, 120 (SD=411) FTE skilled home health providers (e.g., nurses, physical/occupational therapists) and 37 (SD=411) FTE aides. For every 1,000 persons, on average counties had 0.7 (SD=4.6) FTE nurses, 0.9 (SD=4.7) FTE skilled providers, and 0.2 (SD=0.8)) FTE aides. For every 1,000 older adults (>=65), on average counties had 3.6 (SD=23.9)) FTE nurses, 4.8 (SD=24.6) FTE skilled providers and 1.2 (SD=4.4) FTE aides. We also found that counties with moderate (2nd tertile) proportion of Black and Hispanic Americans; counties with highest (3rd title) proportion of Black and Hispanic Americans had the lowest number of FTE home health care aides per every 1,000 persons. Our findings highlight the staff shortage facing home health care and suggest the existence of disparities in availability of home health care workforce.

THE RELATIONSHIP BETWEEN ADULT DAY HEALTH CENTER OWNERSHIP, STAFFING, AND PARTICIPANT OUTCOMES
Joanne Spetz 1 , and Jason Flatt 2 , 1. University of California, San Francisco, San Francisco, California, United States, 2.

University of Nevada, Las Vegas, School of Public Health, Las Vegas, Nevada, United States
Growing demands for specialized care for older adults living with disabilities, including those with Alzheimer's Disease and related dementia (ADRD), and for caregiver respite have resulted in rising use of adult day health centers (ADHCs). ADHCs vary in size, ownership, participant demographics, and services offered, with a many operated by multi-site chain organizations and with for-profit ownership. This study examines whether ADHC ownership is associated with their scope of services, staffing models, and outcomes. We used facility-level data from the restricteduse 2014 National Post-Acute and Long-Term Care Study (NPALs) Adult Day Services Center module, which collects primary data on ADHCs through a nationally representative survey. Key outcome variables were measures of ADHC staffing, and rates of participants' emergency department visits, hospitalizations, and falls. The first part of the analysis was descriptive, focused on participant and staffing patterns. We then estimated ordinary least squares multivariate regressions to learn whether staffing differences exist holding other ADHC characteristics constant, such as size, region, and other services offered. We also estimated Poisson regression models to learn whether there are differences in rates of emergency room visits, hospitalizations, and falls. We found little difference in staffing or participant outcomes between for-profit vs. not-for-profit ADHCs. We found that chainaffiliated ADHCs had different participant populations and sources of revenue. They also had lower levels of staffing in general and for licensed nurses, activity staff, and social workers. Rates of falls and emergency department visits were higher in chain-affiliated versus independent ADHCs when controlling for other characteristics.

PANDEMIC POLICIES MOVING FORWARD: WHAT HAVE WE LEARNED Chair: Brian Lindberg
Leading aging and health policy advocates will present their findings and viewpoints regarding pandemic and postpandemic policy and programmatic changes and innovations. Issues will include elder justice, home and community-based services, Medicaid, nursing home care, and social isolation. The group will discuss what has changed and how will programs and services be different in the future.

MITOCHONDRIAL COMMUNICATION AND AGING Chair: Changhan Lee
Mitochondria evidently originate from endosymbiotic bacteria that presumably provided several advantages for eukaryotic life. For the past 1-2 billion years, mitochondria co-evolved with the ancestral cell to coordinate various cellular functions. Coordination requires communication and mitochondrial signaling has been shown to be vital to cellular fitness and aging. In this symposium, the speakers will discuss the role of mitochondria as a signaling organelle and their impact on key cellular functions in the context of aging. Consistent with emerging evidence of the complexity and sophistication of mitochondrial communication mechanisms, some of the mitochondrial-to-nuclear communication modes, including nuclear transcriptional programs and cellular signaling networks, that regulate molecular and cellular processes to promote fitness will be discussed. Dr. Chen will discuss how a mitochondrial metabolic checkpoint can regulate stem cell quiescence and maintenance that is important to stem cell aging. Dr. Picard will discuss the impact of mitochondrial stress on increased energetic cost of living (i.e. hypermetabolism) and cellular lifespan. Finally, Dr. Lee will discuss how signaling peptides that are encoded withing the mitochondrial genome regulate cellular homeostasis, increase physiological resilience, and promote healthy aging.

MITOCHONDRIA: POWERHOUSE, SLAUGHTERHOUSE, AND SPEAKER OF THE HOUSE Changhan Lee, University of Southern California, Los Angeles, California, United States
The nuclear and mitochondrial genomes have co-evolved since the union forged 1-2 billion years ago between our ancestral cell and free-living bacteria. The bi-genomic system is coordinated by close communication between the two genome-possessing organelles. More recently, peptides that are encoded in the mitochondrial genome have been identified and shown to communicate mitochondrial messages. In this symposium, I will discuss MOTS-c as a mitochondrialencoded communication factor in the context of aging. MOTS-c can translocate to the nucleus under metabolic stress to directly regulate adaptive nuclear gene expression. In humans, MOTS-c levels increase in skeletal muscle and in circulation upon exercise. In mice, MOTS-c treatment significantly reversed physical decline in aged mice (22 mo.), including doubling in treadmill running time. Studies from our lab and others point to a novel class of mitochondrialencoded longevity genes that coordinate cellular homeostasis.

MITOCHONDRIAL METABOLIC CHECKPOINT, STEM CELL AGING AND REJUVENATION Danica Chen, University of California -Berkeley, Berkeley, California, United States
Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. Recent advances in stem cell biology highlight a mitochondrial metabolic checkpoint that is essential for stem cells to return to the quiescent state. As quiescent stem cells enter the cell cycle, mitochondrial biogenesis is induced and mitochondrial stress is increased. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow stem cells to exit the cell cycle and return to quiescence. These processes are critically regulated by several sirtuin family members, which are NAD+-dependent deacetylases. Because loss of stem cell quiescence results in the depletion of the stem cell pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in stem cells will increase our understanding of tissue homeostasis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions. Valentina Perissi, Boston University School of Medicine, Boston, Massachusetts, United States Oxidative stress and increased ROS production, as observed in aging and obesity, commonly lead to the accumulation of mitochondrial dysfunctions. This is met by the activation of a robust mitochondria-to-nucleus stress response promoting the rewiring of nuclear gene expression to limit cellular and tissue damage and promote organelle adaptation. Here we will review previous work uncovering the transcriptional cofactor G-Protein Pathway Suppressor 2 (GPS2) as a mediator of mitochondria retrograde signaling and a key nuclear regulator of nuclear-encoded mitochondrial genes, including mitochondrial chaperones/proteases, mitokines, and other protective enzymes such as the ADP-ribosyltransferase NEURL4. We will also discuss unpublished work showing that shuttling of GPS2 between organelles plays a role in coordinating the transcriptional and translational regulation of antioxidant factors and pro-apoptotic genes by promoting the ubiquitination of mitochondria-associated translation factors.

DOES THE ENERGETIC COST OF STRESS AC-CELERATE BIOLOGICAL AGING AND SHORTEN LIFESPAN?
Martin Picard, Columbia University, New York, New York, United States In humans, chronic activation of cellular stress responses predict functional decline, accelerate aging, and increase mortality, but the cellular basis for the stress-aging cascade remains unclear. Here we induced chronic stress in primary human fibroblasts from multiple donors with constant i) ATPsynthase inhibition (Oligomycin-1nM) or i) glucocorticoid stimulation (Dexamethasone-100nM) cultured for up to 10 months. Stressors triggered mtDNA instability and activated integrated stress responses resulting in both transcriptional activation and secretion of cytokines and metabokines. In parallel, chronic stress increased cellular energy expenditure or the "cost of living" by 62-108% (Ps<0.001). Thus, chronically stressed cells considerably expend more energy to undergo each cell division. This severe state of hypermetabolism led to faster rates of telomere shortening and of genome-wide DNA methylation-based epigenetic aging monitored across the cellular lifespan, reflecting mitonuclear signaling. This accelerated aging phenotype culminated in 20-40% fewer maximal cell divisions (i.e., Hayflick limit). Based on findings that hypermetabolism and increased energy flux through mitochondria may shorten lifespan, we pharmacologically inhibited carbon entry (glutamine, pyruvate, long-chain fatty acids) into the Krebs cycle across the entire cellular lifespan. While this manipulation successfully decreased OxPhos activity, it increased glycolysis-derived ATP synthesis and total energy expenditure, exacerbating the accelerated aging phenotype. Combined, our longitudinal bioenergetic and multi-omic profiling of primary human