antibody (romosozumab-aqqg; Evenity) was recently ap- proved by the FDA to treat patients at increased risk of frac- ture. However, an increased risk of cardiovascular events was reported, resulting in issue a ‘black box warning’ require- ment for romosozumab. One potential solution to lower the risk of adverse events is to reduce the medication dose. Previously, we found that dual inhibition of sclerostin and Dkk1 produced extremely potent synergistic bone anabolic effects, in both genetic and pharmacological models. While Dkk1 inhibition alone has no consistent bone-building ef- fects, combining antibodies that target sclerostin (Scl-mAb) and Dkk1 (Dkk1-mAb) at 3:1 ratio resulted in 2-3X more bone gain as Scl-mAb alone. Further, much lower total doses of dual antibody treatment, given at optimized proportions, generated equivalent bone anabolic effects as Scl-mAb alone (at much higher doses), suggesting that a combinational strategy has obvious translational benefts. Finally, we tested whether low-dose combination therapy can maintain the same osteogenic effect as Scl-mAb in adult (6 month) and aged (20 month) mice. Outcome measures derived from radiographic, biomechanical, and histomorphometric assays revealed that a 3:1 ratio of Scl-mAb:Dkk1-mAb at 12.5mg/ kg was as effcacious as 25mg/kg of Scl-mAb alone, in both age groups. Moreover, cortical porosity—a signifcant factor contributing to skeletal fragility in the aged skeleton—was signifcantly reduced by both Scl-mAb and low-dose com- bination treatment. In conclusion, our fndings suggest that optimized low-dose combinational therapy is viable strategy for improving skeletal fragility. ORALLY ACTIVE, CLINICALLY TRANSLATABLE SENOLYTICS RESTORE Α-KLOTHO IN MICE AND HUMANS Yi Zhu 1 , Larissa Langhi Prata 1 , Erin Wissler Gerdes 1 ,  Jair Netto 1 , Tamar Pirtskhalava 1 , Nino Giorgadze 2 ,  Utkarsh Tripathi 1 , and Christina Inman 1 , 1. Mayo Clinic, Rochester, Minnesota, United States, 2. May Clinic, Rochester, Minnesota, United States Decreased α-Klotho, a geroprotective factor, and in- creased senescent cell burden are both associated with early onset of physical disability, cognitive impairment, and pre- mature all-cause mortality. It has been demonstrated that eliminating senescent cells can enhance physical function, cognition, and survival in mice, as does overexpressing α-Klotho. Mice with low α-Klotho exhibit accelerated sen- escent cell accumulation, recombinant α-Klotho decreases senescent cell burden and restores lifespan in these mice, and senescent epidermal cells are reduced in mice overexpressing α-Klotho. Here, we tested the hypothesis that senescent cells cause decreased α-Klotho and hence that reducing senes- cent cells can increase α-Klotho. Senescent cell conditioned medium (CM) reduced α-Klotho in cultured non-senescent human umbilical vein endothelial cells (HUVECs), renal tubular endothelial cells, and astrocytes. These effects of senescent CM were partially attenuated by neutralizing anti- bodies against the senescence-associated secretory phenotype (SASP) factors, activin A and IL-1α. Transplanting senescent cells into younger mice caused decreased urine and brain α-Klotho. Genetically reducing highly p16Ink4a-expressing cells in old INK-ATTAC mice or administering the senolytics, Dasatinib plus Quercetin (D+Q) or Fisetin (F), to young mice transplanted with senescent cells, young diet-induced obese (DIO) mice, or naturally-aged mice increased urine, kidney, and/or brain α-Klotho. Treating patients with idiopathic pul- monary fbrosis (IPF), a cellular senescence-related disease, with D+Q led to increased urinary α-Klotho. Thus, targeting senescent cells causes increases in the geroprotective factor α-Klotho, potentially amplifying the benefcial effects of senolytic drugs. OXR1 STABILIZES THE RETROMER TO EXTEND LIFESPAN AND NEURONAL HEALTH BY DIETARY RESTRICTION Kenneth Wilson 1 , Sudipta Bar 1 , Eric Dammer 2 ,  Birgit Schilling 1 , Nicholas Seyfried 2 , Hugo Bellen 3 ,  Lisa Ellerby 1 , and Pankaj Kapahi 1 , 1. Buck Institute for Research on Aging, Novato, California, United States, 2. Emory University School of Medicine, Atlanta, Georgia, United States, 3. Baylor College of Medicine, Houston, Texas, United States Dietary restriction (DR) delays aging and neurodegeneration, but the mechanisms behind this remain unclear. We reared over 150 fully sequenced fy strains from the Drosophila Genetic Reference Panel under ad libitum feeding or diet-restricted conditions and measured lifespan as well as healthspan to identify new targets for DR-mediated longevity. Through genome-wide association study, we iden- tifed genetic variants associated with infuencing these traits under each dietary condition. A variant in mustard (mtd, called Oxidation resistance 1, OXR1, in humans), signif- cantly associated with DR-specifc lifespan. We demonstrate that mtd/OXR1 in neurons is necessary for DR-mediated lifespan extension. Neuronal knockdown of mtd also ac- celerates sensory decline, arguing for a specifc role of mtd/ OXR1 in neuroprotection. We show that mtd is essential for stabilizing the retromer complex, which is necessary for traffcking transmembrane proteins and lipids for reuse. As a result of OXR1 defciency, the retromer destabilizes and lysosomes become overused. Overexpression of retromer proteins or supplementation with chaperone compound R55 rescues the lifespan defects and neurodegeneration seen in mtd-defcient fies, and R55 is capable of rescuing lyso- somal aggregation and OXR1-retromer co-localization in cells from humans with OXR1 defciency. We further show through multi-omic analyses in fies and humans that mtd/ OXR1 associates with accelerated transcriptomic aging and proteins involved in neurodegenerative diseases, including Alzheimer's disease (AD). Overexpression of OXR1 and retromer proteins rescued AD-associated phenotypes in a fy model of AD. Thus, mtd/OXR1 enhances protein recycling in response to DR through the retromer, improving neuronal health and lifespan through mechanisms conserved across species. EXTENDING A HEALTHY LIFESPAN WITH 3-HYDROXYANTHRANILIC ACID George Sutphin 1 , Hope Dang 1 , Raul Castro-Portuguez 1 ,  Luis Espejo 1 , Sam Freitas 1 , and Jeremy Meyers 2 , 1. University of Arizona, Tucson, Arizona, United States, 2. University of Washington, Tucson, Arizona, United States Metabolism of tryptophan by the kynurenine pathway is increasingly linked to aging. 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