Aging is the greatest known risk factor for Alzheimer's disease (AD), the most common cause of dementia inolder individuals. However, effective AD therapies remain elusive, which underscores the need to betterunderstand disease etiology and its co-occurrence with advanced age. The apolipoprotein E4 (apoE4) allele isthe strongest genetic risk factor for late-onset AD and it is associated with decreased lifespan. The apoEprotein is crucial to lipid homeostasis through its regulation of cholesterol, triglyceride and phospholipidmetabolism in the blood and the brain.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly and a majority of AD cases issporadic without known causes. While the etiology of AD is multifactorial and complex, growing evidencesuggests that traumatic brain injury (TBI) is a risk factor for development of AD and dementia. Repetitive TBIcauses chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease. Pathological TDP-43 inclusions are one of the important hallmarks of neuropathology in CTE.

Transposable elements, known colloquially as ?jumping genes,? constitute approximately 45% of the humangenome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencingheterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance oftransposable element transcripts. Transposable element activation has recently been identified as a keymediator of neuronal death in tauopathies, a group of neurodegenerative disorders that are pathologicallydefined by deposits of tau protein in the brain.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major contributors to overall morbidity andmortality in patients in the US. The overall objective of the proposed study is to establish untargeted andtargeted spatial metabolomics analysis of tissues from normal and diseased kidneys to assess cellularmetabolic states associated with healthy function, acute injury, chronic condition, and recovery.

Several clinically unrelated neurodegenerative disorders, termed conformational diseases, are character-ized by a common pathophysiology that involves aggregation and accumulation of misfolded proteins. All ofthese diseases activate cell stress signaling pathways, mainly the endoplasmic reticulum (ER) stress-inducedunfolded protein response (UPR) pathway. In particular, the proximal UPR kinase, PERK, is abnormally activein Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP) and Frontal Temporal Dementia (FTD)-affected brain regions.

Identification of small molecules that extend mouse lifespan provides new insights intomechanisms of longevity determination in mammals, and may lay the groundwork for eventualanti-aging therapies in humans. The NIA Interventions Testing Program (ITP) evaluates agentsproposed to extend mouse lifespan by retardation of aging or postponement of late lifediseases.