PROJECT SUMMARY/ABSTRACT Significance: Cell senescence is implicated in many age-related diseases. Drugs which postpone or reverse cellular senescence (SENO drugs) have been developed and three of these drugs are in human clinical trials. The availability of an inexpensive, whole-animal model of SENO drug action will accelerate development of new treatments of Alzheimer’s Disease. Background: SENO drugs ameliorate numerous age-related pathologies through a common pharmacological action: the selective killing or alteration of senescent cells. SENO drugs are expected to postpone diverse causes of human mortality including Parkinson’s Disease, Alzheimer’s Disease, and atherosclerosis, as well as cancer metastasis and recurrence. We propose to study SENO drugs, targeting three distinct pathways. These pathways lead to alternative responses characterized by distinct levels of AMP Kinase and P53. C. elegans transgenic strains have been engineered to express the amyloidogenic human proteins amyloid- beta (Aβ) and tau. We found that treatment with a SENO drug (piperlongumine) resulted in longer life in the wild-type and postponed paralysis in Aβ-expressing transgenic worm strains. Specific Aim 1. Determine if other SENO drugs suppress Aβ and/or tau toxicity. Synopsis: We propose to monitor the efficacy of SENO drugs in the nematode C. elegans. We will utilize the wild-type, as well as Aβ and tau transgenic strains. Several outcome parameters will be assessed: amelioration of Aβ and tau toxicity, longevity, health-span, fertility, development, and analyses of behavior. Specific Aim 2. Molecular studies of SENO action in C. elegans. Synopsis: We will characterize the expression of P53 and AMPK in aging wild-type C. elegans with and without the application of SENO drugs. Worms will be harvested at 4, 7, and 11 days of age. This will allow us to compare the levels of these proteins in aging C. elegans due to SENO treatments, such as those in senescent mammalian cells. C. elegans will lend itself well to detailed molecular studies consequent to our findings. Specific Aim 3. Transcriptome analysis by RNA-Seq. Synopsis: RNA-Seq, using next-generation DNA sequencing, will be used to examine the transcriptome changes in response to SENO drug treatments.

PROJECT NARRATIVE Despite billions of dollars invested in the understanding of Alzheimer’s Disease (AD), we have yet to develop cures, let alone therapeutic agents or molecular diagnostics. We found a pharmacological agent that blocks A- beta-associated toxicity in pre-clinical tests and propose to test similar pharmacological agents to see if these drugs might slow the rate of progress of AD, cell senescence and aging. We utilize C. elegans (a nematode worm), where transgenic strains expressing human A-beta and/or tau protein provide a rapid, whole-animal approach for testing new drugs.