Laura J. Niedernhofer - US grants

DESCRIPTION (provided by applicant): DNA is continuously damaged and repaired. The consequences of unrepaired damage are revealed by genetic diseases in which DNA repair pathways are disrupted. Repair deficiency in humans can lead to a profound risk of cancer or dramatic premature aging. Prevention of cancer and age-related morbidity are therefore dependent upon identifying the sources of DNA damage and mechanisms of damage repair. DNA interstrand crosslinks (ICLs) present a unique challenge to cells because both DNA strands are covalently modified and inseparable, precluding transcription, replication and simple error-free excision repair of the DNA. The mechanism by which ICLs are repaired in mammalian cells is poorly understood, as are levels of endogenous crosslink damage and the physiological impact of these lesions. The long term objectives of this research are to understand the biological impact of unrepaired DNA ICLs and the mechanism by which cells repair ICL damage. Ercc1-Xpf is an endonuclease required for nucleotide excision repair of bulky lesions on one strand of DNA and the repair of bivalent ICLs. Genetic disruption of Ercc1 in the mouse causes accelerated aging, which cannot be attributed to defective nucleotide excision repair. We hypothesize that the phenotype of the Ercc1-deficient mice is due to their inability to repair ICLs, and therefore the consequence of endogenous ICLs. Experiments proposed will utilize Ercc1 mouse models to test this hypothesis and to reveal the consequence of unrepaired ICLs. In addition, cells derived from these animals will be used to delineate the steps of lCL repair. The specific aims of this project are: Aim 1 is to test the hypothesis that unrepaired DNA ICLs contribute to aging and carcinogenesis. We engineered two novel mutations in the mouse Ercc1 genomic locus that result in hypomorphic mice. Preliminary data indicates that these mice have a similar, but more extensive, progeroid phenotype compared to the Ercc1-deficient mice. However, the disease-free period and longevity of the mice are extended proportional to Ercc1-Xpf protein levels. To test our hypothesis, we will treat these mice with a drug that causes ICLs and compare aging parameters to untreated animals. We predict that the phenotype of the Ercc1-depleted mice will be exacerbated by drug treatment indicating a causal role for ICLs. In addition, we will measure aging parameters including tumor incidence in the longest-lived of the Ercc1 mice to determine the contribution of spontaneous ICLs to cancer. Aim 2 is to determine if lipid peroxidation (LPO) promotes aging in mice with defective ICL repair. LPO is caused by oxygen radical damage to membranes and can yield products able to crosslink DNA. We hypothesize that LPO is a source of spontaneous ICLs that contribute to the phenotype of the Ercc1 mice. LPO will be induced in Ercc1 hypomorphic mice chemically and through nutritional intervention. We predict that both will exacerbate the progeria of the mice. Results from these experiments will indicate if LPO can affect the rate of aging and if so whether this effect can be controlled through diet. Aim 3 is to develop a method to locally induce DNA ICLs and to use this technique to determine the sequential steps of lCL repair. The study of ICL repair is hampered by the fact that ICLs are formed inefficiently and drugs that cause ICLs induce a host of other DNA damages. Thus we propose to develop a technique to introduce ICLs only in a well-defined region of cell nuclei using near infrared multiphoton photoactivation of the chemotherapeutic agent psoralen. This method will enable us to discriminate ICL-specific events from other repair events within a single cell. The technique will be applied to wild type and ICL repair-defective Ercc1-/- cells to determine what proteins assemble specifically at sites of lCL damage and in what chronological order.

[unreadable] DESCRIPTION (provided by applicant): The genomic DNA in our cells is continuously damaged and repaired. The damage occurs via exposure to environmental genotoxins such as the UV component of sunlight and spontaneously due to endogenous metabolites that react with DNA. The consequences of not repairing the damage are revealed by genetic diseases in which DNA repair pathways are disrupted. Repair deficiency in humans can lead to a profound increase in the risk of cancer, even in the absence of obvious exposure to environmental genotoxins. Thus prevention of cancer is dependent upon identifying the sources of endogenous DNA damage and means to avoid or attenuate it. Mouse models of these human repair deficiency syndromes offer a sensitive tool for identifying these sources. The long term objective of this research is to use mice, genetically engineered to be deficient in DNA repair to identifying dietary sources of genotoxic stress and nutritional interventions that prevent cancer. ERCC1-XPF is an endonuclease required for nucleotide excision repair (NER) of bulky lesions on one strand of DNA and the repair of bivalent DNA interstrand crosslinks (ICL). Mice hypomorphic for ERCC1-XPF have a very high incidence of solid tumors, which cannot be attributed to their defect in NER. Thus tumorigenesis in ERCC1-XPF-deficient mice can be attributed to their defect in ICL repair, and therefore the consequence of spontaneous ICL. We hypothesize that the ICL damage that promotes spontaneous tumors in this DNA repair-deficient model is caused by lipid peroxidation (LPO). Experiments proposed will test this hypothesis by challenging the ERCC1-XPF hypomorphic mice with a diet rich in polyunsaturated fatty acids, which promote endogenous LPO. The specific aim of this project is to determine if dietary polyunsaturated fatty acids (PUFA) promote cancer. Dietary PUFA assimilate into cell membranes and are particularly vulnerable to oxidation, thus increase lipid peroxidation (LPO) in vivo. LPO of membrane PUFA produces aldehydes able to crosslink DNA. We hypothesize that LPO is a source of spontaneous ICL that contribute to tumorigenesis in the repair-deficient mice. LPO will be induced in ERCC1-XPF hypomorphic mice by administering a diet rich in PUFA. A second cohort of animals will receive an isocaloric diet depleted of PUFA. We predict that animals fed the PUFA-rich diet will have an increased incidence and/or earlier onset of solid tumors. The results from these experiments will indicate if dietary fats increase the amount of endogenous DNA damage and if this damage can promote tumorigenesis. Similarly, the results will reveal if avoiding dietary PUFA reduces cancer risk. Finally, these experiments will reveal if ERCC1-XPF hypomorphic mice are a useful model for screening anti-oxidants that may reduce cancer risk. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Aging is characterized by loss of functional reserve, placing the elderly at increased risk of numerous diseases. Identifying the driving force behind this functional loss is essential for maintaining a healthy populace. Recent evidence from our lab and others implicates DNA damage as a cause of aging. This implies a strong environmental component to aging. The long term objective of this research is to understand the molecular mechanism by which DNA damage promotes aging. This coupled with identifying environmental causes of genotoxic stress will greatly facilitate prevention of age-associated diseases. ERCC1-XPF is an endonuclease required for repair of bulky monoadducts via nucleotide excision repair (NER) and DNA interstrand crosslinks (ICLs) via a distinct mechanism. Deletion of ERCC1-XPF in the mouse causes early onset aging. These mice therefore offer a unique, rapid and sensitive model system for discovering which genotoxins promote aging and how they do so. The phenotype of the Erccl mice cannot be attributed to loss of NER. Thus our working hypothesis is that rapid aging in ERCC1-XPF deficient mice is caused by their inability to repair ICLs and therefore a consequence of endogenous ICLs which are cytotoxic. To test this, the investigators engineered mice hypomorphic for ERCC1-XPF which age over the course of months, permitting interventional studies. These mice will be exposed to DNA crosslinking drugs and environmental agents that promote lipid peroxidation (LPO), a likely source of endogenous ICLs, to determine if these exposures exacerbate the progeroid symptoms of the mice. The investigators discovered a human progeria caused by mutation of XPF. Thus identifying the cause of rapid aging in ERCC1-XPF-deficient mice will have direct implications for human health. The specific aims of this project are: Aim I: To define the cellular response of ERCCl-XPF-deficient cells to DNA ICLs and LPO. ERCCl-XPF-deficient cells will be exposed to 8-MOP or angelicin, plant-derived psoralens. Photoactivation of 8-MOP induces ICLs and monoadducts, whereas angelicin produces only monoadducts. Cell survival, cellular senescence, apoptosis, mutation frequency and chromosomal aberrations will be measured. If our hypothesis is correct then, 8-MOP will be significantly more cytotoxic than angelicin under conditions where an equal number of DNA lesions are induced. ERCCl-XPF-deficient cells will also be exposed to cadmium, an environmental agent that promotes LPO, to determine if LPO elicits the same cellular response as ICLs. Aim II: To directly test the hypothesis that unrepaired DNA ICLs promote aging. ERCC1-XPF hypomorphic mice will be chronically exposed to the crosslinking agent mechlorethamine. A second cohort will be exposed to 2-chloroethylamine (which induces structurally related monoadducts but not ICLs) using a dose that induces the same number of lesions as mechlorethamine. If our hypothesis is correct, mechlorethamine, but not 2-chloroethylamine, will exacerbate the progeria in these mice. Results will be confirmed by comparing skin aging in response to topical 8-MOP versus angelicin plus UV-A in mice genetically deleted for ERCC1-XPF in the skin only. Aim III: To determine if lipid peroxidation (LPO) promotes aging in mice with defective ICL repair. LPO is caused by oxygen radical damage to membranes and yields products able to crosslink DNA. We hypothesize that LPO is a source of ICLs that contribute to the phenotype of the Erccl mice. LPO will be induced in ERCCl-XPF-deficient mice via exposure to CCL4 or cadmium. If our hypothesis is correct, Erccl mice will be hypersensitive to LPO compared to wild type mice and LPO will exacerbate their progeria. Results from these experiments will indicate if LPO promotes aging and if so, whether it does so by inducing DNA damage. These experiments will also reveal if two common industrial exposures promote aging.

ABSTRACT ? PROJECT 2 Although aging is extremely complex, the natural occurrence of genetic variants in humans that affect longevity and healthspan offer an ideal starting point for the systematic identification of targets for interventions that extend human healthspan. Based on the genetically homogeneous Ashkenazi Jewish centenarian resource at the Albert Einstein College of Medicine, for which whole genome and whole exome sequences are now available, we now are able to identify rare, functional genetic variants, pathways and microRNAs associated with healthy longevity that represent potential targets for drug discovery. However, there still is a key need to validate the putative rare variants, pathways and miRNAs linked to longevity in a more defined model system. Here we propose to use mouse models of accelerated and natural aging to not only validate the rare variants and miRNAs identified in Project 1, but to test and validate compounds targeting these rare variants, miRNAs and associated pathways provided by Project 3. We developed a mouse model of accelerated aging (Ercc1-/? mice) and demonstrated that there is a highly significant correlation between the functional, histopathologic, ultra-structural and gene expression changes in liver, cornea, kidney, bone, muscle and bone marrow isolated from 18-20 week-old Ercc1-/? mice and 2-3 year-old wild-type mice. Furthermore, we established that spontaneous, oxidative DNA lesions, cellular senescence and stem cell dysfunction accumulate more rapidly in Ercc1-/? mice than in normal littermates, similar to old wild-type mice. These results strongly suggest that Ercc1-/? age similarly to naturally aging mice, just in an accelerated manner. Thus we are proposing to use both Ercc1-/? and naturally aged mice to validate the different rare variants and miRNAs identified by Project 1 and test compounds targeting these rare variant, miRNAs and associated pathways developed in Project 3. In this regard, we already have used the Ercc1-/? mouse model of accelerated aging to demonstrate that reduction in ATM and NF-?B activity, identified by Project 2 as affected by longevity associated rare variants, generated by heterozygosity in ATM and p65/RelA respectively, extend healthspan. Similarly, Ercc1-/? mice carrying two mutations in the NEMO/IKK? subunit of IKK, preventing activation of NF-?B, by DNA damage, appears to extend healthspan. We also have demonstrated the utility of using Ercc1-/? mice for testing therapeutic interventions where inhibitors of IKK, mitochondrial-targeted free radical scavengers, several different senolytic drugs and young stem cells are able to extend healthspan. The successful completion of the proposed experiments will validate the identified human variants as extending healthy aging and identify therapeutic strategies for the extension of healthspan.

Project Summary Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system and reduce quality of life for the elderly. As our world population ages dramatically over the next three decades, the burden will only increase. Hence, there is a great need to discover fundamental mechanisms of aging to develop rationale strategies for minimizing the impact of aging on our health and economy. There is general agreement that cell autonomous mechanisms contribute to aging. As cells accrue damage over time, they respond by triggering individual cell fate decisions (e.g., senescence and apoptosis) that ultimately disrupt tissue homeostasis and thereby increase risk of morbidity. However, more recently, there are numerous lines of evidence indicating that cell non-autonomous mechanisms are critically important as well. These cell non-autonomous mechanisms are likely much easier and safer to target therapeutically. Therefore identifying and characterizing these mechanisms is a priority. To ask if ?aging? just one tissue in mice is sufficient to drive systemic aging, we generated a series of eight tissue-specific mutant animals in which DNA damage, senescence and tissue dysfunction were increased in only one cell type or tissue at a time. Our preliminary data indicate that ?aged? immune cells play a key role in driving aging non-autonomously. Only in the hematopoietic cell mutant mice were non-targeted, peripheral tissues dramatically affected in the first year of life, showing increased senescence, inflammation and loss of homeostasis. The goal of this project is to fully define this novel mechanism of immune cell-mediated, non-autonomous aging in vivo. The aims of the project are to: 1. Determine the temporal order and extent of secondary senescence driven by an ?aged? immune system. The specific immune and non-immune cell types with increased senescence will be identified by qRT-PCR and CyTOF at different mouse ages. The functional impact of the ?aged? immune system on peripheral tissue homeostasis will be determined by measuring disease-specific endpoints and age-related histopathology. 2. Identify the immune cell type(s) that is most potent at driving systemic aging. This will be accomplished by transplanting splenocytes and isolated immune cell populations into young senescence reporter mice, followed by generation and characterization of cell-type specific mutant mice (e.g., T, B, NK cell or subpopulations). 3. Identify the mechanism by which ?aged? immune cells drive systemic aging. This will be accomplished by serum transfer from the hematopoietic mutant mice into young senescence reporter mice followed by transcriptomic analysis of isolated immune cell populations to identify secreted factors. These putative pro-geronic factors will be validated by proteomics and functional validation. Completion of these aims will identify and characterize a novel mechanism(s) of cell non-autonomous aging driven by an aged immune system, which will lend itself to therapeutic targeting for extending human healthspan.

PROJECT SUMMARY Nucleotide excision repair (NER) is a DNA repair mechanism that recognizes and removes bulky, helix-distorting lesions from the nuclear genome. Key substrates for NER are lesions induced by ultraviolet (UV) radiation upon environmental exposure to sunlight and a subset of oxidative DNA lesions produced endogenously. This is dramatically illustrated by patients with xeroderma pigmentosum (XP), a disease caused by inherited defects in NER. XP patients have a 10,000-fold increased risk of skin cancer and early onset neurodegeneration. XP is heterogeneous, ranging from mild to profoundly debilitating. XP severity is proportional to the extent to which NER is disrupted. This suggests that subtle defects in NER, due to, for example, polymorphisms in NER genes, might modestly but significantly impact one?s risk of skin cancer. Since skin cancer affects 20% of Americans and is preventable (by avoiding environmental exposure to UV), identifying those at risk could have a tremendous impact on the health of Americans and healthcare costs. The greatest barrier to identifying those at risk is the lack of an assay to measure NER that is rapid, inexpensive and applicable to samples safely and easily collected from patients. NER occurs in a series of steps involving the recognition of a site of DNA damage, unwinding the DNA locally, excision of a single-stranded oligonucleotide containing the lesion, and templated DNA synthesis to fill the residual gap. NER is the only way that UV-induced photolesions are removed from the genome in human cells. Therefore, NER is measured by the detection and quantification of UV-induced DNA synthesis outside of the S-phase of the cell cycle, or unscheduled DNA synthesis (UDS). Historically, UDS measurement required the use of radioactively-labeled nucleosides and/or specialized equipment. We developed a method to measure NER that employs the thymidine analog 5-ethynyl-2'-deoxyuridine and Click-iT chemistry for fluorescent detection of UDS by flow cytometry. This can be applied to peripheral blood cells for rapid measurement of NER requiring minimally invasive sample collection. UDS in XP patients ranges from <10% to 50%. Nothing is known about the health implications of having a UDS between 50-100%, or how to define 100% NER capacity. This project aims to correct these gaps in knowledge through optimization of our functional assay and proof-of- concept pilot human studies. The assay will be applied to existing cohorts of patients seen at the University of Miami Skin Cancer Clinics, the NIH Undiagnosed Diseases Program or enrolled in the University of Maryland Amish Longevity Study, to interrogate associations between NER capacity and high risk of skin cancer, early onset neurodegeneration, and within family pedigrees, respectively. This project will yield an NER assay applicable to larger population studies aimed at testing associations between NER capacity, environmental exposures and disease risk, and begin to define ?normal? NER capacity. The assay could have a significant impact on how risk of squamous cell or basal cell carcinoma of the skin, melanoma, lung or head and neck cancer, neurodegeneration, and resistance to cancer chemotherapy is identified and managed.

Project Summary Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system and reduce quality of life for the elderly. As our world population ages dramatically over the next three decades, the burden will only increase. Hence, there is a great need to discover fundamental mechanisms of aging to develop rationale strategies for minimizing the impact of aging on our health and economy. This fostered the Geroscience hypothesis, which posits that therapeutically targeting fundamental mechanisms of aging will yield a larger dividend in terms of improving the health of an aging population than would treating individual age-related diseases. The fundamental mechanism of aging where this has borne out most successfully to date is through elimination of senescent cells. Senolytic drugs were first described by us and others in 2015 and have already fostered multiple clinical trials beginning in 2018. In mice, senolytics improve physical function, tissue health and suppress all cause mortality. COVID-19 has emerged as an urgent threat to our aged population. The goal of the parent project is to fully define the mechanism by which an aged / senescent immune system drives morbidity and mortality using mice as a model organism. The goal of this revision is to use the knowledge and resources we have to study the role of cellular senescence in driving adverse outcomes in aged organisms acutely exposed to novel viral pathogens. Preliminary data indicate that mice with a substantial senescent cell burden respond much worse to inflammatory challenges than mice without senescent cells. Furthermore, exposure to normal pathogens carried by wild or pet store mice is sufficient to kill old experimental mice housed in specified pathogen-free conditions, but it does not kill young mice. Here, we propose to use this experimental paradigm to determine if senolytics, drugs that specifically kill senescent cells, suppress mortality in aged, obese, diabetic or diseased mice. The immediate goal of this revision is to generate sufficient preclinical data to support clinical trials using nutraceuticals with senolytic activity to prevent adverse outcomes in those at high risk of COVID-19 infection or grave illness after infection. The long term goal of this project is to enable rigorously testing the Geroscience hypothesis.

Abstract/Summary A group of investigators at the University of Minnesota seeks to renew ?Functional Proteomics of Aging?, a Training Program that helps exceptional young scientists develop the intellectual and technical tools needed for productive careers as independent investigators and educators in aging research. The program has supported annually 4 predoctoral and 2 postdoctoral trainees. The Training Program is in its 10th year of funding and has trained 16 predoctoral and 9 postdoctoral trainees, who have successful careers. In addition to the research conducted in the mentor?s laboratory, trainees receive didactic (4 courses, 2 workshops) and experiential training in gerontology and proteomics (conferences, seminars, symposia, journal clubs, group meetings with Program faculty members, and a new visitorship program to Nathan Shock Centers). The experiential training is designed to maximize interaction among trainees and Training faculty from multiple labs and with scientists involved in aging research outside the U of MN. Faculty mentors draw trainees from six graduate programs at the University of Minnesota: Biochemistry, Molecular Biology and Biophysics (BMBB), Chemistry (Chem), Experimental and Clinical Pharmacology (ECP), Integrative Biology and Physiology (IBP) and Neuroscience (NSc), and Rehabilitation Sciences (RSc). The mentors? research programs focus on the use proteomic and other advanced state-of-the-art technologies to reveal the molecular details behind the age- related loss in tissue function and/or age-related disease and are conceptually organized into four foci: loss of muscle function with age and disease, decline of the central nervous system with age and disease, the metabolism and signaling of aging and longevity, and development of technology for the advancement of aging research. Our research is supported by outstanding cores equipped with a variety of state-of-the-art mass spectrometers in the Center for Mass Spectrometry and Proteomics and bioinformatics platforms in the Minnesota Supercomputers Institute. Training faculty laboratories also contain specialized analytical equipment that is commonly shared between Program faculty. Together, the cadre of distinguished mentors, the extensive interdisciplinary collaborations among faculty and trainees of multiple departments, the technological resources, and the didactic and experiential training helps our trainees to shape successful careers.

Project Summary Senescent cells (SnCs) are known to play a causal role in aging and numerous age-related diseases. However, they also contribute to wound healing and tissue remodeling. Both physiological and pathological roles are linked to the secretome of SnCs and their complex interaction with the immune system, which is thought to play an important role in clearing SnCs. Most of what we have learned about SnCs is derived from mice where it has been clearly demonstrated that genetic or pharmacologic removal of SnCs in aged or diseased organisms reduces frailty; improves strength, endurance, and resilience; and attenuates a variety of age-related diseases including Alzheimer?s. This novel approach of therapeutically targeting a fundamental aging process common to many diseases ? rather than drugging disease-specific perturbations (e.g., low insulin or hypertension) ? could have a tremendous impact on our aging population. However, much needs to be learned about SnCs in humans to deploy such approaches safely and effectively. This project aims to establish a Tissue Mapping Center at the University of Minnesota (MN TMC) to contribute to the SenNet Consortium, which intends to build a 4D atlas of SnCs in multiple human organs with healthy aging. MN TMC proposes to focus on adipose (omental and subcutaneous), skeletal muscle (Vastus lateralis), liver, and ovarian tissue. This selection is based on MN TMC?s expertise in the biology, cell biology, and immunology of these organs; in studying SnCs in these organs; and experience with single cell technologies in these organs. The MN TMC and its Administrative Core will be led by PIs with complementary expertise in SnCs and computational biology/health informatics. The Biospecimen Core will be led by the UMN Chairman of Surgery and an accomplished pathologist. The Biological Analysis Core will be led by an expert in SnC and a molecular pathologist leading spatial genomics at UMN. The Data Analysis Core will be led by three bioinformaticians with expertise in modeling, single cell, and spatial-omics analysis, and blending patient electronic health records with -omics data. A unique feature of the proposed MN TMC is that the entire workflow will be housed within existing infrastructure/cores: from CTSI and BioNet, which manage human subjects research, tissue procurement, annotation, and distribution/storage, to the genomic/ proteomics/imaging cores, along with the Institute of Health Informatics for data management and multiplexing. Key personnel include leadership of all of these UMN components. This approach provides unequaled stability of our analytical pipeline and in-place quality control and assurance mechanisms. A second unique feature of the proposed MN TMC is our ability to perform spatial transcriptomics and proteomics on formalin-fixed paraffin embedded biospecimens, which enables analysis of the most stable biospecimens and virtually any archived material. Overall, the goal of the MN TMC is to make a significant contribution to the 4D atlas of human SnCs, working closely with NIH and other TMCs to develop and adhere to standards created by the SenNet Consortium.

ABSTRACT The world?s population is rapidly aging. Seventy percent of persons over 65 years of age have two or more chronic diseases1. This includes Alzheimer?s disease (AD) and related dementias, cardiovascular disease, osteoarthritis and diabetes, all of which negatively impact quality of life and resilience. Identifying fundamental cell autonomous and non-autonomous mechanisms driving aging and age-related diseases such as AD and devising strategies to therapeutically target them is imperative to alleviate tremendous disease burden and healthcare costs. It is generally accepted that damaged or stressed cells activate a variety of signaling cascades that regulate cell fate decisions, including senescence and apoptosis. These cell autonomous events can lead to impaired tissue homeostasis via loss of functional, terminally-differentiated cells or via loss of regenerative capacity. For example, senescence increases in different cell types in the brains of mouse models of AD and reduction in this senescent cell burden either genetically or pharmacologically improves pathology. There is also strong evidence for cell non-autonomous mechanisms of aging, including data from experiments implementing heterochronic parabiosis2-7, plasma transfer7 and measurement of the senescence-associated secretory phenotype (SASP) produced by senescent cells8-11. To ask if ?aging? of one organ or cell type is sufficient to drive aging in other tissues, we created a series of mice with tissue-specific ?aging?. Ercc1, a gene that encodes one subunit of the DNA repair endonuclease ERCC1-XPF, was deleted in 7 organs or cell types using Cre-lox technology. Loss of Ercc1 expression destabilizes the holoenzyme ERCC1-XPF in vivo12. As a consequence, spontaneous, endogenous DNA damage accumulates more rapidly in tissues of mutant mice compared to wild- type (WT) mice able to repair the damage13. For example, deletion of Ercc1 in pancreatic ß cells results in a type II diabetes-like condition with evidence of senescence and SASP in fat and liver whereas deletion in podocytes develop chronic kidney disease. Interestingly, deletion of Ercc1 in the hematopoietic compartment using the Vav (HS21/45) promoter to drive Cre expression14 potently drove senescence and loss of tissue homeostasis in the immune compartment, but also in multiple solid organs including the brain. Vav-Cre+/-;Ercc1-/fl mice have premature senescence of immune cells and many characteristics of immunosenescence typical of aged mice and humans15, including impaired immune function. This was accompanied by increased expression of senescence markers p16Ink4a, p21Cip1 and senescence-associated secretory phenotype (SASP) factors in multiple tissues including brain, liver, kidney, lung, GI and aorta. The ?aged? immune system was sufficient to damage and impair function of solid organs as evidenced by increased liver enzymes in the serum, proteinuria, loss of repair of damaged muscle and loss of intervertebral disc proteoglycan. Here we will examine the hypothesis that immune aging contributes to driving senescence, SASP, brain pathology, and loss of memory in the MAPT and APP transgenic mouse models of AD.