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Principal Investigator: JANKO Z. NIKOLICH
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2024
Award: $2,615,632
Funding agency: National Institute on Aging
OVERALL- Abstract
Infectious disease, cancer, and autoimmune disorders affect hundreds of millions of older adults. They
reduce length and quality of life across the globe and inflict a massive economic burden on society, as vividly
exemplified by the SARS-CoV-2 pandemic, that has claimed 93.1% of its victims amongst those 50 years and
older, and 74.4% in those 64 and older. Yet, despite decades of research, restoring protective immunity in
older adults has remained elusive. One critical factor contributing to age-related immune decline is a loss of
naïve T (Tn) cell numbers and function, and their rejuvenation is highly desirable in order to enhance protective
immunity and overall healthspan in older adults.
The renewal of this T cell Rejuvenation Program Project is centered on two key questions: (1) why do Tn
cell numbers and function deteriorate with age; and (2) what can be done about it? The premise of the program
is that Tn cell aging is multifactorial and that it can only be resolved by targeting multiple defects. Thymic
involution and the resulting decline in T cell production is the earliest event leading to immunosenescence.
This reduction is compounded by a decline in bone marrow function, as well as by defects in Tn cell
maintenance and function in the periphery. These deficiencies combine to erode the ability of the older immune
system to detect and eliminate infectious agents and neoplastic cells, and to properly guard against
autoimmunity. In the first program period, we strongly confirmed our initial hypotheses that lymphoid organ
stromal elements deteriorate earlier than previously thought, and in a manner to decisively erode immunity,
with aging. We will build on the synergy and success of the initial program period, where discoveries in one
project are critically informing science in others, and continue to identify mechanistic reasons behind reduced
central and peripheral lymphoid organ function with aging. We will then develop combined strategies to
ameliorate these defects to improve immune defense in the elderly. Our hypothesis is that mechanistic
dissection of defects in both thymic production AND peripheral Tn cell maintenance is required to devise and
test effective interventions for T cell rejuvenation in the elderly.
Three integrated projects led by experts in the field, supported by four cutting-edge cores, will test this
hypothesis and achieve the following Program Goals: 1. Define mechanistic changes in primary and secondary
lymphoid organ aging; 2. Determine the endogenous regenerative capacity of thymic and secondary lymphoid
organ stroma over the lifespan; 3. Relate the progression of murine thymus, lymph node (LN) and T cell aging
phenotypes to humans; and 4. Devise and test rejuvenation strategies to improve thymopoiesis, T cell survival
and peripheral T cell maintenance and function, so as to enhance protective immunity.
Over this support period, the above goals will provide a wealth of basic knowledge that will be translated to
preclinical models and be poised for translation to older adults.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Address><Affect><Age><Aging><Archives><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Bone Marrow><Bone Marrow Reticuloendothelial System><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus><COVID-19 years><COVID19 virus><Cancers><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Count><Cell Function><Cell Growth and Maintenance><Cell Maintenance><Cell Number><Cell Physiology><Cell Process><Cell Senescence><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Aging><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Cellular Senescence><CoV-2><CoV2><Communicable Diseases><Communication><Data Science><Defect><Deterioration><Dissection><Economic Burden><Economics><Elderly><Elements><Event><Failure><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genetic Models><Goals><Health><Healthcare><Human><Immune><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Impairment><Individual><Infection><Infectious Agent><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Informatics><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Laboratories><Length><Life><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Maintenance><Malignant Neoplasms><Malignant Tumor><Mice><Mice Mammals><Modality><Modern Man><Molecular><Monitor><Murine><Mus><Natural regeneration><Output><Pathway interactions><Peripheral><Phenotype><Pre-Clinical Model><Preclinical Models><Process><Production><QOL><Quality of life><Reagent><Regeneration><Regenerative capacity><Rejuvenation><Replicative Senescence><Research><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Savings><Science><Self Tolerance><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Societies><Spleen><Spleen Reticuloendothelial System><Standardization><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Subcellular Process><T-Cell Development><T-Cell Ontogeny><T-Cells><T-Lymphocyte><T-Lymphocyte Development><Testing><Therapeutic><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Transcript Expression Analyses><Transcript Expression Analysis><Translating><Translations><Tumor Cell><Virus><Wuhan coronavirus><advanced age><age associated><age associated alterations><age associated changes><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age linked><age related><age related alterations><age related changes><age specific><age specific alterations><age specific changes><aged><aged mice><aged mouse><ages><alterations with age><analyze gene expression><animal tissue><autoimmune condition><autoimmune disorder><autoimmunity disease><biological signal transduction><central tolerance><changes with age><comparative><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><data sharing><design><designing><economic><effective intervention><elderly mice><experience><gene expression analysis><gene expression assay><geriatric><hCoV19><health care><health-span><healthspan><healthy life span><high throughput analysis><host response><immune function><immune senescence><immune system function><immune system response><immunoresponse><immunosenescence><improved><infectious organism><injuries><interventional strategy><life span><lifespan><lymph gland><lymph nodes><lymph organ><lymphatic organ><lymphnodes><lymphoid organ><malignancy><mortality><mouse model><murine model><nCoV2><neoplasm/cancer><neoplastic cell><novel><old mice><older adult><older adulthood><pathway><peripheral lymph organ><peripheral lymphoid organ><primary lymphatic organ><primary lymphoid organ><programs><regenerate><regeneration ability><regeneration capacity><response><secondary lymph organ><secondary lymphatic organ><secondary lymphoid organ><senior citizen><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><statistical analysis><success><synergism><thymus derived lymphocyte><timeline><transcriptional profiling><translation>