P01AG066603

Skeleton and Joint Degeneration with Aging - Project Summary/Abstract

Decreased mobility significantly increases the risk of many chronic diseases, leading to an acceleration of the normal aging process. Skeletal degeneration, particularly of the spine and joints, is among the most prevalent diseases that lead to a decline in mobility and frailty. Frailty, defined as a state of decreased physiologic reserve, often develops with aging and influences a person's ability to compensate for the additional burden of disease. With the development of frailty, the natural homeostatic reserve is reduced, and the body's ability to compensate for perturbations is reduced.

Degeneration of the spine and joints can substantially accelerate the development of frailty; however, the underlying pathophysiology of this degeneration in aging and the development and progression of resulting low back pain (LBP) and osteoarthritis (OA) is not well understood. There is no disease-modifying treatment for either, largely due to the lack of understanding of the pathophysiology of pain and the unique cellular signaling changes among OA subtypes.

LBP commonly results from degeneration of the amphiarthrodial spinal joints, with pain correlating most strongly with changes in vertebral endplate morphology. Degeneration of diarthrodial joints is a set of diverse processes that are frequently lumped together under the umbrella term "osteoarthritis" but represent a heterogeneous disease process. Osteoclasts (OC) in both vertebral endplates and subchondral bone undergo senescence during aging to generate porous sclerotic endplates, uncoupled remodeling in subchondral bone, and senescent OC secrete netrin-1 to induce axonal extrusion and innervation that potentially lead to pain.

Therefore, we hypothesize that porous sclerotic endplates and uncoupled remodeling of subchondral bone by senescent OC lead to skeletal joint degeneration and pain, severely limiting mobility and increasing frailty to accelerate aging. In Project 1, we will investigate how endplate porosity with aging induces spinal degeneration and sensory innervation to result in LBP. In Project 2, we will investigate the mechanism of the translational application of intermittent parathyroid hormone injection (iPTH) - increased intervertebral disc (IVD) volume to spinal degeneration and reduce endplate nerve innervation and LBP by remodeling of porous sclerotic endplates. In Project 3, we will characterize the mechanism of cellular senescence in two different subtypes of OA: non-traumatic OA that is orchestrated by senescence of pre-OC.

Together, these three projects, supported by the common administrative and biostatistics (Core A) and in vivo model and histology (Core B) cores, will result in a nuanced understanding of the pathophysiology of joint and spinal degeneration associated with aging and will provide foundational mechanistic insights for potential therapeutic targets.

The Johns Hopkins University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Maryland United States

State-Wide

NIA Program Project Applications (P01 Clinical Trial Optional) (PAR-19-314)

Amendment Since initial award the total obligations have increased 389% from $1,888,834 to $9,233,589.