Posted Date: September 19, 2017
Application Due Date: January 31, 2018 by 5:00 PM local time of applicant organization.
Temporal physiological changes in tissues, organs and organ systems are considered a part of normal aging. However, these changes result in an age-associated reduction of tissue resiliency and functional capacity, and contribute to increased incidence of disease. Transition from healthy aging to disease follows a continuum of changes that are modulated by intrinsic and extrinsic factors. Mechanistic studies of inflammation, tissue healing and regeneration, and epigenetic gene regulation revealed interconnected relationships among these processes and led to the development of a new idea that aging is an adaptive and plastic process that could be manipulated for improving healthspan, rather than just extending lifespan. This FOA emphasizes the functional significance of regulation of age-related changes in the areas of immunity, tissue regeneration and epigenetics.
- Alterations that affect the aged innate and adaptive immune system contribute to increased disease susceptibility of the elderly. These alterations drive subclinical inflammation, or inflammaging, and are thought to be responsible for development and progression of age-related diseases such as autoimmune diseases, osteoporosis and neurodegenerative disorders. Mechanisms responsible for producing the increasingly compromised inflammatory status remain unclear. For example, it is unknown whether inflammasomes are activated in human aging and whether they contribute to the onset of age-associated disease. Changes in adaptive immune system are characterized by a decrease in naive T- and B-cells, an increase in memory cells and a progressive reduction in the T-cell and B-cell receptor repertoire. Innate immune system alteration with age, including developmental shift toward the myeloid lineage of hematopoietic stem cells (HSCs), age-related dysfunction of neutrophils, natural killer cells, monocytes, macrophages and dendritic cells has been reported. Changes in the tissue microenvironment, such as accumulation of cell debris, and systemic changes in metabolic and hormonal signals, also likely contribute to development of chronic inflammation.
- Changes leading to collapse of clonal diversity of stem cells, and decreases in age-associated self-renewal and differentiation capacity highlight the need for better understanding of the mechanisms of stem cell regulation and clonal dominance. In this regard, it is noteworthy that amelioration of age-associated changes and improved normal tissue homeostasis have been achieved in aged mice by transient expression of stem cell reprogramming factors. Also, it has been suggested that aging of HSCs at least in part results from chronic activation of inflammatory signaling. Further, it is thought that in addition to altered intrinsic stem cell dysfunction, stem cell niche components, such as growth factors, somatic cells, immune cells, extracellular matrixes (ECM), innervating neuronal fibers, and vasculature, may be affected by aging, and harnessing these different elements could be instrumental for developing new strategies to improve stem cell functions and optimize tissue healing and regeneration. In light of these new findings, it would be important to conduct studies that examine consequences of the ablation of senescent cells and, elucidate how modulation of inflammatory signaling and immune cell phenotypes, and manipulation of intracellular and intercellular signaling pathways among these cells are controlled during the process of aging.
- Epigenetic remodeling in response to environmental stimuli and epigenetic drift reduce genomic stability, drive aging process and affect longevity. These changes include reduced bulk levels of the core histones, altered patterns of histone post-translational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression. These changes result in altered local accessibility to genetic materials, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Understanding the regulation and functional significance of these epigenetic changes with regard to inheritance of aging characteristics, lifespan modulation by chromatin modulators and characterization of epigenetic marks across lifespan are knowledge gaps that remain to be addressed.
Overall, this FOA aims to stimulate hypothesis-driven research to understand mechanisms of healthy aging and disease in DOC tissues with a focus on inflammation, tissue healing and regeneration, and epigenetics.
This FOA invites applications that study more than one system; one of them being a DOC system, compared with those relevant to the hypothesis being tested, such that unique versus common biological processes could be characterized. Collaborative, multidisciplinary studies examining cells and tissues to compare and contrast physiological process of aging in DOC systems with other systems, with regard to healthy aging and disease, are responsive to this FOA. The hypothesis should be focused on understanding underlying mechanisms and include functional studies.
Collaborative applications with combination of relevant expertise in oral biology and aging are required. An expert in aging studies is expected to serve in a PI or co-investigator role, with significant input to the research. The projects may utilize a broad range of approaches, model systems, and tools and technologies to address the research objectives of this FOA.
The key goal of this FOA is the identification and characterization of biological mechanisms of aging with regard to homeostasis or perturbations during aging of DOC tissues. Additionally, understanding of these processes relevant to other systems in the body, with regard to shared commonalities and those unique to the DOC system are of particular interest. A key consideration for this FOA is how well the experimental designs are integrated across systems and how well the design addresses the hypothesis being tested.
To be responsive to this FOA, applicants are required to include collaborations among researchers in oral biology, aging and other areas relevant to the proposed hypothesis. Studies using human tissues, animal models, in vitro and in vivo systems are all considered appropriate in response to this FOA.
Examples of age-related research areas appropriate for this FOA may include:
- Defining age-related inflammatory/regenerative/epigenetic processes
- Characterizing age-related adaptive and maladaptive inflammatory responses
- Identifying key cell/tissue types and their interactions that drive aging processes
- Characterizing signaling networks that drive aging processes
- Elucidating mechanism of impairment of adult stem cell function with age and age-related disease
- Linking environmental inputs with changes in age-related epigenetic signatures
- Developing imaging and single cell analysis strategies to analyze aging processes
- Extending use of accelerated aging models to DOC tissues
- Identifying hallmarks of aging in DOC systems in healthy aging that synergistically or independently contribute to the aging process
- Investigating how biological signals initiate age-associated changes
- Investigating primary causes of the age-associated changes in disease phenotype
Examples of research areas non-responsive to this FOA may include:
- Applications that do not have a primary focus on one or more of the stated physiological processes (immunity, tissue healing and regeneration, and epigenetics)
- Applications that do not propose to study more than one system or extend studies in one system to the DOC system
- Purely correlative or association studies between DOC and other systems or within the DOC system without mechanistic or functional studies
- Purely cataloging of age-related changes with no related functional significance studies
- Tools and technology development lacking a mechanistic focus on physiological processes in response to injury or perturbation or homeostasis during aging process
- Pre- senescence studies focused on radiation/infection/stress.
Investigators considering preparing and submitting an application are strongly encouraged to consult with NIDCR staff prior to beginning the application process to determine NIDCR interest and responsiveness to the FOA. NIDCR staff will not evaluate the technical and scientific merits of the proposed application; technical and scientific merit will be determined during peer review using the review criteria indicated in this FOA.
See Section VIII. Other Information for award authorities and regulations.