NIH – Age-related Microbiota Changes and their Implications in Chronic Disease Prevention, Treatment and Progression (R01, R21 Clinical Trial Optional)

April 11, 2018 by School of Medicine Webmaster

The following description was taken from the R01 version of this FOA.

The overall purpose of this funding opportunity announcement (FOA) is to assess the role of the microbiome in health and disease during aging. This initiative will support research projects designed to:

  • Evaluate changes in the microbiota during lifetime and its influence in health and disease status in the elderly, including those from racial/ethnic minority and underserved populations;
  • Understand the underlying mechanisms of microbiota interactions in aged subjects, in the context of multiple medications and chronic diseases;
  • Investigate how interventions designed to change the microbiota can reduce the risk and progression of age-associated pathologies, or modify the effect of treatment in aged animal models or humans.
  • This FOA is intended for well-developed projects based on strong preliminary data. For exploratory pilot projects of similar scientific scope, prospective applicants are advised to consider the R21 companion FOA (PA-18-739). Both FOAs will support basic, discovery-oriented research.  Both FOAs will support basic, discovery-oriented research.

Background and Rationale

Aging is a complex multifactorial process determined by genetic and environmental factors which involves progressive functional decline of an organism’s physiological functions. Current demographic trends show a considerable growth of the older segment of the United States population, aged 65 and over, with an estimated doubling from the present size of 43 million by 2050. Aging is the highest risk factor for the development of most common chronic illnesses and conditions – cancer, diabetes, and cardiovascular, dental, oral and craniofacial diseases – and, as America grows older, we can expect a significant increase in the incidence of these age-related morbidities. To lessen the impact of this phenomenon on public health, it is imperative to improve our understanding of the mechanisms underlying aging and translate this knowledge into practice, to reduce the risk of and devise interventions for these conditions.

The Human Microbiome Project (HMP) generated resources to facilitate characterization of the human microbiota to further our understanding of how the microbiome impacts human health and disease. Recent research suggests that the microbiome may play a key role in the health and disease status of aging individuals. The human microbiome consists of hundreds of thousands of viruses, bacteria, protists and fungi which, together with the host cells, creates a unique ecosystem segregated by topography and function. Over millions of years of microbial-mammalian coevolution these systems have been shaped into an interdependent balance. Analyses of the bacterial species composition of gut microbiota from large healthy human young and adult cohorts representing different ages and dietary traditions have revealed broad interpersonal variability and significant intrapersonal oscillations over time. Built within this variability, however, is a relatively stable core repertoire of the microbial constituents that contribute to the host’s physiological well-being. Analyses of human fecal microbiota show that disruption of the functional balance or dysbiosis, correlates with disease states for some conditions. Age-related dysbiosis has been linked to immunosenescence, chronic systemic inflammation, and the development of the frailty phenotype along with an increase in the incidence of chronic diseases. This may be a consequence of a dysfunctional relationship between the imbalanced microbiota and its metabolites with the host’s immune system. One potential cause of dysbiosis, besides the physiological aging itself, is the use of medication, including antibiotics, which have been reported to reduce the diversity of the microbiota. Another cause may be the reduction or elimination of fiber-rich food, often a consequence of deteriorating dentition, salivary function, digestion and peristalsis. Assisted-living conditions have been shown to change the proportion of various microorganisms. Human observational studies have documented aging as a significant correlate of microbiome alteration with the fecal microbiota showing much greater interpersonal variability among individuals over 65 and differing considerably as a whole from the core repertoire and diversity levels of younger adults.

Clearly, additional research is needed to delineate more precisely how and why the microbiome changes during aging as well as how those changes affect an individual’s health status, and thereby identify targets for interventions designed to promote healthier aging.

Research Objectives

Biological aging can be defined as the gradual deterioration of function at the physiological, organ or tissue level that involves many molecular and cellular mechanisms (genomic instability, epigenetic alterations, telomere attrition, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication and deregulated nutrient sensing) that also affect the risk of chronic diseases, including cancer. Among other factors, the process of aging can also be influenced by the microbiome. In-depth investigations on viral, and/or bacterial, and/or fungal interactions with the host could identify mechanisms that influence biological aging and the subsequent manifestation of multiple chronic conditions experienced in various racial/ethnic populations.

Investigators are encouraged to propose human prospective studies that identify objective biomarkers to assess the role of the microbiome as an environmental modifier of biological aging; analysis of clinical specimens; and animal models of the impact of age-related changes in the microbiome on risk and outcome of chronic diseases; interventions that modify the aged microbiome in the context of chronic diseases, including cancer.

Relevant studies include but are not limited to:

  • How age-related changes in the microbiome (ex: aging of digestive system including the change in stomach pH, aging microbial biofilm, overgrowing Candida, exposure to heavy metals, chemical pollutants, etc.) may increase the inflammatory status and affect diseases risk and progression. Example:  Studies examining biologic signatures, including changes in microbiota pathobiont overgrowth and toxin production that can nurture a sort of pro-inflammatory loop and, in turn, worsen the health status of aged people.
  • The mechanisms underlying senescence and the role of microbiota and microbially produced metabolites in the progress of aging and age-related diseases. Example:  Studies of symbiotic human microbiota or their metabolites and host neurogenic, immunologic, or metabolic pathways that suggest the potential for microbial-based therapeutic strategies that may aid in the modification of the human microbiome, for healthy aging; or delay progression of age-related disease, including neurological disorders and cancer.
  • How changes in the microbiome in different locations: oral, gut, upper respiratory, sinus, skin, etc.) affect risk of disease locally or at distal sites. Example: Studies focused on the relationship between the microbiota of human ecological niches (e.g., gut, oral cavity, skin, bladder, vagina, brain) and the development of clinical diseases that are common in older adults (e.g., pneumonia, urinary tract infection, reactive airways, disease, malignancies).
  • The influence of diet, supplements, and prescription medication, on the composition of the microbiome and the development of dysbiosis with age. Example: Analysis of different exposures [diet, supplements, medications] in older adults that examine phenotypic correlations between gut microbiota composition and functionality, immunological and inflammatory parameters, and genomic/metabolomic profiles.

Information relevant to Specific Institutes/Centers at NIH

National Cancer Institute (NCI).  NCI will support applications for research to understand how changes in the aged microbiota and its metabolites relate to cancer risk, prevention, progression and treatment:

Division of Cancer Prevention (DCP)at the NCI encourages research to understand, but not limited to:

  • The mechanisms through which microbiome-host gene interactions influence cancer risk and progression.
  • The role of diet, bioactive food components and vaccines in modulating the metabolic output or diversity of the microbiota and how these interactions specifically alter biological aging and cancer risk.
  • The underlying mechanisms of action of microbially produced metabolites including their impact on low grade inflammation, immune-senescence and biofilm.

Division of Cancer Treatment and Diagnosis (DCTD)at the NCI encourages mechanistic and translational researches focusing on:

  • The effect of aged microbiome due to physiological aging related biological changes, or lifestyle and behavior changes (e.g. diet, exercise, and sleep) on cancer treatment outcomes.
  • The effect of microbiome changes due to cancer treatment, comorbidities or medications and their interactions on cancer treatment outcomes, or differential outcome in elderly patients; and
  • What lifestyle and behavior interventions (or other complementary and alternative medicine modalities) can overcome the negative effects as the result of aging-related microbiome changes.

Division of Cancer Biology (DCB)at the NCI is interested in:

  • Basic/mechanistic studies in aged animal models that investigate how the microbiota impacts sporadic and inflammation associated (e.g. inflammatory bowel disease, Barrett’s esophagus) cancer development.
  • Microbiome-gene interactions that affect pathways involved in biological aging and carcinogenesis (e.g. telomere maintenance, mitochondrial function, immune response and immune senescence).
  • The effects of the aging microbiome on differential responses in cancer patients treated with immune-modulating and other therapeutic agents.

Division of Cancer Control and Population Studies (DCCPS)at NCIencourages studies to understand:

  • How changes in diet following geographical relocation related to aging (moving to different geographical locations, living in nursing homes versus home dwellings) impact microbiota and in turn the inflammatory status as it relates to cancer risk and response to treatment
  • How chemotherapy affects microbiota and which lifestyle interventions positively impact the microbiome and potentially enhance the therapeutic effect of cancer treatment in age-associated diseases
  • How age-related changes (e.g., body composition, diet, stress tolerance, sleep pattern, and lifestyle behaviors) impact the microbiota and, in turn, cancer risk and cancer treatment.

Center to Reduce Cancer Health Disparities (CRCHD) at NCI encourages studies to understand the relationship between aging and microbiome in addressing cancer health disparities and explore molecular mechanisms of these relationships.

National Institute on Aging (NIA).  NIA is interested in mechanistic studies on:

  • Interrelationships between the composition of the intestinal microbiota, pro-inflammatory cytokine production and mucosal immune system immunosenescence with aging;
  • Effects of aging on gut-associated lymphoid tissue (GALT) and the impact of immunosenescence of this system on dysbiosis of microbiome with aging;
  • Cross-talk between the host immune system and microbiota in influencing the progression of inflammation-based age-related diseases.
  • National Institute of Dental and Craniofacial Research (NIDCR)

NIDCR will consider project applications for this FOA within the above listed Specific Objectives and Scope only if they pertain to the microbiota of the human oral cavity (specifically those microbial communities composed of oral health related archaea, bacteria, fungi and viruses). Specific interest areas include:

  • Healthy age-related changes in the oral microbiota;
  • Changes in the oral microbiota due to geographical changes/or settings (moving to different locations, living in nursing homes versus home dwellings) and the association of those changes to increases in caries or poor periodontal health;
  • Changes in the oral microbiota due to over the counter and prescription medications and the association of those changes to increases in caries or poor periodontal health;
  • Changes in the oral microbiota due to systemic diseases common in the elderly (such as changes in immune function) and the association of those changes to increases in caries or poor periodontal health.

National Institute of Nursing Research (NINR).  NINR is primarily interested in studies that address:

  • Contribution of the microbiome to health outcomes, including the role of the microbiome in maintaining wellness, conferring risk for disease, and determining symptom onset or severity.
  • Behavioral, environmental, social, or demographic factors that potentially influence the microbiome in predisposing to disease onset or contributing to the observed inter-individual variation in disease trajectory or symptom expression among individuals afflicted with a similar chronic illness.
  • Genomic and epigenomic variants or mechanisms that potentially associate with the microbiome to impact health outcomes.
  • Behavioral Interventions that shift the microbiome toward a “healthier” status in order to maintain health, prevent disease, or reduce symptoms associated with chronic illness.

NINR encourages interdisciplinary collaborations that include nurse scientists in the project team. In general, NINR does not support projects that include drugs or biologics, herbal medicines, dietary supplements, or other interventions considered to be complementary or alternative. Potential applicants are encouraged to contact the NINR Scientific Point of Contact listed in this Program Announcement to discuss proposed research ideas prior to submission of the application.

Deadlines:  standard dates apply


Filed Under: Funding Opportunities