ASH Clinical News spoke with Richard J. Hodes, MD, director of the National Institute on Aging (NIA) at the National Institutes of Health (NIH), about the aging-related mechanisms that contribute to the increased incidence of hematologic conditions in older patients and how NIA initiatives are helping to grow the scientific community’s understanding of those mechanisms.
After more than 25 years at the helm of the NIA, what are the greatest advances you’ve seen in our understanding of aging?
Today’s understanding of aging-related molecular and cellular changes was unimaginable 25 years ago. Some of what we’ve learned about the pathways involved in aging reveals the complexities of cellular and organ systems’ interactions. In animal models, this has led to the development and understanding of genetic manipulations that can have, through identifiable molecular pathways, dramatic effects on lifespan and health span. This research presents opportunities to identify markers of these pathways in humans as well as in animals.
Identifying molecular changes that occur with aging has spurred the development of interventions that target these changes and can be analyzed for their impact on phenotypes of aging. For example, we’ve found that senolytic drugs, which selectively eliminate senescent cells (older cells that have ceased to divide), can prevent or reverse damage caused by senescent cells in mice, extending their health span and life. This is compelling evidence that targeting a fundamental aging process can delay age-related conditions.
I also am encouraged by our studies of age-associated systemic inflammation and immune response and its role in chronic neurologic diseases. In fact, many discoveries of risk and protective factors point to immune pathways.
I’m gratified to see researchers from multiple fields bringing their talents and expertise to the field of aging research. The research conducted by hematologists and immunologists, for example, is relevant far beyond the conventional realm.
An applicable context for some of these approaches is the relatively new field of geroscience, which is based on the concept that changes that normally occur with aging also contribute to increased risk of diseases of aging. Geroscientists focus on understanding the genetic, molecular, and cellular mechanisms that make aging a major risk factor and driver of common chronic conditions and diseases of older people.
What is your vision for NIA? What are the agency’s goals?
My vision, shared by all at NIA, is one in which all Americans enjoy robust health and independence with advancing age. Although we have come far in NIA’s 45 years of existence, we in the scientific community will need to think broadly, creatively, intelligently, and strategically to meet this goal. Our goals center on understanding the nature of aging, the aging process, and the diseases and conditions associated with growing older to extend healthy, active years of life.
What are NIA’s priorities as they relate to hematologic conditions and the aging population? Where are the knowledge gaps about the implications of aging on hematologic disorders?
Aging is associated with a decrease in hematopoiesis, resulting in an increased incidence of anemia and decline in immune function, as well as an increased incidence of hematologic malignancies. Although hematopoietic stem cells are capable of maintaining hematopoiesis through their lifespan, hematopoietic stem cells and associated progenitor cells show significant age-related functional declines. There still is much to be understood regarding how aging affects the microenvironment of the bone marrow, including how increases in chronic inflammation and systemic levels of pro-inflammatory cytokines observed with aging affect hematopoietic stem cells by increasing myelopoiesis and impairing self-renewal.
In addition to improving our understanding of the underlying age-related mechanisms contributing to the increased incidence of anemia and hematologic malignancies and decreased immune function at a preclinical level, NIA also has prioritized clinical studies of these conditions. NIA has directed funding to several areas of hematologic disease in older adults, such as how conditions and syndromes common in older patients (multiple chronic conditions, polypharmacy, frailty, pharmacologic changes, aging of organ systems such as chronic kidney disease) increase the vulnerability to, and affect the diagnosis, management, and prognosis of, hematologic disorders.
Treatment of hematologic malignancies also is associated with specific toxicities that older adults are more susceptible to, so we have funded research investigating whether treatment-related toxicities can be predicted and/or mitigated. Another priority is to develop decision-making tools to assist in treatment decisions, especially in older adults with multiple chronic conditions and/or near the end of life.
We also have supported important research into whether treatment of malignancies in childhood or early adulthood can affect the “downstream” health as patients age, related to changes in immune function, secondary illnesses, and/or malignancies.
“I’m gratified to see researchers from multiple fields bringing their talents and expertise to the field of aging research.”
Other NIA-funded projects include research to determine the optimal methods to study hematologic disease in older adults with complex comorbidities, geriatric syndromes, and/or polypharmacy – most of which are present in “real-world” hematologic patients. This means looking at pragmatic trials, cohort studies, observational trials, and other designs.
How does NIA collaborate with other NIH agencies in these efforts?
NIA has joined a trans-NIH initiative with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung, and Blood Institute (NHLBI) known as SHINE, or Stimulating Hematology Investigation: New Endeavors, to fund more basic and translational research in this area. Our agency also co-organized a 2016 workshop on aging and hematopoiesis that resulted in publication of a notice highlighting this research topic. NIA has funded several research projects on this topic.
Since then, NIA has continued to work with NIDDK and NHBLI and has co-organized several more workshops in research areas such as the role of the niche in hematopoiesis, stress and hematopoiesis, and erythropoiesis. All workshops have included participants with expertise in aging-related aspects of these topics and the notices published in conjunction with funding opportunity announcements have included aging-related items.
In addition, NIA recently collaborated with the National Cancer Institute (NCI) on a workshop in the area of clonal hematopoiesis and aging that covered the role of aging in transformation of stem cells, which leads to the initiation of oncogenesis. In the clinical realm, NIA has partnered with NCI to run a workshop regarding diagnosis, prognoses, treatment toxicities, and decision making in older adults with malignancies, including using geriatric and functional assessment as a prognostic and/or risk management tool prior to chemotherapy. Outcomes of significance to older adults – including functional and cognitive status, well-being, independence, and health-related quality of life – and communication with caregivers have been the focus of these NIA-NCI initiatives. The NIA-funded Cancer and Aging Research Group conference series and now R21/R33, which is building a research and resource infrastructure for optimizing cancer challenges in older adults, has included many hematologic investigators and topics.
What implications might the new NIH policy mandating the inclusion of older adults into all NIH-supported research have on hematology clinical study design and recruitment planning?
NIA recently published a paper on the inclusion of older adults in NIH-funded clinical trials that examined the illnesses that are the top causes for hospitalization and/or worsened disability‐adjusted life years (DALYs) in older adults, several of which could be relevant to underlying hematologic conditions.
We found that the mean age of patients recruited in clinical trials was below the age of the disease in the general population. This finding was in agreement with studies conducted by others across several disease conditions. In addition, certain trial exclusion criteria that were common in older adults would prevent them from participating in those trials.
The new NIH inclusion policy mandates that all NIH‐funded clinical studies include people across the lifespan, as scientifically appropriate. It is hoped that this will enhance the recruitment of older adults into clinical studies and make the results of the studies more applicable to the population that lives with the conditions.
What are NIA’s priorities for the hematology workforce that will address health challenges in the aging population?
The Grants for Early Medical and Surgical Specialists’ Transition to Aging Research (GEMSSTAR) program is a unique NIA-funded award that evolved from the T. Franklin Williams Scholars Program, which the American Society of Hematology (ASH) was involved with for more than a decade.
Launched in 2011, the GEMSSTAR initiative responded to a call from the Institute of Medicine (now called the National Academy of Medicine) for improved training and research of medical and surgical specialist physician scientists in aging/geriatric research. The goal of this funding is for early-career faculty members to garner pilot data and work with a mentor with expertise in aging research to launch a career in the age-related aspects of the awardees’ specialty.
“NIA has directed funding to [study] how conditions and syndromes common in older patients increase the vulnerability to … hematologic disorders.”
Since its inception, the NIA has funded 127 GEMSSTAR scholars in over 32 specialties, including hematology. An NIA U13-funded GEMSSTAR Conference, at which all GEMSSTAR scholars can convene, includes training in aging research, career development, transdisciplinary networking, collaboration, and mentorship. NIA will soon fund a broader research and resource network, the Clinician-Scientists Transdisciplinary Aging Research (Clin-STAR) Coordinating Center, to accelerate the integration of aging research into specialty medicine and surgery. The GEMSSTAR Award is an annual Request for Application (RFA), which is published in May for funding the subsequent July.
Another unique opportunity for early-career researchers is NIA’s Paul B. Beeson Emerging Leaders Career Development Award in Aging (K76), which was established in 1994. This mentored K award is intended for early-stage investigators who have begun to establish research programs and who, through this award, will be ready to assume leadership roles in their field of expertise. NIA supports seven to 10 Beeson Scholars each year with an award that allows up to $225,000 in direct costs for up to five years. There is an annual conference of prior and current Beeson Scholars that fosters networking with peers and national leaders in aging research. The Beeson RFA is published in May for funding to start the subsequent July.
To further enhance the workforce, the NIA holds a competitive NIA Butler-Williams Summer Scholars Program, a weeklong bootcamp on Aging Research at the NIA each summer. This intensive program is intended for early career investigators and is in its 30th year.
Regarding clinical initiatives, the NIA has emphasized those that are transdisciplinary and problem-based, rather than disease-specific, but are all inclusive of hematologic diseases. Some examples of problem-based initiatives include those focused on polypharmacy, deprescribing, and frailty and function as predictors of outcomes; pragmatic trials to study multimorbidity, multiple chronic diseases and cognitive impairment, pain and palliative care, and resiliencies; technology to maintain function and independence; and decision making.
Additionally, NIA initiatives focus on outcomes important to older adults, including physical and cognitive function, independence, well-being, health-related quality of life, and patient goal–directed care.
What is your own approach to aging wellness?
Exercise is a part of my daily life, I don’t smoke, I eat what most consider to be a healthy diet, and I enjoy my work. I also take time for my family, including my newly arrived twin grandsons.