DGCG Research Goals
DGCG's research goals may be summarized in the following framework:
- Goal 1. Identify risk factors, and develop and test prevention or treatment methods for disabilities, symptoms, causes of activity limitation, and high vulnerability to adverse outcomes from illness, injury, or other stressors in older persons.
- Goal 2. Determine the relationship of age-related factors to accuracy or predictive value of diagnostic measures, and efficacy or adverse effects of interventions in older persons. Based on this knowledge, develop approaches to improve diagnoses or outcomes in older persons and determine their effects.
- Goal 3. Determine clinical and functional effects of interactions of comorbid conditions, of interactions of therapies for these conditions, and the efficacy of interventions to optimize the balance of benefits and risks for the older patient with multiple conditions.
- Goal 4. Determine sequences of age-related changes over the life span and how suc sequences can contribute to incidence of age-related conditions, and influence their progression.
- Goal 5. Elucidate relationships of aging processes and age-related changes to development or progression of morbidities, and develop and test diagnostic and treatment approaches based on this information.
- Goal 6. Identify protective factors contributing to exceptionally healthy human aging as expressed by exceptional longevity, exceptional "health span" or exceptionally slow rates of physiologic decline, and test human interventions with potential to contribute to exceptionally healthy aging.
Selected major issues in clinical trials, translational research, career development and the work of the Claude D. Pepper Older Americans Independence Centers (OAICs) as well cross cutting issues involving populations diversity and health disparities addressed by DGCG overlap with some of the goals above.
There has been a continuing focus on research aimed at maintaining independence in mobility in old age. Additional information on vascular, muscular, neuromuscular, and bioenergetic contributors to decreased mobility has been gained. A collaborative project with the Foundation for NIH supported analyses of body composition in relation to mobility to determine clinically meaningful cut-points for muscle mass and physical performance, which will be crucial for testing new interventions. NIA is currently supporting additional studies to refine these cut-points. A Phase III clinical trial demonstrated efficacy of a structured physical activity intervention in preventing mobility disability in high-risk older persons. Other, smaller intervention studies have made preliminary findings that may further increase opportunities to maintain or restore mobility.
Intervention studies on balance-training methods to prevent falls have had positive preliminary results. With support from the Patient-Centered Outcomes Research Institute (PCORI), NIA is supporting a trial to test the effectiveness in real-world health care settings of a multifactorial fall injury prevention strategy that has been found efficacious in more tightly controlled settings.
There has been an increasing focus on vulnerability and resilience, particularly in responses to specific stressors. For example, several studies are assessing new interventions to improve wound healing in older persons. An important new direction has been the extension from research foci on symptoms (e.g., fatigue) to research on susceptibility to symptoms (e.g., fatigability) as potential treatable or preventable conditions. Researchers have developed metrics of fatigability, which will be crucial for studies to understand the physiologic factors that contribute to it. Research on symptoms per se continues as well, with epidemiologic findings indicating that suboptimal pain management in older persons is widespread. Outreach efforts have been made to palliative medicine to increase interest in aging research topics in this field, DGCG is funding a network project to provide the basis for further development of these interests. Collaboration is ongoing with We are also collaborating with DAB on an initiative to develop measures to assess differing types of vulnerability and resilience in laboratory animals and humans.
Possible new directions for research on maintaining independence include further pragmatic studies to evaluate strategies that can be implemented in real-world settings, interdisciplinary studies on mobility that integrate expertise in muscle physiology and neurology (in collaboration with DN), developing more meaningful quality-of-life measures (in collaboration with DBSR), and human intervention studies to characterize mechanistic factors that mediate physical activity's enhancement of mobility function in older persons, which could lead to improved exercise interventions or alternative treatments.
Research on aging-related aspects of specific diseases continues. A new research clinical trials network on anemia in the elderly has had difficulties recruiting, but its adoption of a pragmatic trials design shows promise of better accrual. Continuing research on heart failure with preserved ejection fraction (a strongly age-related condition) has found that extra-cardiac factors such as central arterial stiffening and endothelial dysfunction are important pathophysiologic contributors. A notable decrease in stroke incidence over the last twenty years in the Medicare population has been reported, opening opportunities for further insights into possible protective factors. Research on aging-related aspects of pulmonary conditions has found that genetic variants associated with chronic lung disease are also associated with lung function decline in normal aging, providing opportunities for exploring connections between aging processes and pulmonary diseases.
As cancer increasingly becomes a chronic condition due to longer survivorship, issues regarding appropriate use of definitive vs. palliative treatment for older patients have been addressed in several observational studies to characterize oncologists' treatment strategies for older persons, and generating information on symptomatic effects of cancer treatments in this group. This can provide a better evidentiary basis for treatment choices for older cancer patients. Studies comparing HIV infection and aging have found additional parallels, e.g., in shifts in T-cell subpopulations, which may help to guide intervention development both for HIV infection and other aging-related conditions.
In considering future directions for aging-related research on individual conditions, continuing collaborations with professional societies, with input from laboratory scientists, should be helpful in prioritizing among numerous topics with regard to relevance to clinical aging issues and aging mechanisms.
DGCG-supported researchers have also conducted analyses that can contribute to better-informed preventive guidelines for older persons on topics such as breast cancer and prostate cancer screening. A Phase III trial on multiple effects of low-dose aspirin in healthy elderly, whose primary outcome is disability-free, dementia-free survival, has completed enrollment, and should provide valuable evidence on whether aspirin's preventive benefits outweigh its potential adverse effects (e.g., from GI bleeding or hemorrhagic stroke) in older persons.
DGCG has also supported studies on use of health care quality indicators as a tool in practice redesign studies on outcomes in older persons. Some of these have found beneficial effects, some not. Related studies have found favorable effects of alternative practice models, such as nurse practitioner co-management, on quality of care. Other research has identified factors influencing likelihood of hospital readmissions, a prominent quality indicator.
Research on multiple chronic conditions (MCC) in old age has been a major program focus and has expanded considerably. Studies have found synergistic effects of differing combinations of co-existing conditions on symptoms and functional status in older persons. This approach can be valuable for identifying patient subpopulations with increased morbidity and risk, which are especially important targets for research to discover better treatment options. DGCG has extended this approach through an RFA that yielded additional studies on interactions of coexisting conditions. To enhance the ability of studies to assess and compare effects of health care policies and interventions on persons with MCC, DGCG organized a panel that generated a set of core outcome measures. Research to inform the potential use of such measures as quality indicators is in progress. DGCG has also funded a research network to foster interdisciplinary research on MCC.
Promising future directions for MCC research include continued efforts to provide a sound evidentiary basis for incorporating MCC-related metrics in health care quality measures, as well extension of preliminary studies on effects of interactions among differing conditions, as well as clinical trials on key therapeutic issues posed by coexisting conditions.
Research on factors influencing the progression of chronic diseases over the life span is a continuing focus. There is increasing information about progression of these conditions from early life to mid-life. In particular, there is accumulating evidence that levels of cardiometabolic disease factor levels in youth strongly predict their levels at least through early middle age. During the menopausal transition, risk factors for symptomatic conditions and progression of risk factors and disease have been found to differ at differing menopausal stages. In advanced age, changes with age in predictive factors vary considerably among individuals. Within an individual, correlation among rates of change of different factors is quite low, suggesting the effects of multiple processes.
There is also increasing evidence that factors influencing bone mass in old age operate in early adulthood as well, including control of differentiation of precursor cells to bone forming cells or fat cells. Bone factors have also been found to influence osteoarthritis progression via interactions of subchondral bone with articular cartilage. Relationships of specific circulating growth factors to risk for chronic diseases such as cardiovascular and renal disease found in longitudinal studies suggest potential benefits of interventions to modulate them.
Although several predictive markers for individual conditions have been identified, predictive markers reflecting activity of mechanisms hypothesized to modulate rates of aging changes remain scarce. DGCG and DAB are also collaborating on a workshop and future FOA for research to identify such metrics in human and laboratory animal studies. A key feature of interest for human studies is on opportunities to assess long-term predictive value of markers by linking data from cohorts of different ages.
Future possible directions include human studies on juvenile protective factors – factors expressed at one or more stages of maturation that may repress aging changes while present, but diminish or disappear at a later maturational stage. NIA research on this issue is currently conducted in laboratory animals and supported by other Divisions, not DGCG, However, we been active in developing FOAs in collaboration with them, both because of the intrinsic value of the lab animal studies, and their potential for extension into human studies.
DGCG and DAB share interests in effects of circulating factors, including those identified in DAB-supported heterochronic parabiosis studies and which influence age-related outcomes. We are collaborating with DAB on an initiative on this topic through paired RFAs – DAB's for laboratory animal studies, DGCGs for secondary analysis of human data and analyses of biospecimens from epidemiologic studies and clinical trials.
There have been several findings on interventions designed to address aging changes. A clinical trial has been recently completed (results still blinded) to determine whether estrogen effects on cardiovascular risk factors differ between women who have recently completed menopause and women at ages substantially beyond menopause. Clinical trials have demonstrated the efficacy of non-estrogen therapies – an SSRI and an SNRI – against menopausal vasomotor symptoms (hot flashes).
DGCG has supported considerable research on relationships of testosterone (T) levels in older men to functional outcomes and disease risk. Trials of T administration for physical functional deficits have shown modest effects. Epidemiologic studies have found an inverse relationship to mortality, but noted that the relationship could be due to diminution of T levels. A DGCG-supported clinical trial of T in frail older men found increased risk of cardiac and other events in the treatment group. A recent Phase II trial to test T effects on several symptomatic conditions as well as bone and cardiovascular factors in unambiguously hypogonadal men has recently been completed (results still blinded). Because T is administered widely to older men for a variety of indications in real-world health care session we have funded a group of studies to assess relationships of T treatment to adverse outcomes in health care databases.
There have been important findings on vitamin D, confirming associations of low circulating vitamin D with a variety of health outcomes. A randomized trial has determined the dose response of circulating vitamin D to supplementation both white and African American women, indicating that 800 IU/d is generally sufficient. A recently-started trial will determine whether vitamin D supplementation in older persons with low circulating vitamin D and impaired physical function will reduce falls risk and improve walking speed.
Research has continued on relationships between markers of inflammation and adverse outcomes and risk factors in older persons, including findings of an inverse relationship to telomere length. A persisting issue regarding such findings is the "chicken or egg" question: Do elevated inflammatory factors cause the morbidity or vice versa. To address this problem in regard to the association between elevated inflammatory markers and physical functional impairment, DGCG issued an RFA for a randomized trial to assess effects of modulators of inflammation on physical functional outcomes.
Possible future directions for research on interventions against adverse aging changes include study of additional outcomes beyond vasomotor symptoms in trials of interventions against adverse consequences of menopause. In addition, continued efforts are needed to identify interventions that successfully target pathologies closely linked to aging processes, such as central arterial stiffening, various pathologies contributing to skeletal muscle functional deficits, and heart failure with preserved ejection fraction.
Studies on protective factors contributing to exceptionally healthy aging have identified new predictors of mortality in humans, including factors related to longevity in laboratory animals, as well as a multivariate predictive model. Another study developed a composite metric, the Healthy Aging Index which incorporates diverse physiologic factors, predicts mortality, and has been shown to have substantial heritability.
There has been considerable attention to "endophenotypes" of exceptional longevity and health span: specific domains in which healthy function is maintained in advanced age. These endophenotypes are clustered in exceptionally long-lived families. These include exceptionally good maintenance of cognitive function, which is heritable and for which genetic linkage studies identified a locus associated with exceptional memory. Associations of factors with exceptional health span have been found, including relationships of specific immune/inflammatory profiles to high levels of physical and cognitive function. Rates of change with age in physical function and cognitive function have been associated with rates of change with age in DHEA sulfate and interleukin.
Considerable attention has been given to determining the translational potential of the widely replicated findings on human genetic variants showing relationships of APOE2 and certain FOXO3 intronic variants to longevity. The Longevity Consortium's translational core is conducting pilot clinical and in vitro studies to identify functional pathways that could lead to identification of therapeutic targets. These types of studies can be developed more extensively by a soon-to-be funded network award on this topic
A two-year clinical trial of caloric restriction (CALERIE), which has long been known to extend life span in many, though not all, animal models, demonstrated feasibility of sustained human CR (for at least two years) and favorable effects on predictors of longevity and cardiometabolic risk factors.
Emerging research opportunities on interventions to extend health span include expansion of translational functional studies on effects of human variants associated with exceptional longevity. There is also a need for better long-term predictive human markers to assess potential interventions to extend health span, and consideration of studies to further characterize similarities and differences in effects of caloric restriction and physical activity.