Council Minutes — September 2023

Appropriations Status for the National Institute on Aging

The current fiscal year (FY) 2023 will end on September 30, and the National Institutes of Health (NIH) and NIA are awaiting the next congressional appropriation for FY2024. On June 14, 2023, the House Labor-Department of Health and Human Services spending bill advanced out of the subcommittee and is awaiting consideration by the full committee, followed by the House. If the House spending bill is enacted, NIH would receive $43 billion, a $3.8 billion decrease from FY2023, and NIA would receive $4.41 billion as flat funding relative to FY2023. On July 27, 2023, the Senate Labor, Health and Human Services, Education, and Related Agencies appropriations bill advanced out of the full Committee on Appropriations and now awaits a Senate vote. If the Senate spending bill is enacted, NIH would receive $47.8 billion, a $943 million increase from FY2023, and NIA would receive $4.51 billion, an increase of more than $100 million from FY2023. The proposed Senate bill would also result in a $100 million increase for Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) ($90 million increase to NIA and $10 million increase to the National Institute on Neurological Disorders and Stroke) and an additional $12 million for palliative care research. These appropriations depend on the avoidance of a government shutdown as well as signature from the President.

2025 Professional Judgment Budget for Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias

Each year through 2025, the NIH Director submits a professional judgment budget directly to the President for the NIH initiatives pursuant to the National Alzheimer’s Plan.³ This professional judgment budget reflects input from NIH, academia, industry, other federal agencies, nongovernmental organizations, and advocates. The budget outlines priorities, gaps, and opportunities that are then translated into specific milestones to address the initiatives’ goals as well as funding allocation requests to accomplish each milestone. The

2023 National Institutes of Health Report: Alzheimer’s Disease and Related Dementias Research

The

National Institute on Aging Updates

Dr. Hodes summarized NIA updates. In September 2023, NIA launched the EUREKA challenge prize competition to discover the best data, methods, and strategies for the early prediction of AD/ADRD. This challenge includes an emphasis on building diverse teams and solutions to include groups historically excluded from participation in AD/ADRD research and will offer cash awards totaling $650,000.

Beginning in 2022, NIA has offered several training awards designed to develop a wider range of professional skills and experiences (e.g., bio-entrepreneurship; intellectual property; science communications, policy, and education; regulatory affairs; drug discovery, approval, and production; consulting) both within and outside of academic research under the Research and Entrepreneurial Development Immersion (REDI) Program . The next deadline for the REDI Mentored Entrepreneurial Career Development Award ( PAR-22-227 ) is October 18, 2023. In addition, while a letter of intent is due 30 days prior, the deadline for the REDI Entrepreneurship Enhancement Award ( PAR-22-226 ) is also October 18, 2023.

As required by the FY2023 Consolidated Appropriations Act, NIA and the National Institute on Neurological Disorders and Stroke have entered into an agreement with the National Academies of Sciences, Engineering, and Medicine (NASEM) to identify research priorities for preventing and treating AD/ADRD. The task order was established on March 27, 2023, and the NASEM committee is expected to be established in September 2023. The committee will (1) examine and assess the current state of biomedical research aimed at preventing and effectively treating AD/ADRD, along with the research and development pipeline from basic to translational to clinical research; (2) assess the evidence on nonpharmacological interventions aimed at preventing and treating AD/ADRD; (3) identify key barriers to advancing AD/ADRD prevention and treatment and opportunities to address these key barriers and catalyze advances across the field; and (4) explore the most promising areas of research into preventing and treating AD/ADRD. The final report is anticipated in the beginning of 2025.

NIA has launched OutreachPro , an AD/ADRD clinical trial recruitment tool that helps researchers and grantees create outreach materials designed for and tested with specific audiences. These materials were systematically created through literature reviews, listening sessions with stakeholders, focus groups, surveys, and user feedback testing. Users can develop more than 200 unique, customized materials using combinations of designs, health statuses, demographics, and languages.

NIA, in collaboration with the Foundation for the National Institutes of Health and the McKnight Brain Research Foundation, will host the fourth Cognitive Aging Summit on March 20-21, 2024, at the Bethesda North Marriott Hotel and Conference Center. In addition, since May 2023, NIA has released 20 research highlights featuring NIA-supported publications, 16 blog posts, and 3 news announcements. Dr. Hodes and other senior NIA staff have participated in 15 stakeholder and advocacy group meetings as well as 4 congressional briefings and hearings.

National Institutes of Health Updates

Dr. Hodes also summarized NIH updates. On May 15, 2023, President Joseph R. Biden announced his intent to nominate Dr. Monica Bertagnolli as the NIH Director. She is the current Director of the National Cancer Institute and is a world-renowned surgical oncologist, cancer researcher, and educator. Her appointment as NIH Director requires confirmation by the U.S. Senate, and most recent conversations have suggested this hearing will occur in October 2023.

NIH posted a Request for Information (RFI) inviting comments and suggestions on updating the NIH mission statement ( NOT-OD-23-163 ); the deadline for responses is November 24, 2023. The RFI is requesting feedback on the following proposed revised mission statement: “To seek fundamental knowledge about the nature and behavior of living systems and to apply that knowledge to optimize health and prevent or reduce illness for all people.” This new mission statement removes the intent to reduce disability, and NIH is especially seeking responses from those in the disability community.

NIH has established its Institutional Excellence in Diversity, Equity, Inclusion, and Accessibility (DEIA) in Biomedical and Behavioral Research Prize Competition, which is a new initiative that aims to recognize and reward effective strategies for enhancing DEIA in research environments across the United States. Entries are due September 26, 2023, and NIH will award up to 10 prizes of $100,000 to academic institutions.

Discussion

Dr. Hodes clarified that the additional $318.06 million in funding requested above the baseline from FY2023 is exclusively for new research projects. If approved, these additional funds will become part of the next FY baseline funds.

Nathan Shock Centers of Excellence in the Basic Biology of Aging

The Nathan Shocks Centers of Excellence in the Basic Biology of Aging Program was initiated in 1995 and currently funds eight Centers of Excellence. These Centers provide expertise and core facilities for aging research and have been a cornerstone of basic aging biology research at NIA. These eight Centers cover the breadth of priority areas for DAB, and each offers diverse technologies and expertise to serve the aging research community in most areas supported by DAB. Centers also provide pilot funding for individuals to use core facilities. Although most of this pilot funding is awarded to young investigators at institutions with a Center of Excellence, the Centers are increasingly advertising these opportunities to encourage applications from investigators from any institution and country. Renewal of this concept would provide opportunities for new applications for Centers of Excellence. The Program underwent a review and evaluation between 2022 and 2023, and the evaluation team noted that the Centers were achieving their goals of leading and innovating aging research, attracting and training scholars, and promoting collaboration. The evaluation team identified some areas for improvement in promoting collaborations, and the NOFO addressed these prioritized improvements.

Nathan Shock Centers of Excellence in the Basic Biology of Aging Coordinating Center

The Nathan Shock Centers of Excellence in the Basic Biology of Aging Coordinating Center was established in 2017, well after the initiation of the initial Centers of Excellence. The goal of the Coordinating Center is to provide outreach to the broader aging research community and to track the impact of each Center of Excellence. The Coordinating Center also underwent an evaluation in 2022, and the evaluation team noted significant progress in all goals, including outreach to researchers and enhancement of resource sharing across Centers. The Coordinating Center also provides logistical support to pilot grant recipients and has promoted interactions across Centers and with other aging organizations. When asked for feedback on the Coordinating Center, principal investigators (PIs) of each of the eight Centers expressed positive feedback on its contributions. The Coordinating Center has a broad social media presence where they advertise webinars and have increased the profile of these Centers of Excellence. The evaluation team provided some areas for improvement for the Coordinating Center, although most were strictly administrative.

Research Collaboration Network in Structural Racism Measurement and Modeling

This concept proposes the creation of a new R24 Cooperative Agreement Network to advance the study of health disparities in the context of structural racism. This concept follows recommendations from the 2019 NACA review of BSR and a previous NASEM meeting. Because researchers who study health disparities may not have expertise in measurement and modeling of structural racism, this type of research tends to be performed by social scientists who do not primarily focus on health research. By bringing together these two groups, health disparities researchers and social scientists can collaborate to better model and measure the effects of structural racism on health disparities. Dr. Manly had recommended the applicant improve the presentation and explanation about the specific agenda for this concept.

Centers on the Demography and Economics of Aging, Including Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) and Coordinating Center

The renewal request for this concept would continue support for demography and economics of aging P30 programs that encourage new and innovative research in the field. Renewing this program would add a new emphasis on the inclusion of a more representative group of scholars and institutions. Currently, only 3 out of 15 demography and economics centers focus on AD/ADRD. These three centers support pilot projects, establish research networks, host conferences and workshops, develop and promote research resources and infrastructure, and share results and resources with the scientific community and general public. The new call for centers includes two optional cores—the pilot core and remote data enclave core—in addition to the administration and research support cores. The former would enhance research capacity building outside the boundaries of the respective institution, while the latter would enhance and streamline data access across multiple sources. Dr. Inouye recommended making all three cores required in the Request for Applications (RFA), and WGOP members accepted this recommendation.

Deriving Common Data Elements from Real-World Data for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias

Real-world data have the potential to unlock actionable health care insights not typically obtained from traditional randomized clinical trials or surveys. Implementation of common data elements (CDEs) across data systems can help enable data harmonization and subsequent large-scale data analysis. NIA assembled a technical expert panel that recommended the creation of CDEs that would be acceptable in cross-sectional and longitudinal studies from seven domains using electronic health records (EHRs). Under this concept, researchers will standardize vocabulary and develop and test longitudinal CDEs using EHRs and Centers for Medicare & Medicaid Services data. This effort will complement the Real-World Data Platform RFA that focuses on data transformation and harmonization. In addition, researchers will manage a research study program to encourage researchers to use CDEs.

Open Measurement Coordinating Network for Non-Pharmacological AD/ADRD Primary Prevention Trials

Although midlife is the optimal age group to target for primary prevention of AD/ADRD, many trials do not target this age group. Therefore, NIA formed a working group to discuss the current needs for developing primary prevention trials for AD/ADRD. The working group recommended establishing outcome measurements (e.g., biomarkers, functional outcomes) as the first step toward successful primary prevention trials. The goal of this concept is to establish a measurement coordinating network for non-pharmacological primary prevention trials for AD/ADRD. Specifically, this network will develop a framework of innovation to support, develop, validate, and disseminate measures and methods for AD/ADRD prediction and underlying disease mechanism identification. These measures can then be used to effectively measure trial outcomes. The network will create a platform to enable development of these outcome measures and support trials targeting a broad range of outcomes including cognition, social determinants of health, biomarkers, psychosocial outcomes, and functional outcomes. The platform will also help identify new study designs and factors that may affect measure validation. The network will also evaluate the platform to ensure that it adapts to the changing research environment. In addition, the network will interact with other NIA programs, including the Health and Retirement Study, NIA Toolbox, and Roybal Centers.

Consortium for Palliative Care Research Across the Lifespan

The core elements of this proposed consortium are to treat symptoms (e.g., pain, spiritual, psychological), identify goals of care, and facilitate care coordination at the end of life. The goals of this consortium are to (1) generate new scientific information in geriatric palliative care, (2) foster development of new early- and mid-stage researchers in the field, (3) serve as a national resource center to facilitate high-quality research on palliative care, and (4) engage health care systems and communities. This concept clearly aligns with NIA’s mission. Program development activities for this initiative include workshops involving the National Palliative Care Research Center and other working groups. The concept proposed several essential cores that were appropriate, but there was some discussion about whether AD/ADRD itself should be a core. The Council decided that AD/ADRD would instead be integrated at all the program’s cores rather than comprise a standalone core.

Safety and Early Efficacy Studies of Psychedelic-Assisted Therapy for Chronic Pain in Older Adults

Recent studies have demonstrated the efficacy of psychedelic-assisted treatment (PAT) in major and refractory depression; however, these studies did not include older adults. Therefore, the overarching goal of this concept is to develop a strong evidence base for the safety and preliminary efficacy of PAT for chronic pain in older adults. This concept will use a two-phased approach: (1) safety studies in healthy older adults and (2) expanded safety and preliminary efficacy studies in older adults with chronic pain conditions. Testing of PAT requires careful patient screening and preparatory psychotherapeutic sessions to avoid any counter-indications. PAT uses agents such as psilocybin and 3,4-Methylenedioxymethamphetamine (MDMA) in one to three dosing sessions in combination with psychotherapeutic approaches (e.g., cognitive behavioral therapy) across a week-long intervention period. The concept will include a multi-center consortium to support this two-phased approach to test PAT across a broad older adult age range, including people aged 80 and over and eventually people with mild cognitive impairment and dementia. The Council emphasized the importance of specifically outlining pain sources and developing stratification plans by specific age ranges and people with dementia to detect any differences in safety in those of advanced age. It also recommended developing a more in-depth assessment of PAT acceptability and strategies to reduce or address stigma associated with psychedelic drug use.

Multi-Scale Models Bridging Levels of Analysis in Aging and AD/ADRD

The rapid evolution of computational science, including artificial intelligence and machine learning, is generating new strategies for studying AD/ADRD. These approaches enable multifunctional modeling that can provide useful new insights into aging and AD/ADRD. The concept aims to develop a multi-scale computational framework to model changes associated with aging and AD/ADRD to address a specific research question, and this framework should bridge at least two levels of analysis on the spatial (e.g., cells, behavioral, etc.) or temporal scales (e.g., short snapshots of time, generations, etc.). This integrative approach will help bridge investigators using computational approaches with those using experimental approaches.

Translational Bioinformatics and Experimental Approaches to Advance Drug Repositioning and Combination Therapy Development for Alzheimer’s Disease and Related Dementias

NIA previously established this cross-disciplinary program in 2017 to utilize translational bioinformatics to repurpose drugs and combination therapies for AD/ADRD. By repurposing existing drugs, researchers can shorten drug development times and reduce costs while improving drug development success rates. This program has brought together data science investigators and AD/ADRD investigators to apply computational methods for drug repurposing, identifying hundreds of candidate drugs for AD/ADRD. However, further development of these candidates requires experimental and functional data validating the efficacy of drug and combination therapy for AD/ADRD. With the renewal of this concept, the program will (1) expand NIA’s investment in data-driven approaches to AD/ADRD drug repurposing and combination therapy development and (2) conduct preclinical proof-of-concept efficacy and mechanistic studies in in vitro and in vivo disease models. To support both efforts simultaneously, the program will only support computational approaches when proposed in conjunction with experimental efficacy studies. This program will also facilitate full transparency of methods and data reporting.

Exploring Proteogenomic Approaches to Unravel the Mechanisms of Misfolded Protein Accumulation in Tauopathies

Although misprocessed and misfolded proteins are defining characteristics of AD and many ADRDs, traditional omics approaches cannot detect these protein states. Therefore, this concept aims to use a proteogenomics (i.e., a novel strategy combining proteomics, transcriptomics, and genomics data to identify novel proteins) approach to identify atypical proteins in tauopathies as a proof-of-concept to study the underlying mechanisms of protein processing in early pathogenesis of AD tauopathies. For example, single nucleotide variants, frameshift variants, and alternatively spliced isoforms may be associated with misfolded protein products. The concept will (1) identify and confirm changes in protein processing and folding and (2) use robust biological inference to improve understanding of proteomic data. This concept may require other approaches (e.g., RNA sequencing, mass spectrometry-based deep proteomic analysis, transgenic mice) for functional studies of altered protein homeostasis in response to the accumulation of misprocessed and misfolded proteins in AD.

Small Research Grant Program for the Next Generation of Researchers in Low- and Middle-Income Countries (LMICs) for Aging and Alzheimer’s Disease and AD-Related Dementias Research

Diversity in global AD/ADRD research is critical for ensuring the generalizability of results. However, junior investigators in LMICs often lack sufficient financial support and face challenges in applying for and utilizing NIH K awards, the main mechanism for junior investigator development. Therefore, this concept proposes the use of Small Research Grants (R03) to support junior investigators in LMICs involved in AD/ADRD and aging research. By supporting these investigators, the concept will also advance AD/ADRD and aging research in LMICs, build local capacity for this research in LMICs, and support career development for researchers in the aging and AD/ADRD fields. The concept will also require applicants to include a professional development plan and identify a mentor. This Small Research Grant mechanism will provide LMIC junior investigators with greater flexibility and opportunities for data generation in preparation for later-stage independent funding proposals.

Consortium for Neuroscience AD/ADRD in Low- and Middle-Income Countries

This concept, along with others that will support LMICs, are crucial for future AD/ADRD research because two-thirds of the global population with AD/ADRD live in LMICs. This concept aims to provide five years of funding support to experienced LMIC scientists performing innovative and sustainable AD/ADRD research within their respective LMICs. With this funding, LMIC scientists can enhance their ability to compete for additional, future funding opportunities. This concept proposes using cooperative agreements to facilitate collaboration between LMIC and U.S. investigators. Proposed research should be investigator-initiated, and applicants will need to explain how the proposed research can inform AD/ADRD prevention and treatment strategies across the globe. NIA will dispense awards directly to LMIC institutions.

Coordinating Center to Support the Consortium for Neuroscience AD/ADRD in Low- and Middle-Income Countries

This coordinating center will facilitate outreach, communication, and coordination for the Consortium for Neuroscience AD/ADRD in LMICs, which includes NIA LMIC junior investigator and established investigator awardees. This concept also proposes developing a portal to facilitate data sharing using existing databases in accordance with Findable, Accessible, Interoperable, and Reusable (FAIR) principles. The recipient of this coordinating center award will reside in the United States and have demonstrated expertise in coordination of research projects in LMICs.

Early- and Late-Stage Clinical Trials for the Spectrum of Alzheimer’s Disease/Alzheimer's Related Dementias and Age-Related Cognitive Decline

Previously, this concept was successful in supporting a range of innovative treatment approaches beyond those targeting amyloid. This concept would support clinical testing (Phases I through III) of pharmacological and non-pharmacological interventions for cognitive and psychiatric symptoms in people with age-related cognitive decline and people across AD/ADRD stages. The concept may also support studies aimed at enhancing the design and methodology of AD/ADRD and age-related decline clinical trials, given the high cost of these clinical trials. This concept will require funding recipients to ensure diversity of study participants and make results and biospecimens available to the scientific community in a timely manner.

Alzheimer’s Clinical Trials Consortium (ACTC) Clinical Trials

ACTC consists of NIA-supported clinical trials infrastructure and a network of 38 sites with the mission to provide optimal infrastructure to accelerate development of AD/ADRD interventions. This concept aims to increase the Consortium’s number of pipeline interventions by funding clinical testing of promising interventions that target cognitive and psychiatric changes associated with age-related decline and AD/ADRD across disease stages (i.e., from pre-symptomatic to severe stages). Importantly, the Consortium does not duplicate efforts of pharmaceutical companies. ACTC’s selection process involves a rigorous evaluation by a steering committee, and ACTC provides trial coordination and recruitment infrastructure to selected trials. One trial being launched is a small molecule clinical trial of a sigma-2 receptor antagonist, which may impact synaptic function. Another innovative trial under the ACTC involves testing the safety and efficacy of a combination of cannabinoids in hospice-eligible dementia patients.

Quantitative Systems Pharmacology Approach to Develop Predictive Models of Differential Responsiveness to Treatment

This concept addresses the challenge in AD/ADRD therapeutic development of identifying the patients most likely to respond to a particular treatment due to various patient and disease heterogeneities. This Quantitative Systems Pharmacology (QSP) approach combines computational and translational approaches at a systems level to determine mechanisms of action of drugs in preclinical models and patients. This concept will support the integration of multi-omics data generated from biosamples collected during previous and current AD/ADRD clinical trials. Multi-omics data paired with respective clinical and phenotypic data will enable the construction of AD/ADRD predictive models and the discovery of determinants of treatment responsiveness, such as biomarkers. Importantly, this concept will also include support for QSP modeling of previously failed AD/ADRD therapeutics to understand why they failed. The concept will also encourage collaborations between academia and industry and require adherence to open-science principles.

Limited Competition: Renewal of, and Revisions to, the Alzheimer’s Disease Genetics Consortium (ADGC)

This concept would renew ADGC, the coordinating center for the Alzheimer’s Disease Sequencing Project (ADSP) Consortium. ADSP aims to sequence and analyze human genomes to identify genetic variants associated with increased or reduced risk of AD/ADRD. These results can also extend previous discoveries to result in new therapeutic directions for AD/ADRD. ADSP has more recently launched two initiatives: (1) diversity and phenotype harmonization and (2) functional genomics and AI/ML. Identification of risk variants in globally diverse populations can help identify personalized AD/ADRD interventions as well as more broadly generalizable disease mechanisms. In support of ADSP, ADGC will facilitate collaboration and communications across ADSP-funded projects and other NIA-funded efforts. ADGC will oversee and coordinate the following activities: generation of consortium methodologies, protocols, and tools; development and maintenance of a consortium resources online portal; data use for AI/ML initiatives; data sharing and access; pilot studies; and dissemination of ADSP resources to the research community.

Renewal of Aging Research Dissertation Awards to Increase Diversity

This R36 award was established in 2005 to promote diversity of doctoral-level trainees engaged in aging and aging-related research. Applicants are Ph.D. students from underrepresented groups committed to a career as an aging researcher who require an additional one to two years of funding to complete their dissertation. This financial support provides recipients with a salary and may also cover travel to scientific meetings and other dissertation-related costs. Since its inception, the program has funded 78 awards, with 11 currently active awards. These awards have supported recipient authorship of more than 100 peer-reviewed publications. In the next phase of the program, NIA will set aside funding to support 10 awards per year and continue to identify additional strategies to best support those from groups underrepresented in aging research. Notably, increases in this R36 salary have not kept up with cost-of-living increases; this concept renewal proposes a salary of $42,500 (an increase of $15,356) and additional expenses support of $28,656 (an increase of $8,656).

Small Business Transition Grant for New Entrepreneurs

This concept aims to use lessons learned from the NIA REDI initiative and the National Cancer Institute Small Business Transition Grant to develop a diverse set of trainees with skillsets important for entrepreneurship and research and development. Under this concept, the SBIR/STTR mechanism will facilitate the development and transition of scientists to entrepreneurial roles. This funding would support small businesses in the hiring, salaries, mentorship, and training of scientist-entrepreneurs to become Program Directors and Principal Investigators overseeing research projects. Small business recipients will provide robust training and mentorship to support career growth. This concept will strengthen the interface between small businesses and early career scientists to create new technologies and therapeutics.

Renewal of Institutional Training Programs to Advance Translational Research on Alzheimer’s Disease (AD) and AD-Related Dementias

This concept aims to support the use of data science in AD/ADRD drug discovery by promoting the development of a diverse and interdisciplinary workforce. This concept uses the T32 mechanism to support institutional training programs for predoctoral and postdoctoral trainees with diverse educational backgrounds, emphasizing data science, drug discovery, and AD/ADRD clinical research skills. Trainees under these T32 awards will develop a strong foundational knowledge in AD/ADRD research and establish their scientific independence by conceptualizing their own research projects.

Renewal of NIA MSTEM: Advancing Diversity in Aging Research (ADAR) Through Undergraduate Education

Established in 2011, this R25 program actively supports 30 programs spanning all four NIA scientific divisions. Since its inception, more than 700 undergraduates have participated in these 30 programs, with 71 from underrepresented racial and ethnic groups, one-third from disadvantaged backgrounds, and 6 percent from the disability community. Nearly 400 undergraduates participated in programs funded between 2013 and 2018, with 75 percent from underrepresented racial and ethnic groups. Of these students, 54 percent were accepted to graduate school, and 83 percent of those students were admitted into aging-related programs. To attract and train a diverse workforce in aging and AD/ADRD research, this concept renewal will support creative research education programs with research experiences for undergraduates. Programs should allow for sustained, multi-year undergraduate involvement in programs during the academic year or summer session with various activities, such as structured research experiences, tailored learning opportunities, activities that explain the relevance of aging to students’ lives, and engagement activities to diversify the aging research workforce.

Renewal of Summer Research Training in Aging for Medical Students

The Summer Research Training in Aging for Medical Students is a Ruth L. Kirschstein National Research Service Award program supported by NIA as a short-term training program to encourage medical students to pursue either basic science, health services, or clinical research careers in aging. By extension, this program helps increase the pool of physician scientists in clinical and research areas important to NIA’s mission. Students in this program participate in various classroom, workshop, and research experiences under the supervision of experienced researchers to provide a better understanding of potential clinical and research career directions related to NIA goals, as well as necessary steps for career transitions.

Discussion

Dr. Hodes acknowledged the TRN’s work as a great example of the convergence of basic molecular science and population science, which demonstrates the need for further collaboration to develop and pursue useful telomere length measurement strategies.

Dr. Longo noted that as telomere length measurement assays improve in precision and sophistication, the telomere and neurodegeneration research communities will need to revisit any previously described associations between telomere length and neurodegeneration. Dr. Drury added that studies of telomere length in cerebrospinal fluid and peripheral blood samples will help researchers better understand the role of telomeres in neurocognitive aging and how to use peripheral blood sampling as a proxy for telomere length in the brain.

Dr. Schneider asked about how blood telomere length relates to brain and CSF telomere length. Dr. Drury explained that a trainee in her lab performed a complex cross-tissue correlational analysis and found that different tissue pairs have vastly different telomere levels or correlations, and consideration of biological mechanisms is required for meaningful interpretations of how telomere length in different tissues may relate to tissue-specific diseases (e.g., a specific type of cancer).

Dr. Longo also asked for more detail on the relationship between DNA methylation and other aging indicators. Dr. Drury explained that TRN analyzed an existing dataset containing information on DNA methylation biological clocks and found that each clock is associated with aging outcomes in a different way and is differentially related to telomere length. Therefore, composite markers are likely necessary to better understand biological aging.

Dr. Peterson asked for Dr. Drury’s opinion on the existing mouse telomere literature. Dr. Drury explained that many inbred laboratory mouse strains have very long telomeres whose trajectories do not follow the same age-related decline and changes in structure and length seen in humans. However, wild rodent telomeres do still follow telomere trajectories associated with aging. This difference is likely because repeated inbreeding in a laboratory environment has eliminated many environmental perturbations that may be important determinants for telomere length and aging trajectories. Notably, rhesus macaques have telomeres with very similar characteristics to those of humans.

Dr. Darren Baker noted that based on Dr. Drury’s findings on telomere length assay variability, these assays are likely poor methods to test interventional strategies for aging. Dr. Drury agreed and emphasized that current methods are not precise enough to detect any meaningful change in telomere length within an individual unless length is measured across a decade or longer. Telomeres also have dynamic roles via interactions with mitochondria that may be disrupted when telomeres are artificially lengthened. These dynamic roles, paired with oncogenic chromosomal fusions associated with abnormally long telomeres, indicate that telomeres require a balance of dynamics beyond simply lengthening to potentially improve aging and health outcomes.

Dr. Sohail Khan asked whether Dr. Drury stratified her telomere length analysis by race. Dr. Drury explained that the TRN study comparing telomere length ICCs only included samples from 41 individuals and was therefore not sufficiently powered to stratify by race. However, existing literature contains consistent evidence of racial differences in telomere length and changes in telomere length over time. Part of the accelerated aging seen in minority and marginalized populations is a function of multigenerational exposure to structural racism and inequity; additional data suggest that the effects of these exposures have been embedded across multiple generations. However, studies of racial differences in telomere length are limited to the United States, and further data from international populations are required to separate the effects of genetic ancestry from direct impacts of racism on telomere length. TRN does support some ongoing studies on intergenerational transmission of telomere length and how exposure to structural racism affects this transmission. Notably, a recent publication on accelerated aging in the placentas of women of color as compared to White women explored the implication that this accelerated aging may be related to increased rates of preterm birth in subsequent generations.

Discussion

Dr. Peterson asked what factors were driving the neighborhood effects on birth outcomes. Dr. Gillman explained that maternal obesity, gestational diabetes, and pre-eclampsia had independent effects from neighborhood characteristics on birth outcomes. However, the mediators of neighborhood factors remain unclear. Community norms are very important for changes in behaviors that reduce obesity rates in later childhood and adulthood. In addition, determinants transduced biologically should also be considered. Dr. Peterson further asked whether the study involved data collection on prenatal care. Dr. Gillman explained that investigators were unable to identify the causes of the neighborhood effects on birth outcomes but noted that other studies later in childhood and adulthood suggest that behaviors outside of the medical care system may mediate these neighborhood effects on birth outcomes.

Dr. Hodes noted that years of education is one of the most reliable predictors of dementia risk. He asked whether Dr. Gillman expected that these early life variables will prove to be similarly reliable predictors of dementia risk. Dr. Gillman explained that overlapping determinants identified in future ECHO studies of the prenatal/preconception through adolescence timeframe and the adolescence to early and mid-adulthood timeframe may provide insights into additional factors in early life that affect dementia risk.

Dr. Hodes asked Dr. Gillman whether he anticipates that a panel of biologic measures could help prioritize interventions at different years of development to improve aging outcomes. Dr. Hodes further noted that because some factors that negatively affect health outcomes occur so early in life, interventions to reverse these effects are needed beyond conventional prevention strategies. Dr. Gillman acknowledged the need for interventions that can reverse these effects and noted that better understanding of the biological underpinnings can provide further information about potential interventions and opportunities to reverse negative impacts on health outcomes.

Dr. Asthana explained that another measure of neighborhood disadvantage is the Area Deprivation Index, which consists of 17 variables, and asked how moving during childhood from one neighborhood to another can affect health outcomes. Dr. Gillman explained that the ECHO investigators who developed the COI and SVI are now looking at changes in these indices over time, especially when people move to other neighborhoods. However, results from this study may be confounded by the overall ability and willingness of families to move to other neighborhoods.

Dr. Peterson asked whether ECHO studies have ever analyzed the relationship between epigenetic markers in parents and their offspring. Dr. Gillman explained that several current studies are looking at maternal DNA methylation and DNA methylation of paternal sperm to measure epigenetics prior to conception. Based on rodent studies, certain behaviors that affect sperm epigenetics may impact birth outcomes.

Dr. Longo asked whether ECHO studies have assessed oxidative stress levels and epigenetics in children living in wealthy neighborhoods. Dr. Gillman indicated that ECHO investigators have not proposed studies in this area.

Dr. Nielsen asked about ECHO’s data harmonization efforts across cohorts for cognitive function and educational exposures. Dr. Gillman explained that initial ECHO studies used existing cohorts with different study designs and collection approaches. However, in the second funding cycle of ECHO, the program will use a single standardized protocol, including standardized approaches to collection of cognitive and neurodevelopmental outcomes as well as educational exposures in children and adolescents. He further noted that current ECHO funding only supports following study participants through age 21.

CHAIRPERSON

Hodes, Richard J., M.D.
Director, National Institute on Aging
National Institutes of Health
Bethesda, MD 20892-2292

MEMBERS

Asthana, Sanjay, M.D.
Professor and Associate Dean for Gerontology
Director, Wisconsin Alzheimer’s Disease Research Center
University of Wisconsin School of Medicine and Public Health
Madison, WI

Baker, Darren, M.S., Ph.D.
Associate Professor of Biochemistry and Molecular Biology
Associate Professor of Pediatrics
Mayo Clinic
Rochester, MN

Case, Anne, M.P.A., Ph.D.
Alexander Stewart 1886 Professor of Economics and Public Affairs, Emeritus
School of Public and International Affairs
Princeton University
Princeton, NJ

Ciliberto, Maritza E., Ed.M.
Director of Special Education
Boston Green Academy
Brighton, MA

Cruz, Yanira, M.P.H., Dr.P.H.
President and CEO
National Hispanic Council on Aging
Washington, DC

Greenspan, Susan L., M.D.
Professor of Medicine, Division of Geriatric Medicine
University of Pittsburgh
Pittsburgh, PA

Huang, Yadong, M.D., Ph.D.
Director
Gladstone Center for Translational Advancement
Professor, University of California, San Francisco
San Francisco, CA

Huling Hummel, Cynthia, D.Min.
Honorably Retired Pastor, PCUSA
Dementia Advocate, Advisor, Author, Artist, and Research Participant
Owego, NY

Inouye, Sharon K., M.D., M.P.H.
Professor of Medicine
Harvard Medical School
Director, Aging Brain Center
Marcus Institute for Aging Research, Hebrew SeniorLife
Boston, MA

Khan, Sohail, M.P.H., M.B.B.S.
Director of Health Research
Cherokee Nation Health Services
Tahlequah, OK

Longo, Frank, M.D., Ph.D.
George E. and Lucy Becker Professor and Chair
Department of Neurology and Neurological Sciences, MC5235
Stanford University School of Medicine
Stanford, CA

Lundebjerg, Nancy E., M.P.A.
Chief Executive Officer
American Geriatrics Society
New York, NY

Manly, Jennifer Jaie, Ph.D.
Professor, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain
Columbia University Medical Center
New York, NY

Peterson, Charlotte A., Ph.D.
Professor, College of Health Sciences
University of Kentucky
Lexington, KY

Reuben, David B., M.D.
Professor of Medicine, Division of Geriatrics
David Geffen School of Medicine at UCLA
Los Angeles, CA

Schneider, Julie A., M.D.
Professor and Associate Director, Rush Alzheimer’s Disease Center
Armour Academic Center
Rush University Medical Center
Chicago, IL

Van Eldik, Linda J., Ph.D.
Director, Sanders-Brown Center on Aging
Co-Director, Kentucky Neuroscience Institute
Co-Director, University Neuroscience Research Priority Area
University of Kentucky
Lexington, KY

Weir, David, R., Ph.D.
Research Professor, Survey Research Center
Research Affiliate, Populations Studies Center
University of Michigan
Ann Arbor, MI

EX OFFICIO

Becerra, Xavier, J.D.
Secretary
U.S. Department of Health and Human Services
Washington, DC

Bertagnolli, Monica, M.D.
Director
National Institutes of Health
Bethesda, MD

Holavanahalli, Radha, Ph.D.
Rehabilitation Program Specialist, National Institute on Disability, Independent Living and Rehabilitation Research
Administration for Community Living
U.S. Department of Health and Human Services
Washington, DC

Ordway, Anne, Ph.D.
Program Specialist, National Institute on Disability, Independent Living, and Rehabilitation Research
Administration for Community Living
U.S. Department of Health and Human Services
Washington, DC

AD-HOC MEMBERS

Epel, Elissa, Ph.D.
Professor, Department of Psychiatry and Behavioral Sciences
University of California, San Francisco
Weill Institute for Neurosciences
Vice Chair of Psychology, Director, Aging, Metabolism, and Emotions Center
San Francisco, CA

Hummer, Robert, Ph.D.
Professor, Sociology, Carolina Population Center
University of North Carolina at Chapel Hill
Chapel Hill, NC

EXECUTIVE SECRETARY

Santora, Kenneth, Ph.D.
Director, Division of Extramural Activities
National Institute on Aging
Bethesda, MD