Workshop: Synthetic Biology for Aging Research

cell connecting to human (decorative)

Purpose and Background

The Division of Aging Biology (DAB) at the National Institute on Aging (NIA) and the Division of Discovery Science and Technology (DDST) at the National Institute of Biomedical Imaging and Bioengineering (NIBIB) hosted a workshop on September 6-7, 2023, titled Synthetic Biology for Aging Research. The purpose of this workshop was to define goals and implementation options for synthetic biology to improve our understanding of aging biology and explore mechanisms to impact aging processes (molecular) and aging outcomes (physiology) and explore tools of synthetic biology to advance research on aging. Workshop speakers discussed building synthetic regulatory circuits or biomaterials that could:

  • Create novel clocks to measure rates of aging;
  • Alter hallmarks of aging (globally or with cell-lineage specificity);
  • Accelerate or decelerate rates of aging through identification and manipulation of gene regulatory and signaling networks;
  • Eliminate or regenerate senescent cells that promote "inflammaging".

The workshop brought together researchers from different fields to discuss ways to align toolboxes of synthetic biology to answer significant questions underlying aging biology, with a focus on the identification and manipulation of gene regulatory and signaling networks. Assessing the decline in the integrity and communication of regulatory and signaling networks and the modification of their effectiveness during the aging process requires de novo biological systems with the ability to design and build complex pathways with endogenous or novel functions and with predictable and quantitative responses to endogenous or environmental signals. Achieving this paradigm through synthetic regulatory circuits will allow the testing of hypotheses on complex biological systems and gain fundamental biological knowledge by applying synthetic biology approaches. By answering targeted questions about aging biology, new tools may be developed to identify and modulate the key genes and regulations that significantly affect the mammalian aging process at a cellular level.

Speaker List

  • Caleb Bashor, Ph.D., Rice University

    • Title: We engineer synthetic regulatory circuits in human cells

  • Nathan Basisty, Ph.D., National Institute on Aging (NIA)

    • Title: Geroproteomics unit: developing and applying proteomic tools to enable the translation of age-related disease interventions

  • Joanna Bons, Ph.D., Buck Institute for Research on Aging

    • Title: Investigating dynamic and spatial proteome remodeling during aging using proteomics

  • Amparo Cosio, Ph.D., Northwestern University

    • Title: Can we harness natural receptor mechanisms to engineer synthetic biosensors that respond to therapeutically-relevant molecules?

  • Tara Deans, Ph.D., University of Utah

    • Title: Synthetic biology: engineering synthetic gene circuits to direct cell fate

  • Jennifer Elisseeff, Ph.D., Johns Hopkins University

    • Title: Tissue mapping across the lifespan

  • Nan Hao, Ph.D., University of California San Diego

    • Title: Engineering gene networks to promote longevity

  • Karmella Haynes, Ph.D., Emory Winship Cancer Institute

    • Title: Haynes lab for chromatin epigenetic engineering

  • Seong Hu Kim, Ph.D, Emory University

    • Title: Investigating promoters and enhancers targeted by a synthetic reader-actuator in H3K27me3-enriched chromatin

  • Josh Leonard, Ph.D., Northwestern University (*workshop co-chair)

    • Title: Development of parts & programs for implementing synthetic biosensing, regulation, and control, and application-driven development of next-generation cell and gene therapies

  • Mitchell Lewis, Ph.D., Huntsman Cancer Institute, University of Utah

    • Title: Engineered platelets for therapeutic delivery

  • Joscelyn Mejias, Ph.D., Johns Hopkins University

    • Title: Age and sex differences in the fibrosis immune response

  • Bradley Olinger, Ph.D., National Institute on Aging (NIA)

    • Title: What role do senescence markers play in age-related clinical traits?

  • Patrick Phillips, Ph.D., University of Oregon

    • Title: Genetics of complex traits

  • Birgit Schilling, Ph.D., Buck Institute for Research on Aging (*workshop co-chair)

    • Title: Role of senescence and ECM during aging, and development of biomarkers and aging interventions

  • Laura Sagatori, Ph.D., Rice University

    • Title: Engineering synthetic regulatory systems to program mammalian cells

  • Zach Stevenson, Ph.D., University of Oregon

    • Title: Increasing the throughput of transgenesis in animals for synthetic biology: T.A.R.D.I.S. (Transgenic Arrays Resulting In Diversity of Integrated Sequences)

  • Hetian Su, Ph.D., University of California San Diego

    • Title: Understanding cell longevity as a result of system dynamics

  • A.J. Walters, Ph.D., Rice University

    • Title: What if barriers in MSC-based cell therapy could be overcome with synthetic biology?

Executive Summary

The workshop "Synthetic Biology for Aging Research” was convened on September 6 and 7, 2023, by the Division of Aging Biology of the National Institute on Aging , in conjunction with the National Institute on Biomedical Imaging and Bioengineering . The aims of the workshop were to promote the application of synthetic biology principles to the field of aging research and to stimulate collaborative research across the two disciplines. Research on the biology of aging focuses on understanding the cellular and molecular processes that underlie aging and aging-related changes in organismal health, while synthetic biology is focused on engineering living systems capable of performing useful functions. During the workshop, participants explored how researchers can utilize tools from synthetic biology (e.g., synthetic regulatory circuits) to address questions regarding the biology of aging and to develop the capability to intervene in aging processes and impact aging-related outcomes.

The workshop opened with introductory presentations in the fields of aging research and synthetic biology that outlined foundational concepts and major research questions in the two disciplines. A series of short talks were presented, in which participants highlighted their research. During the first two breakout sessions, participants were divided into four groups—each including individuals from both synthetic biology and aging research backgrounds—to identify opportunities for cross-disciplinary collaboration. These opportunities were discussed further during the third breakout session.

Below are the takeaway messages from the breakout sessions at the workshop.

Discovery

In this breakout session, speakers and participants discussed:

  • Key opportunities to apply synthetic biology to aging research including developing
    • amplifiers, reporters, and recorders of molecular signatures (e.g., biomarkers, phenotypes, dynamics, and heterogeneity) to elucidate aging-related dynamic processes, temporal changes, facets of heterogeneity, and noise;
    • cellular sentinels that can trigger amplifiers that initiate the delivery of a therapy; and
    • molecular readouts of functional metrics or performance that could be used to reflect the state of cell health through its maturation, peak, and decline.
  • Using synthetic biology tools to perturb aging processes and evaluate the reaction of cells or organoids to help distinguish correlation from causation.
  • Integrating synthetic biology approaches to develop new model systems for aging.

Therapeutic Concepts

Regarding therapeutic concepts, collaborative ideas generated included developing:

  • screening tools for drug development; drug delivery strategies;
  • cell-based therapies for modulating the aging environment; and
  • tools for interrogating and perturbing intercellular coordination and communication.

Synthetic biology could enable greater precision in designing safe and effective therapies by determining which targets and tissues underlie greater lifespan. For example, synthetic parabiosis—the idea that complicated interventions can be recapitulated into interventions that are simple and translational—could potentially be used to shift or reprogram the overall aging “state” of a patient. The tools of synthetic biology could be applied to develop strategies for rejuvenation through targeted delivery (e.g., to specific tissues, cell types, and the extracellular matrix), to use chromatin engineering to rejuvenate cell states, and to engineer the microbiome to affect aging. Approaches that focus on the mitochondrial axis as a pillar of aging include mitochondrial therapies, the use of synthetic mitochondria, and interrogating organelle-scale contributions to aging. Moreover, synthetic biology could be applied to create a diversity of natural products as inputs into the drug discovery platform for use in aging treatment.

Potential Research Plans

In the third breakout session, four working groups developed potential research plans.

Working Group A focused on the opportunity to bring orthogonal systems and synthetic biology tools into the C. elegans worm model. This model has great potential to integrate novel synthetic biology approaches with aging biology to perform complex research for which existing foundational tools are insufficient. Beginning this work will require determining what is needed to build circuits to facilitate external control of aging-related genes or autonomous control to change aging phenotypes.

Working Group B discussed collaborative research using sentinel cells—which can report on and respond to cellular biomarkers—to study the aging process. Sentinel cells can report a variety of data (e.g., transcriptomics, proteomics, molecular secretions) that may be used to identify biomarkers of aging. The group also discussed how synthetic biology could be used to interrogate the sender-receiver phenomena within the secretome; this approach could help to elucidate the mechanisms by which senescence spreads and by which the spread is regulated.

Working Group C focused on collaborative opportunities related to precision aging at the cellular level, and specifically on the development of in vitro human cell-culture platforms and synthetic reporters to better understand aging at the single-cell level, induce aged cell states, and screen therapeutics for cellular-level effects. Synthetic biology approaches could be applied to determine whether genes implicated in an aging-related process are causing that process or merely correlated with it—e.g., by applying synthetic regulation to genes or artificially controlling other cellular features—and to build promoters responsive to researcher-selected inputs to control the timing and magnitude of interventions.

Working Group D suggested opportunities for collaborative work on payload delivery and targeting specific cell types. Given that targeting and killing senescent cells can intervene in aging processes, and senescent cells are very heterogenous, it would be useful to apply synthetic biology to identify and specifically target distinct types of senescence. Another area discussed involved the potential for developing a reporter quantifying increasing inflammation that occurs with aging (i.e., inflammaging). This could be achieved with a cell that hones in on sites of inflammation and reports—over the lifetime of an organism—the location and amount of inflammaging. Another opportunity is to use synthetic biology tools to develop markers for early versus late senescence, then quantify those to inform the creation of a reporter for early-senescent cells versus late-senescent cells. Better understanding this temporal aspect of senescent cells, and their dynamic changes, through longitudinal monitoring in a human or model system could yield a host of insights.


Contact Information

Please contact Dr. Fei Wang, NIA, at fei.wang@nih.gov or Dr. Tuba Fehr, NIBIB, at tuba.fehr@nih.gov if you are interested in reading the full workshop summary report or if you have any other questions about the workshop.