Molecular Resiliency and Aging

Resilience is described as the ability to respond to acute forms of stress and recover to normal homeostasis. There is growing evidence that biology of resilience is entwined with the biology of aging. With increasing age, resilience decreases and is a likely contributor to increased morbidity, frailty and susceptibility to death with age. Conversely, increased resilience across numerous physiological markers of function is associated with longevity and healthy aging. The variation in resilience in populations suggests biological and molecular regulatory mechanisms that might provide insight into interventions to improve resilience, healthy aging and longevity. In this session, speakers will provide insight regarding short-term assays of resilience in animal models that prove useful both in delineating these biological mechanisms as well as inform on potential translational models to better understand biological resilience in human populations. The sessions focus is on defining these assays and discussion of the biological relevance each resilience assay in terms of the regulation of aging. The goals of these studies range from identifying potential predictors of individual lifespan within markers of functional resilience to leveraging geroscience to define whether markers of resilience can be modified through interventions to the aging process. Moreover, better understanding of the biology of resilience could assist in defining novel interventions that improve resilience and thereby enhance longevity.

Resilience as a Determinant of Healthspan and Lifespan in Mice

Dynamic measures of physical resilience—the ability to resist and recover from a challenge—may be informative of biological age far prior to overt manifestations such as age-related diseases and geriatric syndromes (i.e., frailty). If true, physical resilience at younger or middle ages may be predictive of future healthspan and lifespan, and provide a unique paradigm in which interventions targeting the fundamental biology of aging can be tested. This seminar will discuss research on the development of clinically relevant measures of physical resilience in mice, including anesthesia, surgery, and cytotoxic drugs. It will further highlight how these measures compare between young, middle-aged, and older mice, and how mid-life resilience relates to later-life healthspan and even lifespan. Finally, it will provide insight into whether interventions targeting the biology of aging can modify physical resilience in mice.

Deep Longitudinal Proteomics Profiling Reveals Biological Pathways Responding to GRF6019 in Two AD Clinical Trials

Blood has been widely investigated to discover biomarkers and gain insights into the biology of aging and age-related diseases. Its protein composition provides insights into complex biological processes, as proteins are often direct regulators of cellular pathways. In clinical trials, selected proteins have been used as primary and secondary endpoints, but recent methodological developments allow the measurement of thousands of proteins with very high sensitivity and specificity. In two phase 2 clinical trials testing the safety, tolerability, and feasibility of infusions of the plasma fraction GRF6019 in Alzheimer's disease (AD), we measured more than 7000 proteins in plasma over the course of the clinical trials. Differential trajectories analysis revealed groups of proteins and pathways that were responding to GRF6019. Several pathways were relevant to the biology of aging and AD and our study suggests that deep proteomics profiling can inform on specific biological processes responding to treatment in clinical trials.

Bridging the gap: A geroscience primer for neuroscientists with potential collaborative applications

While neurodegenerative diseases can strike at any age, the majority of afflicted individuals are diagnosed at older ages. Due to the important impact of age in disease diagnosis, the field of neuroscience could greatly benefit from the many of the theories and ideas from the biology of aging – now commonly referred as geroscience. As discussed in our complementary perspective on the topic, there is often a “silo-ing” between geroscientists who work on understanding the mechanisms underlying aging and neuroscientists who are studying neurodegenerative diseases. While there have been some strong collaborations between the biology of aging and neuroscientists, there is still great potential for enhanced collaborative effort between the two fields. To this end, here, we review the state of the geroscience field, discuss how neuroscience could benefit from thinking from a geroscience perspective, and close with a brief discussion on some of the “missing links” between geroscience and neuroscience and how to remedy them. Notably, we have a corresponding, concurrent review from the neuroscience perspective. Our overall goal is to “bridge the gap” between geroscience and neuroscience such that more efficient, reproducible research with translational potential can be conducted.

The Biology of Aging in Insects: From Drosophila to Other Insects and Back

An enormous amount of work has been done on aging in Drosophila melanogaster, a classical genetic and molecular model system, but also in numerous other insects. However, these two extensive bodies of work remain poorly integrated to date. Studies in Drosophila often explore genetic, developmental, physiological, and nutrition-related aspects of aging in the lab, while studies in other insects often explore ecological, social, and somatic aspects of aging in both lab and natural populations. Alongside exciting genomic and molecular research advances in aging in Drosophila, many new studies have also been published on aging in various other insects, including studies on aging in natural populations of diverse species. However, no broad synthesis of these largely separate bodies of work has been attempted. In this review, we endeavor to synthesize these two semi-independent literatures to facilitate collaboration and foster the exchange of ideas and research tools. While lab studies of Drosophila have illuminated many fundamental aspects of senescence, the stunning diversity of aging patterns among insects, especially in the context of their rich ecology, remains vastly understudied. Coupled with field studies and novel, more easily applicable molecular methods, this represents a major opportunity for deepening our understanding of the biology of aging in insects and beyond. Expected final online publication date for the Annual Review of Entomology, Volume 67 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Organoids: An Emerging Tool to Study Aging Signature across Human Tissues. Modeling Aging with Patient-Derived Organoids

The biology of aging is focused on the identification of novel pathways that regulate the underlying processes of aging to develop interventions aimed at delaying the onset and progression of chronic diseases to extend lifespan. However, the research on the aging field has been conducted mainly in animal models, yeast, Caenorhabditis elegans, and cell cultures. Thus, it is unclear to what extent this knowledge is transferable to humans since they might not reflect the complexity of aging in people. An organoid culture is an in vitro 3D cell-culture technology that reproduces the physiological and cellular composition of the tissues and/or organs. This technology is being used in the cancer field to predict the response of a patient-derived tumor to a certain drug or treatment serving as patient stratification and drug-guidance approaches. Modeling aging with patient-derived organoids has a tremendous potential as a preclinical model tool to discover new biomarkers of aging, to predict adverse outcomes during aging, and to design personalized approaches for the prevention and treatment of aging-related diseases and geriatric syndromes. This could represent a novel approach to study chronological and/or biological aging, paving the way to personalized interventions targeting the biology of aging.

Organoids: An Emerging Tool To Study Aging Signature Across Human Tissues. Modeling Aging With Patient-derived Organoids

The biology of aging is focused on the identification of novel pathways that regulate the underlying processes of aging to develop interventions aimed at delaying the onset and progression of chronic diseases to extend lifespan. However, the research on the aging field has been conducted mainly in animal models, yeast, Caenorhabditis elegans and cell culture. Thus, it is unclear to what extent this knowledge is transferable to humans since they might not reflect the complexity of aging in people. Organoid culture is an in vitro 3D cell-culture technology that reproduces the physiological and cellular composition of the tissues and/or organs. This technology is being used in the cancer field to predict the response of a patient-derived tumor to a certain drug or treatment serving as patient stratification and drug-guidance approaches. Modeling aging with patient-derived organoids has a tremendous potential as a preclinical model tool to discover new biomarkers of aging, to predict adverse outcomes during aging and to design personalized approaches for prevention and treatment of aging-related diseases and geriatric syndromes. This could represent a novel approach to study chronological and/or biological aging paving the way to personalized interventions targeting the biology of aging.