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Healthspan Genetics and Pharmacology: Molecular Promotion of Healthy Aging

The problem of how to maintain strong health and functionality to counter the impact of aging and age-associated disease is a major public health challenge of our time. C. elegans, which lives ~ 21 days in the lab, is a premier model organism in which longevity and healthspan can be studied to reveal conserved molecular mechanisms operative. We have a strong interest in understanding how C. elegans ages at the tissue and cellular levels, and in defining strategies that extend the period of healthy functionality, called healthspan. By deciphering this fundamental biology in a simple model, we expect to generate the molecular ties for analysis in humans and to suggest plausible therapies in the clinic.

In brief, we showed that basic age-associated tissue degeneration is strikingly reminiscent of that that transpires in human muscle, heart and nervous system; and we find evidence of a significant stochastic component(s) that influences the quality of aging (Herndon et al., 2002). In addition to the influence of reduced insulin signaling pathway in promoting neuronal healthspan (Toth et al., 2012; Vayndorf et al., 2016), we have documented a profound impact of growth factor EGF signaling in promoting locomotory health in adults, in part by signal modulation by novel EGF binding protein (high performance in late age hpl genes) availability (Iwasa, Yu, Xue, & Driscoll, 2010). We remain interested in metabolic changes that can promote health, with work including analysis of the effects of the anti-diabetes drug metformin in C. elegans healthspan promotion (Onken & Driscoll, 2010) and the finding that the deleterious effects of glucose, and the benefits of dietary restriction depend on gluconeogenesis pathways (Onken, Kalinava, & Driscoll, 2020).


Understanding of Single Neuron Aging Over Lifetime in Physiological Context

Subtle changes in neuronal morphology are hypothesized to contribute to age-associated functional decline in human brain and may be exacerbated in neurodegenerative disease. Defining the mechanisms by which adult nervous systems maintain their structural integrity is thus of considerable importance to both normal aging and neurodegenerative disease. Our interests in neuronal healthspan led us to show that morphological features of synapses deteriorate with age and that aberrant dendrite restricting is a dramatic feature of some aging neurons (Toth et al., 2012). Two distinct abnormality types, dendrite branching and novel soma outgrowths, may be differentially controlled at the genetic level. Insulin signaling pathways that modulate aging and healthspan on other fronts also influence dendritic restructuring (Scerbak et al., 2014). Our work suggests that proteostasis crises can modulate older age morphological restructuring in single neurons in the living animal (Vayndorf et al., 2016). We also collaborated with Dr. Zu-Hang Sheng to document touch neuron mitochondrial change over adult life to show phases of increase, maintenance, and decrease in mitochondrial volume and in oxidative stress response capacity (Morsci, Hall, Driscoll, & Sheng, 2016).


Exophers–A Novel Neuronal Trash Disposal Mechanism Relevant to Mechanism of Aggregate and Organelle Transfer Between Cells

While observing aging and stress neurons in physiological context, we discovered a previously unknown capacity of young adult C. elegans neurons to extrude noxious material—neurons can release large soma-sized packets of cellular contents, which can include aggregated human neurodegenerative disease proteins, mitochondria and ER(Arnold, Melentijevic, Smart, & Driscoll, 2018; Melentijevic et al., 2017). The ability to throw out cell contents changes with age and is markedly enhanced if proteostasis is disrupted, suggesting the extrusion of “exophers” and their offensive contents may be a previously undescribed last-resort effort to restore proteostasis. Physiological stresses can markedly enhance exopher production (Arnold, Cooper, Grant, & Driscoll, 2020). We propose that the neuronal extrusion phenomenon constitutes a significant but currently uncharacterized pathway in which stressed neurons maintain their functions by ridding themselves of toxic contents. There are many unanswered questions regarding exopher biology that we are currently seeking to answer, including the identification of cell autonomous and cell nonautonomous signals and pathways that regulate exopher production, the nature of neuronal substrates for extrusion, details of an aggresome-like mechanism that distinguishes neurotoxic species and is needed for exopher-genesis, nature of cellular machines that promote extrusion and scission of the exopher from the parent neuronal soma, how and why organelles are extruded, fates of both extruding neuron and the cell that takes up the neuronal debris, and the mechanism by which neighboring glial-like cell encounters and attempts degradation of exopher contents.  Study of the basic biology of exophers in aging and in compromised C. elegans neurons should provide novel insight into the aggregate spreading process relevant to human disease. Our collaborators in this project are our neighbors Dr. Barth Grant and his lab.


The Caenorhabditis Intervention Testing Program

The multi-lab CITP project seeks to identify compounds that robustly extend longevity and/or healthspan across a panel of genetically diverse nematode species/strains from the Caenorhabditis genus. There are two distinctive aspects of the CITP. First, the collaborative group includes three laboratories, that of Dr. Patrick Phillips at the University of Oregon, Dr. Gordon Lithgow at the Buck Institute for Aging Research, and our group at Rutgers, tasked with close reproduction of studies among sites (Lithgow, Driscoll, & Phillips, 2017). Our work underscores both how challenging it actually is to perform precisely the same experiment in different labs, and how critical constant communication is in this effort. Second, the project adds a genetic diversity component to outcome assessment. The idea here is that multiple interventions have been claimed to promote longevity and healthy aging in the reference N2 C. elegans strain. However, real world human populations are heterogeneous in genetic makeup, so attention to intervention impact across the variants of a given species is imperative. CITP tests interventions across a panel of Caenorhabditis strains that encompass genetic diversity on the order of from mouse to humans. The idea is that interventions that improve health or extend longevity across this genetically diverse test set should target highly conserved pathways and should take priority for efficacy testing in higher organisms. Some intervention targets are suggested by outside scientists interested in the potential of compounds they identified. Overall work has produced data on multiple interventions and identified anti-amyloid agent Thioflavin T as a robust anti-aging intervention (Lucanic et al., 2017).  The link to CITP website

As the aging and neuroscience communities progress through the era of an intensive drive to address Alzheimer’s disease, CITP is focusing on assessing anti-AD strategies using novel sets of diverse species genetically engineered to have “at risk” neurons and on testing compounds specifically proposed to have anti-AD or anti-aging impacts.


A C. elegans Exercise Model With Which to Decipher Molecular Mechanisms of Systemic and Sustained Benefits of Exercise

Exercise exerts remarkably powerful effects on metabolism and health, with anti-disease and anti-aging outcomes. To anchor a new field in molecular genetics of exercise and aging, we showed that a single swim exercise confers physiological changes that increase robustness (Laranjeiro, Harinath, Burke, Braeckman, & Driscoll, 2017), and we showed that extended swim training can both confer molecular muscle adaptation similar to mammalian exercise and induce long-lasting benefit to muscle, neurons, intestine and pharynx (Hartman et al., 2018; Laranjeiro et al., 2019). C. elegans swim training is also protective in four different neurodegenerative disease models and in a simple memory paradigm, which anchors our capacity to decipher cell and tissue circuitry by which exercise benefits generate resilience across tissues and against disease-inducing genetics. We have found that some exercise benefits are maintained for long periods after training has ended (Hartman et al., 2018)—we are using the C. elegans model to determine the molecular underpinnings of sustained physiological outcomes of these “legacy”-life effects. Our ongoing work is focused on the identification of molecular factors that maintain the physiological benefits of exercise late into life after exercise training has ended.

The development of a basic exercise model in which we can reproducibly generate systemic long-term health benefits that can be quantitatively measured in multiple tissue types, and can be readily perturbed using molecular genetics approaches opens exciting new avenues in deciphering resilience outcomes of exercise and determining the factors that promote significant anti-aging anti-disease outcomes.