Research | U-M Glenn Center

Lab member conducting research

Our Research

Learn about our innovative and wide-ranging research.

The U-M Glenn Center receives funding from the Glenn Foundation for Medical Research for a wide range of projects focused on the biology of aging. Learn more about our research by clicking each of the project names below.

Research Projects

Goals of the Garcia/Miller project: (a) to evaluate effects of Trametinib, an inhibitor of the ERK1/2 MAP kinase pathway, on protein translation, selective mRNA translation, and mTORC1 function, and (b) to evaluate effects of new candidate anti-aging drugs for effects on MAPK and mTORC1 function in mice.

In previous years, Dr. Garcia conducted a series of experiments on Trametinib, which inhibits the MEK/ERK MAP kinase pathway that modulates protein translation. Another lab group has shown that Trametinib can extend mouse lifespan, on its own and in combination with Rapamycin. Garcia has found that trametinib-treated mice show many of the characteristics of other slow-aging mice, and that this anti-aging drug alters many of the enzymes related to fatty acid metabolism and carbohydrate utilization.

A second set of planned experiments will test for alterations in cap-independent translation, MAPK pathways, and changes in mTOR substrate specificity in mice treated with newer anti-aging drugs, such as meclizine, astaxanthin, and 16-hydroxyestradiol. These data will help confirm, refute, or refine the hypothesis that all anti-aging drugs modulate both the rapamycin-sensitive mTOR pathway and the trametinib-sensitive MEK/ERK pathway.

Recent publications:

Dr. Li is now completing work on a manuscript focused on changes in the enzymes involved in de novo lipogenesis (DNL) in fat and liver; all of the work was funded by her Glenn Center project. The transcription factor ChREBP modulates DNL by control of lipogenic enzymes including FASN and ACC1. Several varieties of slow-aging mice, including PKO, GHRKO, Ames and Snell dwarf, and PTEN-OE mice, as well as calorically-restricted mice, are known to be insulin sensitive.

Li’s new data shows downregulation of FASN, ACC`1, and other DNL enzymes, and of the upstream transcription factor ChREBP, in liver of each of these slow-aging mice. A similar set of changes was seen in mice given a low-isoleucine diet (see Lamming/Garcia collaboration above). Two “new” drugs, astaxanthin and meclizine, only recently shown to extend mouse lifespan, were also found to downregulate this set of hepatic DNL enzymes, along with ChREBP. Surprisingly, these genetic, dietary, and pharmacological interventions produced significant effects, in brown adipose tissue, that were opposite in direction to those seen in the liver. Lastly, Dr. Li noted that all of these changes in enzyme levels were independent of changes in the underlying mRNAs, implying that the levels were controlled by differential translation or degradation rates.

The work planned for the coming year will complete this story by tests of other enzymes critical to de novo lipogenesis and carbohydrate flux, by tests of tissues from other varieties of slow-aging mice (to see how robust the findings are), and by tests of mice exposed to anti-aging drugs for shorter intervals.

Recent publications:

The Pletcher laboratory uses a variety of unconventional techniques to study how sensory neurons communicate information about nutrition, danger, and conspecifics to initiate rapid changes in health and lifespan. Many of these changes occur in coordination with known behavioral outcomes, suggesting similarities in the underlying neural circuitry. We have shown that small groups of neurons and select neuropeptides, which are known to control neural states such as hunger and sexual reward, regulate lifespan. Our discoveries provoke the notion that aging, which has long been considered a process to which animals are passively exposed, may instead have much in common with complex behaviors. It is acutely malleable, susceptible to sensory influences, and strictly controlled by coordinated sets of neurons.

Armed with this perspective together, with novel technology for behavioral and lifespan analyses, we use funds from the Glenn Center to study specific mechanisms through which the brain regulates aging in response to specific motivations and, in so doing, to set the groundwork for a greater understanding of its means of command.

Recent research in our laboratory supported by the Glenn Medical Foundation has led to a greater understanding of how sensory information is processed and about the mechanisms through which the brain orchestrates appropriate behavioral and physiological responses throughout the animal to modulate aging. For example, we recently demonstrated that certain dietary nutrients, branched-chain amino acids and isoleucine in particular, are capable of specifying homeostatic hunger states in Drosophila (i.e., hunger that is driven by caloric deficit). These states appear to be encoded in the neural epigenome, and they slow aging. We are in the process of investigating whether aging is similarly modulated by other types of hunger drives, including, for example, hedonic hunger, which is stimulated by the pleasurable aspects of feeding rather than energetic needs.

Consistent with a long-running focus of our Glenn-funded research, serotonin signaling appears to be influential in the specification of neural states that slow aging. We have, for example, recently completed work demonstrating that a handful of neurons in a structure called the ellipsoid body (EB) of the Drosophila brain, called R2/R4 neurons, respond to serotonin and act as a rheostat in transducing sensory information to modulate lifespan. In response to certain sensory inputs, the R2/R4 rheostat modulates insulin production in a different part of the brain, which then influences physiology and health in the periphery.

Ongoing work is focused on investigating how the R2/R4d system responds to a diverse set of sensory inputs that control aging and on interrogating its neural and peripheral targets to determine whether these circuits recruit well known aging pathways or invoke aging mechanisms yet to be discovered.
 

This project uses the nematode Caenorhabditis elegans to investigate how environmental perception, stress signaling, and stress response modify aging. Because C. elegans is one of the simplest multicellular organisms widely studied, it allows for high throughput studies on healthspan and longevity in a genetically tractable model. The approach of this project is complementary to that of the Glenn project led by Scott Pletcher, and seeks to understand how organisms recognize relay signals in response to real or perceived stress, and subsequently modify their physiology. The eventual goal is to identify new approaches to improve healthspan and longevity through altering stress-response pathways contained within all organisms.

Current emphasis is on the following research questions:

  • Cell non-autonomous regulation of aging. This project focuses on how organisms perceive stresses such as lack of nutrients, lack of oxygen, or presence of pathogens, and signal through the nervous system to modify physiology. By interrogating these pathways, which involve conserved signals such as serotonin and dopamine, we can understand how environmental perception leads to physiological changes and can potentially co-opt these signals to improve health.
  • Small molecule lifespan extension: This project utilizes collaborative efforts to identify small molecule drugs that improve stress response in primary mouse cells by further interrogating hits from this work in a nematode context. The goal is to identify multiple candidates for lifespan extension and to use the genetics of C. elegans to discover the mechanisms and pathways that each drug uses to improve long-term health.
  • Microbiome interplay with stress and longevity: This project tests how the bacteria that worms eat and colonize their intestines modify their health and longevity. Since C. elegans is usually cultured with a single bacteria species, we can modify the microbiome and diet together and learn about how nutrition and signaling from microbes affects the physiology of a host organism.

The Truttmann laboratory focuses on cellular mechanisms that regulate protein homeostasis (proteostasis) in aging and aging-associated diseases of the brain and the heart. The group is particularly interested in elucidating how protein misfolding in the endoplasmic reticulum (ER), the key secretory organelle in eukaryotic cells, is minimized in healthy cells but corrupted during aging-associated diseases.

The lab also studies molecular chaperones of the HSP70 family, which are key regulators of protein folding, recycling, and degradation. They use a multidisciplinary approach including molecular biology, genetics, neuroscience, and biochemistry in conjunction with several model systems (C. elegans, mouse models, cell lines, purified proteins) to comprehensively address their research question.

In the coming year, the Truttmann lab will use funding from the Glenn Center to study how ER phagy contributes to the clearance of misfolded proteins in the context of aging-associated diseases. Another goal is to define if increasing ER phagy enhances lifespan and mitigates protein aggregation-associated toxicity. This work will set the groundwork for a better understanding of how protein folding and stress signaling in the ER contributes to resilience to cellular aging.

The Kaczorowski laboratory focuses on genetic and cellular mechanisms that promote resilience to cognitive aging, Alzheimer's disease, and other age-related dementias. Using mice that model the genetic diversity and phenotypic variation of human populations, the group uses mouse and human datasets, based on genetics, omics, imaging, and behavior, to identify molecules and pathways that could be targeted to promote resilience to cognitive aging. Additional lab studies aim to examine the physiological changes occurring in hippocampus and other memory-relevant brain regions over the course of aging, which will provide insight into the mechanism(s) of preservation of cognitive function in aging.

Goals of the Moore/Kaczorowski project:

  • Assess age-related changes in learning and memory functions in genetically heterogeneous, translationally relevant mouse models.
  • Investigate the neuropathological features associated with age-related cognitive decline.
  • Investigate functional, morphological, and molecular characteristics associated with resilience to age-related cognitive decline.

Our previous work using the genetically heterogenous and highly translationally relevant UM-HET3 mouse panel has demonstrated that age-related deficits in contextual fear memory (CFM) tested 24 hours after training, which is primarily dependent on intact hippocampal function, do not emerge until 28mo of age (H. Kaur, unpublished). We have now developed a paradigm that elucidates earlier age-related deficits (at 24mo of age) in the transfer of hippocampally-encoded memories to the cortex for long-term storage (tested 7 days after training), allowing us to target crucial brain regions, cell types, and mechanisms likely to represent important early mediators of cognitive resilience. These data serve as the critical foundation for our future work discovering interventions to slow cognitive aging.

Work in the coming year will focus on the following topics:

  • Investigating the association of physiological and pathological markers of gliosis, neurogenesis, and inflammation with decline in memory functions with age.
  • Evaluating the functional, morphological, and molecular signatures associated with resilience to age-related cognitive decline using patch clamp recordings in individual memory-relevant neurons.
  • Comparing biochemical, electrophysiological, morphological, and proteomic characteristics between young and aged mice, and between aged mice who show resilience and susceptibility to cognitive decline. Together, this will provide deep, multi-faceted insight into novel mechanistic signatures of resilience to age-related cognitive decline.

Based on Seq-Scope, originally developed in the Lee lab, we proposed to support collaborative work with aging researchers within the Glenn Center. Seq-Scope enables microscopic resolution (0.5–0.7 µm center-to-center distance) examination of the spatial transcriptome. Among the notable projects is one with Dr. Susan Brooks, which focuses on skeletal muscle injury and aging. Together, we successfully profiled a whole longitudinal soleus muscle section, revealing both myofiber diversity and non-myocyte diversity, such as smooth muscle, fibroblasts, and immune cells. Subcellular features, including mitochondria, nuclei, and neuromuscular junction (NMJ) structures, were also analyzed. These results demonstrated that ultra-high-resolution spatial transcriptome analysis is indeed feasible.

Using this platform, we continue to profile muscle tissues undergoing age-related pathologies, such as denervation-induced atrophy, laminopathy-associated perturbations, and mTORC1 upregulation-associated degeneration. Early results from denervation-induced atrophy are promising, as we identified myofiber type-specific denervation responses, including the emergence of type IIb fibers enriched with prominent DNA damage responses. Additionally, we characterized changes in postsynaptic NMJ nuclei profile and perisynaptic populations associated with the NMJ.

Our next project, in collaboration with Drs. Richard Miller and Marianna Sadagurski, focuses on profiling WT and GHRKO brains to examine the spatial molecular basis of extended lifespan in the hippocampus. Initial analyses were challenging due to the limited imaging area confined to a narrow 1.5 mm × 60 mm slit. Furthermore, the discontinuation of Illumina's HISEQ2500 sequencing platform necessitated optimizing our procedures for a newer platform, NOVASEQ. With NOVASEQ, we established a new Seq-Scope procedure capable of profiling a wide square histological area of 7 mm × 7 mm (expandable to 7 mm × 100 mm), which can encompass whole organs, including the brain.

We also streamlined the computational pipeline for processing these new Seq-Scope data (NOVASCOPE), and this updated procedure was recently published in Nature Protocols. These cutting-edge technologies continue to be refined and deployed to support aging-related research by Glenn Center investigators.

The Guo lab uses genetics, genomics, molecular and cell biology to study how two long-lived animals age and regenerate (planarians and leopard geckos). The regenerative biology community has grown substantially in the past two decades along with knowledge from a diverse collection of models. Aging and regeneration, however, has not been extensively characterized and studied. Our work in this direction will not only help us understand the biology of aging, but also provide insights on wound healing in older patients. 

Recent research in our laboratory supported by the Glenn Medical Foundation has led to the discovery that the sexual planarians undergo aging, even though they are traditionally considered “immortal”. Most excitingly, our study also showed that regeneration programs in planarians led to reversal of age-associated phenotypes at whole-body level. We termed this phenomenon as global rejuvenation or whole-body rejuvenation. Ongoing work focuses on the study of its mechanisms. 

Ongoing work funded by the Glenn Medical Foundation also include studies of leopard geckos. We have a large colony of aged geckos in the campus which gives us the unique ability to study aging and regeneration in a vertebrate model. The eventual goal is to characterize the regeneration process in geckos, to determine how such process is altered by aging, and to identify targets that can be perturbed to improve healing.