Aging – basic mechanisms and interventions – Christian Riedel's research group

Aging and age-related diseases are central to human health. We study the molecular mechanisms that regulate ageing and hope to exploit them for therapeutic purposes.

Our research

Our health and longevity is largely determined by the rate at which we age. Fortunately, aging is a plastic process. In our research group we use the nematode Caenorhabditis elegans as a model system to understand the pathways that can accelerate or slow aging. C. elegans is ideal for aging-related research, as it is technically well established, short-lived (allowing for lifespan as an easily measurable phenotype), and very responsive to alterations in its aging-regulatory pathways. These studies are complemented by efforts in human tissue culture, to verify human conservation and further explore our findings for therapeutic purposes. Finally, we are developing and applying screening approaches to identify aging-preventive compounds that have a high probability of working in humans.

Our research combines biochemistry (Proteomics, ChIP-Seq, mRNA-Seq, ATAC-Seq,…) with high-throughput bioinformatic, genetic, and pharmacological screening approaches, to understand the regulation of aging at molecular and mechanistic resolution and to identify aging-preventive interventions.

Projects

The role of DAF-16/FOXO and its cofactors in aging regulation

A current focus of ours is the mechanistic exploration of aging regulatory transcription factors, in particular DAF-16/FOXO – a central driver of longevity that integrates many lifespan extending stimuli, i.e. nutrient deprivation, various stresses, or cues of infertility to confer transcription of a wide range of stress resistance and longevity determining genes. We recently identified a variety of co-factors to DAF-16/FOXO, and now we are exploring their mechanistic role.

The role of the chromatin landscape in aging regulation

Transcription is not only controlled by transcription factors but also the chromatin landscape that they interact with. Hence we are complementing our work by studies on the role of chromatin states, chromatin remodellers and the epigenome in the context of aging and age-related disease.

Search for aging-preventive interventions in humans

In addition to the mechanistic studies from above, we also seek pharmacological interventions against aging in mammalian systems, including humans. For this, we validate aging-regulatory mechanisms of particular appeal that were identified in simpler model organisms and test possible targeting strategies. Further, we develop mammalian screening methodologies that allow for the identification of aging-preventive compounds.

Other projects

We are also interested in stress responses in the context of cancer. And as part of a collaboration with the teams of Sarah Hägg and Per Nilsson, both at Karolinska Institute, we work on the repurposing of FDA-approved drugs for treatment or prevention of Alzheimer’s disease.

Further reading:

Janssens, G.E., Lin, X.X., Millan-Arino, L., Sen, I., Kavsek, A., Seinstra, R.I., Stroustrup, N., Nollen, E.A.A., Riedel, C.G. (2019) Transcriptomics-based screening identifies pharmacological inhibition of Hsp90 as a means to defer aging. Cell Reports 27: 467-480.

Lin, X.X., et al. (2018) DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity. Nature Communications 9(1): 4400.

Riedel, C.G. et al. (2013) DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nature Cell Biology, 15, 491-501.

Kenyon, C. (2010) The genetics of ageing. Nature 464, 504-12.

Calnan, D.R. & Brunet, A. (2008) The FoxO code. Oncogene 27, 2276-88.

Publications

Selected publications

Funding

Grants

  • Swedish Research Council
    1 January 2024 - 31 December 2027
    Aging is the biggest risk factor for human morbidity and mortality, caused by damage accumulation and resulting functional decline of the organism over time. Fortunately, aging can be interfered with, and thus detailed mechanistic understanding of the underlying pathways could instruct powerful therapies to extend our healthspan and lifespan. Our research focuses on one of the most powerful aging regulators, the insulin/IGF signaling (IIS) pathway, relaying nutrient scarcity into a transcriptional program that improves stress resistance, slows damage accumulation, and ultimately defers aging. Much of this program is driven by the transcription factor (TF) DAF-16/FOXO, but it has long been thought that also the chromatin landscape could play an important role in its coordination. Indeed, by ATAC-seq we identified vast changes in chromatin accessibility under reduced IIS, and through different approaches we identified four chromatin-associated proteins that either confer or utilize these changes to contribute to the aging-preventive transcriptional outcomes. These include two chromatin-associated proteins that directly bind to DAF-16/FOXO, namely BAF-1 and PQN-51, and two TFs that bind enhancer regions which open up under reduced IIS, LIN-39 and LIN-32. Each of them are essential for reduced IIS to prevent aging but they function through distinct mechanisms of action, and we think that their full understanding will provide exciting new insights into aging prevention.
  • Swedish Cancer Society
    1 January 2024
    Despite many years of intensive research, there is currently a lack of effective treatment options for many types of cancer. It is clear that to be able to cure more forms of cancer, new therapeutic strategies are required. Treatment of cancer is today focused on the cancer cells themselves, but it is now clear that cancer requires interaction between the cancer cells and surrounding cells, which are in themselves healthy but which support the cancer cells. The molecular mechanisms that make up the interaction between cancer cells and surrounding tissue are currently incompletely mapped. A characteristic of most cancer cells is that they carry an abnormal number of chromosomes compared to normal cells, a condition known as aneuploidy. This chromosomal imbalance facilitates the cancer cells' ability to usurp extreme properties, such as uncontrolled growth through cell division. However, aneuploidy also involves a strain on basal cellular mechanisms. New data indicate that such cellular stress leads to the secretion of signaling molecules that can affect surrounding normal cells. In this project, we wish to validate the existence of this communication between cells and investigate whether it is important in tumor diseases. To begin with, we hope to confirm the existence of this new form of communication between cancer cells and their cellular neighbors in the local tissue. If this works, we will map the underlying molecular mechanisms and test whether they are required for cancer cell survival and the ability to form tumors. If so, manipulation of these communication mechanisms may represent a new strategy for treating cancer.
  • A new mechanism by which mitochondria modulate the outcomes of reduced insulin/IGF-like signaling and slow down the aging process
    Novo Nordisk Foundation
    1 January 2023 - 31 December 2024
  • A new mechanism by which mitochondria modulate the outcomes of reduced insulin/IGF-like signaling and slow down the aging process
    Novo Nordisk Foundation
    1 January 2022 - 31 December 2022
  • National Institute on Aging
    15 August 2021 - 31 July 2026
    PROJECT SUMMARY Age is the major risk factor for Alzheimer´s disease (AD), and as the world’s population is becoming older it is increasingly prevalent. There are many commonalities between aging and AD, both on the molecular and systems level. There is also ample evidence, in particular from work in animal models, that a broad spectrum of aging-preventive interventions that confer longevity have the ability to alleviate diverse aspects of AD pathology, such as Aβ and tau aggregation. These pathologies lead to severe neurodegeneration and occurrence of clinical symptoms such as memory loss, mood swings and changes in personality. No disease-modifying treatments exist, only medications that relieve the symptoms temporarily. To find treatments that prevent disease progression, testing drugs that have already been approved for other indications – a strategy referred to as drug repurposing – may be useful. A major benefit of drug repurposing is that it speeds up drug development and reduces the risks for patients, since these drugs have already passed safety assessment in humans. Thus, we propose a data-driven approach to search among drugs used for other age-related conditions and identify some that can be repurposed for the prevention of AD. Towards this approach, we will investigate the effect of the 20 most commonly used drug classes among 65+ year-olds in Sweden (>200 substances also approved for use in the U.S.) on biological aging and AD in a series of epidemiological analyses. We will use deeply phenotyped longitudinal cohort data to see how drug treatment changes biological aging trajectories, as well as apply Mendelian Randomizations to mimic the modulation on drug targets using large-scale genotyping data and emulated target trials in the Swedish Prescribed Drug Register linked to a quality register on dementia. Following this, the individual substances within the 2-3 most promising drug classes will be screened in vitro in human cellular models of AD and in vivo in C. elegans models of aging and of human Aβ and tau aggregation and toxicity. Top candidates will be tested in established and most relevant AD mouse models and in models of accelerated aging. Taken together, our approach to discover new drugs for AD prevention by screening already approved substances bears great benefits. The fact that much of the testing happens in silico and that the screening focuses only on drugs that are already approved for use in patients makes our approach faster and more cost- effective than conventional de novo compound screens.
  • Swedish Cancer Society
    1 January 2021
    Despite many years of intensive research, there is currently a lack of effective treatment options for many types of cancer. It is clear that to be able to cure more forms of cancer, new therapeutic strategies are required. Treatment of cancer is today focused on the cancer cells themselves, but it is now clear that cancer requires interaction between the cancer cells and surrounding cells, which are in themselves healthy but which support the cancer cells. The molecular mechanisms that make up the interaction between cancer cells and surrounding tissue are currently incompletely mapped. A characteristic of most cancer cells is that they carry an abnormal number of chromosomes compared to normal cells, a condition known as aneuploidy. This chromosomal imbalance facilitates the cancer cells' ability to usurp extreme properties, such as uncontrolled growth through cell division. However, aneuploidy also involves a strain on basal cellular mechanisms. New data indicate that such cellular stress leads to the secretion of signaling molecules that can affect surrounding normal cells. In this project, we wish to validate the existence of this communication between cells and investigate whether it is important in tumor diseases. To begin with, we hope to confirm the existence of this new form of communication between cancer cells and their cellular neighbors in the local tissue. If this works, we will map the underlying molecular mechanisms and test whether they are required for cancer cell survival and the ability to form tumors. If so, manipulation of these communication mechanisms may represent a new strategy for treating cancer.
  • Swedish Research Council
    1 January 2020 - 31 December 2023
  • Swedish Research Council
    1 January 2016 - 31 December 2019
  • Molecular mechanisms of longevity control
    International Human Frontier Science Program Organization
    1 May 2008 - 30 April 2011

Staff and contact

Group leader

All members of the group

Alumni

Hadi Bazzi, Master Student

Ashwini Jatti, Master Student

Sascha Boma Okendi, MSc

Robert Smetana, Master Student

Maite Brachthäuser, Master Student

Ilke Sen, PhD Student/Postdoc

Lluís Millán Ariño, Postdoc

Andrea Stöhr, Postdoc

Xin Zhou, Postdoc

Lioba Körner, Master Student

Naghmeh Rajaei, Postdoc

Marco Lezzerini, Postdoc

Mengshan Liu, Master Student

Bora Baskaner, Research Assistant

Simone Brandenburg, Research Assistant

Nataly Puerta Cavanzo, Master Student

Marlies Oomen, Master Student

Irem Yücel, Bachelor Student

Tanja Iken, Bachelor Student

Georges Janssens, Postdoc

Daniel Edgar, Postdoc

Poomy Pandey, Research Assistant

Xin-Xuan Lin, PhD Student

Sonja Pikkupeura, Master Student

Hazel Ang, Postdoc

Quadri Ajibola Omotesho, Master Student

Manon Chevalier, Postdoc

Alan Kavšek, PhD student

Teodora Pavlicu, Master student

Keywords:
Aging Cell and Molecular Biology Genetics and Genomics (Medical aspects at 30107 and agricultural at 40402) Medical Bioinformatics and Systems Biology Medical Genetics and Genomics
Content reviewer:
06-10-2025