Over the last several decades, studies in model genetic organisms have identified multiple evolutionarily conserved signalling pathways that regulate these processes, including insulin/IGF and mTOR signalling, mitochondrial function, dietary restriction mediated longevity, and signals from the reproductive system. Our lab has been instrumental in elucidating some of the key players at the nexus of these pathways, and ongoing projects include the dissection of nutrient sensing pathways and the role of metabolic signalling and reproduction in regulating animal lifespan.
Our lab uses the model organisms C. elegans, killifish and human cell samples to study the mechanisms of ageing (A). We use a variety of imaging and omics-based approaches to better understand aging-related processes (B).
Our lab uses the model organisms C. elegans, killifish and human cell samples to study the mechanisms of ageing (A). We use a variety of imaging and omics-based approaches to better understand aging-related processes (B).
Much of the work in the field has focused on pathway-specific mediators, but whether the different ageing-related pathways converge on common regulators or shared downstream processes largely remains an open question. Much of our recent work, therefore, has focused on deciphering convergent mechanisms to understand what lies at the heart of longevity and to identify clinical targets that could extend health- and lifespan. This area of research focuses on four main topics:
The nucleolus as a convergence point of longevity regulation
Understanding the role of the nucleolus in ageing. (A) Compared to wild-type (N2) worms, long-lived strains (such as the eat-2(ad465) mutant) have small nucleoli, whereas short-lived strains (such as the ncl-1(e1942) mutant) have enlarged nucleoli. (B) To better understand the role of the nucleolus in ageing we are investigating multiple aspects of nucleolar function in different model organisms.
Understanding the role of the nucleolus in ageing. (A) Compared to wild-type (N2) worms, long-lived strains (such as the eat-2(ad465) mutant) have small nucleoli, whereas short-lived strains (such as the ncl-1(e1942) mutant) have enlarged nucleoli. (B) To better understand the role of the nucleolus in ageing we are investigating multiple aspects of nucleolar function in different model organisms.
We have identified the nucleolus as a central convergence point of longevity regulation and found a number of genes involved in the regulation of nucleolar size and function. We have discovered that small nucleoli are a cellular hallmark of longevity not only in C. elegans but also in flies, fish, mice, and perhaps humans. The mechanisms by which the nucleolus contributes to ageing, however, remain unclear. Thus, unravelling whether and how different nucleolar functions (e.g. rRNA production and biogenesis, assembly of different ribonucleoprotein particles, splicing factors, siRNA pathways) affect longevity is a central research theme in our lab.
Dissecting how the MYC-MONDO and TFEB transcription factor network affects life span
Overview of the helix-loop-helix (HLH) transcription factor network that is required for life extension in different longevity pathways (Nakamura et al, 2016).
Overview of the helix-loop-helix (HLH) transcription factor network that is required for life extension in different longevity pathways (Nakamura et al, 2016).
We have discovered an extensive helix-loop-helix (HLH) transcription factor network, consisting of the MML-1/MYC-MONDO complex and HLH-30/TFEB, which is required for life extension across multiple pathways. Among other things, this network largely regulates the metabolism of lipids, carbohydrates, amino acids, amines, nucleosides and mitochondria. How these processes actually relate to life span, however, remains to be elucidated. Our current work therefore aims to identify both upstream and downstream factors that regulate the MYC-MONDO and TFEB network.
Organellar communication and its role in ageing
Our current work highlights that different organelles (mitochondria, the endoplasmic reticulum, nucleoli and lysosomes) are not only involved in ageing, but that the crosstalk between them also contributes to immunity and longevity. Identifying the factors that mediate this communication and understanding how organelles cooperate to regulate lifespan is a major focus of our ongoing research.
Identification of metabolites that regulate animal health and life span
We have had a long-standing interest in understanding how naturally occurring metabolites can serve as signalling molecules that regulate animal health and life span, and are currently using metabolomic approaches to identify metabolites that impact longevity.
Our mass spectrometry-based approach to identify metabolites that regulate life span. We analyse naturally occurring metabolites in different long- and short-lived C. elegans strains, killifish or mammalian cell culture, and look for compounds that are differentially expressed in different mutants. We further integrate these results with transcriptome data and pathway analysis to identify the genes and networks that are causal for the lifespan effect. These results form the basis for further in vivo analysis, such as supplementation of a given metabolite or genetic perturbation of a pathway, to assess the effect on longevity.
Our mass spectrometry-based approach to identify metabolites that regulate life span. We analyse naturally occurring metabolites in different long- and short-lived C. elegans strains, killifish or mammalian cell culture, and look for compounds that are differentially expressed in different mutants. We further integrate these results with transcriptome data and pathway analysis to identify the genes and networks that are causal for the lifespan effect. These results form the basis for further in vivo analysis, such as supplementation of a given metabolite or genetic perturbation of a pathway, to assess the effect on longevity.
In addition, we are actively investigating different states of long-lived quiescence (called diapause) and how they relate to longevity. We study both dauer diapause, which occurs during the C.elegans third larval stage, as well as adult reproductive diapause (ARD), which animals enter in response to late larval food deprivation. Our current work focuses on unraveling the molecular and physiological pathways governing dauer diapause and ARD.
Adult reproductive diapause (ARD) is a state of reproductive quiescence that C. elegans animals can enter when starved late in larval development. In this state the animals are smaller than ad libitum-fed animals of the same age (left). Moreover, animals in ARD live substantially longer compared to ad libitum-fed worms (right). Our current research focuses on better characterising this state and the pathways that mediate ARD longevity.
Adult reproductive diapause (ARD) is a state of reproductive quiescence that C. elegans animals can enter when starved late in larval development. In this state the animals are smaller than ad libitum-fed animals of the same age (left). Moreover, animals in ARD live substantially longer compared to ad libitum-fed worms (right). Our current research focuses on better characterising this state and the pathways that mediate ARD longevity.